CA3148955A1 - Heterocyclic compound - Google Patents

Abstract

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

Description

I

DESCRIPTION
[Title of the Invention]
HETEROCYCLIC COMPOUND
[Technical Field]
[0001]
The present invention relates to a novel heterocyclic compound having the effect of inducing degradation of interleukin-1 receptor-associated kinase-M (IRAK-M) protein and expected to be useful for the prevention/treatment of cancer, fibrosis, infectious diseases, etc., and a drug containing the same.
[Background Art]

[0002]
Development of compounds that induce ubiquitination of target proteins and proteasome degradation by E3 ligase (referred to as Proteolysis Targeting Chimeras (PROTAC or Specific and Nongenetic IAP-dependent Protein Eraser (SNIPER) and the like in some cases) has been attempted for the purpose of treatment by reducing disease-related proteins (Non-Patent Documents 1 to 9). IRAK-M is a member of the IRAK family of protein kinases and is a pseudokinase having no kinase activity (Non-Patent Document 10). IRAK-M is located downstream of all Toll-like receptors (TLRs) except TLR3 and a protein which acts as a negative feedback regulator of the TLR/interleukin-1 (IL-1) receptor signaling pathway in vivo (Non-Patent Document 11). It is located and expressed in some epithelial cells, including bile duct epithelial cells, lung epithelial cells and intestinal epithelial cells, and in immune cells, especially myeloid cells. IRAK-M plays an important role in maintaining immune homeostasis such as induction of endotoxin tolerance by negatively controlling TLR-mediated induction signals of inflammatory cytokines in innate immunocompetent cells such as macrophages and dendritic cells. (Non-Patent Document 12). IRAK-M has been reported to contribute to cancer growth by contributing to immunosuppression by tumor-related macrophages in the tumor microenvironment, bone marrow-derived immunosuppressive cells, dendritic cells and so on (Non-Patent Documents 13 to 15). Furthermore, IRAK-M has been reported to act on alveolar macrophages phagocytosis, defense against bacteria and collagen production promoting ability, and is involved in fibrosis, asthma, secondary infection after sepsis, and infectious complications of hematopoietic stem cell transplantation (Non-Patent Documents 16-18).
Therefore, compounds that induce the degradation of IRAK-M by linking the X-Linked Inhibitor of Apoptosis Protein (XIAP) binder, which is a type of E3 ligase, and the IRAK-M
binder via a linker can be promising therapeutic agents for cancer, fibrosis, infectious diseases, and IRAK-M
protein-related diseases.

[0003]
Patent Document 1 reports a compound as an IRAK-M protein degradation inducer.
Patent Documents 2 and 3 report compounds as an IRAK (particularly IRAK-4) protein degradation inducer.
Patent Documents 4 to 16 report compounds that induce protein degradation by using IAP
binders.
Patent Documents 17 to 20 reports compounds containing the structure of N-(piperidine-4-y1) thieno [3,2-d] pyrimidin-4-amine or N- (piperidine-4-y1) thieno [3,2-b]
pyridine-7-amine.
[Citation List]
Patent Document

[0004]
Patent Document 1: W02017/211924 Patent Document 2: W02019/099926 Patent Document 3: W02019/133531 Date Recue/Date Received 2022-01-27 Patent Document 4: W02018/066545 Patent Document 5: Japanese Unexamined Patent Application Publication No. 2013-Patent Document 6: W02016/169989 Patent Document 7: W02016/172134 Patent Document 8: W02017/011590 Patent Document 9: W02017/182418 Patent Document 10: W02017/201449 Patent Document 11: US2018/0118733 Al Patent Document 12: US2018/0134688 Al Patent Document 13: W02018/119448 Patent Document 14: W02018/119357 Patent Document 15: US2019/0119271 Al Patent Document 16: US2019/0175612 Al Patent Document 17: W02016/040330 Patent Document 18: W02013/019966 Patent Document 19: US2013/0040957 Al Patent Document 20: CN103242341 A
Non-Patent Document

[0005]
Non-Patent Document 1: Science. 2017 Mar 17;355(6330) 1163-1167.
Non-Patent Document 2: Cell Chem Biol. 2018 Jan 18;25(1):67-77.e3.
Non-Patent Document 3: Cell Chem. Biol. 2017 Sep 21;24(9) 1181-1190.
Non-Patent Document 4: ACS Chem Biol. 2017 Apr 21;12(4):892-898.
Non-Patent Document 5: Cell Chem Biol. 2018 Jan 18;25(1):78-87.e5.
Non-Patent Document 6: Nat Rev Drug Discov. 2017 Feb;16(2):101-114.
Non-Patent Document 7: Nat Chem Biol. 2015 Aug;11(8):611-7.
Non-Patent Document 8: Chemistry & Biology, 2010, 17(6):551-555 Non-Patent Document 9: Chembiochem, 2005, 6(1):40-46 Non-Patent Document 10: J Biol Chem, 1999 Jul 2; 274(27): 19403-19410 Non-Patent Document 11: Cell, 2002 Jul 26; 110(2): 191-202 Non-Patent Document 12: Infect Dis Rep, 2010 Jan 1; 2(1). pii: e9 Non-Patent Document 13: Oncogene, 2011 May 26; 30(21): 2475-2484 Non-Patent Document 14: J Immunol, 2010 Oct 1; 185(7): 4223-4232 Non-Patent Document 15: Mol Immunol, 2007 Jul; 44(14): 3453-3461 Non-Patent Document 16: J Immunol, 2015 Feb 15; 194(4): 1894-1904 Non-Patent Document 17: J Clin Invest, 2006 Sep; 116(9): 2532-2542, Epub 2006 Aug 17 Non-Patent Document 18: J Immunol, 2010 Jun 1; 184(11): 6299-6308 [Summary of the Invention]
[Technical Problem]

[0006]
An object of the present invention is to provide a novel heterocyclic compound and a pharmaceutical compound containing thereof, which have an action of inducing degradation of IRAK-M protein and are expected to be useful for prevention and treatment of cancer, fibrosis, infectious diseases, etc.
[Solution to Problem]

[0007]
The present inventors have diligently studied to find an IRAK-M protein degrader and resultantly found that the compound represented by the following formula provides an excellent Date Recue/Date Received 2022-01-27 degradation-inducing activity of IRAK-M protein, and that the compound may be useful for prevention or treatment of cancer, fibrosis, infectious diseases and the like, leading to completion of the present invention.

[0008]
The present invention is below.
[1] A compound represented by the formula (I):

[0009]
IRAK-M binder Linker E3 ligase binder (M) (L) (E) , or a pharmaceutically acceptable salt thereof.
[2] The compound according to the above [1], wherein the IRAK-M binder (M) is represented by the following formula (II):

[0010]
Rim Rim 0' 'AII
wherein Y represents CH or N, R 1 represents H or Me, R 3 represents a group represented by the following structural formula:

[0011]
* *
*
[wherein * represents the binding position to 0, ** represents the binding position to A, and n is an integer from 0 to 21, A is represented by the following structural formula:

[0012]

*X*
[wherein R 5 each independently represent a hydrogen atom or a C1-6 alkyl group], or R 4 is represented by a group selected from the following structural formulae:

[0013]
O-N
**

[wherein * represents the binding position to A, and ** represents the binding position to the linker], an optionally substituted C1-6 alkylene group, an optionally substituted C3-10 cycloalkylene group, an optionally substituted C6-14 arylene group, or a bond, and the arrow Date Recue/Date Received 2022-01-27 represent the binding to the linker (L), or a pharmaceutically acceptable salt thereof.
[3] The compound according to the above [2], wherein the IRAK-M binder (M) is represented by the following formula (III):

[0014]
A01 ,,--NI" 'IR"
(20 R -oi S"---Y
N
III
wherein Y represents CH or N, R 1 represents H or Me, A 1 represents a group represented by the following structural formula:

[0015]

*x*
[wherein R 5 each independently represent a hydrogen atom or a C1-6 alkyl group], or R" ¨
x represents a group selected from the following structural formulae:

[0016]
* * *
kJ /
[wherein * represents the binding position to A 1, and ** represents the binding position to a linker], and the arrow represents the binding to the linker (L), or a pharmaceutically acceptable salt thereof.
[4] The compound according to the above [2], wherein the IRAK-M binder (M) is a monovalent group derived from the compound selected from the group consisting of (5-((4- (thieno [3,2-b) ] pyridin-7-yloxy) piperidin-1-y1) methyl) isoxazol-3-01), 5-(((4-((2) 2) -methylthieno [3,2-b] pyridin-7-y1) oxy) piperidin-1-y1) methyl) isoxazol-3-01), 1-methyl-5-((( 4- (thieno [3,2-b] pyridin-7-yloxy) piperidin-1-y1) methyl) -1H-pyrazol-3-ol, and 4-((4- (thieno [3,2-d] pyrimidin-4-) yloxy) piperidin-1-y1) sulfonyl) phenol, or a pharmaceutically acceptable salt thereof.
[5] The compound according to any one of the above [1] to [4], wherein the Linker (L) is a group having 5 to 20 carbon atoms optionally containing a heteroatom, or a pharmaceutically acceptable salt thereof.
[6] The compound according to any one of the above [1] to [4], wherein the Linker (L) is represented by the following structural formula:

[0017]
Date Recue/Date Received 2022-01-27 0 * *
* __ [wherein * represents the binding to the IRAK-M binder (M)], *-(CH2CH20)n(CH2)m(NRCO)s(CH2)t-* (n is a natural number from 1 to 5, m is 0, 1, or 2, and s is 0 or 1, t is 0 or 1 and R represents a hydrogen atom or C1-6 alkyl group), or a bond, or a pharmaceutically acceptable salt thereof.
[7] The compound according to any one of the above [1] to [6], wherein the E3 ligase binder (E) is represented by the following structural formula (IV):

[0018]

= 'L01 Ros Ro3 Ro7 R ----E
¨08 (IV) wherein Rol, R02, R03, R04, Ros, Roo, R07 and R08 each independently represent a hydrogen atom or a C1-6 alkyl group which may form a ring with each other, D represents the following formula (V):

[0019]
W-c_vi ,9)n ( n., 0 i j\---NH
HN
H3C/ '-----T
(V) [wherein m is an integer of 0 to 2, n is an integer of 0 to 2, Wii represents a methylene group, a difluoromethylene group, 0, S. SO, SO2, 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 an optionally halogenated C1-3 alkyl group], or the following formula (VI):

[0020]
P
\
Cl¨ __ NH
HN

(VI) [wherein Q represents an oxygen atom, formula-NR2i- (wherein R21 represents a hydrogen atom, a C1-6 alkyl group, or a C1-6 alkyl group which may form a ring with P), or a bond, P represents a hydrogen atom, a C1-6 alkyl group or the binding to the Linker (L) (including the formation of Date Recue/Date Received 2022-01-27 a ring with Q and binding to the linker (L))], E represents the following formula (VII):

[0021]

VII
[wherein R21, R22, and R23 each independently represent a hydrogen atom, a halogen atom, a C1-6 alkyl group, a C1-6 alkoxy group, or an optionally substituted carbamoyl group, and R25 and R26 each independently represent a hydrogen atom, a halogen atom, a C1-6 alkyl group, a C1-6 alkoxy group, an optionally substituted carbamoyl group, or the binding to the Linker (L); R24 represents a hydrogen atom, a methyl group, or the binding to the linker (L), provided that the binding to the linker (L) is any one of R24, R25, or R261, or the following formula (VIII):

[0022]
R
R35 \

I

VIII
[wherein R31, R32, R33, R34, and R35 each independently represent a hydrogen atom, a halogen atom, a C1-6 alkyl group, a C1-6 alkoxy group, or an optionally substituted carbamoyl group, and R represents a hydrogen atom, C1-6 alkyl group, or the binding to the linker (L)], either D or E
binds to the linker (L), or a pharmaceutically acceptable salt thereof.
[8] The compound according to any one of the above [1] to [7], wherein the E3 ligase binder (E) is represented by the following formula (IV):

[0023]

D¨ R01 N ___;02 Ro5 Ro3 Ro5 (IV) wherein Rol, R02, R03, R04, R05, Roo, R07 and R08 each independently represent a hydrogen atom or a methyl group, D represents the following formula (V-1):

[0024]
Date Recue/Date Received 2022-01-27 iµ1_1:______ j\---NH
HN
----(VA) [wherein Wii represents a methylene group or difluoromethylene group], or the following formula (VI-1)

[0025]
CI NH

(VI-1) [wherein Q represents the binding to the Linker (L)], E represents the following formula (VII):

[0026]

VII
[wherein R21, R22 and R23 each independently represent a hydrogen atom, a halogen atom, a C1-6 alkyl group, or a C1-6 alkoxy group; R25, and R26 each independently represent a hydrogen atom, a halogen atom, a C1-6 alkyl group, or the binding to the Linker (L); and R24 represents a hydrogen atom, a methyl group, or the binding to the Linker (L), provided that the binding to the Linker (L) is any one of R24, R25 or R261, or the following formula (VIII):

[0027]
R
R35 \

I

VIII
[wherein R31, R32, R33, R34 and R35 each independently represent a hydrogen atom, a halogen atom, or a C1-6 alkyl group; R represents a hydrogen atom, C1-6 alkyl group, or the binding to the Linker (L)], either D or E binds to the Linker (L), or a pharmaceutically acceptable salt thereof.
[9] The compound according to the above [1], wherein the IRAK-M binder (M) is represented by the following formula (III):

[0028]
Date Recue/Date Received 2022-01-27 'R"
y R .1 III
wherein Y represents CH or N, R01 represents H or Me, A 1 represents *-C1-12-*
or *-S02-*, Rn represents a group selected from the following structural formula:

[0029]

[wherein * represents the binding position to A 1, and ** represents the binding position to a linker], and the arrow represent the binding to the linker (L)], the linker (L) is represented by the following structural formula:

[0030]
0 * *
[wherein * represents the binding to the IRAK-M binder (M)], *-(CH2C1-120)n(CH2)m(NRCO)s(CH2)t-* (n is a natural number from 1 to 5, m is 0, 1, or 2, and s is 0 or 1, t is 0 or 1 and R represents a hydrogen atom or C1-6 alkyl group), or a bond, E3 ligase binder (E) is represented by the following formula (IV):

[0031]

Rol N---1;02 R05 Rog Rog RO4 Rog (IV) [wherein Rol, Roz, R03, R04, Ros, Roo, R07 and R08 each independently represent a hydrogen atom or a methyl group; D represents the following formula (V-2):

[0032]
HN NH
-1¨

(V-2) , or the following formula (VI-1) Date Recue/Date Received 2022-01-27

[0033]
Q NH
HN

(VI-1) [wherein Q represents the binding to the Linker (L)], and E represents the following formula (VII):

[0034]

VII
[wherein R21, R22 and R23 each independently represent a hydrogen atom, a halogen atom, a C1-6 alkyl group, or 1-6 alkoxy group; R25 and R26 each independently represent a hydrogen atom, a halogen atom, a C1-6 alkyl group, or the binding to the Linker (L); R24 represents a hydrogen atom, a methyl group, or the binding to the Linker (L), provided that the binding to the Linker (L) is any one of R24, R25 or R261, or the following formula (VIII):

[0035]
R
R35 isi ,t I

VIII
[wherein R31, R32, R33, R34 and R35 each independently represent a hydrogen atom, or a C1-6 alkyl group and R represents a hydrogen atom, or the binding to the Linker (L)], either D or E binds to the Linker (L)], or a pharmaceutically acceptable salt thereof.

[0036]
[10] The compound according to the above [1], which compound is selected from the group consisting of:
Compound 1: 2-(4-((S)-2-cyclohexy1-2-((S)-2-(methylamino)propanamido)acetyl)piperazine-l-carbony1)-5,6-difluoro-N,1-dimethyl-N-(2-(2-(2-45-44-(thieno[3,2-blpyridin-7-yloxy)piperidin-1-yOmethyDisoxazol-3-yDoxy)ethoxy)ethoxy)ethyl)-1H-indole-3-carboxamide:

[0037]
Date Recue/Date Received 2022-01-27 \ 0 N---0 N/Th \7/40 NH

HN

[0038]
Compound 2: 2-(44(S)-2-cyclohexy1-2-((S)-2-(methylamino)propanamido)acetyl)piperazine-1-carbony1)-6-methoxy-1-methyl-N-(2-(2-(2-(4-44-(thieno[3,2-dlpyrimidin-4-yloxy)piperidin-1-yOsulfonyl)phenoxy)ethoxy)ethoxy)ethyl)-1H-indole-3-carboxamide:

[0039]
/N
Nu?-0 N N
/NH

/NM
o_ro errNH

0) ,,1111 HN

[0040]
Compound 3: 14(R)-4-(5,6-difluoro-1-methy1-1H-indole-2-carbony1)-2-methylpiperazin-1-y1)-2-42R,5R)-5-methyl-2-42-(2-(2-45-((4-(thieno[3,2-blpyridin-7-yloxy)piperidin-1-yOmethyDisoxazol-3-y1)oxy)ethoxy)ethoxy)ethoxy)methyDpiperazin-1-yDethan-1-one:

[0041]

N/-N
LS _______________________________________ 0 / F
0/ oo \./\
I
====,\\µµ NH

[0042]
Date Recue/Date Received 2022-01-27 Compound 4: (S)-N-((S)-1-cyclohexy1-2-(4-(5,6-difluoro-1-methy1-3-(2-(2-(2-45-44-(thieno[3,2-blpyridin-7-yloxy)piperidin-1-yOmethyDisoxazol-3-yDoxy)ethoxy)ethoxy)ethoxy)-1H-indole-2-carbonyl)piperazin-1-y1)-2-oxoethyl)-2-(methylamino)propanamide:

[0043]
/¨\N
S
N 0-....N
\ _____________ F
F
I

\
cN,) co.7NH
)=,, HN ii/
I

[0044]
Compound 5: (S)-N-((S)-1-cyclohexy1-2-(4-(5,6-difluoro-1-(3-methy1-2-oxo-14-45-(thieno[3,2-blpyridin-7-yloxy)piperidin-1-yOmethyDisoxazol-3-yDoxy)-6,9,12-trioxa-3-azatetradecy1)-1H-indole-2-carbonyl)piperazin-1-y1)-2-oxoethyl)-2-(methylamino)propanamide:

[0045]
/¨

N ¨C:0 US _________________________________________ F F
N 0_, \ __________ uNN
o .

N"----NO----N.,--N /

0 NV''') NH
\\\
O'µµ
HN

[0046]
Compound 6: (S)-N-((S)-1-cyclohexy1-2-(4-(5,6-difluoro-1-(2-oxo-24(S)-2-(((54(4-(thieno[3,2-blpyridin-7-yloxy)piperidin-1-yOmethyDisoxazol-3-yDoxy)methyl)pyrrolidin-1-yl)ethyl)-1H-indole-2-carbonyl)piperazin-1-y1)-2-oxoethyl)-2-(methylamino)propanamide:

[0047]
Date Recue/Date Received 2022-01-27 F
/_ N.,-0_ F II

N S I
N 0-, 0 N
\
N
)r--\N---

[0048]
Compound 7: (S)-N-((S)-1-cyclohexy1-2-(4-(5-fluoro-1-(2-oxo-2-((S)-2-(((5-44-(thieno[3,2-blpyridin-7-yloxy)piperidin-1-yOmethyDisoxazol-3-yDoxy)methyl)pyrrolidin-1-yl)ethyl)-1H-indole-2-carbonyl)piperazin-1-y1)-2-oxoethyl)-2-(methylamino)propanamide:

[0049]
F
H 11:
L¨ S I r-NN N
)(N
N 0-, 0)._/ 0 \
... __ITN
\
0---1.11)1

[0050]
Compound 8: (S)-N-((S)-1-cyclohexy1-24(S)-4-(5,6-difluoro-1-(2-oxo-24(S)-2-(45-(thieno[3,2-blpyridin-7-yloxy)piperidin-1-yOmethyDisoxazol-3-yDoxy)methyl)pyrrolidin-1-ypethyl)-1H-indole-2-carbony1)-3-methylpiperazin-1-y1)-2-oxoethyl)-2-(methylamino)propanamide:

[0051]
F
/¨
N? 0_ F 410 N S N I0\__/ N N
F
\ ______________ ......: N
-f----\

[0052]
Compound 9: (S)-N-((S)-1-cyclohexy1-24(S)-4-(5-fluoro-1-(2-oxo-2-((S)-2-(((5-44-(thieno[3,2-blpyridin-7-yloxy)piperidin-1-yOmethyDisoxazol-3-yDoxy)methyl)pyrrolidin-1-yl)ethyl)-1H-indole-2-carbony1)-3-methylpiperazin-1-y1)-2-oxoethyl)-2-(methylamino)propanamide:

[0053]
Date Recue/Date Received 2022-01-27 F
N"

\
. 1 0 I --------\N.-NH F
Ls L
N CL N
0 NN..... j )r--"\N----\
Ul

[0054]
Compound 10: (S)-N-((S)-1-cyclohexy1-2-(4-(5,6-difluoro-l-methyl-4-(2-(2-(2-(24(54(4-(thieno[3,2-blpyridin-7-yloxy)piperidin-l-yOmethyDisoxazol-3-yDoxy)ethoxy)ethoxy)ethoxy)ethoxy)-1H-indole-2-carbonyl)piperazin-l-y1)-2-oxoethyl)-2-(methylamino)propanamide:

[0055]
/¨

N ____ 0 US _____ N ____________ 0-, N F
________ \
.....,.k F

N ---/----\ 0 NH
)----( HN-, and

[0056]
Compound 11: (S)-N-((S)-1-cyclohexy1-2-(4-(2-methy1-1-(2-(2-(2-(2-45-44-(thieno[3,2-blpyridin-7-yloxy)piperidin-l-yOmethyDisoxazol-3-yDoxy)ethoxy)ethoxy)ethoxy)ethyl)-1H-indole-5-carbonyl)piperazin-l-y1)-2-oxoethyl)-2-(methylamino)propanamide:

[0057]
/
o).\_____31____(-111 N ___ ?-0 ---US _____________________________________________ N
N _____________ C)07-r 0 \(( 0,-N
, or a pharmaceutically acceptable salt thereof.

[0058]
[11] A medicament containing the compound according to any one of the above [1] to [10], or a pharmaceutically acceptable salt thereof.
[12] The medicament according to the above [11], wherein the drug is an IRAK-M
protein degradation inducer.
Date Recue/Date Received 2022-01-27 [13] The medicament according to the above [11] or [12], which is a prophylactic or therapeutic agent for cancers.
[14] The medicament according to any one of the above [11] to [13], which is used in combination with another anticancer agent.
[15] A method for inducing IRAK-M protein degradation, comprising administering to a patient in need of treatment an effective amount of the compound or salt thereof according to any one of the above [1] to [10].
[16] A method for prevention or treatment of cancers, comprising administering to a patient in need of treatment an effective amount of the compound or salt thereof according to any one of the above [1] to [10].
[Advantageous Effect of the Invention]

[0059]
The compound of the present invention has an activity of inducing the degradation of IRAK-M
protein and may be useful as a prophylactic or therapeutic agent for cancer, fibrosis and infectious diseases.
[Brief Description of Drawings]

[0060]
FIG. 1 shows the results of the changes in tumor size over time in each group when subcutaneously administering the compounds of Examples 1, 6, 7, 8 and 9 three times every three days into a Lewis lung cancer cell inoculation model. Each compound was used as its salt shown in the figure. The mean standard error is shown in the figure.
[Description of Embodiments]

[0061]
Hereinafter, the present invention as well as compounds of the present invention and the method of producing them and their use will be illustrated with reference to the exemplary embodiments along with the preferred methods and materials which can be used in practice of the present invention. Unless otherwise specified in the sentences, any technical terms and scientific terms used in the present specification have the same meaning as those generally understood by those of ordinary skill in the art to which the present invention belongs. Any materials and methods equivalent or similar to those described in the present specification can be used for practicing the present invention. All publications and patents cited herein in connection with the present invention described herein are incorporated by reference, for example, as indicating methodology, materials, etc. that can be used in the present invention.
In addition, in the present specification, the description of "A - B"
indicating a numerical range means a numerical range including A and B which are end points. The same applies to "A to B".
In the present specification, "Me" means a methyl group unless it has a distinctly different meaning depending on the context.
In the present specification, when describing a compound name of a substituent and so on, a common name may be used instead of the proper name, but they mean the same compound.

[0062]
Hereinafter, the definition of each substituent used in the present specification will be described in detail. Unless otherwise specified, each substituent has the following definition.

[0063]
In the present specification, the "halogen atom" includes, e.g., fluorine, chlorine, bromine and iodine.

[0064]
In the present specification, the "C1-3 alkyl group" includes e.g., methyl, ethyl, propyl, Date Recue/Date Received 2022-01-27 isopropyl and cyclopropyl.

[0065]
In the present specification, the "optionally halogenated C1-3 alkyl group"
includes, e.g., a Cl-3 alkyl group optionally having 1 to 5 halogen atoms. Specific examples thereof 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 and 2,3-difluorocyclopropyl.

[0066]
In the present specification, the "C1-6 alkyl group" includes, e.g., 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.

[0067]
In the present specification, the "optionally halogenated C1-6 alkyl group"
includes, e.g., a Cl-6 alkyl group optionally having 1 to 7, preferably 1 to 5 halogen atoms.
Specific examples thereof include methyl, chloromethyl, fluoromethyl, dichloromethyl, difluoromethyl, trichloromethyl, trifluoromethyl, ethyl, 2-bromoethyl, 2,2,2-trifluoroethyl, tetrafluoroethyl, pentafluoroethyl, propyl, 2,2-difluoropropyl, 3,3,3-trifluoropropyl, isopropyl, butyl, 4,4,4-trifluorobutyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, 5,5,5-trifluoropentyl, hexyl and 6,6,6-trifluorohexyl.

[0068]
In the present specification, the "C2-6 alkenyl group" includes, e.g., ethenyl, 1-propenyl, 2-propenyl, 2-methyl-1-propenyl, 1-butenyl, 2-butenyl, 3-butenyl, 3-methyl-2-butenyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 4-methyl-3-pentenyl, 1-hexenyl, 3-hexenyl and 5-hexenyl.

[0069]
In the present specification, the "C1-6 alkylsulfonyl group" includes, e.g., methylsulfonyl, ethylsulfonyl, propylsulfonyl, isopropylsulfonyl, butylsulfonyl, sec-butylsulfonyl and tert-butylsulfonyl.

[0070]
In the present specification, the "C6-14 aryl group" includes, e.g., phenyl, 1-naphthyl, 2-naphthy1, 1-anthril, 2-anthril and 9-anthril.

[0071]
In the present specification, the "C6-14 arylene group" include, e.g., phenylene, 1,5-naphthylene, 1,4-naphthylene, 2,3-naphthylene, 1,8-anthrylene and 9,10-anthrylene.

[0072]
In the present specification, the "C1-6 alkoxy group" includes, e.g., methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, tert-butoxy, pentyloxy and hexyloxy.

[0073]
In the present specification, examples of the "hydrocarbon group" (including "hydrocarbon group" of "optionally substituted hydrocarbon group") include, e. g., a C1-3 alkyl group, a C1-6 alkyl group, a C1-6 alkylene group, a C2-6 alkenyl group, a C6-14 aryl group and a C6-14 arylene group. In the present specification, examples of the "optionally substituted hydrocarbon group" include a hydrocarbon group optionally having substituent(s) selected from the following Substituent group A

[0074]
"Substituent group A"
(1) a halogen atom, (2) a C1-3 alkyl group, Date Recue/Date Received 2022-01-27 (3) a C1-6 alkoxy group, (4) an amino group.

[0075]
The number of the above-described substituent in the "optionally substituted hydrocarbon group" is, e.g., 1 to 5, preferably 1 to 3. When the number of the substituent is two or more, each substituent may be the same or different.

[0076]
In the present specification, the "optionally substituted C1-6 alkylene group"
or the "optionally substituted C3-10 cycloalkylene group" includes, e.g., a C1-6 alkylene group or a C3-10 cycloalkylene group, optionally having a substituent selected from Substituent Group A described above (a halogen atom, a C1-3 alkyl group, a C1-6 alkoxy group and an amino group). The number of the substituent is, e.g., 1 to 5. When the number of the substituent is two or more, each substituent may be the same or different.

[0077]
In the present specification, the "optionally substituted C6-14 aryl group" or the "optionally substituted C6-14 arylene group" includes, e.g., a C6-14 aryl group or a C6-14 arylene group, optionally having a substituent selected from the above-mentioned Substituent group A (a halogen atom, a C1-3 alkyl group, a C1-6 alkoxy group and an amino group). The number of the substituent is, e.g., 1 to 3. When the number of the substituent is two or more, each substituent may be the same or different.

[0078]
In the present specification, the "optionally substituted carbamoyl group"
includes, e.g., a carbamoyl group optionally having "one or two substituents selected from a Cl -6 alkyl group, a C2-6 alkenyl group and a C3-10 cycloalkyl group, each of which optionally having 1 to 3 substituents selected from the above-mentioned Substituent group A (a halogen atom, a C1-3 alkyl group, a C1-6 alkoxy group and an amino group)."

[0079]
In the present specification, the "C1-6 alkylene group" includes, e.g., 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.

[0080]
In the present specification, the "C3-10 cycloalkylene group" includes, e.g., 1,1-cyclopropylene, cis-1,2-cyclopropylene, trans-1,2-cyclopropylene, 1,1-cyclobutylene, cis-1,2-cyclobutylene, trans-1,2-cyclobutylene, cis-1,3-cyclobutylene, trans-1,3-cyclobutylene, 1,1-cyclopentylene, cis-1,2-cyclopentylene, trans-1,2-cyclopentylene, cis-1,3-cyclopentylene, trans-1,3-cyclopentylene, 1,1-cyclohexylene, cis-1,2-cyclohexylene, trans-1,2-cyclohexylene, cis-1,3-cyclohexylene, trans-1,3-cyclohexylene, cis-1,4-cyclohexylene, trans-1,4-cyclohexylene, 1,1-cycloheptynylene, 1,1-cyclooctynylene, 2,2-dimethy1-1,1-cyclopropylene, 2,3-dimethy1-1,1-cyclopropylene, 2,2,3,3,4,4-tetramethy1-1,1-cyclobutylene, 7,7-norcaranylene, 7,7-norpinanylene and 7,7-norbornanylene.

[0081]
In the present specification, the "linker" refers to a chemical moiety (structure) used to conjugate a part of a subject compound to another compound. Exemplary linkers are described in the present specification. For example, in any compounds described in the present specification, a chemical structure used to conjugate a partial structure of a compound and a partial structure of another compound can be used as a linker, and corresponds to the "linker"
referred to in the present specification.

[0082]
In the present specification, the "group having 5-20 carbon atoms optionally containing a hetero atom" is a linear or branched alkyl group or alkenyl group, a cycloalkyl group, an aryl Date Recue/Date Received 2022-01-27 group, an arylalkyl group or an alkyl aryl group having 5-20 carbon atoms, which may contain at least one hetero atom selected from N or 0, and groups bonded to the same carbon atom can be bonded together to form a ring.

[0083]
In the present specification, the term "bond" indicates a state in which two adjacent groups are bonded by a single bond. Further, when a plurality of the "single bonds" are connected, it indicates a state in which all of them are connected together by a single bond.

[0084]
Hereinafter, each symbol of the formula (II) will be described.
Y is CH or N, preferably CH.
R 1 is H or Me, preferably H.
The arrow means the binding to the Linker (L).

[0085]
R 3 is a group represented by the following structural formula:

[0086]
* *
*
wherein * represents the binding position to 0, ** represents the binding position to A, a nd n is an integer of 0 to 2, preferably a group represented by the following structural formula:

[0087]
**
N/
wherein * represents the binding position to 0, and ** represents the binding position to A.

[0088]
A is a group represented by the following structural formula:

[0089]

*x*
wherein R 5 each independently is a hydrogen atom or a C1-6 alkyl group, or preferably *-CH2 -* or

[0090]
R 4 is any group selected from the following structural formulae:

[0091]
wherein * represents the binding position to A, and ** represents the binding position to the Date Recue/Date Received 2022-01-27 linker, an optionally substituted C1-6 alkylene group, an optionally substituted C3-10 cycloalkylene group, an optionally substituted C6-14 arylene group, or a bond, preferably any group represented by the above-mentioned structures.

[0092]
An example of the "substituent" of "an optionally substituted C1-6 alkylene group" "an optionally substituted C3-10 cycloalkylene group" or "an optionally substituted C6-14 arylene group" shown in R 4 is a substituent selected from the "Substituent group A."
The number of the substituents is for example 1 to 3. When the number of the substituents is two or more, the respective substituents may be the same or different.

[0093]
Hereinafter, each symbol of the formula (IV) will be described.
R01, R02, R03, R04, R05, R06, R07 and Ros each independently represent a hydrogen atom or a Cl-6 alkyl group which may 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, further preferably each independently represent a hydrogen atom or a methyl group.
Either D or E binds to the linker (L).

[0094]
D is represented by the following formula (V):

[0095]
( ln ( HN

(V) wherein m is an integer of 0 to 2, n is an integer of 0 to 2, Wii represents a methylene group, a difluoromethylene group, 0, S. SO, SO2, 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 an optionally halogenated C1-3 alkyl group, or the following formula (VI):

[0096]
CI) __ NH
HN

(VI) wherein Q represents an oxygen atom, formula -NR21- (wherein, R21 represents a hydrogen atom, a C1-6 alkyl group, or an alkyl group which may form a ring with P), or a bond, P represents a hydrogen atom, a C1-6 alkyl group or the binding to the Linker (L) (including the formation of a ring with Q and binding to the linker (L).

[0097]
D is preferably the following formula (V-2):

[0098]
Date Recue/Date Received 2022-01-27 :::0C-_____I
HWY-NH
/ ''---(V-2) or the following formula (VI-1):

[0099]
Q ¨rs1H
HN

(VI-1) wherein Q shows binding to the linker (L).
The structure of D can bind to the linker (L) in the position of P or Q in the formula (VI) or Q in the formula (VI-1).

[0100]
E is represented by the following formula (VII):

[0101]

VII
wherein R21, R22, and R23 each independently represent a hydrogen atom, a halogen atom, a C1-6 alkyl group, a C1-6 alkoxy group, or an optionally substituted carbamoyl group, preferably R21, R22, and R23 each independently represent a hydrogen atom, a halogen atom, a C1-6 alkyl group, or a C1-6 alkoxy group; R25 and R26 each independently represent a hydrogen atom, a halogen atom, a C1-6 alkyl group, a C1-6 alkoxy group, an optionally substituted carbamoyl group, or the binding to the linker (L), preferably R25 and R26 each independently represent a hydrogen atom, a halogen atom, a C1-6 alkyl group, a C1-6 alkoxy group, or the binding to the linker (L); and R24 represents a hydrogen atom, a methyl group, or the binding to the linker (L), provided that the binding to the linker (L) is any one of R24, R25, or R26, or the following formula (VIII):

[0102]
R
R35 \

I

VIII
wherein R31, R32, R33, R34 and R35 each independently represent a hydrogen atom, a halogen atom, a C1-6 alkyl group, a C1-6 alkoxy group, or an optionally substituted carbamoyl group, Date Recue/Date Received 2022-01-27 preferably R31, R32, R33, R34 and R35 each independently represent a hydrogen atom, a halogen atom, or a C1-6 alkyl group; and R represents a hydrogen atom, C1-6 alkyl group, or the binding to the linker (L).

[0103]
Hereinafter, the linker (L) of the formula (I) will be described.
The linker (L) is preferably a group having 5 to 20 carbon atoms which may contain a heteroatom, is more preferably a group represented by the following structural formula:

[0104]
0 *
* __ , *-(CH2CH20)n(CH2)m(NRCO)s(CH2)t-* (n is a natural number from 1 to 5, m is 0, 1, or 2, s is 0 or 1, t is 0 or 1 and R represents a hydrogen atom or C1-6 alkyl group), or a bond, is further preferably a group represented by the following structural formula:

[0105]
0 * *
* __ wherein * represents the binding to the IRAK-M binder (M), or *-(CH2CH20)n-*
(n is a natural number from 1 to 5).

[0106]
In the present specification, the "compound that adds a function" means a ligand of any protein present in a living body, a cell penetrating peptide (CPP), or a kinetophore that keeps a compound in the intestinal tract (e.g., polyethylene oxides capped with a short-chain peptide, a sugar and quaternary ammonium; etc.).

[0107]
In the present specification, the "IRAK-M protein related disease(s)" is a disease or an illness that is described or speculated in association to abnormalities in the IRAK-M
protein itself or its regulation. Protein abnormalities include, but are not limited to, abnormal expression or enhancement of a protein in a living body, and the presence of mutant proteins.

[0108]
A compound included in compound (I) can be used as a synthetic intermediate in producing another compound (I) of the present invention, and is also used as a synthetic intermediate in producing an IRAK-M protein degrader other than compound (I).

[0109]
When compound (I) is in a form of a salt, the salt includes, e.g., metal salts, ammonium salts, salts with organic base, salts with inorganic acid, salts with organic acid, salts with basic or acidic amino acid, and the like. Suitable examples of the metal salt include, e.g., alkali metal salts such as sodium salts, potassium salts and the like; alkaline-earth metal salts such as calcium salts, magnesium salts, barium salts and the like; aluminum salts, and the like. Suitable examples of the salt with organic base include, e.g., salts with trimethylamine, triethylamine, pyridine, picoline, 2,6-rutidine, ethanolamine, diethanolamine, triethanolamine, cyclohexylamine, dicyclohexylamine, N,N'-dibenzylethylenediamine and the like. Suitable examples of the salt with inorganic acid include, e.g., salts with hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid and the like. Suitable examples of the salt with organic acid Date Recue/Date Received 2022-01-27 include, e.g., salts with formic acid, acetic acid, trifluoroacetic acid, phthalic acid, fumaric acid, oxalic acid, tartaric acid, maleic acid, citric acid, succinic acid, malic acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid and the like. Suitable examples of the salt with basic amino acid include, e.g., salts with arginine, lysine, ornithine and the like, and suitable examples of the salts with acidic amino acids include, e.g., salts with aspartic acid, glutamic acid and the like.

[0110]
Among them, pharmaceutically acceptable salts are preferred. For example, when an acidic functional group is present in a compound, the salt includes inorganic salts such as alkali metal salts (e.g., sodium salts, potassium salts, etc.) and alkaline-earth metal salts (e.g., calcium salts, magnesium salts, etc.) and ammonium salts, while when a basic functional group is present in a compound, the salt includes salts with inorganic acid such as hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid and the like, or salts with organic acid 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 and the like.

[0111]
The production method of the compound of the present invention is explained in the followings. The raw material and reagent used and the compound obtained in each step in the following production method may be each in a form of a salt, and examples of such salt include those similar to the salts of the compound of the present disclosure.

[0112]
When the compound obtained in each step is in a free form, it can be converted to the objective salt according to a method known per se. When the compound obtained in each step is in a salt form, it can be converted to the free form or the objective other salt form according to a method known per se.

[0113]
The compound obtained in each step can be used directly as the resultant reaction mixture or as a resultant crude product for the next reaction. Alternatively, the compound obtained in each step can be isolated and/or purified from a reaction mixture according to a method known per se, for example, a separation means such as concentration, crystallization, recrystallization, distillation, solvent extraction, fractional distillation, column chromatography and the like.

[0114]
When the raw material compound and reagent used in each step are commercially available, the commercially available product can also be used directly.

[0115]
In the reaction in each step, while the reaction time varies depending on the kind of the reagent and solvent to be used, it is generally 1 min to 48 hr, preferably 10 min to 8 hr, unless otherwise specified.

[0116]
In the reaction in each step, while the reaction temperature varies depending on the kind of the reagent and solvent to be used, it is generally -78 C to 300 C, preferably -78 C to 150 C, unless otherwise specified.

[0117]
In the reaction in each step, while the pressure varies depending on the kind of the reagent and solvent to be used, it is generally 1 atm to 20 atm, preferably 1 atm to 3 atm, unless otherwise specified.

[0118]
Microwave synthesizer such as Initiator manufactured by Biotage and the like may be used for the reaction in each step. While the reaction temperature varies depending on the kind of the reagent and solvent to be used, it is generally room temperature to 300 C, preferably 50 C to Date Recue/Date Received 2022-01-27 250 C, unless otherwise specified. While the reaction time varies depending on the kind of the reagent and solvent to be used, it is generally 1 min to 48 hr, preferably 1 min to 8 hr, unless otherwise specified.

[0119]
In the reaction in each step, the reagent is used in an amount of 0.5 equivalent to 20 equivalents, preferably 0.8 equivalent to 5 equivalents, relative to the substrate, unless otherwise specified. When the reagent is used as a catalyst, the reagent is used in an amount of 0.001 equivalent to 1 equivalent, preferably 0.01 equivalent to 0.2 equivalent, relative to the substrate.
When the reagent is used as a reaction solvent, the reagent is used in a solvent amount.

[0120]
Unless otherwise specified, the reaction in each step is carried out without solvent, or by dissolving or suspending the raw material compound in a suitable solvent.
Examples of the solvent include those described in Examples and the following solvents.
alcohols: methanol, ethanol, tert-butyl alcohol, 2-methoxyethanol and the like;
ethers: diethyl ether, diphenyl ether, tetrahydrofuran, 1,2-dimethoxyethane and the like;
aromatic hydrocarbons: chlorobenzene, toluene, xylene and the like;
saturated hydrocarbons: cyclohexane, hexane and the like;
amides: N,N-dimethylformamide, N-methylpyrrolidone and the like;
halogenated hydrocarbons: dichloromethane, carbon tetrachloride and the like;
nitriles: acetonitrile and the like;
sulfoxides: dimethyl sulfoxide and the like;
aromatic organic bases: pyridine and the like;
anhydrides: acetic anhydride and the like;
organic acids: formic acid, acetic acid, trifluoroacetic acid and the like;
inorganic acids: hydrochloric acid, sulfuric acid and the like;
esters: ethyl acetate and the like;
ketones: acetone, methyl ethyl ketone and the like;
water.
The above-mentioned solvent can be used in a mixture of two or more kinds thereof in an appropriate ratio.

[0121]
When a base is used for the reaction in each step, examples thereof include those described in Examples and the following bases.
inorganic bases: sodium hydroxide, magnesium hydroxide and the like;
basic salts: sodium carbonate, calcium carbonate, sodium hydrogencarbonate and the like;
organic bases: triethylamine, diethylamine, pyridine, 4-dimethylaminopyridine, N,N-dimethylaniline, 1,4-diazabicyclo[2.2.2loctane,1,8-diazabicyclo[5.4.01-7-undecene, imidazole, piperidine and the like;
metal alkoxides: sodium ethoxide, potassium tert-butoxide and the like;
alkali metal hydrides: sodium hydride and the like;
metal amides: sodium amide, lithium diisopropylamide, lithium hexamethyldisilazide and the like;
organic lithiums: n-butyllithium and the like.

[0122]
When an acid or an acid catalyst is used for the reaction in each step, examples thereof include those described in Examples and the following acids and acid catalysts.
inorganic acids: hydrochloric acid, sulfuric acid, nitric acid, hydrobromic acid, phosphoric acid and the like;
organic acids: acetic acid, trifluoroacetic acid, citric acid, p-toluenesulfonic acid, 10-Date Recue/Date Received 2022-01-27 camphorsulfonic acid and the like;
Lewis acid: boron trifluoride diethyl ether complex, zinc iodide, anhydrous aluminum chloride, anhydrous zinc chloride, anhydrous iron chloride and the like.

[0123]
Unless otherwise specified, the reaction in each step is carried out according to a method known per se, for example, the method described in Jikken Kagaku Kouza, 5th Edition, vol.13-19 (the Chemical Society of Japan ed.); Shin Jikken Kagaku Kouza, vol.14-15 (the Chemical Society of Japan ed.); Fine Organic Chemistry, Revised 2nd Edition (L. F. Tietze, Th.
Eicher, Nankodo);
Organic Name Reactions, the Reaction Mechanism and Essence, Revised Edition (Hideo Togo, Kodansha); ORGANIC SYNTHESES Collective Volume 1-VII (John Wiley & Sons Inc);
Modern Organic Synthesis in the Laboratory A Collection of Standard Experimental Procedures (Jie Jack Li, OXFORD UNIVERSITY); Comprehensive Heterocyclic Chemistry III, Vol.' -Vol.14 (Elsevier Japan); Strategic Applications of Named Reactions in Organic Synthesis (translated by Kiyoshi Tomioka, Kagakudojin); Comprehensive Organic Transformations (VCH
Publishers Inc.), 1989, or the like, or the method described in Examples.

[0124]
In each step, the protection or deprotection reaction of an functional group is carried out according to a method known per se, for example, the method described in "Protective Groups in Organic Synthesis, 4th Ed", Wiley-Interscience, Inc., 2007 (Theodora W.
Greene, Peter G. M.
Wuts); "Protecting Groups 3rd Ed." Thieme, 2004 (P.J.Kocienski), or the like, or the method described in Examples.
Examples of the protecting group for a hydroxy group of an alcohol and the like or a phenolic hydroxy group include ether-type protecting groups such as methoxymethyl ether, benzyl ether, tert-butyldimethylsilyl ether, tetrahydropyranyl ether and the like;
carboxylate ester-type protecting groups such as acetate ester and the like; sulfonate ester-type protecting groups such as methanesulfonate ester and the like; and carbonate ester type protecting groups such as tert-butylcarbonate and the like.
Examples of the protecting group for a carbonyl group of an aldehyde include acetal type protecting groups such as dimethylacetal and the like; and cyclic acetal-type protecting groups such as 1,3-dioxane and the like.
Examples of the protecting group for a carbonyl group of a ketone include ketal -type protecting groups such as dimethylketal and the like; cyclic ketal-type protecting groups such as 1,3-dioxane and the like; oxime-type protecting groups such as 0-methyloxime and the like; and hydrazone-type protecting groups such as N,N-dimethylhydrazone and the like.
Examples of the protecting group for a carboxyl group include ester-type protecting groups such as methyl ester and the like; and amide-type protecting groups such as N,N-dimethylamide and the like.
Examples of the protecting group for a thiol include ether-type protecting groups such as benzyl thioether and the like; and ester-type protecting groups such as thioacetate ester, thiocarbonate, thiocarbamate and the like.
Examples of the protecting group for an amino group and an aromatic heterocycle such as imidazole, pyrrole, indole and the like include carbamate -type protecting groups such as benzyl carbamate and the like; amide-type protecting groups such as acetamide and the like; alkyl amine-type protecting groups such as N-triphenylmethylamine and the like; and sulfonamide-type protecting groups such as methanesulfonamide and the like.
The protecting groups can be removed according to a method known per se, such as a method using acid, base, ultraviolet rays, hydrazine, phenylhydrazine, sodium N-methyldithiocarbamate, tetrabutylammonium fluoride, palladium acetate or trialkylsilyl halide (e.g., trimethylsilyl iodide, trimethylsilyl bromide), or a reduction method.

[0125]
Date Recue/Date Received 2022-01-27 When reduction reaction is carried out in each step, examples of the reducing agent to be used include metal hydrides such as lithium aluminum hydride, sodium triacetoxyborohydride, sodium cyanoborohydride, diisobutylaluminum hydride (DIBAL-H), sodium borohydride, tetramethylammonium triacetoxyborohydride and the like; boranes such as borane tetrahydrofuran complex and the like; Raney nickel; Raney cobalt; hydrogen;
formic acid;
triethylsilane and the like. When carbon-carbon double bond or triple bond is reduced, a method using a catalyst such as palladium-carbon, Lindlar's catalyst and the like may be employed.

[0126]
When oxidation reaction is carried out in each step, examples of the oxidizing agent to be used include peroxides such as m-chloroperbenzoic acid (mCPBA), hydrogen peroxide, tert-butyl hydroperoxide and the like; perchlorates such as tetrabutylammonium perchlorate and the like;
chlorates such as sodium chlorate and the like; chlorites such as sodium chlorite and the like;
periodic acids such as sodium periodate and the like; hypervalent iodine reagents such as iodosylbenzene and the like; reagents containing manganese such as manganese dioxide, potassium permanganate and the like; leads such as lead tetraacetate and the like; reagents containing chromium such as pyridinium chlorochromate (PCC), pyridinium dichromate (PDC), Jones reagent and the like; halogen compounds such as N-bromosuccinimide (NBS) and the like;
oxygen; ozone; sulfur trioxido-pyridine complex; osmium tetroxide; selenium dioxide; 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ) and the like.

[0127]
When radical cyclization reaction is carried out in each step, examples of the radical initiator to be used include azo compounds such as azobisisobutyronitrile (AIBN) and the like; water-soluble radical initiators such as 4,4'-azobis-4-cyanopentanoic acid (ACPA) and the like;
triethylboran in the presence of air or oxygen; benzoyl peroxide and the like.
Examples of the radical reagent to be used include tributylstannane, tristrimethylsilylsilane, 1,1,2,2-tetraphenyldisilane, diphenylsilane, samarium iodide and the like.

[0128]
When Wittig reaction is carried out in each step, examples of the Wittig reagent to be used include alkylidene phosphoranes and the like. The alkylidene phosphoranes can be prepared according to a method known per se, for example, by reacting a phosphonium salt with a strong base.

[0129]
When Horner-Emmons reaction is carried out in each step, examples of the reagent to be used include phosphonoacetates such as methyl dimethylphosphonoacetate, ethyl diethylphosphonoacetate and the like; and bases such as alkali metal hydrides, organic lithiums and the like.

[0130]
When Friedel-Crafts reaction is carried out in each step, examples of the reagent to be used include a combination of a Lewis acid and an acid chloride or a combination of a Lewis acid and an alkylating agent (e.g., an alkyl halide, an alcohol, an olefin).
Alternatively, an organic acid or an inorganic acid can also be used instead of a Lewis acid, and an anhydride such as acetic anhydride and the like can also be used instead of an acid chloride.

[0131]
When aromatic nucleophilic substitution reaction is carried out in each step, a nucleophile (e.g., an amine, imidazole) and a base (e.g., a basic salt, an organic base) are used as a reagent.

[0132]
When nucleophilic addition reaction by a carbo anion, nucleophilic 1,4-addition reaction (Michael addition reaction) by a carbo anion or nucleophilic substitution reaction by a carbo anion is carried out in each step, examples of the base to be used for generation of the carbo anion include organic lithiums, metal alkoxides, inorganic bases, organic bases and the like.
Date Recue/Date Received 2022-01-27

[0133]
When Grignard reaction is carried out in each step, examples of the Grignard reagent to be used include arylmagnesium halides such as phenylmagnesium bromide and the like;
alkylmagnesium halides such as methylmagnesium bromide and the like. The Grignard reagent can be prepared according to a method known per se, for example, by reacting an alkyl halide or an aryl halide with metal magnesium in an ether or tetrahydrofuran as a solvent.

[0134]
When Knoevenagel condensation reaction is carried out in each step, a compound having an activated methylene group with two electron withdrawing groups (e.g., malonic acid, diethyl malonate, malononitrile etc.) and a base (e.g., an organic base, a metal alkoxide, an inorganic base) are used as a reagent.

[0135]
When Vilsmeier-Haack reaction is carried out in each step, phosphoryl chloride and an amide derivative (e.g., N,N-dimethylformamide etc.) are used as a reagent.

[0136]
When azidation reaction of an alcohol, an alkyl halide or a sulfonate is carried out in each step, examples of the azidating agent to be used include diphenylphosphorylazide (DPPA), trimethylsilylazide, sodium azide and the like. For example, for the azidation reaction of an alcohol, a method using diphenylphosphorylazide and 1,8-diazabicyclo[5.4.01undec-7-ene (DBU), a method using trimethylsilylazide and a Lewis acid, and the like are employed.

[0137]
When reductive amination reaction is carried out in each step, examples of the reducing agent to be used include sodium triacetoxyborohydride, sodium cyanoborohydride, hydrogen and formic acid and the like. When the substrate is an amine compound, examples of the carbonyl compound to be used include paraformaldehyde, aldehydes such as acetaldehyde and the like, and ketones such as cyclohexanone and the like. When the substrate is a carbonyl compound, examples of the amine to be used include ammonia, primary amines such as methylamine and the like; secondary amines such as dimethylamine and the like, and the like.

[0138]
When Mitsunobu reaction is carried out in each step, an azodicarboxylate (e.g., diethyl azodicarboxylate (DEAD), diisopropyl azodicarboxylate (DIAD) etc.) and triphenylphosphine are used as a reagent.

[0139]
When esterification reaction, amidation reaction or ureation reaction is carried out in each step, examples of the reagent to be used include acyl halides such as acid chlorides, acid bromides and the like; activated carboxylic acids such as anhydrides, activated esters, sulfates and the like.
Examples of the activating agent of the carboxylic acid include carbodiimide condensing agents such as 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (WSCD) and the like;
triazine condensing agents such as 4-(4,6-dimethoxy 1,3,5-triazin-2-y1)-4-methylmorpholinium chloride n-hydrate (DMT-MM) and the like; carbonate condensing agents such as 1,1-carbonyldiimidazole (CDI) and the like; diphenylphosphoryl azide (DPPA);
benzotriazol-1-yloxy-trisdimethylaminophosphonium salt (BOP reagent); 2-chloro-l-methyl-pyridinium iodide (Mukaiyama reagent); thionyl chloride; lower alkyl haloformates such as ethyl chloroformate and the like; 0-(7-azabenzotriazol-1-y1)-N,N,N,N1-tetramethyluronium hexafluorophosphorate (HATU); sulfuric acid; 2,4,6-tripropy1-1,3,5,2,4,6-trioxatriphosphorinane-2,4,6-trioxide (T3P);
combinations thereof and the like. When carbodiimide condensing agent is used, an additive such as 1-hydroxybenzotriazole (HOBt), N-hydroxysuccinimide (HOSu), dimethylaminopyridine (DMAP) and the like may be added to the reaction system.

[0140]
When coupling reaction is carried out in each step, examples of the metal catalyst to be used Date Recue/Date Received 2022-01-27 include palladium compounds such as palladium(II) acetate, tetrakis(triphenylphosphine)palladium(0), dichlorobis(triphenylpho sphine)palladium(II), dichlorobis(triethylphosphine)palladium(II), tris(dibenzylideneacetone)dipalladium(0), 1,1'-bis(diphenylphosphino)ferrocene palladium(II) chloride, and the like;
nickel compounds such as tetrakis(triphenylphosphine)nickel(0) and the like; rhodium compounds such as tris(triphenylphosphine)rhodium(III) chloride and the like; cobalt compounds;
copper compounds such as copper oxide, copper(I) iodide and the like; platinum compounds and the like. In addition, a base can be added to the reaction system, and examples thereof include inorganic bases, basic salts and the like.

[0141]
When thiocarbonylation reaction is carried out in each step, phosphorus pentasulfide is typically used as the thiocarbonylating agent. Alternatively, a reagent having a 1,3,2,4-dithiadiphosphetane-2,4-disulfide structure (e.g., 2,4-bis(4-methoxypheny1)-1,3,2,4-dithiadiphosphetane-2,4-disulfide (Lawesson's reagent) etc.) can also be used instead of phosphorus pentasulfide.

[0142]
When Wohl-Ziegler reaction is carried out in each step, examples of the halogenating agent to be used include N-iodosuccinimide, N-bromosuccinimide (NBS), N-chlorosuccinimide (NCS), bromine, sulfuryl chloride and the like. In addition, the reaction can be accelerated by subjecting a radical initiator such as heat, light, benzoyl peroxide, azobisisobutyronitrile and the like to the reaction system.

[0143]
When halogenation reaction of a hydroxy group is carried out in each step, examples of the halogenating agent to be used include hydrohalic acids and acid halides of inorganic acids, specifically, hydrochloric acid, thionyl chloride, phosphorus oxychloride and the like for chlorination, 48% hydrobromic acid and the like for bromination. In addition, a method of producing an alkyl halide by reacting an alcohol with triphenylphosphine and carbon tetrachloride or carbon tetrabromide or the like can be employed.
Alternatively, a method of producing an alkyl halide via two-step reaction comprising converting an alcohol to the corresponding sulfonate, and then reacting the sulfonate with lithium bromide, lithium chloride or sodium iodide can also be employed.

[0144]
When Arbuzov reaction is carried out in each step, examples of the reagent to be used include alkyl halides such as ethyl bromoacetate and the like; phosphites such as triethyl phosphite, tri(isopropyl) phosphite and the like.

[0145]
When sulfonate esterification reaction is carried out in each step, examples of the sulfonating agent to be used include methanesulfonyl chloride, p-toluenesulfonyl chloride, methanesulfonic anhydride, p-toluenesulfonic anhydride and the like.

[0146]
When hydrolysis reaction is carried out in each step, an acid or a base is used as a reagent.
When acid hydrolysis reaction of t-butyl ester is carried out, formic acid, triethylsilane and the like may be added to reductively trap t-butyl cation which is by-produced.

[0147]
When dehydration reaction is carried out in each step, examples of the dehydrating agent to be used include sulfuric acid, diphosphorus pentoxide, phosphorus oxychloride, N,N'-dicyclohexylcarbodiimide, alumina, polyphosphoric acid and the like.

[0148]
When the alkylation reaction of alcohols or amines or aromatic heterocyclics having an NH
group in the ring (e.g., imidazole, pyrazole) is performed in each step, the alkylating agent Date Recue/Date Received 2022-01-27 includes optionally substituted alkyl halides (e.g., iodomethane), optionally substituted alkyls having an optionally substituted C1-6 alkylsulfonyloxy group as a leaving group, optionally substituted alkyls having a C6-14 arylsulfonyloxy group optionally substituted with a Ci_6 alkyl group, sodium 2-chloro-2,2-difluoroacetate, 2,2-difluoro-2-(fluorosulfonyl)acetate, and the like.
Further, the base to be used includes organic lithiums, metal alkoxides, inorganic bases, organic bases, and the like.

[0149]
When the fluorination reaction is performed in each step, the fluorinating agent to be used includes DAST (diethylaminosulfur trifluoride), bis(2-methoxyethyl) aminosulfur trifluoride, 1-chloromethy1-4-fluoro-1,4-diazoniabicyclo[2.2.2]octane bis (tetrafluoroborate) (Selectfluor), 4-tert-buty1-2,6-dimethylphenylsulfur trifluoride (FLUOLEAD) and the like.

[0150]
When the Huisgen reaction is performed in each step, an azide compound and an alkyne compound are used as the agent used. The catalyst includes monovalent copper ions, for example, copper iodide, copper chloride, copper cyanide and the like.

[0151]
When the coupling reaction is performed in each step, the coupling reaction includes Su zuki coupling, Stille coupling, Buchwald-Hartwig coupling, Negishi coupling, Mizoroki-Hec k reaction, cyanation reaction using copper cyanide or zinc cyanide, and the like. Reagen ts such as metal catalysts, phosphine ligands, bases and the like used in the coupling reac tion can be used in methods known per se [methods described in, e.g., 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, G
ermany (2004); J. F. Hartwig, in Handbook of Organopalladium Chemistry for Organic Sy nthesis, A. de Meijere, F. Diederich, Eds., Wiley, New York (2002); J. F.
Hartwig, in Mo dern Amination Methods, A. Ricci, Ed., Wiley-VCH, Weinheim, (2000)1 or methods accord ing to them, in addition to reagents described above.

[0152]
Hereinafter, a method for producing compound (I) will be described.
Each symbol in the following reaction schemes has the same meaning as described above unless otherwise specified. When a specific production method is not described, a commercially available raw material compound can be easily obtained, or a raw material compound can be produced by a method known per se or an equivalent method thereof, and a method described in Examples.

[0153]
When performing a reaction in each step, if there is a reactive site where a reaction other than the intended reaction occurs, a protecting group is introduced into the reactive site in advance by means known per se as necessary, and the desired reaction is performed, and thereafter, the protecting group may be removed also by means known per se.
For example, when the raw material compounds or the intermediates have an amino group, a carboxy group or a hydroxyl group as a substituent, these groups may be protected with a protecting group generally used in peptide chemistry and the like. In this case, after the reaction, the target compound can be obtained by removing the protecting group(s) as necessary.

[0154]
Compound (I) can be synthesized from the compound (1) which is an IRAK-M
binder or the compound (4) which is an E3 ligase binder by the method shown in the scheme below. In each scheme, compound (I) and each reaction intermediate may independently form salts.

[0155]
Scheme 1:
Date Recue/Date Received 2022-01-27

[0156]
(2) (4) (1) (2) ___________ M-L _______ M-L-E _______ L-E
(1) (3) I (5) (4) A
(2a) M-L1 L2-E (2b) (3a) (5a)

[0157]
The compound (3) can be produced by subjecting the compound (1) or a reactive derivative thereof and the compound (2) which is a linker (L) or a reactive derivative thereof to an amidation reaction, a Mitsunobu reaction, an alkylation reaction, a coupling reaction, and the like. Compound (I) can be obtained by subjecting the compound (3) or a reactive derivative thereof and the compound (4) or a reactive derivative thereof to an amidation reaction, the Mitsunobu reaction, an alkylation reaction or a coupling reaction, and the like.

[0158]
The compound (5) can be produced by subjecting the compound (4) or a reactive derivative thereof and compound (2) or a reactive derivative thereof to an amidation reaction, a Mitsunobu reaction, an alkylation reaction, a coupling reaction, and the like. Compound (I) can be obtained by subjecting the compound (5) or a reactive derivative thereof and the compound (1) or a reactive derivative thereof to an amidation reaction, the Mitsunobu reaction, an alkylation reaction, a coupling reaction, and the like.

[0159]
The compound (3a) can be produced by subjecting the compound (1) or a reactive derivative thereof and compound (2a) or a reactive derivative thereof to an amidation reaction, a Mitsunobu reaction, an alkylation reaction, a coupling reaction, and the like. The compound (5a) can be produced by subjecting the compound (4) or a reactive derivative thereof and compound (2b) or a reactive derivative thereof to an amidation reaction, the Mitsunobu reaction, an alkylation reaction, a coupling reaction, and the like. Compound (I) can be obtained by subjecting the compound (3a) and the compouynd (5a) or reactive derivatives thereof to an amidation reaction, the Mitsunobu reaction, an alkylation reaction, a coupling reaction, the Huisgen reaction and the like.

[0160]
The method for producing the IRAK-M binder (M) (compound (1)) represented by the following formula (II), which constitutes a part of compound (I), will be described below.

[0161]
Scheme 2

[0162]
Ro3 Ro4 0- O' R 30H (7) A-R 4 (9) ROL yU
\ I

R ) (6) (8) II

[0163]
In the Scheme 2, Xi represents a halogen atom or a leaving group.

[0164]
The compound (8) can be produced by subjecting the compound (6) and the compound Date Recue/Date Received 2022-01-27 (7) to an aromatic nucleophilic substitution reaction, a coupling reaction, and the like.
The compound (II) can be obtained by subjecting the compound (8) and the compound (9) or a reactive derivative thereof to an alkylation reaction, a sulfonylation reaction, a reductive amination reaction, and the like.

[0165]
The "L" (the compound (2)) is a linker (L) constituting a part of compound (I), and "Li" (the compound (2a)) and the "L2" (the compound (2b)) are a part of the linker (L), all of which may be a commercially available product to be used as is or can be produced by a method known per se or a method similar thereto.

[0166]
The production method will be described below when the "E" (the compound (4)) is a compound represented by the following formula (IV-I) and is an XIAP binder which is one of the E3 ligase binders constituting a part of compound (I).

[0167]
Scheme 3

[0168]
%Nil( ln ( ,NõCO2H
CO2H ( R01 RO2 )õ
H21\1 0 0 HN 12304 R057c,NH (11) RoiR02 (13) 0 r RoiR02 4-, H N N NH N
2R05.5<Ro3 __ Ro6 HNYR05 Ro3 R07 ROB RO2 NH R" R06-- NH RO4 (10) (12) (14) HOE HOLE
(15) (15) W11 Wl1 ( N,CO2H ) ( )n co2H
0 (o m 0 Hp( HN R 1Ro2 (11) (13) 02 Ros H N N
2R05. R03 HN---)Hr5 R03 IR06¨t<R04' Ro7 R08 Ro62--N R 4 T R06¨N RO4 (16) (17) IV-I

[0169]
The compound (12) can be produced by subjecting the compound (10) and the compound (11) or a reactive derivative thereof to an amidation reaction and the like. The compound (14) can be produced by subjecting the compound (12) and the compound (13) or a reactive derivative thereof to an amidation reaction, and the like.
The compound (IV-I) can be produced by subjecting the compound (14) and the compo und (15) or a reactive derivative thereof to an amidation reaction, and the like.
Further, the compound (16) can be produced by subjecting the compound (10) and the compound (15) or a reactive derivative thereof to an amidation reaction, and the like. The compound (17) can be produced by subjecting the compound (16) and the compound (11) or a reactive derivative thereof to an amidation reaction, and the like. The compound (IV-I) can be produced by subjecting the compound (17) and the compound (13) or a reactive derivative thereof to an amidation reaction, and the like.

[0170]
The production method will be described below when "E" (the compound (4)) is a compound represented by the following formula (IV-II):
Date Recue/Date Received 2022-01-27

[0171]
Scheme 4

[0172]
/4D¨P
Roir,rc Xi 0 Re H3C¨ 2 H3C¨ ) o2 N 0 i NH Roipo Ros `-`03 (17) N
n (19) RO6 N R 4 Ros RO3 Ro7 . ,08 (16) (18) I \/-II

HOAE
(22) X1 0 HN¨\ /Q¨P HN¨\ Q¨P

Xi 0 Fl 3C 2 ___ FloC 2 __ /

HN R04 (17) 1!5<Rizo3 (19) R01Ro2 Ros71( N H R08 \i5<
Ros RO6 NH R 4 Ros R03 R07 R08 R07 rs.08 R06 ¨NH

mos (10) (20) (21)

[0173]
The compound (18) can be produced by subjecting the compound (16) and the compound (17) to an amidation reaction, and the like. The compound (IV-II) can be produced by subjecting the compound (18) and the compound (19) to an alkylation reaction, and the like.
Further, the compound (20) can be produced by subjecting the compound (10) and the compound (17) to an amidation reaction, and the like. The compound (21) can be produced by subjecting the compound (20) and the compound (19) to an alkylation reaction, and the like. The compound (IV-II) can be produced by subjecting the compound (21) and the compound (22) or a reactive derivative thereof to an amidation reaction, and the like.

[0174]
By converting substituents of compound (I) thus obtained or each intermediate by means known per se (that is, introduction of a substituent or conversion of a functional group), another compound contained in compound (I) can be obtained. Intermediates corresponding thereto or salts thereof can also be obtained.

[0175]
Compound (I) obtained by the above production method can be isolated and purified by known means, e.g., solvent extraction, solution pH conversion, phase transfer, crystallization, recrystallization or chromatography.

[0176]
When compound (I) contains an optical isomer, a stereoisomer, a regioisomer, and a rotational isomer, these are also contained as the compound (I), and each compound can be obtained as a single item by a synthesis method and a separation method known per se. For example, when compound (I) has an optical isomer, the optical isomer resolved from the compound is also included in the compound (I).
Here, the optical isomer can be produced by a method known per se.

[0177]
Compound (I) may be a crystal.
The crystal of compound (I) (hereinafter sometimes abbreviated as crystals of the present Date Recue/Date Received 2022-01-27 invention) can be produced by crystallization of compound (I) by applying a crystallization method known per se.
Compound (I) may be a pharmaceutically acceptable co-crystal or a salt thereof. Here, the co-crystal or the salt thereof mean a crystalline substance constituted of two or more special solids at room temperature, each having different physical properties (e.g., structure, melting point, heat of fusion, hygroscopicity, solubility, and stability). The co-crystal or the salt thereof can be produced according to a co-crystallization method known per se.
Compound (I) may be a hydrate, a non-hydrate, a non-solvate, or a solvate.
Furthermore, deuterium converted materials obtained by converting 1H into 2H(D) are also included in the compound (I).
Compound (I) may be labeled with an isotope (e.g., 3 H, '3 C, '4 C, 1 8 F, 3 5 s, 1 2 5 =
0 and the like. The compound (I) labeled or substituted with an isotope can be used, e.g., as a tracer (PET
tracer) for use in positron emission tomography (PET) and is expected to be useful in fields such as medical diagnosis and the like.

[0178]
Compound (I) may be used as a prodrug.
A prodrug of compound (I) means a compound which is converted into compound (I) with a reaction due to an enzyme, a gastric acid, etc. under the physiological condition in a living body, that is, a compound which is enzymatically oxidized, reduced, hydrolyzed, etc.
to be converted into compound (I), or a compound which is hydrolyzed with gastric acid, etc., to be converted into compound (I).

[0179]
A prodrug of compound (I) includes; a compound in which an amino group of compound (I) is acylated, alkylated or phosphorylated (e.g., compounds in which an amino group of compound (I) is eicosanoylated, alanylated, pentylaminocarbonylated, (5-methy1-2-oxo-1,3-dioxolen-4-y1) methoxycarbonylated, tetrahydrofuranylated, pyrrolidylmethylated, pivaloyloxymethylated or tert-butylated); a compound in which a hydroxy group of compound (I) is acylated, alkylated, phosphorylated or borated (e.g., compounds in which a hydroxy group of compound (I) is acetylated, palmitoylated, propanoylated, pivaloylated, succinylated, fumarylated, alanylated or dimethylaminomethylcarbonylated); a compound in which a carboxy group of compound (I) is esterified or amidated (e.g., compounds in which a carboxy group of compound (I) is ethylesterified, phenylesterified, carboxymethyl esterified, dimethylaminomethyl esterified, pivaloyloxymethyl esterified, ethoxycarbonyloxyethyl esterified, phthalidyl esterified, (5-methyl-2-oxo-1,3-dioxolen-4-yl)methyl esterified, cyclohexyloxycarbonylethyl esterified or methylamidated), and the like. These compounds can be produced from compound (I) by a method known per se.

[0180]
Further, a prodrug of compound (I) may be a compound which is converted to compound (I) under physiological conditions as described in "JYAKUHIN no KAIHATSU
(Development of Pharmaceuticals)", Vol. 7, Design of Molecules, p. 163-198, published by HIROKAWA SHOTEN
(1990).
In the present specification, the prodrug may be in a form of a salt, and examples of such salt include those exemplified as the salt of the compound represented by the formula (I) described above.

[0181]
Compound (I) may be conjugated with a compound that adds a function, e.g., a cell penetrating peptide (CPP), or a kinetophore which keeps a compound in the intestinal tract (e.g., polyethylene oxides capped with a short-chain peptide, sugar and quaternary ammonium; etc.), and the compound (I) may bind directly or via a linker to a compound that adds a function.

[0182]
Date Recue/Date Received 2022-01-27 Compound (I) can also be used as a payload (the moiety corresponding to the drug described above) in an antibody (or peptidic antigen recognition sequence) -drug conjugate. When compound (I) is used as a payload, compound (I) may bind to an antibody (or a peptidic antigen recognition sequence) directly or via a linker. When compound (I) is used as a payload, the linker as 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), W02011/005761, and the like, may be used in addition to the linkers exemplified in the present specification.

[0183]
Compound (I) or a prodrug thereof (herein, these may be collectively abbreviated as "the compound of the present invention") has activity of inducing degradation of IRAK-M and can be useful as a prophylactic or therapeutic agent for cancer, a cancer growth inhibitor, a cancer metastasis inhibitor.
The compound of the present invention exhibits activity of inducing protein degradation of IRAK-M, and the compound of the present invention is useful as a medicament, since it is superior in the points in terms of drug efficacy, pharmacokinetics (e.g., absorption, distribution, metabolism, excretion), solubility (e.g., water solubility), interaction with other medicaments (e.g., drug-metabolizing enzyme inhibitory action), safety (e.g., acute toxicity, chronic toxicity, genetic toxicity, reproductive toxicity, cardiotoxicity, carcinogenicity, central toxicity), and stability (e.g., chemical stability, stability to an enzyme). Among them, it is expected to be effective for the treatment or prophylaxis of cancer, but it is not limited to this.
The compound of the present invention also has activity of inducing degradation of IRAK-M
protein for mammals (e.g., mouse, rat, hamster, rabbit, cat, dog, cow, sheep, monkey, and human), and in view of the mechanism of action can be used as a medicament of a prophylaxis or treatment agent for diseases correlated with IRAK-M protein (herein, these may be collectively abbreviated as "IRAK-M associated diseases"): e.g., colon cancers (e.g., colon cancer, rectal cancer, anus cancer, familial colorectal cancer, hereditary nonpolyposis colorectal cancer, gastrointestinal stromal tumor), lung cancers (e.g., non-small-cell lung cancer, small-cell lung cancer, malignant mesothelioma), mesothelioma, pancreatic cancers (e.g., pancreatic ductal adenocarcinoma, pancreatic endocrine tumor), pharyngeal cancer, laryngeal cancer, esophageal cancer, stomach cancers (e.g., papillary adenocarcinoma, mucinous adenocarcinoma, adenosquamous carcinoma), duodenal cancer, small intestinal cancer, breast cancers (e.g., invasive ductal carcinoma, non-invasive ductal carcinoma, inflammatory breast cancer), ovarian cancers (e.g., ovarian epithelial cancer, extragonadal germ cell tumor, ovarian germ cell tumor, ovarian low-malignant potential tumors), testis tumors, prostate cancers (e.g., hormone-dependent prostate cancer, non-hormone dependent prostate cancer, castration-resistant prostate cancer), liver cancers (e.g., hepatocellular cancer, primary liver cancer, extrahepatic bile duct cancer), thyroid cancers (e.g., medullary thyroid carcinoma), renal cancers (e.g., renal cell carcinomas (e.g., clear cell renal cell carcinoma), transitional cell cancer of the renal pelvis and ureter), uterine cancers (e.g., cervical cancer, uterine body cancer, uterus sarcoma), gestational choriocarcinoma, brain tumors (e.g., medulloblastoma, glioma, pineal astrocytic tumor, pilocytic astrocytoma, diffuse astrocytoma, anaplastic astrocytoma, pituitary adenoma), retinoblastoma, skin cancers (e.g., basalioma, malignant melanoma), sarcomas (e.g., rhabdomyosarcoma, leiomyosarcoma, soft tissue sarcoma, spindle cell sarcoma), malignant bone tumor, bladder cancer, blood cancers (e.g., multiple myeloma, leukemias (e.g., acute myeloid leukemia, chronic lymphocytic leukemia), malignant lymphoma (B-cell lymphoma, diffuse large B-cell lymphoma, MALT lymphoma, follicular lymphoma, mantle cell lymphoma), Hodgkin's disease, chronic myeloproliferative disease), cancer of unknown primary; an inhibition agent of a cancer growth; a suppression agent of metastasis; a promotion agent of apoptosis; or a therapeutic agent of precancerous lesions (e.g., myelodysplastic syndrome).

[0184]
Date Recue/Date Received 2022-01-27 Further, IRAK-M associated diseases other than cancer include, e.g., 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, MERS, SARS), acute bacterial meningitis, Helicobacter pylori infection, invasive staphylococcus aureus infection, tuberculosis, systemic fungal infection, herpes simplex virus infection, varicella zoster virus infection, human papillomavirus infection, acute viral encephalitis, encephalitis, meningitis, decreased immune function associated with infection and the like.

[0185]
The compound of the present invention may be administered orally or parenterally as it is or in a mixture with a pharmacologically acceptable carrier as a medicament to a mammal (preferably, humans).
Hereinafter, the medicament containing the compound of the present invention (sometimes to be abbreviated as "the medicament of the present invention") is described in detail. Examples of the dosage form of the medicament of the present invention include oral preparations such as tablets (e.g., sugar-coated tablets, film-coated tablets, sublingual tablets, buccal tablets, orally disintegrating tablets), pills, granules, powders, capsules (e.g., soft capsules, microcapsule s), syrups, emulsions, suspensions, films (e.g., orally disintegrating films, oral mucosa-sticking films) and the like. Further, examples of the dosage form of the medicament of the present invention include also parenteral preparations such as injections, drip infusions, transdermal absorption type preparations (e.g., iontophoretic transdermal absorption type preparations), suppositories, ointments, nasal preparations, pulmonary preparations, and eye drops and the like.
Also, the medicament of the present invention may be a release control preparation such as an immediate-release preparation or a sustained-release preparation (e.g., a sustained-release microcapsule) and the like.
As a dosage form of the medicament of the present invention, a nanoparticle preparation or a preparation using a bacterial-derived membrane can also be used.

[0186]
The medicament of the present invention may be prepared by a known preparation method generally used in the field of preparation technology (e.g., the method described in the Japanese Pharmacopoeia). The medicament of the present invention may contain a suitable amount of an additive such as an excipient, a binder, a disintegrant, a lubricant, a sweeting agent, a surfactant, a suspending agent, an emulsifier, a colorant, a preservative, an aromatic, a corrigent, a stabilizer, a thickening agent and the like generally used in the field of preparation as necessary.
Examples of the above-mentioned pharmacologically acceptable carriers include these additives.

[0187]
For example, tablet may be prepared using an excipient, a binder, a disintegrant, a lubricant and the like, and pill and granule may be prepared using an excipient, a binder and a disintegrant.
Also, powder and capsule may be prepared using an excipient and the like, syrup may be prepared using a sweeting agent and the like, and emulsion or suspension may be prepared using a suspending agent, a surfactant, an emulsifier and the like.

[0188]
Examples of the excipient include lactose, white sugar, glucose, starch, sucrose, crystalline cellulose, powdered glycyrrhiza, mannitol, sodium hydrogencarbonate, calcium phosphate and calcium sulfate.
Examples of the binder include 5 to 10 wt% starch liquid paste, 10 to 20 wt%
gum arabic solution or gelatin solution, 1 to 5 wt% tragacanth solution, carboxymethyl cellulose solution, sodium alginate solution and glycerin.
Date Recue/Date Received 2022-01-27 Examples of the disintegrant include starch and calcium carbonate.
Examples of the lubricant include magnesium stearate, stearic acid, calcium stearate and purified talc.
Examples of the sweeting agent include glucose, fructose, invert sugar, sorbitol, xylitol, glycerin and simple syrup.
Examples of the surfactant include sodium lauryl sulfate, polysorbate 80, sorbitan mono-fatty acid ester and polyoxyl 40 stearate.
Examples of the suspending agent include gum arabic, sodium alginate, sodium carboxymethyl cellulose, methyl cellulose and bentonite.
Examples of the emulsifier include gum arabic, tragacanth, gelatin and polysorbate 80.

[0189]
For example, when the medicament of the present invention is a tablet, the tablet may be prepared, e.g., by adding an excipient (e.g., lactose, sucrose, 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, compression-molding according to a method known per se, and then, if necessary, coating it for the purpose of taste masking, enteric property or durability to give a tablet according to a method known per se. As the coating agent used for coating, e.g., hydroxypropylmethyl cellulose, ethyl cellulose, hydroxymethyl cellulose, hydroxypropyl cellulose, polyoxyethylene glycol, Tween 80, Pluronic F68, cellulose acetate phthalate, hydroxypropylmethyl cellulose phthalate, hydroxymethyl cellulose acetate succinate, Eudragit (methacrylic acid/acrylic acid copolymer, Rohm, Germany) and pigments (e.g., iron oxide red, titanium dioxide) may be used.

[0190]
Examples of the above-described injection include intravenous injection as well as subcutaneous injection, intradermal injection, intramuscular injection, intraperitoneal injection, drip injection and the like.

[0191]
Such injections are prepared according to a method known per se, that is, by dissolving, suspending or emulsifying the compound of the present invention in a sterilized aqueous liquid or oily liquid. Examples of the aqueous liquid include physiological saline, isotonic solutions containing glucose or other auxiliary drugs (e.g., D-sorbitol, D-mannitol, sodium chloride) and the like. The aqueous liquid may contain a suitable solubilizer, e.g., an alcohol (e.g., ethanol), a polyalcohol (e.g., propylene glycol, polyethylene glycol), a nonionic surfactant (e.g., polysorbate 80, HCO-50). Examples of the oily liquid include sesame oil and soybean oil and the like. The oily liquid may contain a suitable solubilizing agent. Examples of the solubilizing agent include benzyl benzoate, benzyl alcohol and the like. In addition, the injection may be blended with a buffer (e.g., phosphate buffer, sodium acetate buffer), a soothing agent (e.g., benzalkonium chloride, procaine hydrochloride), a stabilizer (e.g., human serum albumin, polyethylene glycol), a preservative (e.g., benzyl alcohol, phenol) and the like. A prepared injection solution may be usually filled into an ampoule.

[0192]
The content of the compound of the present invention in the medicament of the present invention varies depending on the form of the pharmaceutical preparation, and is usually about 0.01 to about 100 wt%, preferably about 2 to about 85 wt%, more preferably about 5 to about 70 wt%, based on the whole preparation.

[0193]
The content of the additive in the medicament of the present invention varies depending on the form of the pharmaceutical preparation, and is usually about 1 to about 99.9 wt%, preferably about 10 to about 90 wt%, based on the whole preparation.
Date Recue/Date Received 2022-01-27

[0194]
The compound of the present invention is stable and has low toxicity and may be used safely.
The daily dose of the compound of the present invention varies depending on the condition and body weight of a patient, the kind of compound, administration route and the like, in the case of, for example, oral administration to patients for the purpose of treating cancer, the daily dose for an adult (body weight about 60 kg) is about 1 to about 1000 mg, preferably about 3 to about 300 mg, and more preferably about 10 to about 200 mg, as the compound of the present invention, which may be administered once or in two or three divided doses.

[0195]
When the compound of the present invention is administered parenterally, it is usually administered in the form of a liquid (e.g., injection). The dose of the compound of the present invention varies depending on the subject of administration, target organ, symptoms, administration method and the like, and for example, it is usually about 0.01 to about 100 mg, preferably about 0.01 to about 50 mg, more preferably about 0.01 to about 20 mg, as the compound of the present invention, relative to 1 kg of body weight, which is preferably given by intravenous injection or subcutaneous injection.

[0196]
The compound of the present invention may be used concurrently with other drugs.
Specifically, the compound of the present invention may be used together with a medicament such as hormonal therapeutic agents, chemotherapeutic agents, immunotherapeutic agents, or medicaments inhibiting the action of cell growth factors or their receptors and the like.
Hereinafter, drugs that can be used in combination or concurrently with the compound of the present invention are abbreviated as concomitant drugs.

[0197]
As the "hormonal therapeutic agents" include fosfestrol, diethylstilbestrol, chlorotrianisene, medroxyprogesterone acetate, megestrol acetate, chlormadinone acetate, cyproterone acetate, danazol, allylestrenol, gestrinone, mepartricin, raloxifene, ormeloxifene, levormeloxifene, anti-estrogens (e.g., tamoxifen citrate, toremifene citrate), pill preparations, mepitiostane, testololactone, aminoglutethimide, LH-RH agonists (e.g. goserelin acetate, buserelin, leuprorelin acetate), droloxifene, epitiostanol, ethinyl estradiol sulfonate, aromatase inhibitors (e.g., fadrozole hydrochloride, anastrozole, letrozole, exemestane, vorozole, formestane), anti-androgens (e.g., flutamide, bicalutamide, nilutamide, enzalutamide), 5a-reductase inhibitors (e.g., finasteride, epristeride, dutasteride), adrenal cortex hormone drugs (e.g., dexamethasone, prednisolone, betamethasone, triamcinolone), androgen synthesis inhibitors (e.g., abiraterone), retinoids and drugs that retard the metabolism of retinoids (e.g., liarozole), thyroid hormone, and their DDS (Drug Delivery System) preparations may be used.

[0198]
As the "chemotherapeutic agents", e.g., alkylating agents, antimetabolites, anticancer antibiotics and plant-derived anticancer agents may be used.

[0199]
As the "alkylating agents", e.g., nitrogen mustard, nitrogen mustard N-oxide hydrochloride, chlorambucil, cyclophosphamide, ifosfamide, thiotepa, carboquone, improsulfan tosylate, busulfan, nimustine hydrochloride, mitobronitol, melphalan, dacarbazine, ranimustine, sodium estramustine phosphate, triethylenemelamine, carmustine, lomustine, streptozocin, pipobroman, etoglucide, carboplatin, cisplatin, miboplatin, nedaplatin, oxaliplatin, altretamine, ambamustine, dibrospidium hydrochloride, fotemustine, prednimustine, pumitepa, ribomustine, temozolomide, treosulfan, trofosfamide, zinostatin stimalamer, adozelesin, cystemustine, bizelesin and their DDS preparations thereof may be used.

[0200]
As the "antimetabolits", e.g., mercaptopurine, 6-mercaptopurine riboside, thioinosine, Date Recue/Date Received 2022-01-27 methotrexate, pemetrexed, enocitabine, cytarabine, cytarabine ocfosphate, ancitabine hydrochloride, 5-FU drugs (e.g., fluorouracil, tegafur, UFT, doxifluridine, carmofur, galocitabine, emitefur, capecitabine), aminopterin, nelzarabine, leucovorin calcium, thioguanine, butocine, calcium folinate, levofolinate calcium, cladribine, emitefur, fludarabine, gemcitabine, hydroxycarbamide, pentostatine, piritrexim, idoxuridine, mitoguazone, thiazofurin, ambamustine, bendamustine and their DDS preparations thereof may be used.

[0201]
As the "anticancer antibiotics", e.g., actinomycin-D, actinomycin-C, mitomycin-C, chromomycin-A3, bleomycin hydrochloride, bleomycin sulfate, peplomycin sulfate, daunorubicin hydrochloride, doxorubicin hydrochloride, aclarubicin hydrochloride, pirarubicin hydrochloride, epirubicin hydrochloride, neocarzinostatin, mithramycin, sarkomycin, carzinophilin, mitotane, zorubicin hydrochloride, mitoxantrone hydrochloride, idarubicin hydrochloride and their DDS
preparations (e.g., doxorubicin-encapsulated PEG liposomes) may be used.

[0202]
As the "plant-derived anticancer agents", e.g., etoposide, etoposide phosphate, vinblastine sulfate, vincristine sulfate, vindesine sulfate, teniposide, paclitaxel, docetaxel, cabazitaxel, vinorelbine and their DDS preparations thereof may be used.

[0203]
As the "immunotherapeutic agents", e.g., picibanil, krestin, schizophyllan, lentinan, ubenimex, interferons, interleukins, macrophage colony stimulating factor, granulocyte colony stimulating factor, erythropoietin, lymphotoxin, BCG vaccine, Corynebacterium parvum, levamisole, Toll-like receptor (TLR) agonist, polysaccharide K, procodazole, anti-CTLA4 antibodies (e.g., ipilimumab, tremelimumab), anti-PD-1 antibodies (e.g., nivolumab, pembrolizumab, cemiplimab, tislelizmab, sintilimab, toripalimab), anti-PD-Li antibody (e.g., atezolizumab, avelumab, durvalumab), and oncolytic viruses may be used.

[0204]
The "cell growth factors" in the "medicaments inhibiting the action of cell growth factors or their receptors" may be any substance that promote cell growth, and usually include peptides having a molecular weight of 20,000 or less and exhibiting the action at low concentrations by binding to a receptor, and specifically, (1) EGF (epidermal growth factor) or substances having substantially the same activity as EGF (e.g., TGFa); (2) insulin or substances having substantially the same activity as insulin (e.g., insulin, IGF (insulin-like growth factor)-1, IGF-2), (3) FGF
(fibroblast growth factor) or substances having substantially the same activity as FGF (e.g., acidic FGF, basic FGF, KGF (keratinocyte growth factor), FGF-10), and (4)other cell growth factors [e.g., CSF (colony stimulating factor), EPO (erythropoietin), IL-2 (interleukin-2), NGF
(nerve growth factor), PDGF (platelet-derived growth factor) TGF-I3 (transforming growth factor 13), HGF (hepatocyte growth factor), VEGF (vascular endothelial growth factor), heregulin, angiopoietin may be used.

[0205]
The "cell growth factor receptors" may be any receptor as long as it has the ability to bind to the above-mentioned cell growth factors, and specifically, EGF receptor, heregulin receptor (e.g., HER3), insulin receptor, IGF receptor-1, IGF receptor-2, FGF receptor-1 or FGF
receptor-2, NGF
receptor, TGFB receptor, HGF receptor, VEGF receptor, angiopoietin receptor (e.g., Tie2), PDGF
receptor and the like may be used.

[0206]
As the "medicament inhibiting the action of cell growth factors or their receptors", EGF
inhibitor, TGFa inhibitor, heregulin inhibitor, insulin inhibitor, IGF
inhibitor, FGF inhibitor, KGF inhibitor, CSF inhibitor, EPO inhibitor, IL-2 inhibitor, NGF inhibitor, PDGF inhibitor, TGFI3 inhibitor, HGF inhibitor, VEGF inhibitor, angiopoietin inhibitor, EGF
receptor inhibitor, HER2 inhibitor, HER3 inhibitor, HER4 inhibitor, insulin receptor inhibitor, IGF -1 receptor Date Recue/Date Received 2022-01-27 inhibitor, IGF-2 receptor inhibitor, FGF receptor-1 inhibitor, FGF receptor-2 inhibitor, FGF
receptor-3 inhibitor, FGF receptor-4 inhibitor, VEGF receptor inhibitor, Tie-2 inhibitor, PDGF
receptor inhibitor, Abl inhibitor, Raf inhibitor, FLT3 inhibitor, c-Kit inhibitor, Src inhibitor, PKC
inhibitor, Smo inhibitor, ALK inhibitor, ROR1 inhibitor, Trk inhibitor, Ret inhibitor, mTOR
inhibitor, Aurora inhibitor, PLK inhibitor, MEK(MEK1/2) inhibitor, MET
inhibitor, CDK
inhibitor, Akt inhibitor, ERK inhibitor, PI3K inhibitor and the like may be used. More specifically, anti-VEGF antibody (e.g., Bevacizumab, Ramucirumab), anti-HER2 antibody (e.g., Trastuzumab, Pertuzumab), anti-EGFR antibody (e.g., Cetuximab, Panitumumab, Matuzumab, Nimotuzumab), anti-HGF antibody, Imatinib, Erlotinib, Gefitinib, Sorafenib, Sunitinib, Dasatinib, Lapatinib, Vatalanib, Ibrutinib, Bosutinib, Cabozantinib, Crizotinib, Alectinib, Vismodegib, Axitinib, Motesanib, Nilotinib, 644-(4-ethy 1piperazin- 1 -y lmethy Opheny11-N4 l(R)-pheny lethy11-7H-pyrrolo [2,3-d]pirimidine-4-amine (AEE-788), Vandetanib, Temsirolimus, Everolimus, Enzastaurin, Tozasertib, 24N434445-[N-(3-fluorophenyl)carbamoylmethy11-1H-pyrazol-3-ylamino]quinazolin-7-yloxy]propy11-N-ethylamino]ethyl phosphate ester (AZD-1152), 449-chloro-7-(2,6-difluoropheny1)-5H-pyrimido[5,4-d][2]benzazepin-2-ylamino]benzoic acid, N-[2-methoxy-5-[(E)-2-(2,4,6-trimethoxyphenyl)vinylsulfonylmethyl]phenyl]glycine sodium salt (ON-1910Na), Volasertib, Selumetinib, Trametinib, N42(R),3-dihydroxypropoxy1-3,4-difluoro-2-(2-fluoro4-iodophenylamino)benzamide (PD-0325901), Bosutinib, Regorafenib, Afatinib, Idelalisib, Ceritinib, Dabrafenib, Ponatinib, Lenvatinib, Midostaurin, Pazopanib and the like may be used.

[0207]
In addition to the above-mentioned drugs, L-asparaginase, L-arginase, arginine deiminases, aceglaton, procarbazine hydrochloride, protoporphyrin-cobalt complex salt, mercury hematoporphyrin-sodium, topoisomerase I inhibitors (e.g., irinotecan, topotecan, indotecan, indimitecan), topoisomerase II inhibitors (e.g., sobuzoxane) ), differentiation-inducing agents (e.g., retinoid, vitamin D), other angiogenesis inhibitors (e.g., fumagillin, shark extract, COX-2 inhibitor), a-blockers (e.g., tamsulosin hydrochloride), bisphosphonic acids ( e.g., pamidronate, zoledronate), thalidomide, lenalidomide, pomalidomide, 5-azacitidine, decitabine, proteasome inhibitors (e.g., bortezomib, carfilzomib, ixazomib), NEDD8 inhibitors (e.g., Pevonedistat), UAE
inhibitors, PARP inhibitors (e.g., Olaparib, Niraparib, Veliparib), anti-tumor antibodies such as anti-CD20 antibodies (e.g., Rituximab, Obinutuzumab), anti-CCR4 antibodies (e.g., Mogamulizumab) and the like, antibody drug conjugates (e.g., Trastuzumab emtansine, Brenximab vedotin) and the like may also be used as a concomitant drug.

[0208]
When the compound of the present invention is used for purposes of IRAK-M
associated diseases other than cancer, besides the above-mentioned concomitants, e.g., antibacterial drugs, antifungal drugs, nonsteroidal anti-inflammatory drugs, steroid drugs, bronchodilating preparations, anticoagulants, antiplatelet drugs, thrombolytic drugs, immunomodulators, antiprotozoal drugs, antitussives/expectorants, sedatives, anesthetics, narcotic antagonists, anti-ulcer drugs, vitamins, vitamins derivatives, antiallergic drugs, anti-asthmatic drugs, therapeutic drugs for dermatitis atopic, signal transduction inhibitors, inflammatory mediator action suppressants, inflammatory mediator action suppression antibodies, inflammatory mediator production suppressants, anti-inflammatory mediator action suppressants, anti-inflammatory mediator action suppression antibodies, anti-inflammatory mediator production suppressants, antifibrotic drug, al-adrenergic agonist, antiemetic, methemoglobin elevation inhibitors, and the like may be used as a concomitant drugs.

[0209]
(1) Antibacterial drugs (i) Sulfa drugs Sulfamethizole, sulfisoxazole, sulfamonomethoxine, sulfamethizole, salazosulfapyridine, silver Date Recue/Date Received 2022-01-27 sulfadiazine, etc.
(ii) Quinoline antibacterial drugs nalidixic acid, pipemidic acid trihydrate, enoxacin, norfloxacin, ofloxacin, tosufloxacin tosylate, ciprofloxacin hydrochloride, lomefloxacin hydrochloride, sparfloxacin, fleroxacin, etc.
(iii) Antiphthisics isoniazid, ethambutol (ethambutol hydrochloride), para-aminosalicylic acid (calcium para-aminosalicylate), pyrazinamide, ethionamide, prothionamide, rifampicin, streptomycin sulfate, kanamycin sulfate, cycloserine, etc.
(iv) Antiacidfast bacterium drug diaminodiphenyl sulfone, rifampicillin, etc.
(v) Antiviral drugs idoxuridine, aciclovir, vidarabine, ganciclovir, favipiravir, etc.
(vi) Anti-HIV drugs zidovudine, didanosine, zalcitabine, indinavir sulfate ethanolate, ritonavir, etc.
(vii) Anti-spirochete drugs (viii) Antibiotics tetracycline hydrochloride, ampicillin, piperacillin, gentamicin, dibekacin, kanendomycin, lividomycin, tobramycin, amikacin, fradiomycin, sisomicin, tetracycline, oxytetracycline, rolitetracycline, doxycycline, ampicillin, piperacillin, ticarcillin, cefalotin, cephapirin, cefaloridine, cefaclor, cefalexin, cefroxadine, cefadroxil, cefamandole, cefuroxime, cefotiam, cefotiam hexetil, cefuroxime axetil, cefdinir, cefditoren pivoxil, ceftazidime, cefpiramide, cefsulodin, cefmenoxime, cefpodoxime proxetil, cefpirome, cefozopran, cefepime, cefsulodin, cefmenoxime, cefmetazole, cefminox, cefoxitin, cefbuperazone, latamoxef, flomoxef, cefazolin, cefotaxime, cefoperazone, ceftizoxime, moxalactam, thienamycin, sulfazecin, aztreonam or salts thereof, griseofulvin, lankacidin, etc.

[0210]
(2) Antifungal drugs (i) Polyene antibiotics (e.g., amphotericin B, nystatin, trichomycin) (ii) Griseofulvin, pyrrolnitrin, etc.
(iii) Cytosine antimetabolites (e.g., flucytosine) (iv) Imidazole derivatives (e.g., econazole, clotrimazole, miconazole nitrate, bifonazole, croconazole) (v) Triazole derivatives (e.g., fluconazole, itraconazole, azole compounds [2-[(1R, 2R)-2-(2,4-difluorophenyl) -2-hydroxy-l-methy1-3-(1H-1, 2,4-triazol-1-y1) propy11-444-(2,2,3,3-tetrafluoropropoxy) pheny11-3-(2H,4H)-1,2,4-triazolonel (vi) Thiocarbamic acid derivatives (e.g., tolnaftate) (vii) Echinocandin derivatives (e.g., caspofungin, micafungin, anidulafungin), etc.

[0211]
(3) Non-steroidal anti-inflammatory drugs acetaminophen, phenacetin, ethenzamide, sulpyrine, antipyrine, migrenin, aspirin, mefenamic acid, flufenamic acid, diclofenac sodium, loxoprofen sodium, phenylbutazone, indomethacin, ibuprofen, ketoprofen, naproxen, oxaprozin, flurbiprofen, fenbufen, pranoprofen, floctafenine, epirizole, tiaramide hydrochloride, zaltoprofen, gabexate mesilate, camostat mesylate, ulinastatin, colchicine, probenecid, sulfinpyrazone, benzbromarone, allopurinol, gold sodium thiomalate, sodium hyaluronate, sodium salicylate, morphine hydrochloride, salicylic acid, atropine, scopolamine, morphine, pethidine, levorphanol, ketoprofen, naproxen, oxymorphone, meloxicam, celecoxib, rofecoxib, or salts thereof.

[0212]
(4) Steroid drugs dexamethasone, hexestrol, methimazole, betamethasone, triamcinolone, triamcinolone Date Recue/Date Received 2022-01-27 acetonide, fluocinonide, fluocinolone acetonide, prednisolone, methylprednisolone, cortisone acetate, hydrocortisone, fluorometholone, beclometasone propionate, estriol, etc.

[0213]
(5) Bronchodilating preparations Metaproterenol, salmeterol, formoterol, carmoterol, etc.

[0214]
(6) Anticoagulants heparin sodium, sodium citrate, activated protein C, tissue factor pathway inhibitor, antithrombin III, dalteparin sodium, warfarin potassium, argatroban, gabexate, sodium citrate, etc.

[0215]
(7) Antiplatelet drugs ozagrel sodium, ethyl icosapentate, beraprost sodium, alprostadil, ticlopidine hydrochloride, pentoxifylline, dipyridamole, etc.

[0216]
(8) Thrombolytic drugs tisokinase, urokinase, streptokinase, etc.

[0217]
(9) Immunomodulators cyclosporin, tacrolimus, gusperimus, azathioprine, anti-lymphocyte serum, freeze-dried sulfonated normal immunoglobulin, erythropoietin, colony stimulating factor, interleukin, interferon, etc.

[0218]
(10) Antiprotozoal drugs metronidazole, tinidazole, diethylcarbamazine citrate, quinine hydrochloride, quinine sulfate, etc.

[0219]
(11) Antitussive and expectorant drugs ephedrine hydrochloride, noscapine hydrochloride, codeine phosphate, dihydrocodeine phosphate, isoproterenol hydrochloride, ephedrine hydrochloride, methylephedrine hydrochloride, noscapine hydrochloride, alloclamide, chlophedianol, pic operidamine, cloperastine, protokylol, isoproterenol, salbutamol, terbutaline, oxymetebanol, morphine hydrochloride, dextropetorphan hydrobromide, oxycodone hydrochloride, dimorphane phosphate, tipepidine hibenzate, pentoxyverine citrate, clofedanol hydrochloride, benzonatate, guaifenesin, bromhexine hydrochloride, ambroxol hydrochloride, acetylcysteine, ethylcysteine hydrochloride, carbocysteine, etc.

[0220]
(12) Sedatives chlorpromazine hydrochloride, atropine sulfate, phenobarbital, barbital, amobarbital, pentobarbital, thiopental sodium, thiamylal sodium, nitrazepam, estazolam, flurazepam, haloxazolam, triazolam, flunitrazepam, bromvalerylurea, chloral hydrate, triclofos sodium, etc.

[0221]
(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) Inhalation anesthetics (e.g., ether, halothane, nitrous oxide, isoflurane, enflurane), (ii) Intravenous anesthetics (e.g., ketamine hydrochloride, droperidol, thiopental sodium, Date Recue/Date Received 2022-01-27 thiamylal sodium, pentobarbital), etc.

[0222]
(14) Narcotic antagonists levallorphan, nalorphine, naloxone or a salt thereof, etc.

[0223]
(15) Anti-ulcer drugs metoclopramide, histidine hydrochloride, lansoprazole, metoclopramide, pirenzepine, cimetidine, ranitidine, famotidine, urogastrone, oxethazaine, proglumide, omeprazole, sucralfate, sulpiride, cetraxate, gefarnate, aldioxa, teprenone, prostaglandin, etc.

[0224]
(16) Vitamin drugs (i) Vitamin A: vitamin Al, vitamin A2 and retinol palmitate (ii) Vitamin D: Vitamin D1, D2, D3, D4 and D5 (iii) Vitamin E: a-tocopherol, 13-tocopherol, y-tocopherol, 6-tocopherol, dl-a-tocopherol nicotinate (iv) Vitamin K: vitamin Kl, K2, K3 and K4 (v) Folic acid (vitamin M) (vi) Vitamin B: vitamin Bl, vitamin B2, vitamin B3, vitamin B5, vitamin B6 and vitamin B12 (vii) Biotin (vitamin H), etc.

[0225]
(17) Vitamin derivatives various derivatives of vitamins, e.g., ascorbic acid, vitamin D3 derivatives such as 5,6-trans-cholecalciferol, 2,5-hydroxycholecalciferol, 1-a-hydroxycholecalciferol, etc., vitamin D2 derivatives such as 5,6-trans-ergocalciferol, etc., etc.

[0226]
(18) Antiallergic drugs diphenhydramine, chlorpheniramine, tripelennamine, clemizole, diphenylpyraline, methoxyphenamine, sodium cromoglicate, tranilast, repirinast, amlexanox, ibudilast, ketotifen, terfenadine, mequitazine, azelastine, epinastine, ozagrel hydrochloride, pranlukast hydrate, seratrodast, etc.

[0227]
(19) Anti-asthmatic drugs isoprenaline hydrochloride, salbutamol sulfate, procaterol hydrochloride, terbutaline sulfate, trimetoquinol hydrochloride, tulobuterol hydrochloride, orciprenaline sulfate, fenoterol hydrobromide, ephedrine hydrochloride, ipratropium bromide, oxitropium bromide, flutropium bromide, theophylline, aminophylline, sodium cromoglicate, tranilast, repirinast, ibudilast, ketotifen, terfenadine, mequitazine, azelastine, epinastine, ozagrel hydrochloride, pranlukast hydrate, seratrodast, dexamethasone, prednisolone, hydrocortisone, beclomethasone propionate, etc.

[0228]
(20) Therapeutic drugs for Dermatitis atopic sodium cromoglicate, etc.

[0229]
(21) Antiemetics phenothiazine derivatives, 5-HT3 receptor antagonists, etc.

[0230]
(22) Methemoglobin elevation inhibitors methylene blue, ascorbic acid, etc.

[0231]
(23) Integrin inhibitors Date Recue/Date Received 2022-01-27 natalizumab, vedolizumab, AJM300, TRK-170, E-6007, etc.

[0232]
(24) Antifibrotic drugs pirfenidone nintedanib B-aminopropionitrile (BAPN), ursodeoxycholic acid, etc.

[0233]
(25) Others hydroxycam, diacerein, megestrol acetate, nicergoline, prostaglandins, etc.

[0234]
By combining the compound of the present invention and a concomitant drug, a superior effect may be obtained such as (1) the dose of the compound of the present invention or the concomitant drug may be reduced as compared with a case where the compound is administered alone, (2) the drug to be used in combination with the compound of the present invention may be selected depending on the patient's condition (mild case, severe case, etc.), (3) the treatment period may be set longer, (4) a therapeutic effect maintaining longer is designed, and (5) by using the compound of the present invention in combination with a concomitant drug, a synergistic effect may be obtained.

[0235]
Hereinafter, when the compound of the present invention is used in combination with a concomitant drug, it is referred to as the "combination drug of the present invention".
When using the combination drug of the present invention, the administration time of the compound of the present invention and the concomitant drug is not limited, and the compound of the present invention and the concomitant drug may be administered simultaneously to a subject to be administered, or with a time interval. When the administration is carried out with a time interval, the time interval varies depending on the effective ingredient to be administered, dosage form and administration method, and for example, when the concomitant drug is administered first, the compound of the present invention may be administered within 1 minute to 3 days, preferably within 10 minutes to 1 day, more preferably within 15 minutes to 1 hour after administration of the concomitant drug. When the compound of the present invention is administered first, the concomitant drug may be administered within 1 minute to 1 day, preferably within 10 minutes to 6 hours, more preferably within 15 minutes to 1 hour after administering the compound of the present invention. The dosage of the concomitant drug may be in accordance with the dose clinically used, and may be appropriately selected depending on the administration subject, administration route, disease, combination, and the like.

[0236]
Examples of the administration mode when the compound of the present invention and the concomitant drug are used concurrently include (1) administration of a single preparation obtained by simultaneously preparing the compound of the present invention and the concomitant drug, (2) simultaneous administration by the same administration route of two preparations obtained by separately preparing the compound of the present invention and a concomitant drug, (3) administration with an time interval by the same administration route of two preparations obtained by separately preparing the compound of the present invention and a concomitant drug, (4) simultaneous administration by the different administration routes of two preparations obtained by separately preparing the compound of the present invention and a concomitant drug, and (5) administration with a time interval by the different administration routes of two preparations obtained by separately preparing the compound of the present invention and a concomitant drug (e.g., administration in the order of the compound of the present invention and the concomitant drug, or administration in the reverse order).
The dose of the concomitant drug may be appropriately determined based on the clinically used dose. The ratio of the compound of the present invention and the concomitant drug may be appropriately determined depending on the administration subject, administration route, target Date Recue/Date Received 2022-01-27 disease, symptom, combination and the like. For example, when the administration subject is a human, the concomitant drug may be used in an amount of 0.01 to 100 parts by weight relative to 1 part by weight of the compound of the present invention.

[0237]
Further, the compound of the present invention or the combination drug of the present invention may be used in combination with non-drug therapy. Specifically, the compound of the present invention or the combination drug of the present invention may be combined with non-drug therapy such as (1) surgery, (2) hypertensive chemotherapy using angiotensin II and the like, (3) gene therapy, (4) thermotherapy, (5) cryotherapy, (6) laser cauterization and (7) radiotherapy.

[0238]
For example, by using the compound of the present invention or the combination drug of the present invention before or after the above-mentioned surgery and the like, or using the compound or the drug before or after a combined treatment of two or three kinds thereof, effects may be obtained such as prevention of the onset of resistance, prolongation of disease-free survival, suppression of metastasis or recurrence of cancer, prolongation of life, and the like.

[0239]
Further, it is possible to combine a treatment with the compound of the present invention or the combination drug of the present invention with a supportive therapy [(i) administration of antibiotics (e.g., 13-lactam type such as pansporin and the like, macrolide type such as clarithromycin and the like) for the complication with various infectious diseases, (ii) administration of high-calorie transfusion, amino acid preparation or multivitamin preparation for improving malnutrition, (iii) morphine administration for pain relief, (iv) administration of a drug for ameliorating side effects such as nausea, vomiting, anorexia, diarrhea, leukopenia, thrombocytopenia, decreased hemoglobin concentration, hair loss, liver damage, renal damage, DIC, fever and the like, and (v) administration of a drug for suppressing multiple drug resistance of cancer, etc..
[EXAMPLES]

[0240]
Further, the present invention is explained in detail by referring to the following References, Examples, Experimental Examples and Formulation Examples, which are not to be construed as limitative, and the disclosure may be changed within the scope of the present invention.
In the following Examples, the "room temperature" generally means about 10 C
to about 35 C. The ratios indicated for mixed solvents are volume mixing ratios, unless otherwise specified. "%" means "wt%," unless otherwise specified.
In silica gel column chromatography, "NH" means use of aminopropyl silane -bound silica gel and "C18" means use of octadecyl-bound silica gel. In HPLC (high-performance liquid chromatography), "C18" means use of octadecyl-bonded silica gel. The ratios of elution solvents are volume mixing ratios, unless otherwise specified.
In Examples, the following abbreviations are used.
MS: mass spectrum M: mol concentration DMSO-do: deuterated dimethyl sulfoxide 11-1 NMR: proton nuclear magnetic resonance LC/MS: liquid chromatograph mass spectrometer ESI: Electrospray ionization APCI: Atmospheric pressure chemical ionization DCM: dichloromethane DIEA: diisopropylethylamine Date Recue/Date Received 2022-01-27 DMAP: 4-dimethylaminopyridine DMF: N,N-dimethylformamide HATU: 2-(7-azabenzotriazol-1-y1)-1,1,3,3-tetrametyluroniumhexafluorophosphate TEA: triethylamine THF: tetrahydrofuran TFA: trifluoroacetate

[0241]
111 NMR was measured by Fourier-transform type NMR. For the analysis, ACD/SpecManager (trade name) or MestreNova (trade name) and the like were used. Peaks with very mild protons such as a hydroxy group, an amino group and the like are not described.
MS was measured by LC/MS. As an ionization method, ESI method or APCI method was used. The data indicates actual measured value (found). Generally, a molecular ion peak ([M+111 , EM-111-, etc.) is observed. In the case of a compound having a tert-butoxycarbonyl group, a peak after elimination of a tert-butoxycarbonyl (Boc) group or a tert-butyl (tBu) group may be observed as a fragment ion. In the case of a compound having a carboxyl group, a peak of sodium adduct thereof may be observed. In the case of a compound having a hydroxy group, a peak after elimination of water may be observed as a fragment ion. In the case of a salt, a molecular ion peak or fragment ion peak of free form is generally observed.
Sample concentration (c) used in the optical rotation (MD) is g/100 mL.
Elemental analysis value (Anal.) indicates both calculated value (Calcd) and measured value (Found).

[0242]
Example 1 2-(44(S)-2-Cyclohexy1-2-((S)-2-(methylamino)propanamido)acetyl)piperazine-1-carbony1)-5,6-difluoro-N,1-dimethyl-N-(2-(2-(2-45-44-(thieno[3,2-blpyridin-7-yloxy)piperidin-l-yOmethyDisoxazol-3-y1)oxy)ethoxy)ethoxy)ethyl)-1H-indole-3-carboxamide hydrochloride

[0243]
A) 7-(Piperidin-4-yloxy)thieno[3,2-blpyridine dihydrochloride To a mixture of tert-butyl 4-hydroxypiperidine-1-carboxylate (14.9 g) and DMF
(100 mL) was added sodium hydride (60%, dispersion in paraffin liquid, 3.0 g) under ice-cooling. The reaction mixture was stirred for 10 min, 7-chlorothieno[3,2-blpyridine (10.4 g) was added thereto, and stirred at 60 C overnight. To the reaction mixture was added water and extracted with ethyl acetate. The organic layer was washed with water and brine, dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. To a mixture of tert-butyl 4-(thieno[3,2-blpyridin-7-yloxy)piperidine-1-carboxylate thus obtained and ethyl acetate (100 mL) was added 4 M hydrogen chloride ethyl acetate solution (100 mL). The reaction mixture was stirred at room temperature for 2 h, diisopropyl ether (70 mL) was added thereto, and the precipitates were collected by filtration to give the title compound (16.8 g).
MS: [M+111+ 235.2.

[0244]
B) Methyl 3-(allyloxy)isoxazole-5-carboxylate To a mixture of methyl 3-hydroxyisoxazole-5-carboxylate (15.0 g), potassium carbonate (17.4 g) and DMF (200 mL) was added 3-bromoprop-1-ene (13.6 mL), and the reaction mixture was stirred at 60 C for 16 h. The reaction mixture was diluted with ethyl acetate and water, and the aqueous layer was extraceted with ethyl acetate. The organic layer was washed with water and brine, dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (16.6 g).
MS: [M+111+ 184.3.

[0245]
Date Recue/Date Received 2022-01-27 C) (3-(Allyloxy)isoxazol-5-yOmethanol To a mixture of methyl 3-(allyloxy)isoxazole-5-carboxylate (16.6 g) and methanol (300 mL) was added sodium borohydride (4.80 g). The reaction mixture was stirred at room temperature for 16 h and the solvent was removed under reduced pressure. The residue was diluted with ethyl acetate and water, and the aqueous layer was extraceted with ethyl acetate.
The organic layer was washed with water and brine, dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure to give the title compound (13.2 g).
MS: [M+111+ 156.3.

[0246]
D) (3-(Allyloxy)isoxazol-5-yOmethyl methanesulfonate To a mixture of (3-(allyloxy)isoxazol-5-yOmethanol (13.2 g), TEA (24 mL) and THF (200 mL) was added methanesulfonyl chloride (9.94 mL) under ice-cooling. The reaction mixture was stirred at room temperature for 1 h, diluted with water, and the aqueous layer was extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure to give the title compound (18.9 g).
MS: [M+111+ 234.2.

[0247]
E) 3-(Allyloxy)-5-((4-(thieno[3,2-b]pyridin-7-yloxy)piperidin-1-yl)methyl)isoxazole A mixture of 7-(piperidin-4-yloxy)thieno[3,2-b]pyridine dihydrochloride (6.16 g), (3-(allyloxy)isoxazol-5-yl)methyl methanesulfonate (5.14 g), tetrabutylammonium iodide (4.44 g), potassium carbonate (9.70 g) and DMF (100 mL) was stirred at room temperature for 24 h. To the reaction mixture was added water and the resultant mixture was filtered, and the filtrate was extracted with ethyl acetate. The organic layer was washed with water and brine, dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography (NH, ethyl acetate/hexane) to give the title compound (6.25 g).
MS: [M+111+ 372.2.

[0248]
F) Benzyl (S)-4-(2-((tert-butoxycarbonyl)amino)-2-cyclohexylacetyl)piperazine-l-carboxylate To a mixture of (S)-2-((tert-butoxycarbonyl)amino)-2-cyclohexylacetic acid (2.5 g), benzyl piperazine-l-carboxylate (2.14 g), DIEA (5.09 mL) and DMF (48.6 mL) was added HATU (5.54 g) at room temperature. The reaction mixture was stirred at the same temperature for 6 h. The reaction mixture was diluted with ethyl acetate and water, and the aqueous layer was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate and the solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (4.34 g).
MS: [M+111+ 460.2.

[0249]
G) Benzyl (S)-4-(2-amino-2-cyclohexylacetyl)piperazine-1-carboxylate hydrochloride To a mixture of benzyl (S)-4-(2-((tert-butoxycarbonyl)amino)-2-cyclohexylacetyl)piperazine-l-carboxylate (4.34 g) and ethyl acetate (18.9 mL) was added 4 M hydrogen chloride ethyl acetate solution (18.9 mL) at room temperature, and the reaction mixture was stirred at 45 C for 1 h.
The reaction mixture was concentrated under reduced pressure and the crude product was recrystallized from ethyl acetate/hexane to give the title compound (2.96 g).
MS: [M+111+ 360.2.

[0250]
H) Benzyl 4-((S)-2-((S)-2-((tert-butoxycarbonyl)(methyl)amino)propanamido)-2-cyclohexylacetyl)piperazine-l-carboxylate To a mixture of (S)-2-((tert-butoxycarbonyl)(methyl)amino)propanoic acid (1.63 g), benzyl (S)-4-(2-amino-2-cyclohexylacetyl)piperazine-1-carboxylate hydrochloride (2.96 g), DIEA (5.22 mL) Date Recue/Date Received 2022-01-27 and DMF (37.4 mL) was added HATU (4.26 g) at room temperature. The reaction mixture was stirred at the same temperature for 6 h. The reaction mixture was diluted with ethyl acetate and water, and the aqueous layer was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate and the solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (3.62 g).
MS: [M+111+ 545.4.

[0251]
I) tert-Butyl ((S)-1-(((S)-1-cy clohexy1-2-oxo-2-(piperazin-l-yDethyDamino)-1-oxopropan-2-yl)(methyl)carbamate To a mixture of benzyl 4-((S)-2-((S)-2-((tert-butoxycarbonyl)(methyl)amino)propanamido)-2-cyclohexylacetyl)piperazine-l-carboxylate (3.62 g), 10% palladium on carbon (362 mg) and ethyl acetate (67 mL) was stirred under the normal pressure hydrogen atmosphere at room temperature for 1 h. The catalysts were filtered off and the filtrate was concentrated under reduced pressure to give the title compound (2.46 g).
MS: [M+111+ 411.3.

[0252]
J) Methyl 5,6-difluoro-1-methy1-1H-indole-2-carboxylate To a mixture of 5,6-difluoro-1H-indole-2-carboxylic acid (20 g) and DMF (200 mL) was added potassium carbonate (42.0 g) and iodomethane (18.9 mL) at room temperature.
The reaction mixture was stirred at the same temperature for 18 h, and then stirred at 40 C for 6 h. To the reaction mixture was added water, and the precipitates were collected by filtration and washed with hexane to give the title compound (20 g).
111 NMR (400 MHz, DMSO-do) 6 3.85 (3H, s), 3.99 (3H, s), 7.26 (1H, s), 7.70 (1H, dd, J = 8.24 Hz, 10.84 Hz), 7.78 (1H, dd, J = 6.96 Hz, 11.68 Hz).

[0253]
K) Methyl 5,6-difluoro-3-formy1-1-methy1-1H-indole-2-carboxylate To a mixture of methyl 5,6-difluoro-l-methyl-1H-indole-2-carboxylate (2 g) and DCM (20 mL) was 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 h. The reaction mixture was diluted with water and neutralized with saturated aqueous sodium bicarbonate. The precipitates were filtered off with Celite and the filtrate was extracted with DCM. The organic layer was dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure to give the title compound (1.9 g).
111 NMR (400 MHz, DMSO-d6) 6 3.99 (3H, s), 4.02 (3H, s), 8.0 (1H, dd, J = 6.92 Hz, 11.4 Hz), 8.12 (1H, dd, J = 8.24 Hz, 10.76 Hz), 10.34 (1H, s).

[0254]
L) 5,6-Difluoro-3-formy1-1-methy1-1H-indole-2-carboxylic acid To a mixture of methyl 5,6-difluoro-3-formy1-1-methyl-1H-indole-2-carboxylate (15 g), THF
(225 mL), methanol (75 mL) and water (75 mL) was added lithium hydroxide monohydrate (3.73 g), and the reaction mixture was stirred at room temperature for 3 h. The reaction mixture was concentrated under reduced pressure and acidified with aqueous potassium hydrogen sulfate.
The precipitates were collected by filtration to give the title compound (13 g).
MS: [MA41+ 240.1.

[0255]
M) 2-(44(S)-24(S)-2-((tert-Butoxycarbonyl)(methyDamino)propanamido)-2-cy clohexylac ety Opiperazine -1-carbony1)-5,6-difluoro-l-methyl-1H-indole -3-carboxylic acid To a mixture of tert-butyl ((S)-1-4(S)-1-cyclohexy1-2-oxo-2-(piperazin-l-y1)ethyDamino)-1-oxopropan-2-y1)(methyl)carbamate (4.63 g), 5,6-difluoro-3-formy1-1-methy1-1H-indole-2-carboxylic acid (2.45 g), DIEA (2.7 mL) and DMF (50 mL) was added HATU (4.67 g). After Date Recue/Date Received 2022-01-27 the reaction mixture was stirred at room temperature for 2 h, water was added thereto and extracted with ethyl acetate. The organic layer was washed with 0.1 M
hydrochloric acid, saturated aqueous sodium bicarbonate and brine, respectively and then dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane).
To a mixture of tert-butyl ((S)-1-4(S)-1-cyclohexy1-2-(4-(5,6-difluoro-3-formy1-1-methy1-1H-indole-2-carbonyl)piperazin-l-y1)-2-oxoethyDamino)-1-oxopropan-2-y1)(methyl)carbamate thus obtained, sodium dihydrogen phosphate (4.90 g), 2-methylbut-2-ene (3.58 g), tert-butanol (90 mL) and water (30 mL) was added sodium chlorite (2.24 g). The reaction mixture was stirred at room temperature overnight, aqueous sodium thiosulfate solution was added thereto and extracted with ethyl acetate. The organic layer was washed with water and brine, dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane and methanol/ethyl acetate) to give the title compound (5.46 g).
MS: [M+141+ 648.5.

[0256]
N) tert-Butyl ((S)-1-4(S)-1-cyclohexy1-2-(4-(5,6-difluoro-34(2-(2-(2-hydroxyethoxy)ethoxy)ethyl)(methyl)carbamoy1)-1-methyl-1H-indole-2-carbonyl)piperazin-l-y1)-2-oxoethyDamino)-1-oxopropan-2-y1)(methyl)carbamate To a mixture of 2-(44(S)-24(S)-2-((tert-butoxycarbonyl)(methyDamino)propanamido)-2-cy clohexylac ety Opiperazine -1-carbony1)-5,6-difluoro-l-methyl-1H-indole -3-carboxylic acid (5.46 g), 2-(2-(2-(methylamino)ethoxy)ethoxy)ethan-l-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 h, water was added thereto, and extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium bicarbonate and brine, dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography (methanol/ethyl acetate) to give the title compound (3.10 g).
MS: [M+141+ 793.5.

[0257]
0) 5-((4-(Thieno[3,2-blpyridin-7-yloxy)piperidin-l-yl)methyl)isoxazol-3-ol To a mixture of 3-(allyloxy)-5((4-(thieno[3,2-blpyridin-7-yloxy)piperidin-l-yOmethyDisoxazole (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 h and the solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography (methanol) and the compound thus obtained was washed with ethyl acetate to give the title compound (2.50 g).
11-1NMR (300 MHz, DMSO-do) 6 1.68-1.84 (2H, m), 1.95-2.09 (2H, m), 2.35-2.49 (2H, m), 2.63-2.75 (2H, m), 3.58 (2H, s), 4.74-4.87 (1H, m), 5.93 (1H, s), 7.07 (1H, d, J =
5.5 Hz), 7.50 (1H, d, J = 5.6 Hz), 8.04 (1H, d, J = 5.4 Hz), 8.50 (1H, d, J = 5.4 Hz), 11.16 (1H, s).

[0258]
P) tert-Butyl ((S)-1-4(S)-1-cyclohexy1-2-(4-(5,6-difluoro-l-methyl-3-(methyl(2-(2-(2-45-44-(thieno[3,2-blpyridin-7-yloxy)piperidin-l-yOmethyDisoxazol-3-yDoxy)ethoxy)ethoxy)ethyl)carbamoy1)-1H-indole-2-carbonyl)piperazin-l-y1)-2-oxoethyDamino)-1-oxopropan-2-y1)(methyl)carbamate To a mixture of 5((4-(thieno[3,2-blpyridin-7-yloxy)piperidin-l-y1)methyDisoxazol-3-ol (1.50 g), tert-butyl ((S)-1-4(S)-1-cyclohexy1-2-(4-(5,6-difluoro-34(2-(2-(2-hydroxyethoxy)ethoxy)ethyl)(methyl)carbamoy1)-1-methyl-1H-indole-2-carbonyl)piperazin-l-y1)-2-oxoethyDamino)-1-oxopropan-2-y1)(methyl)carbamate (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 h and the solvent was removed under reduced pressure.
Date Recue/Date Received 2022-01-27 The residue was purified by silica gel column chromatography (C18, acetonitrile/5 mM aqueous ammonium acetate) to give the title compound (2.37 g).
MS: [M+111+ 1106.6.

[0259]
Q) 2-(4-((S)-2-cyclohexy1-2-((S)-2-(methylamino)propanamido)acetyl)piperazine-l-carbony1)-5,6-difluoro-N,1-dimethyl-N-(2-(2-(2-45-44-(thieno [3,2-blpyridin-7-yloxy)piperidin- 1 -yOmethyDisoxazol-3-yl)oxy)ethoxy)ethoxy)ethyl)-1H-indole-3-carboxamide hydrochloride To a mixture of tert-butyl ((S)-1-4(S)-1-cyclohexy1-2-(4-(5,6-difluoro-l-methyl-3-(methyl(2-(2-(2-45-44-(thieno[3,2-blpyridin-7-yloxy)piperidin-l-y1)methyDisoxazol-3-yDoxy)ethoxy)ethoxy)ethyl)carbamoy1)-1H-indole-2-carbonyl)piperazin-l-y1)-2-oxoethyDamino)-1-oxopropan-2-y1)(methyl)carbamate (2.37 g) and ethyl acetate (10 mL) was added 4 M hydrogen chloride ethyl acetate solution (16.1 mL), and the reaction mixture was stirred at room temperature for 1 h. The reaction mixture was concentrated under reduced pressure to give the title compound (2.16 g).
1H NMR (300 MHz, DMSO-do ) 60.72-1.26 (7H, m), 1.35 (3H, d, J = 6.8 Hz), 1.50-1.83 (7H, m), 2.11-2.48 (7H, m), 2.97 (3H, s), 3.20-3.97 (21H, m), 4.13-4.37 (2H, m), 4.39-4.82 (3H, m), 4.90-5.59 (2H, m), 6.65 (1H, s), 7.46 (1H, dd, J = 10.9, 7.9 Hz), 7.54-7.96 (4H, m), 8.53 (1H, d, J =
5.6 Hz), 8.66-9.12 (2H, m), 9.27-9.65 (1H, m), 11.79-12.71 (1H, m).

[0260]
Example 2 2-(4-((S)-2-Cyclohexy1-2-((S)-2-(methylamino)propanamido)acetyl)piperazine-l-carbony1)-6-methoxy-1-methyl-N-(2-(2-(2-(4-44-(thieno[3,2-dlpyrimidin-4-yloxy)piperidin-1-yOsulfonyl)phenoxy)ethoxy)ethoxy)ethyl)-1H-indole-3-carboxamide

[0261]
A) Methyl 6-methoxy-1-methy1-1H-indole-2-carboxylate To a mixture of methyl 6-methoxy-1H-indole-2-carboxylate (11.6 g) and DMF (100 mL) was added sodium hydride (60%, dispersion in paraffin liquid, 2.93 g) under ice-cooling. After the reaction mixture was stirred at the same temperature for 15 min, iodomethane (3.88 mL) was added to the reaction mixture and the reaction mixture was stirred at the same temperature for 1 h. To the reaction mixture was added water (150 mL) and 1 M hydrochloric acid (250 mL) under ice-cooling and the aqueous layer was extracted with diethyl ether. The organic layer was washed with brine and then dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure to give the title compound (11.4 g).
MS: [M+111+ 220Ø

[0262]
B) 6-Methoxy-l-methy1-1H-indole-2-carboxylic acid To a mixture of methyl 6-methoxy-l-methyl-1H-indole-2-carboxylate (11.4 g) and methanol (100 mL) was added 2 M aqueous sodium hydroxide (52.0 mL) at room temperature and the reaction mixture was stirred at 60 C for 1 h. The reaction mixture was cooled to 0 C
and neutralized with 1 M hydrochloric acid (110 mL), and the precipitates were collected by filtration to give the title compound (9.87 g).
MS: [M+111+ 206Ø

[0263]
C) tert-Butyl 4-(6-methoxy-l-methy1-1H-indole-2-carbonyl)piperazine-l-carboxylate To a mixture of 6-methoxy-l-methyl-1H-indole-2-carboxylic acid (9.87 g), tert-butyl piperazine-l-carboxylate (9.41 g), 1-hydroxy-1H-benzotriazole 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 h. After the reaction mixture was cooled to 0 C, water was added thereto, and the precipitates were collected by filtration to give the title compound (16.8 g).
Date Recue/Date Received 2022-01-27 MS: [M+1-11+ 374.1.

[0264]
D) tert-Butyl 4-(3-formy1-6-methoxy-1-methy1-1H-indole-2-carbonyl)piperazine-1-carboxylate To a mixture of tert-butyl 4-(6-methoxy-l-methy1-1H-indole-2-carbonyl)piperazine-l-carboxylate (10.4 g) and DMF (100 mL) was added (chloromethylene)dimethylammonium chloride (7.13 g), and the reaction mixture was stirred at room temperature for 2 h. To the reaction mixture was added water and the resultant mixture was stirred for 30 min, and then the aqueous layer was extracted with ethyl acetate. The organic layer was washed with water and brine, and then dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure to give the title compound (10.6 g).
MS: [M+111+ 402.1.

[0265]
E) 6-Methoxy-l-methy1-2-(piperazine -1-carbony1)-1H-indole -3-carbaldehyde hydrochloride To a mixture of tert-butyl 4-(3-formy1-6-methoxy-l-methy1-1H-indole-2-carbonyl)piperazine-1-carboxylate (10.6 g), dimethyl sulfide (25 mL) and ethyl acetate (100 mL) was added 4 M
hydrogen chloride ethyl acetate solution (198 mL), and the reaction mixture was stirred at room temperature for 1 h. To the reaction mixture was added diisopropyl ether, and the precipitates were collected by filtration and washed with diisopropyl ether to give the title compound (8.1 g).
MS: [M+111+ 302Ø

[0266]
F) tert-Butyl ((S)-1-4(S)-1-cyclohexy1-2-(4-(3-formy1-6-methoxy-l-methy1-1H-indole-2-carbonyl)piperazin-l-y1)-2-oxoethyl)amino)-1-oxopropan-2-y1)(methyl)carbamate To a mixture of (S)-2-((tert-butoxycarbonyl)amino)-2-cyclohexylacetic acid (1.96 g), 6-methoxy-1-methy1-2-(piperazine-l-carbony1)-1H-indole-3-carbaldehyde hydrochloride (2.57 g), DIEA
(2.66 mL) and DMF (38 mL) was added HATU (3.47 g) at room temperature, and the reaction mixture was stirred at the same temperature for 1 h. The reaction mixture was diluted with ethyl acetate and water, and the aqueous layer was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate and the solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane).
To a mixture of the product thus obtained and ethyl acetate (38 mL) was added 4 M hydrogen chloride ethyl acetate solution (38 mL) at room temperature, the reaction mixture was stirred at the same temperature for 1 h and the reaction mixture was concentrated under reduced pressure.
To a mixture of (S)-2-(4-(2-amino-2-cyclohexylacetyl)piperazine-l-carbony1)-6-methoxy-1-methy1-1H-indole-3-carbaldehyde (3.35 g) thus obtained, (S)-2-((tert-butoxycarbonyl)(methyl)amino)propanoic acid (1.55 g), DIEA (6.65 mL) and DMF
(38.1 mL) was added HATU (4.34 g) at room temperature. The reaction mixture was stirred at the same temperature for 1 h. The reaction mixture was diluted with ethyl acetate and water, and the aqueous layer was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate and the solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (2.12 g).
MS: [M+111+ 626.3.

[0267]
G) 2-(44(S)-24(S)-2-((tert-Butoxycarbonyl)(methyDamino)propanamido)-2-cyclohexylacetyl)piperazine-1-carbonyl)-6-methoxy-1-methyl-1H-indole-3-carboxylic acid To a mixture of tert-butyl ((S)-1-(((S)-1-cyclohexy1-2-(4-(3-formy1-6-methoxy-l-methyl-1H-indole-2-carbonyl)piperazin-l-y1)-2-oxoethyDamino)-1-oxopropan-2-y1)(methyl)carbamate (2.30 g), sodium dihydrogen phosphate (1.76 g), 2-methylbut-2-ene (1.95 mL), tert-butyl alcohol (29.4 mL) and water (7.4 mL) was added sodium chlorite (665 mg) at room temperature.
The reaction mixture was stirred at the same temperature for 4 h. The reaction mixture was diluted with ethyl Date Recue/Date Received 2022-01-27 acetate and saturated aqueous sodium thiosulfate, and the aqueous layer was extracted with ethyl acetate. The organic layer was washed with water and brine subsequently, dried over anhydrous magnesium sulfate and the solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography (methanol/ethyl acetate) to give the title compound (770 mg).
MS: [M+111+ 642.4.

[0268]
H) tert-Butyl ((S)-1-4(S)-1-cyclohexy1-2-(4-(34(2-(2-(2-hydroxyethoxy)ethoxy)ethyl)carbamoy1)-6-methoxy-l-methyl-1H-indole-2-carbonyl)piperazin-l-y1)-2-oxoethyDamino)-1-oxopropan-2-y1)(methyl)carbamate A mixture of 2-(44(S)-24(S)-2-((tert-butoxycarbonyl)(methypamino)propanamido)-cyclohexylacetyl)piperazine-1-carbonyl)-6-methoxy-1-methyl-1H-indole-3-carboxylic acid (147 mg), triethylene glycol monoamine (41.0 mg), DIEA (120 L), HATU (131 mg) and DMF (1.15 mL) was stirred at room temperature for 1 h. 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 removed under reduced pressure. The residue was purified by silica gel column chromatography (C18, acetonitrile/5 mM aqueous ammonium acetate) to give the title compound (133 mg).
MS: [M+111+ 773.5.

[0269]
I) tert-Butyl 4-(thieno[3,2-dlpyrimidin-4-yloxy)piperidine-l-carboxylate To a mixture of tert-butyl 4-hydroxypiperidine-l-carboxylate (2.42 g) and DMF
(60.1 mL) was added sodium hydride (60%, dispersion in paraffin liquid, 0.577 g). The reaction mixture was stirred for 30 min, 4-chlorothieno[3,2-dlpyrimidine (2.05 g) was added thereto, and stirred at room temperature for 1 h, 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 removed under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (3.75 g).
MS: [M+111+ 336Ø

[0270]
J) 4-(Piperidin-4-yloxy)thieno[3,2-dlpyrimidine hydrochloride To a mixture of tert-butyl 4-(thieno[3,2-dlpyrimidin-4-yloxy)piperidine-l-carboxylate (3.75 g) and ethyl acetate (22.4 mL) was added 4 M hydrogen chloride ethyl acetate solution (55.9 mL).
The reaction mixture was stirred for 30 min, and the solvent was removed under reduced pressure. The residue was washed with ethyl acetate to give the title compound (3.25 g).
1H NMR (300 MHz, DMSO-do ) 62.00-2.12 (2H, m), 2.17-2.33 (2H, m), 3.02-3.37 (4H, m), 5.52-5.67 (1H, m), 7.62 (1H, d, J = 5.29 Hz), 8.40 (1H, d, J = 5.29 Hz), 8.79 (1H, s), 8.98-9.34 (2H, m).
K) 4-((4-(Thieno[3,2-dlpyrimidin-4-yloxy)piperidin-l-y1)sulfonyl)phenol To a mixture of 4-(piperidin-4-yloxy)thieno[3,2-dlpyrimidine hydrochloride (215 mg) and pyridine (2.64 mL) was added 4-hydroxybenzene-l-sulfonyl chloride (152 mg).
The reaction mixture was stirred for 16 h, and the solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography (C18, acetonitrile/5 mM
aqueous ammonium acetate) to give the title compound (43.5 mg).
1H NMR (300 MHz, DMSO-d6) 6 1.75-1.95 (2H, m), 2.00-2.19 (2H, m), 2.83-3.01 (2H, m), 3.05-3.21 (2H, m), 5.15-5.51 (1H, m), 6.96 (2H, d, J = 8.69 Hz), 7.46-7.72 (3H, m), 8.32 (1H, d, J =
5.29 Hz), 8.70 (1H, s), 10.10-11.07 (1H, m).
[0272]
L) 2-(4-((S)-2-Cyclohexy1-2-((S)-2-(methylamino)propanamido)acetyl)piperazine -1-carbony1)-6-methoxy-l-methyl-N-(2-(2-(2-(44(4-(thieno[3,2-dlpyrimidin-4-yloxy)piperidin-1-Date Recue/Date Received 2022-01-27 yOsulfonyl)phenoxy)ethoxy)ethoxy)ethyl)-1H-indole-3-carboxamide To a mixture of 4((4-(thieno[3,2-dlpyrimidin-4-yloxy)piperidin-l-y1)sulfonyl)phenol (35.5 mg), tert-butyl ((S)-1-4(S)-1-cyclohexy1-2-(4-(34(2-(2-(2-hydroxyethoxy)ethoxy)ethyl)carbamoy1)-6-methoxy-l-methyl-1H-indole-2-carbonyl)piperazin-l-y1)-2-oxoethyDamino)-1-oxopropan-2-y1)(methyl)carbamate (70.0 mg), triphenylphosphine (119 mg) and toluene (0.45 mL) was added di-tert-butyl azodicarboxylate (62.6 mg). The reaction mixture was stirred at room temperature for 2 h and the solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography (C18, acetonitrile/5 mM aqueous ammonium acetate).
To the product thus obtained was added ethyl acetate (0.2 mL) then added 4 M hydrogen chloride ethyl acetate solution (679 ttL). After being stirred at room temperature for 1 h, the solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography (C18, acetonitrile/5 mM aqueous ammonium acetate). The product thus obtained was dissolved in methanol, desalted by Amberlyst A21, and the solvent was removed under reduced pressure to give the title compound (19.5 mg) 1H NMR (300 MHz, DMSO-d6) 6 0.63-4.78 (54H, m) 5.26-5.43 (1H, m) 6.75-6.95 (1H, m) 7.05-7.20 (3H, m) 7.37-7.51 (1H, m) 7.55 (1H, d, J = 5.29 Hz) 7.65 (2H, d, J = 9.06 Hz) 7.75-7.85 (1H, m) 7.88-7.99 (1H, m) 8.30 (1H, d, J = 5.29 Hz) 8.69 (1H, s).
[0273]
Example 3 14(R)-4-(5,6-Difluoro-l-methy1-1H-indole-2-carbony1)-2-methylpiperazin-1-y1)-2-42R,5R)-5-methyl-2-42-(2-(2-45-44-(thieno[3,2-blpyridin-7-yloxy)piperidin-l-yOmethyDisoxazol-3-yDoxy)ethoxy)ethoxy)ethoxy)methyDpiperazin-l-y1)ethan-l-one hydrochloride [0274]
A) 5,6-Difluoro-l-methy1-1H-indole-2-carboxylic acid To a mixture of methyl 5,6-difluoro-l-methyl-1H-indole-2-carboxylate (2 g), THF (14 mL), methanol (7 mL) and water (7 mL) was added lithium hydroxide monohydrate (1.1 g) and the reaction mixture was stirred at room temperature for 4 h. The reaction mixture was concentrated under reduced pressure and the residue was dissolved in water, acidified by adding aqueous potassium hydrogen sulfate, and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure to give the title compound (1.8 g).
MS: [M-11[11 210Ø
[0275]
B) (R)-(5,6-Difluoro-l-methy1-1H-indo1-2-y1)(3-methylpiperazin-1-yOmethanone To a mixture of 5,6-difluoro-l-methyl-1H-indole-2-carboxylic acid (1.8 g) and DMF (45 mL) was added DIEA (4.4 mL), (R)-2-methylpiperazine (1.02 g) and HATU (4.8 g). The reaction mixture was stirred at room temperature for 3 h, poured into ice-cold water, and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography (methanol/DCM) to give the title compound (1.9 g).
MS: [M+111+ 294.4.
[0276]
C) (R)-2-Chloro-1-(4-(5,6-difluoro-l-methy1-1H-indole-2-carbony1)-2-methylpiperazin-1-yDethan-1-one To a mixture of (R)-(5,6-difluoro-l-methy1-1H-indo1-2-y1)(3-methylpiperazin-1-y1)methanone (1.9 g) and DCM (25 mL) was added TEA (1.35 mL) and chloroacetyl chloride (0.6 mL) under ice-cooling. The reaction mixture was stirred at room temperature for 3 h, diluted with DCM, and washed with water and brine. The organic layer was dried over anhydrous sodium sulfate and the solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (1.8 g).
Date Recue/Date Received 2022-01-27 MS: [M+1-11+ 370.2.
[0277]
D) 2-(2-(2-(Benzyloxy)ethoxy)ethoxy)ethyl methanesulfonate To a mixture of 2-(2-(2-benzyloxyethoxy)ethoxy)ethanol (2 g) and DCM (15 mL) was added TEA
(1.7 mL) and methanesulfonyl chloride (0.77 mL) under ice-cooling. The reaction mixture was stirred at room temperature for 12 h, diluted with DCM, washed with water and brine, dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure to give the title compound (2.5 g).
NMR (400 MHz, CDC13) 6 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).
[0278]
E) tert-Butyl (2R,5R)-4-benzy1-2-methy1-5-(12-phenyl-2,5,8,11-tetraoxadodecyl)piperazine-1-carboxylate To a mixture of tert-butyl (2R,5R)-4-benzy1-5-hydroxymethy1-2-methyl-piperazine-1-carboxylate (700 mg) and DMF (10 mL) was added sodium hydride (60%, dispersion in paraffin liquid, 105 mg). The reaction mixture was stirred for 1 h, 2-(2-(2-(benzyloxy)ethoxy)ethoxy)ethyl methanesulfonate (695 mg) was added thereto and additionally stirred at 60 C
for 4 h. The reaction mixture was cooled to room temperature and 2-(2-(2-(benzyloxy)ethoxy)ethoxy)ethyl methanesulfonate (556 mg) was added thereto and additionally stirred at 60 C
for 5 h. To the reaction mixture was added water and the aqueous layer was extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (900 mg).
MS: [M+1-11+ 543.2.
[0279]
F) tert-Butyl (2R,5R)-5-((2-(2-(2-hydroxyethoxy)ethoxy)ethoxy)methyl)-2-methylpiperazine-1-carboxylate To a mixture of tert-butyl (2R,5R)-4-benzy1-2-methy1-5-(12-phenyl-2,5,8,11-tetraoxadodecyl)piperazine-1-carboxylate (900 mg), acetic acid (0.1 mL) and ethanol (10 mL) was added 10% palladium on carbon (200 mg). The reaction mixture was stirred under the normal pressure hydrogen atmosphere at room temperature for 16 h and filtered with Celite , and the filtrate was concentrated under reduced pressure. To the residue was added 10%
methanol/DCM, and the organic layer was washed with saturated aqueous sodium bicarbonate and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure to give the title compound (600 mg).
1H NMR (400 MHz, DMSO-d6) 6 1.12 (3H, d, J = 6.72 Hz), 1.39 (9H, s), 2.41 (1H, dd, J = 2.74, 12.5 Hz), 2.88-2.94 (2H, m), 3.07 (1H, dd, J = 4.16, 13.5 Hz), 3.31-3.52 (15H, m), 3.60-3.62 (1H, m), 3.98 (1H, bs).
[0280]
G) tert-Butyl (2R,5R)-4-(24(R)-4-(5,6-difluoro-1-methy1-1H-indole-2-carbony1)-methylpiperazin-1-y1)-2-oxoethyl)-5-42-(2-(2-hydroxyethoxy)ethoxy)ethoxy)methyl)-2-methylpiperazine-1-carboxylate To a mixture of tert-butyl (2R,5R)-5-((2-(2-(2-hydroxyethoxy)ethoxy)ethoxy)methyl)-2-methylpiperazine-l-carboxylate (592 mg) and THF (15 mL) was added TEA (0.3 mL), (R)-2-chloro-1-(4-(5,6-difluoro-l-methy1-1H-indole-2-carbony1)-2-methylpiperazin-1-yDethan-1-one (550 mg) and tetrabutylammonium iodide (549 mg) and the resultant mixture was stirred at 60 C
for 24 h. The reaction mixture added ethyl acetate was washed with water and brine subsequently, dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography (methanol/ethyl acetate) to give the title compound (740 mg).
Date Recue/Date Received 2022-01-27 MS: [M+1-11+ 696.5.
[0281]
H) tert-Butyl (2R,5R)-4-(24(R)-4-(5,6-difluoro-1-methy1-1H-indole-2-carbony1)-methylpiperazin-1-y1)-2-oxoethyl)-2-methyl-5-42-(2-(2-45-44-(thieno[3,2-blpyridin-7-yloxy)piperidin-l-yOmethyDisoxazol-3-yDoxy)ethoxy)ethoxy)ethoxy)methyDpiperazine -1-carboxylate To a mixture of tert-butyl (2R,5R)-4-(24(R)-4-(5,6-difluoro-l-methy1-1H-indole-2-carbony1)-2-methylpiperazin-1-y1)-2-oxoethyl)-5-42-(2-(2-hydroxyethoxy)ethoxy)ethoxy)methyl)-2-methylpiperazine-1-carboxylate (30 mg), 54(4-(thieno[3,2-blpyridin-7-yloxy)piperidin-1-yOmethyDisoxazol-3-ol (17.1 mg), triphenylphosphine (56.5 mg) and toluene (2 mL) was added di-tert-butyl azodicarboxylate (29.7 mg). The reaction mixture was stirred at room temperature for 16 h and the solvent was removed under reduced pressure. The residue was purified by preparative thin layer chromatography to give the title compound (26 mg).
MS: [M+111+ 1008.8.
[0282]
I) 14(R)-4-(5,6-Difluoro-l-methy1-1H-indole-2-carbony1)-2-methylpiperazin-1-y1)-2-42R,5R)-5-methyl-2-42-(2-(2-45-44-(thieno[3,2-blpyridin-7-yloxy)piperidin-l-yOmethyDisoxazol-3-yDoxy)ethoxy)ethoxy)ethoxy)methyDpiperazin-l-y1)ethan-l-one hydrochloride To a mixture of tert-butyl (2R,5R)-4-(24(R)-4-(5,6-difluoro-l-methy1-1H-indole-2-carbony1)-2-methylpiperazin-1-y1)-2-oxoethyl)-2-methyl-5-42-(2-(2-45-44-(thieno[3,2-blpyridin-7-yloxy)piperidin-l-yOmethyDisoxazol-3-yDoxy)ethoxy)ethoxy)ethoxy)methyDpiperazine -1-carboxylate (25 mg) and DCM (1 mL) was added 4 M hydrogen chloride dioxane solution (0.3 mL) under ice-cooling. The reaction mixture was stirred at room temperature for 1 h, and the solvent was removed under reduced pressure. The residue was washed with ether and pentane to give the title compound (19 mg).
1H NMR (400 MHz, DMSO-d6, 1 00 C) 6 1.15-1.28 (6H, m), 2.19-2.36 (4H, m), 2.76-2.98 (3H, m), 3.20-4.36 (36H, m), 5.15 (1H, m), 5.66 (1H, s), 6.56 (1H, s), 7.30 (1H, d, J = 8.0 Hz), 7.53-7.59 (2H, m), 7.63 (1H, d, J = 8.0 Hz), 8.22 (1H, d, J = 8.0 Hz), 8.68 (1H, d, J = 8.0 Hz), 9.01-9.40 (1H, m).
[0283]
Example 4 (S)-N-((S)-1-cyclohexy1-2-(4-(5,6-difluoro- 1 -methy1-3-(2-(2-(24(5-44-(thieno [3,2-blpyridin-7-yloxy)piperidin- 1 -yOmethyDisoxazol-3-yDoxy)ethoxy)ethoxy)ethoxy)-1H-indole-2-carbonyl)piperazin- 1 -y1)-2-oxoethyl)-2-(methylamino)propanamide hydrochloride [0284]
A) Methyl 5,6-difluoro-3-hy droxy-l-methy1-1H-indole-2-carboxy late To a mixture of methyl 5,6-difluoro-3-formy1-1-methyl-1H-indole-2-carboxylate (3.5 g) and chloroform (50 mL) was added 3-chloroperoxybenzoic acid (5.88 g) and p-toluenesulfonic acid (3.15 g) at 5 to 10 C. The reaction mixture was stirred at the same temperature for 2 h. To the reaction mixture was added 2 M ammonia methanol solution (30 mL) and the reaction mixture was stirred at room temperature for 30 min. The solvent was removed under reduced pressure and the residue was diluted with saturated aqueous sodium bicarbonate, and extracted with DCM.
The organic layer was washed with 10% aqueous sodium thiosulfate, dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure to give the title compound (3 g).
1H NMR (400 MHz, DMSO-d6) 63.81 (3H, s), 3.82 (3H, s), 7.56-7.69 (2H, m), 9.36 (1H, s).
[0285]
B) tert-Butyl 4-(5,6-difluoro-3-hydroxy-l-methy1-1H-indole-2-carbonyl)piperazine-l-carboxylate To a mixture of methyl 5,6-difluoro-3-hydroxy-l-methyl-1H-indole-2-carboxylate (4.4 g), tert-butyl piperazine-l-carboxylate (5.1 g) and toluene (45 mL) was added and 2 M
Date Recue/Date Received 2022-01-27 trimethylaluminum toluene solution (18.2 mL) under argon atmosphere at room temperature.
The reaction mixture was stirred at 100 C for 3 h. To the reaction mixture was added water, the precipitates were filtered off, and the filtrate was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and the solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (3 g).
MS: [M+H1+ 393.8.
[0286]
C) 2-(2-(2-(benzyloxy)ethoxy)ethoxy)ethyl 4-methylbenzenesulfonate To a mixture of 2-(2-(2-(benzyloxy)ethoxy)ethoxy)ethan-1-ol (5 g) and DCM (100 mL) was added TEA (4.4 mL), DMAP (1.27 g) and p-toluenesulfonyl chloride (4.8 g) under ice-cooling, and the reaction mixture was stirred at room temperature for 2 h. The reaction mixture was diluted with DCM and washed with water and brine subsequently. The organic layer was dried over anhydrous sodium sulfate and the solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (5.2 g).
MS: [M+H1+ 395Ø
[0287]
D) tert-Butyl 4-(3-(2-(2-(2-(benzyloxy)ethoxy)ethoxy)ethoxy)-5,6-difluoro-1-methy1-1H-indole-2-carbonyl)piperazine-l-carboxylate To a mixture of tert-butyl 4-(5,6-difluoro-3-hydroxy-l-methy1-1H-indole-2-carbonyl)piperazine-l-carboxylate (1 g) and DMF (10 mL) was added cesium carbonate (2.06 g) and 2-(2-(2-(benzyloxy)ethoxy)ethoxy)ethyl 4-methylbenzensulfonate (1.49 g), and the reaction mixture was stirred at room temperature for 6 h. To the reaction mixture was added water and the reaction mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure.
The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (1.26 g).
MS: [M+H1+ 618Ø
[0288]
E) (3-(2-(2-(2-(Benzyloxy)ethoxy)ethoxy)ethoxy)-5,6-difluoro-l-methy1-1H-indo1-y1)(piperazin-1-y1)methanone hydrochloride To a mixture of tert-butyl 4-(3-(2-(2-(2-(benzyloxy)ethoxy)ethoxy)ethoxy)-5,6-difluoro-1-methy1-1H-indole-2-carbonyl)piperazine-l-carboxylate (1.2 g) and DCM (12 mL) was added 4 M
hydrogen chloride dioxane solution (2 mL) under ice-cooling. The reaction mixture was stirred at room temperature for 4 h and the solvent was removed under reduced pressure. The residue was washed with diethyl ether to give the title compound (1 g).
MS: [M+H1+ 517.9.
[0289]
F) tert-Butyl (S)-(2-(4-(3-(2-(2-(2-(benzyloxy)ethoxy)ethoxy)ethoxy)-5,6-difluoro-l-methy1-1H-indole-2-carbonyl)piperazin-l-y1)-1-cyclohexyl-2-oxoethyl)carbamate To a mixture of (3-(2-(2-(2-benzyloxyethoxy)ethoxy)ethoxy)-5,6-difluoro-l-methy1-1H-indo1-2-yDpiperazin-l-yl-methanone hydrochloride (1.1 g) and DMF (10 mL) was added DIEA (0.694 mL). The reaction mixture was stirred at room temperature for 15 min and then (S)-tert-butoxycarbonylaminocyclohexylacetic acid (0.512 g), 1-hydroxybenzotriazole (366 mg) and 1-ethy1-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (458 mg) were added thereto. The reaction mixture was stirred at room temperature for 2 h, poured into ice-cold water, and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and the solvent was removed under reduced pressure to give the title compound (1.1 g).
MS: [M+H1+ 757Ø
Date Recue/Date Received 2022-01-27 [0290]
G) (S)-2-Amino-1-(4-(3-(2-(2-(2-(benzyloxy)ethoxy)ethoxy)ethoxy)-5,6-difluoro-1-methy1-1H-indole-2-carbonyl)piperazin-l-y1)-2-cyclohexylethan-1-one hydrochloride To a mixture of tert-butyl (S)-(2-(4-(3-(2-(2-(2-(benzyloxy)ethoxy)ethoxy)ethoxy)-5,6-difluoro-l-methy1-1H-indole-2-carbonyl)piperazin-1-y1)-1-cyclohexyl-2-oxoethyl)carbamate (1.1 g) and DCM (10 mL) was added 4 M hydrogen chloride dioxane solution (10 mL) under ice-cooling.
The reaction mixture was stirred at room temperature for 3 h and the solvent was removed under reduced pressure to give the title compound (1.1 g).
MS: [M+111+ 657.2.
[0291]
H) tert-Butyl ((S)-1-4(S)-2-(4-(3-(2-(2-(2-(benzyloxy)ethoxy)ethoxy)ethoxy)-5,6-difluoro-l-methyl-1H-indole-2-carbonyl)piperazin-l-y1)-1-cyclohexy1-2-oxoethyDamino)-1-oxopropan-2-y1)(methyl)carbamate To a mixture of (S)-2-amino-1-(4-(3-(2-(2-(2-(benzyloxy)ethoxy)ethoxy)ethoxy)-5,6-difluoro-1-methy1-1H-indole-2-carbonyl)piperazin-l-y1)-2-cyclohexylethan-l-one hydrochloride (1.1 g) and DMF (10 mL) was added DIEA (0.83 mL). The reaction mixture was stirred for 15 min, (S)-2-(tert-butoxycarbonyl-methyl-amino)-propionic acid (0.323 g) and HATU (0.905 g) were added thereto, and the reaction mixture was stirred at room temperature for 16 h.
The reaction mixture was poured into ice-cold water and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (850 mg).
MS: [MA41+ 842.1.
[0292]
I) tert-Butyl ((S)-1-(((S)-1-cyclohexy1-2-(4-(5,6-difluoro-3-(2-(2-(2-hydroxyethoxy)ethoxy)ethoxy)-1-methy1-1H-indole-2-carbonyl)piperazin-l-y1)-2-oxoethyDamino)-1-oxopropan-2-y1)(methyl)carbamate To a mixture of tert-butyl ((S)-1-4(S)-2-(4-(3-(2-(2-(2-(benzyloxy)ethoxy)ethoxy)ethoxy)-5,6-difluoro-l-methyl-1H-indole-2-carbonyl)piperazin-l-y1)-1-cyclohexy1-2-oxoethyDamino)-1-oxopropan-2-y1)(methyl)carbamate (850 mg) and ethanol (10 mL) was added 10%
palladium on carbon (200 mg) at room temperature and the reaction mixture was stirred under the normal pressure hydrogen atmosphere for 3 h. The reaction mixture was filtered with Celite , rinsed with ethanol, and the filtrate was concentrated under reduced pressure to give the title compound (740 mg).
MS: [M+111+ 752.6.
[0293]
J) tert-Butyl ((S)-1-4(S)-1-cyclohexy1-2-(4-(5,6-difluoro-l-methyl-3-(2-(2-(24(54(4-(thieno[3,2-b] pyridin-7-yloxy)piperidin-l-y DmethyDisoxazol-3-y Doxy)ethoxy)ethoxy)ethoxy)-1H-indole -2-carbonyl)piperazin-l-y1)-2-oxoethyl)amino)-1-oxopropan-2-y1)(methypc arbamate To a mixture of tert-butyl ((S)-1-(((S)-1-cyclohexy1-2-(4-(5,6-difluoro-3-(2-(2-(2-hydroxyethoxy)ethoxy)ethoxy)-1-methy1-1H-indole-2-carbonyl)piperazin-l-y1)-2-oxoethyDamino)-1-oxopropan-2-y1)(methyl)carbamate (40 mg), 5-((4-(thieno[3,2-b]pyridin-7-yloxy)piperidin-l-yl)methyl)isoxazol-3-ol (21.1 mg), triphenylphosphine (69.7 mg) and toluene (1.5 mL) was added di-tert-butyl azodicarboxylate (36.7 mg), and the reaction mixture was stirred at room temperature for 16 h and concentrated under reduced pressure. The residue was purified by preparative thin layer chromatography to give the title compound (36 mg).
MS: [M+111+ 1064.8.
[0294]
K) (S)-N-((S)-1-Cyclohexy1-2-(4-(5,6-difluoro-l-methyl-3-(2-(2-(24(54(4-(thieno [3,2-b]pyridin-7-yloxy)piperidin-l-yl)methyDisoxazol-3-y1)oxy)ethoxy)ethoxy)ethoxy)-1H-indole-Date Recue/Date Received 2022-01-27 carbonyl)piperazin-l-y1)-2-oxoethyl)-2-(methylamino)propanamide hydrochloride To a mixture of tert-butyl ((S)-1-4(S)-1-cyclohexy1-2-(4-(5,6-difluoro-l-methyl-3-(2-(2-(24(5-44-(thieno[3,2-b]pyridin-7-yloxy)piperidin-l-yl)methyl)isoxazol-3-yl)oxy)ethoxy)ethoxy)ethoxy)-1H-indole-2-carbonyl)piperazin-l-y1)-2-oxoethyDamino)-1-oxopropan-2-y1)(methyl)carbamate (36 mg) and DCM (1 mL) was added 4 M hydrogen chloride dioxane solution (0.3 mL) under ice-cooling and the reaction mixture was stirred at room temperature for 2 h. The reaction mixture was concentrated under reduced pressure and the residue was washed with diethyl ether and pentane to give the title compound (24 mg).
1H NMR (400 MHz, DMSO-do) 6 1.03-1.23 (5H, m), 1.33 (3H, d, J = 6.76 Hz), 1.60-1.68 (4H, m), 2.16 (2H, m), 2.32 (2H, m), 3.12-3.20 (3H, m), 3.47-3.50 (8H, m), 3.57-3.74 (15H, m), 3.85-3.86 (2H, m), 4.14 (2H, s), 4.31 (2H, s), 4.54-4.64 (3H, m), 5.08-5.29 (2H, m), 6.63 (1H, s), 7.46 (1H, m), 7.65-7.69 (2H, m), 8.35 (1H, m), 8.79-8.80 (2H, m), 9.14 (1H, s), 11.7 (1H, br).
[0295]
Example 5 (S)-N-((S)-1-Cyclohexy1-2-(4-(5,6-difluoro-1-(3-methy1-2-oxo-14-45-44-(thieno[3,2-b]pyridin-7-yloxy)piperidin-l-y1)methyDisoxazol-3-y1)oxy)-6,9,12-trioxa-3-azatetradecy1)-1H-indole-2-carbonyl)piperazin-l-y1)-2-oxoethyl)-2-(methylamino)propanamide hydrochloride [0296]
A) tert-Butyl ((S)-1-(((S)-1-cyclohexy1-2-(4-(5,6-difluoro-1H-indole-2-carbonyl)piperazin-l-y1)-2-oxoethyDamino)-1-oxopropan-2-y1)(methyl)carbamate To a mixture of tert-butyl ((S)-1-4(S)-1-cyclohexy1-2-oxo-2-(piperazin-l-y1)ethyDamino)-1-oxopropan-2-y1)(methyl)carbamate (2.29 g), 5,6-difluoro-1H-indole-2-carboxylic acid (1.00 g), DIEA (2.72 mL) and DMF (20 mL) was added HATU (2.89 g) and the reaction mixture was stirred at room temperature for 1 h. To the reaction mixture was added water and ethyl acetate and the aqueous layer was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate and the solvent was removed under reduced pressure to give the title compound (2.64 g).
MS: [M+111+ 490.3.
[0297]
B) Methyl 2-(2-(44(S)-24(S)-2-((tert-butoxycarbonyl)(methyDamino)propanamido)-cyclohexylacetyl)piperazine-1-carbonyl)-5,6-difluoro-1H-indo1-1-yDacetate A mixture of tert-butyl ((S)-1-4(S)-1-cyclohexy1-2-(4-(5,6-difluoro-1H-indole-carbonyl)piperazin-l-y1)-2-oxoethyl)amino)-1-oxopropan-2-y1)(methyl)carbamate (2.64 g), potassium carbonate (681 mg), methyl 2-bromoacetate (753 mg) and DMF (20 mL) was stirred at room temperature for 16 h. The reaction mixture was diluted with water and ethyl acetate and the aqueous layer was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate and the solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (2.96 g).
MS: [M+111+ 662.4.
[0298]
C) 2-(2-(44(S)-24(S)-2-((tert-Butoxycarbonyl)(methypamino)propanamido)-2-cyclohexylacetyl)piperazine-1-carbonyl)-5,6-difluoro-lH-indol-1-yDacetic acid To a mixture of methyl 2-(2-(44(S)-24(S)-2-((tert-butoxycarbonyl)(methyDamino)propanamido)-2-cyclohexylacetyl)piperazine-1-carbonyl)-5,6-difluoro-1H-indo1-1-yDacetate (2.76 g) and methanol (20 mL) was added 2 M aqueous sodium hydroxide (10.4 mL). The reaction mixture was stirred at room temperature for 2 h, acidified with 1 M hydrochloric acid, and extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate and the solvent was removed under reduced pressure to give the title compound (2.16 g).
MS: [M+111+ 648.4.
Date Recue/Date Received 2022-01-27 [0299]
D) tert-Butyl ((S)-1-4(S)-1-cyclohexy1-2-(4-(5,6-difluoro-1-(14-hydroxy-3-methy1-2-oxo-6,9,12-trioxa-3-azatetradecy1)-1H-indole-2-carbonyl)piperazin-l-y1)-2-oxoethyl)amino)-1-oxopropan-2-y1)(methyl)carbamate To a mixture of 2-(2-(44(S)-24(S)-2-((tert-butoxycarbonyl)(methyDamino)propanamido)-2-cyclohexylacetyl)piperazine-1-carbonyl)-5,6-difluoro-1H-indo1-1-yDacetic acid (1.20 g), 5,8,11-trioxa-2-azatridecan-13-ol (422 mg), DIEA (0.65 mL) and DMF (9.3 mL) was added HATU (986 mg) and the reaction mixture was stirred at room temperature for 1 h. 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 removed under reduced pressure.
The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (695 mg).
MS: [M+111+ 837.5.
[0300]
E) tert-Butyl ((S)-1-4(S)-1-cyclohexy1-2-(4-(5,6-difluoro-1-(3-methy1-2-oxo-14-(thieno[3,2-blpyridin-7-yloxy)piperidin-l-yOmethyDisoxazol-3-yDoxy)-6,9,12-trioxa-3-azatetradecy1)-1H-indole-2-carbonyl)piperazin-l-y1)-2-oxoethyDamino)-1-oxopropan-2-y1)(methyl)carbamate To a mixture of 54(4-(thieno[3,2-blpyridin-7-yloxy)piperidin-1-y1)methyDisoxazol-3-ol (265 mg), tert-butyl ((S)-1-4(S)-1-cyclohexy1-2-(4-(5,6-difluoro-1-(14-hydroxy-3-methy1-2-oxo-6,9,12-trioxa-3-azatetradecy1)-1H-indole-2-carbonyl)piperazin-l-y1)-2-oxoethyDamino)-1-oxopropan-2-y1)(methyl)carbamate (670 mg), triphenylphosphine (1.05 g) and toluene (8 mL) was added di-tert-butyl azodicarboxylate (553 mg) and the reaction mixture was stirred at room temperature for 1 h. The reaction mixture was concentrated under reduced pressure and the residue was purified by silica gel column chromatography (C18, acetonitrile/5 mM aqueous ammonium acetate) to give the title compound (575 mg).
MS: [M+111+ 1150.4.
[0301]
F) (S)-N-((S)-1-Cyclohexy1-2-(4-(5,6-difluoro-1-(3-methy1-2-oxo-14-45-44-(thieno[3,2-blpyridin-7-yloxy)piperidin-l-yOmethyDisoxazol-3-yDoxy)-6,9,12-trioxa-3-azatetradecy1)-1H-indole-2-carbonyl)piperazin-l-y1)-2-oxoethyl)-2-(methylamino)propanamide hydrochloride To a mixture of tert-butyl ((S)-1-4(S)-1-cyclohexy1-2-(4-(5,6-difluoro-1-(3-methy1-2-oxo-14-45-44-(thieno[3,2-blpyridin-7-yloxy)piperidin-l-yOmethyDisoxazol-3-y1)oxy)-6,9,12-trioxa-3-azatetradecy1)-1H-indole-2-carbonyl)piperazin-l-y1)-2-oxoethyDamino)-1-oxopropan-2-y1)(methyl)carbamate (575 mg) and ethyl acetate (1 mL) was added 4 M hydrogen chloride ethyl acetate solution (2 mL) and the reaction mixture was stirred at room temperature for 1 h. The reaction mixture was concentrated under reduced pressure to give the title compound (549 mg).
1H NMR (400 MHz, DMSO-d6, 1 00 C) 6 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).
[0302]
Example 6 (S)-N-((S)-1-Cyclohexy1-2-(4-(5,6-difluoro-1-(2-oxo-24(S)-2-(((54(4-(thieno[3,2-blpyridin-7-yloxy)piperidin-l-yOmethyDisoxazol-3-yDoxy)methyl)pyrrolidin-l-y1)ethyl)-1H-indole-2-carbonyl)piperazin-l-y1)-2-oxoethyl)-2-(methylamino)propanamide hydrochloride [0303]
A) (S)-3-(Pyrrolidin-2-ylmethoxy)-5-((4-(thieno[3,2-blpyridin-7-yloxy)piperidin-1-yOmethyDisoxazole Date Recue/Date Received 2022-01-27 To a mixture of 54(4-(thieno[3,2-blpyridin-7-y1oxy)piperidin-1-y1)methyDisoxazol-3-ol (398.8 mg), (9H-fluoren-9-yl)methyl (S)-2-(hydroxymethyl)pyrrolidine-1-carboxylate (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 min and concentrated under reduced pressure. The residue was dissolved in DMF (4 mL) and tetrabutylammonium fluoride (6 mL). The reaction mixture was stirred at room temperature for 15 min and concentrated under reduced pressure, and TFA (5 mL) was added to the residue.
The reaction mixture was stirred at room temperature for 5 min, diluted with water and washed with ethyl acetate. The aqueous layer was basified with aqueous 2 M sodium hydroxide solution and extracted with ethyl acetate. The organic layer was washed with water and brine, dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography (NH, methanol/ethyl acetate) to give the title compound (199.4 mg).
MS: [M+111+ 415.2.
[0304]
B) tert-Butyl ((S)-1-4(S)-1-cyclohexy1-2-(4-(5,6-difluoro-1-(2-oxo-24(S)-2-(((5-44-(thieno[3,2-blpyridin-7-yloxy)piperidin-l-yOmethyDisoxazol-3-yDoxy)methyl)pyrrolidin-l-y1)ethyl)-1H-indole-2-carbonyl)piperazin-l-y1)-2-oxoethyDamino)-1-oxopropan-2-y1)(methyl)carbamate To a mixture of 2-(2-(44(S)-24(S)-2-((tert-butoxycarbonyl)(methyDamino)propanamido)-2-cyclohexylacetyl)piperazine-1-carbonyl)-5,6-difluoro-1H-indo1-1-yDacetic acid (199.8 mg), (S)-3-(pyrrolidin-2-ylmethoxy)-5-((4-(thieno[3,2-blpyridin-7-yloxy)piperidin-1-yl)methyl)isoxazole (140.7 mg), DIEA (107 ttL), 1-hydroxybenzotriazole (83.37 mg) and DMF (3 mL) was added 1-ethy1-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (118.3 mg). The reaction mixture was stirred at room temperature for 2 h, water was added thereto, and the precipitates were collected by filtration and washed with water to give the title compound (320.8 mg).
MS: [MA41+ 1044.3.
[0305]
C) (S)-N-((S)-1-Cyclohexy1-2-(4-(5,6-difluoro-1-(2-oxo-24(S)-2-(((54(4-(thieno[3,2-blpyridin-7-yloxy)piperidin-l-yl)methyDisoxazol-3-yl)oxy)methyl)pyrrolidin-l-y1)ethyl)-1H-indole-2-carbonyl)piperazin-l-y1)-2-oxoethyl)-2-(methylamino)propanamide hydrochloride To a mixture of tert-butyl ((S)-1-4(S)-1-cyclohexy1-2-(4-(5,6-difluoro-1-(2-oxo-24(S)-2-(((5-44-(thieno[3,2-blpyridin-7-yloxy)piperidin-l-yOmethyDisoxazol-3-y1)oxy)methyl)pyrrolidin-l-yDethyl)-1H-indole-2-carbonyl)piperazin-l-y1)-2-oxoethyDamino)-1-oxopropan-2-y1)(methyl)carbamate (380.2 mg) and ethyl acetate (1.5 mL) was added 4 M
hydrogen chloride ethyl acetate solution (1 mL). The reaction mixture was stirred at room temperature for 1.5 h and diisopropyl ether was added thereto. The precipitates were collected by filtration and washed with diisopropyl ether to give the title compound (280.3 mg).
MS: [M+111+ 944.2.
The title compound was neutralized with saturated aqueous sodium bicarbonate and the precipitates were collected by filtration as free base, subjected to 1H NMR
was measurement.
1H NMR (300 MHz, DMSO-do) 60.78-1.27 (7H, m), 1.45-2.21 (19H, m), 2.41 (3H, s), 2.58-2.78 (2H, m), 2.86-3.03 (1H, m), 3.18-3.85 (10H, m), 4.02-4.31 (3H, m), 4.53-4.87 (3H, m), 5.04-5.38 (2H, m), 6.10-6.39 (1H, m), 6.76 (1H, s), 7.05 (1H, dd, J = 5.6, 2.7 Hz), 7.49 (1H, dd, J = 5.5, 2.1 Hz), 7.62 (1H, dd, J = 10.9, 8.0 Hz), 7.66-7.84 (1H, m), 7.93 (1H, d, J = 8.6 Hz), 8.02 (1H, dd, J
= 5.4, 3.3 Hz), 8.49 (1H, d, J = 5.4 Hz).
[0306]
Example 7 (S)-N-((S)-1-Cyclohexy1-2-(4-(5-fluoro-1-(2-oxo-2-((S)-2-(((5-44-(thieno[3,2-blpyridin-7-yloxy)piperidin-l-yOmethyDisoxazol-3-yDoxy)methyl)pyrrolidin-l-y1)ethyl)-1H-indole-2-carbonyl)piperazin-l-y1)-2-oxoethyl)-2-(methylamino)propanamide Date Recue/Date Received 2022-01-27 [0307]
A) tert-Butyl ((S)-1-(((S)-1-cyclohexy1-2-(4-(5-fluoro-1H-indole-2-carbonyl)piperazin-l-y1)-2-oxoethyDamino)-1-oxopropan-2-y1)(methyl)carbamate To a mixture of tert-butyl ((S)-1-4(S)-1-cyclohexy1-2-oxo-2-(piperazin-l-y1)ethyDamino)-1-oxopropan-2-y1)(methyl)carbamate (7 g) and DMF (60 mL) was added 5-fluoro-1H-indole-2-carboxylic acid (3.36 g), 1-hydroxybenzotriazole (3.00 g), DIEA (11.9 mL) and 1-ethy1-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (4.25 g). The reaction mixture was stirred at room temperature for 16 h, water was added thereto, and extracted with ethyl acetate. The organic layer was washed with water, saturated aqueous ammonium chloride, saturated aqueous sodium bicarbonate and brine subsequently, and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure to give the title compound (9.5 g).
MS: [M+111+ 572Ø
[0308]
B) Methyl 2-(2-(44(S)-24(S)-2-((tert-butoxycarbonyl)(methyDamino)propanamido)-cyclohexylacetyl)piperazine-1-carbonyl)-5-fluoro-1H-indo1-1-yl)acetate To a mixture of tert-butyl ((S)-1-4(S)-1-cyclohexy1-2-(4-(5-fluoro-1H-indole-2-carbonyl)piperazin-l-y1)-2-oxoethyl)amino)-1-oxopropan-2-y1)(methyl)carbamate (9.5 g) and DMF (50 mL) was added potassium carbonate (6.89 g) and methyl bromoacetate (4.59 mL) under ice-cooling, the reaction mixture was stirred at room temperature for 16 h, and water was added thereto and extracted with ethyl acetate. The organic layer was washed with water and brine, dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (8.6 g).
MS: [MA41+ 644.1.
[0309]
C) 2-(2-(4-((S)-2-((S)-2-((tert-Butoxycarbonyl)(methyl)amino)propanamido)-2-cyclohexylacetyl)piperazine-l-carbonyl)-5-fluoro-lH-indol-1-y1)acetic acid To a mixture of methyl 2-(2-(4-((S)-2-((S)-2-((tert-butoxycarbonyl)(methyl)amino)propanamido)-2-cyclohexylacetyl)piperazine-l-carbonyl)-5-fluoro-lH-indol-1-yDacetate (8.6 g) and methanol (25 mL) was added aqueous 2 M sodium hydroxide solution (13.4 mL) and the reaction mixture was stirred at room temperature for 20 min. The reaction mixture was diluted with water and washed with diethyl ether. The organic layer was extracted with aqueous 0.01 M
sodium hydroxide solution. The aqueous layer was acidified with 6 M hydrochloric acid and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and the solvent was removed under reduced pressure to give the title compound (8.1 g).
MS: [M+111+ 630.2.
[0310]
D) tert-Butyl ((S)-1-4(S)-1-cyclohexy1-2-(4-(5-fluoro-1-(2-oxo-24(S)-2-(((5-44-(thieno[3,2-blpyridin-7-yloxy)piperidin-l-yOmethyDisoxazol-3-yDoxy)methyl)pyrrolidin-l-y1)ethyl)-1H-indole-2-carbonyl)piperazin-l-y1)-2-oxoethyDamino)-1-oxopropan-2-y1)(methyl)carbamate To a mixture of 2-(2-(44(S)-24(S)-2-((tert-butoxycarbonyl)(methyDamino)propanamido)-2-cyclohexylacetyl)piperazine-1-carbonyl)-5-fluoro-1H-indo1-1-yl)acetic acid (700 mg) and DMF
(10 mL) was added (S)-3-(pyrrolidin-2-ylmethoxy)-54(4-(thieno[3,2-blpyridin-7-yloxy)piperidin-1-yOmethyDisoxazole (506.8 mg), DIEA (0.78 mL) and HATU (507.8 mg), and the reaction mixture was stirred at room temperature for 16 h. To the reaction mixture was added ice-cooling water and the reaction mixture was extracted with ethyl acetate. The organic layer was washed with water and brine, dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (950 mg).
MS: [M+111+ 1025.8.
Date Recue/Date Received 2022-01-27 [0311]
E) (S)-N-((S)-1-cyclohexy1-2-(4-(5-fluoro-1-(2-oxo-2-((S)-2-(((5-44-(thieno[3,2-blpyridin-7-yloxy)piperidin-l-yOmethyDisoxazol-3-yDoxy)methyl)pyrrolidin-l-y1)ethyl)-1H-indole-2-carbonyl)piperazin-l-y1)-2-oxoethyl)-2-(methylamino)propanamide To a mixture of tert-butyl ((S)-1-4(S)-1-cyclohexy1-2-(4-(5-fluoro-1-(2-oxo-2-((S)-2-(((5-44-(thieno[3,2-blpyridin-7-yloxy)piperidin-l-yOmethyDisoxazol-3-yDoxy)methyl)pyrrolidin-l-yDethyl)-1H-indole-2-carbonyl)piperazin-l-y1)-2-oxoethyDamino)-1-oxopropan-2-y1)(methyl)carbamate (60 mg) and ethyl acetate (0.2 mL) was added 4 M hydrogen chloride ethyl acetate solution (0.043 mL), and the reaction mixture was stirred at room temperature for 4 h.
The precipitates were collected by filtration. To a mixture of (S)-N-((S)-1-cyclohexy1-2-(4-(5-fluoro-1-(2-oxo-2-((S)-2-(((5-44-(thieno[3,2-blpyridin-7-yloxy)piperidin-1-yl)methyl)-1,2-oxazol-3-yl)oxy)methyl)pyrrolidin-1-yDethyl)-1H-indole-2-carbonyl)piperazin-1-y1)-2-oxoethyl)-2-(methylamino)propanamide hydrochloride thus obtained and water (0.2 mL) was added saturated aqueous sodium bicarbonate (0.043 mL). The reaction mixture was stirred at room temperature for 30 min, and the precipitates were collected by filtration to give the title compound (46 mg).
1H NMR (400 MHz, DMSO-d6, 1 0 0 C) 61.07-1.25 (m, 6H), 1.55-1.76(m, 6H), 1.76-1.88(m, 2H), 1.88-2.12 (m, 7H), 2.24 (s, 3H), 2.32 (s, 2H), 2.70-2.79 (m, 2H), 2.95-3.05 (m, 2H), 3.57-3.72 (m, 12H), 4.09-4.40 (m, 3H), 4.65 (s, 1H), 4.79 (s, 1H), 5.17-5.23 (m, 2H), 5.99-6.29 (m, 1H), 6.70 (s, 1H), 6.98 (d, J = 5.3 Hz, 1H), 7.01-7.06 (m, 1H), 7.12-7.21 (m, 1H), 7.20-7.29 (m, 1H), 7.34 (d, J = 8.5 Hz, 1H), 7.42-7.55 (m, 2H), 7.67 (s, 1H), 7.95 (d, J =
5.1 Hz, 1H), 8.49 (d, J
= 5.2 Hz, 1H).
[0312]
Example 8 (S)-N-((S)-1-Cyclohexy1-24(S)-4-(5,6-difluoro-1-(2-oxo-24(S)-2-(((5-44-(thieno[3,2-blpyridin-7-yloxy)piperidin-l-yl)methyDisoxazol-3-yl)oxy)methyl)pyrrolidin-l-y1)ethyl)-1H-indole-2-carbony1)-3-methylpiperazin-l-y1)-2-oxoethyl)-2-(methylamino)propanamide [0313]
A) (S)-3-(Pyrrolidin-2-ylmethoxy)-5-((4-(thieno[3,2-blpyridin-7-yloxy)piperidin-1-yOmethyDisoxazole trihydrochloride A mixture of methyl 3-hydroxyisoxazole-5-carboxylate (3.79 g), tert-butyl (S)-(hydroxymethyl)pyrrolidine-1-carboxylate (4.84 g) and triphenylphosphine (6.94 g) was azeotroped with toluene. To a mixture of the residue and toluene (50 mL) was added 40%
diethyl azodicarboxylate toluene solution (14 mL) under ice-cooling. The reaction mixture was stirred at room temperature for 1 h, the solvent was reduced to half volume under reduced pressure, and the reaction mixture was purified by silica gel column chromatography (ethyl acetate/hexane). To a mixture of methyl (S)-3-((1-(tert-butoxycarbonyl)pyrrolidin-2-yl)methoxy)isoxazole-5-carboxylate thus obtained and methanol (100 mL) was added sodium borohydride (1.18 g). The reaction mixture was stirred at room temperature for 4 h, water was added thereto, and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. To a mixture of tert-butyl (S)-2-4(5-(hydroxymethyDisoxazol-3-yDoxy)methyl)pyrrolidine-1-carboxylate thus obtained and THF (100 mL) was added methanesulfonyl chloride (2.10 mL).
The reaction mixture was stirred at room temperature for 2 h, saturated aqueous sodium bicarbonate was added thereto, and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. A mixture of tert-butyl (S)-2-4(5-(((methylsulfonyl)oxy)methyDisoxazol-3-yDoxy)methyl)pyrrolidine-l-carboxylate thus obtained, 7-(piperidin-4-yloxy)thieno[3,2-blpyridine dihydrochloride (8.85 g), potassium carbonate (19.9 g), tetrabutylammonium iodide (5.32 g) and DMF (50 mL) was stirred at room temperature for 16 h. To the reaction mixture Date Recue/Date Received 2022-01-27 was added water and ethyl acetate, and the reaction mixture was extracted with ethyl acetate.
The organic layer was washed with water and brine, dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography (NH, ethyl acetate/hexane). To a mixture of tert-butyl (S)-2-4(54(4-(thieno[3,2-blpyridin-7-yloxy)piperidin-1-yOmethyDisoxazol-3-yDoxy)methyl)pyrrolidine-1-carboxylate thus obtained and ethyl acetate (20 mL) was added 4 M hydrogen chloride ethyl acetate solution (40 mL). The reaction mixture was stirred at room temperature for 1 h and the solvent was removed under reduced pressure to give the title compound (8.03 g).
MS: [M+111+ 415.2.
[0314]
B) tert-Butyl (S)-4-(5,6-difluoro-1H-indole-2-carbony1)-3-methylpiperazine-1-carboxylate To a mixture of tert-butyl (S)-3-methylpiperazine-1-carboxylate (1.12 g), 5,6-difluoro-1H-indole-2-carboxylic acid (1.00 g), DIEA (2.72 mL) and DMF (20 mL) was added HATU
(2.89 g). The reaction mixture was stirred at room temperature for 1 h, diluted with water and ethyl acetate, and extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate and the solvent was removed under reduced pressure to give the title compound (1.61 g).
MS: [M+H-tBul+ 324.2.
[0315]
C) Methyl 2-(24(S)-44(S)-2-((tert-butoxycarbonyDamino)-2-cyclohexylacety1)-2-methylpiperazine-1-carbonyl)-5,6-difluoro-lH-indol-1-yDacetate A mixture of tert-butyl (S)-4-(5,6-difluoro-1H-indole-2-carbony1)-3-methylpiperazine-1-carboxylate (1.61 g), potassium carbonate (762 mg), methyl 2-bromoacetate (0.629 mL) and DMF
(15 mL) was stirred at room temperature for 16 h. To the reaction mixture was added water and ethyl acetate, and the reaction mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure.
The residue was purified by silica gel column chromatography (ethyl acetate/hexane). To a mixture of tert-butyl (S)-4-(5,6-difluoro-1-(2-methoxy-2-oxoethyl)-1H-indole-2-carbony1)-3-methylpiperazine-1-carboxylate thus obtained and ethyl acetate (10 mL) was added 4 M hydrogen chloride ethyl acetate solution (21.2 mL). The reaction mixture was stirred at room temperature for 1 h and the solvent was removed under reduced pressure. To a mixture of methyl (S)-2-(5,6-difluoro-2-(2-methylpiperazine-1-carbony1)-1H-indol-1-y1)acetate hydrochloride thus obtained, (S)-2-((tert-butoxycarbonyl)amino)-2-cyclohexylacetic acid (1.20 g), DIEA (3.0 mL) and DMF
(20 mL) was added HATU (3.22 g). The reaction mixture was stirred at room temperature for 1 h, water and ethyl acetate were added thereto, and extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure to give the title compound (639 mg).
MS: [M+111+ 591.5.
[0316]
D) Methyl 2-(24(S)-44(S)-2-((S)-2-((tert-butoxycarbonyl)(methypamino)propanamido)-2-cyclohexylacety1)-2-methylpiperazine-1-carbonyl)-5,6-difluoro-lH-indol-1-y1)acetate To a mixture of methyl 2-(24(S)-44(S)-2-((tert-butoxycarbonyl)amino)-2-cyclohexylacety1)-2-methylpiperazine-l-carbony1)-5,6-difluoro-1H-indo1-1-yDacetate (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 h and the solvent was removed under reduced pressure. To a mixture of methyl 2-(24(S)-44(S)-2-amino-2-cyclohexylacety1)-2-methylpiperazine-l-carbony1)-5,6-difluoro-1H-indo1-1-yDacetate hydrochloride thus obtained, N-(tert-butoxycarbony1)-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 h, water and ethyl acetate were added thereto, and extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate and the solvent was removed under reduced pressure. The residue was Date Recue/Date Received 2022-01-27 purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (450 mg).
MS: [M+111+ 676.5.
[0317]
E) 2-(24(S)-44(S)-2-((S)-2-((tert-Butoxycarbonyl)(methypamino)propanamido)-2-cyclohexylacety1)-2-methylpiperazine-1-carbonyl)-5,6-difluoro-lH-indol-1-y1)acetic acid To a mixture of methyl 2-(24(S)-44(S)-2-((S)-2-((tert-butoxycarbonyl)(methyDamino)propanamido)-2-cyclohexylacety1)-2-methylpiperazine-1-carbonyl)-5,6-difluoro-lH-indol-1-yDacetate (225 mg) and methanol (1.6 mL) was added 2 M
aqueous sodium hydroxide (0.8 mL). The reaction mixture was stirred at room temperature for 1 h, acidified with 1 M hydrochloric acid, and extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure to give the title compound (221 mg).
MS: [M+111+ 662.4.
[0318]
F) tert-Butyl ((S)-1-4(S)-1-cyclohexy1-24(S)-4-(5,6-difluoro-1-(2-oxo-24(S)-2-(45-44-(thieno[3,2-blpyridin-7-yloxy)piperidin-l-yOmethyDisoxazol-3-yDoxy)methyl)pyrrolidin-l-yDethyl)-1H-indole-2-carbony1)-3-methylpiperazin-l-y1)-2-oxoethyDamino)-1-oxopropan-2-y1)(methyl)carbamate To a mixture of 2-(24(S)-44(S)-2-((S)-2-((tert-butoxycarbonyl)(methypamino)propanamido)-2-cyclohexylacety1)-2-methylpiperazine-1-carbonyl)-5,6-difluoro-lH-indol-1-y1)acetic acid (336 mg), (S)-3-(pyrrolidin-2-ylmethoxy)-5-((4-(thieno[3,2-blpyridin-7-yloxy)piperidin-1-yOmethyDisoxazole trihydrochloride (319 mg), DIEA (0.53 mL) and DMF (3 mL) was added and HATU (386 mg). The reaction mixture was stirred at room temperature for 2 h, water was added thereto, and the precipitates were collected by filtration and purified by silica gel column chromatography (C18, acetonitrile/5 mM aqueous ammonium acetate /acetonitrile). To the product thus obtained was added ethyl acetate and saturated aqueous sodium bicarbonate, the organic layer was dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure to give the title compound (320 mg).
MS: [M+111+ 1058.5.
[0319]
G) (S)-N-((S)-1-Cyclohexy1-24(S)-4-(5,6-difluoro-1-(2-oxo-24(S)-2-(((5-44-(thieno[3,2-blpyridin-7-yloxy)piperidin-l-yOmethyDisoxazol-3-yDoxy)methyl)pyrrolidin-l-y1)ethyl)-1H-indole-2-carbony1)-3-methylpiperazin-l-y1)-2-oxoethyl)-2-(methylamino)propanamide To a mixture of tert-butyl ((S)-1-4(S)-1-cyclohexy1-24(S)-4-(5,6-difluoro-1-(2-oxo-24(S)-2-(45-44-(thieno[3,2-blpyridin-7-yloxy)piperidin-l-yl)methyDisoxazol-3-yl)oxy)methyl)pyrrolidin-l-yl)ethyl)-1H-indole-2-carbonyl)-3-methylpiperazin-1-y1)-2-oxoethyDamino)-1-oxopropan-2-y1)(methyl)carbamate (320 mg) and ethyl acetate (2 mL) was added 4 M hydrogen chloride ethyl acetate solution (2 mL). The reaction mixture was stirred at room temperature for 1.5 h and the solvent was removed under reduced pressure.
To the residue was added saturated aqueous sodium bicarbonate, and the precipitates were collected by filtration to give the title compound (216 mg).
1H NMR (300 MHz, DMSO-d6) 60.77-1.33 (10H, m), 1.40-2.24 (19H, m), 2.31-2.46 (2H, m), 2.58-3.49 (8H, m), 3.53-3.70 (3H, m), 3.82-4.86 (8H, m), 5.01-5.48 (2H, m), 6.07-6.39 (1H, m), 6.67-6.81 (1H, m), 7.05 (1H, dd, J = 5.6, 1.9 Hz), 7.49 (1H, dd, J = 5.6, 3.0 Hz), 7.62 (1H, dd, J =
10.9, 8.1 Hz), 7.68-7.83 (1H, m), 7.89 (1H, t, J = 9.4 Hz), 7.97-8.07 (1H, m), 8.49 (1H, d, J = 5.7 Hz).
[0320]
Example 9 (S)-N-((S)-1-cyclohexy1-24(S)-4-(5-fluoro-1-(2-oxo-24(S)-2-(((5-44-(thieno[3,2-blpyridin-7-Date Recue/Date Received 2022-01-27 yloxy)piperidin-l-yOmethyDisoxazol-3-yDoxy)methyl)pyrrolidin-l-y1)ethyl)-1H-indole-2-carbony1)-3-methylpiperazin-l-y1)-2-oxoethyl)-2-(methylamino)propanamide [0321]
A) Benzyl (S)-44(S)-2-((tert-butoxycarbonyDamino)-2-cyclohexylacety1)-2-methylpiperazine-1-carboxylate To a mixture of (S)-2-((tert-butoxycarbonyl)amino)-2-cyclohexylacetic acid (5 g), benzyl (S)-2-methylpiperazine-1-carboxylate hydrochloride (5.26 g), 1-hydroxybenzotriazole (3.4 g), DIEA
(10.2 mL) and DMF (50 mL) was added 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (4.8 g). The reaction mixture was stirred at room temperature for 2 h, ice-cooling water was added thereto, and the aqueous layer was extracted with ethyl acetate. The organic layer was washed with water, saturated aqueous sodium bicarbonate and brine subsequently, dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure to give the title compound (6.7 g).
MS: [M+111+ 474.2.
[0322]
B) Benzyl (S)-44(S)-2-amino-2-cyclohexylacety1)-2-methylpiperazine-1-carboxylate hydrochloride To a mixture of benzyl (S)-44(S)-2-(((tert-butoxy)carbonyDamino)-2-cyclohexylacety1)-2-methylpiperazine-1-carboxylate (6.7 g) and DCM (60 mL) was added 4 M hydrogen chloride dioxane solution (30 mL). The reaction mixture was stirred at room temperature for 3 h and the solvent was removed under reduced pressure. The residue was washed with DCM to give the title compound (6 g).
1H NMR (400 MHz, DMSO-do ) 6 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).
[0323]
C) Benzyl (S)-44(S)-24(S)-2-((tert-butoxycarbonyl)(methypamino)propanamido)-2-cyclohexylacety1)-2-methylpiperazine-1-carboxylate To a mixture of N-(tert-butoxycarbony1)-N-methyl-L-alanine (3 g) and DMF (30 mL) was added benzyl (S)-44(S)-2-amino-2-cyclohexylacety1)-2-methylpiperazine-1-carboxylate hydrochloride (6 g), DIEA (10.3 mL) and HATU (7.3 g). The reaction mixture was stirred at room temperature for 16 h, ice-cooling water was added thereto, and the aqueous layer was extracted with ethyl acetate. The organic layer was washed with water, saturated aqueous sodium bicarbonate, and brine subsequently, dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (6 g).
MS: [M+111+ 559.1.
[0324]
D) tert-Butyl ((S)-1-4(S)-1-cyclohexy1-24(S)-3-methylpiperazin-l-y1)-2-oxoethyDamino)-1-oxopropan-2-y1)(methyl)carbamate To a mixture of benzyl (S)-44(S)-24(S)-2-((tert-butoxycarbonyl)(methyDamino)propanamido)-2-cyclohexylacety1)-2-methylpiperazine-1-carboxylate (3.8 g) and ethanol (50 mL) was added 10%
palladium on carbon (1 g). The reaction mixture was stirred under the normal pressure hydrogen atmosphere at room temperature for 16 h and filtered with Celite .
The filtrate was concentrated under reduced pressure to give the title compound (2.3 g).
MS: [M+111+ 425.2.
[0325]
E) Methyl 2-(24(S)-44(S)-2-((S)-2-((tert-butoxycarbonyl)(methypamino)propanamido)-2-cyclohexylacety1)-2-methylpiperazine-1-carbonyl)-5-fluoro-lH-indol-1-y1)acetate To a mixture of tert-butyl ((S)-1-4(S)-1-cyclohexy1-24(S)-3-methylpiperazin-l-y1)-2-oxoethyDamino)-1-oxopropan-2-y1)(methyl)carbamate (901 mg), 5-fluoro-1H-indole-2-carboxylic Date Recue/Date Received 2022-01-27 acid (380 mg), DIEA (1.14 mL) and DMF (12 mL) was added HATU (1.21 g). The reaction mixture was stirred at room temperature for 1 h and poured into water, and the precipitates were collected by filtration and azeotroped with toluene. A mixture of tert-butyl ((S)-1-4(S)-1-cyclohexy1-24(S)-4-(5-fluoro-1H-indole-2-carbony1)-3-methylpiperazin-1-y1)-2-oxoethyDamino)-1-oxopropan-2-y1)(methyl)carbamate thus obtained, potassium carbonate (322 mg), methyl 2-bromoacetate (356 mg) and DMF (12 mL) was stirred at room temperature for 16 h. 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 removed under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (979 mg).
MS: [M+111+ 658.4.
[0326]
F) 2-(24(S)-44(S)-2-((S)-2-((tert-Butoxycarbonyl)(methyDamino)propanamido)-2-cyclohexylacety1)-2-methylpiperazine-1-carbonyl)-5-fluoro-lH-indol-1-y1)acetic acid To a mixture of methyl 2-(24(S)-44(S)-2-((S)-2-((tert-butoxycarbonyl)(methyDamino)propanamido)-2-cyclohexylacety1)-2-methylpiperazine-1-carbonyl)-5-fluoro-lH-indol-1-yDacetate (979 mg) and methanol (8 mL) was added 2 M aqueous sodium hydroxide (3.72 mL). The reaction mixture was stirred at room temperature for 1 h, acidified with 1 M hydrochloric acid, and extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure to give the title compound (915 mg).
MS: [M+111+ 644.4.
[0327]
G) tert-Butyl ((S)-1-4(S)-1-cyclohexy1-24(S)-4-(5-fluoro-1-(2-oxo-24(S)-2-(((5-44-(thieno[3,2-blpyridin-7-yloxy)piperidin-l-yOmethyDisoxazol-3-yDoxy)methyl)pyrrolidin-l-y1)ethyl)-1H-indole-2-carbony1)-3-methylpiperazin-l-y1)-2-oxoethyDamino)-1-oxopropan-2-y1)(methyl)carbamate To a mixture of 2-(24(S)-44(S)-2-((S)-2-((tert-butoxycarbonyl)(methypamino)propanamido)-2-cyclohexylacety1)-2-methylpiperazine-1-carbonyl)-5-fluoro-lH-indol-1-yDacetic acid (621 mg), (S)-3-(pyrrolidin-2-ylmethoxy)-5-((4-(thieno[3,2-blpyridin-7-yloxy)piperidin-1-yOmethyDisoxazole trihydrochloride (606 mg), DIEA (1.0 mL) and DMF (5 mL) was added HATU (734 mg). The reaction mixture was stirred at room temperature for 2 h, water was added thereto, and the precipitates were collected by filtration and purified by silica gel column chromatography (C18, acetonitrile/5 mM aqueous ammonium acetate). The product thus obtained was diluted with ethyl acetate and the organic layer was washed with saturated aqueous sodium bicarbonate. The organic layer was dried over anhydrous sodium sulfate and the solvent was removed under reduced pressure to give the title compound (367 mg).
MS: [M+111+ 1040.5.
[0328]
H) (S)-N-((S)-1-cyclohexy1-24(S)-4-(5-fluoro-1-(2-oxo-24(S)-2-(((5-44-(thieno[3,2-blpyridin-7-yloxy)piperidin-l-yOmethyDisoxazol-3-yDoxy)methyl)pyrrolidin-l-y1)ethyl)-1H-indole-2-carbony1)-3-methylpiperazin-l-y1)-2-oxoethyl)-2-(methylamino)propanamide To a mixture of tert-butyl ((S)-1-4(S)-1-cyclohexy1-24(S)-4-(5-fluoro-1-(2-oxo-24(S)-2-(((5-44-(thieno[3,2-blpyridin-7-yloxy)piperidin-l-yOmethyDisoxazol-3-y1)oxy)methyl)pyrrolidin-l-yDethyl)-1H-indole-2-carbony1)-3-methylpiperazin-l-y1)-2-oxoethyDamino)-1-oxopropan-2-y1)(methyl)carbamate (367 mg) and ethyl acetate (2 mL) was added 4 M hydrogen chloride ethyl acetate solution (3 mL). The reaction mixture was stirred at room temperature for 1.5 h and the solvent was removed under reduced pressure. To the residue was added saturated aqueous sodium bicarbonate, and the precipitates were collected by filtration to give the title compound (249 mg).
Date Recue/Date Received 2022-01-27 'H NMR (300 MHz, DMSO-do) 60.74-1.34 (10H, m), 1.38-2.25 (19H, m), 2.33-2.46 (2H, m), 2.60-3.50 (8H, m), 3.55-3.71 (3H, m), 3.79-4.94 (8H, m), 5.00-5.50 (2H, m), 6.03-6.43 (1H, m), 6.61-6.82 (1H, m), 6.98-7.19 (2H, m), 7.26-7.71 (3H, m), 7.89 (1H, t, J = 9.7 Hz), 7.98-8.13 (1H, m), 8.49 (1H, d, J = 5.5 Hz).
[0329]
Example 10 (S)-N-((S)-1-Cyclohexy1-2-(4-(5,6-difluoro-l-methyl-4-(2-(2-(2-(24(54(4-(thieno[3,2-b]pyridin-7-yloxy)piperidin-l-yl)methyDisoxazol-3-yl)oxy)ethoxy)ethoxy)ethoxy)ethoxy)-1H-indole-2-carbonyl)piperazin-l-y1)-2-oxoethyl)-2-(methylamino)propanamide hydrochloride [0330]
A) 2-(Benzyloxy)-3, 4-difluorobenzaldehyde To a mixture of 3,4-difluoro-2-hydroxy-benzaldehyde (5 g) and acetonitrile (50 mL) was added potassium carbonate (6.56 g), benzyl bromide (4.51 mL) and sodium iodide (2.37 g). The reaction mixture was stirred at 60 C for 6 h, filtered with Celite , and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (7.0 g).
1H NMR (400 MHz, DMSO-do): 6 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).
[0331]
B) Methyl (Z)-2-azido-3-(2-(benzyloxy)-3,4-difluorophenyl)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 argon atmosphere. The reaction mixture was stirred at the same temperature for 4 h and stirred at 4 C for 16 h. To the reaction mixture was added ice-cold water and the precipitates were collected by filtration to give the title compound (2.1 g).
1H NMR (400 MHz, DMSO-do): 63.83 (3H, s), 5.14 (2H, s), 6.94 (1H, s), 7.26 (1H, m), 7.38-7.40 (5H, m), 7.97 (1H, t, J = 6.9 Hz).
[0332]
C) Methyl 4-(benzyloxy)-5,6-difluoro-1H-indole-2-carboxylate A mixture of methyl (Z)-2-azido-3-(2-(benzyloxy)-3,4-difluorophenyl)acrylate (2.0 g) and xylene (30 mL) was stirred at 140 C for 2 h. The reaction mixture was cooled, and the precipitates were collected by filtration to give the title compound (700 mg).
1H NMR (400 MHz, DMSO-do): 63.87 (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).
[0333]
D) Methyl 4-(benzyloxy)-5,6-difluoro-1-methy1-1H-indole-2-carboxylate To a mixture of methyl 4-(benzyloxy)-5,6-difluoro-1H-indole-2-carboxylate (1.7 g) and DMF (20 mL) was added potassium carbonate (1.1 g) and iodomethane (0.4 mL). The reaction mixture was stirred at room temperature for 2 h, and ice-cold water was added thereto and extracted with ethyl acetate. The organic layer was washed with water and brine, dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure to give the title compound (1.5 g).
MS: [M+111+ 332.1.
[0334]
E) 4-(Benzy loxy)-5,6-difluoro-l-methy1-1H-indole -2-carboxylic acid To a mixture of methyl 4-(benzyloxy)-5,6-difluoro-l-methy1-1H-indole-2-carboxylate (1.5 g) and THF (30 mL) was added water (6.0 mL) and lithium hydroxide monohydrate (0.285 g). The reaction mixture was stirred at room temperature for 6 h and the solvent was removed under reduced pressure. The residue was acidified with 1 M hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with water and brine, dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure to give the title compound (1.35 g).
Date Recue/Date Received 2022-01-27 MS: [M+1-11+ 318.1.
[0335]
F) tert-Butyl ((S)-1-4(S)-2-(4-(4-(benzyloxy)-5,6-difluoro-l-methyl-1H-indole-carbonyl)piperazin-l-y1)-1-cyclohexy1-2-oxoethyDamino)-1-oxopropan-2-y1)(methyl)carbamate To a mixture of 4-(benzyloxy)-5,6-difluoro-l-methy1-1H-indole-2-carboxylic acid (1.4 g) and DMF (20 mL) was added tert-butyl ((S)-1-4(S)-1-cyclohexy1-2-oxo-2-(piperazin-l-yDethyDamino)-1-oxopropan-2-y1)(methyl)carbamate (1.81 g), HATU (2.52 g) and DIEA (1.9 mL). The reaction mixture was stirred at room temperature for 2 h, ice-cold water was added thereto, and extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium bicarbonate, water, and brine, dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (2.1 g).
MS: [M+111+ 710.1.
[0336]
G) tert-Butyl ((S)-1-4(S)-1-cyclohexy1-2-(4-(5,6-difluoro-4-hydroxy-l-methyl-1H-indole-2-carbonyl)piperazin-l-y1)-2-oxoethyl)amino)-1-oxopropan-2-y1)(methyl)carbamate To a mixture of tert-butyl ((S)-1-4(S)-2-(4-(4-(benzyloxy)-5,6-difluoro-l-methyl-1H-indole-2-carbonyl)piperazin-l-y1)-1-cyclohexy1-2-oxoethyDamino)-1-oxopropan-2-y1)(methyl)carbamate (2.1 g) and ethanol (50 mL) was added palladium on carbon (400 mg), and the reaction mixture was stirred under the normal pressure hydrogen atmosphere at room temperature for 2 h. The reaction mixture was filtered with Celite and the filtrate was concentrated under reduced pressure to give the title compound (1.7 g).
MS: [M+111+ 620.4.
[0337]
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 (15 g) and DCM (250 mL) was added TEA (11.03 mL), DMAP (3.22 g) and p-toluenesulfonyl chloride (12.07 g) under ice-cooling and the reaction mixture was stirred at room temperature for 2 h. The reaction mixture was diluted with DCM and washed with water and brine. The organic layer was dried over anhydrous sodium sulfate and the solvent was removed under reduced pressure.
The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (14g).
MS: [M+111+ 439.2.
[0338]
I) tert-Butyl ((S)-1-4(S)-1-cyclohexy1-2-(4-(5,6-difluoro-l-methyl-4-((1-phenyl-2,5,8,11-tetraoxatridecan-13-yl)oxy)-1H-indole-2-carbonyl)piperazin-l-y1)-2-oxoethyDamino)-1-oxopropan-2-y1)(methyl)carbamate To a mixture of tert-butyl ((S)-1-(((S)-1-cyclohexy1-2-(4-(5,6-difluoro-4-hydroxy-l-methyl-1H-indole-2-carbonyl)piperazin-l-y1)-2-oxoethyDamino)-1-oxopropan-2-y1)(methyl)carbamate (450 mg) and DMF (5 mL) was added cesium carbonate (591 mg) and 2-(2-(2-(2-(benzyloxy)ethoxy)ethoxy)ethoxy)ethyl 4-methylbenzenesulfonate (573 mg). The reaction mixture was stirred at room temperature for 16 h, ice-cold water was added thereto and extracted with ethyl acetate. The organic layer was washed with water and brine, dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (490 mg).
MS: [M+111+ 886.4.
[0339]
J) tert-Butyl ((S)-1-4(S)-1-cyclohexy1-2-(4-(5,6-difluoro-4-(2-(2-(2-(2-hydroxyethoxy)ethoxy)ethoxy)ethoxy)-1-methy1-1H-indole-2-carbonyl)piperazin-l-y1)-2-oxoethyDamino)-1-oxopropan-2-y1)(methyl)carbamate Date Recue/Date Received 2022-01-27 To a mixture of tert-butyl ((S)-1-4(S)-1-cyclohexy1-2-(4-(5,6-difluoro-l-methyl-4-((1-phenyl-2,5,8,11-tetraoxatridecan-13-yl)oxy)-1H-indole-2-carbonyl)piperazin-l-y1)-2-oxoethyDamino)-1-oxopropan-2-y1)(methyl)carbamate (490 mg) and ethanol (15 mL) was added palladium on carbon (100 mg). The reaction mixture was stirred under the normal pressure hydrogen atmosphere at room temperature for 16 h, filtered with Celite and the filtrate was concentrated under reduced pressure to give the title compound (360 mg).
MS: [M+111+ 796.2.
[0340]
K) tert-Butyl ((S)-1-4(S)-1-cyclohexy1-2-(4-(5,6-difluoro-l-methyl-4-(2-(2-(2-(24(54(4-(thieno[3,2-blpyridin-7-yloxy)piperidin-l-yOmethyDisoxazol-3-yDoxy)ethoxy)ethoxy)ethoxy)ethoxy)-1H-indole-2-carbonyl)piperazin-l-y1)-2-oxoethyDamino)-1-oxopropan-2-y1)(methyl)carbamate To a mixture of tert-butyl ((S)-1-4(S)-1-cyclohexy1-2-(4-(5,6-difluoro-4-(2-(2-(2-(2-hydroxyethoxy)ethoxy)ethoxy)ethoxy)-1-methyl-1H-indole-2-carbonyl)piperazin-l-y1)-2-oxoethyDamino)-1-oxopropan-2-y1)(methyl)carbamate (20 mg), 54(4-(thieno[3,2-blpyridin-7-yloxy)piperidin-l-yOmethyDisoxazol-3-ol (12.4 mg), triphenylphosphine (32.9 mg) and toluene (2 mL) was added di-tert-butyl azodicarboxylate (17.3 mg). The reaction mixture was stirred at room temperature for 16 h and the solvent was removed under reduced pressure.
The residue was purified by preparative thin layer chromatography to give the title compound (25 mg).
MS: [M+111+ 1109.8.
[0341]
L) (S)-N-((S)-1-cyclohexy1-2-(4-(5,6-difluoro-l-methyl-4-(2-(2-(2-(24(54(4-(thieno[3,2-blpyridin-7-yloxy)piperidin-l-yOmethyDisoxazol-3-yDoxy)ethoxy)ethoxy)ethoxy)ethoxy)-1H-indole-2-carbonyl)piperazin-l-y1)-2-oxoethyl)-2-(methylamino)propanamide hydrochloride To a mixture of tert-butyl ((S)-1-4(S)-1-cyclohexy1-2-(4-(5,6-difluoro-l-methyl-4-(2-(2-(2-(2-45-44-(thieno[3,2-blpyridin-7-yloxy)piperidin-l-yOmethyDisoxazol-3-yDoxy)ethoxy)ethoxy)ethoxy)ethoxy)-1H-indole-2-carbonyl)piperazin-l-y1)-2-oxoethyDamino)-1-oxopropan-2-y1)(methyl)carbamate (25 mg) and DCM (1 mL) was added 4 M
hydrogen chloride dioxane solution (0.3 mL) at 0 C. The reaction mixture was stirred at room temperature for 1 h, the solvent was removed under reduced pressure, and the residue was washed with diethyl ether to give the title compound (17 mg).
1H NMR (400 MHz, DMSO-d6) 60.83-1.34 (9H, m), 1.60-1.69 (5H, m), 2.07-2.18 (3H, m), 3.17 (3H, s), 3.44-3.74 (25H, m), 3.85-4.66 (9H, m), 5.01-5.27 (2H, m), 6.63 (1H, bs), 6.81 (1H, s), 7.36-7.44 (2H, m), 7.66 (1H, d, J = 5.32 Hz), 8.35-8.36 (1H, m), 8.74-8.80 (2H, m), 9.10-9.11 (1H, m), 11.36 (1H, brs).
[0342]
Example 11 (S)-N-((S)-1-Cyclohexy1-2-(4-(2-methy1-1-(2-(2-(2-(2-45-44-(thieno[3,2-blpyridin-7-yloxy)piperidin-l-yOmethyDisoxazol-3-yDoxy)ethoxy)ethoxy)ethoxy)ethyl)-1H-indole-5-carbonyl)piperazin-l-y1)-2-oxoethyl)-2-(methylamino)propanamide [0343]
A) tert-Butyl ((S)-1-4(S)-1-cyclohexy1-2-(4-(2-methy1-1H-indole-5-carbonyl)piperazin-l-y1)-2-oxoethyDamino)-1-oxopropan-2-y1)(methyl)carbamate To a mixture of tert-butyl ((S)-1-4(S)-1-cyclohexy1-2-oxo-2-(piperazin-l-y1)ethyDamino)-1-oxopropan-2-y1)(methyl)carbamate (4 g) and DMF (70 mL) was added 2-methy1-1H-indole-5-carboxylic acid (1.9 g), DIEA (6.8 mL) and HATU (4.45 g), and the reaction mixture was stirred at room temperature for 16 h. The reaction mixture was diluted with water and the aqueous layer was extracted with ethyl acetate. The organic layer was washed with water and brine subsequently, dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) Date Recue/Date Received 2022-01-27 to give the title compound (4 g).
MS: [M+111+ 568.3.
[0344]
B) tert-Butyl ((S)-1-4(S)-1-cyclohexy1-2-(4-(2-methy1-1-(1-phenyl-2,5,8,11-tetraoxatridecan-13-y1)-1H-indole-5-carbonyl)piperazin-l-y1)-2-oxoethyDamino)-1-oxopropan-2-y1)(methyl)carbamate To a mixture of tert-butyl ((S)-1-4(S)-1-cyclohexy1-2-(4-(2-methy1-1H-indole-5-carbonyl)piperazin-l-y1)-2-oxoethyl)amino)-1-oxopropan-2-y1)(methyl)carbamate (2 g) and DMF
(30 mL) was added cesium carbonate (2.87 g), the resultant mixture was stirred at room temperature for 5 min, 2-(2-(2-(2-(benzyloxy)ethoxy)ethoxy)ethoxy)ethyl 4-methylbenzensulfonate (2.78 g) was added thereto, and the reaction mixture was stirred at 80 C
for 16 h. The reaction mixture was diluted with water and the aqueous layer was extracted with ethyl acetate. The organic layer was washed with water and brine, dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography (NH, ethyl acetate/hexane) to give the title compound (1.3 g).
MS: [M+111+ 834.4.
[0345]
C) tert-Butyl ((S)-1-4(S)-1-cyclohexy1-2-(4-(1-(2-(2-(2-(2-hydroxyethoxy)ethoxy)ethoxy)ethyl)-2-methyl-1H-indole-5-carbonyl)piperazin-l-y1)-2-oxoethyl)amino)-1-oxopropan-2-y1)(methyl)carbamate To a mixture of tert-butyl ((S)-1-4(S)-1-cyclohexy1-2-(4-(2-methy1-1-(1-phenyl-2,5,8,11-tetraoxatridecan-13-y1)-1H-indole-5-carbonyl)piperazin-l-y1)-2-oxoethyl)amino)-1-oxopropan-2-y1)(methyl)carbamate (1.3 g) and ethanol (50 mL) was added 10% palladium on carbon (250 mg), and the reaction mixture was stirred under the normal pressure hydrogen atmosphere at 25 C for 16 h. The reaction mixture was filtered with Celite and the filtrate was concentrated under reduced pressure to give the title compound (1.1 g).
MS: [M+111+ 744.3.
[0346]
D) tert-Butyl ((S)-1-4(S)-1-cyclohexy1-2-(4-(2-methy1-1-(2-(2-(2-(2-45-44-(thieno[3,2-blpyridin-7-yloxy)piperidin-l-yOmethyDisoxazol-3-yDoxy)ethoxy)ethoxy)ethoxy)ethyl)-1H-indole-5-carbonyl)piperazin-l-y1)-2-oxoethyDamino)-1-oxopropan-2-y1)(methyl)carbamate To a mixture of tert-butyl ((S)-1-4(S)-1-cyclohexy1-2-(4-(1-(2-(2-(2-(2-hydroxyethoxy)ethoxy)ethoxy)ethyl)-2-methyl-1H-indole-5-carbonyl)piperazin-l-y1)-2-oxoethyDamino)-1-oxopropan-2-y1)(methyl)carbamate (20 mg), 54(4-(thieno[3,2-blpyridin-7-yloxy)piperidin-l-yOmethyDisoxazol-3-ol (10.6 mg), triphenylphosphine (32.5 mg) and toluene (2 mL) was added di-tert-butyl azodicarboxylate (24.7 mg), and the reaction mixture was stirred at 25 C for 16 h. The reaction mixture was concentrated under reduced pressure and the residue was purified by preparative thin layer chromatography to give the title compound (17 mg).
MS: [M+111+ 1057.3.
[0347]
E) (S)-N-((S)-1-Cyclohexy1-2-(4-(2-methy1-1-(2-(2-(2-(2-45-44-(thieno[3,2-blpyridin-7-yloxy)piperidin-l-yOmethyDisoxazol-3-yDoxy)ethoxy)ethoxy)ethoxy)ethyl)-1H-indole-5-carbonyl)piperazin-l-y1)-2-oxoethyl)-2-(methylamino)propanamide To a mixture of tert-butyl ((S)-1-4(S)-1-cyclohexy1-2-(4-(2-methy1-1-(2-(2-(2-(2-45-44-(thieno[3,2-blpyridin-7-yloxy)piperidin-l-yOmethyl)isoxazol-3-yDoxy)ethoxy)ethoxy)ethoxy)ethyl)-1H-indole-5-carbonyl)piperazin-l-y1)-2-oxoethyDamino)-1-oxopropan-2-y1)(methyl)carbamate (17 mg) and DCM (1 mL) was added TFA (0.01 mL) at 0 C, and the reaction mixture was stirred at 25 C for 1 h. The reaction mixture was concentrated under reduced pressure and the residue was purified by preparative HPLC (C18, mobile phase:
Date Recue/Date Received 2022-01-27 acetonitrile/20 mM aqueous ammonium bicarbonate) to give the title compound (4 mg).
MS: [M+1-11+ 957.8.
[0348]
The example compounds 1 to 11 produced are shown below. For each compound, the compound name, structural formula, salt type and MS value (MS is the measured value) are shown.
[0349]
Example No.1 (compound 1): 2-(4-((S)-2-cyclohexy1-2-((S)-2-(methylamino)propanamido)acetyl)piperazine-l-carbony1)-5,6-difluoro-N,1-dimethyl-N-(2-(2-(2-((5-((4-(thieno[3,2-blpyridin-7-yloxy)piperidin-1-yOmethyDisoxazol-3-yDoxy)ethoxy)ethoxy)ethyl)-1H-indole-3-carboxamide, [0350]
N/ \ 0 0 F F
-S \1 0-N
I
N-0 N/"Th NH

HN
salt type: HC1; MS value: 1006.6 [0351]
Example No.2 (compound 2): 2-(4-((S)-2-cyclohexy1-2-((S)-2-(methylamino)propanamido)acetyl)piperazine-l-carbony1)-6-methoxy-1-methyl-N-(2-(2-(2-(4-((4-(thieno[3,2-dlpyrimidin-4-yloxy)piperidin-1-yOsulfonyl)phenoxy)ethoxy)ethoxy)ethyl)-1H-indole-3-carboxamide, [0352]
/N 0-..._ N.,?-0_ N , \ N
\ ,.. \
o'ss..) /-NH

= Orj / iNTh - \......-N
0_O
crrNH

0) "1111 HN
\
salt type: - ; MS value: 1046.5 [0353]
Example No.3 (compound 3): 14(R)-4-(5,6-difluoro-1-methy1-1H-indole-2-carbony1)-2-Date Recue/Date Received 2022-01-27 methylpiperazin-l-y1)-24(2R,5R)-5-methyl-2-42-(2-(2-45-44-(thieno[3,2-blpyridin-7-yloxy)piperidin-1-yOmethyDisoxazol-3-yDoxy)ethoxy)ethoxy)ethoxy)methyDpiperazin-l-yDethan-1-one, [0354]

N/¨
N

________________ 0 F
OOO
I
NH
salt type: HC1; MS value: 909.7 [0355]
Example No.4 (compound 4): (S)-N-((S)-1-cyclohexy1-2-(4-(5,6-difluoro-l-methyl-3-(2-(2-(2-45-44-(thieno[3,2-blpyridin-7-yloxy)piperidin-l-yOmethyDisoxazol-3-yDoxy)ethoxy)ethoxy)ethoxy)-1H-indole-2-carbonyl)piperazin-l-y1)-2-oxoethyl)-2-(methylamino)propanamide, [0356]
/¨

çs /

cN

coy NH
HN
salt type: HC1; MS value: 966.4 [0357]
Example No.5 (compound 5): (S)-N-((S)-1-cyclohexy1-2-(4-(5,6-difluoro-1-(3-methy1-2-oxo-14-45-44-(thieno[3,2-blpyridin-7-yloxy)piperidin-1-yOmethyDisoxazol-3-yDoxy)-6,9,12-trioxa-3-azatetradecy1)-1H-indole-2-carbonyl)piperazin-l-y1)-2-oxoethyl)-2-(methylamino)propanamide, [0358]
Date Recue/Date Received 2022-01-27 /-N ___ 0 us L F F
N 0_, 0----N.---- 0 N------NO---N--- N.N)N /
I

NH
\\\
Os's HN
salt type: HC1; MS value: 1050.3 [0359]
Example No.6 (compound 6): (S)-N-((S)-1-cyclohexy1-2-(4-(5,6-difluoro-1-(2-oxo-24(S)-2-(((5-44-(thieno[3,2-blpyridin-7-yloxy)piperidin-l-yOmethyDisoxazol-3-y1)oxy)methyl)pyrrolidin-l-yDethyl)-1H-indole-2-carbonyl)piperazin-l-y1)-2-oxoethyl)-2-(methylamino)propanamide, [0360]
F
/¨
N\ ¨C) F =

-:--N 0,N 0 N N
\ ______________ salt type: HC1; MS value: 944.2 [0361]
Example No.7 (compound 7): (S)-N-((S)-1-cyclohexy1-2-(4-(5-fluoro-1-(2-oxo-24(S)-2-(((54(4-(thieno[3,2-blpyridin-7-yloxy)piperidin-l-yOmethyDisoxazol-3-yDoxy)methyl)pyrrolidin-l-yDethyl)-1H-indole-2-carbonyl)piperazin-l-y1)-2-oxoethyl)-2-(methylamino)propanamide, [0362]
F
H f N ON
H
\ ______________ salt type: - ; MS value: 926.1 [0363]
Example No.8 (compound 8): (S)-N-((S)-1-cyclohexy1-24(S)-4-(5,6-difluoro-1-(2-oxo-24(S)-2-(45-44-(thieno[3,2-blpyridin-7-yloxy)piperidin-l-yl)methyDisoxazol-3-yl)oxy)methyl)pyrrolidin-l-yl)ethyl)-1H-indole-2-carbonyl)-3-methylpiperazin-1-y1)-2-oxoethyl)-2-(methylamino)propanamide, Date Recue/Date Received 2022-01-27 [0364]
F
/¨

N? 0_ F\ 0 N =

\
ON1 NN__, j salt type: - ; MS value: 958.4 [0365]
Example No.9 (compound 9): (S)-N-((S)-1-cyclohexy1-24(S)-4-(5-fluoro-1-(2-oxo-24(S)-2-(((5-44-(thieno[3,2-blpyridin-7-yloxy)piperidin-l-yOmethyDisoxazol-3-y1)oxy)methyl)pyrrolidin-l-yDethyl)-1H-indole-2-carbony1)-3-methylpiperazin-l-y1)-2-oxoethyl)-2-(methylamino)propanamide, [0366]
F
/¨
N? 0 N S_ . I 0 -------NN,,- NH 3-:z.--N 0 c \ N 0 N
_________________ JIN NN..... j T------\N ---j salt type: - ; MS value: 940.4 [0367]
Example No.10 (compound 10): (S)-N-((S)-1-cyclohexy1-2-(4-(5,6-difluoro-l-methyl-4-(2-(2-(2-(24(54(4-(thieno[3,2-blpyridin-7-yloxy)piperidin-l-yl)methyDisoxazol-3-yDoxy)ethoxy)ethoxy)ethoxy)ethoxy)-1H-indole-2-carbonyl)piperazin-l-y1)-2-oxoethyl)-2-(methylamino)propanamide, [0368]
N/¨
\
S
________ N 0-...N F
\ __ ......k F

N----\____1 Nr---- 04 NH
( )----- HN---salt type: HC1; MS value: 1009.7, and [0369]
Example No.11 (compound 11): (S)-N-((S)-1-cyclohexy1-2-(4-(2-methy1-1-(2-(2-(2-(2-45-44-Date Recue/Date Received 2022-01-27 (thieno[3,2-blpyridin-7-yloxy)piperidin-1-yOmethyDisoxazol-3-yl)oxy)ethoxy)ethoxy)ethoxy)ethyl)-1H-indole-5-carbonyl)piperazin-1-y1)-2-oxoethyl)-2-(methylamino)propanamide, [0370]
/

H

\¨N 0 \
0¨N
salt type: - ; MS value: 957.8 [0371]
Experimental Example 1: Measurement of XIAP Binding Inhibitory Activity Human XIAP binding inhibitory activity was measured by the Homogeneous Time Resolved Fluorescence (HTRF) method with using commercially available human XIAP_BIR3 domain purified protein (R & D) and as a ligand a Smac N-terminal peptide (AVPIAQK
(SEQ ID NO: 1)) (hereinafter referred to as "b-Smac"; Peptide Research Laboratories, Inc.) biotinylated at the C-terminus according to a conventional method.
The HTRF method will be described in detail below.
The test compound diluted with a reaction buffer (25 mM HEPES Buffer containing 100 mM
NaCl, 0.1% BSA, and0.1% triton X-100, pH 7.5) was added to a 384-well white shallow bottom plate (Greiner 784076) at 1 )(1_, / well and flash centrifuged for 30 seconds.
Subsequently, human XIAP_BIR3 domain purified protein was diluted with the reaction buffer to obtain a 90nM
sample diluent, and the resultant sample diluent was added to the above-mentioned white superficial plate at 4.5 )(1_, / well and flash centrifuged for 30 seconds.
Subsequently, b-Smac diluted to 90 nM with the reaction buffer was added to the above-mentioned white superficial plat at 4.5 )(1_, / well and flash centrifuged for 30 seconds. A mixed solution of Anti-6 HIS-Cryptate (Eu3+ Cryptate-conjugated mouse monoclonal antibody anti-6 Histidine ; cisbio) and Streptavidin-XL' (Highgrade XL665-conjugated streptavidin; cisbio) both diluted 100-fold with HTRF detection buffer (cisbio) at a volume ratio of 1: 1 was added to the above white superficial plate at 10 )(1_, / well. After flash centrifuging the white shallow bottom plate for 30 seconds, the white shallow bottom plate was left at room temperature for 4 hours or more in the dark. The white superficial plate after being left was subjected to fluorescence intensity measurement (excitation wavelength: 320 nm, fluorescence wavelength: 665 nm and 615 nm) by EnVision (Perkin Elmer).
The binding inhibition rate (%) was calculated based on the HTRF ratio in the presence of the test compound to the HTRF ratio in the absence of the test compound (fluorescence intensity at 665 nm / fluorescence intensity at 615 nm).
The XIAP binding inhibition rate (%) of test compounds was evaluated. The XIAP
binding inhibition ratio described as A 75%, 75%> B 50%, 50%> C 25%, D >25% when the concentration of the test compound is 3 ,M, or 50% inhibitory concentration (IC50 value) described as A<0.3 04, 0.3 04 B< 3 04, 3 1\4 C< 30 ,M, is shown in the table below.
[0372]
[Table 1]
Date Recue/Date Received 2022-01-27 *Binding inhibition Compound rate Example 1 -/B
Example 2 -/B
Example 3 -/A
Example 4 C/-Example 5 -/C
Example 6 -/C
Example 7 -/C
Example 8 -/C
Example 9 -/C
Example 10 -/B
Example 11 -/B
*Binding inhibition rate: binding inhibition rate when the concentration of the test compound is 3 [tM / IC50 value [0373]
From the above results, it was shown that the compounds of the present invention have an excellent TAP (in particular XIAP) binding (inhibition) activities.
[0374]
Experimental Example 2: Measurement of Binding Inhibitory Activity of IRAK-M
IRAK-M binding inhibitory activity was evaluated using active site-dependent competitive assay KINOMEscan provided by Eurofins Discover X (Goldstein, D. M. et al.
High-throughput kinase profiling as a platform for drug discovery. Nat. Rev. Drug Discovery.
7, 391-397 (2008)).
IRAK-M binding inhibitory activity of the test compound was evaluated. The "%Ctrl" when the concentration of the test compound is 1 [tM described as A < 25%, 50% > B 25%, 75%>
C 50%, D 75%, or IC50 value described as A <0.03 04, 0.03 [tM B< 0.1 04, 0.1 [tM C
<0.3 [tM, 0.3 [tM D< 1 [tM is shown in the table below. The "%Ctrl" is calculated by the following formula.
(test compound signal ¨ positive control compound signal) / (negative control compound signal ¨
positive control compound signal) x 100 Negative control compound = DMSO (100% Ctrl) Positive control compound = control compound (0% Ctrl) [0375]
[Table 2]
Date Recue/Date Received 2022-01-27 Compound *Binding inhibition activity Example 1 -/D
Example 2 -/D
Example 3 -/D
Example 4 B/-Example 5 A/-Example 6 A/-Example 7 -/D
Example 8 -/D
Example 9 -/D
Example 10 A/-Example 11 A/-*Binding inhibition activity: %Ctrl/IC50 value when the concentration of the test compound is 1 M
[0376]
Experimental Example 3: Measurement of in vitro Degradation Activity of Target Protein In vitro degradation activities of target protein of the example compounds were evaluated using Enzyme-linked immuno-sorbent assay (ELISA) by the following assay steps. THP1 cells (ATCC, TIB-202) were cultured in RPMI-1640 supplemented with 10% FBS, lx sodium pyruvate, lx HEPES, D-(+)- glucose and 1% penicillin/streptomycin. THP1 cells were seeded at a density of 1x106 cells/well in 24-well plate and treated with DMSO control or test compound, and then incubated for 24 hours. The cells were collected and lysed on ice for 30 minutes in lysis buffer (PBS containing 0.1% Triton X-100) containing a protease inhibitor cocktail (Roche, Cat#
11836170001). The lysates were sonicated for 30sec ON/ 30sec OFF for ten cycles and centrifuged for 10 minutes at 13k rpm at 4 C. Protein concentrations were determined by the BCA assay (Sigma, Cat # QPBCA-1KT). The ELISA assay was performed using the Human IRAK3 / IRAKM /IRAK-M ELISA Kit (LifeSpan BioSciences, Cat # LS-F35271) , and the protein levels of IRAK-M were evaluated according to the kit protocol. As to the IRAK-M
degradation rate of test compounds, protein degradation rate (%) when the concentration of the test compound is 1 M described as A75%, 50% B<75%, 25% C<50%, D<25%, or 50% degradation concentration (DC50 value) described as A< 0.03 M, 0.03 M B<
0.1 M
, 0.1 M C< 0.3 M, 0.3 M D< 1 M, is shown in the table below.
[0377]
[Table 3]
Date Recue/Date Received 2022-01-27 Compound *Degradation rate Example 1 -/D
Example 2 C/-Example 3 C/-Example 4 A/-Example 5 -/D
Example 6 -/B
Example 7 -/A
Example 8 -/A
Example 9 -/A
Example 10 -/C
Example 11 A/-*Degradation rate: protein degradation rate when the concentration of the test compound is 1 M/DC50 value [0378]
Experimental example 4: Antitumor Effect in a Mouse Lewis Lung Cancer Cell Inoculation Model C57BL/6 mice (Charles River Laboratories Japan, male, 7-8W) were subcutaneously inoculated with 2x104 cells/mouse of mouse Lewis lung carcinoma LL/2 (Lewis lung carcinoma, LLC) (ATCC, CRL-1642) along with Matrigel on the flank of the mouse. Tumor size was measured by electronic calipers 7 days after inoculation, and the groups were divided so that each group had an equivalent size, and administration of the compound was started 8 days later. Tumor size was calculated by the formula, major diameter of the tumor x minor diameter x minor diameter 2.
The test compound was suspended in 0.5% methylcellulose or dissolved in saline and administered subcutaneously every 3 days for 3 times. Tumor size was measured periodically until 16-18 days after the start of the study, and a two-tailed test was performed for tumor size in the test compound-treated group and the solvent-treated group on the last day of the study.
Daily changes of tumor size in each group of example compounds 1, 6, 7, 8, and 9, are shown in Figure 1. Each compound was used with the salt shown in the figure. Figure shows the mean standard error.
From the above results, it was shown that these compounds have suppressive effects on tumor growth.
[0379]
Formulation Example 1 A medicament containing the compound of the present invention as an active ingredient can be produced, for example, by the following composition.
1. Capsule (1) Compound obtained in Example 1 40 mg (2) Lactose 70 mg (3) Microcrystalline cellulose 9 mg (4) Magnesium stearate 1 mg 1 capsule 120 mg After mixing (1), (2), (3) and 1/2 volume of (4), the mixture is granulated.
The remaining (4) is added to this, and then the whole is encapsulated in a gelatin capsule.
Date Recue/Date Received 2022-01-27 [0380]
2. Tablet (1) Compound obtained in Example 1 40 mg (2) Lactose 58 mg (3) Corn starch 18 mg (4) Microcrystalline cellulose 3.5 mg (5) Magnesium stearate 0.5 mg 1 tablet 120 mg After mixing (1), (2), (3) and 2/3 volume of (4) and 1/2 volume of (5), the mixture is granulated. Then, the remaining (4) and (5) are added to the granules and pressed-molded into tablets.
[0381]
Formulation Example 2 After dissolving 50 mg of the compound obtained in Example 1 in 50 mL of distilled water for injection (Japanese Pharmacopoeia grade), the distilled water for injection is added to make 100 mL. The solution is filtered under sterile conditions, then, 1 mL each of this solution is taken, filled under sterile conditions into vials for injection, lyophilized and sealed.
[0382]
The foregoing merely illustrates objects and subjects of the present invention, and is not intended to be limiting the accompanying Claims. Without departing from the accompanying Claims, various modifications and alterations to the described embodiments will be apparent to those skilled in the art in view of the teachings herein.
[Industrial Applicability]
[0383]
The compounds of the present invention are capable of degrading IRAK-M protein as a target. Therefore, it is expected to provide effective drugs for the prevention or treatment of cancer and other IRAK-M associated diseases.
Date Recue/Date Received 2022-01-27

Claims (16)

CA 03148955 2022-01-27

1. A compound represented by the following formula (I):
IRAK-M binder ______ Linker E3 ligase binder (M) (L) (E) , or a pharmaceutically acceptable salt thereof.

2. The compound according to claim 1, wherein the IRAK-M binder (M) is represented by the following formula (II):
Roa Ro4 0' wherein Y represents CH or N, R 1 represents H or Me, R 3 represents a group represented by the following structural formula:
* *
*
wherein * represents the binding position to 0, ** represents the binding position to A, and n is an integer from 0 to 2, A is represented by the following structural formula:

*x*
wherein R 5 each independently represent a hydrogen atom or a C1-6 alkyl group, or *-502-*, Ro4 is represented by a group selected from the following structural formula:
N-N
**

wherein * represents the binding position to A, and ** represents the binding position to the linker, an optionally substituted C1-6 alkylene group, an optionally substituted C3-10 cycloalkylene group, an optionally substituted C6-14 arylene group, or a bond, and the arrow represent the binding to the linker (L), or a pharmaceutically acceptable salt thereof.

3. The compound according to claim 2, wherein the IRAK-M binder (M) is represented by the following formula (III):
Date Recue/Date Received 2022-01-27 Isl" 'R"
0) R I
oi S----Y
N
III
wherein Y represents CH or N, R 1 represents H or Me, A 1 represents a group represented by the following structural formula:

*x*
wherein R 5 each independently represent a hydrogen atom or a C1-6 alkyl group, or *-S02-*, Ri 1 represents a group selected from the following structural formula:
* * *
*x-,.., v /
wherein * represents the binding position to A 1, and ** represents the binding position to a linker], and the arrow represents the binding to the linker (L), or a pharmaceutically acceptable salt thereof.

4. The compound according to claim 2, wherein, the IRAK-M binder (M) is a monovalent group derived from the compound selected from the group consisting of (5-((4- (thieno [3,2-b) ] pyridin-7-yloxy) piperidin-1-y1) methyl) isoxazol-3-ol), 5-(((4-((2) 2) -methylthieno [3,2-b] pyridin-7-y1) oxy) piperidin-1-y1) methyl) isoxazol-3-ol), 1-methy1-5-((( 4- (thieno [3,2-b] pyridin-7-yloxy) piperidin-1-y1) methyl) -1H-pyrazol-3-ol, and 4-((4- (thieno [3,2-d] pyrimidin-4-) yloxy) piperidin-1-y1) sulfonyl) phenol, or a pharmaceutically acceptable salt thereof.

5. The compound according to any one of claims 1 to 4, wherein the Linker (L) is a group having to 20 carbon atoms optionally containing a heteroatom, or a pharmaceutically acceptable salt thereof.

6 The compound according to any one of claims 1 to 4, wherein the Linker (L) is represented by the following structural formula:
0 * *
*
wherein * represents the binding to the IRAK-M binder (M), *-(CH2CH20)n(CH2)m(NRCO)s(CH2)t-* (n is a natural number from 1 to 5, m is 0, 1 or 2, and s is 0 or 1, t is 0 or 1 and R represents a hydrogen atom or C1-6 alkyl group), or a bond, or a pharmaceutically acceptable salt thereof.

7. The compound according to any one of claims 1 to 6, wherein the E3 ligase binder (E) is Date Recue/Date Received 2022-01-27 represented by the following structural formula (IV):

D-- D
..01 Ros Rog ----E
Rog (IV) wherein Rol, R02, R03, Ro4, Ros, RO6, RO2 and RO8 each independently represent a hydrogen atom or a C1-6 alkyl group which may form a ring with each other, D represents the following formula (V):
_A/1. 1_,_____ ( )n ( m 0 i NH
HN---)\--/ -----(V) wherein m is an integer of 0 to 2, n is an integer of 0 to 2, Wil represents a methylene group, a difluoromethylene group, 0, S, SO, SO2, 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 an optionally halogenated C1-3 alkyl group, or the following formula (VI):
P
\
CI) NH

(VI) wherein Q represents an oxygen atom, formula-NR2i- (wherein, R21 represents a hydrogen atom, a C1-6 alkyl group, or a C1-6 alkyl group which may form a ring with P), or a bond, P represents a hydrogen atom, a C1-6 alkyl group or the binding to the Linker (L) (including the formation of a ring with Q and binding to the linker (L), E represents the following formula (VII):

VII
wherein R21, R22 and R23 each independently represent a hydrogen atom, a halogen atom, a C1-6 alkyl group, a C1-6 alkoxy group, or an optionally substituted carbamoyl group, and R28 and R26 each independently represent a hydrogen atom, a halogen atom, a C1-6 alkyl group, a C1-6 alkoxy group, an optionally substituted carbamoyl group, or the binding to the Linker (L); R24 represents a hydrogen atom, a methyl group, or the binding to the linker (L), provided that the binding to the linker (L) is any one of R24, R28 or R26, or the following formula (VIII):
Date Recue/Date Received 2022-01-27 R
R35 \

I

VIII
wherein R31, R32, R33, R34 and R38 each independently represent a hydrogen atom, a halogen atom, a C1-6 alkyl group, a C1-6 alkoxy group, or an optionally substituted carbamoyl group, and R
represents a hydrogen atom, C1-6 alkyl group, or the binding to the linker (L), either D or E
binds to the linker (L), or a pharmaceutically acceptable salt thereof.

8. The compound according to any one of claims 1 to 7, wherein the E3 ligase binder (E) is represented by the following formula (IV):

D D
"01 N 1 l<10 2 R05 Ro3 (IV) wherein Rol, R02, R03, Ro4, Ros, Ro6, RO7 and RO8 each independently represent a hydrogen atom or a methyl group, D represents the following formula (V-1):
IN_v______ i¨NH
HN

(V-1) wherein Wi 1 represents a methylene group or difluoromethylene group, or the following formula (VI-1) Q NH
HN

(VI-1) wherein Q represents the binding to the Linker (L), E represents the following formula (VII):

VII
Date Recue/Date Received 2022-01-27 wherein R21, R22 and R23 each independently represent a hydrogen atom, a halogen atom, a Cl -6 alkyl group, or a C1-6 alkoxy group; R25 and R26 each independently represent a hydrogen atom, a halogen atom, a C1-6 alkyl group, or the binding to the Linker (L); and R24 represents a hydrogen atom, a methyl group, or the binding to the Linker (L), provided that the binding to the Linker (L) is any one of R24, R25 or R26 or the following formula (VIII):
R35 \

wherein R31, R32, R33, R34 and R35 each independently represent a hydrogen atom, a halogen atom, or a C1-6 alkyl group; R represents a hydrogen atom, Cl -6 alkyl group, or the binding to the Linker (L), either D or E binds to the Linker (L), or a pharmaceutically acceptable salt thereof.

9. The compound according to claim 1, wherein the IRAK-M binder (M) is represented by the following formula (III):

'R"
y i I
wherein Y represents CH or N, R 1 represents H or Me, A 1 represents *-CH2-*
or *-S02-*, R
represents a group selected from the following structural formulae:
wherein * represents the binding position to A 1, and ** represents the binding position to a linker], and the arrow represent the binding to the linker (L), the linker (L) is represented by the following structural formula:
0 *
wherein * represents the binding to the IRAK-M binder (M), *-(CH2CH20)n(CH2)m(NRCO)s(CH2)t-* (n is a natural number from 1 to 5, m is 0, 1 or 2, and s is 0 or 1, t is 0 or 1 and R represents a hydrogen atom or C1-6 alkyl group), or a bond, E3 ligase binder (E) is represented by the following structural formula (IV):
Date Recue/Date Received 2022-01-27 .,01 RH -----E

(IV) wherein Rol, R02, R03, Ro4, Ros, RO6, RO7 and RO8 each independently represent a hydrogen atom or a methyl group; D represents the following formula (V-2):
N
HW HY-/ c---(V-2) , or the following formula (VI-1) Q NH
HN

(VI-1) wherein Q represents the binding to the Linker (L), and E represents the following formula (VII):

N

VII
wherein R21, R22 and R23 each independently represent a hydrogen atom, a halogen atom, a Cl -6 alkyl group, or C1-6 alkoxy group; R25 and R26 each independently represent a hydrogen atom, a halogen atom, a C1-6 alkyl group, or the binding to the Linker (L); R24 represents a hydrogen atom, a methyl group, or the binding to the Linker (L), provided that the binding to the Linker (L) is any one of R24, R25 or R26, or the following formula (VIII):
R
R35 \

I

VIII
wherein R31, R32, R33, R34 and R35 each independently represent a hydrogen atom, or a C1-6 alkyl group and R represents a hydrogen atom, or the binding to the Linker (L), either D or E binds to the Linker (L), or a pharmaceutically acceptable salt thereof.
Date Recue/Date Received 2022-01-27

10. The compound according to claim 1, which compound is selected from the group consisting of:
Compound 1: 2-(4-((S)-2-cyclohexy1-2-((S)-2-(methylamino)propanamido)acetyl)piperazine-l-carbony1)-5,6-difluoro-N,1-dimethyl-N-(2-(2-(2-45-44-(thienop,2-b]pyridin-7-yloxy)piperidin-1-yOmethyDisoxazol-3-yDoxy)ethoxy)ethoxy)ethyl)-1H-indole-3-carboxamide:
N \ 0 O¨N
N---Oo 0 NrTh NH
Compound 2: 2-(44(S)-2-cyclohexy1-2-((S)-2-(methylamino)propanamido)acetyl)piperazine-1-carbony1)-6-methoxy-1-methyl-N-(2-(2-(2-(4-44-(thieno[3,2-dlpyrimidin-4-yloxy)piperidin-l-yOsulfonyl)phenoxy)ethoxy)ethoxy)ethyl)-1H-indole-3-carboxamide:
N __ ?-0 N
t-/ N
_/-NH

= Orj /NM

0.XNHO
0) HN
Compound 3: 14(R)-4-(5,6-difluoro-1-methyl-1H-indole-2-carbony1)-2-methylpiperazin-1-y1)-2-42R,5R)-5-methyl-2-42-(2-(2-45-44-(thieno[3,2-blpyridin-7-y1oxy)piperidin-1-yOmethyDisoxazol-3-y1)oxy)ethoxy)ethoxy)ethoxy)methyDpiperazin-1-yDethan-1-one:

N/¨
N
N \ 0 / N F
V.11 N
I
NH
Date Recue/Date Received 2022-01-27 Compound 4: (S)-N-((S)-1-cyclohexy1-2-(4-(5,6-difluoro-l-methyl-3-(2-(2-(24(54(4-(thieno[3,2-blpyridin-7-yloxy)piperidin-l-yOmethyDisoxazol-3-yDoxy)ethoxy)ethoxy)ethoxy)-1H-indole-2-carbonyl)piperazin-l-y1)-2-oxoethyl)-2-(methylamino)propanamide:
/¨
Ny?
S
N 0-....N
\ _____________ c.... ..11x \ F
OC N-N
0----N...--- F
I

\
cN,) clyNH
õ..-1,,, HN //
I
Compound 5: (S)-N-((S)-1-cyclohexy1-2-(4-(5,6-difluoro-1-(3-methy1-2-oxo-14-((5-((4-(thienop,2-blpyridin-7-yloxy)piperidin-l-yOmethyDisoxazol-3-yDoxy)-6,9,12-trioxa-3-azatetradecy1)-1H-indole-2-carbonyl)piperazin-l-y1)-2-oxoethyl)-2-(methylamino)propanamide:
/¨ N ¨(3 NN s F F
________ N O.__ o .
0 - - " - N - - - N . , - - - N
0 = - - - -N)CN /
i 0 Nr''''') NH
\\\
HN
Compound 6: (S)-N-((S)-1-cyclohexy1-2-(4-(5,6-difluoro-1-(2-oxo-24(S)-2-(((54(4-(thieno[3,2-b]pyridin-7-yloxy)piperidin-l-yOmethyDisoxazol-3-yDoxy)methyl)pyrrolidin-l-y1)ethyl)-1H-indole-2-carbonyl)piperazin-l-y1)-2-oxoethyl)-2-(methylamino)propanamide:
Date Recue/Date Received 2022-01-27 F
/_ N-OL F II

\ __________________ ._..1 0 N \__/
)r--\ N ---Compound 7: (S)-N-((S)-1-cyclohexy1-2-(4-(5-fluoro-1-(2-oxo-2-((S)-2-(((5-((4-(thieno[3,2-blpyridin-7-yloxy)piperidin-1-yOmethyDisoxazol-3-yDoxy)methyl)pyrrolidin-1-yl)ethyl)-1H-indole-2-carbonyl)piperazin-1-y1)-2-oxoethyl)-2-(methylamino)propanamide:
F

.7s L 1 r---NN N
)(N
N
N= 0 H
N 0 0)_1 \ ___________________ CINI
\ I 0 Compound 8: (S)-N-((S)-1-cyclohexy1-2-((S)-4-(5,6-difluoro-1-(2-oxo-2-((S)-2-(((5-((4-(thieno[3,2-blpyridin-7-y1oxy)piperidin-1-yOmethyDisoxazol-3-yDoxy)methyl)pyrrolidin-1-yDethyl)-1H-indole-2-carbony1)-3-methylpiperazin-1-y1)-2-oxoethyl)-2-(methylamino)propanamide:
F
/-Ncy? __ OL F *

N =

\ ______________ ...._:, N J
)r---\ N ---Compound 9: (S)-N-((S)-1-cyclohexy1-2-((S)-4-(5-fluoro-1-(2-oxo-2-((S)-2-(((5-((4-(thieno[3,2-b]pyridin-7-yloxy)piperidin-1-yOmethyDisoxazol-3-yDoxy)methyl)pyrrolidin-1-yl)ethyl)-1H-indole-2-carbony1)-3-methylpiperazin-1-y1)-2-oxoethyl)-2-(methylamino)propanamide:
F
/-N? OL 4$ , 0 , N S
N 0 \ N 0 N
NN____ j )r--\N----Date Recue/Date Received 2022-01-27 Compound 10: (S)-N-((S)-1-cyclohexy1-2-(4-(5,6-difluoro-l-methyl-4-(2-(2-(2-(24(54(4-(thieno[3,2-b]pyridin-7-yloxy)piperidin-l-yOmethyDisoxazol-3-yl)oxy)ethoxy)ethoxy)ethoxy)ethoxy)-1H-indole-2-carbonyl)piperazin-l-y1)-2-oxoethyl)-2-(methylamino)propanamide:
/¨

N \ ¨(:) s ( N O¨N F
\
F
0-..--'13 N----NH
)----( HN¨

, and Compound 11: (S)-N-((S)-1-cyclohexy1-2-(4-(2-methy1-1-(2-(2-(2-(2-45-44-(thieno[3,2-blpyridin-7-yloxy)piperidin-1-yOmethyDisoxazol-3-yDoxy)ethoxy)ethoxy)ethoxy)ethyl)-1H-indole-5-carbonyl)piperazin-l-y1)-2-oxoethyl)-2-(methylamino)propanamide:
/

)Niii) N \ ¨C) N N

\ _______________ Or or a pharmaceutically acceptable salt thereof.

11. A medicament containing the compound according to any one of claims 1 to 10, or a pharmaceutically acceptable salt thereof.

12. The medicament according to claim 11, wherein the drug is an IRAK-M
protein degradation inducer.

13. The medicament according to claim 11 or 12, which is a prophylactic or therapeutic agent for cancers.

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

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

16. A method for prevention or treatment of cancers, comprising administering to a patient in Date Recue/Date Received 2022-01-27 need of treatment an effective amount of the compound or salt thereof according to any one of claims 1 to 10.
Date Recue/Date Received 2022-01-27