JP6899993B2 - Heterocyclic compound - Google Patents

Description

The present invention relates to a compound in which a specific IAP ligand and an intracellular protein ligand are bound via a linker.
[Background of invention]

Abbreviated as Specific and Nongeneticic IAP-dependent Protein Eraser, which induces ubiquitination and proteasome degradation of target proteins by E3 ligase (specifically, Inhibitor of Apoptosis Protein (IAP)) for the purpose of treatment by reducing pathologically related proteins. Therefore, SNIPER or Proteolysis Targeting Chimeras may be abbreviated as PROTAC. In the present specification, it may be referred to as SNIPER compound). For example, the ligand that binds to E3 ligase includes MV1, MeBS, Nutlin-3, IкBα peptide, HIF-1α peptide, or VHL ligand, and the target protein is CRABP2, RICK2, ERα, TACC3, AR, ERRα, FRS2α, or SNIPER compounds such as PI3K have been proposed (Non-Patent Documents 1 to 10, 12 and 13, Patent Documents 1 to 9). In addition, various IAP inhibitors or dimers of IAP inhibitors are disclosed (Patent Documents 10, 11, 12 and 13).
Further, the use of a thalidomide derivative as a ligand that binds to a ubiquitin ligase complex is disclosed (Non-Patent Document 11).
Further, a drug for the indication of advanced solid tumor containing LCL161 as an active ingredient is disclosed (Non-Patent Document 14).

Japanese Unexamined Patent Publication No. 2013-056837 International Publication No. 2014/108452 International Publication No. 2015/000867 International Publication No. 2015/000868 International Publication No. 2013/106643 U.S. Patent Application Publication No. 2002/0068063 International Publication No. 2013/170147 International Publication No. 2016/0022642 U.S. Patent Application Publication No. 2015/0291562 Chinese Patent Application Publication No. 104558102 International Publication No. 2011/104266 International Publication No. 2010/015090 International Publication No. 2008/134679

J. Am. Chem. Soc. 132 (2010) 5820-5826 Bioorg. Med. Chem. Lett. 19 (2011) 3229-3241 FEBS Lett. 585 (2011) 1147-1152 Bioorg. Med. Chem. 19 (2011) 6768-6778 Cancer Sci. 104 (2013), 1492-1498 Bioorg. Med. Chem. Lett. 22 (2011) 1793-1796 Cell Death Dis. 5 (2014) e1513 Org. Biomol. Chem. 13 (2015), 9746-9750 Bioorg. Med. Chem. Lett. 22 (2012) 4453-4457 Curr. Cancer Drug Targets 16 (2016) 136-146 Science. 348 (2015) 1376-1381 Nat. Chem. Biol. 11 (2015) 611-617 Proc. Natl. Acad. Sci. USA. 113 (2016) 7124-7129 J. Clin. Oncol. 32 (2014) 3103-3110

An object of the present invention is to provide a novel SNIPER compound having excellent activity of inducing degradation of a target protein (sometimes referred to as "knockdown (KD) activity" in the present specification).

[式中、［Ｚ］は、細胞内タンパク質に特異的に結合するリガンドを示し;
［Ｌ］は、その内部に下式（ＩＩ）

（式中、Ｌ^１、Ｌ^２およびＬ^３は、それぞれ独立して、炭素原子、酸素原子、窒素原子および硫黄原子からなる群から選択される無置換の原子を示し、
−−は、それぞれ独立して、単結合、二重結合または三重結合を示す。）で示される直鎖状リンカーを含むリンカーを示し；
［Ｘ］は、下式（ＩＩＩ）

（式中、
Ｒは、置換されていてもよいアルキル基または置換されていてもよいシクロアルキル基を示し、
環Ａは、さらに置換されていてもよい複素環を示し、
環Ｂは、さらに置換されていてもよい環を示す。）、
下式（ＩＶ）

（式中、各記号は前記と同意義を示す。）、
下式（Ｖ）

（式中、
Ｂ^１は、さらに置換されていてもよい縮合環を示し、
その他の記号は前記と同意義を示す。）、または
下式（ＶＩ）

（式中、Ｙは、結合手またはカルボニル基を示し、
その他の記号は前記と同意義を示す。）を示す。]
で表される化合物またはその塩（本明細書中、「化合物（Ｉ）」と略記することがある）。 As a result of diligent research, the present inventors have found that a SNIPER compound in which a specific IAP ligand and a ligand that specifically binds to a target intracellular protein are bound via a linker induces degradation of the target protein. They have found excellent activity and have completed the present invention. That is, the present invention is as follows.
[1] The following formula (I)

[In the formula, [Z] indicates a ligand that specifically binds to intracellular proteins;
[L] is the following equation (II) inside.

(In the equation, L ¹ , L ² and L ³ each independently represent an unsubstituted atom selected from the group consisting of a carbon atom, an oxygen atom, a nitrogen atom and a sulfur atom.
−− Indicates a single bond, a double bond or a triple bond independently of each other. ) Indicates a linker containing a linear linker;
[X] is the following equation (III)

(During the ceremony,
R indicates an alkyl group which may be substituted or a cycloalkyl group which may be substituted.
Ring A represents a heterocycle which may be further substituted.
Ring B represents a ring that may be further substituted. ),
Equation (IV)

(In the formula, each symbol has the same meaning as above.),
The following formula (V)

(During the ceremony,
B ¹ represents a fused ring which may be further substituted.
Other symbols have the same meaning as described above. ), Or the following formula (VI)

(In the formula, Y represents a bond or a carbonyl group,
Other symbols have the same meaning as described above. ) Is shown. ]
(In the present specification, it may be abbreviated as "Compound (I)").

（式中、
Ｒは、置換されていてもよいアルキル基または置換されていてもよいシクロアルキル基を示し、
環Ａは、さらに置換されていてもよい複素環を示し、
環Ｂは、さらに置換されていてもよい環を示す。）である、上記［１］記載の化合物またはその塩。 [2] [X] is
Equation (III) below

(During the ceremony,
R indicates an alkyl group which may be substituted or a cycloalkyl group which may be substituted.
Ring A represents a heterocycle which may be further substituted.
Ring B represents a ring that may be further substituted. ), The compound according to the above [1] or a salt thereof.

（式中、
環Ａは、さらに置換されていてもよい複素環を示し、
環Ｂは、さらに置換されていてもよい環を示す。）である、上記［１］記載の化合物またはその塩。 [3] [X] is the following formula (VII)

(During the ceremony,
Ring A represents a heterocycle which may be further substituted.
Ring B represents a ring that may be further substituted. ), The compound according to the above [1] or a salt thereof.

（式中、
環Ｂは、さらに置換されていてもよい環を示す。）である、上記［１］記載の化合物またはその塩。 [4] [X] is the following equation (VIII)

(During the ceremony,
Ring B represents a ring that may be further substituted. ), The compound according to the above [1] or a salt thereof.

である、上記［１］記載の化合物またはその塩。 [5] [X] is the following formula (IX)

The compound according to the above [1] or a salt thereof.

である、上記［１］記載の化合物またはその塩。
［７］ 上記［１］〜［６］の何れかに記載の化合物またはその塩を含有してなる医薬。
［８］ 蛋白分解誘導薬である、上記［７］記載の医薬。
［９］ 癌の予防または治療薬である、上記［７］記載の医薬。 [6] [X] is the following formula (X)

The compound according to the above [1] or a salt thereof.
[7] A drug containing the compound according to any one of the above [1] to [6] or a salt thereof.
[8] The medicament according to the above [7], which is a proteolytic inducer.
[9] The drug according to the above [7], which is a preventive or therapeutic agent for cancer.

The compound of the present invention may have an activity of inducing the degradation of a target intracellular protein, and may be effective in the prevention or treatment of a disease (for example, cancer) in which the target protein is involved.

FIG. 1A shows the ERα protein knockdown (KD) activity of SNIPER (ER) -087 in MCF7 human breast cancer cells. The bar graph data shows the mean ± SD of three independent experiments. An asterisk indicates p <0.05 when compared to vehicle control. FIG. 1B shows that SNIPER (ER) -087 or SNIPER (ER) -088 reduces the ERα protein within 1 hour and its activity lasts for 48 hours or longer. FIG. 1C shows that knockdown activity is attenuated in SNIPER (ER) -089 with a linker shorter than SNIPER (ER) -087. FIG. 1D shows that SNIPER (ER) -087 also degrades ERα in human breast cancer T47D and ZR75-1 cells. 2A and 2B show that the ERα protein KD activity of SNIPER (ER) -087 is canceled by the proteasome inhibitor MG132. ERα protein was detected by Western blot in FIG. 2A and by immune cell staining in FIG. 2B (scale bar in FIG. 2B shows 20 μm). FIG. 2C shows the ubiquitination of ERα by SNIPER (ER) -087. FIG. 2D shows the effects of various inhibitors on the KD activity of SNIPER (ER) -087. It is shown that bortezomib (proteasome inhibitor) and MLN7243 (UAE inhibitor) suppressed KD activity, but MLN4924 (Nedd8 inhibitor) did not. This result indicates that KD activity of SNIPER (ER) -087 requires ubiquitination and proteasome, but does not involve ubiquitin ligase containing Cullin, which requires Nedd8 modification. FIG. 3 shows that SNIPER (ER) -087 knocks down the target protein, ERα, but does not knock down other proteins and is selective for the target protein. FIGS. 4A and 4B show that SNIPER (ER) -087 binds XIAP and cIAP1 to the ERα protein, and a comparison of the two shows that XIAP preferentially binds to ERα over cIAP1. FIG. 4C shows that when the intracellular XIAP expression level is reduced, SNIPER (ER) -087 increases cIAP1 that binds to ERα. Asterisks on the XIAP panel indicate IgG heavy chain bands. FIG. 5A shows that lowering the intracellular XIAP expression level suppresses SNIPER (ER) -087-induced ERα degradation, but lowering the cIAP1 expression level hardly suppresses ERα degradation. FIG. 5B shows that when wild-type (WT) XIAP is returned to cells in which the expression level of XIAP has been reduced in advance, the knockdown activity of SNIPER (ER) -087 is restored, but RING mutant XIAP (H467A and ΔRING) is returned. However, the knockdown activity does not recover. FIG. 5C shows that overexpression of the RING mutant XIAP (ΔRING) suppresses ERα degradation by SNIPER (ER) -087. 5B and 5C show that the function of the XIAP RING domain is essential for the knockdown activity of SNIPER (ER) -087. FIG. 5D shows that the decrease in the expression level of XIAP does not suppress the degradation of ERα by fulvestrant and β-estradiol, and thus the mechanism of degradation of the ERα protein by these is different from that of SNIPER (ER) -087. FIG. 6A shows the in vivo KD activity of SNIPER (ER) -087 in mouse ovaries (n = 3, 2, 2: 6 hours, n = 4, 3, 3: 24 hours). 6B and 6C show the in vivo KD activity of SNIPER (ER) -087 in the ovary (FIG. 6B) and tumor (FIG. 6C) in a cancer-bearing mouse model in which human breast cancer cell MCF-7 was transplanted into the mammary gland of a nude mouse. (FIG. 6B: n = 5, FIG. 6C: n = 12, ^* p <0.0001 in bilateral student's t-test). FIG. 7A shows the suppression of estrogen-dependent gene expression by SNIPER (ER) -087. The data represent the mean ± SD (n = 3). FIG. 7B shows the suppression of proliferation of ERα-positive human breast cancer cells by treatment with SNIPER (ER) -087. The data represent the mean ± SD (n = 3). 7C and 7D show the results of pharmacokinetic tests when SNIPER (ER) -087 was intraperitoneally administered to mice. Eight hours after administration, the blood concentration was sufficient, but 24 hours later, SNIPER (ER) -087 was almost eliminated from the blood. FIG. 7E shows a heterologous breast cancer orthotopic transplantation model in which human breast cancer cells MCF-7 were transplanted into the breast of a nude mouse, and SNIPER (ER) -087 suppresses the growth of MCF-7 tumors (mouse: both groups). n = 9, tumor: n = 18 in both groups, ^* p <0.001 in bilateral Student t test. FIG. 7F shows that 14 days of SNIPER (ER) -087 administration did not affect the body weight of the mice and showed no significant toxicity. 8A and 8B show the activity of Sniper (ABL) -038, SNIPER (BRD4) -001 and SNIPER (PDE4) -09 to knock down their respective target proteins. The bar graph data show the mean ± SD of the three independent experiments. Asterisk indicates p <0.05 when compared to vehicle control. FIG. 8C shows the effects of the proteasome inhibitor MG132 and the ubiquitin activating enzyme (UAE) inhibitor MLN7243 on the KD activity of Sniper (ABL) -038, SNIPER (BRD4) -001 and SNIPER (PDE4) -09.

(Detailed description of the invention)
Hereinafter, the compounds of the present invention, their production methods and uses will be described.

Hereinafter, the definition of each substituent used in the present specification will be described in detail. Unless otherwise specified, each substituent has the following definition.
In the present specification, examples of the "halogen atom" include fluorine, chlorine, bromine and iodine.
In the present specification, the "C _1-6 alkyl group" includes, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, 1-ethylpropyl, hexyl. , Isohexyl, 1,1-dimethylbutyl, 2,2-dimethylbutyl, 3,3-dimethylbutyl, 2-ethylbutyl.
In the present specification, the "optionally halogenated C _1-6 alkyl group", for example, 1 to 7, preferably which may have 1 to 5 halogen atoms C _1-6 Alkyl groups can be mentioned. Specific examples include methyl, chloromethyl, difluoromethyl, trichloromethyl, trifluoromethyl, ethyl, 2-bromoethyl, 2,2,2-trifluoroethyl, tetrafluoroethyl, pentafluoroethyl, propyl, 2,2-. Difluoropropyl, 3,3,3-trifluoropropyl, isopropyl, butyl, 4,4,4-trifluorobutyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, 5,5,5-tri Fluoropentyl, hexyl, 6,6,6-trifluorohexyl can be mentioned.
In the present specification, the "C _2-6 alkenyl group" includes, for example, ethenyl, 1-propenyl, 2-propenyl, 2-methyl-1-propenyl, 1-butenyl, 2-butenyl, 3-butenyl, 3-. Examples thereof include methyl-2-butenyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 4-methyl-3-pentenyl, 1-hexenyl, 3-hexenyl and 5-hexenyl.
In the present specification, the "C _2-6 alkynyl group" includes, for example, ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, 3-butynyl, 1-pentynyl, 2-pentynyl, 3-. Examples thereof include pentynyl, 4-pentynyl, 1-hexynyl, 2-hexynyl, 3-hexynyl, 4-hexynyl, 5-hexynyl and 4-methyl-2-pentynyl.
In the present specification, the "C _3-10 cycloalkyl group" includes, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, bicyclo [2.2.1] heptyl, bicyclo [2.2. 2] Octyl, bicyclo [3.2.1] Octyl, adamantyl.
In the present specification, the "optionally halogenated C _3-10 also be cycloalkyl group", for example, 1 to 7, preferably which may have 1 to 5 halogen atoms C _{3- Examples include 10} cycloalkyl groups. Specific examples include cyclopropyl, 2,2-difluorocyclopropyl, 2,3-difluorocyclopropyl, cyclobutyl, difluorocyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl.
In the present specification _{, examples of the "C 3-10} cycloalkenyl group" include cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, and cyclooctenyl.
In the present specification _{, examples of the "C 6-14} aryl group" include phenyl, 1-naphthyl, 2-naphthyl, 1-anthryl, 2-anthryl, and 9-antryl.
In the present specification, _{examples of the "C 7-16} aralkyl group" include benzyl, phenethyl, naphthylmethyl and phenylpropyl.

In the present specification _{, examples of the "C 1-6} alkoxy group" include methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, tert-butoxy, pentyloxy, and hexyloxy.
In the present specification, the "optionally halogenated C _1-6 alkoxy group", for example, 1 to 7, preferably which may have 1 to 5 halogen atoms C _1-6 Alkoxy groups can be mentioned. Specific examples include methoxy, difluoromethoxy, trifluoromethoxy, ethoxy, 2,2,2-trifluoroethoxy, propoxy, isopropoxy, butoxy, 4,4,4-trifluorobutoxy, isobutoxy, sec-butoxy, and pentyl. Examples include oxy and hexyloxy.
In the present specification _{, examples of the "C 3-10} cycloalkyloxy group" include cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy, cycloheptyloxy, and cyclooctyloxy.
In the present specification _{, examples of the "C 1-6} alkylthio group" include methylthio, ethylthio, propylthio, isopropylthio, butylthio, sec-butylthio, tert-butylthio, pentylthio and hexylthio.
In the present specification, the "optionally halogenated C _1-6 alkylthio group optionally", for example, 1 to 7, preferably which may have 1 to 5 halogen atoms C _1-6 Alkylthio groups can be mentioned. Specific examples include methylthio, difluoromethylthio, trifluoromethylthio, ethylthio, propylthio, isopropylthio, butylthio, 4,4,4-trifluorobutylthio, pentylthio and hexylthio.
In the present specification, the "C _1-6 alkyl-carbonyl group" includes, for example, acetyl, propanoyl, butanoyl, 2-methylpropanoyl, pentanoyl, 3-methylbutanoyl, 2-methylbutanoyl, 2,2-. Examples thereof include dimethylpropanoyl, hexanoyl and heptanoyle.
In the present specification, as the "C _{1-6 alkyl-carbonyl group which may be halogenated", for example, C 1} which may have 1 to 7 halogen atoms, preferably 1 to 5 halogen atoms. _-6 Alkyl-carbonyl groups can be mentioned. Specific examples include acetyl, chloroacetyl, trifluoroacetyl, trichloroacetyl, propanoyl, butanoyl, pentanoyl and hexanoyl.
In the present specification, the "C _1-6 alkoxy-carbonyl group" includes, for example, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl, sec-butoxycarbonyl, tert-butoxycarbonyl, Examples thereof include pentyloxycarbonyl and hexyloxycarbonyl.
In the present specification _{, examples of the "C 6-14} aryl-carbonyl group" include benzoyl, 1-naphthoyl, and 2-naphthoyl.
In the present specification, _{examples of the "C 7-16} aralkyl-carbonyl group" include phenylacetyl and phenylpropionyl.
In the present specification, examples of the "5- to 14-membered aromatic heterocyclic carbonyl group" include nicotinoyle, isonicotinoyl, tenoyl, and floyl.
In the present specification, examples of the "3- to 14-membered non-aromatic heterocyclic carbonyl group" include morpholinylcarbonyl, piperidinylcarbonyl, and pyrrolidinylcarbonyl.

In the present specification, examples of the "mono- or di-C _1-6 alkyl-carbamoyl group" include methylcarbamoyl, ethylcarbamoyl, dimethylcarbamoyl, diethylcarbamoyl, and N-ethyl-N-methylcarbamoyl.
In the present specification, examples of the "mono- or di-C _7-16 aralkyl-carbamoyl group" include benzylcarbamoyl and phenethylcarbamoyl.
In the present specification _{, examples of the "C 1-6} alkyl sulfonyl group" include methyl sulfonyl, ethyl sulfonyl, propyl sulfonyl, isopropyl sulfonyl, butyl sulfonyl, sec-butyl sulfonyl, and tert-butyl sulfonyl.
In the present specification, the "optionally halogenated C _1-6 alkyl sulfonyl group", for example, 1 to 7, preferably which may have 1 to 5 halogen atoms C _{1- 6} Alkylsulfonyl groups can be mentioned. Specific examples include methyl sulfonyl, difluoromethyl sulfonyl, trifluoromethyl sulfonyl, ethyl sulfonyl, propyl sulfonyl, isopropyl sulfonyl, butyl sulfonyl, 4,4,4-trifluorobutyl sulfonyl, pentyl sulfonyl and hexyl sulfonyl.
In the present specification _{, examples of the "C 6-14} aryl sulfonyl group" include phenylsulfonyl, 1-naphthylsulfonyl, and 2-naphthylsulfonyl.

In the present specification, the "substituent" includes, for example, a halogen atom, a cyano group, a nitro group, a optionally substituted hydrocarbon group, an optionally substituted heterocyclic group, an acyl group, or a substituted group. May amino group, optionally substituted carbamoyl group, optionally substituted thiocarbamoyl group, optionally substituted sulfamoyl group, optionally substituted hydroxy group, optionally substituted sulfanyl ( SH) groups and optionally substituted silyl groups can be mentioned.
In the present specification, examples of the "hydrocarbon group" (including the "hydrocarbon group" in the "optionally substituted hydrocarbon group") include a C _1-6 alkyl group and a C _2-6 alkenyl group. Examples thereof include a C _2-6 alkynyl group, a C _3-10 cycloalkyl group, a C _3-10 cycloalkenyl group, a C _6-14 aryl group and a C _7-16 aralkyl group.

In the present specification, examples of the "optionally substituted hydrocarbon group" include a hydrocarbon group which may have a substituent selected from the following substituent group A.
[Substituent group A]
(1) Halogen atom,
(2) Nitro group,
(3) Cyano group,
(4) Oxo group,
(5) Hydroxy group,
(6) C _1-6 alkoxy group, which may be halogenated,
(7) C _6-14 aryloxy groups (eg, phenoxy, naphthoxy),
(8) C _7-16 aralkyloxy group (eg, benzyloxy),
(9) 5- to 14-membered aromatic heterocyclic oxy groups (eg, pyridyloxy),
(10) 3- to 14-membered non-aromatic heterocyclic oxy groups (eg, morpholinyloxy, piperidinyloxy),
(11) C _1-6 alkyl-carbonyloxy group (eg acetoxy, propanoyloxy),
(12) C _6-14 aryl-carbonyloxy groups (eg, benzoyloxy, 1-naphthoyloxy, 2-naphthoyloxy),
(13) C _1-6 alkoxy-carbonyloxy group (eg, methoxycarbonyloxy, ethoxycarbonyloxy, propoxycarbonyloxy, butoxycarbonyloxy),
(14) Mono- or di-C _1-6 alkyl-carbamoyloxy groups (eg, methylcarbamoyloxy, ethylcarbamoyloxy, dimethylcarbamoyloxy, diethylcarbamoyloxy),
(15) C _6-14 aryl-carbamoyloxy group (eg, phenylcarbamoyloxy, naphthylcarbamoyloxy),
(16) 5- to 14-membered aromatic heterocyclic carbonyloxy group (eg, nicotinoyyloxy),
(17) 3- to 14-membered non-aromatic heterocyclic carbonyloxy group (eg, morpholinylcarbonyloxy, piperidinylcarbonyloxy),
(18) C _1-6 alkylsulfonyloxy groups that may be halogenated (eg, methylsulfonyloxy, trifluoromethylsulfonyloxy),
(19) C _6-14 arylsulfonyloxy groups optionally substituted with _{C 1-6} alkyl groups (eg, phenylsulfonyloxy, toluenesulfonyloxy),
(20) C _1-6 alkylthio group, which may be halogenated,
(21) 5- to 14-membered aromatic heterocyclic group,
(22) 3- to 14-membered non-aromatic heterocyclic group,
(23) Holmil group,
(24) Carboxy group,
(25) C _1-6 alkyl-carbonyl group, which may be halogenated,
(26) C _6-14 aryl-carbonyl group,
(27) 5- to 14-membered aromatic heterocyclic carbonyl group,
(28) 3- to 14-membered non-aromatic heterocyclic carbonyl group,
(29) C _1-6 alkoxy-carbonyl group,
(30) C _6-14 aryloxy-carbonyl group (eg, phenyloxycarbonyl, 1-naphthyloxycarbonyl, 2-naphthyloxycarbonyl),
(31) C _7-16 aralkyloxy-carbonyl group (eg, benzyloxycarbonyl, phenethyloxycarbonyl),
(32) Carbamoyl group,
(33) Thiocarbamoyl group,
(34) Mono- or di-C _1-6 alkyl-carbamoyl group,
(35) C _6-14 aryl-carbamoyl group (eg, phenylcarbamoyl),
(36) 5- to 14-membered aromatic heterocyclic carbamoyl groups (eg, pyridylcarbamoyl, thienylcarbamoyl),
(37) 3- to 14-membered non-aromatic heterocyclic carbamoyl groups (eg, morpholinyl carbamoyl, piperidinyl carbamoyl),
(38) C _1-6 alkylsulfonyl group, which may be halogenated,
(39) C _6-14 arylsulfonyl group,
(40) 5- to 14-membered aromatic heterocyclic sulfonyl groups (eg, pyridylsulfonyl, thienylsulfonyl),
(41) C _1-6 alkylsulfinyl group, which may be halogenated,
(42) C _6-14 arylsulfinyl groups (eg, phenylsulfinyl, 1-naphthylsulfinyl, 2-naphthylsulfinyl),
(43) 5- to 14-membered aromatic heterocyclic sulfinyl groups (eg, pyridylsulfinyl, thienylsulfinyl),
(44) Amino group,
(45) Mono- or di-C _1-6 alkylamino groups (eg, methylamino, ethylamino, propylamino, isopropylamino, butylamino, dimethylamino, diethylamino, dipropylamino, dibutylamino, N-ethyl-N -Methylamino),
(46) Mono- or di-C _6-14 arylamino groups (eg, phenylamino),
(47) 5- to 14-membered aromatic heterocyclic amino groups (eg, pyridylamino),
(48) C _7-16 aralkylamino group (eg, benzylamino),
(49) Formylamino group,
(50) C _1-6 alkyl-carbonylamino group (eg, acetylamino, propanoylamino, butanoylamino),
(51) (C _1-6 alkyl) (C _1-6 alkyl-carbonyl) amino group (eg, N-acetyl-N-methylamino),
(52) C _6-14 aryl-carbonylamino group (eg, phenylcarbonylamino, naphthylcarbonylamino),
(53) C _1-6 alkoxy-carbonylamino group (eg, methoxycarbonylamino, ethoxycarbonylamino, propoxycarbonylamino, butoxycarbonylamino, tert-butoxycarbonylamino),
(54) C _7-16 aralkyloxy-carbonylamino group (eg, benzyloxycarbonylamino),
(55) C _1-6 alkylsulfonylamino group (eg, methylsulfonylamino, ethylsulfonylamino),
(56) C _6-14 arylsulfonylamino groups optionally substituted with _{C 1-6} alkyl groups (eg, phenylsulfonylamino, toluenesulfonylamino),
(57) C _1-6 alkyl group, which may be halogenated,
(58) C _2-6 alkenyl group,
(59) C _2-6 alkynyl group,
(60) C _3-10 cycloalkyl group,
(61) C _3-10 cycloalkenyl group and (62) C _6-14 aryl group.

The number of the above-mentioned substituents in the "optionally substituted hydrocarbon group" is, for example, 1 to 5, preferably 1 to 3. When the number of substituents is two or more, each substituent may be the same or different.
In the present specification, the "heterocyclic group" (including the "heterocyclic group" in the "optionally substituted heterocyclic group") includes, for example, a nitrogen atom, a sulfur atom and a sulfur atom in addition to a carbon atom as ring constituent atoms. Examples thereof include (i) aromatic heterocyclic groups, (ii) non-aromatic heterocyclic groups and (iii) 7 to 10-membered heterobridged ring groups each containing 1 to 4 heteroatoms selected from oxygen atoms. ..

In the present specification, the "aromatic heterocyclic group" (including "5- to 14-membered aromatic heterocyclic group") is selected from, for example, a nitrogen atom, a sulfur atom and an oxygen atom in addition to a carbon atom as a ring-constituting atom. Examples thereof include 5- to 14-membered (preferably 5- to 10-membered) aromatic heterocyclic groups containing 1 to 4 heteroatoms.
Preferable examples of the "aromatic heterocyclic group" include thienyl, frill, pyrrolyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxazolyl, isooxazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridadinyl, 1,2,4-oxadiazolyl, 1. , 3,4-Oxaziazolyl, 1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl, triazolyl, tetrazolyl, triazinyl and other 5- to 6-membered monocyclic aromatic heterocyclic groups;
Benzothiophenyl, benzofuranyl, benzoimidazolyl, benzoxazolyl, benzoisoxazolyl, benzothiazolyl, benzoisothiazolyl, benzotriazolyl, imidazolypyridinyl, thienopyridinyl, flopyridinyl, pyrrolopyrizinyl, pyrazolopyridinyl, oxazolo Pyridinyl, thiazolopyridinyl, imidazolopyridinyl, imidazolipyrimidinyl, thienopyrimidinyl, flopyrimidinyl, pyrrolopyrimidinyl, pyrazolopyrimidinyl, oxazolopyrimidinyl, thiazolopyrimidinyl, pyrazorotriadinyl, naphtho [2,3 -B] Thienyl, phenoxatinyl, indolyl, isoindyl, 1H-indazolyl, prynyl, isoquinolyl, quinolyl, phthalazinyl, naphthyldinyl, quinoxalinyl, quinazolinyl, cinnolinyl, carbazolyl, β-carbolinyl, phenanthridinyl, acridinyl, phenazinyl, pheno Examples thereof include 8- to 14-membered condensed polycyclic (preferably 2- or 3-cyclic) aromatic heterocyclic groups such as thiazinyl and phenoxadinyl.

In the present specification, the "non-aromatic heterocyclic group" (including "3- to 14-membered non-aromatic heterocyclic group") is, for example, a nitrogen atom, a sulfur atom and an oxygen atom in addition to a carbon atom as a ring-constituting atom. Examples thereof include a 3- to 14-membered (preferably 4- to 10-membered) non-aromatic heterocyclic group containing 1 to 4 heteroatoms selected from.
Preferable examples of the "non-aromatic heterocyclic group" are aziridinyl, oxylanyl, thiylanyl, azetidinyl, oxetanyl, thietanyl, tetrahydropyran, tetrahydrofuranyl, pyrrolinyl, pyrrolidinyl, imidazolinyl, imidazolidinyl, oxazolinyl, oxazolidinyl, pyrazolinyl. Thiazolinyl, thiazolidinyl, tetrahydroisothiazolyl, tetrahydrooxazolyl, tetrahydroisooxazolyl, piperidinyl, piperazinyl, tetrahydropyranyl, dihydropyridinyl, dihydrothiopyranyl, tetrahydropyrimidinyl, tetrahydropyridazinyl, dihydropyrani 3- to 8-membered monocyclic non-aromatic heterocyclic groups such as le, tetrahydropyranyl, tetrahydrothiopyranyl, morpholinyl, thiomorpholinyl, azepanyl, diazepanyl, azepinyl, oxepanyl, azocanyl, diazocanyl;
Dihydrobenzofuranyl, dihydrobenzoimidazolyl, dihydrobenzoxazolyl, dihydrobenzothiazolyl, dihydrobenzoisothiazolyl, dihydronaphtho [2,3-b] thienyl, tetrahydroisoquinolyl, tetrahydroquinolyl, 4H-quinolidinyl, Indolinyl, isoindolinyl, tetrahydrothieno [2,3-c] pyridinyl, tetrahydrobenzoazepinyl, tetrahydroquinoxalinyl, tetrahydrophenanthridinyl, hexahydrophenothiazine, hexahydrophenoxadinyl, tetrahydrophthalazinyl, tetrahydro 9-14 such as naphthyldinyl, tetrahydroquinazolinyl, tetrahydrosinnolinyl, tetrahydrocarbazolyl, tetrahydro-β-carbolinyl, tetrahydroaclicinyl, tetrahydrophenazinyl, tetrahydrothioxanthenyl, octahydroisoquinolyl, etc. Included are member-condensed polycyclic (preferably 2- or tricyclic) non-aromatic heterocyclic groups.

In the present specification, preferred examples of the "7 to 10-membered complex crosslinked ring group" include quinucridinyl and 7-azabicyclo [2.2.1] heptanyl.
In the present specification, the "nitrogen-containing heterocyclic group" includes a "heterocyclic group" containing at least one nitrogen atom as a ring-constituting atom.
In the present specification, examples of the “optionally substituted heterocyclic group” include a heterocyclic group which may have a substituent selected from the above-mentioned Substituent Group A.
The number of substituents in the "optionally substituted heterocyclic group" is, for example, 1 to 3. When the number of substituents is two or more, each substituent may be the same or different.

In the present specification, the "acyl group" is selected from, for example, "halogen atom, C _1-6 alkoxy group which may be halogenated, hydroxy group, nitro group, cyano group, amino group and carbamoyl group1". _{C 1-6} alkyl group, C _2-6 alkenyl group, C _3-10 cycloalkyl group, C _3-10 cycloalkenyl group, C _6-14 aryl, each of which may have 3 or 3 substituents, respectively. It may have one or two substituents selected from a group, a C _7-16 aralkyl group, a 5- to 14-membered aromatic heterocyclic group and a 3- to 14-membered non-aromatic heterocyclic group, respectively, formyl. Examples thereof include a group, a carboxy group, a carbamoyl group, a thiocarbamoyl group, a sulfino group, a sulfo group, a sulfamoyl group and a phosphono group.
In addition, examples of the "acyl group" include a hydrocarbon-sulfonyl group, a heterocyclic-sulfonyl group, a hydrocarbon-sulfinyl group, and a heterocyclic-sulfinyl group.
Here, the hydrocarbon-sulfonyl group is a sulfonyl group to which a hydrocarbon group is bonded, the heterocyclic-sulfonyl group is a sulfonyl group to which a heterocyclic group is bonded, and the hydrocarbon-sulfinyl group is a hydrocarbon group. Means a sulfinyl group bonded with, and a heterocyclic-sulfinyl group means a sulfinyl group to which a heterocyclic group is bonded.
Preferable examples of the "acyl group" include formyl groups, carboxy groups, C _1-6 alkyl-carbonyl groups, C _2-6 alkenyl-carbonyl groups (eg, crotonoyl), C _3-10 cycloalkyl-carbonyl groups (eg, crotonoyl). Examples, cyclobutanecarbonyl, cyclopentanecarbonyl, cyclohexanecarbonyl, cycloheptanecarbonyl), C _3-10 cycloalkenyl-carbonyl group (eg, 2-cyclohexenecarbonyl), C _6-14aryl- carbonyl group, C _7-16 aralkyl- Carbonyl group, 5- to 14-membered aromatic heterocyclic carbonyl group, 3- to 14-membered non-aromatic heterocyclic carbonyl group, C _1-6 alkoxy-carbonyl group, C _6-14 aryloxy-carbonyl group (eg, phenyloxycarbonyl) , Naftyloxycarbonyl), C _7-16 aralkyloxy-carbonyl group (eg, benzyloxycarbonyl, phenethyloxycarbonyl), carbamoyl group, mono- or di-C _1-6 alkyl-carbamoyl group, mono- or di-C _2-6 alkenyl-carbonyl group (eg, diallyl carbamoyl), mono- or di-C _3-10 cycloalkyl-carbamoyl group (eg, cyclopropyl carbamoyl), mono- or di-C _6-14 aryl-carbamoyl group (eg, di-C 6-14 aryl-carbamoyl group) Eg, phenylcarbamoyl), mono- or di-C _7-16 aralkyl-carbamoyl group, 5- to 14-membered aromatic heterocyclic carbamoyl group (eg, pyridylcarbamoyl), thiocarbamoyl group, mono- or di-C _1-6. Alkyl-thiocarbamoyl group (eg, methylthiocarbamoyl, N-ethyl-N-methylthiocarbamoyl), mono- or di-C _2-6 alkenyl-thiocarbamoyl group (eg, diallylthiocarbamoyl), mono- or di-C _{3 -10} Cycloalkyl-thiocarbamoyl group (eg, cyclopropylthiocarbamoyl, cyclohexylthiocarbamoyl), mono- or di-C _6-14aryl- thiocarbamoyl group (eg, phenylthiocarbamoyl), mono- or di-C _{7 -16} Aralkyl-thiocarbamoyl group (eg, benzylthiocarbamoyl, phenethylthiocarbamoyl), 5- to 14-membered aromatic heterocyclic thiocarbamoyl group (eg, pyridylthiocarbamoyl), sulfino group, C _1-6 alkylsulfinyl group (eg) , Methylsulfinyl, ethylsulfinyl), sulfo group, C _1-6 a Examples include rukirsulfonyl groups, C _6-14 arylsulfonyl groups, phosphono groups, mono- or di-C _1-6 alkylphosphono groups (eg, dimethylphosphono, diethylphosphono, diisopropylphosphono, dibutylphosphono). ..

In the present specification, the "optionally substituted amino group" includes, for example, a C _1-6 alkyl group, which may have 1 to 3 substituents selected from the substituent group A, respectively. C _2-6 alkenyl group, C _3-10 cycloalkyl group, C _6-14 aryl group, C _7-16 aralkyl group, C _1-6 alkyl-carbonyl group, C _6-14 aryl-carbonyl group, C _{7- 16-} aralkyl-carbonyl group, 5- to 14-membered aromatic heterocyclic carbonyl group, 3- to 14-membered non-aromatic heterocyclic carbonyl group, C _1-6 alkoxy-carbonyl group, 5- to 14-membered aromatic heterocyclic group, carbamoyl group 1 or 2 selected from mono- or di-C _1-6 alkyl-carbamoyl groups, mono- or di-C _7-16 aralkyl-carbamoyl groups, C _1-6 alkylsulfonyl groups and C _{6-14 arylsulfonyl groups.} Examples thereof include amino groups which may have "substituents".
Suitable examples of optionally substituted amino groups include amino groups, mono- or di- (possibly halogenated C _1-6 alkyl) amino groups (eg, methylamino, trifluoromethylamino, etc.). Dimethylamino, ethylamino, diethylamino, propylamino, dibutylamino), mono- or di-C _2-6 alkenylamino groups (eg, diallylamino), mono- or di-C _3-10 cycloalkylamino groups (eg, eg) Cyclopropylamino, cyclohexylamino), mono- or di-C _6-14 arylamino groups (eg, phenylamino), mono- or di-C _7-16 aralkylamino groups (eg, benzylamino, dibenzylamino), Mono- or di- (C _1-6 alkyl which may be halogenated) -carbonylamino group (eg, acetylamino, propionylamino), mono- or di-C _6-14 aryl-carbonylamino group (eg, eg) Benzoylamino), mono- or di-C _7-16 aralkyl-carbonylamino groups (eg, benzylcarbonylamino), mono- or di-5 to 14-membered aromatic heterocyclic carbonylamino groups (eg, nicotinoylinamino, iso). Nicotinoylamino), mono- or di-3 to 14-membered non-aromatic heterocyclic carbonylamino groups (eg, piperidinylcarbonylamino), mono- or di-C _1-6 alkoxy-carbonylamino groups (eg, tert). − Butoxycarbonylamino), 5- to 14-membered aromatic heterocyclic amino group (eg, pyridylamino), carbamoylamino group, (mono- or di-C _1-6 alkyl-carbamoyl) amino group (eg, methylcarbamoylamino), (Mono- or di-C _7-16 aralkyl-carbamoyl) Amino group (eg, benzylcarbamoylamino), C _1-6 alkylsulfonylamino group (eg, methylsulfonylamino, ethylsulfonylamino), C _{6-14arylsulfonyl} Amino groups (eg, phenylsulfonylamino), (C _1-6 alkyl) (C _1-6 alkyl-carbonyl) Amino groups (eg, N-acetyl-N-methylamino), (C _1-6 alkyl) (C _6-14 aryl-carbonyl) amino groups (eg, N-benzoyl-N-methylamino) can be mentioned.

In the present specification, the "optionally substituted carbamoyl group" is, for example, a C _1-6 alkyl group which may have 1 to 3 substituents selected from the substituent group A, respectively. , C _2-6 alkenyl group, C _3-10 cycloalkyl group, C _6-14 aryl group, C _7-16 aralkyl group, C _1-6 alkyl-carbonyl group, C _6-14 aryl-carbonyl group, C _{7 -16} Aralkyl-carbonyl group, 5- to 14-membered aromatic heterocyclic carbonyl group, 3- to 14-membered non-aromatic heterocyclic carbonyl group, C _1-6 alkoxy-carbonyl group, 5- to 14-membered aromatic heterocyclic group, carbamoyl A carbamoyl group may have one or two substituents selected from a group, a mono- or di-C _1-6 alkyl-carbamoyl group and a mono- or di-C _{7-16 aralkyl-carbamoyl group.} Can be mentioned.
Preferable examples of optionally substituted carbamoyl groups are carbamoyl groups, mono- or di-C _1-6 alkyl-carbamoyl groups, mono- or di-C _2-6 alkenyl-carbamoyl groups (eg, diallyl carbamoyl). ), Mono- or di-C _3-10 cycloalkyl-carbamoyl group (eg, cyclopropylcarbamoyl, cyclohexylcarbamoyl), mono- or di-C _6-14aryl- carbamoyl group (eg, phenylcarbamoyl), mono- or Di-C _7-16 aralkyl-carbamoyl group, mono- or di-C _1-6 alkyl-carbonyl-carbamoyl group (eg, acetylcarbamoyl, propionylcarbamoyl), mono- or di-C _6-14aryl- carbonyl-carbamoyl Groups (eg, benzoylcarbamoyl), 5- to 14-membered aromatic heterocyclic carbamoyl groups (eg, pyridylcarbamoyl) can be mentioned.

In the present specification, the "optionally substituted thiocarbamoyl group" includes, for example, "C _1-6 alkyl which may each have 1 to 3 substituents selected from the substituent group A". Group, C _2-6 alkenyl group, C _3-10 cycloalkyl group, C _6-14 aryl group, C _7-16 aralkyl group, C _1-6 alkyl-carbonyl group, C _6-14 aryl-carbonyl group, C _7-16 Aralkyl-carbonyl group, 5- to 14-membered aromatic heterocyclic carbonyl group, 3- to 14-membered non-aromatic heterocyclic carbonyl group, C _1-6 alkoxy-carbonyl group, 5- to 14-membered aromatic heterocyclic group, Thiocarbamoyl may have one or two substituents selected from a carbamoyl group, a mono- or di-C _1-6 alkyl-carbamoyl group and a mono- or di-C _{7-16 aralkyl-carbamoyl group.} The group is mentioned.
Preferable examples of optionally substituted thiocarbamoyl groups are thiocarbamoyl groups, mono- or di-C _1-6 alkyl-thiocarbamoyl groups (eg, methylthiocarbamoyl, ethylthiocarbamoyl, dimethylthiocarbamoyl, diethylthio). Carbamoyl, N-ethyl-N-methylthiocarbamoyl), mono- or di-C _2-6 alkenyl-thiocarbamoyl group (eg, diallylthiocarbamoyl), mono- or di-C _3-10 cycloalkyl-thiocarbamoyl group (eg, diallylthiocarbamoyl) Examples, cyclopropylthiocarbamoyl, cyclohexylthiocarbamoyl), mono- or di-C _6-14aryl- thiocarbamoyl groups (eg, phenylthiocarbamoyl), mono- or di-C _7-16 aralkyl-thiocarbamoyl groups (eg). , Benzylthiocarbamoyl, phenethylthiocarbamoyl), mono- or di-C _1-6 alkyl-carbonyl-thiocarbamoyl groups (eg, acetylthiocarbamoyl, propionylthiocarbamoyl), mono- or di-C _6-14 aryl-carbonyl -Thiocarbamoyl groups (eg, benzoylthiocarbamoyl), 5- to 14-membered aromatic heterocyclic thiocarbamoyl groups (eg, pyridylthiocarbamoyl).

In the present specification, the "optionally substituted sulfamoyl group" is, for example, a C _1-6 alkyl group which may have 1 to 3 substituents selected from the substituent group A, respectively. , C _2-6 alkenyl group, C _3-10 cycloalkyl group, C _6-14 aryl group, C _7-16 aralkyl group, C _1-6 alkyl-carbonyl group, C _6-14 aryl-carbonyl group, C _{7 -16} Aralkyl-carbonyl group, 5- to 14-membered aromatic heterocyclic carbonyl group, 3- to 14-membered non-aromatic heterocyclic carbonyl group, C _1-6 alkoxy-carbonyl group, 5- to 14-membered aromatic heterocyclic group, carbamoyl A sulfamoyl group may have one or two substituents selected from a group, a mono- or di-C _1-6 alkyl-carbamoyl group and a mono- or di-C _{7-16 aralkyl-carbamoyl group.} Can be mentioned.
Preferable examples of optionally substituted sulfamoyl groups are sulfamoyl groups, mono- or di-C _1-6 alkyl-sulfamoyl groups (eg, methyl sulfamoyl, ethyl sulfamoyl, dimethyl sulfamoyl, diethyl). Sulfamoyl, N-ethyl-N-methylsulfamoyl), mono- or di-C _2-6 alkenyl-sulfamoyl group (eg, diallyl sulfamoyl), mono- or di-C _3-10 cycloalkyl- Sulfamoyl group (eg, cyclopropylsulfamoyl, cyclohexylsulfamoyl), mono- or di-C _6-14 aryl-sulfamoyl group (eg, phenylsulfamoyl), mono- or di-C _7-16 aralkyl- Sulfamoyl group (eg, benzyl sulfamoyl, phenethyl sulfamoyl), mono- or di-C _1-6 alkyl-carbonyl-sulfamoyl group (eg, acetylsulfamoyl, propionyl sulfamoyl), mono- or di- Examples include C _6-14 aryl-carbonyl-sulfamoyl groups (eg, benzoyl sulfamoyl) and 5- to 14-membered aromatic heterocyclic sulfamoyl groups (eg, pyridyl sulfamoyl).

In the present specification, the “optionally substituted hydroxy group” is, for example, a C _1-6 alkyl group which may have 1 to 3 substituents selected from the substituent group A, respectively. , C _2-6 alkenyl group, C _3-10 cycloalkyl group, C _6-14 aryl group, C _7-16 aralkyl group, C _1-6 alkyl-carbonyl group, C _6-14 aryl-carbonyl group, C _{7 -16} Aralkyl-carbonyl group, 5- to 14-membered aromatic heterocyclic carbonyl group, 3- to 14-membered non-aromatic heterocyclic carbonyl group, C _1-6 alkoxy-carbonyl group, 5- to 14-membered aromatic heterocyclic group, carbamoyl Substituents selected from groups, mono- or di-C _1-6 alkyl-carbamoyl groups, mono- or di-C _7-16 aralkyl-carbamoyl groups, C _1-6 alkyl sulfonyl groups and C _{6-14 aryl sulfonyl groups} , A hydroxy group which may have.
Preferable examples of optionally substituted hydroxy groups are hydroxy groups, C _1-6 alkoxy groups, C _2-6 alkenyloxy groups (eg, allyloxy, 2-butenyloxy, 2-pentenyloxy, 3-hexenyloxy). ), C _3-10 cycloalkyloxy group (eg, cyclohexyloxy), C _6-14 aryloxy group (eg, phenoxy, naphthyloxy), C _7-16 aralkyloxy group (eg, benzyloxy, phenethyloxy), C _1-6 Alkoxy-carbonyloxy groups (eg, acetyloxy, propionyloxy, butyryloxy, isobutyryloxy, pivaloyloxy), C _6-14 aryl-carbonyloxy groups (eg, benzoyloxy), C _{7-16 aralkyl-} Carbonyloxy groups (eg, benzylcarbonyloxy), 5- to 14-membered aromatic heterocyclic carbonyloxy groups (eg, nicotinoyyloxy), 3- to 14-membered non-aromatic heterocyclic carbonyloxy groups (eg, piperidinylcarbonyloxy) ), C _1-6 alkoxy-carbonyloxy group (eg, tert-butoxycarbonyloxy), 5 to 14-membered aromatic heterocyclic oxy group (eg, pyridyloxy), carbamoyloxy group, C _1-6 alkyl-carbamoyloxy Group (eg, methylcarbamoyloxy), C _7-16 aralkyl-carbamoyloxy group (eg, benzylcarbamoyloxy), C _1-6 alkylsulfonyloxy group (eg, methylsulfonyloxy, ethylsulfonyloxy), C _6-14 Arylsulfonyloxy groups (eg, phenylsulfonyloxy) can be mentioned.

In the present specification, the “optionally substituted sulfanyl group” is, for example, a C _1-6 alkyl group which may have 1 to 3 substituents selected from the substituent group A, respectively. , C _2-6 alkenyl group, C _3-10 cycloalkyl group, C _6-14 aryl group, C _7-16 aralkyl group, C _1-6 alkyl-carbonyl group, C _6-14 aryl-carbonyl group and 5 to Examples thereof include a sulfanyl group which may have a "substituted group selected from a 14-membered aromatic heterocyclic group" and a halogenated sulfanyl group.
Suitable examples of optionally substituted sulfanyl groups include sulfanyl (-SH) group, C _1-6 alkylthio group, C _2-6 alkenylthio group (eg, allylthio, 2-butenylthio, 2-pentenylthio, 3-hexenylthio), C _3-10 cycloalkylthio group (eg, cyclohexylthio), C _6-14 arylthio group (eg, phenylthio, naphthylthio), C _7-16 aralkylthio group (eg, benzylthio, phenethylthio), C _1-6 alkyl - carbonyl thio group (e.g., acetylthio, propionylthio, butyrylthio, isobutyrylthio, _{Pibaroiruchio), C 6-14} aryl - carbonyl thio group (e.g., benzoylthio), 5 to 14-membered aromatic heterocyclic thio group (Example, pyridylthio), halogenated thio group (eg, pentafluorothio) can be mentioned.

In the present specification, the “optionally substituted silyl group” is, for example, a C _1-6 alkyl group which may have 1 to 3 substituents selected from the substituent group A. , A silyl group which may have "1 to 3 substituents selected from _{C 2-6} alkenyl group, C _3-10 cycloalkyl group, C _6-14 aryl group and C _{7-16 aralkyl group"} Can be mentioned.
Preferable examples of optionally substituted silyl groups include tri-C _1-6 alkylsilyl groups (eg, trimethylsilyl, tert-butyl (dimethyl) silyl).

In the present specification, the “C _1-6 alkylene group” includes, for example, −CH ₂ −, − (CH ₂ ) ₂ −, − (CH ₂ ) ₃ −, − (CH ₂ ) ₄ −, − (CH). ₂ ) ₅ -,-(CH ₂ ) _6- , -CH (CH ₃ )-, -C (CH ₃ ) _2- , -CH (C ₂ H ₅ )-, -CH (C ₃ H ₇ )-, −CH (CH (CH ₃ ) ₂ ) −, − (CH (CH ₃ )) ₂ −, _{−CH 2} −CH (CH ₃ ) −, −CH (CH ₃ ) −CH ₂ −, −CH _{2 −CH 2 -C (CH 3) 2 -} , - C (CH 3) 2 -CH 2 -CH 2 -, - CH 2 -CH 2 -CH 2 -C (CH 3) 2 -, - C (CH 3) 2 −CH ₂ −CH ₂ −CH ₂ − can be mentioned.
In the present specification, the “C _2-6 alkenylene group” includes, for example, −CH = CH −, _{−CH 2} −CH = CH −, −CH = CH −CH ₂ −, −C (CH ₃ ) ₂ −. _{CH = CH -, - CH =} CH-C (CH 3) 2 -, - CH 2 -CH = CH-CH 2 -, - CH 2 -CH 2 -CH = CH -, - CH = CH-CH 2 - _{CH 2 -, - CH = CH} -CH = CH -, - CH = CH-CH 2 -CH 2 -CH 2 -, - CH 2 -CH 2 -CH 2 -CH = CH- and the like.
In the present specification, the _{"C 2-6} alkynylene group", for _{example, -C≡C -, - CH 2 -C≡C} -, - C≡C-CH 2 -, - C (CH 3) 2 - _{C≡C -, - C≡C-C (} CH 3) 2 -, - CH 2 -C≡C-CH 2 -, - CH 2 -CH 2 -C≡C -, - C≡C-CH 2 - _{CH 2 -, - C≡C-C≡C} -, - C≡C-CH 2 -CH 2 -CH 2 -, - CH 2 -CH 2 -CH 2 -C≡C- , and the like.

In the present specification, examples of the "hydrocarbon ring" include C _6-14 aromatic hydrocarbon ring, C _3-10 cycloalkane, and C _3-10 cycloalkene.
In the present specification _{, examples of the "C 6-14} aromatic hydrocarbon ring" include benzene and naphthalene.
In the present specification _{, examples of "C 3-10} cycloalkane" include cyclopropane, cyclobutane, cyclopentane, cyclohexane, cycloheptane, and cyclooctane.
In the present specification _{, examples of "C 3-10} cycloalkene" include cyclopropene, cyclobutene, cyclopentene, cyclohexene, cycloheptene, and cyclooctene.
In the present specification, the "heterocycle" includes, for example, an aromatic heterocycle containing 1 to 4 heteroatoms selected from nitrogen atom, sulfur atom and oxygen atom in addition to carbon atom as ring constituent atoms. Examples include non-aromatic heterocycles.

In the present specification, the "aromatic heterocycle" includes, for example, 5 to 14 members (for example, 1 to 4 heteroatoms selected from a nitrogen atom, a sulfur atom and an oxygen atom in addition to a carbon atom as a ring-constituting atom. Aromatic heterocycles (preferably 5 to 10 members) can be mentioned. Preferable examples of the "aromatic heterocycle" are thiophene, furan, pyrrole, imidazole, pyrazole, thiazole, isothiazole, oxadiazole, isooxazole, pyridine, pyrazine, pyrimidine, pyridazine, 1,2,4-oxadi. 5- to 6-membered monocyclic aromatic heterocycles such as azole, 1,3,4-oxadiazole, 1,2,4-thiadiazole, 1,3,4-thiadiazole, triazole, tetrazole, triazine;
Benzothiophene, benzofuran, benzoimidazole, benzoxazole, benzoisoxazole, benzothiazole, benzoisothiazole, benzotriazole, imidazolepyridine, thienopyridine, flopyridine, pyrolopyridine, pyrazolopyridine, oxazolopyridine, thiazolopyridine, imidazolepyrimidine, Imidazopyrimidines, thienopyrimidines, flopyrimidines, pyrolopyrimidines, pyrazolopyrimidines, oxazolopyrimidines, thiazolopyrimidines, pyrazolopyrimidines, pyrazolotriadins, naphtho [2,3-b] thiophenes, phenoxatiins, indols, 8- to 14-membered fused polycycles of isoindole, 1H-indazole, purine, isoquinoline, quinoline, phthalazine, naphthylidine, quinoxalin, quinazoline, synnoline, carbazole, β-carboline, phenanthridin, aclysine, phenazine, phenothiidine, phenoxazine, etc. Aromatic heterocycles of the formula (preferably two or three ring formulas) can be mentioned.

In the present specification, the "non-aromatic heterocycle" is, for example, 3 to 14 members containing 1 to 4 heteroatoms selected from a nitrogen atom, a sulfur atom and an oxygen atom in addition to a carbon atom as a ring-constituting atom. Examples thereof include non-aromatic heterocycles (preferably 4 to 10 members). Preferable examples of the "non-aromatic heterocycle" are aziridine, oxylan, thiirane, azetidine, oxetane, thietan, tetrahydropyran, tetrahydrofuran, pyrrolin, pyrrolidine, imidazoline, imidazolidine, oxazoline, oxazolidine, pyrazoline, pyrazolidine, thiazolin. , Thiazolidine, tetrahydroisothiazole, tetrahydrooxazole, tetrahydroisoxazole, piperidine, piperazin, tetrahydropyridine, dihydropyridine, dihydrothiopyran, tetrahydropyranidin, tetrahydropyrandazine, dihydropyran, tetrahydropyran, tetrahydrothiopyran, morpholine, thiomorpholin, azepanine, 3- to 8-membered monocyclic non-aromatic heterocycles such as diazepan, azepine, azocan, diazocan, oxepan;
Dihydrobenzofuran, dihydrobenzimidazole, dihydrobenzoxazole, dihydrobenzothiazole, dihydrobenzoisothiazole, dihydronaphtholine [2,3-b] thiophene, tetrahydroisoquinoline, tetrahydroquinoline, 4H-quinoline, indolin, isoinazoline, tetrahydrothieno [2] , 3-c] Pyridine, tetrahydrobenzoazepine, tetrahydroquinoxaline, tetrahydrophenanthridine, hexahydrophenanthridine, hexahydrophenanthridine, tetrahydrophthalazine, tetrahydronaphthiridine, tetrahydroquinazoline, tetrahydrocinnoline, tetrahydrocarbazole, tetrahydro-β-carbolin , Tetrahydroacridine, tetrahydrophenanthridine, tetrahydrothioxanthene, octahydroisoquinoline and the like, 9 to 14-membered fused polycyclic (preferably 2 or 3 ring) non-aromatic heterocycles.
In the present specification, the "nitrogen-containing heterocycle" includes a "heterocycle" containing at least one nitrogen atom as a ring-constituting atom.
Examples of the "optionally substituted ring" in the present specification include a optionally substituted hydrocarbon ring and an optionally substituted heterocycle.

In the present specification, the "ligand that specifically binds to an intracellular protein" represented by [Z] in the formula (I) constitutes a part of the compound (I) and is arbitrarily present in the cells of a living body. Means a structural unit having a specific binding activity to a protein (sometimes referred to as "ligand activity against an intracellular protein" in the present specification). The substance constituting the structural unit may be a substance that specifically binds to an intracellular protein, and examples thereof include DNA, RNA, nucleosides, nucleotides, proteins, peptides, amino acids, lipids, alkaloids, terpenes and derivatives thereof. Examples thereof include coenzymes and low molecular weight compounds (particularly low molecular weight compounds).
As used herein, the term "intracellular protein" refers to a protein that binds to the atomic group represented by [Z] in compound (I). The "intracellular protein" may be any protein as long as at least a part thereof is present in the cell, and the cell type is not limited. As the cells, mammalian cells (eg, mice, rats, hamsters, rabbits, cats, dogs, cows, sheep, monkeys, humans) are preferable. As the intracellular protein, an intracellular protein related to a pathological condition (particularly, an intracellular protein related to a human pathological condition) is preferable. Examples of the pathologically-related intracellular proteins include ABL, AR, ER (particularly ERα), BRD4, Ras, FRS2α, CRABP2, TACC3, PI3K, and PDE4, among which ABL, AR, and ER (particularly ERα). ), BRD4, PDE4, Ras are preferable.

（式中、Ｌ^１、Ｌ^２およびＬ^３は、それぞれ独立して、炭素原子、酸素原子、窒素原子および硫黄原子からなる群から選択される無置換の原子を示し、
−−は、それぞれ独立して、単結合、二重結合または三重結合を示す。）で示される直鎖状リンカーを含む。Ｌ^１、Ｌ^２およびＬ^３は、リンカー内部に存在する当該リンカーを構成する原子を示し、Ｌ^１及び／又はＬ^３が［Ｚ］又は［Ｘ］と直接に結合してもよい。式（ＩＩ）で示されるリンカーは、置換基を持たない炭素、酸素、窒素、および硫黄からなる群から選択される１種以上の原子が複数連結した直鎖を含む。この直鎖を構成する原子であるＬ^１、Ｌ^２およびＬ^３は、互いに単結合、二重結合または三重結合で結合していてもよい。Ｌ^１、Ｌ^２およびＬ^３で表される原子およびその原子の結合の具体例としては、−ＣＨ_２−、−ＣＨ＝、＝ＣＨ−、−Ｃ≡、≡Ｃ−、−ＮＨ−、−Ｎ＝、＝Ｎ−、−Ｏ−、及び−Ｓ−が挙げられる。
「リンカー」は、上記直鎖の何れかの端部又は両端に他の基を有してもよく、そのような基としては、例えば、−Ｃ（Ｏ）−、−Ｃ（Ｓ）−、−Ｃ（ＮＨ）−および−ＣＨ＝Ｎ−（これらは、置換可能な位置で１ないし３個のハロゲン原子で置換されていてもよい）が挙げられる。
なお、リガンド［Ｚ］にリンカー［Ｌ］が結合した化合物（Ｉ）の一部を構成する構造単位は、細胞内タンパク質に対するリガンド活性を有し得る。また、ＩＡＰリガンドであるリガンド［Ｘ］にリンカー［Ｌ］が結合した化合物（Ｉ）の一部を構成する構造単位はＩＡＰに対するリガンド活性を有し得る。 In the present specification, the term "linker" is used as an interposition between two atomic groups (specifically, [Z] and [X] in the formula (I)) to connect the two atomic groups. Indicates the atomic group to be used. The linker that constitutes a part of compound (I) has the following formula (II) inside it.

(In the equation, L ¹ , L ² and L ³ each independently represent an unsubstituted atom selected from the group consisting of a carbon atom, an oxygen atom, a nitrogen atom and a sulfur atom.
−− Indicates a single bond, a double bond or a triple bond independently of each other. ) Includes a linear linker. L ¹ , L ² and L ³ indicate the atoms constituting the linker existing inside the linker, and L ¹ and / or L ³ may be directly bonded to [Z] or [X]. The linker represented by the formula (II) contains a linear chain in which one or more atoms selected from the group consisting of carbon, oxygen, nitrogen, and sulfur having no substituent are linked. The atoms constituting this straight chain, L ¹ , L ² and L ³ , may be bonded to each other by a single bond, a double bond or a triple bond. Specific examples of the atoms represented by L ¹ , L ² and L ³ and the bonds between the atoms are −CH _2- , −CH =, = CH−, −C≡, ≡C−, −NH−, −. Examples include N =, = N-, -O-, and -S-.
The "linker" may have other groups at any end or both ends of the straight chain, such groups include, for example, -C (O)-, -C (S)-,. Included are -C (NH)-and -CH = N-, which may be substituted with 1 to 3 halogen atoms at substitutable positions.
The structural unit constituting a part of the compound (I) in which the linker [L] is bound to the ligand [Z] may have a ligand activity for the intracellular protein. Further, the structural unit constituting a part of the compound (I) in which the linker [L] is bound to the ligand [X] which is an IAP ligand may have a ligand activity for IAP.

Preferred examples of [Z], [L], and [X] in the formula (I) will be described.
[Z] in the formula (I) is preferably a ligand for the intracellular protein associated with the pathological condition. For example, ligands that specifically bind to pathological condition-related proteins described in Patent Documents 1-9 and 14-17 and Non-Patent Documents 1-10, 12, 13, 15-18 can be mentioned. Specifically, ABL (involved in chronic myelogenous leukemia, etc.), AR (involved in prostate cancer, etc.), ER (particularly, ERα) (involved in breast cancer, etc.), BRD4 (multiple myeloma, acute myelogenous leukemia, etc.) (Involved in), Ras (involved in colon cancer, pancreatic cancer, etc.), CRABP2 (involved in vitamin A deficiency), TACC3, FRS2α (cancer), PI3K (inflammation), and PDE4 (inflammation, especially bronchial asthma, atopic skin) A ligand that specifically binds to (involved in inflammation) can be mentioned.
[Z] is more preferably a ligand that specifically binds to ABL, AR, ER (particularly ERα), BRD4, Ras, or PDE4.

を挙げられる。 As a ligand for ABL, for example

Can be mentioned.

が挙げられる。 As a ligand for AR, for example

Can be mentioned.

が挙げられ、ＢＲＤ４に対するリガンドとしては、例えば

が挙げられ、ＰＤＥ４に対するリガンドとしては、例えば

が挙げられる。 As a ligand for ERα, for example

As a ligand for BRD4, for example.

As a ligand for PDE4, for example.

Can be mentioned.

が挙げられる。 Ligands for Ras include, for example, the ligands described in the following literature; Nature, 2013, 503, 548-551; WO 2013/155223; Science, 2016, 351, 604-608; WO 2014152588. Issue; International Publication 2015/054572; International Publication 2016/049524; Nat. Rev. Drug Discov., 2014, 13, 828-851; Chem. Soc. Rev., 2016, advance article (DOI: 10.1039 / C5CS00911A) ..
As a ligand for Ras, for example,

Can be mentioned.

[L] in the formula (I) is preferably at least the formula:-(CH _2- CH _2- O) _n- (in the formula, n is 1 to 20 (preferably 1 to 10, more preferably 1 to 1). It is a linker containing a straight chain formed of ethylene glycol units represented by 5), more preferably 2 to 5).
The linker may have other groups at any end or both ends of this straight chain, and preferred examples of such groups are -CH _2- , -C (= O)-, -O. _{-, - CH 2 -, -} C≡C-, and -C≡C-CH ₂ - group is selected, or these can be mentioned two or more linked group.
When [X] of the compound of formula (I) has the structure of formula (III), [L] is preferably of the formula: − (CH _2- CH _2- O) _{n − (n in the} formula is 1). a 5, preferably comprises linear chains are formed by ethylene glycol unit represented by a is) 3 to 5, _-CH 2 -O to [Z] side _{-, - CH 2 -, -} CH 2 -CH ₂ -, - C≡C-, or -C≡C-CH ₂ - may be added, is a linker. When [X] of the compound of the formula (I) has a structure represented by the formula (IV), (V) or (VI) (or a structure represented by the formula (V') described later), [ L] is preferably _{an ethylene glycol unit represented by the formula:-(CH 2-} CH _2- O) _{n- (n in the} formula is 2 to 5, preferably 3 to 5). _{A linker containing a formed straight chain, to which -CH 2} , -CH _2- O- or -CH _2- CH ₂ -S- may be added to either one end or both ends of the straight line. ..

（式中、各記号は前記と同意義を示す。）
で表される構造であってもよい。 [X] in the formula (I) is a structure represented by any of the above formulas (III) to (VI), and is preferably any of the above formulas (III), (IV) or (VI). The structure represented, more preferably the structure represented by the above formula (III) (more preferably the structure represented by the above formula (VII), still more preferably the structure represented by the above formula (IX), in particular. The structure represented by (X) above is preferable.
Further, [X] in the formula (I) is the following formula (V').

(In the formula, each symbol has the same meaning as above.)
It may have a structure represented by.

R is preferably a C _3-10 cycloalkyl group (particularly cyclohexyl), a C _1-6 alkyl group (particularly isopropyl, tert-butyl), or 1 to 3 (particularly 1) C _{6-14. It is a C 1-6} alkyl group (particularly methyl) substituted with an aryl group (particularly phenyl) _{, more preferably a C 3-10} cycloalkyl group (particularly cyclohexyl).

Ring A is preferably a 5- to 6-membered monocyclic aromatic heterocycle containing 1 to 4 heteroatoms selected from a nitrogen atom, a sulfur atom and an oxygen atom in addition to a carbon atom as a ring-constituting atom (particularly, a ring A). 8- to 14-membered fused polycyclic (preferably 2 or 3) containing 1 to 4 heteroatoms selected from nitrogen, sulfur and oxygen atoms in addition to carbon atoms as the thiazole ring and pyridine ring) or ring constituent atoms. It is a cyclic) aromatic heterocycle (particularly, a thiazolopyridine ring), and more preferably contains 1 to 4 heteroatoms selected from a nitrogen atom, a sulfur atom and an oxygen atom in addition to a carbon atom as a ring-constituting atom. It is a 5- to 6-membered monocyclic aromatic heterocycle (particularly, a thiazole ring or a pyridine ring).

When X is the above formula (III) and (IV), the ring A preferably contains 1 to 4 heteroatoms selected from a nitrogen atom, a sulfur atom and an oxygen atom in addition to a carbon atom as a ring-constituting atom. A 5- to 6-membered monocyclic aromatic heterocycle (particularly, a thiazole ring and a pyridine ring), more preferably 1 to 3 selected from a nitrogen atom, a sulfur atom and an oxygen atom in addition to a carbon atom as a ring-constituting atom. It is a 5-membered monocyclic aromatic heterocycle (particularly, a thiazole ring) containing the heteroatom of.
When X is the above formula (VI), the ring A preferably contains 1 to 4 heteroatoms selected from a nitrogen atom, a sulfur atom and an oxygen atom in addition to a carbon atom as a ring constituent atom, and has 5 to 6 members. A monocyclic aromatic heterocycle (particularly a pyridine ring) or an 8- to 14-membered fused polycyclic (preferably a 2- or 3-cyclic) aromatic heterocycle (particularly a thiazolopyridine ring), more preferably a ring. A 6-membered monocyclic aromatic heterocycle (particularly a pyridine ring) or an 8- to 14-membered condensation 2 containing 1 to 3 heteroatoms selected from a nitrogen atom, a sulfur atom and an oxygen atom in addition to a carbon atom as a constituent atom. Alternatively, it is a tricyclic aromatic heterocycle (particularly, a thiazolopyridine ring).

_{Ring B is preferably a C 6-14} aromatic hydrocarbon ring (particularly a benzene ring, a naphthalene ring) which may be substituted with 1 to 3 halogen atoms (particularly a fluorine atom), _{and more preferably C 6 -14} Aromatic hydrocarbon rings (particularly benzene rings).
When X is of the above formula (III), the ring B is preferably a C _6-14 aromatic hydrocarbon ring (particularly a benzene ring).
When X is of the above formula (IV), the ring B is preferably a C _6-14 aromatic hydrocarbon ring (particularly a benzene ring) substituted with 1 to 3 halogen atoms (particularly a fluorine atom). ..
When X is of the above formula (VI), ring B is preferably a C _6-14 aromatic hydrocarbon ring (particularly a benzene ring) which may be substituted with 1 to 3 halogen atoms (particularly fluorine atoms). Is.

Preferable specific examples of compound (1) include:
Compound (A)
[Z] is a ligand that specifically binds to ABL, AR, ER (particularly ERα), BRD4, Ras, or PDE4;
[L] is a linker containing a straight chain formed of ethylene glycol units represented by at least the formula: − (CH _2- CH _2- O) _{n − (n in the formula is 1 to 5).} Is;
[X] is the formula (III), (IV), (V) or (VI).
R is a C _3-10 cycloalkyl group (particularly cyclohexyl), a C _1-6 alkyl group (particularly isopropyl, tert-butyl) or 1 to 3 (particularly 1) C _6-14 aryl group (particularly 1). In particular, it is a C _1-6 alkyl group (particularly methyl) substituted with phenyl).
Ring A is a 5- to 6-membered monocyclic aromatic heterocycle containing 1 to 4 heteroatoms selected from nitrogen atom, sulfur atom and oxygen atom in addition to carbon atom as a ring constituent atom (particularly, thiazole ring, 8- to 14-membered fused polycyclic type (preferably 2 or 3 ring type) containing 1 to 4 heteroatoms selected from nitrogen atom, sulfur atom and oxygen atom in addition to carbon atom as pyridine ring) or ring constituent atom. It is an aromatic heterocycle (particularly a thiazolopyridine ring), and ring B may be substituted with 1 to 3 halogen atoms (particularly a fluorine atom) C _6-14 aromatic hydrocarbon ring (particularly). Benzene ring, naphthalene ring),
Y is a bond or carbonyl group,
The compound of formula (I).

Compound (B)
[Z] is a ligand that specifically binds to ABL, AR, ER (particularly ERα), BRD4, Ras, or PDE4;
[L] is a linker containing a straight chain formed of ethylene glycol units represented by the formula: − (CH _2- CH _2- O) n- (n in the formula is 1 to 5). ;
[X] is the formula (III).
R is C _3-10 cycloalkyl group (particularly cyclohexyl), C _1-6 alkyl group (particularly isopropyl group, tert-butyl group), or 1 to 3 (particularly 1) C _{6-14. A C 1-6} alkyl group (particularly a methyl group) substituted with an aryl group (particularly phenyl).
Ring A is a 5- to 6-membered monocyclic aromatic heterocycle containing 1 to 4 heteroatoms selected from nitrogen atom, sulfur atom and oxygen atom in addition to carbon atom as a ring constituent atom (particularly, thiazole ring, 8- to 14-membered fused polycyclic (preferably 2- or 3-cyclic) containing 1 to 4 heteroatoms selected from nitrogen, sulfur and oxygen atoms in addition to carbon atoms as ring-constituting atoms. It is an aromatic heterocycle (particularly the thiazolopyridine ring),
Ring B is a C _6-14 aromatic hydrocarbon ring (particularly a benzene ring).
The compound of formula (I).

（式中、環Ａは、環構成原子として炭素原子以外に窒素原子、硫黄原子および酸素原子から選ばれる１ないし４個のヘテロ原子を含有する５ないし６員単環式芳香族複素環（特に、チアゾール環、ピリジン環）で示される部分構造を示し、
環Ｂが、Ｃ_６−１４芳香族炭化水素環（特に、ベンゼン環）を示す。）である、
式（Ｉ）の化合物。 Compound (C)
[Z] is a ligand that specifically binds to ABL, AR, ER (particularly ERα), BRD4, Ras, or PDE4;
[L] is formed of ethylene glycol units represented by the formula: − (CH _2- CH _2- O) n- (n in the formula is 1 to 5 (particularly 2 to 5)). A linker containing a straight chain;
[X] is the following formula (VII)

(In the formula, ring A is a 5- to 6-membered monocyclic aromatic heterocycle containing 1 to 4 heteroatoms selected from a nitrogen atom, a sulfur atom and an oxygen atom in addition to a carbon atom as a ring-constituting atom (particularly). , Thiazole ring, pyridine ring)
Ring B represents a C _6-14 aromatic hydrocarbon ring (particularly a benzene ring). )
The compound of formula (I).

The salt in compound (I) is preferably a pharmacologically acceptable salt, for example, a salt with an inorganic base, a salt with an organic base, a salt with an inorganic acid, a salt with an organic acid, basic or acidic. Examples include salts with amino acids.
Preferable examples of salts with inorganic bases include alkali metal salts such as sodium salt and potassium salt; alkaline earth metal salts such as calcium salt and magnesium salt; aluminum salt and ammonium salt.
Preferable examples of salts with organic bases include trimethylamine, triethylamine, pyridine, picolin, ethanolamine, diethanolamine, triethanolamine, tromethamine [tris (hydroxymethyl) methylamine], tert-butylamine, cyclohexylamine, benzylamine, Examples thereof include salts with dicyclohexylamine and N, N-dibenzylethylenediamine.
Preferable examples of salts with inorganic acids include salts with hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid and phosphoric acid.
Preferable examples of salts with organic acids are 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. , Salt with p-toluenesulfonic acid.
Preferable examples of salts with basic amino acids include salts with arginine, lysine and ornithine.
Preferable examples of the salt with an acidic amino acid include a salt with aspartic acid and glutamic acid.

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

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

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

When a compound of a raw material or a reagent for each step is commercially available, the commercially available product can be used as it is.
In the reaction of each step, the reaction time may vary depending on the reagent and solvent used, but unless otherwise specified, it is usually 1 minute to 48 hours, preferably 10 minutes to 8 hours.

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

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

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

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

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

When a base is used in the reaction of each step, for example, the base shown below or the base described in Examples is used.
Inorganic bases: sodium hydroxide, magnesium hydroxide, potassium carbonate, sodium carbonate, cesium carbonate, calcium carbonate, sodium hydrogen carbonate, potassium phosphate, etc .;
Organic bases: triethylamine, diethylamine, pyridine, 4-dimethylaminopyridine, N, N-dimethylaniline, 1,4-diazabicyclo [2.2.2] octane, 1,8-diazabicyclo [5.4.0]- 7-Undecene, imidazole, piperidine, etc .;
Metal alkoxides: sodium ethoxide, potassium tert-butoxide, etc .;
Alkali metal hydrides: sodium hydride, etc .;
Metal amides: sodium amide, lithium diisopropylamide, lithium hexamethyldisilazide, etc .;
Organolithium: n-butyllithium, etc.

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

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

［式中、各記号は前記と同意義を示す。］ Compound (I) can be produced, for example, by the methods shown in Reaction Schemes 1 to 21 below.

[In the formula, each symbol has the same meaning as described above. ]

Compound (4) comprises compound (2) or a reactive derivative thereof and compound (3) or a reactive derivative thereof in an amidation reaction, an N-alkylation reaction, an O-alkylation reaction, an S-alkylation reaction or It can be produced by subjecting it to a coupling reaction.
Compound (I) comprises compound (4) or a reactive derivative thereof and compound (5) or a reactive derivative thereof in an amidation reaction, an N-alkylation reaction, an O-alkylation reaction, an S-alkylation reaction or It can be produced by subjecting it to a coupling reaction.

Further, the compound (I) is obtained by subjecting compound (5) or a reactive derivative thereof and compound (3) or a reactive derivative thereof to an amidation reaction, an N-alkylation reaction, an O-alkylation reaction, or an S-alkylation reaction. Compound (6) is produced by subjecting it to a reaction or a coupling reaction, and then compound (6) or a reactive derivative thereof and compound (2) or a reactive derivative thereof are subjected to amidation reaction, N-alkylation. It can also be produced by subjecting it to a reaction, an O-alkylation reaction, an S-alkylation reaction or a coupling reaction.
When the amino group, hydroxyl group or carboxyl group is protected in the product obtained in each step, it is induced to be a free amino group, hydroxyl group or carboxyl group by carrying out a deprotection reaction known per se. Is possible.

Compound (I) and compounds (2) to (6) may each independently form a salt.
Examples of the reactive derivative of the compounds (2) to (6) include an acyl halide, an acid anhydride, a sulfonic acid ester, and an alkyl halide.
When the product obtained in each step has an azide group, it can be induced to an amino group by subjecting it to a reduction reaction known per se, if desired.
Examples of the reducing agent used in the reduction reaction include metal hydrides such as lithium aluminum hydride, diisobutylaluminum hydride (DIBAL-H) and sodium borohydride; boranes such as borane tetrahydrofuran complex; triphenylphosphine and the like. Phosphins; triethylsilane and the like. Further, as the reduction reaction, a catalytic hydrogen reduction method using a catalyst such as palladium-carbon or Lindlar catalyst under a hydrogen atmosphere can be used.
If the product obtained in each step has a hydroxyl group, it can be induced into a sulfonic acid ester or an alkyl halide, if desired, and then amino can be obtained by a method known per se, such as a reaction with ammonia or a Gabriel reaction. It can be guided to the group.
When the product obtained in each step has a carboxyl group, it can be converted to an amino group by a method known per se, such as a Curtius rearrangement reaction or a Hofmann rearrangement reaction after induction to a carbamoyl group, if desired. it can.

The sulfonic acid ester compound can be produced by a sulfonic acid esterification reaction of a hydroxy group. Examples of the sulfonylating agent used in the sulfonic acid esterification reaction include methanesulfonyl chloride, p-toluenesulfonyl chloride, methanesulfonic acid anhydride, p-toluenesulfonic acid anhydride, trifluoromethanesulfonic anhydride and the like. ..

The above alkyl halide can be produced by a halogenation reaction of a hydroxy group. Examples of the halogenating agent used in the halogenation reaction include acid halides of hydrohalic acid and inorganic acids (specifically, hydrochloric acid, thionyl chloride, phosphorus oxychloride, etc. for chlorination, 48 for bromination. % Hydrochloric acid bromide) and the like. Further, an alkyl halide can be produced from an alcohol by the action of triphenylphosphine and carbon tetrachloride or carbon tetrabromide. Alternatively, an alkyl halide can also be produced by reacting the sulfonic acid ester with an alkali metal halide such as lithium bromide, lithium chloride or sodium iodide.

When the amidation reaction is carried out, it can be produced by using an acyl halide, an acid anhydride, and an activated carboxylic acid such as an active ester or a sulfate ester. Carboxylic acid activators include carbodiimide-based condensing agents such as 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (WSCD); 4- (4,6-dimethoxy-1,3,5- Triazine-2-yl) -4-methylmorpholinium chloride-n-hydrate (DMT-MM) and other triazine-based condensing agents; 1,1-carbonyldiimidazole (CDI) and other carbonate-based condensing agents; diphenyl Phosphic acid azide (DPPA); benzotriazole-1-yloxy-trisdimethylaminophosphonium salt (BOP reagent); 2-chloro-1-methyl-pyridinium iodide (Mukoyama reagent); thionyl chloride; halogic acid such as ethyl chlorogitate Lower alkyl; O- (7-azabenzotriazole-1-yl) -N, N, N', N'-tetramethyluronium hexafluorophosphate (HATU); or a combination thereof. When a carbodiimide-based condensing agent is used, additives such as 1-hydroxybenzotriazole (HOBt), N-hydroxysuccinimide (HOSu), and dimethylaminopyridine (DMAP) may be further added to the reaction.

In the N-alkylation reaction, O-alkylation reaction or S-alkylation reaction, the above-mentioned sulfonic acid ester or alkyl halide is used, and the base and, if desired, sodium iodide or potassium iodide or the like are iodide. This can be done in the presence of alkali metals, correlated transfer catalysts, crown ethers and the like.
The O-alkylation reaction can also be produced by performing a Mitsunobu reaction. Reagents include azodicarboxylic acid esters (eg, diethyl azodicarboxylate (DEAD), diisopropyl azodicarboxylate (DIAD), etc.) and triphenylphosphine.

Examples of the metal catalyst used in the coupling reaction include palladium (II) acetate, tetrakis (triphenylphosphine) palladium (0), dichlorobis (triphenylphosphine) palladium (II), dichlorobis (triethylphosphine) palladium (II), and the like. Tris (dibenzylideneacetone) dipalladium (0), 1,1'-bis (diphenylphosphino) ferrocene palladium (II), [2- (2-aminophenyl) phenyl] -chloro-palladium dicyclohexyl- [3- (2,4,6-triisopropylphenyl) phenyl] Palladium compounds such as phosphane; nickel compounds such as tetrakis (triphenylphosphine) nickel (0); rhodium compounds such as tris (triphenylphosphine) rhodium (III) chloride; Cobalt compounds; copper compounds such as copper oxide and copper (I) iodide; platinum compounds and the like can be mentioned. Further, a base may be added to the reaction, and examples of such a base include inorganic bases.

The protecting or deprotecting reaction of a functional group is carried out by a method known per se, for example, Wiley-Interscience, 2007, "Protective Groups in Organic Synthesis, 4th Ed." (Theodora W. Greene, Peter GM Wuts); Thieme, 2004. Methods described in "Protecting Groups 3rd Ed." (PJ Koienski), such as acids, bases, ultraviolet light, hydrazine, phenylhydrazine, sodium N-methyldithiocarbamate, tetrabutylammonium fluoride, palladium acetate, tri. It is carried out according to a method using an alkylsilyl halide (for example, trimethylsilyl iodide or trimethylsilyl bromide), a reduction method, a catalytic reduction method using a catalyst such as palladium-carbon, or a method described in Examples.

Examples of the protecting group for hydroxyl groups such as alcohols and phenolic hydroxyl groups include ether-type protecting groups such as methoxymethyl ether, benzyl ether, tert-butyldimethylsilyl ether, and tetrahydropyranyl ether; and carboxylic acid ester-type protecting groups such as acetate. Sulfonic acid ester-type protecting groups such as methane sulfonic acid ester; carbonic acid ester-type protecting groups such as tert-butyl carbonate and the like.
Examples of the thiol protecting group include ether-type protecting groups such as benzylthioether; ester-type protecting groups such as thioacetic acid ester, thiocarbonate, and thiocarbamate.

Examples of the amino group and the protecting group for aromatic heterocycles such as imidazole, pyrrole, and indol include a carbamate-type protecting group such as benzyl carbamate; an amide-type protecting group such as acetamide; Examples thereof include type protecting groups and sulfonamide-type protecting groups such as methanesulfonamide.
Examples of the carboxyl-protecting group include ester-type protecting groups such as methyl ester, benzyl ester, and tert-butyl ester; and amide-type protecting groups such as N and N-dimethylamide.

［式中、Ｒ^１は水素原子、ハロゲン原子、保護基で置換されていてもよい水酸基、もしくは保護基で置換されていてもよいカルボキシル基を示し、Ｒ²は水素原子、保護基で置換されていてもよい水酸基、保護基で置換されていてもよいアミノ基、もしくは保護基で置換されていてもよいチオール基を示し、Ｐ^１はアミノ基の保護基を示し、Ｐ^２はカルボキシル基の保護基を示し、他の各記号は前記と同意義を示す。] Reaction equation 2
The compound (6A-1) or the compound (6A-2) contained in the compound (6) can be produced by the following method.

[In the formula, R ¹ represents a hydrogen atom, a halogen atom, a hydroxyl group optionally substituted with a protecting group, or a carboxyl group optionally ^{substituted with a protecting group, and R 2} is substituted with a hydrogen atom, a protecting group. It represents a hydroxyl group which may be present, an amino group which may be substituted with a protecting group, or a thiol group which may be substituted with a protecting group, P ¹ indicates a protecting group of an amino group, and P ² is a carboxyl group. It indicates a protecting group, and each of the other symbols has the same meaning as described above. ]

Compound (12) can be produced by subjecting compound (10) or a salt thereof to compound (11) or a reactive derivative thereof in an amidation reaction, followed by a deprotection reaction known per se. ..
Compound (5A) can be produced from compound (12) or a salt thereof and compound (13) or a reactive derivative thereof in the same manner as in the method for producing compound (12).
Compound (5A) can also be produced by the following method. Compound (14) or a salt thereof and compound (13) or a reactive derivative thereof are used in the same manner as in the method for producing compound (12) to produce compound (15), followed by compound (15) or its reactivity. The compound (5A) is produced from the derivative and the compound (10) or a salt thereof in the same manner as in the production method of the compound (12).
Compound (6A-1) and compound (6A-2) can be produced by independently subjecting compound (5A) and compound (3) to the reaction represented by the above-mentioned reaction formula 1. ..

［式中、各記号は前記と同意義を示す。] Reaction equation 3
The compound (5B-1) or the compound (5B-2) contained in the compound (6) can be produced by the following method.

[In the formula, each symbol has the same meaning as described above. ]

Compound (5B) can be produced from compound (20) or a salt thereof by carrying out the same method as for producing compound (5A).
The compound (5B-1) and the compound (5B-2) can be produced from the compound (5B) in the same manner as in the production method of the compound (6A-1) and the compound (6A-2).

［式中、Ｐ^３はＰ^１とは異なるアミノ基の保護基を示し、他の各記号は前記と同意義を示す。] Reaction equation 4
The compound (6C) contained in the compound (6) can be produced by the following method.

[In the formula, P ³ represents ^{a protecting group of an amino group different from P 1,} and each of the other symbols has the same meaning as described above. ]

Compound (31) can be produced from compound (30) or a salt thereof and compound (11A) or a reactive derivative thereof in the same manner as in the method for producing compound (12).
Compound (5C) can be produced from compound (31) or a salt thereof by carrying out the same method as for producing compound (5A).
Compound (6C) can be produced from compound (5C) by subjecting it to the reaction represented by Reaction Scheme 1 above.

［式中、Ｌ^４はハロゲン原子を示し、Ｒ^３はＣ_１−６アルキル基を示し、Ｍは金属（例えば、リチウム、マグネシウム、銅、水銀、亜鉛、ホウ素、スズなどを示し、これらは錯化していてもよい）を示し、他の各記号は前記と同意義を示す。] Reaction equation 5
The compound (10) used in Reaction Scheme 2 can be produced by the following method.

[In the formula, L ⁴ represents a halogen atom, R ³ represents a C _1-6 alkyl group, and M represents a metal (eg, lithium, magnesium, copper, mercury, zinc, boron, tin, etc., which are complex. Each other symbol has the same meaning as described above. ]

Compound (42) can be produced by reacting compound (40) with compound (41).
The compound (41) used in this reaction is preferably organolithiums such as methyllithium, n-butyllithium and phenyllithium; Grignard reagents such as methylmagnesium bromide, ethylmagnesium chloride and phenylmagnesium bromide. Can be mentioned.
Compound (42) can also be produced by reacting compound (40) with a method known per se, for example, by reacting compound (40) with metallic magnesium using ether or tetrahydrofuran as a solvent.
Compound (44) can be produced by reacting compound (42) with compound (43).
Compound (45) can be produced by subjecting compound (44) to an oxidation reaction.
Oxidizing agents used include peracids such as m-chloroperbenzoic acid (mCPBA), hydrogen peroxide, tert-butylhydroperoxide; perchlorates such as tetrabutylammonium perchlorate; sodium chlorate and the like. Chlorates; chlorates such as sodium chlorate; periodic acids such as sodium periodate; high valence iodine reagents such as iodosylbenzene; reagents having manganese such as manganese dioxide and potassium permanganate; Leads such as lead tetraacetate; reagents with chromium such as pyridinium chlorochromate (PCC), pyridinium dichromate (PDC), Jones reagents; halogen compounds such as N-bromosuccinimide (NBS); oxygen; ozone; Examples thereof include sulfur trioxide / pyridine complex; osmium tetroxide; selenium dioxide; 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ).
Compound (47) can be produced by subjecting compound (45) and compound (46) or a salt thereof to a reductive amination reaction known per se.
Examples of the reducing agent used in this reaction include sodium borohydride, sodium cyanoborohydride, hydrogen, formic acid and the like.
Compound (48) can be produced from compound (47) in the same manner as in the method for producing compound (42).

Compound (10) can be produced by reacting compound (48) with compound (49) and then carrying out a deprotection reaction known per se.
In this reaction, a commercially available compound (49) is used, or a compound produced by an amidation reaction known per se from a corresponding known carboxylic acid or a reactive derivative thereof and N, O-dimethylhydroxylamine or a salt thereof ( 49) can be used.
Compound (10) can also be produced by the method shown in Reaction Scheme 6 below.

［式中、各記号は前記と同意義を示す。] Reaction equation 6
The compound (10) used in Reaction Scheme 2 can be produced by the following method.

[In the formula, each symbol has the same meaning as described above. ]

Compound (51) can be produced from compound (50) in the same manner as in the method for producing compound (42).
Compound (53) can be produced by subjecting compound (52) or a reactive derivative thereof and N, O-dimethylhydroxylamine or a salt thereof to an amidation reaction known per se.
Compound (10) can be produced by reacting compound (51) with compound (53) and then subjecting it to a deprotection reaction known per se.
Compound (10) can also be produced by the following method.
Compound (54) can be produced by subjecting compound (53) to a reduction reaction.
Compound (55) can be produced by reacting compound (54) with compound (55).
Compound (10) can be produced by subjecting compound (55) to a reduction reaction followed by a deprotection reaction known per se.

［式中、Ｒ^４はＣ_１−６アルキル基を示し、他の各記号は前記と同意義を示す。] Reaction equation 7
The compound (52A) contained in the compound (52) used in the reaction formula 6 can be produced by the following method.

[In the formula, R ⁴ represents a C _1-6 alkyl group, and each of the other symbols has the same meaning as described above. ]

Compound (52A) can be produced from compound (60) according to the method described in WO2008016893A1.
Compound (61) can be produced by reacting compound (60) with diphosphorus pentasulfide or Lawesson's reagent.
Compound (52A) can be produced by reacting compound (61) with compound (62) and then subjecting it to a hydrolysis reaction.

［式中、環Ａ２は置換されていてもよい複素環を示し、他の各記号は前記と同意義を示す。] Reaction equation 8
The compound (20) used in the reaction formula 3, the compound (20A) and the compound (20B) contained in the compound (20) can be produced by the following methods.

[In the formula, ring A2 represents a heterocyclic ring which may be substituted, and each of the other symbols has the same meaning as described above. ]

Compound (20) can be produced by subjecting compound (70) and compound (51) to a coupling reaction, followed by a deprotection reaction known per se.
Compound (20A) can be produced by reacting compound (61) with compound (71) and then carrying out a deprotection reaction known per se.
Compound (74) can be produced by subjecting compound (72) to a compound (73) known per se to an amidation reaction.
Compound (20B) can be produced by reacting compound (74) with diphosphorus pentasulfide or Lawesson's reagent, followed by a deprotection reaction known per se.

［式中、各記号は前記と同意義を示す。] Reaction equation 9
The compound (1A) contained in the compound (I) can be produced by the following method.

[In the formula, each symbol has the same meaning as described above. ]

When compound (3) has an amino group, compound (4A) can be produced by subjecting compound (2A) known per se or a reactive derivative thereof and compound (3) to an amidation reaction.
The compound (2A) used in this reaction can be produced according to the method described in Journal of medicinal chemistry 2010, Vol. 53, Section 6934-6946.
Compound (1A) can be produced by subjecting compound (4A) or a reactive derivative thereof and compound (5) or a reactive derivative thereof to the reaction represented by the above-mentioned reaction formula 1.
When the product obtained in each step has a protected amino group, hydroxyl group or carboxyl group, it is converted to a free amino group, hydroxyl group or carboxyl group by carrying out a deprotection reaction known per se. It is possible to induce.

［式中、他の各記号は前記と同意義を示す。] Reaction equation 10
The compound (1B) contained in the compound (I) can be produced by the following method.

[In the formula, each of the other symbols has the same meaning as described above. ]

Compound (4B) can be produced by subjecting compound (2A) or a salt thereof known per se to the reaction represented by Reaction Scheme 1 above with compound (3) or a reactive derivative thereof.
The compound (2B) used in this reaction can be produced according to the method described in Journal of medicinal chemistry 2010, Vol. 53, Section 6934-6946.
Compound (1B) can be produced by subjecting compound (4B) or a reactive derivative thereof and compound (5) or a reactive derivative thereof to the reaction represented by the above-mentioned reaction formula 1.
When the product obtained in each step has a protected amino group, hydroxyl group or carboxyl group, it is converted to a free amino group, hydroxyl group or carboxyl group by carrying out a deprotection reaction known per se. It is possible to induce.

［式中、Ｒ^４は水素原子、置換されていてもよいアルキルカルボニル基、置換されていてもよいシクロアルキルカルボニル基もしくは置換されていてもよいアルコキシカルボニル基を示し、Ｌ^５はハロゲン原子もしくは置換されていてもよい水酸基を示し、Ｒ^４−Ｌ^５自体が酸無水物を示していてもよく、Ｒ^５は水素原子、エチル基もしくはtert-ブトキシカルボニル基を示し、他の各記号は前記と同意義を示す。] Reaction equation 11
The compound (1C-1) and the compound (1C-2) contained in the compound (I) can be produced by the following methods.

[In the formula, R ⁴ represents a hydrogen atom, an optionally substituted alkylcarbonyl group, an optionally substituted cycloalkylcarbonyl group or an optionally substituted alkoxycarbonyl group, and L ⁵ is a halogen atom or substituted. R ^4- L ⁵ itself may indicate an acid anhydride, R ⁵ indicates a hydrogen atom, an ethyl group or a tert-butoxycarbonyl group, and the other symbols are as described above. Show the same meaning. ]

Compound (82) can be produced by reacting compound (80) or a salt thereof, which is known per se, with compound (81), if desired, in the presence of a base.
Compound (80) used in this reaction can be produced according to the method described in Blood 2010, Vol. 115, Section 4206-4216. Moreover, as a preferable example of the compound (81) used in this reaction, cyclopropylcarbonyl chloride, di-tert-butyl dicarbonate and the like can be mentioned.
Compound (83) can be produced by subjecting compound (82) to a hydrolysis reaction known per se using an acid or a base.
Compound (2C) can be produced by subjecting compound (83) or a reactive derivative thereof and a compound (84) known per se or a salt thereof to an amidation reaction.
Compound (84) used in this reaction can be produced according to the method described in Blood 2010, Vol. 115, Section 4206-4216 or WO2007067444A1.
^{If R 4} or R ⁵ of compound (2C) exhibits a tert-butoxycarbonyl group, it can be removed by subjecting it to a deprotection reaction with an acid, if desired.
When R ⁴ is hydrogen, compound (1C-1) is produced by subjecting compound (2C) or a salt thereof and compound (6) or a reactive derivative thereof to the reaction represented by the above reaction formula 1. be able to.
When R ⁵ is hydrogen, compound (1C-2) is produced by subjecting compound (2C) or a salt thereof and compound (6) or a reactive derivative thereof to the reaction represented by the above reaction formula 1. be able to.
When the product obtained in each step has a protected amino group, hydroxyl group or carboxyl group, it is converted to a free amino group, hydroxyl group or carboxyl group by carrying out a deprotection reaction known per se. It is possible to induce.

［式中、各記号は前記と同意義を示す。] Reaction equation 12
The compound (1D) contained in the compound (I) can be produced by the following method.

[In the formula, each symbol has the same meaning as described above. ]

Compound (1D) can be produced by subjecting compound (2D) known per se or a salt thereof and compound (6) or a reactive derivative thereof to the reaction represented by the above reaction formula 1.
The compound (2D) used in this reaction is the Journal of Medicinal Chemistry 2006, Vol. 49, 6819-6832 or the Journal of Medicinal Chemistry 2007, Vol. 50, 5583- It can be manufactured according to the method described in paragraph 5857.
When compound (1D) has a protected amino group, hydroxyl group or carboxyl group, it can be induced to a free amino group, hydroxyl group or carboxyl group by carrying out a deprotection reaction known per se. It is possible.

［式中、各記号は前記と同意義を示す。] Reaction equation 13
The compound (1E) contained in the compound (I) can be produced by the following method.

[In the formula, each symbol has the same meaning as described above. ]

Compound (1E) can be produced by subjecting compound (2E) known per se or a salt thereof and compound (6) or a reactive derivative thereof to the reaction represented by the above reaction formula 1.
The known compound (2E) used in this reaction can be produced according to the method described in Journal of Nuclear Medicine 2011, Vol. 52, Section 1301-1307.
When compound (1E) has a protected amino group, hydroxyl group or carboxyl group, it can be induced to a free amino group, hydroxyl group or carboxyl group by carrying out a deprotection reaction known per se. It is possible.

［式中、Ｒ^１０およびＲ^１１はそれぞれ独立してハロゲン原子、シアノ基もしくはトリフルオロメチル基を示し、Ｒ^１２はハロゲン原子、置換されていてもよい水酸基もしくは置換されていてもよいカルボキシル基を示し、Ｙ^１およびＹ^２はそれぞれ独立して炭素原子もしくは窒素原子を示し、他の各記号は前記と同意義を示す。] Reaction equation 14
The compound (1F-1), the compound (1F-2) and the compound (1F-3) contained in the compound (I) can be produced by the following methods.

[In the formula, R ¹⁰ and R ¹¹ each independently represent a halogen atom, a cyano group or a trifluoromethyl group, and R ¹² is a halogen atom, a hydroxyl group which may be substituted or a carboxyl group which may be substituted. As shown, Y ¹ and Y ² independently indicate a carbon atom or a nitrogen atom, and the other symbols have the same meanings as described above. ]

Compound (2F) can be produced by reacting compound (90) with compound (91) or compound (92) with compound (93).
The compound (90) and the compound (92) used in this reaction are raw material compounds known per se, and are Bioorganic & Medicinal Chemistry 2012, Vol. 20, Section 422-434 or Bioorganic And. It can be manufactured according to the method described in Bioorganic & Medicinal Chemistry 2012, Vol. 20, Section 2338-2352. The compound (91) and the compound (93) can be produced by a method known per se using commercially available raw material compounds. When the compound (91) and the compound (93) are commercially available, the commercially available products can be used as they are.

Compound (1F-1) can be produced by subjecting compound (2F) or a reactive derivative thereof and compound (6) or a reactive derivative thereof to the reaction represented by the above-mentioned reaction formula 1.
When R ¹² is a halogen atom, compound (4F-1) is prepared by subjecting compound (2F) and compound (3-1) to a sonogashira coupling reaction known per se in the presence of an organic base of amines. , Can be manufactured.
The metal catalysts used in the Sonogashira coupling reaction include palladium (II) acetate, tetrakis (triphenylphosphine) palladium (0), dichlorobis (triphenylphosphine) palladium (II), and dichlorobis (triethylphosphine) palladium (II). ), Tris (dibenzylideneacetone) dipalladium (0), 1,1'-bis (diphenylphosphino) ferrocene palladium (II) and other palladium compounds; copper oxide, copper iodide (I) and other copper compounds Can be mentioned.
Compound (1F-2) can be produced by subjecting compound (4F-1) or a reactive derivative thereof and compound (5) or a reactive derivative thereof to the reaction represented by the above reaction formula 1. ..
Compound (4F-2) can be produced by subjecting compound (4F-1) to a catalytic reduction reaction using a catalyst such as palladium-carbon or Lindlar catalyst under a hydrogen atmosphere.
Compound (1F-3) can be produced by subjecting compound (4F-2) or a reactive derivative thereof and compound (5) or a reactive derivative thereof to the reaction represented by the above reaction formula 1. ..
When the product obtained in each step has a protected amino group, hydroxyl group or carboxyl group, it is converted to a free amino group, hydroxyl group or carboxyl group by carrying out a deprotection reaction known per se. It is possible to induce.

［式中、各記号は前記と同意義を示す。］ Reaction equation 15
The compound (1G-1) and the compound (1G-2) contained in the compound (I) can be produced by the following methods.

[In the formula, each symbol has the same meaning as described above. ]

For compound (4G-1), a compound (2G) known per se or a salt thereof was subjected to a protective reaction known per se, and then compound (3) or a reactive derivative thereof was represented by the above reaction formula 1. It can be produced by subjecting it to a reaction.
The compound (2G) used in this reaction can be produced according to the method described in WO2005034856A2.
Compound (1G-1) can be produced by subjecting compound (4G-1) or a reactive derivative thereof and compound (5) or a reactive derivative thereof to the reaction represented by the above reaction formula 1. ..
Compound (4G-2) can be produced by reacting compound (4G-1) with compound (99), if desired, in the presence of a base.
When compound (5) has an amino group, compound (1G-2) is subjected to an amidation reaction by subjecting compound (4G-2) or a reactive derivative thereof and compound (5) or a reactive derivative thereof to an amidation reaction. Can be manufactured.
When the product obtained in each step has a protected amino group, hydroxyl group or carboxyl group, it is converted to a free amino group, hydroxyl group or carboxyl group by carrying out a deprotection reaction known per se. It is possible to induce.

［式中、Ｐ^４は水酸基の保護基を示し、他の各記号は前記と同意義を示す。] Reaction equation 16
The compound (1H) contained in the compound (I) can be produced by the following method.

Wherein, P ⁴ represents a protecting group for a hydroxyl group, the other symbols are as defined above. ]

Compound (4H-2) can be produced according to the method described in WO2013106643A2.
Compound (4H-1) can be produced by reacting compound (2H) with compound (3) or a reactive derivative thereof in the presence of a base, if desired.
The known compound (2H) used in this reaction can be produced according to the method described in WO2003004515A1.
Compound (4H-2) can be produced by subjecting it to a compound (4H-1) reduction reaction.
The reducing agent used in this reaction includes lithium aluminum borohydride, sodium triacetoxyborohydride, sodium cyanoborohydride, diisobutylaluminum hydride (DIBAL-H), sodium borohydride, and tetraacetoxyboron hydride tetra. Metal hydrides such as methylammonium; boranes such as borane tetrahydrofuran complex; Raney nickel; Raney cobalt; hydrogen; formic acid; hydrazine; triethylsilane and the like.
In compound (1H), compound (4H-2) or a reactive derivative thereof and compound (5) or a reactive derivative thereof are subjected to the reaction represented by the above-mentioned reaction formula 1, and subsequently, deprotection known per se. It can be produced by subjecting it to a reaction.

［式中、各記号は前記と同意義を示す。] Reaction equation 17
The compound (1J) contained in the compound (I) can be produced by the following method.

[In the formula, each symbol has the same meaning as described above. ]

Compound (1J) can be produced by subjecting compound (2J) or a reactive derivative thereof and compound (6) or a salt thereof to the reaction represented by the above-mentioned reaction formula 1.
The known compound (2J) used in this reaction can be produced according to the method described in WO2008006051A2 or Bioorganic & Medicinal Chemistry Letters 2010, Vol. 20, 2928-2932. ..
When compound (1J) has a protected amino group, hydroxyl group or carboxyl group, it can be induced to a free amino group, hydroxyl group or carboxyl group by carrying out a deprotection reaction known per se. It is possible.

［式中、各記号は前記と同意義を示す。] Reaction equation 18
The compound (1K) contained in the compound (I) can be produced by the following method.

[In the formula, each symbol has the same meaning as described above. ]

The compound (2K-2) can be produced by subjecting a compound (2K-1) known per se to a hydrolysis reaction in the presence of an acid or a base.
Compound (1K) can be produced by subjecting compound (2K-2) or a reactive derivative thereof and compound (6) or a salt thereof to the reaction represented by the above reaction formula 1.
The compound (2K-1) used in this reaction can be produced according to the method described in Nature 2010, Vol. 468, Paragraph 1067-1073.
When compound (1K) has a protected amino group, hydroxyl group or carboxyl group, it can be induced to a free amino group, hydroxyl group or carboxyl group by carrying out a deprotection reaction known per se. It is possible.

［式中、Ｒ^６はハロゲン原子で置換されていてもよいアルキル基もしくはハロゲン原子で置換されていてもよいアルコキシ基を示し、Ｒ^７は置換されていてもよい水酸基もしくは置換されていてもよいカルボキシル基を示し、他の各記号は前記と同意義を示す。] Reaction equation 19
The compound (1L-1) and the compound (1L-2) contained in the compound (I) can be produced by the following methods.

[In the formula, R ⁶ represents an alkyl group which may be substituted with a halogen atom or an alkoxy group which may be substituted with a halogen atom, and R ⁷ may be a hydroxyl group which may be substituted or a hydroxyl group which may be substituted. It indicates a carboxyl group, and each of the other symbols has the same meaning as described above. ]

Compound (2L) can be produced according to the production method described in WO213171639A1.
Compound (102) can be produced by reacting compound (100) with compound (101) or a salt thereof in the presence of a base, if desired.
Compound (2L) can be produced by subjecting compound (102) and compound (103) to a coupling reaction.
The compound (1L-1) is subjected to the reaction represented by the above reaction formula 1 with the compound (2L) or a reactive derivative thereof and the compound (6) or the reactive derivative thereof, and subsequently subjected to a deprotection reaction. As a result, it can be manufactured.
Compound (1L-2) is produced by subjecting compound (2L) to a deprotection reaction, followed by subjecting compound (6) or a reactive derivative thereof to the reaction represented by Reaction Scheme 1 above. Can be done.
When the product obtained in each step has a protected amino group, hydroxyl group or carboxyl group, it is converted to a free amino group, hydroxyl group or carboxyl group by carrying out a deprotection reaction known per se. It is possible to induce.

［式中、Ｒ^８は水素原子もしくはＣ_１−６アルキル基を示し、Ｌ^６はハロゲン原子もしくはスルホニルオキシ基を示し、他の各記号は前記と同意義を示す。] Reaction equation 20
The compound (3C) contained in the compound (3) can be produced by the following method.

[In the formula, R ⁸ represents a hydrogen atom or a C _1-6 alkyl group, L ⁶ represents a halogen atom or a sulfonyloxy group, and the other symbols have the same meanings as described above. ]

Compound (3B) can be produced by reacting compound (3A) with compound (110), if desired, in the presence of a base.
Compound (3C) can be produced by subjecting compound (3B) to a deprotection reaction, followed by a sulfonylation or halogenation reaction represented by Reaction Scheme 1.
When the product obtained in each step has a protected amino group, hydroxyl group or carboxyl group, it is converted to a free amino group, hydroxyl group or carboxyl group by carrying out a deprotection reaction known per se. It is possible to induce.

［式中、Ｐ^５は水素原子もしくはＰ^１と同意義を示し、Ｐ^６は水素原子もしくはＰ^２と同意義を示し、他の各記号は前記と同意義を示す。] Reaction equation 21
The compound (11A) contained in the compound (11) used in the reaction formula 2 or the like can be produced by the following method.

[In the formula, P ⁵ has the same meaning as a hydrogen atom or P ^{1 , P 6} has the same meaning as a hydrogen atom or P ^2, and each of the other symbols has the same meaning as described above. ]

Compound (131) can be produced by subjecting compound (130) to a reduction reaction according to the production method described in WO2003010130A1.
The compound (130) used in this reaction can be produced according to the production method described in Bioorganic & Medicinal Chemistry 2012, Vol. 20, Section 3551-3564. When the compound (130) is commercially available, the commercially available product can be used as it is.
Compound (11A) can be produced by subjecting it to a protection reaction and a deprotection reaction known per se.
Compound (11A) can be optionally split into optically active substances.
Examples of the optical resolution method include a method by chromatography using a chiral column, a method of forming a diastereomer salt and recrystallization, and the like.

When compound (I) has isomers such as optical isomers, steric isomers, positional isomers, and rotational isomers, either one isomer or a mixture is included in compound (I). For example, when the optical isomer is present in the compound (I), the optical isomer separated from the racemic mixture is also included in the compound (I). Each of these isomers can be obtained as a single product by a synthesis method and a separation method (eg, concentration, solvent extraction, column chromatography, recrystallization) known per se.

Compound (I) may be crystalline and is included in compound (I) whether it has a single crystalline form or a crystalline mixture. Crystals can be produced by crystallization by applying a crystallization method known per se.
In addition, compound (I) may be a pharmaceutically acceptable co-crystal or co-crystal salt. Here, a co-crystal or a co-crystal salt is composed of two or more unique solids at room temperature, each of which has different physical properties (eg, structure, melting point, heat of fusion, hygroscopicity, stability). It means a crystalline substance to be produced. The co-crystal or co-crystal salt can be produced according to a co-crystallization method known per se.
Compound (I) may be a hydrate, a non-hydrate, a solvate, or a non-solvate, all of which are included in compound (I). To.
Compounds labeled with isotopes (eg, ² H, ³ H, ¹¹ C, ¹⁴ C, ¹⁸ F, ³⁵ S, ¹²⁵ I) and the like are also included in compound (I). The isotope-labeled or substituted compound (I) can be used, for example, as a tracer (PET tracer) used in positron emission tomography (PET), and is useful in fields such as medical diagnosis.

Compound (I) may be a prodrug.
The prodrug of compound (I) is a compound that is converted into compound (I) by a reaction with an enzyme, gastric acid, or the like under physiological conditions in vivo, that is, a compound (I) that is enzymatically oxidized, reduced, hydrolyzed, or the like. ), A compound that undergoes hydrolysis or the like due to gastric acid or the like and changes to compound (I).

Examples of the prodrug of compound (I) include, for example.
(1) A compound in which the amino of compound (I) is acylated, alkylated, or phosphorylated (for example, the amino of compound (I) is ecosanoidized, alanylated, pentylaminocarbonylated, (5-methyl-2-). Oxo-1,3-dioxolen-4-yl) methoxycarbonylation, tetrahydrofuranylation, pyrrolidylmethylation, pivaloyloxymethylation, tert-butylation, ethoxycarbonylation, tert-butoxycarbonylation, acetylation, Cyclopropylcarbonylated compounds, etc.);
(2) The hydroxy of compound (I) is acylated, alkylated, phosphorylated, or booxidized (for example, the hydroxy of compound (I) is acetylated, palmitoylated, propanoylated, pivaloylated, or succinylated. , Fumarylation, alanylation, dimethylaminomethylcarbonylated compounds, etc.);
(3) The carboxy of the compound (I) is esterified and amidated (for example, the carboxy of the compound (I) is ethyl esterified, phenyl esterified, carboxymethyl esterified, dimethylaminomethyl esterified, pi Valoyloxymethyl esterification, ethoxycarbonyloxyethyl esterification, phthalidyl esterification, (5-methyl-2-oxo-1,3-dioxolen-4-yl) methylesterification, cyclohexyloxycarbonylethyl esterification, methylamide Esterified compounds, etc.);
Can be mentioned. These compounds can be produced from compound (I) by a method known per se.

In addition, the prodrug of compound (I) changes to compound (I) under physiological conditions as described in Hirokawa Shoten, 1990, "Drug Development," Vol. 7, Molecular Design, pp. 163 to 198. There may be.

Compound (I) or a prodrug thereof (these may be collectively abbreviated as "the compound of the present invention" in the present specification) is a target intracellular protein (particularly, an intracellular protein associated with a pathological condition). It has the activity of inducing degradation and is useful as a prophylactic or therapeutic agent for diseases involving a target intracellular protein. The SNIPER compound of the present invention may be effective in the prevention or treatment of any disease involving a targeted intracellular protein in light of its mechanism of action. Above all, it is expected to be effective in treating or preventing cancer, inflammatory diseases, autoimmune diseases, and bone / joint degenerative diseases.

Examples of cancer treatment or preventive agents include colon cancer (eg, colon cancer, rectal cancer, anal cancer, familial colon cancer, hereditary non-polyposis colon cancer, gastrointestinal stromal tumor), lung cancer (eg, non-small). Cellular lung cancer, small cell lung cancer, malignant mesoderma), mesopharyngoma, pancreatic cancer (eg, pancreatic duct cancer, pancreatic endocrine tumor), pharyngeal cancer, laryngeal cancer, esophageal cancer, gastric cancer (eg, papillary adenocarcinoma, mucinous adenocarcinoma) , Glandular squamous epithelial cancer), duodenal cancer, small intestine cancer, breast cancer (eg, invasive ductal carcinoma, non-invasive ductal carcinoma, inflammatory breast cancer), ovarian cancer (eg, epithelial ovarian cancer, gonadematode cell tumor) , Ovarian embryonic cell tumor, low-grade ovarian tumor), testicular tumor, prostate cancer (eg, hormone-dependent prostate cancer, hormone-independent prostate cancer, castration-resistant prostate cancer), liver cancer (eg, hepatocytes) Cancer, primary liver cancer, extrahepatic bile duct cancer), thyroid cancer (eg, thyroid medullary cancer), kidney cancer (eg, renal cell carcinoma (eg, clear cell type renal cell cancer), transition epithelium of renal pelvis and urinary tract Cancer), uterine cancer (eg, cervical cancer, uterine body cancer, uterine sarcoma), gestational chorionic villus cancer, brain tumor (eg, medullary cell tumor, glioma, pine needle cell tumor, hairy cell type Star cell tumor, diffuse stell cell tumor, degenerative stell cell tumor, pituitary adenoma), retinoblastoma, skin cancer (eg, basal cell tumor, malignant melanoma), sarcoma (eg, rhizome myoma, Prevention of smooth muscle tumor, soft sarcoma, spindle cell sarcoma), malignant bone tumor, bladder cancer, hematological cancer (eg, multiple myeloma, leukemia, malignant lymphoma, Hodgkin's disease, chronic myeloproliferative disease), cancer of unknown primary origin, etc. Examples thereof include agents or therapeutic agents, cancer growth inhibitors, cancer metastasis inhibitors, apoptosis promoters, and therapeutic agents for precancerous lesions (eg, myeloid atypia syndrome).

Examples of the therapeutic or prophylactic agent for an inflammatory disease, an autoimmune disease, or a bone / joint degenerative disease include a therapeutic or prophylactic agent for the following diseases.
(1) Inflammatory diseases (eg, rheumatoid arthritis, acute pancreatitis, chronic pancreatitis, asthma, bronchial asthma, adult respiratory distress syndrome, chronic obstructive pulmonary disease (COPD), inflammatory bone disease, inflammatory lung disease, inflammatory bowel Diseases, Celiac disease, Bechette's disease, hepatitis, alcoholic liver fibrosis, alcoholic hepatitis, alcoholic liver cirrhosis, hepatitis B viral liver injury, primary biliary cirrhosis (PBC), primary sclerosing cholangitis (PSC) , Transient cerebral ischemic attack (TIA), systemic inflammatory reaction syndrome (SIRS), dry eye, glaucoma, vaginitis, orbital honeycomb inflammation, idiopathic orbital inflammation, age-related luteal degeneration, inflammation after surgery or trauma , Hepatic disorder, pneumonia, nephritis, meningitis, cystitis, pharyngolaryngitis, gastromucosal injury, spondylitis, arthritis, dermatitis, chronic pneumonia, bronchitis, pulmonary infarction, siliceous pneumonia, pulmonary sarcoidosis, autoimmune anemia , Good Bascher syndrome, Graves' disease, Hashimoto thyroiditis, vasculitis, Basedou's disease, sinusitis, allergic rhinitis, chronic hypertrophic rhinitis),
(2) Autoimmune diseases (eg, rheumatoid arthritis, tonic spondylitis, psoriasis, multiple sclerosis (MS), polymyositis, neuromyelitis optica (NMO), chronic inflammatory demyelitis polyneuritis (CIDP) ), Dermatomyositis (DM), Nodular Polyarteritis (PN), Mixed Connective Tissue Disease (MCTD), Muscle Atrophic Lateral Sclerosis (ALS), Gillan Valley Syndrome, Severe Myasthenia, Parkinson's Disease , Spinal muscle atrophy, spinal cerebral atrophy, progressive supranuclear palsy, Fisher syndrome, central nervous system lupus, acute diffuse neuromyelitis, multisystem atrophy, Huntington's disease, Alzheimer's disease, cerebrovascular dementia, Chronic Levy body disease, cerebrovascular disorder, cerebral infarction, transient cerebral ischemic attack, cerebral hemorrhage, spinal canal disorder, spinal cord infarction, polyneuritis, Lampert-Eaton syndrome, muscular dystrophy, metabolic myopathy, inflammatory myopathy, inclusion Somatic myositis, encephalitis, meningitis, Sjogren's syndrome, systemic erythematosus, scleroderma, asthma, deep erythema, chronic thyroiditis, Graves' disease, autoimmune gastric inflammation, type I and type II diabetes, Autoimmune hemolytic anemia, autoimmune neutrophilia, thrombocytopenia, atopic dermatomyositis, chronic active hepatitis, severe myasthenia, inflammatory bowel disease (IBD), ulcerative colitis (UC) , Crohn's disease, transplant-to-host disease, Addison's disease, abnormal immune response, arthritis, dermatomyositis, radiation dermatomyositis, sarcoidosis, type 1 diabetes),
(3) Bone and joint degenerative diseases (eg, rheumatoid arthritis, osteoporosis, osteoarthritis)

Among them, the compounds of the present invention include cancers (particularly chronic myelogenous leukemia, prostate cancer, breast cancer, multiple myeloma, acute myelogenous leukemia, colon cancer, pancreatic cancer) and inflammatory diseases (particularly bronchial asthma and atopic cancer). It is effective for dermatitis).
The compound of the present invention can be used for treating or preventing the above-mentioned diseases in mammals (eg, mice, rats, hamsters, rabbits, cats, dogs, cows, sheep, monkeys, humans).

The compound of the present invention can be administered orally or parenterally to a mammal (preferably human) as a pharmaceutical by blending a carrier as it is or a pharmacologically acceptable carrier.
Hereinafter, a drug containing the compound of the present invention (may be abbreviated as “the drug of the present invention”) will be described in detail. Examples of the dosage form of the medicament of the present invention include tablets (including sugar-coated tablets, film-coated tablets, sublingual tablets, buccal tablets, and quick-disintegrating tablets in the oral cavity), pills, granules, powders, and capsules (soft capsules, soft capsules, etc.). Oral preparations such as microcapsules), syrups, emulsions, suspensions, film preparations (eg, sublingual films, oral mucosal patches). The dosage forms of the medicament of the present invention include, for example, injections, infusions, transdermal agents (eg, iontophoresis transdermal agents), suppositories, ointments, nasal agents, pulmonary agents, and eye drops. Oral preparations such as, etc. are also mentioned. Further, the medicament of the present invention may be a release-controlled preparation such as an immediate-release preparation and a sustained-release preparation (including sustained-release microcapsules).

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

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

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

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

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

Such injections are prepared by a method known per se, that is, by dissolving, suspending or emulsifying the compound of the present invention in a sterile aqueous or oily solution. Examples of the aqueous solution include physiological saline, an isotonic solution containing glucose and other auxiliary agents (eg, D-sorbitol, D-mannitol, sodium chloride) and the like. The aqueous solution contains suitable solubilizers such as alcohols (eg ethanol), polyalcohols (eg propylene glycol, polyethylene glycol), nonionic surfactants (eg polysorbate 80, HCO-50). You may. Examples of the oily liquid include sesame oil and soybean oil. The oily liquid may contain a suitable dissolution aid. Examples of the solubilizing agent include benzyl benzoate and benzyl alcohol. In addition, the injection includes a buffer (eg, phosphate buffer, sodium acetate buffer), a soothing agent (eg, benzalkonium chloride, prokine hydrochloride), and a stabilizer (eg, human serum albumin, polyethylene glycol). , Preservatives (eg, benzyl alcohol, phenol) and the like may be blended. The prepared injection solution is usually filled in an ampoule.

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

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

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

When the compound of the present invention is administered parenterally, it is usually administered in the form of a liquid preparation (eg, injection). The single dose of the compound of the present invention varies depending on the administration subject, target organ, symptom, administration method, etc., but for example, it is usually about 0.01 to about 100 mg, preferably about 0.01 to about 50 mg per 1 kg of body weight. More preferably, about 0.01 to about 20 mg of the compound of the present invention is administered by intravenous injection.

The compound of the present invention can be used in combination with other drugs. Specifically, when the compound of the present invention is used as a therapeutic or prophylactic agent for various cancers, drugs such as hormone therapeutic agents, chemotherapeutic agents, immunotherapeutic agents or cell growth factors and agents that inhibit the action of their receptors. Can be used in combination with. Hereinafter, a drug that can be used in combination with the compound of the present invention is abbreviated as a concomitant drug.

Examples of the "hormone therapy agent" include phosfestol, diethylstilbestrol, chlorotrianisen, medroxyprogesterone acetate, megestrol acetate, chlormaginone acetate, ciproterone acetate, dannazole, allylestradiol, guestlinone, mepartricin, and the like. Laroxyphene, olmeroxyphene, revolmeroxyphene, anti-estrogen (eg, tamoxyphene citrate, tremiphen citrate), pills, mepitiostane, testrolactone, aminoglutetiimide, LH-RH agonists (eg, goseleline acetate, busererin) , Leuprolerin acetate), droroxyphene, epithiostanol, ethinylestradiol sulfonate, aromatase inhibitors (eg, fadrosole hydrochloride, anastrosol, retrozol, exemestane, borozol, formestan), antiandrogens (eg, flutamide) , Bicalutamide, niltamide, enzaltamide), 5α-reductase inhibitors (eg, finasteride, epristeride, dutasteride), corticohormonal agents (eg, dexamethasone, prednisolone, betamethasone, triamcinolone), androgen synthesis inhibitors (eg, avirateron), Drugs that slow the metabolism of retinoids and retinoids (eg, rialozole), thyroid hormones, and their DDS (Drug Delivery System) preparations are used.

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

Examples of the "alkylating agent" include nitrogen mustard, nitrogen mustard-N-oxide hydrochloride, chlorambutyl, cyclophosphamide, ifosfamide, thiotepa, carbocon, improsulfan tosylate, busulfan, nimustine hydrochloride, mitobronitol, and melphalan. Farang, dacarbazine, lanimustin, sodium estramustine phosphate, triethylenemelamine, carmustine, lomustine, streptozocin, pipobroman, etoglucid, carboplatin, cisplatin, miboplatin, nedaplatin, oxaliplatin, altretamine, ambamustin, dibrospinate hydrochloride, phosphamide Prednimustin, pumitepa, ribomustine, temozolomide, treosfamide, trophosphamide, diostatin stimalamer, adzelesin, cisplatin, busulfan and their DDS preparations are used.

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

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

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

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

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

The "receptor of the cell growth factor" may be any receptor having the ability to bind to the above-mentioned cell growth factor, and specifically, an EGF receptor and a hellegrin receptor (eg, HER3). ), Insulin receptor, IGF receptor-1, IGF receptor-2, FGF receptor-1 or FGF receptor-2, VEGF receptor, angiopoietin receptor (eg, Tie2), PDGF receptor and the like are used. ..

Examples of "drugs that inhibit the action of cell growth factors and their receptors" include EGF inhibitors, TGFα inhibitors, haregulin inhibitors, insulin inhibitors, IGF inhibitors, FGF inhibitors, KGF inhibitors, CSF inhibitors, and the like. EPO inhibitor, IL-2 inhibitor, NGF inhibitor, PDGF inhibitor, TGFβ inhibitor, HGF inhibitor, VEGF inhibitor, angiopoetin inhibitor, EGF receptor inhibitor, HER2 inhibitor, HER4 inhibitor, insulin acceptance Body inhibitor, IGF-1 receptor inhibitor, IGF-2 receptor inhibitor, FGF receptor-1 inhibitor, FGF receptor-2 inhibitor, FGF receptor-3 inhibitor, FGF receptor-4 inhibitor Agents, VEGF receptor inhibitors, Tie-2 inhibitors, PDGF receptor inhibitors, ABL inhibitors, Raf inhibitors, FLT3 inhibitors, c-Kit inhibitors, Src inhibitors, PKC inhibitors, Smo inhibitors, ALK inhibitor, ROR1 inhibitor, Trk inhibitor, Ret inhibitor, mTOR inhibitor, Aurora inhibitor, PLK inhibitor, MEK (MEK1 / 2) inhibitor, MET inhibitor, CDK inhibitor, Akt inhibitor, ERK Inhibitors, PI3K inhibitors and the like are used. More specifically, anti-VEGF antibodies (eg, Bevacizumab, Ramuculumab), anti-HER2 antibodies (eg, Trastuzumab, Pertuzumab), anti-EGFR antibodies (eg, Cetuximab, Panitumuba, Methylib, Anti-Gymab, Matuzumab, Nimuta). , Gefitinib, Sorafenib, sunitinib, dasatinib, lapatinib, Vatalanib ,, Ibrutinib, Bosutinib, Cabozantinib, Crizotinib, Alectinib, Vismodegib, Cediranib, Tivantinib, Quizartinib, Dovitinib ,, axitinib, Motesanib, nilotinib, 6- [4- (4- ethyl Piperazin-1-ylmethyl) phenyl] -N- [1 (R) -phenylethyl] -7H-pyrrolo [2,3-d] pyrimidin-4-amine (AEE-788), Vandetanib, Temsirolimus, Everolimus, Enzastaurin, Tozasertib, phosphate 2- [N- [3- [4- [5- [N- (3-fluorophenyl) carbamoylmethyl] -1H-pyrazol-3-ylamino] quinazoline-7-yloxy] propyl] -N- Ethylamino] ethyl ester (AZD-1152), 4- [9-chloro-7- (2,6-difluorophenyl) -5H-pyrimid [5,4-d] [2] benzazepin-2-ylamino] benzoic acid , N- [2-methoxy-5-[(E) -2- (2,4,6-trimethoxyphenyl) vinylsulfonylmethyl] phenyl] glycine sodium salt (ON-1910Na), Volassertib, Cetuximab, Trastuzumab, N -[2 (R), 3-dihydroxypropoxy] -3,4-difluoro-2- (2-fluoro-4-iodophenylamino) benzamide (PD-0325901), Bostinib, Regorafenib, Afatinib, Idealisib, Cetuximab, Dabrafenib Etc. are used.

In addition to the above drugs, L-asparaginase, L-arginase, arginine deiminase, acegraton, procarbazine hydrochloride, protoporphyrin-cobalt complex salt, mercury hematoporphyrin sodium, topotecanase I inhibitor (eg, irinotecan, topotecan, indotecan, indimitecan) ), Topotecanase II inhibitors (eg, sobzoxane), differentiation inducers (eg, retinoids, vitamin Ds), angiogenesis inhibitors (eg, fumagirin, shark extract, COX-2 inhibitors), α-blockers (eg) , Tamsulosin hydrochloride), bisphosphonic acid (eg, pamidronate, zoredronate), salidamide, lenalidomide, pomalidemide, 5 azacitidine, decitabine, proteasome inhibitors (eg, bortezomib, calphizomib, iximab), NEDD8 inhibitors (eg, Ated) Antitumor antibodies such as drugs, PARP inhibitors (eg, Olaparib, Niraparib, Veliparib), anti-CD20 antibodies (eg, Rituximab, Obinutuzumab), anti-CCR4 antibodies (eg, Mogamulizumab), antibody drug complexes (eg, topotecan). , Brenximab vedotin) and the like can also be used as concomitant drugs.

When the compound of the present invention is used as a therapeutic or prophylactic agent for inflammatory diseases, autoimmune diseases, or bone / joint degenerative diseases, it can be used in combination with the drugs shown in (1) to (19) below.
(1) Non-steroidal anti-inflammatory drugs (NSAIDs)
(I) Classical NSAIDs
Alcophenac, acecrophenac, slindac, tolmethin, etodolac, phenoprofen, thiaprofenic acid, meclofenamic acid, meroxycam, teoxycam, lornoxicum, nabmeton, acetaminophen, phenacetin, etenzamid, sulpyrine, antipyrine, migrenin, aspirin Diclofenac sodium, loxoprofen sodium, phenylbutazone, indomethacin, ibuprofen, ketoprofen, naproxen, oxaprozin, flurbiprofen, fenbufen, planoprofen, floctaphenin, pyroxicum, epilyzole, thiaramid hydrochloride, zartprofen, gabexate mesilate, camostate mesilate, Urinastatin, corhitin, probenecid, sulfinpyrazone, benzbromalone, alloprinol, sodium gold thioappleate, sodium hyaluronate, sodium salicylate, morphine hydrochloride, salicylic acid, atropin, scopolamine, morphine, petidin, levorphanol, oxymorphone or salts thereof etc.
(Ii) Cyclooxygenase inhibitor (COX-1 selective inhibitor, COX-2 selective inhibitor, etc.)
Salicylic acid derivatives (eg, celecoxib, aspirin), etoricoxib, valdecoxib, diclofenac, indomethacin, loxoprofen, etc.
(Iii) Nitric oxide free NSAIDs

(2) Disease-modifying anti-rheumatic drugs (DMARDs)
(I) Gold preparation Auranofin and the like.
(Ii) Penicillamine D-penicillamine.
(Iii) Aminosalicylic acid preparations Sulfasalazine, mesalamine, orsalazine, balsalazide.
(Iv) Antimalaria drug Chloroquine and the like.
(V) Pyrimidine synthesis inhibitor leflunomide and the like.
(Vi) Tacrolimus

(3) Anti-cytocytogene drug (I) Protein preparation (i) TNF inhibitor Etanercept, Infliximab, Adalimumab, Certolizumab pegol, Golimumab, PASSTNF-α, Soluble TNF-α receptor, TNF-α binding protein, Anti-TNF-α antibody etc.
(Ii) Interleukin-1 inhibitor Anakinra (interleukin-1 receptor antagonist), soluble interleukin-1 receptor and the like.
(Iii) Interleukin-6 inhibitor Tocilizumab (anti-interleukin-6 receptor antibody), anti-interleukin-6 antibody and the like.
(Iv) Interleukin-10 drug Interleukin-10 and the like.
(V) Interleukin-12 / 23 inhibitors ustekinumab, briaquinumab (anti-interleukin-12 / 23 antibody) and the like.
(Vi) B cell activation inhibitor Rituxan, Benlista, etc.
(Vii) Co-stimulatory molecule-related protein preparation Avadacept and the like.
(II) Non-protein preparation (i) MAPK inhibitor BMS-582949 and the like.
(Ii) Gene regulators NF-κ, NF-κB, IKK-1, IKK-2, AP-1, and other inhibitors of molecules involved in signal transduction.
(Iii) Cytokine production inhibitor iguratimod, tetomilast, etc.
(Iv) TNF-α converting enzyme inhibitor (v) Interleukin-1β converting enzyme inhibitor Belnacasan and the like.
(Vi) Interleukin-6 antagonist HMPL-004 and the like.
(Vii) Interleukin-8 inhibitor IL-8 antagonist, CXCR1 & CXCR2 antagonist, reparexin and the like.
(Viii) Chemokine antagonist CCR9 antagonist (Vercilnon sodium, CCX025, N- {4-chloro-2-[(1-oxidepyridin-4-yl) carbonyl] phenyl} -4- (propane-2-) Iloxy) benzenesulfonamide), MCP-1 antagonist, etc.
(Ix) Interleukin-2 receptor antagonist Deniloukin, Difchitox and the like.
(X) Therapeutic vaccines
TNF-α vaccine, etc.
(Xi) Gene therapy drug A gene therapy drug aimed at enhancing the expression of genes having an anti-inflammatory effect such as interleukin-4, interleukin-10, soluble interleukin-1 receptor, and soluble TNF-α receptor. ..
(Xii) Antisense compound ISIS-104838 and the like.

(4) Integrin inhibitors Natalizumab, vedolizumab, AJM300, TRK-170, E6007, etc.
(5) Immunomodulators (immunosuppressive drugs)
Methotrexate, Cyclophosphamide, MX-68, Atiprimodo dihydrochloride, Abatacept, CKD-461, Limexolone, Cyclosporine, Tacrolimus, Gusperimus, Azathioprine, Antilymphatic serum, Dry sulfonated immunoglobulin, Erythropoietin, Colony Stimulating factors, interleukins, interferons, etc.
(6) Proteasome inhibitor Velcade, etc.
(7) JAK inhibitor tofacitinib, etc.
(8) Topical steroids Dexamethasone, hexestrol, methimazole, betamethasone, triamcinolone, triamcinolone acetonide, fluocinonide, fluocinolone acetonide, prednisolone, methylprednisolone, cortisol acetate, hydrocortisol, fluoromethasone, propionate, etc.
(9) Angiotensin converting enzyme inhibitor Enalapril, captopril, ramipril, lisinopril, silazapril, perindopril, etc.

(10) Angiotensin II receptor blocker candesartan cilexetil, valsartan, irbesartan, olmesartan, eprosartan and the like.
(11) Diuretics Hydrochlorothiazide, spironolactone, furosemide, indapamide, bendrofluazide, cyclopentiazide and the like.
(12) Cardiotonic drugs Digoxin, dobutamine, etc.
(13) β-receptor antagonist carvedilol, metoprolol, atenolol and the like.
(14) Ca sensitivity enhancer Caldaret hydrate and the like.
(15) Ca channel antagonist nifedipine, diltiazem, verapamil and the like.
(16) Antiplatelet drug, anticoagulant heparin, aspirin, warfarin, etc.
(17) HMG-CoA reductase inhibitor atorvastatin, simvastatin and the like.

(18) Contraceptives (i) Progesterone or its derivatives Progesterone or its derivatives (progesterone, 17α-hydroxyprogesterone, medroxyprogesterone, medroxyprogesterone acetate, norethisterone, norethisterone enantate, norethindron, norethisterone acetate, norethinodorel, levonorgesterone , Norgestrell, ethinol diacetate, desogestrel, norgestimate, guestden, progestin, etnogestrel, drospyrenone, dienogest, trimegean, nestron, chromadinone acetate, mifepriston, nomegestrol acetate, tosagestin (Tosagestin), TX-25 (Ethinyl estradiol / TX525)) or progesterone or derivatives thereof and follicular hormones or derivatives thereof (ethradiol, estradiol benzoate, estradiol cypionate, estradiol dipropionate, estradiol enantate, estradiol hexahydrobenzoate, estradiol phenyl propionate) , Estradiol undecanoate, estradiol valerate, estrone, ethinyl estradiol, mestranol), etc.
(Ii) Anti-estrogen agents Olmeroxyphene, mifepristone, Org-33628 and the like.
(Iii) Spermicide Ushelcell, etc.

(19) Others (i) T cell inhibitor (ii) Inosinic acid dehydrogenase (IMPDH) inhibitor Mycophenolate mofetil and the like.
(Iii) Adhesion molecule inhibitor Alicaforsen sodium, selectin inhibitor, ELAM-1 inhibitor, VCAM-1 inhibitor, ICAM-1 inhibitor and the like.
(Iv) Thalidomide (v) Cathepsin Inhibitor (vi) Matrix Metalloproteinase (MMPs) Inhibitor V-85546 and the like.
(Vii) Glucose-6-phosphate dehydrogenase inhibitor (viii) Dihydroorotate dehydrogenase (DHODH) inhibitor (ix) Phosphodiesterase IV (PDEIV) inhibitor Roflumilast, apremilast, CG-1088 and the like.
(X) Phospholipase A2 inhibitor (xi) iNOS inhibitor VAS203 and the like.
(Xii) Microtubule stimulant paclitaxel and the like.
(Xiii) Microtubule inhibitor Ryumacon and the like.
(Xiv) MHC class II antagonist (xv) Prosta cyclin activator Iloprost and the like.
(Xvi) CD4 antagonist Zanolimumab and the like.
(XVii) CD23 antagonist (xvii) LTD4 receptor antagonist DW-1350 and the like.
(Xix) 5-lipoxygenase inhibitor diluton and the like.
(Xx) Cholinesterase inhibitor Galantamine and the like.
(Xxi) Tyrosine kinase inhibitor Tyk2 inhibitor (WO2010 / 142752) and the like.
(Xxii) Calepsin B inhibitor (xxxii) Adenosine deaminase inhibitor Pentostatin and the like.
(Xxiv) Bone formation stimulant (xxv) Dipeptidyl peptidase inhibitor (xxvi) Collagen agonist (xxvii) Capsaicin cream (xxviii) Hyaluronic acid derivative Symbisc (hylan GF 20), orthobisc and the like.
(Xxxx) Glucosamine sulfate (xxx) Amiprirose (xxxi) CD-20 inhibitor Rituximab, ibritumomab, tositumomab, ofatumab and the like.
(Xxxxii) BAFF inhibitors belimumab, tabalumab, atacicept, brisibimod and the like. (Xxxxii) CD52 inhibitor alemtuzumab and the like.

By combining the compound of the present invention and the concomitant drug, the dose can be reduced as compared with the case where (1) the compound of the present invention or the concomitant drug is administered alone, and (2) the patient's symptoms (mild). Depending on the severity, etc.), a drug to be used in combination with the compound of the present invention can be selected, (3) the treatment period can be set longer, (4) the therapeutic effect can be sustained, (5). By using the compound of the present invention in combination with a concomitant drug, excellent effects such as a synergistic effect can be obtained.

Hereinafter, the case where the compound of the present invention and the concomitant drug are used in combination is referred to as "the concomitant drug of the present invention".
When using the concomitant drug of the present invention, the administration time of the compound of the present invention and the concomitant drug is not limited, and the compound of the present invention and the concomitant drug may be administered to the administration subject at the same time, with a time lag. It may be administered. When administered at different times, the time difference varies depending on the active ingredient to be administered, the dosage form, and the administration method. For example, when the concomitant drug is administered first, within 1 minute to 3 days after the concomitant drug is administered, preferably within 1 minute to 3 days. The compound of the present invention may be administered within 10 minutes to 1 day, more preferably within 15 minutes to 1 hour. When the compound of the present invention is administered first, the concomitant drug may be administered within 1 minute to 1 day, preferably within 10 minutes to 6 hours, more preferably within 15 minutes to 1 hour after the administration of the compound of the present invention. .. The dose of the concomitant drug may be based on the clinically used dose, and can be appropriately selected depending on the administration target, administration route, disease, combination and the like.

Examples of the administration form when the compound of the present invention and the concomitant drug are used in combination include (1) administration of a single preparation obtained by simultaneously formulating the compound of the present invention and the concomitant drug, and (2) concomitant use with the compound of the present invention. Simultaneous administration of two types of preparations obtained by separately formulating a drug by the same administration route, (3) By the same administration route of two types of preparations obtained by separately formulating the compound of the present invention and a concomitant drug. (4) Simultaneous administration of two kinds of preparations obtained by separately formulating the compound of the present invention and the concomitant drug by different administration routes, (5) the compound of the present invention and the concomitant drug Examples thereof include administration of two types of preparations obtained by separately formulating with a time lag in different administration routes (for example, administration in the order of the compound of the present invention → the concomitant drug, or administration in the reverse order).
The dose of the concomitant drug can be appropriately selected based on the clinically used dose. In addition, the compounding ratio of the compound of the present invention and the concomitant drug can be appropriately selected depending on the administration target, administration route, target disease, symptom, combination and the like. For example, when the administration target is a human, 0.01 to 100 parts by weight of the concomitant drug may be used with respect to 1 part by weight of the compound of the present invention.

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

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

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

The present invention will be further described in detail with reference to the following Examples, Test Examples and Formulation Examples, but these are not limited to the present invention and may be changed without departing from the scope of the present invention.
"Room temperature" in the following examples usually indicates about 10 ° C to about 35 ° C. The ratio shown in the mixed solvent indicates the volume ratio unless otherwise specified. % Indicates% by weight unless otherwise specified.
In silica gel column chromatography, NH is described as aminopropylsilane-bonded silica gel, Diol is described as 3- (2,3-dihydroxypropoxy) propylsilane-bonded silica gel, and DiNH is described as N-. (2-Aminoethyl) -3-aminopropylsilane-bonded silica gel was used. When described as C18 in HPLC (High Performance Liquid Chromatography), octadecyl-bonded silica gel was used. The ratio of elution solvents indicates the volume ratio unless otherwise specified.
The following abbreviations are used in the following examples.
mp: Melting point MS: Mass spectrum [M + H] ⁺ , [MH] ⁻ : Molecular ion peak M: Molar concentration N: Specified CDCl ₃ : Deuterated chloroform CD ₃ OD: Deuterated methanol DMSO-d ₆ : Deuterated dimethyl sulfoxide
¹ H NMR: Proton Nuclear Magnetic Resonance LC / MS: Liquid Chromatograph Mass Analyzer ESI: Electrospray Ionization APCI: Atmospheric Pressure Chemical Ionization DMSO: Dimethyl Sulfoxide DME: 1,2-Dimethoxyethane DMF: N, N-Dimethylformamide DMA : N, N-Dimethylacetamide THF: tetrahydrofuran TFA: Trifluoroacetate DIPEA: N, N-diisopropylethylamine MOMCl: Chloromethylmethyl ether t-BuOK: Potassium tert-butoxide LDA: Lithium diisopropylamide DMTMM: 4- (4,6) −Dimethoxy-1,3,5-triazine-2-yl) -4-methylmorpholinium chloride N-hydrate HATU: 2- (7-azabenzotriazole-1-yl) -1,1,3 3-Tetramethyluronium hexafluorophosphate HOBt: 1-hydroxybenzotriazole WSC: 1-ethyl-3- (3-dimethylaminopropyl) Carbodiimide Boc: tert-butoxycarbonyl t-Bu: tert-butyl

^{1 1} HNMR was measured by Fourier transform type NMR. ACD / SpecManager (trade name) or the like was used for the analysis. It does not describe peaks with very gentle protons such as hydroxyl groups and amino groups.
MS was measured by LC / MS. As the ionization method, the ESI method or the APCI method was used. For the data, the measured value (found) is described. Normally, a molecular ion peak is observed, but in the case of a compound having a tert-butoxycarbonyl group, a peak in which the tert-butoxycarbonyl group or the tert-butyl group is eliminated may be observed as a fragment ion. Further, in the case of a compound having a hydroxyl group, a _{peak in which H 2} O is eliminated may be observed as a fragment ion. In the case of salts, free molecular ion peaks or fragment ion peaks are usually observed.
The unit of sample concentration (c) in optical rotation ([α] _{D) is g / 100 mL.}
For the elemental analysis value (Anal.), The calculated value (Calcd) and the measured value (Found) are described.

Example 1
N-(2- (2- (2- (3-((2-((2S) -1-((2S) -2-cyclohexyl-2-((N-methyl-L-alanyl) amino) acetyl)) Pyrrolidine-2-yl) -1,3-thiazole-4-yl) carbonyl) phenoxy) ethoxy) ethoxy) ethyl) -3- (6-((4- (trifluoromethoxy) phenyl) amino) pyrimidine-4- Il) benzamide

A) 6-Chloro-N- (4- (trifluoromethoxy) phenyl) pyrimidine-4-amine
Triethylamine (5.08 mL) was added to a mixture of 4,6-dichloropyrimidine (3.62 g), 4- (trifluoromethoxy) aniline (4.3 g) and ethanol (10 mL) at room temperature. The mixture was stirred at 80 ° C. overnight. The mixture was cooled to room temperature and water was added. The resulting solid was collected by filtration to give the title compound (5.52 g).
MS: [M + H] ⁺ 290.2.

B) 3-(6-((4- (Trifluoromethoxy) phenyl) amino) pyrimidine-4-yl) benzoic acid
6-Chloro-N- (4- (trifluoromethoxy) phenyl) pyrimidine-4-amine (4.0 g), 3- (dihydroxyboryl) benzoic acid (2.3 g), tetrakis (triphenylphosphine) palladium (0) ( A mixture of 797 mg), sodium carbonate (5.9 g) and acetonitrile-water (1: 1,200 mL) was stirred at 90 ° C. for 16 hours under a nitrogen atmosphere. After hot filtration of the mixture, the filtrate was cooled to room temperature and the pH was adjusted to 4 with 6N hydrochloric acid. The resulting solid was collected by filtration to give the title compound (3.11 g).
MS: [M + H] ⁺ 376.1.

C) N- (2- (2- (2-Hydroxyethoxy) ethoxy) ethyl) -3-(6-((4- (trifluoromethoxy) phenyl) amino) pyrimidine-4-yl) benzamide
3- (6-((4- (Trifluoromethoxy) phenyl) amino) pyrimidin-4-yl) benzoic acid (1.0 g), 2- (2- (2-aminoethoxy) ethoxy) ethanol (0.72 g), HATU (1.22 g) was added to a mixture of DIPEA (0.70 mL) and anhydrous DMF (10 mL) at 0 ° C., and the mixture was stirred at room temperature for 3 hours. The reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with water, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (NH, methanol / ethyl acetate) to give the title compound (1.06 g).
MS: [M + H] ⁺ 507.3.

D) 2- (2- (2-((3- (6-((4- (Trifluoromethoxy) phenyl) amino) pyrimidine-4-yl) benzoyl) amino) ethoxy) ethoxy) ethyl 4-methylbenzenesulfo Nart
N-(2- (2- (2-Hydroxyethoxy) ethoxy) ethyl) -3-(6-((4- (trifluoromethoxy) phenyl) amino) pyrimidine-4-yl) benzamide (660 mg) anhydrous 4-Methylbenzenesulfonyl chloride (497 mg) was added to a DMF (13.2 mL) solution at 0 ° C., and the mixture was stirred at room temperature for 3 hours. 1N Hydrochloric acid was added to the mixture at room temperature, and the mixture was extracted with ethyl acetate. The organic layer was separated, washed with 1N hydrochloric acid and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / hexane) to give the title compound (567 mg).
MS: [M + H] ⁺ 661.4.

E) tert-Butyl (2S) -2-carbamoylpyrrolidine-1-carboxylate
WSC (13.1 g) was added to a mixture of 1- (tert-butoxycarbonyl) -L-proline (10.0 g), HOBt (9.00 g), and acetonitrile (200 mL), and the mixture was stirred at room temperature for 3 hours. Ammonia water (30 mL) was added at 0 ° C. and the mixture was stirred at room temperature for 12 hours. The reaction mixture was concentrated, water was added and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether) to give the title compound (10.2 g).
^{1 1} H NMR (400 MHz, DMSO-d ₆ ) δ 1.34-1.39 (9H, m), 1.70-1.83 (3H, m), 2.01-2.11 (1H, m), 3.23-3.29 (1H, m), 3.34 -3.38 (1H, m), 3.96-4.00 (1H, m), 6.86-6.90 (1H, m), 7.26-7.30 (1H, m).

F) tert-Butyl (2S) -2-carbamoti oil pyrrolidine-1-carboxylate
A mixture of tert-butyl (2S) -2-carbamoylpyrrolidine-1-carboxylate (4.78 g), Lawesson's reagent (9.47 g), and anhydrous THF (130 mL) was stirred at 60 ° C. for 2 hours. The reaction mixture was cooled, poured into saturated aqueous sodium hydrogen carbonate solution, and extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (NH, ethyl acetate / hexane, methanol / ethyl acetate) to give the title compound (4.21 g).
MS: [M + H-Boc + H] ⁺ 131.2.

G) Ethyl 2-((2S) -1- (tert-butoxycarbonyl) pyrrolidine-2-yl) -1,3-thiazole-4-carboxylate
A mixture of tert-butyl (2S) -2-carbamotioil pyrrolidine-1-carboxylate (2.32 g), ethyl bromopyruvic acid (1.7 mL), and ethanol (50 mL) was stirred at 60 ° C. for 3 hours. After cooling the reaction mixture, saturated aqueous sodium hydrogen carbonate solution (5 mL) was added, and the mixture was concentrated under reduced pressure. The residue was dissolved in THF (30 mL) -saturated aqueous sodium hydrogen carbonate solution (20 mL) and di-tert-butyl dicarbonate (2.4 mL) was added at 0 ° C. The mixture was stirred at room temperature for 3 hours. Ethyl acetate was added to the reaction mixture, the mixture was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (NH, ethyl acetate / hexane) to give the title compound (2.93 g).
MS: [M + H-Boc + H] ⁺ 227.2.

H) 2-((2S) -1- (tert-butoxycarbonyl) pyrrolidine-2-yl) -1,3-thiazole-4-carboxylic acid ethyl 2-((2S) -1- (tert-butoxycarbonyl)) A mixture of pyrrolidine-2-yl) -1,3-thiazole-4-carboxylate (2.92 g), methanol (36 mL), and 1N aqueous sodium hydroxide solution (18 mL) was stirred overnight at room temperature. 1N Hydrochloric acid (18 mL) was added to the reaction mixture, and the organic solvent was evaporated under reduced pressure. The precipitate was collected by filtration, washed with water and dried to give the title compound (2.48 g).
MS: [M + H-Boc + H] ⁺ 199.2.

I) tert-Butyl (2S) -2- (4- (methoxy (methyl) carbamoyl) -1,3-thiazole-2-yl) pyrrolidine-1-carboxylate
2-((2S) -1- (tert-butoxycarbonyl) pyrrolidine-2-yl) -1,3-thiazole-4-carboxylic acid (1.2 g), DIPEA (2.1 mL), N, O-dimethoxyhydroxyamine A mixture of hydrochloride (0.471 g), HOBt (0.652 g), WSC (0.85 mL), and DMF (16 mL) was stirred overnight at room temperature. Ethyl acetate was added to the reaction mixture, the mixture was washed with 5% aqueous sodium hydrogen carbonate solution and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / hexane) to give the title compound (1.33 g).
MS: [M + H] ⁺ 342.2.

J) tert-Butyl (2S) -2- (4- (methoxy (methyl) carbamoyl) -1,3-thiazole-2-yl) pyrrolidine-1-carboxylate
In a mixture of tert-butyl (2S) -2- (4- (methoxy (methyl) carbamoyl) -1,3-thiazole-2-yl) pyrrolidine-1-carboxylate (640 mg) and anhydrous THF (18 mL) 0.5 M (3- (tetrahydro-2H-pyran-2-yloxy) phenyl) magnesium bromide THF solution (11.3 mL) was added at -55 ° C. The mixture was stirred at −55 ° C. for 30 minutes under an argon atmosphere and heated to -10 ° C. over 50 minutes. The reaction mixture was cooled to −55 ° C. again, and a saturated aqueous solution of ammonium chloride (15 mL) was added dropwise. The reaction mixture was partitioned between ethyl acetate and water, the organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / hexane) to give the title compound (847 mg).
^{1 1} H NMR (300 MHz, CDCl ₃ ) δ 1.30-1.56 (9H, m), 1.57-2.13 (8H, m), 2.19-2.51 (2H, m), 3.32-3.74 (3H, m), 3.82-3.98 (1H, m), 5.12-5.38 (1H, m), 5.44-5.54 (1H, m), 7.23-7.33 (1H, m), 7.34-7.45 (1H, m), 7.71-7.88 (2H, m) , 8.08 (1H, s).

K) (3-Hydroxyphenyl) (2-((2S) -pyrrolidine-2-yl) -1,3-thiazole-4-yl) methanone dihydrochloride
With tert-butyl (2S) -2- (4- (3- (tetrahydro-2H-pyran-2-yloxy) benzoyl) -1,3-thiazole-2-yl) pyrrolidine-1-carboxylate (840 mg) A mixture of 2M hydrogen chloride methanol solution (4.5 mL) was stirred at room temperature overnight. The reaction mixture was diluted with toluene (10 mL) and concentrated under reduced pressure to give the title compound. The obtained compound was used in the next reaction without further purification.
MS: [M + H] ⁺ 275.1.

L) tert-Butyl ((1S) -1-cyclohexyl-2-((2S) -2-(4- (3-hydroxybenzoyl) -1,3-thiazole-2-yl) pyrrolidine-1-yl)- 2-oxoethyl) carbamate
A mixture of (2S)-((tert-butoxycarbonyl) amino) (cyclohexyl) acetic acid (1.42 g), HOBt (0.75 g), WSC (0.96 mL), and THF (4.5 mL) was stirred at 0 ° C. for 1 hour. .. The resulting reaction mixture was mixed with (3-hydroxyphenyl) (2-((2S) -pyrrolidin-2-yl) -1,3-thiazole-4-yl) metanone dihydrochloride (0.635 g) and saturated hydrochloric acid. It was added to a mixture of aqueous sodium solution (4.5 mL) at 0 ° C. The mixture was stirred at room temperature for 4 hours, ethyl acetate was added, the mixture was washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was dissolved in methanol (15 mL), an aqueous solution of potassium carbonate (0.38 g) (3.8 mL) was added at 0 ° C, and the mixture was stirred at 0 ° C for 2 hours. 1N Hydrochloric acid (5 mL) and ethyl acetate were added to the reaction mixture, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / hexane) to give the title compound (935 mg).
MS: [M + H] ⁺ 514.3.

M) (2S) -2-amino-2-cyclohexyl-1-((2S) -2- (4- (3-hydroxybenzoyl) -1,3-thiazole-2-yl) pyrrolidine-1-yl) etanone Dihydrochloride
tert-Butyl ((1S) -1-cyclohexyl-2-((2S) -2-(4- (3-hydroxybenzoyl) -1,3-thiazole-2-yl) pyrrolidine-1-yl) -2- A mixture of oxoethyl) carbamate (935 mg), methanol (1 mL) -THF (3 mL), and 4M hydrogen chloride cyclopentyl methyl ether solution (4.5 mL) was stirred at room temperature for 4 hours. The reaction mixture was diluted with toluene (10 mL) and concentrated under reduced pressure to give the title compound. The obtained compound was used in the next reaction without further purification.
MS: [M + H] ⁺ 414.2.

N) tert-Butyl ((2S) -1-(((1S) -1-cyclohexyl-2-((2S) -2-(4- (3-hydroxybenzoyl) -1,3-thiazole-2-yl) ) Pyrrolidine-1-yl) -2-oxoethyl) amino) -1-oxopropan-2-yl) methylcarbamate
(2S) -2-amino-2-cyclohexyl-1-((2S) -2-(4- (3-hydroxybenzoyl) -1,3-thiazole-2-yl) pyrrolidine-1-yl) etanone dihydrochloride Salt (0.89 g), DIPEA (0.96 mL), N- (tert-butoxycarbonyl) -N-methyl-L-alanine (1.11 g), HOBt (0.74 g), WSC (0.96 mL), and DMF (6 mL) ) Was stirred at room temperature for 2 hours. Ethyl acetate was added to the reaction mixture, the mixture was washed with 5% aqueous sodium hydrogen carbonate solution and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was dissolved in methanol (15 mL), aqueous potassium carbonate (0.38 g) solution (3.8 mL) was added at 0 ° C, and the mixture was stirred at 0 ° C for 2 hours. 1N Hydrochloric acid (6 mL) and ethyl acetate were added to the reaction mixture, washed 3 times with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / hexane) and silica gel column chromatography (NH, methanol / ethyl acetate) to give the title compound (458 mg).
MS: [M + H] ⁺ 599.4.

O) tert-butyl ((2S) -1-(((1S) -1-cyclohexyl-2-oxo-2-((2S) -2- (4- (3- (2- (2- (2- (2- (2-) 2-) ((3- (6-((4- (Trifluoromethoxy) phenyl) amino) pyrimidine-4-yl) benzoyl) amino) ethoxy) ethoxy) ethoxy) benzoyl) -1,3-thiazole-2-yl) pyrrolidine -1-yl) ethyl) amino) -1-oxopropan-2-yl) methylcarbamate
tert-butyl ((2S) -1-(((1S) -1-cyclohexyl-2-((2S) -2-(4- (3-hydroxybenzoyl) -1,3-thiazole-2-yl) pyrrolidine) -1-yl) -2-oxoethyl) amino) -1-oxopropan-2-yl) methylcarbamate (231 mg), 2- (2-(2-((3- (6-((4- (4- (4-( Trifluoromethoxy) phenyl) amino) pyrimidin-4-yl) benzoyl) amino) ethoxy) ethoxy) ethyl 4-methylbenzenesulfonate (283 mg) and anhydrous DMF (5.6 mL) mixed with potassium carbonate (71 mg) added. The mixture was stirred at 60 ° C. for 5 hours under an argon atmosphere. Water was added to the mixture at room temperature, and the mixture was extracted with ethyl acetate. The organic layer was separated, washed with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (methanol / ethyl acetate) to give the title compound (274 mg).
MS: [M + H] ⁺ 1087.8.

P) N- (2- (2- (2- (3-((2-((2S) -1-((2S) -2-cyclohexyl-2-((N-methyl-L-alanyl) amino)) Acetyl) pyrrolidine-2-yl) -1,3-thiazole-4-yl) carbonyl) phenoxy) ethoxy) ethoxy) ethyl) -3- (6-((4- (trifluoromethoxy) phenyl) amino) pyrimidine- 4-Il) benzamide
tert-Butyl ((S) -1-(((S) -1-cyclohexyl-2-oxo-2-((S) -2- (4- (3- (2- (2- (2- (3) -(6-((4- (Trifluoromethoxy) phenyl) amino) pyrimidine-4-yl) benzamide) ethoxy) ethoxy) ethoxy) benzoyl) thiazole-2-yl) pyrrolidine-1-yl) ethyl) amino)- A mixture of 1-oxopropan-2-yl) (methyl) carbamate (271 mg) and TFA (1.92 mL) was stirred at room temperature for 30 minutes. Toluene (5 mL) was added to the mixture and concentrated under reduced pressure. Ethyl acetate and saturated aqueous sodium hydrogen carbonate solution were added to the residue, and the organic layer was separated. After washing with saturated aqueous sodium hydrogen carbonate solution and saturated brine, the mixture was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (methanol / ethyl acetate) to give the title compound (168 mg).
^{1 1} H NMR (300 MHz, DMSO-d ₆ ) δ 0.83-1.01 (3H, m), 1.01-1.29 (7H, m), 1.47-1.77 (6H, m), 1.91-2.12 (2H, m), 2.12 -2.27 (4H, m), 2.96 (1H, q, J = 6.6 Hz), 3.42-3.52 (2H, m), 3.54-3.66 (6H, m), 3.73-3.83 (4H, d, J = 5.0 Hz) ), 4.10-4.16 (2H, m), 4.45-4.52 (1H, m), 5.38 (1H, dd, J = 7.9, 3.0 Hz), 7.21 (1H, dd, J = 7.8, 2.3 Hz), 7.32- 7.46 (4H, m), 7.58-7.68 (3H, m), 7.82-7.92 (3H, m), 7.98 (1H, d, J = 7.6 Hz), 8.17 (1H, d, J = 8.1 Hz), 8.47 (1H, s), 8.52 (1H, s), 8.67-8.73 (1H, m), 8.77 (1H, s), 9.92 (1H, s).

Example 2
N- (2- (2- (2- (4-((2-((2S) -1-((2S) -2-cyclohexyl-2-((N-methyl-L-alanyl) amino) acetyl)) Pyrrolidine-2-yl) -1,3-thiazole-4-yl) carbonyl) phenoxy) ethoxy) ethoxy) ethyl) -3- (6-((4- (trifluoromethoxy) phenyl) amino) pyrimidine-4- Il) benzamide

A) tert-Butyl (2S) -2- (4- (4- (tetrahydro-2H-pyran-2-yloxy) benzoyl) -1,3-thiazole-2-yl) pyrrolidine-1-carboxylate
0.5 in anhydrous THF (18 mL) solution of tert-butyl (2S) -2- (4- (methoxy (methyl) carbamoyl) -1,3-thiazole-2-yl) pyrrolidine-1-carboxylate (640 mg) M (4- (Tetrahydro-2H-pyran-2-yloxy) phenyl) magnesium bromide (11.3 mL) was added at -55 ° C. The mixture was stirred at −55 ° C. for 30 minutes under an argon atmosphere and then warmed to -10 ° C. over 40 minutes. The reaction mixture was cooled to −55 ° C. again, and saturated aqueous ammonium chloride solution (15 mL) was added dropwise. The reaction mixture was partitioned between ethyl acetate and water, the organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / hexane) to give the title compound (817 mg).
MS: [M + H] ⁺ 459.3.

B) (4-Hydroxyphenyl) (2-((2S) -pyrrolidine-2-yl) -1,3-thiazole-4-yl) methanone dihydrochloride
tert-butyl (2S) -2- (4- (4- (tetrahydro-2H-pyran-2-yloxy) benzoyl) -1,3-thiazole-2-yl) pyrrolidine-1-carboxylate (812 mg), A mixture of 2M hydrogen chloride methanol solution (4.5 mL) was stirred at room temperature overnight. The reaction mixture was diluted with toluene (10 mL) and concentrated under reduced pressure to give the title compound (615 mg). The obtained compound was used in the next reaction without further purification.
MS: [M + H] ⁺ 275.1.

C) tert-Butyl ((1S) -1-cyclohexyl-2-((2S) -2-(4- (4-hydroxybenzoyl) -1,3-thiazole-2-yl) pyrrolidine-1-yl)- 2-oxoethyl) carbamate
(4-Hydroxyphenyl) (2-((2S) -pyrrolidin-2-yl) -1,3-thiazole-4-yl) metanone dihydrochloride (0.62 g), DIPEA (0.95 mL), (2S)- A mixture of ((tert-butoxycarbonyl) amino) (cyclohexyl) acetic acid (1.37 g), HOBt (0.72 g), WSC (0.93 mL), and DMF (6 mL) was stirred at room temperature for 2 hours. The reaction mixture was diluted with ethyl acetate, washed with 5% aqueous sodium hydrogen carbonate solution and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was dissolved in methanol (25 mL), a mixture of potassium carbonate (0.75 g) and water (7.5 mL) was added, and the mixture was stirred at room temperature for 1 hr. 1N Hydrochloric acid (12 mL) and ethyl acetate were added to the reaction mixture, washed 3 times with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / hexane) to give the title compound (845 mg).
MS: [M + H] ⁺ 514.3.

D) (2S) -2-amino-2-cyclohexyl-1-((2S) -2-(4- (4-hydroxybenzoyl) -1,3-thiazole-2-yl) pyrrolidine-1-yl) etanone Dihydrochloride
tert-Butyl ((1S) -1-cyclohexyl-2-((2S) -2-(4- (4-hydroxybenzoyl) -1,3-thiazole-2-yl) pyrrolidine-1-yl) -2- A mixture of oxoethyl) carbamate (840 mg) and 2M hydrogen chloride methanol solution (6 mL) was stirred at room temperature overnight. The reaction mixture was diluted with toluene (10 mL) and concentrated under reduced pressure to give a crude title compound. The obtained compound was used in the next reaction without further purification.
MS: [M + H] ⁺ 414.3.

E) tert-Butyl ((2S) -1-(((1S) -1-cyclohexyl-2-((2S) -2-(4- (4-hydroxybenzoyl) -1,3-thiazole-2-yl) ) Pyrrolidine-1-yl) -2-oxoethyl) amino) -1-oxopropan-2-yl) methylcarbamate
(2S) -2-amino-2-cyclohexyl-1-((2S) -2-(4- (4-hydroxybenzoyl) -1,3-thiazole-2-yl) pyrrolidine-1-yl) etanone dihydrochloride Salt (1.84 g), DIPEA (2.0 mL), N- (tert-butoxycarbonyl) -N-methyl-L-alanine (2.31 g), HOBt (1.56 g), WSC (2.0 mL), and DMF (12 mL) ) Was stirred at room temperature for 2 hours. Ethyl acetate was added to the reaction mixture, the mixture was washed with 5% aqueous sodium hydrogen carbonate solution and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue was dissolved in methanol (50 mL) and a mixture of potassium carbonate (1.0 g) and water (10 mL) was added at 0 ° C. The mixture was stirred at 0 ° C. for 20 minutes. 1N Hydrochloric acid (16 mL) and ethyl acetate were added to the reaction mixture, washed 3 times with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / hexane) to give the title compound (1.57 g).
MS: [M + H] ⁺ 599.5.

F) tert-butyl ((2S) -1-(((1S) -1-cyclohexyl-2-oxo-2-((2S) -2-(4- (4- (2- (2- (2- (2-) 2-) ((3- (6-((4- (Trifluoromethoxy) phenyl) amino) pyrimidine-4-yl) benzoyl) amino) ethoxy) ethoxy) ethoxy) benzoyl) -1,3-thiazole-2-yl) pyrrolidine -1-yl) ethyl) amino) -1-oxopropan-2-yl) methylcarbamate
2- (2- (2-((3- (6-((4- (Trifluoromethoxy) phenyl) amino) pyrimidin-4-yl) benzoyl) amino) ethoxy) ethoxy) ethyl 4-methylbenzenesulfonate ( 283 mg) and tert-butyl ((S) -1-(((S) -1-cyclohexyl-2-((S) -2-(4- (4-hydroxybenzoyl) thiazole-2-yl) pyrrolidine- Add potassium carbonate to an anhydrous DMF (5.6 mL) solution of 1-yl) -2-oxoethyl) amino) -1-oxopropan-2-yl) (methyl) carbamate (231 mg) at room temperature to create an argon atmosphere. Below, it was stirred at 60 ° C. for 5 hours. Water was added to the mixture at room temperature, and the mixture was extracted with ethyl acetate. The organic layer was separated, washed with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (methanol / ethyl acetate) to give the title compound (298 mg).
MS: [M + H] ⁺ 1087.8.

G) N- (2- (2- (2- (4-((2-((2S) -1-((2S) -2-cyclohexyl-2-((N-methyl-L-alanyl) amino)) Acetyl) pyrrolidine-2-yl) -1,3-thiazole-4-yl) carbonyl) phenoxy) ethoxy) ethoxy) ethyl) -3- (6-((4- (trifluoromethoxy) phenyl) amino) pyrimidine- 4-Il) benzamide
tert-Butyl ((S) -1-(((S) -1-cyclohexyl-2-oxo-2-((S) -2- (4- (4- (2- (2- (2- (3) -(6-((4- (Trifluoromethoxy) phenyl) amino) pyrimidine-4-yl) benzamide) ethoxy) ethoxy) ethoxy) benzoyl) thiazole-2-yl) pyrrolidine-1-yl) ethyl) amino)- A mixture of 1-oxopropan-2-yl) (methyl) carbamate (291 mg) and TFA (2.06 mL) was stirred at room temperature for 30 minutes. Toluene (5 mL) was added to the mixture and concentrated under reduced pressure. Ethyl acetate and saturated aqueous sodium hydrogen carbonate solution were added to the residue, and the organic layer was separated. The organic layer was washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (methanol / ethyl acetate) to give the title compound (195 mg).
^{1 1} H NMR (300 MHz, DMSO-d ₆ ) δ 0.84-1.25 (10H, m) 1.48-1.78 (6H, m), 1.93-2.11 (2H, m), 2.12-2.28 (4H, m), 2.96 ( 1H, q, J = 6.8 Hz), 3.42-3.53 (2H, m), 3.55-3.66 (6H, m), 3.73-3.85 (4H, m), 4.15-4.21 (2H, m), 4.46-4.53 ( 1H, m), 5.39 (1H, dd, J = 8.0, 3.0 Hz), 7.04 (2H, d, J = 8.2 Hz), 7.33 (2H, s, J = 3.8 Hz), 7.37 (1H, s, J) = 6.9 Hz), 7.62 (1H, t, J = 7.8 Hz), 7.82-7.92 (3H, m), 7.99 (1H, d, J = 7.7 Hz), 8.12-8.20 (3H, m), 8.38-8.42 (1H, m), 8.53 (1H, s), 8.68-8.77 (2H, m), 9.92 (1H, s).

Example 7
N-((1S) -1-cyclohexyl-2-oxo-2-((2S) -2- (4- (3- (2- (2- (2- (4- (6- ((4- ( Trifluoromethoxy) phenyl) amino) pyrimidine-4-yl) -1H-pyrazol-1-yl) ethoxy) ethoxy) ethoxy) benzoyl) -1,3-thiazole-2-yl) pyrrolidine-1-yl) ethyl) -N ² -methyl-L-alanine amide

A) 2- (2- (2- (4- (4- (6-((4- (Trifluoromethoxy) Phenyl) Amino) Pyrimidine-4-yl) -1H-Pyrazole-1-yl) ethoxy) ethoxy) Ethanol
6- (1H-Pyrazole-4-yl) -N- (4- (trifluoromethoxy) phenyl) pyrimidine-4-amine (200 mg), 2- (2- (2-chloroethoxy) ethoxy) ethanol (157) Cesium carbonate (264 mg) was added to an anhydrous DMF (4.0 mL) solution of mg) and sodium iodide (103 mg) at room temperature. The mixture was stirred at 80 ° C. overnight under an atmosphere of argon. Water was added to the mixture at room temperature, and the mixture was extracted with ethyl acetate. The organic layer was separated, washed with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / hexane) to give the title compound (208 mg).
The above 6- (1H-pyrazole-4-yl) -N- (4- (trifluoromethoxy) phenyl) pyrimidine-4-amine is a method known per se (eg, Journal of Medicinal Chemistry 2010, It can be synthesized by the method described in 53, 6934-6946).
MS: [M + H] ⁺ 454.3.

B) 2- (2- (2- (4- (4- (6-((4- (Trifluoromethoxy) phenyl) amino) pyrimidine-4-yl) -1H-pyrazole-1-yl) ethoxy) ethoxy) ethyl 4 -Methylbenzene sulfonate
2- (2- (2- (4- (4- ((4- (Trifluoromethoxy) Phenyl) Amino) Pyrimidine-4-yl) -1H-Pyrazole-1-yl) ethoxy) ethoxy) Ethanol (1.01 g ) To a solution of 4-methylbenzenesulfonyl chloride (0.85 g) under ice-cooling. The mixture was stirred at room temperature for 3 hours. 1N Hydrochloric acid was added to the mixture at room temperature, and the mixture was extracted with ethyl acetate. The organic layer was separated, washed with 1N hydrochloric acid and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / hexane) to give the title compound (1.05 g).
MS: [M + H] ⁺ 608.3.

C) tert-butyl ((2S) -1-(((1S) -1-cyclohexyl-2-oxo-2-((2S) -2-(4- (3- (2- (2- (2- (2- (2-) 2-) (4- (6-((4- (Trifluoromethoxy) phenyl) amino) pyrimidine-4-yl) -1H-pyrazol-1-yl) ethoxy) ethoxy) ethoxy) benzoyl) -1,3-thiazole-2 -Il) Pyrimidine-1-yl) Ethyl) Amino) -1-oxopropan-2-yl) Methylcarbamate
2- (2- (2- (4- (4- ((4- (Trifluoromethoxy) phenyl) amino) pyrimidin-4-yl) -1H-pyrazol-1-yl) ethoxy) ethoxy) ethyl 4-methyl Benzene Sulfonate (255 mg) and tert-butyl ((S) -1-(((S) -1-Cyclohexyl-2-((S) -2- (4- (3-Hydroxybenzoyl) thiazole-2-) Add potassium carbonate (68.5 mg) to an anhydrous DMF (3.8 mL) solution of yl) pyrrolidine-1-yl) -2-oxoethyl) amino) -1-oxopropan-2-yl) (methyl) carbamate (190 mg). The mixture was stirred at 60 ° C. for 5 hours under an argon atmosphere. Water was added to the mixture at room temperature, and the mixture was extracted with ethyl acetate. The organic layer was separated, washed with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (methanol / ethyl acetate) to give the title compound (256 mg).
MS: [M + H] ⁺ 1034.8.

D) N-((1S) -1-cyclohexyl-2-oxo-2-((2S) -2- (4- (3- (2- (2- (2- (4- (6- ((4)) -(Trifluoromethoxy) phenyl) amino) pyrimidine-4-yl) -1H-pyrazol-1-yl) ethoxy) ethoxy) ethoxy) benzoyl) -1,3-thiazole-2-yl) pyrrolidine-1-yl) Ethyl) -N ² -methyl-L-alanine amide
tert-butyl ((S) -1-(((S) -1-cyclohexyl-2-oxo-2-((S) -2- (4- (3- (2- (2- (2- (4) -(6-((4- (Trifluoromethoxy) phenyl) amino) pyrimidine-4-yl) -1H-pyrazol-1-yl) ethoxy) ethoxy) ethoxy) benzoyl) thiazole-2-yl) pyrrolidine-1- A mixture of yl) ethyl) amino) -1-oxopropan-2-yl) (methyl) carbamate (253 mg) and TFA (2.0 mL) was stirred at room temperature for 20 minutes. Toluene (5 mL) was added to the mixture and concentrated under reduced pressure. Ethyl acetate and saturated aqueous sodium hydrogen carbonate solution were added to the residue, and the organic layer was separated. The organic layer was washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (NH, methanol / ethyl acetate) to give the title compound (154 mg).
^{1 1} H NMR (300 MHz, DMSO-d ₆ ) δ 0.83-1.00 (3H, m), 1.00-1.26 (7H, m), 1.46-1.77 (6H, m), 1.91-2.12 (2H, m), 2.12 -2.27 (4H, m), 2.96 (1H, q, J = 6.8 Hz), 3.57 (4H, s), 3.69-3.86 (6H, m), 3.99-4.14 (2H, m), 4.33 (2H, t) , J = 5.2 Hz), 4.45-4.52 (1H, m), 5.38 (1H, dd, J = 7.9, 3.1 Hz), 6.90 (1H, s), 7.19 (1H, dd, J = 8.0, 2.3 Hz) , 7.29-7.45 (3H, m), 7.60-7.67 (2H, m), 7.78 (2H, d, J = 8.1 Hz), 7.89 (1H, d, J = 9.0 Hz), 7.98 (1H, s), 8.33 (1H, s), 8.46 (1H, s), 8.55 (1H, s), 9.71 (1H, s).

Example 8
N-((1S) -1-cyclohexyl-2-oxo-2-((2S) -2- (4- (3- (2- (2- (2- (2- (4- (6- (() 4- (Trifluoromethoxy) phenyl) amino) pyrimidine-4-yl) -1H-pyrazol-1-yl) ethoxy) ethoxy) ethoxy) ethoxy) benzoyl) -1,3-thiazole-2-yl) pyrrolidine-1 -Il) Ethyl) -N ² -Methyl-L-Alaninamide

A) 2- (2- (2- (2- (2- (4- (6-((4- (Trifluoromethoxy) phenyl) amino) pyrimidine-4-yl) -1H-pyrazol-1-yl) ethoxy) ethoxy) ) Ethoxy) Ethyl 4-methylbenzenesulfonate
2- (2- (2- (2- (4- (4- (6-((4- (Trifluoromethoxy) Phenyl) Amino) Pyrimidine-4-yl) -1H-Pyrazole-1-yl) ethoxy) ethoxy) ethoxy) ) 4-Methylbenzenesulfonyl chloride (527 mg) was added to a solution of ethanol (688 mg) in pyridine (14 mL) under ice-cooling. The mixture was stirred under an argon atmosphere at room temperature for 3 hours. 1N Hydrochloric acid was added to the mixture at room temperature, and the mixture was extracted with ethyl acetate. The organic layer was separated, washed with 1N hydrochloric acid and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (methanol / ethyl acetate) to give the title compound (614 mg).
2- (2- (2- (2- (4- (6-((4- (Trifluoromethoxy) phenyl) amino) pyrimidine-4-yl) -1H-pyrazol-1-yl) ethoxy) ethoxy) Ethoxy) ethanol can be synthesized by a method known per se (eg, the method described in WO2015106292).
MS: [M + H] ⁺ 652.4.

B) tert-Butyl ((2S) -1-(((1S) -1-cyclohexyl-2-oxo-2-((2S) -2-(4- (3- (2- (2- (2- (2-) 2-) (2- (4- (6-((4- (Trifluoromethoxy) phenyl) amino) pyrimidine-4-yl) -1H-pyrazol-1-yl) ethoxy) ethoxy) ethoxy) ethoxy) benzoyl) -1, 3-Thiazole-2-yl) pyrrolidine-1-yl) ethyl) amino) -1-oxopropan-2-yl) methylcarbamate
2- (2- (2- (2- (4- (4- (6-((4- (Trifluoromethoxy) phenyl) amino) pyrimidin-4-yl) -1H-pyrazol-1-yl) ethoxy) ethoxy) ethoxy) ) Ethyl 4-methylbenzenesulfonate (239 mg) and tert-butyl ((S) -1-(((S) -1-cyclohexyl-2-((S) -2- (4- (3-hydroxybenzoyl)) ) Thiazol-2-yl) Pyrrolidine-1-yl) -2-oxoethyl) Amino) -1-oxopropan-2-yl) (Methyl) Carbamate (200 mg) in DMF (4.0 mL) solution with potassium carbonate (60 mL) mg) was added, and the mixture was stirred at 60 ° C. for 5 hours under an argon atmosphere. Water was added to the mixture at room temperature, and the mixture was extracted with ethyl acetate. The organic layer was separated, washed with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (methanol / ethyl acetate) to give the title compound (235 mg).
MS: [M + H] ⁺ 1078.9.

C) N-((1S) -1-cyclohexyl-2-oxo-2-((2S) -2- (4- (3- (2- (2- (2- (2- (4- (6-) 6-) ((4- (Trifluoromethoxy) phenyl) amino) pyrimidine-4-yl) -1H-pyrazol-1-yl) ethoxy) ethoxy) ethoxy) ethoxy) benzoyl) -1,3-thiazole-2-yl) pyrrolidine -1-yl) ethyl) -N ² -methyl-L-alanine amide
tert-butyl ((S) -1-(((S) -1-cyclohexyl-2-oxo-2-((S) -2- (4- (3- (2- (2- (2- (2) 2) -(4- (6-((4- (Trifluoromethoxy) phenyl) amino) pyrimidine-4-yl) -1H-pyrazol-1-yl) ethoxy) ethoxy) ethoxy) ethoxy) benzoyl) thiazole-2-yl) A mixture of pyrrolidine-1-yl) ethyl) amino) -1-oxopropan-2-yl) (methyl) carbamate (230 mg) and TFA (2.4 mL) was stirred at room temperature for 20 minutes. Toluene (5 mL) was added to the mixture and concentrated under reduced pressure. Ethyl acetate and saturated aqueous sodium hydrogen carbonate solution were added to the residue, and the organic layer was separated. After washing with saturated aqueous sodium hydrogen carbonate solution and saturated brine, the mixture was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (NH, methanol / ethyl acetate) to give the title compound (141 mg).
^{1 1} H NMR (300 MHz, DMSO-d ₆ ) δ 0.83-1.02 (3H, m), 1.02-1.28 (7H, m), 1.47-1.75 (6H, m), 1.96-2.13 (2H, m), 2.13 -2.27 (4H, m), 2.99 (1H, q, J = 6.7 Hz), 3.46-3.58 (8H, m), 3.69-3.85 (6H, m), 4.09-4.16 (2H, m), 4.32 (2H) , t, J = 5.3 Hz), 4.45-4.52 (1H, m), 5.38 (1H, dd, J = 7.8, 3.1 Hz), 6.91 (1H, d, J = 0.9 Hz), 7.21 (1H, dd, J = 7.7, 2.2 Hz), 7.31 (2H, d, J = 8.3 Hz), 7.44 (1H, t, J = 7.9 Hz), 7.61-7.68 (2H, m), 7.75-7.82 (2H, m), 7.90-7.99 (2H, m), 8.31 (1H, s), 8.47 (1H, s), 8.57 (1H, s), 9.72 (1H, s).

Example 9
3- (2-(((2- (2- (2- (3-((2-((2S) -1-((2S) -2-cyclohexyl-2-((N-methyl-L-alanyl) ) Amino) acetyl) pyrrolidine-2-yl) -1,3-thiazole-4-yl) carbonyl) phenoxy) ethoxy) ethoxy) ethoxy) acetyl) amino) [1,3] thiazolo [5,4-b] pyridine -5-yl) -N-(4-((4-ethylpiperazin-1-yl) methyl) -3- (trifluoromethyl) phenyl) benzamide

A) Methyl 1-Phenyl-2,5,8,11-Tetraoxatridecane-13-Oart
Add 60% sodium hydride (1.248 g) to a mixture of 2- (2- (2- (benzyloxy) ethoxy) ethoxy) ethanol (5 g) and THF (60 mL) under ice-cooling and ice-cool. Was stirred for 5 minutes. A mixture of methyl bromoacetate (2.76 mL) and THF (20 mL) was added dropwise to the reaction mixture under ice-cooling, and the mixture was stirred under ice-cooling for 2 hours. Acetic acid (4 mL) and methanol (1 mL) were added to the reaction mixture under ice-cooling, and the mixture was concentrated under reduced pressure. The residue was dissolved in hexane / ethyl acetate and filtered to remove insoluble material. The filtrate was concentrated, and the obtained residue was purified by silica gel column chromatography (ethyl acetate / hexane) to give the title compound (6.0 g).
MS: [M + H] ⁺ 313.3.

B) Methyl (2- (2- (2-Hydroxyethoxy) ethoxy) ethoxy) Acetate Methyl 1-Phenyl-2,5,8,11-Tetraoxatridecane-13-Oate (1.0 g) and 10% palladium carbon A mixture of (170 mg) methanol (30 mL) was stirred overnight at room temperature under a hydrogen atmosphere at atmospheric pressure. The catalyst was removed by filtration and the filtrate was concentrated under reduced pressure to give the title compound (680 mg).
^{1 1} H NMR (300 MHz, CDCl ₃ ) δ 2.24 (1H, brs), 3.58-3.80 (15H, m), 4.18 (2H, s).

C) Methyl (2- (2- (2-(((4-methylphenyl) sulfonyl) oxy) ethoxy) ethoxy) ethoxy) acetyl Methyl (2- (2- (2-hydroxyethoxy) ethoxy) ethoxy) acetyl P-Toluenesulfonyl chloride (583 mg) was added to a mixture of 680 mg) and pyridine (12 mL) at 0 ° C. The mixture was stirred at room temperature for 4 hours. The reaction mixture was concentrated under reduced pressure, and the obtained residue was diluted with ethyl acetate, washed successively with 1N hydrochloric acid, saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / hexane) to give the title compound (670 mg).
MS: [M + H] ⁺ 377.2.

D) Methyl (2- (2- (2- (3-((2-((2S) -1-((2S) -2-((N- (tert-butoxycarbonyl) -N-methyl-L- Alanyl) amino) -2-cyclohexylacetyl) pyrrolidine-2-yl) -1,3-thiazole-4-yl) carbonyl) phenoxy) ethoxy) ethoxy) ethoxy) acetate methyl (2- (2- (2-(((() (4-Methylphenyl) sulfonyl) Oxy) ethoxy) ethoxy) ethoxy) Acetyl) Acetyl (320 mg), tert-butyl ((2S) -1-(((1S) -1-Cyclohexyl-2-((2S) -2) -(4- (3-Hydroxybenzoyl) -1,3-thiazole-2-yl) pyrrolidine-1-yl) -2-oxoethyl) amino) -1-oxopropan-2-yl) methylcarbamate (509 mg) ), Potassium carbonate (235 mg), and DMSO (3 mL) were stirred at 50 ° C. overnight. The reaction mixture was cooled, diluted with ethyl acetate, washed with 5% aqueous sodium hydrogen carbonate solution and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (NH, ethyl acetate / hexane) to give the title compound (506 mg).
MS: [M + H] ⁺ 803.7.

E) (2- (2- (2- (3-((2-((2S) -1-((2S) -2-((N- (tert-butoxycarbonyl) -N-methyl-L-alanyl) ) Amino) -2-cyclohexylacetyl) pyrrolidine-2-yl) -1,3-thiazole-4-yl) carbonyl) phenoxy) ethoxy) ethoxy) ethoxy) methyl acetate (2- (2- (2- (3- (3-)3-) ((2-((2S) -1-((2S) -2-((N- (tert-butoxycarbonyl) -N-methyl-L-alanyl) amino) -2-cyclohexylacetyl) pyrrolidine-2-yl) ) -1,3-Thiazol-4-yl) carbonyl) phenoxy) ethoxy) ethoxy) ethoxy) acetyl (506 mg) and THF (5 mL) -methanol (5 mL) -water (5 mL) in a mixture of 4N water An aqueous solution of lithium oxide (0.5 mL) was added at room temperature. The mixture was stirred at room temperature for 30 minutes. 1N Hydrochloric acid (2.5 mL) was added to the mixture, diluted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give the title compound (486 mg).
MS: [M + H] ⁺ 789.6.

F) Ethyl 3-(2-((tert-butoxycarbonyl) amino) [1,3] thiazolo [5,4-b] pyridin-5-yl) benzoate ethyl 3- (2-amino [1,3] A mixture of thiazolo [5,4-b] pyridin-5-yl) benzoate (4.00 g) and di-tert-butyl dicarbonate (50 mL) was stirred at 120 ° C. for 16 hours. The solid was collected by filtration from the reaction mixture, washed with petroleum ether, and dried to give the title compound (3.85 g).
The above ethyl 3- (2-amino [1,3] thiazolo [5,4-b] pyridin-5-yl) benzoart can be synthesized by a method known per se (eg, the method described in WO2010144909). ..
^{1 1} H NMR (400 MHz, DMSO-d ₆ ) δ 1.34 (3H, t, J = 7.06 Hz), 1.51 (9H, s), 4.36 (2H, q, J = 7.20 Hz), 7.64 (1H, t, J = 7.72 Hz), 7.99 (1H, dt, J = 7.83, 1.38 Hz), 8.05-8.12 (2H, m), 8.33-8.37 (1H, m), 8.65 (1H, t, J = 1.76 Hz).

G) 3-(2-((tert-Butyloxycarbonyl) amino) [1,3] thiazolo [5,4-b] pyridin-5-yl) ethyl benzoate 3-(2-((tert-butoxycarbonyl)) 4N sodium hydroxide in a mixture of amino) [1,3] thiazolo [5,4-b] pyridin-5-yl) benzoate (3.80 g) and methanol-THF-water (1: 1: 1, 90 mL) Aqueous solution (4.75 mL) was added. The mixture was stirred at 30 ° C. overnight. The reaction mixture was concentrated under reduced pressure, neutralized with hydrochloric acid, and the resulting solid was collected by filtration and dried to give the title compound (2.60 g).
MS: [M + H] ⁺ 372.1.

H) tert-butyl (5-(3-((4-((4-ethylpiperazin-1-yl) methyl) -3- (trifluoromethyl) phenyl) carbamoyl) phenyl) [1,3] thiazolo [5] , 4-b] Pyridine-2-yl) Carbamate
3-(2-((tert-butoxycarbonyl) amino) [1,3] thiazolo [5,4-b] pyridin-5-yl) benzoic acid (371 mg), 4-((4-ethylpiperazin-1) -A mixture of methyl) -3- (trifluoromethyl) aniline (287 mg), WSC (221 mg), HOBt (189 mg) and anhydrous DMF (6 mL) Stir overnight at room temperature and further at 50 ° C. 3 Stirred for hours. The reaction mixture was cooled, diluted with ethyl acetate, washed with 5% saturated aqueous sodium carbonate solution and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (NH, ethyl acetate / hexane) to give the title compound (497 mg).
MS: [M + H] ⁺ 641.5.

I) 3- (2-amino [1,3] thiazolo [5,4-b] pyridin-5-yl) -N- (4-((4-ethylpiperazin-1-yl) methyl) -3- ( Trifluoromethyl) phenyl) benzamide
tert-Butyl (5-(3-((4-((4-ethylpiperazin-1-yl) methyl) -3- (trifluoromethyl) phenyl) carbamoyl) phenyl) [1,3] thiazolo [5,4 A mixture of -b] pyridin-2-yl) carbamate (508 mg) and TFA (6 mL) was stirred at room temperature for 10 minutes. The reaction mixture was concentrated under reduced pressure, diluted with ethyl acetate, washed with 5% aqueous sodium carbonate solution and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained solid was crystallized from toluene to give the title compound (388 mg).
MS: [M + H] ⁺ 541.3.

J) tert-butyl ((2S) -1-(((1S) -1-cyclohexyl-2-((2S) -2-(4- (3- (2- (2- (2- (2- (2- ( (5-(3-((4-((4-Ethylpiperazin-1-yl) methyl) -3- (trifluoromethyl) phenyl) carbamoyl) phenyl) [1,3] thiazolo [5,4-b] Pyridine-2-yl) amino) -2-oxoethoxy) ethoxy) ethoxy) ethoxy) benzoyl) -1,3-thiazole-2-yl) pyrrolidine-1-yl) -2-oxoethyl) amino) -1-oxo Propane-2-yl) Methylcarbamate
3- (2-Amino [1,3] thiazolo [5,4-b] pyridine-5-yl) -N- (4-((4-ethylpiperazin-1-yl) methyl) -3- (trifluoro) Methyl) phenyl) benzamide (92 mg), (2-(2- (2- (3-((2-((2S) -1-((2S) -2-((N- (tert-butoxycarbonyl)) -N-methyl-L-alanyl) amino) -2-cyclohexylacetyl) pyrrolidine-2-yl) -1,3-thiazole-4-yl) carbonyl) phenoxy) ethoxy) ethoxy) ethoxy) acetic acid (150 mg), A mixture of triethylamine (0.07 mL), N, N-dimethylaminopyridine (21 mg), anhydrous DMF (1.5 mL), and 2-methyl-6-nitrobenzoic acid anhydride (118 mg) was stirred overnight at room temperature. .. Triethylamine (0.07 mL) and 2-methyl-6-nitrobenzoic acid anhydride (118 mg) were added to the reaction mixture, and the mixture was further stirred at room temperature for 1 hr. The reaction mixture was diluted with ethyl acetate, washed with 5% aqueous sodium carbonate solution and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (NH, methanol / ethyl acetate) to give the title compound (170 mg).
MS: [M + H] ⁺ 1311.9.

K) 3-(2-(((2- (2- (2- (3-((2-((2S) -1-((2S) -2-Cyclohexyl-2-L) -Alanyl) amino) acetyl) pyrrolidine-2-yl) -1,3-thiazole-4-yl) carbonyl) phenoxy) ethoxy) ethoxy) ethoxy) acetyl) amino) [1,3] thiazolo [5,4-b ] Pyridine-5-yl) -N-(4-((4-ethylpiperazin-1-yl) methyl) -3- (trifluoromethyl) phenyl) benzamide
tert-butyl ((2S) -1-(((1S) -1-cyclohexyl-2-((2S) -2- (4- (3- (2- (2- (2- (2-((5)) -(3-((4-((4-Ethylpiperazin-1-yl) methyl) -3- (trifluoromethyl) phenyl) carbamoyl) phenyl) [1,3] thiazolo [5,4-b] pyridine- 2-yl) amino) -2-oxoethoxy) ethoxy) ethoxy) ethoxy) ethoxy) benzoyl) -1,3-thiazole-2-yl) pyrrolidine-1-yl) -2-oxoethyl) amino) -1-oxopropane- A mixture of 2-yl) methylcarbamate (165 mg) and TFA (3 mL) was stirred at room temperature for 10 minutes. Toluene (5 mL) was added to the reaction mixture, and the mixture was concentrated under reduced pressure. Ethyl acetate was added to the obtained residue, the mixture was washed with 5% aqueous sodium carbonate solution and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (NH, methanol / ethyl acetate /) to give the title compound (123 mg).
^{1 1} H NMR (300 MHz, CD ₃ OD) δ 0.95-1.27 (12H, m), 1.48-1.81 (6H, m), 2.03-2.35 (7H, m), 2.40-2.74 (9H, m), 3.13 ( 1H, q, J = 6.9 Hz), 3.66 (2H, s), 3.71-3.99 (12H, m), 4.12-4.19 (2H, m), 4.29 (2H, s), 4.44-4.57 (1H, m) , 5.37-5.62 (1H, m), 7.11 (1H, ddd, J = 8.3, 2.5, 0.9 Hz), 7.25-7.37 (1H, m), 7.55-7.69 (3H, m), 7.76 (1H, d, J = 8.6 Hz), 7.89-8.05 (4H, m), 8.14-8.29 (3H, m), 8.60 (1H, t, J = 1.7 Hz).

Example 11
14-(3-((2-((2S) -1-((2S) -2-cyclohexyl-2-((N-methyl-L-alanyl) amino) acetyl) pyrrolidine-2-yl) -1, 3-Thiazol-4-yl) carbonyl) phenoxy) -N- (3-((4-((4-ethylpiperazin-1-yl) methyl) -3- (trifluoromethyl) phenyl) carbamoyl) Phenyl) [1,3] thiazolo [5,4-b] pyridin-2-yl) -3,6,9,12-tetraoxatetradecane-1-amide

A) Methyl 1-Phenyl-2,5,8,11,14-Pentaoxahexadecane-16-Oart
Add 60% sodium hydride (2.11 g) to a mixture of 1-phenyl-2,5,8,11-tetraoxatridecane-13-ol (10 g) and THF (160 mL) under ice cooling. The mixture was stirred under ice cooling for 5 minutes. A mixture of methyl bromoacetate (4.66 mL) and THF (20 mL) was added dropwise to the reaction mixture under ice-cooling, and the mixture was stirred under ice-cooling for 2 hours. Acetic acid (4 mL) and methanol (1 mL) were added to the reaction mixture under ice-cooling, and the mixture was concentrated under reduced pressure. The residue was dissolved in hexane / ethyl acetate and filtered to remove insoluble material. The filtrate was concentrated and the obtained residue was purified by silica gel column chromatography (ethyl acetate / hexane) to give the title compound (9.10 g).
MS: [M + H] ⁺ 357.3.

B) Methyl 14-hydroxy-3,6,9,12-tetraoxatetradecane-1-oate Methyl 1-phenyl-2,5,8,11,14-pentaoxahexadecane-16-oart (1.0 g) and 10 A mixture of% palladium carbon (170 mg) in methanol (30 mL) was stirred overnight at room temperature under a hydrogen atmosphere at atmospheric pressure. The catalyst was removed by filtration and the filtrate was concentrated under reduced pressure to give the title compound (826 mg).
^{1 1} H NMR (300 MHz, CDCl ₃ ) δ 2.05 (1H, brs), 3.57-3.82 (19H, m), 4.17 (2H, s).

C) Methyl 14-(((4-methylphenyl) sulfonyl) oxy) -3,6,9,12-tetraoxatetradecane-1-oart Methyl 14-hydroxy-3,6,9,12-tetraoxatetradecane- P-Toluenesulfonyl chloride (2.14 g) was added to a mixture of 1-oart (747 mg) and pyridine (12 mL) at 0 ° C. The mixture was stirred at room temperature for 4 hours. The reaction mixture was concentrated under reduced pressure, ethyl acetate was added to the obtained residue, the mixture was washed successively with 1N hydrochloric acid, saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / hexane) to give the title compound (613 mg).
MS: [M + H] ⁺ 421.2.

D) Methyl 14-(3-((2-((2S) -1-((2S) -2-((N- (tert-butoxycarbonyl) -N-methyl-L-alanyl) amino) -2-) Cyclohexylacetyl) pyrrolidine-2-yl) -1,3-thiazole-4-yl) carbonyl) phenoxy) -3,6,9,12-tetraoxatetradecane-1-oate methyl 14-(((4-methylphenyl) ) Hydroxy) Oxy) -3,6,9,12-Tetraoxatetradecane-1-oate (300 mg), tert-butyl ((2S) -1-(((1S) -1-cyclohexyl-2-(((1S) -1-cyclohexyl-2-(() 2S) -2- (4- (3-Hydroxybenzoyl) -1,3-thiazole-2-yl) pyrrolidine-1-yl) -2-oxoethyl) amino) -1-oxopropan-2-yl) methylcarba A mixture of Methyl (427 mg), potassium carbonate (148 mg), and anhydrous DMF (3 mL) was stirred at 50 ° C. for 2 days. The reaction mixture was cooled, ethyl acetate was added, the mixture was washed with 5% aqueous sodium hydrogen carbonate solution and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (NH, ethyl acetate / hexane) to give the title compound (376 mg).
MS: [M + H] ⁺ 847.7.

E) 14-(3-((2-((2S) -1-((2S) -2-((N- (tert-butoxycarbonyl) -N-methyl-L-alanyl) amino) -2-cyclohexyl Acetyl) pyrrolidine-2-yl) -1,3-thiazole-4-yl) carbonyl) phenoxy) -3,6,9,12-Tetraoxatetradecane-1-ate Methyl 14-(3-((2-(2-( (2S) -1-((2S) -2-((N- (tert-butoxycarbonyl) -N-methyl-L-alanyl) amino) -2-cyclohexylacetyl) pyrrolidine-2-yl) -1,3 -Thiazol-4-yl) carbonyl) phenoxy) -3,6,9,12-tetraoxatetradecane-1-oate (376 mg) and THF (3.5 mL)-methanol (3.5 mL)-water (3.5 mL) A 4N aqueous solution of lithium hydroxide (0.35 mL) was added to the mixture at room temperature. The mixture was stirred at room temperature for 30 minutes. 1N Hydrochloric acid (1.7 mL) was added to the mixture, diluted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give the title compound (335 mg).
MS: [M + H] ⁺ 833.7.

F) tert-butyl ((2S) -1-(((1S) -1-cyclohexyl-2-((2S) -2-(4- (3-((14-((5- (3- (3-(() 4-((4-Ethylpiperazin-1-yl) methyl) -3- (trifluoromethyl) phenyl) carbamoyl) phenyl) [1,3] thiazolo [5,4-b] pyridin-2-yl) amino) -14-oxo-3,6,9,12-tetraoxatetradeca-1-yl) oxy) benzoyl) -1,3-thiazole-2-yl) pyrrolidine-1-yl) -2-oxoethyl) amino) -1-oxopropan-2-yl) methylcarbamate
3- (2-Amino [1,3] thiazolo [5,4-b] Pyridine-5-yl) -N- (4-((4-ethylpiperazin-1-yl) methyl) -3- (trifluoro) Methyl) Phenyl) benzamide (107 mg), 14-(3-((2-((2S) -1-((2S) -2-((N- (tert-butoxycarbonyl) -N-methyl-L- Alanyl) amino) -2-cyclohexylacetyl) pyrrolidine-2-yl) -1,3-thiazole-4-yl) carbonyl) phenoxy) -3,6,9,12-tetraoxatetradecane-1-ic acid (165 mg) ), Triethylamine (0.11 mL), N, N-dimethylaminopyridine (24 mg), and anhydrous DMF (1.5 mL) plus 2-methyl-6-nitrobenzoic acid anhydride (204 mg) at 0 ° C. It was. The mixture was stirred at room temperature for 1 hour. The reaction mixture was diluted with ethyl acetate, washed with 5% aqueous sodium carbonate solution and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (NH, methanol / ethyl acetate) to give the title compound (161 mg).
MS: [M + H] ⁺ 1355.9.

G) 14-(3-((2-((2S) -1-((2S) -2-cyclohexyl-2-((N-methyl-L-alanyl) amino) acetyl) pyrrolidine-2-yl)- 1,3-thiazole-4-yl) carbonyl) phenoxy) -N-(5-(3-((4-((4-ethylpiperazin-1-yl) methyl) -3- (trifluoromethyl) phenyl)) Carbamoyl) Phenyl) [1,3] Thiazolo [5,4-b] Pyridine-2-yl) -3,6,9,12-Tetraoxatetradecane-1-amide
tert-butyl ((2S) -1-(((1S) -1-cyclohexyl-2-((2S) -2- (4- (3-((14-((5- (3- ((4-) 4- ((4-Ethylpiperazin-1-yl) methyl) -3- (trifluoromethyl) phenyl) carbamoyl) phenyl) [1,3] thiazolo [5,4-b] pyridin-2-yl) amino) -14 -Oxo-3,6,9,12-tetraoxatetradeca-1-yl) oxy) benzoyl) -1,3-thiazole-2-yl) pyrrolidine-1-yl) -2-oxoethyl) amino) -1 A mixture of -oxopropan-2-yl) methylcarbamate (155 mg) and TFA (4.5 mL) was stirred at room temperature for 10 minutes. The reaction mixture was diluted with toluene (5 mL), concentrated under reduced pressure, ethyl acetate was added to the obtained residue, washed with 5% aqueous sodium carbonate solution and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. did. The residue was purified by silica gel column chromatography (NH, methanol / ethyl acetate) to give the title compound (124 mg).
^{1 1} H NMR (300 MHz, CD ₃ OD) δ 0.95-1.36 (11H, m), 1.47-1.81 (6H, m), 2.03-2.35 (7H, m), 2.39-2.78 (10H, m), 3.14 ( 1H, q, J = 6.9 Hz), 3.59-4.01 (18H, m), 4.08-4.16 (2H, m), 4.28 (2H, s), 4.44-4.57 (1H, m), 5.37-5.63 (1H, m) m), 7.08-7.18 (1H, m), 7.33 (1H, t, J = 8.2 Hz), 7.55-7.68 (3H, m), 7.76 (1H, d, J = 8.6 Hz), 7.88-8.08 (4H) , m), 8.13-8.28 (3H, m), 8.55-8.65 (1H, m).

Example 12
N- (2-Chloro-6-methylphenyl) -2-((6- (4-((2- (2- (3- ((2-((2S) -1-((2S) -2-S) -2- Cyclohexyl-2-((N-methyl-L-alanyl) amino) acetyl) pyrrolidine-2-yl) -1,3-thiazole-4-yl) carbonyl) phenoxy) ethoxy) ethoxy) acetyl) piperazin-1-yl ) -2-Methylpyrimidin-4-yl) amino) -1,3-thiazole-5-carboxamide

A) 2-Chloro-N- (2-chloro-6-methylphenyl) -1,3-thiazole-5-carboxamide
A 1.6 M n-butyllithium hexane solution (16 mL) was added dropwise at -78 ° C to a mixture of 2-chloro-1,3-thiazole (2.92 g) and anhydrous THF (60 mL). The mixture was stirred at −78 ° C. for 15 minutes, then a solution of 1-chloro-2-isocyanato-3-methylbenzene (4.5 g) in anhydrous THF (30 mL) was added dropwise and stirred at −78 ° C. for 2 hours. A saturated aqueous solution of ammonium chloride (60 mL) was added to the mixture at −78 ° C., and the mixture was partitioned between ethyl acetate and water. The organic layer was separated, washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained solid was crystallized from ethyl acetate / hexane to give the title compound (5.43 g).
MS: [M + H] ⁺ 287.1.

B) 2-Chloro-N- (2-Chloro-6-methylphenyl) -N- (4-Methoxybenzyl) -1,3-thiazole-5-carboxamide
Add 60% sodium hydride (0.91 g) to a mixture of 2-chloro-N- (2-chloro-6-methylphenyl) -1,3-thiazole-5-carboxamide (5.43 g) and anhydrous DMF (36 mL). Added at 0 ° C. The mixture was stirred at 0 ° C. for 30 minutes, 1- (chloromethyl) -4-methoxybenzene (3.58 g) and tetrabutylammonium iodide (1.4 g) were added, and the mixture was stirred overnight at room temperature. The reaction mixture was poured into water and extracted with ethyl acetate. The extract was washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / hexane) to give the title compound (6.03 g).
MS: [M + H] ⁺ 407.1.

C) N- (2-chloro-6-methylphenyl) -2-((6-chloro-2-methylpyrimidine-4-yl) amino) -N- (4-methoxybenzyl) -1,3-thiazole- 5-Carboxamide
6-Chloro-2-methylpyrimidine-4-amine (3.19 g) was added to a mixture of 60% sodium hydride (2.66 g) and anhydrous THF (50 mL) at 0 ° C. After stirring the mixture at 0 ° C. for 30 minutes, 2-chloro-N- (2-chloro-6-methylphenyl) -N- (4-methoxybenzyl) -1,3-thiazole-5-carboxamide (6.03 g) An anhydrous THF (20 mL) solution was added. The mixture was stirred at 70 ° C. for 4 hours. The reaction mixture was cooled to 0 ° C. and water (2 mL) was added. The mixture was neutralized with 1N hydrochloric acid at 0 ° C. and extracted with ethyl acetate. The organic layer was separated, washed successively with 1N hydrochloric acid, saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was solidified with ether to give the title compound (6.99 g).
MS: [M + H] ⁺ 514.2.

D) N- (2-chloro-6-methylphenyl) -2-((6-chloro-2-methylpyrimidine-4-yl) amino) -1,3-thiazole-5-carboxamide
N- (2-Chloro-6-methylphenyl) -2-((6-chloro-2-methylpyrimidine-4-yl) amino) -N- (4-methoxybenzyl) -1,3-thiazole-5- A mixture of carboxamide (2.1 g), TFA (16 mL), and trifluoromethanesulfonic acid (1.3 mL) was stirred at room temperature for 3 hours. The reaction mixture was poured into crushed ice and neutralized with 8N aqueous sodium hydroxide solution. The precipitate was collected by filtration, washed with water and ether, and dried to give the title compound (1.68 g).
MS: [M + H] ⁺ 394.1.

E) N- (2-Chloro-6-methylphenyl) -2-((2-methyl-6- (piperazine-1-yl) pyrimidine-4-yl) amino) -1,3-thiazole-5-carboxamide
N- (2-chloro-6-methylphenyl) -2-((6-chloro-2-methylpyrimidine-4-yl) amino) -1,3-thiazole-5-carboxamide (750 mg), piperazine (1.64) A mixture of g), DIPEA (0.066 mL) and DMSO (6 mL) was stirred at 60 ° C. for 3 hours. Water (12 mL) was added and cooled. The precipitate was collected by filtration, washed with water and dried to give the title compound (776 mg).
MS: [M + H] ⁺ 444.2.

F) Methyl (2- (2- (benzyloxy) ethoxy) ethoxy) acetate
To a mixture of 2- (2- (benzyloxy) ethoxy) ethanol (5.47 g) and THF (80 mL) was added 60% sodium hydride (1.672 g) under ice cooling and stirred under ice cooling for 10 minutes. .. Methyl bromoacetate (3.69 mL) was added dropwise to the reaction mixture under ice-cooling, and the mixture was stirred under ice-cooling for 2 hours. Acetic acid (4 mL) and methanol (1 mL) were added to the reaction mixture under ice-cooling, and the mixture was concentrated under reduced pressure. Water was added to the residue, and the mixture was extracted with ethyl acetate. The organic layer was separated, washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (NH, ethyl acetate / hexane) to give the title compound (5.47 g).
MS: [M + H] ⁺ 269.2.

G) Methyl (2- (2-hydroxyethoxy) ethoxy) acetate Methyl (2- (2- (benzyloxy) ethoxy) ethoxy) acetate (1.0 g) and 10% palladium carbon (170 mg) in methanol (30 mL) The mixture was stirred overnight at room temperature under a normal pressure hydrogen atmosphere. The catalyst was removed by filtration and the filtrate was concentrated under reduced pressure to give the title compound (672 mg).
^{1 1} H NMR (300 MHz, CDCl ₃ ) δ 2.57 (1H, brs), 3.58-3.66 (2H, m), 3.68-3.81 (9H, m), 4.17 (2H, s).

H) Methyl (2-(2-(((4-Methylphenyl) sulfonyl) oxy) ethoxy) ethoxy) acetylate Methyl (2- (2-hydroxyethoxy) ethoxy) acetylate (667 mg) and pyridine (16 mL) P-Toluenesulfonyl chloride (2.85 g) was added to the mixture at 0 ° C. The mixture was stirred at room temperature for 4 hours. The reaction mixture was concentrated under reduced pressure, ethyl acetate was added to the obtained residue, washed successively with 1N hydrochloric acid, saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / hexane) to give the title compound (606 mg).
MS: [M + H] ⁺ 333.2.

I) Methyl (2- (2- (3-((2-((2S) -1-((2S) -2-((N- (tert-butoxycarbonyl) -N-methyl-L-alanyl) amino) ) -2-Cyclohexylacetyl) Pyrrolidine-2-yl) -1,3-thiazole-4-yl) carbonyl) Phenoxy) ethoxy) ethoxy) Acetate methyl (2- (2-(((4-methylphenyl) sulfonyl)) Oxy) ethoxy) ethoxy) acetate (200 mg), tert-butyl ((2S) -1-(((1S) -1-cyclohexyl-2-((2S) -2- (4- (3-hydroxybenzoyl)) -1,3-thiazole-2-yl) pyrrolidine-1-yl) -2-oxoethyl) amino) -1-oxopropan-2-yl) methylcarbamate (360 mg), potassium carbonate (125 mg), and The mixture of anhydrous DMF (3 mL) was stirred at 50 ° C. for 2 days. The reaction mixture was cooled, diluted with ethyl acetate, washed with 5% aqueous sodium carbonate solution and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (NH, ethyl acetate / hexane) to give the title compound (306 mg).
MS: [M + H] ⁺ 759.5.

J) (2- (2- (3-((2-((2S) -1-((2S) -2-((N- (tert-butoxycarbonyl) -N-methyl-L-alanyl) amino)) -2-cyclohexylacetyl) pyrrolidine-2-yl) -1,3-thiazole-4-yl) carbonyl) phenoxy) ethoxy) ethoxy) methyl acetate (2- (2- (3-((2-((2S))) -1-((2S) -2-((N- (tert-butoxycarbonyl) -N-methyl-L-alanyl) amino) -2-cyclohexylacetyl) pyrrolidine-2-yl) -1,3-thiazole- 4-Il) carbonyl) phenoxy) ethoxy) ethoxy) ethoxy) Acetyl (306 mg) and THF (3 mL) -methanol (3 mL) -water (3 mL) mixed with 4N aqueous lithium hydroxide solution (0.3 mL) at room temperature added. The mixture was stirred at room temperature for 30 minutes. 1N Hydrochloric acid (1.4 mL) was added to the mixture, diluted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give the title compound (308 mg).
MS: [M + H] ⁺ 745.5.

K) tert-butyl ((2S) -1-(((1S) -2-((2S) -2- (4- (3- (2- (2- (2- (4- (6- ((() 5-((2-Chloro-6-methylphenyl) carbamoyl) -1,3-thiazole-2-yl) amino) -2-methylpyrimidine-4-yl) piperazine-1-yl) -2-oxoethoxy) Ethoxy) ethoxy) benzoyl) -1,3-thiazole-2-yl) pyrrolidine-1-yl) -1-cyclohexyl-2-oxoethyl) amino) -1-oxopropan-2-yl) methylcarbamate
N- (2-Chloro-6-methylphenyl) -2-((2-Methyl-6- (piperazin-1-yl) pyrimidin-4-yl) amino) -1,3-thiazole-5-carboxamide (89) mg), (2- (2- (3-((2-((2S) -1-((2S) -2-((N- (tert-butoxycarbonyl) -N-methyl-L-alanyl) amino) )-2-Cyclohexylacetyl) Pyrrolidine-2-yl) -1,3-thiazole-4-yl) Carbonyl) Phenoxy) ethoxy) ethoxy) Acetic acid (149 mg), HOBt (38 mg), WSC (0.05 mL), And the mixture of DMF (1.5 mL) was stirred overnight at room temperature. The reaction mixture was diluted with ethyl acetate, washed with 5% aqueous sodium hydrogen carbonate solution and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (methanol / ethyl acetate) to give the title compound (197 mg).
MS: [M + H] ⁺ 1170.8.

L) N- (2-Chloro-6-methylphenyl) -2-((6- (4-((2- (2- (3-((2-((2S) -1-((2S)-)- 2-Cyclohexyl-2-((N-methyl-L-alanyl) amino) acetyl) pyrrolidine-2-yl) -1,3-thiazole-4-yl) carbonyl) phenoxy) ethoxy) ethoxy) acetyl) piperazin-1 -Il) -2-methylpyrimidine-4-yl) amino) -1,3-thiazole-5-carboxamide
tert-Butyl ((2S) -1-(((1S) -2-((2S) -2- (4- (3- (2- (2- (2- (4- (6- ((5-)- ((2-Chloro-6-methylphenyl) carbamoyl) -1,3-thiazole-2-yl) amino) -2-methylpyrimidine-4-yl) piperazine-1-yl) -2-oxoethoxy) ethoxy) Ethoxy) benzoyl) -1,3-thiazole-2-yl) pyrrolidine-1-yl) -1-cyclohexyl-2-oxoethyl) amino) -1-oxopropan-2-yl) methylcarbamate (189 mg) The mixture of TFA (4.5 mL) was stirred at room temperature for 10 minutes. The reaction mixture was diluted with toluene (5 mL) and concentrated under reduced pressure. Ethyl acetate was added to the obtained residue, the mixture was washed with 5% aqueous sodium carbonate solution and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (NH, methanol / ethyl acetate) to give the title compound (163 mg).
¹ H NMR (300 MHz, CD ₃ OD) δ 0.96-1.35 (8H, m), 1.50-1.85 (6H, m), 2.05-2.48 (13H, m), 3.13 (1H, q, J = 6.8 Hz) , 3.49-4.03 (16H, m), 4.20 (2H, dd, J = 5.2, 3.6 Hz), 4.28 (2H, s), 4.50-4.59 (1H, m), 5.40-5.66 (1H, m), 5.87 (1H, s), 7.14-7.41 (5H, m), 7.61-7.74 (2H, m), 8.15 (1H, s), 8.21-8.29 (1H, m).

Example 13
N- (2-Chloro-6-methylphenyl) -2-((6- (4-((2- (2- (2- (3-((2-((2S) -1-((2S)) -2-Cyclohexyl-2-((N-methyl-L-alanyl) amino) acetyl) pyrrolidine-2-yl) -1,3-thiazole-4-yl) carbonyl) phenoxy) ethoxy) ethoxy) ethoxy) acetyl) Piperazin-1-yl) -2-methylpyrimidine-4-yl) amino) -1,3-thiazole-5-carboxamide

A) tert-butyl ((2S) -1-(((1S) -2-((2S) -2- (4- (3- (2- (2- (2- (2- (4- (6) -((5-((2-Chloro-6-methylphenyl) carbamoyl) -1,3-thiazole-2-yl) amino) -2-methylpyrimidine-4-yl) piperazine-1-yl) -2- Oxoethoxy) ethoxy) ethoxy) ethoxy) benzoyl) -1,3-thiazole-2-yl) pyrrolidine-1-yl) -1-cyclohexyl-2-oxoethyl) amino) -1-oxopropan-2-yl) methyl Carbamate
N- (2-Chloro-6-methylphenyl) -2-((2-Methyl-6- (piperazin-1-yl) pyrimidin-4-yl) amino) -1,3-thiazole-5-carboxamide (89) mg), (2- (2- (2- (3-((2-((2S) -1-((2S) -2-((N- (tert-butoxycarbonyl) -N-methyl-L- Alanyl) amino) -2-cyclohexylacetyl) pyrrolidine-2-yl) -1,3-thiazole-4-yl) carbonyl) phenoxy) ethoxy) ethoxy) ethoxy) acetic acid (158 mg), HOBt (38 mg), WSC A mixture of (0.05 mL) and DMF (1.5 mL) was stirred overnight at room temperature. The reaction mixture was diluted with ethyl acetate, washed with 5% aqueous sodium hydrogen carbonate solution and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (methanol / ethyl acetate) to give the title compound (250 mg).
MS: [M + H] ⁺ 1214.8.

B) N- (2-Chloro-6-methylphenyl) -2-((6- (4-((2- (2- (2- (3-((2-((2S) -1-(( 2S) -2-cyclohexyl-2-((N-methyl-L-alanyl) amino) acetyl) pyrrolidine-2-yl) -1,3-thiazole-4-yl) carbonyl) phenoxy) ethoxy) ethoxy) ethoxy) Acetyl) piperazin-1-yl) -2-methylpyrimidine-4-yl) amino) -1,3-thiazole-5-carboxamide
tert-Butyl ((2S) -1-(((1S) -2-((2S) -2- (4- (3- (2- (2- (2- (2- (4- (6- (6) (5-((2-Chloro-6-methylphenyl) carbamoyl) -1,3-thiazole-2-yl) amino) -2-methylpyrimidine-4-yl) piperazine-1-yl) -2-oxoethoxy ) Ethoxy) ethoxy) ethoxy) benzoyl) -1,3-thiazole-2-yl) pyrrolidine-1-yl) -1-cyclohexyl-2-oxoethyl) amino) -1-oxopropan-2-yl) methylcarbamate A mixture of (242 mg) and TFA (4.5 mL) was stirred at room temperature for 10 minutes. The reaction mixture was diluted with toluene (5 mL) and concentrated under reduced pressure. Ethyl acetate was added to the obtained residue, the mixture was washed with 5% aqueous sodium carbonate solution and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (NH, ethyl acetate / hexane) to give the title compound (168 mg).
^{1 1} H NMR (300 MHz, CD ₃ OD) δ 0.95-1.36 (8H, m), 1.51-1.85 (6H, m), 2.04-2.54 (13H, m), 3.14 (1H, q, J = 6.9 Hz) , 3.51-3.77 (16H, m), 3.80-4.03 (4H, m), 4.14-4.21 (2H, m), 4.27 (2H, s), 4.50-4.60 (1H, m), 5.42-5.68 (1H, m), 5.93 (1H, s), 7.12-7.42 (5H, m), 7.63-7.73 (2H, m), 8.14 (1H, s), 8.23-8.30 (1H, m).

Example 14
3- (2-(((2- (2- (2- (3-((5-((2S) -1-((2S) -2-cyclohexyl-2-((N-methyl-L-alanyl) ) Amino) Acetyl) Pyrrolidine-2-yl) Pyridine-3-yl) Carbonyl) Phenoxy) ethoxy) ethoxy) ethoxy) Acetyl) Amino) [1,3] Thiazolo [5,4-b] Pyridine-5-yl) -N-(4-((4-ethylpiperazin-1-yl) methyl) -3- (trifluoromethyl) phenyl) benzamide

A) Benzyl (2S)-((N- (tert-butoxycarbonyl) -N-methyl-L-alanyl) amino) (cyclohexyl) acetate benzyl (2S) -amino (cyclohexyl) acetate monohydrochloride (11.0 g), DIPEA (15.0 g) was added to a mixture of N- (tert-butoxycarbonyl) -N-methyl-L-alanine, HATU (14.8 g) and dichloromethane (200 mL), and the mixture was stirred at room temperature for 16 hours. Water was added to the mixture, the organic layer was extracted, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether) to give the title compound (14.0 g).
The above-mentioned benzyl (2S) -amino (cyclohexyl) acetate monohydrochloride can be synthesized by a method known per se (for example, the method described in WO2008040934).
^{1 1} H NMR (400 MHz, CDCl ₃ ) δ 0.92-1.25 (5H, m), 1.34-1.35 (3H, m), 1.50 (9H, s), 1.66-1.82 (6H, m), 2.80-2.82 (3H) , m), 4.54-4.58 (1H, m), 4.59-4.61 (1H, m), 5.14-5.22 (2H, m), 6.45-6.75 (1H, m), 7.33-7.41 (5H, m).

B) (2S)-((N- (tert-butoxycarbonyl) -N-methyl-L-alanyl) amino) (cyclohexyl) benzyl acetate (2S)-((N- (tert-butoxycarbonyl) -N-methyl) A mixture of -L-alanyl) amino) (cyclohexyl) acetate (14.0 g) and 10% palladium carbon (2.0 g) in ethanol (300 mL) was stirred at room temperature for 16 hours under a hydrogen atmosphere of 15 psi. The catalyst was removed by filtration, and the filtrate was concentrated under reduced pressure to give the title compound (11.4 g).
^{1 1} H NMR (400 MHz, CDCl ₃ ) δ 1.0-1.45 (8H, m), 1.50 (9H, s), 1.55-1.87 (6H, m), 2.82 (3H, s), 4.51-4.53 (1H, m) ), 4.54-4.81 (1H, m), 6.60-7.01 (1H, m), 7.79 (1H, brs).

C) 3-Bromo-5-((2S) -1-((1R) -1- (4-methoxyphenyl) ethyl) pyrrolidine-2-yl) pyridine
Acetic acid (50 mL) and sodium triacetoxyborohydride (224 g) in a solution of 4- (5-bromopyridin-3-yl) -4-oxobutanal (109 g) in dichloromethane (2.00 L) at -78 ° C. Was added, and then R- (+)-1- (4-methoxyphenyl) ethylamine (84.6 g) was gradually added with stirring. After stirring at -70 ° C for 1 hour, the mixture was further stirred at room temperature for 2 hours. The reaction mixture was diluted with dichloromethane (200 mL) and washed twice with water (500 mL), saturated aqueous sodium hydrogen carbonate solution (200 mL) and water (1 L). The separated organic layer was concentrated, and the residue was purified by silica gel column chromatography (ethyl acetate / hexane) to give the title compound (106 g).
^{1 1} H NMR (400 MHz, CD ₃ OD) δ 1.40 (3H, d, J = 6.62 Hz), 1.58-1.72 (1H, m), 1.86-1.95 (1H, m), 1.99-2.05 (1H, m) , 2.27 (1H, dq, J = 12.79, 8.67 Hz), 2.69 (1H, td, J = 9.37, 7.28 Hz), 3.30 (1H, d, J = 1.32 Hz), 3.38-3.46 (1H, m), 3.58 (1H, q, J = 6.62 Hz), 3.69 (3H, s), 6.57 (2H, d, J = 8.82 Hz), 6.97 (2H, s), 7.50-7.55 (1H, m), 8.09-8.15 (1H, s), 8.20-8.28 (1H, s).

D) Methyl 5-((2S) -1-((1R) -1- (4-methoxyphenyl) ethyl) pyrrolidine-2-yl) nicotinate
3-Bromo-5-((2S) -1-((1R) -1- (4-methoxyphenyl) ethyl) pyrrolidine-2-yl) pyridine (16.0 g), [1,1-bis (diphenylphosphino) ) Ferrocene] A mixture of dichloropalladium (II) (3.3 g), triethylamine (50 mL) and methanol (250 mL) was stirred under a carbon monoxide atmosphere (50 psi) at 80 ° C. for 16 hours. Impurities were removed by filtration, the filtrate was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether) to give the title compound (13.0 g).
^{1 1} H NMR (400 MHz, CDCl ₃ ) δ 1.35 (3H, d, J = 6.4 Hz), 1.60-1.66 (1H, m), 1.73-1.96 (2H, m), 2.20-2.26 (1H, m), 2.58-2.61 (1H, m), 3.18-3.20 (1H, m), 3.57-3.59 (1H, m), 3.68-3.83 (4H, m), 3.96 (3H, s), 6.18 (2H, d, J) = 8.8 Hz), 7.04 (2H, d, J = 8.4 Hz), 8.0 (1H, t, J = 2.0 Hz), 8.57 (1H, d, J = 2.0 Hz), 9.94 (1H, d, J = 2.0) Hz).

E) N-Methoxy-5-((2S) -1-((1R) -1- (4-Methoxyphenyl) ethyl) pyrrolidine-2-yl) -N-methylnicotinamide Methyl 5-((2S)- 1-((1R) -1- (4-Methoxyphenyl) ethyl) pyrrolidine-2-yl) nicotinate (12.0 g), lithium hydroxide monohydrate (4.5 g) and methanol (150 mL) -water (50) The mixture of mL) was stirred at room temperature for 3 hours. The reaction mixture was concentrated to give the crude title compound. A mixture of the resulting residue, N, O-dimethoxyhydroxyamine hydrochloride (6.8 g), HATU (14.7 g), triethylamine (14.3 g) and DMF (100 mL) was stirred at room temperature for 16 hours. Water was added to the mixture, and the mixture was extracted three times with ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether) to give the title compound (10.0 g).
^{1 1} H NMR (400 MHz, CDCl ₃ ) δ1.32 (3H, d, J = 6.8 Hz), 1.55-1.65 (1H, m), 1.73-1.89 (2H, m), 2.20-2.24 (1H, m) , 2.58-2.62 (1H, m), 3.05-3.09 (1H, m), 3.38 (3H, s), 3.53 (3H, s), 3.55-3.65 (1H, m), 3.73-3.78 (4H, m) , 6.67 (2H, d, J = 8.8 Hz), 7.11 (2H, d, J = 8.4 Hz), 7.90 (1H, s), 8.50 (1H, d, J = 2.0 Hz), 8.70 (1H, d, J = 1.6 Hz).

F) (5-((2S) -1-((1R) -1- (4-methoxyphenyl) ethyl) pyrrolidine-2-yl) pyridin-3-yl) (3- (tetrahydro-2H-pyran-2) -Iloxy) Phenyl) Metanon
A catalytic amount of 1,2-dibromoethane is added to a mixture of 2- (3-bromophenoxy) tetrahydro-2H-pyran (2.08 g), magnesium (1.95 g) and anhydrous THF (50 mL) under a nitrogen atmosphere at room temperature. It was. A solution of 2- (3-bromophenoxy) tetrahydro-2H-pyran (18.7 g) in anhydrous THF (150 mL) was added dropwise, and the mixture was stirred under reflux conditions for 1 hour. After cooling to room temperature, N-methoxy-5-((2S) -1-((1R) -1- (4-methoxyphenyl) ethyl) pyrrolidine-2-yl) -N-methylnicotinamide (10.0 g) Anhydrous THF (50 mL) solution was added dropwise. The reaction mixture was stirred at room temperature for 16 hours, saturated aqueous ammonium chloride solution was added to the mixture, and the mixture was extracted three times with ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether) to give the title compound (12.0 g).
^{1 1} H NMR (400 MHz, CDCl ₃ ) δ 1.37 (3H, d, J = 6.4 Hz), 1.60-2.07 (9H, m), 2.20-2.30 (1H, m), 2.58-2.62 (1H, m), 3.15-3.24 (1H, m), 3.60-3.75 (6H, m), 3.85-3.92 (1H, m), 5.55 (1H, dd, J = 6.4, 3.2 Hz), 6.63 (2H, dd, J = 8.4) , 2.0 Hz), 7.06 (2H, dd, J = 8.8, 2.4 Hz), 7.33-7.35 (2H, m), 7.40-7.45 (1H, m), 7.50 (1H, s), 7.82-7.84 (1H, s) m), 8.62 (1H, t, J = 2.8 Hz), 8.69 (1H, t, J = 2.0 Hz).

G) (3-Hydroxyphenyl) (5-((2S) -pyrrolidin-2-yl) pyridin-3-yl) metanone hydrochloride
(5-((2S) -1-((1R) -1- (4-Methoxyphenyl) ethyl) pyrrolidine-2-yl) pyridin-3-yl) (3- (tetrahydro-2H-pyran-2-yloxy) ) Phenyl) A mixture of methanone (10.0 g) and TFA (30 mL) was microwaved at 100 ° C. for 30 minutes. The reaction mixture was concentrated. Di-tert-butyl dicarbonate (5.65 g) was added to the resulting mixture of triethylamine (5.0 g) and dichloromethane (120 mL) at room temperature. After stirring at room temperature for 5 hours, the reaction mixture was washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The mixture of the obtained residue and 4N ethyl acetate solution of hydrogen chloride (50 mL) was stirred at room temperature for 3 hours. The solid was collected by filtration and dried under reduced pressure to give the title compound (7.0 g).
MS: [M + H] ⁺ 269.0.

H) tert-Butyl ((2S) -1-(((1S) -1-cyclohexyl-2-((2S) -2-(5-(3-hydroxybenzoyl) pyridin-3-yl) pyrrolidine-1- Il) -2-oxoethyl) amino) -1-oxopropan-2-yl) methylcarbamate
(2S)-((N- (tert-butoxycarbonyl) -N-methyl-L-alanyl) amino) (cyclohexyl) acetate (1.3 g), (3-hydroxyphenyl) (5-((2S) -pyrrolidin- HATU (2.43 g) is added to a mixture of 2-yl) pyridine-3-yl) metanone hydrochloride (2.2 g), DIPEA (2.2 g) and dichloromethane (100 mL) at room temperature, and after stirring for 16 hours, the reaction mixture is mixed. Concentrated. Methanol (80 mL) and saturated aqueous lithium hydroxide solution (20 mL) were added to the residue, and the mixture was stirred for 2 hours to concentrate the reaction mixture. The residue was diluted with water and the pH was adjusted to 6 with 1N hydrochloric acid. After adjusting the pH to 8 with aqueous ammonia, the mixture was extracted with ethyl acetate. The organic layer was separated, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether) to give the title compound (1.1 g).
MS: [M + H] ⁺ 593.3.

I) Methyl (2- (2- (2- (3-((5-((2S) -1-((2S) -2-((N- (tert-butoxycarbonyl) -N-methyl-L- Alanyl) amino) -2-cyclohexylacetyl) pyrrolidine-2-yl) pyridin-3-yl) carbonyl) phenoxy) ethoxy) ethoxy) ethoxy) acetate
tert-butyl ((2S) -1-(((1S) -1-cyclohexyl-2-((2S) -2-(5-(3-hydroxybenzoyl) pyridin-3-yl) pyrrolidine-1-yl)) -2-oxoethyl) amino) -1-oxopropan-2-yl) methylcarbamate (297 mg), methyl (2-(2-(2-(((4-methylphenyl) sulfonyl) oxy) ethoxy) ethoxy) A mixture of ethoxy) acetate (189 mg), potassium carbonate (138 mg), and DMSO (1.5 mL) was stirred at 60 ° C. overnight. The reaction mixture was cooled, diluted with ethyl acetate, washed with 5% aqueous sodium hydrogen carbonate solution and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (NH, ethyl acetate / hexane) to give the title compound (220 mg).
MS: [M + H] ⁺ 797.4.

J) (2- (2- (2- (3-((5-((2S) -1-((2S) -2-((N- (tert-butoxycarbonyl) -N-methyl-L-alanyl) ) Amino) -2-cyclohexylacetyl) Pyrrolidine-2-yl) Pyridine-3-yl) Carbonyl) Phenoxy) ethoxy) ethoxy) ethoxy) Methyl acetate (2- (2- (2- (3-((5- (5-() (2S) -1-((2S) -2-((N- (tert-butoxycarbonyl) -N-methyl-L-alanyl) amino) -2-cyclohexylacetyl) pyrrolidine-2-yl) pyridine-3- Il) Carbonyl) Phenoxy) ethoxy) ethoxy) ethoxy) ethoxy) Acetyl (213 mg) and THF (2 mL) -methanol (2 mL) -water (2 mL) mixed with 4N aqueous lithium hydroxide solution (0.20 mL) at room temperature added. The mixture was stirred at room temperature for 30 minutes. 1N Hydrochloric acid (0.84 mL) was added to the reaction mixture, diluted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give the title compound (209 mg).
MS: [M + H] ⁺ 783.4.

K) tert-butyl ((2S) -1-(((1S) -1-cyclohexyl-2-((2S) -2-(5-(3- (2- (2- (2- (2- (2-( (5-(3-((4-((4-ethylpiperazin-1-yl) methyl) -3- (trifluoromethyl) phenyl) carbamoyl) phenyl) [1,3] thiazolo [5,4-b] Pyridine-2-yl) Amino) -2-oxoethoxy) ethoxy) ethoxy) ethoxy) Benzoyl) Pyridine-3-yl) Pyrrolidine-1-yl) -2-oxoethyl) Amino) -1-oxopropan-2-yl ) Methylcarbamate
3- (2-Amino [1,3] thiazolo [5,4-b] Pyridine-5-yl) -N- (4-((4-ethylpiperazin-1-yl) methyl) -3- (trifluoro) Methyl) phenyl) benzamide (115 mg), (2- (2- (2- (3-((5-((2S) -1-((2S) -2-((N- (tert-butoxycarbonyl)) -N-methyl-L-alanyl) amino) -2-cyclohexylacetyl) pyrrolidine-2-yl) pyridin-3-yl) carbonyl) phenoxy) ethoxy) ethoxy) ethoxy) acetic acid (200 mg), triethylamine (0.09 mL) , N, N-Dimethylaminopyridine (26 mg), and anhydrous DMF (2 mL) were added with 2-methyl-6-nitrobenzoic acid anhydride (147 mg) at 0 ° C. The mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated, and the obtained residue was diluted with ethyl acetate, washed with 5% aqueous sodium carbonate solution and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (NH, methanol / ethyl acetate) to give the title compound (213 mg).
MS: [M + H] ⁺ 1305.4.

L) 3-(2-(((2- (2- (2- (3-((5-((2S) -1-((2S) -2-cyclohexyl-2-L) -Alanyl) Amino) Acetyl) Pyrrolidine-2-yl) Pyridine-3-yl) Carbonyl) Phenoxy) ethoxy) ethoxy) ethoxy) Acetyl) Amino) [1,3] Thiazolo [5,4-b] Pyridine-5- Il) -N- (4-((4-ethylpiperazin-1-yl) methyl) -3- (trifluoromethyl) phenyl) benzamide
tert-butyl ((2S) -1-(((1S) -1-cyclohexyl-2-((2S) -2-(5-(3- (2- (2- (2- (2-((5)) -(3-((4-((4-ethylpiperazin-1-yl) methyl) -3- (trifluoromethyl) phenyl) carbamoyl) phenyl) [1,3] thiazolo [5,4-b] pyridine- 2-Il) Amino) -2-oxoethoxy) ethoxy) ethoxy) ethoxy) benzoyl) Pyridine-3-yl) Pyrrolidine-1-yl) -2-oxoethyl) Amino) -1-oxopropan-2-yl) Methyl A mixture of carbamate (207 mg) and TFA (4.5 mL) was stirred at room temperature for 10 minutes. The reaction mixture was concentrated under reduced pressure, ethyl acetate was added to the obtained residue, the mixture was washed with 5% aqueous sodium carbonate solution and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (NH, methanol / ethyl acetate) to give the title compound (165 mg).
^{1 1} H NMR (300 MHz, CD ₃ OD) δ 0.94-1.38 (11H, m), 1.43-1.79 (6H, m), 1.82-2.20 (5H, m), 2.30-2.90 (11H, m), 3.12 ( 1H, q, J = 6.8 Hz), 3.66 (2H, s), 3.71-3.92 (11H, m), 4.01-4.20 (4H, m), 4.29 (2H, s), 4.53 (1H, d, J = 7.1 Hz), 5.06-5.49 (1H, m), 7.11-7.40 (4H, m), 7.61 (1H, t, J = 7.7 Hz), 7.77 (1H, d, J = 8.5 Hz), 7.85-8.09 ( 5H, m), 8.17 (1H, s), 8.23 (1H, d, J = 7.3 Hz), 8.52-8.72 (3H, m).

Example 15
N-(4-((4-ethylpiperazin-1-yl) methyl) -3- (trifluoromethyl) phenyl) -3- (2-(((2- (2- (2- (4-((() 1S) -1-((N-methyl-L-alanyl) amino) -2-oxo-2-((2S) -2- (4-phenyl [1,3] thiazolo [4,5-c] pyridine- 2-Il) Pyrrolidine-1-yl) Ethyl) Piperidine-1-yl) -2-oxoethoxy) ethoxy) ethoxy) Acetyl) Amino) [1,3] Thiazolo [5,4-b] Pyridine-5-yl ) Benzamide

A) 4-Phenyl-2-((2S) -pyrrolidin-2-yl) [1,3] thiazolo [4,5-c] pyridine hydrochloride benzyl (2S) -2- (4-phenyl [1,3] ] Thioanisole (8.2 mL) was added to a mixture of thiazolo [4,5-c] pyridin-2-yl) pyrrolidine-1-carboxylate (3.60 g) and TFA (20 mL), and the mixture was stirred at 40 ° C. for 16 hours. .. After concentrating the reaction solution, the residue was washed with petroleum ether. A 4N ethyl acetate solution of hydrogen chloride (30 mL) was added to the residue after washing, and the mixture was stirred at 0 ° C. for 30 minutes. The resulting residue was washed with ethyl acetate to give the crude title compound (2.10 g).
The above benzyl (2S) -2- (4-phenyl [1,3] thiazolo [4,5-c] pyridin-2-yl) pyrrolidine-1-carboxylate is described in a method known per se (eg, WO2008134679). It can be synthesized by the method).
^{1 1} H NMR (400 MHz, DMSO-d ₆ ) δ 2.06-2.13 (2H, m), 2.26-2.28 (1H, m), 2.48-2.56 (1H, m), 3.37-3.44 (2H, m), 5.31 -5.34 (1H, m), 7.56-7.58 (3H, m), 8.38-8.45 (3H, m), 8.70 (1H, d, J = 5.6 Hz), 9.71 (1H, brs), 10.74 (1H, brs) ).

B) tert-butyl (2S) -2- (4-phenyl [1,3] thiazolo [4,5-c] pyridin-2-yl) pyrrolidine-1-carboxylate
4-Dimethylamino in a mixture of 4-phenyl-2-((2S) -pyrrolidin-2-yl) [1,3] thiazolo [4,5-c] pyridine hydrochloride (10.0 g), dichloromethane (85 mL) Pyridine (8.30 g) and di-tert-butyl dicarbonate (7.70 g) were added. The mixture was stirred at 20 ° C. for 16 hours. The reaction mixture was concentrated under reduced pressure and the residue was purified by preparative HPLC to give the title compound (3.50 g).
MS: [M + H] ⁺ 382.2.

C) 4-Phenyl-2-((2S) -pyrrolidine-2-yl) [1,3] thiazolo [4,5-c] pyridine dihydrochloride
tert-Butyl (2S) -2- (4-phenyl [1,3] thiazolo [4,5-c] pyridin-2-yl) pyrrolidine-1-carboxylate (1.0 g) and 2M hydrogen chloride methanol solution (20) The mixture of mL) was stirred overnight at room temperature. The reaction mixture was washed with ethyl acetate (40 mL) to give the title compound (0.90 g).
MS: [M + H] ⁺ 282.1.

D) Ethyl (2-E / Z)-(hydroxyimino) (pyridin-4-yl) acetate metallic sodium (50.2 g) is added little by little to absolute ethanol (2 L) under a nitrogen atmosphere to completely remove the metallic sodium. The mixture was stirred under a nitrogen atmosphere for 2 hours until it was dissolved. Ethyl pyridine-4-ylacetate (240 g) was added to the mixture at 0 ° C. After stirring at 15 ° C for 30 minutes, amyl nitrite (170 g) was added and the mixture was stirred at 15 ° C overnight. Water (200 mL) was added to the mixture and acetic acid was added to adjust the pH to 5. The precipitate was collected by filtration and washed with ethanol to give the title compound (225 g).
MS: [M + H] ⁺ 195.1.

E) Ethyl 2-amino (piperidine-4-yl) acetate Ethyl (2-E / Z)-(hydroxyimino) (pyridin-4-yl) acetate (225 g), 5% palladium carbon (40 g), ethanol The mixture of (6 L) was stirred overnight at 50 ° C. under a hydrogen atmosphere of 50 psi. Concentrated hydrochloric acid (20 mL) was added to the mixture, and the mixture was further stirred at 60 ° C. for 16 hours under a hydrogen atmosphere of 50 psi. The catalyst was removed by filtration, and the filtrate was concentrated under reduced pressure to give the title compound (220 g).
MS: [M + H] ⁺ 187.1.

F) 9H-Fluorene-9-ylmethyl 4- (1-amino-2-ethoxy-2-oxoethyl) piperidine-1-carboxylate Ethyl 2-amino (piperidine-4-yl) acetate (253 g), sodium hydrogen carbonate 1,4-dioxane (458 g) of N-((9H-fluorene-9-ylmethoxy) carbonyloxy) succinimide (458 g) in a mixture of (114 g), 1,4-dioxane (3 L), water (1 L) 5 L) The solution was added dropwise at 0-5 ° C over 3 days. The mixture was extracted with ethyl acetate and concentrated under reduced pressure. N-((9H-fluorene-9-ylmethoxy) carbonyloxy) succinimide (50 g) was added to the aqueous layer over 1 day. The mixture was extracted with ethyl acetate and concentrated under reduced pressure. The residues were combined and purified by silica gel column chromatography (ethyl acetate / petroleum ether) to give the title compound (120 g).
^{1 1} H NMR (400MHz, DMSO-d ₆ ) δ = 7.95 (2H, d, J = 7.5 Hz), 7.67 (2H, d, J = 7.9 Hz), 7.47 (2H, t, J = 7.2 Hz), 7.41 --7.36 (2H, m), 4.52 --4.29 (4H, m), 4.15 (2H, dq, J = 3.1, 7.1 Hz), 3.47 --3.41 (2H, m), 2.71 (2H, brd, J = 11.5 Hz) ), 1.76 --1.41 (3H, m), 1.30 --1.15 (5H, m).

G) 9H-fluorene-9-ylmethyl 4-(1-((tert-butoxycarbonyl) amino) -2-ethoxy-2-oxoethyl) piperidine-1-carboxylate
9H-Fluorene-9-ylmethyl 4- (1-amino-2-ethoxy-2-oxoethyl) piperidine-1-carboxylate (120 g), di-tert-butyl dicarbonate (51.3 g), 1,4-dioxane The mixture of (2 L) was heated to reflux overnight. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether) to give the title compound (85 g).
1H NMR (400MHz, DMSO-d6) δ = 7.84 (2H, d, J = 7.3 Hz), 7.65 (2H, brd, J = 7.5 Hz), 7.38 --7.32 (2H, m), 7.28 (3H, t, J = 7.3 Hz), 4.18 --4.02 (4H, m), 3.95 --3.84 (2H, m), 3.06 (2H, brd, J = 8.2 Hz), 2.04 --1.93 (2H, m), 1.75 --1.46 (5H) , m), 1.38 (9H, s), 1.20 --1.13 (3H, m).

H) (2S)-((tert-butoxycarbonyl) amino) (1-((9H-fluorene-9-ylmethoxy) carbonyl) piperidine-4-yl) acetic acid
9H-Fluoren-9-ylmethyl 4-(1-((tert-butoxycarbonyl) amino) -2-ethoxy-2-oxoethyl) piperidine-1-carboxylate (85 g), lithium hydroxide monohydrate (13.4) A mixture of g), THF (500 mL), methanol (500 mL) and water (500 mL) was stirred at 15 ° C overnight and further at 80 ° C overnight. After washing the mixture with petroleum ether to remove the organic layer, sodium hydrogen carbonate was added to the aqueous layer to adjust the pH to 8, and N-((9H-fluorene-9-ylmethoxy) carbonyloxy) succinimide (56.1). A solution of g) in THF (2 L) was added dropwise at 0 ° C over 1 day. The mixture is extracted with ethyl acetate, concentrated under reduced pressure and the residue is purified by HPLC (Phenomenex Luna (2) C18, mobile phase: water / acetonitrile (0.09% TFA-containing system)) and 2-((tert-butoxy). Carbonyl) amino) (1-((9H-fluoren-9-ylmethoxy) carbonyl) piperidine-4-yl) acetic acid (75 g) was obtained. 2-((tert-Butoxycarbonyl) amino) (1-((9H-fluorene-9-ylmethoxy) carbonyl) piperidine-4-yl) acetic acid (75 g) HPLC (Chiralcel OJ-H, 30 mm ID x 250 mm) , Mobile phase: carbon dioxide, methanol), and the one with the smaller retention time was concentrated under reduced pressure to give the title compound (20 g).
^{1 1} H NMR (400MHz, DMSO-d ₆ ) δ = 7.89 (2H, d, J = 7.5 Hz), 7.62 (2H, d, J = 7.3 Hz), 7.44 --7.39 (2H, m), 7.36 --7.31 ( 2H, m), 7.03 (1H, brd, J = 8.4 Hz), 4.33 (2H, brs), 4.29 --4.24 (1H, m), 4.06 --3.75 (3H, m), 2.81 --2.56 (3H, m) , 1.85 (1H, brs), 1.58 --1.43 (2H, m), 1.39 (9H, s), 1.22 --1.00 (2H, m).

I) 9H-Fluorene-9-ylmethyl 4-((1S) -1-((tert-butoxycarbonyl) amino) -2-oxo-2-((2S) -2- (4-phenyl [1,3]] Thiazolo [4,5-c] Pyridine-2-yl) Pyrrolidine-1-yl) Ethyl) Piperidine-1-carboxylate
4-Phenyl-2-((2S) -pyrrolidin-2-yl) [1,3] thiazolo [4,5-c] pyridine dihydrochloride (354 mg), (2S)-((tert-butoxycarbonyl) 0 DIPEA (0.70 mL) in a mixture of amino) (1-((9H-fluorene-9-ylmethoxy) carbonyl) piperidine-4-yl) acetic acid (480 mg), HATU (456 mg), DMF (10 mL) Added at ° C. The mixture was stirred at 0 ° C. for 1 hour. The reaction mixture was diluted with ethyl acetate, washed with 5% aqueous sodium hydrogen carbonate solution and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / hexane) to give the title compound (598 mg).
MS: [M + H] ⁺ 744.6.

J) 9H-Fluorene-9-ylmethyl 4-((1S) -1-amino-2-oxo-2-((2S) -2- (4-phenyl [1,3] thiazolo [4,5-c]] Pyridine-2-yl) pyrrolidine-1-yl) ethyl) piperidine-1-carboxylate dihydrochloride
9H-Fluoren-9-ylmethyl 4-((1S) -1-((tert-butoxycarbonyl) amino) -2-oxo-2-((2S) -2- (4-phenyl [1,3] thiazolo [ A mixture of 4,5-c] pyridin-2-yl) pyrrolidine-1-yl) ethyl) piperidine-1-carboxylate (593 mg) and 2M hydrogen chloride methanol solution (10 mL) was stirred overnight at room temperature. The reaction mixture was concentrated to give the title compound (571 mg).
MS: [M + H] ⁺ 644.3.

K) 9H-Fluorene-9-ylmethyl 4-((1S) -1-((N- (tert-butoxycarbonyl) -N-methyl-L-alanyl) amino) -2-oxo-2-((2S)) -2- (4-Phenyl [1,3] thiazolo [4,5-c] pyridin-2-yl) pyrrolidine-1-yl) ethyl) piperidine-1-carboxylate
9H-Fluoren-9-ylmethyl 4-((1S) -1-amino-2-oxo-2-((2S) -2- (4-phenyl [1,3] thiazolo [4,5-c] pyridine- 2-Il) Pyrrolidine-1-yl) Ethyl) Piperidine-1-carboxylate dihydrochloride (592 mg), N- (tert-butoxycarbonyl) -N-methyl-L-alanine (194 mg), HATU (364 mg) DIPEA (0.70 mL) was added to the mixture of mg) and DMF (10 mL) at 0 ° C. The mixture was stirred at 0 ° C. for 1 hour. The reaction mixture was diluted with ethyl acetate, washed with 5% aqueous sodium hydrogen carbonate solution and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate) to give the title compound (549 mg).
MS: [M + H] ⁺ 829.4.

L) tert-Butyl Methyl ((2S) -1-oxo-1-(((1S) -2-oxo-2-((2S) -2- (4-phenyl [1,3] thiazolo [4,5] -c] Pyridine-2-yl) pyrrolidine-1-yl) -1- (piperidine-4-yl) ethyl) amino) propan-2-yl) carbamate
9H-Fluoren-9-ylmethyl 4-((1S) -1-((N- (tert-butoxycarbonyl) -N-methyl-L-alanyl) amino) -2-oxo-2-((2S) -2) -(4-Phenyl [1,3] thiazolo [4,5-c] pyridin-2-yl) pyrrolidine-1-yl) ethyl) piperidine-1-carboxylate (543 mg) and methanol (8 mL) mixture 2M dimethylamine methanol solution (16 mL) was added to the mixture at room temperature. The mixture was stirred at room temperature overnight. The reaction mixture was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (NH, methanol / ethyl acetate) to give the title compound (369 mg).
MS: [M + H] ⁺ 607.4.

M) (2- (2- (2- (4-((1S) -1-((N- (tert-butoxycarbonyl) -N-methyl-L-alanyl) amino) -2-oxo-2-( (2S) -2- (4-phenyl [1,3] thiazolo [4,5-c] pyridin-2-yl) pyrrolidine-1-yl) ethyl) piperidine-1-yl) -2-oxoethoxy) ethoxy ) Ethoxy) acetic acid
Tetrahydrofuran Methyl ((2S) -1-oxo-1-(((1S) -2-oxo-2-((2S) -2- (4-phenyl [1,3] thiazolo [4,5-c] ] Pyridine-2-yl) pyrrolidine-1-yl) -1- (piperidine-4-yl) ethyl) amino) propan-2-yl) carbamate (160 mg), 2,2'-(oxybis (ethane-2) , 1-Diyloxy)) A mixture of diacetic acid (176 mg), HOBt (50 mg), WSC (0.07 mL), and THF (3 mL) -DMF (0.6 mL) was stirred at room temperature for 1 hour. A 1N aqueous sodium hydroxide solution (1.5 mL) was added to the reaction mixture, and the mixture was stirred at room temperature for 10 minutes. The pH of the reaction solution was adjusted to 3-4 by adding a 5% aqueous sodium hydrogensulfate solution, the salt was saturated, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (methanol / ethyl acetate) to give the title compound (142 mg).
MS: [M + H] ⁺ 811.2.

N) tert-butyl ((2S) -1-(((1S) -1- (1-((2- (2- (2-((5- (3-((4-ethylpiperazine) -1-yl) methyl) -3- (trifluoromethyl) phenyl) carbamoyl) phenyl) [1,3] thiazolo [5,4-b] pyridin-2-yl) amino) -2-oxoethoxy) ethoxy) Ethoxy) acetyl) piperidine-4-yl) -2-oxo-2-((2S) -2- (4-phenyl [1,3] thiazolo [4,5-c] pyridin-2-yl) pyrrolidine-1 -Il) Ethyl) Amino) -1-oxopropan-2-yl) Methylcarbamate
(2-(2- (2- (4-((1S) -1-((N- (tert-butoxycarbonyl) -N-methyl-L-alanyl) amino) -2-oxo-2-((2S) ) -2- (4-Phenyl [1,3] thiazolo [4,5-c] pyridin-2-yl) pyrrolidine-1-yl) ethyl) piperidine-1-yl) -2-oxoethoxy) ethoxy) ethoxy ) Acetic acid (136 mg), 3- (2-amino [1,3] thiazolo [5,4-b] pyridin-5-yl) -N- (4-((4-ethylpiperazin-1-yl) methyl) ) -3- (Trifluoromethyl) Phenyl) benzamide (91 mg), triethylamine (0.07 mL), N, N-dimethylaminopyridine (21 mg) and anhydrous DMF (2 mL) in a mixture of 2-methyl-6- Nitrobenzoic acid anhydride (116 mg) was added at 0 ° C. The mixture was stirred at 0 ° C. for 2 hours. The reaction mixture was diluted with ethyl acetate, washed with 5% aqueous sodium carbonate solution and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (NH, methanol / ethyl acetate) to give the title compound (135 mg).
MS: [M + H] ⁺ 1333.5.

O) N- (4-((4-ethylpiperazin-1-yl) methyl) -3- (trifluoromethyl) phenyl) -3- (2-(((2- (2- (2- (4-) 4-) ((1S) -1-((N-methyl-L-alanyl) amino) -2-oxo-2-((2S) -2- (4-phenyl [1,3] thiazolo [4,5-c]] Pyridine-2-yl) pyrrolidine-1-yl) ethyl) piperidine-1-yl) -2-oxoethoxy) ethoxy) ethoxy) acetyl) amino) [1,3] thiazolo [5,4-b] pyridine-5 -Il) Benzamide
tert-Butyl ((2S) -1-(((1S) -1-(1-((2- (2- (2-((5- (3-((4-ethylpiperazin-1) -Il) Methyl) -3- (Trifluoromethyl) Phenyl) Carbamoyl) Phenyl) [1,3] Thiazolo [5,4-b] Pyridine-2-yl) Amino) -2-oxoethoxy) ethoxy) ethoxy) Acetyl) piperidine-4-yl) -2-oxo-2-((2S) -2- (4-phenyl [1,3] thiazolo [4,5-c] pyridin-2-yl) pyrrolidine-1-yl A mixture of) ethyl) amino) -1-oxopropan-2-yl) methylcarbamate (128 mg) and TFA (3 mL) was stirred at room temperature for 10 minutes. Ethyl acetate was added to the residue obtained by concentrating the reaction mixture under reduced pressure, the mixture was washed with 5% aqueous sodium carbonate solution and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (NH, methanol / ethyl acetate) to give the title compound (88 mg).
^{1 1} H NMR (300 MHz, CD ₃ OD) δ 0.80-1.38 (8H, m), 1.54-1.76 (2H, m), 1.83-2.92 (20H, m), 3.10 (1H, q, J = 6.7 Hz) , 3.59-4.02 (13H, m), 4.06-4.42 (5H, m), 4.59 (1H, t, J = 8.4 Hz), 5.41-5.83 (1H, m), 7.40-7.52 (3H, m), 7.59 (1H, t, J = 7.9 Hz), 7.75 (1H, d, J = 8.4 Hz), 7.86-8.10 (5H, m), 8.12-8.29 (4H, m), 8.42 (1H, d, J = 5.4) Hz), 8.61 (1H, d, J = 6.4 Hz).

Example 16
N-(4-((4- (2- (2- (2- (2- (3-((2-((2S) -1-((2S) -2-Cyclohexyl-2-((N- Methyl-L-alanyl) amino) acetyl) pyrrolidine-2-yl) -1,3-thiazole-4-yl) carbonyl) phenoxy) ethoxy) ethoxy) ethoxy) ethyl) piperazin-1-yl) methyl) -3- (Trifluoromethyl) phenyl) -3- (2-((cyclopropylcarbonyl) amino) [1,3] thiazolo [5,4-b] pyridin-5-yl) benzamide

A) 2- (2- (2- (2- (3-((2-((2S) -1-((2S) -2-((N- (tert-butoxycarbonyl) -N-methyl-L) -Alanyl) amino) -2-cyclohexylacetyl) pyrrolidine-2-yl) -1,3-thiazole-4-yl) carbonyl) phenoxy) ethoxy) ethoxy) ethoxy) ethyl 4-methylbenzenesulfonate
tert-butyl ((2S) -1-(((1S) -1-cyclohexyl-2-((2S) -2-(4- (3-hydroxybenzoyl) -1,3-thiazole-2-yl) pyrrolidine) -1-yl) -2-oxoethyl) amino) -1-oxopropan-2-yl) methylcarbamate (599 mg), oxybis (ethane-2,1-diyloxyethane-2,1-diyl) bis ( A mixture of 4-methylbenzenesulfonate) (1.51 g), potassium carbonate (277 mg), and DMF (5 mL) was stirred at 50 ° C. overnight. The reaction mixture was cooled, diluted with ethyl acetate, washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / hexane) to give the title compound (584 mg).
^{1 1} H NMR (300 MHz, CD ₃ OD) δ 0.93-1.37 (8H, m), 1.42-1.50 (9H, m), 1.52-1.84 (6H, m), 2.06-2.51 (7H, m), 2.66- 2.90 (3H, m), 3.48-3.74 (10H, m), 3.81-4.02 (4H, m), 4.08-4.15 (2H, m), 4.20 (2H, dd, J = 5.4, 3.8 Hz), 4.45- 4.69 (2H, m), 5.42-5.67 (1H, m), 7.19-7.28 (1H, m), 7.36-7.48 (3H, m), 7.66-7.82 (4H, m), 8.28-8.34 (1H, m) ).

B) Ethyl 3-(2-((cyclopropylcarbonyl) amino) [1,3] thiazolo [5,4-b] pyridin-5-yl) benzoate ethyl 3- (2-amino [1,3] thiazolo [5,4-b] Pyridine-5-yl) Cyclopropanecarbonyl chloride (0.78 mL) was added to the mixture of benzoate (300 mg) and DMA (1.5 mL) at 0 ° C. The mixture was stirred at room temperature overnight. The reaction mixture was poured into a 5% aqueous sodium hydrogen carbonate solution and extracted with ethyl acetate. The extract was washed with 5% aqueous sodium hydrogen carbonate solution and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / hexane) to give the title compound (344 mg).
MS: [M + H] ⁺ 368.2.

C) 3-(2-((Cyclopropylcarbonyl) amino) [1,3] thiazolo [5,4-b] pyridin-5-yl) ethyl benzoate 3-(2-((cyclopropylcarbonyl) amino) [1,3] Thiazolo [5,4-b] Pyridine-5-yl) A mixture of benzoate (339 mg), THF (1.5 mL) -ethanol (1.5 mL), and 1N aqueous sodium hydroxide solution (3 mL). Was stirred overnight at room temperature. The reaction mixture was neutralized with 1N hydrochloric acid (3 mL), diluted with ethyl acetate and THF, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give the title compound (347 mg). ..
^{MS: [M + H] +} 340.1.

D) tert-Butyl 4- (4-nitro-2- (trifluoromethyl) benzyl) piperazine-1-carboxylate
1- (Bromomethyl) -4-nitro-2- (trifluoromethyl) benzene (300) in a mixture of tert-butyl piperazine-1-carboxylate (393 mg), triethylamine (0.30 mL), and anhydrous THF (3 mL) A solution of mg) anhydrous THF (1 mL) was added at 0 ° C. The mixture was stirred at room temperature overnight. The reaction mixture was diluted with ethyl acetate, washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (NH, ethyl acetate / hexane) to give the title compound (401 mg).
MS: [M + H] ⁺ 390.2.

E) tert-Butyl 4- (4-amino-2- (trifluoromethyl) benzyl) piperazine-1-carboxylate
tert-Butyl 4- (4-nitro-2- (trifluoromethyl) benzyl) piperazin-1-carboxylate (357 mg), iron powder (256 mg), calcium chloride (51 mg), and ethanol (8 mL) -A mixture of water (2 mL) was stirred at 70 ° C. overnight. The reaction mixture was cooled, filtered through Celite, and the filtrate was concentrated under reduced pressure. Ethyl acetate was added to the obtained residue, the mixture was washed with 5% aqueous sodium hydrogen carbonate solution and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (NH, ethyl acetate / hexane) to give the title compound (241 mg).
MS: [M + H] ⁺ 360.3.

F) tert-Butyl 4-(4-((3- (2-((cyclopropylcarbonyl) amino) [1,3] thiazolo [5,4-b] pyridin-5-yl) benzoyl) amino) -2 -(Trifluoromethyl) benzyl) piperazin-1-carboxylate
tert-butyl 4- (4-amino-2- (trifluoromethyl) benzyl) piperazin-1-carboxylate (237 mg), 3-(2-((cyclopropylcarbonyl) amino) [1,3] thiazolo [ 5,4-b] Pyridine-5-yl) 2-methyl in a mixture of benzoic acid (269 mg), triethylamine (0.28 mL), N, N-dimethylaminopyridine (81 mg), and anhydrous DMF (5 mL) -6-Nitrobenzoic anhydride (454 mg) was added at 0 ° C. The mixture was stirred at room temperature overnight. The reaction mixture was diluted with ethyl acetate, washed with 5% aqueous sodium carbonate solution and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (NH, methanol / ethyl acetate) to give the title compound (413 mg).
MS: [M + H] ⁺ 681.0.

G) 3-(2-((Cyclopropylcarbonyl) amino) [1,3] thiazolo [5,4-b] pyridin-5-yl) -N- (4- (piperazin-1-ylmethyl) -3- (Trifluoromethyl) phenyl) benzamide
tert-butyl 4-(4-((3- (2-((cyclopropylcarbonyl) amino) [1,3] thiazolo [5,4-b] pyridin-5-yl) benzoyl) amino) -2- ( A mixture of trifluoromethyl) benzyl) piperazin-1-carboxylate (413 mg) and TFA (4.5 mL) was stirred at room temperature for 20 minutes. Ethyl acetate and THF were added to the residue obtained by concentrating the reaction solution under reduced pressure, the mixture was washed with 5% aqueous sodium carbonate solution and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (NH, methanol / ethyl acetate) to give the title compound (340 mg).
MS: [M + H] ⁺ 581.2.

H) tert-butyl ((2S) -1-(((1S) -1-cyclohexyl-2-((2S) -2-(4- (3- (2- (2- (2- (2- (2-( 4- (4-((3- (2-((Cyclopropylcarbonyl) amino) [1,3] thiazolo [5,4-b] pyridin-5-yl) benzoyl) amino) -2- (trifluoromethyl) ) Benzyl) piperazin-1-yl) ethoxy) ethoxy) ethoxy) ethoxy) benzoyl) -1,3-thiazol-2-yl) pyrrolidine-1-yl) -2-oxoethyl) amino) -1-oxopropane-2 -Il) Methylcarbamate
3- (2-((Cyclopropylcarbonyl) amino) [1,3] thiazolo [5,4-b] pyridin-5-yl) -N- (4- (piperazin-1-ylmethyl) -3- (tri) Fluoromethyl) phenyl) benzamide (100 mg), 2-(2- (2- (2- (3-((2-((2S) -1-((2S) -2-((N- (tert- Butoxycarbonyl) -N-methyl-L-alanyl) amino) -2-cyclohexylacetyl) pyrrolidine-2-yl) -1,3-thiazole-4-yl) carbonyl) phenoxy) ethoxy) ethoxy) ethoxy) ethyl 4- A mixture of methylbenzene sulfonate (192 mg), potassium carbonate (48 mg), and anhydrous DMF (1.5 mL) was stirred at 50 ° C. overnight. The reaction mixture was cooled, ethyl acetate was added, the mixture was washed with 5% aqueous sodium carbonate solution and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (NH, methanol / ethyl acetate) and silica gel column chromatography (methanol / ethyl acetate) to give the title compound (56 mg).
MS: [M + H] ⁺ 1337.6.

I) N- (4-((4- (2- (2- (2- (2- (3-((2-((2S) -1-((2S) -2-Cyclohexyl-2-(( N-methyl-L-alanyl) amino) acetyl) pyrrolidine-2-yl) -1,3-thiazole-4-yl) carbonyl) phenoxy) ethoxy) ethoxy) ethoxy) ethyl) piperazin-1-yl) methyl)- 3- (Trifluoromethyl) phenyl) -3- (2-((Cyclopropylcarbonyl) amino) [1,3] thiazolo [5,4-b] pyridin-5-yl) benzamide
tert-butyl ((2S) -1-(((1S) -1-cyclohexyl-2-((2S) -2- (4- (3- (2- (2- (2- (2- (4-) 4-) (4-((3- (2-((Cyclopropylcarbonyl) amino) [1,3] thiazolo [5,4-b] pyridin-5-yl) benzoyl) amino) -2- (trifluoromethyl) benzyl ) Piperazin-1-yl) ethoxy) ethoxy) ethoxy) ethoxy) benzoyl) -1,3-thiazole-2-yl) pyrrolidine-1-yl) -2-oxoethyl) amino) -1-oxopropan-2-yl ) A mixture of methylcarbamate (56 mg) and TFA (3 mL) was stirred at room temperature for 10 minutes. Ethyl acetate was added to the residue obtained by concentrating the reaction solution under reduced pressure, the mixture was washed with 5% aqueous sodium carbonate solution and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (NH, methanol / ethyl acetate) to give the title compound (38 mg).
^{1 1} H NMR (300 MHz, CD ₃ OD) δ 0.96-1.27 (12H, m), 1.50-1.82 (6H, m), 1.87-2.00 (1H, m), 2.04-2.39 (6H, m), 2.43- 2.71 (9H, m), 3.14 (1H, q, J = 6.9 Hz), 3.52-3.75 (14H, m), 3.78-4.03 (4H, m), 4.14-4.22 (2H, m), 4.47-4.58 ( 1H, m), 5.40-5.64 (1H, m), 7.15-7.23 (1H, m), 7.39 (1H, t, J = 8.2 Hz), 7.57-7.78 (4H, m), 7.89-8.18 (5H, m) m), 8.22-8.31 (2H, m), 8.59-8.69 (1H, m).

Example 19
N- (2-Chloro-6-Methylphenyl) -2-((6- (4- (14-(3-((2-((2S) -1-((2S) -2-Cyclohexyl-2- ((N-Methyl-L-alanyl) amino) acetyl) pyrridine-2-yl) -1,3-thiazole-4-yl) carbonyl) phenoxy) -3,6,9,12-tetraoxatetradecane-1- Oil) Piperazin-1-yl) -2-Methylpyrimidine-4-yl) Amino) -1,3-Thiazole-5-Carboxamide

A) tert-butyl ((2S) -1-(((1S) -2-((2S) -2- (4- (3-((14- (4- (6- ((5- ((2) -Chloro-6-methylphenyl) carbamoyl) -1,3-thiazole-2-yl) amino) -2-methylpyrimidine-4-yl) piperazine-1-yl) -14-oxo-3,6,9, 12-Tetraoxatetradeca-1-yl) oxy) benzoyl) -1,3-thiazole-2-yl) pyrrolidine-1-yl) -1-cyclohexyl-2-oxoethyl) amino) -1-oxopropane-2 -Il) Methylcarbamate
N- (2-Chloro-6-methylphenyl) -2-((2-Methyl-6- (piperazin-1-yl) pyrimidin-4-yl) amino) -1,3-thiazole-5-carboxamide (150) mg), 14-(3-((2-((2S) -1-((2S) -2-((N- (tert-butoxycarbonyl) -N-methyl-L-alanyl) amino) -2-) Cyclohexylacetyl) pyrrolidine-2-yl) -1,3-thiazole-4-yl) carbonyl) phenoxy) -3,6,9,12-tetraoxatetradecane-1-ic acid (281 mg), WSC (63 mg) , A mixture of HOBt (55 mg) and DMF (1.5 mL) was stirred overnight at room temperature. The mixture was diluted with ethyl acetate, washed with water, saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (NH, methanol / ethyl acetate) and silica gel column chromatography (methanol / ethyl acetate) to give the title compound (307 mg).
MS: [M + Na] ⁺ 1280.3.

B) N- (2-Chloro-6-methylphenyl) -2-((6- (4- (14- (3-((2-((2S) -1-((2S) -2-cyclohexyl- 2-((N-Methyl-L-alanyl) amino) acetyl) pyrridine-2-yl) -1,3-thiazole-4-yl) carbonyl) phenoxy) -3,6,9,12-tetraoxatetradecane- 1-Oil) Piperazin-1-yl) -2-Methylpyrimidine-4-yl) Amino) -1,3-Thiazole-5-Carboxamide
tert-Butyl ((2S) -1-(((1S) -2-((2S) -2- (4- (3-((14-(4- (6- ((5- ((2-Chloro) -6-methylphenyl) carbamoyl) -1,3-thiazole-2-yl) amino) -2-methylpyrimidine-4-yl) piperazine-1-yl) -14-oxo-3,6,9,12- Tetraoxatetradec-1-yl) oxy) benzoyl) -1,3-thiazole-2-yl) pyrrolidine-1-yl) -1-cyclohexyl-2-oxoethyl) amino) -1-oxopropan-2-yl ) A mixture of methylcarbamate (190 mg) and TFA (3 mL) was stirred at room temperature for 10 minutes. After concentrating the reaction solution, the obtained residue was dissolved in ethyl 2-propanol acetate (4: 1), washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. .. The residue was purified by silica gel column chromatography (methanol / ethyl acetate) to give the title compound (100 mg).
^{1 1} H NMR (300 MHz, CD ₃ OD) δ 0.86-1.19 (8H, m), 1.44-1.74 (6H, m), 1.98-2.38 (13H, m), 3.02-3.16 (1H, m), 3.48- 3.62 (20H, m), 3.73-3.94 (4H, m), 4.04-4.12 (2H, m), 4.13-4.21 (2H, m), 4.42-4.51 (1H, m), 5.28-5.43 (1H, m) ), 5.89 (1H, s), 7.01-7.19 (3H, m), 7.22-7.36 (2H, m), 7.53-7.67 (2H, m), 8.05 (1H, s), 8.19 (1H, s).

Example 20
4-((4-((2- (2- (2- (3-((2-((2S) -1-((2S) -2-cyclohexyl-2-((N-methyl-L-alanyl) ) Amino) acetyl) pyrrolidine-2-yl) -1,3-thiazole-4-yl) carbonyl) phenoxy) ethoxy) ethoxy) ethoxy) acetyl) piperazin-1-yl) methyl) -N- (4-methyl- 3-((4- (Pyridine-3-yl) pyrimidin-2-yl) amino) phenyl) benzamide

A) tert-Butyl 4- (4- (ethoxycarbonyl) benzyl) piperazine-1-carboxylate Ethyl 4- (chloromethyl) benzoate (2.0 g), tert-butyl piperazine-1-carboxylate (1.88 g), A mixture of potassium carbonate (1.67 g) and ethanol (25 mL) was stirred at 60 ° C overnight. The mixture was allowed to warm to room temperature and then concentrated under reduced pressure. The residue was diluted with ethyl acetate, washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (NH, ethyl acetate / hexane) to give the title compound (3.4 g).
MS: [M + H] ⁺ 349.2.

B) 4-((4- (tert-butoxycarbonyl) piperazin-1-yl) methyl) benzoic acid
Atmosphere a mixture of tert-butyl 4- (4- (ethoxycarbonyl) benzyl) piperazin-1-carboxylate (1.65 g), 1N aqueous sodium hydroxide solution (7 mL), ethanol (7 mL) and THF (14 mL) Below, the mixture was stirred overnight at room temperature. The mixture was neutralized with 1N hydrochloric acid and concentrated under reduced pressure. The residue was collected by filtration, washed with water and dried to give the title compound (1.40 g).
MS: [M + H] ⁺ 321.2.

C) tert-Butyl 4-(4-((4-methyl-3-((4- (pyridin-3-yl) pyrimidin-2-yl) amino) phenyl) carbamoyl) benzyl) piperazin-1-carboxylate
4-methyl -N ³ - (4- (pyridin-3-yl) pyrimidin-2-yl) benzene-1,3-diamine (878 mg), 4 - ( (4- (tert- butoxycarbonyl) piperazine -1 -Il) Methyl) benzoic acid (1.22 g), triethylamine (944 mg), N, N-dimethylaminopyridine (387 mg) and anhydrous DMF (20 mL) in a mixture of 2-methyl-6-nitrobenzoic acid anhydride (2.18 g) was added at 0 ° C. The mixture was stirred at 0 ° C. for 1 hour. The mixture was diluted with ethyl acetate, washed with 5% aqueous sodium carbonate solution and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was washed with ethyl acetate to give the title compound (1.87 g).
MS: [M + H] ⁺ 580.3.

D) N- (4-methyl-3-((4- (pyridin-3-yl) pyrimidin-2-yl) amino) phenyl) -4- (piperazine-1-ylmethyl) benzamide tetrachloride
tert-butyl 4-(4-((4-Methyl-3-((4- (pyridin-3-yl) pyrimidin-2-yl) amino) phenyl) carbamoyl) benzyl) piperazin-1-carboxylate (930 mg) ) And a mixture of 2M hydrogen chloride methanol solution (30 mL) were stirred overnight at room temperature. The resulting solid was collected by filtration, washed with methanol and dried to give the title compound (947 mg).
^{1 1} H NMR (300 MHz, DMSO-d ₆ ) δ 2.24 (3H, s), 3.50 (4H, brs), 4.50 (2H, s), 4.98 (7H, brs), 7.24 (1H, d, J = 8.3) Hz), 7.49 (1H, d, J = 8.5 Hz), 7.62 (1H, d, J = 5.1 Hz), 7.84 (2H, d, J = 8.1 Hz), 8.01-8.13 (3H, m), 8.17 ( 1H, s), 8.65 (1H, d, J = 5.1 Hz), 8.98 (1H, d, J = 5.4 Hz), 9.12 (1H, d, J = 8.3 Hz), 9.26 (1H, s), 9.52 ( 1H, s), 9.95 (2H, brs), 10.39 (1H, s).

E) tert-butyl ((2S) -1-(((1S) -1-cyclohexyl-2-((2S) -2-(4- (3- (2- (2- (2- (2- (2-( 4- (4-((4-Methyl-3-((4- (Pyridine-3-yl) pyrimidin-2-yl) amino) phenyl) carbamoyl) benzyl) piperazin-1-yl) -2-oxoethoxy) Ethoxy) ethoxy) ethoxy) benzoyl) -1,3-thiazole-2-yl) pyrrolidine-1-yl) -2-oxoethyl) amino) -1-oxopropan-2-yl) methylcarbamate
N-(4-Methyl-3-((4- (Pyridine-3-yl) pyrimidin-2-yl) amino) phenyl) -4- (piperazin-1-ylmethyl) benzamide tetrahydrochloride (79 mg), ( 2- (2- (2- (3-((2-((2S) -1-((2S) -2-((N- (tert-butoxycarbonyl) -N-methyl-L-alanyl) amino)) -2-cyclohexylacetyl) pyrridine-2-yl) -1,3-thiazole-4-yl) carbonyl) phenoxy) ethoxy) ethoxy) ethoxy) acetic acid (100 mg), WSC (24 mg), HOBt (21 mg) Triethylamine (51 mg) was added to the mixture of and DMF (1.5 mL) at room temperature. The mixture was stirred at room temperature overnight. The mixture was diluted with ethyl acetate, washed with water, saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (NH, methanol / ethyl acetate) to give the title compound (118 mg).
MS: [M + Na] ⁺ 1272.4.

F) 4-((4-((2- (2- (2- (3-((2-((2S) -1-((2S) -2-cyclohexyl-2-L) -Alanyl) amino) acetyl) pyrrolidine-2-yl) -1,3-thiazole-4-yl) carbonyl) phenoxy) ethoxy) ethoxy) ethoxy) acetyl) piperazin-1-yl) methyl) -N- (4-) Methyl-3-((4- (pyridin-3-yl) pyrimidin-2-yl) amino) phenyl) benzamide
tert-butyl ((2S) -1-(((1S) -1-cyclohexyl-2-((2S) -2- (4- (3- (2- (2- (2- (2- (4-) 4-) (4-((4-Methyl-3-((4- (Pyridine-3-yl) pyrimidin-2-yl) amino) phenyl) carbamoyl) benzyl) piperazin-1-yl) -2-oxoethoxy) ethoxy) Ethoxy) ethoxy) benzoyl) -1,3-thiazole-2-yl) pyrrolidine-1-yl) -2-oxoethyl) amino) -1-oxopropan-2-yl) methylcarbamate (105 mg) and TFA ( The mixture (3 mL) was stirred at room temperature for 10 minutes. After concentrating the reaction solution, the obtained residue was dissolved in ethyl 2-propanol acetate (4: 1), washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. .. The residue was purified by silica gel column chromatography (NH, methanol / ethyl acetate) to give the title compound (65 mg).
¹ H NMR (300 MHz, CD ₃ OD) δ 0.87-1.06 (5H, m), 1.12 (3H, d, J = 6.9 Hz), 1.43-1.71 (6H, m), 1.94-2.25 (10H, m) , 2.34 (4H, t, J = 4.9 Hz), 3.04 (1H, q, J = 6.8 Hz), 3.36-3.61 (14H, m), 3.71-3.92 (4H, m), 4.04-4.09 (2H, m) ), 4.11 (2H, s), 4.45 (1H, d, J = 7.2 Hz), 5.36 (1H, dd, J = 7.6, 3.3 Hz), 7.07-7.12 (1H, m), 7.15 (1H, d, J = 8.3 Hz), 7.25 (1H, d, J = 5.2 Hz), 7.26-7.38 (4H, m), 7.44 (1H, dd, J = 8.0, 4.9 Hz), 7.56-7.65 (2H, m), 7.75-7.82 (2H, m), 8.10 (1H, d, J = 2.0 Hz), 8.17 (1H, s), 8.36 (1H, d, J = 5.2 Hz), 8.46-8.51 (1H, m), 8.53 (1H, dd, J = 4.9, 1.6 Hz), 9.13-9.20 (1H, m).

Example 21
4-((3-Cyano-4- (4-cyanophenyl) -2,5-dimethyl-1H-pyrrole-1-yl) methyl) -N- (2- (2- (2- (3-((() 2-((2S) -1-((2S) -2-cyclohexyl-2-((N-methyl-L-alanyl) amino) acetyl) pyrrolidine-2-yl) -1,3-thiazole-4-yl) ) Carbonyl) phenoxy) ethoxy) ethoxy) ethyl) benzamide

A) Methyl 2-acetyl-4-oxopentanoate Methyl 3-oxobutanoate (300 g), potassium iodide (85.7 g), and acetone (2.0 L) in a suspension with potassium carbonate (713 g). ) Was added at once. After 5 minutes, 1-chloroacetone (278 g) was added dropwise. The mixture was stirred at 60 ° C. for 3 hours. The reaction mixture was cooled, filtered, and washed with acetone. The acetone solution was concentrated under reduced pressure and the crude product was distilled to give the crude title compound (242 g). The obtained compound was used in the next reaction without further purification.
^{1 1} H NMR (400 MHz, DMSO-d ₆ ) δ 2.12 (3H, s), 2.25 (3H, s), 2.90-3.11 (2H, m), 3.65 (3H, s), 3.98 (1H, t, J = 7.20 Hz).

B) Methyl 2,5-dimethyl-1H-pyrrole-3-carboxylate Methyl 2-acetyl-4-oxopentanoate (242 g) and ethanol (2.5 L) mixed with ammonium acetate (543 g) and molecular sieve 4A (280 g) was added and the mixture was stirred at 80 ° C. for 2 hours. The reaction solution was filtered and the filtrate was concentrated. The residue was diluted with ethyl acetate and neutralized with saturated aqueous sodium hydrogen carbonate solution. The organic layer was separated, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give the title compound (160 g).
MS: [M + H] ⁺ 154.0.

C) 1-tert-Butyl 3-methyl 2,5-dimethyl-1H-pyrrole-1,3-dicarboxylate Methyl 2,5-dimethyl-1H-pyrrole-3-carboxylate (147 g), N, N Di-tert-butyl dicarbonate (230 g) was slowly added to the mixture of -dimethylaminopyridine (5.9 g) and acetonitrile (1.5 L). The mixture was stirred at room temperature for 16 hours. The reaction mixture was concentrated and the obtained residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether) to give the title compound (200 g).
^{1 1} H NMR (400 MHz, CDCl ₃ ) δ 1.60 (9H, s), 2.33 (3H, s), 2.70 (3H, s), 3.78 (3H, s), 6.21 (1H, s).

D) 1-tert-Butyl 3-methyl 4-bromo-2,5-dimethyl-1H-pyrrole-1,3-dicarboxylate
Pyridinium bromide perbromid (264 g) in a mixture of 1-tert-butyl 3-methyl 2,5-dimethyl-1H-pyrrole-1,3-dicarboxylate (100 g), triethylamine (120 g) and dichloromethane (2 L) g) was added little by little at 0 ° C. The mixture was stirred at room temperature overnight. The reaction mixture was poured into saturated brine and extracted with dichloromethane. The extract was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether) to give the title compound (100 g).
^{1 1} H NMR (400 MHz, CDCl ₃ ) δ 1.60 (9H, s), 2.37 (3H, s), 2.63 (3H, s), 3.84 (3H, s).

E) Methyl 4- (4-cyanophenyl) -2,5-dimethyl-1H-pyrrole-3-carboxylate
1-tert-Butyl 3-methyl 4-bromo-2,5-dimethyl-1H-pyrrole-1,3-dicarboxylate (70.0 g), (4-cyanophenyl) boronic acid (34.3 g), tetrakistriphenyl A mixture of phosphine palladium (0) (12.2 g), sodium carbonate (66.8 g), and DMF (1.12 L) -water (280 mL) was stirred overnight at 130 ° C. under a nitrogen atmosphere. The reaction mixture was cooled, partitioned with ethyl acetate-water, the organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether) to give the title compound (20.0 g).
^{1 1} H NMR (400 MHz, CDCl ₃ ) δ 2.09 (3H, s), 2.48 (3H, s), 3.62 (3H, s), 7.30 --7.38 (2H, d, J = 7.94 Hz), 7.59 (2H, d, J = 8.60), 8.72 (1H, brs).

F) 4- (4-Cyanophenyl) -2,5-dimethyl-1H-pyrrole-3-carboxylic acid Methyl 4- (4-cyanophenyl) -2,5-dimethyl-1H-pyrrole-3-carboxylate ( A 1 M boron tribromide dichloromethane solution (945 mL) was added dropwise to a mixture of 40.0 g) and dichloromethane (400 mL) at 0 ° C. The mixture was stirred at 0 ° C. for 1 hour. The reaction solution was poured into saturated brine, and the precipitate was collected by filtration. The filtrate was extracted with ethyl acetate, and the extract was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue and the collected precipitate were combined and crystallized from ethyl acetate to give the title compound (30.0 g).
^{1 1} H NMR (400 MHz, DMSO-d ₆ ) δ 2.03 (3H, s), 2.37 (3H, s), 7.34 (2H, d, J = 7.94 Hz), 7.70 (2H, d, J = 8.38 Hz) , 11.25 (1H, brs).

G) 4- (4-Cyanophenyl) -2,5-dimethyl-1H-pyrrole-3-carboxamide
Thionyl chloride (36.0 mL) was added dropwise at 0 ° C. to a mixture of 4- (4-cyanophenyl) -2,5-dimethyl-1H-pyrrole-3-carboxylic acid (30.0 g) and THF (500 mL). The mixture was stirred at room temperature for 1 hour and concentrated under reduced pressure. The residue was dissolved in THF (200 mL) and a 2M ammonia THF solution (1.0 L) was added at 0 ° C. After stirring at room temperature for 1 hour, the reaction solution was concentrated under reduced pressure. The obtained solid was recrystallized from ethyl acetate to give the title compound (25.0 g).
^{1 1} H NMR (400 MHz, DMSO-d ₆ ) δ 2.11 (3H, s), 2.26 (3H, s), 6.56 (1H, brs), 6.79 (1H, brs), 7.34 (2H, d, J = 7.94) Hz), 7.72 (2H, d, J = 7.94 Hz), 10.96 (1H, brs).

H) 4- (4-Cyanophenyl) -2,5-dimethyl-1H-pyrrole-3-carbonitrile
0 0 oxalyl chloride (11.0 mL) in a mixture of 4- (4-cyanophenyl) -2,5-dimethyl-1H-pyrrole-3-carboxamide (25.0 g), pyridine (13.0 mL), and DMF (300 mL) Added at ° C. The mixture was stirred at 0 ° C. for 30 minutes. The reaction mixture was poured into saturated brine and extracted with ethyl acetate. The extract was dried over anhydrous sodium sulfate and concentrated under reduced pressure to give the title compound (18.0 g).
^{1 1} H NMR (400 MHz, CDCl ₃ ) δ 2.31 (3H, s), 2.43 (3H, s), 7.50-7.55 (2H, d, J = 8.40 Hz), 7.67-7.72 (2H, d, J = 8.80) Hz), 8.37 (1H, brs).

I) Methyl 4-((3-cyano-4- (4-cyanophenyl) -2,5-dimethyl-1H-pyrrole-1-yl) methyl) benzoart
60% sodium hydride (0.84 g) in a mixture of 4- (4-cyanophenyl) -2,5-dimethyl-1H-pyrrole-3-carbonitrile (4.20 g) and anhydrous DMF (120 mL) at 0 ° C. added. The mixture was stirred at 0 ° C. for 20 minutes under a nitrogen atmosphere. Methyl 4- (bromomethyl) benzoate (4.57 g) was added to the reaction mixture, and the mixture was stirred at room temperature for 18 hours. Water was added to the mixture at 0 ° C. and the mixture was extracted with ethyl acetate. The organic layer was separated, washed with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained solid was crystallized from ethyl acetate / hexane to give the title compound (5.93 g).
^{MS: [M + H] +} 370.3.

J) 4-((3-Cyano-4- (4-Cyanophenyl) -2,5-dimethyl-1H-pyrrole-1-yl) methyl) Methyl benzoate 4-((3-Cyano-4- (4) A mixture of -cyanophenyl) -2,5-dimethyl-1H-pyrrole-1-yl) methyl) benzoate (3.2 g) and THF (30 mL) was added 2N aqueous sodium hydroxide solution (4.33 mL) at room temperature. .. The mixture was stirred at room temperature overnight. A 2N aqueous sodium hydroxide solution (4.33 mL) was added to the reaction solution at room temperature, and the mixture was stirred overnight at room temperature. The reaction mixture was diluted with water and washed with diisopropyl ether. The aqueous layer was acidified with 1N hydrochloric acid and extracted with ethyl acetate-THF. The separated organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. Diisopropyl ether was added to the residue, the mixture was stirred, and the mixture was collected by filtration to give the title compound (3.03 g).
MS: [M + H] ⁺ 356.2.

K) tert-butyl ((2S) -1-(((1S) -2-((2S) -2- (4- (3- (2- (2- (2- (2-aminoethoxy) ethoxy) ethoxy) benzoyl) ) -1,3-Thiazol-2-yl) pyrrolidine-1-yl) -1-cyclohexyl-2-oxoethyl) amino) -1-oxopropan-2-yl) methylcarbamate with triphenylphosphine (425 mg) A 40% diethylazodicarboxylate toluene solution (0.71 mL) was added to a mixture of anhydrous THF (1.5 mL) at 0 ° C. After stirring the mixture at 0 ° C. for 10 minutes, tert-butyl ((2S) -1-(((1S) -1-cyclohexyl-2-((2S) -2- (4- (3-hydroxybenzoyl) -1) , 3-Thiazole-2-yl) Pyrrolidine-1-yl) -2-oxoethyl) Amino) -1-oxopropan-2-yl) Methylcarbamate (194 mg), anhydrous THF (3 mL), and 0.5 M A mixture of 2- (2- (2-azidoethoxy) ethoxy) ethanol in a t-butyl methyl ether solution (3.3 mL) was added. After stirring the mixture at room temperature for 5 hours, water (0.4 mL) and triphenylphosphine (850 mg) were added to the reaction solution. The mixture was stirred at room temperature overnight. Ethyl acetate was added to the reaction mixture, the mixture was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (NH, methanol / ethyl acetate) to give the title compound (308 mg). The resulting compound was used in the next reaction without further purification.
MS: [M + H] ⁺ 730.6.

L) tert-Butyl ((2S) -1-(((1S) -2-((2S) -2- (4- (3- (2- (2- (2-((4- ((3-)- Cyan-4- (4-cyanophenyl) -2,5-dimethyl-1H-pyrrole-1-yl) methyl) benzoyl) amino) ethoxy) ethoxy) ethoxy) benzoyl) -1,3-thiazole-2-yl) Pyrrolidine-1-yl) -1-cyclohexyl-2-oxoethyl) amino) -1-oxopropan-2-yl) methylcarbamate
tert-Butyl ((2S) -1-(((1S) -2-((2S) -2- (4- (3- (2- (2- (2- (2-aminoethoxy) ethoxy) ethoxy) benzoyl)- 1,3-thiazole-2-yl) pyrrolidine-1-yl) -1-cyclohexyl-2-oxoethyl) amino) -1-oxopropan-2-yl) methylcarbamate (234 mg), 4-((3) -Cyano-4- (4-cyanophenyl) -2,5-dimethyl-1H-pyrrol-1-yl) methyl) Benzoic acid (341 mg), HOBt (130 mg), WSC (0.17 mL), and THF ( The mixture of 3 mL) -DMF (1 mL) was stirred at room temperature for 3 hours. Ethyl acetate was added to the reaction mixture, the mixture was washed with 5% aqueous sodium hydrogen carbonate solution and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (NH, methanol / ethyl acetate) and silica gel column chromatography (methanol / ethyl acetate) to give the title compound (125 mg).
MS: [M + H] ⁺ 1067.9.

M) 4-((3-Cyano-4- (4-cyanophenyl) -2,5-dimethyl-1H-pyrrole-1-yl) methyl) -N- (2- (2- (2- (3- (3-) 3-yl) methyl) ((2-((2S) -1-((2S) -2-cyclohexyl-2-((N-methyl-L-alanyl) amino) acetyl) pyrrolidine-2-yl) -1,3-thiazole-4) -Il) carbonyl) phenoxy) ethoxy) ethoxy) ethyl) benzamide
tert-Butyl ((2S) -1-(((1S) -2-((2S) -2- (4- (3- (2- (2- (2-((4- ((3-Cyano-) 4- (4-Cyanophenyl) -2,5-dimethyl-1H-pyrrole-1-yl) methyl) benzoyl) amino) ethoxy) ethoxy) ethoxy) benzoyl) -1,3-thiazole-2-yl) pyrrolidine- 1-Il) -1-cyclohexyl-2-oxoethyl) amino) -1-oxopropan-2-yl) methylcarbamate (120 mg), THF (3 mL), and 4N hydrogen chloride cyclopentylmethyl ether solution (3 mL) ) Was stirred at room temperature for 4 hours. The reaction mixture was diluted with toluene (5 mL) and concentrated under reduced pressure. The obtained residue was dissolved in ethyl acetate-THF (1: 1), washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (NH, methanol / ethyl acetate) to give the title compound (82 mg).
^{1 1} H NMR (300 MHz, CD ₃ OD) δ 0.95-1.35 (8H, m), 1.52-1.83 (6H, m), 2.07-2.42 (13H, m), 2.86-3.19 (1H, m), 3.50- 4.04 (12H, m), 4.13 (2H, t, J = 4.5 Hz), 4.47-4.62 (1H, m), 5.26 (2H, s), 5.41-5.70 (1H, m), 7.03 (2H, d, J = 8.4 Hz), 7.16 (1H, dd, J = 8.3, 1.7 Hz), 7.38 (1H, t, J = 8.0 Hz), 7.50-7.86 (8H, m), 8.25-8.32 (1H, m).

Example 22
N-((1S) -2-((2S) -2- (4- (4- (2- (2- (2- (2- (4-((3-Cyano-4- (4-Cyanophenyl) ) -2,5-dimethyl-1H-pyrrole-1-yl) methyl) phenoxy) ethoxy) ethoxy) ethoxy) ethoxy) benzoyl) -1,3-thiazole-2-yl) pyrrolidine-1-yl) -1- Cyclohexyl-2-oxoethyl) -N ² -methyl-L-alanine amide

A) (4- (Trityloxy) phenyl) methanol
A mixture of 4-hydroxybenzaldehyde (5 g), trityl chloride (22.8 g), potassium carbonate (11.3 g), and DMF (100 mL) was stirred overnight at room temperature. The reaction mixture was poured into ice water and extracted with ethyl acetate. The extract was washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue was dissolved in methanol (150 mL) and sodium borohydride (1.86 g) was added at 0 ° C. The mixture was stirred at 0 ° C. for 3 hours and then at room temperature overnight. Ethyl acetate was added to the residue obtained by concentrating the reaction solution under reduced pressure, the mixture was washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / hexane) to give the title compound (12.7 g).
^{1 1} H NMR (300 MHz, CDCl ₃ ) δ 1.59 (1H, brs), 4.47 (2H, s), 6.59-6.73 (2H, m), 6.91-7.03 (2H, m), 7.17-7.35 (9H, m) ), 7.39-7.52 (6H, m).

B) 4- (4-Cyanophenyl) -2,5-dimethyl-1- (4- (trityloxy) benzyl) -1H-pyrrole-3-carbonitrile
Methanesulfonyl chloride (1.6 mL) was added to a mixture of (4- (trityloxy) phenyl) methanol (6.35 g), triethylamine (4.8 mL), and THF (100 mL) at 0 ° C. The mixture was stirred at 0 ° C. for 1 hour. After concentrating the reaction solution under reduced pressure, the residue was dissolved in acetone (100 mL), sodium iodide (5.19 g) was added, and the mixture was stirred at room temperature for 1 hr. After concentrating the reaction solution under reduced pressure, hexane was added to the residue, and the mixture was washed successively with 5% aqueous sodium hydrogen carbonate solution, 5% aqueous sodium thiosulfate solution and saturated brine, and dried over anhydrous sodium sulfate. Toluene (10 mL) was added to the obtained solution and concentrated to about 10 mL under reduced pressure to obtain a toluene solution of 1- (iodomethyl) -4- (trityloxy) benzene (the obtained compound is extremely unstable). Therefore, it was immediately used for the next reaction without further purification).
4- (4-Cyanophenyl) -2,5-dimethyl-1H-pyrrole-3-carbonitrile (1.91 g) in a mixture of 60% sodium hydride (414 mg) and anhydrous DMF (30 mL) at 0 ° C. added. The mixture was stirred at 0 ° C. for 20 minutes, and then a toluene solution of 1- (iodomethyl) -4- (trityloxy) benzene (10 mL) was added. The mixture was stirred at 0 ° C. for 1 hour. The reaction mixture was poured into a 5% aqueous sodium hydrogen carbonate solution and extracted with ethyl acetate. The extract was washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / hexane) to give the title compound (2.72 g).
^{1 1} H NMR (300 MHz, CDCl ₃ ) δ 2.11 (3H, s), 2.26 (3H, s), 4.90 (2H, s), 6.50-6.60 (2H, m), 6.62-6.71 (2H, m), 7.16-7.34 (9H, m), 7.37-7.54 (8H, m), 7.64-7.73 (2H, m).

C) 4- (4-Cyanophenyl) -1- (4-hydroxybenzyl) -2,5-dimethyl-1H-pyrrole-3-carbonitrile
4- (4-Cyanophenyl) -2,5-dimethyl-1- (4- (trityloxy) benzyl) -1H-pyrrole-3-carbonitrile (2.72 g), p-toluenesulfonic acid monohydrate ( A mixture of 91 mg) and THF (50 mL) -methanol (50 mL) was stirred at room temperature for 3 days. The reaction mixture was neutralized with a 5% aqueous sodium hydrogen carbonate solution and concentrated under reduced pressure. Ethyl acetate was added to the obtained residue, the mixture was washed with 5% aqueous sodium carbonate solution and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / hexane) to give the title compound (1.30 g).
MS: [M + H] ⁺ 328.2.

D) 4- (4-Cyanophenyl) -1- (4- (2- (2- (2- (2- (2-hydroxyethoxy) ethoxy) ethoxy) ethoxy) benzyl) -2,5-dimethyl-1H-pyrrole- 3-Carbonitrile
4- (4-Cyanophenyl) -1- (4-hydroxybenzyl) -2,5-dimethyl-1H-pyrrole-3-carbonitrile (392 mg), tetraethylene glycol (1.28 mL), triphenylphosphine (960) Diethylazodicarboxylate (3.2 mL) was added dropwise at 0 ° C. to a mixture of mg) and anhydrous THF (12 mL). The mixture was stirred at room temperature overnight. Ethyl acetate was added to the reaction mixture, the mixture was washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (methanol / ethyl acetate) to give the title compound (440 mg).
MS: [M + H] ⁺ 504.4.

E) tert-Butyl ((2S) -1-(((1S) -2-((2S) -2- (4- (4- (2- (2- (2- (2- (4- ((() 3-Cyano-4- (4-cyanophenyl) -2,5-dimethyl-1H-pyrrole-1-yl) methyl) phenoxy) ethoxy) ethoxy) ethoxy) ethoxy) benzoyl) -1,3-thiazole-2- Il) pyrrolidine-1-yl) -1-cyclohexyl-2-oxoethyl) amino) -1-oxopropan-2-yl) methylcarbamate
4- (4-Cyanophenyl) -1- (4- (2- (2- (2- (2-hydroxyethoxy) ethoxy) ethoxy) ethoxy) benzyl) -2,5-dimethyl-1H-pyrrole-3- Carbonitrile (263 mg), tert-butyl ((2S) -1-(((1S) -1-cyclohexyl-2-((2S) -2-(4- (4-hydroxybenzoyl) -1,3- Thiazol-2-yl) pyrrolidine-1-yl) -2-oxoethyl) amino) -1-oxopropan-2-yl) methylcarbamate (313 mg), triphenylphosphine (205 mg), and anhydrous THF (3) Diethylazodicarboxylate (0.34 mL) was added dropwise to the mixture of mL) at 0 ° C. The mixture was stirred at 0 ° C. for 4 hours. Ethyl acetate was added to the reaction mixture, the mixture was washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / hexane) to give the title compound (433 mg).
MS: [M + H] ⁺ 1084.9.

F) N-((1S) -2-((2S) -2- (4- (4- (2- (2- (2- (2- (4-((3-Cyan-4- (4- (4-) 4-) Cyanophenyl) -2,5-dimethyl-1H-pyrrole-1-yl) methyl) phenoxy) ethoxy) ethoxy) ethoxy) ethoxy) benzoyl) -1,3-thiazole-2-yl) pyrrolidine-1-yl)- 1-Cyclohexyl-2-oxoethyl) -N ² -methyl-L-alanine amide
tert-Butyl ((2S) -1-(((1S) -2-((2S) -2- (4- (4- (2- (2- (2- (2- (4- ((3-) Cyan-4- (4-cyanophenyl) -2,5-dimethyl-1H-pyrrole-1-yl) methyl) phenoxy) ethoxy) ethoxy) ethoxy) ethoxy) benzoyl) -1,3-thiazole-2-yl) A mixture of pyrrolidine-1-yl) -1-cyclohexyl-2-oxoethyl) amino) -1-oxopropan-2-yl) methylcarbamate (423 mg) and TFA (4.5 mL) was stirred at room temperature for 10 minutes. Toluene (10 mL) was added to the reaction mixture, and the mixture was concentrated under reduced pressure. Ethyl acetate was added to the residue, the mixture was washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (NH, methanol / ethyl acetate) to give the title compound (320 mg).
¹ H NMR (300 MHz, CD ₃ OD) δ 0.96-1.39 (8H, m), 1.52-1.88 (6H, m), 2.04-2.40 (13H, m), 3.14 (1H, d, J = 6.9 Hz) , 3.58-3.72 (8H, m), 3.76-4.09 (8H, m), 4.16-4.24 (2H, m), 4.50-4.61 (1H, m), 5.12 (2H, s), 5.43-5.69 (1H, m), 6.86-6.94 (4H, m), 6.97-7.07 (2H, m), 7.55 (2H, d, J = 8.5 Hz), 7.75 (2H, d, J = 8.4 Hz), 8.13-8.22 (2H) , m), 8.24 (1H, s).

Example 23
N-((1S) -2-((2S) -2- (4- (3- (2- (2- (2- (2- (4-((3-Cyano-4- (4-Cyanophenyl) ) -2,5-dimethyl-1H-pyrrole-1-yl) methyl) phenoxy) ethoxy) ethoxy) ethoxy) ethoxy) benzoyl) -1,3-thiazole-2-yl) pyrrolidine-1-yl) -1- Cyclohexyl-2-oxoethyl) -N ² -methyl-L-alanine amide

A) 2- (2- (2- (2- (4-((3-Cyano-4- (4-cyanophenyl) -2,5-dimethyl-1H-pyrrole-1-yl) methyl) phenoxy) ethoxy) ) Ethoxy) ethoxy) ethyl 4-methylbenzenesulfonate
4- (4-Cyanophenyl) -1- (4- (2- (2- (2- (2-hydroxyethoxy) ethoxy) ethoxy) ethoxy) benzyl) -2,5-dimethyl-1H-pyrrole-3- P-Toluenesulfonyl chloride (239 mg) was added to a mixture of carbonitrile (210 mg) and pyridine (3.0 mL) at 0 ° C. The mixture was stirred at room temperature for 4 hours. Ethyl acetate was added to the reaction mixture, and the mixture was washed successively with 1N hydrochloric acid, saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / hexane) to give the title compound (208 mg).
MS: [M + H] ⁺ 658.4.

B) tert-Butyl ((2S) -1-(((1S) -2-((2S) -2- (4- (3- (2- (2- (2- (2- (4- (() 3-Cyano-4- (4-cyanophenyl) -2,5-dimethyl-1H-pyrrole-1-yl) methyl) phenoxy) ethoxy) ethoxy) ethoxy) ethoxy) benzoyl) -1,3-thiazole-2- Il) pyrrolidine-1-yl) -1-cyclohexyl-2-oxoethyl) amino) -1-oxopropan-2-yl) methylcarbamate
2- (2- (2- (2- (4-((3-Cyano-4- (4-cyanophenyl) -2,5-dimethyl-1H-pyrrole-1-yl) methyl) phenoxy) ethoxy) ethoxy) ) Ethyl) ethyl 4-methylbenzenesulfonate (208 mg), tert-butyl ((2S) -1-(((1S) -1-cyclohexyl-2-((2S) -2- (4- (3- (3-)3-) Hydroxybenzoyl) -1,3-thiazole-2-yl) pyrrolidine-1-yl) -2-oxoethyl) amino) -1-oxopropan-2-yl) methylcarbamate (189 mg), potassium carbonate (87 mg) ), And a mixture of anhydrous DMF (1.5 mL) was stirred at 50 ° C. overnight. The reaction mixture was cooled, ethyl acetate was added, the mixture was washed with 5% aqueous sodium hydrogen carbonate solution and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (methanol / ethyl acetate) to give the title compound (299 mg).
MS: [M + H] ⁺ 1084.8.

C) N-((1S) -2-((2S) -2- (4- (3- (2- (2- (2- (2- (4-((3-cyano-4- (4- (4-) 4-) Cyanophenyl) -2,5-dimethyl-1H-pyrrole-1-yl) methyl) phenoxy) ethoxy) ethoxy) ethoxy) ethoxy) benzoyl) -1,3-thiazole-2-yl) pyrrolidine-1-yl)- 1-Cyclohexyl-2-oxoethyl) -N ² -methyl-L-alanine amide
tert-Butyl ((2S) -1-(((1S) -2-((2S) -2- (4- (3- (2- (2- (2- (2- (4- ((3-) Cyan-4- (4-cyanophenyl) -2,5-dimethyl-1H-pyrrole-1-yl) methyl) phenoxy) ethoxy) ethoxy) ethoxy) ethoxy) benzoyl) -1,3-thiazole-2-yl) A mixture of pyrrolidine-1-yl) -1-cyclohexyl-2-oxoethyl) amino) -1-oxopropan-2-yl) methylcarbamate (291 mg) and TFA (3 mL) was stirred at room temperature for 10 minutes. The reaction mixture was diluted with toluene (10 mL) and concentrated under reduced pressure. Ethyl acetate was added to the obtained residue, the mixture was washed with 5% aqueous sodium carbonate solution and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (NH, methanol / ethyl acetate) to give the title compound (217 mg).
^{1 1} H NMR (300 MHz, CD ₃ OD) δ 0.98-1.38 (8H, m), 1.49-1.84 (6H, m), 2.03-2.42 (13H, m), 3.14 (1H, q, J = 6.8 Hz) , 3.59-3.73 (8H, m), 3.75-4.02 (6H, m), 4.02-4.08 (2H, m), 4.15 (2H, dd, J = 5.4, 3.8 Hz), 4.45-4.61 (1H, m) , 5.12 (2H, s), 5.41-5.67 (1H, m), 6.83-6.92 (4H, m), 7.19 (1H, ddd, J = 8.2, 2.5, 0.9 Hz), 7.34-7.44 (1H, m) , 7.51-7.59 (2H, m), 7.65-7.72 (2H, m), 7.73-7.82 (2H, m), 8.25-8.30 (1H, m).

Example 25
N-((1S) -2-((2S) -2- (4- (3- (2- (2- (2- (2- (4-((1- (3-Chloro-4-cyanophenyl) ) -3,5-dimethyl-1H-pyrazol-4-yl) methyl) phenoxy) ethoxy) ethoxy) ethoxy) ethoxy) benzoyl) -1,3-thiazole-2-yl) pyrrolidine-1-yl) -1- Cyclohexyl-2-oxoethyl) -N ² -methyl-L-alanine amide

A) 3- (4-Hydroxybenzylidene) pentane-2,4-dione
A mixture of 4-hydroxybenzaldehyde (8.00 g), pentane-2,4-dione (6.74 mL), acetic acid (0.938 mL), piperidine (0.13 mL) and anhydrous toluene (50 mL) overnight using a Dean-Stark tube. After refluxing, the reaction solution was concentrated. The obtained residue was washed with diethyl ether to give a crude title compound. The obtained compound was used in the next reaction without further purification.
MS: [M + H] ⁺ 205.2.

B) 3-(4-((2- (Trimethylsilyl) ethoxy) methoxy) benzylidene) pentane-2,4-dione
Potassium carbonate (0.81 g) and (2- (chloromethoxy) ethyl) (trimethyl)silane in a mixture of 3- (4-hydroxybenzylidene) pentane-2,4-dione (1.00 g) and anhydrous DMF (25 mL) 1.04 mL) was added. The mixture was stirred at room temperature for 4 hours. The mixture was neutralized with saturated aqueous ammonium chloride solution and extracted with ethyl acetate. The organic layer was separated, washed with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / hexane) to give the title compound (1.16 g).
MS: [M + H] ⁺ 335.3.

C) 3,5-dimethyl-4-(4-((2- (trimethylsilyl) ethoxy) methoxy) benzyl) -1H-pyrazole
A mixture of 3- (4-((2- (trimethylsilyl) ethoxy) methoxy) benzylidene) pentane-2,4-dione (1.16 g) and 10% palladium on carbon (211 mg) in ethanol (20 mL) at atmospheric pressure. The mixture was stirred overnight at room temperature under a hydrogen atmosphere. The catalyst was filtered off and the filtrate was concentrated under reduced pressure. The mixture of the obtained residue (1.07 g), hydrazine monohydrate (0.19 g) and ethanol (16 mL) was refluxed for 2 hours, and the reaction mixture was concentrated. The residue was purified by silica gel column chromatography (ethyl acetate / hexane) to give the title compound (973 mg).
MS: [M + H] ⁺ 333.3.

D) 2-Chloro-4- (3,5-dimethyl-4- (4-((2- (trimethylsilyl) ethoxy) methoxy) benzyl) -1H-pyrazole-1-yl) benzonitrile
60% sodium hydride (140 mg) in a mixture of 3,5-dimethyl-4- (4-((2- (trimethylsilyl) ethoxy) methoxy) benzyl) -1H-pyrazole (970 mg) and anhydrous DMF (15 mL) ) Was added at 0 ° C. The reaction mixture was stirred at 0 ° C. for 10 minutes, 2-chloro-4-fluorobenzonitrile (908 mg) was added, and the mixture was stirred at room temperature overnight. Water was added to the mixture at 0 ° C. and the mixture was extracted with ethyl acetate. The organic layer was separated, washed with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / hexane) to give the title compound (1.28 g).
^{1 1} H NMR (300 MHz, DMSO-d ₆ ) δ -0.04 (9H, s), 0.82-0.91 (2H, m), 2.09 (3H, s), 2.39 (3H, s), 3.63-3.73 (4H, s) m), 5.17 (2H, s), 6.89-6.95 (2H, m), 7.04-7.12 (2H, m), 7.74 (1H, dd, J = 8.6, 2.1 Hz), 7.93 (1H, d, J = 2.1 Hz), 8.07 (1H, d, J = 8.6 Hz).

E) 2-Chloro-4- (4- (4-hydroxybenzyl) -3,5-dimethyl-1H-pyrazol-1-yl) benzonitrile
2-Chloro-4- (3,5-dimethyl-4- (4-((2- (trimethylsilyl) ethoxy) methoxy) benzyl) -1H-pyrazole-1-yl) benzonitrile (1.28 g), 1M tetrabutyl A mixture of ammonium fluoride THF solution (13.6 mL) and anhydrous THF (10 mL) was refluxed for 9 hours. 1M tetrabutylammonium fluoride THF solution (13.6 mL) was added to the mixture, and the mixture was further refluxed overnight. The reaction mixture was added to water and extracted with ethyl acetate. The organic layer was separated, washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / hexane) and silica gel column chromatography (NH, ethyl acetate / hexane). The obtained solid was crystallized from ethyl acetate / hexane to give the title compound (378 mg).
MS: [M + H] ⁺ 338.2.

F) 2-Chloro-4- (4- (4- (2- (2- (2- (2-hydroxyethoxy) ethoxy) ethoxy) ethoxy) benzyl) -3,5-dimethyl-1H-pyrazole-1- Il) Benzonitrile
2-Chloro-4- (4- (4-hydroxybenzyl) -3,5-dimethyl-1H-pyrazol-1-yl) benzonitrile (348 mg), 2,2'-tetraethylene glycol (1.07 mL)
, Triphenylphosphine (1.62 g), anhydrous THF (10 mL) was added bis (2-methoxyethyl) azodicarboxylate (1.45 g) at 0 ° C. The mixture was stirred at room temperature overnight. Water was added to the mixture at 0 ° C. and the mixture was extracted with ethyl acetate. The organic layer was separated, washed with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / hexane) to give the title compound (368 mg).
MS: [M + H] ⁺ 514.4.

G) 2- (2- (2- (2- (4-((1- (3-Chloro-4-cyanophenyl) -3,5-dimethyl-1H-pyrazole-4-yl) methyl) phenoxy) ethoxy) ) Ethoxy) ethoxy) ethyl 4-methylbenzenesulfonate
2-Chloro-4- (4- (4- (2- (2- (2- (2- (2-hydroxyethoxy) ethoxy) ethoxy) ethoxy) benzyl) -3,5-dimethyl-1H-pyrazole-1-yl) 4-Methylbenzenesulfonyl chloride (205 mg) was added to a mixture of benzonitrile (368 mg) and pyridine (4 mL) at 0 ° C. The mixture was stirred at room temperature for 4 hours. 1N Hydrochloric acid was added to the mixture at 0 ° C., and the mixture was extracted with ethyl acetate. The organic layer was separated, washed with 1N hydrochloric acid, saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / hexane) to give the title compound (316 mg).
MS: [M + H] ⁺ 668.4.

H) tert-Butyl ((2S) -1-(((1S) -2-((2S) -2- (4- (3- (2- (2- (2- (2- (4- ((() 1- (3-Chloro-4-cyanophenyl) -3,5-dimethyl-1H-pyrazole-4-yl) methyl) phenoxy) ethoxy) ethoxy) ethoxy) ethoxy) benzoyl) -1,3-thiazole-2- Il) pyrrolidine-1-yl) -1-cyclohexyl-2-oxoethyl) amino) -1-oxopropan-2-yl) methylcarbamate
tert-butyl ((2S) -1-(((1S) -1-cyclohexyl-2-((2S) -2-(4- (3-hydroxybenzoyl) -1,3-thiazole-2-yl) pyrrolidine) -1-yl) -2-oxoethyl) amino) -1-oxopropan-2-yl) methylcarbamate (214 mg), 2- (2- (2- (2- (4-((1- (3) -) -Chloro-4-cyanophenyl) -3,5-dimethyl-1H-pyrazol-4-yl) methyl) phenoxy) ethoxy) ethoxy) ethoxy) ethyl 4-methylbenzenesulfonate (310 mg), anhydrous DMF (2 mL) ) Was added with potassium carbonate (66 mg) at room temperature. The mixture was stirred at 60 ° C. for 5 hours. Water was added to the mixture at 0 ° C. and the mixture was extracted with ethyl acetate. The organic layer was separated, washed with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / hexane) to give the title compound (353 mg).
MS: [M + H] ⁺ 1094.8.

I) N-((1S) -2-((2S) -2- (4- (3- (2- (2- (2- (2- (4-((1- (3-Chloro-4-) Cyanophenyl) -3,5-dimethyl-1H-pyrazol-4-yl) methyl) phenoxy) ethoxy) ethoxy) ethoxy) ethoxy) benzoyl) -1,3-thiazole-2-yl) pyrrolidine-1-yl)- 1-Cyclohexyl-2-oxoethyl) -N ² -methyl-L-alanine amide
tert-Butyl ((2S) -1-(((1S) -2-((2S) -2- (4- (3- (2- (2- (2- (2- (4- ((1-) (3-Chloro-4-cyanophenyl) -3,5-dimethyl-1H-pyrazol-4-yl) methyl) phenoxy) ethoxy) ethoxy) ethoxy) ethoxy) benzoyl) -1,3-thiazole-2-yl) A mixture of pyrrolidine-1-yl) -1-cyclohexyl-2-oxoethyl) amino) -1-oxopropan-2-yl) methylcarbamate (353 mg) and TFA (2 mL) was stirred at room temperature for 20 minutes. The mixture was neutralized with saturated aqueous sodium hydrogen carbonate solution at 0 ° C. and extracted with ethyl acetate. The organic layer was separated, washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (methanol / ethyl acetate) to give the title compound (262 mg).
^{1 1} H NMR (300 MHz, CD ₃ OD) δ 0.96-1.32 (8H, m), 1.51-1.84 (6H, m), 2.05-2.42 (13H, m), 3.10-3.38 (1H, m), 3.58- 3.71 (10H, m), 3.72-4.16 (10H, m), 4.49-4.61 (1H, m), 5.41-5.65 (1H, m), 6.78 (2H, d, J = 7.1 Hz), 7.00 (2H, m) d, J = 7.8 Hz), 7.16 (1H, d, J = 8.1 Hz), 7.36 (1H, t, J = 7.4 Hz), 7.58 (1H, d, J = 8.4 Hz), 7.64-7.72 (2H, m), 7.77 (1H, brs), 7.85 (1H, dd, J = 8.4, 3.0 Hz), 8.26 (1H, s).

Example 27
N-((1S) -2-((2S) -2- (4- (3- (2- (2- (2-((3- (4-((3-cyano-4- (4-cyano) Phenyl) -2,5-dimethyl-1H-pyrrole-1-yl) methyl) phenyl) propa-2-in-1-yl) oxy) ethoxy) ethoxy) ethoxy) benzoyl) -1,3-thiazole-2- Il) pyrrolidine-1-yl) -1-cyclohexyl-2-oxoethyl) -N ² -methyl-L-alanine amide

A) 1- (4-Bromobenzyl) -4- (4-Cyanophenyl) -2,5-dimethyl-1H-pyrrole-3-carbonitrile
4- (4-Cyanophenyl) -2,5-dimethyl-1H-pyrrole-3-carbonitrile (1.88 g) in a mixture of 60% sodium hydride (0.41 g) and anhydrous DMF (30 mL) at 0 ° C. added. The mixture was stirred at 0 ° C. for 10 minutes and then 1-bromo-4- (bromomethyl) benzene (2.56 g) was added. The mixture was stirred at 0 ° C. for 2 hours. The reaction mixture was poured into saturated aqueous sodium hydrogen carbonate solution and extracted with ethyl acetate. The extract was washed with saturated aqueous sodium carbonate solution and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate) and recrystallized from ethyl acetate / hexane to give the title compound (2.70 g).
MS: [M + H] ⁺ 390.2.

B) 2- (2- (2- (propa-2-in-1-yloxy) ethoxy) ethoxy) ethanol
2,2'-(ethane-1,2-diylbis (oxy)) diethanol (5.56 g) was added to a mixture of t-butoxypotassium (2.57 g) and anhydrous THF (150 mL). The mixture was stirred at room temperature for 30 minutes, and then a mixed solution of 80% 3-bromoprop-1-in toluene solution (2.12 mL) and anhydrous THF (60 mL) was added dropwise. The mixture was stirred at room temperature overnight, the reaction mixture was filtered through Celite, and the obtained filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / hexane) to give the title compound (3.20 g).
MS: [M + H] ⁺ 189.2.

C) 4- (4-Cyanophenyl) -1- (4- (3- (2- (2- (2-hydroxyethoxy) ethoxy) ethoxy) propa-1-in-1-yl) benzyl) -2, 5-Dimethyl-1H-Pyrrole-3-Carbonitrile
1- (4-bromobenzyl) -4- (4-cyanophenyl) -2,5-dimethyl-1H-pyrrole-3-carbonitrile (780 mg), 2- (2- (2- (propa-2-) In-1-yloxy) ethoxy) ethoxy) ethanol (752 mg), triethylamine (1.2 mL), copper (I) iodide (38 mg), bistriphenylphosphine palladium dichloride (140 mg), and DMF (6 mL) The mixture was stirred overnight at 60 ° C. under an argon atmosphere. The reaction mixture was cooled, ethyl acetate was added, the mixture was washed with saturated aqueous ammonium chloride solution and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (NH, methanol / ethyl acetate) to give the title compound (320 mg).
MS: [M + H] ⁺ 498.4.

D) 2- (2-(2-((3- (4-((3-Cyano-4- (4-cyanophenyl) -2,5-dimethyl-1H-pyrrole-1-yl) methyl) phenyl)) Propa-2-in-1-yl) oxy) ethoxy) ethoxy) ethyl 4-methylbenzenesulfonate
4- (4-Cyanophenyl) -1- (4- (3- (3- (2- (2- (2-hydroxyethoxy) ethoxy) ethoxy) propa-1-in-1-yl) benzyl) -2,5- P-Toluenesulfonyl chloride (184 mg) was added to a mixture of dimethyl-1H-pyrrole-3-carbonitrile (320 mg) and pyridine (4.5 mL) at 0 ° C. After stirring the mixture at room temperature for 4 hours, p-toluenesulfonyl chloride (184 mg) was added, and the mixture was further stirred at room temperature for 1 hour. Ethyl acetate was added to the reaction mixture, and the mixture was washed successively with 1N hydrochloric acid, saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / hexane) to give the title compound (302 mg).
MS: [M + H] ⁺ 652.5.

E) tert-Butyl ((2S) -1-(((1S) -2-((2S) -2- (4- (3- (2- (2- (2-((3- (4- (4-) (3-Cyano-4- (4-cyanophenyl) -2,5-dimethyl-1H-pyrrole-1-yl) methyl) phenyl) propa-2-in-1-yl) oxy) ethoxy) ethoxy) ethoxy) Benzoyl) -1,3-thiazole-2-yl) pyrrolidine-1-yl) -1-cyclohexyl-2-oxoethyl) amino) -1-oxopropan-2-yl) methylcarbamate
2-(2-(2-((3- (4-((3-Cyano-4- (4-Cyanophenyl) -2,5-dimethyl-1H-pyrrole-1-yl) methyl) phenyl) propa- 2-In-1-yl) oxy) ethoxy) ethoxy) ethyl 4-methylbenzenesulfonate (302 mg), tert-butyl ((2S) -1-(((1S) -1-cyclohexyl-2-(((1S)-1-cyclohexyl-2-(() 2S) -2- (4- (3-Hydroxybenzoyl) -1,3-thiazole-2-yl) pyrrolidine-1-yl) -2-oxoethyl) amino) -1-oxopropan-2-yl) methylcarba A mixture of Methyl (277 mg), potassium carbonate (77 mg), and anhydrous DMF (2 mL) was stirred at room temperature for 3 days and then at 50 ° C. for 24 hours. The reaction mixture was cooled, ethyl acetate was added, the mixture was washed with 5% aqueous sodium hydrogen carbonate solution and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / hexane) and silica gel column chromatography (NH, ethyl acetate / hexane) to give the title compound (334 mg).
MS: [M + H] ⁺ 1078.8.

F) N-((1S) -2-((2S) -2- (4- (3- (2- (2- (2-((3- (4-((3-Cyan-4- (4) -Cyanophenyl) -2,5-dimethyl-1H-pyrrole-1-yl) methyl) phenyl) propa-2-in-1-yl) oxy) ethoxy) ethoxy) ethoxy) benzoyl) -1,3-thiazole- 2-yl) pyrrolidine-1-yl) -1-cyclohexyl-2-oxoethyl) -N ² -methyl-L-alanine amide
tert-Butyl ((2S) -1-(((1S) -2-((2S) -2- (4- (3- (2- (2- (2-((3- (4- ((3)) -Cyano-4- (4-cyanophenyl) -2,5-dimethyl-1H-pyrrole-1-yl) methyl) phenyl) propa-2-in-1-yl) oxy) ethoxy) ethoxy) ethoxy) benzoyl) -1,3-thiazole-2-yl) pyrrolidine-1-yl) -1-cyclohexyl-2-oxoethyl) amino) -1-oxopropan-2-yl) methylcarbamate (334 mg) and TFA (3 mL) ) Was stirred at room temperature for 10 minutes. The reaction mixture was diluted with toluene (5 mL) and concentrated under reduced pressure. Ethyl acetate was added to the obtained residue, the mixture was washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (NH, methanol / ethyl acetate) to give the title compound (239 mg).
^{1 1} H NMR (300 MHz, CD ₃ OD) δ 0.96-1.35 (8H, m), 1.49-1.84 (6H, m), 2.04-2.45 (13H, m), 2.87-3.20 (1H, m), 3.63- 3.76 (8H, m), 3.83-4.04 (4H, m), 4.14-4.21 (2H, m), 4.38 (2H, s), 4.49-4.62 (1H, m), 5.23 (2H, s), 5.43- 5.67 (1H, m), 6.94 (2H, d, J = 8.2 Hz), 7.16-7.24 (1H, m), 7.34-7.45 (3H, m), 7.53-7.61 (2H, m), 7.65-7.73 ( 2H, m), 7.77 (2H, d, J = 8.5 Hz), 8.25-8.31 (1H, m).

Example 28
N-((1S) -2-((2S) -2- (4- (3- (2- (2- (2-((3- (3-((3-cyano-4- (4-cyano) Phenyl) -2,5-dimethyl-1H-pyrrole-1-yl) methyl) phenyl) propa-2-in-1-yl) oxy) ethoxy) ethoxy) ethoxy) benzoyl) -1,3-thiazole-2- Il) pyrrolidine-1-yl) -1-cyclohexyl-2-oxoethyl) -N ² -methyl-L-alanine amide

A) 1- (3-Bromobenzyl) -4- (4-Cyanophenyl) -2,5-dimethyl-1H-pyrrole-3-carbonitrile
Add 4- (4-cyanophenyl) -2,5-dimethyl-1H-pyrrole-3-carbonitrile (1.88 g) to a mixture of 60% sodium hydride (0.41 g) and anhydrous DMF (30 mL) little by little. Added at ° C. The mixture was stirred at 0 ° C. for 10 minutes and then 1-bromo-3- (bromomethyl) benzene (2.56 g) was added. The mixture was stirred at 0 ° C. for 2 hours. The reaction mixture was poured into a 5% aqueous sodium hydrogen carbonate solution and extracted with ethyl acetate. The extract was washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate), and the obtained solid was recrystallized from ethyl acetate to give the title compound (2.56 g).
MS: [M + H] ⁺ 390.2.

B) 4- (4-Cyanophenyl) -1- (3- (3- (2- (2- (2- (2-hydroxyethoxy) ethoxy) ethoxy) propa-1-in-1-yl) benzyl) -2, 5-Dimethyl-1H-Pyrrole-3-Carbonitrile
1- (3-bromobenzyl) -4- (4-cyanophenyl) -2,5-dimethyl-1H-pyrrole-3-carbonitrile (390 mg), 2- (2- (2- (propa-2-) In-1-yloxy) ethoxy) ethoxy) ethanol (376 mg), triethylamine (0.56 mL), copper (I) iodide (19 mg), tetrakistriphenylphosphine palladium (0) (116 mg), and DMF (3) The mixture of mL) was stirred overnight at 60 ° C. under an argon atmosphere. The reaction mixture was cooled, ethyl acetate was added, the mixture was washed with saturated aqueous ammonium chloride solution and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (NH, methanol / ethyl acetate) to give the title compound (425 mg).
MS: [M + H] ⁺ 498.4.

C) 2- (2-(2-((3- (3-((3-Cyano-4- (4-cyanophenyl) -2,5-dimethyl-1H-pyrrole-1-yl) methyl) phenyl)) Propa-2-in-1-yl) oxy) ethoxy) ethoxy) ethyl 4-methylbenzenesulfonate
4- (4-Cyanophenyl) -1- (3- (3- (3- (2- (2- (2-hydroxyethoxy) ethoxy) ethoxy) propa-1-in-1-yl) benzyl) -2,5- P-Toluenesulfonyl chloride (489 mg) was added to a mixture of dimethyl-1H-pyrrole-3-carbonitrile (425 mg) and pyridine (4.5 mL) at 0 ° C. The mixture was stirred at room temperature for 2 hours. Ethyl acetate was added to the reaction mixture, and the mixture was washed successively with 1N hydrochloric acid, saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / hexane) to give the title compound (447 mg).
MS: [M + H] ⁺ 652.7.

D) tert-Butyl ((2S) -1-(((1S) -2-((2S) -2- (4- (3- (2- (2- (2-((3- (3- (3-) (3-Cyano-4- (4-cyanophenyl) -2,5-dimethyl-1H-pyrrole-1-yl) methyl) phenyl) propa-2-in-1-yl) oxy) ethoxy) ethoxy) ethoxy) Benzoyl) -1,3-thiazole-2-yl) pyrrolidine-1-yl) -1-cyclohexyl-2-oxoethyl) amino) -1-oxopropan-2-yl) methylcarbamate
2- (2-(2-((3- (3-((3-Cyano-4- (4-Cyanophenyl) -2,5-dimethyl-1H-pyrrole-1-yl) methyl) phenyl) propa- 2-In-1-yl) oxy) ethoxy) ethoxy) ethyl 4-methylbenzenesulfonate (447 mg), tert-butyl ((2S) -1-(((1S) -1-cyclohexyl-2-(((1S)-1-cyclohexyl-2-(( 2S) -2- (4- (3-Hydroxybenzoyl) -1,3-thiazole-2-yl) pyrrolidine-1-yl) -2-oxoethyl) amino) -1-oxopropan-2-yl) methylcarba A mixture of Methyl (342 mg), potassium carbonate (111 mg), and anhydrous DMF (2 mL) was stirred at room temperature for 3 days and then at 50 ° C. for 4 hours. The reaction mixture was cooled, ethyl acetate was added, the mixture was washed with 5% aqueous sodium hydrogen carbonate solution and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / hexane) and silica gel column chromatography (NH, ethyl acetate / hexane) to give the title compound (410 mg).
MS: [M + H] ⁺ 1078.9.

E) N-((1S) -2-((2S) -2- (4- (3- (2- (2- (2-((3- (3-((3-cyano-4- (4) -Cyanophenyl) -2,5-dimethyl-1H-pyrrole-1-yl) methyl) phenyl) propa-2-in-1-yl) oxy) ethoxy) ethoxy) ethoxy) benzoyl) -1,3-thiazole- 2-yl) pyrrolidine-1-yl) -1-cyclohexyl-2-oxoethyl) -N ² -methyl-L-alanine amide
tert-Butyl ((2S) -1-(((1S) -2-((2S) -2- (4- (3- (2- (2- (2-((3- (3- (3- ((3)) -Cyano-4- (4-cyanophenyl) -2,5-dimethyl-1H-pyrrole-1-yl) methyl) phenyl) propa-2-in-1-yl) oxy) ethoxy) ethoxy) ethoxy) benzoyl) -1,3-thiazole-2-yl) pyrrolidine-1-yl) -1-cyclohexyl-2-oxoethyl) amino) -1-oxopropan-2-yl) methylcarbamate (410 mg) and TFA (4.5 mL) ) Was stirred at room temperature for 10 minutes. Toluene (5 mL) was added to the reaction mixture, and the mixture was concentrated under reduced pressure. Ethyl acetate was added to the residue, the mixture was washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (NH, methanol / ethyl acetate) to give the title compound (312 mg).
^{1 1} H NMR (300 MHz, CD ₃ OD) δ 0.96-1.37 (8H, m), 1.48-1.88 (6H, m), 2.04-2.58 (13H, m), 2.87-3.20 (1H, m), 3.60- 3.76 (8H, m), 3.81-4.02 (4H, m), 4.14-4.23 (2H, m), 4.37 (2H, s), 4.49-4.61 (1H, m), 5.21 (2H, s), 5.42- 5.68 (1H, m), 6.97 (1H, dd, J = 5.7, 1.9 Hz), 7.01 (1H, s), 7.16-7.24 (1H, m), 7.27-7.44 (3H, m), 7.57 (2H, 2H, d, J = 8.4 Hz), 7.65-7.72 (2H, m), 7.76 (2H, d, J = 8.4 Hz), 8.24-8.32 (1H, m).

Example 29
N-((1S) -2-((2S) -2- (4- (3- (2- (2- (2- (3- (4-((3-Cyano-4- (4-Cyanophenyl) ) -2,5-dimethyl-1H-pyrrole-1-yl) methyl) phenyl) propoxy) ethoxy) ethoxy) ethoxy) benzoyl) -1,3-thiazole-2-yl) pyrrolidine-1-yl) -1- Cyclohexyl-2-oxoethyl) -N ² -methyl-L-alanine amide

A) 4- (4-Cyanophenyl) -1- (4- (3- (2- (2- (2- (2-hydroxyethoxy) ethoxy) ethoxy) propyl) benzyl) -2,5-dimethyl-1H-pyrrole- 3-Carbonitrile
4- (4-Cyanophenyl) -1- (4- (3- (3- (2- (2- (2-hydroxyethoxy) ethoxy) ethoxy) propa-1-in-1-yl) benzyl) -2,5- A mixture of dimethyl-1H-pyrrole-3-carbonitrile (365 mg) and 10% palladium carbon (73 mg) in ethyl acetate (3 mL) was stirred at room temperature for 2 hours under atmospheric hydrogen atmosphere. The catalyst was filtered off and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate) to give the title compound (310 mg).
MS: [M + H] ⁺ 502.4.

B) 2- (2- (2- (3- (4-((3-Cyano-4- (4-cyanophenyl) -2,5-dimethyl-1H-pyrrole-1-yl) methyl) phenyl) propoxy) ) Ethoxy) ethoxy) ethyl 4-methylbenzenesulfonate
4- (4-Cyanophenyl) -1- (4- (3- (3- (2- (2- (2-hydroxyethoxy) ethoxy) ethoxy) propyl) benzyl) -2,5-dimethyl-1H-pyrrole-3- P-Toluenesulfonyl chloride (353 mg) was added to a mixture of carbonitrile (310 mg) and pyridine (4.5 mL) at 0 ° C. The mixture was stirred at room temperature for 3 hours. Ethyl acetate was added to the reaction mixture, and the mixture was washed successively with 1N hydrochloric acid, saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / hexane) to give the title compound (338 mg).
MS: [M + H] ⁺ 656.5.

C) tert-Butyl ((2S) -1-(((1S) -2-((2S) -2- (4- (3- (2- (2- (2- (3- (4- ((() 3-Cyano-4- (4-cyanophenyl) -2,5-dimethyl-1H-pyrrole-1-yl) methyl) phenyl) propoxy) ethoxy) ethoxy) ethoxy) benzoyl) -1,3-thiazole-2- Il) pyrrolidine-1-yl) -1-cyclohexyl-2-oxoethyl) amino) -1-oxopropan-2-yl) methylcarbamate
tert-Butyl ((2S) -1-(((1S) -1-cyclohexyl-2-((2S) -2-(4- (3-hydroxybenzoyl) -1,3-thiazole-2-yl) pyrrolidine) -1-yl) -2-oxoethyl) amino) -1-oxopropan-2-yl) methylcarbamate (299 mg), 2- (2- (2- (3- (4-((3-cyano-)- 4- (4-Cyanophenyl) -2,5-dimethyl-1H-pyrrole-1-yl) methyl) phenyl) propoxy) ethoxy) ethoxy) ethyl 4-methylbenzenesulfonate (338 mg), potassium carbonate (97 mg) ), And a mixture of anhydrous DMF (2 mL) was stirred at 60 ° C. overnight. The reaction mixture was cooled, ethyl acetate was added, the mixture was washed with 5% aqueous sodium hydrogen carbonate solution and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / hexane) and silica gel column chromatography (NH, ethyl acetate / hexane) to give the title compound (387 mg).
MS: [M + H] ⁺ 1082.9.

D) N-((1S) -2-((2S) -2- (4- (3- (2- (2- (2- (3- (4- ((3-Cyan-4- (4- (4-) Cyanophenyl) -2,5-dimethyl-1H-pyrrole-1-yl) methyl) phenyl) propoxy) ethoxy) ethoxy) ethoxy) benzoyl) -1,3-thiazole-2-yl) pyrrolidine-1-yl)- 1-Cyclohexyl-2-oxoethyl) -N ² -methyl-L-alanine amide
tert-Butyl ((2S) -1-(((1S) -2-((2S) -2- (4- (3- (2- (2- (2- (3- (4- ((3-) Cyan-4- (4-cyanophenyl) -2,5-dimethyl-1H-pyrrole-1-yl) methyl) phenyl) propoxy) ethoxy) ethoxy) ethoxy) benzoyl) -1,3-thiazole-2-yl) A mixture of pyrrolidine-1-yl) -1-cyclohexyl-2-oxoethyl) amino) -1-oxopropan-2-yl) methylcarbamate (387 mg) and TFA (4.5 mL) was stirred at room temperature for 10 minutes. The reaction mixture was diluted with toluene (5 mL) and concentrated under reduced pressure. Ethyl acetate was added to the obtained residue, the mixture was washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (NH, methanol / ethyl acetate) to give the title compound (303 mg).
^{1 1} H NMR (300 MHz, CD ₃ OD) δ 0.96-1.39 (8H, m), 1.50-1.93 (8H, m), 2.02-2.42 (13H, m), 2.64 (2H, t, J = 7.6 Hz) , 3.14 (1H, q, J = 6.9 Hz), 3.42 (2H, t, J = 6.3 Hz), 3.50-3.76 (8H, m), 3.81-4.03 (4H, m), 4.17 (2H, dd, J = 5.5, 3.9 Hz), 4.47-4.64 (1H, m), 5.17 (2H, s), 5.42-5.68 (1H, m), 6.87 (2H, d, J = 8.2 Hz), 7.10-7.23 (3H, s) m), 7.33-7.44 (1H, m), 7.52-7.60 (2H, m), 7.66-7.81 (4H, m), 8.24-8.31 (1H, m).

Example 31
N-((1S) -2-((2S, 4S) -4-(((2- (2- (2- (4-((3-cyano-4- (4-cyanophenyl) -2,5) -Dimethyl-1H-pyrrole-1-yl) methyl) phenoxy) ethoxy) ethoxy) ethoxy) acetyl) amino) -2- (4- (4-fluoro-1-naphthyl) -1,3-thiazole-2-yl ) Pyrrolidine-1-yl) -1-cyclohexyl-2-oxoethyl) -N ² -methyl-L-alanine amide
A) tert-Butyl (2S, 4S) -2-carbamoyl-4-(((9H-fluorene-9-ylmethoxy) carbonyl) amino) pyrrolidine-1-carboxylate
(4S) -1- (tert-butoxycarbonyl) -4-(((9H-fluoren-9-ylmethoxy) carbonyl) amino) -L-proline (106 g), HATU (116 g), HOBt (41.1 g) , DIPEA (302 g) and dichloromethane (1.6 L) were stirred at room temperature for 30 minutes. Ammonium bicarbonate (55.5 g) was added to the reaction mixture, and the mixture was stirred overnight at room temperature.
The mixture was added to water and extracted with dichloromethane. The organic layer was separated, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained crude product was purified by silica gel column chromatography (ethyl acetate / petroleum ether) to give the title compound (100 g).
^{1 1} H NMR (400 MHz, DMSO-d ₆ ) δ 1.32-1.39 (9H, m), 1.69-1.72 (1H, m), 2.26-2.39 (1H, m), 3.07-3.11 (1H, m), 3.59 -3.63 (1H, m), 3.95-4.04 (2H, m), 4.20-4.31 (3H, m), 7.03-7.10 (1H, m), 7.32-7.35 (2H, m), 7.40-7.44 (2H, m) m), 7.47-7.58 (2H, m), 7.67 (2H, d, J = 7.6 Hz), 7.90 (2H, d, J = 7.6 Hz).

B) tert-Butyl (2S, 4S) -2-carbamoti oil-4-(((9H-fluorene-9-ylmethoxy) carbonyl) amino) pyrrolidine-1-carboxylate
tert-Butyl (2S, 4S) -2-carbamoyl-4-(((9H-fluorene-9-ylmethoxy) carbonyl) amino) pyrrolidine-1-carboxylate (30.0 g), Lawesson's reagent (32.3 g), toluene ( A mixture of 200 mL) and dichloromethane (200 mL) was stirred at room temperature overnight. The above reaction was carried out a total of 3 times, and the obtained reaction mixture was combined and concentrated. The residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether) to give the title compound (70.0 g).
MS: [M + H] ⁺ 468.2.

C) 9H-Fluorene-9-ylmethyl ((3S, 5S) -5- (4- (4-fluoro-1-naphthyl) -1,3-thiazole-2-yl) pyrrolidine-3-yl) carbamate tri Fluoracetate
A mixture of tert-butyl (2S, 4S) -2-carbamoti oil-4-(((9H-fluoren-9-ylmethoxy) carbonyl) amino) pyrrolidine-1-carboxylate (35.0 g) and ethanol (300 mL) 2-Bromo-1- (4-fluoro-1-naphthyl) etanone (24.0 g) was added to the mixture, and the mixture was stirred at 80 ° C. overnight. The above reaction was repeated and the resulting two reaction mixtures were combined and concentrated. The obtained residue was diluted with water, saturated aqueous sodium carbonate solution was added, the pH was adjusted to 9-10, and the mixture was extracted with dichloromethane. The organic layer was separated, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether, methanol / dichloromethane). A mixture of the resulting compound (65.0 g), TFA (23.3 g) and dichloromethane (500 mL) was stirred overnight at room temperature. The reaction mixture was concentrated under reduced pressure to give the title compound (66 g).
^{MS: [M + H] +} 536.2.

D) 9H-Fluorene-9-ylmethyl ((3S, 5S) -1-((2S) -2-((tert-butoxycarbonyl) amino) -2-cyclohexylacetyl) -5- (4- (4-fluoro) -1-naphthyl) -1,3-thiazole-2-yl) pyrrolidine-3-yl) carbamate
A mixture of (2S)-((tert-butoxycarbonyl) amino) (cyclohexyl) acetic acid (26.1 g), HATU (77.2 g), HOBt (27.4 g), DIPEA (52.4 g) and DMF (650 mL) at room temperature. Stir for 30 minutes, 9H-fluoren-9-ylmethyl ((3S, 5S) -5- (4- (4-fluoro-1-naphthyl) -1,3-thiazole-2-yl) pyrrolidine-3-yl) Carbamate trifluoroacetate (66.0 g) was added and stirred overnight at room temperature. The mixture was added to water at room temperature, and the resulting precipitate was collected by filtration, washed with water and hexane, and dried. The obtained crude product was purified by silica gel column chromatography (ethyl acetate / petroleum ether) to give the title compound (61.0 g).
MS: [M + H] ⁺ 775.6.

E) 9H-Fluorene-9-ylmethyl ((3S, 5S) -1-((2S) -2-amino-2-cyclohexylacetyl) -5- (4- (4-fluoro-1-naphthyl) -1, 3-thiazole-2-yl) pyrrolidine-3-yl) carbamate
9H-Fluorene-9-ylmethyl ((3S, 5S) -1-((2S) -2-((tert-butoxycarbonyl) amino) -2-cyclohexylacetyl) -5- (4- (4-fluoro-1) A mixture of -naphthyl) -1,3-thiazole-2-yl) pyrrolidine-3-yl) carbamate (61.0 g) and TFA (40 mL) was stirred overnight at room temperature. The mixture was concentrated, ice water was added to the obtained residue, saturated aqueous sodium carbonate solution was added to adjust the pH to 9, and the mixture was extracted with dichloromethane. The organic layer was separated, washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (methanol / dichloromethane) to give the title compound (38.6 g).
MS: [M + H] ⁺ 675.3.

F) 9H-Fluorene-9-ylmethyl ((3S, 5S) -1-((2S) -2-(((2S) -2-((tert-butoxycarbonyl) (methyl) amino) propanoyl) amino)- 2-Cyclohexylacetyl) -5-(4- (4-fluoro-1-naphthyl) -1,3-thiazole-2-yl) pyrrolidine-3-yl) carbamate
A mixture of N- (tert-butoxycarbonyl) -N-methyl-L-alanine (13.9 g), HATU (43.5 g), HOBt (15.4 g), DIPEA (22.1 g) and DMF (300 mL) at room temperature 30 After stirring for minutes, 9H-fluoren-9-ylmethyl ((3S, 5S) -1-((2S) -2-amino-2-cyclohexylacetyl) -5- (4- (4-fluoro-1-naphthyl)-)- 1,3-Thiazole-2-yl) pyrrolidine-3-yl) carbamate (38.6 g) was added, and the mixture was stirred overnight at room temperature. The mixture was added to water at room temperature and extracted with dichloromethane. The organic layer was separated, washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (methanol / dichloromethane) to give the title compound (35.0 g).
^{MS: [M + H] +} 860.4.

G) tert-Butyl ((2S) -1-(((1S) -2-((2S, 4S) -4-amino-2- (4- (4-fluoro-1-naphthyl) -1,3- Thiazole-2-yl) pyrrolidine-1-yl) -1-cyclohexyl-2-oxoethyl) amino) -1-oxopropan-2-yl) methylcarbamate
9H-Fluoren-9-ylmethyl ((3S, 5S) -1-((2S) -2-(((2S) -2-((tert-butoxycarbonyl) (methyl) amino) propanoyl) amino) -2- Cyclohexylacetyl) -5-(4- (4-fluoro-1-naphthyl) -1,3-thiazole-2-yl) pyrrolidine-3-yl) Carbamate (157 mg) plus methanol (4 mL) 2M Dimethylamine methanol solution (3.70 mL) was added at room temperature. The mixture was stirred at room temperature overnight. The reaction mixture was concentrated, and the obtained residue was purified by silica gel column chromatography (NH, methanol / ethyl acetate) to give the title compound (100 mg).
MS: [M + H] ⁺ 638.6.
H) Methyl (2- (2- (2- (4-((3-cyano-4- (4-cyanophenyl) -2,5-dimethyl-1H-pyrrole-1-yl) methyl) phenoxy) ethoxy) Ethoxy) ethoxy) acetate
4- (4-Cyanophenyl) -1- (4-Hydroxybenzyl) -2,5-dimethyl-1H-pyrrole-3-carbonitrile (100 mg), methyl (2- (2- (2-(((() A mixture of 4-methylphenyl) sulfonyl) oxy) ethoxy) ethoxy) ethoxy) ethoxy) acetate (138 mg), potassium carbonate (135 mg) and DMF (3 mL) was stirred overnight at 60 ° C. A saturated ammonium chloride solution was added to the mixture at room temperature, and the mixture was extracted with ethyl acetate. The organic layer was separated, washed with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / hexane) to give the title compound (143 mg).
MS: [M + H] ⁺ 532.5.

I) (2- (2- (2- (4-((3-Cyano-4- (4-cyanophenyl) -2,5-dimethyl-1H-pyrrole-1-yl) methyl) phenoxy) ethoxy) ethoxy) ) Ethoxy) Methyl acetate (2- (2- (2- (4-((3-cyano-4- (4-cyanophenyl) -2,5-dimethyl-1H-pyrrole-1-yl) methyl) phenoxy)) To a mixture of ethoxy) ethoxy) ethoxy) acetate (1.95 g), THF (30 mL) and methanol (15 mL) was added 2N aqueous sodium hydroxide solution (7.34 mL) at room temperature. The mixture was stirred at room temperature for 1 hour. The mixture was adjusted to acidity by adding 1N hydrochloric acid at room temperature and extracted with ethyl acetate. The organic layer was separated, washed with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (methanol / ethyl acetate) to give the title compound (1.88 g).
MS: [M + H] ⁺ 518.5.

J) tert-Butyl ((2S) -1-(((1S) -2-((2S, 4S) -4-(((2- (2- (2- (4-((3-Cyano-4) -(4-Cyanophenyl) -2,5-dimethyl-1H-pyrrole-1-yl) methyl) phenoxy) ethoxy) ethoxy) ethoxy) acetyl) amino) -2- (4- (4-fluoro-1-naphthyl) ) -1,3-Thiazole-2-yl) pyrrolidine-1-yl) -1-cyclohexyl-2-oxoethyl) amino) -1-oxopropan-2-yl) methylcarbamate
(2- (2- (2- (4-((3-cyano-4- (4-Cyanophenyl) -2,5-dimethyl-1H-pyrrole-1-yl) methyl) phenoxy) ethoxy) ethoxy) ethoxy) ethoxy ) Acetate (89 mg), tert-butyl ((2S) -1-(((1S) -2-((2S, 4S) -4-amino-2- (4- (4-fluoro-1-naphthyl)) -1,3-thiazole-2-yl) pyrrolidine-1-yl) -1-cyclohexyl-2-oxoethyl) amino) -1-oxopropan-2-yl) methylcarbamate (100 mg), DIPEA (0.08 mL) ), HOBt monohydrate (48.0 mg), WSC (0.06 mL) and THF (3 mL) were stirred at room temperature for 6 hours. The mixture was added to water at room temperature and extracted with ethyl acetate. The organic layer was separated, washed with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (NH, methanol / ethyl acetate) to give the title compound (150 mg).
MS: [M + H] ⁺ 1137.9.

K) N-((1S) -2-((2S, 4S) -4-(((2- (2- (2- (4-((3-cyano-4- (4-cyanophenyl) -2) -2 , 5-Dimethyl-1H-pyrrole-1-yl) methyl) phenoxy) ethoxy) ethoxy) ethoxy) acetyl) amino) -2- (4- (4-fluoro-1-naphthyl) -1,3-thiazole-2 -Il) pyrrolidine-1-yl) -1-cyclohexyl-2-oxoethyl) -N ² -methyl-L-alanine amide
tert-Butyl ((2S) -1-(((1S) -2-((2S, 4S) -4-(((2- (2- (2- (4-((3-cyano-4-)) 4-Cyanophenyl) -2,5-dimethyl-1H-pyrrole-1-yl) methyl) phenoxy) ethoxy) ethoxy) ethoxy) acetyl) amino) -2- (4- (4-fluoro-1-naphthyl)- 1,3-thiazole-2-yl) pyrrolidine-1-yl) -1-cyclohexyl-2-oxoethyl) amino) -1-oxopropan-2-yl) methylcarbamate (150 mg) and TFA (5.08 mL) The mixture was stirred at room temperature for 15 minutes. After concentrating the mixture, saturated aqueous sodium hydrogen carbonate solution was added to neutralize the mixture, and the mixture was extracted with ethyl acetate. The organic layer was separated, washed with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (NH, methanol / ethyl acetate) and HPLC (L-Column 2 ODS, mobile phase: water / acetonitrile (0.1% TFA-containing system)) to give the title compound (70 mg).
^{1 1} H NMR (300 MHz, CD ₃ OD) δ 0.93-1.21 (5H, m), 1.25 (3H, d, J = 6.89 Hz), 1.47-1.83 (6H, m), 2.19 (3H, s), 2.33 (3H, s), 2.35 (3H, s), 2.46 (1H, dt, J = 13.41, 5.19 Hz), 2.69-2.81 (1H, m), 3.13-3.27 (5H, m), 3.41-3.47 (2H) , m), 3.50-3.58 (2H, m), 3.67-3.82 (5H, m), 3.98-4.06 (2H, m), 4.37 (1H, dd, J = 10.76, 6.80 Hz), 4.50 (1H, d) , J = 7.27 Hz), 4.60-4.72 (1H, m), 5.14 (2H, s), 5.57 (1H, dd, J = 8.59, 4.91 Hz), 6.87 (4H, d, J = 3.30 Hz), 7.22 (1H, dd, J = 10.43, 7.98 Hz), 7.52-7.65 (6H, m), 7.76 (2H, d, J = 8.59 Hz), 8.09-8.21 (2H, m)

Example 33
N-((1S) -1-cyclohexyl-2-((2S) -2-(4-(3-((14-(4-((1- (E / Z))-1- (4-hydroxy Phenyl) -2-phenylbut-1-en-1-yl) phenoxy) -12-methyl-11-oxo-3,6,9-trioxa-12-azatetradeca-1-yl) oxy) benzoyl) -1, 3-thiazole-2-yl) pyrrolidine-1-yl) -2-oxoethyl) -N ² -methyl-L-alanine amide

A) 1-Phenyl-2,5,8,11-Tetraoxatridecane-13-Methyl 1-phenyl-2,5,8,11-Tetraoxatridecane-13-Oart (6 g), THF A 2M aqueous sodium hydroxide solution (19.2 mL) was added to a mixture of 80 mL) and methanol (40 mL), and the mixture was stirred at room temperature for 2 hours. The reaction mixture was adjusted to be acidic by adding 1N hydrochloric acid at room temperature, and then extracted with ethyl acetate. The organic layer was separated, washed with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (methanol / ethyl acetate) to give the title compound (4.96 g).
MS: [M + H] ⁺ 299.3.

B) (2- (2- (2-Hydroxyethoxy) ethoxy) ethoxy) acetic acid
A mixture of 1-phenyl-2,5,8,11-tetraoxatridecane-13-acid (1.84 g), 10% palladium carbon (1.313 g) and ethanol (60 mL) in a hydrogen atmosphere at room temperature 3 Stirred for hours. The reaction mixture was filtered to remove insoluble material, and the filtrate was concentrated under reduced pressure to give the title compound (1.28 g).
^{1 1} H NMR (300 MHz, CDCl ₃ ) δ 3.59-3.81 (12H, m), 4.15 (2H, s), 4.96 (2H, br s).

C) 1- (4- (2-Chloroethoxy) phenyl) -2-phenylbutane-1-one
A mixture of 2-phenylbutanoyl chloride (5.01 g) and chlorobenzene (10 mL) in a mixture of (2-chloroethoxy) benzene (4.3 g), aluminum chloride (4.39 g) and chlorobenzene (15 mL) under ice-cooling. And stirred at room temperature for 1 hour. The mixture was added to saturated aqueous sodium hydrogen carbonate solution at room temperature and extracted with ethyl acetate. The organic layer was separated, washed with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate / hexane) to give the title compound (7.6 g).
MS: [M + H] ⁺ 303.0.

D) 1- (4- (2-Chloroethoxy) phenyl) -2-phenyl-1-(4- (tetrahydro-2H-pyran-2-yloxy) phenyl) butane-1-ol
To a mixture of 1- (4- (2-chloroethoxy) phenyl) -2-phenylbutane-1-one (7.6 g) and diethyl ether (100 mL), 0.5 M (4- (tetrahydro-2H-pyran-2) A THF solution (100 mL) of -yloxy) phenyl) magnesium bromide was added dropwise under ice-cooling, and the mixture was stirred at 50 ° C. for 30 minutes under an argon atmosphere. The mixture was added to saturated aqueous ammonium chloride solution at room temperature and extracted with ethyl acetate. The organic layer was separated, washed with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate / hexane) to give the title compound (12.5 g).
^{1 1} H NMR (300 MHz, CDCl ₃ ) δ 0.73 (3H, t, J = 7.32 Hz), 1.57-1.74 (4H, m), 1.74-1.91 (4H, m), 1.93-2.05 (1H, m), 3.49 (1H, brs), 3.63 (1H, brs), 3.69-3.76 (2H, m), 3.87-3.99 (1H, m), 4.05-4.16 (2H, m), 5.21-5.46 (1H, m), 6.57-6.69 (2H, m), 6.98-7.19 (9H, m), 7.43 (2H, dd, J = 8.88, 1.13 Hz)

E) 4-((1- (E / Z))-1-(4- (2-chloroethoxy) phenyl) -2-phenylbut-1-en-1-yl) phenol
1-(4- (2-Chloroethoxy) phenyl) -2-phenyl-1-(4- (tetrahydro-2H-pyran-2-yloxy) phenyl) butane-1-ol (12.5 g) and methanol (100 mL) ), Concentrated hydrochloric acid (10.8 mL) was added at room temperature, and the mixture was heated under reflux for 1 hour. The mixture was added to saturated aqueous sodium hydrogen carbonate solution at room temperature and extracted with ethyl acetate. The organic layer was separated, washed with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate / hexane) to give the title compound (9.70 g).
MS: [MH] ^- 377.0.

F) 4-((1- (E / Z))-1-(4- (2- (methylamino) ethoxy) phenyl) -2-phenylbut-1-en-1-yl) phenol hydrochloride
4-((1- (E / Z))-1-(4- (2-chloroethoxy) phenyl) -2-phenylbut-1-en-1-yl) phenol (13.0 g), 7.6M Methylamine A mixture of methanol solution (36.4 mL), triethylamine (19.1 mL) and methanol (80 mL) was sealed and stirred at 130 ° C. for 6 hours. A saturated aqueous ammonium chloride solution was added to the reaction mixture at room temperature, and the mixture was extracted with ethyl acetate. The organic layer was separated, washed with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (methanol / dichloromethane) to obtain a crude product. The obtained crude product was crystallized from dichloromethane / methanol to obtain a free form (58 g). The obtained crystals were dissolved in methanol (50 mL), 6M hydrochloric acid (100 mL) was added to the mixture, and the mixture was stirred at 60 ° C. for 6 hours. The mixture was concentrated under reduced pressure to give the title compound (60 g).
¹ H NMR (400 MHz, CD ₃ OD) δ 0.94 (3H, t, J = 7.2 Hz), 2.46-2.52 (2H, m), 2.82 (3H, d, J = 27.2 Hz), 3.39 (1H, t) , J = 4.4 Hz), 3.49 (1H, t, J = 4.8 Hz), 4.16 (1H, t, J = 4.8 Hz), 4.33 (1H, t, J = 4.8 Hz), 6.42 (1H, d, J) = 8.4 Hz), 6.65-6.67 (2H, m), 6.77-6.84 (2H, m), 7.02-7.20 (8H, m).

G) Benzyl (2- (4-(((1- (E / Z)) -1- (4-hydroxyphenyl) -2-phenylbut-1-en-1-yl) phenoxy) ethyl) methylcarbamate
4-((1- (E / Z))-1-(4- (2- (methylamino) ethoxy) phenyl) -2-phenylbut-1-en-1-yl) phenol hydrochloride (2.5 g) 2M aqueous sodium hydroxide solution (9.15 mL) was added to the mixture of and THF (25 mL) under ice-cooling, and the mixture was stirred under ice-cooling for 5 minutes. Benzyl chloroformate (1.05 mL) was added to the reaction mixture under ice-cooling, and the mixture was stirred overnight at room temperature. The mixture was neutralized with saturated aqueous ammonium chloride solution and extracted with ethyl acetate. The organic layer was separated, washed with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (NH, ethyl acetate / hexane) to give the title compound (2.4 g).
MS: [M + H] ⁺ 508.5.

H) Benzyl methyl (2- (4-((1- (E / Z)) -2-phenyl-1-(4-((2- (trimethylsilyl) ethoxy) methoxy) phenyl) buta-1-ene-1 -Il) phenoxy) ethyl) carbamate benzyl (2- (4-((1- (E / Z)) -1- (4-hydroxyphenyl) -2-phenylbut-1-en-1-yl) phenoxy) A mixture of ethyl) methylcarbamate (2.4 g), 60% sodium hydride (0.21 g) and DMF (25 mL) was stirred under ice cooling for 5 minutes. (2- (Chloromethoxy) ethyl) (trimethyl)silane (0.87 g) was added to the reaction mixture under ice-cooling, and the mixture was stirred overnight at room temperature. The mixture was added to water at room temperature and extracted with ethyl acetate. The organic layer was separated, washed with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (NH, ethyl acetate / hexane) to give the title compound (2.93 g).
^{1 1} H NMR (300 MHz, CDCl ₃ ) δ -0.06-0.02 (9H, m), 0.84-1.01 (5H, m), 2.40-2.53 (2H, m), 2.98-3.10 (3H, m), 3.52- 3.62 (1H, m), 3.64-3.72 (2H, m), 3.74-3.82 (1H, m), 3.88-4.03 (1H, m), 4.04-4.19 (1H, m), 5.09 (2H, d, J) = 4.72 Hz), 5.14 (1H, s), 5.23 (1H, s), 6.42-6.56 (1H, m), 6.65 (1H, d, J = 8.70 Hz), 6.70-6.89 (3H, m), 7.00 (1H, d, J = 8.70 Hz), 7.04-7.20 (7H, m), 7.27-7.40 (5H, m).

I) N-Methyl-2- (4-(((1- (E / Z)) -2-phenyl-1-(4-((2- (trimethylsilyl) ethoxy) methoxy) phenyl) buta-1-ene- 1-Il) Phenoxy) Ethanamine Benzyl Methyl (2- (4-((1- (E / Z))-2-Phenyl-1-(4-((2- (trimethylsilyl) ethoxy) Methoxy) Phenyl) Phenyl) Buta- Add triethylsilane (1.80 mL) to a mixture of 1-en-1-yl) phenoxy) ethyl) carbamate (400 mg), triethylamine (0.52 mL), palladium (II) chloride (222 mg) and ethyl acetate (10 mL). In addition, it was stirred at room temperature for 1 hour. The mixture was diluted with ethyl acetate and the insoluble material was filtered off. The filtrate was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (NH, ethyl acetate / hexane) to give the title compound (250 mg).
MS: [M + H] ⁺ 504.5.

J) 2- (2- (2- (2- (2-Hydroxyethoxy) ethoxy) ethoxy) -N-methyl-N- (2- (4-((1- (E / Z)) -2-phenyl-1- (4-((2- (Trimethylsilyl) ethoxy) methoxy) phenyl) buta-1-en-1-yl) phenoxy) ethyl) acetamide
N-Methyl-2-(4-((1- (E / Z))-2-phenyl-1-(4-((2- (trimethylsilyl) ethoxy) methoxy) phenyl) buta-1-en-1- Il) Phenoxy) ethaneamine (250 mg), (2- (2- (2-hydroxyethoxy) ethoxy) ethoxy) acetic acid (114 mg), HOBt monohydrate (114 mg), DIPEA (0.26 mL), WSC ( A mixture of 0.13 mL) and THF (10 mL) was stirred overnight at room temperature. The mixture was added to water at room temperature and extracted with ethyl acetate. The organic layer was separated, washed with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (NH, methanol / ethyl acetate) to give the title compound (250 mg).
MS: [M + H] ⁺ 694.6.

K) 12-Methyl-11-oxo-14-(4-((1- (E / Z))-2-phenyl-1-(4-((2- (trimethylsilyl) ethoxy) methoxy) phenyl) porcine- 1-En-1-yl) Phenoxy) -3,6,9-Trioxa-12-azatetradec-1-yl 4-Methylbenzene Sulfonate
2- (2- (2- (2- (2-Hydroxyethoxy) ethoxy) ethoxy) -N-methyl-N- (2- (4-((1- (E / Z))-2-phenyl-1- (4) -((2- (trimethylsilyl) ethoxy) methoxy) phenyl) buta-1-en-1-yl) phenoxy) ethyl) Acetamide (250 mg) and pyridine (5 mL) in a mixture of 4-methylbenzenesulfonyl chloride (275) After adding mg) under ice-cooling, the mixture was stirred at room temperature for 6 hours. The mixture was concentrated under reduced pressure and azeotropically distilled with toluene. A saturated aqueous solution of ammonium chloride was added to the obtained residue, and the mixture was extracted with ethyl acetate. The organic layer was separated, washed with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (methanol / ethyl acetate) to give the title compound (259 mg).
MS: [M + H] ⁺ 848.7.

L) tert-Butyl ((2S) -1-(((1S) -1-cyclohexyl-2-((2S) -2-(4-(3-((12-methyl-11-oxo-14-) 4-((1- (E / Z)) -2-phenyl-1-(4-((2- (trimethylsilyl) ethoxy) methoxy) phenyl) buta-1-en-1-yl) phenoxy) -3, 6,9-Trioxa-12-azatetradec-1-yl) oxy) benzoyl) -1,3-thiazole-2-yl) pyrrolidine-1-yl) -2-oxoethyl) amino) -1-oxopropan-2- Il) Methylcarbamate
12-Methyl-11-oxo-14-(4-((1- (E / Z))-2-phenyl-1-(4-((2- (trimethylsilyl) ethoxy) methoxy) phenyl) buta-1- En-1-yl) phenoxy) -3,6,9-trioxa-12-azatetradeca-1-yl 4-methylbenzenesulfonate (255 mg), tert-butyl ((2S) -1-(((1S)) -1-cyclohexyl-2-((2S) -2-(4- (3-hydroxybenzoyl) -1,3-thiazole-2-yl) pyrrolidine-1-yl) -2-oxoethyl) amino) -1- A mixture of oxopropan-2-yl) methylcarbamate (180 mg), potassium carbonate (50 mg) and anhydrous DMF (3 mL) was stirred at 60 ° C. overnight. The reaction mixture was added to saturated aqueous ammonium chloride solution and extracted with ethyl acetate. The organic layer was separated, washed with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (methanol / ethyl acetate) to give the title compound (347 mg).
^{1 1} H NMR (300 MHz, CD ₃ OD) δ -0.07-0.00 (9H, m), 0.81-2.56 (32H, m), 2.68-3.13 (10H, m), 3.57-4.03 (15H, m), 4.09 -4.38 (5H, m), 4.46-4.65 (2H, m), 5.07 (1H, s), 5.23 (1H, s), 5.42-5.52 (1H, m), 6.47-6.56 (1H, m), 6.58 -6.67 (1H, m), 6.69-6.80 (2H, m), 6.84-6.92 (1H, m), 6.96-7.46 (9H, m), 7.63-7.77 (2H, m), 7.97 (1H, s) , 8.23-8.30 (1H, m)

M) N-((1S) -1-cyclohexyl-2-((2S) -2-(4-(3-((14-(4-((1- (E / Z)) -1- (4) -Hydroxyphenyl) -2-phenylbut-1-en-1-yl) phenoxy) -12-methyl-11-oxo-3,6,9-trioxa-12-azatetradeca-1-yl) oxy) benzoyl)- 1,3-thiazole-2-yl) pyrrolidine-1-yl) -2-oxoethyl) -N ² -methyl-L-alanine amide
tert-butyl ((2S) -1-(((1S) -1-cyclohexyl-2-((2S) -2-(4-(3-((12-methyl-11-oxo-14-(4-) ((1- (E / Z))-2-phenyl-1-(4-((2- (trimethylsilyl) ethoxy) methoxy) phenyl) buta-1-en-1-yl) phenoxy) -3,6, 9-Trioxa-12-azatetradeca-1-yl) oxy) benzoyl) -1,3-thiazole-2-yl) pyrrolidine-1-yl) -2-oxoethyl) amino) -1-oxopropan-2-yl) To a mixture of methylcarbamate (340 mg) and THF (1 mL) was added 4M hydrogen chloride cyclopentylmethyl ether solution (3.33 mL) at room temperature, and the mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated, neutralized with saturated aqueous sodium hydrogen carbonate solution, and extracted with ethyl acetate. The organic layer was separated, washed with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (NH, methanol / ethyl acetate), HPLC (L-Column2 ODS, mobile phase: water / acetonitrile (0.1% trifluoroacetic acid-containing system)) and HPLC (L-Column 2 ODS, mobile phase: Purification with water / acetonitrile (10 mM ammonium bicarbonate) gave the title compound (90 mg).
^{1 1} H NMR (300 MHz, CD ₃ OD) δ 0.82-1.34 (11H, m), 1.51-1.84 (6H, m), 1.96-2.53 (9H, m), 2.88-3.19 (4H, m), 3.52- 4.38 (20H, m), 4.48-4.62 (1H, m), 5.43-5.51 (1H, m), 6.38 (1H, d, J = 7.36 Hz), 6.48-6.56 (1H, m), 6.59-6.65 ( 1H, m), 6.69-6.78 (2H, m), 6.83-6.93 (1H, m), 6.97-7.25 (8H, m), 7.35-7.45 (1H, m), 7.67-7.73 (2H, m), 8.21-8.32 (1H, m)

Example 34
14-(3-((2-((2S) -1-((2S) -2-cyclohexyl-2-((N-methyl-L-alanyl) amino) acetyl) pyrrolidine-2-yl) -1, 3-Thiazole-4-yl) carbonyl) phenoxy) -N- (2- (4-((1- (E / Z)) 1- (4-hydroxyphenyl) -2-phenylbut-1-ene-1 -Il) Phenoxy) Ethyl) -N-Methyl-3,6,9,12-Tetraoxatetradecane-1-amide

A) 1-Phenyl-2,5,8,11,14-Methyl pentaoxahexadecane-16-acid 1-Phenyl-2,5,8,11,14-Pentaoxahexadecan-16-oart (3 g), A 2M aqueous sodium hydroxide solution (8.42 mL) was added to a mixture of THF (40 mL) and methanol (20 mL), and the mixture was stirred at room temperature for 2 hours. The reaction mixture was adjusted to be acidic by adding 1N hydrochloric acid at room temperature, and then extracted with ethyl acetate. The organic layer was separated, washed with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (methanol / ethyl acetate) to give the title compound (2.46 g).
MS: [M + H] ⁺ 343.4.

B) 14-Hydroxy-3,6,9,12-Tetraoxatetradecane-1-acid
A mixture of 1-phenyl-2,5,8,11,14-pentaoxahexadecane-16-acid (2.46 g), 10% palladium carbon (0.38 g) and methanol (80 mL) at room temperature in a hydrogen atmosphere. The mixture was stirred for 6 hours. The reaction mixture was filtered to remove insoluble material, and the filtrate was concentrated under reduced pressure to give the title compound (1.81 g). ^{1 1} H NMR (300 MHz, CD ₃ OD) δ 3.52-3.76 (16H, m), 4.12 (2H, s)

C) 14-Hydroxy-N-methyl-N-(2- (4-((1- (E / Z))-2-phenyl-1-(4-((2- (trimethylsilyl) ethoxy) methoxy) phenyl) ) Buta-1-en-1-yl) Phenoxy) Ethyl) -3,6,9,12-Tetraoxatetradecane-1-amide
N-Methyl-2-(4-((1- (E / Z) -2-phenyl-1-(4-((2- (trimethylsilyl) ethoxy) methoxy) phenyl) buta-1-en-1-yl ) Phenoxy) Ethanamine (350 mg), 14-Hydroxy-3,6,9,12-Tetraoxatetradecane-1-ic acid (210 mg), HOBt monohydrate (160 mg), DIPEA (0.36 mL), WSC The mixture of (0.18 mL) and THF (10 mL) was stirred at room temperature overnight. The mixture was added to water at room temperature and extracted with ethyl acetate. The organic layer was separated, washed with water and saturated saline, and anhydrous sulfuric acid. The mixture was dried over magnesium and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (NH, methanol / ethyl acetate) to give the title compound (471 mg).
MS: [M + H] ⁺ 738.7.

D) 15-Methyl-14-oxo-17-(4-((1- (E / Z))-2-phenyl-1-(4-((2- (trimethylsilyl) ethoxy) methoxy) phenyl) porcine- 1-En-1-yl) Phenoxy) -3,6,9,12-Tetraoxa-15-azaheptadeca-1-yl 4-Methylbenzenesulfonate
14-Hydroxy-N-Methyl-N-(2-(4-((1- (E / Z))-2-phenyl-1-(4-((2- (trimethylsilyl) ethoxy) methoxy) Phenyl) Phenyl) Buta -1-En-1-yl) Phenoxy) Ethyl) -3,6,9,12-Tetraoxatetradecane-1-amide (471 mg) and pyridine (5 mL) in a mixture under ice-cooling, 4-methyl Benzenesulfonyl chloride (487 mg) was added, and the mixture was stirred at room temperature for 6 hours. The reaction mixture was azeotropically distilled with toluene, diluted with ethyl acetate, added to saturated aqueous ammonium chloride solution at room temperature, and extracted with ethyl acetate. The organic layer was separated, washed with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (methanol / ethyl acetate) to give the title compound (463 mg).
^{1 1} H NMR (400 MHz, CD ₃ OD) δ -0.08-0.03 (9H, m), 0.80-1.03 (5H, m), 2.36-2.54 (5H, m), 2.86-3.17 (3H, m), 3.44 -3.83 (18H, m), 3.97-4.42 (6H, m), 5.08 (1H, s), 5.24 (1H, s), 6.52-6.59 (1H, m), 6.64 (1H, d, J = 7.65 Hz) ), 6.72-6.80 (2H, m), 6.92 (1H, t, J = 5.83 Hz), 7.01 (1H, d, J = 7.65 Hz), 7.04-7.19 (7H, m), 7.41 (2H, d, J = 7.53 Hz), 7.78 (2H, d, J = 7.53 Hz)

E) tert-Butyl ((2S) -1-(((1S) -1-cyclohexyl-2-((2S) -2-(4-(3-((15-methyl-14-oxo-17-) 4-((1- (E / Z)) -2-phenyl-1-(4-((2- (trimethylsilyl) ethoxy) methoxy) phenyl) buta-1-en-1-yl) phenoxy) -3, 6,9,12-Tetraoxa-15-azaheptadeca-1-yl) oxy) benzoyl) -1,3-thiazole-2-yl) pyrrolidine-1-yl) -2-oxoethyl) amino) -1-oxopropane- 2-Il) Methylcarbamate
15-Methyl-14-oxo-17-(4-((1- (E / Z))-2-phenyl-1-(4-((2- (trimethylsilyl) ethoxy) methoxy) phenyl) buta-1- En-1-yl) phenoxy) -3,6,9,12-tetraoxa-15-azaheptadeca-1-yl 4-methylbenzenesulfonate (463 mg), tert-butyl ((2S) -1-(((( 1S) -1-cyclohexyl-2-((2S) -2-(4- (3-hydroxybenzoyl) -1,3-thiazole-2-yl) pyrrolidine-1-yl) -2-oxoethyl) amino)- A mixture of 1-oxopropan-2-yl) methylcarbamate (311 mg), potassium carbonate (86 mg) and DMF (3 mL) was stirred at 60 ° C. overnight. The mixture was neutralized by adding saturated aqueous ammonium chloride solution at room temperature, and extracted with ethyl acetate. The organic layer was separated, washed with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (NH, methanol / ethyl acetate) to give the title compound (444 mg).
^{1 1} H NMR (400 MHz, CD ₃ OD) δ -0.11-0.07 (9H, m), 0.81-2.55 (35H, m), 2.66-3.19 (6H, m), 3.52-4.04 (20H, m), 4.07 -4.41 (5H, m), 4.45-4.69 (2H, m), 5.08 (1H, s), 5.24 (1H, s), 5.48 (1H, d, J = 7.40 Hz), 6.50-6.57 (1H, m) ), 6.64 (1H, d, J = 7.78 Hz), 6.72-6.80 (2H, m), 6.86-6.95 (1H, m), 6.97-7.34 (9H, m), 7.39-7.48 (1H, m), 7.66-7.79 (2H, m), 8.23-8.32 (1H, m)

F) 14-((2-((2S) -1-((2S) -2-cyclohexyl-2-((N-methyl-L-alanyl) amino) acetyl) pyrrolidine-2-yl)- 1,3-thiazole-4-yl) carbonyl) phenoxy) -N- (2- (4-((1- (E / Z)) 1- (4-hydroxyphenyl) -2-phenylbuta-1-ene) -1-yl) Phenoxy) Ethyl) -N-Methyl-3,6,9,12-Tetraoxatetradecane-1-amide
tert-butyl ((2S) -1-(((1S) -1-cyclohexyl-2-((2S) -2- (4- (3-((15-methyl-14-oxo-17- (4-) ((1- (E / Z))-2-phenyl-1-(4-((2- (trimethylsilyl) ethoxy) methoxy) phenyl) buta-1-en-1-yl) phenoxy) -3,6, 9,12-Tetraoxa-15-azaheptadeca-1-yl) oxy) benzoyl) -1,3-thiazole-2-yl) pyrrolidine-1-yl) -2-oxoethyl) amino) -1-oxopropan-2- Il) To a mixture of methylcarbamate (200 mg) and THF (3 mL), 6N hydrochloric acid (3.29 mL) was added at room temperature, and the mixture was stirred at room temperature for 4 hours. The mixture was added to saturated aqueous sodium hydrogen carbonate solution at room temperature and extracted with ethyl acetate. The organic layer was separated, washed with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (NH, methanol / ethyl acetate) and HPLC (L-Column 2 ODS, mobile phase: water / acetonitrile (10 mM ammonium bicarbonate)) and the title compound (100 mg). Got
^{1 1} H NMR (400 MHz, CD ₃ OD) δ 0.89 (3H, t, J = 6.96 Hz), 0.96-1.35 (8H, m), 1.54-1.83 (6H, m), 1.98-2.52 (9H, m) , 2.88-3.20 (4H, m), 3.53-4.03 (19H, m), 4.12-4.39 (5H, m), 4.56 (1H, d, J = 6.90 Hz), 5.43-5.51 (1H, m), 6.39 (1H, d, J = 7.40 Hz), 6.49-6.56 (1H, m), 6.63 (1H, d, J = 7.40 Hz), 6.71-6.79 (2H, m), 6.86-7.24 (9H, m) ), 7.37-7.45 (1H, m), 7.71 (2H, brs), 8.27 (1H, brs)

Example 35
N-((1S) -1-cyclohexyl-2-((2S) -2- (4- (3- (2- (2- (2-((2- (4-((1- (E / Z) )) -1- (4-Hydroxyphenyl) -2-phenylbut-1-en-1-yl) phenoxy) ethyl) (methyl) amino) -2-oxoethoxy) ethoxy) ethoxy) benzoyl) -1,3 -Thiazol-2-yl) pyrrolidine-1-yl) -2-oxoethyl) -N ² -methyl-L-alanine amide

A) Methyl acetate (2- (2- (benzyloxy) ethoxy) ethoxy) acetate (3 g), THF (40 mL) and methanol (20 mL) A 2N aqueous sodium hydroxide solution (11.2 mL) was added to the mixture, and the mixture was stirred at room temperature for 2 hours. The reaction mixture was adjusted to be acidic by adding 1N hydrochloric acid at room temperature, and then extracted with ethyl acetate. The organic layer was separated, washed with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (methanol / ethyl acetate) to give the title compound (2.62 g).
MS: [M + Na] ⁺ 277.3.

B) (2- (2-Hydroxyethoxy) ethoxy) acetic acid
A mixture of (2- (2- (benzyloxy) ethoxy) ethoxy) acetic acid (2.62 g), 10% palladium carbon (0.55 g) and methanol (100 mL) was stirred under a hydrogen atmosphere at room temperature for 6 hours. The reaction mixture was filtered to remove insoluble material, and the filtrate was concentrated under reduced pressure to give the title compound (1.69 g).
^{1 1} H NMR (300 MHz, CD ₃ OD) δ 3.49-3.82 (9H, m), 4.13 (2H, s)

C) 2- (2- (2-Hydroxyethoxy) ethoxy) -N-methyl-N- (2- (4-((1- (E / Z))-2-phenyl-1- (4-(( 2- (Trimethylsilyl) ethoxy) methoxy) phenyl) buta-1-en-1-yl) phenoxy) ethyl) acetamide
N-Methyl-2-(4-((1- (E / Z))-2-phenyl-1-(4-((2- (trimethylsilyl) ethoxy) methoxy) phenyl) Buta-1-en-1- Il) Phenoxy) ethaneamine (350 mg), (2- (2-hydroxyethoxy) ethoxy) acetic acid (137 mg), HOBt monohydrate (160 mg), DIPEA (0.36 mL), WSC (0.18 mL) and THF The mixture (10 mL) was stirred overnight at room temperature. The mixture was added to water at room temperature and extracted with ethyl acetate. The organic layer was separated, washed with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (NH, methanol / ethyl acetate) to give the title compound (316 mg).
MS: [M + H] ⁺ 650.6.

D) 2- (2- (2- (Methyl (2- (4-((1- (E / Z)) -2-phenyl-1- (4-((2- (trimethylsilyl) ethoxy) methoxy) phenyl) ) Buta-1-en-1-yl) phenoxy) ethyl) amino) -2-oxoethoxy) ethoxy) ethyl 4-methylbenzenesulfonate
2- (2- (2-Hydroxyethoxy) ethoxy) -N-methyl-N- (2- (4-((1- (E / Z))-2-phenyl-1- (4-((2-) 4-Methylbenzenesulfonyl chloride (371) in a mixture of (trimethylsilyl) ethoxy) methoxy) phenyl) buta-1-en-1-yl) phenoxy) ethyl) acetamide (316 mg) and pyridine (5 mL) under ice-cooling mg) was added, and the mixture was stirred at room temperature for 6 hours. The reaction mixture was azeotropically distilled with toluene, diluted with ethyl acetate, added to saturated aqueous ammonium chloride solution at room temperature, and extracted with ethyl acetate. The organic layer was separated, washed with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (methanol / ethyl acetate) to give the title compound (331 mg).
^{1 1} H NMR (400 MHz, CD ₃ OD) δ -0.13-0.06 (9H, m), 0.79-1.01 (5H, m), 2.34-2.52 (5H, m), 2.89-3.19 (3H, m), 3.44 -3.86 (10H, m), 3.95-4.39 (6H, m), 5.08 (1H, s), 5.24 (1H, s), 6.52-6.58 (1H, m), 6.64 (1H, d, J = 8.03 Hz) ), 6.72-6.80 (2H, m), 6.88-6.94 (1H, m), 7.01 (1H, d, J = 7.40 Hz), 7.04-7.19 (7H, m), 7.36-7.43 (2H, m), 7.73-7.80 (2H, m)

E) tert-butyl ((2S) -1-(((1S) -1-cyclohexyl-2-((2S) -2-(4- (3- (2- (2- (2- (methyl (2) methyl) -(4-((1- (E / Z))-2-phenyl-1-(4-((2- (trimethylsilyl) ethoxy) methoxy) phenyl) but-1-en-1-yl) phenoxy) ethyl ) Amino) -2-oxoethoxy) ethoxy) ethoxy) benzoyl) -1,3-thiazole-2-yl) pyrrolidine-1-yl) -2-oxoethyl) amino) -1-oxopropan-2-yl) methyl Carbamate
tert-butyl ((2S) -1-(((1S) -1-cyclohexyl-2-((2S) -2-(4- (3-hydroxybenzoyl) -1,3-thiazole-2-yl) pyrrolidine) -1-yl) -2-oxoethyl) amino) -1-oxopropan-2-yl) methylcarbamate (246 mg), 2- (2- (2- (methyl (2- (4- ((1-) 1-) (E / Z)) -2-phenyl-1-(4-((2- (trimethylsilyl) ethoxy) methoxy) phenyl) buta-1-en-1-yl) phenoxy) ethyl) amino) -2-oxoethoxy A mixture of ethoxy) ethyl 4-methylbenzenesulfonate (330 mg), potassium carbonate (68 mg) and anhydrous DMF (3 mL) was stirred at 60 ° C. overnight. The mixture was added to saturated aqueous ammonium chloride solution at room temperature and extracted with ethyl acetate. The organic layer was separated, washed with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (NH, methanol / ethyl acetate) to give the title compound (370 mg).
^{1 1} H NMR (400 MHz, CD ₃ OD) δ -0.09-0.05 (9H, m), 0.82-2.51 (32H, m), 2.78-3.17 (10H, m), 3.56-4.02 (11H, m), 4.05 -4.40 (5H, m), 4.52 (2H, d, J = 7.28 Hz), 5.07 (1H, s), 5.23 (1H, s), 5.46 (1H, brs), 6.45-6.56 (1H, m), 6.62 (1H, d, J = 8.16 Hz), 6.67-6.79 (2H, m), 6.84-7.45 (9H, m), 7.70 (2H, brs), 7.98 (2H, s), 8.19-8.36 (1 H) , m)

F) N-((1S) -1-cyclohexyl-2-((2S) -2- (4- (3- (2- (2- (2-((2- (4-((1- (E) / Z)) -1- (4-Hydroxyphenyl) -2-phenylbut-1-en-1-yl) phenoxy) ethyl) (methyl) amino) -2-oxoethoxy) ethoxy) ethoxy) benzoyl) -1 , 3-Thiazole-2-yl) Pyrrolidine-1-yl) -2-oxoethyl) -N ² -methyl-L-alanine amide
tert-Butyl ((2S) -1-(((1S) -1-cyclohexyl-2-((2S) -2- (4- (3- (2- (2- (2- (methyl (2- ( 4-((1- (E / Z))-2-phenyl-1-(4-((2- (trimethylsilyl) ethoxy) methoxy) phenyl) buta-1-en-1-yl) phenoxy) ethyl) amino ) -2-oxoethoxy) ethoxy) ethoxy) benzoyl) -1,3-thiazole-2-yl) pyrrolidine-1-yl) -2-oxoethyl) amino) -1-oxopropan-2-yl) methylcarbamate To a mixture of (185 mg) and THF (3 mL) was added 6M hydrochloric acid (3.26 mL) at room temperature and stirred at room temperature for 4 hours. The mixture was added to saturated aqueous sodium hydrogen carbonate solution at room temperature and extracted with ethyl acetate. The organic layer was separated, washed with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (NH, methanol / ethyl acetate) and HPLC (L-Column 2 ODS, mobile phase: water / acetonitrile (5 mM ammonium acetate)) to give the title compound (80 mg). Got
^{1 1} H NMR (400 MHz, CD ₃ OD) δ 0.81-0.94 (3H, m), 1.00-1.41 (8H, m), 1.54-1.85 (6H, m), 1.93-2.54 (10H, m), 2.86- 3.14 (3H, m), 3.47-4.41 (16H, m), 4.50-4.60 (1H, m), 5.46 (1H, d, J = 6.53 Hz), 6.38 (1H, d, J = 8.03 Hz), 6.48 -6.56 (1H, m), 6.58-6.66 (1H, m), 6.69-6.79 (2H, m), 6.84-7.25 (9H, m), 7.33-7.45 (1H, m), 7.69 (2H, brs) , 8.26 (1H, d, J = 11.80 Hz)

Example 36
N-((1S) -1-cyclohexyl-2-((2S) -2-(4-(3-((16-((7alpha, 17beta) -3,17-dihydroxyestra-1 (10), 2) , 4-Triene-7-yl) -3,6,9,12-tetraoxahexadec-1-yl) oxy) benzoyl) -1,3-thiazole-2-yl) pyrrolidine-1-yl) -2 -Oxoethyl) -N ² -methyl-L-alanine amide

A) (17beta) -3,17-bis (methoxymethoxy) estra-1 (10), 2,4-triene
(17beta)-Estra-1,3,5 (10) -Triene-3,17-diol (60 g), DIPEA (230 mL) and THF (600 mL) in a mixture with MOMCl (83.4 mL) and THF ( 200 mL) of the mixture was added dropwise under ice cooling. The reaction mixture was heated to room temperature, stirred at room temperature for 1 hour, and then heated to reflux for 15 hours. A saturated ammonium chloride solution was added to the reaction mixture at room temperature, and the mixture was extracted with dichloromethane. The organic layer was separated, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate) to give the title compound (66 g).
MS: [MH] ^- 359.1.

B) (17beta) -3,17-bis (methoxymethoxy) estra-1 (10), 2,4-triene-6-ol
A 2MLDA / THF solution (166 mL) was added to a mixture of t-BuOK (37.2 g) and THF (300 mL) at -78 ° C. The mixture was stirred at -78 ° C for 30 minutes. Add a mixture of (17beta) -3,17-bis (methoxymethoxy) estra-1 (10), 2,4-triene (30 g) and THF (150 mL) to the reaction mixture and stir at -78 ° C for 3 hours. did. Trimethoxyborane (114 mL) was added to the reaction mixture, the temperature was raised to 0 ° C., and the mixture was stirred for 2 hours. Hydrogen peroxide solution (129 mL) was added to the reaction mixture, and the mixture was stirred at room temperature for 1 hour. A 10% aqueous sodium thiosulfate solution (510 mL) was added to the mixture under ice-cooling, and the mixture was stirred at room temperature for 2 hours. The mixture was extracted with ethyl acetate to separate the organic layer, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether) to give the title compound (28.8 g).
MS: [M + Na] ⁺ 399.1.

C) To -78 ° C in a mixture of (17beta) -3,17-bis (methoxymethoxy) estra-1 (10), 2,4-triene-6-one oxalyl chloride (7.8 mL) and dichloromethane (200 mL) DMSO (13.1 mL) was added dropwise, and the mixture was stirred for 4 minutes. A mixture of (17beta) -3,17-bis (methoxymethoxy) estra-1 (10), 2,4-triene-6-ol (28.8 g) and dichloromethane (150 mL) was added dropwise to the reaction mixture, and -78 was added dropwise. The mixture was stirred at ° C for 25 minutes. Triethylamine (54 mL) was added to the reaction mixture, and the mixture was stirred at −78 ° C. for 5 minutes, then heated to room temperature and stirred for 15 hours. The mixture was added to water and extracted with dichloromethane. The organic layer was separated, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether) to give the title compound (25 g).
MS: [M + H] ⁺ 375.1.

D) 18-Bromo-1-phenyl-2,5,8,11,14-pentaoxaoctadecane
Mixture of 1-Phenyl-2,5,8,11-Tetraoxatridecane-13-ol (20 g) and DMF (150 mL) in a mixture of 60% sodium hydride (4.22 g) and DMF (50 mL) Was added under ice-cooling and stirred for 25 minutes. A mixture of 1,4-dibromobutane (68.3 g) and DMF (50 mL) was added to the reaction mixture, and the mixture was stirred at room temperature for 2.5 hours under a nitrogen atmosphere. 60% sodium hydride (4.22 g) was added to the reaction mixture under ice-cooling, and the mixture was stirred under ice-cooling for 30 minutes and at room temperature for 30 minutes. Further 60% sodium hydride (4.22 g) was added to the reaction mixture, and the mixture was stirred for 15 hours. A saturated aqueous solution of ammonium chloride was added to the reaction mixture under ice-cooling, and the mixture was extracted with ethyl acetate. The obtained organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether) to give the title compound (18 g).
MS: [M + H] ⁺ 442.9.

E) 18-iodo-1-phenyl-2,5,8,11,14-pentaoxaoctadecane
Sodium iodide (12.8 g) was added to a mixture of 18-bromo-1-phenyl-2,5,8,11,14-pentaoxaoctadecane (18 g) and acetone (150 mL), and the mixture was heated under reflux for 3 hours. The reaction mixture was filtered to remove insoluble matter, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether) to give the title compound (19 g).
MS: [M + Na] ⁺ 489.0.

F) (7alpha,17beta) -3,17-bis (methoxymethoxy) -7- (1-phenyl-2,5,8,11,14-pentaoxaoctadecane-18-yl) estra-1 (10), 2,4-Trien-6-on
A mixture of t-BuOK (5.87 g) and THF (50 mL) with (17beta) -3,17-bis (methoxymethoxy) estra-1 (10), 2,4-triene-6-one (9.8 g) and A mixture of THF (100 mL) was added dropwise under ice cooling. The reaction mixture was stirred under ice cooling for 45 minutes and then cooled to -78 ° C. A mixture of 18-iodo-1-phenyl-2,5,8,11,14-pentaoxaoctadecane (19 g) and THF (50 mL) was added to the reaction mixture, and the mixture was stirred at −78 ° C. for 2 minutes. The reaction mixture was heated to 0 ° C. and stirred at room temperature for 1.5 hours. The mixture was added to water and extracted with ethyl acetate. The obtained organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether) to give the title compound (14.0 g).
MS: [M + H] ⁺ 713.3.

G) (7alpha,17beta) -3,17-dihydroxy-7- (1-phenyl-2,5,8,11,14-pentaoxaoctadecane-18-yl) estra-1 (10), 2,4- Trien-6-on
(7alpha, 17beta) -3,17-bis (methoxymethoxy) -7- (1-phenyl-2,5,8,11,14-pentadecane octadecane-18-yl) estra-1 (10), 2, 6N Hydrochloric acid (150 mL) was added to a mixture of 4-trien-6-one (14.0 g) and THF (120 mL), and the mixture was stirred at room temperature for 20 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was separated, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give the crude title compound (13.2 g).
MS: [M + H] ⁺ 625.3.

H) (7alpha,17beta) -7- (1-phenyl-2,5,8,11,14-pentaoxaoctadecane-18-yl) estra-1 (10), 2,4-triene-3,17- Diol
(7alpha,17beta) -3,17-dihydroxy-7- (1-phenyl-2,5,8,11,14-pentaoxaoctadecane-18-yl) estra-1 (10), 2,4-triene- Triethylsilane (31.8 mL) was added to a mixture of 6-one (13.2 g) and TFA (133 mL), and the mixture was stirred under a nitrogen atmosphere at room temperature for 16 hours. The reaction mixture was partitioned between ethyl acetate and brine, and the organic layer was separated. The obtained organic layer was washed with saturated brine and saturated aqueous sodium hydrogen carbonate solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was dissolved in methanol (150 mL), 2N aqueous sodium hydroxide solution (150 mL) was added, and the mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure, partitioned between ethyl acetate and 1N hydrochloric acid, and the organic layer was separated. The obtained organic layer was washed with 1N hydrochloric acid and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether) to give the title compound (9.5 g).
MS: [M + H] ⁺ 611.3.

I) (7alpha,17beta) -3,17-bis (methoxymethoxy) -7- (1-phenyl-2,5,8,11,14-pentaoxaoctadecane-18-yl) estra-1 (10), 2,4-Trien
(7alpha, 17beta) -7- (1-phenyl-2,5,8,11,14-pentadecane octadecane-18-yl) estra-1 (10), 2,4-triene-3,17-diol ( MOMCl (18.6 g) was added dropwise to a mixture of 9.5 g), DIPEA (49 mL) and THF (200 mL) under ice cooling. The reaction mixture was stirred at room temperature for 1 hour and heated to reflux for 15 hours. Water was added to the mixture and the mixture was extracted with dichloromethane. The organic layer was separated, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether) to give the title compound (8.76 g).
MS: [M + Na] ⁺ 721.3.

J) 16-((7alpha, 17beta) -3,17-bis (methoxymethoxy) estra-1 (10), 2,4-triene-7-yl) -3,6,9,12-tetraoxahexadecane- 1-all
(7alpha, 17beta) -3,17-bis (methoxymethoxy) -7- (1-phenyl-2,5,8,11,14-pentaoxaoctadecan-18-yl) Estra-1 (10), 2, A mixture of 4-triene (8.76 g), 10% palladium carbon (1 g) and ethanol (150 mL) was stirred at room temperature for 15 hours under a hydrogen atmosphere. The reaction mixture was filtered to remove insoluble matters, washed with ethanol, and the filtrate was concentrated under reduced pressure to give the title compound (7 g).
¹ H NMR (400 MHz, CDCl ₃ ) δ 0.819 (3H, s), 0.96-1.14 (1H, m), 1.21-1.64 (11H, m), 1.78-1.724 (1H, m), 1.93-2.13 (2H) , m), 2.35-2.30 (2H, m), 2.48 (2H, brs.), 2.70-2.80 (1H, m), 2.85-2.95 (1H, m), 3.39 (3H, s), 3.44 (2H, t, J = 6.5 Hz), 3.50 (3H, s), 3.56-3.71 (15H, m), 3.72-3.76 (2H, m), 4.68 (2H, d, J = 2.0 Hz), 5.16 (2H, s) ), 6.76 (1H, d, J = 2.4 Hz), 6.84 (1H, dd, J = 8.4, 2.4 Hz), 7.21 (1H, d, J = 8.4 Hz).

K) 16-((7alpha, 17beta) -3,17-bis (methoxymethoxy) estra-1 (10), 2,4-triene-7-yl) -3,6,9,12-tetraoxahexadeca -1-yl 4-methylbenzenesulfonate
16-((7alpha, 17beta) -3,17-bis (methoxymethoxy) estra-1 (10), 2,4-triene-7-yl) -3,6,9,12-tetraoxahexadecane-1- 4-Methylbenzenesulfonyl chloride (551 mg) was added to a mixture of oar (440 mg) and pyridine (5 mL) under ice-cooling, and the mixture was stirred at room temperature for 6 hours. The reaction mixture was concentrated and azeotropically distilled with toluene, and then saturated aqueous ammonium chloride solution was added at room temperature for neutralization, and the mixture was extracted with ethyl acetate. The organic layer was separated, washed with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate / hexane) to give the title compound (441 mg).
MS: [M + Na] ⁺ 785.6.

L) tert-Butyl ((2S) -1-(((1S) -2-((2S) -2- (4- (3-((16-((7alpha, 17beta) -3,17-bis) Methoxymethoxy) estra-1 (10), 2,4-triene-7-yl) -3,6,9,12-tetraoxahexadeca-1-yl) oxy) benzoyl) -1,3-thiazole-2 -Il) Pyrrolidine-1-yl) -1-cyclohexyl-2-oxoethyl) amino) -1-oxopropan-2-yl) methylcarbamate
16-((7alpha, 17beta) -3,17-bis (methoxymethoxy) estra-1 (10), 2,4-triene-7-yl) -3,6,9,12-tetraoxahexadeca-1 -Il 4-methylbenzenesulfonate (432 mg), tert-butyl ((2S) -1-(((1S) -1-cyclohexyl-2-((2S) -2- (4- (3-hydroxybenzoyl)) ) -1,3-Thiazol-2-yl) Pyrrolidine-1-yl) -2-oxoethyl) Amino) -1-oxopropan-2-yl) Methylcarbamate (339 mg), potassium carbonate (94 mg) and The mixture of DMF (5 mL) was stirred at 60 ° C. overnight. The mixture was added to saturated aqueous ammonium chloride solution at room temperature and extracted with ethyl acetate. The organic layer was separated, washed with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (NH, methanol / ethyl acetate) to give the title compound (471 mg).
^{1 1} H NMR (300 MHz, CDCl ₃ ) δ 0.74-0.84 (3H, m), 0.91-1.81 (35H, m), 1.90-2.54 (9H, m), 2.68-2.95 (5H, m), 3.31-3.50 (8H, m), 3.53-3.93 (18H, m), 4.13-4.24 (2H, m), 4.55-4.71 (4H, m), 5.09-5.19 (2H, m), 5.55 (1H, dd, J = 7.6, 2.5 Hz), 6.74 (1H, d, J = 2.5 Hz), 6.78-6.86 (1H, m), 7.12-7.23 (2H, m), 7.37 (1H, t, J = 8.0 Hz), 7.65- 7.71 (1H, m), 7.79 (1H, d, J = 7.7 Hz), 8.10 (1H, s).

M) N-((1S) -1-cyclohexyl-2-((2S) -2-(4-(3-((16-((7alpha, 17beta) -3,17-dihydroxyestra-1 (10)) , 2,4-Triene-7-yl) -3,6,9,12-tetraoxahexadec-1-yl) oxy) benzoyl) -1,3-thiazole-2-yl) pyrrolidine-1-yl) -2-oxoethyl) -N ² -methyl-L-alanine amide
tert-Butyl ((2S) -1-(((1S) -2-((2S) -2- (4- (3-((16-((7alpha, 17beta) -3,17-bis (methoxymethoxy) ) Estra-1 (10), 2,4-triene-7-yl) -3,6,9,12-tetraoxahexadec-1-yl) oxy) benzoyl) -1,3-thiazole-2-yl) ) Pyrrolidine-1-yl) -1-cyclohexyl-2-oxoethyl) amino) -1-oxopropan-2-yl) Methylcarbamate (471 mg) and THF (3 mL) in a mixture of 6M hydrochloric acid (2.97 mL) Was added, and the mixture was stirred at room temperature for 6 hours. The mixture was added to saturated aqueous sodium hydrogen carbonate solution at room temperature and extracted with ethyl acetate. The organic layer was separated, washed with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (NH, methanol / ethyl acetate) and HPLC (L-Column 2 ODS, mobile phase: water / acetonitrile (10 mM ammonium bicarbonate)) and the title compound (160 mg). ) Was obtained.
^{1 1} H NMR (300 MHz, CD ₃ OD) δ 0.75 (3H, s), 0.90-2.43 (39H, m), 2.58-2.86 (2H, m), 3.10-3.22 (1H, m), 3.37-3.74 ( 15H, m), 3.79-4.04 (4H, m), 4.12-4.21 (2H, m), 4.56 (1H, d, J = 7.18 Hz), 5.47 (1H, dd, J = 7.60, 3.45 Hz), 6.45 (1H, d, J = 2.45 Hz), 6.53 (1H, dd, J = 8.45, 2.50 Hz), 7.06 (1H, d, J = 8.40 Hz), 7.18-7.26 (1H, m), 7.38-7.46 ( 1H, m), 7.68-7.75 (2H, m), 8.26-8.31 (1H, m).

Example 41
N-((1S) -1-Cyclohexyl-2-((2S) -2- (5-(3-((14-(4-((1- (E / Z))-1- (4-Hydroxy) Phenyl) -2-phenylbut-1-en-1-yl) phenoxy) -12-methyl-11-oxo-3,6,9-trioxa-12-azatetradeca-1-yl) oxy) benzoyl) pyridine-3 -Il) pyrrolidine-1-yl) -2-oxoethyl) -N ² -methyl-L-alanine amide

A) tert-Butyl ((2S) -1-(((1S) -1-cyclohexyl-2-((2S) -2-(5-(3-((12-methyl-11-oxo-14-) 4-((1- (E / Z)) -2-phenyl-1-(4-((2- (trimethylsilyl) ethoxy) methoxy) phenyl) buta-1-en-1-yl) phenoxy) -3, 6,9-Trioxa-12-azatetradeca-1-yl) oxy) benzoyl) pyridin-3-yl) pyrrolidine-1-yl) -2-oxoethyl) amino) -1-oxopropan-2-yl) methylcarbamate
12-Methyl-11-oxo-14-(4-((1- (E / Z))-2-phenyl-1-(4-((2- (trimethylsilyl) ethoxy) methoxy) phenyl) buta-1- En-1-yl) phenoxy) -3,6,9-trioxa-12-azatetradeca-1-yl 4-methylbenzenesulfonate (611 mg), tert-butyl ((2S) -1-(((1S)) -1-cyclohexyl-2-((2S) -2- (5- (3-hydroxybenzoyl) pyridin-3-yl) pyrrolidine-1-yl) -2-oxoethyl) amino) -1-oxopropan-2- A mixture of (yl) methylcarbamate (356 mg), potassium carbonate (207 mg) and anhydrous DMF (3 mL) was stirred at 60 ° C. for 6 days under an argon atmosphere. Water was added to the mixture at room temperature, and the mixture was extracted three times with ethyl acetate. The organic layer was separated, washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (NH, ethyl acetate / hexane) to give the title compound (607 mg).
MS: [M + H] ⁺ 1268.8.

B) N-((1S) -1-cyclohexyl-2-((2S) -2-(5-(3-((14-(4-((1- (E / Z)) -1- (4) -Hydroxyphenyl) -2-phenylbut-1-en-1-yl) phenoxy) -12-methyl-11-oxo-3,6,9-trioxa-12-azatetradeca-1-yl) oxy) benzoyl) pyridine -3-yl) pyrrolidine-1-yl) -2-oxoethyl) -N ² -methyl-L-alanine amide
tert-butyl ((2S) -1-(((1S) -1-cyclohexyl-2-((2S) -2-(5-(3-((12-methyl-11-oxo-14-(4-) ((1- (E / Z))-2-phenyl-1-(4-((2- (trimethylsilyl) ethoxy) methoxy) phenyl) buta-1-en-1-yl) phenoxy) -3,6, 9-Trioxa-12-azatetradeca-1-yl) oxy) benzoyl) pyridin-3-yl) pyrrolidine-1-yl) -2-oxoethyl) amino) -1-oxopropan-2-yl) methylcarbamate (877) 6N hydrochloric acid (2.5 mL) was added to the mixture of mg) and THF (2.5 mL) at room temperature, and the mixture was stirred at room temperature for 6 hours. The mixture was neutralized with saturated aqueous sodium hydrogen carbonate solution and extracted twice with ethyl acetate. The combined organic layers were separated, washed with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (NH, methanol / ethyl acetate) and HPLC (L-Column 2 ODS, mobile phase: water / acetonitrile (5 mM ammonium acetate). Saturated sodium hydrogen carbonate in the obtained fraction. An aqueous solution was added, and the mixture was extracted with ethyl acetate. The organic layer was separated, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to give the title compound (374 mg).
^{1 1} H NMR (300 MHz, DMSO-d ₆ ) δ 0.76-1.11 (11H, m), 1.42-1.95 (9H, m), 2.15 (3H, s), 2.23-2.47 (4H, m), 2.78-3.05 (4H, m), 3.43-3.90 (15H, m), 4.09-4.27 (5H, m), 4.49 (1H, t, J = 7.5 Hz), 5.05-5.47 (1H, m), 6.38 (1H, d) , J = 8.3 Hz), 6.57 (2H, d, J = 5.4 Hz), 6.65-6.77 (2H, m), 6.86-7.22 (8H, m), 7.23-7.56 (4H, m), 7.75-7.91 ( 2H, m), 8.60-8.77 (2H, m), 9.11-9.49 (1H, m).

Example 42
14-(4-((1S) -2-((2S) -2- (5- (4-fluorobenzoyl) pyridin-3-yl) pyrrolidine-1-yl) -1-((N-methyl-L) -Alanyl) amino) -2-oxoethyl) piperidine-1-yl) -N-(2-(4-((1- (E / Z)) -1- (4-hydroxyphenyl) -2-phenylbuta- 1-En-1-yl) Phenoxy) Ethyl) -N-Methyl-14-oxo-3,6,9,12-Tetraoxatetradecane-1-amide

A) tert-Butyl 15-methyl-14-oxo-17-(4-((1- (E / Z))-2-phenyl-1-(4-((2- (trimethylsilyl) ethoxy) methoxy) phenyl) ) Butyl-1-en-1-yl) Phenoxy) -3,6,9,12-Tetraoxa-15-azaheptadecan-1-oart
2- (2- (2- (2- (2-Hydroxyethoxy) ethoxy) ethoxy) -N-methyl-N- (2- (4-((1- (E / Z))-2-phenyl-1- (4) -((2- (trimethylsilyl) ethoxy) methoxy) phenyl) buta-1-en-1-yl) phenoxy) ethyl) acetamide (2.60 g) and anhydrous DMF (30 mL) in a mixture of 60% sodium hydride (0.235) g) was added at 0 ° C. After stirring the reaction mixture at 0 ° C. for 10 minutes, tert-butyl 2-bromoacetate (0.760 mL) was added at 0 ° C. After stirring the mixture at room temperature for 20 hours, 60% sodium hydride (0.22 g) and tert-butyl 2-bromoacetate (0.74 mL) were added at 0 ° C. The mixture was stirred at room temperature for 3 hours, water was added to the mixture at 0 ° C., and the mixture was extracted with ethyl acetate. The organic layer was separated, washed with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (NH, ethyl acetate / hexane) to give the title compound (2.30 g).
MS: [M + H-tBu + H] ⁺ 752.6.

B) 17-(4-((1- (E / Z)) -1- (4-hydroxyphenyl) -2-phenylbut-1-en-1-yl) phenoxy) -15-methyl-14-oxo -3,6,9,12-tetraoxa-15-azaheptadecan-1-acid
tert-Butyl 15-methyl-14-oxo-17-(4-((1- (E / Z))-2-phenyl-1-(4-((2- (trimethylsilyl) ethoxy) methoxy) phenyl) porcine) -1-En-1-yl) Phenoxy) -3,6,9,12-Tetraoxa-15-azaheptadecan-1-Oart (2.30 g) and THF (10 mL) mixed with 6N hydrochloric acid (10 mL) It was added at room temperature and stirred at room temperature for 6 hours. The mixture was added to water at 0 ° C. and extracted with a mixed solvent of ethyl acetate and THF. The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (methanol / ethyl acetate) to give the title compound (1.65 g).
^{1 1} H NMR (300 MHz, CDCl ₃ ) δ 0.92 (3H, t, J = 7.4 Hz), 2.47 (2H, quin, J = 7.0 Hz), 2.90-3.13 (3H, m), 3.54-3.80 (14H, m), 3.92-4.36 (6H, m), 6.43-6.54 (2H, m), 6.63-6.88 (4H, m), 7.01-7.21 (7H, m).

C) (4-Fluorophenyl) (5-((2S) -1-((1R) -1- (4-methoxyphenyl) ethyl) pyrrolidine-2-yl) pyridin-3-yl) metanone
3-Bromo-5-((2S) -1-((1R) -1- (4-methoxyphenyl) ethyl) pyrrolidine-2-yl) Pyridine (38.0 g) in diethyl ether (1.0 L) solution 2.5 M A solution of n-butyllithium hexane (46.6 mL) was added at -70 ° C. The reaction mixture was stirred at −70 ° C. for 1 hr, then a mixture of 4-fluoro-N-methoxy-N-methylbenzamide (29.0 g) and dityl ether (15 mL) was added. The reaction mixture was stirred at −70 ° C. for 1.5 hours, water was added, and the mixture was extracted with ethyl acetate. The organic layer was separated, washed with water, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / hexane) to give the title compound (12.0 g).
^{1 1} H NMR (400 MHz, CD ₃ OD) δ 1.37 (3H, d, J = 6.62 Hz), 1.54-1.67 (1H, m), 1.82-1.94 (1H, m), 1.94-2.04 (1H, m) , 2.23-2.36 (1H, m), 2.53-2.66 (1H, m), 3.33-3.42 (1H, m), 3.51 (1H, q, J = 6.62 Hz), 3.60 (3H, s), 3.71 (1H) , dd, J = 9.26, 5.73 Hz), 6.48-6.55 (2H, m), 6.93-7.00 (2H, m), 7.24-7.33 (2H, m), 7.64-7.69 (1H, m), 7.74-7.82 (2H, m), 8.43-8.49 (2H, m).
D) (4-Fluorophenyl) (5-((2S) -pyrrolidin-2-yl) pyridin-3-yl) metanone
(4-Fluorophenyl) (5-((2S) -1-((1R) -1- (4-methoxyphenyl) ethyl) pyrrolidine-2-yl) pyridin-3-yl) metanone (20.0 g) and TFA The mixture (200 mL) was stirred at 100 ° C. for 10 hours, and the reaction mixture was concentrated. The obtained residue was partitioned with a dichloromethane-saturated aqueous sodium carbonate solution, and the organic layer was concentrated under reduced pressure to give the title compound (10 g).
^{1 1} H NMR (400 MHz, CD ₃ OD) δ 2.18-2.40 (3H, m), 2.52-2.66 (1H, m), 3.47-3.55 (3H, m), 7.32 (2H, s), 7.86-8.00 ( 2H, m), 8.28-8.36 (1H, m), 8.87-8.92 (1H, s), 8.92-8.98 (1H, s).

E) 9H-Fluorene-9-ylmethyl 4-((1S) -1-((tert-butoxycarbonyl) amino) -2-((2S) -2- (5- (4-fluorobenzoyl) pyridine-3-) Il) pyrrolidine-1-yl) -2-oxoethyl) piperidine-1-carboxylate
(4-Fluorophenyl) (5-((2S) -Pyrrolidine-2-yl) Pyridine-3-yl) Metanone (2.43 g), (2S)-((tert-butoxycarbonyl) amino) (1-((( A mixture of 9H-fluoren-9-ylmethoxy) carbonyl) piperidine-4-yl) acetic acid (3.60 g), DIPEA (3.87 mL), DMTMM (3.07 g) and dichloromethane (100 mL) was stirred at 14 ° C. for 10 hours. The reaction mixture was concentrated and the residue was purified by silica gel column chromatography (ethyl acetate / hexane) to give the title compound (3.20 g).
¹ H NMR (400 MHz, CD ₃ OD) δ 1.18 --1.28 (1H, m), 1.39 (1H, brs), 1.46 (9H, brs), 1.93-2.02 (1H, m), 2.05-2.19 (1H, m), 2.42-2.56 (1H, m), 2.65 (1H, d, J = 5.29 Hz), 2.86 (1H, s), 2.99 (1H, s), 3.25 (1H, s), 3.34 (2H, s) ), 3.91 (1H, brs), 4.00 (4H, s), 4.03-4.12 (1H, m), 4.18-4.31 (2H, m), 5.13-5.22 (1H, m), 7.31 (4H, t, J) = 7.28 Hz), 7.38 (2H, brs), 7.59 (2H, d, J = 7.50 Hz), 7.80 (2H, d, J = 7.50 Hz), 7.88 (2H, dd, J = 8.60, 5.51 Hz), 7.98 (1H, d, J = 4.41 Hz), 8.67-8.73 (2H, m).

F) 9H-Fluorene-9-ylmethyl 4-((1S) -1-((N- (tert-butoxycarbonyl) -N-methyl-L-alanyl) amino) -2-((2S) -2-( 5- (4-Fluorobenzoyl) Pyridine-3-yl) Pyrrolidine-1-yl) -2-oxoethyl) Piperidine-1-carboxylate
9H-Fluorene-9-ylmethyl 4-((1S) -1-((tert-butoxycarbonyl) amino) -2-((2S) -2- (5- (4-fluorobenzoyl) pyridin-3-yl)) A mixture of pyrrolidine-1-yl) -2-oxoethyl) piperidine-1-carboxylate (3.2 g), TFA (25 mL) and dichloromethane (25 mL) was stirred at 15 ° C. for 20 minutes. Residue obtained by concentrating the reaction solution (2.76 g), (S) -2-((tert-butoxycarbonyl) (methyl) amino) propanoic acid (1.33 g), DIPEA (2.25 mL), DMTMM (1.79 g) ) And dichloromethane (100 mL) were stirred at 14 ° C. for 10 hours. The reaction mixture was concentrated and the residue was purified by preparative HPLC to give the title compound (1.10 g).
MS: [M + H] ⁺ 818.5.

G) tert-Butyl ((2S) -1-(((1S) -2-((2S) -2- (5- (4-fluorobenzoyl) pyridin-3-yl) pyrrolidine-1-yl) -2) -Oxo-1- (piperidine-4-yl) ethyl) amino) -1-oxopropan-2-yl) methylcarbamate
9H-Fluoren-9-ylmethyl 4-((1S) -1-((N- (tert-butoxycarbonyl) -N-methyl-L-alanyl) amino) -2-((2S) -2- (5-) (4-Fluorobenzoyl) Pyridine-3-yl) Pyrrolidine-1-yl) -2-oxoethyl) Piperidine-1-carboxylate (200 mg) and methanol (4 mL) in a mixture of 2M dimethylamine methanol solution (8 mL) ) Was added at room temperature. The mixture was stirred at room temperature for 5 hours and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (NH, methanol / ethyl acetate) to give the title compound (127 mg).
MS: [M + H] ⁺ 596.4.

H) tert-Butyl ((2S) -1-(((1S) -2-((2S) -2- (5- (4-fluorobenzoyl) pyridin-3-yl) pyrrolidine-1-yl) -1) -(1-(17-(4-((1- (E / Z)) -1- (4-Hydroxyphenyl) -2-phenylbut-1-en-1-yl) phenoxy) -15-methyl- 14-oxo-3,6,9,12-tetraoxa-15-azaheptadecan-1-oil) piperidine-4-yl) -2-oxoethyl) amino) -1-oxopropan-2-yl) methylcarbamate
17-(4-((1- (E / Z)) -1- (4-Hydroxyphenyl) -2-phenylbut-1-en-1-yl) phenoxy) -15-methyl-14-oxo-3 , 6,9,12-Tetraoxa-15-azaheptadecan-1-acid (152 mg), tert-butyl ((2S) -1-(((1S) -2-((2S) -2- (5-( 4-Fluorobenzoyl) Pyridine-3-yl) Pyrrolidine-1-yl) -2-oxo-1- (piperidine-4-yl) ethyl) Amino) -1-oxopropan-2-yl) Methylcarbamate (127) A mixture of mg), WSC (0.06 mL), HOBt (43 mg) and anhydrous DMF (3 mL) was stirred at room temperature for 18 hours. Water was added to the mixture and the mixture was extracted with ethyl acetate. The organic layer was separated, washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (NH, methanol / ethyl acetate) to give the title compound (215 mg).
MS: [M + H] ⁺ 1199.8.

I) 14-(4-((1S) -2-((2S) -2- (5- (4-fluorobenzoyl) pyridin-3-yl) pyrrolidine-1-yl) -1-((N-methyl) -L-alanyl) amino) -2-oxoethyl) piperidine-1-yl) -N-(2-(4-((1- (E / Z))-1- (4-hydroxyphenyl) -2-phenyl) Buta-1-en-1-yl) phenoxy) ethyl) -N-methyl-14-oxo-3,6,9,12-tetraoxatetradecane-1-amide
tert-Butyl ((2S) -1-(((1S) -2-((2S) -2- (5- (4-fluorobenzoyl) pyridin-3-yl) pyrrolidine-1-yl) -1-( 1-(17-(4-(((1- (E / Z)) -1- (4-Hydroxyphenyl) -2-phenylbut-1-en-1-yl) phenoxy) -15-methyl-14- Oxo-3,6,9,12-Tetraoxa-15-azaheptadecan-1-oil) piperidine-4-yl) -2-oxoethyl) amino) -1-oxopropan-2-yl) methylcarbamate (215 mg) TFA (1 mL) was added to the mixture of and THF (1 mL) at 0 ° C, and the mixture was stirred at 0 ° C for 1 hour and at room temperature for 2 hours. The mixture was neutralized with saturated sodium hydrogen carbonate solution at 0 ° C. and extracted with a mixed solvent of ethyl acetate and THF. The organic layer was separated, washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (NH, methanol / ethyl acetate) and HPLC (L-Column 2 ODS, mobile phase: water / acetonitrile (0.1% TFA-containing system)). A saturated aqueous sodium hydrogen carbonate solution was added to the obtained fraction, and the mixture was extracted with ethyl acetate. The organic layer was separated, dried over anhydrous magnesium sulfate, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (NH, methanol / ethyl acetate) to give the title compound (79 mg).
^{1 1} H NMR (300 MHz, CD ₃ OD) δ 0.84-1.03 (4H, m), 1.09-1.44 (5H, m), 1.61 (2H, t, J = 13.3 Hz), 1.86-2.18 (4H, m) , 2.28 (2H, s), 2.38-2.63 (4H, m), 2.82-3.18 (5H, m), 3.52-4.71 (25H, m), 5.10-5.52 (1H, m), 6.34-6.42 (1H, m) m), 6.50-6.58 (1H, m), 6.63 (1H, d, J = 8.7 Hz), 6.74 (2H, dt, J = 8.5, 2.4 Hz), 6.86-6.94 (1H, m), 6.95-7.18 (7H, m), 7.30 (2H, t, J = 8.7 Hz), 7.84-8.06 (3H, m), 8.57-8.76 (2H, m).

Example 43
N-(2-(4-((1- (E / Z)) -1- (4-Hydroxyphenyl) -2-phenylbut-1-en-1-yl) phenoxy) ethyl) -N-methyl- 14-(4-((1S) -1-((N-methyl-L-alanyl) amino) -2-oxo-2-((2S) -2- (4-phenyl [1,3] thiazolo [4] , 5-c] Pyridin-2-yl) pyrrolidine-1-yl) ethyl) piperidine-1-yl) -14-oxo-3,6,9,12-tetraoxatetradecane-1-amide

A) tert-butyl ((2S) -1-(((1S) -1-(1-(17-(4-((1- (E / Z))-1- (4-hydroxyphenyl) -2) -Phenylbuta-1-en-1-yl) phenoxy) -15-methyl-14-oxo-3,6,9,12-tetraoxa-15-azaheptadecan-1-oil) piperidine-4-yl) -2- Oxo-2-((2S) -2- (4-phenyl [1,3] thiazolo [4,5-c] pyridin-2-yl) pyrrolidine-1-yl) ethyl) amino) -1-oxopropane- 2-Il) Methylcarbamate
17-(4-((1- (E / Z)) -1- (4-hydroxyphenyl) -2-phenylbut-1-en-1-yl) phenoxy) -15-methyl-14-oxo-3 , 6,9,12-Tetraoxa-15-azaheptadecan-1-acid (143 mg), tert-butyl methyl ((2S) -1-oxo-1-(((1S) -2-oxo-2-(((1S) -2-oxo-2-(() 2S) -2- (4-phenyl [1,3] thiazolo [4,5-c] pyridin-2-yl) pyrrolidine-1-yl) -1- (piperidine-4-yl) ethyl) amino) propane- A mixture of 2-yl) carbamate (116 mg), WSC (0.05 mL), HOBt (39 mg) and anhydrous DMF (3 mL) was stirred at room temperature for 19 hours. Water was added to the mixture at 0 ° C., and the mixture was extracted with a mixed solvent of ethyl acetate and THF. The organic layer was separated, washed with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (NH, ethyl acetate / methanol) to give the title compound (205 mg).
MS: [M + H] ⁺ 1210.8.

B) N-(2- (4-((1- (E / Z)) -1- (4-hydroxyphenyl) -2-phenylbut-1-en-1-yl) phenoxy) ethyl) -N- Methyl-14-(4-((1S) -1-((N-methyl-L-alanyl) amino) -2-oxo-2-((2S) -2- (4-phenyl [1,3] thiazolo) [4,5-c] Pyridin-2-yl) Pyrrolidine-1-yl) Ethyl) Piperidine-1-yl) -14-oxo-3,6,9,12-Tetraoxatetradecane-1-amide
tert-butyl ((2S) -1-(((1S) -1- (1-(17-(4-((1- (E / Z))-1- (4-hydroxyphenyl) -2-phenyl Buta-1-en-1-yl) phenoxy) -15-methyl-14-oxo-3,6,9,12-tetraoxa-15-azaheptadecan-1-oil) piperidine-4-yl) -2-oxo- 2-((2S) -2- (4-Phenyl [1,3] thiazolo [4,5-c] pyridin-2-yl) pyrrolidine-1-yl) ethyl) amino) -1-oxopropan-2- Il) A mixture of methylcarbamate (205 mg) and TFA (1 mL) was stirred at room temperature for 20 minutes. The mixture was neutralized with saturated aqueous sodium hydrogen carbonate solution at 0 ° C. and extracted with a mixed solvent of ethyl acetate and THF. The organic layer was separated, washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. Residues were subjected to silica gel column chromatography (NH, ethyl acetate / methanol), HPLC (L-Column 2 ODS, mobile phase: water / acetonitrile (5 mM ammonium acetate)), silica gel column chromatography (methanol / ethyl acetate, 0.5%). Purification with v / v triethylamine addition) gave the title compound (16 mg).
^{1 1} H NMR (300 MHz, CD ₃ OD) δ 0.88 (3H, td, J = 7.3, 2.6 Hz), 1.07-1.37 (7H, m), 1.54-1.75 (2H, m), 1.88-2.76 (12H, m), 2.89-3.12 (3H, m), 3.37-3.79 (15H, m), 3.89-4.39 (8H, m), 4.66 (1H, t, J = 6.7 Hz), 5.49-5.78 (1H, m) , 6.38 (1H, d, J = 8.4 Hz), 6.48-6.67 (2H, m), 6.70-7.18 (10H, m), 7.45-7.60 (3H, m), 7.93-8.01 (1H, m), 8.23 -8.35 (2H, m), 8.50 (1H, dd, J = 5.4, 1.3 Hz).

Example 44
N-((1S) -1-cyclohexyl-2-((2S) -2-(4-(2-((14-(4-((1- (E / Z))-1- (4-hydroxy Phenyl) -2-phenylbut-1-en-1-yl) phenoxy) -12-methyl-11-oxo-3,6,9-trioxa-12-azatetradeca-1-yl) oxy) benzoyl) -1, 3-thiazole-2-yl) pyrrolidine-1-yl) -2-oxoethyl) -N ² -methyl-L-alanine amide

A) tert-Butyl (2S) -2- (4-formyl-1,3-thiazole-2-yl) pyrrolidine-1-carboxylate
Hydrogen in a mixture of tert-butyl (2S) -2- (4- (methoxy (methyl) carbamoyl) -1,3-thiazole-2-yl) pyrrolidine-1-carboxylate (1.0 g) and THF (20 mL) Lithium aluminum hydride (55 mg) was added at room temperature and the mixture was stirred for 1 hour. Sodium sulfate decahydrate was added to the reaction mixture, and impurities were removed by filtration. The filtrate was evaporated under reduced pressure, diluted with water, and then extracted three times with ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure to give the title compound (600 mg).
MS: [M + H] ⁺ 282.9.

B) tert-Butyl (2S) -2- (4-((2- (benzyloxy) phenyl) (hydroxy) methyl) -1,3-thiazole-2-yl) pyrrolidine-1-carboxylate
In a mixture of tert-butyl (2S) -2- (4-formyl-1,3-thiazole-2-yl) pyrrolidine-1-carboxylate (4.36 g) and THF (20 mL) (2- (benzyloxy) Phenyl) (bromo) magnesium (2.86 g) was added at room temperature and the reaction mixture was stirred overnight. Water was added to the mixture, and the mixture was extracted three times with ethyl acetate. The combined organic layers were washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether) to give the title compound (4.6 g).
MS: [M + H] ⁺ 466.9.

C) tert-Butyl (2S) -2- (4- (2- (benzyloxy) benzoyl) -1,3-thiazole-2-yl) pyrrolidine-1-carboxylate
tert-Butyl (2S) -2- (4-((2- (benzyloxy) phenyl) (hydroxy) methyl) -1,3-thiazole-2-yl) pyrrolidine-1-carboxylate (4.60 g), dioxide A mixture of manganese (8.57 g) and dichloromethane (100 mL) was stirred overnight at room temperature. Impurities were removed by filtration and the filtrate was washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine. The separated organic layer was distilled off under reduced pressure to give the title compound (4.40 g).
^{MS: [M + H] +} 465.2.

D) (2- (benzyloxy) phenyl) (2-((2S) -pyrrolidin-2-yl) -1,3-thiazole-4-yl) methanonetrifluoroacetate
tert-Butyl (2S) -2- (4- (2- (benzyloxy) benzoyl) -1,3-thiazole-2-yl) pyrrolidine-1-carboxylate (4.40 g), TFA (8 mL) and dichloromethane The mixture (50 mL) was stirred at room temperature overnight. The reaction mixture was concentrated to give the title compound (2.50 g).
MS: [M + H] ⁺ 365.2.

E) tert-butyl ((1S) -2-((2S) -2- (4- (2- (benzyloxy) benzoyl) -1,3-thiazole-2-yl) pyrrolidine-1-yl) -1 -Cyclohexyl-2-oxoethyl) carbamate
(2- (benzyloxy) phenyl) (2-((2S) -pyrrolidin-2-yl) -1,3-thiazole-4-yl) methanone trifluoroacetate (2.10 g) and dichloromethane (50 mL) To the mixture of (2S)-((tert-butoxycarbonyl) amino) (cyclohexyl) acetic acid (1.78 g), DIPEA (2.23 g) and HATU (3.28 g) were added at room temperature and stirred overnight. The reaction mixture was concentrated, the resulting residue was diluted with water and then extracted three times with ethyl acetate. The combined organic layers were washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether) to give the title compound (3.00 g).
MS: [M + H] ⁺ 604.4.

F) (2S) -2-amino-1-((2S) -2-(4- (2- (benzyloxy) benzoyl) -2-thienyl) pyrrolidine-1-yl) -2-cyclohexylethaneonetrifluoroacetic acid salt
tert-Butyl ((1S) -2-((2S) -2-(4- (2- (benzyloxy) benzoyl) -1,3-thiazole-2-yl) pyrrolidine-1-yl) -1-cyclohexyl A mixture of -2-oxoethyl) carbamate (3.00 g), TFA (6 mL) and dichloromethane (50 mL) was stirred overnight at room temperature. The reaction mixture was concentrated to give the title compound (2.40 g).
^{1 1} H NMR (400 MHz, DMSO-d ₆ ) δ1.07-1.24 (4H, m), 1.62-1.70 (7H, m), 1.80-1.95 (3H, m), 2.14-2.19 (1H, m), 3.62-3.65 (1H, m), 3.69-3.72 (1H, m), 4.02-4.06 (1H, m), 5.09-5.13 (2H, m), 5.33-5.35 (1H, m), 7.06-7.11 (3H) , m), 7.24-7.32 (4H, m), 7.41-7.45 (1H, m), 7.52-7.57 (1H, m), 8.12 (2H, brs), 8.35 (1H, s).

G) tert-Butyl ((2S) -1-(((1S) -2-((2S) -2- (4- (2- (benzyloxy) benzoyl) -1,3-thiazole-2-yl)) Pyrrolidine-1-yl) -1-cyclohexyl-2-oxoethyl) amino) -1-oxopropan-2-yl) methylcarbamate
(2S) -2-amino-1-((2S) -2- (4- (2- (benzyloxy) benzoyl) -2-thienyl) pyrrolidine-1-yl) -2-cyclohexylethanetrifluoroacetate ( Add N- (tert-butoxycarbonyl) -N-methyl-L-alanine (1.16 g), DIPEA (1.85 g) and HATU (2.72 g) to a mixture of 2.40 g) and dichloromethane (40 mL) overnight. Stirred. The reaction mixture was concentrated, the resulting residue was diluted with water and then extracted three times with ethyl acetate. The combined organic layers were washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether) to give the title compound (2.20 g).
MS: [M + H] ⁺ 688.9.

H) N-((1S) -1-cyclohexyl-2-((2S) -2-(4- (2-hydroxybenzoyl) -1,3-thiazole-2-yl) pyrrolidine-1-yl) -2 -Oxoethyl) -N ² -methyl-L-alanine amide trifluoroacetate
tert-Butyl ((2S) -1-(((1S) -2-((2S) -2- (4- (2- (benzyloxy) benzoyl) -1,3-thiazole-2-yl) pyrrolidine- Mixture of 1-yl) -1-cyclohexyl-2-oxoethyl) amino) -1-oxopropan-2-yl) methylcarbamate (1.6 g), methanesulfonic acid (10 mL) and dichloromethane (40 mL) at room temperature Stirred overnight. The reaction mixture was concentrated to give the title compound (0.8 g).
MS: [M + H] ⁺ 499.3.

I) tert-butyl ((2S) -1-(((1S) -1-cyclohexyl-2-((2S) -2-(4- (2-hydroxybenzoyl) -1,3-thiazole-2-yl) ) Pyrrolidine-1-yl) -2-oxoethyl) amino) -1-oxopropan-2-yl) methylcarbamate
N-((1S) -1-cyclohexyl-2-((2S) -2-(4- (2-hydroxybenzoyl) -1,3-thiazole-2-yl) pyrrolidine-1-yl) -2-oxoethyl )-N ² -Methyl-L-alanine amide A mixture of trifluoroacetate (1.3 g), di-tert-butyl dicarbonate (0.57 g) and THF (20 mL) was stirred overnight at room temperature. The residue was purified by HPLC (L-Column 2 ODS, mobile phase: water / acetonitrile (10 mM ammonium acetate-containing system)) to give the title compound (0.53 g).
MS: [M + H] ⁺ 599.3.

J) tert-Butyl ((2S) -1-(((1S) -1-cyclohexyl-2-((2S) -2-(4-(2-((12-methyl-11-oxo-14-) 4-((1- (E / Z)) -2-phenyl-1-(4-((2- (trimethylsilyl) ethoxy) methoxy) phenyl) buta-1-en-1-yl) phenoxy) -3, 6,9-Trioxa-12-azatetradec-1-yl) oxy) benzoyl) -1,3-thiazole-2-yl) pyrrolidine-1-yl) -2-oxoethyl) amino) -1-oxopropan-2- Il) Methylcarbamate
12-Methyl-11-oxo-14-(4-((1- (E / Z))-2-phenyl-1-(4-((2- (trimethylsilyl) ethoxy) methoxy) phenyl) buta-1- En-1-yl) phenoxy) -3,6,9-trioxa-12-azatetradeca-1-yl 4-methylbenzenesulfonate (153 mg), tert-butyl ((2S) -1-(((1S)) -1-cyclohexyl-2-((2S) -2-(4- (2-hydroxybenzoyl) -1,3-thiazole-2-yl) pyrrolidine-1-yl) -2-oxoethyl) amino) -1- A mixture of oxopropan-2-yl) methylcarbamate (90 mg), potassium carbonate (52 mg) and anhydrous DMF (1 mL) was stirred overnight at 60 ° C. under an argon atmosphere. Water was added to the mixture at room temperature, and the mixture was extracted twice with ethyl acetate. The organic layer was separated, washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (NH, ethyl acetate / hexane) to give the title compound (138 mg).
MS: [M + H] ⁺ 1274.7.

K) N-((1S) -1-cyclohexyl-2-((2S) -2-(4-(2-((14-(4-((1- (E / Z)) -1- (4) -Hydroxyphenyl) -2-phenylbut-1-en-1-yl) phenoxy) -12-methyl-11-oxo-3,6,9-trioxa-12-azatetradeca-1-yl) oxy) benzoyl)- 1,3-thiazole-2-yl) pyrrolidine-1-yl) -2-oxoethyl) -N ² -methyl-L-alanine amide
tert-butyl ((2S) -1-(((1S) -1-cyclohexyl-2-((2S) -2-(4-(2-((12-methyl-11-oxo-14-(4-) ((1- (E / Z))-2-phenyl-1-(4-((2- (trimethylsilyl) ethoxy) methoxy) phenyl) buta-1-en-1-yl) phenoxy) -3,6, 9-Trioxa-12-azatetradeca-1-yl) oxy) benzoyl) -1,3-thiazole-2-yl) pyrrolidine-1-yl) -2-oxoethyl) amino) -1-oxopropan-2-yl) 6N Hydrochloric acid (1.5 mL) was added to a mixture of methylcarbamate (138 mg) and anhydrous THF (1.5 mL) at room temperature, and the mixture was stirred at room temperature for 2 hours. The mixture was neutralized with saturated aqueous sodium hydrogen carbonate solution at 0 ° C. and extracted with ethyl acetate. The organic layer was separated, washed with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by HPLC (L-Column 2 ODS, mobile phase: water / acetonitrile (5 mM ammonium bicarbonate-containing system). The obtained fraction was concentrated under reduced pressure to give the title compound (69 mg).
^{1 1} H NMR (300 MHz, DMSO-d ₆ ) δ 0.80-1.21 (12H, m), 1.64 (6H, d, J = 10.9 Hz), 1.91-2.07 (3H, m), 2.11-2.26 (4H, m) ), 2.39 (2H, t, J = 7.8 Hz), 2.79-3.02 (4H, m), 3.34-3.57 (12H, m), 3.60-3.80 (3H, m), 4.01-4.25 (5H, m), 4.44-4.54 (1H, m), 5.21-5.32 (1H, m), 6.39 (1H, d, J = 8.4 Hz), 6.54-6.63 (2H, m), 6.68-6.79 (2H, m), 6.94 ( 2H, dd, J = 15.1, 8.0 Hz), 7.01-7.23 (8H, m), 7.37 (1H, d, J = 7.2 Hz), 7.49 (1H, t, J = 7.7 Hz), 7.89 (1H, d) , J = 8.7 Hz), 8.24 (1H, brs), 9.11-9.47 (1H, m).

Example 45
N-((1S) -1-cyclohexyl-2-((2S, 4S) -2-(4- (4-fluorobenzoyl) -1,3-thiazole-2-yl) -4-((14-( 4-((1- (E / Z))-1- (4-Hydroxyphenyl) -2-phenylbut-1-en-1-yl) phenoxy) -12-methyl-11-oxo-3,6, 9-Trioxa-12-azatetradeca-1-yl) sulfanyl) pyrrolidine-1-yl) -2-oxoethyl) -N ² -methyl-L-alanine amide

A) tert-Butyl (2S, 4R) -4- (benzyloxy) -2-carbamoylpyrrolidine-1-carboxylate
A mixture of (4R) -4- (benzyloxy) -1- (tert-butoxycarbonyl) -L-proline (255 g), WSC (182 g), HOBt (129 g) and acetonitrile (2.5 L) at room temperature Stirred overnight. 25% aqueous ammonia (300 mL) was added to the reaction mixture at 0 ° C., and the mixture was stirred at 0 ° C. for 30 minutes and then at room temperature overnight. The reaction mixture was concentrated, water was added to the residue, and the mixture was extracted with ethyl acetate. The extract was washed with 0.5 N hydrochloric acid, saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure.
The residue was purified by silica gel chromatography (methanol / dichloromethane) to give the title compound (180 g).
MS: [M + H-Boc + H] ⁺ 221.2.

B) tert-Butyl (2S, 4R) -4- (benzyloxy) -2-carbamoti oil pyrrolidine-1-carboxylate
A mixture of tert-butyl (2S, 4R) -4- (benzyloxy) -2-carbamoylpyrrolidine-1-carboxylate (180 g), Lawesson's reagent (227 g) and THF (1.8 L) was stirred overnight at room temperature. .. The reaction mixture was concentrated, water was added to the residue, and the mixture was extracted with ethyl acetate. The extract was washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel chromatography (dichloromethane / methanol) to give the title compound (165 g).
MS: [M + H-Boc + H] ⁺ 237.2.

C) Ethyl 2-((2S, 4R) -4- (benzyloxy) -1- (tert-butoxycarbonyl) pyrrolidine-2-yl) -1,3-thiazole-4-carboxylate
60 Mixtures of tert-Butyl (2S, 4R) -4- (benzyloxy) -2-carbamotioil pyrrolidine-1-carboxylate (165 g), ethyl bromopyruvic acid (191 g) and ethanol (1.5 L) The mixture was stirred at ° C. for 3 hours. The reaction mixture was concentrated, THF (1.5 L), water (1.5 L) and sodium hydrogen carbonate (82.3 g) were added to the residue, cooled to 0 ° C., and di-tert-butyl dicarbonate (107 g) was added. .. The reaction mixture was stirred at room temperature overnight. The reaction mixture was concentrated, diluted with ethyl acetate, washed with water and saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel chromatography (ethyl acetate / petroleum ether) to give the title compound (130 g).
MS: [M + H] ⁺ 432.9.

D) 2-((2S, 4R) -4- (benzyloxy) -1- (tert-butoxycarbonyl) pyrrolidine-2-yl) -1,3-thiazole-4-carboxylate ethyl 2-((2S,,) 4R) -4- (benzyloxy) -1- (tert-butoxycarbonyl) pyrrolidine-2-yl) -1,3-thiazole-4-carboxylate (130 g), 1N aqueous sodium hydroxide solution (602 mL) and The mixture of methanol (1 L) was stirred at room temperature overnight. A 0.33 N aqueous citric acid solution was added to the reaction mixture at 0 ° C. to adjust the pH to 6, then the mixture was concentrated and extracted with ethyl acetate. The extract was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to give the title compound (110 g).
MS: [M + H] ⁺ 404.9.

E) tert-Butyl (2S, 4R) -4- (benzyloxy) -2- (4- (methoxy (methyl) carbamoyl) -1,3-thiazole-2-yl) pyrrolidine-1-carboxylate
2-((2S, 4R) -4- (benzyloxy) -1- (tert-butoxycarbonyl) pyrrolidine-2-yl) -1,3-thiazole-4-carboxylic acid (110 g), DIPEA (105 g) ), HOBt (47.8 g), WSC (67.9 g) and DMF (900 mL) were stirred at 0 ° C. for 30 minutes and N, O-dimethylhydroxylamine hydrochloride (34.5 g) was added at 0 ° C. The mixture was stirred overnight at room temperature, water was added, and the mixture was extracted with ethyl acetate. The extract was washed with 5% aqueous sodium hydrogen carbonate solution and then saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel chromatography (ethyl acetate / petroleum ether) to give the title compound (100 g).
MS: [M + H] ⁺ 447.9.

F) tert-Butyl (2S, 4R) -4- (benzyloxy) -2- (4- (4-fluorobenzoyl) -1,3-thiazole-2-yl) pyrrolidine-1-carboxylate
Of tert-butyl (2S, 4R) -4- (benzyloxy) -2- (4- (methoxy (methyl) carbamoyl) -1,3-thiazole-2-yl) pyrrolidine-1-carboxylate (100 g) To a solution of THF (1 L) was added 1 M solution of bromo (4-fluorophenyl) magnesium THF (669 mL) at room temperature. The reaction mixture was stirred at room temperature overnight, water was added and extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel chromatography (ethyl acetate / petroleum ether) to give the title compound (50.0 g).
MS: [M + H] ⁺ 483.2.

G) (2-((2S, 4R) -4- (benzyloxy) pyrrolidine-2-yl) -1,3-thiazole-4-yl) (4-fluorophenyl) methanone monohydrochloride
Acetate of tert-butyl (2S, 4R) -4- (benzyloxy) -2- (4- (4-fluorobenzoyl) -1,3-thiazole-2-yl) pyrrolidine-1-carboxylate (50.0 g) A 4N ethyl chloride ethyl acetate solution (260 mL) was added to the ethyl (250 mL) solution, and the mixture was stirred overnight at room temperature. The reaction mixture was concentrated to give the title compound (24.0 g).
MS: [M + H] ⁺ 383.1.

H) tert-Butyl ((1S) -2-((2S, 4R) -4- (benzyloxy) -2- (4- (4-fluorobenzoyl) -1,3-thiazole-2-yl) pyrrolidine- 1-yl) -1-cyclohexyl-2-oxoethyl) carbamate
(2-((2S, 4R) -4- (benzyloxy) pyrrolidine-2-yl) -1,3-thiazole-4-yl) (4-fluorophenyl) metanone monohydrochloride (24.0 g), (2S )-((tert-Butyloxycarbonyl) amino) (cyclohexyl) acetic acid (17.7 g), DIPEA (29.5 g), HOBt (15.4 g), WSC (13.7 g) and DMF (170 mL) are stirred overnight at room temperature. did. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel chromatography (ethyl acetate / petroleum ether) to give the title compound (29.0 g).
MS: [M + H] ⁺ 622.3

I) (2S) -2-amino-1-((2S, 4R) -4- (benzyloxy) -2- (4- (4-fluorobenzoyl) -1,3-thiazole-2-yl) pyrrolidine- 1-yl) -2-cyclohexylethaneone monohydrochloride
tert-Butyl ((1S) -2-((2S, 4R) -4- (benzyloxy) -2- (4- (4-fluorobenzoyl) -1,3-thiazole-2-yl) pyrrolidine-1- To a solution of -1-cyclohexyl-2-oxoethyl) carbamate (24.0 g) in ethyl acetate (250 mL) was added a solution of 4N ethyl hydrogen chloride acetate (250 mL), and the mixture was stirred overnight at room temperature. The reaction mixture was concentrated to give the title compound (20.0 g).
^{MS: [M + H] +} 522.2.

J) tert-Butyl ((2S) -1-(((1S) -2-((2S, 4R) -4- (benzyloxy) -2- (4- (4-fluorobenzoyl) -1,3- Thiazole-2-yl) pyrrolidine-1-yl) -1-cyclohexyl-2-oxoethyl) amino) -1-oxopropan-2-yl) methylcarbamate
(2S) -2-amino-1-((2S, 4R) -4- (benzyloxy) -2- (4- (4-fluorobenzoyl) -1,3-thiazole-2-yl) pyrrolidine-1- Il) -2-cyclohexylethaneone monohydrochloride (20.0 g), N- (tert-butoxycarbonyl) -N-methyl-L-alanine (9.45 g), DIPEA (18.4 g), HOBt (6.28 g), WSC The mixture of (8.91 g) and DMF (200 mL) was stirred overnight at room temperature. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel chromatography (ethyl acetate / petroleum ether) to give the title compound (25.0 g).
MS: [M + H] ⁺ 707.3.

K) tert-Butyl ((2S) -1-(((1S) -1-cyclohexyl-2-((2S, 4S) -2- (4- (4-fluorobenzoyl) -1,3-thiazole-2) -Il) -4-hydroxypyrrolidine-1-yl) -2-oxoethyl) amino) -1-oxopropan-2-yl) methylcarbamate
tert-Butyl ((2S) -1-(((1S) -2-((2S, 4R) -4- (benzyloxy) -2- (4- (4-fluorobenzoyl) -1,3-thiazole- 2-Il) pyrrolidine-1-yl) -1-cyclohexyl-2-oxoethyl) amino) -1-oxopropan-2-yl) methylcarbamate (25.0 g), methanesulfonic acid (68.0 g) and dichloromethane (125) The mixture of mL) was stirred overnight at room temperature. The reaction mixture was neutralized with saturated aqueous sodium hydrogen carbonate solution and extracted with dichloromethane. The extract was washed with water and then saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was dissolved in dichloromethane (125 mL) and di-tert-butyl dicarbonate (11.6 g) and sodium hydrogen carbonate (7.43 g) were added. The reaction mixture was stirred at room temperature overnight and concentrated. The residue was purified by silica gel chromatography (methanol / dichloromethane) to give the title compound (19.0 g).
MS: [M + H] ⁺ 617.3.

L) S-((3S, 5S) -1-((2S) -2-((N- (tert-butoxycarbonyl) -N-methyl-L-alanyl) amino) -2-cyclohexylacetyl) -5- (4- (4-Fluorobenzoyl) -1,3-thiazole-2-yl) pyrrolidine-3-yl) ethanethioart
tert-butyl ((2S) -1-(((1S) -1-cyclohexyl-2-((2S, 4R) -2-(4- (4-fluorobenzoyl) -1,3-thiazole-2-yl) ) -4-Hydroxypyrrolidine-1-yl) -2-oxoethyl) amino) -1-oxopropan-2-yl) In a mixture of methylcarbamate (3.00 g), triethylamine (915 mg) and dichloromethane (50 mL) Methanesulfonyl chloride (1.11 g) was added and stirred overnight at room temperature. The reaction mixture was neutralized with 10% aqueous sodium hydrogen carbonate solution and extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. A mixture of the resulting residue, potassium thioacetate (2.72 g) and DMF (30 mL) was stirred at 40 ° C. overnight. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel chromatography (ethyl acetate / petroleum ether) to give the title compound (1.60 g).
MS: [M + H] ⁺ 675.2.

M) 2- (2- (2- (2- (2-iodoethoxy) ethoxy) ethoxy) -N-methyl-N- (2- (4-((1- (E / Z)) -2-phenyl-1- (4-((2- (Trimethylsilyl) ethoxy) methoxy) phenyl) buta-1-en-1-yl) phenoxy) ethyl) acetamide
2- (2- (2- (2- (2-Hydroxyethoxy) ethoxy) ethoxy) -N-methyl-N- (2- (4-((1- (E / Z))-2-phenyl-1- (4) -Methylsulfonyl in a mixture of ((2- (trimethylsilyl) ethoxy) methoxy) phenyl) buta-1-en-1-yl) phenoxy) ethyl) acetamide (1.43 g), triethylamine (1.15 mL) and THF (20 mL) A solution of chloride (0.32 mL) in THF (2 mL) was added at 0 ° C. over 20 minutes. After stirring at 0 ° C. for 30 minutes, ice water was added to the mixture, and the mixture was extracted with ethyl acetate. The organic layer was separated, washed with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. Sodium iodide (1.54 g) was added to the mixture of the obtained residue and acetone (20.0 mL), and the mixture was stirred at 40 ° C. for 2 hours. The insoluble material was filtered off, the filtrate was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (NH, ethyl acetate) to give the title compound (1.66 g).
MS: [M + H] ⁺ 803.8.

N) tert-Butyl ((2S) -1-(((1S) -1-cyclohexyl-2-((2S, 4S) -2- (4- (4-fluorobenzoyl) -1,3-thiazole-2) -Il) -4-((12-Methyl-11-oxo-14-(4-((1- (E / Z))-2-phenyl-1-(4-((2- (trimethylsilyl) ethoxy) Methoxy) phenyl) but-1-en-1-yl) phenoxy) -3,6,9-trioxa-12-azatetradec-1-yl) sulfanyl) pyrrolidine-1-yl) -2-oxoethyl) amino) -1 -Oxopropan-2-yl) methylcarbamate
S-((3S, 5S) -1-((2S) -2-((N- (tert-butoxycarbonyl) -N-methyl-L-alanyl) amino) -2-cyclohexylacetyl) -5- (4 -(4-Fluorobenzoyl) -1,3-thiazole-2-yl) pyrrolidine-3-yl) ethanethioate (71.4 mg), 2- (2- (2- (2-iodoethoxy) ethoxy) ethoxy) -N-Methyl-N-(2- (4-((1- (E / Z))-2-phenyl-1-(4-((2- (trimethylsilyl) ethoxy) methoxy) Phenyl) Buta-1- A mixture of en-1-yl) phenoxy) ethyl) acetamide (85 mg), potassium carbonate (29.2 mg) and methanol (4 mL) was stirred at room temperature overnight. Water was added to the mixture at room temperature, and the mixture was extracted with ethyl acetate. The organic layer was separated, washed with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (NH, ethyl acetate / hexane) to give the title compound (121 mg).
MS: [M + H] ⁺ 1308.6.

O) N-((1S) -1-cyclohexyl-2-((2S, 4S) -2- (4- (4-fluorobenzoyl) -1,3-thiazole-2-yl) -4-((14) -(4-((1- (E / Z))-1- (4-Hydroxyphenyl) -2-phenylbut-1-en-1-yl) phenoxy) -12-methyl-11-oxo-3, 6,9-Trioxa-12-azatetradec-1-yl) sulfanyl) pyrrolidine-1-yl) -2-oxoethyl) -N ² -methyl-L-alanine amide
tert-butyl ((2S) -1-(((1S) -1-cyclohexyl-2-((2S, 4S) -2-(4- (4-fluorobenzoyl) -1,3-thiazole-2-yl) ) -4-((12-Methyl-11-oxo-14-(4-((1- (E / Z))-2-phenyl-1-(4-((2- (trimethylsilyl) ethoxy) methoxy)) Phenyl) Buta-1-en-1-yl) Phenoxy) -3,6,9-Trioxa-12-azatetradeca-1-yl) Sulfanyl) Pyrrolidine-1-yl) -2-oxoethyl) Amino) -1-oxo A mixture of propan-2-yl) methylcarbamate (225 mg), 6N hydrochloric acid (4 mL) and THF (4 mL) was stirred overnight at room temperature. The mixture was neutralized with saturated aqueous sodium hydrogen carbonate solution and extracted with ethyl acetate. The organic layer was separated, washed with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (NH, methanol / ethyl acetate) to give the title compound (116 mg).
^{1 1} H NMR (300 MHz, CD ₃ OD) δ 0.79-1.40 (13H, m), 1.45-1.85 (6H, m), 2.18-2.55 (6H, m), 2.59-3.21 (7H, m), 3.47- 3.70 (13H, m), 3.76 (1H, t, J = 5.0 Hz), 3.92-4.06 (1H, m), 4.10-4.41 (3H, m), 4.44-4.62 (1H, m, J = 7.2 Hz) , 4.68-4.82 (1H, m), 5.34-5.51 (1H, m), 6.39 (1H, d, J = 8.5 Hz), 6.48-6.58 (1H, m), 6.63 (1H, d, J = 8.4 Hz) ), 6.69-6.81 (2H, m), 6.85-7.32 (10H, m), 8.15-8.36 (3H, m).

Example 46
N-((1S) -1-cyclohexyl-2-((2S, 4R) -2-(4- (4-fluorobenzoyl) -1,3-thiazole-2-yl) -4-((14-( 4-((1- (E / Z))-1- (4-Hydroxyphenyl) -2-phenylbut-1-en-1-yl) phenoxy) -12-methyl-11-oxo-3,6, 9-Trioxa-12-azatetradeca-1-yl) sulfanyl) pyrrolidine-1-yl) -2-oxoethyl) -N ² -methyl-L-alanine amide

A) tert-Butyl (2S, 4S) -4- (benzyloxy) -2-carbamoylpyrrolidine-1-carboxylate
A mixture of (4S) -4- (benzyloxy) -1- (tert-butoxycarbonyl) -L-proline (200 g), WSC (131 g), HOBt (92.4 g) and acetonitrile (2 L) at room temperature Stirred overnight. 25% aqueous ammonia (240 mL) was added to the reaction mixture at 0 ° C., and the mixture was stirred at 0 ° C. for 30 minutes and then at room temperature overnight. The reaction mixture was concentrated, water was added to the residue, and the mixture was extracted with ethyl acetate. The extract was washed with 0.5 N hydrochloric acid, saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel chromatography (methanol / dichloromethane) to give the title compound (140 g).
MS: [M + H] ⁺ 321.3.

B) tert-Butyl (2S, 4S) -4- (benzyloxy) -2-carbamoti oil pyrrolidine-1-carboxylate
A mixture of tert-butyl (2S, 4S) -4- (benzyloxy) -2-carbamoylpyrrolidine-1-carboxylate (140 g), Lawesson's reagent (177 g) and THF (1 L) was stirred overnight at room temperature. .. The reaction mixture was concentrated, water was added to the residue, and the mixture was extracted with ethyl acetate. The extract was washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel chromatography (ethyl acetate / petroleum ether) to give the title compound (120 g).
^{1 1} H NMR (400 MHz, DMSO-d ₆ ) δ 1.34-1.40 (9H, m), 2.00-2.30 (1H, m), 3.35-3.48 (2H, m), 3.58-3.63 (1H, m), 4.00 -4.11 (1H, m), 4.42-4.44 (3H, m), 7.27-7.35 (5H, m), 8.99-9.07 (1H, m), 9.62 (1H, s).

C) Ethyl 2-((2S, 4S) -4- (benzyloxy) -1- (tert-butoxycarbonyl) pyrrolidine-2-yl) -1,3-thiazole-4-carboxylate
60 Mixtures of tert-Butyl (2S, 4S) -4- (benzyloxy) -2-carbamotioil pyrrolidine-1-carboxylate (120 g), ethyl bromopyruvic acid (83.5 g) and ethanol (2 L) The mixture was stirred at ° C. for 3 hours. The reaction mixture was concentrated, THF (1 L), water (1 L) and sodium hydrogen carbonate (90.0 g) were added to the residue, cooled to 0 ° C., and di-tert-butyl dicarbonate (156 g) was added. .. The reaction mixture was stirred at room temperature overnight. The reaction mixture was concentrated, diluted with ethyl acetate, washed with water and saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel chromatography (ethyl acetate / petroleum ether) to give the title compound (72.0 g).
MS: [M + H] ⁺ 433.2.

D) 2-((2S, 4S) -4- (benzyloxy) -1- (tert-butoxycarbonyl) pyrrolidine-2-yl) -1,3-thiazole-4-carboxylate ethyl 2-((2S,,) 4S) -4- (benzyloxy) -1- (tert-butoxycarbonyl) pyrrolidine-2-yl) -1,3-thiazole-4-carboxylate (72.0 g), 1N aqueous sodium hydroxide solution (332 mL) and The mixture of methanol (1 L) was stirred at room temperature overnight. A 0.33 N aqueous citric acid solution was added to the reaction mixture at 0 ° C. to adjust the pH to 6, then the mixture was concentrated and extracted with ethyl acetate. The extract was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to give the title compound (59.0 g).
MS: [M + H] ⁺ 405.1.

E) (2-((2S, 4R) -4- (benzyloxy) pyrrolidine-2-yl) -1,3-thiazole-4-yl) (4-fluorophenyl) methanone
2-((2S, 4S) -4- (benzyloxy) -1- (tert-butoxycarbonyl) pyrrolidine-2-yl) -1,3-thiazole-4-carboxylic acid (59.0 g), DIPEA (75.5 g) ), HOBt (39.5 g), WSC (56.0 g) and DMF (500 mL) were stirred at 0 ° C. for 30 minutes and N, O-dimethylhydroxylamine hydrochloride (29.1 g) was added at 0 ° C. The mixture was stirred overnight at room temperature, water was added, and the mixture was extracted with ethyl acetate. The extract was washed with 5% aqueous sodium hydrogen carbonate solution and saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel chromatography (ethyl acetate / petroleum ether) to give the title compound (45.0 g).
MS: [M + H] ⁺ 448.2.

F) tert-Butyl (2S, 4S) -4- (benzyloxy) -2- (4- (4-fluorobenzoyl) -1,3-thiazole-2-yl) pyrrolidine-1-carboxylate
THF (1 L) of (2-((2S, 4R) -4- (benzyloxy) pyrrolidine-2-yl) -1,3-thiazole-4-yl) (4-fluorophenyl) methanone (45.0 g) A 1 M bromo (4-fluorophenyl) magnesium THF solution (303 mL) was added to the solution at room temperature. The reaction mixture was stirred at room temperature overnight, water was added at 0 ° C., and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel chromatography (ethyl acetate / petroleum ether) to give the title compound (32.0 g).
MS: [M + H] ⁺ 483.0.

G) (2-((2S, 4S) -4- (benzyloxy) pyrrolidine-2-yl) -1,3-thiazole-4-yl) (4-fluorophenyl) methanone monohydrochloride
Acetate of tert-butyl (2S, 4S) -4- (benzyloxy) -2- (4- (4-fluorobenzoyl) -1,3-thiazole-2-yl) pyrrolidine-1-carboxylate (32.0 g) A 4N ethyl acetate solution (166 mL) was added to the ethyl (100 mL) solution, and the mixture was stirred overnight at room temperature. The reaction mixture was concentrated to give the title compound (20.0 g).
MS: [M + H] ⁺ 383.1.

H) tert-Butyl ((1S) -2-((2S, 4S) -4- (benzyloxy) -2- (4- (4-fluorobenzoyl) -1,3-thiazole-2-yl) pyrrolidine- 1-yl) -1-cyclohexyl-2-oxoethyl) carbamate
(2-((2S, 4S) -4- (benzyloxy) pyrrolidine-2-yl) -1,3-thiazole-4-yl) (4-fluorophenyl) methanone monohydrochloride (20.0 g), (2S )-((tert-Butyloxycarbonyl) amino) (cyclohexyl) acetic acid (14.7 g), DIPEA (18.5 g), HOBt (9.67 g), WSC (13.7 g) and dichloromethane (500 mL) are stirred overnight at room temperature. did. The reaction mixture was washed with 0.5N hydrochloric acid, saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel chromatography (ethyl acetate / petroleum ether) to give the title compound (20.1 g).
MS: [M + H] ⁺ 622.3.

I) (2S) -2-amino-1-((2S, 4S) -4- (benzyloxy) -2- (4- (4-fluorobenzoyl) -1,3-thiazole-2-yl) pyrrolidine- 1-yl) -2-cyclohexylethaneone monohydrochloride
tert-Butyl ((1S) -2-((2S, 4S) -4- (benzyloxy) -2- (4- (4-fluorobenzoyl) -1,3-thiazole-2-yl) pyrrolidine-1- Il) -1-cyclohexyl-2-oxoethyl) carbamate (15.0 g) and 4N ethyl hydrogen chloride acetate solution (100 mL) were added, and the mixture was stirred at room temperature for 2 days. The precipitate was collected by filtration, washed with ethyl acetate, and dried to give the title compound (12.5 g).
^{MS: [M + H] +} 522.2.

J) tert-Butyl ((2S) -1-(((1S) -2-((2S, 4S) -4- (benzyloxy) -2- (4- (4-fluorobenzoyl) -1,3- Thiazole-2-yl) pyrrolidine-1-yl) -1-cyclohexyl-2-oxoethyl) amino) -1-oxopropan-2-yl) methylcarbamate
(2S) -2-amino-1-((2S, 4S) -4- (benzyloxy) -2- (4- (4-fluorobenzoyl) -1,3-thiazole-2-yl) pyrrolidine-1- Il) -2-cyclohexylethaneone monohydrochloride (15.0 g), N- (tert-butoxycarbonyl) -N-methyl-L-alanine (7.03 g), DIPEA (11.2 g), HOBt (8.90 g), WSC A mixture of (6.63 g) and dichloromethane (200 mL) was stirred overnight at room temperature. The reaction mixture was washed with 0.5N hydrochloric acid, saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over anhydrous sodium sulfate, and the solvent was concentrated under reduced pressure. The residue was purified by silica gel chromatography (ethyl acetate / petroleum ether) to give the title compound (15.1 g).
MS: [M + H] ⁺ 707.0.

K) tert-Butyl ((2S) -1-(((1S) -1-cyclohexyl-2-((2S, 4S) -2- (4- (4-fluorobenzoyl) -1,3-thiazole-2) -Il) -4-hydroxypyrrolidine-1-yl) -2-oxoethyl) amino) -1-oxopropan-2-yl) methylcarbamate
tert-Butyl ((2S) -1-(((1S) -2-((2S, 4S) -4- (benzyloxy) -2- (4- (4-fluorobenzoyl) -1,3-thiazole- 2-Il) pyrrolidine-1-yl) -1-cyclohexyl-2-oxoethyl) amino) -1-oxopropan-2-yl) methylcarbamate (13.0 g), methanesulfonic acid (50.0 g) and dichloromethane (200) The mixture of mL) was stirred overnight at room temperature. The reaction mixture was neutralized with saturated aqueous sodium hydrogen carbonate solution and extracted with dichloromethane. The extract was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was dissolved in THF (200 mL) and di-tert-butyl dicarbonate (12.0 g) and saturated aqueous sodium hydrogen carbonate solution (100 mL) were added. The reaction mixture was stirred at room temperature overnight and extracted with ethyl acetate. The extract was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel chromatography (ethyl acetate / petroleum ether) to give the title compound (10.0 g).
MS: [M + H] ⁺ 617.3.

L) S-((3R, 5S) -1-((2S) -2-((N- (tert-butoxycarbonyl) -N-methyl-L-alanyl) amino) -2-cyclohexylacetyl) -5- (4- (4-Fluorobenzoyl) -1,3-thiazole-2-yl) pyrrolidine-3-yl) ethanethioart
tert-butyl ((2S) -1-(((1S) -1-cyclohexyl-2-((2S, 4S) -2-(4- (4-fluorobenzoyl) -1,3-thiazole-2-yl) ) -4-Hydroxypyrrolidine-1-yl) -2-oxoethyl) amino) -1-oxopropan-2-yl) In a mixture of methylcarbamate (1.80 g), triethylamine (590 mg) and dichloromethane (50 mL) Methanesulfonyl chloride (669 mg) was added and stirred overnight at room temperature. A 10% aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. A mixture of the resulting residue, potassium thioacetate (1.67 g) and DMF (30 mL) was stirred at 40 ° C. overnight. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (ethyl acetate / petroleum ether) to give the title compound (901 mg).
MS: [M + H] ⁺ 675.3.

M) tert-Butyl ((2S) -1-(((1S) -1-cyclohexyl-2-((2S, 4R) -2- (4- (4-fluorobenzoyl) -1,3-thiazole-2) -Il) -4-((12-Methyl-11-oxo-14-(4-((1- (E / Z))-2-phenyl-1-(4-((2- (trimethylsilyl) ethoxy)) Methoxy) phenyl) but-1-en-1-yl) phenoxy) -3,6,9-trioxa-12-azatetradec-1-yl) sulfanyl) pyrrolidine-1-yl) -2-oxoethyl) amino) -1 -Oxopropan-2-yl) methylcarbamate
S-((3R, 5S) -1-((2S) -2-((N- (tert-butoxycarbonyl) -N-methyl-L-alanyl) amino) -2-cyclohexylacetyl) -5- (4 -(4-Fluorobenzoyl) -1,3-thiazole-2-yl) pyrrolidine-3-yl) ethanethioate (200 mg), 2- (2- (2- (2-iodoethoxy) ethoxy) ethoxy) -N-Methyl-N-(2- (4-((1- (E / Z))-2-phenyl-1-(4-((2- (trimethylsilyl) ethoxy) methoxy) Phenyl) Buta-1- A mixture of en-1-yl) phenoxy) ethyl) acetamide (240 mg), potassium carbonate (82 mg) and methanol (6 mL) was stirred at room temperature overnight. Water was added to the mixture at room temperature, and the mixture was extracted with ethyl acetate. The organic layer was separated, washed with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (NH, ethyl acetate / hexane) to give the title compound (214 mg).
^{1 1} H NMR (300 MHz, CDCl ₃ ) δ -0.05-0.04 (9H, m), 0.85-1.39 (14H, m), 1.49 (9H, s), 1.59-1.79 (6H, m), 2.19-2.36 ( 1H, m, J = 11.6 Hz), 2.40-2.55 (2H, m), 2.72-2.86 (6H, m), 2.92-3.18 (3H, m), 3.52-4.38 (21H, m), 4.52-4.76 ( 2H, m), 5.09 (1H, s), 5.24 (1H, s), 5.62 (1H, d, J = 5.8 Hz), 6.45-7.22 (15H, m), 8.20 (1H, s), 8.24-8.36 (2H, m).

N) N-((1S) -1-cyclohexyl-2-((2S, 4R) -2- (4- (4-fluorobenzoyl) -1,3-thiazole-2-yl) -4-((14) -(4-((1- (E / Z))-1- (4-Hydroxyphenyl) -2-phenylbut-1-en-1-yl) phenoxy) -12-methyl-11-oxo-3, 6,9-Trioxa-12-azatetradec-1-yl) sulfanyl) pyrrolidine-1-yl) -2-oxoethyl) -N ² -methyl-L-alanine amide
tert-butyl ((2S) -1-(((1S) -1-cyclohexyl-2-((2S, 4R) -2-(4- (4-fluorobenzoyl) -1,3-thiazole-2-yl) ) -4-((12-Methyl-11-oxo-14-(4-((1- (E / Z))-2-phenyl-1-(4-((2- (trimethylsilyl) ethoxy) methoxy)) Phenyl) Buta-1-en-1-yl) Phenoxy) -3,6,9-Trioxa-12-azatetradeca-1-yl) Sulfanyl) Pyrrolidine-1-yl) -2-oxoethyl) Amino) -1-oxo A mixture of propan-2-yl) methylcarbamate (214 mg), 6N hydrochloric acid (4 mL) and THF (4 mL) was stirred overnight at room temperature. The mixture was neutralized with saturated aqueous sodium hydrogen carbonate solution and extracted with ethyl acetate. The organic layer was separated, washed with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (NH, methanol / ethyl acetate) to give the title compound (118 mg).
^{1 1} H NMR (300 MHz, CD ₃ OD) δ 0.80-1.35 (13H, m), 1.46-1.84 (6H, m), 2.19-2.84 (9H, m), 2.87-3.22 (4H, m), 3.42- 4.06 (16H, m), 4.10-4.39 (4H, m), 4.52 (1H, d, J = 7.6 Hz), 5.43-5.75 (1H, m), 6.33-7.31 (15H, m), 8.14-8.39 ( 3H, m).

Example 47
N-((1S) -1-cyclohexyl-2-((2S, 4S) -2-(4- (4-fluorobenzoyl) -1,3-thiazole-2-yl) -4- (3-(( 14-(4-((1- (E / Z)) -1- (4-Hydroxyphenyl) -2-phenylbut-1-en-1-yl) phenoxy) -12-methyl-11-oxo-3 , 6,9-Trioxa-12-azatetradec-1-yl) oxy) phenoxy) pyrrolidine-1-yl) -2-oxoethyl) -N ² -methyl-L-alanine amide

A) tert-Butyl ((2S) -1-(((1S) -1-cyclohexyl-2-((2S, 4S) -2- (4- (4-fluorobenzoyl) -1,3-thiazole-2) -Il) -4- (3-Hydroxyphenoxy) pyrrolidine-1-yl) -2-oxoethyl) amino) -1-oxopropan-2-yl) methylcarbamate
tert-butyl ((2S) -1-(((1S) -1-cyclohexyl-2-((2S, 4R) -2-(4- (4-fluorobenzoyl) -1,3-thiazole-2-yl) ) -4-Hydroxypyrrolidine-1-yl) -2-oxoethyl) amino) -1-oxopropan-2-yl) Methylcarbamate (300 mg), triphenylphosphine (255 mg), 3-hydroxyphenylbenzoate Diisopropyl azodicarboxylate (0.51 mL) was added to the mixture of (208 mg) and THF (10 mL) at room temperature. The mixture was stirred at room temperature for 2 hours and the reaction mixture was concentrated. A 2N aqueous sodium hydroxide solution (0.49 mL) was added to the mixture of the resulting residue and methanol (10 mL) at room temperature. The mixture was stirred at room temperature overnight. The mixture was neutralized with 10% aqueous citric acid and extracted with ethyl acetate. The organic layer was separated, washed with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (NH, ethyl acetate / hexane) to give the title compound (164 mg).
MS: [M + H] ⁺ 709.3.

B) tert-butyl ((2S) -1-(((1S) -1-cyclohexyl-2-((2S, 4S) -2- (4- (4-fluorobenzoyl) -1,3-thiazole-2) -Il) -4- (3-((12-Methyl-11-oxo-14-(4-((1- (E / Z))-2-phenyl-1- (4-((2- (trimethylsilyl) ) Ethoxy) methoxy) phenyl) but-1-en-1-yl) phenoxy) -3,6,9-trioxa-12-azatetradeca-1-yl) oxy) phenoxy) pyrrolidine-1-yl) -2-oxoethyl ) Amino) -1-oxopropan-2-yl) methylcarbamate
tert-butyl ((2S) -1-(((1S) -1-cyclohexyl-2-((2S, 4S) -2-(4- (4-fluorobenzoyl) -1,3-thiazole-2-yl) ) -4- (3-Hydroxyphenoxy) pyrrolidine-1-yl) -2-oxoethyl) amino) -1-oxopropan-2-yl) methylcarbamate (164 mg), 2- (2- (2- (2-( 2-Iodoethoxy) ethoxy) ethoxy) -N-methyl-N- (2- (4-((1- (E / Z))-2-phenyl-1- (4-((2- (trimethylsilyl) ethoxy) A mixture of) methoxy) phenyl) buta-1-en-1-yl) phenoxy) ethyl) acetamide (205 mg), potassium carbonate (96 mg) and DMF (3 mL) was stirred at 60 ° C. overnight. Water was added to the mixture at room temperature, and the mixture was extracted with ethyl acetate. The organic layer was separated, washed with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / hexane) to give the title compound (288 mg).
MS: [M + H] ⁺ 1384.7.

C) N-((1S) -1-cyclohexyl-2-((2S, 4S) -2- (4- (4-fluorobenzoyl) -1,3-thiazole-2-yl) -4- (3-) ((14-(4-((1- (E / Z)) -1- (4-Hydroxyphenyl) -2-phenylbut-1-en-1-yl) phenoxy) -12-methyl-11-oxo) -3,6,9-Trioxa-12-azatetradeca-1-yl) oxy) phenoxy) pyrrolidine-1-yl) -2-oxoethyl) -N ² -methyl-L-alanine amide
tert-butyl ((2S) -1-(((1S) -1-cyclohexyl-2-((2S, 4S) -2-(4- (4-fluorobenzoyl) -1,3-thiazole-2-yl) ) -4- (3-((12-Methyl-11-oxo-14-(4-((1- (E / Z))-2-phenyl-1-(4-((2- (trimethylsilyl) ethoxy) ) Methoxy) Phenyl) Buta-1-en-1-yl) Phenoxy) -3,6,9-Trioxa-12-azatetradeca-1-yl) Oxy) Phenoxy) Pyrrolidine-1-yl) -2-oxoethyl) Amino A mixture of -1-oxopropan-2-yl) methylcarbamate (288 mg), 6N hydrochloric acid (4 mL) and THF (4 mL) was stirred at room temperature overnight. The mixture was neutralized with saturated aqueous sodium hydrogen carbonate solution and extracted with ethyl acetate. The organic layer was separated, washed with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (NH, methanol / ethyl acetate) to give the title compound (94 mg).
^{1 1} H NMR (300 MHz, CD ₃ OD) δ 0.82-0.95 (3H, m), 1.00-1.41 (9H, m), 1.49-2.03 (6H, m), 2.17-2.67 (6H, m), 2.79- 3.24 (5H, m), 3.50-4.40 (20H, m), 4.57 (1H, d, J = 6.4 Hz), 4.86-4.91 (1H, m), 5.06-5.26 (1H, m), 5.47-5.74 ( 1H, m, J = 8.8 Hz), 6.03-7.20 (19H, m), 7.88-8.09 (2H, m, J = 8.3, 5.7 Hz), 8.29-8.37 (1H, m).

Example 49
N-((1S) -2-((2S) -2- (4- (3-((14-(4-((3-cyano-4- (4-cyanophenyl) -2,5-dimethyl- 1H-pyrrole-1-yl) methyl) phenoxy) -3,6,9,12-tetraoxatetradeca-1-yl) oxy) benzoyl) -1,3-thiazole-2-yl) pyrrolidine-1-yl ) -1-Cyclohexyl-2-oxoethyl) -N ² -methyl-L-alanine amide

A) 14-(4-((3-Cyano-4- (4-cyanophenyl) -2,5-dimethyl-1H-pyrrole-1-yl) methyl) phenoxy) -3,6,9,12-tetra Oxatetradec-1-yl 4-methylbenzenesulfonate
4- (4-Cyanophenyl) -1- (4-Hydroxybenzyl) -2,5-dimethyl-1H-pyrrole-3-carbonitrile (213 mg), 3,6,9,12-tetraoxatetradecane-1 A mixture of 14-diylbis (4-methylbenzenesulfonate) (0.85 mL), potassium carbonate (124 mg) and anhydrous DMF (3 mL) was stirred at 50 ° C. for 16 hours. The reaction mixture was added to water at 0 ° C., and the mixture was extracted with ethyl acetate. The organic layer was separated, washed with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / hexane) to give the title compound (208 mg).
MS: [M + H] ⁺ 702.4.

B) tert-Butyl ((2S) -1-(((1S) -2-((2S) -2- (4- (3-((14-(4-((3-cyano-4- (4) -Cyanophenyl) -2,5-dimethyl-1H-pyrrole-1-yl) methyl) phenoxy) -3,6,9,12-tetraoxatetradeca-1-yl) oxy) benzoyl) -1,3- Thiazol-2-yl) pyrrolidine-1-yl) -1-cyclohexyl-2-oxoethyl) amino) -1-oxopropan-2-yl) methylcarbamate
14-(4-((3-Cyano-4- (4-cyanophenyl) -2,5-dimethyl-1H-pyrrole-1-yl) methyl) phenoxy) -3,6,9,12-tetraoxatetra Deca-1-yl 4-methylbenzenesulfonate (205 mg), tert-butyl ((2S) -1-(((1S) -1-cyclohexyl-2-((2S) -2- (4- (3) -Hydroxybenzoyl) -1,3-thiazole-2-yl) pyrrolidine-1-yl) -2-oxoethyl) amino) -1-oxopropan-2-yl) methylcarbamate (195 mg), anhydrous DMF (2) Potassium carbonate (55.5 mg) was added to the mixture of mL), and the mixture was stirred at 50 ° C. for 24 hours. The reaction mixture was added to water at 0 ° C., and the mixture was extracted with ethyl acetate. The organic layer was separated, washed with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / hexane, methanol / ethyl acetate) and silica gel column chromatography (NH, ethyl acetate / hexane) to give the title compound (220 mg).
MS: [M + H] ⁺ 1128.7.

C) N-((1S) -2-((2S) -2- (4- (3-((14-(4-((3-Cyano-4- (4-Cyanophenyl) -2,5-) Dimethyl-1H-pyrrole-1-yl) methyl) phenoxy) -3,6,9,12-tetraoxatetradec-1-yl) oxy) benzoyl) -1,3-thiazole-2-yl) pyrrolidine-1 -Il) -1-cyclohexyl-2-oxoethyl) -N ² -methyl-L-alanine amide
tert-Butyl ((2S) -1-(((1S) -2-((2S) -2- (4- (3-((14-(4-((3-cyano-4- (4-cyano) Phenyl) -2,5-dimethyl-1H-pyrrole-1-yl) methyl) phenoxy) -3,6,9,12-tetraoxatetradeca-1-yl) oxy) benzoyl) -1,3-thiazole- A mixture of 2-yl) pyrrolidine-1-yl) -1-cyclohexyl-2-oxoethyl) amino) -1-oxopropan-2-yl) methylcarbamate (220 mg) and TFA (1 mL) at room temperature 15 Stirred for minutes. A saturated aqueous sodium hydrogen carbonate solution was added to the mixture at 0 ° C., and the mixture was extracted with a mixed solvent of ethyl acetate and THF. The organic layer was separated, washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (NH, methanol / ethyl acetate) to give the title compound (181 mg).
¹ H NMR (300 MHz, CD ₃ OD) δ 0.99-1.26 (8H, m), 1.54-1.82 (6H, m), 2.06-2.41 (13H, m), 3.14 (1H, q, J = 6.8 Hz) , 3.59-3.71 (12H, m), 3.76-4.03 (6H, m), 4.07 (2H, dd, J = 5.5, 3.7 Hz), 4.17 (2H, dd, J = 5.4, 3.8 Hz), 4.49-4.59 (1H, m), 5.14 (2H, s), 5.43-5.65 (1H, m), 6.88-6.93 (4H, m), 7.17-7.23 (1H, m), 7.37-7.44 (1H, m), 7.53 -7.59 (2H, m), 7.67-7.73 (2H, m), 7.73-7.80 (2H, m), 8.27-8.31 (1H, m).

Example 50
N-((1S) -2-((2S) -2-(4-(3-((14-((6S) -4- (4-chlorophenyl) -2,3,9-trimethyl-6H-thieno) [3,2-f] [1,2,4] Triazolo [4,3-a] [1,4] Diazepine-6-yl) -13-oxo-3,6,9-Trioxa-12-Azatetradeca- 1-yl) oxy) benzoyl) -1,3-thiazole-2-yl) pyrrolidine-1-yl) -1-cyclohexyl-2-oxoethyl) -N ² -methyl-L-alanine amide
A) ((6S) -4- (4-chlorophenyl) -2,3,9-trimethyl-6H-thieno [3,2-f] [1,2,4] triazolo [4,3-a] [1 , 4] Diazepine-6-yl) acetic acid
(S) -tert-Butyl 2- (4- (4-chlorophenyl) -2,3,9-trimethyl-6H-thieno [3,2-f] [1,2,4] triazolo [4,3-a] ] [1,4] A mixture of diazepine-6-yl) acetate (70 mg) and TFA (10 mL) was stirred at 0 ° C. for 1 hr. The reaction mixture was concentrated under reduced pressure. The resulting solid was crystallized from ether / hexane to give the title compound (49 mg).
MS: [M + H] ⁺ 401.2.

B) tert-Butyl ((2S) -1-(((1S) -2-((2S) -2- (4- (3-((14-((6S) -4- (4-chlorophenyl)-) 2,3,9-trimethyl-6H-thieno [3,2-f] [1,2,4] triazolo [4,3-a] [1,4] diazepine-6-yl) -13-oxo-3 , 6,9-Trioxa-12-azatetradec-1-yl) oxy) benzoyl) -1,3-thiazole-2-yl) pyrrolidine-1-yl) -1-cyclohexyl-2-oxoethyl) amino) -1- Oxopropan-2-yl) methylcarbamate
2- (2- (2- (2- (3-((2-((2S) -1-((2S) -2-((N- (tert-butoxycarbonyl) -N-methyl-L-alanyl) ) Amino) -2-cyclohexylacetyl) pyrrolidine-2-yl) -1,3-thiazole-4-yl) carbonyl) phenoxy) ethoxy) ethoxy) ethoxy) ethyl 4-methylbenzenesulfonate (342 mg) and 28% A mixture of aqueous ammonia (3 mL) and ethanol (3 mL) was microwaved at 100 ° C. for 20 minutes. Water was added to the mixture at room temperature, and the mixture was extracted with ethyl acetate. The organic layer was separated, washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The resulting residue, ((6S) -4- (4-chlorophenyl) -2,3,9-trimethyl-6H-thieno [3,2-f] [1,2,4] triazolo [4,3-a] ] [1,4] HATU (280 mg) was added to a mixture of diazepine-6-yl) acetic acid (148 mg), DIPEA (0.13 mL) and acetonitrile (3 mL) at room temperature. After stirring at room temperature for 1 hour, the reaction mixture was concentrated. The obtained residue was purified by silica gel column chromatography (NH, methanol / ethyl acetate) to give the title compound (211 mg).
MS: [M + H] ⁺ 1156.3.

C) N-((1S) -2-((2S) -2- (4- (3-((14-((6S) -4- (4-chlorophenyl) -2,3,9-trimethyl-6H) -Chieno [3,2-f] [1,2,4] triazolo [4,3-a] [1,4] diazepine-6-yl) -13-oxo-3,6,9-trioxa-12- Azatetradec-1-yl) oxy) benzoyl) -1,3-thiazole-2-yl) pyrrolidine-1-yl) -1-cyclohexyl-2-oxoethyl) -N ² -methyl-L-alanine amide
tert-Butyl ((2S) -1-(((1S) -2-((2S) -2- (4- (3-((14-((6S) -4- (4-chlorophenyl) -2, 3,9-trimethyl-6H-thieno [3,2-f] [1,2,4] triazolo [4,3-a] [1,4] diazepine-6-yl) -13-oxo-3,6 , 9-Trioxa-12-azatetradeca-1-yl) oxy) benzoyl) -1,3-thiazole-2-yl) pyrrolidine-1-yl) -1-cyclohexyl-2-oxoethyl) amino) -1-oxopropane A mixture of -2-yl) methylcarbamate (211 mg), 6 N hydrochloric acid (2 mL) and THF (6 mL) was stirred at room temperature for 5 hours. The mixture was neutralized with saturated aqueous sodium hydrogen carbonate solution and extracted with ethyl acetate. The organic layer was separated, washed with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (NH, methanol / ethyl acetate) to give the title compound (121 mg).
^{1 1} H NMR (300 MHz, CD ₃ OD) δ 1.23 (9H, d, J = 6.9 Hz), 1.51-1.84 (9H, m), 2.03-2.38 (6H, m), 2.43 (3H, s), 2.68 (3H, s), 3.15 (1H, q, J = 6.8 Hz), 3.37-3.76 (14H, m), 3.82-4.04 (4H, m), 4.13-4.24 (2H, m), 4.51-4.66 (2H) , m), 5.47 (1H, dd, J = 7.6, 3.3 Hz), 7.18 (1H, dd, J = 8.2, 1.7 Hz), 7.34-7.48 (5H, m), 7.63-7.73 (2H, m), 8.30 (1H, s).

Example 51
N-((1S) -2-((2S) -2- (4- (3-((17-((6S) -4- (4-chlorophenyl) -2,3,9-trimethyl-6H-thieno) [3,2-f] [1,2,4] Triazolo [4,3-a] [1,4] Diazepine-6-yl) -16-oxo-3,6,9,12-Tetraoxa-15- Azaheptadeca-1-yl) oxy) benzoyl) -1,3-thiazole-2-yl) pyrrolidine-1-yl) -1-cyclohexyl-2-oxoethyl) -N ² -methyl-L-alanine amide

A) 14-(3-((2-((2S) -1-((2S) -2-((N- (tert-butoxycarbonyl) -N-methyl-L-alanyl) amino) -2-cyclohexyl) Acetyl) pyrrolidine-2-yl) -1,3-thiazole-4-yl) carbonyl) phenoxy) -3,6,9,12-tetraoxatetradeca-1-yl 4-methylbenzenesulfonate
tert-Butyl ((2S) -1-(((1S) -1-cyclohexyl-2-((2S) -2-(4- (3-hydroxybenzoyl) -1,3-thiazole-2-yl) pyrrolidine) -1-yl) -2-oxoethyl) amino) -1-oxopropan-2-yl) methylcarbamate (0.90 g), 3,6,9,12-tetraoxatetradecane-1,14-diylbis (4) -A mixture of methylbenzene sulfonate) (1.65 g) and potassium carbonate (0.42 g) was stirred at 50 ° C overnight. Water was added to the mixture and the mixture was extracted with ethyl acetate. The organic layer was separated, washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / hexane) to give the title compound (0.80 g).
MS: [M + H] ⁺ 973.3.

B) tert-Butyl ((2S) -1-(((1S) -2-((2S) -2- (4- (3-((17-((6S) -4- (4-chlorophenyl)-) 2,3,9-trimethyl-6H-thieno [3,2-f] [1,2,4] triazolo [4,3-a] [1,4] diazepine-6-yl) -16-oxo-3 , 6,9,12-Tetraoxa-15-azaheptadeca-1-yl) oxy) benzoyl) -1,3-thiazole-2-yl) pyrrolidine-1-yl) -1-cyclohexyl-2-oxoethyl) amino)- 1-oxopropan-2-yl) methylcarbamate
14-(3-((2-((2S) -1-((2S) -2-((N- (tert-butoxycarbonyl) -N-methyl-L-alanyl) amino) -2-cyclohexylacetyl)) Pyrrolidine-2-yl) -1,3-thiazole-4-yl) carbonyl) phenoxy) -3,6,9,12-tetraoxatetradec-1-yl 4-methylbenzenesulfonate (390 mg) and 28 A mixture of% aqueous ammonia (3 mL) and ethanol (3 mL) was microwaved at 100 ° C. for 20 minutes. Water was added to the mixture at room temperature, and the mixture was extracted with ethyl acetate. The organic layer was separated, washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The resulting residue, ((6S) -4- (4-chlorophenyl) -2,3,9-trimethyl-6H-thieno [3,2-f] [1,2,4] triazolo [4,3-a] ] [1,4] HATU (305 mg) was added to a mixture of diazepine-6-yl) acetic acid (160 mg), DIPEA (0.14 mL) and acetonitrile (3 mL) at room temperature. After stirring at room temperature for 1 hour, the reaction mixture was concentrated. The obtained residue was purified by silica gel column chromatography (NH, methanol / ethyl acetate) to give the title compound (307 mg).
MS: [M + H] ⁺ 1200.3.

C) N-((1S) -2-((2S) -2- (4- (3-((17-((6S) -4- (4-chlorophenyl) -2,3,9-trimethyl-6H) -Chieno [3,2-f] [1,2,4] Triazolo [4,3-a] [1,4] Diazepine-6-yl) -16-oxo-3,6,9,12-Tetraoxa- 15-azaheptadeca-1-yl) oxy) benzoyl) -1,3-thiazole-2-yl) pyrrolidine-1-yl) -1-cyclohexyl-2-oxoethyl) -N ² -methyl-L-alanine amide
tert-Butyl ((2S) -1-(((1S) -2-((2S) -2- (4- (3-((17-((6S) -4- (4-chlorophenyl) -2, 3,9-trimethyl-6H-thieno [3,2-f] [1,2,4] triazolo [4,3-a] [1,4] diazepine-6-yl) -16-oxo-3,6 , 9,12-Tetraoxa-15-azaheptadeca-1-yl) oxy) benzoyl) -1,3-thiazole-2-yl) pyrrolidine-1-yl) -1-cyclohexyl-2-oxoethyl) amino) -1- A mixture of oxopropan-2-yl) methylcarbamate (307 mg) and trifluoroacetic acid (2.96 g) was stirred at room temperature for 1 hour. The reaction solution was concentrated. The obtained residue was neutralized with saturated aqueous sodium hydrogen carbonate solution and extracted with ethyl acetate. The organic layer was separated, washed with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by HPLC (L-Column 2 ODS, mobile phase: water / acetonitrile (0.1% TFA-containing system)). A saturated aqueous sodium hydrogen carbonate solution was added to the obtained fraction, and the mixture was extracted with ethyl acetate. The organic layer was separated, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to give the title compound (66 mg).
^{1 1} H NMR (300 MHz, CD ₃ OD) δ 0.93-1.36 (9H, m), 1.45-1.84 (9H, m), 2.05-2.51 (7H, m), 2.68 (3H, brs), 3.07-3.60 ( 19H, m), 3.66-4.24 (8H, m), 4.46-4.69 (2H, m), 5.47 (1H, d, J = 3.8 Hz), 7.20 (1H, d, J = 7.2 Hz), 7.42 (5H) , d, J = 8.9 Hz), 7.68 (2H, brs), 8.31 (1H, brs).

Example 52
N-(2- (2- (2- (2- (3-((2-((2S) -1-((2S) -2-cyclohexyl-2-((N-methyl-L-alanyl) amino) ) Acetyl) pyrrolidine-2-yl) -1,3-thiazole-4-yl) carbonyl) phenoxy) ethoxy) ethoxy) ethoxy) ethyl) -7-((4-((3,5-dichloropyridin-4-yl) Il) amino) -7-methoxy-2-oxo-2H-chromen-8-yl) oxy) heptaneamide

A) tert-Butyl ((2S) -1-(((1S) -1-cyclohexyl-2-((2S) -2-(4- (3-((19-((4- ((3,5)) -Dichloropyridin-4-yl) amino) -7-methoxy-2-oxo-2H-chromen-8-yl) oxy) -13-oxo-3,6,9-trioxa-12-azanonadeca-1-yl) Oxy) benzoyl) -1,3-thiazole-2-yl) pyrrolidine-1-yl) -2-oxoethyl) amino) -1-oxopropan-2-yl) methylcarbamate
2- (2- (2- (2- (3-((2-((2S) -1-((2S) -2-((N- (tert-butoxycarbonyl) -N-methyl-L-alanyl) ) Amino) -2-cyclohexylacetyl) pyrrolidine-2-yl) -1,3-thiazole-4-yl) carbonyl) phenoxy) ethoxy) ethoxy) ethoxy) ethyl 4-methylbenzenesulfonate (68 mg) and 28% A mixture of aqueous ammonia (1.5 mL) and ethanol (1.5 mL) was microwaved at 100 ° C. for 20 minutes. Water was added to the mixture at room temperature, and the mixture was extracted with ethyl acetate. The organic layer was separated, washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The resulting residue, 7-((4-((3,5-dichloropyridin-4-yl) amino) -7-methoxy-2-oxo-2H-chromen-8-yl) oxy) heptanoic acid (35 mg) ), DIPEA (0.02 mL) was added to the mixture of HATU (42 mg) and acetonitrile (3 mL) at room temperature. The mixture was stirred at room temperature overnight. Water was added to the mixture at room temperature, and the mixture was extracted with ethyl acetate. The organic layer was separated, washed with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (methanol / ethyl acetate) to give the title compound (61 mg).
The above 7-((4-((3,5-dichloropyridine-4-yl) amino) -7-methoxy-2-oxo-2H-chromen-8-yl) oxy) heptanic acid is a method known per se (for example, , Bioorganic & Medicinal Chemistry Letters 2010, 20, 2928-2932.
MS: [M + H] ⁺ 1258.1.

B) N- (2- (2- (2- (2- (3-((2-((2S) -1-((2S) -2-cyclohexyl-2-((N-methyl-L-alanyl) ) Amino) acetyl) pyrrolidine-2-yl) -1,3-thiazole-4-yl) carbonyl) phenoxy) ethoxy) ethoxy) ethoxy) ethyl) -7-((4-((3,5-dichloropyridine-) 4-yl) amino) -7-methoxy-2-oxo-2H-chromen-8-yl) oxy) heptaneamide
tert-Butyl ((2S) -1-(((1S) -1-cyclohexyl-2-((2S) -2- (4- (3-((19-((4- ((3,5-dichloro)) Pyridine-4-yl) amino) -7-methoxy-2-oxo-2H-chromen-8-yl) oxy) -13-oxo-3,6,9-trioxa-12-azanonadeca-1-yl) oxy) Benzoyl) -1,3-thiazole-2-yl) pyrrolidine-1-yl) -2-oxoethyl) amino) -1-oxopropan-2-yl) methylcarbamate (61 mg) and TFA (3 mL) The mixture was stirred at room temperature for 30 minutes. After concentrating the reaction solution, the obtained residue was dissolved in ethyl 2-propanol acetate (4: 1), washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. .. The residue was purified by silica gel column chromatography (NH, methanol / ethyl acetate) to give the title compound (38 mg).
^{1 1} H NMR (300 MHz, CD ₃ OD) δ 0.96-1.29 (9H, m), 1.34-1.45 (2H, m), 1.46-1.87 (13H, m), 2.31 (9H, s), 3.08-3.24 ( 1H, m), 3.46-3.74 (11H, m), 3.77-4.00 (7H, m), 4.06 (2H, t, J = 6.4 Hz), 4.19 (2H, dd, J = 5.2, 4.0 Hz), 4.55 (1H, d, J = 7.2 Hz), 5.47 (1H, dd, J = 7.7, 3.3 Hz), 7.13 (1H, d, J = 9.2 Hz), 7.17-7.24 (1H, m), 7.41 (1H, m) t, J = 8.2 Hz), 7.66-7.75 (2H, m), 7.82 (1H, d, J = 9.1 Hz), 8.30 (1H, s), 8.67 (2H, s).

Example 53
N- (4- (Chloro (difluoro) Methoxy) Phenyl)-6-(3-((2- (2- (2- (3-((2-((2S) -1-((2S))-2 -Cyclohexyl-2-((N-methyl-L-alanyl) amino) acetyl) pyrrolidine-2-yl) -1,3-thiazole-4-yl) carbonyl) phenoxy) ethoxy) ethoxy) ethyl) carbamoyl) pyrrolidine- 1-yl) -5- (1H-pyrazole-5-yl) nicotine amide

A) 2- (2- (2- (3-((2-((2S) -1-((2S) -2-((N- (tert-butoxycarbonyl) -N-methyl-L-alanyl)) Amino) -2-cyclohexylacetyl) pyrrolidine-2-yl) -1,3-thiazole-4-yl) carbonyl) phenoxy) ethoxy) ethoxy) ethyl 4-methylbenzenesulfonate
tert-Butyl ((2S) -1-(((1S) -1-cyclohexyl-2-((2S) -2-(4- (3-hydroxybenzoyl) -1,3-thiazole-2-yl) pyrrolidine) -1-yl) -2-oxoethyl) amino) -1-oxopropan-2-yl) methylcarbamate (299 mg), ethane-1,2-diylbis (oxyethane-2,1-diyl) bis (4-yl) A mixture of methylbenzene sulfonate) (1.38 g), potassium carbonate (111 mg) and DMF (3 mL) was stirred at 50 ° C. overnight. The mixture was allowed to warm to room temperature and then diluted with ethyl acetate. After washing with 5% aqueous sodium hydrogen carbonate solution and saturated brine, the mixture was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / hexane) to give the title compound (336 mg).
MS: [M + H] ⁺ 885.6.

B) 5-Bromo-6-chloro-N- (4- (chloro (difluoro) methoxy) phenyl) nicotinamide
DMF (26 mL) and thionyl chloride (30.2 g) were added dropwise to a suspension of 5-bromo-6-chloro-pyridine-3-carboxylic acid (20.0 g) and toluene (175 mL). The mixture was stirred at 80 ° C. for 2 hours and then concentrated under reduced pressure at 50 ° C. The resulting residue was dissolved in THF (160 mL) and DIPEA (21.9 g), followed by a solution of 4- [chloro (difluoro) methoxy] aniline (18.0 g) in THF (160 mL) at -15 ° C for 30 minutes. Dropped. The mixture was stirred at room temperature for 1 hour and then concentrated under reduced pressure at 50 ° C. The residue was dissolved in ethyl acetate, washed with 1N hydrochloric acid, saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether) to give the title compound (9.3 g).
MS: [M + H] ⁺ 410.9, 412.9.

C) Methyl 1- (3-bromo-5-((4- (chloro (difluoro) methoxy) phenyl) carbamoyl) pyridin-2-yl) pyrrolidine-3-carboxylate
DIPEA (7.8 g) and methylpyrrolidine-3-carboxylate in a mixture of 5-bromo-6-chloro-N- (4- (chlorodifluoromethoxy) phenyl) nicotinamide (5.0 g) and 2-propanol (24 mL) Hydrochloride (2.6 g) was added at room temperature and sealed. The mixture was stirred at 130 ° C. for 10 hours. After returning the reaction mixture to room temperature, it was poured into ice water and the pH was adjusted to 5-6 with 1N hydrochloric acid. The aqueous layer was extracted with ethyl acetate, and the obtained organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether) to give the title compound (4.0 g).
^{1 1} H NMR (400 MHz, CDCl ₃ ) δ 2.18-2.32 (2H, m), 3.10-3.23 (1H, m), 3.75 (3H, s), 3.82-3.96 (2H, m), 3.99-4.06 (2H) , m), 7.19-7.25 (2H, m), 7.63-7.69 (2H, m), 8.02 (1H, s), 8.16 (1H, d, J = 2.0 Hz), 8.55 (1H, s).

D) Methyl 1-(5-((4- (chloro (difluoro) methoxy) phenyl) carbamoyl) -3- (1- (tetrahydro-2H-pyran-2-yl) -1H-pyrazol-5-yl) pyridine -2-yl) pyrrolidine-3-carboxylate Methyl 1- (3-bromo-5-((4- (chlorodifluoromethoxy) phenyl) carbamoyl) pyridin-2-yl) pyrrolidine-3-carboxylate (4.0 g) , 1- (tetrahydro-2H-pyran-2-yl) -5- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -1H-pyrazole (3.3 g), Tripotassium phosphate (3.4 g) and chloro (2-dicyclohexylphosphino-2', 4', 6'-triisopropyl-1,1'-biphenyl) in a mixture of water (10 mL) and THF (100 mL) [2- (2'-Amino-1,1'-biphenyl)] Pyran (II) (623 mg) was added all at once in a nitrogen atmosphere at room temperature. The mixture was stirred at 100 ° C for 16 hours and then concentrated under reduced pressure at 50 ° C. The obtained residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether) to give the title compound (4.2 g).
MS: [M + H] ⁺ 576.1.

E) 1-(5-((4- (Chloro (difluoro) methoxy) phenyl) carbamoyl) -3- (1- (tetrahydro-2H-pyran-2-yl) -1H-pyrazole-5-yl) pyridine- 2-Il) Pyrrolidine-3-Carboxylic Acid Methyl 1-(5-((4- (Chlorodifluoromethoxy) phenyl) Carbamoyl) -3- (1- (Tetrahydro-2H-Pyran-2-yl) -1H-Pyrazole) -5-Il) Pyridine-2-yl) Pyrrolidine-3-carboxylate (4.0 g), methanol (100 mL), water (10 mL) mixed with lithium hydroxide monohydrate (874 mg) at room temperature Added at once. After stirring at room temperature for 16 hours, the mixture was concentrated under reduced pressure at 50 ° C. The residue was poured into ice water and the pH was adjusted to 6-7 with a 50% aqueous citric acid solution. The aqueous layer was extracted with ethyl acetate, and the obtained organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by HPLC (Phenomenex Gemini, mobile phase: water / acetonitrile (0.05% ammonia-containing system)) to give the title compound (4.0 g).
^{MS: [M + H] +} 562.2.

F) tert-butyl ((2S) -1-(((1S) -2-((2S) -2- (4- (3- (2- (2- (2-(((1- (5-) 5-) ((4- (Chloro (difluoro) methoxy) phenyl) carbamoyl) -3- (1- (tetrahydro-2H-pyran-2-yl) -1H-pyrazol-5-yl) pyridin-2-yl) pyrrolidine-3 -Il) carbonyl) amino) ethoxy) ethoxy) ethoxy) benzoyl) -1,3-thiazole-2-yl) pyrrolidine-1-yl) -1-cyclohexyl-2-oxoethyl) amino) -1-oxopropane-2 -Il) Methylcarbamate
2- (2- (2- (3-((2-((2S) -1-((2S) -2-((N- (tert-butoxycarbonyl) -N-methyl-L-alanyl) amino)) -2-cyclohexylacetyl) pyrrolidine-2-yl) -1,3-thiazole-4-yl) carbonyl) phenoxy) ethoxy) ethoxy) ethyl 4-methylbenzenesulfonate (70 mg) and 28% aqueous ammonia (1.5 mL) ) And ethanol (1.5 mL) were microwaved at 100 ° C. for 20 minutes. Water was added to the mixture at room temperature, and the mixture was extracted with ethyl acetate. The organic layer was separated, washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The resulting residue, 1- (5-((4- (chloro (difluoro) methoxy) phenyl) carbamoyl) -3- (1- (tetrahydro-2H-pyran-2-yl) -1H-pyrazole-5-yl) ) Pyridine-2-yl) DIPEA (0.02 mL) was added to a mixture of pyrrolidine-3-carboxylic acid (44 mg), HATU (45 mg) and acetonitrile (3 mL) at room temperature. The mixture was stirred at room temperature overnight. Water was added to the mixture at room temperature, and the mixture was extracted with ethyl acetate. The organic layer was separated, washed with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (methanol / ethyl acetate) to give the title compound (40 mg).
MS: [M + Na] ⁺ 1295.4.

G) N- (4- (Chloro (difluoro) methoxy) Phenyl)-6-(3-((2- (2- (2- (3-((2-((2S) -1-((2S)) -2-Cyclohexyl-2-((N-methyl-L-alanyl) amino) acetyl) pyrrolidine-2-yl) -1,3-thiazole-4-yl) carbonyl) phenoxy) ethoxy) ethoxy) ethyl) carbamoyl) Pyrrolidine-1-yl) -5- (1H-pyrazole-5-yl) nicotinamide
tert-butyl ((2S) -1-(((1S) -2-((2S) -2- (4- (3- (2- (2- (2-(((1- (5- (() 4- (Chloro (difluoro) methoxy) phenyl) Carbamoyl) -3- (1- (Tetrahydro-2H-pyran-2-yl) -1H-pyrazole-5-yl) Pyridine-2-yl) Pyrrolidine-3-yl ) Carbonyl) amino) ethoxy) ethoxy) ethoxy) benzoyl) -1,3-thiazole-2-yl) pyrrolidine-1-yl) -1-cyclohexyl-2-oxoethyl) amino) -1-oxopropan-2-yl ) A mixture of methylcarbamate (40 mg) and TFA (1 mL) was stirred at room temperature for 30 minutes. After concentrating the reaction solution, the obtained residue was dissolved in ethyl 2-propanol acetate (4: 1), washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. .. The residue was purified by silica gel column chromatography (NH, methanol / ethyl acetate) to give the title compound (17 mg).
¹ H NMR (300 MHz, CD ₃ OD) δ 0.84-1.19 (5H, m), 1.22 (3H, d, J = 6.8 Hz), 1.48-1.85 (7H, m), 2.02-2.42 (8H, m) , 2.82-2.97 (1H, m), 3.13 (1H, q, J = 6.9 Hz), 3.21-3.29 (1H, m), 3.35 (3H, d, J = 5.7 Hz), 3.44 (2H, d, J) = 7.9 Hz), 3.49-3.57 (2H, m), 3.58-3.66 (2H, m), 3.68-3.78 (2H, m), 3.84-4.02 (4H, m), 4.17-4.26 (2H, m), 4.55 (1H, d, J = 7.2 Hz), 5.46 (1H, dd, J = 7.7, 3.3 Hz), 6.43 (1H, d, J = 2.1 Hz), 7.17-7.31 (3H, m), 7.36-7.46 (1H, m), 7.65-7.82 (5H, m), 8.04 (1H, d, J = 2.5 Hz), 8.29 (1H, s), 8.70 (1H, d, J = 2.5 Hz).

Compounds of Examples 3-6, 10, 17, 18, 24, 26, 30, 32, 38-40, 48 in the table below, according to the methods shown in the above Examples or similar methods. Manufactured. Example compounds are shown in the table below. MS in the table shows the measured value.

(Test Example 1: In vitro degradation-inducing activity of target protein)
The in vitro degradation-inducing activity of the example compound was evaluated by the following test.
[Evaluation method]
(A) MCF-7 cells were purchased from ATCC and cultured in RPMI-1640 (Sigma) supplemented with 10% FBS (MBL) and 100 μg / mL kanamycin (Sigma). MCF-7 cells seeded in 6-well plates are used in DMSO control and the compounds shown in Example 33 (sometimes referred to herein as SNIPER (ER) -087) (1, 3, 10, 30, 100, 300). , 1000 or 3000 nM) and cultured for 6 hours. Cells were harvested and lysed in SDS lysis buffer (0.1 M Tris-HCl at pH 8.0, 10% glycerol, 1% SDS). Immediately boiled for 10 minutes and centrifuged at 16,000 g for 10 minutes to clarify the cell extract. The supernatant was separated by SDS-PAGE and analyzed by Western blotting (standard protocol) using an antibody against ERα (Cell Signaling # 8644) or β-actin (Sigma # A5316). The band (emission intensity) was quantified with a LAS-3000 lumino image analyzer (Fuji), the ERα value was corrected with the internal standard β-actin value, and the correction value was expressed as a relative value with the DMSO control as 100. .. The results of three independent experiments are shown in a bar graph (Fig. 1A).
(B) MCF-7 cells seeded in 6-well plates were subjected to DMSO control, SNIPER compounds (specifically, SNIPER (ER) -087 and the compounds shown in Example 34 (in the present specification, SNIPER (ER) -088). (Sometimes referred to as)) (10 or 100 nM) or a mixture of LCL161 derivative and 4-OHT (100 nM each) and cultured for 1, 3, 6, 24, 48 or 72 hours. Cells were harvested and lysed in SDS lysis buffer (0.1 M Tris-HCl at pH 8.0, 10% glycerol, 1% SDS). Immediately boiled for 10 minutes and centrifuged at 16,000 g for 10 minutes to clarify the cell extract. The supernatant was separated by SDS-PAGE and analyzed by Western blotting (standard protocol) using an antibody against ERα (Cell Signaling # 8644) or β-actin (Sigma # A5316). The band (emission intensity) is quantified by the LAS-3000 lumino image analyzer (Fuji), the ERα value is corrected by the internal standard β-actin value, and the correction value is expressed as a relative value with the DMSO control as 100. (Fig. 1B).
(C) MCF-7 cells seeded in 6-well plates are subjected to DMSO control, SNIPER compounds (specifically, SNIPER (ER) -087, SNIPER (ER) -088 and the compounds shown in Example 35 (in the present specification). , SNIPER (ER) -089)) (3, 10, 30 or 100 nM) or a mixture of LCL161 derivative and 4-OHT (3, 10 or 30 nM each) and cultured for 6 hours. .. Cells were harvested and lysed in SDS lysis buffer (0.1 M Tris-HCl at pH 8.0, 10% glycerol, 1% SDS). Immediately boiled for 10 minutes and centrifuged at 16,000 g for 10 minutes to clarify the cell extract. The supernatant was separated by SDS-PAGE and analyzed by Western blotting (standard protocol) using an antibody against ERα (Cell Signaling # 8644) or β-actin (Sigma # A5316). The band (emission intensity) is quantified by the LAS-3000 lumino image analyzer (Fuji), the ERα value is corrected by the internal standard β-actin value, and the correction value is expressed as a relative value with the DMSO control as 100. (Fig. 1C).
(D) T47D cells and ZR75-1 cells were purchased from ATCC and cultured in RPMI-1640 (Sigma) supplemented with 10% FBS (MBL) and 100 μg / mL kanamycin (Sigma). T47D cells and ZR75-1 cells seeded on a 6-well plate were treated with DMSO control or SNIPER (ER) -087 (10 or 100 nM) and cultured for 3 or 6 hours. Cells were harvested and lysed in SDS lysis buffer (0.1 M Tris-HCl, pH 8.0, 10% glycerol, 1% SDS). Immediately boiled for 10 minutes and centrifuged at 16,000 g for 10 minutes to clarify the cell extract. The supernatant was separated by SDS-PAGE and analyzed by Western blotting (standard protocol) using an antibody against ERα (Cell Signaling # 8644), cIAP1 (R & D systems # AF8181) or β-actin (Sigma # A5316) (standard protocol). FIG. 1D).

[result]
Human breast cancer cell MCF-7 expressing ERα was treated with various compound concentrations for 6 hours, and the activity was evaluated by analyzing the amount of ERα protein by Western blotting. As a result, the compound shown in Example 33 was the smallest. The amount of ERα protein was effectively reduced at an effective concentration of 3 nM (Fig. 1A). When the compound shown in Example 34 and the compound shown in Example 35 in which the length of the polyethylene glycol (PEG) linker of the compound shown in Example 33 was changed were synthesized and the KD activity was compared, SNIPER (ER) -088 was found. The KD activity was equivalent to that of SNIPER (ER) -087, but the KD activity was attenuated in the compound shown in Example 35, which had one less PEG unit (Fig. 1C). The KD activity of the compound shown in Example 33 and the compound shown in Example 34 was observed from 1 hour after the compound treatment, and the effect lasted up to 48 hours (Fig. 1B). In addition, when ER ligand (4-OHT) and IAP ligand (LCL161 derivative) were mixed and treated, the amount of ERα did not decrease, so it is important for KD activity to link both ligands with a linker. It was suggested that there was (Fig. 1B, 1C). Similarly, the KD effect of the compound shown in Example 33 was confirmed in human breast cancer cells T-47D and ZR75-1, which are different from MCF-7 (Fig. 1D).

(Test Example 2: Evaluation of in vitro target protein lowering effect)
The target proteolytic activity of the Example compound in vitro was measured as follows.
1. BCR-ABL protein lowering effect evaluation method
K562 cells were purchased from ATCC and cultured in RPMI-1640 (Sigma) supplemented with 10% FBS (MBL) and 100 μg / mL kanamycin (Sigma). K562 cells seeded in 6-well plates were treated with DMSO control and SNIPER compounds (1, 3, 10, 30, 100, 300, 1000, 3000 or 10000 nM) and cultured for 4, 6 or 24 hours. Cells are harvested and lysed in Triton X-100 lysis buffer (0.1 M Tris-HCl at pH 7.5, 150 nM NaCl, 0.5% Triton X-100, 1 x complete protease inhibitor cocktail (Roche)) or SDS lysis buffer (SDS lysis buffer (Roche). Immediately after dissolution in 0.1 M Tris-HCl, 10% glycerol, 1% SDS) at pH 8.0, boiled for 10 minutes. The cell extract was centrifuged at 20,000 g for 10 minutes to clarify. The supernatant is separated by SDS-PAGE and antibody against ABL (Cell Signaling # 2862), GAPDH (Santa Cruz sc-25778), β-tubulin (Abcam ab6046) or β-actin (Sigma # A5316) is used. It was analyzed by Western blotting (standard protocol). The band (emission intensity) is quantified with a LAS-3000 lumino image analyzer (Fuji), the BCR-ABL value is corrected with the internal standards GAPDH, β-tubulin or β-actin, and the correction value is DMSO controlled. Was evaluated as a relative value with 100 as 100 (Table 2-1 and Table 2-2).

2. AR protein lowering effect evaluation method
22Rv1 cells were purchased from ATCC and cultured in RPMI-1640 (Sigma) supplemented with 10% FBS (MBL) and 100 μg / mL kanamycin (Sigma). 22Rv1 cells seeded in 6-well plates were treated with DMSO control and SNIPER compounds (1, 3, 10, 30, 100, 300, 1000, 3000, 10000 or 30000 nM) and cultured for 6 hours. Cells were harvested and lysed in SDS lysis buffer (0.1 M Tris-HCl, pH 8.0, 10% glycerol, 1% SDS). Immediately boiled for 10 minutes and centrifuged at 16,000 g for 10 minutes to clarify the cell extract. The supernatant was separated by SDS-PAGE and analyzed by Western blotting (standard protocol) using an antibody against AR (Cell Signaling # 5153), GAPDH (Santa Cruz sc-25778) or β-tubulin (Abcam ab6046). .. The band (emission intensity) was quantified with a LAS-3000 lumino image analyzer (Fuji), the AR value was corrected with the internal standard GAPDH or β-tubulin value, and the correction value was a relative value with DMSO control as 100. (Table 2-1 and Table 2-2).

3. ER protein lowering effect evaluation method
MCF-7 cells were purchased from ATCC and cultured in RPMI-1640 (Sigma) supplemented with 10% FBS (MBL) and 100 μg / mL kanamycin (Sigma). MCF-7 cells seeded in 6-well plates were treated with DMSO control and SNIPER compound (1, 3, 10, 30, 100, 300, 1000 or 3000 nM) and cultured for 3, 4, 6, 24 or 48 hours. .. Cells were harvested and lysed in SDS lysis buffer (0.1 M Tris-HCl, pH 8.0, 10% glycerol, 1% SDS). Immediately boiled for 10 minutes and centrifuged at 16,000 g for 10 minutes to clarify the cell extract. The supernatant was separated by SDS-PAGE and analyzed by Western blotting (standard protocol) using an antibody against ERα (Cell Signaling # 8644) or β-actin (Sigma # A5316). The band (emission intensity) was quantified with a LAS-3000 lumino image analyzer (Fuji), the ERα value was corrected with the internal standard β-actin value, and the correction value was evaluated as a relative value with the DMSO control as 100. (Table 2-1 and Table 2-2).

4. BRD4 protein lowering effect evaluation method
LNCaP cells were purchased from ATCC and cultured in RPMI-1640 (Sigma) supplemented with 10% FBS (MBL) and 100 μg / mL kanamycin (Sigma). LNCaP cells seeded in 6-well plates were treated with DMSO control and SNIPER compound (3, 10, 30, 100, 300 or 1000 nM) and cultured for 6 or 24 hours. Cells were harvested and lysed in SDS lysis buffer (0.1 M Tris-HCl at pH 8.0, 10% glycerol, 1% SDS). Immediately boiled for 10 minutes and centrifuged at 16,000 g for 10 minutes to clarify the cell extract. The supernatant was separated by SDS-PAGE and analyzed by Western blotting (standard protocol) using an antibody against BRD4 (Cell Signaling # 13440) or β-actin (Sigma # A5316). The band (emission intensity) was quantified with a LAS-3000 lumino image analyzer (Fuji), the BRD4 value was corrected with the internal standard β-actin value, and the correction value was evaluated as a relative value with the DMSO control as 100. (Table 2-2).

5. PDE4 protein lowering effect evaluation method
HT1080 cells were purchased from ATCC and cultured in DMEM (Sigma) supplemented with 10% FBS (MBL) and 100 μg / mL kanamycin (Sigma). HT1080 cells seeded in 6-well plates were treated with DMSO control and SNIPER compound (1, 3, 10, 30, 100, 300 or 1000 nM) and cultured for 6 or 24 hours. Cells were harvested and lysed in SDS lysis buffer (0.1 M Tris-HCl at pH 8.0, 10% glycerol, 1% SDS). Immediately boiled for 10 minutes and centrifuged at 16,000 g for 10 minutes to clarify the cell extract. The supernatant was separated by SDS-PAGE and analyzed by Western blotting (standard protocol) using an antibody against PDE4 (Santa Cruz # sc-25810) or β-actin (Sigma # A5316). The band (emission intensity) was quantified with a LAS-3000 lumino image analyzer (Fuji), the PDE4 value was corrected with the internal standard β-actin value, and the correction value was evaluated as a relative value with the DMSO control as 100. (Table 2-2).

(Test Example 3: Molecular mechanism-ubiquitin-proteasome system dependence test)
[Test method]
(A) MCF-7 cells seeded in 6-well plates in the presence or absence of 10 μM MG132 mixed with DMSO control, SNIPER (ER) -087 (100 nM) or LCL161 derivative and 4-OHT ( Each was treated with 100 nM) and cultured for 6 hours. Cells were harvested and lysed in SDS lysis buffer (0.1 M Tris-HCl at pH 8.0, 10% glycerol, 1% SDS). Immediately boiled for 10 minutes and centrifuged at 16,000 g for 10 minutes to clarify the cell extract. The supernatant was separated by SDS-PAGE and analyzed by Western blotting (standard protocol) using an antibody against ERα (Cell Signaling # 8644) or β-actin (Sigma # A5316). The band (emission intensity) is quantified by the LAS-3000 lumino image analyzer (Fuji), the ERα value is corrected by the internal standard β-actin value, and the correction value is expressed as a relative value with the DMSO control as 100. (Fig. 2A).
(B) MCF-7 cells seeded on a 3.5 cm glass bottom dish were treated with DMSO control or 100 nM SNIPER (ER) -087 in the presence or absence of 10 μM MG132 and cultured for 3 hours. Cells were fixed on ice with 100% methanol, washed 4 times with PBS, blocked with PBS containing 3% BSA and 0.1% Triton X-100 at room temperature for 1 hour, and immunostained as described below (standard protocol). Analyzed in. Antibodies to ERα (Cell Signaling # 8644) or α-tubulin (Sigma # T-5168) as primary antibodies for 2 hours, Alexa Fluor 488-conjugated anti-rabbit IgG or Alexa Fluor 568-conjugated anti-mouse IgG 2 It was treated with Hoechst 33342 as the next antibody for 1 hour. Fluorescent images were analyzed with BZ-9000 (Keyence) (Fig. 2B).
(C) MCF-7 cells seeded in a 10 cm dish were transiently transfected with the pcDNA3-HA-ubiquitin expression plasmid using Lipofectamine 2000 (Life Technologies) using a standard protocol. After 24 hours, cells were mixed with DMSO control, SNIPER (ER) -087 (10 or 100 nM), fulvestrant (10 or 100 nM) or LCL161 derivative and 4-OHT in the presence of 10 μM MG132 (each). It was treated with 100 nM) and cultured for 3 hours. Cells were harvested and lysed in SDS lysis buffer (0.1 M Tris-HCl at pH 8.0, 10% glycerol, 1% SDS). Immediately boiled for 10 minutes and centrifuged at 16,000 g for 10 minutes to clarify the cell extract. The supernatant was diluted 10-fold with 0.1 M Tris-HCl (pH 7.5) and immunoprecipitated with anti-HA agarose conjugated beads (Sigma # E6779). The precipitate was washed 4 times with an IP lysis buffer (10 mM Hepes, 142.5 mM KCl, 5 mM MgCl ₂ , 1 mM EGTA and 0.1% Triton X-100 at pH 7.4), followed by the precipitate (IP) and whole cell extract. (Total lysate) was separated by SDS-PAGE and analyzed by Western blotting (standard protocol) using an antibody against ERα (Cell Signaling # 8644) or β-actin (Sigma # A5316) (Fig. 2C).
(D) MCF-7 cells seeded in 6-well plates in the presence or absence of bortezomib (10 μM), MLN7243 (1 μM) or MLN4924 (1 or 10 μM), DMSO control or SNIPER (ER)- It was treated with 087 (30 nM) and cultured for 6 hours. Cells were harvested and lysed in SDS lysis buffer (0.1 M Tris-HCl at pH 8.0, 10% glycerol, 1% SDS). Immediately boiled for 10 minutes and centrifuged at 16,000 g for 10 minutes to clarify the cell extract. The supernatant was separated by SDS-PAGE and analyzed by Western blotting (standard protocol) using an antibody against ERα (Cell Signaling # 8644) or β-actin (Sigma # A5316). The band (emission intensity) was quantified with a LAS-3000 lumino image analyzer (Fuji), the ERα value was corrected with the internal standard β-actin value, and the correction value was a relative value (residual) with DMSO control as 100. Rate) (Fig. 2D).

[result]
To investigate whether the reduction of ERα protein by SNIPER (ER) -087 is mediated by degradation by the ubiquitin-proteasome system (UPS), the effect of UPS inhibitor cotreatment was investigated. Western blotting and fluorescent immunostaining showed that the reduction of ERα by SNIPER (ER) -087 was completely inhibited in the presence of the proteasome inhibitor MG132 (Figs. 2A and 2B). Similar results were also obtained when treated with another proteasome inhibitor, bortezomib, or the ubiquitin activating enzyme (UAE) inhibitor, MLN7243, indicating that SNIPER (ER) -087 is UPS-dependent. It was suggested that ERα was decomposed (Fig. 2D). Cullin-based ubiquitin ligases are involved in this degradation, as treatment with the NEDD8 activator (NAE) inhibitor MLN4924 had no effect on the degradation of ERα by SNIPER (ER) -087. No (Fig. 2D). Next, a ubiquitination assay was performed. MCF-7 cells transfected with the HA-tag-labeled ubiquitin gene were treated with SNIPER (ER) -087 or a control compound in the presence of MG132, immunoprecipitated with an antibody against HA (ubiquitin), and then ubiquitinated. ERα was detected by Western blotting (Fig. 2C). As a result, it was shown that SNIPER (ER) -087 induces a high degree of ubiquitination of ERα, similar to fulvestrant, which is a clinically approved ERα degradation inducer. From the above results, it was clarified that SNIPER (ER) -087 induces ubiquitination of ERα and degradation by the proteasome.

(Test Example 4: Target Selectivity of SNIPER Compound)
The following tests were conducted to investigate the target selectivity of SNIPER compounds.
[Test method]
MCF-7 cells seeded in 6-well plates were treated with DMSO control, SNIPER (ER) -087 (10 nM) or cyclohexidine (CHX) (10 μg / ml) and cultured for 0, 3 or 6 hours. Cells were harvested at each time and lysed in SDS lysis buffer (0.1 M Tris-HCl, pH 8.0, 10% glycerol, 1% SDS). Immediately boiled for 10 minutes and centrifuged at 16,000 g for 10 minutes to clarify the cell extract. Separation of supernatant by SDS-PAGE, ERα (Cell Signaling # 8644), MCL1 (BD # 559027), p53 (Santa Cruz # sc-126), cFLIP (AdipoGen Life Science # AG-20B-0005-C100) , Cyclin B (Santa Cruz # sc-245), Cyclin A (Santa Cruz # sc-751), TACC3 (Santa Cruz # sc-22773), p27 (BD # 610242), p21 (Santa Cruz # sc-6246), Western blotting using antibodies against AR (Cell Signaling # 5153), AhR (Cell Signaling # 13790), VDR (Cell Signaling # 12550), CRABP2 (Bethyl Laboratories # A300-809A) or β-actin (Sigma # A5316) Analysis was performed using the standard protocol) (Fig. 3).

[result]
To examine the selectivity of SNIPER (ER) -087 for the target protein (ERα), we examined the expression levels of various proteins when MCF-7 cells were treated with SNIPER (ER) -087. SNIPER (ER) -087 reduced the expression of ERα, but did not affect the expression levels of various short-lived proteins, cell cycle-dependently degraded proteins (Fig. 3). On the other hand, the protein synthesis inhibitor cycloheximide (CHX) rapidly reduced the amount of these proteins. SNIPER (ER) -087 also did not induce degradation of another nuclear receptor (AR, AhR, VDR) or another SNIPER target molecule, CRABP2. This result suggests that SNIPER (ER) -087 can selectively degrade ERα.

(Test Example 5: Molecular mechanism-Identification test of IAP molecule to be used (three-party complex formation))
[Test method]
(A) MCF-7 cells seeded in a 10 cm dish in the presence of 10 μM MG132 mixed with DMSO control, SNIPER (ER) -087 (1, 10, 100 nM) or LCL161 derivative and 4-OHT ( Each was treated with 100 nM) and cultured for 3 hours. Cells were harvested and lysed by adding an IP lysis buffer (pH 7.4 10 mM Hepes, 142.5 mM KCl, 5 mM MgCl ₂ , 1 mM EGTA, and 0.1% Triton X-100) containing a cocktail of protease inhibitors (pH 7.4). 4 ° C, 15 minutes, rotation). To clarify the cell extract, it was centrifuged at 16,000 g for 10 minutes at 4 ° C. The supernatant was pretreated with untreated protein G-sepharose to remove non-specifically adsorbed proteins, and then pre-incubated with ERα antibody (Santa Cruz # sc-543) at 4 ° C for 2 hours. Immunoprecipitation. After washing the precipitate with IP lysis buffer four times, the precipitate (IP) and total lysate were separated by SDS-PAGE, and ERα (Cell Signaling # 8644) and XIAP (Cell Signaling # 2042). Alternatively, it was analyzed by Western blotting (standard protocol) using an antibody against cIAP1 (R & D systems # AF8181) (Fig. 4A).
(B) MCF-7 cells seeded in a 10 cm dish were treated with DMSO control or 10 nM SNIPER (ER) -087 in the presence of 10 μM MG132 and cultured for 3 hours. Cells were harvested and lysed by adding an IP lysis buffer (pH 7.4 10 mM Hepes, 142.5 mM KCl, 5 mM MgCl ₂ , 1 mM EGTA, and 0.1% Triton X-100) containing a cocktail of protease inhibitors (pH 7.4). Rotate at 4 ° C for 15 minutes). To clarify the cell extract, it was centrifuged at 16,000 g for 10 minutes at 4 ° C. The supernatant was pretreated with untreated protein G-sepharose to remove non-specifically adsorbed proteins, and then pre-incubated with XIAP antibody (MBL # M044-3) for 2 hours at 4 ° C. Immunoprecipitation. After washing the precipitate with an IP lysis buffer four times, the precipitate (IP) is separated by SDS-PAGE and Western blotting (standard) using an antibody against ERα (Cell Signaling # 8644) or XIAP (Cell Signaling # 2042). (Protocol) was analyzed (Fig. 4B).
(C) Transfect negative control siRNA (QIAGEN), siRNA against cIAP1 or XIAP (Life Technologies) to MCF-7 cells in a 10 cm dish using lipofectamine RNAi MAX (Life Technologies) by standard protocol. Ection. After 42 hours, cells were treated with DMSO control or 10 nM SNIPER (ER) -087 in the presence of 10 μM MG132 and cultured for 3 hours. Cells were harvested and lysed by adding an IP lysis buffer (pH 7.4 10 mM Hepes, 142.5 mM KCl, 5 mM MgCl ₂ , 1 mM EGTA, and 0.1% Triton X-100) containing a cocktail of protease inhibitors (pH 7.4). Rotate at 4 ° C for 15 minutes). To clarify the cell extract, it was centrifuged at 16,000 g for 10 minutes at 4 ° C. The supernatant was pretreated with untreated protein G-sepharose to remove non-specifically adsorbed proteins, and then pre-incubated with ERα antibody (Santa Cruz # sc-543) at 4 ° C for 2 hours. Immunoprecipitation. After washing the precipitate with IP lysis buffer four times, the precipitate (IP) and total lysate were separated by SDS-PAGE, and ERα (Cell Signaling # 8644) and XIAP (Cell Signaling # 2042). , CIAP1 (R & D systems # AF8181) or β-actin (Sigma # A5316) was analyzed by Western blotting (standard protocol) (Fig. 4C).
The siRNA sequence used is as follows in Test Example 6 (A).
human cIAP1 # 2 (5'-GCUGUAGCUUUAUUCAGAAUCUGGU -3') (SEQ ID NO: 2)
human XIAP # 3 (5'-CCAGAAUGGUCAGUACAAAGUUGAA -3') (SEQ ID NO: 6)

[result]
Whether SNIPER (ER) -087 cross-links ERα and IAP in cells (forms a tripartite complex) was examined by immunoprecipitation. After treating MCF-7 cells with DMSO control or SNIPER (ER) -087 for 3 hours in the presence of MG132, the cell extract was immunoprecipitated with an antibody against ERα, and coprecipitating IAP was detected by Western blotting (Western blotting). Figure 4A). Since the binding of ERα and XIAP or ERα and cIAP1 was detected only when treated with SNIPER (ER) -087, it is clear that these IAPs bind to ERα in a SNIPER (ER) -087-dependent manner. Became. On the other hand, these IAP-ERα bonds were not observed at all when 4-OHT and LCL161 derivatives were mixed and treated, suggesting that cross-linking with compounds is important. In addition, when comparing the amount of each IAP that coprecipitates with ERα in a SNIPER (ER) -087-dependent manner with respect to the total intracellular amount (total lysate), XIAP is more efficient than cIAP1. It can be seen that it is coprecipitating with (Fig. 4A). Binding of XIAP to ERα by SNIPER (ER) -087 was also confirmed when immunoprecipitated with an antibody against XIAP (Fig. 4B). SNIPER (ER) -087-dependent binding of XIAP and ERα does not change at all when cIAP1 is knocked down with siRNA, but knocking down of XIAP significantly increases the binding amount of cIAP1 and ERα. In the state, it is suggested that SNIPER (ER) -087 mainly crosslinks XIAP and ERα (Fig. 4C: Comparison of lanes 2 and lanes 3 and 4).

(Test Example 6: Molecular mechanism-Identification test of IAP molecule to be used (IAP knockdown, etc.))
[Test method]
(A) Transfect 6-well plate MCF-7 cells transiently with standard protocol into negative control siRNA (QIAGEN), cIAP1 or XIAP siRNA (Life Technologies) using lipofectamine RNAi MAX (Life Technologies) did. After 42 hours, cells were treated with DMSO control or 10 nM SNIPER (ER) -087 and cultured for 3 hours. Cells were harvested and lysed in SDS lysis buffer (0.1 M Tris-HCl at pH 8.0, 10% glycerol, 1% SDS). Immediately boiled for 10 minutes and centrifuged at 16,000 g for 10 minutes to clarify the cell extract. The supernatant is separated by SDS-PAGE and Western blotting using an antibody against ERα (Cell Signaling # 8644), XIAP (Cell Signaling # 2042), cIAP1 (R & D systems # AF8181) or β-actin (Sigma # A5316). (Standard protocol) was used for analysis. The band (emission intensity) was quantified with a LAS-3000 lumino image analyzer (Fuji), the ERα value was corrected with the internal standard β-actin value, and the correction value was a relative value (residual) with DMSO control as 100. Rate) (Fig. 5A).
The siRNA sequence used is as follows.
human cIAP1 # 1 (5'-UCAUAGAGCAGUUGAAGACAUCUCUU -3') (SEQ ID NO: 1)
human cIAP1 # 2 (5'-GCUGUAGCUUUAUUCAGAAUCUGGU -3') (SEQ ID NO: 2)
human cIAP1 # 3 (5'-GGAAUGCUGCGGCCAACAUCUUCA -3') (SEQ ID NO: 3)
human XIAP # 1 (5'-ACACUGGCACGAGCAGGGUUUCUUU -3') (SEQ ID NO: 4)
human XIAP # 2 (5'-GAAGGAGAUACCGUGCGGUGCUUUA -3') (SEQ ID NO: 5)
human XIAP # 3 (5'-CCAGAAUGGUCAGUACAAAGUUGAA -3') (SEQ ID NO: 6)
(B) Lentivirus expression plasmid pCSII-EF-MCS-IRES-Venus-mock or pCSII-EF-MCS-IRES-Venus-XIAP siRNA in 293T cells seeded in a 10 cm dish to prepare a gene-expressing lentivirus. Calcium phosphate method of # 3-resistant Myc-XIAP (WT, H467A, ΔRing, respectively) with packaging plasmid (pCAG-HIVgp) and VSV-G- / Rev expression plasmid (pCMV-VSV-G-RSV-Rev) Transfected at. After 48 hours, the lentivirus-producing medium was collected and filtered. Further, PEG-it was mixed and then centrifuged to concentrate and purify. 6-well plates of MCF-7 cells were transiently transfected with a negative control siRNA (QIAGEN) or siRNA against XIAP (Life Technologies) using lipofectamine RNAi MAX (Life Technologies) using a standard protocol. After 24 hours, gene-expressing lentiviruses (mock, XIAP WT, XIAP H467A, XIAP ΔRing) mixed with 10 μg / ml polybrene were infected by centrifugation (2,500 rpm, 90 minutes). After 45 hours, cells were treated with DMSO control or 10 nM SNIPER (ER) -087 and cultured for 3 hours. Cells were harvested and lysed in SDS lysis buffer (0.1 M Tris-HCl at pH 8.0, 10% glycerol, 1% SDS). Immediately boiled for 10 minutes and centrifuged at 16,000 g for 10 minutes to clarify the cell extract. The supernatant is separated by SDS-PAGE and Western blotting using an antibody against ERα (Cell Signaling # 8644), XIAP (Cell Signaling # 2042), cIAP1 (R & D systems # AF8181) or β-actin (Sigma # A5316). (Standard protocol) was used for analysis. The band (emission intensity) was quantified with a LAS-3000 lumino image analyzer (Fuji), the ERα value was corrected with the internal standard β-actin value, and the correction value was a relative value (residual rate) with DMSO control as 100. ) (Fig. 5B).
The siRNA sequence used is as follows in Test Example 6 (A).
human XIAP # 3 (5'-CCAGAAUGGUCAGUACAAAGUUGAA -3') (SEQ ID NO: 6)
(C) MCF-7 cells seeded on a 6-well plate were infected with a gene-expressing lentivirus (mock or XIAP ΔRing) mixed with 10 μg / ml polybrene by centrifugation (2,500 rpm, 90 minutes). After 45 hours, cells were treated with DMSO control or 10 nM SNIPER (ER) -087 and cultured for 3 hours. Cells were harvested and lysed in SDS lysis buffer (0.1 M Tris-HCl at pH 8.0, 10% glycerol, 1% SDS). Immediately boiled for 10 minutes and centrifuged at 16,000 g for 10 minutes to clarify the cell extract. The supernatant is separated by SDS-PAGE and Western using an antibody against ERα (Cell Signaling # 8644), Myc-tag (Cell Signaling # 2276), GFP (BD # 632375) or β-actin (Sigma # A5316). It was analyzed by blotting (standard protocol). The band (emission intensity) is quantified by the LAS-3000 lumino image analyzer (Fuji), the ERα value is corrected by the internal standard β-actin value, and the correction value is expressed as a relative value with the DMSO control as 100. (Fig. 5C).
(D) 6-well plate MCF-7 cells were transiently transfected with negative control siRNA (QIAGEN) or siRNA against XIAP (Life Technologies) using lipofectamine RNAi MAX (Life Technologies) using a standard protocol. After 42 hours, cells were treated with DMSO control, SNIPER (ER) -087 (10 nM), fulvestrant (10 nM) or β-estradiol (10 nM) and cultured for 3 hours. Cells were harvested and lysed in SDS lysis buffer (0.1 M Tris-HCl at pH 8.0, 10% glycerol, 1% SDS). Immediately boiled for 10 minutes and centrifuged at 16,000 g for 10 minutes to clarify the cell extract. The supernatant was separated by SDS-PAGE and analyzed by Western blotting (standard protocol) using an antibody against ERα (Cell Signaling # 8644), XIAP (Cell Signaling # 2042) or β-actin (Sigma # A5316). The band (emission intensity) is quantified by the LAS-3000 lumino image analyzer (Fuji), the ERα value is corrected by the internal standard β-actin value, and the correction value is expressed as a relative value with the DMSO control as 100. (Fig. 5D).
The siRNA sequence used is as follows in Test Example 6 (A).
human XIAP # 3 (5'-CCAGAAUGGUCAGUACAAAGUUGAA -3') (SEQ ID NO: 6)

[result]
When the expression of each IAP was suppressed by siRNA and the effect of SNIPER (ER) -087 on the KD effect of ERα was examined, it was effective when the expression of XIAP was suppressed, and slightly SNIPER (ER) when suppressing cIAP1. )-087 suppressed the decrease in ERα (Fig. 5A). On the other hand, suppression of XIAP had little effect on the degradation of ERα by fulvestrant and β-estradiol (Fig. 5D). From the above results, the decomposition mechanism of ERα by SNIPER (ER) -087 is different from the decomposition mechanism of ERα by fulvestrant and β-estradiol, and it is mainly used for SNIPER (ER) -087-dependent decomposition of ERα. It was suggested that XIAP is needed.
SNIPER (ER) -087-dependent degradation of ERα, which is inhibited by suppression of XIAP expression, is restored when wild-type XIAP expression is restored by the lentivirus expression system, but it is a RING domain function-deficient mutant. XIAP H467A (a point mutant in the Ring finger region of the catalytic domain) and XIAP ΔRing (a mutant lacking the Ring finger region in the catalytic domain) did not recover (Fig. 5B). In addition, overexpression of XIAP ΔRing inhibited SNIPER (ER) -087-dependent degradation of ERα, indicating that XIAP ΔRing acts dominantly negatively (Fig. 5C). The above results strongly suggest that SNIPER (ER) -087 induces the degradation of ERα in an activity-dependent manner in the RING domain of XIAP.

(Test Example 7: Evaluation of knockdown activity in vivo)
[Evaluation method]
(A) Mice were bred in the animal experiment control area of the National Institute of Health Sciences (pathogen-free, 12-hour light-dark cycle) in a rodent diet and drinking water in an environment of free intake, and all subsequent experiments were conducted. It was carried out in compliance with the basic guidelines for conducting animal experiments, etc. approved by the National Institute of Health Sciences. Seventeen 6-week-old female Balb / c mice (CLEA) were randomized and divided into 6 groups. Each group is as follows. (1): Vehicle treatment 6 hours (n = 3), (2): 10 mg / kg SNIPER (ER)-087 Treatment 6 hours (n = 2), (3): 30 mg / kg SNIPER (ER)- 087 Treatment 6 hours (n = 2), (4): Vehicle treatment 24 hours (n = 4), (5): 10 mg / kg SNIPER (ER)-087 Treatment 24 hours (n = 3), (6) : 30 mg / kg SNIPER (ER)-087 24 hours of treatment (n = 3). Compound treatment was performed by intraperitoneal administration. After each dosing time, mice were euthanized and dissected, and ovarian tissue was resected. Ovarian tissue is lysed with SDS lysis buffer (0.1 M Tris-HCl, 10% glycerol, 1% SDS at pH 8.0), separated by SDS-PAGE, then ERα (Santa Cruz # sc-542), cIAP1 (Enzo Life). It was analyzed by Western blotting (standard protocol) using an antibody against Sciences # 1E1-1-10) or β-actin (Sigma # A5316). The band (emission intensity) was quantified with a LAS-3000 lumino image analyzer (Fuji), the ERα value was corrected with the internal standard β-actin value, and the average of the corrected vehicle control values was set to 100 (relative value). (Average of each group) (Fig. 6A).
(B, C) 1x10 ⁷ MCF-7 cells (50 μL) suspended in HBSS were mixed with equal volumes of Matrigel (Corning Life Sciences) and 10 6-week-old female Balb / c nude mice (CLEA). It was injected into the left and right mammary gland fat bands (100 μL each at one site, 24 sites in total). Shortly after cell inoculation, β-estradiol solution was administered subcutaneously to the neck, and 7 days later, it was administered again in the same manner. Fourteen days after the second dose, the cancer-transplanted mice were randomized and divided into two groups of five, one group receiving vehicle treatment and the other group receiving 30 mg / kg SNIPER (ER) -087 treatment intraperitoneally. went. Twenty-four hours after administration, the mice were euthanized and dissected, and the ovarian tissue (n = 5) and the transplanted cancer tissue (n = 12) were resected. Each of these tissues was dissolved in SDS lysis buffer (0.1 M Tris-HCl, 10% glycerol, 1% SDS at pH 8.0), separated by SDS-PAGE, and then ERα (Santa Cruz # sc-542: (B)). , Cell Signaling # 8644: (C)) or β-actin (Sigma # A5316) was analyzed by Western blotting (standard protocol). The band (emission intensity) is quantified by the LAS-3000 Lumino Image Analyzer (Fuji), the ERα value is corrected by the internal standard β-actin value, and the average of the corrected vehicle control is 100. Evaluated (FIGS. 6B and 6C).

[result]
The in vivo KD activity was evaluated by SNIPER (ER) -087. First, SNIPER (ER) -087 was intraperitoneally administered to female Balb / c mice, and the expression level of ERα in ovarian tissue was measured. As a result, 10 mg / kg or 30 mg / kg of SNIPER (ER) -087 was administered. Confirmed a marked decrease in ERα (Fig. 6A). In order to evaluate in vivo KD activity in a human cancer cell transplantation model, a Xenograft model in which MCF-7 cells were transplanted into the mammary gland adipose band of female Balb / c nude mice was prepared. In this model mouse as well, administration of 30 mg / kg of SNIPER (ER) -087 showed an effective reduction in ERα in ovarian tissue (Fig. 6B), and about 50% of ERα in engrafted cancer tissue. Was seen to decrease (Fig. 6C). From the above results, it was clarified that SNIPER (ER) -087 shows in vivo KD activity in ovary and transplanted breast cancer cells.

(Test Example 8: Evaluation of estrogen signal inhibitory activity and in vivo antitumor effect)
[Evaluation method]
(A) Estrogen response in 3 tandems using lipofectamine LTX (Life Technologies) to MCF-7 cells seeded in a phenolic red-free medium containing 4% charcoal / dextran-treated FBS on 24 well plates. The firefly-derived luciferase reporter plasmid containing the sequence and the sea pansy-derived luciferase control plasmid containing the SV40 promoter were transiently transfected with the standard protocol. After 24 hours, DMSO control, SNIPER (ER) -087 (1, 3, 10, 30, 100, 300, 1000 nM) or in phenol-red free medium containing 0.2% charcoal / dextran-treated FBS. Treated with β-estradiol (0.1 nM). After an additional 24 hours, ERα-dependent transcriptional activity was measured by luciferase assay (standard protocol). The value of firefly luciferase activity in the cell extract was corrected by the value of sea shiitake mushroom luciferase activity (Fig. 7A).
(B) MDA-MB-231 cells were purchased from ATCC and cultured in RPMI-1640 (Sigma) with 10% FBS (MBL) and 100 μg / mL kanamycin (Sigma). SNIPER (ER) -087 (0, 0.1, 0.3, 1, 3, 10, 30, 100, 300, 1000 nM) on MCF-7 cells, T47D cells or MDA-MB-231 cells seeded on a 96-well plate. Processed with. After 72 hours, surviving cells were stained with a 0.1% crystal violet solution containing 1% ethanol for 15 minutes at room temperature. The cells were thoroughly washed with purified water and then lysed in 1% SDS solution. The absorbance (600 nm) of the cell extract was measured with an EnVision Multilabel Plate Reader (PerkinElmer) (Fig. 7B).
(C, D) Female BALB / C mice (Charles River Laboratories Japan) arrived at 6 weeks of age and bred under a 12-hour light-dark cycle, CE-2 solid feed (Claire Japan) and free water supply. did. After 1 week of acclimation, SNIPER (ER) -87 was dissolved in 10% DMSO / 10% Cremophor EL / 20% PEG 400/60% DW and administered intraperitoneally at a dose of 10 mg / kg. Blood was collected 0.5, 1, 2, 4, 8 and 24 hours after administration under 2.5-5% isoflurane anesthesia and collected in the presence of heparin. Plasma was collected after centrifugation (12,000 rpm, 5 min). Acetonitrile was added to the collected plasma to perform deproteinization treatment. After centrifugation, the supernatant was injected into LC / MS / MS and the plasma concentration was measured. PK parameters were calculated by moment analysis (FIGS. 7C and D).
(E, F) HBSS-suspended 1 x 10 ⁷ MCF-7 cells (50 μl) were mixed with equal volumes of Corning Life Sciences and 18 6-week-old female Balb / c nude mice ( It was injected into the left and right mammary gland fat bands of CLEA) (100 μL each at one site, 36 sites in total). Shortly after cell inoculation, β-estradiol pellets were implanted subcutaneously in the neck. Four days after the transplanted cancer had engrafted and reached approximately 100 mm ³ , the cancer-transplanted mice were randomized and divided into two groups, one group (n = 9) treated with a vehicle and the other group (n = 9). ) Was treated with 30 mg / kg SNIPER (ER) -087 every 24 hours by intraperitoneal administration for 14 days. The size of the cancer was measured every two days using a caliper, ^{and the volume was calculated using the standard formula ((length x width 2} ) / 2) and graphed (Fig. 7E). After 14 days, the mice were euthanized and dissected, and the transplanted cancer tissue that had engrafted and proliferated was isolated and photographed, and a representative example (photograph) is shown in the figure (Fig. 7E). The body weight of each mouse was measured and graphed before vehicle treatment or SNIPER (ER) -087 treatment and after 14 days of administration (Fig. 7F).

[result]
Since ERα transmits estrogen-induced proliferation signals and plays an important role in the proliferation of ERα-positive breast cancer cells, we tested the effect of SNIPER (ER) -087 on estrogen-dependent gene expression and cancer proliferation. SNIPER (ER) -087 inhibited ERα-dependent transcriptional activation by estrogen (β-estradiol), but this activity correlates well with the KD activity of ERα, and remarkable inhibitory activity is observed from about 10 nM. (Fig. 7A). In addition, SNIPER (ER) -087 strongly suppressed the growth of breast cancer cell lines (MCF-7, T47D) that proliferate in an ERα-dependent manner from about 10 nM (IC50 values: 15.6 nM in MCF7 and 9.6 nM in T47D). , ERα did not affect the growth of breast cancer cell lines (MDA-MB-231) (Fig. 7B). To test the in vivo importance of these findings, we evaluated the in vivo antitumor activity of SNIPER (ER) -087 in a mouse model of MCF-7 cancer cell transplantation. In a pharmacokinetic study, intraperitoneally administered SNIPER (ER) -087 maintained a sufficient blood concentration that could be expected to be active for 8 hours or more, but almost disappeared from the blood within 24 hours (Fig. 7C, D). ), Daily administration (every 24 hours). After transplanting MCF-7 cells into nude mice and engrafting, SNIPER (ER) -087 was continuously administered at 30 mg / kg every 24 hours for 14 days, and the size of the transplanted cancer cells was significantly larger than that in the control group. The weight and weight were reduced (Fig. 7E). On the other hand, administration of SNIPER (ER) -087 for 2 weeks had almost no effect on the body weight of the mice, and no significant toxicity was observed (Fig. 7F). These results suggest the efficacy of SNIPER (ER) -087 in the treatment of ERα-positive breast cancer.

(Test Example 9: Application of LCL161 derivative to SNIPER development for other target proteins)
[Evaluation method]
(A, B) K562 cells were purchased from ATCC and cultured in RPMI-1640 (Sigma) supplemented with 10% FBS (MBL) and 100 μg / mL kanamycin (Sigma). LNCaP cells were purchased from ATCC and cultured in RPMI-1640 (Sigma) supplemented with 10% FBS (MBL) and 100 μg / mL kanamycin (Sigma). HT1080 cells were purchased from ATCC and cultured in DMEM (Sigma) supplemented with 10% FBS (MBL) and 100 μg / mL kanamycin (Sigma). K562 cells (BCR-ABL), LNCaP cells (BRD4) or HT1080 cells (PDE4) seeded in a 6-well plate are DMSO-controlled, and the compound shown in Example 12 (referred to as SNIPER (ABL) -038 in the present specification). (1, 3, 10, 30, 100, 300, 1000 or 3000 nM), the compound shown in Example 50 (sometimes referred to herein as SNIPER (BRD4) -001) (3, 10). , 30, 100, 300 or 1000 nM) or the compound shown in Example 52 (sometimes referred to herein as SNIPER (PDE4) -009) (1, 3, 10, 30, 100, 300, or 1000). It was treated with nM) and cultured for 6 hours (A) or 24 hours (B). Cells were harvested and lysed in SDS lysis buffer (0.1 M Tris-HCl at pH 8.0, 10% glycerol, 1% SDS). Immediately boiled for 10 minutes and centrifuged at 16,000 g for 10 minutes to clarify the cell extract. Separation of the supernatant by SDS-PAGE was performed to obtain antibodies against c-ABL (Cell Signaling # 2862), BRD4 (Cell Signaling # 13440), PDE4 (Santa Cruz # sc-25810) or β-actin (Sigma # A5316). It was analyzed by Western blotting (standard protocol). The band (emission intensity) is quantified with a LAS-3000 lumino image analyzer (Fuji), the BCR-ABL, BRD4 or PDE4 values are corrected with the internal standard β-actin value, and the correction value is 100 for DMSO control. Notated as a relative value. The results of three independent experiments are shown in a bar graph (FIGS. 8A and B).
(C) DMSO of K562 cells (BCR-ABL), LNCaP cells (BRD4) or HT1080 cells (PDE4) seeded in a 6-well plate in the presence or absence of MG132 (10 μM) or MLN7243 (10 μM). Controls were treated with SNIPER (ABL) -038 (30, 100 nM), SNIPER (BRD4) -001 (30, 100 nM) or SNIPER (PDE4) -090 (10, 30 nM) and cultured for 6 hours. Cells were harvested and lysed in SDS lysis buffer (0.1 M Tris-HCl, pH 8.0, 10% glycerol, 1% SDS). Immediately boiled for 10 minutes and centrifuged at 16,000 g for 10 minutes to clarify the cell extract. Separation of the supernatant by SDS-PAGE was performed to obtain antibodies against c-ABL (Cell Signaling # 2862), BRD4 (Cell Signaling # 13440), PDE4 (Santa Cruz # sc-25810) or β-actin (Sigma # A5316). It was analyzed by Western blotting (standard protocol). The band (emission intensity) is quantified by the LAS-3000 lumino image analyzer (Fuji), the ERα value is corrected by the internal standard β-actin value, and the correction value is expressed as a relative value with the DMSO control as 100. (Fig. 8C).

[result]
SNIPER (ABL) -038, in which dasatinib, JQ-1, a known PDE4 inhibitor [(1) WO2008006051A2, (2) Bioorg. Med. Chem. Lett., 2010, 20, 2928-2932] ligand was linked to an LCL161 derivative. Both SNIPER (BRD4) -001 and SNIPER (PDE4) -090 showed KD activity that effectively degrades target proteins from low concentrations of 1 nM to 10 nM (Figs. 8A and 8B). In addition, these KDs were suppressed by MG132 and MLN7243, indicating that they were mediated by UPS (Fig. 8C). These results suggest that the LCL161 derivative is an IAP ligand useful for the development of SNIPER, which degrades various target proteins.

Pharmaceutical example 1
A drug containing the compound of the present invention as an active ingredient can be produced, for example, by the following formulation.
1. 1. Capsule (1) Compound 40 mg obtained in Example 1
(2) Lactose 70 mg
(3) Microcrystalline cellulose 9 mg
(4) Magnesium stearate 1 mg
1 capsule 120 mg
After mixing 1/2 of (1), (2), (3) and (4), it is granulated. The remaining (4) is added to this, and the whole is encapsulated in a gelatin capsule.

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

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

The compound of the present invention can specifically degrade a target intracellular protein. Therefore, it is expected to provide a drug effective for the prevention or treatment of diseases involving the target protein.

Claims (4)

Equation (I) below
[Z]-[L]-[X] (I)
[In the formula, [Z] indicates a ligand that specifically binds to intracellular proteins;
[L] is the following equation (II) inside.

(In the equation, L ¹ , L ² and L ³ each independently represent an unsubstituted atom selected from the group consisting of a carbon atom, an oxygen atom, a nitrogen atom and a sulfur atom.
−− Indicates a single bond, a double bond or a triple bond independently of each other. ) Indicates a linker containing a linear linker;
[X] is

Is. ]
A compound represented by or a salt thereof. A medicament containing the compound according to claim 1 or a salt thereof. The medicament according to claim 2 , which is a proteolytic inducer. The medicament according to claim 2 , which is a preventive or therapeutic agent for cancer.

Images