GB2562777A - Novel alpha-amino amide derivatives - Google Patents

Novel alpha-amino amide derivatives Download PDF

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Publication number
GB2562777A
GB2562777A GB1708390.8A GB201708390A GB2562777A GB 2562777 A GB2562777 A GB 2562777A GB 201708390 A GB201708390 A GB 201708390A GB 2562777 A GB2562777 A GB 2562777A
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United Kingdom
Prior art keywords
esi
compound
chiral
amino
phenyl
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GB1708390.8A
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GB201708390D0 (en
Inventor
Takashima Hajime
Ushiyama Fumihito
Yamada Yousuke
Matsuda Yohei
Yoshizumi Takashi
Kim Chunhae
Yamagishi Junya
Teresa Macias Arrate Alba
David Roughley Stephen
Mckenna Sean
Lee Walmsley David
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Taisho Pharmaceutical Co Ltd
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Taisho Pharmaceutical Co Ltd
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Priority to GB1708390.8A priority Critical patent/GB2562777A/en
Publication of GB201708390D0 publication Critical patent/GB201708390D0/en
Priority to PCT/JP2018/021101 priority patent/WO2018216823A1/en
Publication of GB2562777A publication Critical patent/GB2562777A/en
Withdrawn legal-status Critical Current

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/08—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms
    • C07D211/18—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D211/20—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by singly bound oxygen or sulphur atoms
    • C07D211/22—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by singly bound oxygen or sulphur atoms by oxygen atoms
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    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/08—Indoles; Hydrogenated indoles with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, directly attached to carbon atoms of the hetero ring
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    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/16—Amides, e.g. hydroxamic acids
    • A61K31/165—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide
    • A61K31/167—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide having the nitrogen of a carboxamide group directly attached to the aromatic ring, e.g. lidocaine, paracetamol
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    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
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    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
    • A61K31/404—Indoles, e.g. pindolol
    • A61K31/4045—Indole-alkylamines; Amides thereof, e.g. serotonin, melatonin
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    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
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    • A61K31/427—Thiazoles not condensed and containing further heterocyclic rings
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    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4402—Non condensed pyridines; Hydrogenated derivatives thereof only substituted in position 2, e.g. pheniramine, bisacodyl
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    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
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    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/444—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring heteroatom, e.g. amrinone
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    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
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    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A61K31/4535—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a heterocyclic ring having sulfur as a ring hetero atom, e.g. pizotifen
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    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A61K31/454—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. pimozide, domperidone
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    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A61K31/4545—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring hetero atom, e.g. pipamperone, anabasine
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    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C237/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups
    • C07C237/02—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of the carbon skeleton
    • C07C237/04—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton being acyclic and saturated
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    • C07C237/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups
    • C07C237/28—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atom of at least one of the carboxamide groups bound to a carbon atom of a non-condensed six-membered aromatic ring of the carbon skeleton
    • C07C237/40—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atom of at least one of the carboxamide groups bound to a carbon atom of a non-condensed six-membered aromatic ring of the carbon skeleton having the nitrogen atom of the carboxamide group bound to a carbon atom of a six-membered aromatic ring
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    • C07D209/30—Indoles; Hydrogenated indoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to carbon atoms of the hetero ring
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    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/08—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms
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Abstract

A compound represented by the general formula [1] or a pharmaceutically acceptable salt thereof, wherein X represents a group selected from formula [2], Y represents a group as herein defined and * indicates the site of the attachment of a moiety. A pharmaceutical composition comprising the compound or the pharmaceutically acceptable salt thereof. An LpxC inhibitor comprising the compound represented by the general formula [1] or pharmaceutically acceptable salt thereof. An antimicrobial agent comprising the compound represented by the general formula [1] or pharmaceutically acceptable salt thereof.

Description

NOVEL ALPHA-AMINO AMIDE DERIVATIVES
This invention relates to novel alpha-amino amide derivatives or salts thereof, which exhibit an activity for inhibiting uridyldiphospho(UDP)-3-O-acyl-N-acetylglucosamine deacetylase (LpxC) and antimicrobial pharmaceuticals comprising the same.
Gram-negative bacteria have an outer membrane composed of a lipid bilayer inexistent in gram-positive bacteria, and thus are more resistant to drugs, as compared with gram-positive bacteria, due to the problem of drug permeability. Gram-negative bacteria are also known to have a plurality of drug efflux proteins, which are known to be involved in drug resistance (Non-Patent Document 1). Furthermore, lipopolysaccharide (LPS), one of the main constituents of the outer membrane, is involved in toxicity as an endotoxin.
Among gram-negative bacteria, Pseudomonas aeruginosa, in particular, has a strong tendency to show natural resistance to various antimicrobial agents. In recent years, Pseudomonas aeruginosa strains, which has gained resistance to carbapenem drugs, quinolone drugs or aminoglycoside drugs, has been clinically isolated in medical settings (Non-Patent Document 2). Moreover, multi-drug resistant Pseudomonas aeruginosa which has obtained resistance to all of these three types of drugs has been isolated (Non-Patent Document 3). Emergence of multi-drug resistant Pseudomonas aeruginosa has become a major healthcare problem worldwide, because there have been few useful therapeutic drugs. Hence, there is a keen demand for the development of a drug having a novel mechanism of action.
UDP-3-O-acyl-N-acetylglucosamine deacetylase (LpxC) is an enzyme in charge of the synthesis of lipid A (hydrophobic anchor of LPS which is the constituent of the outer membrane). Lipid A biosynthesis consists of reactions in ten stages, and LpxC catalyzes the second stage of the biosynthesis reactions to remove the acetyl group of UDP-3-O-acyl-Nacetylglucosamine (Non-Patent Document 4). Lipid A is a component essential for the formation of the outer membrane, and is consequently indispensable for the survival of gramnegative bacteria (Non-Patent Document 5). LpxC is a rate-determining enzyme in the process of lipid A biosynthesis, and is an indispensable enzyme for lipid A biosynthesis. Thus, a drug inhibiting the activity of LpxC is highly expected to be an antimicrobial agent effective against gram-negative bacteria including Pseudomonas aeruginosa, particularly against drug resistant Pseudomonas aeruginosa and other gram-negative bacteria, because such a drug has a mechanism of action different from those of conventional drugs. LpxC has been the focus of several pharmaceutical drug development programs over the last decade. LpxC has the catalytic zinc ion in its active site and many of the potent LpxC inhibitors identified so far contain a zinc-binding hydroxamic acid group. The Non-Patent
-2Documents 6 and 7 summarize reported hydroxamic acid LpxC inhibitors. However, the hydroxamic acid group has been found to cause several problems associated with off-target toxicities and poor pharmacokinetics properties. All previous attempts to solve the problems have turned out unsuccessful.
Very few LpxC inhibitors are known that do not contain a hydroxamic acid group. Cohen’s group reported LpxC inhibitors that contain a kojic acid group instead of a hydroxamic acid group. They also presented a non-hy dr oxami c acid LpxC inhibitor at the ASM Microbe 2016 / ICAAC2016 poster No. LB-056 but its chemical structure is not disclosed.
Thus there is an urgent need for a novel and effective antibacterial drug that does not contain a hydroxamic acid group and which works with a novel mechanism of action.
Patent Document 1: International Publication 15/085238 pamphlet.
Non-Patent Document 1: Antimicrobial Resistance (2002) Mar 1, 34, pp. 634-640. Non-Patent Document 2: J. Antimicrob. Chemother. (2003) Jan 14, 51, pp. 347-352. Non-Patent Document 3: J Hosp Med. (2013) Sep 10, 8, pp. 559-563.
Non-Patent Document 4: J. Biol. Chem. (1995) Dec 22, 270, pp. 30384-30391.
Non-Patent Document 5: J. Bacteriol. (1987), 169, pp. 5408-5415.
Non-Patent Document 6: Cold Spring Harb PerspectMed. (2016), July 1; 6(7), a025304. Non-Patent Document 7: Curr Top Med Chem. (2016) 16(21), pp. 2379-2430.
An object of the present invention is to find novel compounds that do not contain a hydroxamic acid group and inhibit LpxC or pharmaceutically acceptable salts thereof, and provide new pharmaceutical drugs that exhibit antimicrobial activity against gram-negative bacteria including Pseudomonas aeruginosa and their drug resistant strains and that are useful in treating bacterial infections.
The present inventors have conducted in-depth studies in an attempt to find out a compound having LpxC-inhibiting activity. As a result, they have found that a non-hydroxamic acid compound represented by the following general formula [1] or a pharmaceutically acceptable salt thereof attains the above object. Based on this finding, they have accomplished the present invention. The present invention will be described below. The present invention provides (1) A compound represented by the following general formula [1] or a pharmaceutically acceptable salt thereof:
-3 wherein
X represents a group selected from the following formula [2]:
*
[2],
Y represents a group selected from the following formula [3]:
* * * *
R1 represents a group selected from the following formula [4]:
[3],
C2_4 alkynyl —*
alkyl—*
L1 represents a bond or a C1.4 alkylene group,
R represents a phenyl group or a halogen atom, □
R represents a group selected from the following formula [5]:
W L3—* Halogen—* [5], wherein the phenylene group represented by formula [5] may be substituted with a halogen atom, □
L represents a Ci.4 alkylene group, a Ci.4 alkynylene group, -0-, -OCH2- -CH2O- or a bond,
R4 represents a group selected from the following formula [6]:
WL4—* Halogen—* [6],
L4 represents -C=C-, a Ci.4 alkylene group or a bond,
R5 represents a group selected from the following formula [7]:
W—6 h—L5—* Halogen—* [7],
L5 represents -C=C- a Ci.4 alkylene group or a bond, R6 represents a group selected from the following formula [8]:
L6 represents -C=C- a Ci.4 alkylene group or a bond, and
W represents a hydrogen atom, a halogen atom, a phenyl group, a Ci-4 hydroxyalkyl group, HOCH2CH2O-, HOOC-CH2CH2- or N-morpholinomethyl group, n represents 1 or 2, and * indicates the site of the attachment of a moiety;
(2) The compound or the pharmaceutically acceptable salt thereof, according to item (1), wherein X is selected from the following formula [2a]:
[2a];
wherein R1, R3, R4 and R5 are as defined in item (1).
(3) The compound or the pharmaceutically acceptable salt thereof, according to item (1) or (2), wherein Y is selected from the following formula [3a]:
OH *
HO'
2 Me [3a];
(4) The compound or the pharmaceutically acceptable salt thereof, according to item (3), wherein Y is selected from the following formula [3b]:
O2S
Me Me Me [3b];
(5) The compound or the pharmaceutically acceptable salt thereof, according to any one of items (1) to (4), wherein R1 is selected from the following formula [4]:
[4a];
wherein W is as defined in item (1).
(6) The compound or the pharmaceutically acceptable salt thereof, according to item (1), wherein X is selected from the following formula [2b]:
[2b], wherein R6 is as defined in item (1) and Y is selected from the following formula [3c]:
* * * * * * (7) A pharmaceutical composition comprising the compound or the pharmaceutically acceptable salt thereof according to any one of items (1) to (6);
(8) An LpxC inhibitor comprising the compound or the pharmaceutically acceptable salt thereof according to any one of items (1) to (6).
(9) An antimicrobial agent comprising the compound or the pharmaceutically acceptable salt thereof according to any one of items (1) to (6).
The compound or the pharmaceutically acceptable salt thereof according to the present invention has a strong LpxC-inhibiting action. Thus, the compound or its pharmaceutically acceptable salt is useful as a pharmaceutical composition and as an antimicrobial agent against gram-negative bacteria.
The present invention will be described in further detail below. The terms and phrases used herein will be explained first.
-6In the present invention, n- means normal, i- iso, sec- secondary, tert- tertiary, c- cyclo, o- ortho, m- meta, and p- para.
The halogen atom means a fluorine atom, a chlorine atom, a bromine atom, and an iodine atom.
The Ci-4 alkyl group refers to a straight-chain or branched-chain alkyl group having 1 to 4 carbon atoms. Its examples are a methyl group, an ethyl group, a n-propyl group, a n-butyl group, an isopropyl group, an isobutyl group, a tert-butyl group and a sec-butyl group.
The C2-4 alkynyl group refers to a straight-chain or branched-chain alkynyl group with 2 to 4 carbon atoms which has one or more triple bonds at any position(s) of the above-mentioned Ci-8 alkyl group. Its examples are an ethynyl group, a 1-propynyl group, a 2-propynyl group, a 1-butynyl group and a 3-butynyl group.
The C1.4 hydroxyalkyl group refers to an alkyl group in which one or more of the hydrogen atoms of the above-mentioned C1.4 alkyl group has been or have been substituted with a hydroxyl group or hydroxyl groups. Its examples are a hydroxymethyl group, a 1hydroxyethyl group, a 2-hydroxyethyl group, a 2-hydroxypropyl group, a 3-hydroxypropyl group, a 1-hydroxybutyl group, a 2-hydroxybutyl group, a 3-hydroxybutyl group and a 4hydroxybutyl group.
The C1.4 alkylene group refers to a straight-chain or branched-chain alkylene group having 1 to 4 carbon atoms. Its examples are -CH2-, -(CH2)2-, -(CH2)3-, -CH2-CH(CH3)-, -C(CH3)2-, -(CH2)4-, -(CH2)2-CH(CH3)-, -CH2-CH(CH3)-CH2- and -CH(CH3)-(CH2)2-.
The C2-4 alkynylene group refers to a straight-chain or branched-chain alkynylene group having 2 to 4 carbon atoms which has one or more triple bonds in the chain.
The protecting group for an amino group include all groups usable usually as protecting groups for an amino group, and includes, for example, the groups described in P.G.M. Wuts et al., Protective Groups in Organic Synthesis, 5th Ed., 2014, John Wiley Sons, Inc.
The leaving group includes, for example, a halogen atom, a methnesulfonyloxy group, a ethanesulfonyloxy group, a isopropanesulfonyloxy group, a trifluoromethanesulfonyloxy group, benzensulfonyloxy group and a p-toluenesulfonyloxy group.
The antimicrobial agent refers to a substance which has the ability to act on bacteria, such as gram-positive bacteria or gram-negative bacteria, thereby suppressing their growth or destroying them. The antimicrobial agent may be one which keeps down propagation of bacteria, or kills some of bacteria to decrease their count. Examples of gram-positive bacteria
-7are the genus Staphylococcus (Staphylococcus aureus, Staphylococcus epidermidis, etc.), the genus Streptococcus (Streptococcus pyogenes, Streptococcus agalactiae, Streptococcus pneumoniae, etc.), and the genus Enterococcus (Enterococcus faecalis, Enterococcus faecium, etc ). Examples of gram-negative bacteria are the genus Pseudomonas (Pseudomonas aeruginosa, etc.), the genus Escherichia (Escherichia coli, etc.), the genus Klebsiella (Klebsiella pneumoniae, Klebsiella oxytoca, etc.), the genus Haemophilus (Haemophilus influenzae, Haemophilus parainfluenzae, etc.), the genus Bordetella (Bordetella pertussis, Bordetella bronchiseptica, etc.), the genus Serratia (Serratia marcescens, etc.), the genus Proteus (Proteus mirabilis, etc.), the genus Enterobacter (Enterobacter cloacae, etc.), the genus Campylobacter (Campylobacter jejuni, etc.), the genus Citrobacter, the genus Vibrio (Vibrio parahaemolyticus, Vibrio cholerae, etc.), the genus Morganella (Morganella morganii, etc ), the genus Salmonella (Salmonella typhi, Salmonella paratyphi, etc.), the genus Shigella (Shigella dysenteriae, etc.), the genus Acinetobacter (Acinetobacter baumannii, Acinetobacter calcoaceticus, etc.), the genus Legionella (Legionella pneumophila, etc.), the genus Bacteroides (Bacteroides fragilis, etc.), the genus Neisseria (Neisseria gonorrhoeae, Neisseria meningitides, etc.), the genus Moraxella (Moraxella catarrhalis, etc.), the genus Chlamydia (Chlamydia trachomatis, Chlamydia psittaci, etc.), and the genus Helicobacter (Helicobacter pylori, etc.).
The preferred embodiments of the compound according to the present invention are as follows:
Preferred X is a group represented by the following formula [2a]:
wherein R1, R3, R4 and R5 are defined above, and more preferred X is a group represented by the following formula:
wherein R1 is defined above.
Preferred Y is a group represented by the following formula [3a]:
* * * * * *
more preferred X is a group represented by the following formula [3b]:
Me [3b], * *
S...
Me and the most preferred X is a group represented by the following formula:
*
HO °2^'Me.
Preferred R1 is a group represented by the following formula [4]:
w
* [4]· where the definition of Wis described above. Preferred W is a hydrogen atom, a C1.4 hydroxyalkyl group, HOCH2CH2O- or N-morpholinomethyl group.
A preferred embodiment of the compound according to the present invention is as follows:
where the definition and preferred embodiment of W are described above.
The compounds represented by the formula [1] of the present invention have asymmetric carbon at alpha-carbon atom. The compounds of the present invention may be used in racemic form or as a specific enantiomer. As the specific enantiomer, the compounds represented by the following formula [10] are preferred:
where the definitions and preferred forms of X and Y are described previously.
The compounds of the present invention can exist as tautomers, stereoisomers such as geometrical isomers, and optical isomers, and the present invention includes them. The present invention also includes various hydrates, solvates and polymorphic substances of the compounds of the invention and their salts.
In the present invention, the pharmaceutically acceptable salts refer to salts which are used in
-9chemotherapy and prevention of bacterial infections. Their examples are salts with acids such as formic acid, acetic acid, propionic acid, butyric acid, trifluoroacetic acid, maleic acid, tartaric acid, citric acid, stearic acid, succinic acid, ethylsuccinic acid, malonic acid, lactobionic acid, gluconic acid, glucoheptonic acid, benzoic acid, methanesulfonic acid, ethanesulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid (tosic acid), laurylsulfuric acid, malic acid, aspartic acid, glutamic acid, adipic acid, hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, hydriodic acid, nicotinic acid, oxalic acid, picric acid, thiocyanic acid, undecanoic acid, acrylic polymer, and carboxyvinyl polymer; salts with inorganic bases such as lithium salt, sodium salt, potassium salt, magnesium salt and calcium salt; salts with organic amines such as morpholine and piperidine; and salts with amino acids. For reference see for example “Handbook of Pharmaceutical Salts. Properties, Selection and Use.” P. Heinrich Stahl, Camille G. Wermuth (Eds.), Wiley-VCH (2008).
The compound of the present invention can be made into a medicinal preparation upon combination with one or more pharmaceutically acceptable carriers, excipients or diluents. Examples of such carriers, excipients and diluents include water, lactose, dextrose, fructose, sucrose, sorbitol, mannitol, polyethylene glycol, propylene glycol, starch, gum, gelatin, alginate, calcium silicate, calcium phosphate, cellulose, aqueous syrup, methyl cellulose, polyvinyl pyrrolidone, alkylparahydroxybenzosorbate, talc, magnesium stearate, stearic acid, glycerin, sesame oil, olive oil, soy oil, and various other seed oils. Moreover, the above carriers, excipients or diluents can be mixed, as needed, with commonly used additives such as thickeners, binders, disintegrants, pH regulators, and solvents, and can be prepared as an oral or parenteral drug, such as tablets, pills, capsules, granules, powders, liquids, emulsions, suspensions, ointments, injections, or skin patches, by a customary pharmaceutical technology.
The compound of the present invention can be administered intravenously, orally or parenterally to an adult patient in a dose of 10 to 5,000 mg as a single daily dose or as divided portions per day. This dose can be increased or decreased, as appropriate, according to the type of the disease to be treated, or the age, body weight, symptoms, etc. of the patient. The compound of the present invention can also be used in combination with other drugs. The compound of the present invention can be synthesized, for example, by methods to be shown below, but the present invention is in no way limited to these methods of manufacturing the compound.
Scheme I:
(l-A) (l-B) (l-C) (l-D)
A compound represented by the general formula (I-A) (where RIa-NH-RIb is a compound represented in formula [2] defined above) is reacted with a compound represented by the general formula (I-B) (where Rlc is a hydroxyl group or a halogen atom, PG is a protecting group for an amino group, and Y is as defined above) in the presence of a condensing agent (in case Rlc is a hydroxyl group) and in the presence or absence of a base, whereby a compound represented by the general formula (I-C) can be obtained. Then, the compound represented by the general formula (I-C) is reacted under appropriate conditions in accordance with the type of the protecting group PG, whereupon the compound represented by the general formula (I-D) can be obtained.
A compound having a benzylpiperidine group represented in formula [2] can be synthesized in the following scheme II.
A compound represented by the general formula (II-A) (where W is as defined above) is reacted with a compound represented by the general formula (II-B) (where RIIa is a leaving group, PG is a protecting group for an amino group, and the other symbol is as defined above) in the presence of catalysts, such as bis(triphenylphosphine)dichloropalladium and cupper iodide, in the presence or absence of a base, and in the presence or absence of a ligand, whereby a compound represented by the general formula (II-C) (where the symbols are as defined above) can be obtained. Then, the compound represented by the general formula (IIC) is reacted under appropriate conditions in accordance with the type of the protecting group PG, whereupon the compound represented by the general formula (II-D) can be obtained.
A compound having the other group represented in formula [2] (a benzylidenepiperidine group substituted by R , an indoline group substituted by R , a 1,2,3,4-tetrahydroisoquinoline
- 11 group substituted by R4, a lH-indol-3-amine group substituted by R5 or an aniline group substituted by R6) can be synthesized in the same manner as scheme II by replacing the compound of the general formula (II-B) with the corresponding compound.
In the methods of synthesis shown above, the sequence of the reaction steps can be changed as needed. If an amino group, a hydroxyl group, a formyl group, and a carboxy group are present in the compounds obtained in the respective reaction steps and their intermediates, the reactions can be performed, with the protective groups for them being removed for deprotection or being used in appropriately changed combinations.
Unless otherwise specified, examples of the base used in any of the above reactions are sodium carbonate, potassium carbonate, cesium carbonate, sodium hydrogen carbonate, potassium hydrogen carbonate, sodium acetate, potassium acetate, potassium hydroxide, sodium hydroxide, lithium hydroxide, sodium methoxide, potassium tert-butoxide, sodium hydride, lithium hydride, triethylamine, diisopropylethylamine, dimethylaniline, diethylaniline, pyridine, pyrrolidine, and N-methylmorpholine.
Examples of the catalyst are palladium acetate, palladium chloride, bis(triphenylphosphine)palladium(II) dichloride, tetrakis(triphenylphosphine)palladium, bis(acetonitrile)dichloropalladium, bis(benzonitrile)dichloropalladium, tris(dibenzylideneacetone)dipalladium, bis(dibenzylideneacetone)palladium, 1,1'bis(diphenylphosphino)ferrocenedichloropalladium, bis(tricyclohexylphosphine)dichloropalladium, bis(tri-o-tolylphosphine)dichloropalladium, bis(tri-tert-butylphosphine)dichloropalladium, (l,3-bis(2,6diisopropylphenyl)imidazolidene)(3-chloropyridyl)palladium(II) dichloride, palladium on carbon, palladium hydroxide, and copper iodide.
Examples of the ligand are tri-tert-butylphosphine, tricyclohexylphosphine, triphenylphosphine, tritolylphosphine, tributyl phosphite, tricyclohexyl phosphite, triphenyl phosphite, 1,1 '-bis(diphenylphosphino)ferrocene, 2,2'-bis(diphenylphosphino)-1,1'binaphthyl, 2-dicyclohexylphosphino-2',6'-dimethoxybiphenyl, 2-dicyclohexylphosphino2',4',6'-triisopropylbiphenyl, 2-(di-tert-butylphosphino)-2',4',6'-triisopropylbiphenyl, and 2(di-tert-butylphosphino)biphenyl.
The solvent is not limited, if it is stable under the reaction conditions concerned, is inert, and does not impede the reaction. Examples of the solvent are polar solvents (e.g., water and alcoholic solvents such as methanol, ethanol and isopropanol), inert solvents (e.g., halogenated hydrocarbon-based solvents such as chloroform, methylene chloride, dichloroethane and carbon tetrachloride, ether-based solvents such as diethyl ether, diisopropyl ether, tetrahydrofuran, 1,4-dioxane and dimethoxyethane, aprotic solvents such as dimethylformamide, dimethyl sulfoxide, ethyl acetate, tert-butyl acetate, acetonitrile and propionitrile, aromatics such as benzene, toluene and anisole, or hydrocarbons such as
- 12 cyclohexane), and mixtures of these solvents.
The reaction can be performed at an appropriate temperature selected from a range of from -78°C to the boiling point of the solvent used in the reaction, at ordinary pressure or under pressurized conditions, and under microwave irradiation or the like.
Experimental Procedures
Herein below, the present invention will be described in further detail by examples of preparation of Intermediates, Compounds in the Examples, and Reference Compounds. The compounds of the present invention are in no way limited to the compounds described in the Examples presented below.
Unless otherwise described, the following conditions were used for compound synthesis, purification and analysis.
A microwave synthesizer Initiator+ (Biotage) was used for a microwave reaction condition. OH-type silica gel column chromatography was performed using SNAP Ultra (Biotage) or using REVELERIS 40 pm (Grace), and amino-type type silica gel chromatography was performed using SNAPCartridge ISOLUTE Flash-NH2 (Biotage) or Grace REVELERIS Amino 40 pm (Grace). Preparative chromatography was performed using PLC Silica gel 60F254 (Merck), and amino-type preparative chromatography was performed using NH2 Silica Gel 60 F254 Plate- Wako (Wako).
The prep-HPLC purifications were performed using Agilent 1260 Infinity or Agilent 6130 (ionization method: Electron Spray Ionization (ESI)), and Agilent 385-ELSD were used when the ELSD detector was attached.
Columns: YMC-Actus Triart C18, 5.0 pm, Φ30 x 50 mm.
Xbridge Prep C18, 5.0 pm OBD, Φ 30 x 50 mm.
Waters XSlect CSH 5.0 pm, Φ 30 x 50 mm.
Eluents: A(H2O + 0.1% HCOOH), B(CH3CN + 0.1% HCOOH).
One of the following conditions was used for purifications:
1. Elow rate 50mL/min; 0-0.5 min (A/B = 90/10), 0.5-7.5 min (A/B = 90/10-20/80, gradient), 7.5-7.95 min (A/B = 20/80), 7.95-8.0 min (A/B = 20/80-5/95, gradient), 8.09.0 min (A/B = 5/95).
2. Elow rate 50mL/min; 0-0.5 min (A/B = 95/5), 0.5-7.5 min (A/B = 95/5-50/50, gradient), 7.5-7.95 min (A/B = 50/50), 7.95-8.0 min (A/B = 50/50-5/95, gradient), 8.0-9.0 min (A/B = 5/95).
3. Flow rate 50mL/min; 0-0.5 min (A/B = 80/20), 0.5-7.0 min (A/B = 80/20-5/95, gradient), 7.0-7.45 min (A/B = 5/95), 7.45-7.5 min (A/B = 5/95-1/99, gradient), 7.5-9.0 min (A/B = 1/99).
4. Flow rate 40mL/min; 0-2.0 min (A/B = 90/10), 2.0-11.0 min (A/B = 90/10-20/80, gradient), 11.0-12.0 min (A/B = 20/80-5/95, gradient), 12.0-13.5 min (A/B = 5/95).
NMR spectra were run on JNM-ECA600 (600 MHz, JEOL), JNM-ECA500 (500 MHz, JEOL) or AVANCE III HD 400 (400 MHz, BRUKER). Chemical shifts for 1H NMR are reported in parts per million (ppm). Abbreviations used in the 'H NMR data are shown below, s: Singlet br.s.: Broad singlet d: Doublet dd: Double doublet dt: Double triplet t: Triplet td: Triple doublet tt: Triple triplet q: Quartet quin: Quintet m: Multiplet
Mass spectra (MS) and the retention time (RT, minutes) were run on LC-MS systems with one of the following Methods and Conditions:
A Agilent 1290 Infinity for LC system, Agilent 6130 or 6150 for Quadrupole LC/MS system, and Agilent 385-ELSD when a ELSD detector is attached.
Column: ACQUITY CSH C18 (Waters), 1.7 qm, Φ2.1 x 50 mm.
Ionization method: ESI.
Eluents: A(H2O + 0.1% HCOOH), B(CH3CN + 0.1% HCOOH).
Flow rate: 0.8 mL/min.
Detection: 254nm, 210nm or ELSD.
Gradient: 0.0-0.8 min (A/B = 95/5-60/40), 0.8-1.08 min (A/B = 60/40-1/99), 1.081.38 min (A/B = 1/99).
B Equipment, column, ionization method, eluents, flow rate and detection are the same as condition 1.
Gradient: 0.0-1.2 min (A/B = 80/20-1/99), 1.2-1.4 min (A/B = 1/99).
C Equipment, column, ionization method, eluents, flow rate and detection are the same as condition 1.
Gradient: 0.0-0.8 min (A/B = 70/30-1/99), 0.8-1.4 min (A/B = 1/99).
D Equipment: LCMS-2010EV (Shimadzu).
Column: XR-ODS (Shimadzu), 2.2 qm, Φ2.0 x 30 mm.
Ionization method: ESEAPCI (atmospheric pressure chemical ionization) dual source.
Eluents: A(H2O + 0.1% HCOOH), B(CH3CN + 0.1% HCOOH).
Flow rate: 0.6 mL/min.
- 14 Detection: 254nm or210nm.
Gradient: 0.0-0.5 min (A/B = 90/10), 0.5-1.5 min (A/B = 90/10-60/40), 1.5-2.5 min (A/B = 60/40-1/99), 2.5-5.0 min (A/B = 1/99).
E Equipment; Agilent 1290 Infinity II series instrument connected to an Agilent TOF 6230 single quadrupole with a ESI source.
Column C18, Φ50 x 2.1 mm, 2.5 pm (Phenomenex).
Eluents: A (H2O + 10 mmol / ammonium formate + 0.08% (v/v) formic acid at pH ca 3.5), B (95% Acetonitrile + 5% A + 0.08% (v/v) formic acid).
Detection: 230 nm, 254 nm and 270 nm.
Gradient: 0.0-0.12 min (A/B = 95/5 flow 1.3 mL/min), 0.12-1.30 min (A/B = 95/55/95 flow 1.3 mL /min), 1.30-1.35 min (A/B = 5/95 flow 1.3-1.6 mL/min), 1.35-1.85 min (A/B = 5/95 flow 1.6 mL/min), 1.85-1.90 min (A/B = 5/95 flow 1.6-1.3 mL/min), 1.901.95 min (A/B = 5/95-95/5 flow 1.3 mL/min).
Mass spectra (MS) were performed with the following conditions: F Equipment: LCMS-IT-TOF (Shimadzu).
Ionization method: ESEAPCI (electrospray ionization / atmospheric pressure c hemical ionization) dual source.
Eluents: 90% CH3OH.
Flow rate: 0.2 mL/min.
Chemical names of compounds in the Examples, Intermediates and Reference Compounds are generated by ACD/Name 2015 (ACD Labs 2015 LSM, Advanced Chemistry Development Inc.,).
Abbreviations used in the Experimental procedures are shown below.
(+)-CSA: (+)-10-camphorsulfonic acid
APCI: Atmospheric pressure chemical ionization aq.: Aqueous solution
Boc: t-Butoxycarbonyl (Boc)2O: Di-tert-butyl dicarbonate
Bn: Benzyl
Bu: Butyl
BuOAc: n-Butyl acetate
CHCf: Chloroform
CS2CO3: Cesium carbonate
Cui: Copper(I) iodide
DEAD: Diethyl azodicarboxylate
Dess-Martin Periodinane: 1,1,1 -Triacetoxy-1,1 -dihydro-1,2-benziodoxol-3(lH)-one DIPEA: N,N-diisopropylethylamine
- 15 DMAP: A,A-dimethyl-4-aminopyridine
DME: Dimethoxy ethane
DMF: N,N-dimethylformamide
DMSO-d6: Hexadeuterodimethyl sulfoxide
DPPA: Diphenylphosphoryl azide ee: Enantiomeric excess
ESI: Electrospray ionization
Et: Ethyl
EtOAc: Ethyl acetate
EtOH: Ethanol
HATU: O-(7-azabenzotriazol-1 -yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate
HC1: Hydrochloride
HMDS: Hexamethyldisilazane
HOBt · H2O: 1-Hydroxybenzotriazole monohydrate
IP A: Isopropyl alcohol
IPE: Diisopropyl ether
LC: Liquid chromatography
LDA: Lithium diisopropylamide
Me: Methyl
MeOH: Methanol
Ms: Methanesulfonyl
NaBH4: S odium tetrahydrob orate
NaBH(OAc)3: Sodium tri acetoxyb orohydri de
NH4CI: Ammonium chloride
NMM: 4-Methylmorphiline
NMP: l-Methyl-2-pyrrolidone
OTHP: l-Tetrahydropyran-2-yloxy
OTBDPS: Tert-butyl diphenylsilyl oxy
OTBS: Tert-butyldimethylsilyloxy
OMs: Methanesulfonyl oxy
OTs: 4-Methylbenzenesulfonyloxy
PEPPSI: (l,3-bis(2,6-diisopropylphenyl)imidazolidene)(3-chloropyridyl)palladium(II) di chloride
PdChCdppf) CH2C12: l,T-bis(diphenylphosphino)ferrocenepalladium(II) chloride dichloromethane complex
PdC12(PPh3)2: Bis(triphenylphosphine)palladium(II) dichloride
Pd(PPh3)4: Tetrakis(triphenylphosphine)palladium(0)
- 16 PPh3: Triphenylphosphine
PPTS: Pyridine 4-methylbenzenesulfonate (p-Tol)3P: Tri(4-methylphenyl)phosphine p-TsOH: p-Toluenesulfonic acid quant.: Quantitative yield
RT: Retention time (minutes) measured by LCMS
SFC: Supercritical Fluid Chromatography
SUPERSTABLE PD(0) CATALYST: Tris{tris[3,5-bis(trifluoromethyl)phenyl]phosphine} palladium(O)
T3P: Propylphosphonic anhydride
TBAF: Tetra-n-butylammonium fluoride
TBDPS: Tert-butyl diphenylsilyl
TBS: Tert-butyl dimethylsilyl
TEA: Triethylamine
TFA: Trifluoroacetic acid
THF: Tetrahydrofuran
THP: Tetrahydropyranyl
TMAD: 3-(Dimethylcarbamoylimino)-l, 1-dimethylurea
TMS: Trimethyl silyl
TIPS: Triisopropylsilyl
TrCl : Triphenylmethyl chloride
Ts : 4-Methylbenzenesulfonyl
TsCl: 4-Methylbenzenesulfonyl chloride
WSCHCl: l-Ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride
Reference Compounds
Table 1. Reference Compound List. Reference Compound ID, chemical structures, MS data, LCMS retention time (minutes) data and LCMS (MS) condition are shown.
ID Structure MS Retention time (minutes) Conditions
R-l HCI N N H2 F H MS (ESI) m/z : 235 [M+l]+ 0.352 B
R-2 ° HCI MS (ESI) m/z : 227 [M+l]+ 0.478 B
R-3 HCI N N H2 MS (ESI) m/z : 249 [M+l]+ 0.260 B
R-4 HCI f fx0XXV. r H MS (ESI) m/z : 263 [M+l]+ 0.416 B
R-5 HCI F rf^i 0 r H MS (ESI) m/z : 332 [M+l]+ 0.500 B
R-6 Α0Χ^Χ N A^ N r H MS (ESI) m/z : 305 [M+l]+ 0.491 B
R-7 iiA ° ρΛΛΛΝΗ/ K'n/\/xq1^\A' HCI u MS (ESI) m/z : 370 [M+l]+ 0.514 A
R-8 fxoJ0^n4Xnh2 hf f F MS (ESI) m/z : 303 [M+l]+ 0.808 B
R-9 F 0 Chira' FX0'^X'N'XNH2 ΌΗ MS (ESI) m/z : 265 [M+l]+ 0.746 A
R-10 F F 0 Chiral a0AX-nXaH2 HCI Cr OH MS (ESI) m/z : 307 [M+l]+ 0.435 B
R-ll F F A 9 Chiral ΚΑΛΑ >nh2 F H Γ N hn-A MS (ESI) m/z : 315 [M+l]+ 0.408 A
R-12 f F KY 0 “''θ' F H HCI f |] HC A-N MS (ESI) m/z : 326 [M+l]+ 0.620 A
R-13 F F A 0 Chiral F H I HCI II HCI MS (ESI) m/z : 326 [M+l]+ 0.705 A
R-14 HCI 0 HCI OH H MS (LCMS-ITTOF with ESI/APCI dual) m/z : 168 [M+l]+ ND F
R-15 HCI Λ 0 HCI BrAANA^NH2 OH H MS (LCMS-ITTOF with ESPAPCI dual)m/z : 246 [M+l]+ ND F
R-16 F^'U 0 HCI UANJfoNH2 OH H MS (ESI) m/z : 236 [M+l]+ 0.259 A
R-17 p F o Chiral ;aAA^nh2 OH MS (ESI) m/z : 279 [M+l]+ 0.774 A
R-18 Ρ>^ο^θχΝχ^γΝΗ2 HCI H MS (ESI) m/z : 269 [M+l]+ 0.755 A
R-19 F^0^^N^<NH2 HCI Ο^·ΝΗ2 MS (ESI) m/z : 198 [M+l]+ 0.177 A
R-20 F F A 0 Chiral XAArA··'™2 F Η I Fll HCI L X MS (ESI) m/z : 341 [M+l]+, 339 [Μ-l]’ 0.900 A
R-21 Chiral HNS°0 MS (ESI) m/z : 356 [M+l]+ 0.456 B
R-22 F F A 0 Chiral Ao4^ANAxNH2 F H HCI HCI 40] MS (ESI) m/z : 326 [M+l]+, 324 [M-l] 0.908 A
R-23 P F kA o Chiral A0AAfjA^,NH2 nh2 MS (ESI) m/z : 278 [M+l]+ 0.374 A
R-24 %o^O^n'0NH2 F HCI H oA MS (ESI) m/z : 293 [M+l]+ 0.478 B
R-25 ---NH2 M HCI MS (ESI) m/z : 269 [M+l]+ 0.755 A
R-26 Chiral ^o^^nx^NH2 HV 0 MS (ESI) m/z : 320 [M+l]+ 0.812 A
R-27 hn-~. h HCI MS (ESI) m/z : 190 [M+l]+ 0.216 B
R-28 F (fA 0 Chiral ..,nh2 Η I 3 0 kA H MS (ESI) m/z : 334 [M+l]+ 0.406 B
R-29 HCI 0 HCI ''oAAA--nh2 OH H MS (ESI) m/z : 198 [M+l]+ 0.177 A
R-30 F O Chiral F HCI Η 1 1 °w° L S' A' H MS (ESI) m/z : 370 [M+l]+ 0.453 B
R-31 F 0 Chiral FJ<0A^NAy'NH2 H ^νη2 MS (ESI) m/z : 292 [M+l]+ 0.322 A
R-32 HCI Ck ,N. Ύ ° HCI U^N^NH2 oh h MS (LCMS-ITTOF with ESI/APCI dual) m/z : 202 [M+l]+ ND F
R-33 HN—. q Chiral 0 MS (ESI) m/z : 306 [M+l]+ 0.762 A
R-34 F F [f^l o Chiral ^NH O=S. II 0 MS (ESI) m/z : 342 [M+l]+ 0.783 A
R-35 0 Chiral LAnA-NH2 Η T HCI OH MS (ESI) m/z : 181 [M+l]+ 0.261 A
R-36 F 0 Chiral FA0J^ANA „,nh2 Η I nh2 MS (ESI) m/z : 306 [M+l]+ 0.222 B
R-37 F 0 Chira' ...nh2 H k HN^O MS (ESI) m/z : 348 [M+l]+ 0.457 B
R-38 F f A 0 Chiral H < HN <P MS (ESI) m/z : 384 [M+l]+ 0.887 A
R-39 F <^1 0 HCI ΑΟΆνΑζΝΗ2 δ 0 0 MS (ESI) m/z : 367 [M+l]+ 0.838 A
R-40 ANH2 HCI Η X Ο^ΌΗ MS (ESI) m/z : 279 [M+l]+ 0.947 A
R-41 °2Νυν 0 Η HCI HCI MS (ESI) m/z : 197 [M+l]+ 0.233 A
R-42 F δΑ 0 HCI Α0ΑΑνΑ<ΝΗ2 HCI MS (ESI) m/z : 312 [M+l]+ 0.468 B
R-43 0 Chiral ίΜ Η Π'Αδ \MAnA ,..nh2 F ΌΗ MS (ESI) m/z : 223 [M+l]+ 0.756 A
R-44 f%0XXnmnh2 F H HCI Y \ N-# MS (ESI) m/z : 332 [M+l]+ 0.529 B
R-45 Chiral ρΥΟχΠ ? hA F A-NH2 F ΌΗ MS (ESI) m/z : 265 [M+l]+ 0.737 A
R-46 F 0 Chira' λνη 2 ^CFg MS (ESI) m/z : 317 [M+l]+ 0.961 A
R-47 >L0XXnA,nh2 H Y> MS (ESI) m/z : 331 [M+l]+ 0.603 B
R-48 Chiral ^οΑΧν1.λνη2 f %H MS (ESI) m/z : 225 [M+l]+ 0.562 A
R-49 I θ Chiral Α^Α'ν%0Λ^ρ Sh F MS (ESI) m/z : 239 [M+l]+ 0.667 A
R-50 JL nh 0 Chiral ur OH F MS (ESI) m/z : 247 [M+l]+ 0.569 A
R-51 ίΓΐ fl Chiral qUA-^ MS (ESI) m/z : 287 [M+l]+ 0.510 A
R-52 CA0Oa£.NH^C“ OH f F MS (ESI) m/z : 301 [M+l]+ 0.568 B
R-53 ill 9 Chiral OH p F MS (ESI) m/z : 281 [M+l]+ 0.653 B
R-54 F AA o HCI ρ7'ΌΑ%Ν4γΝΗ2 H Vr° 1 NH MS (ESI) m/z : 392 [M+l]+ 0.509 B
R-55 . o HCI Chiral 0AnAnh2 ΌΗ MS (ESI) m/z : 221 [M+l]+ 0.542 A
R-56 Chiral uHCI Γ J] UH MS (ESI) m/z : 281 [M+l]+ 0.595 B
R-57 Ϊ ϊ H F N ^i\r H MS (ESI) m/z : 304 [M+l]+ 0.341 B
R-58 HCI oHCI Chiral H2N^j^^N-^NH2 MS (ESI) m/z : 224 [M+l]+ 0.276 A
R-59 HCI 0 HCI Chiral <^n\'NH2 H2N\XY H L ^QH MS (ESI) m/z : 224 [M+l]+ 0.233 A
R-60 q HCI Chiral MS (ESI) m/z : 273 [M+l]+ 0.595 A
R-61 Br 0 HCI Chiral X MS (ESI) m/z : 273 [M+l]+ 0.561 A
R-62 0 HCI Chiral ΌΗ MS (ESI) m/z : 277 [M+l]+ 0.909 A
R-63 ._ F Chiral F\l HCI FO 0 X MS (ESI) m/z : 279 [M+l]+ 0.696 A
R-64 Chiral fl Π f—Uf η I ΐ th MS (ESI) m/z : 365 [M+l]+ 1.147 A
R-65 0 HC|hira' ΌΗ MS (ESI) m/z : 238 [M+l]+ 0.329 A
R-66 HN~n o Chiral -NH2 hci ΌΗ MS (ESI) m/z : 247 [M+l]+ 0.536 A
R-67 q HCI Chiral wa: MS (ESI) m/z : 279 [M+l]+ 0.976 A
R-68 q HCI Chiral /.M.' MS (ESI) m/z : 279 [M+l]+ 0.962 A
R-69 HCI Chiral ^^33νΛ;ΝΗ2 MS (ESI) m/z : 289 [M+l]+ 0.941 A
R-70 F 0HCI Chiral ΌΗ MS (ESI) m/z : 293 [M+l]+ 0.921 A
R-71 Ργ<γχ 0 HCI Chiral F F UZA.« ΌΗ MS (EST) m/z : 293 [M+l]+ 0.863 A
R-72 0 Chiral v^AnA-NH2 ΌΗ MS (ESI) m/z : 220 [M+l]+ 0.245 A
R-73 Chiral HN rs HCI AM1 O ” MS (ESI) m/z : 250 [M+l]+ 0.193 A
R-74 q q HCI Chiral Η4γνΛΝΗ2 ΌΗ MS (ESI) m/z : 274 [M+l]+ 0.230 A
R-75 0 HCI Chiral NH? MS (ESI) m/z : 274 [M+l]+ 0.229 A
R-76 HCI HCI “θ1 0 H ^OH ND ND ND
R-77 HCI Chiral o HCI Ν^ρΑ·..ΝΗ2 'oh ND ND ND
R-78 HCI HCI Chiral l^ll H 9 ^^n^nA.-nh2 ΌΗ MS (ESI) m/z : 238 [M+l]+ 0.231 A
R-79 FY0 HCI 0HCI Chiral F F nAx'-nA·'™2 U h L MS (ESI) m/z : 294 [M+l]+ 0.610 A
R-80 AA) r^/1 0 HCI Chiral ,λΝΗ2 - H L MS (ESI) m/z : 317 [M+l]+ 0.821 A
R-81 c F (fN 0 HC' Chir£ /A^sA'NH2 ΌΗ MS (ESI) m/z : 282 [M+l]+ 0.799 A
R-82 N θ Chiral bMA« ΌΗ MS (ESI) m/z : 260 [M+l]+ 0.238 A
R-83 o Chiral BrT Λ™2 ΌΗ MS (ESI) m/z : 273 [M+l]+ 0.622 A
R-84 F 0 Chiral H J MS (ESI) m/z : 328 [M+l]+ 0.541 B
R-85 HCI Chiral 'OpY' o MS (ESI) m/z : 296 [M+l]+ 0.279 A
R-86 0 Chiral ΌΗ MS (ESI) m/z : 234 [M+l]+ 0.360 A
R-87 rfofo rfofo θ °hiral MxJU-jA.anh, Ί3Η MS (ESI) m/z : 271 [M+l]+ 0.909 A
R-88 HCI Chiral 0 MS (ESI) m/z : 334 [M+l]+ 0.925 A
R-89 HCI HCI Chiral Xu/A· ΌΗ MS (ESI) m/z : 282 [M+l]+ 0.271 A
R-90 HCI o HCI Chiral •'ixoV ΌΗ MS (ESI) m/z : 342 [M+l]+ 0.262 A
R-91 qHCI Chiral φχΑΖ MS (ESI) m/z : 277 |M+1J 0.897 A
R-92 HCI Chiral xuA: MS (ESI) m/z : 277 [M+l]+ 1.275 A
R-93 HCI Chiral oxA: MS (ESI) m/z : 265 [M+l]+ 0.690 A
R-94 HCI Chiral 0 pNA-NH2 1 Ά Ah σ MS (ESI) m/z : 291 [M+l]+ 0.752 A
R-95 q HCI Chiral rtX oh MS (ESI) m/z : 341 [M+l]+ 1.046 A
R-96 qHCI Chiral aXr u ΌΗ MS (ESI) m/z : 237 [M+l]+ 0.536 A
R-97 /=\ HN-—. q Chiral ΌΗ MS (ESI) m/z : 247 [M+l]+ 0.298 A
R-98 F 0 Chiral >nh2 H A^ L S-° ^'b MS (ESI) m/z : 382 [M+l]+ 0.471 B
R-99 F gN ° Chiral AoAAnA..'nh2 o Η 1 A H MS (ESI) m/z : 370 [M+l]+ 0.414 B
R-100 F ί ° HCI sA II u 0 MS (ESI) m/z : 339 [M+l]+ 1.230 A
R-1O1 F 0 Chiral Αο-ΑΑ^Α -'nh2 MS (ESI) m/z : 295 [M+l]+ 0.507 B
R-102 F FA 0 Chiral ,„nh2 X 0 o MS (ESI) m/z : 327 [M+l]+ 0.419 B
R-103 /=s, o Chiral rCAV· \=/ ΌΗ Cl· MS (ESI) m/z : 295 [M+l]+ 0.722 A
R-104 ρ>^οΧΧνΑ^νη2 HhoV OH MS (ESI) m/z : 309 [M+l]+ 0.910 A
R-105 HCI 0 HCI Chiral ^νΑ·ΝΗ2 iDH MS (ESI) m/z : 250 [M+l]+ 0.505 A
R-106 0 HCI Chiral p?yNHi |j^]^ ^0H MS (ESI) m/z : 247 [M+l]+ 0.693 A
R-107 0 HCI Chiral ^n\'NH2 \h MS (ESI) m/z : 207 [M+l]+ 0.279 A
R-108 0 HCI Chiral ^nJCnH2 un MS (ESI) m/z : 249 [M+l]+ 0.692 A
R-109 0 HCI Chiral OoY OH MS (ESI) m/z : 235 [M+l]+ 0.596 A
R-110 q HCI Chiral O<j*f XOH MS (ESI) m/z : 235 [M+l]+ 0.595 A
R-lll θ HCI Chiral aaU Gh MS (ESI) m/z : 235 [M+l]+ 0.579 A
R-112 q HCI Chiral JL λΝΗ2 qA x MS (ESI) m/z : 221 [M+l]+ 0.475 A
R-113 q Chiral uuA L ii A^ > A AH 0 HCI MS (ESI) m/z : 327 [M+l]+ 0.621 A
R-114 H N^. q Chiral dvr ΌΗ MS (ESI) m/z : 221 [M+l]+ 0.231 A
R-115 HN—. O Chiral <XWH2 HCI X?S MS (ESI) m/z : 287 [M+l]+ 0.245 B
R-116 O HCI Chiral cwt MS (ESI) m/z : 263 [M+l]+ 0.812 A
R-117 ifX 0 Chiral ^ύ^υ^0ΑΑνΑ,..-νη2 UU H I XOH MS (ESI) m/z : 337 [M+l]+ 0.648 B
R-118 yGnAnh. ^OH MS (ESI) m/z : 237 [M+l]+ 0.675 A
R-119 0 OH chiral k0 MS (ESI) m/z : 249 [M+l]+ 0.700 A
R-120 HQ Chiral 11 0 MS (ESI) m/z : 249 [M+l]+ 0.695 A
R-121 0 Chiral h I P II OH MS (ESI) m/z : 251 [M+l]+ 0.782 A
R-122 0 HCI \AAnA^nh2 T V OH MS (ESI) m/z : 251 [M+l]+ 0.725 A
R-123 /=¾. q Chiral \=/ ΌΗ MS (ESI) m/z : 261 [M+l]+ 0.565 A
R-124 f^XXaah2 ΗΟ^γ°\^ 0 MS (ESI) m/z : 337 [M+l]+ 0.485 B
R-125 0 HCI Chiral ps -νΑ.·'ΝΗ2 \q H MS (ESI) m/z : 253 [M+l]+ 0.646 A
R-126 0 HCI Chiral π Α··'ΝΗζ C0H MS (ESI) m/z : 251 [M+l]+ 0.782 A
R-127 0 N H2 MS (ESI) m/z : 247 [M+l]+ 0.544 B
R-128 0 Chiral CcoX; MS (ESI) m/z : 261 [M+l]+ 0.782 A
R-129 θ Chiral cuoA 0^k.,xNH2 ΌΗ MS (ESI) m/z : 350 [M+l]+ 0.818 A
R-130 Chiral AXW- '/S\\ o o MS (ESI) m/z : 339 [M+l]+ 0.849 A
R-131 H N-^ q Chiral s·. MS (ESI) m/z : 264 [M+l]+ 0.689 A
R-132 Chiral 0 LAnA,.nh2 HCI MS (ESI) m/z : 267 [M+l]+ 0.510 B
R-133 HCI o Chiral p. ρΝΛ·ΝΗ2 ^0H MS (ESI) m/z : 363 [M+l]+ 0.739 B
R-134 o HCI Chiral pNA-NH2 ^OH MS (ESI) m/z : 339 [M+l]+ 0.665 B
R-135 0 Chiral rj^ pNA-NH2 ^OH OH MS (ESI) m/z : 279 [M+l]+ 0.521 A
R-136 0 Chiral oaA: OH MS (ESI) m/z : 279 [M+l]+ 0.511 A
R-137 0 Chiral OH MS (ESI) m/z : 275 [M+l]+ 0.820 A
R-138 0 Chiral χχΧ 0 MS (ESI) m/z : 291 [M+l]+ 0.747 A
R-139 0 HCI Chiral p pA-NH2 ^0H MS (ESI) m/z : 367 [M+l]+ 0.735 B
R-140 q Chiral ^JU-A..>nh2 ΌΗ MS (ESI) m/z : 257 [M+l]+ 0.465 B
R-141 0 Chiral uxAr MS (ESI) m/z : 275 [M+l]+ 0.514 B
R-142 HCI Chiral 0 MS (ESI) m/z : 299 [M+l]+ 0.710 A
R-143 rrrxJr HCI MS (ESI) m/z : 318 [M+l]+ 0.678 B
R-144 F 0 HC|Chiral MS (ESI) m/z : 261 [M+l]+ 0.751 A
R-145 F 0 HCI Chiral FAoA^n^''NH2 MS (ESI) m/z : 261 [M+l]+ 0.750 A
R-146 hna u Chiral (PA'NH2 HCI O.S^ 0 MS (ESI) m/z : 296 [M+l]+ 0.434 A
R-147 Chiral θΑυ/-· MS (ESI) m/z : 283 [M+l]+ 0.571 B
R-148 Chiral MS (ESI) m/z : 297 [M+l]+ 0.587 B
R-149 if Ch'ral MS (ESI) m/z : 285 [M+l]+ 0.700 A
R-150 O Chiral \A>NH2 Ay^ ΌΗ ΒγΑα HCI MS (ESI) m/z : 287 [M+l]+ 0.256 B
R-151 0 HCI Chiral ιΠ ™V2 L0H MS (ESI) m/z : 237 [M+l]+ 0.730 A
R-152 A] o hci Aw* MS (ESI) m/z : 256 [M+l]+ 0.531 A
R-153 Chiral A rci ΛΑγ* MS (ESI) m/z : 318 [M+l]+ 0.579 A
R-154 /===r\ 0 Chiral OW r“ OH 0 MS (ESI) m/z : 299 [M+l]+ 0.586 B
R-155 AA, o QjAAJyNH2 MS (ESI) m/z : 253 [M+l]+ 0.482 B
R-156 A ?HCI MS (ESI) m/z : 277 [M+l]+ 0.599 B
R-157 /=:N 0 Chiral ΌΗ MS (ESI) m/z : 208 [M+l]+ 0.249 A
R-158 0 Chiral N ΌΗ MS (ESI) m/z : 208 [M+l]+ 0.188 A
R-159 /=¾. 0 Chiral ΌΗ MS (ESI) m/z : 208 [M+l]+ 0.190 A
R-160 Chiral 0 HCI /=\ /^¼2 <x // N' Λ J L MS (ESI) m/z : 287 [M+l]+ 0.631 A
R-161 HN— Q Chiral Cj h\'NH2 ΌΗ MS (ESI) m/z : 221 [M+l]+ 0.252 A
R-162 0 Chiral ^oh ό MS (ESI) m/z : 287 [M+l]+ 0.566 A
R-163 HO Chiral ΌΗ MS (ESI) m/z : 223 [M+l]+ 0.229 A
R-164 0 Chiral γη, pNA<H2 ΌΗ MS (ESI) m/z : 291 [M+l]+ 0.948 A
R-165 0 Chiral ΌΗ MS (ESI) m/z : 237 [M+l]+ 0.764 A
R-166 uoA MS (ESI) m/z : 277 [M+l]+ 0.926 A
R-167 /=¾. 0 Chiral ιλΑρ ' \ ΌΗ MS (ESI) m/z : 221 [M+l]+ 0.539, 0.559 A
R-168 0 Chiral vAnA-'nh2 MS (ESI) m/z : 247 [M+l]+ 0.756 A
R-169 /===, 0 Chiral ιΛ-γ’ h2n MS (ESI) m/z : 250 [M+l]+ 0.168 A
R-170 HN—. q Chiral (piV2 N ΌΗ MS (ESI) m/z : 221 [M+l]+ ND A
R-171 MS (ESI) m/z : 267 [M+l]+ 0.517 B
R-172 n Chiral H HCI 09Y MS (ESI) m/z : 247 [M+l]+ 0.659 A
R-173 ljm Chiral COR...... V 0 MS (ESI) m/z : 249 [M+l]+ 0.249 A
R-174 0 Chiral ^nA-'NH2 l0H MS (ESI) m/z : 285 [M+l]+ 0.648 A
R-175 0 Chiral Brvp^ MS (ESI) m/z : 285 [M+l]+ 0.617 A
R-176 „xroj MS (ESI) m/z : 239 [M+l]+ 0.770 E
R-177 αΎΝ Cn MS (ESI) m/z : 280 [M+l]+ 0.850 E
R-178 o' '0 MS (ESI) m/z : 323 [M+l]+ 0.900 E
R-179 o MS (ESI) m/z : 350 [M+l]+ 1.404 E
R-180 lCN U^sJUyOH o MS (ESI) m/z : 336 [M+l]+ 1.132 E
R-181 ND ND ND
R-182 'Τ'Ί 0 H w MS (ESI) m/z : 250 [M+l]+ 0.705 A
R-183 nr°^o CI-^ h2An MS (ESI) m/z : 238 [M+1J 0.827 A
R-184 ΊΠ /° an ND ND ND
R-185 NH2 f=N x yyO-^M'-A C|AJ MS (ESI) m/z : 252 [M+l]+ 0.277 A
R-186 nXr°~~tH ND ND ND
R-187 Tu,, V MS (ESI) m/z : 235 [M+l]+ 0.570 B
R-188 C|A^ n=n' MS (ESI) m/z : 225 [M+1J 0.841 B
R-189 C|A^ n=n MS (ESI) m/z : 225 [M+l]+ 0.867 B
R-190 C,JU NH2 MS (ESI) m/z : 250 [M+l]+ 1.004 A
R-191 -o'Ni° MS (ESI) m/z : 266 [M+l]+ 0.979 B
R-192 nh2 cixr^0 MS (ESI) m/z : 236 [M+l]+ 0.906 A
R-193 Ύ ND ND ND
R-194 ~°r ο£ΓΆ MS (ESI) m/z : 293 [M+l]+ 0.931 B
R-195 0 MS (ESI) m/z : 307 [M+l]+ 1.010 B
R-196 0 ΗΟ^γ=Ν MS (ESI) m/z : 279 [M+l]+ 0.730 B
R-197 οΛ~ΝΗ2 MS (ESI) m/z : 264 [M+l]+ 0.844 B
R-198 “ΧΚΟ ,^ΝΗ 0 \ MS (ESI) m/z : 278 [M+l]+ 0.905 B
R-199 MS (ESI) m/z : 299 [M+l]+ 1.021 B
R-200 °OuK- MS (ESI) m/z : 299 [M+l]+ 0.709 B
R-201 MS (ESI) m/z : 235 [M+l]+ 0.235 C
R-202 CIX^ xo V^nXn MS (ESI) m/z : 279 [M+l]+ 0.804 B
R-203 c'ya / 0 x=0 MS (ESI) m/z : 279 [M+l]+ 0.836 B
R-204 HO \=0 MS (ESI) m/z : 265 [M+l]+ 0.631 B
R-205 Clx^ OH O^^x, Ax/X MS (ESI) m/z : 265 [M+l]+, 263 [M-l] 0.574 B
R-206 “Ό \^X/S\A T /> n-n MS (ESI) m/z : 254 [M+l]+, 252 [M-l]’ 0.935 B
R-207 X HCI NH2 \xAXN MS (ESI) m/z : 236 [M+l]+ 0.831 A
R-208 X v30n MS (ESI) m/z : 235 [M+l]+ 0.522 B
R-209 X vX> MS (ESI) m/z : 268 [M+l]+ 1.024 B
R-210 X hcih2n Lx) MS (ESI) m/z : 236 [M+l]+ 0.822 A
R-211 X rXNH MS (ESI) m/z : 356 [M+l]+ 0.881 A
R-212 “X .xsAA0 OH MS (ESI) m/z : 294 [M+l]+ 1.030 E
R-213 Cl τα ^SA^J MS (ESI) m/z : 250 [M+l]+ 0.900 E
R-214 Cl xr υ NH ’^0 MS (ESI) m/z : 280 [M+l]+ 0.821 A
R-215 Cl F ND ND ND
R-216 ['i M o o I MS (ESI) m/z : 214 [M+l]+ 0.860 E
R-217 x xc MS (ESI) m/z : 248 [M+l]+ 1.110 E
R-218 a. OX MS (ESI) m/z : 282 [M+l]+ 1.190 E
R-219 c r0^ -A. MS (ESI) m/z : 264 [M+l]+ 0.850 E
R-220 X jX MS (ESI) m/z : 232 [M+l]+ 0.860 E
R-221 k>Jk. (f> h1 —o o MS (ESI) m/z : 338 [M+l]+ 1.066 E
R-222 P/k xX MS (ESI) m/z : 324 [M+l]+ 1.070 E
R-223 CK ca OX MS (ESI) m/z : 280 [M+l]+ 1.449 E
R-224 a —o o-\ MS (ESI) m/z : 324 [M+l]+ 1.466 E
H
ci A MS (ESI)
R-225 1 1 y I m/z : 1.148 E
γ yy Y 296 [M+l]+
Cl H ,N. <° MS (ESI)
R-226 ΊΑ ί Ί s' m/z : 1.134 E
MX/· γ· AA 266 [M+l]+
Cl H
(T MS (ESI)
R-227 τ 1 m/z : 1.178 E
xs >< N Y 297 [M+l]+
F 1 H χΝ, xO MS (ESI)
R-228 A π m/z : 1.070 E
238 [M+l]+
— s OH
H
Cl MX A u MS (ESI)
R-229 y 1 ί I m/z : 0.991 E
Y' ΛΑ Y 283 [M+l]+
H
F 1 H N V° MS (ESI)
R-230 A if m/z : 0.930 E
. JL xA. xA. 272 [M+l]+
cr v s OH
H
Cl iA MS (ESI)
R-231 I J ' JL xJ m/z : 1.259 E
XYZ XS‘ -Xjfo Y 332 [M+l]+
Cl H xO MS (ESI)
R-232 dA ί Ί s' m/z : 1.178 E
\X\x xs AA Y 284 [M+l]+
CL A Ay xA MS (ESI)
R-233 1 1 1 11 m/z : 1.383 E
Vxx ''S'' X 'NH 319 [M+l]+
ci. H X-N\X >° MS (ESI)
R-234 >A ί d X m/z : 1.231 E
''S' AA Yi 301 [M+l]+
R-235 MS (ESI) m/z : 305 [M+l]+ 1.207 E
R-236 ϊ H rS ί T MS (ESI) m/z : 296 [M+l]+ 1.010 E
R-237 jOl Λ° MS (ESI) m/z : 282 [M+l]+ 1.137 E
R-238 c,ya ιίΝγ° MS (ESI) m/z : 254 [M+l]+ 1.140 E
R-239 Cl^ fNY° 0 MS (ESI) m/z : 310 [M+l]+ 1.145 E
R-240 °ixAX OH MS (ESI) m/z : 296 [M+l]+ 1.076 E
R-241 H0V^i rV° MS (ESI) m/z : 236 [M+l]+ 0.890 E
R-242 / y° MS (ESI) m/z : 296 [M+l]+ 1.203 E
R-243 A °ν^Ί ίΎ° MS (ESI) m/z : 354 [M+l]+ 1.250 E
R-244 tiNY° 0' '0 MS (ESI) m/z : 312 [M+l]+ 0.963 E
R-245 ΗΟγ^ ζΝγ° AA^SAAOH MS (ESI) m/z : 264 [M+l]+ 0.893 E
R-246 MS (ESI) m/z : 362 [M+l]+ 1.387 E
R-247 A MS (ESI) m/z : 338 [M+l]+ 1.330 E
R-248 H fNY° MS (ESI) m/z : 348 [M+l]+ 1.344 E
R-249 // γ^Ίτ .✓Ay A^ii MS (ESI) m/z : 366 [M+1J 1.385 E
R-250 oULjX H MS (ESI) m/z : 288 [M+l]+ 0.687 E
R-251 ^Α&. h χNr° ΑΆη MS (ESI) m/z : 377 [M+l]+ 1.230 E
R-252 c'aa iNY° AX^sA^0H F MS (ESI) m/z : 300 [M+l]+ 1.163 E
R-253 Γ- ΟΗ °O MS (ESI) m/z : 456 [M+l]+ 1.078 E
0.../.. Λη
R-254 CR o N' MT o o I MS (ESI) m/z : 283 [M+l]+ 1.138 E
R-255 Q H c c MS (ESI) m/z : 245 [M+l]+ 1.017 E
R-256 ox 0„ MS (ESI) m/z : 303 [M+l]+ 1.490 E
R-257 Cl xx XT °< E)H ΓοΗ 0 MS (ESI) m/z : 269 [M-l] 0.766 C
R-258 ci- -O N-N n o n-N MS (ESI) m/z : 294 [M+l]+ 0.748 B
R-259 ( ok V-OH MS (ESI) m/z : 188 [M+l]+ 0.806 B
R-260 HCI Χχ H2N—^NH MS (ESI) m/z : 187 [M+l]+ 0.260 A
R-261 ci— xy nsN X-n^ cc MS (ESI) m/z : 303 [M+l]+ 0.800 E
R-262 Ck O H Ny° Ύόη MS (ESI) m/z : 261 [M+l]+ 0.940 E
R-263 Cl H N ^X) H MS (ESI) m/z : 261 [M+l]+ 0.950 E
ND: not determined
-44 'H-NHR of the Compounds without LCMS data are follows:
Reference Compound R-14: 'H NMR (400 MHz, METHANOL-d4) δ ppm 4.03 (s, 2 H), 7.32 (d, J=6.7 Hz, 1 H), 8.34 (dd, J=6.7, 1.2 Hz, 1 H), 9.43 (s, 1 H).
Reference Compound R-15: XH NMR (400 MHz, DMSO-d6) δ ppm 3.92 (br d, J=5.0 Hz, 2 H), 8.08 - 8.18 (m, 3 H), 8.23 (br d, J=5.3 Hz, 1 H), 8.70 - 8.77 (m, 1 H), 9.96 (s, 1 H), 12.12 (br s, 1 H).
Reference Compound R-32: 'Η NMR (400 MHz, METHANOL-d4) δ ppm 3.95 (s, 2 H), 6.83 (s, 1 H), 8.89 (s, 1 H).
Reference Compound R-76: 'H NMR (400 MHz, DEUTERIUM OXIDE) δ ppm 3.93 - 4.07 (m, 2 H), 4.18 (dd, J=5.6, 4.3 Hz, 1 H), 4.40 - 4.58 (m, 2 H), 7.10 (d, J=8.4 Hz, 2 H), 7.42 (d, J=8.2 Hz, 2 H), 7.62 (br d, J=8.4 Hz, 2 H), 7.66 (br d, J=8.2 Hz, 2 H).
Reference Compound R-77: 'H NMR (400 MHz, DEUTERIUM OXIDE) δ ppm 3.91 - 4.03 (m, 2 H), 4.12 - 4.17 (m, 1 H), 4.44 (s, 2 H), 4.84 (q, J=8.6 Hz, 2 H), 7.03 (d, J=8.6 Hz, 1 H), 7.82 (dd, J=8.6, 2.4 Hz, 1 H), 8.09 (d, J=2.4 Hz, 1 H).
Reference Compound R-170: 'H NMR (400 MHz, METHANOL-d4) δ ppm 3.98 - 4.14 (m, 2 H), 4.19 - 4.32 (m, 1 H), 7.84 (d, J=6.5 Hz, 1 H), 8.10 (s, 1 H), 8.32 (br d, J=6.5 Hz, 1 H), 9.27 (br s, 1 H).
Reference Compound R-181: XH NMR (600 MHz, CHLOROFORM-d) δ ppm 4.70 (s, 2 H), 5.13 (s, 2 H), 6.94 (d, J=8.3 Hz, 2 H), 7.05 - 7.15 (m, 3 H), 7.35 - 7.38 (m, 2 H), 7.47 (s, 1 H). Reference Compound R-184: 'H NMR (400 MHz, CHLOROFORM-d) δ ppm 3 .43 (s, 3 H), 3.69 -3.82 (m, 2H), 3.91 -3.96 (m, 1 H), 4.11 -4.19(m, 1 H), 4.21 -4.31 (m, 1 H), 6.80 6.85 (m, 2 H), 6.94 - 6.97 (m, 1 H), 7.05 (s, 1 H), 7.19 - 7.31 (m, 2 H), 7.50 (s, 1 H).
Reference Compound R-186: 'H NMR (400 MHz, METHANOL-d4) δ ppm 4.31 (t, J=4.9 Hz, 2 H), 4.52 (t, J=4.9 Hz, 2 H), 6.92 (d, J=7.1 Hz, 2 H), 7.25 (d, J=7.1 Hz, 2 H), 7.83 (d, J=1.5 Hz, 1 H), 8.23 (d, J=1.5 Hz, 1 H).
Reference Compound R-193: 'H NMR (400 MHz, METHANOL-d4) δ ppm 2.13 (quin, J=7.4 Hz, 2 H), 2.54 - 2.67 (m, 2 H), 4.08 (t, J=7.1 Hz, 2 H), 7.10 (br s, 1 H), 7.14 - 7.22 (m, 2 H), 7.22 - 7.32 (m, 3 H).
Reference Compound R-215: 'H NMR (400 MHz, CHLOROFORM-d) δ ppm 2.03 - 2.14 (m, 2 H), 2.59 (t, J=7.5 Hz, 2 H), 3.85 (t, J=7.0 Hz, 2 H), 6.41 (dd, J=8.3, 1.8 Hz, 1 H), 7.01 7.03 (m, 1 H), 7.05 - 7.10 (m, 2 H), 7.26 - 7.31 (m, 2 H).
Chemical names of the Reference Compounds in Table-1 are follows:
R-l: N-[3-(trifluoromethoxy)phenyl]glycinamide— hydrochloride
R-2: N-[l,l'-biphenyl]-3-ylglycinamide— hydrochloride
R-3: N-methyl-N-[3-(trifluoromethoxy)phenyl]glycinamide— hydrochloride
R-4: N ,N -dimethyl-N-[3-(trifluoromethoxy)phenyl]glycinamide— hydrochloride
-45 R-5: 2-(4-ethylpiperazin-l-yl)-N-[3-(trifluoromethoxy)phenyl]acetamide— hydrochloride
R-6: 2-(morpholin-4-yl)-N-[3-(trifluoromethoxy)phenyl]acetamide
R-7: N-[4'-[3-(morpholin-4-yl)propoxy][l,r-biphenyl]-3-yl}glycinamide— hydrochloride
R-8: 3,3,3-trifluoro-N-[3-(trifluoromethoxy)phenyl]alaninamide
R-9: N-[3-(trifluoromethoxy)phenyl]-L-serinamide
R-10: N-[3-(trifluoromethoxy)phenyl]-D-alpha-glutamine— hydrochloride
R-l 1: N-[3-(trifluoromethoxy)phenyl]-D-histidinamide
R-12: 3-pyridin-4-yl-N-[3-(trifluoromethoxy)phenyl]-D-alaninamide— 2 hydrochloride
R-13: 3-pyridin-3-yl-N-[3-(trifluoromethoxy)phenyl]-D-alaninamide— 2 hydrochloride
R-14: N-(4-hydroxypyridin-3-yl)glycinamide— 2 hydrochloride
R-l5: N-(5-bromo-4-hydroxypyridin-3-yl)glycinamide— 2 hydrochloride
R-l6: N-[4-hydroxy-6-(trifluoromethyl)pyridin-3-yl]glycinamide— hydrochloride
R-l7: N-[3-(trifluoromethoxy)phenyl]-D-homoserinamide
R-18: 2-amino-N -methyl-N -[3-(trifluoromethoxy)phenyl]propanediamide— hydrochloride
R-19: 2-amino-N1-[3-(trifluoromethoxy)phenyl]propanediamide— hydrochloride
R-20: N-[3-(trifluoromethoxy)phenyl]-D-tyrosinamide— hydrochloride
R-21: (2R)-2-amino-4-[(methanesulfonyl)amino]-N-[3-(trifluoromethoxy)phenyl]butanamide
R-22: 3-pyridin-2-yl-N-[3-(trifluoromethoxy)phenyl]-L-alaninamide— 2 hydrochloride
R-23: (2R)-2,4-diamino-N-[3-(trifluoromethoxy)phenyl]butanamide
R-24: l-[(O-methyl-3-oxoseryl)amino]-3-(trifluoromethoxy)benzene— hydrochloride
R-25: N-(3-bromo-2-propylphenyl)-N-methylglycinamide— hydrochloride
R-26: (2R)-4-acetamido-2-amino-N-[3-(trifluoromethoxy)phenyl]butanamide
R-27: N-lH-indol-3-ylglycinamide— hydrochloride
R-28: N5-acetyl-N-[3-(trifluoromethoxy)phenyl]-D-omithinamide
R-29: N-(4-hydroxy-5-methoxypyridin-3-yl)glycinamide— 2 hydrochloride
R-30: N5-(methanesulfonyl)-N-[3-(trifluoromethoxy)phenyl]-D-ornithinamide— hydrochloride
R-31: N-[3-(trifluoromethoxy)phenyl]-D-ornithinamide
R-32: N-(6-chloro-4-hydroxypyridin-3-yl)glycinamide— 2 hydrochloride
R-33: 3-acetamido-N-[3-(trifluoromethoxy)phenyl]-D-alaninamide
R-34: 3-[(methanesulfonyl)amino]-N-[3-(trifluoromethoxy)phenyl]-D-alaninamide
R-3 5: N-phenyl-D-serinamide— hydrochloride
R-36: N-[3-(trifluoromethoxy)phenyl]-D-lysinamide
R-37: N6-acetyl-N-[3-(trifluoromethoxy)phenyl]-D-lysinamide
R-38: N6-(methanesulfonyl)-N-[3-(trifluoromethoxy)phenyl]-D-lysinamide
R-39: 2-amino-2-(l,l-dioxo-llambda6-thian-4-yl)-N-[3-(trifluoromethoxy)phenyl]acetamide- hydrochloride
-46 R-40: l-[(3-oxidanylideneseryl)amino]-3-(trifluoromethoxy)benzene— hydrochloride
R-41: N-(5-nitropyridin-2-yl)glycinamide— 2 hydrochloride
R-42: 2-amino-2-(pyridin-3-yl)-N-[3-(trifluoromethoxy)phenyl]acetamide— 2 hydrochloride
R-43: N-[3-(propan-2-yl)phenyl]-D-serinamide —trifluoroacetate
R-44: 3-(l,3-thiazol-2-yl)-N-[3-(trifluoromethoxy)phenyl]alaninamide— hydrochloride
R-45: N-[4-(trifluoromethoxy)phenyl]-D-serinamide —trifluoroacetate
R-46: (2R)-2-amino-4,4,4-trifluoro-N-[3-(trifluoromethoxy)phenyl]butanamide
R-47: 3-thiophen-2-yl-N-[3-(trifluoromethoxy)phenyl]alaninamide
R-48: N-(3-ethoxyphenyl)-D-serinamide —trifluoroacetate
R-49: N-{3-[(propan-2-yl)oxy]phenyl}-D-serinamide —trifluoroacetate
R-50: N-(l-phenyl-lH-pyrazol-3-yl)-D-serinamide —trifluoroacetate
R-51: N-[3-(benzyloxy)phenyl]-D-serinamide —trifluoroacetate
R-52: N-[3-(2-phenylethoxy)phenyl]-D-serinamide —trifluoroacetate
R-53: N-[3-(hexyloxy)phenyl]-D-serinamide —trifluoroacetate
R-54: 3-(2-oxo-l,2-dihydroquinolin-4-yl)-N-[3-(trifluoromethoxy)phenyl]alaninamide— hydrochloride
R-55: N-(2,3-dihydro-lH-inden-l-yl)-D-serinamide— hydrochloride
R-56: N-[3-(phenylethynyl)phenyl]-D-serinamide— hydrochloride
R-57: (2R)-6-oxo-N-[3-(trifluoromethoxy)phenyl]piperazine-2-carboxamide
R-58: N-{[3-(aminomethyl)phenyl]methyl}-D-serinamide— 2 hydrochloride
R-59: N-{[4-(aminomethyl)phenyl]methyl}-D-serinamide— 2 hydrochloride
R-60: N-[(3-bromophenyl)methyl]-D-serinamide— hydrochloride
R-61: N-[(2-bromophenyl)methyl]-D-serinamide— hydrochloride
R-62: (2R)-2-amino-3-hydroxy- l-[4-(2-phenylethyl)piperidin-l-yl]propan-l-one— hydrochloride
R-63: N-{[2-(trifluoromethoxy)phenyl]methyl}-D-serinamide— hydrochloride
R-64: 3-(l-benzofuran-2-yl)-N-[3-(trifluoromethoxy)phenyl]-D-alaninamide
R-65: N-l,3-benzothiazol-6-yl-D-serinamide— hydrochloride
R-66: N-(5-phenyl-lH-pyrazol-3-yl)-D-serinamide— hydrochloride
R-67: N-{[3-(trifluoromethoxy)phenyl]methyl}-D-serinamide— hydrochloride
R-68: N-{[4-(trifluoromethoxy)phenyl]methyl}-D-serinamide— hydrochloride
R-69: (2R)-2-amino-3-hydroxy-l-[7-(trifluoromethyl)-3,4-dihydroisoquinolin-2(lH)yl]propan-l-one— hydrochloride
R-70: N-{2-[3-(trifluoromethoxy)phenyl]ethyl}-D-serinamide— hydrochloride
R-71: N-{2-[4-(trifluoromethoxy)phenyl]ethyl}-D-serinamide— hydrochloride
R-72: N-lH-indol-5-yl-D-serinamide
R-73: N-(4-phenylpyrrolidin-3-yl)-D-serinamide— 2 hydrochloride
-47 R-74: N-[(3-sulfamoylphenyl)methyl]-D-serinamide— hydrochloride
R-75: N-[(4-sulfamoylphenyl)methyl]-D-serinamide— hydrochloride
R-76: N-[(4'-amino[l,r-biphenyl]-4-yl)methyl]-D-serinamide-- 2 hydrochloride
R-77: N-{[6-(2,2,2-trifluoroethoxy)pyridin-3-yl]methyl}-D-serinamide— 2 hydrochloride
R-78: N-[2-(benzylamino)ethyl]-D-serinamide— 2 hydrochloride
R-79: N-{[2-(2,2,2-trifluoroethoxy)pyridin-3-yl]methyl}-D-serinamide— 2 hydrochloride
R-80: N-[2-hydroxy-2-(3-phenoxyphenyl)ethyl]-D-serinamide— hydrochloride
R-81: S-[3-(trifluoromethoxy)phenyl] (2R)-2-amino-3-hydroxypropanethioate— hydrochloride
R-82: N-(5-bromopyridin-3-yl)-D-serinamide
R-83: N-(3-bromo-2-methylphenyl)-D-serinamide
R-84: 3-[(2,2-difluoroethyl)amino]-N-[3-(trifluoromethoxy)phenyl]-D-alaninamide
R-85: (2R)-2-amino-1 -[4-(4-fluorobenzoyl)piperazin-1 -yl]-3-hydroxypropan-1 -one— hydrochloride
R-86: N-(2-methyl-lH-indol-5-yl)-D-serinamide
R-87: N-(3-benzylphenyl)-D-serinamide
R-88: l-[(4-tert-butylphenyl)methyl]-4-D-serylpiperazin-2-one— hydrochloride
R-89: (2R)-2-amino-l-{4-[(4-fluorophenyl)methyl]piperazin-l-yl}-3-hydroxypropan-l-one— hydrochloride
R-90: (2R)-2-amino-l-{4-[(4-bromophenyl)methyl]piperazin-l-yl}-3-hydroxypropan-l-one— hydrochloride
R-91: (2R)-2-amino-3-hydroxy-l-{4-[(2-methylphenyl)methyl]piperidin-l-yl}propan-l-one— hydrochloride
R-92: (2R)-2-amino-3-hydroxy-l-{4-[(3-methylphenyl)methyl]piperidin-l-yl}propan-l-one— hydrochloride
R-93: (2R)-2-amino-3-hydroxy- l-(4-phenoxypiperidin-l-yl)propan-l -one— hydrochloride
R-94: (2R)-2-amino-3-hydroxy-1-(1 'H,2H,4H-spiro[ 1 -benzopyran-3,4'-piperidin]-1 'yl)propan-l-one— hydrochloride
R-95: (2R)-2-amino-1 -[3 -(4-benzylphenoxy)pyrrolidin-1 -yl]-3-hydroxypropan-1 -one— hydrochloride
R-96: (2R)-2-amino-3-hydroxy-1 -(3-phenoxyazetidin-1 -yl)propan-1 -one— hydrochloride
R-97: N-(2-phenyl-lH-imidazol-4-yl)-D-serinamide
R-98: 3-(1,1 -dioxo-llambda6,4-thiazinan-4-yl)-N-[3-(trifluoromethoxy)phenyl]-Dalaninamide
R-99: 3-{[2-(methanesulfonyl)ethyl]amino}-N-[3-(trifluoromethoxy)phenyl]-D-alaninamide R-100: 3-amino-l,l-dioxo-N-[3-(trifluoromethoxy)phenyl]-llambda6-thiolane-3carboxamide— hydrochloride
-48 R-101: S-methyl-N-[3-(trifluoromethoxy)phenyl]-D-cysteinamide
R-102: 3-(methanesulfonyl)-N-[3-(trifluoromethoxy)phenyl]-D-alaninamide
R-103: N-{l-[(4-chlorophenyl)methyl]-lH-pyrazol-3-yl}-D-serinamide
R-104: 3 -hydroxy-N- [3 -(trifluoromethoxy)phenyl] -alpha-asparagine
R-105: (2R)-2-amino-3-hydroxy-l-(4-phenylpiperazin-l-yl)propan-l-one— 2 hydrochloride
R-106: (2R)-2-amino-3 -hydroxy-1 -(4-phenyl-3,6-dihydropyridin-1 (2H)-yl)propan-1 -one— hydrochloride
R-107: (2R)-2-amino-1-(1,3 -dihydro-2H-i soindol-2-yl)-3 -hydroxypropan-1 -one— hydrochloride
R-108: (2R)-2-amino-3-hydroxy-1 -(4-phenylpiperidin-1 -yl)propan-1 -one— hydrochloride
R-109: (2R)-2-amino-3-hydroxy-1 -[(3 S)-3-phenylpyrrolidin-1 -yljpropan-1 -one— hydrochloride
R-l 10: (2R)-2-amino-3-hydroxy-l-[(3R)-3-phenylpyrrolidin-l-yl]propan-l-one— hydrochloride
R-l 11: (2R)-2-amino-3-hydroxy-l-(l,2,4,5-tetrahydro-3H-3-benzazepin-3-yl)propan-l-one— hydrochloride
R-l 12: (2R)-2-amino-3-hydroxy-1-(3-phenylazetidin-l-yl)propan-l-one— hydrochloride
R-113: (2R)-2-amino-3-hydroxy-1 -[4-(4-methylbenzene-1 -sulfonyl)piperidin-1 -yljpropan-1 one— hydrochloride
R-l 14: N-lH-pyrrolo[3,2-b]pyridin-3-yl-D-serinamide
R-l 15: N-lH-indol-3-yl-3-(l,3-thiazol-4-yl)-D-alaninamide— hydrochloride
R-l 16: (2R)-2-amino-l-(4-benzylpiperidin-l-yl)-3-hydroxypropan-1-one— hydrochloride
R-l 17: N-{3-[(naphthalen-2-yl)methoxy]phenyl}-D-serinamide
R-l 18: N-(2-hydroxyethyl)-N-[3-(propan-2-yl)phenyl]glycinamide
R-l 19: (2R)-2-amino-3-hydroxy-1-[(3S)-3-phenylpiperidin-l-yl]propan-l-one formate
R-120: formic acid—(2R)-2-amino-3-hydroxy-l-[(3R)-3-phenylpiperidin-l-yl]propan-l-one formate
R-121: N-{3-[([ 1,1 '-biphenyl]-4-yl)methoxyjphenyl}-D-serinamide
R-122: glycyl-N-[3-(propan-2-yl)phenyl]glycine— hydrochloride
R-123: N-(l-benzyl-lH-pyrazol-3-yl)-D-serinamide
R-124: ethyl 3 -hydroxy-N- [3 -(trifluoromethoxy)phenyl] -alpha-asparaginate
R-l25: N-methyl-N-(3-phenoxypropyl)-D-serinamide— hydrochloride
R-l26: N-m ethyl-N-(4-phenylbutyl)-D-serinamide— hydrochloride
R-127: 2-amino-1 -{4-[(4-methylphenyl)methyl]piperidin-1 -yl}ethan-1 -one
R-128: (2R)-2-amino-1 -(4-benzyl-3,6-dihydropyridin-1 (2H)-yl)-3-hydroxypropan-1 -one
R-l29: (2R)-2-amino-3-(4-benzylpiperidin-l-yl)-3-oxopropyl D-serinate— 2 hydrochloride
R-l30: (2R)-2-amino-2-(l,l-dioxo-llambda6-thietan-3-yl)-N-[3-49 (trifluoromethoxy)phenyl]acetamide— hydrochloride
R-131: N-lH-indol-3-yl-D-methioninamide
R-132: (3R)-3-amino-1 -([ 1,1 '-biphenyl]-4-yl)piperidin-2-one— hydrochloride
R-13 3: (2R)-2-amino-3 -hydroxy-1 -(4- {[3 -(phenylethynyl)phenyl]methyl} piperidin-1 yl)propan-l-one— hydrochloride
R-134: (2R)-2-amino-l-{4-[([l,r-biphenyl]-3-yl)methyl]piperidin-l-yl}-3-hydroxypropan-lone— hydrochloride
R-13 5: (2R)-2-amino-1 -(4-benzyl-4-hydroxypiperidin-1 -yl)-3-hydroxypropan-1 -one
R-136: (2R)-2-amino-3-hydroxy-l-{4-[hydroxy(phenyl)methyl]piperidin-l-yl}propan-l-one
R-137: (2R)-2-amino-1-(1,3-dihydro-1 'H-spiro[indene-2,4'-piperidin]-1'-y 1 )-3hydroxypropan-1 -one
R-13 8: (2R)-2-amino-3-hydroxy-1 -[4-(4-methylbenzoyl)piperidin-1 -yl]propan-1 -one
R-139: (2R)-2-amino-3-hydroxy-1 -(4-{[3-(2-phenylethyl)phenyl]methyl(piperidin-1 yl)propan-l-one— hydrochloride
R-140: N-[l,r-biphenyl]-3-yl-D-serinamide
R-141: (2R)-2-amino-3-hydroxy-l-{4-[(4-methylphenyl)methyl]-3,6-dihydropyridin-l(2H)yl} propan-1-one
R-142: (2R)-2-amino-1-(7-bromo-3,4-dihydroi soquinolin-2( 1 H)-yl)-3 -hydroxypropan-1 -one- hydrochloride
R-143: 2-amino-6-[(naphthalen-2-yl)methoxy]-3,4-dihydronaphthalen-l(2H)-one— hydrochloride
R-144: (3 S)-3-amino-1 -[3-(trifluoromethoxy)phenyl]pyrrolidin-2-one— hydrochloride
R-145: (3R)-3-amino-1-[3-(trifluoromethoxy)phenyl]pyrrolidin-2-one— hydrochloride
R-146: (2R)-2-amino-N-(lH-indol-3-yl)-4-(methanesulfonyl)butanamide— hydrochloride
R-147: (3R)-3-amino-1-[3-(benzyloxy)phenyl]pyrrolidin-2-one— hydrochloride
R-148: (3R)-3-amino-l-{3-[(4-methylphenoxy)methyl]phenyl}pyrrolidin-2-one— hydrochloride
R-149: (2R)-2-amino-1 -(5 -bromo-2,3 -dihydro-1 H-indol-1 -yl)-3 -hydroxypropan-1 -one
R-l50: N-[(4-bromophenyl)methyl]-N-methyl-D-serinamide— hydrochloride
R-151: N-(4-phenylbutyl)-D-serinamide— hydrochloride
R-l52: 3-amino-l-(6-bromopyridin-2-yl)pyrrolidin-2-one— hydrochloride
R-l53: (3R)-3-amino-l-(6-iodopyridin-2-yl)piperidin-2-one— hydrochloride
R-l54: formic acid—(2R)-2-amino-3-hydroxy-l-(4-phenoxy-2,3-dihydro-1 H-indol-1yl)propan-l-one (1/1)
R-155: 3-amino-1 -([ 1,1 '-biphenyl]-3-yl)pyrrolidin-2-one
R-l56: 3-amino-l-[3-(phenylethynyl)phenyl]pyrrolidin-2-one— hydrochloride
R-l57: (2R)-2-amino-l-(2,3-dihydro-lH-pyrrolo[2,3-b]pyridin-l-yl)-3-hydroxypropan-l-one
-50R-158: (2R)-2-amino-1-(2,3-dihydro-lH-pyrrolo[3,2-c]pyridin-l-yl)-3-hydroxypropan-l-one
R-159: (2R)-2-amino-1-(2,3-dihydro-lH-pyrrolo[3,2-b]pyridin-l-yl)-3-hydroxypropan-l-one
R-160: (2R)-2-amino-3-hydroxy-l-(2-phenyl-2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridin5-yl)propan-l -one— hydrochloride
R-161: N-lH-pyrrolo[2,3-b]pyridin-3-yl-D-serinamide
R-162: (2R)-2-amino-3-hydroxy-1-(1 -phenyl-1,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridin5 -yl)propan-1 -one
R-163: (2R)-2-amino-3-hydroxy-1 -(6-hydroxy-2,3 -dihydro-ΙΗ-indol-1 -yl)propan-1 -one
R-164: (2R)-2-amino-3-hydroxy-2-methyl-l-{4-[(4-methylphenyl)methyl]piperidin-lyl} propan-1-one
R-165: 2-methyl-N-[3-(propan-2-yl)phenyl]-D-serinamide
R-166: 3 -amino-2-hydroxy-1 - { 4- [(4-methylphenyl)methyl]piperidin-1 -yl} propan-1 -one
R-167: (2R)-2-amino-3 -hydroxy-1 -(2-methyl-2,3 -dihydro-1 H-indol-1 -yl)propan-1 -one
R-168: (2R)-2-amino-3-hydroxy-1 -(spirofcyclobutane-1,3 '-indol]-1 '(2'H)-yl)propan-1 -one
R-169: (2R)-2-amino-1 -[3-(2-aminoethyl)-2,3-dihydro-1 H-indol-1 -yl]-3-hydroxypropan-1 one
R-170: N-lH-pyrrolo[3,2-c]pyridin-3-yl-D-serinamide
R-171: 3-amino-1 -[([ 1,1 '-biphenyl]-4-yl)methyl]pyrrolidin-2-one
R-172: (2R)-2-amino-3-hydroxy-1-(1 'H-spiro[cyclopropane-1,4'-isoquinolin]-2'(3Ή)yl)propan-l-one— hydrochloride
R-173: N-lH-pyrrolo[2,3-b]pyridin-5-yl-D-alpha-asparagine
R-174: (2R)-2-amino-1 -(5 -bromo-1,3 -dihydro-2H-i soindol-2-yl)-3 -hydroxypropan-1 -one
R-175: (2R)-2-amino-1 -(4-bromo-1,3-dihydro-2H-isoindol-2-yl)-3-hydroxypropan-1 -one
R-176: 5 - {[2-(4-chlorophenyl)ethyl] sulfanyl} -1 H-imidazole
R-177: (4-{[2-(4-chlorophenyl)ethyl]sulfanyl}pyridin-2-yl)methanol
R-178: N-({4-[(2-phenylethyl)sulfanyl]pyridin-2-yl}methyl)methanesulfonamide
R-179: methyl 4-{[2-([l,r-biphenyl]-4-yl)ethyl]sulfanyl}pyridine-2-carboxylate
R-180: 4-{[2-([l,r-biphenyl]-4-yl)ethyl]sulfanyl}pyridine-2-carboxylic acid
R-181: 1-(1 H-imidazol-1 -y 1)-3 -phenoxypropan-2-one
R-182: N-(4-chlorophenyl)-3-(lH-imidazol-l-yl)propanamide
R-183: l-[2-(4-chlorophenoxy)ethyl]-lH-imidazol-2-amine
R-184: l-[3-(4-chlorophenoxy)-2-methoxypropyl]-lH-imidazole
R-185: 1 -(4-chlorophenoxy)-3 -(lH-imidazol-1 -yl)propan-2-amine
R-186: l-[2-(4-chlorophenoxy)ethyl]-4-nitro-lH-imidazole
R-187: l-[4-(4-chlorophenyl)butyl]-lH-imidazole
R-188: l-[2-(4-chlorophenoxy)ethyl]-lH-tetrazole
R-l89: 2-[2-(4-chlorophenoxy)ethyl]-2H-tetrazole
-51 R-190: l-[4-(4-chlorophenyl)butyl]-lH-imidazol-2-amine
R-191: l-[3-(4-chlorophenyl)propyl]-4-nitro-lH-imidazole
R-192: l-[3-(4-chlorophenyl)propyl]-lH-imidazol-2-amine
R-193: l-[3-(4-chlorophenyl)propyl]-lH-imidazole-2-carboxylic acid
R-194: ethyl l-[3-(4-chlorophenyl)propyl]-lH-imidazole-2-carboxylate
R-195: ethyl l-[4-(4-chlorophenyl)butyl]-lH-imidazole-2-carboxylate
R-196: l-[4-(4-chlorophenyl)butyl]-lH-imidazole-2-carboxylic acid
R-197: l-[3-(4-chlorophenyl)propyl]-lH-imidazole-2-carboxamide
R-198: 1 -[3 -(4-chl orophenyl)propyl]-N-m ethyl- lH-imidazole-2-carboxamide
R-199: 4-bromo-1 -[3-(4-chlorophenyl)propyl]- lH-imidazole
R-200: 5-bromo-l-[3-(4-chlorophenyl)propyl]-lH-imidazole
R-201: l-[3-(4-chlorophenyl)propyl]-4-methyl-lH-imidazole
R-202: methyl l-[3-(4-chlorophenyl)propyl]-lH-imidazole-5-carboxylate
R-203: methyl l-[3-(4-chlorophenyl)propyl]-lH-imidazole-4-carboxylate
R-204: l-[3-(4-chlorophenyl)propyl]-lH-imidazole-4-carboxylic acid
R-205: l-[3-(4-chlorophenyl)propyl]-lH-imidazole-5-carboxylic acid
R-206: 3-{[3-(4-chlorophenyl)propyl]sulfanyl}-4H-l,2,4-triazole
R-207: l-[3-(4-chlorophenyl)propyl]-lH-imidazol-4-amine— hydrochloride
R-208: l-[3-(4-chlorophenyl)propyl]-5-methyl-lH-imidazole
R-209: 2-[3-(4-chlorophenyl)propyl]-4-methyl-2,4-dihydro-3H-l,2,4-triazole-3-thione
R-210: l-[3-(4-chlorophenyl)propyl]-lH-imidazol-5-amine— hydrochloride
R-211: N-({l-[3-(4-chlorophenyl)propyl]-lH-imidazol-2-yl}methyl)-2(methanesulfonyl)ethan-1 -amine
R-212: 4-{[2-(4-chlorophenyl)ethyl]sulfanyl}pyridine-2-carboxylic acid
R-213: 4-{[2-(4-chlorophenyl)ethyl]sulfanyl}pyridine
R-214: N-{l-[2-(4-chlorophenoxy)ethyl]-lH-imidazol-2-yl}acetamide
R-215: l-[3-(4-chlorophenyl)propyl]-4-fluoro-lH-imidazole
R-216: 3-hydroxy-5-[(E)-2-phenylethenyl]pyridin-2(lH)-one
R-217: 3-hydroxy-5-[(2-phenylethyl)sulfanyl]pyridin-2(lH)-one
R-218: 5-{[2-(4-chlorophenyl)ethyl]sulfanyl}-3-hydroxypyridin-2(lH)-one
R-219: 3-hydroxy-5-[(2-phenoxyethyl)sulfanyl]pyridin-2(lH)-one
R-220: 5-[(2-phenylethyl)sulfanyl]pyridin-2(lH)-one
R-221: 5-{[2-([l,r-biphenyl]-4-yl)ethyl]sulfanyl}-3-methoxypyridin-2(lH)-one
R-222: 5-{[2-([l,r-biphenyl]-4-yl)ethyl]sulfanyl}-3-hydroxypyridin-2(lH)-one
R-223: 5-{[2-(4-chlorophenyl)ethyl]sulfanyl}-2-methoxypyridine
R-224: 5-{[2-(4-chlorophenyl)ethyl]sulfanyl}-2-ethoxy-3-methoxypyridine
R-225: 5-{[2-(4-chlorophenyl)ethyl]sulfanyl}-3-methoxypyridin-2(lH)-one
-52R-226: 5-{[2-(4-chlorophenyl)ethyl]sulfanyl}pyridin-2(lH)-one
R-227: 5-{[2-(4-chlorophenyl)ethyl]sulfanyl}-3-methoxypyrazin-2(lH)-one
R-228: 5-[(3-fluorophenyl)sulfanyl]-3-hydroxypyridin-2(lH)-one
R-229: 5-{[2-(4-chlorophenyl)ethyl]sulfanyl}-l,4-dihydropyrazine-2,3-dione
R-230: 5-[(3-chloro-5-fluorophenyl)sulfanyl]-3-hydroxypyridin-2(lH)-one
R-231: 4-{[2-(4-chlorophenyl)ethyl]sulfanyl}thieno[2,3-c]pyridin-7(6H)-one
R-232: 5-{[2-(4-chlorophenyl)ethyl]sulfanyl}-3-fluoropyridin-2(lH)-one
R-233: 4-{[2-(4-chlorophenyl)ethyl]sulfanyl}-7-methoxy-lH-pyrrolo[2,3-c]pyridine
R-234: 3-chloro-5-{[2-(4-chlorophenyl)ethyl]sulfanyl}pyridin-2(lH)-one
R-235: 4-{[2-(4-chlorophenyl)ethyl]sulfanyl}-l,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one
R-236: 5-[(3-fluoro-5-propoxyphenyl)sulfanyl]-3-hydroxypyridin-2(lH)-one
R-23 7: 5 - {[2-(3 -chiorophenyl)ethyl] sulfanyl} -3 -hydroxypyridin-2( 1 H)-one
R-238: 5-[(4-chlorophenyl)sulfanyl]-3-hydroxypyridin-2(lH)-one
R-239: 5-{[2-(4-chlorophenyl)ethyl]sulfanyl}-2-oxo-l,2-dihydropyridine-3-carboxylic acid
R-240: 5-{[2-(4-chlorophenyl)ethyl]sulfanyl}-3-(hydroxymethyl)pyridin-2(lH)-one
R-241: 3-hydroxy-5-[(4-hydroxyphenyl)sulfanyl]pyridin-2(lH)-one
R-242: 5-{[3-(4-chlorophenyl)propyl]sulfanyl}-3-hydroxypyridin-2(lH)-one
R-243: 5-({2-[4-(benzyloxy)phenyl]ethyl}sulfanyl)-3-hydroxypyridin-2(lH)-one
R-244: 5-[2-(4-chlorophenyl)ethanesulfonyl]-3-hydroxypyridin-2(lH)-one
R-245: 3-hydroxy-5-{[2-(4-hydroxyphenyl)ethyl]sulfanyl}pyridin-2(lH)-one
R-246: 3-hydroxy-5-({3-[4-(phenylethynyl)phenyl]propyl}sulfanyl)pyridin-2(lH)-one
R-247: 5-{[3-([l,r-biphenyl]-4-yl)propyl]sulfanyl}-3-hydroxypyridin-2(lH)-one
R-248: 3-hydroxy-5-({2-[4-(phenylethynyl)phenyl]ethyl}sulfanyl)pyridin-2(lH)-one
R-249: 3-hydroxy-5-({3-[4-(2-phenylethyl)phenyl]propyl}sulfanyl)pyridin-2(lH)-one
R-250: 3-hydroxy-5-{[5-(pyridin-4-yl)-4H-l,2,4-triazol-3-yl]sulfanyl}pyridin-2(lH)-one
R-251: 3-hydroxy-5-[(4-{[4-(3-hydroxypropyl)phenyl]ethynyl}phenyl)sulfanyl]pyridin2(lH)-one
R-252: 5-{[2-(4-chlorophenyl)ethyl]sulfanyl}-4-fluoro-3-hydroxypyridin-2(lH)-one
R-253: 3-hydroxy-5-({2-[4'-(3-hydroxypropoxy)[l,r-biphenyl]-4-yl]ethyl}sulfanyl)-l-(3hydroxypropyl)pyridin-2( 1 H)-one
R-254: 6-{[2-(4-chlorophenyl)ethyl]sulfanyl}-4-hydroxypyridazin-3(2H)-one
R-255: 3-hydroxy-4-[(3-phenylpropyl)amino]pyridin-2(lH)-one
R-256: 5-{[3-(4-chlorophenyl)-lH-l,2,4-triazol-l-yl]methyl}-3-hydroxypyridin-2(lH)-one
R-257: [4-(4-chlorophenyl)butyl]propanedioic acid
R-258: 2-(4-chlorophenyl)-5-{ [(4H-1,2,4-triazol-3 -yl)sulfanyl]methyl}-1,3,4-oxadiazole
R-259: 2-(lH-pyrrol-l-yl)benzoic acid
R-260: (3-ethyl-l,2,4-oxadiazol-5-yl)methyl carbamimidothioate— hydrochloride
-53 R-261: 5-{ [4-(4-chlorophenyl)-1,2,3-triazol-1 -yl]methyl}-3-hydroxy-lH-pyridin-2-one
R-262: (E)-5 -(3 -(4-chlorophenyl)prop-1 -en-1 -y 1)-3 -hydroxypyridin-2( 1 H)-one
R-263: (E)-5-(2-(4-chlorophenyl)prop-l-en-l-yl)-3-hydroxypyridin-2(lH)-one
Synthesis of Compound-1
2-Amino-3-hydroxy-l-{4-[(4-{[4-(hydroxymethyl)phenyl]ethynyl}phenyl)methyl]piperidin-
-yl} -4-(m ethanesulfonyl )butan-1 -one
Ethyl 2-(dibenzylamino)-3-hydroxy-4-(methylthio)butanoate
O Bn O Bn II 1
N Bn + —s 0 H 'A/vYn
HoY
To a stirred solution of diisopropylamine (4.7 mL) in THF (0.21 L) was added 1.6 mol/L nbutyllithium in hexane (20 mL) at -78 °C. The mixture was allowed to warm to 0 °C, stirred for 30 minutes, then cooled to -78 °C and ethyl 2-(dibenzylamino)acetate (6 g) in THF was added into the mixture. After stirring for 30 minutes, 2-methylsulfanylacetaldehyde (2.3 g) in THF was added into the resulting mixture. The reaction mixture was allowed to warm to room temperature, stirred further 3 hours, quenched with a saturated aqueous sodium bicarbonate and extracted with CHCI3 three times. The organic layer was passed through a phase separator and concentrated in vacuo onto ISOLUTE® HM-N. The residue was purified with OH-type silica gel column chromatography (8-31 % EtOAc in n-hexane) to give the title compound (1.2 g, 15 % yield) as a yellow oil.
MS (ESI) m/z : 374 [M+l]+.
RT = 0.981 min.
LCMS condition : C.
Step 2)
Ethyl 2-(dibenzylamino)-3-hydroxy-4-(methylsulfonyl)butanoate
-54Ο
Το a stirred solution of ethyl 2-(dibenzylamino)-3-hydroxy-4-methylsulfanyl-butanoate (1.2
g) in CHCf (10 mL) was added m-chloroperbenzoic acid (2.0 g) at 0 °C. The reaction mixture was stirred at room temperature overnight, quenched with a saturated aqueous sodium thiosulfate and extracted with CHCI3 twice. The organic layer was passed through a phase separator and concentrated in vacuo onto ISOLUTE® HM-N. The residue was purified with OH-type silica gel column chromatography (8-100 % EtOAc in n-hexane) to give the title compound (0.58 g, 47 % yield) as colorless powder.
MS (ESI) m/z : 406 [M+l]+.
RT = 0.847 min.
LCMS condition : C.
Step 3)
Ethyl 2-amino-3 -hydroxy-4-(methyl sulfonyl)butanoate
To a solution of ethyl 2-(dibenzylamino)-3-hydroxy-4-methylsulfonyl-butanoate (0.40 g) in EtOH (9.9 mL) was added palladium hydroxide on carbon (50 mg). The mixture was stirred at room temperature overnight under hydrogen atmosphere. The reaction mixture was filtered and filtrate was concentrated in vacuo to give the title compound (0.24 g, quant.) as a crude oil, which was used in the next step without further purification.
MS (ESI) m/z : 226 [M+l]+.
RT = 0.258 min.
LCMS condition : B.
Step 4)
Ethyl 2-((tert-butoxycarbonyl)amino)-3-hydroxy-4-(methylsulfonyl)butanoate
To a stirred solution of ethyl 2-amino-3-hydroxy-4-methylsulfonyl-butanoate (0.17 g as crude material) in THF (3.8 mL) and EtOH (1.5 mL) were added (Boc)2O (0.20 g) and potassium carbonate (0.27 g). After stirring for 3 hours at room temperature, the reaction mixture was quenched with water and extracted with CHC13 three times. The organic layer was concentrated in vacuo onto ISOLUTE® HM-N. The residue was purified with OH-type silica gel column chromatography (30-100 % EtOAc in n-hexane) to give the title compound (0.27 g, quant.) as a colorless oil.
MS (ESI) m/z : 348 [M+23]+.
RT = 0.635 min.
LCMS condition : B.
Step 5)
Sodium 2-((tert-butoxycarbonyl)amino)-3-hydroxy-4-(methylsulfonyl)butanoate
To a solution of ethyl 2-(tert-butoxycarbonylamino)-3-hydroxy-4-methylsulfonyl-butanoate (0.28 g) in EtOH (2.9 mL) was added 10 mol/L aqueous sodium hydroxide (0.26 mL). After stirring for 3 hours at room temperature, the resulting precipitates were filtered and collected to give the title compound (0.20 g, 73 % yield) as a colorless solid.
MS (ESI) m/z : 296 [M-l]'.
RT = 0.879 min.
LCMS condition : A.
Step 6)
Tert-butyl 4-(4-((4-(hydroxymethyl)phenyl)ethynyl)benzyl)piperidine-1 -carboxylate
A mixture of tert-butyl 4-((4-(trifluorom ethyl sulfonyl oxy )phenyl)methyl)piperi dine-1carboxylate (0.37 g), (4-(hydroxymethyl)phenyl)acetylene (0.37 mL), Cui (17 mg),
-56PdC12(PPh3)2 (61 mg) and TEA (5 mL) in DMF (5 mL) was stirred at 70 °C for 15 hours. After cooling the mixture to room temperature, the insoluble matter was removed by filtration through Celite® and washed with EtOAc. The filtrate was concentrated in vacuo. The residue was purified with OH-type silica gel column chromatography (EtOAc in nhexane) to give the title compound (0.14 g, 40 % yield) as a pale orange solid.
MS (ESI) m/z : 428 [M+23]+.
RT= 1.024 min.
LCMS condition : C.
Step 7) (4-((4-(Piperidin-4-ylmethyl)phenyl)ethynyl)phenyl)methanol hydrochloride
To a solution of tert-butyl 4-(4-((4-(hydroxymethyl)phenyl)ethynyl)benzyl)piperidine-lcarboxylate (0.14 g) in 1,4-dioxane (4 mL) was added 4 mol/L HCI in 1,4-dioxane (8 mL) at room temperature. The reaction mixture was stirred at the same temperature for 4 hours and concentrated in vacuo to give the title compound (0.13 g, quant.) as a pale yellow solid. MS (ESI) m/z : 306 [M+l]+.
RT = 0.543 min.
LCMS condition : B.
Step 8)
Tert-butyl (3-hydroxy-1 -(4-(4-((4-(hydroxymethyl)phenyl)ethynyl)benzyl)piperidin-1 -yl)-4-
To a stirred solution of [4-[2-[4-(4-piperidylmethyl)phenyl]ethynyl]phenyl]methanol hydrochloride (34 mg) in DMF (2.0 mL) were added sodium 2-(tert-butoxycarbonylamino)-
3-hydroxy-4-methylsulfonyl-butanoate (35 mg), HATU (57 mg) and DIPEA (52 pL). The mixture was stirred for 3 hours at room temperature. The reaction mixture was purified with prep-HPLC to give the title compound (56 mg, 96 % yield) as an amorphous.
MS (ESI) m/z : 607 [M+23]+.
RT = 0.786 min.
LCMS condition : C.
-57Step 9)
2-Amino-3-hydroxy-l-{4-[(4-{[4-(hydroxymethyl)phenyl]ethynyl}phenyl)methyl]piperidin-
-yl}-4-(methanesulfonyl)butan-1 -one (Compound-1)
A solution of tert-butyl N-[2-hydroxy-l-[4-[[4-[2-[4(hydroxymethyl)phenyl]ethynyl]phenyl]methyl]piperidine-l-carbonyl]-3-methylsulfonylpropyljcarbamate (53 mg) in formic acid (1.5 mL) was stirred for 2 hours at room temperature. The reaction mixture was diluted with CHCI3 and concentrated in vacuo. To the residue was added 7 mol/L ammonia in MeOH (2 mL) and the resulting mixture was stirred for 10 minutes at room temperature. The reaction mixture was concentrated in vacuo and purified with prep-HPLC to give the title compound (Compound-1, 11 mg, 35 % yield) as a colorless powder.
'H-NMR, MS and LCMS retention time data of Compound-1 are shown in Table 2.
Synthesis of Compound-16 (2R)-2-amino-3 -hydroxy-1 -(4- { 2-[4-(2-hydroxyethoxy)phenyl] ethyl)-2,3 -dihydro-1 H-indol-
Tert-butyl 4-((4-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethoxy)phenyl)ethynyl)indoline-lcarboxylate
A solution of tert-butyl 4-bromoindoline-l -carboxylate (0.50 g), bis(triphenylphosphine)palladium(II) di chloride (0.24 g), copper iodide (64 mg), triphenylphosphine (0.18 g), hexamethyldisilazane (0.52 mL) and tri ethylamine (1.7 g) in DMF (8.4 mL) was evacuated and backfilled with nitrogen three times. The mixture was stirred for 10 minutes at 110 °C. 2-[2-(4-Ethynylphenoxy)ethoxy]tetrahydropyran (0.83 g) was added into the mixture. The reaction mixture was stirred for 5 hours at 110 °C and overnight at room temperature, quenched with water and extracted with EtOAc. The organic layer was washed with water twice, dried over MgSCU, filtered and concentrated in vacuo. The residue was charged onto ISOLUTE® HM-N and purified with OH-type silica gel column chromatography (3-100 % EtOAc in n-hexane) to give the title compound (0.57 g, 73 % yield) as a colorless solid.
'H NMR (600 MHz, CHLOROFORM-d) δ ppm 1.50 - 1.67 (m, 13 H), 1.71 - 1.79 (m, 1 H), 1.81 - 1.89 (m, 1 H), 3.18 - 3.25 (m, 2 H), 3.51 - 3.57 (m, 1 H), 3.80 - 3.86 (m, 1 H), 3.87 3.93 (m, 1 H), 3.96 - 4.10 (m, 3 H), 4.13 - 4.23 (m, 2 H), 4.68 - 4.74 (m, 1 H), 6.89 - 6.94 (m, 2 H), 7.05 - 7.17 (m, 2 H), 7.26 - 7.27 (m, 1 H), 7.40 - 7.48 (m, 2 H).
Step 2)
2-(4-(Indolin-4-ylethynyl)phenoxy)ethanol hydrochloride
The title compound was obtained in the manner as with the “Synthesis of Compound-1: step7” using the corresponding materials.
MS (ESI) m/z : 280 [M+l]+.
RT = 0.635 min.
LCMS condition : B.
Step 3) (R)-tert-butyl (3 -hydroxy-1 -(4-((4-(2-hydroxyethoxy)phenyl)ethynyl)indolin-1-y 1)-1oxopropan-2-yl)carbamate
-59To a solution of (2R)-2-(tert-butoxycarbonylamino)-3-hydroxy-propanoic acid (51 mg) and HATU (0.12 g) in DMF (2.1 mL) were added DIPEA (0.11 mL) and 2-[4-(2-indolin-4ylethynyl)phenoxy]ethanol hydrochloride (65 mg). The mixture was stirred for 3 hours at room temperature. The reaction was quenched with water and extracted with EtOAc. The organic layer was washed with water twice, dried over MgSO4, filtered and concentrated in vacuo. The residue was charged onto ISOLUTE® HM-N and purified with OH-type silica gel column chromatography (5-50 % EtOAc in n-hexane) to give the title compound (92 mg, 96 % yield) as a light yellow solid.
MS (ESI) m/z : 489 [M+23]+.
RT = 0.952 min.
LCMS condition : B.
Step 4) (R)-tert-butyl (3 -hydroxy-1 -(4-(4-(2-hydroxyethoxy)phenethyl)indolin-1 -yl)-1 -oxopropan-2yl)carbamate
The solution of (R)-tert-butyl (3-hydroxy-l-(4-((4-(2-hydroxyethoxy)phenyl)ethynyl)indolinl-yl)-l-oxopropan-2-yl)carbamate (68 mg) in MeOH was added palladium on carbon (7 mg). The reaction mixture was stirred under hydrogen atmosphere for 2 hours at room temperature. The mixture was filtered by a phase separator and rinsed with MeOH and EtOAc. The filtrate was concentrated in vacuo. The residue was charged onto ISOLUTE® HM-N and purified with OH-type silica gel column chromatography (5-100 % EtOAc in n-hexane) to give the title compound (50 mg, 73 % yield) as a colorless solid.
MS (ESI) m/z : 493 [M+23]+.
RT = 0.944 min.
LCMS condition : B.
Step 5) (2R)-2-amino-3 -hydroxy-1 -(4- { 2-[4-(2-hydroxyethoxy)phenyl] ethyl )-2,3 -dihydro-1 H-indoll-yl)propan-l-one hydrochloride (Compound-16)
The title compound was obtained in the manner as with the “Synthesis of Compound-1: step7” using the corresponding materials.
'H-NMR, MS and LCMS retention time data of Compound-16 are shown in Table 2.
Synthesis of Compound-27 (2R)-2-amino-3 -hydroxy-1 -[6- {[4-(hydroxymethyl)phenyl] ethynyl} -3,4-dihydroi soquinolin2(lH)-yl]propan-1 -one hydrochloride
A mixture of tert-butyl 6-bromo-3,4-dihydroisoquinoline-2(lH)-carboxylate (0.18 g), PdCl2(PPh3)2 (82 mg), Cui (22 mg), triphenylphosphine (62 mg), hexamethyldisilazane (0.18 mL) and TEA (0.82 mL) in DMF (3 mL) was stirred at 110 °C. The mixture was stirred for 5 minutes, and then, (4-ethynylphenyl)methanol (0.23 g) was added into the mixture. The reaction mixture was stirred at the same temperature for 5 hours. After cooling the reaction mixture to room temperature, EtOAc (15 mL) and water (15 mL) were added and an organic layer was separated. The organic layer was washed with brine, dried over MgSO4 and concentrated in vacuo. The residue was purified with OH-type silica gel column chromatography (EtOAc in n-hexane) to give the title compound (0.12 g, 56 % yield) as a yellow solid.
MS (ESI) m/z : 386 [M+23]+.
RT = 1.221 min.
LCMS condition : B.
Step 2)
-61 (4-((l,2,3,4-Tetrahydroisoquinolin-6-yl)ethynyl)phenyl)methanol hydrochloride
The title compound was obtained in the manner as with the “Synthesis of Compound-1: step7” using the corresponding materials.
MS (ESI) m/z : 264 [M+l]+.
RT = 0.256 min.
LCMS condition : B.
Step 3) (R)-tert-butyl (3-hydroxy-l-(6-((4-(hydroxymethyl)phenyl)ethynyl)-3,4-dihydroisoquinolin2(lH)-yl)-l-oxopropan-2-yl)carbamate
The title compound was obtained in the manner as with the “Synthesis of Compound-16: step-3” using the corresponding materials.
MS (ESI) m/z : 451 [M+l]+.
RT = 0.907 min.
LCMS condition : B.
Step 4) (2R)-2-amino-3 -hydroxy-1 -[6- {[4-(hydroxymethyl)phenyl] ethynyl} -3,4-dihydroi soquinolin2(lH)-yl]propan-l-one — hydrochloride (Compound-27)
The title compound was obtained in the manner as with the “Synthesis of Compound-16: step-5” using the corresponding materials.
'H-NMR, MS and LCMS retention time data of Compound-27 are shown in Table 2.
Synthesis of Compound-33 (R)-3-amino-4-((6-(4-(3-hydroxypropyl)phenyl)-lH-indol-3-yl)amino)-4-oxobutanoic acid
Compound-33
Step 1)
Tert-butyl (6-bromo-1 H-indol-3 -yl)carbamate
To a solution of 6-bromo-lH-indole-3-carboxylic acid (2.5 g) in toluene (35 mL) and THF (35 mL) was added TEA (2.9 mL) at room temperature. After stirring the mixture for 10 minutes, DPPA (3.7 g) was added into the mixture and the resulting mixture was stirred for 3 hours at room temperature. The mixture was concentrated and the residue was dissolved in tert-butyl alcohol (21 mL) followed by addition of pyridine (2.9 mL). After the solution was refluxed for 3 hours, an additional pyridine (1.0 mL) was added and the mixture was refluxed for another 10 hours. The mixture was concentrated and the residue was dissolved in ethyl acetate and then washed with 0.5 mol/L aqueous HCI and half-saturated brine. The organic phase was separated, dried over MgSO4 and concentrated in vacuo. The residue was purified with OH-type silica gel column chromatography (10-50 % EtOAc in n-hexane) to give the title compound (1.6 g, 51 % yield) as a pale green solid.
MS (ESI) m/z :311 [M+l]+.
RT= 1.081min.
LCMS condition : B.
Step 2)
Tert-butyl (6-(4-(3-hydroxypropyl)phenyl)-lH-indol-3-yl)carbamate
A round bottomed flask was charged with tert-butyl (6-bromo-lH-indol-3-yl)carbamate (0.75 g), [4-(3-hydroxypropyl)phenyl]boronic acid (0.56 g) and Pd(PPh3)4 (0.28 g). The flask was evacuated and backfilled with nitrogen followed by addition of EtOH (4.8 mL), toluene (19 mL) and 2 mol/L aqueous sodium carbonate (3.6 mL). The resulting mixture was heated to 90 °C for 3 hours and then allowed to cool to room temperature. The reaction mixture was poured into water and extracted three times with CHC13. The combined organic layer was
-63 washed with a saturated aqueous sodium bicarbonate, dried over MgSO4 and concentrated in vacuo. The residue was purified with OH-type silica gel column chromatography (0-8 % MeOH in CHC13) to give the title compound (0.24 g, 27 % yield) as a pale brown solid. MS (ESI) m/z : 367 [M+l]+.
RT= 1.014min.
LCMS condition : B.
Step 3)
3-(4-(3-Amino-lH-indol-6-yl)phenyl)propan-l-ol hydrochloride
To a suspension of tert-butyl (6-(4-(3-hydroxypropyl)phenyl)-lH-indol-3-yl)carbamate (0.23 g) in 1,4-dioxane (4.3 mL) was added 4 mol/L HCI in 1.4-dioxane (4.0 mL) at room temperature. After stirring for 3 hours, the reaction mixture was concentrated and the residue was co-evaporated with 1,4-dioxane to remove excess hydrogen chloride to give the title compound (0.19 g, crude) as a solid, which was used in next step without further purification. MS (ESI) m/z : 267 [M+l]+.
RT = 0.696min.
LCMS condition : A.
Step 4) (R)-benzyl 3-(((benzyloxy)carbonyl)amino)-4-((6-(4-(3-hydroxypropyl)phenyl)-lH-indol-3yl)amino)-4-oxobutanoate
To a solution of Z-D-Asp(OBzl)-OH (0.15 g) and 3-(4-(3-amino-lH-indol-6yl)phenyl)propan-l-ol hydrochloride (0.17 g) in DMF (1.4 mL) were sequentially added NMM (0.21 g) and T3P (0.32 mL, 50 wt% in EtOAc) at room temperature. After stirring for 16 hours, the mixture was diluted with CHCI3 and then washed with 5% aqueous sodium bicarbonate and brine. The organic phase was separated, dried over MgSO4 and concentrated in vacuo. The residue was purified with OH-type silica gel column chromatography (40-80 % EtOAc in n-hexane) to give the title compound (54 mg, 21 % yield) as a colorless oil. MS (ESI) m/z : 606 [M+l]+.
RT= l.llOmin.
LCMS condition : B.
-64 Step 5) (R)-3-amino-4-((6-(4-(3-hydroxypropyl)phenyl)-lH-indol-3-yl)amino)-4-oxobutanoic acid
To a solution of (R)-benzyl 3-(((benzyl oxy)carbonyl)amino)-4-((6-(4-(3hydroxypropyl)phenyl)-lH-indol-3-yl)amino)-4-oxobutanoate (53 mg) in MeOH (4.0 mL) was added 10% Pd-C (15 mg) under inert atmosphere. The flask was flushed with hydrogen gas and the mixture was vigorously stirred for 3 hours at ambient temperature. The reaction mixture was filtered through a pad of Celite® and the cake was washed with MeOH. The filtrate was concentrated under reduced pressure to give the title compound (Compound-33, 11 mg, 33 % yield) as a colorless solid.
'H-NMR, MS and LCMS retention time data of Compound-33 are shown in Table 2.
Synthesis of Compound-42 2-Amino-2-(l,l-dioxidothiomorpholin-3-yl)-l-(4-(4-methylbenzyl)piperidin-l-yl)ethanone
Step 1)
2-((Tert-butoxycarbonyl)amino)-2-(4-(tert-butoxycarbonyl)thiomorpholin-3-yl)acetic acid
1) (NH4)2CO3aq KCN, MeOH
2) (Boc)2O, TEA, THF
3) LiOHaq, THF, 70°C
4) (Boc)2O, NaOHaq, THF
To a solution of tert-butyl 3-formylthiomorpholine-4-carboxylate (1.0 g) in MeOH (10 mL) was added 10 % aqueous ammonium carbonate (10 mL). The reaction mixture was stirred at 0°C for 1 hour and then potassium cyanide (0.45 g) was added into the mixture. After stirring for 1 hour, the mixture was allowed to warm to room temperature and stirred for 1.5 hour. The mixture was concentrated in vacuo and the residue was diluted with water and extracted with EtOAc. The organic phase was dried over MgSO4 and concentrated in vacuo. The residue was purified with OH-type silica gel column chromatography (25-40 % EtOAc in n
-65 hexane) to give a crude product (98 mg), which was used in the next step.
To a solution of the crude product (98 mg) and (Boc)2O (0.21 g) in THF (6 mL) were sequentially added TEA (50 pL) and DMAP (3.9 mg). The reaction mixture was stirred at room temperature overnight and concentrated in vacuo. The residue was used in the next step without further purification.
To the crude product dissolved in THF (2 mL) was added 1 mol/L aqueous lithium hydroxide (2 mL). The mixture was stirred at room temperature for 2.5 hour and then heated to 70°C and stirred for 1 hour. After cooling to room temperature, the mixture was concentrated in vacuo to obtain a crude residue (20 mg), which was used in next step without further purification.
To the crude product (20 mg) in THF (2 mL) were sequentially added 1 mol/L aqueous sodium hydroxide (2 mL) and (Boc)2O (0.29 g) and the mixture was stirred at room temperature for 2 days. The mixture was diluted with CHCf (15 mL) and extracted with a saturated aqueous sodium bicarbonate (15 mL) twice. The combined aqueous phase was adjusted to pH 2 with 1 mol/L aqueous potassium hydrogen sulfate. The resulting mixture was extracted with EtOAc (15 mL) twice. The combined organic extracts were combined, dried over MgSCfr and concentrated in vacuo to give the title compound (15 mg, 2.8 % yield in 4 steps) as a colorless amorphous.
MS (ESI) m/z : 399 [M+23]+.
RT = 1.040 min and 1.367 min (each diastereomer peak was observed).
LCMS condition : B.
Step 2)
Tert-butyl 3-(l-((tert-butoxycarbonyl)amino)-2-(4-(4-methylbenzyl)piperidin-l-yl)-2oxoethyl)thiomorpholine-4-carboxylate
To a solution of 4-(4-methyl-benzyl)-piperidine hydrochloride (11 mg) in DMF (2 mL) were sequentially added HATU (20 mg) and DIPEA (25 pL) at room temperature. After stirring the mixture for 30 minutes, 2-((tert-butoxycarbonyl)amino)-2-(4-(tertbutoxycarbonyl)thiomorpholin-3-yl)acetic acid (15 mg) was added into the mixture. The mixture was stirred for 6 hours and diluted with EtOAc and then washed with a saturated aqueous sodium bicarbonate and brine. The organic phase was separated, dried over MgSO4 and concentrated in vacuo. The residue was purified with OH-type silica gel column chromatography (10-50 % EtOAc n-hexane) to give the title compound (10 mg, 46 % yield). MS (ESI) m/z : 548 [M+l]+.
-66 RT = 1.061 min.
LCMS condition : C.
Step 3)
Tert-butyl 3-(l-((tert-butoxycarbonyl)amino)-2-(4-(4-methylbenzyl)piperidin-l-yl)-2oxoethyl)thiomorpholine-4-carboxylate 1,1 -dioxide
To a cooled (0 °C) solution of tert-butyl 3-(l-((tert-butoxycarbonyl)amino)-2-(4-(4methylbenzyl)piperidin-l-yl)-2-oxoethyl)thiomorpholine-4-carboxylate (23 mg) in CHCI3 (2 mL) was added 3-chloroperbenzoic acid (21 mg). After stirring for 5 minutes at 0 °C, the mixture was allowed to warm to room temperature and stirred for 6 hours. The reaction was quenched with 2% aqueous sodium thiosulfate (5mL) and a saturated aqueous sodium bicarbonate, and extracted with CHC13. The organic layers were dried over MgSO4 and concentrated in vacuo. The residue was purified with amino-type silica gel column chromatography (20-80 % EtOAc in n-hexane) to give the title compound (9.0 mg, 37 % yield) as a colorless amorphous.
MS (ESI) m/z : 580 [M+l]+.
RT = 0.972 min and 0.997min (each diastereomer peak was observed).
LCMS condition : C.
Step 4) 2-Amino-2-(l,l-dioxidothiomorpholin-3-yl)-l-(4-(4-methylbenzyl)piperidin-l-yl)ethanone
The title compound was obtained in the manner as with the “Synthesis of Compound-16: step-5” using the corresponding materials.
MS and LCMS retention time data of Compound-42 are shown in Table 3.
Synthesis of Compound-48
2-Amino-2- [3 -hydroxy-1 -(m ethanesulfonyl )pyrrolidin-3 -yl] -1 - { 4-[(4methylphenyl)methyl]piperidin-1 -yl} ethan-1 -one
-67 Ο
Single diastereomer (high-polar)
Step 1)
Tert-butyl 3-(l-(dibenzylamino)-2-(4-(4-methylbenzyl)piperidin-l-yl)-2-oxoethyl)-3hydroxypyrrolidine-1-carboxylate
O
Boc
To a stirred solution of diisopropylamine (0.15 mL) in THF (6.6 mL) was added 1.6 mol/L nbutyllithium in hexane (0.62 mL) at -78 °C. The reaction mixture was allowed to warm to 0°C and was stirred for 30 minutes. The reaction mixture was then cooled at -78 °C and 2(dibenzylamino)-l-[4-(p-tolylmethyl)-l-piperidyl]ethanone (0.28 g) in THF was added into the mixture. After stirring the mixture for 30 minutes, tert-butyl 3-oxopyrrolidine-1carboxylate (0.15 g) in THF was added into the mixture. The reaction mixture was allowed to warm to room temperature and stirred further 2 hours. The mixture was quenched with a saturated aqueous sodium bicarbonate and extracted three times with CHC13. The organic layer was passed through a phase separator and concentrated in vacuo onto ISOLUTE® HMN. The residue was purified with OH-type silica gel column chromatography (8-66 % EtOAc in n-hexane) to give the title compound as a separated single diastereomer (0.18 g, 44 % yield as a low-polar diastereomer (oil) and 84 mg, 21 % yield as a high-polar diastereomer (oil), respectively). The high-polar diastereomer was used in the next step.
High-polar diastereomer:
'H NMR (400 MHz, CHLOROFORM-d) δ ppm 0.79 - 1.19 (m, 2 H), 1.38 - 1.90 (m, 15 H), 2.26 - 2.95 (m, 6 H), 3.10 - 3.97 (m, 7 H), 4.27 - 4.46 (m, 2 H), 4.64 - 4.85 (m, 1 H), 5.06 5.38 (m, 1 H), 6.90 - 7.55 (m, 14 H).
Step 2) 2-(Dibenzylamino)-2-(3-hydroxypyrrolidin-3-yl)-l-(4-(4-methylbenzyl)piperidin-lyl)ethanone
-68 Ο
To a stirred solution of tert-butyl 3-[l-(dibenzylamino)-2-oxo-2-[4-(p-tolylmethyl)-lpiperidyl]ethyl]-3-hydroxy-pyrrolidine-l-carboxylate (84 mg, high-polar diastereomer) in 1,4-dioxane (1.4 mL) was added 4 mol/L hydrogen chloride in 1,4-dioxane (0.34 mL). After stirring for 2 hours at room temperature, the reaction mixture was quenched with a saturated aqueous sodium bicarbonate and extracted with CHCfi three times. The organic layer was passed through a phase separator and concentrated in vacuo onto ISOLUTE® HM-N. The residue was purified with amino-type silica gel column chromatography (0-9 % MeOH in EtOAc) to give the title compound (86 mg, quant.) as an oil.
MS (ESI) m/z : 512 [M+l]+.
RT = 0.972 min.
LCMS condition : B.
Step 3)
2-(Dibenzyl amino)-2-(3 -hydroxy-1 -(methyl sulfonyl)pyrrolidin-3 -yl)-1 -(4-(4methylbenzyl)piperidin-1 -yl)ethanone
OH
To a stirred solution of 2-(dibenzylamino)-2-(3-hydroxypyrrolidin-3-yl)-l-[4-(ptolylmethyl)-l-piperidyl]ethanone (86 mg) in CHCI3 (3.4 mL) were added TEA (0.12 mL) and methansulfonyl chloride (20 pL) at 0 °C. After stirring for 5 hours at room temperature, the reaction mixture was quenched with a saturated aqueous sodium bicarbonate and extracted twice with CHCI3. The organic layer was passed through a phase separator and concentrated in vacuo onto ISOLUTE® HM-N. The residue was purified with OH-type silica gel column chromatography (8-51 % EtOAc in n-hexane) to give the title compound (63 mg, 64 % yield) as an oil.
MS (ESI) m/z 590 [M+l]+.
RT= 1.440 min.
LCMS condition : B.
Step 4)
-69 2-Amino-2- [3 -hydroxy-1 -(m ethanesulfonyl )pyrrolidin-3 -yl] -1 - { 4-[(4methylphenyl)methyl]piperidin-1 -yl}ethan-1 -one (Compound-48)
Compound-48
To a solution of 2-(dibenzylamino)-2-(3-hydroxy-l-methylsulfonyl-pyrrolidin-3-yl)-l-[4-(ptolylmethyl)-l-piperidyl]ethanone (63 mg) in MeOH (0.53 mL) was added palladium hydroxide on carbon (20 mg). The mixture was stirred at room temperature for 2 hours under hydrogen atmosphere. The reaction mixture was filtered and filtrate was concentrated in vacuo. The residue was diluted with CHCf and washed with a saturated aqueous sodium bicarbonate. The organic layer was concentrated in vacuo onto ISOLUTE® HM-N. The residue was purified with amino-type silica gel column chromatography (2-14 % MeOH in CHCI3) to give the title compound (30 mg, 69 % yield) as a colorless powder.
MS and LCMS retention time data of Compound-48 are shown in Table 3.
Synthesis of Compound-61
2-Amino-2- [4-hydroxy-1 -(m ethanesulfonyl )piperi din-4-yl] -1 - { 4- [(4methylphenyl)methyl]piperidin-1 -yl} ethan-1 -one
Step 1)
Tert-butyl 4-(2-(4-(4-methylbenzyl)piperidin-1 -yl)-2-oxoethylidene)piperidine-1 -carboxylate
O
Boc
The title compound was obtained in the manner as with the “Synthesis of Compound-16: step-3” using the corresponding materials.
MS (ESI) m/z : 413 [M+l]+, 435 [M+23]+.
RT = 1.285 min.
-70 LCMS condition : B.
Step 2) l-(4-(4-Methylbenzyl)piperidin-l-yl)-2-(l-(methylsulfonyl)piperidin-4-ylidene)ethanone
To a solution of tert-butyl 4-(2-(4-(4-methylbenzyl)piperidin-l-yl)-2oxoethylidene)piperidine-l-carboxylate (0.86 g) in 1,4-dioxane (4 mL) was added 4 mol/L HCI in 1,4-dioxane (8 mL). The mixture was stirred at room temperature for 2.5 hours. The reaction mixture was quenched with aqueous potassium carbonate under ice-bath cooling and extracted with CHC13. The organic phase was separated, dried over MgSO4 and concentrated in vacuo to give a crude product (0.63 g) as a light yellow syrup, which was used in the next step without further purification.
To a solution of the crude product (0.63 g) in CHC13 (10 mL) were added DIEA (1.5 mL) and methansulfonyl chloride (0.21 pL) at 0 °C. After stirring for 1 hour at room temperature under nitrogen atmosphere, the reaction mixture was quenched with a saturated aqueous sodium bicarbonate and extracted with CHC13. The organic layer was passed through a phase separator and concentrated in vacuo onto ISOLUTE® HM-N. The residue was purified with OH-type silica gel column chromatography (30-100 % EtOAc in n-hexane and then 2-10 % MeOH in CHC13) to give the title compound (0.65 g, 80 % yield in 2 steps) as a yellow syrup. MS (ESI) m/z : 391 [M+l]+, 413 [M+23]+.
RT= 1.045 min.
LCMS condition : B.
Step 3) (4-(4-Methylbenzyl)piperidin-l-yl)(6-(methylsulfonyl)-l-oxa-6-azaspiro[2.5]octan-2yl)methanone
To a solution of l-(4-(4-methylbenzyl)piperidin-l-yl)-2-(l-(methylsulfonyl)piperidin-4ylidene)ethanone (0.45 g) in 1,2-dichloroethane (20 mL) was added m-chloroperbenzoic acid
-71 (0.40 g) and the mixture was stirred overnight at room temperature. m-Chloroperbenzoic acid (0.16 g) was added into the mixture and the mixture was stirred for 8 hours. The reaction mixture was quenched with aqueous sodium thiosulfate and extracted with CHCf. The organic phase was washed with aqueous sodium thiosulfate and saturated aqueous sodium bicarbonate twice, passed through a phase separator and concentrated in vacuo onto ISOLUTE® HM-N. The residue was purified with OH-type silica gel column chromatography (2-15 % MeOH in CHC13) to give the title compound (0.43 g, 91 % yield) as a brown amorphous.
MS (ESI) m/z : 407 [M+l]+, 429 [M+23]+.
RT = 0.988 min.
LCMS condition : B.
Step 4) 2-(Benzylamino)-2-(4-hydroxy-l-(methylsulfonyl)piperidin-4-yl)-1-(4-(4methylbenzyl)piperidin-1 -yl)ethanone
O O
To a solution of (4-(4-methylbenzyl)piperidin-l-yl)(6-(methylsulfonyl)-l-oxa-6azaspiro[2.5]octan-2-yl)methanone (0.42 g) in MeOH (7 mL) and THF (7 mL) was added benzylamine (2 mL). The mixture was stirred for 90 minutes at 140 °C under microwave irradiation. After cooling to room temperature, the reaction mixture was concentrated in vacuo onto ISOLUTE® HM-N. The residue was purified with OH-type silica gel column chromatography (30-100 % AcOEt in n-hexane and then 2-5 % MeOH in CHCI3) to give a crude product, which was re-purified with OH-type silica gel column chromatography (40100 % AcOEt in n-hexane) to give the title compound (76 mg, 14 % yield) as a light yellow syrup.
MS (ESI) m/z : 514 [M+l]+.
RT = 0.752 min.
LCMS condition : B.
Step 5)
2-Amino-2- [4-hydroxy-1 -(m ethanesulfonyl )piperi din-4-yl] -1 - { 4- [(4methylphenyl)methyl]piperidin-1 -yl}ethan-1 -one (Compound-61)
To a solution of 2-(benzylamino)-2-(4-hydroxy-l-(methylsulfonyl)piperidin-4-yl)-1-(4-(4methylbenzyl)piperidin-l-yl)ethanone (50 mg) in MeOH (1 mL) was added palladium hydroxide on carbon (6 mg). The mixture was stirred at room temperature for 1 hour under hydrogen atmosphere. Palladium hydroxide on carbon (25 mg) was added into the mixture and the mixture was stirred at room temperature for 5 hours under hydrogen atmosphere. To another solution of 2-(benzylamino)-2-(4-hydroxy-l-(methylsulfonyl)piperidin-4-yl)-l-(4-(4methylbenzyl)piperidin-l-yl)ethanone (25 mg) in MeOH (1 mL) was added palladium hydroxide on carbon (25 mg) and the mixture was stirred at room temperature overnight under hydrogen atmosphere. The two reaction mixtures were combined and filtered through Celite®. The filtrate was concentrated in vacuo and the residue was purified with preparative chromatography (7% MeOH in CHCI3) to give the title compound (Compound-61, 30 mg, 49 % yield) as a colorless solid.
MS and LCMS retention time data of Compound-53 are shown in Table 3.
Synthesis of Compound-89
N-[3-(trifluoromethoxy)phenyl]-D-serinamide
Compound-89
Step 1) (R)-tert-butyl (3-hydroxy-1 -oxo-1 -((3-(trifluoromethoxy)phenyl)amino)propan-2yl)carbamate
The title compound was obtained in the manner as with the “Synthesis of Compound-16: step-3” using the corresponding materials.
MS (ESI) m/z : 387 [M+23]+.
RT = 0.980 min.
LCMS condition : B.
-73 N-[3-(trifluoromethoxy)phenyl]-D-serinamide (Compound-89)
Step 2)
The title compound was obtained in the manner as with the “Synthesis of Compound-16: step-5” using the corresponding materials.
MS and LCMS retention time data of Compound-89 are shown in Table 3.
Synthesis of Compound-99
N-{3-[4-(phenylethynyl)phenoxy]phenyl}-D-serinamide
Compound-99
Step 1)
3-(4-(Phenylethynyl)phenoxy)aniline
A flask was charged with l-iodo-4-(phenylethynyl)benzene (0.40 g), 3-aminophenol (0.22 g), Cui (75 mg), pyridine-2-carboxylic acid (97 mg) and K3PO4 (0.56 g). The flask was evacuated and backfilled with nitrogen followed by addition of DMSO (2.6 mL). After stirring for 3 hours at 90 °C, the mixture was diluted with EtOAc, filtered through a pad of Celite® and rinsed with EtOAc. The filtrate was sequentially washed with half-saturated aqueous ammonium chloride, water and brine. The organic phase was separated, dried over MgSO4, filtered and concentrated in vacuo. The residue was purified with OH-type silica gel column chromatography (20-80 % EtOAc n-hexane) to give the title compound (0.31 g, 83 % yield) as a pale yellow solid.
MS (ESI) m/z : 286 [M+l]+.
RT = 1.270min.
LCMS condition : B.
Step 2) (R)-tert-butyl (3 -Hydroxy-1 -oxo-1 -((3 -(4-(phenyl ethynyl)phenoxy)phenyl)amino)propan -2-yl)carbamate
To a solution of 3-(4-(Phenylethynyl)phenoxy)aniline (0.15 g) in DMF were sequentially added Boc-D-Ser-OH (80 mg), NMM (0.12 g) and T3P (0.30 mL, 50 wt% in EtOAc) at room temperature. After stirring for 48 hours, the mixture was diluted with EtOAc and then washed with 5% aqueous sodium bicarbonate, water and brine. The organic phase was separated, dried over MgSO4 and concentrated in vacuo. The residue was purified with OH-type silica gel column chromatography (20-80 % EtOAc n-hexane) to give the title compound (67 mg, 36 % yield) as an amorphous.
MS (ESI) m/z : 495 [M+23]+.
RT = 1.269min.
LCMS condition : B.
Step 3)
N-{3-[4-(phenylethynyl)phenoxy]phenyl}-D-serinamide (Compound-99)
Compound-99
A solution of (R)-tert-butyl (3-hydroxy-1-oxo-1-((3-(4(phenylethynyl)phenoxy)phenyl)amino)propan-2-yl)carbamate (66 mg) in formic acid (1.0 mL) was stirred for 2 hours. The reaction mixture was concentrated and the residue was coevaporated twice with CHCfi. The residue was dissolved in MeOH-CHCfi (1:1) followed by addition of BIOT AGE® MP-TsOH. After stirring for 16 hours, the resin was collected, washed with MeOH-CHCfi (1:1) and MeOH, and then eluted with 7 mol/L ammonia in MeOH to give the title compound (Compound-99, 39 mg, 76 % yield) as a pale yellow oil. MS and LCMS retention time data of Compound-99 are shown in Table 3.
Example Compounds in Table 2 and Table 3 were obtained in a manner as with above experimental procedures or general procedures using the corresponding materials.
Table 2. Example Compounds (Compound-1 to Compound-33). Compound ID, chemical structures, 1H-NMR data, MS data and LCMS retention time (minutes) data are shown.
ID Structure 'H-NMR MS Retention time (min) (Condition)
1 o=s=o 1 'H NMR (400 MHz, METHANOL-d4) δ ppm 1.09 1.47 (m, 2H), 1.68- 1.80 (m, 2 H), 1.83 - 1.96 (m, 1 H), 2.55 2.77 (m, 3 H), 2.99 - 3.21 (m, 5 H), 3.37 - 3.53 (m, 1 H), 3.91 4.05 (m, 1 H), 4.32 - 4.58 (m, 3 H), 4.62 (s, 2 H), 7.20 (d, J=7.8 Hz, 2 H), 7.36 (d, J=8.3 Hz, 2 H), 7.43 (d, J=7.8 Hz, 2 H), 7.47 (d, J=8.3 Hz, 2 H) MS (ESI) m/z : 485 [M+l]+ 0.590 (B)
2 Chiral Γ N Γ |l HCI °xx^ HCI 9 X-nA-nh’ '/x% Uh 'H NMR (400 MHz, DMSOd6) δ ppm 0.88 - 1.27 (m, 2 H), 1.50 - 1.92 (m, 3 H), 2.53 - 2.67 (m, 4 H), 2.93 - 3.25 (m, 3 H), 3.45 -4.03 (m, 8H), 4.34 (brs, 4 H), 5.31-5.65 (m, 1 H), 7.15 -7.34 (m, 2 H), 7.39- 7.79 (m, 4 H), 7.97 - 8.26 (m, 2 H), 11.47 (brs, 1 H) MS (ESI) m/z : 462 [M+l]+ 0.710 (A)
3 HO^^U Chiral UL ^Cl An pV2 laaa L)H Ή NMR (400 MHz, DMSOd6) δ ppm 0.94- 1.21 (m, 2H), 1.56 - 1.69 (m, 2H), 1.76- 1.90 (m, 1H), 2.57 (brd, J=6.8 Hz, 2 H), 2.95 -3.09 (m, 1 H), 3.50-3.61 (m, 1 H), 3.63 - 3.73 (m, 1 H), 3.82 - 3.93 (m, 1 H), 4.23 - 4.43 (m, 2 H), 4.53 (d, J=5.6 Hz, 2 H), 5.27 (t, J=5.7 Hz, 1 H), 5.32 - 5.45 (m, 1H), 7.23 (brd, J=8.1Hz,2 H), 7.36 (d, J=8.1Hz,2H), 7.43 -7.56 (m,4H), 7.93 (br s, 2H) MS (ESI) m/z : 393 [M+l]+ 0.575 (B)
4 ΗΟ/\χΟγ^. Chiral pUNH2 AA Xh 'H NMR (600 MHz, CHLOROFORM-d) δ ppm 1.09 - 1.31 (m, 5H), 1.68 1.77 (m, 1H), 2.50-2.61 (m, 3 H), 2.94 -3.04 (m, 1 H), 3.413.49 (m, 1 H), 3.59 - 3.66 (m, 1 H), 3.72 -3.79 (m, 1 H), 3.88 4.01 (m, 3H), 4.08-4.13 (m, 2 H), 4.55 - 4.62 (m, 1 H), 6.90 (d, J=8.7 Hz, 2 H), 7.10 (d, J=8.3 Hz, 2 H), 7.40 - 7.49 (m, 4H) MS (ESI) m/z : 423 [M+l]+ 0.589 (B)
5 ηο^ΎΥ Chiral ΓνΛΓ A 'H NMR (400 MHz, CHLOROFORM-d) δ ppm 0.77 -0.94 (m, 2H), 1.061.23 (m, 2H), 1.67- 1.82 (m, 3 H), 1.83 - 1.94 (m, 2H), 2.11 (d, J=10.9 Hz, 3 H), 2.50 - 2.75 (m, 7 H), 2.89 -3.05 (m, 1 H), 3.64-3.71 (m,2H), 3.86 (brs, 1H), 3.95 (brd, J=13.1Hz, 1 H), 4.61 (brd, J=13.1 Hz, 1 H), 7.11 (d, J=7.9 Hz, 2H), 7.18 (d, J=7.9 Hz, 2 H), 7.45 (d, J=7.9 Hz, 4 H) MS (ESI) m/z : 465 [M+l]+ 0.743 (B)
6 Ηθ-^-'ογ=Α Chiral γΝ^ΝΗ2 °=,Α 0 'H NMR (600 MHz, CHLOROFORM-d) δ ppm 0.79 -0.97 (m, 1 H), 1.121.30 (m, 4 H), 1.68- 1.90 (m, 2 H), 2.10-2.20 (m, 1 H), 2.512.62 (m, 3 H), 2.90 - 3.04 (m, 4 H), 3.10 -3.21 (m, 1 H), 3.30 3.40 (m, 1 H), 3.89 - 3.95 (m, 2 H), 3.96 -4.00 (m, 2 H), 4.08 4.13 (m, 2 H), 4.54-4.62 (m, 1 H), 6.89 (d, J=8.7 Hz, 2 H), 7.08-7.13 (m, 2 H), 7.427.49 (m, 4 H) MS (ESI) m/z : 499 [M+l]+ 0.616 (B)
7 Chiral Γ jl HCI ο ϊ$κΆι AV2 ΑαΑΑχΑ <οη 'H NMR (400 MHz, DEUTERIUM OXIDE) δ ppm 0.90 - 1.32 (m, 2H), 1.32 1.55 (m, 1 H), 1.55 - 1.75 (m, 2 H), 2.29-2.40 (m, 1 H), 2.412.62 (m, 2 H), 2.93 -3.11 (m, 1 H), 3.75 - 3.85 (m, 1 H), 3.93 4.05 (m, 2 H), 4.23 - 4.40 (m, 1 H), 4.56 - 4.69 (m, 1 H), 6.93 7.04 (m, 2 H), 7.04 -7.18 (m, 3 H), 7.24 - 7.48 (m, 4 H) MS (ESI) m/z : 363 [M+l]+ 1.195 (A)
8 Ηο^γΑ Chiral cAOH ο lfl Pi o=s=o 1 'H NMR (400 MHz, METHANOL-d4) δ ppm 1.10 1.34 (m, 2 H), 1.69- 1.82 (m, 2 H), 1.84 - 1.97 (m, 1 H), 2.04 2.32 (m, 2 H), 2.54 - 2.76 (m, 3 H), 2.94 -3.23 (m, 6 H), 3.914.02 (m, 1 H), 4.34 - 4.44 (m, 1 H), 4.50 (br d, J=12.6 Hz, 1 H), 4.59 -4.65 (m, 2 H), 7.17- 7.23 (m, 2 H), 7.36 (br d, J=7.9 Hz, 2 H), 7.43 (br d, J=7.8 Hz, 2 H), 7.47 (br d, J=7.9Hz,2 H), 8.46 (br s, 1 H) MS (ESI) m/z : 469 [M+l]+ 1.020 (A)
-η -
9 \ 0 kk ^νη2 γχ f^N |^ ΗΟ^Ρ HCI θΧ Λ XH NMR (400 MHz, METHANOL-d4) δ ppm 1.07 1.41 (m, 3 H), 1.74 (brt, J=11.5 Hz, 2 H), 2.00 (s, 3 H), 2.47 - 2.80 (m, 2 H), 2.89 3.00 (m, 1H), 3.02-3.10 (m, 3 H), 3.66 (s, 3 H), 3.86-3.98 (m, 1 H), 4.45 - 4.58 (m, 3 H), 7.10 (br d, J=7.2 Hz, 2 H), 7.26 (d, J=7.2 Hz, 2 H) MS (ESI) m/z : 393 [M+lf 0.591 (B)
10 \ ll Chiral 0 ρΧ χΑ'2 o^sx 0 TH NMR (400 MHz, CHLOROFORM-d) δ ppm 1.09 - 1.29 (m, 2H), 1.651.88 (m, 4 H), 2.08 - 2.23 (m, 1 H), 2.51-2.63 (m, 3 H), 2.883.04 (m, 4 H), 3.10-3.22 (m, 1 H), 3.29 -3.42 (m, 1 H), 3.873.98 (m, 2 H), 4.58 (br d, J=13.0Hz, 1H), 7.08-7.19 (m, 2 H), 7.30 - 7.39 (m, 3 H), 7.46 (d, J=8.1Hz, 2 H), 7.51 7.55 (m, 2 H) MS (ESI) m/z : 439 [M+lf 0.756 (B)
11 0 Chiral ΜγΧ Χ-νΑ>νη* kok/kk ^0Η HCI Ή NMR (600 MHz, Methanold) δ ppm 1.13 -1.30 (m, 3 H), 1.72 - 1.97 (m, 6 H), 2.56- 2.76 (m, 6 H), 3.07-3.17 (m, 1 H), 3.56 -3.62 (m, 2 H), 3.65- 3.75 (m, 1 H), 3.84 - 3.92 (m, 2 H), 4.36 - 4.44 (m, 1 H), 4.47 - 4.54 (m, 1H), 7.21-7.29 (m, 4 H), 7.47 - 7.55 (m, 4 H) MS (ESI) m/z : 397 [M+lf 0.565 (B)
12 rXX Chiral ^γχ χνΧ/2 a. 'H NMR (400 MHz, CHLOROFORM-d) δ ppm 0.78 -0.92 (m, 1 H), 1.04 1.23 (m, 2H), 1.67- 1.84 (m, 4 H), 2.11 (d, J=ll.lHz, 3 H), 2.50 - 2.80 (m, 5 H), 2.89 3.03 (m, 1H), 3.86 (brs, 1 H), 3.95 (brd, J=12.8 Hz, 1 H), 4.61 (brd, J=12.8 Hz, 1 H), 7.12 (d, J=8.0 Hz, 2 H), 7.29- 7.40 (m, 3 H), 7.46 (d, J=8.0 Hz, 2 H), 7.48 - 7.57 (m, 2 H) MS (ESI) m/z : 407 [M+lf 0.839 (B)
13 HO^VX Chiral UL °^OH o X ANH? Ή NMR (600 MHz, DMSOd6) δ ppm 0.86 (dt, 1=16.8,7.1 Hz, 3 H), 0.96-1.15 (m, 2 H), 1.24 - 1.38 (m, 3 H), 1.41 - 1.52 (m, 1 H), 1.54 - 1.67 (m, 2 H), 1.74- 1.84 (m, 1 H), 2.512.57 (m, 4 H), 2.89 - 3.03 (m, 1 H), 3.77 -3.90 (m, 2 H), 4.34- 4.40 (m, 1 H), 4.53 (s, 2 H), 7.22 - 7.25 (m, 2 H), 7.36 (d, J=8.3 Hz, 2 H), 7.47 (br d, J=8.3 Hz, 2 H), 7.49 (d, J=7.8 Hz, 2 H), 8.27 (s, 1 H) MS (ESI) m/z : 405 [M+lf 0.685 (B)
14 0 XAs ρΝ^γΝΗ, AXXX HCT^I o=s. Single diastereomer θ' 'H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.08 - 1.33 (m, 2 H) 1.68 -1.84 (m, 3 H) 2.32 (s, 3 H) 2.42 2.64 (m, 2 H) 2.97 -3.09 (m, 5 H) 3.09 - 3.23 (m, 2 H) 3.783.86 (m, 1H) 3.86 -3.99 (m, 1 H) 4.16-4.27 (m, 1 H) 4.48 4.61 (m, 1 H) 7.03 (d, J=7.70 Hz, 2H)7.10(d, J=7.70 Hz, 2 H) MS (ESI) m/z : 369 [M+l]+ 0.552 (B)
15 0 Chiral ^χχνΛ'ΝΗ2 Χα ‘•’π 'H NMR (400 MHz, DMSOd6) δ ppm 2.71 - 2.92 (m, 4 H), 2.95-3.10 (m, 2 H), 3.35- 3.46 (m, 1 H), 3.47 - 3.59 (m, 1 H), 3.60 -3.73 (m, 1 H), 4.08 - 4.29 (m, 2 H), 4.78 (br s, 1 H), 6.87 (d, J=7.6 Hz, 1 H), 7.04- 7.13 (m, 1H), 7.15 -7.31 (m, 5 H), 7.99 (br d, J=7.6 Hz, 1 H) MS (ESI) m/z : 311 [M+l]+ 0.605 (B)
16 /===, 0 Chiral _LAnJAnh2 Χλ <oh X/ hc| ηο-Ά'0 Ή NMR (600 MHz, DMSOd6) δ ppm 2.73 - 2.84 (m, 4 H), 3.03-3.13 (m, 2 H), 3.66- 3.72 (m, 2 H), 3.72 - 3.79 (m, 1 H), 3.80 -3.87 (m, 1 H), 3.913.96 (m, 2 H), 4.14-4.31 (m, 4 H), 5.52 - 5.58 (m, 1 H), 6.83 (d, J=8.7 Hz, 2 H), 6.94 (d, J=7.8 Hz, 1 H), 7.08 - 7.18 (m, 3 H), 7.95 (d, J=8.3 Hz, 1 H), 8.20 - 8.34 (m, 3 H) MS (ESI) m/z : 371 [M+l]+ 0.473 (B)
17 /=¾. O Chiral x XX-V* qX/'0 %H Ή NMR (600 MHz, DMSOd6) δ ppm 2.97 (t, J=8.7 Hz, 2 H), 3.40 -3.46 (m, 1 H), 3.52 (br d, J=5.8 Hz, 2H), 3.64 (br s, 1H), 4.19-4.33 (m, 2 H), 4.77 - 4.83 (m, 1 H), 6.68 (d, J=8.3 Hz, 1H), 6.91 -6.94 (m, 1 H), 7.00 - 7.02 (m, 1H), 7.12 -7.28 (m, 3 H), 7.39 (t, J=8.3 Hz, 1 H), 8.00 (br d, J=8.3 Hz, 1H) MS (ESI) m/z : 333 [M+l]+ 1.046 (A)
18 /=¾ 0 Chiral D / / 'X ΌΗ Ή NMR (600 MHz, DMSOd6) δ ppm 1.81 - 1.89 (m, 2H), 2.52 - 2.57 (m, 2 H), 2.59 - 2.66 (m, 2 H), 2.98-3.10 (m, 2 H), 3.37 -3.44 (m, 1 H), 3.48- 3.56 (m, 1 H), 3.62 - 3.70 (m, 1 H), 4.14 -4.30 (m, 2 H), 4.73 - 4.82 (m, 1 H), 6.82 - 6.90 (m, 1 H), 7.06-7.13 (m, 1 H), 7.15 - 7.24 (m, 3 H), 7.25-7.31 (m, 2 H), 7.95 -8.01 (m, 1 H) MS (ESI) m/z : 325 [M+l]+ 0.655 (B)
19 /=¾. 0 Chiral ίΛ NANH2 Ο οϋΧ 0 4Η NMR (400 MHz, DMSOd6) δ ppm 2.77 - 2.88 (m, 4 Η), 2.98 (s, 3 Η), 3.02 -3.09 (m, 2 Η), 3.19-3.28 (m, 4 Η), 3.643.71 (m, 1 Η), 4.04 - 4.29 (m, 2 Η), 6.88 (d, J=7.6 Hz, 1 Η), 7.07-7.13 (m, 1 Η), 7.16- 7.30 (m, 5 Η), 7.98 (br d, J=7.6 Hz, 1 H) MS (ESI) m/z : 387 [M+lf 0.648 (B)
20 /=¾. 0 Chiral μ £ΛΑ'νη2 χΛ~ο \_J L οΧ TH NMR (400 MHz, DMSOd6) δ ppm 1.72 - 1.87 (m, 1 H), 1.98-2.11 (m, 1 H), 2.95 - 3.04 (m, 5 H), 3.19-3.28 (m, 2 H), 3.61-3.72 (m, 1 H), 4.10- 4.35 (m, 2 H), 6.69 (d, J=8.2 Hz, 1 H), 6.90 - 6.96 (m, 1 H), 6.97 -7.05 (m, 1 H), 7.15- 7.27 (m, 2 H), 7.39 (t, J=8.1 Hz, 1 H), 7.95 - 8.04 (m, 1 H) MS (ESI) m/z : 409 [M+lf 0.641 (B)
21 θ Chiral Ν X...» Ν Η2 ΛΑ Αοη ΗΟ^-ο'^/ 1Γ 0 TH NMR (400 MHz, DMSOd6) δ ppm 2.26 (dd, J=16.2, 8.5 Hz, 1 H), 2.59 (dd, J=16.2, 5.7 Hz, 1 H), 2.75 - 2.78 (m, 4 H), 2.99-3.11 (m, 2 H), 3.69 (t, J=5.1Hz, 2 H), 3.90 -4.03 (m, 4H), 4.05 -4.18 (m, 2 H), 4.22 -4.32(m, 1H), 6.81 -6.90 (m, 3 H), 7.06-7.15 (m, 3 H), 7.94 (brd, J=7.9Hz, 1 H) MS (ESI) m/z : 399 [M+lf 0.935 (A)
22 /=¾. 0 Chiral Α>Λ^ Ο° ^0Η TH NMR (600 MHz, DMSOd6) δ ppm 2.94 - 3.06 (m, 2 H), 3.36 - 3.45 (m, 1 H), 3.46- 3.56 (m, 1 H), 3.59 - 3.66 (m, 1 H), 3.77 (s, 2H), 4.11 -4.29 (m, 2 H), 4.72 - 4.80 (m, 1 H), 6.64 - 6.69 (m, 2 H), 6.82 (d, J=7.4 Hz, 1 H), 6.94 - 6.97 (m, 2H), 7.06-7.13 (m, 1 H), 7.99 (br d, J=7.4 Hz, 1 H), 9.17 (s, 1 H) MS (ESI) m/z : 313 [M+lf 0.771 (A)
23 /=¾. 0 Chiral TH NMR (400 MHz, DMSOd6) δ ppm 2.64 - 2.76 (m, 2 H), 2.80 -2.88 (m, 4H), 3.01 - 3.18 (m, 3 H), 4.12-4.27 (m, 2 H), 4.44 - 4.50 (m, 1 H), 6.95 6.99 (m, 1H), 7.14-7.30 (m, 6 H), 7.93 - 7.97 (m, 1 H) MS (ESI) m/z : 339 [M+lf 0.678 (B)
24 0 ΠΓνΛυΝΗ2 °*s ho^0AJ Οζ TH NMR (400 MHz, METHANOL-d4) δ ppm 2.88 (brt, J=5.9Hz, 1 H), 2.953.06 (m, 4H), 3.33 - 3.43 (m, 4 H), 3.80 -3.91 (m, 4 H), 3.994.20 (m, 4 H), 6.95 (d, J=8.8 Hz, 2 H), 7.14-7.19 (m, 1 H), 7.29 - 7.34 (m, 2 H), 7.42 (d, J=8.8 Hz, 2 H) MS (ESI) m/z : 473 [M+lf 0.485 (B)
25 0 Chiral γΧΧνΑ^ΝΗ2 x<Ax Ah ΓΊι hci ho^oAJ 'H NMR (400 MHz, DMSOd6) δ ppm 2.91 (br s, 1 H), 3.63 -3.86 (m, 6H), 3.93 -4.19(m, 3H), 4.42-4.91 (m, 4 H), 5.51 (br s, 1 H), 6.98 (d, J=8.8 Hz, 2 H), 7.19 -7.32 (m, 1 H), 7.33- 7.41 (m, 2H), 7.46 (d, J=8.8 Hz, 2H), 8.17 (br s, 3 H) MS (ESI) m/z : 381 [M+lf 0.446 (B)
26 0 Chiral XXnANH2 'H NMR (400 MHz, DMSOd6) δ ppm 2.75 - 2.93 (m, 2 H), 3.27 -3.50 (m, 2H), 3.73 - 3.87 (m, 3 H), 4.63 - 4.85 (m, 3 H), 7.23 -7.28 (m, 1 H), 7.357.46 (m, 5 H), 7.51-7.58 (m, 2 H) MS (ESI) m/z : 321 [M+lf 0.638 (B)
27 0 Chiral ^^nA-NH2 Ah A^r HCI h°AU Ή NMR (400 MHz, DMSOd6) δ ppm 2.84 (br s, 1 H), 2.92 (brs, 1H), 3.64 -3.72 (m, 1 H), 3.73 - 3.82 (m, 1 H), 4.47 (brs, 1H), 4.53 (s, 2 H), 4.564.80 (m, 3H), 5.28 (brs, 1 H), 5.48 (brs, 1 H), 7.27 - 7.32 (m, 1 H), 7.33 - 7.44 (m, 4 H), 7.47 -7.52 (m,2H), 8.14 (br s, 2 H) MS (ESI) m/z : 351 [M+lf 0.809 (A)
28 0 Chiral ^XnANH2 XX/NY Ή NMR (400 MHz, DMSOd6) δ ppm 2.81 -2.98 (m, 2H), 3.37 - 3.50 (m, 2 H), 3.67- 3.86 (m, 3 H), 4.63 - 4.86 (m, 3 H), 7.26-7.31 (m, 1 H), 7.337.38 (m, 1 H), 7.42 - 7.52 (m, 4 H), 7.62 - 7.67 (m, 2 H) MS (ESI) m/z : 297 [M+lf 0.541 (B)
29 HN—. q Chiral r=yY)XXNH2 HO q/ Ή NMR (400 MHz, DMSOd6) δ ppm 1.70 - 1.81 (m, 2 H), 2.01 -2.27 (m, 2 H), 2.562.70 (m, 2 H), 2.99 (s, 3 H), 3.15-3.26 (m, 2 H), 3.33- 3.48 (m, 2 H), 3.50 - 3.58 (m, 1 H), 4.46 (t, J=5.1 Hz, 1 H), 7.27 (d, J=8.2 Hz, 2 H), 7.32 (dd, J=8.4, 1.5 Hz, 1 H), 7.56 (s, 1 H), 7.58 (d, J=8.2 Hz, 2 H), 7.72 - 7.79 (m, 2 H), 9.85 (br s, 1 H), 10.87 (br s, 1 H) MS (ESI) m/z : 430 [M+lf 0.335 (B)
30 HN—. q Chiral rfoAz A™2 Ah Ή NMR (400 MHz, DMSOd6) δ ppm 3.49 - 3.58 (m, 2 H), 3.58 - 3.72 (m, 1 H), 4.87 (brs, 1 H), 7.26 - 7.39 (m, 2 H), 7.42 -7.49 (m, 2 H), 7.56 - 7.59 (m, 1H), 7.64-7.71 (m, 2 H), 7.75 - 7.79 (m, 2 H), 10.88 (s, 1 H) MS (ESI) m/z : 296 [M+lf 0.474 (B)
31 ΗΝ-—, q Chiral ό'ΝΗ2 HO 'H NMR (400 MHz, DMSOd6) δ ppm 1.69 - 1.80 (m, 2 H), 2.59 -2.70 (m, 2 H), 3.203.68 (m, 9H), 7.27 (d, J=8.1 Hz, 2 H), 7.31 (dd, J=8.4, 1.5 Hz, 1 H), 7.53 - 7.57 (m, 1 H), 7.58 (d, J=8.1Hz, 2 H), 7.727.78 (m, 2 H), 10.86 (d, J=2.0 Hz, 1 H) MS (ESI) m/z : 354 [M+l]+ 0.737 (A)
32 HN-—. q Chiral ^°h Ή NMR (600 MHz, DMSOd6) δ ppm 3.27 - 3.29 (m, 2 H), 3.44 -3.56 (m, 2 H), 3.573.65 (m, 1 H), 4.81 (t, J=5.4 Hz, 1H), 7.18 (d, J=8.3 Hz, 1 H), 7.28 - 7.33 (m, 1 H), 7.377.47 (m, 3 H), 7.53 - 7.59 (m, 2 H), 7.69 - 7.75 (m, 1 H), 7.82 - 7.85 (m, 1H), 11.02 (s, 1 H) MS (ESI) m/z : 320 [M+l]+ 0.584 (B)
33 HN-~. q Chiral H 17 0 Ή NMR (600 MHz, DMSOd6) δ ppm 1.72 - 1.78 (m, 2 H), 2.40 - 2.54 (m, 2 H), 2.60 2.67 (m, 2 H), 3.45 (t, J=6.4 Hz, 2 H), 4.00 - 4.05 (m, 1 H), 4.49 (br s, 1 H), 7.28 (d, J=8.3 Hz, 2 H), 7.32 (d, J=8.3 Hz, 1 H), 7.52 - 7.64 (m, 3 H), 7.74 (d, J=2.1Hz, 1H),7.79 (d, J=8.3 Hz, 1 H), 10.90 - 10.93 (m, 1H) MS (ESI) m/z : 382 [M+l]+ 0.805 (B)
Compound-1 :
2-amino-3-hydroxy-1-(4-((4-( [4-(hydroxymethyl)phenyl]ethynyl}phenyl)methyl]piperidin1 -yl} -4-(m ethanesulfonyl )butan-1 -one
Compound-2 :
(2R)-2-amino-3 -hydroxy-1-(4-( [4-(( 4- [(morpholin-4yl)methyl]phenyl}ethynyl)phenyl]methyl (piperidin-1 -yl)propan-1 -one 2 hydrochloride Compound-3 :
(2R)-2-amino-3-hydroxy-l-{4-[(4-{[4(hydroxymethyl)phenyl]ethynyl }phenyl)methyl]piperidin-l -yl (propan-1 -one hydrochloride
Compound-4 :
(2R)-2-amino-3 -hydroxy-1 -(4-((4- ([4-(2hydroxyethoxy)phenyl]ethynyl }phenyl)methyl]piperidin-l -yl }propan-l -one
Compound-5 :
(2R)-2-amino-l-(4-((4-( [4-(3-hydroxypropyl)phenyl]ethynyl}phenyl)methyl]piperidin-l15 yl }-4-(methyl sulfanyl)butan-l -one
Compound-6 :
(2R)-2-amino-l-(4-((4-( [4-(2-hydroxyethoxy)phenyl]ethynyl}phenyl)methyl]piperidin-lyl }-4-(m ethanesulfonyl )butan-1 -one
-82Compound-7 :
(2R)-2-amino-3 -hydroxy-1 -(4-( [4-(phenylethynyl)phenyl]methyl} pi peri di n-1 -yl)propan-1 one hydrochloride
Compound-8 :
(2R)-2-amino-l-(4-((4-( [4-(hydroxymethyl)phenyl]ethynyl}phenyl)methyl]piperidin-l-yl}-
4-(methanesulfonyl)butan-l-one formic acid (1/1)
Compound-9 :
2-amino-3 -hydroxy-4-(m ethanesulfonyl)-1 -(4- {[4-(prop-1 -yn-1 -yl)phenyl]methyl (piperidinl-yl)butan-l-one hydrochloride
Compound-10 :
(2R)-2-amino-4-(methanesulfonyl)-l-(4-( [4-(phenylethynyl)phenyl]methyl}piperidin-lyl)butan-l-one
Compound-11 :
(2R)-2-amino-3-hydroxy-1-(4-( [4'-(3-hydroxypropyl)[ 1, r-biphenyl]-4-yl]methyl Jpiperidin-
1- yl)propan-l-one hydrochloride
Compound-12 :
(2R)-2-amino-4-(methyl sulfanyl)-1 -(4- {[4-(phenylethynyl)phenyl]methyl (piperidin-1 yl)butan-l-one
Compound-13 :
(2R)-2-amino-l-(4-((4-( [4-(hydroxymethyl)phenyl]ethynyl}phenyl)methyl]piperidin-lyl(pentan-1-one formic acid (1/1)
Compound-14 :
2- amino-3-hydroxy-4-(methanesulfonyl)-l-{4-[(4-methylphenyl)methyl]piperidin-lyl}butan-l-one
Compound-15 :
(2R)-2-amino-3 -hydroxy-1 -[4-(2-phenyl ethyl)-2,3 -dihydro- ΙΗ-indol-1 -yljpropan-1 -one
Compound-16 :
(2R)-2-amino-3 -hydroxy-1 -(4- ( 2-[4-(2-hydroxyethoxy)phenyl] ethyl (-2,3 -dihydro-1 H-indoll-yl)propan-l-one hydrochloride
Compound-17 :
(2R)-2-amino-l-[4-(3-chlorophenoxy)-2,3 -dihydro- lH-indol-l-yl]-3-hydroxypropan-l-one
Compound-18 :
(2R)-2-amino-3 -hydroxy-1 -(4-(3-phenylpropyl)-2,3 -dihydro- ΙΗ-indol-1 -yljpropan-1 -one Compound-19 :
(2R)-2-amino-4-(methanesulfonyl)-l-[4-(2-phenylethyl)-2,3-dihydro-lH-indol-l-yl]butan-lone
Compound-20 :
-83 (2R)-2-amino-1 -[4-(3-chlorophenoxy)-2,3 -dihydro- ΙΗ-indol-1 -yl ] -4(m ethanesulfonyl )butan-1 -one
Compound-21 :
(3R)-3-amino-4-(4-{2-[4-(2-hydroxyethoxy)phenyl]ethyl)-2,3-dihydro-lH-indol-l-yl)-4oxobutanoic acid
Compound-22 :
(2R)-2-amino-3 -hydroxy-1 -[4-(phenoxym ethyl)-2,3 -dihydro- ΙΗ-indol-1 -yl]propan-1 -one
Compound-23 : (3R)-3-amino-4-oxo-4-[4-(2-phenylethyl)-2,3-dihydro-lH-indol-l-yl]butanoic acid
Compound-24 :
2-amino-3 -hydroxy-1 - [6- {[4-(2-hydroxyethoxy)phenyl] ethynyl) -3,4-dihydroi soquinolin2(lH)-yl]-4-(methanesulfonyl)butan-l-one
Compound-25 :
(2R)-2-amino-3 -hydroxy-1 -[6- {[4-(2-hydroxy ethoxy )phenyl] ethynyl )-3,4dihydroisoquinolin-2(lH)-yl]propan-l-one hydrochloride
Compound-26 :
(2R)-2-amino-3 -hydroxy-1 -[6-(phenylethynyl)-3,4-dihydroisoquinolin-2(l H)-yl]propan-1 one
Compound-27 :
(2R)-2-amino-3 -hydroxy-1 -[6- {[4-(hydroxymethyl)phenyl] ethynyl )-3,4-dihydroi soquinolin2(lH)-yl]propan-1 -one hydrochloride
Compound-28 :
(2R)-2-amino-3 -hydroxy-1 -(6-phenyl -3,4-dihydroi soquinolin-2( 1 H)-yl)propan-1 -one
Compound-29 :
(2R)-2-amino-N - { 6- [4-(3 -hydroxypropyl )phenyl] -1 H-indol-3 -yl )-4(methanesulfonyl)butanamide
Compound-30 : N-(6-phenyl-lH-indol-3-yl)-D-serinamide
Compound-31 : N-{6-[4-(3-hydroxypropyl)phenyl]- lH-indol-3-yl)-D-serinamide
Compound-32 : N-[6-(phenylethynyl)-lH-indol-3-yl]-D-serinamide
Compound-33 :
(R)-3-amino-4-((6-(4-(3-hydroxypropyl)phenyl)-lH-indol-3-yl)amino)-4-oxobutanoic acid Table 3. Example Compounds (Compound-34 to Compound-104). Compound ID, chemical structures, MS data, LCMS retention time (minute) data and LCMS(MS) condition are shown.
ID Structure MS Retention time (minutes) Condition
34 r Α'ΝΗ! 1 s Ν=/ MS (ESI) m/z : 488 [M+l]+ 0.709 B
35 OH Chiral Αίί~·. 0 HCJ |^νΑ·ΝΗ2 ^ΑΑ^ΑΑ ^Ν||2 MS (ESI) m/z : 392 [M+l]+ 0.844 A
36 |<ίί\| θ Chiral AJA ° η(/ Α% AAA> ifOH 0 MS (ESI) m/z : 391 [M+l]+ 0.784 B
37 Chiral MS (ESI) m/z : 375 [M+l]+ 0.841 B
38 AA o HCI Chiral UA^. ^nA.^h2 AAj Ah MS (ESI) m/z : 339 [M+l]+ 0.674 B
39 Chiral ^^A% i^nA.nH2 V^s N=/ MS (ESI) m/z : 430 [M+l]+ 0.802 B
40 OH Chiral ^A%i AA >x0H 0 MS (ESI) m/z : 421 [M+l]+ 0.628 B
41 Chiral fA\ O HCI A<y ^Α··'ΝΗ2 UJ-J L HCI MS (ESI) m/z : 362 [M+l]+ 0.670 B
42 0 MS (ESI) m/z : 380 [M+l]+ 0.561 B
43 Chiral (Αγγ OHCI MS (ESI) m/z : 445 [M+l]+ 0.825 B
44 0 Chiral Ό/' MS (ESI) m/z : 321 [M+l]+ 0.668 B
45 q HCI Chiral όΜ' MS (ESI) m/z : 277 [M+l]+ 0.916 A
46 0 HCI Chiral σΎχοΑ MS (ESI) m/z : 355 [M+l]+ 1.131 A
47 0 ucA L Single diastereomer S^q 0 MS (ESI) m/z : 395 [M+l]+ 0.553 B
48 uc/ Single diastereomer S X. /'0 MS (ESI) m/z : 410 [M+l]+ 0.588 B
49 0 Chiral ucA AA 0 MS (ESI) m/z : 353 [M+l]+ 0.576 B
50 τυο0 Single diastereomer 0q MS (ESI) m/z : 381 [M+l]+ 0.950 A
51 AiA-'NH2 MS (ESI) m/z : 367 [M+l]+ 1.197 A
52 Chiral AA ° hci Aa, ανΑ·'νΗ2 V 'N n~nh MS (ESI) m/z : 415 [M+l]+ 0.814 B
53 0 Chiral wA: MS (ESI) m/z : 291 [M+l]+ 0.537 B
54 Χα/ώΐ Single diastereomer 0 MS (ESI) m/z : 369 [M+l]+ 0.551 B
55 HCI Chiral ΑΧΟΥ MS (ESI) m/z : 291 [M+l]+ 1.030 A
56 0 Chiral OjA? MS (ESI) m/z : 291 [M+l]+ 0.543 B
57 HCI Chiral 0 HCI ΎΧΟΧ T s MS (ESI) m/z : 344 [M+l]+ 0.619 B
58 0 Chiral XLO0U 0 MS (ESI) m/z : 305 [M+l]+ 0.997 A
59 ucA A-n η Single diastereomer /'θ MS (ESI) m/z : 410 [M+l]+ 0.586 B
60 0 HCI XcOA” MS (ESI) m/z : 338 [M+l]+ 1.046 A
61 £ £ o=(V^ o o o MS (ESI) m/z : 424 [M+l]+ 1.016 A
62 0 HCIChiral ΑΑγ γΝΑ..'ΝΗ2 UUU Ah MS (ESI) m/z : 337 [M+l]+ 0.676 B
63 0 HCIChiral xuA: MS (ESI) m/z : 339 [M+l]+ 0.573 B
64 /γ 0 Chiral LAnA-'nh2 '0H MS (ESI) m/z : 321 [M+l]+ 0.630 B
65 /γ 0 Chiral iAnA-'nh2 CToK: Ύοη MS (ESI) m/z : 313 [M+l]+ 0.932 A
66 /==λ O Chiral £ΧνΧ.λΝΗ2 HCI A-z n-nh MS (ESI) m/z : 363 [M+l]+ 0.709 B
67 /=== 0 Chiral 1ΑνΑ-'νη2 /¾ %η2 MS (ESI) m/z : 310 [M+l]+ 0.863 A
68 /=λ θ HCI L™2 MS (ESI) m/z : 372 [M+l]+ 0.697 B
69 /==> ο Chiral βΛ^,Λ-2 ΌΗ MS (ESI) m/z : 285 [M+l]+ 0.689 B
70 /=== 0 Chiral ίΛιΑ·''ΝΗ2 ΌΗ HCI ΗΟ-Ά'0 MS (ESI) m/z : 367 [M+l]+ 0.470 B
71 /=== 0 Chiral LAnA-'nH2 '’Π MS (ESI) m/z : 307 [M+l]+ 0.623 B
72 /=== 0 Chiral i^N^NH2 C\ 0=^ V/ 0 MS (ESI) m/z : 383 [M+l]+ 0.662 B
73 /===1 0 Chiral l-AA™2 UH MS (ESI) m/z : 283 [M+l]+ 0.504 B
74 /===1 0 o Chiral βλΛΑ·'νΗ2 f fAoh Br V-J \/0H r F 0 MS (ESI) m/z : 313 [M+l]+ 0.799 A
75 Ζ==λ 0 Chiral Br \_J iHCI O=S. II 0 MS (ESI) m/z : 361 [M+l]+ 0.361 B
76 0 Chiral AAnX'NH2 V°H HO^qXJ MS (ESI) m/z : 409 [M+l]+ 0.908 A
77 0 Chiral ocnVH2 H0\Xa/ q// MS (ESI) m/z : 427 [M+l]+ 0.861 A
78 0 Chiral Αγ-ΝΑ·ΝΗ2 Ay^KAj ^oh MS (ESI) m/z : 325 [M+l]+ 0.637 B
79 O HCI Chiral AA A MS (ESI) m/z : 355 [M+l]+ 0.808 A
80 0 Chiral BrXU k °=s A MS (ESI) m/z : 375 [M+l]+ 0.409 B
81 O HCI Chiral ^Y^nA'NH2 BrAxZ %Η MS (ESI) m/z : 299 [M+l]+ 0.727 A
82 0 0 Chiral .W\A 0 MS (ESI) m/z : 327 [M+l]+ 0.826 A
83 0 HCI HCI ΧΥνΑι Ax MS (ESI) m/z : 360 [M+lf 0.870 A
84 HN—. o Chiral - YXYnh2 XU H l ήη2 MS (ESI) m/z : 353 [M+lf 0.579 A
85 HN— o Chiral Χ'ΛΝΗ; OH MS (ESI) m/z : 324 [M+lf 0.593 B
86 HN— Q Chiral Xr ΌΗ MS (ESI) m/z : 298 [M+lf 0.643 A
87 HN— Q Chiral ΑχΑΛ'ΝΗ2 ΌΗ MS (ESI) m/z : 310 [M+lf 0.526 B
88 HN—. q Chiral ΓνΥ-Λ X Xu H I PX <H MS (ESI) m/z : 368 [M+lf 0.757 A
89 F RR] 0 Chiral YoXAjjY->nh2 ΌΗ MS (ESI) m/z : 265 [M+lf 0.739 A
90 F X 0 HCI χχχ X N b MS (ESI) m/z : 392 [M+l]+, 390 [M-l]’ 0.628 B
91 F F X 0 Chiral Χ0ΧΛνΑ „nh2 A-qH MS (ESI) m/z : 279 [M+lf 0.798 A
92 “Π -η ο X Chiral MS (ESI) m/z : 279 [M+l]+ 0.869 A
V s''· ,'NH2 ΌΗ
x<x Chiral
c F r 'll o
X- A- 1 Nx H >nh2 MS (ESI)
93 F Ο m/z : 0.517 B
HCI \χΝ Ύ N 317 [M+l]+
n-nh
F ί XI 0 Chiral
SL ΑΧ· KN mh2 MS (ESI)
94 H m/z : 0.538 B
HCI HCI ZN. u 326 [M+l]+
Chiral
c F 0
UV Ax 1 Nx H .,λ'ΝΗ2 MS (ESI)
95 F 0 m/z : 0.770 A
332 [M+l]+
HCI T s
N^/
0 II Chiral
A \\ I MS (ESI)
96 ~N' A ,λΝΗ2 m/z : 0.436 A
F u H 1 ^nh2 264 [M+l]+
HCI HCI
Λ Chiral 0 MS (ESI)
97 XPvA c> Α^λΝγ^ m/z : 0.631 B
H ΌΗ 323 [M+l]+
ifA Chiral
0 II MS (ESI)
98 m/z : 0.703 B
A xn,.,'NH2 349 [M+l]+
H ΌΗ
ifA Chiral
MS (ESI)
99 li 0 m/z : 0.785 B
<A XT X L.A ΛΝΗ2 373 [M+l]+
NX H L
OH
100 ίΐ Ί fl 1 h* Chiral V^0AAnA-NH2 ? F H I hctA ΌΗ p F MS (ESI) m/z : 273 [M+l]+ 0.863 A
101 o Chiral H V OH MS (ESI) m/z : 301 [M+l]+ 0.560 B
102 o Chiral Η 1 hci X> MS (ESI) m/z : 340 [M+l]+ 0.585 B
103 Chiral ΌΗ MS (ESI) m/z : 377 [M+l]+ 0.777 B
104 r^ 0 Chiral u h A MS (ESI) m/z : 349 [M+l]+ 0.694 B
Compound-34 :
(2R)-2-amino-l-{4-[(4-{[4-(3-hydroxypropyl)phenyl]ethynyl}phenyl)methyl]piperidin-lyl} -3 -(1,3 -thiazol-4-yl)propan-1 -one
Compound-35 :
(2R)-2,3-diamino-l-{4-[(4-{[4-(hydroxym ethyl )phenyl]ethynyl}phenyl)methyl]piperi din-1yl}propan-1 -one formic acid(l/l)
Compound-36 : (3R)-3-amino-4-oxo-4-(4-{[4-(phenylethynyl)phenyl]methyl}piperidin-l-yl)butanoic acid formic acid (1/1)
Compound-37 : (2R)-2-amino-l-(4-{[4-(phenylethynyl)phenyl]methyl}piperidin-l-yl)pentan-l-one
Compound-38 :
(2R)-2-amino-1 -{4-[([ 1,1 '-biphenyl] -4-yl )methyl]piperi din-1 -yl} -3 -hydroxypropan-1 -one hydrochloride
Compound-39 :
(2R)-2-amino-l-(4-{[4-(phenylethynyl)phenyl]methyl}piperidin-l-yl)-3-(l,3-thiazol-4yl)propan-l-one
-93 Compound-40 :
(3R)-3-amino-4-{4-[(4-{[4-(hydroxymethyl)phenyl]ethynyl}phenyl)methyl]piperidin-l-yl}-
4-oxobutanoic acid
Compound-41 :
(2R)-2,3 -diamino-1 -(4- {[4-(phenylethynyl)phenyl]methyl} pi peri di n-1 -yl)propan-1 -one 2 hydrochloride
Compound-42 :
2-amino-2-(l,l-dioxidothiomorpholin-3-yl)-l-(4-(4-methylbenzyl)piperidin-l-yl)ethanone
Compound-43 : (2R)-2-amino-l-[4-({4-[([l,r-biphenyl]-4-yl)methoxy]phenyl}methyl)piperidin-l-yl]-3hydroxypropan-1-one hydrochloride
Compound-44 :
(2R)-2-amino-l-{4-[(4-methylphenyl)methyl]piperidin-l-yl}-4-(methylsulfanyl)butan-l-one
Compound-45 :
(2R)-2-amino-3 -hydroxy-1 -{4-[(4-methylphenyl)methyl]piperidin-1 -yl} propan-1 -one hydrochloride
Compound-46 :
(2R)-2-amino-3 -hydroxy-1 -{4-[(4-phenoxyphenyl)methyl]piperidin-l -yl} propan-1 -one hydrochloride
Compound-47 :
2-amino-2-(3-hydroxy-l,l-dioxidotetrahydro-2H-thiopyran-3-yl)-l-(4-(4methylbenzyl)piperidin-1 -yl)ethanone formate
Compound-48 :
2-amino-2- [3 -hydroxy-1 -(m ethanesulfonyl )pyrrolidin-3 -yl] -1 - { 4- [(4methylphenyl)methyl]piperidin-1 -yl} ethan-1 -one
Compound-49 :
(2R)-2-amino-4-(m ethanesulfonyl)-1 - {4-[(4-methylphenyl)methyl]piperidin-1 -yl }butan-1 one
Compound-50 :
2-amino-2-(3-hydroxy-l,l-dioxidotetrahydrothiophen-3-yl)-l-(4-(4-methylbenzyl)piperidinl-yl)ethanone
Compound-51 :
(2R)-2-amino-3 -hydroxy-1 -(4-{ [4-(2-phenylethyl)phenyl]methyl }piperidin-1 -yl)propan-1 one hydrochloride
Compound-52 : (2R)-2-amino-l-(4-{[4-(phenylethynyl)phenyl]methyl}piperidin-l-yl)-3-(2H-tetrazol-5yl)propan-l-one hydrochloride
-94 Compound-53 :
(2R,3S)-2-amino-3-hydroxy-l-{4-[(4-methylphenyl)methyl]piperidin-l-yl}butan-l-one
Compound-54 :
2-amino-3-hydroxy-l-(4-(4-methylbenzyl)piperidin-l-yl)-4-(methylsulfonyl)butan-l-one
Compound-55 :
(2R)-2-amino-l-{4-[(4-ethylphenyl)methyl]piperidin-l-yl}-3-hydroxypropan-l-one hydrochloride
Compound-56 : (2R, 3 S)-2-amino-3 -hydroxy-1 -(4-(4-methylb enzyl)piperidin-1 -yl)butan-1 one
Compound-57 : (2R)-2-amino-l-{4-[(4-methylphenyl)methyl]piperidin-l-yl}-3-(l,3-thiazol-4-yl)propan-lone 2 hydrochloride
Compound-58 : (3R)-3-amino-4-{4-[(4-methylphenyl)methyl]piperidin-l-yl}-4-oxobutanoic acid formic acid (1/1)
Compound-59 :
2-amino-2-(3-hydroxy-l-(methylsulfonyl)pyrrolidin-3-yl)-l-(4-(4-methylbenzyl)piperidin-lyl)ethanone
Compound-60 :
2-amino-l-{4-[(4-methylphenyl)methyl]piperidin-l-yl}-3-(pyridin-2-yl)propan-l-one 2 hydrochloride
Compound-61 :
2-amino-2-[4-hydroxy-l-(methanesulfonyl)piperidin-4-yl]-l-{4-[(4methylphenyl)methyl]piperidin-1 -yl} ethan-1 -one
Compound-62 :
(2R)-2-amino- l-{4-[([l,l '-biphenyl] -4-yl )methylidene]piperi din-1 -yl} -3 -hydroxypropan-1 one hydrochloride
Compound-63 :
(2R)-2-amino-l-{4-[(4-bromophenyl)methylidene]piperidin-l-yl}-3-hydroxypropan-l-one hydrochloride
Compound-64 :
(2R)-2-amino-3 -hydroxy-1 - [4-(3 -phenylprop-1 -yn-1 -yl)-2,3-dihydro- ΙΗ-indol-1 -yl]propan1-one
Compound-65 : (2R)-2-amino-1 -[4-(benzyloxy)-2,3-dihydro-ΙΗ-indol-1 -yl]-3hydroxypropan-1 -one
Compound-66 : (2R)-2-amino-l-[4-(2-phenylethyl)-2,3-dihydro-lH-indol-l-yl]-3-(2H-tetrazol-5-yl)propan1 -one hydrochi ori de
-95 Compound-67 : (2R)-2,3-diamino-1 -[4-(2-phenylethyl)-2,3 -dihydro-1 H-indol-1 -yl]propan-1 one
Compound-68 :
2-amino-1 - [4-(2-phenyl ethyl)-2,3 -dihydro- ΙΗ-indol-1 -yl]-3 -(pyridin-2-yl)propan-1 -one hydrochloride
Compound-69 : (2R)-2-amino-1 -(4-bromo-2,3-dihydro-1 H-indol-1 -y 1)-3-hydroxypropan-1 one
Compound-70 :
(2R)-2-amino-3 -hydroxy-1 -(4-{ [4-(2-hydroxyethoxy)phenyl]ethynyl}-2,3-dihydro- lH-indoll-yl)propan-l-one hydrochloride
Compound-71 :
(2R)-2-amino-3 -hydroxy-1 -[4-(phenyl ethynyl)-2,3 -dihydro- ΙΗ-indol-1 -yl] propan-1 -one
Compound-72 : (2R)-2-amino-4-(methanesulfonyl)-l-[4-(phenylethynyl)-2,3-dihydro-lH-indol-l-yl]butan-lone
Compound-73 : (2R)-2-amino-3-hydroxy-1 -(4-phenyl-2,3-dihydro-ΙΗ-indol-1 -yl)propan-1 one
Compound-74 :
(3R)-3-amino-4-(4-bromo-2,3-dihydro-lH-indol-l-yl)-4-oxobutanoic acid trifluoroacetic acid (1/1)
Compound-75 : (2R)-2-amino-l-(4-bromo-2,3-dihydro-lH-indol-l-yl)-4-(methanesulfonyl)butan-l-one hydrochloride
Compound-76 :
(3 R)-3-amino-4-[6-{ [4-(2-hydroxyethoxy )phenyl]ethynyl }-3,4-dihydroisoquinolin-2(lH)yl]-4-oxobutanoic acid
Compound-77 :
(2R)-2-amino-l-[6-{[4-(hydroxymethyl)phenyl]ethynyl}-3,4-dihydroisoquinolin-2(lH)-yl]4-(m ethanesulfonyl )butan-1 -one
Compound-78 :
(2R)-2-amino-3 -hydroxy-1 -[6-(2-phenylethyl)-3,4-dihydroisoquinolin-2(l H)-yl]propan-1 one
Compound-79 :
(2R)-2-amino-3 -hydroxy-1 - { 6- [4-(3 -hydroxypropyl )phenyl] -3,4-dihydroisoquinolin-2(lH)yl} propan-1-one hydrochloride
Compound-80 :
(2R)-2-amino-l-(6-bromo-3,4-dihydroisoquinolin-2(lH)-yl)-4-(methanesulfonyl)butan-l-one
-96 Compound-81 :
(2R)-2-amino-1 -(6-bromo-3,4-dihydroi soquinolin-2( 1 H)-yl)-3 -hydroxypropan-1 -one hydrochloride
Compound-82 : (3R)-3-amino-4-(6-bromo-3,4-dihydroisoquinolin-2(lH)-yl)-4-oxobutanoic acid trifluoroacetic acid (1/1)
Compound-83 :
2-amino-l-(6-bromo-3,4-dihydroisoquinolin-2(lH)-yl)-3-(pyridin-2-yl)propan-l-one 2 hydrochloride 2 hydrochloride
Compound-84 : 3-amino-N-{6-[4-(3-hydroxypropyl)phenyl]-lH-indol-3-yl}-D-alaninamide
Compound-85 : N-[6-(2-phenylethyl)-lH-indol-3-yl]-D-serinamide
Compound-86 : N-(6-bromo-lH-indol-3-yl)-D-serinamide
Compound-87 : N-(6-benzyl-lH-indol-3-yl)-D-serinamide
Compound-88 : 3-{4-[3-(D-serylamino)-lH-indol-6-yl]phenyl}propanoic acid
Compound-89 : N-[3-(trifluoromethoxy)phenyl]-D-serinamide
Compound-90 : 3-(l-phenyl-lH-l,2,3-triazol-4-yl)-N-[3(trifluoromethoxy)phenyl ] al aninami de hy drochl ori de
Compound-91 : N-[3-(trifluoromethoxy)phenyl]-D-threoninamide
Compound-92 : N-[3-(trifluoromethoxy)phenyl]-D-allothreoninamide
Compound-93 : 3-(2H-tetrazol-5-yl)-N-[3-(trifluoromethoxy)phenyl]-D-alaninamide hydrochloride
Compound-94 : 3-pyridin-2-yl-N-[3-(trifluoromethoxy)phenyl]-D-alaninamide 2 hydrochloride
Compound-95 : 3-(l,3-thiazol-4-yl)-N-[3-(trifluoromethoxy)phenyl]-D-alaninamide hydrochloride
Compound-96 : 3-amino-N-[3-(trifluoromethoxy)phenyl]-D-alaninamide 2 hydrochloride
Compound-97 : N-{3-[(naphthalen-2-yl)oxy]phenyl}-D-serinamide
Compound-98 : N-{3-[([l,r-biphenyl]-4-yl)oxy]phenyl}-D-serinamide
Compound-99 : N-{3-[4-(phenylethynyl)phenoxy]phenyl}-D-serinamide
Compound-100 : trifluoroacetic acid N-(3-phenoxyphenyl)-D-serinamide (1/1)
Compound-101 : (R)-3-amino-4-oxo-4-((3-phenoxyphenyl)amino)butanoic acid
Compound-102 : N-(3-phenoxyphenyl)-3-(l,3-thiazol-4-yl)-D-alaninamide hydrochloride
Compound-103 : N-{3-[4-(2-phenylethyl)phenoxy]phenyl}-D-serinamide
Compound-104 : N-{3-[([l,l'-biphenyl]-3-yl)oxy]phenyl}-D-serinamide
Test examples
The following pharmacological tests were conducted to verify the action of inventive compounds.
Test 1: Evaluation of the inhibitory activities on Pseudomonas aeruginosa LpxC enzyme
-97 Inhibitory activities on P.aeruginosa LpxC enzyme of compounds were evaluated using the following LCMS method.
(LC/MS method)
To assay the activity of P. aeruginosa LpxC enzyme, LpxC was reacted with its substrate UDP-3-O-(R-3-hydroxydecanoyl)-N-acetylglucosamine. The amounts of substrate and reacted product were determined with a liquid chromatography-tandem mass spectrometry (LC/MS/MS). Specifically, 3.6 nmol/L of P. aeruginosa LpxC enzyme (as acquired by preparing chromosomal DNA from P. aeruginosa, subjecting the DNA to PCR (polymerase chain reaction) using LpxC specific primers to acquire P. aeruginosa LpxC genes, incorporating the genes into a vector, and expressing in Escherichia coli) was mixed with 20 pmol/L of UDP-3-O-(R-3-hydroxydecanoyl)-N-acetylglucosamine (Alberta Research Council) and the mixture was incubated at room temperature for 60 minutes. The reaction was performed in 40 mmol/L of Hepes buffer solution (pH 8.0) supplemented with 0.02% (v/v) Brij 35 and 25 nmol/L of ZnCA To terminate the reaction, acetonitrile containing 25 pmol/L of UDP-GlcNAc as internal standard was added. The mixture was centrifuged and supernatant was injected into LC/MS/MS. The samples were separated with Inertsil Amide (3.0 pm, 50 mm * 2.1 mm I.D., GLScience, Japan). The mobile phase was 8 mmol/L ammonium acetate containing 72% acetonitrile and flow rate was 0.2mL/min. MS/MS detection of each component was performed using a TSQ Quantum system with electrospray interface (ThermoFisher Scientific, USA) in negative ion detection mode. An inhibition curve was constructed for each test compound by performing the aforementioned reaction at varying concentrations of the test compound. From this inhibition curve, the concentration of the test compound at which the formation of the reaction product was suppressed by 50% was determined as the IC50 of the test compound, which was an index for the inhibitory activity on P. aeruginosa LpxC enzyme.
Geometric means of IC50 values from two independent tests for various test compounds are shown in Table 4.
-98 Table 4 Inhibitory activities IC50 (μΜ) on P. aeruginosa LpxC enzyme.
Compound IC50 (μΜ)
1 0.0060
2 0.018
3 0.022
4 0.023
5 0.026
6 0.028
7 0.034
8 0.038
9 0.054
10 0.068
11 0.077
12 0.10
13 0.15
14 0.22
15 0.061
16 0.070
17 0.088
18 0.14
19 0.14
20 0.19
21 0.25
22 0.27
23 0.32
24 0.052
25 0.087
26 0.13
27 0.17
28 0.27
29 0.078
30 0.13
31 0.13
32 0.14
33 0.19
Compound IC50 (μΜ)
34 0.23
35 0.30
36 0.65
37 0.51
38 0.66
39 0.61
40 0.52
41 0.81
42 0.67
43 0.83
44 1.3
45 1.6
46 3.6
47 5.0
48 3.2
49 1.9
50 3.2
51 4.5
52 5.1
53 4.5
54 4.7
55 7.2
56 8.9
57 15
58 49
59 16
60 56
61 71
62 1.1
63 4.3
64 0.59
65 0.58
66 0.71
-99 Table 4 (continued)
Compound IC50 (μΜ)
67 0.80
68 1.2
69 1.5
70 1.5
71 0.92
72 2.5
73 3.9
74 7.4
75 10
76 0.25
77 0.32
78 0.47
79 0.82
80 1.6
81 1.6
82 3.4
83 12
84 0.51
85 0.56
Compound IC50 (μΜ)
86 0.88
87 0.88
88 1.8
89 9.1
90 10
91 12
92 19
93 28
94 18
95 39
96 37
97 3.0
98 2.8
99 1.2
100 4.3
101 5.5
102 8.1
103 13
104 30
The present invention enables providing novel compounds that inhibit LpxC or pharmaceutically acceptable salts thereof, as well as new pharmaceutical drugs exhibiting antimicrobial activity against gram-negative bacteria and useful in the treatment of bacterial infections which comprise those compounds or pharmaceutically acceptable salts thereof.

Claims (9)

We Claim:
1. A compound represented by the following general formula [1] or a pharmaceutically acceptable salt thereof:
O «ΑηΗ· Y [1] wherein
X represents a group selected from the following formula [2]:
* [2],
Y represents a group selected from the following formula [3]:
R1 represents a group selected from the following formula [4]:
[3],
- 101 - alkyl—* C2.4 alkynyl —* W
L1 represents a bond or a Ci.4 alkylene group,
R represents a phenyl group or a halogen atom, □
R represents a group selected from the following formula [5]:
W——L3—* Halogen—* the phenylene group represented by formula [5] may be substituted with a halogen atom, □
L represents a C4.4 alkylene group, a C4.4 alkynylene group, -0-, -OCH2-, -CH2O-, or a bond, R4 represents a group selected from the following formula [6]:
W—\—L4—* Halogen—* [6],
L4 represents -C=C-, a C4.4 alkylene group or a bond,
R5 represents a group selected from the following formula [7]:
W—\—L5—* Halogen—* [7],
L5 represents -C=C-, a Ci.4 alkylene group or a bond,
R6 represents a group selected from the following formula [8]:
L6 represents -C=C-, a Ci.4 alkylene group or a bond, and
W represents a hydrogen atom, a halogen atom, a phenyl group, a Ci-4 hydroxyalkyl group, HOCH2CH2O-, HOOC-CH2CH2- or N-morpholinomethyl group, n represents 1 or 2, and * indicates the site of the attachment of a moiety.
2. The compound or the pharmaceutically acceptable salt thereof, according to claim 1, wherein X is selected from the following formula [2a]:
[2a],
- 102 wherein R1, R3, R4 and R5 are as defined in claim 1.
3. The compound or the pharmaceutically acceptable salt thereof, according to claim 1 or 2, wherein Y is selected from the following formula [3a]:
* * * * * *
4. The compound or the pharmaceutically acceptable salt thereof, according to claim 3, wherein Y is selected from the following formula [3b]:
5. The compound or the pharmaceutically acceptable salt thereof, according to any one of claims 1 to 4, wherein R1 is selected from the following formula [4]:
wherein W is as defined in claim 1.
6. The compound or the pharmaceutically acceptable salt thereof, according to claim 1, wherein X is selected from the following formula [2b]:
n [2b], wherein R6 is as defined in claim 1.
* and Y is selected from the following formula [3c]:
* * * * * *
A pharmaceutical composition comprising the compound or the pharmaceutically acceptable salt thereof according to any one of claims 1 to 6.
8. An LpxC inhibitor comprising the compound or the pharmaceutically acceptable salt thereof according to any one of claims 1 to 6.
9. An antimicrobial agent comprising the compound or the pharmaceutically acceptable salt thereof according to any one of claims 1 to 6.
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