JP2017071567A - Anticancer agent delivery molecule - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a compound which can be used as an anticancer agent targeting a cancer cell that highly expresses Lysine-specific demethylase 1 (LSD1) or salt thereof.SOLUTION: The present invention provides a compound represented by the following formula (I) or a pharmaceutically acceptable salt thereof, where Ar, R, R, L, Z, p, q, *1 and *2 are as defined in the specifications.SELECTED DRAWING: None

Description

  The present invention mainly relates to a compound or a salt thereof that can be used as an anticancer agent targeting cancer cells that highly express lysine-specific demethylase 1, LSD1. The present invention also relates to a pharmaceutical composition containing the compound or the like as an active ingredient.

  Cancer chemotherapy is generally carried out by using a combination of cytotoxic anticancer agents and molecular targeted therapeutic agents. However, while anticancer agents can achieve a certain therapeutic effect, they show serious side effects. In recent years, biopharmaceuticals have been developed, and antibody drugs targeting markers that are specifically expressed in cancer have brought high therapeutic effects. Recently, antibody-drug conjugates (ADCs), which combine antibody preparations and drugs with strong side effects, have been developed, and it has become possible to selectively develop the effects of anticancer drugs with strong side effects. . On the other hand, since ADC is a biologic, there are many problems such as low oral absorption, low tissue permeability, high molecular weight, and high production cost.

  Lysine-specific demethylase 1 (LSDine-specific demethylase 1, LSD1) is highly expressed in breast cancer, leukemia cells, neuroblastoma, glioma and other cancers, and is attracting attention as a biomarker and molecular target for cancer. Yes. LSD1 is mainly involved in cancer growth by oxidatively demethylating histone mono- and dimethylated lysine residues.

  It has been reported that trans-phenylcyclopropylamine (PCPA), a typical LSD1 inhibitor, forms an adduct with FAD, which is a coenzyme of LSD1, and irreversibly inhibits LSD1 (Non-patent Document 1). In addition, LSD1 selective inhibitors having a lysine-like structure have been reported as anticancer agents (Non-patent Documents 2 to 3, Patent Documents 1 and 2). However, these compounds are not effective enough for clinical application, and further development is required at present.

International Publication WO2010 / 143582 International Publication WO2014 / 084298

Biochemistry 2007, 46, pp4408-4416 J. Am. Chem. Soc, 2009, 131, pp17536-17537 Angew. Chem. Int. Ed. 2013, 52, 8620-8624.

  The present inventor has shown that a compound in which an anticancer agent is bonded to a nitrogen atom of PCPA via a suitable linker as a molecule for selectively delivering the anticancer agent to cancer cells is highly expressed in cancer. It was found that LSD1 was irreversibly inhibited, releasing a free amine compound out of the enzyme activity center, and releasing the amine compound caused intramolecular cyclization to release an anticancer drug. The inventor has further conducted intensive studies and completed the present invention.

The present invention includes the following embodiments:
Item 1. A compound represented by the following formula (I) or a pharmaceutically acceptable salt thereof:

[Where:
Ar represents an aryl group which may have a substituent or a heteroaryl group which may have a substituent.
* 1 and * 2 indicate asymmetric carbon.
R ¹ and R ² independently represent a hydrogen atom or an alkyl group.
YL represents a linker group (Y represents O, S, or NH).
ZH represents a pharmaceutical compound represented by DOH, DSH, DNH ₂ or D ₁ D ₂ NH.
p shows the integer of 1-3.
q represents 0 or 1; ]
Item 2. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein the pharmaceutical compound represented by ZH is an antitumor agent.

  Item 3. The compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein the linker group is a linker group that can be removed via an elimination reaction.

Item 4, one of the following compounds or a pharmaceutically acceptable salt thereof:
(E / Z) -4- (1- (4- (2- (Dimethylamino) ethoxy) phenyl) -2-phenylbut-1-en-1-yl) phenyl (2- (methyl (2-phenylcyclopropyl ) Amino) ethyl) carbamate;
(E / Z) -4- (1- (4- (2- (Dimethylamino) ethoxy) phenyl) -2-phenylbut-1-en-1-yl) phenylmethyl (2- (methyl (2-phenylcyclo Propyl) amino) ethyl) carbamate
N ¹ -{{{[N-methyl-N- (trans-2-phenylcyclopropyl) amino] ethyl} carbamoyl} oxy} -N8-phenyloctanediamide;
N ¹ -((methyl (2- (methyl (2-phenylcyclopropyl) amino) ethyl) carbamoyl) oxy) -N8-phenyloctanediamide;
Pyridin-3-ylmethyl 4-((2- (3- (2- (methyl (2-phenylcyclopropyl) amino) ethyl) ureido) phenyl) carbamoyl) benzylcarbamate;
Pyridin-3-ylmethyl 4-((2- (3-methyl-3- (2- (methyl (2-phenylcyclopropyl) amino) ethyl) ureido) phenyl) carbamoyl) benzylcarbamate;
4-(((2- (methyl (2-phenylcyclopropyl) amino) ethyl) carbamoyl) (5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl) carbamoyl )benzoic acid;
4-((Methyl (2- (methyl (2-phenylcyclopropyl) amino) ethyl) carbamoyl) (5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl) Carbamoyl) benzoic acid;
4-((Methyl (3- (methyl (2-phenylcyclopropyl) amino) propyl) carbamoyl (5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl) carbamoyl )benzoic acid;
4-((Methyl (4- (methyl (2-phenylcyclopropyl) amino) butyl) carbamoyl) (5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl) Carbamoyl) benzoic acid;
4-((((8-oxo-8- (phenylamino) octanamido) oxy) methyl) phenylmethyl (2- (methyl (2-phenylcyclopropyl) amino) ethyl) carbamate;
4-((4-((methyl (2- (methyl (2-phenylcyclopropyl) amino) ethyl) carbamoyl) oxy) benzyl) (5,5,8,8-tetramethyl-5,6,7,8 -Tetrahydronaphthalen-2-yl) carbamoyl) benzoic acid;
4-((3- (4-Cyano-3- (trifluoromethyl) phenyl) -5,5-dimethyl-2,4-dioxoimidazolidin-1-yl) methyl) phenylmethyl (2- (methyl ( 2-phenylcyclopropyl) amino) ethyl) carbamate A pharmaceutical composition comprising the compound according to any one of Items 5 and 1-4 or a pharmaceutically acceptable salt thereof.

  Item 6. An antitumor agent comprising the compound according to item 6, item 2 or 4, or a pharmaceutically acceptable salt thereof as an active ingredient.

  The present invention provides a compound capable of selectively delivering a pharmaceutical compound such as an antitumor agent to cancer cells. The compounds of the present invention release pharmaceutical compounds in cancer cells but not in normal cells that hardly express LSD1. Therefore, it is possible to release a pharmaceutical compound selective for cancer. Furthermore, the compound of the present invention can be synthesized easily and at low cost, and since it is a low molecular compound, improvement in oral absorption and tissue permeability can be expected as compared with ADC and the like.

a) Structure of PCPA and LSD1 inhibition mechanism. b) An example of a compound of the present invention An example of a compound of the invention acting on a target associated with LSD1 Examples of linker groups PCOH-Tm-a / b 4OHT release ability in the presence of LSD1 Effect of PCPA-Tm-a / b on breast cancer cell MCF7 and normal cell HMEC

1. Compound The compound of the present invention is a compound represented by the following general formula (I) or a pharmaceutically acceptable salt thereof.

  Ar is an aryl group which may have a substituent or a heteroaryl group which may have a substituent.

  The “aryl group” means a monocyclic or polycyclic group mainly composed of a 6-membered aromatic hydrocarbon ring. Specific examples include phenyl, naphthyl, fluorenyl, anthryl, biphenylyl, tetrahydronaphthyl, and phenanthryl.

  The “heteroaryl group” means a monocyclic or polycyclic group consisting of a 5- or 6-membered aromatic ring containing 1 to 3 heteroatoms selected from a nitrogen atom, an oxygen atom and a sulfur atom. In the case of a polycyclic system, at least one ring may be an aromatic ring. Specific examples include furyl, thienyl, pyrrolyl, imidazolyl, pyrazolyl, oxazolyl, thiazolyl, isoxazolyl, isothiazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, indolyl, quinolyl, isoquinolyl, benzo [b] thienyl, benzimidazolyl, benzothiazolyl, benzox Zoryl is mentioned.

  Ar is preferably an aryl group which may have a substituent, more preferably a phenyl group which may have a substituent or a biphenyl group which may have a substituent.

  One preferred embodiment of Ar is a phenyl group which may have a substituent of the following formula.

[Wherein, R represents a substituent. m represents an integer of 0 to 5. ]
m represents the number of substituents. m is preferably an integer of 0 to 3, more preferably 0 or 1. The substituent is preferably a halogen atom, an alkyl group, an alkoxy group, a perfluoroalkyl group or nitro, more preferably a fluorine atom, a chlorine atom, methyl, tert-butyl, methoxy, trifluoromethyl or nitro. The position of the substituent is not particularly limited. When m = 1, the position of the substituent may be any of ortho, meta, and para.

  Another preferred embodiment of Ar includes a biphenyl group which may have a substituent represented by the following formula.

[Wherein, R represents a substituent. m represents the integer of 0-5, respectively. ]
m represents the number of substituents. m is preferably an integer of 0 to 3, more preferably 0 or 1. The substituent is preferably a halogen atom, an alkyl group, an alkoxy group, a perfluoroalkyl group or nitro, more preferably a fluorine atom, a chlorine atom, methyl, tert-butyl, methoxy, trifluoromethyl or nitro. The position of the substituent is not particularly limited.

R ¹ and R ² independently represent a hydrogen atom or an alkyl group.

  “Alkyl group” means a linear or branched alkyl group such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl, isopentyl, n-hexyl. Examples thereof include an alkyl group having 1 to 6 carbon atoms. Preferably it is a C1-C3 alkyl group, Most preferably, it is methyl.

  In general formula (I), * 1 and * 2 represent asymmetric carbons.

C ^{* 1} and Ar site for binding to, the nitrogen atom bonded to ^{C * 2,} with respect to the cyclopropane ring ^{of C * 1} and ^{C * 2} is configured, the relative arrangement following trans-configuration

[Wherein, R ¹ and Ar are the same as defined above. ]
Or the relative configuration is the following cis configuration

[Wherein, R ¹ and Ar are the same as defined above. ]
Any of these may be used, and a trans configuration is preferable.

  The compound of the present invention may be any one of the above stereoisomers (enantiomer) or a mixture of two or more.

  p is an integer of 1 to 3, preferably 1 or 2.

ZH represents a pharmaceutical compound represented by either DOH, DSH, DNH ₂ or D ¹ D ² NH. That is, ZH is —OH group (hydroxyl group), —SH group (mercapto group), —NH ₂ group or —NH— group (primary or secondary amino group) (hereinafter, sometimes simply referred to as XH group). .). “Pharmaceutical compound” means a compound having physiological activity that can be used for diagnosis, treatment or prevention of human or animal diseases and can be used as a medicine.

  Medicinal compounds include central nervous system drugs, peripheral nervous system drugs, sensory organ drugs, and other nervous system and sensory organ drugs; cardiovascular drugs, respiratory drugs, gastrointestinal drugs, hormone drugs, urogenital medicine Drugs for individual organ systems such as organ and anal drugs, skin drugs, etc .; metabolic drugs such as vitamins and nourishing tonics; tissue cell functions such as cell stimulants and tumor drugs (antitumor drugs, etc.) Drugs: Drugs against pathogenic organisms such as antibiotics are exemplified.

  A preferred pharmaceutical compound is an antitumor agent (anticancer agent), particularly preferably an antitumor agent that acts on factors involved in cancer cell proliferation in cooperation with LSD1. Examples of factors that cooperate with LSD1 in cancer cell growth include histone modifying enzymes such as HDAC1 / 2, SIRT1, and KDM4C; and nuclear receptors such as AR, ERα, and RAR.

  Anti-tumor agents that act on factors that are involved in cancer cell growth in cooperation with LSD1 include 4-hydroxy tamoxifen (metabolism that has the therapeutic effect of tamoxifen, an anti-tumor agent of an estrogen receptor (ERα) antagonist) ), Vorinostat (also known as suberoylanilide hydroxamic acid (SAHA); histone deacetylase (HDAC) inhibitor), entinostat (development name: MS275; histone deacetylase (HDAC) inhibitor), tamibarotene ( Development name: Am80; androgen receptor (AR) antagonist), nilutamide (retinoic acid receptor (RAR) agonist), azacitidine (DNA methyltransferase (DNMT) inhibitor) and other antitumor agents.

  Formulas representing the compounds exemplified above are shown below.

  As a pharmaceutical compound represented by ZH, by using an antitumor agent that acts on factors that are involved in the growth of cancer cells in cooperation with LSD1, in addition to drug delivery selective for cancer cells, LSD1 and Factors that are cooperatively involved in the growth of cancer cells are inhibited, and a synergistic anticancer effect is expected.

The following literature discloses that a combination of an LSD1 inhibitor and an HDAC, RAR agonist, or histone demethylation inhibitor shows a synergistic effect on blood tumors, glioma, breast cancer, prostate cancer. .
1) Nat. Med. 2012, 18, 605-611
2) Leukemia. 2014, 28, 2155-2164
3) Neuro Oncol. 2015 Mar 19
4) Carcinogenesis 2013, 34, 1196-1207
5) J. Med. Chem. 2010, 53, 5629-5638.

  In the pharmaceutical compound represented by ZH, the —OH group, —SH group, —NH 2 group or —NH— group is substituted with H to give the compound of the present invention, whereby its activity (for example, represented by ZH) is represented. When the pharmaceutical compound is an antitumor agent, it is preferably a group at a position that reduces or eliminates the antitumor activity.

  Specific examples of -Z include those represented by any of formulas (d1) to (d6):

  For example, the formula (d1) (the pharmaceutical compound represented by ZH is vorinostat), the formula (d3) (the pharmaceutical compound represented by ZH is hydroxytamoxifen) and the formula (d6) (the pharmaceutical compound represented by ZH are: In the case of azacitidine), -Z can be represented as -OD. In other words, examples of the pharmaceutical compound represented by DOH include vorinostat, hydroxytamoxifen, and azacitidine.

For example, in the case of the formula (d2) (the pharmaceutical compound represented by ZH is entinostat), -Z can be represented as -NHD. In other words, an example of a pharmaceutical compound represented by DNH ₂ is entinostat.

For example, in the case of formula (d4) (the pharmaceutical compound represented by ZH is nilutamide) and formula (d5) (the pharmaceutical compound represented by ZH is Tamibarotene), -Z can be represented as -ND ¹ D ^2. . That is, examples of the pharmaceutical compound represented by D ¹ D ² NH include nilutamide and tamibarotene.

In the pharmaceutical compound represented by D ¹ D ² NH, even independent part, each ^{D 1} and ^{D 2} are are attached to the N atom ^one of D 1 ^{D 2} is bonded to N atom at two locations There may be one part.

For example, in the formula (d4), D ¹ D ² refers to one part surrounded by a broken line below.

For example, in the formula (d5), D ¹ and D ² are each one of two parts surrounded by a broken line below.

Other pharmaceutical compounds represented by ZH include camptothecin (type I topoisomerase inhibitor), 5-FU (5-fluorouracil; thymidine synthase inhibitor), mercaptopurine (nucleoside biosynthesis inhibitor), doxorubicin (nucleoside biosynthesis) Synthesis inhibitor), paclitaxel (microtubule depolymerization inhibitor), 5-carboxy-8-hydroxyquinoline (IOX1; histone demethylase inhibitor), EPZ-6438 (histone methyltransferase EZH2 enzyme inhibitor), GSK343 ( Histone methyltransferase EZH2 enzyme inhibitor), GSK126 (histone methyltransferase EZH2 enzyme inhibitor)
3-Deazaneplanocin A (DZNep; histone methyltransferase EZH2 enzyme inhibitor) can also be mentioned.

  Formulas representing the compounds exemplified above are shown below.

  In this case, specific examples of -Z include those represented by any of formulas (d7) to (d15):

  For example, formula (d7) (the pharmaceutical compound represented by ZH is camptothecin), formula (d10) (the pharmaceutical compound represented by ZH is doxorubicin), formula (d11) (the pharmaceutical compound represented by ZH is IOX1 ) And formula (d15) (the pharmaceutical compound represented by ZH is DZNep), -Z can be represented as -OD. In other words, camptothecin, doxorubicin, IOX1, DZNep are also exemplified as examples of the pharmaceutical compound represented by DOH.

  For example, in the case of formula (d9) (the pharmaceutical compound represented by ZH is mercaptopurine), -Z can be represented as -NHD. In other words, an example of a pharmaceutical compound represented by DSH is mercaptopurine.

For example, the formula (d8) (the pharmaceutical compound represented by ZH is 5-FU), the formula (d12) (the pharmaceutical compound represented by ZH is EPZ-6438), the formula (d13) (the pharmaceutical represented by ZH In the case where the compound is GSK343) and formula (d14) (the pharmaceutical compound represented by ZH is GSK126), -Z can be represented as -ND ¹ D ² . That is, examples of the pharmaceutical compound represented by D ¹ D ² NH include 5-FU, EPZ-6438, GSK343, and GSK126.

  Derivatives of pharmaceutical compounds represented by ZH can also be used within the range having physiological activity that can be used as pharmaceuticals.

  For example, as -Z, a compound represented by the following formula (d4 ') can be used instead of the compound represented by the formula (d4).

  Cyanonyltamide has been reported as a derivative of nilutamide having higher activity as a pharmaceutical compound than nilutamide (J. Med. Chem. 2003, 46, 5258-5270).

  -YL- (Y represents O, S, or NH) is a linker group. When q = 1, the compound of the present invention has a linker group.

  As the linker group, various linker groups can be used, but a linker group that can be removed through an elimination reaction is preferable. Linker groups that can be removed via elimination reaction include 1,6-elimination type that can be eliminated via 1,6-elimination reaction, and can be eliminated via 1,4-elimination reaction. 1,6-elimination type, 1,6-elimination reaction and 1,6- / 1-elimination type, which can be eliminated via 1,4-elimination reaction, via lactone formation reaction Detachable lactone formation type, 1,6-elimination reaction and 1,6-elimination-decarboxylation type detachable via carbon dioxide elimination reaction, elimination via formaldehyde elimination reaction Illustrative are linker groups such as possible formaldehyde releasing forms.

  As the 1,6-elimination type linker, for example, those described in the literature: J. Med. Chem. 1981, 24, 479-480 can be used.

  By having a linker group, the reactivity and / or stability of the compound of the present invention can be adjusted.

  Specific examples of the linker group include those represented by any of the following formulas (l1) to (l6):

[Wherein Z is the same as defined above. R represents a substituent. m represents an integer of 0 to 4.
Bonded with NR ² C (═O)-in the # 1 direction and -Z in the # 2 direction. ]
The substituent is preferably a halogen atom, an alkyl group, an alkoxy group, a perfluoroalkyl group or nitro, more preferably a fluorine atom, a chlorine atom, methyl, tert-butyl, methoxy, trifluoromethyl or nitro.

  Among these, (l1) is 1,6-elimination type, (l2) is 1,6 / 1,4-elimination type, (l3) is lactone-forming type, (l4) is 1,4-elimination type (L5) is a specific example of 1,6-desorption-decarboxylation type, and (l6) is a formaldehyde release type.

As a particularly preferred embodiment of the compound of the present invention, the following compounds described in Examples can be exemplified.
(E / Z) -4- (1- (4- (2- (Dimethylamino) ethoxy) phenyl) -2-phenylbut-1-en-1-yl) phenyl (2- (methyl (2-phenylcyclopropyl ) Amino) ethyl) carbamate;
(E / Z) -4- (1- (4- (2- (Dimethylamino) ethoxy) phenyl) -2-phenylbut-1-en-1-yl) phenylmethyl (2- (methyl (2-phenylcyclo Propyl) amino) ethyl) carbamate
N ¹ -{{{[N-methyl-N- (trans-2-phenylcyclopropyl) amino] ethyl} carbamoyl} oxy} -N8-phenyloctanediamide;
N ¹ -((methyl (2- (methyl (2-phenylcyclopropyl) amino) ethyl) carbamoyl) oxy) -N8-phenyloctanediamide;
Pyridin-3-ylmethyl 4-((2- (3- (2- (methyl (2-phenylcyclopropyl) amino) ethyl) ureido) phenyl) carbamoyl) benzylcarbamate;
Pyridin-3-ylmethyl 4-((2- (3-methyl-3- (2- (methyl (2-phenylcyclopropyl) amino) ethyl) ureido) phenyl) carbamoyl) benzylcarbamate;
4-(((2- (methyl (2-phenylcyclopropyl) amino) ethyl) carbamoyl) (5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl) carbamoyl )benzoic acid;
4-((Methyl (2- (methyl (2-phenylcyclopropyl) amino) ethyl) carbamoyl) (5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl) Carbamoyl) benzoic acid;
4-((Methyl (3- (methyl (2-phenylcyclopropyl) amino) propyl) carbamoyl (5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl) carbamoyl )benzoic acid;
4-((Methyl (4- (methyl (2-phenylcyclopropyl) amino) butyl) carbamoyl) (5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl) Carbamoyl) benzoic acid;
4-((((8-oxo-8- (phenylamino) octanamido) oxy) methyl) phenylmethyl (2- (methyl (2-phenylcyclopropyl) amino) ethyl) carbamate;
4-((4-((methyl (2- (methyl (2-phenylcyclopropyl) amino) ethyl) carbamoyl) oxy) benzyl) (5,5,8,8-tetramethyl-5,6,7,8 -Tetrahydronaphthalen-2-yl) carbamoyl) benzoic acid;
4-((3- (4-Cyano-3- (trifluoromethyl) phenyl) -5,5-dimethyl-2,4-dioxoimidazolidin-1-yl) methyl) phenylmethyl (2- (methyl ( 2-Phenylcyclopropyl) amino) ethyl) carbamate.

The following compounds are also mentioned as preferred embodiments of the present invention.
4-((((methyl (2- (methyl (2-phenylcyclopropyl) amino) ethyl) carbamoyl) oxy) methyl) (5,5,8,8-tetramethyll-5,6,7,8- Tetrahydronaphthalen-2-yl) carbamoyl) benzoic acid;
8-((methyl (2- (methyl (2-phenylcyclopropyl) amino) ethyl) carbamoyl) oxy) quinoline-5-carboxylic acid;
((2R, 3S, 4R, 5R) -5- (4-Amino-2-oxo-1,3,5-triazin-1 (2H) -yl) -3,4-dihydroxytetrahydrofuran-2-yl) methyl Methyl (2- (methyl (2-phenylcyclopropyl) amino) ethyl) carbamate;
4-(((((2- (4-((((Pyridin-3-ylmethoxy) carbonyl) amino) methyl) benzamido) phenyl) carbamoyl) oxy) methyl) phenyl methyl (2- (methyl (2-phenylcyclopropyl ) Amino) ethyl) carbamate
3-((5- (Ethyl (tetrahydro-2H-pyran-4-yl) amino) -4-methyl-4 '-(morpholinomethyl)-[1,1'-biphenyl] -3-ylcarboxamido) methyl ) -N, 4,6-trimethyl-N- (2- (methyl (2-phenylcyclopropyl) amino) ethyl) -2-oxopyridine-1 (2H) -carboxamide;
1-isopropyl-N-((6-methyl-1- (methyl (2- (methyl (2-phenylcyclopropyl) amino) ethyl) carbamoyl) -2-oxo-4-propyl-1,2-dihydropyridine-3 -Yl) methyl) -6- (2- (4-methylpiperazin-1-yl) pyridin-4-yl) -1H-indazol-4-carboxamide;
4-((Methyl (2- (methyl (2-phenylcyclopropyl) amino) ethyl) carbamoyl) oxy) benzyl 4- (5- (1-((S) -sec-butyl) -4-((((4 , 6-Dimethyl-2-oxo-1,2-dihydropyridin-3-yl) methyl) carbamoyl) -3-methyl-1H-indol-6-yl) pyridin-2-yl) piperazine-1-carboxylate;
((3R, 4S, 5R) -3- (4-Amino-1H-imidazo [4,5-c] pyridin-1-yl) -4,5-dihydroxycyclopent-1-en-1-yl) methyl Methyl (2- (methyl (2-phenylcyclopropyl) amino) ethyl) carbamate acid.

The pharmaceutically acceptable salt of the compound represented by formula (I) is an acid addition salt or a base salt. Acid addition salts include inorganic salts such as hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, hydrobromic acid, perchloric acid, citric acid, succinic acid, maleic acid, fumaric acid, malic acid, tartaric acid, p-toluenesulfonic acid And salts of organic acids such as benzenesulfonic acid, methanesulfonic acid and trifluoroacetic acid. Examples of the base salt include alkali metal salts such as sodium, potassium and lithium, alkaline earth metal salts such as calcium and magnesium, etc. The compound of the present invention may be a solvate such as a hydrate. The solvent is not particularly limited as long as it is a pharmaceutically acceptable solvent.

When the compound of the present invention has an optical isomer or a geometric isomer (for example, it may be generated depending on the type of substituent), the present invention includes both of them. These isomers can be divided into single isomers or used as a mixture.
[Production method]
The compound represented by the general formula (I) can be synthesized using a known organic synthesis technique. For example, it can be produced by a synthesis method according to the following reaction scheme.

  A moiety to be added to the pharmaceutical compound is synthesized by any of steps 1-1 to 1-3.

[Wherein, Ar, R ¹ (excluding a hydrogen atom), R ² , * 1, * 2 are the same as above. Y ¹ and Y ² represent a halogen atom. ]
Step 1-1 is a reaction according to an alkylation reaction of an amino group.

The halogen atom represented by Y ¹ and Y ² is not particularly limited, and examples thereof include a fluorine atom, a chlorine atom, a bromine atom, and an iodine atom.

  Compound (i) can be produced, for example, by a conventional organic synthesis technique according to or in accordance with a known production method of trans-2-phenylcyclopropylamine (tranylcypromine).

  With respect to 1 mol of compound (i) or compound (iii), compound (ii) or (iv) can be reacted with about 0.1 to 10 mol, preferably about 0.5 to 2 mol of the compound to be reacted.

  The reaction proceeds advantageously in the presence of a base. For example, in the case of a reaction using an alkyl halide, an inorganic base such as an alkali metal or alkaline earth metal hydride such as sodium hydride, potassium hydride or calcium hydride, or an organic base such as triethylamine or diisopropylethylamine is used. Can be used. If necessary, the base can be used in an amount of about 0.1 to an excess amount, preferably about 0.5 to 10 mol.

[In the formula, Ar, R ¹ , R ² , * 1, * 2 are the same as above. ]
Compound (v) can also be synthesized by the reductive amination reaction using the aldehyde or ketone in Step 1-2.

  About 1 to 10 mol, preferably about 0.5 to 2 mol of the compound to be reacted can be reacted with 1 mol of the compound (i).

  The reaction proceeds advantageously in the presence of a reducing agent. In the case of the reductive amination reaction, a reducing agent such as sodium triacetoxyborohydride or sodium cyanoborohydride can be used. If necessary, about 0.1 to excess moles, preferably about 0.5 to 10 moles can be used. The reducing agent can be used in an amount of about 0.1 to excess mole, preferably about 0.5 to 10 mole, if necessary.

  The reaction temperature and reaction time can be appropriately set by those skilled in the art. For example, the reaction temperature can be about 0 to 40 ° C. The reaction time can be about 30 minutes to 24 hours.

  The reaction proceeds advantageously by carrying out the reaction in a suitable solvent. Examples of the solvent include, but are not limited to, organic solvents such as ethyl acetate, N, N-dimethylformamide (DMF), dimethyl sulfoxide (DMSO), 1,4-dioxane, tetrahydrofuran (THF), acetonitrile, and dichloromethane. Is not to be done. The solvent may be either a single solvent or a mixed solvent of two or more solvents.

[Wherein Ar, * 1, * 2 are the same as above. ]
When p = 0, as another embodiment, compound (ix) can be obtained by Michael addition reaction.

  Methyl acrylate (vii) can be reacted with about 0.1 to 10 mol, preferably about 0.5 to 2 mol, with respect to 1 mol of compound (i).

  The reaction temperature and reaction time can be appropriately set by those skilled in the art. For example, the reaction temperature can be about 0 to 40 ° C. The reaction time can be about 30 minutes to 24 hours.

  The reaction proceeds advantageously by carrying out the reaction in a suitable solvent. Examples of the solvent include, but are not limited to, organic solvents such as ethyl acetate, N, N-dimethylformamide (DMF), dimethyl sulfoxide (DMSO), 1,4-dioxane, tetrahydrofuran (THF), acetonitrile, and dichloromethane. Is not to be done. The solvent may be either a single solvent or a mixed solvent of two or more solvents.

[In the formula, Ar, R ¹ , R ² , Z, p, * 1, * 2 are the same as above. ]
When q = 0 and the compound of the present invention does not have a linker group, the compound (v) and the pharmaceutical compound (x) represented by DXH can be reacted to obtain the compound (I-1). .

  Specifically, by reacting the pharmaceutical compound (x) with 4-nitrobenzyl chloroformate in the presence of a base such as pyridine, triethylamine, 4- (dimethylamino) pyridine (DMAP), a chloroformate is obtained. And a reaction of condensation with the compound (ii-1).

  The condensation reaction proceeds advantageously by performing it in the presence of a base such as pyridine, triethylamine, 4- (dimethylamino) pyridine (DMAP), etc. in an amount of 0.1 mol to excess, preferably about 0.5 mol to 10 mol.

  With respect to 1 mol of compound (v), a compound to be reacted with about 0.1 to 10 mol, preferably about 0.5 to 2 mol, of pharmaceutical compound (x) can be reacted.

  The reaction temperature and reaction time can be appropriately set by those skilled in the art. For example, the reaction temperature can be about 0 to 40 ° C. The reaction time can be about 30 minutes to 24 hours.

  The reaction proceeds advantageously by carrying out the reaction in a suitable solvent. Examples of the solvent include, but are not limited to, organic solvents such as ethyl acetate, N, N-dimethylformamide (DMF), dimethyl sulfoxide (DMSO), 1,4-dioxane, tetrahydrofuran (THF), acetonitrile, and dichloromethane. Is not to be done. The solvent may be either a single solvent or a mixed solvent of two or more solvents.

  When q = 1 and the compound of the present invention has a linker group, the linker group is introduced and added to the compound (v) or the pharmaceutical compound (x) by an appropriate method, and then a condensation reaction is performed according to Step 2-1. The compound (I) of the present invention can be obtained.

  In Step 2-1, instead of the pharmaceutical compound (x) represented by DXH, the compound (x-1) represented by D′ XH, which is a part thereof, is used, and then another part D ″ is added. Thus, compound (I) can also be obtained. Specific examples are shown in Examples 5, 9, 11, 13 and the like.

[In the formula, Ar, R ¹ , Z, p, * 1, * 2 are the same as above. ]
As shown in Example 3, the carboxylic acid compound (ix) is reacted with diphenylphosphoric acid azide (DPPA) to obtain the isocyanate compound (xi) via the azide compound; the isocyanate compound is reacted with the pharmaceutical compound (x). To obtain compound (I-1) of the present invention.

  In each step, a functional group such as a hydroxyl group, a carboxyl group, or an amino group that does not participate in the reaction is converted into a tert-butoxycarbonyl group (Boc group), a benzyloxycarbonyl group (Cbz group), a 9-fluorenylmethyloxycarbonyl group ( Fmoc group) and the like can be protected. The reaction for introducing a protecting group and the deprotection reaction can be carried out according to known methods.

[Mechanism of action]
Although not wishing to be bound by theory, the following presumed mechanism of action is described.

  FIG. 1a shows a reaction mechanism in which trans-phenylcyclopropylamine (PCPA) forms an adduct with FAD, which is a coenzyme of LSD1, and irreversibly inhibits LSD1 (Non-patent Document 1). At this time, the nitrogen atom derived from PCPA is released from the enzyme active center as an ammonia molecule.

  While not limiting the present invention, an example of the expected mechanism of action of the compounds of the present invention is shown in FIG. By binding an antitumor agent to a nitrogen atom corresponding to the nitrogen atom of PCPA via a predetermined structure, the compound of the present invention irreversibly inhibits and releases LSD1 that is highly expressed in cancer cells. Are released out of the enzyme active center. The liberated amine compound then causes intramolecular cyclization and releases the antitumor agent.

  Although not limiting the present invention, FIG. 2 shows an example of the mechanism of action by which the compound of the present invention acting on a target related to LSD1 exerts a synergistic antitumor effect.

  FIG. 3 shows an example of a reaction in which the linker group is eliminated by 1,6 elimination reaction when the compound of the present invention has a linker group.

  In the figure, 1) to 6) show examples of linker group elimination via elimination reaction.

2. Pharmaceutical Composition The present invention also provides a pharmaceutical composition (medicine, pharmaceutical preparation) containing the above compound or a salt thereof as an active ingredient.

  The administration target of the pharmaceutical composition of the present invention is not particularly limited. For example, mammals including humans are suitable administration subjects. The race, sex, and age of humans are not particularly limited. Examples of mammals other than humans include pet animals such as dogs and cats.

  In one embodiment of the pharmaceutical composition of the present invention, it is provided as a pharmaceutical composition (antitumor agent, anticancer agent) for treating malignant tumor or cancer. The type of malignant tumor or cancer to be treated is not particularly limited as long as the compound of the present invention exhibits sensitivity. Specifically, solid cancer in stomach, large intestine, lung, liver, prostate, pancreas, esophagus, bladder, gallbladder / bile duct, breast, uterus, thyroid, ovary, etc .; acute myeloid leukemia, acute lymphocytic leukemia, chronic myelogenous Examples include leukemia and leukemia including chronic lymphocytic leukemia. Preferred malignant tumors or cancers include malignant tumors or cancers that highly express LSD1. LSD1 is known to be highly expressed in a part of blood tumors, gliomas, breast cancers, prostate cancers and the like.

  The medical composition of the present invention comprises pharmaceutically acceptable additives such as fillers, extenders, binders, moisturizers, disintegrants, surfactants, lubricants and other commonly used diluents or additives. It is obtained by formulating the compound of the present invention into a general pharmaceutical preparation using a dosage form.

  The route of administration of the pharmaceutical composition according to the present invention is not limited, and the preparation can be administered by a method depending on the form of the preparation, the age and sex of the patient, the state of the disease, and other conditions. For example, tablets, pills, solutions, suspensions, emulsions, granules and capsules are administered orally. Injections are administered intravenously, intramuscularly, intradermally, subcutaneously or intraperitoneally. Suppositories are administered rectally.

  The dosage of the pharmaceutical composition of the present invention is not particularly limited as long as it is an effective amount that exhibits a medicinal effect. In the case of oral administration, it is 0.1 to 1000 mg per day, preferably 0.5 to 50 mg body weight per day in adult humans, and 0.01 to 100 mg per day in the case of parenteral administration. Preferably it is 0.1-10 mg. The above dose is preferably administered once a day or divided into 2 to 3 times a day, and may be appropriately increased or decreased depending on age, disease state, and symptoms.

  The present invention also relates to the use of a compound represented by the general formula (I) or a pharmaceutically acceptable salt thereof for treating the above-mentioned subject to be treated; a compound represented by the general formula (I) or a pharmaceutically acceptable salt thereof A compound represented by the general formula (I) or a pharmaceutically acceptable salt thereof for treating the above-mentioned subject or the like, which will be described later, Also provide.

  EXAMPLES The present invention will be described more specifically with reference to examples and test examples below, but these do not limit the present invention.

<Examples of compound synthesis>
In Examples 1 to 13, the compounds shown below were synthesized. Details are shown below.

[Reverse phase HPLC analysis conditions]
(1) Conditioning solvent for purification A: Distilled water (0.1% trifluoroacetic acid)
Solvent B: Acetonitrile (0.1% trifluoroacetic acid)
Column: COSMOSIL PACKED COLUMN for HPLC (250 mm x 10 mm, Nakarai)
Measurement wavelength: 254 nm
Flow rate: 2.5 mL / min
Gradient (I): 0 min (20% B) -30 min (100% B)
Gradient (II): 0 min (5% B) -30 min (50% B)
(2) Conditions for analysis Solvent A: Distilled water (0.1% trifluoroacetic acid)
Solvent B: Acetonitrile (0.1% trifluoroacetic acid)
Column: COSMOSIL PACKED COLUMN for HPLC (150 mm x 4.6 mm, Nakarai)
Measurement wavelength: 254 nm
Flow rate: 1 mL / min
Gradient (I): 0 min (20% B) -30 min (100% B)
Gradient (II): 0 min (5% B) -30 min (50% B)

  [Example 1 (Scheme 1): Synthesis of PCPA-Tm-a]

Step 1-1: Synthesis of tert-butyl (trans-2-phenylcyclopropyl) carbamate (2)
trans-2-Phenylcyclopropylamine hemisulfate (1) (9.11 g) was dissolved in water, made alkaline with 2N aqueous sodium hydroxide solution, and extracted with diethyl ether. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. After filtration and concentration under reduced pressure, free trans-2-phenylcyclopropylamine was obtained. Free trans-2-phenylcyclopropylamine and triethylamine (7.59 g) were dissolved in dichloromethane (50 mL). Under ice-cooling, di-tert-butyl dicarbonate (16.4 g) dissolved in dichloromethane (25 mL) was added dropwise to the reaction solution, and the reaction solution was stirred at room temperature for 14 hours. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel flash column chromatography (developing solvent n-hexane: ethyl acetate = 7: 1 to 5: 1) to give the title compound (2) (11.2 g, yield 95.7%) Was obtained as a white solid.
¹ H NMR (CDCl ₃ , 300 MHz, δ; ppm) 7.29-7.24 (2H, m), 7.19-7.11 (3H, m), 4.82 (1H, broad s), 2.73 (1H, broad s), 2.07- 2.01 (1H, m), 1.45 (9H, s), 1.24-1.11 (2H, m);
¹³ C NMR (CDCl ₃ , 75 MHz, δ; ppm) 156.27, 140.71, 128.31, 126.46, 126.01, 79.63, 32.46, 28.40, 25.04, 16.40;
MS (ESI) m / z 256 [MNa ⁺ ].

Step 1-2: Synthesis of tert-butyl (trans-2-phenylcyclopropyl) methylcarbamate (3)
Obtained in Step 1-1, dissolved in N, N-dimethylformamide (70 mL) in 60% sodium hydride (2.88 g) suspended in N, N-dimethylformamide (70 mL) under ice-cooling. Compound (2) (11.2 g) was added dropwise. After stirring for 30 minutes under ice cooling, methyl iodide (9.0 mL) dissolved in N, N-dimethylformamide (15 mL) was added dropwise, and the mixture was stirred at room temperature for 10 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The obtained residue was purified by silica gel flash column chromatography (developing solvent n-hexane: ethyl acetate = 8: 1) to give the title compound (3) (11.9 g, yield 100%) as a colorless oil.
¹ H NMR (CDCl ₃ , 300 MHz, δ; ppm) 7.29-7.24 (2H, m), 7.20-7.09 (3H, m), 2.90 (3H, s), 2.73-2.68 (1H, m), 2.14- 2.04 (1H, m), 1.43 (9H, s), 1.32-1.18 (2H, m);
¹³ C NMR (CDCl ₃ , 75 MHz, δ; ppm) 156.78, 141.04, 128.26, 126.17, 125.93, 79.61, 40.02, 34.52, 28.51, 26.15, 17.56;
MS (ESI) m / z 270 [MNa ⁺ ].

Step 1-3: Synthesis of N-methyl-trans-2-phenylcyclopropylamine hydrochloride (4) Compound (3) (11.9 g) obtained in Step 1-2 was dissolved in dichloromethane (380 mL). 4N hydrochloric acid-dioxane solution (120 mL) was added dropwise under ice cooling. After stirring at room temperature for 5 hours, the reaction solution was concentrated under reduced pressure. N-Hexane was added to the residue, and the resulting precipitate was collected by filtration and washed with n-hexane to give the title compound (4) (8.63 g, yield 97.6%) as a light brown solid.
¹ H NMR (CDCl ₃ , 300 MHz, δ; ppm) 9.94 (1H, broad s), 7.32-7.19 (3H, m), 7.13-7.10 (2H, m), 3.04-2.71 (5H, m), 1.87 -1.80 (1H, m), 1.31-1.24 (1H, m);
¹³ C NMR (CDCl ₃ , 75 MHz, δ; ppm) 137.98, 128.82, 127.12, 126.71, 39.60, 33.54, 21.54, 13.23;
MS (ESI) m / z 148 [MH ⁺ ].

Step 1-4: Synthesis of tert-butyl {2- [methyl (2-phenylcyclopropyl) amino] ethyl} carbamate (5) N-methyl-trans-2-obtained in Step 1-3 Phenylcyclopropylamine hydrochloride (4) (492 mg), diisopropylethylamine (1384 μL) and 2- (tert-butoxycarbonylamino) ethyl bromide (900 mg) were dissolved in dehydrated acetonitrile (10 mL) at 60 ° C. Stir for 12 hours. After returning the reaction solution to room temperature, the reaction solution was diluted with ethyl acetate and washed with water and saturated brine. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel flash column chromatography (developing solvent n-hexane: ethyl acetate = 2: 1 to 1: 1) to obtain the title compound (5) (513 mg, yield 65.9%) as a pale yellow oil. .
¹ H NMR (CDCl ₃ , 300 MHz, δ; ppm) 7.28-7.23 (2H, m), 7.18-7.15 (1H, m), 7.06-7.03 (2H, m), 4.84 (1H, broad s) 3.24- 3.22 (2H, m), 2.68-2.63 (2H, m), 2.35 (3H, s), 1.94-1.86 (2H, m), 1.46 (9H, s), 1.09-1.04 (1H, m), 1.02- 0.96 (1H, m);
¹³ C NMR (CDCl ₃ , 75 MHz, δ; ppm) 156.01, 141.87, 128.30, 125.93, 125.67, 79.14, 56.77, 49.29, 42.15, 37.93, 28.46, 25.40, 17.16;
MS (ESI) m / z 291 [MH ⁺ ].

Step 1-5: Synthesis of N ¹ -methyl-N ^1- (2-phenylcyclopropyl) ethane-1,2-diamine (6) tert-Butyl {2- [Methyl (2-phenylcyclopropyl) amino] ethyl} carbamate (5) (502 mg) was dissolved in dichloromethane (17 mL), and 4N hydrochloric acid-ethyl acetate solution (4.33 mL) was added dropwise under ice cooling. The reaction solution was stirred at room temperature for 12 hours and then concentrated under reduced pressure. Water was added to the obtained residue and washed with dichloromethane. The aqueous layer was made alkaline with 2N aqueous sodium hydroxide solution and extracted with dichloromethane. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give the title compound (6) (302 mg, yield 91.8%) as a yellow oil.
¹ H NMR (CDCl ₃ , 300 MHz, δ; ppm) 7.28-7.23 (2H, m), 7.18-7.12 (1H, m), 7.07-7.04 (2H, m), 2.82-2.77 (2H, m), 2.64-2.59 (2H, m), 2.36 (3H, s), 1.99-1.93 (1H, m), 1.90-1.85 (1H, m), 1.34 (2H, broad s), 1.13-1.07 (1H, m) , 1.01-0.95 (1H, m);
¹³ C NMR (CDCl ₃ , 75 MHz, δ; ppm) 142.27, 128.38, 126.04, 125.70, 60.08, 49.74, 42.59, 39.64, 25.63, 17.43;
MS (ESI) m / z 191 [MH ⁺ ].

Step 1-6: Synthesis of 4,4 ′-(2-phenylbut-1-ene-1,1-diyl) diphenol (8) In a nitrogen atmosphere, zinc powder (10.0 g) was added to tetrahydrofuran (80 After adding titanium tetrachloride (7.5 mL) dropwise at −10 ° C., the reaction solution was heated to reflux for 2 hours. The reaction mixture was cooled to 0 ° C., 4,4′-hydroxybenzophenone (7) (2.51 g) and propiophenone (5.03 g) dissolved in tetrahydrofuran (50 mL) were added, and the mixture was heated to reflux for 2 hours in the dark. The reaction solution was returned to room temperature, 10% aqueous potassium carbonate solution was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. After filtration and concentration under reduced pressure, the residue was purified by silica gel flash column chromatography (developing solvent n-hexane: ethyl acetate = 4: 1) to give the title compound (8) (3.29 g, yield 88.7%) as a pale yellow solid. Obtained.
¹ H NMR (DMSO-d ₆ , 300 MHz, δ; ppm) 9.39 (1H, broad s), 9.14 (1H, broad s), 7.19-7.14 (2H, m), 7.10-7.06 (3H, m), 6.98-6.95 (2H, d, m), 6.76-6.72 (2H, m), 6.61-6.57 (2H, m), 6.41-6.36 (2H, m), 2.40 (2H, q, J = 7.3 Hz), 0.836 (3H, t, J = 7.3 Hz);
¹³ C NMR (DMSO-d ₆ , 75 MHz, δ; ppm) 156.02, 155.15, 142.41, 139.35, 138.23, 134.10, 133.84, 131.38, 130.09, 129.40, 127.81, 125.81, 114.90, 114.24, 28.48, 13.45;
MS (ESI) m / z 315 (MH -).

Step 1-7: Synthesis of (E / Z) -4- (1- (4- (2- (dimethylamino) ethoxy) phenyl) -2-phenylbut-1-en-1-yl) phenol (9) < The compound (8) (2.61 g) obtained in step 1-6 was dissolved in N, N-dimethylformamide (16 mL), cesium carbonate (6.45 g) was added, and then at 80 ° C. for 10 minutes. Stir. To the obtained suspension, 2- (dimethylamino) ethyl chloride hydrochloride (4.28 g) was added little by little over 15 minutes, and the mixture was stirred at 80 ° C. for 4.5 hours. Further, 2- (dimethylamino) ethyl chloride hydrochloride (1.43 g) was treated in the same manner as the reaction solution, and stirred at 80 ° C. for 1 hour. After returning the reaction solution to room temperature, a saturated aqueous ammonium chloride solution was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. After filtration and concentration under reduced pressure, the residue was purified by silica gel flash column chromatography (developing solvent: chloroform: methanol = 10: 1) to obtain the title compound (9) (434 mg, yield: 13.6%) as a brown solid.
¹ H NMR (MeOD, 300 MHz, δ; ppm) 7.18-7.08 (6H, m), 7.03 (1H, d, J = 8.6 Hz), 6.93 (1H, J = 8.7 Hz), 6.76 (2H, J = 8.9 Hz), 6.65 (1H, d, J = 8.67 Hz), 6.58 (1H, d, J = 8.82 Hz), 6.40 (1H, d, J = 8.7 Hz), 4.13 (1H, t, J = 5.46 Hz ), 3.97 (1H, t, J = 5.46 Hz), 2.82 (1H, t, J = 5.49 Hz), 2.72 (1H, t, J = 5.46 Hz), 2.53-2.43 (2H, m), 2.38 (3H , s), 2.32 (3H, s), 0.91 (3H, J = 7.38 Hz);
¹³ C NMR (CDCl ₃ , 75 MHz, δ; ppm) 158.81, 157.95, 157.30, 156.40, 144.12, 144.09, 142.11, 141.88, 139.73, 139.69, 138.06, 137.71, 136.31, 135.96, 133.04, 133.01, 131.63, 131.58, 130.90, 130.88, 129.48, 129.39, 128.85, 128.43, 126.96, 115.87, 115.18, 115.11, 114.37, 79.45, 71.55, 66.27, 65.98, 59.03, 58.93, 45.64, 45.56, 30.73, 29.89, 29.84, 13.91, 13.89;
MS (ESI) m / z 388 [MH ⁺ ].

Step 1-8: (E / Z) -4- (1- (4- (2- (dimethylamino) ethoxy) phenyl) -2-phenylbut-1-en-1-yl) phenyl (2- (methyl ( Synthesis of 2-phenylcyclopropyl) amino) ethyl) carbamate (PCPA-Tm-a, Example 1) Compound (9) (82.4 mg) obtained in step 1-7 was dissolved in dichloromethane (2 mL) In an ice bath, pyridine (51.6 μL) and p-nitrophenyl chloroformate (85.8 mg) were added, and the mixture was stirred at room temperature for 24 hours. The reaction solution was diluted with dichloromethane and washed with water, saturated aqueous sodium hydrogen carbonate solution and saturated brine. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resulting residue and triethylamine (88.6 μL) were dissolved in dichloromethane (2 mL), and the compound (6) (48.7 mg) obtained in step 1-5 dissolved in dichloromethane (0.5 mL) was added under ice-cooling. After that, the mixture was stirred at room temperature for 22 hours. The reaction mixture was diluted with dichloromethane and washed with water and saturated brine. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resulting residue was purified by silica gel flash column chromatography (developing solvent chloroform: methanol = 20: 1) and purified by preparative thin layer chromatography (developing solvent chloroform: methanol = 15: 1) to give the title compound (PCPA -Tm-a, Example 1) (87.6 mg, yield 68.4%) was obtained as a pale yellow amorphous.
¹ H NMR (CDCl ₃ , 300 MHz, δ; ppm) 7.29-7.02 (13H, m), 6.90-6.74 (4H, m), 6.55 (1H, J = 9.0 Hz), 5.42 (0.5H, broad s) , 5.29 (0.5H, broad s), 4.10 (1H, t, J = 6.0 Hz), 3.95 (1H, t, J = 6.0 Hz), 3.42-3.23 (3H, m), 2.80-2.65 (4H, m ), 2.53-2.31 (11H, m), 2.01-1.87 (2H, m), 1.15-0.89 (5H, m);
¹³ C NMR (CDCl ₃ , 75 MHz, δ; ppm) 157.56, 156.74, 154.61, 154.45, 149.76, 148.93, 142.39, 142.28, 142.09, 141.69, 140.73, 140.22, 137.61, 137.50, 135.98, 135.51, 131.93, 131.66, 130.66, 130.35, 129.68, 128.35, 127.87, 126.14, 126.03, 125.95, 125.93, 125.76, 121.14, 120.25, 114.15, 113.43, 65.79, 65.54, 58.20, 58.12, 57.22, 56.50, 56.44, 49.32, 49.26, 49.23, 45. 45.69, 42.25, 42.15, 42.08, 38.45, 38.33, 37.86, 29.08, 28.99, 25.50, 25.46, 25.34, 17.20, 17.05, 13.56;
MS (ESI) m / z 604 [MH ⁺ ];
HRMS (FAB) calcd for C ₃₉ H ₄₆ N ₃ O ₃ [MH +] 604.3539, found 604.3535.

  [Example 2 (Scheme 2): Synthesis of PCPA-Tm-b]

Step 2-1: Synthesis of tert-butylmethyl {2- [methyl (2-phenylcyclopropyl) amino] ethyl} carbamate (10) Compound (4) obtained in Step 1-3 of Example 1 (742 mg), triethylamine (1232 μL) and N-Boc- (methylamino) acetaldehyde (769 mg) were added to chloroform (16 mL), and the mixture was stirred at room temperature for 30 minutes. Sodium triacetoxyborohydride (1.28 g) was added to the reaction solution, and the mixture was stirred at room temperature for 3 hours. Saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted with chloroform. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. After filtration and concentration under reduced pressure, the resulting residue was purified by silica gel flash column chromatography (developing solvent n-hexane: ethyl acetate = 1: 1) to give the title compound (10) (1.08 g, yield 87.8%) Obtained as a yellow oil.
¹ H NMR (CDCl ₃ , 300 MHz, δ; ppm) 7.27-7.22 (2H, m), 7.18-7.12 (1H, m), 7.06-7.03 (2H, m), 3.32 (2H, broad s), 2.86 (3H, s), 2.72-2.67 (2H, m), 2.41 (3H, s), 1.95-1.89 (2H, m), 1.43 (9H, s), 1.11-1.05 (1H, m), 1.00-0.94 (1H, m);
¹³ C NMR (CDCl ₃ , 75 MHz, δ; ppm) 155.73, 142.04, 128.31, 125.99, 125.65, 79.26,77.59, 77.16, 76.74, 55.42, 49.39, 47.10, 42.40, 34.71, 28.50, 25.72, 17.56;
MS (ESI) m / z 305 [MH ⁺ ].

Step 2-2: N ^1, N ² - dimethyl -N ¹ - obtained in Synthesis <br/> step 2-1 (2-phenyl-cyclopropyl) ethane-1,2-diamine dihydrochloride (11) Compound (10) (1.08 g) was dissolved in dichloromethane (35 mL), and 4N hydrochloric acid-ethyl acetate solution (9.0 mL) was added dropwise under ice cooling. The reaction mixture was stirred at room temperature for 5 hours, and the obtained precipitate was collected by filtration and washed with dichloromethane to give the title compound (11) (848 mg, yield 86.2%) as a white solid.
¹ H NMR (MeOD, 300 MHz, δ; ppm) 7.36-7.19 (5H, m), 3.71-3.50 (2H, m), 3.22-3.18 (2H, m), 3.09 (3H, s), 2.80 (4H , m), 1.85-1.78 (1H, m), 1.53-1.46 (1H, m);
¹³ C NMR (MeOD, 75 MHz, δ; ppm) 138.65, 129.85, 128.23, 127.45, 53.62, 48.79, 44.50, 42.33, 33.99, 23.54, 14.72;
MS (ESI) m / z 205 [MH ⁺ ].

Step 2-3: (E / Z) -4- (1- (4- (2- (dimethylamino) ethoxy) phenyl) -2-phenylbut-1-en-1-yl) phenylmethyl (2- (methyl Synthesis of (2-phenylcyclopropyl) amino) ethyl) carbamate (PCPA-Tm-b, Example 2) In a manner similar to Example 1 Steps 1-8, Step 1 of Example 1 From the compound (9) (98.6 mg) obtained in 7 and the compound (11) (84.6 mg) obtained in Step 2-2 of Example 2, the title compound (PCPA-Tm-b, Example 2) (93.3 mg, yield 59.4%) was obtained as a pale yellow amorphous.
¹ H NMR (CDCl ₃ , 300 MHz, δ; ppm) 7.22-7.00 (13H, m), 6.90-6.69 (4H, m), 6.55 (1H, J = 9.0 Hz), 4.11 (1H, t, J = 6.0 Hz), 3.95 (1H, t, J = 6.0 Hz), 3.57-3.42 (2H, m), 3.11-2.95 (3H, m), 2.89-2.67 (4H, m), 2.53-2.32 (11H, m ), 2.04-1.94 (2H, m), 1.14-0.88 (5H, m);
¹³ C NMR (CDCl ₃ , 75 MHz, δ; ppm) 157.53, 156.71, 154.74, 154.60, 150.13, 149.30, 142.40, 142.31, 141.99, 141.84, 141.64, 140.69, 140.14, 137.63, 137.53, 136.07, 135.54, 131.95, 131.63, 130.68, 130.31, 129.69, 128.30, 128.28, 127.91, 127.87, 126.14, 126.00, 125.98, 125.64, 121.25, 120.39, 114.14, 113.42, 65.75, 65.50, 58.17, 58.09, 55.54, 54.72, 49.31, 47.70 45.65, 42.29, 35.23, 35.02, 29.12, 29.00, 25.72, 25.60, 17.50, 13.56;
MS (ESI) m / z 618 [MH ⁺ ]. HRMS (FAB) calcd for C ₄₀ H ₄₈ N ₃ O ₃ [MH +] 618.3696, found 618.3691.

  [Example 3 (Scheme 3): Synthesis of PCPA-SAHA-a]

Step 3-1: Synthesis of methyl 3- [N-methyl-N- (trans-2-phenylcyclopropyl) amino] propanoate (12) The compound obtained in Step 1-3 of Example 1 ( 4) (792 mg) was dissolved in water, made alkaline with 1N aqueous sodium hydroxide solution, and extracted with diethyl ether. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. After filtration and concentration under reduced pressure, a mixture of the obtained residue and methyl acrylate (466 μL) was stirred at room temperature for 4 days. The reaction mixture was concentrated under reduced pressure, and the obtained residue was purified by silica gel flash column chromatography (developing solvent hexane: ethyl acetate = 2: 1) to give the title compound (12) (960 mg, yield 95.4%) as pale yellow Obtained as an oil.
¹ H NMR (CDCl ₃ , 300 MHz, δ; ppm) 7.28-7.22 (2H, m), 7.18-7.12 (1H, m), 7.07-7.04 (2H, m), 3.66 (3H, s), 2.93- 2.83 (2H, m), 2.55-2.50 (2H, m), 2.38 (3H, s), 1.98-1.92 (1H, m), 1.88-1.83 (1H, m), 1.12-1.06 (1H, m), 1.00-0.94 (1H, m);
¹³ C NMR (CDCl ₃ , 75 MHz, δ; ppm) 173.02, 142.00, 128.28, 125.94, 125.62, 53.18, 51.55, 48.78, 42.42, 32.59, 25.49, 17.21;
MS (ESI) m / z 234 [MH ⁺ ].

Step 3-2: Synthesis of [N-methyl-N- (trans-2-phenylcyclopropyl) amino] propionic acid (13) Compound obtained in Step 3-1 (12) (941 mg) Water (50 mL) was added to and stirred at 70 ° C. for 24 hours. The reaction mixture was concentrated under reduced pressure, and the obtained residue was purified by silica gel flash column chromatography (developing solvent: chloroform: methanol = 5: 1) to give the title compound (13) (387 mg, yield 43.8%) as pale yellow Obtained as an oil.
¹ H NMR (CDCl ₃ , 300 MHz, δ; ppm) 7.31-7.15 (3H, m), 7.07-7.04 (2H, m), 3.00-2.95 (2H, m), 2.58-2.53 (5H, m), 2.23-2.10 (2H, m), 1.32-1.25 (1H, m), 1.18-1.11 (1H, m);
¹³ C NMR (CDCl ₃ , 75 MHz, δ; ppm) 173.34, 140.19, 128.57, 126.35, 125.97, 53.17, 48.56, 41.25, 30.59, 24.57, 16.17;
MS (ESI) m / z 220 [MH ⁺ ].

Step 3-3: N ¹ -{{{[N-methyl-N- (trans-2-phenylcyclopropyl) amino] ethyl} carbamoyl} oxy} -N ⁸ -phenyloctanediamide (PCPA-SAHA-a, carried out) Example 3) Synthesis of Compound (13) (220 mg) obtained in Step 3-1 was dissolved in toluene (5 mL), and triethylamine (166 uL), diphenylphosphoric acid azide ( 260 μL) was added. The reaction solution was stirred at room temperature for 30 minutes and then heated to reflux for 1 hour. The reaction solution was returned to room temperature, and SAHA (317 mg) dissolved in triethylamine (166 μL) and N, N-dimethylformamide (2 mL) was added under ice cooling, and the reaction solution was stirred at room temperature for 14 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine. After drying over anhydrous sodium sulfate, filtration and concentration under reduced pressure were performed. The obtained residue was purified by silica gel flash column chromatography (developing solvent: chloroform: methanol = 20: 1) to give the title compound (PCPA-SAHA-a, Example 3) (224 mg, yield 46.5%) as a white solid Got as. Further purification was performed by RP-HPLC (Gradient (I)) to obtain the title compound (PCPA-SAHA-a, Example 3) (22.8 mg) as a white solid.
mp 119-122 ° C;
¹ H NMR (MeOD 300 MHz, δ; ppm) 7.54-7.51 (2H, m), 7.30-7.18 (4H, m), 7.13-7.04 (4H, m), 2.73 (2H, t, J = 6 Hz) , 2.40 (3H, s), 2.36 (2H, t, J = 9 Hz), 2.20 (2H, t, J = 9 Hz), 2.00-1.94 (1H, m), 1.91-1.86 (1H, m), 1.76-1.58 (4H, m), 1.48-1.33 (4H, m), 1.12-1.05 (1H, m), 1.03-0.97 (1H, m);
¹³ C NMR (MeOD, 75 MHz, δ; ppm) 174.65, 173.41, 157.32, 142.96, 139.90, 129.75, 129.30, 126.93, 126.70, 125.11, 121.32, 57.84, 50.22, 42.85, 39.97, 37.81, 33.53, 29.83, 29.71 , 26.68, 26.29, 26.09, 17.28;
MS (ESI) m / z 481 [MH ⁺ ];
HRMS (FAB) calcd for C ₂₇ H ₃₇ N ₄ O ₄ [MH +] 481.2815, found 481.2811;
HPLC t _R = 11.98 min (Gradient (I), purity 99.6%).

  [Example 4 (Scheme 4): Synthesis of PCPA-SAHA-b]

Step 4-1: N ¹ -((Methyl (2- (methyl (2-phenylcyclopropyl) amino) ethyl) carbamoyl) oxy) -N ⁸ -phenyloctanediamide (PCPA-SAHA-b, Example 4) Composition
SAHA (50.0 mg) was suspended in acetonitrile (1.5 mL), the reaction mixture was cooled to 10 ° C., carbonyldiimidazole (33.7 mg) was added, and the mixture was stirred for 20 min. Next, the compound (11) (57.7 mg) and diisopropylethylamine (78 μL) were added to the reaction solution, and the mixture was stirred at room temperature for 12 hours. The reaction mixture was diluted with ethyl acetate, washed with water and saturated brine, and dried over anhydrous sodium sulfate. After filtration and concentration under reduced pressure, the obtained residue was purified by silica gel flash column chromatography (developing solvent n-hexane: ethyl acetate = 3: 2) to give the title compound (PCPA-SAHA-b, Example 4) (77.4 mg , Yield 82.7%) was obtained as a pale yellow solid. The obtained white solid was recrystallized from ethyl acetate to give the title compound (PCPA-SAHA-b, Example 4) (32.7 mg) as a white solid.
mp 97-98 ℃;
¹ H NMR (CDCl ₃ , 300 MHz, δ; ppm) 9.07 (0.5 H, broad s), 8.99 (0.5 H, broad s), 7.76 (1H, broad s), 7.54 (2H, d, J = 9 Hz ), 7.32-7.22 (4H, m), 7.17-7.02 (4H, m), 3.47-3.39 (2H, m), 3.00 (1.5H, s), 2.95 (1.5 H, s), 2.84-2.71 (2.03 ), 2.40 (1.5H, s), 2.37 (1.5H, s), 2.33 (2H, t, J = 6 Hz), 2.23 (2H, t, J = 6 Hz), 1.95-1.90 (2H, m) , 1.75-1.66 (4H, m), 1.40-1.38 (4H, m), 1.07-1.03 (1H, m), 0.98-0.94 (1H, m);
¹³ C NMR (CDCl ₃ , 75 MHz, δ; ppm) 172.05, 171.68, 155.18, 141.83, 138.23, 128.92, 128.28, 125.98, 125.67, 124.03, 119.80, 55.25, 54.60, 49.28, 48.03, 47.02, 42.26, 37.10, 36.04, 34.50, 32.62, 28.15, 27.99, 25.58, 25.08, 24.60, 17.49;
MS (ESI) m / z 495 [MH ⁺ ]; Anal. Calcd. For C ₂₈ H ₃₈ N ₄ O ₄ : C, 67.99; H, 7.74; N, 11.33. Found: C, 67.77; H, 7.48; N , 11.36.

  [Example 5 (Scheme 5): Synthesis of PCPA-MS-275-a]

Step 5-1: Synthesis of 4-(((((pyridin-3-ylmethoxy) carbonyl) amino) methyl) benzoic acid (16) Carbonyldiimidazole (4.05 g) was dissolved in tetrahydrofuran (19 mL). Under ice cooling, 3-pyridinemethanol (14) (2.73 g) dissolved in tetrahydrofuran (8 mL) was added dropwise. After stirring the reaction solution at room temperature for 1 hour, under cooling with ice, 4- (aminoethyl) benzoic acid (15) (3.78 g) suspended in tetrahydrofuran (40 mL), diazabicycloundecene ( 3.81 g) and triethylamine (2.53 g) were added dropwise, and the mixture was stirred at room temperature for 6 hours. The reaction mixture was concentrated under reduced pressure, and the residue was dissolved in water and adjusted to pH 5 with 1N aqueous hydrochloric acid. The resulting precipitate was collected by filtration and washed with water (50 mL) and methanol (10 mL) to give the title compound (16) (4.16 g, yield 58.1%) as a white solid.
¹ H NMR (DMSO-d ₆ , 300 MHz, δ; ppm) 8.61-8.53 (2H, m), 7.96-7.88 (3H, m), 7.84-7.77 (1H, m) 7.44-7.34 (3H, m) , 5.09 (2H, s), 4.27 (2H, J = 6 Hz);
¹³ C NMR (DMSO-d ₆ , 75 MHz, δ; ppm) 167.14, 156.24, 149.07, 144.68, 135.69, 132.63, 129.44, 129.35, 126.96, 123.48, 63.26, 43.65;
MS (ESI) m / z 287 [MH ⁺ ].

Step 5-2: Synthesis of pyridin-3-ylmethyl 4- (chlorocarbonyl) benzylcarbamate hydrochloride (17) Compound (16) (23.0 mg) obtained in Step 5-1 was added to dichloromethane (1 mL). ), And oxalyl chloride (20.7 μL) and N, N-dimethylformamide (1 drop) were added under ice cooling, followed by stirring at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure to give the title compound (17) as a crude product.

Step 5-3-1: Synthesis of 1- (2- (methyl (2-phenylcyclopropyl) amino) ethyl) -3- (2-nitrophenyl) urea (19a)
Dissolve o-nitroaniline (18) (156 mg) and pyridine (274 μL) in dichloromethane (10 mL), add p-nitrophenyl chloroformate (456 mg) under ice cooling, and stir at room temperature for 2 hours. did. The reaction mixture was diluted with dichloromethane and washed with 1N aqueous hydrochloric acid solution, saturated aqueous sodium hydrogen carbonate solution and saturated brine. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The obtained residue was dissolved in dichloromethane (10 mL). Under ice-cooling, triethylamine (189 μL) and compound (4) (259 mg) dissolved in dichloromethane (4 mL) were added, and the mixture was stirred at room temperature for 24 hours. did. The reaction mixture was diluted with dichloromethane and washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resulting residue was purified by silica gel flash column chromatography (developing solvent: chloroform: methanol = 100: 0 to 50: 1) to give the title compound (19a) (211 mg, yield 52.8%) as a pale yellow amorphous product. It was.
¹ H NMR (CDCl ₃ , 300 MHz, δ; ppm) 9.75 (1H, broad s), 8.67 (1H, dd, J = 1.2, 8.7 Hz), 8.18 (1H, dd, J = 1.5, 8.4 Hz), 7.62-7.56 (1H, m), 7.28-7.22 (2H, m), 7.18-7.12 (1H, m), 7.07-7.02 (3H, m), 5.26 (1H, broad s), 3.45-3.40 (2H, m), 2.83-2.71 (2H, m), 2.40 (3H, s), 2.01-1.89 (2H, m), 1.15-1.08 (1H, m), 1.05-0.99 (1H, m);
¹³ C NMR (CDCl ₃ , 75 MHz, δ; ppm) 154.05, 141.65, 137.14, 135.90, 135.56, 128.36, 125.96, 125.78, 125.72, 121.48, 121.32, 56.48, 49.25, 42.24, 37.82, 25.39, 17.12;
MS (ESI) m / z 355 [MH ⁺ ].

Step 5-4-1: Synthesis of 1- (2-aminophenyl) -3- {2- [methyl (2-phenylcyclopropyl) amino] ethyl} urea (20a) Step 5-3-1 The compound (19a) (206 mg) obtained in 1 above was dissolved in methanol (5 mL), and ammonium chloride (310 mg) and zinc powder (192 mg) were added. After stirring the reaction solution at room temperature for 7.5 hours, the reaction solution was diluted with methanol and filtered through celite. The filtrate was concentrated under reduced pressure, and the residue was dissolved in ethyl acetate and washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The obtained residue was purified by silica gel flash column chromatography (developing solvent: chloroform: methanol = 30: 1) to obtain the title compound (20a) (85.0 mg, yield 45.0%) as a pale yellow amorphous.
¹ H NMR (CDCl ₃ , 300 MHz, δ; ppm) 7.26-7.22 (2H, m), 7.17-7.08 (3H, m), 7.01-6.98 (2H, m), 6.80-6.74 (2H, m), 6.08 (1H, broad s), 5.15 (1H, broad s), 3.32-3.27 (2H, m), 2.66-2.59 (2H, m), 2.28 (3H, s), 1.88-1.83 (1H, m), 1.73-1.68 (1H, m), 0.92-0.83 (2H, m);
¹³ C NMR (CDCl ₃ , 75 MHz, δ; ppm) 157.67, 142.88, 141.84, 128.33, 127.72, 127.64, 125.96, 125.71, 123.48, 118.89, 116.62, 56.83, 49.24, 41.87, 37.61, 25.38, 17.16;
MS (ESI) m / z 325 [MH ⁺ ].

Step 5-5-1: Pyridin-3-ylmethyl 4-((2- (3- (2- (methyl (2-phenylcyclopropyl) amino) ethyl) ureido) phenyl) carbamoyl) benzylcarbamate ditrifluoroacetate ( Synthesis of PCPA-MS275-a, Example 5) Compound (20a) (21.6 mg) obtained in step 5-4-1 and triethylamine (27.7 μL) were dissolved in dichloromethane (1 mL). Under ice-cooling, the compound (17) obtained in Step 5-2 dissolved in dichloromethane (0.5 mL) was added, and the mixture was stirred at room temperature for 3 hours. The reaction mixture was diluted with dichloromethane and washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The obtained residue was purified by silica gel flash column chromatography (developing solvent chloroform: methanol = 15: 1) and further purified by reverse phase HPLC (Gradient (II)) to give the title compound (PCPA-MS275-a, Example 5) (34.2 mg, yield 62.6%) was obtained as a pale yellow amorphous.
¹ H NMR (MeOD, 300 MHz, δ; ppm) 8.82 (1H, s), 8.74 (1H, d, J = 5.4 Hz), 8.45 (1H, d, J = 7.8 Hz), 7.96-7.92 (3H, m), 7.57 (1H, dd, J = 1.5, 7.8 Hz), 7.49-7.42 (3H, m), 7.33-7.15 (8H, m), 5.30 (2H, s), 4.38 (2H, s), 3.63 -3.59 (2H, m), 3.51-3.47 (2H, m), 3.15-3.10 (1H, m), 3.07 (3H, s), 2.64-2.57 (1H, m), 1.63-1.56 (1H, m) , 1.47-1.400 (1H, m);
¹³ C NMR (MeOD, 75 MHz, δ; ppm) 157.38, 143.09, 141.79, 128.29, 128.05, 127.93, 125.91, 125.68, 123.12, 118.95, 116.53, 56.67, 49.20, 41.69, 37.54, 25.43, 17.18;
MS (ESI) m / z 593 [MH ⁺ ];
HRMS (FAB) calcd for C ₃₄ H ₃₇ N ₆ O ₄ [MH ⁺ ] 593.2876, found 593.2872;
HPLC t _R = 20.3 min (Gradient (II), purity 98.8%).

[Example 6 (Scheme 5): Synthesis of PCPA-MS275-b]
Step 5-3-2: Synthesis of 1-methyl-1- (2- (methyl (2-phenylcyclopropyl) amino) ethyl) -3- (2-nitrophenyl) urea (19b) Examples Using the same method as in Step 5-3-1 in Step 5, from the o-nitroaniline (18) (56.5 mg) and the compound (11) (136 mg, 0.491 mmol) to the title compound (19b) (145 mg, (96% yield) was obtained as a pale yellow amorphous.
¹ H NMR (CDCl ₃ , 300 MHz, δ; ppm) 10.1 (1H, broad s), 8.60 (1H, d, J = 8.1 Hz), 8.18 (1H, dd, J = 1.5, 8.7 Hz), 7.61- 7.56 (1H, m), 7.28-7.02 (6H, m), 3.64-3.47 (2H, m), 3.10 (3H, s), 2.88-2.79 (2H, m), 2.47 (3H, s), 2.04- 1.94 (2H, m), 1.14-1.08 (1H, m), 1.02-0.98 (1H, m);
¹³ C NMR (CDCl ₃ , 75 MHz, δ; ppm) 154.58, 141.85, 137.37, 135.90, 135.78, 128.28, 125.95, 125.67, 125.65, 121.86, 121.33, 55.41, 49.51, 47.66, 42.54, 35.08, 25.61, 17.61;
MS (ESI) m / z 369 [MH ⁺ ].

Step 5-4-2: Synthesis of 3- (2-aminophenyl) -1-methyl-1- (2- (methyl (2-phenylcyclopropyl) amino) ethyl) urea (20b) Example Using the same method as in Step 5-4-1 in Step 5, from the compound (19b) (144 mg) obtained in Step 5-3-2 to the title compound (20b) (58.5 mg, yield 44.3%) Was obtained as an orange amorphous.
¹ H NMR (CDCl ₃ , 300 MHz, δ; ppm) 7.28-7.13 (3H, m), 7.06-6.93 (4H, m), 6.79-6.73 (2H, m), 3.47-3.43 (2H, m), 3.01 (3H, s), 2.88-2.85 (2H, m), 2.50 (3H, s), 2.10-2.01 (2H, m), 1.22-1.16 (1H, m), 1.07-1.01 (1H, m);
¹³ C NMR (CDCl ₃ , 75 MHz, δ; ppm) 157.55, 141.41, 141.06, 128.44, 126.52, 126.10, 125.96, 125.79, 124.58, 119.35, 118.03, 57.87, 50.21, 49.17, 42.80, 35.51, 25.51, 17.41;
MS (ESI) m / z 339 [MH ⁺ ].

Step 5-5-2: Pyridin-3-ylmethyl 4-((2- (3-methyl-3- (2- (methyl (2-phenylcyclopropyl) amino) ethyl) ureido) phenyl) carbamoyl) benzylcarbamate ditri Synthesis of fluoroacetate (PCPA-MS275-b, Example 6) Compound obtained in Step 5-4-2 using the same method as in Step 5-5-1 of Example 5 The title compound (PCPA-MS275-b, Example 6) (76.4 mg, yield 55.8%) was obtained as a pale yellow amorphous product from (20b) (55.4 mg).
¹ H NMR (MeOD, 300 MHz, δ; ppm) 8.98 (1H, broad s), 8.82 (1H, broad s), 8.59 (1H, d, J = 8.4 Hz), 8.08-8.04 (1H, m), 7.93 (2H, d, J = 8.1 Hz), 7.53-7.43 (4H, m), 7.32-7.14 (7H, m), 5.33 (2H, s), 4.38 (2H, s), 3.87-3.71 (2H, m), 3.54-3.49 (2H, m), 3.16-3.10 (1H, m), 3.06 (3H, s), 3.03 (3H, s), 2.67-2.60 (1H, m), 1.66-1.59 (1H, m), 1.44-1.37 (1H, m);
¹³ C NMR (MeOD, 75 MHz, δ; ppm) 1685.51, 161.98, 159.23, 158.85, 158.68, 158.01, 146.27, 145.05, 142.08, 138.84, 134.13, 133.80, 132.57, 129.79, 129.00, 128.56, 128.15, 127.55, 127.42 , 127.36, 126.83, 126.65, 117.90, 114.13, 63.56, 56.43, 45.39, 45.24, 42.34, 35.54, 23.35, 14.46;
MS (ESI) m / z 607 [MH ⁺ ];
HRMS (FAB) calcd for C ₃₅ H ₃₉ N ₆ O ₄ [MH ⁺ ] 607.3033, found 607.3039;
HPLC t _R = 20.6 min (Gradient (II), purity 97.4%).

  [Example 7 (Scheme 6): Synthesis of PCPA-Am80-a]

Step 6-1: Synthesis of 2,5-dichloro-2,5-dimethylhexane (22)
2,5-dimethyl-2,5-hexanediol (21) (7.31 g) was added to concentrated hydrochloric acid (100 mL), and the mixture was vigorously stirred at room temperature for 30 minutes. The resulting precipitate was collected by filtration, washed with water, and dissolved in dichloromethane. After washing with water and saturated brine, the organic layer was dried over anhydrous sodium sulfate. Filtration and concentration under reduced pressure gave the title compound (22) (7.93 g, yield 86.7%) as a white solid.
¹ H NMR (CDCl ₃ , 300 MHz, δ; ppm) 1.95 (4H, s), 1.60 (12H, s);
¹³ C NMR (CDCl ₃ , 75 MHz, δ; ppm) 70.44, 41.34, 32.69;
MS (ESI) not detected.

Step 6-2: Synthesis of N- (5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl) acetamide (23) Acetanilide (2.70 g) After dissolving in dichloromethane (20 mL) and cooling to −20 ° C., aluminum chloride (5.33 g) and the compound (22) (7.32 g) obtained in step 6-1 were added and stirred for 4 hours. Ice water was added to the reaction mixture, and the mixture was extracted with dichloromethane. The organic layer was washed with water and saturated brine, and then dried over anhydrous sodium sulfate. After filtration and concentration under reduced pressure, the resulting residue was purified by silica gel flash column chromatography (developing solvent n-hexane: ethyl acetate = 2: 1) to give the title compound (23) as a pale yellow solid (3.44 g, yield). 70.2%). The product was recrystallized from ethanol and water to give the title compound (23) (2.65 g) as a white solid.
¹ H NMR (CDCl ₃ , 300 MHz, δ; ppm) 7.35-7.22 (3H, m), 7.15 (1H, br), 2.14 (3H, s), 1.67 (4H, s), 1.26 (6H, s) , 1.25 (6H, s);
¹³ C NMR (CDCl ₃ , 75 MHz, δ; ppm) 168.11, 145.67, 141.17, 135.32, 127.14, 118.00, 117.90, 35.09, 34.39, 33.96, 31.85, 31.81, 31.37, 24.53;
MS (ESI) m / z 246 [MH ⁺ ].

Step 6-3: Synthesis of 5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-amine (24) Compound obtained in Step 6-2 (23) (2.50 g) was added to 6N aqueous hydrochloric acid (50 mL), and the mixture was stirred at 100 ° C. for 10.5 hours. After returning to room temperature, the reaction mixture was made alkaline with 6N aqueous sodium hydroxide solution under ice cooling and extracted with diethyl ether. The organic layer was separated, washed with saturated brine, and dried over anhydrous sodium sulfate. After filtration and concentration under reduced pressure, the resulting residue was purified by silica gel flash column chromatography (developing solvent n-hexane: ethyl acetate = 4: 1) to give the title compound (24) (1.45 g, 70% yield) Obtained as a brown solid.
¹ H NMR (CDCl ₃ , 300 MHz, δ; ppm) 7.10 (1H, d, J = 9 Hz), 6.63 (1H, d, J = 3 Hz), 6.51 (1H, dd, J = 3, 9 Hz) ), 3.48 (2H, br), 1.64 (4H, s), 1.25 (6H, s), 1.23 (6H, s);
¹³ C NMR (CDCl ₃ , 75 MHz, δ; ppm) 145.85, 143.72, 135.37, 127.38, 113.62, 112.86, 35.32, 34.22, 33.55, 32.02, 31.83;
MS (ESI) m / z 204 [MH ⁺ ].

Step 6-4: Synthesis of 4- (tert-butoxycarbonyl) benzoic acid (26) Terephthalic acid (25) (1.66 g), di-tert-butyl dicarbonate (2.18 g), 4-dimethylamino Pyridine (305 mg) was added to a mixed solution of t-butanol (15 mL) / tetrahydrofuran (5 mL) and heated under reflux for 24 hours. After returning to room temperature, the reaction mixture was concentrated under reduced pressure, and the resulting residue was purified by silica gel flash column chromatography (developing solvent: chloroform: methanol = 20: 1) to give the title compound (26) (371 mg, yield 16.7). %) As a white solid.
¹ H NMR (CDCl ₃ , 300 MHz, δ; ppm) 8.16 (2H, d, J = 9 Hz), 8.08 (2H, d, J = 9 Hz), 1.62 (9H, s);
¹³ C NMR (CDCl ₃ , 75 MHz, δ; ppm) 171.23, 164.83, 136.71, 132.65, 130.07, 129.50, 81.93, 28.17;
MS (ESI) not detected.

Step 6-5: Synthesis of tert-butyl 4- (chlorocarbonyl) benzoate (27) The compound (26) (96.0 mg) obtained in Step 6-4 was dissolved in dichloromethane (4.5 mL). Under ice-cooling, oxalyl chloride (185 μL) and N, N-dimethylformamide (3 drops) were added, and the mixture was stirred at room temperature for 4 hours. The reaction mixture was concentrated under reduced pressure, toluene (1 mL) was added to the resulting residue, and azeotroped to give the title compound (27).

Step 6-6: 1- (2- (methyl (2-phenylcyclopropyl) amino) ethyl) -3- (5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalene-2 Synthesis of (-yl) urea (28) The compound (13) (359 mg) obtained in Step 3-2 of Example 3 was dissolved in toluene (6 mL), and triethylamine (273 μL was added under ice cooling. ), Diphenyl phosphate azide (425 μL) was added. The reaction was stirred at room temperature for 30 minutes and then heated to reflux for 1 hour. After returning the reaction solution to room temperature, the compound (24) (401 mg) obtained in Step 6-3 dissolved in toluene (3 mL) was added to the reaction solution under ice cooling, followed by stirring at room temperature for 2 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The obtained residue was purified by silica gel flash column chromatography (developing solvent: chloroform: methanol = 50: 1) to obtain a crude product (208 mg) as a yellow amorphous. Hexane was added to the obtained crude product and cooled to 4 ° C., and then the resulting precipitate was collected by filtration to give the title compound (28) (178 mg, yield 25.9%) as a white solid.
¹ H NMR (CDCl ₃ , 300 MHz, δ; ppm) 7.27-6.99 (8H, m), 6.74 (1H, br), 5.20 (1H, t, J = 3 Hz), 3.37-3.32 (2H, m) , 2.77-2.63 (2H, m), 2.35 (3H, s), 1.92-1.80 (2H, m), 1.67 (4H, s), 1.27 (6H, s), 1.26 (6H, s), 0.99-0.94 (2H, m);
¹³ C NMR (CDCl ₃ , 75 MHz, δ; ppm) 156.58, 146.09, 141.59, 141.10, 135.90, 128.36, 127.47, 125.96, 125.79, 119.98, 119.81, 57.36, 49.40, 42.06, 37.91, 35.10, 34.39, 33.94, 31.87, 31.86, 25.40, 17.11;
MS (ESI) m / z 420 [MH ⁺ ].

Step 6-7: tert-butyl 4-(((2- (methyl (2-phenylcyclopropyl) amino) ethyl) carbamoyl) (5,5,8,8-tetramethyl-5,6,7,8- Synthesis of tetrahydronaphthalen-2-yl) carbamoyl) benzoate (29) Compound (28) (145 mg) obtained in step 6-6, triethylamine (57.5 μL) was dissolved in dichloromethane (8 mL). Under ice-cooling, compound (27) dissolved in dichloromethane (4 mL) was added and stirred for 30 minutes. Further, the reaction solution was returned to room temperature and stirred for 20 hours. The reaction mixture was diluted with dichloromethane and washed with saturated aqueous sodium hydrogencarbonate solution and saturated brine. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The obtained residue was purified by silica gel flash column chromatography (developing solvent n-hexane: ethyl acetate = 2: 1) to give the title compound (29) (50 mg, yield 23%) as a colorless amorphous.
¹ H NMR (CDCl ₃ , 300 MHz, δ; ppm) 8.87 (1H, t, J = 3 Hz), 7.75 (2H, d, J = 9 Hz), 7.28-7.13 (6H, m), 7.08-7.06 (2H, m), 6.96 (1H, dd, J = 3, 9 Hz), 6.85 (1H, d, J = 3 Hz), 3.52-3.47 (2H, m), 2.88-2.73 (2H, m), 2.42 (3H, s), 2.07-2.00 (1H, m), 1.97-1.93 (1H, m), 1.56 (4H, s), 1.56 (4H, s), 1.55 (9H, s), 1.18 (6H, s), 1.01 (7H, m), 095-0.80 (1H, m);
¹³ C NMR (CDCl ₃ , 75 MHz, δ; ppm) 172.83, 164.82, 154.51, 145.52, 144.88, 141.99, 140.18, 135.67, 132.87, 128.63, 128.29, 128.10, 127.52, 127.06, 126.77, 125.99, 125.63, 81.45, 56.31, 49.30, 42.19, 38.93, 34.82, 34.71, 34.11, 34.06, 31.70, 31.45, 29.71, 28.12, 25.51, 17.39;
MS (ESI) m / z 624 [MH ⁺ ].

Step 6-8: 4-(((2- (methyl (2-phenylcyclopropyl) amino) ethyl) carbamoyl) (5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalene- Synthesis of 2-yl) carbamoyl) benzoic acid tolylfluoroacetate (PCPA-Am80-a, Example 7) The compound (29) (41.5 mg) obtained in step 6-7 was dissolved in dichloromethane (500 μL ), And trifluoroacetic acid (500 μL) was added under ice cooling, followed by stirring at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure, and toluene (1 mL) was added to the residue and azeotroped. The resulting crude product was purified by reverse phase HPLC (Gradient (I)) to give the title compound (PCPA-Am80-a, Example 7) (42 mg, 95% yield) as a pale yellow amorphous product. .
¹ H NMR (MeOD, 300 MHz, δ; ppm) 7.81 (2H, d, J = 6 Hz), 7.36-7.19 (8H, m), 7.00-6.95 (2H, m), 3.81 (2H, t, J = 6 Hz), 3.67-3.61 (2H, m), 3.24-3.18 (1H, m), 3.13 (3H, s), 2.69-2.62 (1H, m), 1.70-1.63 (1H, m), 1.59 ( 4H, s), 1.54-1.47 (1H, m), 1.18 (6H, s), 1.03 (6H, s);
¹³ C NMR (MeOD, 75 MHz, δ; ppm) 174.14, 168.57, 157.37, 147.01, 146.45, 141.38, 138.71, 136.97, 133.22, 130.04, 129.89, 129.33, 128.94, 128.35, 128.29, 127.83, 127.42, 57.78, 42.56 , 37.12, 35.88, 35.77, 35.16, 35.05, 35.02, 31.82, 23.58, 14.49;
MS (ESI) m / z 568 [MH ⁺ ];
HRMS (FAB) calcd for C ₃₅ H ₄₂ N ₃ O ₄ [MH ⁺ ] 568.3175, found 568.3171;
HPLC t _R = 15.8 min (Gradient (I), purity 98.2%).

  [Example 8 (Scheme 7): Synthesis of PCPAP-Am80-b]

Step 7-1: Synthesis of 4-nitrophenyl (5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl) carbamate (30) Compound (24) (652 mg) obtained in step 6-3 and pyridine (707 μL) are dissolved in dichloromethane (30 mL), and p-nitrophenyl chloroformate (589 mg) is added under ice-cooling. Stir at room temperature for 21 hours. The reaction mixture was diluted with dichloromethane and washed with water, 1N aqueous hydrochloric acid solution and saturated brine. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The obtained residue was purified by silica gel flash column chromatography (developing solvent n-hexane: ethyl acetate = 10: 1 to 6: 1) to give the title compound (30) (979 mg, 90.6% yield) as a pale yellow solid Got as.
¹ H NMR (CDCl ₃ , 300 MHz, δ; ppm) 8.31-8.25 (2H, m), 7.41-7.36 (3H, m), 7.31-7.26 (1H, m), 7.19 (1H, dd, J = 3 , 9 Hz), 6.92 (1H, broad s), 1.69 (4H, s), 1.28 (6H, s), 1.27 (6H, s);
¹³ C NMR (CDCl ₃ , 75 MHz, δ; ppm) 155.54, 150.33, 146.16, 145.04, 141.52, 133.98, 127.47, 125.21, 122.15, 117.14, 116.92, 34.99, 34.47, 33.97, 31.84, 31.79;
MS (ESI) m / z 369 [MH ⁺ ].

Step 7-2: 1-methyl-1- (2- (methyl (2-phenylcyclopropyl) amino) ethyl) -3- (5,5,8,8-tetramethyl-5,6,7,8- Synthesis of tetrahydronaphthalen-2-yl) urea (31) Compound (11) (790 mg) obtained in Step 2-2 of Example 2 and compound (30) obtained in Step 7-1 (1.04 g) was suspended in acetonitrile (28 mL), and diisopropylethylamine (2.43 mL) was added under ice cooling, followed by stirring at room temperature for 11 hours. The reaction solution was concentrated under reduced pressure, and the resulting residue was purified by silica gel flash column chromatography (developing solvent n-hexane: ethyl acetate = 1: 1 to 1: 2) to obtain a crude product as a pale yellow amorphous. The product was added with n-hexane and allowed to stand at 4 ° C. overnight, and the resulting precipitate was collected by filtration and washed with n-hexane to give the title compound (31) (975 mg, yield 79.9% ) Was obtained as a pale yellow solid.
¹ H NMR (CDCl ₃ , 300 MHz, δ; ppm) 9.11 (1H, broad s), 7.28-7.23 (3H, m), 7.20-7.14 (2H, m), 7.11-7.03 (3H, m), 3.36 -3.33 (2H, m), 2.99 (3H, s), 2.88-2.85 (2H, m), 2.56 (3H, s), 2.19-2.06 (2H, m), 1.67 (4H, s), 1.30-1.25 (12H, m), 1.22-1.17 (1H, m), 1.08-1.02 (1H, m);
¹³ C NMR (CDCl ₃ , 75 MHz, δ; ppm) 157.62, 145.36, 141.24, 138.51, 137.78, 128.40, 127.01, 125.97, 125.93, 116.64, 116.37, 58.47, 50.30, 49.09, 42.46, 35.22, 35.18, 34.35, 33.76, 31.92, 25.70, 17.68;
MS (ESI) m / z 434 [MH ⁺ ].

Step 7-3: tert-butyl 4-((methyl (2- (methyl (2-phenylcyclopropyl) amino) ethyl) carbamoyl) (5,5,8,8-tetramethyll-5,6,7, Synthesis of 8-tetrahydronaphthalen-2-yl) carbamoyl) benzoate (32) The compound (31) (222 mg) obtained in Step 7-2 by the same method as in Step 6-7 of Example 7. ) Afforded the title compound (32) (71.8 mg, 22% yield) as a colorless solid.
¹ H NMR (CDCl ₃ , 300 MHz, δ; ppm) 7.94 (2H, d, J = 9 Hz), 7.59 (2H, d, J = 9 Hz), 7.26-7.21 (4H, m), 7.19-7.14 (1H, m), 7.03-7.14 (3H, m), 3.50 (2H, broad s), 2.99 (3H, s), 2.74 (2H, broad s), 2.38 (3H, m), 2.19-1.88 (2H , m), 1.63 (4H, s), 1.58 (9H, m), 1.24 (6H, s), 1.11 (6H, s), 1.07-0.94 (1H, m);
¹³ C NMR (CDCl ₃ , 75 MHz, δ; ppm) 169.42, 164.95, 156.55, 146.21, 144.09, 141.87, 138.97, 136.02, 134.21, 129.67, 129.31, 128.39, 128.12, 127.72, 126.22, 126.04, 125.78, 124.77, 122.93, 81.62, 54.84, 54.37, 49.39, 47.47, 42.88, 42.37, 36.64, 34.97, 34.90, 34.38, 34.18, 31.86, 31.69, 29.78, 28.48, 28.23, 25.63, 17.45;
MS (ESI) m / z 638 [MH ⁺ ].

Step 7-4: 4-((methyl (2- (methyl (2-phenylcyclopropyl) amino) ethyl) carbamoyl) (5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalene) -2-yl) carbamoyl) benzoic acid trifluoroacetate (PCPA-Am80-b, Example 8)
In the same manner as in Step 6-8 of Example 7, from the compound (32) (71.4 mg) obtained in Step 7-3, the title compound (PCPA-Am80-b, Example 8) (76.4 mg, 98.1%) was obtained as a colorless amorphous.
¹ H NMR (MeOD, 300 MHz, δ; ppm) 7.97 (2H, d, J = 9 Hz), 7.61 (2H, d, J = 8 Hz), 7.37-7.17 (6H, m), 7.02-6.94 ( 2H, m), 6.94-6.94 (1H, m), 3.93 (2H, broad s), 3.63 (2H, broad s), 3.25-3.12 (7H, m), 2.69-2.62 (1H, m), 1.69- 1.61 (5H, m), 1.52-1.45 (1H, m), 1.24 (6H, s), 1.04 (3H, s), 1.04 (3H, s);
¹³ C NMR (CDCl ₃ , 75 MHz, δ; ppm) 171.63, 168.52, 158.91, 147.72, 146.17, 139.52, 138.64, 137.18, 134.61, 130.60, 129.87, 129.84, 129.15, 128.27, 127.44, 127.03, 124.47, 115.59, 54.67, 45.85, 42.48, 37.04, 35.86, 35.74, 35.25, 35.10, 32.06, 31.84, 23.66, 14.51;
MS (ESI) m / z 582 [MH ⁺ ];
HRMS (FAB) calcd for C ₃₇ H ₄₆ N ₃ O ₄ [MH ⁺ ] 582.3332, found 582.3334;
HPLC t _R = 17.4 min (Gradient (I), purity 97.4%).

  [Example 9 (Scheme 8): Synthesis of PCPA-Am80-e]

Step 8-1: Synthesis of tert-butyl (3-hydroxypropyl) methylcarbamate (34)
3- (Methylamino) -1-propanol (33) (1.81 g, 20.3 mmol) and triethylamine (3 mL) were dissolved in dichloromethane (30 mL), and di-tert-butyl dicarbonate (3.72 g) was cooled with ice. ) Was added and stirred for 5 minutes, and then the reaction solution was returned to room temperature and stirred for 11 hours. Under ice-cooling, 1N aqueous hydrochloric acid solution was added to the reaction mixture, and the mixture was further diluted with dichloromethane. After separating the organic layer, the obtained organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. After filtration and concentration under reduced pressure, the resulting residue was purified by silica gel flash column chromatography (developing solvent n-hexane: ethyl acetate = 3: 2 to 1: 1) to give the title compound (34) (3.35 g, qy) Obtained as a colorless oil.
¹ H NMR (CDCl ₃ , 300 MHz, δ; ppm) 3.73 (1H, broad s), 3.55 (2H, broad s), 3.41-3.37 (2H, m), 2.84 (3H, s), 1.68-1.64 ( 2H, m), 1.50 (9H, s);
¹³ C NMR (CDCl ₃ , 75 MHz, δ; ppm) 157.20, 79.95, 58.24, 44.40, 34.18, 29.81, 28.41;
MS (ESI) m / z 212 [M + Na ⁺ ].

Step 8-2: Synthesis of tert-butyl (3-oxopropyl) methylcarbamate (35) Oxalyl chloride (710 µL) was dissolved in dichloromethane (10 mL) and cooled to -78 ° C. Dimethyl sulfoxide (1.2 mL) dissolved in dichloromethane (10 mL) was added dropwise to the reaction solution over 15 minutes, followed by stirring for 5 minutes. Further, the compound (34) (1.04 g) obtained in Step 8-1 dissolved in dichloromethane (8 mL) was added dropwise to the reaction mixture over 15 minutes, and after stirring for 20 minutes, triethylamine (3.5 mL) was added. Stir at 78 ° C. for 1 hour. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction solution, and the temperature was returned to room temperature. The organic layer was separated, washed with water and saturated brine, and then washed with anhydrous sodium sulfate. After filtration and concentration, the resulting residue was purified by silica gel flash column chromatography (developing solvent n-hexane: ethyl acetate = 4: 1) to give the title compound (35) (803 mg, yield 78.0%) as a colorless oil Got as.
¹ H NMR (CDCl ₃ , 300 MHz, δ; ppm) 9.81 (1H, t, J = 1.8 Hz), 3.55 (2H, t, J = 6.6 Hz), 2.87 (3H, s), 2.67 (2H, dt , J = 1.5, 6.6 Hz), 1.46 (9H, s);
¹³ C NMR (CDCl ₃ , 75 MHz, δ; ppm) 200.85, 155.55, 79.88, 42.84, 34.73, 28.42;
MS (ESI) m / z 210 [M + Na ⁺ ].

Step 8-3: Synthesis of tert-butylmethyl (3- (methyl (2-phenylcyclopropyl) amino) propyl) carbamate (36) Using the same method as in Step 2-1 of Example 2, From the compound (4) (675 mg) obtained in Step 1-3 of Example 1 and the compound (35) (754 mg) obtained in Step 8-2, the title compound (36) (1.00 g, yield) 85.5%) as a pale yellow oil.
¹ H NMR (CDCl ₃ , 300 MHz, δ; ppm) 7.27-7.22 (2H, m), 7.17-7.11 (1H, m), 7.06-7.03 (2H, m), 3.25-3.18 (2H, m), 2.83 (3H, s), 2.58-2.48 (2H, m), 2.36 (3H, s), 1.98-1.92 (1H, m), 1.84-1.79 (1H, m), 1.77-1.65 (2H, m), 1.44 (9H, s), 1.12-1.06 (1H, m), 0.994-0.934 (1H, m);
¹³ C NMR (CDCl ₃ , 75 MHz, δ; ppm) 155.77, 142.11, 128.24, 125.94, 125.56, 79.16, 55.42, 49.38, 47.35, 42.50, 34.18, 28.47, 25.84, 25.41, 17.14;
MS (ESI) m / z 319 [MH ⁺ ].

Step 8-4: N ^1, N ³ - dimethyl -N ¹ - (2-phenyl-cyclopropyl) Step 2-2 Synthesis <br/> Example 2 of propane-1,3-diamine dihydrochloride (37) Using the same procedure as described above, the title compound (37) (875 mg, yield 95.6%) was obtained as a white solid from the compound (36) (1.00 g) obtained in Step 8-3.
¹ H NMR (MeOD, 300 MHz, δ; ppm) 7.35-7.29 (2H, m), 7.27-7.19 (3H, m), 3.50-3.40 (2H, m), 3.18-3.10 (3H, m), 3.05 (3H, s), 2.72 (4H, s), 2.29-2.22 (2H, m), 1.80-1.70 (1H, m), 1.50-1.43 (1H, m);
¹³ C NMR (MeOD, 75 MHz, δ; ppm) 138.92, 129.86, 128.19, 127.49, 55.37, 47.26, 42.24, 33.73, 24.09, 22.64, 15.29, 14.02;
MS (ESI) m / z 219 [MH ⁺ ].

Step 8-5: 1-methyl-1- (3- (methyl (2-phenylcyclopropyl) amino) propyl) -3- (5,5,8,8-tetramethyl-5,6,7,8- Synthesis of tetrahydronaphthalen-2-yl) urea (38) In the same manner as in Step 7-2 of Example 8, compound (37) (439 mg) obtained in Step 8-4 and compound ( 30) From the (503 mg), the title compound (38) (581 mg, 95.1% yield) was obtained as a pale yellow amorphous.
¹ H NMR (CDCl ₃ , 300 MHz, δ; ppm) 8.26 (1H, broad s), 7.29-7.23 (3H, m), 7.20-7.14 (3H, m), 7.03-7.00 (2H, m), 3.54 -3.30 (2H, m), 2.92 (3H, s), 2.70-2.52 (2H, m), 2.46 (3H, s), 2.08-2.01 (1H, m), 1.86-1.78 (3H, m), 1.66 (4H, s), 1.29 (6H, s), 1.25 (6H, s), 1.22-1.16 (1H, m), 1.10-1.04 (1H, m);
¹³ C NMR (CDCl ₃ , 75 MHz, δ; ppm) 157.45, 145.34, 141.94, 138.78, 137.87, 128.56, 127.06, 126.03, 125.89, 117.21, 116.75, 54.27, 49.22, 47.00, 44.41, 35.38, 35.34, 34.49, 33.89, 33.53, 32.07, 32.04, 24.80, 24.76, 16.49;
MS (ESI) m / z 448 [MH ⁺ ].

Step 8-6: tert-butyl 4-((methyl (3- (methyl (2-phenylcyclopropyl) amino) propyl) carbamoyl) (5,5,8,8-tetramethyl-5,6,7,8 Synthesis of -tetrahydronaphthalen-2-yl) carbamoyl) benzoate (39) From compound (38) (258 mg) obtained in step 8-5 according to the same method as in step 6-7 of example 7. The title compound (39) (98.6 mg) was obtained as a yellow amorphous.

Step 8-7: 4-((methyl (3- (methyl (2-phenylcyclopropyl) amino) propyl) carbamoyl (5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalene- Synthesis of 2-yl) carbamoyl) benzoic acid trifluoroacetate (PCPA-Am80-e, Example 9) Obtained in Step 8-6 by a method similar to Step 6-8 of Example 7. From the compound (39) (98.6 mg), the title compound (PCPA-Am80-e, Example 9) (46.4 mg, yield 11.4% in two steps from the compound (38)) was obtained as a pale yellow amorphous product.
¹ H NMR (MeOD, 300 MHz, δ; ppm) 7.95 (2H, d, J = 8.4 Hz), 7.57 (2H, d, J = 8.1 Hz), 7.36-7.18 (6H, m), 7.01 (1H, dd, J = 1.8, 8.1 Hz), 6.90 (1H, s), 3.75-3.42 (4H, m), 3.16-3.07 (7H, m), 2.70-2.50 (1H, m), 2.32-2.05 (2H, m), 1.72-1.55 (5H, m), 1.48-1.41 (1H, m), 1.23 (6H, s), 1.02 (6H, s);
¹³ C NMR (MeOD, 75 MHz, δ; ppm) 171.31, 168.51, 159.01, 147.59, 145.97, 139.73, 138.85, 137.35, 134.47, 130.58, 129.81, 129.11, 128.18, 127.50, 127.12, 124.25, 56.11, 47.31, 42.08 , 36.45, 35.86, 35.73, 35.21, 35.07, 32.05, 31.83, 23.42, 14.10;
MS (ESI) m / z 596 [MH ⁺ ];
HRMS (FAB) calcd for C ₃₇ H ₄₆ N ₃ O ₄ [MH ⁺ ] 596.3488, found 596.3491;
HPLC t _R = 17.4 min (Gradient (I), purity 98.4%).

  [Example 10 (Scheme 9): Synthesis of PCPA-Am80-f]

Step 9-1: Synthesis of tert-butyl (4-hydroxybutyl) carbamate (41)
7-Amino-1-butanol (40) (2.97 g) and triethylamine (5 mL) are dissolved in dichloromethane (60 mL), and di-tert-butyl dicarbonate (6.61 g) is added under ice-cooling for 5 minutes. Stir. The reaction solution was returned to room temperature and stirred for 12 hours. Under ice-cooling, 1N aqueous hydrochloric acid solution was added to the reaction mixture, and the mixture was further diluted with dichloromethane. After separating the organic layer, the obtained organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. Filtration and concentration under reduced pressure gave the title compound (41) (5.71 g, yield 90.5%) as a pale yellow oil.
¹ H NMR (CDCl ₃ , 300 MHz, δ; ppm) 4.61 (1H, broad s), 3.70-3.64 (2H, m), 3.19-3.13 (2H, m), 1.62-1.55 (4H, m), 1.44 (9H, s);
¹³ C NMR (CDCl ₃ , 75 MHz, δ; ppm) 156.31, 79.15, 62.10, 40.36, 29.75, 28.45, 26.58;
MS (ESI) m / z 210 [M + Na ⁺ ].

Step 9-2: Synthesis of tert-butyl (4-((tert-butyldimethylsilyl) oxy) butyl) carbamate (42) Compound (41) (5.71 g) obtained in Step 9-1 was prepared. Dissolved in N, N-dimethylformamide (30 mL), imidazole (3.63 g) and tert-butyldimethylchlorosilane (6.88 g) were added under ice cooling, and the mixture was stirred at room temperature for 24 hours. The reaction mixture was diluted with ethyl acetate and washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine. The extract was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The obtained residue was purified by silica gel flash column chromatography (developing solvent n-hexane: ethyl acetate = 20: 1 to 5: 1) to give the title compound (42) (8.06 g, yield 88.0%) as a colorless oil. Got as.
¹ H NMR (CDCl ₃ , 300 MHz, δ; ppm) 4.68 (1H, broad s), 3.64-3.60 (2H, m), 3.14-3.12 (2H, m), 1.56-1.52 (4H, m), 1.44 (9H, s), 0.892 (9H, s), 0.049 (6H, s);
¹³ C NMR (CDCl ₃ , 75 MHz, δ; ppm) 156.10, 78.96, 62.85, 40.50, 30.16, 28.52, 26.66, 26.04, 18.39, -5.25;
MS (ESI) m / z 304 [MH ⁺ ].

Step 9-3: Synthesis of tert-butyl (4-((tert-butyldimethylsilyl) oxy) butyl) methylcarbamate (43)
60% sodium hydride (786 mg) was dissolved in N, N-dimethylformamide (20 mL) and dissolved in N, N-dimethylformamide (20 mL) under ice-cooling. 42) (3.93 g) was added dropwise and stirred for 30 minutes. Methyl iodide (2.5 mL) dissolved in N, N-dimethylformamide (10 mL) was added dropwise to the reaction solution, and the mixture was stirred at room temperature for 3 hours. Ice water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was separated, washed with water and saturated brine, and dried over anhydrous sodium sulfate. After filtration and concentration under reduced pressure, the resulting residue was purified by silica gel flash column chromatography (developing solvent n-hexane: ethyl acetate = 20: 1 to 15: 1 to 10: 1) to give the title compound (43) ( 4.00 g, 97.3% yield) was obtained as a colorless oil.
¹ H NMR (CDCl ₃ , 300 MHz, δ; ppm) 3.62 (2H, t, J = 6.3 Hz), 3.21 (2H, t, J = 4.8 Hz-), 2.83 (3H, s), 1.57-1.47 ( 4H, m), 1.45 (9H, s), 0.892 (9H, s), 0.0457 (6H, s);
¹³ C NMR (CDCl ₃ , 75 MHz, δ; ppm) 155.77, 78.99, 62.77, 48.65, 33.97, 29.98, 28.46, 25.94, 24.37, 18.28, -5.31;
MS (ESI) m / z 341 [M + Na ⁺ ].

Step 9-4: Synthesis of tert-butyl (4-hydroxybutyl) methylcarbamate (44) The compound (43) (4.00 g) obtained in Step 9-3 was dissolved in tetrahydrofuran (45 mL). After dropwise addition of 1M TBAF tetrahydrofuran solution (15 mL) at 0 ° C., the mixture was stirred for 1.5 hours. The reaction mixture was diluted with ethyl acetate, washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine, and dried over anhydrous sodium sulfate. After filtration and concentration under reduced pressure, the resulting residue was purified by silica gel flash column chromatography (developing solvent n-hexane: ethyl acetate = 1: 1) to give the title compound (44) (2.59 g, qy) as a pale yellow oil. Got as.
¹ H NMR (CDCl ₃ , 300 MHz, δ; ppm) 3.70-3.66 (2H, m) 3.25-3.23 (2H, m), 2.84 (3H, s), 1.66-1.52 (5H, m), 1.46 (9H , s);
¹³ C NMR (CDCl ₃ , 75 MHz, δ; ppm) 155.93, 79.28, 62.07, 48.22, 34.02, 29.62, 28.41, 24.09;
MS (ESI) m / z 204 [MH ⁺ ], 226 [M + Na ⁺ ].

Step 9-5: Synthesis of tert-butylmethyl (4-oxobutyl) carbamate (45) In the same manner as in Step 8-2 of Example 9, compound (44) (1.32 The title compound (45) (1.17 g, 89.3% yield) was obtained as a colorless oil from g).
¹ H NMR (CDCl ₃ , 300 MHz, δ; ppm) 9.79 (1H, t, J = 1.2 Hz), 3.26 (2H, t, J = 6.9 Hz), 2.84 (3H, s), 2.46 (2H, dt , J = 1.2, 7.2 Hz,), 1.89-1.82 (2H, m), 1.45 (9H, s);
¹³ C NMR (CDCl ₃ , 75 MHz, δ; ppm) 201.49, 155.72, 79.38, 47.72, 40.84, 34.04, 28.37, 20.25;
MS (ESI) m / z 224 [M + Na ⁺ ].

Step 9-6: Synthesis of tert-butylmethyl (4- (methyl (2-phenylcyclopropyl) amino) butyl) carbamate (46) Using a method similar to step 2-1 of Example 2, The title compound (46) (1.69 g, yield 96.0%) was obtained as a pale yellow oil from the compound (45) (1.17 g) obtained in Step 9-5.
¹ H NMR (CDCl ₃ , 300 MHz, δ; ppm) 7.28-7.23 (2H, m), 7.17-7.12 (1H, m), 7.07-7.04 (2H, m), 3.25-3.16 (2H, m), 2.83 (3H, s), 2.56-2.52 (2H, m), 2.35 (3H, s), 1.98-1.92 (1H, m), 1.85-1.80 (1H, m), 1.50-1.47 (2H, m), 1.45 (9H, s), 1.12-1.06 (1H, m), 0.995-0.935 (1H, m);
¹³ C NMR (CDCl ₃ , 75 MHz, δ; ppm) 155.83, 142.26, 128.30, 125.99, 125.60, 79.14, 57.86, 49.45, 48.81, 42.53, 34.15, 28.56, 26.03, 25.45, 24.63, 17.32;
MS (ESI) m / z 333 [MH ⁺ ].

Step 9-7: Synthesis of N ¹ , N ⁴ -dimethyl-N ^1- (2-phenylcyclopropyl) butane-1,4-diamine dihydrochloride (47) Step 2-2 of Example 2 The title compound (47) (1.44 g, yield 92.9%) was obtained as a white solid from the compound (46) obtained in Step 9-6, using the same procedure as described above.
¹ H NMR (MeOD, 300 MHz, δ; ppm) 7.35-7.18 (5H, m), 3.43-3.35 (2H, m), 3.15-3.11 (3H, m), 3.04 (3H, s), 2.72 (4H , s), 2.05-1.33 (6H, m);
¹³ C NMR (MeOD, 75 MHz, δ; ppm) 138.98, 129.82, 128.14, 127.36, 57.82, 48.19, 42.40, 41.99, 33.62, 24.25, 22.67, 15.34, 13.83;
MS (ESI) m / z 233 [MH ⁺ ].

Step 9-8: 1-methyl-1- (4- (methyl (2-phenylcyclopropyl) amino) butyl) -3- (5,5,8,8-tetramethyl-5,6,7,8- Synthesis of tetrahydronaphthalen-2-yl) urea (48) In the same manner as in Example 8, step 7-2, compound (47) (477 mg) obtained in step 9-7 and compound (30 ) (522 mg) gave the title compound (48) (569 mg, 87.0% yield) as a white solid.
¹ H NMR (CDCl ₃ , 300 MHz, δ; ppm) 7.28-7.20 (4H, m), 7.17-7.10 (2H, m), 7.04-7.01 (2H, m), 6.23 (1H, broad s), 3.35 (2H, t, J = 6.6 Hz), 2.99 (3H, s), 2.62-2.52 (2H, m), 2.36 (3H, s), 1.96-1.90 (1H, m), 1.86-1.81 (1H, m ), 1.66 (4H, s), 1.61-1.52 (4H, m), 1.27 (6H, s), 1.25 (6H, s), 1.12-1.06 (1H, m), 0.985-0.926 (1H, m);
¹³ C NMR (CDCl ₃ , 75 MHz, δ; ppm) 155.69, 145.53, 142.30, 139.87, 136.62, 128.39, 127.09, 126.05, 125.69, 118.44, 118.20, 57.69, 49.64, 49.00, 42.62, 35.35, 35.29, 34.87, 34.49, 33.96, 32.03, 31.96, 26.08, 25.53, 24.65, 17.39;
MS (ESI) m / z 462 [MH ⁺ ].

Step 9-9: tert-butyl 4-((methyl (4- (methyl (2-phenylcyclopropyl) amino) butyl) carbamoyl) (5,5,8,8-tetramethyl-5,6,7,8 Synthesis of -tetrahydronaphthalen-2-yl) carbamoyl) benzoate (49) Compound (48) (244 mg) obtained in Step 9-8 by the same method as in Step 6-7 of Example 7. Gave the title compound (49) (51.9 mg, 14.7% yield) as a pale yellow amorphous product.
¹ H NMR (CDCl ₃ , 300 MHz, δ; ppm) 7.93 (2H, d, J = 7.8 Hz), 7.58 (2H, d, J = 8.1 Hz), 7.29-7.22 (3H, m), 7.17-7.12 (1H, m), 7.04-6.93 (4H, m), 3.35 (2H, broad s), 2.99 (3H, s), 2.52 (2H, broad s), 2.32 (3H, s), 1.91-1.79 (2H , m), 1.63-1.58 (15H, m), 1.24 (6H, s), 1.12 (6H, s), 0.977-0.939 (1H, m);
¹³ C NMR (CDCl ₃ , 75 MHz, δ; ppm) 169.45, 164.97, 156.45, 146.26, 144.10, 142.18, 139.04, 135.99, 134.20, 129.34, 128.37, 128.09, 127.74, 126.00, 125.70, 124.44, 122.98, 81.65, 70.68, 57.60, 49.44, 42.50, 36.19, 34.98, 34.92, 34.40, 34.20, 31.89, 31.73, 28.25, 25.48, 24.76, 24.56, 17.34;
MS (ESI) m / z 666 [MH ⁺ ].

Step 9-10: 4-((methyl (4- (methyl (2-phenylcyclopropyl) amino) butyl) carbamoyl) (5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalene Synthesis of 2-yl) carbamoyl) benzoic acid trifluoroacetate (PCPA-Am80-f, Example 10) Obtained in Step 9-9 by the same method as in Step 6-8 of Example 7. The title compound (PCPA-Am80-f, Example 10) (52.8 mg, yield 93.6%) was obtained as a colorless amorphous form from the obtained compound (49) (51.9 mg).
¹ H NMR (MeOD, 300 MHz, δ; ppm) 7.96 (2H, d, J = 8.4 Hz), 7.57 (2H, d, J = 8.4 Hz), 7.36-7.15 (6H, m), 7.01-6.99 ( 2H, m), 6.91 (1H, m), 3.65-3.34 (4H, m), 3.16-2.93 (7H, m), 2.69-2.52 (1H, m), 1.99-1.68 (4H, m), 1.67- 1.55 (5H, m), 1.48-1.41 (1H, m), 1.22 (6H, s), 1.03 (6H, s);
¹³ C NMR (MeOD, 75 MHz, δ; ppm) 171.11, 168.54, 158.49, 147.53, 145.84, 139.92, 138.90, 137.41, 134.37, 130.56, 129.81, 129.73, 129.07, 128.15, 127.38, 126.94, 124.10, 58.26, 42.20 , 36.29, 35.86, 35.73, 35.21, 35.06, 32.06, 31.84, 24.74, 23.30, 22.39, 14.40
MS (ESI) m / z 610 [MH ⁺ ];
HRMS (FAB) calcd for C ₃₈ H ₄₈ N ₃ O ₄ [MH ⁺ ] 610.3645, found 610.3640;
HPLC t _R = 17.6 min (Gradient (I), purity 99.6%).

  [Example 11 (Scheme 10): Synthesis of PCPA-SAHA-c]

Step 10-1: Synthesis of 4-(((tert-butyldimethylsilyl) oxy) methyl) phenol (51)
p-Hydroxybenzyl alcohol (50) (5.00 g) was dissolved in N, N-dimethylformamide (40 mL). Under ice cooling, imidazole (3.02 g, 44.4 mmol) and tert-butyldimethylchlorosilane (6.68 g) were dissolved. The mixture was further stirred at room temperature for 2.5 hours. The reaction mixture was diluted with ethyl acetate and washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The obtained residue was purified by silica gel flash column chromatography (developing solvent n-hexane: ethyl acetate = 9: 1 to 1: 1) to give the title compound (51) (8.91 g, yield 92.8%) as a colorless oil Got as.
¹ H NMR (CDCl ₃ , 300 MHz, δ; ppm) 7.19 (2H, dt, J = 2.7, 8.7 Hz), 6.78 (2H, dt, J = 2.7, 8.7 Hz), 4.69 (1H, s), 4.66 (2H, s), 0.928 (9H, s), 0.0847 (6H, s);
¹³ C NMR (CDCl ₃ , 75 MHz, δ; ppm) 155.00, 132.94, 128.17, 115.42, 65.21, 26.12, 18.57, -5.02;
MS (ESI) m / z not detected.

Step 10-2: Synthesis of 4-(((tert-butyldimethylsilyl) oxy) methyl) phenylmethyl (2- (methyl (2-phenylcyclopropyl) amino) ethyl) carbamate (52) Step 10 -1 (134 mg) and pyridine (136 μL) obtained in -1 were dissolved in dichloromethane (5 mL), and p-nitrophenyl chloroformate (229 mg) was added under ice-cooling at room temperature. Stir for 16 hours. The reaction mixture was diluted with dichloromethane and washed with 1N aqueous hydrochloric acid solution, saturated aqueous sodium hydrogen carbonate solution and saturated brine. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The obtained residue, compound (11) (171 mg) was suspended in dichloromethane (5 mL), triethylamine (234 μL) was added under ice cooling, and the mixture was stirred at room temperature for 24 hours. The reaction mixture was diluted with dichloromethane and washed with water and saturated brine. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resulting residue was purified by silica gel flash column chromatography (developing solvent n-hexane: ethyl acetate = 1: 1 to 1: 2) to give the title compound (52) (167 mg, yield 63.5%) as a colorless amorphous Got as.
¹ H NMR (CDCl ₃ , 300 MHz, δ; ppm) 7.30-7.21 (4H, m), 7.17-7.14 (1H, m), 7.07-7.01 (4H, m), 4.71 (2H, s), 3.60- 3.43 (2H, m) 3.09 (1.4H, s), 3.01 (1.6H, s), 2.86-2.81 (2H, m), 2.43 (3H, s), 1.99-1.93 (2H, m), 1.14-1.07 (1H, m), 1.02-0.960 (1H, m), 0.935 (9H, s), 0.0907 (6H, s);
¹³ C NMR (CDCl ₃ , 75 MHz, δ; ppm) 154.84, 150.41, 141.96, 141.85, 138.29, 128.29, 126.90, 126.00, 125.65, 121.42, 121.36, 64.54, 55.59, 54.76, 49.36, 47.33, 42.31, 35.29, 35.08, 25.96, 25.78, 25.62, 18.40, 17.52, 14.21, -5.23;
MS (ESI) m / z 469 [MH ⁺ ].

Step 10-3: Synthesis of 4- (hydroxymethyl) phenylmethyl (2- (methyl (2-phenylcyclopropyl) amino) ethyl) carbamate (53) Compound obtained in Step 10-2 (52 ) (166 mg) was dissolved in tetrahydrofuran (6 mL), and 1M TBAF tetrahydrofuran solution (425 μL) was added under ice cooling, followed by stirring for 1 hour. The reaction mixture was diluted with ethyl acetate and washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The obtained residue was purified by silica gel flash column chromatography (developing solvent n-hexane: ethyl acetate = 1: 4) to give the title compound (53) (121 mg, yield 96.0%) as a colorless oil.
¹ H NMR (CDCl ₃ , 300 MHz, δ; ppm) 7.35 (2H, d, J = 8.4 Hz), 7.26-7.22 (2H, m), 7.18-7.04 (5H, m), 4.67 (2H, s) , 3.58-3.45 (2H, m) 3.09 (1.4H, s), 3.01 (1.6H, s), 2.86-2.78 (2H, m), 2.43 (3H, s), 1.99-1.93 (2H, m), 1.13-1.07 (1H, m), 1.02-0.96 (1H, m);
¹³ C NMR (CDCl ₃ , 75 MHz, δ; ppm) 154.86, 150.72, 141.76, 138.25, 128.33, 127.82, 126.00, 125.71, 121.70, 121.60, 64.40, 55.56, 54.71, 49.35, 49.26, 47.28, 42.39, 35.30, 35.09, 25.71, 25.51, 17.43;
MS (ESI) m / z 355 [MH ⁺ ].

Step 10-4: 4-(((8-oxo-8- (phenylamino) octanamido) oxy) methyl) phenylmethyl (2- (methyl (2-phenylcyclopropyl) amino) ethyl) carbamate (PCPA-SAHA -c, Synthesis of Example 11) Compound (53) (210 mg) obtained in Step 10-3 was dissolved in dichloromethane (6 mL), and thionyl chloride (86.4 μL) was added under ice-cooling. In addition, the mixture was stirred for 5 minutes and then stirred at room temperature for 3 hours. Saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted with dichloromethane. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure.

60% sodium hydride (27.0 mg) was suspended in N, N-dimethylformamide (4 mL), and SAHA (142 mg) was added under ice cooling, followed by stirring for 30 minutes. The residue obtained previously was dissolved in N, N-dimethylformamide (2 mL), and the resulting mixture was added dropwise to the reaction solution, followed by stirring at room temperature for 19 hours. Ice water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was separated, washed with water and saturated brine, and dried over anhydrous sodium sulfate. After filtration and concentration under reduced pressure, the resulting residue was purified by silica gel flash column chromatography (developing solvent: ethyl acetate) to give the title compound (PCPA-SAHA-c, Example 11) (190 mg, yield 58.8%). Obtained as a pale yellow solid. The obtained solid was recrystallized from ethyl acetate to give the title compound (PCPA-SAHA-c, Example 11) (84.5 mg) as a white powder.
mp 102-104 ° C; ¹ H NMR (CDCl ₃ , 300 MHz, δ; ppm) 7.55-7.52 (2H, m), 7.43-7.41 (2H, m), 7.31-7.18 (4H, m), 7.13-7.04 (6H, m), 4.83 (2H, s), 3.66-3.48 (2H, m), 3.09-2.99 (3H, m), 2.90-2.79 (2H, m), 2.45 (3H, s), 2.35 (2H , t, J = 7.5 Hz), 2.05 (2H, t, J = 7.2 Hz), 2.01-1.94 (2H, m), 1.73-1.56 (4H, m), 1.43-1.33 (4H, m), 1.12- 0.998 (2H, m);
¹³ C NMR (CDCl ₃ , 75 MHz, δ; ppm) 174.55, 172.91, 156.45, 153.03, 142.91, 139.93, 134.31, 131.46, 129.77, 129.35, 126.93, 126.75, 125.09, 122.91, 122.75, 121.26, 78.16, 56.46, 55.58, 50.44, 50.32, 48.05, 42.64, 42.60, 37.85, 35.56, 35.36, 33.66, 29.87, 29.75, 26.67, 26.52, 26.43, 26.23, 17.60, 17.52;
MS (ESI) m / z 601 [MH ⁺ ]; Anal. Calcd. For C ₃₅ H ₄₄ N ₄ O ₅ : C, 69.98; H, 7.38; N, 9.33. Found: C, 69.81; H, 7.15; N , 9.31.

  [Example 12 (Scheme 11): Synthesis of PCPA-Am80-c]

Step 11-1: Synthesis of tert-butyl 4-((5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl) carbamoyl) benzoate (54) compound (26) (113 mg), was dissolved EDCI (119 mg), HOBt · H 2 O a (95.0 mg) N, N- dimethylformamide (5 mL), compound (24) (124 mg) was added, Stir at room temperature for 38 hours. The reaction mixture was diluted with ethyl acetate and washed with saturated aqueous sodium hydrogen carbonate solution, water and saturated brine. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The obtained residue was purified by silica gel flash column chromatography (developing solvent n-hexane: ethyl acetate = 10: 1 to 5: 1) to give the title compound (54) (226 mg, qy) as a pale yellow solid. It was.
¹ H NMR (CDCl ₃ , 300 MHz, δ; ppm) 8.09 (2H, d, J = 8.4 Hz), 7.90 (2H, d, J = 8.4 Hz), 7.73 (1H, broad s), 7.54 (1H, d, J = 2.1 Hz), 7.43 (1H, dd, J = 2.4, 8.7 Hz), 7.31 (1H, d, J = 8.7 Hz), 1.70 (4H, s), 1.62 (9H, s), 1.31 ( 6H, s), 1.28 (6H, s);
¹³ C NMR (CDCl ₃ , 75 MHz, δ; ppm) 164.88, 164.82, 145.92, 141.79, 138.62, 135.11, 134.87, 129.84, 127.32, 126.88, 118.26, 118.17, 81.75, 35.10, 35.06, 34.47, 34.05, 31.86, 31.83, 28.19;
MS (ESI) m / z 408 [MH ⁺ ].

Step 11-2: 4-((4-((methyl (2- (methyl (2-phenylcyclopropyl) amino) ethyl) carbamoyl) oxy) benzyl) (5,5,8,8-tetramethyl-5, Synthesis of 6,7,8-tetrahydronaphthalen-2-yl) carbamoyl) benzoic acid trifluoroacetate (PCPA-Am80-c, Example 12) Compound (53) (102 mg) was dissolved in dichloromethane (3 The reaction mixture was dissolved in mL), and thionyl chloride (41.8 μL) was added under ice-cooling. After stirring for 5 minutes, the mixture was stirred at room temperature for 1 hour. Saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted with dichloromethane. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure.

  Obtained in Step 11-1 where 60% sodium hydride (14.4 mg) was suspended in N, N-dimethylformamide (2 mL) and dissolved in N, N-dimethylformamide (1 mL) under ice-cooling. Compound (54) (71.8 mg) was added, and the mixture was stirred at room temperature for 30 min. The residue obtained previously was dissolved in N, N-dimethylformamide (1 mL), added dropwise to the reaction solution, and then stirred at room temperature for 2 hours. To the reaction solution was added potassium iodide (30.0 mg), and the mixture was stirred at 80 ° C. for 16 hours. After returning to room temperature, the reaction mixture was diluted with ethyl acetate and washed with saturated brine. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The obtained residue was purified by silica gel flash column chromatography (developing solvent n-hexane: ethyl acetate = 3: 2) to obtain a crude product (78.9 mg) as a yellow amorphous.

The obtained crude product (78.9 mg) was dissolved in dichloromethane (1 mL), trifluoroacetic acid (1 mL) was added dropwise under ice cooling, and the reaction solution was stirred for 5 hours. The reaction solution was concentrated under reduced pressure and further azeotroped with toluene (1 mL), and then the resulting residue was purified by reversed-phase HPLC (Gradient (I)) to give the title compound (PCPA-Am80-c, Example 12) (64.6 mg, 28% yield) was obtained as a pale yellow amorphous.
¹ H NMR (MeOD, 300 MHz, δ; ppm) 7.82 (2H, d, J = 8.1 Hz), 7.38-7.08 (12H, m), 6.93 (1H, dd, J = 2.4, 8.4 Hz), 6.66 ( 1H, s), 5.14 (2H, s), 3.90-3.64 (4H, m), 3.19-3.04 (7H, m), 2.64 (1H, broad s), 1.67-1.46 (6H, m), 1.17 (6H , s), 0.893 (6H, s);
¹³ C NMR (MeOD, 75 MHz, δ; ppm) 172.04, 168.79, 156.88, 151.96, 146.99, 145.36, 141.90, 140.78, 138.76, 136.11, 132.70, 130.58, 130.16, 129.84, 129.38, 128.67, 128.52, 128.22, 127.38 , 125.29, 122.84, 55.35, 55.73, 45.42, 42.32, 35.86, 35.70, 35.28, 35.02, 34.92, 32.02, 31.76, 23.36, 14.37;
MS (ESI) m / z 688 [MH ⁺ ];
HRMS (FAB) calcd for C ₄₃ H ₅₀ N ₃ O ₅ [MH ⁺ ] 688.3750, found 688.3753;
HPLC t _R = 18.6 min (Gradient (I), purity 98.6%).

  [Example 13 (Scheme 12): Synthesis of PCPA-cyano-nilutamide-a]

Step 12-1: Synthesis of 4- (4,4-dimethyl-2,5-dioxoimidazolidin-1-yl) -2- (trifluoromethyl) benzonitrile (57)
4-Fluoro-2-trifluorobenzonitrile (55) (994 mg), 5,5-dimethylhydantoin (56) (3.37 g), potassium carbonate (1.11 g) in N, N-dimethylformamide (15 mL) In addition, the mixture was stirred at 45 ° C. for 42 hours under a nitrogen atmosphere. After returning the reaction solution to room temperature, the reaction solution was diluted with ethyl acetate and washed with water and saturated brine. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The obtained residue was purified by silica gel flash column chromatography (developing solvent: chloroform: methanol = 50: 1) to give the title compound (57) (503 mg, yield 32.2%) as a white solid.
¹ H NMR (DMSO-d ₆ , 300 MHz, δ; ppm) 8.81 (1H, broad s), 8.29 (1H, d, J = 8.4 Hz), 8.18 (1H, d, J = 1.8 Hz), 8.02 ( 1H, dd, 1.8, 8.4 Hz), 1.42 (6H, s);
¹³ C NMR (DMSO-d6, 75 MHz, δ; ppm); 175.75, 152.95, 137.01, 135.99, 131.06 (q, J = 32 Hz), 129.92, 124.02 (q, J = 4.5 Hz), 120.44, 115.21, 106.57 (q, J = 1.8 Hz), 57.97, 24.58;
MS (ESI) m / z 296 [MH -].

Step 12-2: 4-((3- (4-Cyano-3- (trifluoromethyl) phenyl) -5,5-dimethyl-2,4-dioxoimidazolidin-1-yl) methyl) phenylmethyl ( Synthesis of 2- (methyl (2-phenylcyclopropyl) amino) ethyl) carbamate trifluoroacetate (PCPA-cyano-nilutamide-a, Example 13) Compound (53) (120 mg) was dissolved in dichloromethane ( 3 mL), thionyl chloride (50 μL) was added under ice cooling, and the mixture was stirred for 5 minutes and then at room temperature for 1 hour. Saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted with dichloromethane. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure.

60% Sodium hydride (20.1 mg) was suspended in N, N-dimethylformamide (2 mL), and 57 (91.5 mg) obtained in Step 12-1 was added under ice cooling, followed by stirring for 35 minutes. The previously obtained residue dissolved in N, N-dimethylformamide (1 mL) was added to the reaction solution, and the mixture was stirred at room temperature for 6 hours. Ice water was added to the reaction solution, followed by extraction with ethyl acetate, and the organic layer was separated. The organic layer was washed with water and saturated brine, and then dried over anhydrous sodium sulfate. After filtration and concentration, the resulting residue was repeatedly purified by silica gel flash column chromatography (developing solvent n-hexane: ethyl acetate = 1: 1 to 1: 2) and reverse phase HPLC (Gradient (I)) to give the title compound. (PCPA-cyano-nilutamide, Example 13) (166 mg, yield 65.5%) Obtained as a pale yellow amorphous.
¹ H NMR (MeOD, 300 MHz, δ; ppm) 8.24 (1H, s), 8.10 (2H, d, J = 1.2 Hz), 7.48 (2H, d, J = 8.1 Hz), 7.31-7.12 (7H, m), 4.68 (2H, s), 3.98-3.63 (4H, m), 3.15-3.04 (7H, m), 2.70-2.63 (1H, m), 1.70-1.62 (1H, m), 1.58-1.47 ( 1H, m), 1.45 (6H, s);
¹³ C NMR (MeOD, 75 MHz, δ; ppm) 176.41, 156.91, 155.14, 152.07, 138.74, 138.30, 136.82, 136.61, 133.93 (q, J = 33 Hz), 130.34, 130.11, 129.85, 128.25, 127.39, 125.54 , 124.82 (q, J = 5.3 Hz), 123.00, 121.92, 116.11, 109.12, 109.09, 63.57, 55.40, 45.47, 43.69, 42.34, 35.32, 23.53, 14.39;
MS (ESI) m / z 634 [MH ⁺ ];
HRMS (FAB) calcd for C ₃₄ H ₃₅ F ₃ N ₅ O ₄ [MH ⁺ ] 634.2641, found 634.2635;
HPLC t _R = 17.4 min (Gradient (I), purity 99.2%).
<Test example>
Test Example 1: Evaluation of LSD1 inhibitory activity The LSD1 inhibitory activity of the compounds of Examples 1 to 13 was evaluated using an LSD1 fluorescent assay kit (BML-AK544-0001) manufactured by Enzo life science. Preincubate various concentrations of inhibitor (final concentration 100-0.01 μM) and LSD1 (0.5 μg / well) on a 96-well plate for 15 minutes at room temperature, then add H3K4me2 peptide (final concentration 20 μM) to all but the blank. And incubated for 30 minutes at room temperature. Hydrogen peroxide detection reagent (CeLLestial ^™ Red and HRP mixed solution) was added to all wells, incubated at room temperature for 5 minutes, and then fluorescence intensity (excitation wavelength: 540 nm, perkinelmer 2030 ARVO ^™ X3 multilabel reader) (Fluorescence wavelength: 590 nm) was measured, and the IC ₅₀ value (inhibitor concentration that inhibits enzyme activity by 50%) was calculated.

  The results are shown in Table 1. The measured value is an average of three independent trials.

Test Example 2: MAO inhibitory activity evaluation The compounds were evaluated for MAO inhibitory activity using MAO-Glo ^™ assay system (V1401) from Promega and MAO-A and MAO-B purchased from Sigma. Enzyme [final concentration 9 unit / mL MAO-A or 3 unit / mL MAO-B], MAO substrate [final concentration 40 μM (MAO-A) or 4 μM (MAO-B)] Concentration inhibitors (final concentration 100-0.01 μM) were mixed and incubated for 1 hour at room temperature. After adding a luciferin detection reagent to the reaction solution and incubating at room temperature for 20 minutes, chemiluminescence intensity was measured with a PerkinElmer 2030 ARVO ^™ X3 multilabel reader to calculate an IC ₅₀ value.

  The results are shown in Table 1. The measured value is an average of three independent trials.

[Consideration of Test Examples 1 and 2]
All the compounds strongly inhibited LSD1, and the selectivity for LSD1 could be confirmed.

Test Example 3: Analysis of LSD1 enzyme reaction solution: Determination of 4-hydroxytamoxifen (4OHT)
The ability of PCPA-Tm-a / b to release 4-hydroxytamoxifen (4OHT) in the presence of LSD1 was evaluated using ESI-MS.

LSD1 (final concentration 5 μM) and PCPA-Tm-a / b (Examples 1 and 2) (final concentration 10 μM) were reacted at 37 ° C. in assay buffer. After reacting for a predetermined time, 0.2% TFA aqueous solution (40 μL) containing 6M guanidine hydrochloride aqueous solution (20 μL) and 2.5 μM 4OHT-d ₅ (internal standard substance) was added to the enzyme reaction solution (20 μL). . The resulting mixture using a GL science's Mono Tip ^TM, desalted, concentrated (eluted in acetonitrile / water = 1/1 solution 40 [mu] L containing 0.1% formic acid), Bruker Inc. HCT-plus (ESI -MS). The relative detection intensity of 4OHT when the detection intensity of the internal standard substance was assumed to be 1 was calculated, and the 4OHT concentration of the LSD1 enzyme reaction solution was determined from the calibration curve. A comparative control experiment was also performed in which LSD1 was replaced with FAD (5 μM).

The results are shown in FIG. Only in the presence of LSD1, the amount of 4OHT increased in a time-dependent manner.
Test Example 4: Cell growth inhibition test or cytotoxicity test
The effect of PCPA-Tm-a / b (Examples 1 and 2) on breast cancer cells (MCF7) and normal cells (HMEC) was evaluated.

Each cell was seeded on a 96-well plate at 2,000 cells / well on the day before compound treatment. Various concentrations of compounds dissolved in the medium were treated and cultured in an incubator (37 ° C., 5% CO ₂ ) for 3 days. Add 10-fold concentration of alamar Blue to all wells, incubate in an incubator (37 ° C, CO ₂ ), and then intensify fluorescence with PerkinElmer 2030 ARVO ^™ X3 multilabel reader (excitation wavelength: 540 nm, fluorescence wavelength: 590 nm) ) Was measured. The compound was treated, and the relative cell number (% growth or% viability) was determined using the fluorescence intensity data on the third day, where the number of cells not treated with the compound was defined as 100. Note that DMEM (10% FBS) was used as the medium for MCF7, and HEBM from LONZA was used as the medium for HMEC.

  The results are shown in FIG.

  PCPA-Tm-a / b completely inhibited the growth of MCF7 dependent on estradiol (E2) at a concentration of 0.1 μM. On the other hand, HMEC showed no toxicity within the effective concentration range for cancer cells.

Claims (6)

A compound represented by the following formula (I) or a pharmaceutically acceptable salt thereof.
[Where:
Ar represents an aryl group which may have a substituent or a heteroaryl group which may have a substituent.
* 1 and * 2 indicate asymmetric carbon.
R ¹ and R ² independently represent a hydrogen atom or an alkyl group.
YL represents a linker group (Y represents O, S, or NH).
ZH represents a pharmaceutical compound represented by DOH, DSH, DNH ₂ or D ₁ D ₂ NH.
p shows the integer of 1-3.
q represents 0 or 1; ]   The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein the pharmaceutical compound represented by ZH is an antitumor agent.   The compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein the linker group is a linker group that can be removed via an elimination reaction. Any one of the following compounds or a pharmaceutically acceptable salt thereof:
(E / Z) -4- (1- (4- (2- (Dimethylamino) ethoxy) phenyl) -2-phenylbut-1-en-1-yl) phenyl (2- (methyl (2-phenylcyclopropyl ) Amino) ethyl) carbamate;
(E / Z) -4- (1- (4- (2- (Dimethylamino) ethoxy) phenyl) -2-phenylbut-1-en-1-yl) phenylmethyl (2- (methyl (2-phenylcyclo Propyl) amino) ethyl) carbamate
N ¹ -{{{[N-methyl-N- (trans-2-phenylcyclopropyl) amino] ethyl} carbamoyl} oxy} -N8-phenyloctanediamide;
N ¹ -((methyl (2- (methyl (2-phenylcyclopropyl) amino) ethyl) carbamoyl) oxy) -N8-phenyloctanediamide;
Pyridin-3-ylmethyl 4-((2- (3- (2- (methyl (2-phenylcyclopropyl) amino) ethyl) ureido) phenyl) carbamoyl) benzylcarbamate;
Pyridin-3-ylmethyl 4-((2- (3-methyl-3- (2- (methyl (2-phenylcyclopropyl) amino) ethyl) ureido) phenyl) carbamoyl) benzylcarbamate;
4-(((2- (methyl (2-phenylcyclopropyl) amino) ethyl) carbamoyl) (5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl) carbamoyl )benzoic acid;
4-((Methyl (2- (methyl (2-phenylcyclopropyl) amino) ethyl) carbamoyl) (5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl) Carbamoyl) benzoic acid;
4-((Methyl (3- (methyl (2-phenylcyclopropyl) amino) propyl) carbamoyl (5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl) carbamoyl )benzoic acid;
4-((Methyl (4- (methyl (2-phenylcyclopropyl) amino) butyl) carbamoyl) (5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl) Carbamoyl) benzoic acid;
4-((((8-oxo-8- (phenylamino) octanamido) oxy) methyl) phenylmethyl (2- (methyl (2-phenylcyclopropyl) amino) ethyl) carbamate;
4-((4-((methyl (2- (methyl (2-phenylcyclopropyl) amino) ethyl) carbamoyl) oxy) benzyl) (5,5,8,8-tetramethyl-5,6,7,8 -Tetrahydronaphthalen-2-yl) carbamoyl) benzoic acid;
4-((3- (4-Cyano-3- (trifluoromethyl) phenyl) -5,5-dimethyl-2,4-dioxoimidazolidin-1-yl) methyl) phenylmethyl (2- (methyl ( 2-Phenylcyclopropyl) amino) ethyl) carbamate   A pharmaceutical composition comprising the compound according to any one of claims 1 to 4 or a pharmaceutically acceptable salt thereof.   An antitumor agent comprising the compound according to claim 2 or 4 or a pharmaceutically acceptable salt thereof as an active ingredient.