WO2018216822A1 - Novel imidazole derivatives - Google Patents

Abstract

Provided are novel compounds represented by the following general formula [1] or pharmaceutically acceptable salts thereof, that inhibit LpxC, as well as pharmaceutical drugs comprising those compounds or pharmaceutically acceptable salts thereof, that exhibit antimicrobial activity against gram-negative bacteria including multi-drug resistant strains and that are useful in the treatment of bacterial infections.

Description

DESCRIPTION

Title of Invention: NOVEL IMIDAZOLE DERIVATIVES

TECHNICAL FIELD

This invention relates to novel imidazole derivatives or salts thereof, which exhibit an activity for inhibiting uridyldiphospho(UDP)-3^_0-acyl-N-acetylglucosamine deacetylase (LpxC) and antimicrobial pharmaceuticals comprising the same. BACKGROUND ART

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 l). Furthermore, lipopolysaccharide (LPS), one of the main constituents of the outer membrane, is involved in toxicity as an endotoxin.

In recent years, gram-negative bacteria such as Pseudomonas aeruginosa and Enterobacteriaceae, which have gained resistance to carbapenem drugs, quinolone drugs or aminoglycoside drugs, has been isolated in clinical settings (Non-Patent Document 2 and 3). Emergence of multi-drug resistant gram-negative bacteria including Pseudomonas aeruginosa and Enterobacteriaceae 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 -acyl-N- acetylglucosamine (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 gram-negative 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 multi-drug resistant strains, 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 Documents 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 unsucessful.

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- hydroxamic 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.

CITATION LIST PATENT DOCUMENTS

Patent Document 1- International Publication 15/085238 pamphlet.

NON-PATENT DOCUMENTS

Non-Patent Document L 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: Virulence. (2017), 8(4), pp. 460-469.

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 Perspect Med. (2016), July l; 6(7), a025304. Non-Patent Document 7- Curr Top Med Chem. (2016) 16(21), pp. 2379-2430.

SUMMARY OF INVENTION

TECHNICAL PROBLEMS

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 multi-drug resistant strains and that are useful in treating bacterial infections.

SOLUTION TO PROBLEMS 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 [l] 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

(l) A compound represented by the following general formula [l] or a pharmaceutically acceptable salt thereof:

wherein

Z represents a hydroxyl group or an amino group,

R¹ represents a hydrogen atom, a Ci-4 alkyl group, a Ci-4 haloalkyl group or a cyclopropyl group,

R² represents a hydrogen atom, -COOH or -CONH2, provided that R¹ and R² are not a hydrogen atom at the same time,

R³ represents a hydrogen atom or a C1-4 alkyl group,

R⁴ represents a hydrogen atom, a Ci-4 alkyl group, a Ci-4 hydroxyalkyl group or a C1-4 aminoalkyl group (the amino group of the Ci 4 aminoalkyl group may be substituted with a C2 4 alkanoyl group or a Ci-4 alkylsulfonyl group),

R⁵ represents a hydrogen atom,

R⁴ and R⁵ may form a Ci-4 alkylidene group together,

L¹ represents a bond, a Ci-4 alkylene group (the C1-4 alkylene group may be substituted with a hydroxyl group), -OCH2 - or -C(=0) -,

A¹ represents a divalent 5-membered heteroaromatic group, a 1,4-divalent 6-membered heteroaromatic group, a 1,4-phenylene group (the divalent 5-membered heteroaromatic group, the 1,4-divalent 6-membered heteroaromatic group and the 1,4-phenylene group may be substituted with 1 to 3 substituents which are the same or different and are selected from "a halogen atom and a Ci-4 alkyl group") or a benzoisoxazolylene group, L² represents -C≡G- -C≡C~C≡C- -CH=CH- a Ci-₄ alkylene group, 1,3- cyclobutylene group or a bond,

W¹ represents W²-A²-, a Ci-8 alkyl group (the Ci-e alkyl group may be substituted with a hydroxyl group), a chlorine atom or a bromine atom,

A² represents a divalent 5-membered heteroaromatic group, a 1,4-divalent 6-membered heteroaromatic group, a 1,4-phenylene group or a divalent group selected from the following formula [2A] X

QA : a C₃.₉ cycloalkylene group

(the divalent 5-membered heteroaromatic group, the 1,4-divalent 6-membered heteroaromatic group, the 1,4-phenylene group and the divalent group selected from the formula [2A] may be substituted with 1 to 3 substituents which are the same or different and are selected from "a halogen atom, a hydroxyl group, a C alkyl group and a Ci-4 hydroxyalkyl group"),

G represents N or CH,

W² represents Re-X"-, R6-Xⁱ-Yi-Xn-, R6-X²-Y²-Xⁱ-Yⁱ-XH- Q-Χ^ΐ-, Q-X"-Yⁱ-X»- or <¾-Χΐ -Υ²-Χΐ-Υΐ-Χ"- or <¾-Υ3-Χΐ2-Υ2-χΐ-γΐ-χ^η-

Y¹ represents -(CH₂)mO-, -NR⁷-, -SO2-, -C(=0)- or -NR C(=0)- wherein m is 0 to 3, Y² represents -0(CH₂)n- -NR (CH₂)_n- -NHC(=0)0- -C(=0)0- or -OC(=0)- wherein each n is 0 to 3,

Y³ represents -NR⁷-,

X¹ and X² are the same or different and each represent a Ci-8 alkylene group or a C3-9 cycloalkylene group (the Ci-8 alkylene group and the C3-9 cycloalkylene group may be substituted with 1 to 3 substituents which are the same or different and are selected from "a halogen atom, a hydroxyl group or an amino group"),

X¹¹ and X¹² are the same or different and each represent a Ci-s alkylene group (the Ci-8 alkylene group may be substituted with 1 to 3 substituents which are the same or different and are selected from "a halogen atom, a hydroxyl group and an amino group"), a C3-9 cycloalkylene group, or a bond,

R⁶ represents a hydrogen atom, a halogen atom, a hydroxyl group, a C1-4 hydroxyalkyl group, an amino group, a Ci-4 aminoalkyl group, a carbamoyl group, -SO2NH2, or

-COOR⁷,

R⁷ represents a hydrogen atom, C1-4 hydroxyalkyl group or a Ci-₄ alkyl group, and Q represents a nitrogen-containing 4- to 7-membered saturated heterocyclic group wherein the ring-constituting atoms may optionally contain 1 or 2 oxygen or sulfur atoms, or an oxygen-containing 4- to 7-membered saturated heterocyclic group (the nitrogen-containing 4- to 7-membered saturated heterocyclic group and the oxygen- containing 4- to 7-membered saturated heterocyclic group may be substituted with 1 or 2 oxo groups and may be substituted with 1 to 3 substituents which are the same or different and are selected from "a halogen atom, a hydroxyl group, Ci-4 alkyl group, Ci-4 alkoxy group, a Ci-s hydroxyalkyl group or a Ci-4 alkylsulfonyl group"), and

* indicates the site of attachment of a moiety;

(2) A compound represented by the following general formula [l] or a pharmaceutically acceptable salt thereof:

wherein

Z represents a hydroxyl group or an amino group,

R¹ represents a hydrogen atom, a Ci-4 alkyl group, a Ci-4 haloalkyl group or a cyclopropyl group,

R² represents a hydrogen atom, -COOH or -CONH2, provided that R¹ and R² are not a hydrogen atom at the same time,

R³ represents a hydrogen atom or a C1-4 alkyl group,

R⁴ represents a hydrogen atom, a Ci-4 alkyl group, a Ci-4 hydroxyalkyl group or a Ci-4 aminoalkyl group (the amino group of the Ci-4 aminoalkyl group may be substituted with a C2 4 alkanoyl group or a Ci-4 alkylsulfonyl group),

R⁵ represents a hydrogen atom,

R⁴ and R⁵ may form a Ci alkylidene group together,

L¹ represents a bond, a Ci-4 alkylene group (the Ci-4 alkylene group may be substituted with a hydroxyl group), -OCH2 - or -C(=0) -,

A¹ represents a divalent 5-membered heteroaromatic group, a 1,4-divalent 6-membered heteroaromatic group, a 1,4-phenylene group (the divalent 5-membered heteroaromatic group, the 1,4-divalent 6-membered heteroaromatic group and the 1,4-phenylene group may be substituted with 1 to 3 substituents which are the same or different and are selected from "a halogen atom and a Ci-4 alkyl group") or a benzoisoxazolylene group, L² represents -C≡ C-, -C≡ C-C≡ C- -CH=CH- a Ci-4 alkylene group, 1,3- cyclobutylene group or a bond,

W¹ represents W²-A²-, a Ci-e alkyl group (the Ci-8 alkyl group may be substituted with a hydroxyl group), a chlorine atom or a bromine atom,

A² represents a divalent 5-membered heteroaromatic group, a 1,4-divalent 6-membered heteroaromatic group, a 1,4-phenylene group or a divalent group selected from the following formula [2]

divalent 5-membered heteroaromatic group, the 1,4-divalent 6-membered heteroaromatic group, the 1,4-phenylene group and the divalent group selected from the formula [2] may be substituted with 1 to 3 substituents which are the same or different and are selected from "a halogen atom, a hydroxyl group, a Ci-4 alkyl group and a Ci-4 hydroxyalkyl group"),

G represents N or CH,

W² represents R6-X"- Re-χι-γι-χιι- R6-X²-Y²-Xⁱ-Yⁱ-Xn- Q-Χ^ΐ-, Q-X"-Yⁱ-X"- or <¾-Χ^ΐ -Υ²-Χ^ΐ-Υ^ΐ-χι^ΐ-,

Yⁱ represents -0-, -NR⁷-, -S0₂-, -C(=0)- or -NR⁷C(=0)-,

Y² represents -O - -NR⁷ - or -0C(=0)-,

X¹ and X² are the same or different and each represent a Ci-8 alkylene group, a C3 9 cycloalkylene group (the Ci-8 alkylene group and the C3 9 cycloalkylene group may be substituted with 1 to 3 substituents which are the same or different and are selected from "a halogen atom, a hydroxyl group or an amino group"),

X^u and X¹² are the same or different and each represent a Ci-8 alkylene group (the Ci-8 alkylene group may be substituted with 1 to 3 substituents which are the same or different and are selected from "a halogen atom, a hydroxyl group and an amino group"), a C3 9 cycloalkylene group, or a bond,

R⁶ represents a hydrogen atom, a halogen atom, a hydroxyl group, an amino group, a carbamoyl group, -SO2NH2, or -COOR⁷,

R⁷ represents a hydrogen atom, Ci-4 hydroxyalkyl group or a C1-4 alkyl group, and Q represents a nitrogen-containing 4- to 7-membered saturated heterocyclic group wherein the ring-constituting atoms may optionally contain 1 or 2 oxygen or sulfur atoms, or an oxygen-containing 4- to 7-membered saturated heterocyclic group (the nitrogen-containing 4- to 7-membered saturated heterocyclic group and the oxygen- containing 4- to 7-membered saturated heterocyclic group may be substituted with 1 or 2 oxo groups and may be substituted with 1 to 3 substituents which are the same or different and are selected from "a halogen atom, a hydroxyl group, a Ci-4 alkyl group, a Ci 4 alkoxy group, a C hydroxyalkyl group or a

alkylsulfonyl group"), and

* indicates the site of attachment of a moiety ;

(3) The compound or the pharmaceutically acceptable salt thereof, according to item (l) or (2), wherein R² is a hydrogen atom!

(4) The compound or the pharmaceutically acceptable salt thereof, according to any one of items (l) to (3), wherein R¹ is a methyl group, an ethyl group, a difluoromethyl group or a trifluoromethyl group!

(5) The compound or the pharmaceutically acceptable salt thereof, according to item (4), wherein R¹ is a methyl group;

(6) The compound or the pharmaceutically acceptable salt thereof, according to any one of items (l) to (5), wherein Z is a hydroxyl group,'

(7) The compound or the pharmaceutically acceptable salt thereof, according to any one of items (l) to (6), wherein R³ is a hydrogen atom,^'

(8) The compound or the pharmaceutically acceptable salt thereof, according to any one of items (l) to (7), wherein R⁴ is a hydrogen atom, a Ci-4 hydroxyalkyl group or a Ci-4 aminoalkyl group and R⁵ is a hydrogen atom!

(9) The compound or the pharmaceutically acceptable salt thereof, according to any one of items (l) to (8), wherein A¹ is a divalent group selected from the following formula [3],

[3]

where R^A1, R^A2, R^A3, R^A4, R^A5 and R^A6 are the same or different and each represent a hydrogen atom, halogen atom or a methyl group!

(10) The compound or the pharmaceutically acceptable salt thereof, according to item (9), wherein A¹ is a divalent group represented by the following formula [4]

(11) The compound or the pharmaceutically acceptable salt thereof, according to any one of items (l) to (10), wherein L¹ is a bond;

(12) The compound or the pharmaceutically acceptable salt thereof, according to any one of items (l) to (ll), wherein L² is -C≡C-, a 1,3-cyclobutylene group or a bond;

(13) The compound or the pharmaceutically acceptable salt thereof, according to item (12), wherein L² is -C≡ C-;

(14) The compound or the pharmaceutically acceptable salt thereof, according to any one of items (1) to (13), wherein W¹ is W²-A²-;

(15) The compound or the pharmaceutically acceptable salt thereof, according to amy one of items (l) to (14) wherein A² is a divalent group selected from the following formula [5]

wherein the above formula [5] may be substituted by 1 to 3 substituents which are the same or different and are selected from "a halogen atom, a hydroxyl group, a Ci-4 alkyl group and a Ci-4 hydroxyalkyl group";

(16) The compound or the pharmaceutically acceptable salt thereof, according to item (15), wherein A² is a 1,4-phenylene group wherein the 1,4-phenylene group may be substituted by 1 to 3 substituents which are the same or different and are selected from "a halogen atom, a hydroxyl group, a_Ci-4 alkyl group and a C.i-4 hydroxyalkyLgroup"; _

(17) The compound or the pharmaceutically acceptable salt thereof, according to any one of items (1) to (16), wherein W² is R6-X¹¹-, RG-X^!-Y¹- R6-X²-Y -Xⁱ-Yⁱ-, or Q-X^-Y¹- wherein Y¹ represents -0-, Y² represents -0- or -NR⁷ wherein R⁷ represents a hydrogen atom, Ci-4 hydroxyalkyl group or a C alkyl group, X¹ and X² are the same or different and each represent a Ci-8 alkylene group (the Ci-8 alkylene group may be substituted with 1 to 3 hydroxyl groups), X¹¹ and X¹² are the same or different and each represent a Ci-8 alkylene group (the Ci-8 alkylene group may be substituted with 1 to 3 hydroxyl groups) or a bond, R⁶ is a hydroxyl group, an amino group a carbamoyl group, and Q represents a nitrogen-containing 4· to 7-membered saturated heterocyclic group wherein the nitrogen-containing 4- to 7-membered saturated heterocyclic group may be substituted with 1 to 3 substituents which are the same or different and are selected from a hydroxyl group and a Ci 4 hydroxyalkyl group;

(18) The compound or the pharmaceutically acceptable salt thereof, according to any one of items (1) to (16), wherein W² is Re-X^!-Y¹- wherein Y¹ represents -(CH2)mO- m is 0 to 3, X¹ represents a C3 6 cycloalkyl group and R⁶ represents an amino group or a C1-4 aminoalkyl group;

(19) The compound or the pharmaceutically acceptable salt thereof, according to any one of items (l) to (15), wherein A² is the following formula

W² is R⁶-X^H- Rs-X^!-Y^!-X¹¹-, wherein Y¹ represents -0-, X¹ represents a Ci-e alkylene group (the Ci-8 alkylene group may be substituted with 1 to 3 hydroxyl groups), X¹¹ represents a Ci-s alkylene group (the Ci-8 alkylene group may be substituted with 1 to 3 hydroxyl groups) and R⁶ is a hydrogen or a hydroxyl group,^'

(20) A pharmaceutical composition comprising the compound or the pharmaceutically acceptable salt thereof according to any one of items (1) to (19);

(21) An LpxC inhibitor comprising the compound or the pharmaceutically acceptable salt thereof according to any one of items (l) to (19);

(22) An antimicrobial agent comprising the compound or the pharmaceutically acceptable salt thereof according to any one of items (l) to (19). ADVANTAGEOUS EFFECTS OF INVENTION

The compound or the pharmaceutically acceptable salt thereof according to the present invention has a strong LpxC -inhibiting action and exhibits potent antimicrobial activity against gram-negative bacteria including Pseudomonas aeruginosa. Thus, the compound or its pharmaceutically acceptable salt is useful as a pharmaceutical composition and as an antimicrobial agent against these bacteria.

DESCRIPTION OF EMBODIMENT The present invention will be described in further detail below. The terms and phrases used herein will be explained first.

In the present invention, "n-" means normal, "r" iso, "sec-" secondary, "tert-" tertiary, "c-" cyclo, "0-" ortho, "nr" 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 "Ci-6 alkyl group" refers to a straight-chain or branched-chain alkyl group having 1 to 6 carbon atoms. Its examples are a n-pentyl group, a n-hexyl group, an isopentyl group, a neopentyl group, a tert-pentyl group and a 1,2-dimethylpropyl group, in addition to the above-mentioned examples of the "Ci-4 alkyl group".

The "Ci-8 alkyl group" refers to a straight-chain or branched-chain alkyl group having 1 to 8 carbon atoms. Its examples are a n-heptyl group and a n-octyl group, in addition to the above-mentioned examples of the "Ci-6 alkyl group".

The "C2-8 alkenyl group" refers to a straight-chain or branched-chain alkenyl group with 2 to 8 carbon atoms which has one or more double bonds at any position(s) of the above- mentioned "Ci-e alkyl group". Its examples are a vinyl group, a 1-propenyl group, a 2- propenyl group, an isopropenyl group, a 2-butenyl group, a 1,3-butadienyl group, a 2- pentenyl group, a 3-pentenyl group, a 2-hexenyl group, a 2"heptenyl group and a 2-octenyl group.

The "C2-8 alkynyl group" refers to a straight-chain or branched-chain alkynyl group with 2 to 8 carbon atoms which has one or more triple bonds at any position(s) of the above-mentioned "Ci-e alkyl group". Its examples are an ethynyl group, a 1-propynyl group, a 2-propynyl group, a l'butynyl group, a 3"butynyl group, a 1-pentynyl group, a 4-pentynyl group, a 1- hexynyl group, a 5-hexynyl group, a 1-heptynyl group and a 1-octynyl group.

The "C3 6 cycloalkyl group" refers to a cycloalkyl group having 3 to 6 carbon atoms. The C3-6 cycloalkyl group include includes not only a monocyclic cycloalkyl group but also a fused cycloalkyl group and a bridged cycloalkyl group. Its examples are a c-propyl group, a c-butyl group, a c-pentyl group, a c-hexyl group and a bicyclo[l.l.l]pentanyl group.

The "C3 9 cycloalkyl group" refers to a cycloalkyl group having 3 to 9 carbon atoms. The C3 9 cycloalkyl group include includes not only a monocyclic cycloalkyl group but also a fused cycloalkyl group and a bridged cycloalkyl group. Its examples are a cheptyl group, a c-octyl group, a bicyclo[2.2.2]octanyl group, a norbornyl group and an adamantyl group, in addition to the above-mentioned examples of the "C3-6 cycloalkyl group".

The "Ci-4 alkoxy group" refers to a straight-chain or branched-chain alkoxy group having 1 to 4 carbon atoms. Its examples are a methoxy group, an ethoxy group, a 1-propoxy group, an isopropoxy group, a 1-butoxy group, a 1-methyl- 1-propoxy group and a tert-butoxy group. The "Ci-6 alkoxy group" refers to a straight-chain or branched-chain alkoxy group having 1 to 6 carbon atoms. Its examples are a 1-pentyloxy group and 1-hexyloxy group, in addition to the above-mentioned examples of the "Ci-4 alkoxy group".

The "Ci-4 haloalkyl group" refers to an alkyl group in which one or more of the hydrogen atoms of the above-mentioned "Ci-4 alkyl group" has been or have been substituted with a halogen atom or halogen atoms. Its examples are a fluoromethyl group, a difluoromethyl group, a trifluoromethyl group, a 2,2,2-trifluoroethyl group, a 2,2,2-trichloroethyl group, a pentafluoroethyl group, a 3,3,3-trifluoropropyl group, a perfluoropropyl group, a 4- fluorobutyl group, a 4-chlorobutyl group and a 4-bromobutyl group.

The "Ci-4 hydroxyalkyl group" refers to an alkyl group in which one or more of the hydrogen atoms of the above-mentioned "Ci-4 alkyl group" has been or have been substituted with a hydroxyl group or hydroxyl groups. Its examples are a hydroxymethyl group, a 1- hydroxyethyl 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 4- hydroxybutyl group.

The "Ci-8 hydroxyalkyl group" refers to an alkyl group in which one or more of the hydrogen atoms of the above-mentioned "Ci-8 alkyl group" has been or have been substituted with a hydroxyl group or hydroxyl groups. Its examples are a hydroxypentyl group, a hydroxyhexyl group, a hydroxyheptyl group and a hydroxyoctyl group, in addition to the above-mentioned examples of the "Ci-4 hydroxyalkyl group".

The "C2-4 hydroxyalkyl group" is the same as Ci-4 hydroxyalkyl group except for a hydroxymethyl group.

The "Ci-4 aminoalkyl group" refers to an alkyl group in which one or more of the hydrogen atoms of the above-mentioned "Ci-4 alkyl group" has been or have been substituted with a an amino group or amino groups. Its examples are an aminomethyl group, a 1-aminoethyl group, a 2-aminoethyl group, a 2-aminopropyl group, a 3-aminopropyl group, a 1-aminobutyl group, a 2-aminobutyl group, a 3-aminobutyl group and a 4-aminobutyl group.

The "C2-4 alkanoyl group" refers to a straight-chain or branched-chain alkanoyl group having 2 to 4 carbon atoms. Its examples are an acetyl group, a propionyl group, a butyryl group and a pivaloyl group.

The "Ci 4 alkylsulfonyl group" refers to a straight-chain or branched-chain alkylsulfonyl group having 1 to 4 carbon atoms. Its examples are a methylsulfonyl group, an ethylsulfonyl group and a propylsulfonyl group.

The "Ci-4 alkylidene group" refers to a straight-chain or branched-chain alkylidene group having 1 to 4 carbon atoms, and includes, for example, a methylidene group, an ethylidene group, a n-propylidene group, a n-butylidene group and an isopropylidene group.

The "aryl group" refers to a monocyclic to tetracyclic aromatic carbocyclic group composed of 6 to 18 carbon atoms. Its examples are a phenyl group, a naphthyl group, an anthryl group, a phenanthrenyl group, a tetracenyl group and a pyrenyl group. The "partially saturated fused polycyclic hydrocarbon ring group" refers to a fused polycyclic hydrocarbon ring group having a part hydrogenated. Its examples are an indanyl group and an acenaphthenyl group.

The "heterocyclic group" refers to a cyclic group which contains, as a ring-constituting atom(s), any 1 to 5 atoms selected from a nitrogen atom, an oxygen atom and a sulfur atom. If the hetero atom is a sulfur atom, a dioxide compound is also included in the present invention.

The "saturated heterocyclic group" refers to a heterocyclic group having a ring constituted only by saturated bonds, and may be substituted with 1 to 2 oxo groups.

The "nitrogen-containing 4- to 7-membered saturated heterocyclic group" refers to a saturated heterocyclic group which consists of 4 to 7 atoms as ring-constituting atoms and contains 1 or 2 nitrogen atoms. This nitrogen-containing 4- to 7-membered saturated heterocyclic group may contain 1 or 2 oxygen atoms or 1 or 2 sulfur atoms as ring- constituting atoms, and may be substituted with 1 or 2 oxo groups. A fused ring group and a spiro ring group are also included. Its examples are an azetidinyl group, a pyrrolidinyl group, a piperidinyl group, a piperazinyl group, a morpholinyl group, a homopiperazinyl group, a homomorpholinyl group, an imidazolidyl group, a pyrazolidinyl group, an oxazolidinyl group, an 2-oxo-oxazolidinyl group, an isoxazolidinyl group, a 2-oxa-6-azaspiro[3.3]heptanyl group, a l-oxa-6-azaspiro[3.3]heptanyl group, a 6-oxa-l-azaspiro[3.3]heptanyl group, a 1- azaspiro[3.3]heptanyl group, a 2-azaspiro[3.3]heptyl group, a 2,6'diazaspiro[3.3]heptyl and 3-azabicyclo[3.1.0]hexanyl group.

The "oxygen-containing 4- to 7-membered saturated heterocyclic group" refers to a saturated heterocyclic group which consists of 4 to 7 atoms as ring-constituting atoms and contains 1 or 2 oxygen atoms. Its examples are an oxetanyl group,' a tetrahydrofuranyl group and a tetrahydropyranyl group.

The "5-membered heteroaromatic group" refers to an aromatic ring group which consists of 5 atoms as ring-constituting atoms and contains at least one hetero atom selected from the group consisting of nitrogen, oxygen and sulfur. Its examples are a thienyl group, a pyrrolyl group, a thiazolyl group, an isothiazolyl group, a pyrazolyl group, an imidazolyl group, a furyl group, an oxazolyl group, an isoxazolyl group, an oxadiazolyl group, a 1,3,4-thiadiazolyl group, a 1,2,3-triazolyl group, a 1,2,4-triazolyl group and a tetrazolyl group.

The "6-membered heteroaromatic group" refers to an aromatic ring ring group which consists of 6 atoms as ring-constituting atoms and contains at least one nitrogen atom. Its examples are a pyridyl group, a pyridazinyl group, a pyrimidinyl group and a pyrazinyl group.

The "Ci-4 alkylene group" refers to a straight-chain or branched-chain alkylene group having 1 to 4 carbon atoms. Its examples are -CH2-, "(CH k, -(CHs s-, -GH₂-CH(CH₃)-, -CiCHs , - (CH₂)₄-, -(CH2)2-CH(CH₃)-, -CH2-CH(CH₃)-CH₂- and -CH(CH₃)-(CH₂)₂-.

The "Ci-8 alkylene group" refers to a straight-chain or branched-chain alkylene group having 1 to 8 carbon atoms. Its examples are -(CH₂)5-, -(CH₂)₃-CH(CH₃)-, -(CH2)₂-CH(C₂H₅) -,^■ (CH₂)₆-, -(CH₂)3-CH(CH₃)-CH₂-, and -CH₂-CH(CH₃)-(CH₂)₃-, C )r, -(CH₂)₅-CH(CH₃)-, - (CH₂)4^_CH(C₂H5)-, -(CH₂)8-, in addition to the above-mentioned examples of the "Ci-4 alkylene group".

The "C₂-8 alkenylene group" refers to a straight-chain or branched-chain alkenylene group having 2 to 8 carbon atoms which has one or more double bonds in the chain. Its examples are -CH=CH-, -CH=CH-CH₂-, -CH₂-CH=CH-, -CH=C(CH₃)-, -(CH₂)2-CH=CH-, -CH(CHs)- CH=CH-, -CH₂-CH=CH-CH₂-, -CH=GH-CH=CH-, -(CH₂)₃-CH=CH-, -(CH₂)₂-CH=C(CH₃)-, - (CH₂)₄-CH=CH-, -(CH₂)₂-CH=C(C₂H₅)-, -(CH₂)₅-CH=CH-, -(CH₂)₅-CH=C(CH₃)- and -(CH₂)₆- CH=CH-.

The "C₂-8 alkynylene group" , refers to a straight-chain or branched-chain alkynylene group having 2 to 8 carbon atoms which has one or more triple bonds in the chain. Its example is a divalent group having a triple bond formed by further eliminatins-, a hydrogen atom from the carbon atom in the double bond moiety of the "C₂-8 alkenylene group" mentioned above. The "C₃-G cycloalkylene group" refers to a divalent group formed by further eliminating any one hydrogen atom from the C₃ 6 cycloalkyl group. Two bonds where hydrogen atoms are eliminated may be attached on the same carbon atom. Its examples are a 1, 1-c-propylene group, a 1,2-c-propylene group, a Ι, ΐ -butylene group, a 1,2-cbutylene group, a 1,3-c- butylene group, a 1,2-c-pentylene group, a 1, 1-c-hexylene group, a 1.2'C-hexylene group, a 1,3-c-hexylene group and a 1,4'c-hexylene group.

The "C₃-9 cycloalkylene group" refers to a divalent group formed by further eliminating any one hydrogen atom from the C₃-9 cycloalkyl group. Its examples are a 1,4-c-heptylene group, a l,3-bicyclo[l. l.l]pentanylene group, a l,4-bicyclo[2.2.2]octanyl group, a 1,4-norbornylene group and a 1,4-adamantylene group, in addition to the above mentioned examples of the "C₃-6 cycloalkylene group".

The "divalent 5-membered heteroaromatic group" refers to a divalent group formed by further eliminating any one hydrogen atom from the 5-membered heteroaromatic group. Its examples are a 2,5-thienylene group, a 2,5-pyrrolylene group, a 2,5-thiazolylene group, an 3,5-isothiazolylene group, a 3,5-pyrazolylene group, a 2,5-imidazolylene group, a 1,5" furylene group, a 2,5-oxazolylene group, a 3,5-isoxazolylene group, a 2,5-(l,3,4-oxadiazolyl)- ene and a 2,5-(l,3,4-thiadiazolyl)-ene group.

The "1,4-divalent 6-membered heteroaromatic group" refers to a divalent group formed by further eliminating one hydrogen atom at the p -position from the 6-membered heteroaromatic group. Its examples are 2,5-pyridylene group, a 3,6-pyridazinylene group, a 2,5-pyrimidinylene group and a 2,5-pyrazinylene group. The "optionally protected hydroxyl group" means an unprotected or protected hydroxyl group.

The "protected hydroxyl group" means a hydroxyl group protected with a "protective group for a hydroxyl group".

The "optionally protected amino group" means an unprotected or protected amino group. The "protected amino group" means an amino group protected with a "protective group for an amino group".

The "optionally protected carboxy group" means an unprotected or protected carboxy group. The "protected carboxy group" means a carboxy group protected with a "protective group for a carboxy group".

The "protected imidazole group" means an imidazole group protected with a "protective group for an imidazole group".

The "protective group for a hydroxyl group", the "protective group for an amino group", the "protective group for a carboxy group" and the "protective group for an imidazole group" include all groups usable usually as protective groups for a hydroxyl group, an amino group, an carboxy group and an imidazole group, respectively, 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 are 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 parahemolyticus, 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 R² is a hydrogen atom.

Preferred R¹ is a methyl group, an ethyl group, a difluoromethyl group or a trifluoromethyl group, and more preferred R¹ is a methyl group.

Preferred Z is a hydroxyl group.

Preferred R³ is a hydrogen atom.

Preferred R⁴ is a hydrogen atom, a hydroxy methyl group or an aminomethyl group.

Preferred R⁵ is a hydrogen atom.

Preferred A¹ is a divalent group selected from the following formula [6],

where R^A1, R^A2, R^A3, R^A4, R^A5 and R^A6 are the same or different and each represent a hydrogen atom, halogen atom or a methyl group, and more preferred A¹ is a divalent group represented by the following formula [7]

Preferred L¹ is a bond.

Preferred L² is -C=C- or a bond, and more preferred L² is -C=C^~.

Preferred W¹ is W -A²-.

Preferred A² is a divalent group selected from the following formula [8]

wherein G represents N or CH, the above formula [2] may be substituted by 1 to 3 substituents which are the same or different and are selected from "a halogen atom, a hydroxyl group, a Ci-4 alkyl group and a Ci-4 hydroxyalkyl group", and more preferred A² is a 1,4-phenylene group wherein the 1,4-phenylene group may be substituted by 1 to 3 substituents which are the same or different and are selected from "a halogen atom, a hydroxyl group, a Ci-4 alkyl group and a Ci-4 hydroxyalkyl group".

Preferred W² is R6-X"- Re-χι-γι- R6-X²-Y -Xⁱ-Yⁱ- or Q-Xⁱ -Yⁱ- wherein Yⁱ represents -0-, Y² represents -O- or -NR⁷ wherein R⁷ represents a hydrogen atom, Ci-4 hydroxyalkyl group or a Ci-4 alkyl group, X¹ and X² are the same or different and each represent a Ci-e alkylene group (the Ci-s alkylene group may be substituted with 1 to 3 hydroxyl groups), X^u and X¹² are the same or different and each represent a Ci-8 alkylene group (the Ci-e alkylene group may be substituted with 1 to 3 hydroxyl groups) or a bond, R⁶ is a hydroxyl group, an amino group a carbamoyl group, and Q represents a nitrogen- containing 4- to 7-membered saturated heterocyclic group wherein the nitrogen-containing 4- to 7-membered saturated heterocyclic group may be substituted with 1 to 3 substituents which are the same or different and are selected from a hydroxyl group and a Ci-4 hydroxyalkyl group.

Another preferred W² is R^X^!-Y¹- wherein Y¹ represents -(CH2)mO-, m is 0 to 3, X¹ represents a C3 6 cycloalkyl group and R⁶ represents an amino_.group or„a Ci-4 aminoalkyl group, more preferred W² is R^X^!-Y¹-, wherein Y¹ represents -(CH2)mO- wherein m is 0 or 1, X¹ represents a cyclopropyl group and R⁶ represents an amino group.

Another more preffered A2 and W2 is the the following formula

wherein W² is R⁶-X^u- e-X^!-Y^!-X¹¹-, wherein Y¹ represents -0-, X¹ represents a Ci-8 alkylene group (the Ci-e alkylene group may be substituted with 1 to 3 hydroxyl groups), X¹¹ represents a Ci-8 alkylene group (the Ci-8 alkylene group may be substituted with 1 to 3 hydroxyl groups) and R⁶ is a hydrogen or a hydroxyl group.

A preferred embodiment of the compound according to the present invention is as follows^*

where the definitions and preferred embodiment of R⁴ and W² are described above.

The compounds represented by the formula [l] of the present invention have asymmetric carbon at the 2-position of the imidazole group. The compounds of the present invention may be used in racemic form or as a specific enantiomer. As the specific enantiomer, the compounds repre [10] are preferred^'

[10]

where the definitions and preferred forms of Z, R¹, R², R³, R⁴, R⁵, L¹, A¹, L² and W¹ 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 chemotherapy 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.), WileyVCH (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 R^Ia is a leaving group or a hydroxyl group, and the other symbols are as defined above) and a compound represented by the general formula (I-B) (where R^Ib is a protected hydroxyl group or a protected amino group, and the other symbols are as defined above) are reacted in the presence of a base (when R^Ia is a leaving group) or in the Mitsunobu reaction condition (when R^Ia is a hydroxyl group), whereby a compound represented by a general formula (I'C) (where the symbols are as defined above) can be obtained. A deprotection reaction is performed under appropriate conditions in accordance with the type of this protective group, whereupon the target compound represented by the general formula (I-D) (where the symbols are as defined above) can be obtained. heme II'

A compound represented by the general formula (II -A) (where R^IIa is a leaving group, and the other symbols are as defined above) and a compound represented by the general formula (II-B) (where R^IIb is a protecting group for an imidazole group, R^IIc is a protected hydroxyl group or a protected amino group, and the other symbols are as defined above) are reacted in the presence or absence of a base, followed by an appropriate treatment for R^IIb deprotection, whereby a compound represented by a general formula (II -D) (where the symbols are as defined above) can be obtained via an intermediate compound represented by a general formula (II-C) (where the symbols are as defined above). A deprotection reaction is performed under appropriate conditions in accordance with the type of this protective group, whereupon the target compound represented by the general formula (Π ) (where the symbols are as defined above) can be obtained.

Scheme III^:

(IH-A) (lll-B) (lll-C) (lll-D)

A compound represented by the general formula (III-A) (where R^IIIa is a leaving group, R^IIIb is a protected hydroxyl group or a protected amino group, and the other symbols are as defined above) and a boronic acid compound represented by the general formula (ΙΙΓΒ) (where _the_symbols are as defined above) are reacted -in-t-he presence of a catalyst^ in the presence or absence of a base, and in the presence or absence of a ligand, whereby a compound represented by a general formula (III-C) (where the symbols are as defined above) can be obtained. A corresponding boronic ester compound can be used instead of a boronic acid compound represented by the general formula (III-B). A deprotection reaction is performed under appropriate conditions in accordance with the type of this protective group, whereupon the target compound represented by the general formula (III-D) (where the symbols are as defined above) can be obtained.

Scheme IV:

(IV-A) (IV-B) (IV-C) (IV-D)

A compound represented by the general for ula (IV-A) (where R^IVa is a leaving group, R^IVb is a protected hydroxyl group or a protected amino group, and the other symbols are as defined above) and a compound represented by the general formula (I B) (where the symbols are as defined above) are reacted in the presence of a catalyst, in the presence or absence of a base, and in the presence or absence of a ligand, whereby a compound represented by a general formula (IVC) (where the symbols are as defined above) can be obtained. A deprotection reaction is performed under appropriate conditions in accordance with the type of this protective group, whereupon the target compound represented by the general formula (IV-D) (where the symbols are as defined above) can be obtained.

Scheme V

A compound represented by the general formula (V-A) (where R^Va is a protected hydroxyl group or a protected amino group, and the other symbols are as defined above) and a compound represented by the general formula (V-B) (where is a leaving group, and the symbols are as defined above) are reacted in the presence of a catalyst, in the presence or absence of a base, and in the presence or absence of a ligand, whereby a compound represented by a general formula (V-C) (where the symbols are as defined above) can be obtained. A deprotection reaction is performed under appropriate conditions in accordance with the type of this protective group, whereupon the target compound represented by the general formula (V-D) (where the symbols are as defined above) can be obtained.

The compounds represented by the general formulas (III -A), (IV'A) and (V-A) can be obtained, for example, by the methods described in Scheme VI, VII or VIII.

Scheme VI:

(Vl-A) -(VI-BJ (Vl-C)

A compound represented by the general formula (VI -A) (where R^³ is a leaving group or a protected ethynyl group, R™ is a leaving group or a hydroxyl group, and the other symbols are as defined above) and a compound represented by the general formula (VTB) (where ΉΧ¹ is a protected hydroxyl group or a protected amino group, and the other symbols are as defined above) are reacted in the presence of a base (when R^VIb is a leaving group) or in the Mitsunobu reaction condition (when R^VIb is a hydroxyl group), whereby a compound represented by a general formula (VI- C) (where the symbols are as defined above) can be obtained. When RV¹³ is a protected ethynyl group, R^VIa can be transformed to an unprotected ethynyl group by a deprotection reaction under appropriate conditions in accordance with the type of the protective group. Scheme VII:

(Vll-A) (Vll-B) (Vll-C)

A compound represented by the general formula (VII-A) (where R^V"³ is a leaving group or a protected ethynyl group, R^™ is a leaving group, and the other symbols are as defined above) and a compound represented by the general formula (VII-B) (where B¹¹⁰ is a protecting group for an imidazole group, R^VIId is a protected hydroxyl group or a protected amino group, and the other symbols are as defined above) are reacted in the presence or absence of a base, followed by an appropriate R™⁰ deprotection treatment, whereby a compound represented by a general formula (VII-C) (where the symbols are as defined above) can be obtained. When R™³ is a protected ethynyl group,

_{can De} transformed to an unprotected ethynyl group by a deprotection reaction under appropriate conditions in accordance with the type of the protective group. Scheme VIII:

(Vlll-A) (Vlll-B) (Vlll-C)

A compound represented by the general formula _(VIII:A) (where.R^VIIIa is a leaving group or a protected ethynyl group, and the other symbols are as defined above), a compound represented by the general formula (Vffl-B) (where R n^ib is a protected hydroxyl group or a protected amino group) and glyoxal are reacted in the presence of an ammonia source such as ammonia solution or ammonium bicarbonate, whereby a compound represented by a general formula (VlirO (where the symbols are as defined above) can be obtained.

The imidazole compounds represented by the general formulas (I-B), (II-B), CVTB) and (VII- B) can be obtained, for example, by the methods described in Scheme IX or X.

Scheme IX:

(IX-A) (IX-B) (IX-C) (IX-D)

A compound represented by the general formula (IX-A) (where R^IXa is a protected hydroxyl group or a protected amino group) and a compound represented by the general formula (IX - B) (where R³ is as defined above) are reacted in the presence of an ammonia source such as ammonia solution or ammonium bicarbonate, whereby a compound represented by a general formula (ΓΧ-C) (where the symbols are as defined above) can be obtained. The compound represented by the general formula (IX-C) is subjected to a protection reaction under approximate conditions according to the type of the protective group R^IXb, whereby a compound represented by a general formula (IX"D) (where the symbols are as defined above) can be obtained.

reacted in the presence of a condensing agent and in the presence or absence of a base, whereby a compound represented by a general formula (X"C) (where the symbols are as defined above) can be obtained. The compound represented by the general formula (X"C) is subjected to a ring-forming reaction under approximate conditions in the presence of an ammonia source such as ammonia solution or ammonium bicarbonate, whereby a compound represented by a general formula (X-D) (where the symbols are as defined above) can be obtained. The compound represented by the general formula (X-D) is subjected to a protection reaction under approximate conditions according to the type of the protective group R⁵^, whereby a compound represented by a general formula (X-E) (where the symbols are as defined above) can be obtained.

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, NaOH, lithium hydroxide, sodium methoxide, potassium tert-butoxide, sodium hydride, lithium hydride, trie thy lamine, diisopropylethylamine, dimethylaniline, diethylaniline, pyridine, pyrrolidine, and N-methylmorpholine.

Examples of the acid are inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and polyp hosphoric acid, and organic acids such as p-toluenesulfonic acid, methanesulfonic acid, trifluoroacetic acid, formic acid, and acetic acid. Examples of the condensing agent are o-(7-azabenzotriazol-l-yl)-N,N,N',N'- tetramethyluronium hexafiuorophosphate, l-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride, dicyclohexylcarbodiimide, carbonyldiimidazole, 2-chloro-l-methylpyridinium iodide, 4-(4,6-dimethoxy- l,3,5-triazin-2-yl)-4-methylmorpholine chloride, <r(7- azabenzotriazol-l-ylVN.N.N^N'-tetramethyluronium hexafiuorophosphate, and benzotriazol- 1-yl-oxy-tris-pyrrolidino-phosphonium hexafiuorophosphate.

Examples of the activator used in employing the method conducted via an acid chloride or an acid anhydride are thionyl chloride, oxalyl chloride, phosphoryl chloride, acetic anhydride, and chloroformic esters.

Examples of the catalyst are palladium acetate, palladium chloride, bis(triphenylphosphine)palladium(II) dichloride, tetrakis(triphenylphosphine)palladium, bis(acetonitrile)palladium(II) dichloride,, 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(2,6- diisopropylphenyl)imidazolidene)(3-chloropyridyl)palladium(II) dichloride, palladium on carbon, palladium hydroxide, and copper iodide.

Examples of the ligand are trrtert-butylphosphine, tricyclohexylphosphine, triphenylphosphine, tritolylphosphine, tributyl phosphite, tricyclohexyl phosphite, triphenyl phosphite, 1, l'-bis(diphenylphosphino)ferrocene, 2,2'-bis(diphenylphosphino)- 1, l'-binaphthyl, 2-dicyclohexylphosphino-2',6'"dimethoxybiphenyl, 2-dicyclohexylphosphino-2',4',6'- triisopropylbiphenyl, 2-(di-tert-butylphosphino)-2',4',6'-triisopropylbiphenyl, and 2-(drtert- butylphosphino)biphenyl.

Examples of the oxidizing agent are inorganic and organic peroxides such as potassium permanganate, chromium oxide, potassium dichromate, hydrogen peroxide, nv chloroperbenzoic acid, urea hydrogen peroxide adduct/phthalic anhydride, tert-butyl hydroperoxide, and cumene hydroperoxide, selenium dioxide, lead(IV) acetate, tert-butyl hypochlorite, sodium hypochlorite, and l, l,l-triacetoxy- l, l-dihydro-l,2-benziodoxol-3(lH)' one.

Examples of the reducing agent are hydrogenated complex compounds such as lithium aluminum hydride, sodium triacetoxyborohydride, sodium cyanoborohydride, sodium borohydride, lithium borohydride, and diisobutylaluminum hydride, boranes, sodium, and sodium amalgam.

Examples of the metal salt are zinc chloride, zirconium chloride, indium chloride, and magnesium chloride.

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 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, Reference Compounds and Example 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 irradiation.

OH-type silica gel column chromatography's were performed using SNAP Ultra (Biotage) or using REVELERIS 40 μηι (Grace), and amino-type type silica gel chromatography's were performed using SNAPCartridge ISOLUTE Flash-NH₂ (Biotage) or Grace REVELERIS Amino 40 μιη (Grace). Preparative chromatography's were performed using PLC Silica gel 60F254 (Merck), and amino-type preparative chromatography's were 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 μπι, Φ 30 x 50 mm.

Xbridge Prep C18, 5.0 μπι OBD, <Z> 30 x 50 mm.

Waters XSlect CSH 5.0 μπι, Φ 30 x 50 mm.

Eluents: A(H₂0 + 0.1% HCOOH), B(CH₃CN + 0.1% HCOOH).

One of the following conditions was used for purifications:

1. Flow 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), 8.0-9.0 min (A/B = 5/95).

2. Flow 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 Ή NMR are reported in parts per million (ppm). Abbreviations used in the Ή 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 LOMS 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 μιη, 2.1 x 50 mm.

Ionization method: ESI.

Eluents: A(H₂0 + 0.1% HCOOH), B(CH₃CN + 0.1% HCOOH).

Flow rate: 0.8 niL/min.

Detection: 254nm, 2 lOnm 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), 1.08- 1.38 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 μιη, 2.0 x 30 mm.

Ionization method: ESI/APCI (atmospheric pressure chemical ionization) dual source. Eluents: A(H₂0 + 0.1% HCOOH), B(CH₃CN + 0.1% HCOOH).

Flow rate: 0.6 mL/min.

Detection: 254nm or 2 lOnm.

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, Φ 50 x 2.1 mm, 2.5 μηι (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 = 95/5-5/95 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), 1.90-1.95 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: ESI/APCI (electrospray ionization / atmospheric pressure chemical ionization) dual source.

Eluents: 90% CHsOH.

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)20: Drtert-butyl dicarbonate

Bn: Benzyl

Bu: Butyl

BuOAc: n-Butyl acetate

CHC1₃: Chloroform

CS2CO3: Cesium carbonate

Cul: Copper(I) iodide

DEAD: Diethyl azodicarboxylate

Dess-Martin Periodinane: 1,1,1-Triacetoxy- l, 1-dihydro- l,2-benziodoxol"3(lH)-one

DIBAL: Diisobutylaluminum hydride

DIPEA: N,N-diisopropylethylamine

DMAP: NNdimethyl-4-aminopyridine

DME: Dimethoxy ethane

DMF: N,N-dimethylformamide

DMSOd6: Hexadeuterodimethyl sulfoxide

DPPA: Diphenylphosphoryl azide ee: Enantiomeric excess

ESI: Electrospray ionization

Et: Ethyl

EtOAc: Ethyl acetate

EtOH: Ethanol

HATU: 0-(7-azabenzotriazol-l-yl)"N,N,N',N'-tetramethyluronium hexafluorophosphate

HCl: Hydrochloride

HMDS: Hexamethyldisilazane

HOBt · Η20·' l-Hydroxybenzotriazole monohydrate

IPA: Isopropyl alcohol

IPE: Diisopropyl ether

LC: Liquid chromatography

LDA: Lithium diisopropylamide

Me-^" Methyl

Me OH: Methanol

MgSO<i: Magnesium sulfate anhydrous

Ms: Methanesulfonyl

NaBH^Sodium tetrahydroborate

NaBH(OAc)₃-^' Sodium triacetoxyborohydride

NH4CI: Ammonium chloride

NMM: 4-Methylmorphiline

NMP: 1 -Methyl- 2 -pyrrolidone

OTHP: l-Tetrahydropyran-2-yloxy

OTBDPS: Tert-butyldiphenylsilyloxy

OTBS: Tert-butyldimethylsilyloxy

OMs: Methanesulfonyloxy

OTs: 4-Methylbenzenesulfonyloxy

PEPPSI: (1,3 bis(2,6-diisopropylphenyl)imidazolidene)(3-chloropyridyl)palladium(II) dichloride

PdCbCdppf) CH₂CI2: l,l'-bis(diphenylphosphino)ferrocenepalladium(II) chloride dichloromethane complex

PdCl2(CH₃CN)2: Bis(acetonitrile)palladium(II) dichloride

PdCl2(PPh₃)2^: Bis(triphenylphosphine)palladium(II) dichloride

Pd(PPh₃)4: Tetrakis(triphenylphosphine)palladium(0)

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-butyldiphenylsilyl

TBS: Tert-butyldimethylsilyl

TBSCl: tert-Butyldimethylsilyl chloride

TEA: Triethylamine

TEMPO: 2,2,6,6-Tetramethyl- l-piperidinyloxy, free radical, 2,2,6,6-Tetramethylpiperidine 1- oxyl

TFA: Trifluoroacetic acid

THF: Tetrahydrofuran

THP^: Tetrahydropyranyl

TMAD: 3-(Dimethylcarbamoylimino)-l, l"dimethylurea

TMS: Trimethylsilyl

TIPS^'- Triisopropylsilyl

TrCl : Triphenylmethyl chloride

Ts : 4-Methylbenzenesulfonyl

TsCl: 4-Methylbenzenesulfonyl chloride

WSC -HCl: l-Ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride

XPhos: 2-Dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl

Intermediates

Synthesis of Intermediate- 1

l-{l-[3-(4-Chlorophenyl)propyl]- lH-imidazol-2-yl}ethan- l-one

lntermediate-1

Step- 1) l'{l-[3-(4-Chlorophenyl)propyl]- lH-imidazol-2-yl}ethan- l-one (Intermediate'!)

lntermediate-1

To a stirred solution of l-(3-bromopropyl)-4-chlorobenzene (1.5 g) and 2-acetylimidazole (0.87 g) in DMF (15 mL) was added potassium carbonate (3.6 g). The mixture was stirred for 1.5 hours at 70 °C and allowed to cool to room temperature. The reaction was quenched with water and extracted with EtOAc. The organic layer was washed with brine three times and concentrated in vacuo onto ISOLUTE® HM-N. The residue was purified with OH-type silica gel column chromatography (1-20 % MeOH in CHCI3) to give the title compound (Intermediate- 1, 1.6 g, 94 % yield) as light yellow oil.

Ή-NMR, MS and LCMS retention time data of Intermediate- 1 are shown in Table 1. Synthesis of Intermediate - 2

l-[3-(4-Chlorophenyl)propyl]-lH-imidazole-2-carbaldehyde

lntermediate-2

Step- 1)

l-[3-(4-Chlorophenyl)propyl]- lH-imidazole-2-carbaldehyde (Intermediate-2)

lntermediate-2

To a stirred solution of l-(3-bromopropyl)-4-chloro-benzene (0.30 g) and lH-imidazole-2- carbaldehyde (0.15 g) in acetonitrile (6.4 mL) was added potassium carbonate (0.71 g). The mixture was stirred for 1 hour at 80°C and allowed to cool to room temperature. The reaction was quenched with water and extracted with EtOAc. The organic layer was washed with brine and passed through a phase separator and concentrated in vacuo onto ISOLUTE® HM-N. The residue was purified with OH-type silica gel column chromatography (30-70 % EtOAc in n-hexane) to give the title compound (lntermediate-2, 0.31 g, 96 % yield) as yellow oil.

Ή-NMR, MS and LCMS retention time data of Intermediate-2 are shown in Table 1.

Synthesis of Intermediate -3

l-(lH-imidazol-2-yl)ethan-l-ol

lntermediate-3

Step-1)

l-(lH-imidazol-2-yl)ethan-l-ol (Intermediate -3)

lntermediate-3

To an ice ooled solution of l-(lH-imidazol-2-yl)ethanone (2.0 g) in MeOH (36 mL) was added NaBH4 (0.69 g). After stirring for 30 minutes at 0°C, the reaction mixture was concentrated in vacuo. The residue was purified with amino-type silica gel column chromatography (0- 10 % MeOH in CHCb) to give the title compound (lntermediate-3, 1.9g, 96 % yield) as colorless solid.

Ή-NMR data of Intermediate -3 is shown in Table 1. Synthesis of Intermediate -4

l-{l-[(5-Ethynyl- l,2-oxazol-3-yl)methyl]- lH-imidazol-2-yl}ethan-l-ol

lntermediate-4

Step-1)

Ethyl 5-{[tri(propan-2-yl)silyl]ethynyl}- l,2'Oxazole-3-carboxylate

A round bottomed flask was charged with ethyl 5-iodo-l,2-oxazole-3^_carboxylate (18 g), ethynyltri(propan-2-yDsilane (12 g), DMF (52 niL), and TEA (73 mL). The flask was evacuated and backfilled with nitrogen followed by addition of Pd(PPhs)4 (2.4 g) and Cul (0.80 g). After stirring for 1 hour at 80 °C, the mixture was poured into a half-saturated aqueous ammonium chloride and extracted three times with EtOAc-hexane (l:i). The combined organic layer was washed with water, dried over MgS04 and concentrated in vacuo. The residue was purified with OH-type silica gel column chromatography (0-15% EtOAc in n-hexane) to give the title compound (12 g, 69 % yield) as pale yellow oil.

Ή NMR (400 MHz, CHLOROFORM-d) 8 ppm 1.09 - 1.23 (m, 21 H), 1.42 (t, J=7.1 Hz, 3 H), 4.45 (q, J=7.1 Hz, 2 H), 6.81 (s, 1 H).

MS (ESI/APCI) m/z : 322 [M+l]⁺.

MS Condition : F. Step-2)

(5-{[Tri(propan-2-yl)silyl]ethynyl}- l,2-oxazol-3-yl)methanol

To a cooled (0 °C) solution of ethyl 5-{[tri(propan-2-yl)silyl]ethynyl}- l,2-oxazole-3-carboxylate (12 g) in EtOH (60 mL) and THF (120 mL) was added NaBH₄ (3.4 g) in portions, while keeping the internal temperature below 5 °C. After stirring for 4 hours at 0 °C, a half- saturated aqueous ammonium chloride was added to the reaction mixture while keeping the internal temperature below 15 °C. The mixture was concentrated under reduced pressure and the resulting aqueous solution was extracted three times with CHCk. The combined organic layer was washed with brine, dried over MgSOi 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 (8.4 g, 84 % yield) as colorless oil.

MS (ESI) m/z : 280 [M+l]⁺.

RT = 1.078 min.

LCMS condition : C.

Step -3)

(5-{[Tri(propan-2-yl)silyl]ethynyl}- l,2-oxazol-3-yl)methyl 4-methylbenzene- 1- sulfonate

To a solution of (5-{[tri(propan-2-yl)silyl]ethynyl}- l,2-oxazol-3-yl)methanol (2.5 g) in CHC (36 mL) were sequentially added trimethylamine hydrochloride (0.22 g), TEA (1.4 g), and TsCl (2.0 g) at 0 °C. After stirring for 30 minutes, the reaction was quenched with a half saturated aqueous ammonium chloride. The aqueous layer was extracted twice with CHCI3 and the combined organic layer was washed with brine (30 mL), dried over MgS04 and concentrated in vacuo. The residue was purified with OH-type silica gel column chromatography (10-40 % EtOAc in n-hexane) to give the title compound (3.6 g, 93 % yield) as pale yellow oil.

MS (ESI) m/z : 456 [M+23]⁺.

RT = 1.220 min.

LCMS condition : C.

Step -4)

l-{l-[(5-Ethynyl-l,2-oxazol-3-yl)methyl]- lH-imidazol-2-yl}ethan-l-ol (Intermediate-4)

To a solution of (5-{[tri(propan-2-yl)silyl]ethynyl}-l,2-oxazol-3-yl)methyl 4-methylbenzene-l- sulfonate (1.5 g) and l-(lH-imidazol-2-yl)ethan- l-ol (Intermediate-3, 0.43 g) in DMF (17 mL) was added cesium carbonate (2.8 g) at room temperature. After stirring for 10 minutes, the mixture was heated to 60 °C for 1 hour. The mixture was diluted with EtOAc followed by washing with brine. The organic layer was dried over MgSC , filtered and concentrated in vacuo. The residue was purified with OH-type silica gel column chromatography (0"10 % MeOH in CHCb) to give the title compound (Intermediate-4, 0.27 g, 36 % yield) as pale orange solid.

Ή-NMR, MS and LCMS retention time data of Intermediate-4 are shown in Table 1.

Synthesis of Intermediate -5

2 - {( 1 S) - 1 - [(oxan - 2 -yDoxy] ethyl} - 1 H-imidazole

lntermediate-5

Step-1)

2-{(lS)-l-[(oxan-2-yl)oxy]ethyl}-lH-imidazole (Intermediate-5)

lntermediate-5

To a solution of (2S)-2-tetrahydropyran-2-yloxypropanal (36 g) in MeOH (0.77 L) was added 28% aqueous ammonia (92 mL) and 8.8 mol/L glyoxal (78 mL) successively. The mixture was stirred for 16 hours at room temperature and evaporated. The residue was charged onto ISOLUTE® HM-N and purified with OH-type silica gel column chromatography (0-8 % MeOH in CHCI3) to give a crude material (50 g) as brown oil. The crude material (45 g) was dissolved CHCI3 (0.50 L). After addition of an activated carbon (10 g) and amino-type silica gel (0.20 L), the suspension was stirred for 2 hours at room temperature. The mixture was filtered and the filtrate was evaporated. The residue was charged onto ISOLUTE® HM-N and purified with amino-type silica gel column chromatography (50-100 % CHCI3 in n- hexane) to give the title compound (lntermediate-5, 28 g, 63 % yield) as pale pink solid. Ή-NMR, MS and LCMS retention time data of lntermediate-5 are shown in Table 1.

The enantiomeric excess (ee) was identified by the following method.

To a solution of 2-[(lS)- l-tetrahydropyran-2-yloxyethyl]- lH-imidazole (52 mg) in MeOH (1.3 mL) was added 4 mol L HC1 in 1,4-dioxane (0.66 mL) at room temperature and stirred for 3 hours. The^' reaction mixture was evaporated to give (lS)-l-(lH-imidazol-2-yl)ethanol hydrochloride (42 mg, quant., 99.0 % ee) as pale yellowish solid. The chiral analysis was done by following SFC systems.

UPLC : WATERS ACQUITY UPC2. Chiral Column : DAICEL CHIRALCEL OD-H 4.6 x 250 mm.

Mobile phase : MeOH/EtOH/C02 = 3/3/94.

Flow Rate : 3 ml/min.

Temp. : 40 °C.

Time^ io min.

Sample concentration: lmg/mL in MeOH.

The race mic compound (Intermediate-3) has retention time of 4.45 and 5.00 min while the title compound has retention time of 5.00 min.

Synthesis of Intermediate -6_ .

5-Eth nyl-3-[(2-{(lS)-l-[(oxan-2-yDoxy]ethyl}-lH-imidazol-l-yl)methyl]-l,2-oxazole

lntermediate-6

Step-1)

3-[(2-{(lS)-l-[(oxan-2-yl)oxy]ethyl}-lH-imidazol- l-yl)methyl]-5-{[tri(propan-2- yl) silyl] ethy nyl} - 1 , 2 - oxazole

To a cooled (0 °C) solution of (5'{[tri(propan-2-yl)silyl]ethynyl}- l,2-oxazol-3-yl)methanol (8.4 g) and 2-{(lS)- l-[(oxan-2-yl)oxy]ethyl}- lH-imidazole (Intermediate-5, 7.6 g) in THE (0.12 L) were sequentially added TMAD (6.7 g) and tributylphosphine (7.9 g). After 10 minutes with stirring, the mixture was allowed to warm to room temperature and stirred for 4 hours. The mixture was concentrated and the residue was dissolved in EtOAc followed by washing with water and brine. The organic phase was separated, dried over MgS04 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 (12 g, 88 % yield) as pale yellow oil.

MS (ESI) m/z : 458 [M+l]⁺.

RT = 1.096 min.

LCMS condition : B. Step -2) 5-Ethynyl-3-[(2-{(lS)- l-[(oxan-2-yl)oxy]ethyl}- lH-imidazol- l-yl)methyl]- l,2-oxazole

(Intermediate -6)

lntermediate-6 To a cooled (0 °C) solution of 3-[(2-{(lS)- l- [(oxan-2-yDoxy]ethyl}- lH-imidazol- l-yDmethyl]-5- {[tri(propan-2-yl)silyl]ethynyl}- l,2-oxazole (12 g) in THF (0.18 L) was added TBAF (28 mL, 1 mol/L solution in THF) , while the internal temperature below 5 °C. After stirring for 1 hour at 0 °C, the mixture was concentrated and the residue was diluted with EtOAc followed by washing with water and brine. The organic phase was separated, dried over MgS04 and concentrated under reduced pressure. The residue was purified with OH-type silica gel column chromatography (50- 100% EtOAc in n-hexane and then 0- 10 % MeOH in EtOAc) to give the title compound (Intermediate-6, 6.5 g, 82 % yield) as brown oil.

Ή-NMR, MS and LCMS retention time data of Intermediate-6 are shown in Table 1. Synthesis of Intermediate- 7

4-({3-[(2-{(lS)- l-[(oxan-2-yl)oxy]ethyl}- lH-imidazol- l-yl)methyl]- l,2-oxazol-5- yl}eth nyl)phenol

lntermediate-7 Step-1)

Ethyl 5-[(4-{[tert-butyl(diphenyl)silyl]oxy}phenyl)ethynyl]- l,2-oxazole-3-carboxylate

To a solution of ethyl 5-iodoisoxazole-3-carboxylate (3.6 g) and tert"butyl-(4-ethynylphenoxy)- diphenyl-silane (5.3 g) in acetonitrile (67 mL) were added Cul (0.26 g), SUPERSTABLE Pd(0) CATALYST (0.85 g) and TEA (9.3 mL) at room temperature. The reaction mixture was stirred at the same temperature for 30 minutes. 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 (5-20 % EtOAc in n-hexane) to give the title compound (3.9 g, 58 % yield) as yellow oil.

Ή NMR (400 MHz, CHLOROFORM-d) 8 ppm 1.10 (s, 9 H), 1.42 (t, J=7.1 Hz, 3 H), 4.45 (q, J=7.1 Hz, 2 H), 6.73 - 6.80 (m, 3 H), 7.29 - 7.48 (m, 8 H), 7.66 - 7.74 (m, 4 H).

Step -2)

{5-[(4-{[Tert-butyl(diphenyl)silyl]oxy}phenyl)ethynyl]- l,2-oxazol-3-yl}methanol

The title compound was obtained in the manner as with the "Synthesis of Intermediated step-2" using the corresponding materials.

Ή NMR (400 MHz, CHLOROFORM-d) δ ppm 1.10 (s, 9 H), 1.90 - 1.98 (m, 1 H), 4.77 (d, J=6.0 Hz, 2 H), 6.46 (s, 1 H), 6.71 - 6.79 (m, 2 H), 7.27 - 7.47 (m, 8 H), 7.65 - 7.77 (m, 4 H).

Step -3)

{5-[(4-{[Tert-butyl(diphenyl)silyl]oxy}phenyl)ethynyl]-l,2-oxazol-3-yl}methyl 4- methylbenzene- 1-sulfonate

The title compound was obtained in the manner as with the "Synthesis of Intermediated step-3" using the corresponding materials.

Ή NMR (400 MHz, CHLOROFORM-d) 8 ppm 1.10 (s, 9 H), 2.45 (s, 3 H), 5.11 (s, 2 H), 6.41 (s, 1 H), 6.75 (d, J=8.7 Hz, 2 H), 7.27 - 7.48 (m, 10 H), 7.69 (d, J=6.6 Hz, 4 H), 7.80 (d, J=8.2 Hz, 2 H).

Step-4)

4-({3-[(2-{(lS)-l-[(Oxan-2-yl)oxy]ethyl}- lH-imidazol- l-yl)methyl]-l,2-oxazol-5- yl}ethynyl)phenol (Intermediate-7)

To a solution of 2-[(lS)- l-tetrahydropyran-2-yloxyethyl]-lH-imidazole (0.26 g) in DMF (6.6 mL) was added sodium hydride (64 mg) at 0 °C. After stirring for 30 minutes, [5-[2-[4-[tert- butyl(diphenyl)silyl]oxyphenyl]ethynyl]isoxazol"3-yl]methyl 4-methylbenzenesulfonate (0.81 g) in DMF (3 mL) was added. The mixture was allowed to warm to room temperature and stirred for 2 hours. The reaction mixture-was quenched with water and a saturated aqueous ammonium chloride and extracted with EtOAc. The organic extract was concentrated in vacuo. The residue was purified with OH-type silica gel column chromatography (10-100 % EtOAc in n-hexane) to give the title compound (Intermediate-7, 0.41 g, 78 % yield) as colorless powder.

Ή-NMR, MS and LCMS retention time data of Intermediate-7 are shown in Table 1.

Synthesis of Intermediate-8

(5-{[4-(3-{[tert-butyl(dimethyl)silyl]oxy}propoxy)phenyl]ethynyl}- l,2-oxazol-3-yl)methanol

Step-1)

Ethyl 5-((4-(3-hydrox pro oxy)phen l)ethynyl)isoxazole-3-carboxylate

The title compound was obtained in the manner as with the "Synthesis of Intermediate-7: step-1" using the corresponding materials.

MS (ESI) m/z : 338 [M+23]⁺.

RT = 1.042 min.

LCMS condition : B. Step-2)

Ethyl 5-((4-(3-((tert-butyldimethylsilyl)oxy)propoxy)phenyl)ethynyl)isoxazole-3'carboxylate

To a stirred solution of ethyl 5-[2-[4-(3-hydroxypropoxy)phenyl]ethynyl]isoxazole^_3- carboxylate (5.6 g) in DMF (59 mL) were added imidazole (1.8 g) and tert-butyl-chloro- dimethyl-silane (3.4 g). The mixture was stirred for 3 hours at room temperature. The reaction was quenched with water and extracted with 50 % EtOAc in n-hexane twice. The organic layer was washed with brine, dried over MgS04 and concentrated in vacuo onto ISOLUTE® HM-N. The residue was purified with OH-type silica gel column chromatography (4- 15 % EtOAc in n-hexane) to give the title compound (6.7 g, 87 % yield) as colorless oil.

MS. (ESI) m/z : 452 [M+23]⁺.

RT = 1.237 min.

LCMS condition : A.

Step -3)

(5-{[4-(3-{[tert-butyl(dimethyl)silyl]oxy}propoxy)phenyl]ethynyl}-l,2-oxazol-3-yl)methanol (Intermediate-8)

Intermediated was obtained in the manner as with the "Synthesis of Intermediated step-2" using the corresponding materials.

Ή-NMR, MS and LCMS retention time data of Intermediate-8 are shown in Table 1. Synthesis of Intermediate-9

(5-{[4-(3-{[Tert-butyl(dimethyl)silyl]oxy}propyl)phenyl]ethynyl}- l,2-oxazol-3-yl)methanol

Intermediate -9 was obtained in the manner as with the "Synthesis of Intermediate-8" using the corresponding materials.

Ή-NMR, MS and LCMS retention time data of Intermediate-9 are shown in Table 1. Synthesis of Intermediate - 10

2-yl)oxy]ethyl}-lH-imidazol-l-yl)methyl]-l,2-oxazole

lntermediate-10 Step-1)

3-({[Tert-butyl(dimethyl)silyl]oxy}methyl)-5-iodo-l,2-oxazole

To a mixture of (lZ)'2-[tert-butyl(dimethyl)silyl]oxy-N'hydroxy-acetimidoyl chloride (8.3 g) and tributyKethynyDstannane (12 g) was added dropwise TEA (10 mL) in THF (37 mL) at 0 °C. The reaction mixture was stirred at room temperature for 1 hour and quenched with water. The organic layer was washed with brine, dried over MgS04 and concentrated in vacuo. The residue was dissolved in THF (60 mL) and then iodinejll g) in THF (33 mL) was added dropwise at 0°C.The reaction mixture was stirred at room temperature for 40 minutes and quenched with aqueous sodium thiosulfate and saturated aqueous sodium bicarbonate. The bi'layer was separated and the aqueous layer was extracted with EtOAc. The combined organic extracts were washed with brine, dried over MgSC and concentrated in vacuo. The residue was purified with OH-type silica gel column chromatography (l- 15% EtOAc in n- hexane) to give the title compound (5.0 g, 39% yield) as light yellow oil.

MS (ESI) m/z : 340 [M+l]⁺.

RT = 0.968 min.

LCMS condition : C.

Step-2) (5-Iodo-l,2-oxazol-3-yl)methanol

To a solution of 3-({[tert-butyl(dimethyl)silyl]oxy}methyl)-5-iodo- l,2-oxazole (2.2 g) in THF (22 mL) was added 1 mol/L aqueous HC1 (2.2 mL). After stirring for 7 hours at room temperature, the reaction mixture was quenched with I mol/L aqueous NaOH and extracted with CHCI3. The organic layer was passed through a phase separator and concentrated in vacuo. The residue was purified with OH'type silica gel column chromatography (20-30% EtOAc in n'hexane) to give the title compound (0.49 g, 34% yield) as colorless solid.

MS (ESI) m/z : 226 [M+l]⁺.

RT = 0.496 min.

LCMS condition : B.

Step -3)

5-Iodo-3-[(2-{(lS)- l-[(oxan-2-yl)oxy]ethyl}- lH-imidazol- l-yl)methyl]- l,2-oxazole

lntermediate-10

To a mixture of (5-iodo-l,2-oxazol-3-yl)methanol (0,84 g), 2-{(lS)- l-[(oxan-2-yl)oxy]ethyl}-lH- imidazole (0.95 g) and TMAD (0.84 g) in THF (15 mL) was added Tributylphosphine (1.2 mL) at room temperature. The reaction mixture was stirred at the same temperature for 4 hours, then diluted with EtOAc, quenched with water and separated. The organic extract was washed with brine, dried over MgS04 and concentrated in vacuo. The residue was purified with OH'type silica gel column chromatography (15- 100% EtOAc in n-hexane) to give the title compound (0.70 g, 46% yield) as pale brown oil.

Ή-NMR, MS and LCMS retention time data of Intermediate- 10 are shown in Table 1.

Synthesis of Intermediate- 11

3-({2-[(lS)- l-{[tert-butyl(dimethyl)silyl]oxy}ethyl]-lH-imidazol- l-yl}methyl)-5-iodo-l,2- oxazole

lntermediate-1 1

Step-1)

lS)-l-{l-[(5-iodo- l,2-oxazol-3-yDmethyl]-lH-imidazol-2-yl}etha

To a solution of Intermediate- 10 (1.4 g) in MeOH (11 mL) was added p-TsOH monohydrate (0.98 g) at room temperature. The reaction mixture was stirred at the same temperature for 3 hours and concentrated in vacuo. The residue was purified with NH-type silica gel column chromatography (0-10% MeOH in CHCI3) to give the title compound (0.94 g, 85% yield) as pale yellow solid.

MS (ESI) m/z : 320 [M+l]⁺.

RT = 0.221 min.

LCMS condition : A. Step-2)

3-({2-[(lS)-l-{[tert-butyl(dimethyl)silyl]oxy}ethyl]-lH-imidazol-l-yl}methyl)-5-iodo-l,2- oxazole

(Intermediate- 11)

To a solution of (lS)-l-{l-[(5-iodo- l,2-oxazol-3-yl)methyl]- lH-imidazol-2-yl}ethan-l-ol (0.94 g) in DMF (15 mL) were added imidazole (0.60 g) and TBSC1 (0.89 g) at room temperature. The reaction mixture was stirred at the same temperature for 20 hours and then quenched with saturated aqueous sodium bicarbonate and extracted with EtOAc. The aqueous layer was extracted with EtOAc. The combined organic extracts were washed with brine, dried over MgS04 and concentrated in vacuo. The residue was purified with NH-type silica gel column chromatography (7-60% EtOAc in n-hexane) and OH'type silica gel column chromatography (5-60% EtOAc in n-hexane) to give the title compound (1.2 g, 96% yield) as pale yellow oil. Ή-NMR, MS and LCMS retention time data of Intermediate- 11 are shown in Table 1.

Synthesis of Intermediate- 12

azol-3-yl)methyl]- lH-imidazol-2-yl}ethyl acetate

lntermediate-12

Step-1)

(lS)- l-{l-[(5-ethynyl-l,2-oxazol-3-yl)meth l]- lH-imidazol-2-yl}ethan- l-ol

To a solution of Intermediate-6 (0.89 g) in MeOH (10 niL) was added p-TsOH monohydrate (0.84 g) at room temperature. The reaction mixture was stirred at the same temperature for 1.5 hours and concentrated in vacuo. The residue was purified with NH-type silica gel column chromatography (0-10% MeOH in CHCI3) to give the title compound (0.59 g, 92% yield) as colorless solid.

MS (ESI) m/z : 218 [M+l]⁺.

RT = 0.221 min.

LCMS condition : A.

Step -2)

( 1 S) - 1 - { 1 - [(5 - ethy nyl; 1,2- oxazol - 3 -y 1) .me thyll; lH-imidazol-.2:yl}ethyl acetate

Intermediate- 12)

lntermediate-12

To a solution of - (lS)- l-{l-[(5-ethynyl- l,2-oxazol-3-yl)methyl]-lH-imidazol-2-yl}ethan-l-ol (0.59 g) in THF (9.1 mL) were added TEA (0.95 mL) and acetic anhydride (0.38 mL) at 0 °C. The reaction mixture was stirred at room temperature for 14 hours. After cooling, CHCI3 and saturated aqueous sodium bicarbonate were added. The bi-layer was separated and the aqueous layer was extracted with CHCI3. The combined organic extracts were passed through a phase separator and concentrated in vacuo. The residue was purified with NH- type silica gel column chromatography (22-100% EtOAc in n-hexane) to give the title compound (0.67 g, 95% yield) as pale beige solid.

Ή-NMR, MS and LCMS retention time data of Intermediate- 12 are shown in Table 1. Synthesis of Intermediate- 13

3-({2-[(lS)-l-{[tert-butyl(dimethyl)silyl]oxy}ethyl]-lH-imidazol l-yl}methyl)-5-[(4- iodophenyOethynyl] - 1 , 2 -oxazole

Step-1)

Ethyl 5-[(trimethylsilyl)ethyn l]- l,2-oxazole-3-carboxylate

A round bottomed flask was charged with ethyl 5-iodoisoxazole-3-carboxylate (4.7 g), Pd(PPh₃)₄ (0.62 g), Cul (0.20 g), TEA (18 mL) and THF (5.9 mL). The flask was evacuated and backfilled with nitrogen followed by addition of ethynyl(trimethyl)silane (7.4 mL). After stirring for 2 hours at room temperature, the reaction mixture was filtered through a pad of Celite® and NH-type silica gel, and concentrated in vacuo. The residue was-charged onto ISOLUTE® HM-N and purified by OH-type silica gel column chromatography (0-10 % EtOAc in /rhexane) to give the title compound (2.6 g, 63% yield) as pale yellow oil.

MS (ESI) m/z : 238 [M+l]⁺, 260 [M+23]⁺.

RT = 0.965 min.

LCMS condition : C.

Step-2)

(5-Ethynyl-l,2-oxazol-3-yl)methanol

To an ice-cooled solution of ethyl 5-(2-trimethylsilylethynyl)isoxazole-3-carboxylate (2.6 g) in EtOH (18 niL) and THF (36 mL) was added NaBH₄ (0.82 g). The mixture was allowed to warm to room temperature and stirred overnight. The reaction was quenched with a saturated aqueous ammonium chloride and water and then extracted with EtOAc three times. The organic layer was dried over MgSO-i, filtered, and concentrated in vacuo. The -residue was purified with ΘΗ-type silica gel column chromatography (25-45 % EtOAc in /r hexane) to give the title compound (0.65mg, 49% yield) as pale yellow oil.

MS (ESI) m/z : 124 [M+l]⁺.

RT = 0.692 min.

LCMS condition : A.

Step -3)

{5- [(4-Iodophenyl)ethynyl]- l,2-oxazol-3-yl}methanol

A round bottomed flask was charged with 1,4-diiodobenzene (3.8 g), Pd(PPh3)4 (0.22 g), Cul (0.073 g). The flask was evacuated and backfilled with nitrogen followed by addition of TEA (39 mL) and a solution of (5-ethynylisoxazol-3-yl)methanol (0.48 g) in acetonitrile (3.9 mL). After stirring for 1 hour at room temperature, a saturated aqueous sodium bicarbonate was added to the reaction mixture. The whole mixture was extracted with CHCI3 and the organic layer was passed through a phase separator and concentrated in vacuo. The residue was charged onto ISOLUTE® HM-N and purified by OH-type silica gel column chromatography (IO-5O % EtOAc in /j-hexane) to give the title compound (0.76 g, 60% yield) as pale yellow solid.

MS (ESI) m/z : 326 [M+l]⁺.

RT = 0.958 min.

LCMS condition : B.

Step-4)

5-[(4-Iodophenyl)ethynyl]-3- [(2-{(lS)- l- [(oxan-2-yl)oxy]ethyl}- lH-imidazol- l-yl)methyl] oxazole

The title compound was obtained in the manner as with the "Synthesis of Intermediate- 10: step-3" using the corresponding materials.

MS (ESI) m/z : 504 [M+l]⁺, 526 [M+23]⁺.

RT = 0.856 min.

LCMS condition : B. Step-5)

3-({2-[(lS)-l-{[tert-butyl(dimethyl)silyl]oxy}ethyl]- lH-imidazol- l-yl}methyl)-5-[(4- iodophenyl)ethynyl]- 1,2-oxazole

Intermediate- 13 was obtained in the manner as with the "Synthesis of Intermediate- 11 step-1 and step-2" using the corresponding materials.

Ή-NMR, MS and LCMS retention time data of Intermediate- 13 are shown in Table 1. Synthesis of Intermediate- 14

(5-{[4-(3-{[Tert-butyl(dimethyl)silyl]oxy}propoxy)phenyl]ethynyl}- l,2-oxazol-3-yl)methyl 4 methylbenzene- 1-sulfonate

Step- 1)

(5-{[4-(3-{[Tert-butyl(dimethyl)silyl]oxy}propoxy)phenyl]ethynyl}-l,2-oxazol-3-yl)methyl methylbenzene- 1-sulfonate

The title compound was obtained in the manner as with the "Synthesis of Intermediate-4: step -3" using the corresponding materials.

Ή-NMR, MS and LCMS retention time data of Intermediate- 14 are shown in Table 1.

Synthesis of Intermediate- 15

Tert-butyl[3-(4-ethynylphenoxy)propoxy]dimethylsilane

lntermediate-15

Step-l)

To a solution of tert-butyl-[3-(4-iodophenoxy)propoxy]-dimethyl-silane (3.0 g) in DMF (7.7 mL) were sequentially added TEA (11 mL), PdCl₂(PPh₃)2 (0.22 g), and Cul (0.12 g). After stirring for 1 hour at room temperature, the reaction mixture was poured into water and extracted with EtOAc. The organic layer was washed with water, dried over MgSC , and concentrated in vacuo. The residue was purified by OH-type silica gel column chromatography (0-20 % EtOAc in /rhexane) to give the title compound (1.6 g, 56 % yield) as pale brown oil.

Ή NMR (600 MHz, CHLOROFORM-d) δ ppm 0.03 (s, 6 H), 0.23 (s, 9 H), 0.88 (s, 9 H), 1.93 - 2.01 (m, 2 H), 2.05 (s, 2 H), 3.79 (t, J=6.0 Hz, 2 H), 6.81 (d, J=8.7 Hz, 2 H), 7.39 (d, J=8.7 Hz, 2 H). Step -2)

Tert-butyl[3-(4-ethynylphenoxy)propoxy]dimethylsilane

(Intermediate- 15)

lntermediate-15

To a solution of tert-butyl(dimethyl)(3-{4-[(trimethylsilyl)ethynyl]phenoxy}propoxy)silane (1.5 g) in MeOH (14 mL) was added potassium carbonate (0.057 g). After stirring for 3 hours at room temperature, the reaction mixture was concentrated and the residue was purified by OH-type silica gel column chromatography (5-50 % EtOAc in /rhexane) to give the title compound (l.l g, 89 % yield) as colorless oil.

Ή-NMR, MS and LCMS retention time data of Intermediate- 15 are shown in Table 1. Synthesis of Intermediate -16

l-(3-{[Tert-butyl(dimethyl)silyl]oxy}propyl)-3-(4-iodophenoxy)azetidine

Intermediate- 16

Step-l)

l-(3"{[Tert-butyl(dimethyl)silyl]oxy}propyl)-3-(4-iodophenoxy)azetidine

lntermediate-16

A microwave vial was charged with 3-(4-iodophenoxy)azetidine (l.0-g), DIPEA (0.82 mL) and acetonitrile (12 mL). The vial was sealed with a Teflon® cap and the mixture was irradiated in a microwave reactor at 110 °C for 30 minutes. The mixture was diluted with chloroform followed by washing with water and brine. The organic layer was dried over MgS04, filtered, and concentrated in vacuo. The residue was purified by OH-type silica gel column chromatography (0Ί0 % MeOH in CHCI3) to give the title compound (2.4 g, 74 % yield) as pale yellow oil.

Ή-NMR, MS and LCMS retention time data of Intermediate- 16 are shown in Table 1. Synthesis of Intermediate- 17

l-(3-{[Tert-butyl(dimethyl)silyl]oxy}propyl)-3-(4-ethynylphenoxy)azetidine

lntermediate-17

Step-l)

-(3-{[Tert-butyl(dimethyl)silyl]oxy}propyl)-3-{4-[(trimethylsilyl)ethynyl]phenoxy}azetidi^^

To a solution of tert-butyl-[3-[3-(4-iodophenoxy)azetidin l-yl]propoxy]'dimethyl-silane (1.2 g) and trimethylsilylacetylerte (0.53 mL) in THF (8.9, mL) were added TEA (7.5 mL), bis(triphenylphosphine)palladium(II) dichloride (94 mg) and Cul (26 mg) at room temperature. The reaction mixture was stirred at the same temperature for 30 minutes. The insoluble matter was removed by filtration through Celite® and washed with EtOAc. The filtrate was concentrated in vacuo. To this obtained residvie were added staturated aqueous sodium bicarbonate and EtOAc. The layers were separated and the aqueous layer was extracted with EtOAc. The combined organic layer was dried over Na2S04 and concentrated in vacuo. The residue was purified with OH'type silica gel column chromatography (20- 100 % EtOAc in n-hexane) to give the title compound (1.0 g, 89 % yield) as yellow oil.

MS (ESI) m/z : 418 [M+l]⁺.

RT = 1.013 min.

LCMS condition : B. Step -2)

l-(3-{[Tert-butyl(dimethyl)silyl]oxy}propyl)-3'(4-ethynylphenoxy)azetidine

(Intermediate- 17)

lntermediate-17

To a solution of l-(3-{[tert-butyl(dimethyl)silyl]oxy}propyl)-3-{4-

[(trimethylsilyl)ethynyl]phenoxy}azetidine (1.0 g) in MeOH (12 mL) was added potassium carbonate (0.50 g) at room temperature and stirred at the same temperature for 1 hour. The reaction mixture was added water and CHCb. The layers were separated and the aqueous layer was extracted with CHCI3. The organic extract was passed through a phase separator and concentrated in vacuo. The residue was purified with OH-type silica gel column chromatography (5"30 % EtOAc in n-hexane) to give the title compound (0.46 g, 55 % yield) as white powder.

Ή-NMR, MS and LCMS retention time data of Intermediate- 17 are shown in Table 1.

Table 1. Intermediate Compounds (Intermediate- 1 to 17). ID, chemical structures, Ή-NMR data, MS data, LCMS retention time (minute) data and LCMS(MS) conditions are shown. I-

1 to I- 17 corresponds to Intermediate- 1 to Intermediate- 17, respectively.

ND : not determined.

Reference Compounds

Synthesis of Reference Compound-Rl

l-(3-(4-Chloro henyl)propyl)-2-(l-methoxyethyl)-lH"imidazole

Reference Compound-R1

Step-1)

-(3-(4"Chloro henyl)propyl)-2-(l-methoxyethyl)- IH-imidazole (Reference Compound-Rl)

Reference Compound-R1

To an ice-cooled solution of l-(l-(3-(4-chlorophenyl)propyl)-lH-imidazol-2-yl)ethanol (Compound-2, 0.22 g) in DMF (6 mL) was added sodium hydride (59 mg). After 5 minutes with stirring, methyl iodide (56 μΌ was added. The mixture was allowed to warm to room temperature and stirred for 1 hour. The reaction was quenched with a saturated aqueous sodium bicarbonate and extracted with EtOAc. The organic layer was washed with brine three times and concentrated in vacuo onto ISOLUTE® HM-N. The residue was purified with OH-type silica gel column chromatography (1-7 % MeOH in CHCI3) to give the title compound (67 mg, 29 % yield) as light yellow oil. Ή-NMR, MS and LCMS retention time data of Reference Comopund-Rl are shown in Table 2A.

Synthesis of Reference Compound-R12

{l-[3-(4-Chlorophenyl)propyl]-lH-imidazol-2-yl}methanol

Reference Compound-R12

Step-l)

{l-[3-(4-Chlorophenyl)propyl]-lH-imidazol-2-yl}methanol (Reference Compound-R12)

To a stirred solution of ethyl l-(3-(4-chlorophenyl)propyl)-lH-imidazole-2-carboxylate (0.28 g) in THF (5 mL) was added L1BH4 (23 mg). The mixture was stirred under nitrogen atmosphere at room temperature for 1 day. The reaction was quenched with a saturated aqueous sodium bicarbonate and extracted with CHCI3. The organic layer was passed through a phase separator and concentrated in vacuo. The residue was purified with prep- HPLC to obtain pale brown syrup (0.23 g). The crude product was dissolved in EtOAc and the solution was washed with brine three times and concentrated in vacuo to give the title compound (0.15 g, 64 % yield) as pale brown syrup.

Ή-NMR, MS and LCMS retention time data of Reference Comopund-R12 are shown in Table 2A.

Table 2A. Reference Compound List (Rl - R15). Reference compound ID, chemical structures, Ή-NMR data, MS data and LCMS retention time (minute) data are shown.

Retention

ID Structure Ή-NMR MS time (min)

(Condition)

Ή NMR (600 MHz, CHLOROFORM-d)

8 ppm 1.58 (d, J=6.7 Hz, 3 H), 2.09

(quin, J=7.7 Hz, 2 H), 2.64 (t, J=7.7 Hz, MS (ESI) m/z : 0.959

Rl

2 H), 3.21 (s, 3 H), 3.98 - 4.09 (m, 2 H), 279 [M+l]⁺ (B) 4.60 (q, J=6.7 Hz, 1 H), 6.89 (d, J=1.2

Hz, 1 H), 6.98 (d, J=1.2 Hz, 1 H), 7.11 (d,

Table 2B. List of Reference Compounds (R16-R70). Reference Compound ID, chemical structures, MS data, LCMS retention time (minutes) data and LCMS (MS) condition are shown.

Retention

ID Structure MS time Conditions

(minutes)

ND: not determined.

Ή-NHR of the reference compounds without LCMS data are follows:

R16: Ή NMR (400 MHz, CHLOROFORM-d) δ ppm 1.25 - 1.30 (m, 3 H), 2.07 - 2.19 (m, 2 H), 2.59 - 2.67 (m, 2 H), 3.62 (br s, 1 H), 3.93 - 4.07 (m, 2 H), 4.22 - 4.39 (m, 2 H), 5.22 (s, 1 H), 6.89 (d, J=1.0 Hz, 1 H), 7.01 (d, J=1.0 Hz, 1 H), 7.10 (d, J=8.3 Hz, 2 H), 7.24 - 7.30 (m, 2 H). R17: Ή NMR (400 MHz, DMSO"d6) δ ppm 2.02 - 2.14 (m, 2 H), 2.61 - 2.70 (m, 2 H), 4.28 (t, J=7.5 Hz, 2 H), 4.45 (s, 2 H), 7.25 - 7.30 (m, 2 H), 7.33 - 7.38 (m, 2 H), 7.71 (d, J=1.8 Hz, 1 H), 7.79 (d, J=1.8 Hz, 1 H), 9.07 (br s, 2 H).

R22: Ή NMR (400 MHz, CHLOROFORM-d) 8 ppm 1.50 (d, J=6.5 Hz, 1.5 H), 1.61 (br d, J=6.5 Hz, 1.5 H), 1.80 - 1.85 (m, 3 H), 4.80 (q, J=6.5 Hz, 0.5 H), 4.92 (q, J=6.5 Hz, 0.5 H), 5.59 - 5.73 (m, 1 H), 6.95 (s, 0.5 H), 7.01 (s, 0.5 H), 7.03 - 7.06 (m, 1 H), 7.06 - 7.10 (m, 1 H), 7.14 - 7.19 (m, 1 H), 7.27 - 7.36 (m, 3 H).

R23: Ή NMR (400 MHz, CHLOROFORM-d) δ ppm 1.60 (d, J=6.5 Hz, 3 H), 2.29 (s, 3 H), 4.88 (q, J=6.5 Hz, 1 H), 5.12 - 5.26 (m, 2 H), 6.73 (d, J=l. l Hz, 1 H), 6.75 - 6.80 (m, 1 H), 7.00 (d, J=l. l Hz, 1 H), 7.13 - 7.25 (m, 3 H).

R24: Ή NMR (400 MHz, CHLOROFORM-d) δ ppm 1.58 (d, J=6.5 Hz, 3 H), 2.32 (s, 3 H), 4.88 (q, J=6.5 Hz, 1 H), 5.11 - 5.24 (m, 2 H), 6.85 (s, 1 H), 6.88 - 6.94 (m, 2 H), 7.00 (s, 1 H), 7.09 - 7.14 (m, 1 H), 7.20 - 7.25 (m, 1 H).

R25: Ή NMR (400 MHz, CHLOROFORM-d) δ ppm 1.67 (d, J=6.5 Hz, 3 H), 3.16 - 3.29 (m, 4 H), 3.68 (br s, 2 H), 3.81 (br s, 2 H), 4.85 - 5.03 (m, 3 H), 6.86 (d, J=l. l Hz, 1 H), 6.90 - 6.97 (m, 3 H), 7.02 (d, J=l. l Hz, 1 H), 7.27 - 7.33 (m, 2 H).

R34: Ή NMR (400 MHz, DMSO-d6) δ ppm 1.42 (d, J=6.5 Hz, 3 H), 4.82 (q, J=6.5 Hz, 1 H), 5.06 - 5.30 (m, 3 H), 6.70 - 6.80 (m, 3 H), 6.82 - 6.86 (m, 1 H), 7.00 (d, J=1.2 Hz, 1 H), 7.07 - 7.14 (m, 1 H), 9.76 (br s, 1 H).

R45: Ή NMR (400 MHz, DMSO-d6) δ ppm 1.45 (d, J=6.4 Hz, 3 H), 4.79 (q, J=6.4 Hz, 0.5 H), 4.93 (q, J=6.4 Hz, 0.5 H), 6.35 (br s, 0.5 H), 6.40 (br s, 0.5 H), 6.71 - 6.78 (m, 1 H), 6.90 (s, 0.5 H), 6.99 (s, 0.5 H), 7.33 - 7.43 (m, 5 H).

R46: Ή NMR (400 MHz, CHLOROFORM-d) δ ppm 1.64 (d, J=6.5 Hz, 1.5 H), 1.68 (d, J=6.5 Hz, 1.5 H), 2.83 - 2.90 (m, 3 H), 4.91 - 5.00 (m, 1 H), 5.81 (br s, 0.5 H), 5.95 (br s, 0.5 H), 6.23 (s, 0.5 H), 6.35 (s, 0.5 H), 6.81 (d, J=1.3 Hz, 0.5 H), 6.93 - 6.99 (m, 1.5 H), 7.24 - 7.31 (m, 1 H), 7.31 - 7.35 (m, 1 H), 7.36 - 7.43 (m, 3 H).

R47:ⁱH NMR (400 MHz, CHLOROFORM-d) δ ppm 1.60 (d, J=6.5 Hz, 3 H), 2.04 - 2.15 (m, 2 H), 2.63 (t, J=7.6 Hz, 2 H), 3.85 - 4.00 (m, 2 H), 4.56 (s, 2 H), 4.81 (q, J=6.6 Hz, 1 H), 6.80 (s, 1 H), 7.07 - 7.12 (m, 2 H), 7.26 - 7.29 (m, 2 H).

R49: Ή NMR (400 MHz, DMSO"d6) 8 ppm 1.44 (d, J=6.5 Hz, 3 H), 2.18 (s, 3 H), 4.83 (q, J=6.5 Hz, 1 H), 5.12 - 5.19 (m, 1 H), 5.25 - 5.32 (m, 1 H), 6.62 - 6.66 (m, 1 H), 6.67 - 6.72 (m, 1 H), 6.77 (d, J=1.0 Hz, 1 H), 6.97 (d, J=1.0 Hz, 1 H), 7.00 - 7.05 (m, 1 H).

R50: Ή NMR (400 MHz, DMSOd6) 8 ppm 1.43 (d, J=6.5 Hz, 3 H), 2.12 (s, 3 H), 4.83 (q, J=6.5 Hz, 1 H), 5.02^■ 5.08 (m, 1 H), 5.19 - 5.26 (m, 1 H), 6.63 (d, J=1.8 Hz, 1 H), 6.73 (d, J=8.2 Hz, 1 H), 6.76 (d, J=l. l Hz, 1 H), 6.90 (dd, J=8.2, 1.8 Hz, 1 H), 6.98 (d, J=l. l Hz, 1 H). R5 i: Ή NMR (400 MHz, CHLOROFORM-d) 8 ppm 1.52 (d, J=6.6 Hz, 3 H), 3.68 (s, 3 H), 4.81 (q, J=6.6 Hz, 1 H), 5.22^■ 5.33 (m, 2 H), 6.16 (d, J=1.5 Hz, 1 H), 6.82 (d, J=l. l Hz, 1 H), 6.88 (d, J=l. l Hz, 1 H), 7.36 - 7.39 (m, 1 H), 7.40 (d, J=2.0 Hz, 1 H), 7.49 (t, J=7.4 Hz, 1 H), 7.72 (br s, 1 H), 7.87 (d, J=7.4 Hz, 1 H), 8.68 (br s, 1 H).

R52: Ή NMR (400 MHz, DMSOd6) 8 ppm 1.42 (d, J=6.5 Hz, 3 H), 2.39^■ 2.43 (m, 3 H), 4.72^■ 4.79 (m, 1 H), 5.33 (d, J=6.1 Hz, 1 H), 5.38 (s, 2 H), 6.74 (s, I H), 6.83 (d, J=1.0 Hz, 1 H), 7.11 (d, J=l. l Hz, 1 H), 7.28 (d, J=8.3 Hz, 2 H), 7.97 (d, J=8.3 Hz, 2 H), 11.25 (s, 1 H).

R53: Ή NMR (400 MHz, CHLOROFORM-d) 8 ppm 1.57 (d, J=6.5 Hz, 3 H), 2.57 (br s, 1 H), 3.92 (s, 3 H), 4.84 (q, J=6.5 Hz, 1 H), 5.59^■ 5.72 (m, 2 H), 6.70 (d, J=7.7 Hz, 1 H), 6.80 (d, J=l. l Hz, 1 H), 7.04 (d, J=l. l Hz, 1 H), 7.34 - 7.41 (m, 1 H), 7.44 - 7.49 (m, 1 H), 8.05 (dd, J=7.7, 1.3 Hz, 1 H).

R54:ⁱH NMR (400 MHz, CHLOROFORM-d) 8 ppm 1.60 (d, J=6.5 Hz, 3 H), 2.52 (br s, 1 H), 3.91 (s, 3 H), 4.88 (q, J=6.5 Hz, 1 H), 5.22 - 5.35 (m, 2 H), 6.85 (d, J=l. l Hz, 1 H), 7.01 (d, J=l. l Hz, 1 H), 7.24 - 7.31 (m, 1 H), 7.43 (t, J=7.7 Hz, 1 H), 7.85 (s, 1 H), 7.98 (d, J=7.7 Hz, 1 H).

R55: Ή NMR (400 MHz, CHLOROFORM-d) 8 ppm 1.58 (d, J=6.5 Hz, 3 H), 4.17 - 4.31 (m, 2 H), 4.87 (q, J=6.5 Hz, 0.5 H), 4.98 (q, J=6.5 Hz, 0.5 H), 5.64 - 5.70 (m, 0.5 H), 5.75 - 5.81 (m, 0.5 H), 6.98 (d, J=l. l Hz, 0.5 H), 6.99 (d, J=l. l Hz, 0.5 H), 7.05 (d, J=l. l Hz, 0.5 H), 7.09 (d, J=l. l Hz, 0.5 H), 7.16 - 7.19 (m, 1 H), 7.20 - 7.24 (m, 1 H), 7.31 - 7.40 (m, 3 H).

R56: Ή NMR (400 MHz, CHLOROFORM-d) 8 ppm 1.60 (d, J=6.5 Hz, 3 H), 4.63 (s, 2 H), 4.88 (q, J=6.5 Hz, 1 H), 5.33 - 5.46 (m, 2 H), 6.76 (d, J=l. l Hz, 1 H), 6.91 - 6.96 (m, 1 H), 6.97 (d, J=l. l Hz, 1 H), 7.28 - 7.39 (m, 3 H).

R57: Ή NMR (400 MHz, CHLOROFORM-d) 8 ppm 1.57 (d, J=6.5 Hz, 3 H), 4.67 (s, 2 H), 4.86 (q, J=6.5 Hz, 1 H), 5.16 - 5.30 (m, 2 H), 6.85 (d, J=l. l Hz, 1 H), 6.98 (d, J=l. l Hz, 1 H), 7.03 (d, J=7.3 Hz, 1 H), 7.14 (s, 1 H), 7.28 - 7.36 (m, 2 H).

R58: Ή NMR (400 MHz, DMSO-d6) 8 ppm 1.39 (d, J=6.5 Hz, 3 H), 4.66 (q, J=6.5 Hz, 1 H), 5.27 (br s, 1 H), 5.57 - 5.65 (m, 1 H), 5.71 - 5.78 (m, 1 H), 6.55 (d, J=7.8 Hz, 1 H), 6.86 (d, J=1.0 Hz, 1 H), 7.05 (d, J=1.0 Hz, 1 H), 7.35 - 7.42 (m, 1 H), 7.46 - 7.52 (m, 1 H), 7.94 (dd, J=7.8, 1.3 Hz, 1 H), 13.30 (br s, 1 H).

R60: Ή NMR (400 MHz, DMSO-d6) 8 ppm 1.41 (d, J=6.5 Hz, 3 H), 4.75 (quin, J=6.5 Hz, 1 H), 5.32 - 5.40 (m, 3 H), 6.82 (d, J=l. l Hz, 1 H), 7.10 (d, J=l. l Hz, 1 H), 7.40 - 7.51 (m, 2 H), 7.75 (s, 1 H), 7.85 (d, J=7.5 Hz, 1 H), 12.96 (br s, 1 H). Chemical names of the Reference Compounds in Table-2A and Table-2B are follows.

Rl : l-(3-(4-Chlorophenyl)propyl)-2-(l-methoxyethyl)-lH"imidazole

R2 : l-{l-[(3-iodophenyl)methyl]-lH-imidazol-2-yl}ethan-l-ol

R3 : 2-(l-(3-(4-Chlorophenyl)propyl)- lH-imidazol-2-yl)propan-2-ol

R4 : l-{l-[3-(4-Chlorophenyl)propyl]-4-methyl-lH-imidazol-2-yl}ethan-l-ol

R5 : l-(3-(4-Chlorophenyl)propyl)-2-ethyl-lH-imidazole

R6 : l-(3-(4-Chlorophenyl)propyl)-2-isopropyl-lH-imidazole

R7 : l-[l-(3-Phenylpropyl)-lH-imidazol-2-yl]ethan-l-ol

R8 : l-(4-Methyl- l-((5-phenylisoxazol-3-yl)methyl)- lH-imidazol-2-yl)ethanol

R9 : l-(l-(3-(4-chlorophenyl)propyl)-lH-imidazol-2-yl)ethane-l,2-diol

RIO '· l-(3-(4-chlorophenyl)propyl)-2-(l-fluoroethyl)- lH-imidazole

Rll : l-(3-(4-chlorophenyl)propyl)-2-(l, 1-difluoroethyl)- lH-imidazole

R12 : {l-[3-(4-Chlorophenyl)propyl]-lH-imidazol-2-yl}methanol

R13 : 4-{[3-({2-[(lS)-l-hydroxyethyl]-lH-imidazol-l-yl}methyl)-l,2-oxazol-5-yl]ethynyl}-l-(3- hydroxypropyl)pyridin-2(lH)-one

R14 : 4-{[3-({2-[(lS)-l-hydroxyethyl]-lH-imidazol-l-yl}methyl)-l,2-oxazol-5- yl] ethy ny l}pyridin- 2 ( 1H) -one

R15 : (lS)-l-[l-({5-[(l-{[(3S)-oxolan-3-yl]amino}-2,3-dihydro-lH-inden-5-yl)ethynyl]-l,2- oxazol-3-yl}methyl)- lH-imidazol-2-yl]ethan- l-ol

R16 : ethyl {l-[3-(4-chlorophenyl)propyl]-lH-imidazol-2-yl}(hydroxy)acetate

R17 : l-{l-[3-(4-chlorophenyl)propyl]-lH-imidazol-2-yl}methanamine--hydrogen chloride (1/2)

R18 : l-{l-[(4-iodophenyl)methyl]-lH-imidazol-2-yl}ethan-l-ol

R19 : ethyl amino{l-[3-(4-chlorophenyl)propyl]-lH-imidazol-2-yl}acetate

R20 : [2-(l-hydroxyethyl)-lH-imidazol"l-yl](4-iodophenyl)methanone

R21 : 2-[2-(l-hydroxyethyl)-lH-imidazol-l-yl]-N-phenylacetamide

R22 : l-[l-(l-phenylethyl)-lH-imidazol-2-yl]ethan-l-ol

R23 : l-{l-[(2-methylphenyl)methyl]-lH-imidazol-2-yl}ethan-l-ol

R24 : l-{l-[(3-methylphenyl)methyl]-lH-imidazol-2-yl}ethan-l-ol

R25 : 2-[2-(l-hydroxyethyl)-lH-imidazol-l-yl]-l-(4-phenylpiperazin-l-yl)ethan-l-one R26 : 6-{[2-(l-hydroxyethyl)- IH-imidazol- 1-yllmethyl}- l-methylpyridin-2(lH)-one

R27 : l-{l-[(lH-benzimidazol-2-yl)methyl]-lH-imidazol-2-yl}ethan-l-ol

R28 : l-{l-[([l,2,4]triazolo[l,5-a]pyridin-2-yl)methyl]-lH-imidazol-2-yl}ethan-l-ol

R29 : l-{l-[(l-methyl-lH-benzimidazol-2-yl)methyl]-lH-imidazol-2-yl}ethan-l-ol

R30 : 2-[2-(l-hydroxyethyl)-lH-imidazol-l-yl]-N-methyl"N-phenylacetamide

R31 : l-{l-[(naphthalen-2-yl)methyl]-lH-imidazol-2-yl}ethan-l-ol

R32 : l-{l-[(quinolin-2-yl)methyl]-lH-imidazol-2-yl}ethan-l-ol R33 : l-{l-[(l,3-benzothiazol-2-yl)methyl]-lH-imidazol-2-yl}ethan-l-ol

R34 : 2-{[2-(l-hydroxyethyl)-lH-imidazol-l-yl]methyl}phenol

R35 : 3-{[2-(l-hydroxyethyl)- lH-imidazol" l-yl]methyl}quinoxalin-2(lH)-one

R36 : 3-{[2-(l-hydroxyethyl)- lH-imidazol- 1-yUmethyl}- l-methylquinoxalin-2(lH)-one R37 : l-{l-[(lH-pyrrolo[2,3-b]pyridin-6-yl)methyl]-lH-imidazol-2-yl}ethan-l-ol

R38 : l-{l-[(l,5-naphthyridin-2-yl)methyl]-lH-imidazol-2-yl}ethan-l-ol

R39 : 3-{[2-(l-hydroxyethyl)-lH midazol-l-yl]methyl}-l-methyl-6-(4-methylphenyl)pyridin- 2(lH)-one

R40 : 3-{[2-(l-hydroxyethyl)-lH-imidazol-5-yl]methyl}-l-methyl-6-(4-methylphenyl)pyridin- 2(lH)-one .

R41 : l-{l-[(5-fluoro-l,3-benzoxazol-2-yl)methyl]-lH-imidazol-2-yl}ethan-l-ol

R42 : l-{l-[(quinoxalin-2-yl)methyl]-lH-imidazol"2-yl}ethan-l-ol

R43 : l-{l-[(4,5,6,7-tetrahydro-l,2-benzoxazol-3-yl)methyl]-lH-imidazol-2-yl}ethan-l-ol R44 : l-{l-[(imidazo[l,2-a]pyridin-2-yl)methyl]-lH-imidazol-2-yl}ethan-l-ol

R45 : [2-(l-hydroxyethyl)-lH-imidazol"l-yl](phenyl)acetic acid

R46 : 2-[2-(l-hydroxyethyl)-lH-in idazol-l-yl]-N-methyl-2-phenylacetamide

R47 : l-{l-[3-(4-chlorophenyl)propyl]-4-(hydroxymethyl)-lH"imidazol-2-yl}ethan-l-ol

R48 : l-{l-[([l,l'-biphenyl]-4-yl)methyl]-lH-l,2,4-triazol-5-yl}ethan-l-ol

R49 : 2-{[2-(l-hydroxyethyl)- lH-imidazol- l-yl]methyl}-6-methylphenol

R50 : 2-{[2-(l-hydroxyethyl)- lH-imidazol- l-yl]methyl}-4-methylphenol

R51 : 3-{[2-(l-hydroxyethyl)-lH-imidazol-l-yl]methyl}-N-(l-methyl-lH-pyrazol-5- y benzamide

R52 : 4-{[2-(l-hydroxyethyl)- lH-imidazol- l-yl]methyl}-N-(5-methyl- l,2-oxazol-3- yl)benzamide

R53 : methyl 2-{[2-(l-hydroxyethyl)-lH-imidazoM-yl]methyl}benzoate

R54 : methyl 3-{[2-(l-hydroxyethyl)-lH-imidazol-l-yl]methyl}benzoate

R55 : 2-[2-(l-hydroxyethyl)-lH-imidazol-l-yl]-2-phenylethan-l-ol

R56 : l-(l-{[2-(hydroxymethyl)phenyl]methyl}- lH-imidazol-2-yDethan- l-ol

R57 : l-(l-{[3-(hydroxymethyl)phenyl]methyl}- lH"imidazol-2-yl)ethan- l-ol

R58 : 2-{[2-(l-hydroxyethyl)-lH-imidazol-l-yl]methyl}benzoic acid

R59 : l-[2-(l-hydroxyethyl)-lH-imidazol-l-yl]-3-phenylpropan-2-ol

R60 : 3-{[2-(l-hydroxyethyl)-lH-imidazol-l-yl]methyl}benzoic acid

R61 : 2-[2-(l-hydroxyethyl)-lH imidazol-l-yl]-2-phenylacetamide

R62 : 3-{[2-(l-hydroxyethyl)- lH-imidazol- l-yl]methyl}-N,N-dimethylbenzamide

R63 : l-[l-(2-amino-3-phenylpropyl)-lH-imidazol-2-yl]ethan-l-ol

R64 : l-{l-[(3-fluoro-4-iodophenyl)methyl]-lH-imidazol-2-yl}ethan-l-ol

R65 : N-{l-[2-(l-hydroxyethyl)-lH"imidazol-l-yl]-3-phenylpropan-2-yl}methanesulfonamide-- hydrogen chloride (l/l)

R66 : l-{l-[3-(4-chlorophenyl)propyl]-lH-imidazol-2-yl}-2-(methanesulfonyl)ethan-l-ol R67 : 2-benzyl-3-[2-(l-hydroxyethyl)-lH-imidazol-l-yl]propan-l-ol

R68 : 3-{[2-(l-hydroxyethyl)-lH-imidazol-l-yl]methyl}benzamide

R69 : 3-{[2-(oxolan-2-yl)-lH-imidazol-l-yl]methyl}-5-phenyl-l,2-oxazole

R70 : 2-hydroxy-2-{l-[(5-{[4-(3-hydroxypropyl)phenyl]ethynyl}-l,2-oxazol-3-yl)methyl]-lH- imidazol" 2 -yl} · N- methylprop anamide

Examples

Synthesis of Compound-2

l-{l-[3-(4-Chlorophenyl)propyl]-lH"imidazol-2-yl}ethan-l-ol

Compound-2 Step-1)

l-{l-[3-(4-Chlorophenyl)propyl]-lH-imidazol-2-yl}ethan-l-ol (Compound-2)

Compound-2

To an ice-cooled solution of l-(l-(3-(4-chlorophenyl)propyl)-lH-imidazol-2-yl)ethanone (35 mg) in MeOH (lmL) was added NaBE (5 mg). The mixture was allowed to warm to room temperature and stirred for 3 hours. The reaction was quenched with a saturated aqueous sodium bicarbonate and extracted 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 (2-7 % MeOH in CHCI3) to give the title compound (35 mg, 98 % yield) as pale brown oil.

Ή-NMR, MS and LCMS retention time data of Compound-2 are shown in Table 3.

Preparation of Compound-4 and Compound-5

(1R)- l-{l-[4-(4-chlorophenyl)butyl] - lH-imidazol-2-yl}ethan- l-ol (Compound-4: chiral) (lS)-l-{l-[4-(4-chlorophenyl)butyl]-lH-imidazol-2-yl}ethan-l-ol (Compound-5: chiral)

Compound-4 Compound-5

(chiral) (chiral)

Step- 1)

(lR)-l-{l-[4-(4-chlorophenyl)butyl]-lH-imidazol-2-yl}ethan-l-ol (Compound-4: chiral) (IS)- l-{l- [4-(4-chloro henyl)butyl]- lH-imidazol"2-yl}ethan- l-ol (Compound-5: chiral)

Compound-4 Compound-5

(chiral) (chiral)

Compound-3 (30 mg) was separated with prep-HPLC to afford the first eluting isomer

(Compound-4, 12 mg, >99 % ee) as colorless oil and the second eluting isomer (Compound-5,

14 mg, >93 % ee) as colorless oil.

HPLC separation condition:

Instrumentation: GILSON Preparative HPLC System.

Column: DAICEL CHIRALPAK ΑΌΉ 20 x 250 mm, 5 pm.

Mobile phase: EtOH/Hex = 5/95.

Flow rate: 10 mL/min.

Detection: 254 nm.

MS and LCMS retention time data of Compound-4 are shown in Table 3.

MS and LCMS retention time data of Compound-5 are shown in Table 3.

Synthesis of Compound- 10

{l-[3-(4-Chlorophenyl)propyl]-lH-imidazol-2-yl}(hydroxy)acetic acid

Compound-10

Step 1)

Ethyl {l-[3-(4-chlorophenyl)propyl]-lH-imidazol-2-yl}(oxo)acetate

To an ice-cooled solution of l-[3-(4-chlorophenyl)propyl]imidazole (0.10 g) in acetonitrile (2.3 mL) was added ethyl oxalyl chloride (56 μΐ ) and TEA (82 μθ. After stirring for 1 hour at 0 °C, the reaction was quenched with a saturated aqueous sodium bicarbonate and extracted with CHCb. The organic layer was passed through a phase separator and concentrated in vacuo. The residue was purified with OH-type silica gel column chromatography (30-65 % EtOAc in n-hexane) to give the title compound (0.15 g, quant.) as pale yellow oil.

MS (ESI) m/z : 321 [M+l]⁺.

RT = 1.116 min.

LCMS condition : B.

Step 2)

Ethyl {l-[3-(4-chloro henyl)propyl]-lH-imidazol-2-yl}(hydroxy)acetate

The title compound was obtained in the manner as with the "Synthesis of Compound-2" using the corresponding materials.

MS (ESI) m/z : 323 [M+lh

RT = 0.598 min.

LCMS condition : B.

Step 3)

{l-[3-(4-Chlorophenyl)propyl]-lH-imidazol-2-yl}(hydroxy)acetic acid (Compound- 10)

Compound-10

To a solution of ethyl 2-[l" [3-(4-chlorophenyl)propyl]imidazol-2-yl] -2-hydroxyacetate (40 mg) in THF (1.0 niL) and Me OH (1.0 mL) was added 1 mol/L aqueous NaOH (1.0 mL). The mixture was stirred at room temperature for 15 hours. Aqueous HC1 (l mol/L) was added to the mixture to adjust the pH 5"6 and then the mixture was extracted with CHCI3. The organic layer was passed through a phase separator and concentrated in vacuo to give the title compound (36 mg, 98 % yield) as colorless powder.

Ή-NMR, MS and LCMS retention time data of Compound- 10 are shown in Table 3. Synthesis of Compound- 11

2-{l- [3-(4-Chlorophenyl)propyl]- lH-imidazol-2-yl}-2-hydroxyacetamide

Compound-11

Step- 1)

2-{l- [3-(4-Chlorophenyl)propyl]- lH-imidazol-2-yl}-2-hydroxyacetamide (Compound- 11)

Compound-11

A round bottomed flask was charged with ethyl 2- [l- [3-(4-chlorophenyl)propyl]imidazol-2-yl]- 2-hydroxy-acetate (30 mg) and 7 mol/L ammonia in MeOH (2.0 mL). The mixture was stirred at room temperature for 17 hours. The resulting mixture was concentrated in vacuo to give the title compound (27 mg, quant.) as colorless powder. Ή-NMR, MS and LCMS retention time data of Compound- 11 are shown in Table 3. Synthesis of Compound- 12

Amino{l-[3-(4-chlorophenyl)propyl]-lH-imidazol-2-yl}acetic acid

Compound-12

Step-1)

Ethyl (2Z)-{l-[3-(4-chlorophenyl)propyl]-lH-imidazol-2-yl}(hydroxyimino)acetate

To a solution of ethyl 2-[l"[3-(4-chlorophenyl)propyl]imidazol-2-yl]-2-oxo-acetate (0.10 g) in EtOH (1.6 mL) were added sodium acetate (28 mg) and hydroxylamine hydrochloride (35 mg). The mixture was stirred at 90 °C for 1.5 hours. The reaction was quenched with a saturated aqueous sodium bicarbonate and extracted with CHC . The organic layer was passed through a phase separator and concentrated in vacuo to give the title compound (0.12 g, quant.) as pale yellow oil.

MS (ESI) m/z : 336 [M+l]⁺.

RT = 0.673 min.

LCMS condition : B. Step-2)

Ethyl amino{l-[3-(4-chlorophenyl)propyl]-lH-imidazol-2-yl}acetate

To an ice-cooled solution of ethyl (2Z)-2-[l-[3-(4-chlorophenyl)propyl]imidazol-2-yl]-2- hydroxyimino-acetate (0.12 g) in THF (1.7 niL) were added acetic acid (1.7 mL), water (1.7 mL) and zinc (0.17 g). The mixture was stirred for 15 minutes at 0 °C. The reaction was quenched with a saturated aqueous sodium bicarbonate and extracted with EtOAc. The organic layer was washed with brine and passed through a phase separator and concentrated in vacuo. The residue was purified with amino-type silica gel column chromatography (50-100% EtOAc in n-hexane and then 5% MeOH in CHCI3) and with OH" type silica gel column chromatography (0"5% MeOH in CHCI3) to give the title compound (35 mg, 32 % yield) as colorless oil.

MS (ESI) m/z : 322 [M+l]⁺.

RT = 0.585 min.

LCMS Condition : B.

Step -3)

Amino{l-[3-(4-chlorophenyl)propyl]-lH-imidazol-2-yl}acetic acid (Compound-12)

Compound-12

To a solution of ethyl 2-amino-2-[l-[3-(4-chlorophenyl)propyl]imidazol-2-yl]acetate (25 mg) in THF (1.0 mL) and MeOH (1.0 mL) was added 1 mol/L aqueous NaOH (1.0 mL). The mixture was stirred at room temperature for 1 hour. The resulting mixture was concentrated in vacuo, and the residue was purified with OH-type preparative chromatography (20 % MeOH in CHCI3) to give the title compound (12 mg, 53 % yield) as colorless amorphous. Ή-NMR data of Compound-12 is shown in Table 3. Synthesis of Compound- 13

l-{l-[3-(4-Chlorophenyl)propyl]-lH-imidazol-2-yl}ethan-l-amine

Compound-13 Step-1)

l-{l-[3-(4-Chlorophenyl)propyl]-lH-imidazol"2-yl}ethan-l-amine (Compound- 13)

Compound-13

To a solution of l-(l-(3-(4-chlorophenyl)propyl)-lH-imidazol-2-yl)ethanone (0.10 g) in EtOH (2 mL) were added ammonium chloride (4 ^jng), Jitanium (IV) isopropoxide (0.22 g) and- trimethylamine (0.11 mL). The mixture was stirred overnight under nitrogen atmosphere at room temperature. Sodium borohydride (22 mg) was added and the mixture was stirred under nitrogen atmosphere overnight at room temperature. The reaction was quenched with a saturated aqueous sodium bicarbonate and extracted with CHC . 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 (50-100 % EtOAc in n-hexane and then 1-10 % MeOH in CHCI3) to obtain a crude product, which was purified with amino-type preparative chromatography (14 % MeOH in CHCb) to give the title compound (6.2 mg, 6.2 % yield) as light brown syrup.

Ή-NMR, MS and LCMS retention time data of Compound-13 are shown in Table 3.

Synthesis of Compound- 14

2-{l-[3-(4-Chlorophenyl)propyl]-lH-imidazol-2-yl}alanine

Compound-14

Step-1)

5-{l-[3-(4-Chlorophenyl)propyl]-lH-imidazol-2-yl}-5-methylimidazolidine-2,4-dione

A 100 mL autoclave was charged with potassium cyanide (l.O g), water (38 mL), a solution of l"[l"[3-(4-chlorophenyl)propyl]imidazol-2-yl]ethanone (l.O g) in MeOH (38 mL) and ammonium carbonate(3.7 g), and the mixture was stirred for 15 hours at 90 °C. After addition of total amount (11.0 g) of ammonium chloride in three portions, the mixture was stirred for additional 39 hours at 90 °C. The mixture was allowed to cool to room temperature and concentrated in vacuo. The resulting residue was diluted with MeOH and the insoluble matters were filtered out. The filtrate was concentrated in vacuo to give the title compound (2.2 g) as a crude product of orange solid, which was used in the next step without further purification.

Ή NMR (400 MHz, CHLOROFORM-d) δ ppm 1.91 (s, 3 H), 1.94^■ 2.12 (m, 2 H), 2.56 - 2.65 (m, 2 H), 4.03 (t, J=7.7 Hz, 2 H), 6.93 (d, J=l.l Hz, 1 H), 6.98 (d, J=l.l Hz, 1 H), 7.06^■ 7.10 (m, 2 H), 7.23 - 7.26 (m, 2 H), 8.43 (s, 2 H).

LCMS : not determined.

Step-2)

2-{l-[3-(4-Chlorophenyl)propyl]-lH-imidazol-2-yl}alanine (Compound- 14)

To a solution of the crude material (obtained in the step-1, 2.2 g) in DME (38 mL) were added (Boc)₂0 (2.5 g), TEA (1.6 mL), DMAP (23 mg). The reaction mixture was stirred overnight at room temperature. The resulting precipitate was removed by filtration and the filtrate was concentrated in vacuo. The residue was purified with OH-type silica gel column chromatography (0"10 % MeOH in CHCI3) to give a crude material (1.4 g) which was used in the next step without further purification.

To an ice-cooled solution of the crude material (1.4 g) in THF (33 mL) and water (20 mL) was added lithium hydroxide monohydrate (0.69 g). After stirring overnight at room temperature, the reaction was allowed to reflux for 6 hours. After cooling, the reaction mixture was neutralized by 1 mol/L aqueous HCl and concentrated in vacuo. A small amount (46 mg) of the crude material was purified with prep-HPLC to give the title compound (9 mg) as pale yellow oil.

Ή-NMR data of Compound- 14 is shown in Table 3. Synthesis of Compound-15

2-{l-[3-(4-Chlorophenyl)propyl]^_lH-imidazol-2-yl}-2-hydrox^ropanoic acid

Compound-15 Step-1)

Ethyl 2-(l-(3-(4-chlorophenyl)propyl)-lH"imidazol-2-yl)-2-hydroxypropanoate

To a cooled (-70 °C) solution of ethyl 2-(l-(3-(4-chlorophenyl)propyl)-lH-imidazol-2-yl)-2- oxoacetate (85 mg) in THF (3 mL) in a dry ice bath was added 35% methyl magnesium bromide in THF solution (0.11 mL) under nitrogen atmosphere. The dry ice bath was taken off and the mixture was stirred for 1 hour. The reaction was quenched with saturated aqueous ammonium chloride and extracted with CHC . 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 (1-5 % MeOH in CHCb) to give the title compound (51 mg, 57 % yield) as light yellow syrup.

MS (ESI) m/z : 337 [M+l]⁺.

RT = 0.629 min.

LCMS condition : B.

Step-2)

2-{l-[3-(4-Chlorophenyl)propyl]-lH-imidazol-2-yl}-2-hydroxypropanoic acid (Compound-15)

Compound-15

To a stirred solution of ethyl 2-(l-(3-(4-chlorophenyl)propyl)-lH-imidazol-2-yl)-2- hydroxypropanoate (49 mg) in THF (0.5 mL) were added MeOH (l mL) and 2 mol/L aqueous NaOH (0.5 mL). The mixture was stirred for overnight at room temperature and

concentrated in vacuo. The resulting residue was triturated with EtOH, the precipitated solid was filtrated off and the filtrate was concentrated in vacuo. The residue was purified with OH-type preparative chromatography (9 % MeOH in CHCI3) to give the title compound (20 mg, 45 % yield) as light yellow solid.

^!H-NMR, MS and LCMS retention time data of Compound-15 are shown in Table 3. Synthesis of Compound- 16

l-{l-[3-(4-Chlorophenyl)propyl]-lH-imidazol-2-yl}propan-l-ol

Compound-16 Step-1)

l-{l-[3-(4-Chlorophenyl)propyl]-lH-imidazol-2-yl}propan-l-ol (Compound-16)

Compound-16

To an ice-cooled solution of l-[3-(4-chlorophenyl)propyl]imidazole-2-carbaldehyde (50 mg) in THF (1.0 mL) was added ethyl magnesium bromide (O.IO mL). The mixture was stirred for 1 hour at room temperature. The reaction was quenched with a saturated aqueous ammonium chloride and extracted with CHCI3. The organic layer was passed through a phase separator and concentrated in vacuo. The residue was purified with OH-type silica gel column chromatography (O-IO % MeOH in CHCI3) to give a crude product, which was re-purified with OH-type preparative chromatography (10 % MeOH in CHCI3) to give the title compound (13 mg, 24 % yield) as colorless oil.

Ή-NMR, MS and LCMS retention time data of Compound- 16 are shown in Table 3. Synthesis of Compound- 19

l-(l-{[4-(Phenylethynyl)phenyl]methyl}-lH-imidazol-2-yl)ethan-l-ol

Step-1)

l-(l-{[4-(Phenylethynyl)phenyl]methyl}-lH-imidazol-2-yl)ethan-l-

A round bottomed flask was charged with l-[l-[(4-iodophenyl)methyl]imidazol-2-yl]ethanone (0.10 g), PdCl₂(PPh₃)2 (43 mg), Cul (12 mg), PPh₃ (32 mg), HMDS (96 μΌ, TEA (0.43 mL) and DMF (1.5 mL). The flask was evacuated and backfilled with nitrogen atmosphere. After stirring for 1 hour at 110 °C, ethynylbenzene (94 mg) was added dropwise to the solution and the reaction mixture was stirred for 3 hours at the same temperature. After cooling, the reaction mixture was poured into a saturated aqueous sodium bicarbonate and extracted with EtOAc. The organic layer was washed with brine, passed through a phase separator, and concentrated in vacuo. The residue was purified with amino-type silica gel column chromatography (6"30 % EtOAc in n-hexane) to give the title compound (O.IO g, quant.) as a brown solid.

MS (ESI) m/z 301 [M+l]⁺.

RT = 1.136 min.

LCMS condition : B.

Step -2)

l-(l-{[4-(Phenylethynyl)phenyl]methyl}-lH-imidazol-2-yl)ethan-l-ol (Compound- 19)

Compound-19

Compound 19 was obtained in the manner as with the "Synthesis of Compound-2" using the corresponding materials.

Ή-NMR, MS and LCMS retention time data of Compound-19 are shown in Table 3. Synthesis of Compound-25

l-{l-[3-(4-Chlorophenyl)propyl]-lH-imidazol-2-yl}-2,2,2-trifluoroethan-l-ol

Compound-25 Step-1)

-{l-[3-(4-Chlorophenyl)propyl]-lH-imidazol-2-yl}-2,2,2-trifluoroethan-l-ol (Compound-25)

Compound-25

To an ice-cooled suspension of l-[3-(4-chlorophenyl)propyl]imidazole-2-carbaldehyde (31 mg) and potassium carbonate (34 mg) in DMF (0.62 mL) was added trimethyl(trifluoromethyl)silane (37 μΐ dropwise. The reaction mixture was stirred for 1 hour at room temperature. Potassium carbonate (34 mg) and trimethyl(trifluoromethyl)silane (37 μϋι) was added and the reaction was stirred for 1 hour. After cooling, the reaction was diluted with THF and acidified by addition of 1 mol/L aqueous HC1. After stirring for 30 minutes at room temperature, the reaction was neutralized by a saturated aqueous sodium bicarbonate and extracted with CHCI3. The organic layer was washed with brine, dried over Na2SC*4 and concentrated in vacuo. The residue was purified with prep HPLC to give the title compound (11 mg, 29 % yield) as pale yellow solid. Ή-NMR, MS and LCMS retention time data of Compound-25 are shown in Table 3.

Synthesis of Compound-27

l- l-[3-(4-Chlorophenyl)propyl]-5-methyl-lH-imidazol-2-yl}ethan-l-ol

Compound-27

Step-1)

N-methox N,4-dimethyl-lH-imidazole-2-carboxamide

To a stirred solution of 4-methyMH-imidazole-2-carboxylic acid (0.50 g) in DMF (20 mL) were added N,Odimethyl hydroxylamine hydrochloride (0.43 g), TEA (1.7 mL) and HATU (1.8 g). The mixture was stirred for 4 hours at 80° C and stirred at room temperature for 2 days. The reaction mixture was concentrated in vacuo and the precipitates were filtered out. The filtrate was concentrated in vacuo and the residue was purified with amino-type silica gel chromatography (0"5 % MeOH in CHCI3) to give the title compound (0.41 g, 61 % yield) as pale yellow oil.

MS (ESI) m/z : 170 [M+l]⁺.

RT = 0.206 min.

LCMS condition : A.

Step -2)

Mixture of l-[3-(4-Chlorophenyl)propyl]-N-methoxyN,5-dimethyl-lH-imidazole-2- carboxamide and l-[3-(4-chlorophenyl)propyl]-N-methoxyN,4-dimethyl- lH-imidazole-2- carboxamide

To a stirred solution of l-(3-bromopropyl)-4-chloro-benzene (0.62 g) and N-methox -N.4- dimethyl-lH-imidazole-2-carboxamide (0.41 g) in acetonitrile (2.1 mL) was added potassium carbonate (1.3 g). After stirring for 1.5 hours at 80 °C, the reaction was allowed to cool to room temperature, quenched with water and extracted with CHC . The organic layer was passed through a phase separator and concentrated in vacuo. The residue was purified with OH-type silica gel chromatography (l-5 % MeOH in CHCb) to give the mixture of the title compounds (0.60 g, 76 % yield) as colorless oil.

MS (ESI) m/z : 322 [M+l]⁺.

RT = 0.745 min.

LCMS condition : A. Step -3)

l-(l-(3-(4-Chlorophenyl)propyl)-4-methyl-lH-imidazol-2-yl)ethanone (Intermediate 27- 1) and l-(l-(3-(4-chloro henyl)propyl)-5-methyl-lH-imidazol-2-yl)ethanone (Intermediate 27-2)

Intermediate 27-1 Intermediate 27-2

To an ice-cooled solution of the mixture (O.IO g) of l-[3-(4-chlorophenyl)propyl]-N-methoxy N,5-dimethyl-lH-imidazole-2-carboxamide and l-[3-(4-chlorophenyl)propyl]-N-methoxy-N,4- dimethyl-lH-imidazole-2-carboxamide in THF (3.1 mL) was added 3 mol/L methyl magnesium bromide in THF (0.31 mL). After stirring for 30 minutes at 0 °C, the reaction was quenched with a saturated aqueous ammonium chloride and extracted with CHCI3. The organic layer was passed through a phase separator and concentrated in vacuo. The residue was purified with prep-HPLC to afford the first eluting isomer as Intermediate 27-1 (42 mg, colorless oil) and the second eluting isomer as Intermediate 27-2 (15 mg, colorless oil).

The chemical structures of both products were analyzed and determined by Ή-NMR NOE signal between a hydrogen atom on the imidazole ring and hydrogen atoms on the carbom atom linked to the imidazole nitrogen atom. NOE signal was observed in Intermediate 27-1 while the signal was not observed in Intermediate 27-2.

HPLC separation condition:

Instrumentation: GILSON Preparative HPLC System.

Column: DAICEL CHIRALPAK ID 20 x 250 mm, 5 pm.

Mobile phase: EtOH/Hex = 5/95. Flow rate: 10 mL/min.

Detection: 254nm.

Intermediate 27-1:

Ή NMR (400 MHz, CHLOROFORM-d) δ ppm 2.00 - 2.12 (m, 2 H), 2.26 (s, 3 H), 2.57 - 2.67 (m, 5 H), 4.29 - 4.36 (m, 2 H), 6.76 (s, 1 H), 7.09 (d, J=8.3 Hz, 2 H), 7.22 - 7.29 (m, 2 H).

MS (ESI) m/z : 277 [M+l]⁺.

RT = 1.035 min.

LCMS Condition : B.

Intermediate 27-2:

Ή NMR (400 MHz, CHLOROFORM-d) δ ppm 1.93 - 2.05 (m, 2 H), 2.18 (s, 3 H), 2.63 (s, 3 H), 2.64 - 2.70 (m, 2 H), 4.26 - 4.34 (m, 2 H), 6.92 (s, 1 H), 7.12 (d, J=8.4 Hz, 2 H), 7.22 - 7.30 (m, 2 H).

MS (ESI) m/z : 277 [M+l]⁺.

RT = 0.985 min.

LCMS Condition : B.

Step-4) l-{l-[3-(4-Chlorophenyl)propyl]-5-methyl-lH-imidazol-2-yl}ethan-l-ol (Compound- 2

Compound-27

Compound-27 was obtained in the manner as with the "Synthesis of Compound-2" using Intermediate 27-2 and corresponding materials.

Ή-NMR data of Compound-27 is shown in Table 3.

Synthesis of Compound-28

-{l-[2-([l,r-Biphenyl]-4-yl)ethyl]-lH-imidazol-2-yl}ethan-l-ol

Compound-28

Step-1) l-(l-(2-([l,l'-Biphenyl]-4-yl)ethyl)-lH-imidazol-2-yl)ethanone

To a stirred solution of l-[l-[2-(4-bromophenyl)ethyl]imidazol-2-yl]ethanone (0.15 g) in 1,4- dioxane (5 mL) were added water (0.5 mL), SUPERSTABLE Pd(0) CATALYST (0.43 g), potassium carbonate (0.21 g) and phenylboronic acid (0.12 g). The mixture was stirred under nitrogen atmosphere at 80 °C for 3 hours^ After cooling to room temperature, the insoluble matter was removed by filtration through Celite®. The filtrate was added to water and extracted with EtOAc twice. The combined organic layer was passed through a phase separator and concentrated in vacuo. The residue was purified with amino-type silica gel column chromatography (0-50 % EtOAc in n-hexane) to give the title compound (0.11 g, 73 % yield) as yellow oil.

MS (ESI) m/z : 29l[M+l]⁺.

RT = 1.099 min.

LCMS condition : B.

Step -2)

-{l-[2-([l,r-Biphenyl]-4-yl)ethyl]-lH-imidazol-2-yl}ethan-l-ol (Compound-28)

Compound-28

Compound-28 was obtained in the manner as with the "Synthesis of Compound-2" using the corresponding materials.

Ή-NMR, MS and LCMS retention time data of Compound-28 are shown in Table 3.

Synthesis of Compound-31

l-{l-[(4-Bromo-3-methylphenyl)methyl]-lH-imidazol-2-yl}ethan-l-ol

Compound-31 Step-1)

l-{l-[(4-Bromo-3-methylphenyl)methyl]-lH-imidazol-2-yl}ethan-l-ol (Compound-31)

Compound-31 The suspension of l-(lH-imidazol-2-yl)ethanol (0.10 g), potassium carbonate (0.49 g) and 1- bromo-4-(bromomethyl)-2-methyl"benzene (0.35 g) in acetonitrile (4.5 mL) was stirred for 4 hours at 80 °C. The mixture was allowed to cool to room temperature and filtered. The filtrate was diluted with water and was extracted with EtOAc. The organic layer was dried over MgS04, filtered and evaporated. The residue was charged onto ISOLUTE® HM-N, purified with OH-type silica gel column chromatography (0"10 % MeOH in CHC ) twice and then re-purified with amino-type silica gel column chromatography (0"10 % MeOH in CHCb) to give the title compound (46 mg, 17 % yield) as pale yellowish solid.

!H-NMR, MS and LCMS retention time data of Compound-31 are shown in Table 3. Synthesis of Compound-34

l-([l,r-Biphenyl]-4-yl)-2-[2-(l-hydroxyethyl)-lH-imidazol-l-yl]ethan-l-ol

Compound-34

Step-1)

l-([l,r-Biphenyl]-4-yl)-2-[2-(l-hydroxyethyl)-lH-imidazol-l-yl]ethan-l-ol (Compound-34)

Compound-34

-cooled solution of 2-[2-(l-hydroxyethyl)imidazol-l-yl]-l-(4-phenylphenyl)ethanone (24 mg) in MeOH (0.80 mL) was added sodium borohydride (3.0 mg). After stirring for 30 minutes at 0 °C, the reaction was quenched with water and extracted with CHCI3. The organic layer was passed through a phase separator and concentrated in vacuo. The residue was purified with OH-type silica gel column chromatography (l-lO % MeOH in CHCI3) to give the title compound (22 mg, 90 % yield) as colorless powder.

Ή-NMR, MS and LCMS retention time data of Compound-34 are shown in Table 3.

Synthesis of Compound-35

1-{1- [(5-Phenyl- l,3-thiazol"2-yl)methyl]- lH-imidazol-2-yl}ethan- l-ol

Compound-35

Step-1)

l- -[(5-Phenyl-l,3-thiazol-2-yl)methyl]-lH-imidazol-2-yl}ethan-l-ol (Compound-35)

Compound-35

To a stirred solution of l-(lH-imidazol-2-yl)ethanol (80 mg) and 2-(chloromethyl)-5-phenyl- thiazole (0.26 g) in DMF (5 mL) were added sodium iodide (0.14 g) and potassium carbonate (0.30 g). The mixture was stirred for 2 hours at 80 °C and allowed to cool to room

temperature. The reaction was quenched with water and extracted with EtOAc twice. The combined organic layer was passed through a phase separator and concentrated in vacuo. The residue was purified with OH-type silica gel column chromatography (0-10 % MeOH in CHCI3) to give the title compound (22 mg, 11 % yield) as yellow solid.

Ή-NMR, MS and LCMS retention time data of Compound-35 are shown in Table 3.

Synthesis of Compound-43

l-{l-[(5-Phenyl-l,2-oxazol-3-yl)methyl]-lH-imidazol-2-yl}ethan-l-ol

Compound-43

(5-Phenyl- l,2-oxazol-3-yl)methyl methanesulfonate

The title compound was obtained in the manner as with the "Synthesis of Intermediated step-3" using the corresponding materials.

MS (ESI) m/z : 254 [M+l]⁺.

RT = 0.907 min.

LCMS condition : B.

Step 2)

l-{l-[(5-Phen l-l,2-oxazol-3-yl)methyl]-lH-imidazol-2-yl}ethan-l-ol (Compound-43)

Compound-43

To a solution of ethyl (5-phenylisoxazol-3-yl)methyl methanesulfonate (0.43 g) and 1-(1H- imidazol-2-yl)ethanol (0.20 g) in acetonitrile (8.6 mL) was added potassium carbonate (0.71 g). After stirring for 7 hours at 90 °C, the reaction was quenched with water and extracted with CHCI3. The organic layer was passed through a phase separator and concentrated in vacuo. The residue was purified with OH-type silica gel column chromatography (0"5 % MeOH in CHCls) to give the title compound (0.31 g, 68 % yield) as pale yellow oil.

Ή-NMR, MS and LCMS retention time data of Compound-43 are shown in Table 3.

Synthesis of Compound-50

3-{4-[(2-Fluoro-4-{[2-(l-hydroxyethyl)-lH-imidazol-l- yl]methyl}phenyl)ethynyl]phenyl}propan-l-ol

Step-1)

l-{l'[(3-Fluoro-4-iodophenyl)methyl]-lH-imidazol-2-yl}ethan-l-ol

The suspension of 4-(bromomethyl)-2-fluoro^_l^_iodo-benzene (0.12 g), l-(lH-imidazol^_2- yDethanol (51 mg) and potassium carbonate (0.21 g) in acetonitrile (1.9 mL) was stirred for 10 minutes at room temperature and then 2 hours at 80 °C. The mixture was allowed to cool to room temperature and concentrated under reduced pressure. The residue was charged onto ISOLUTE® HM-N and purified with OH-type silica gel column chromatography (3- 80 % EtOAc in n-hexane) to give the title compound (57 mg, 43 % yield) as colorless solid. MS(ESI) m/z 347 [M+l]⁺.

RT = 0.399 min.

LCMS condition : B.

Step -2)

3-{4-[(2-Fluoro-4-{[2-(l-hydroxyethyl)-lH-imidazol-l- yl]methyl}phenyl)ethynyl]phenyl}propan- l"ol (Compound"50)

The mixture of l-[l-[(3-fluoro-4-iodo-phenyl)methyl]imidazol-2-yl]ethanol (45 mg), PdCl₂(PPh₃)2 (18 mg), Cul (5 mg), PPhs (14 mg), HMDS (31 mg) and TEA (0.13 g) in DMF (0.65 mL) was evacuated and backfilled by nitrogen three times. The mixture was heated to 110 °C under nitrogen for 10 minutes. The solution of 3-(4-ethynylphenyl)propan-l-ol (37 mg) in DMF (2 mL) was added dropwise to the mixture above at 110 °C and stirred 4.5 hours. The reaction was allowed to cool to room temperature, quenched with water and extracted with EtOAc. The organic layer was washed by water twice, dried over MgSO<i, filtered and evaporated. The residue was charged onto ISOLUTE® HM-N, purified with OH-type silica gel column chromatography (0"10 % MeOH in CHCI3) and then purified with amino-type silica gel column chromatography (O-IO % MeOH in CHCI3) to obtain a crude product, followed by re -purification with prep-HPLC to give the title compound (18 mg, 37 % yield) as colorless solid.

Ή-NMR, MS and LCMS retention time data of Compound-50 are shown in Table 3.

Synthesis of Compound-53

3-{4- [(3-{[2-(l-Hydroxyethyl)- lH-imidazol- l-yl]methyl}- l,2-oxazol-5- l)ethynyl]phenyl}propan- l-ol

Step-1)

(5-((4-(3-((Tert-butyldimethylsilyl)oxy)propyl)phenyl)ethynyl)isoxazol-3-yl)methyl

methanesulfonate

The title compound was obtained in the manner as with the "Synthesis of Intermediate -4- step-3" using the corresponding materials.

MS (ESI) m/z : 450[M+l]⁺.

RT = 1.172 min.

LCMS condition : C.

Step -2)

l-(l-((5-((4-(3-((Tert-butyldimethylsilyl)oxy)propyl)phenyl)ethynyl)isoxazol-3-yl)methyl)-lH- imidazol-2-yl)ethanol

To a solution of [5-[2-[4-[3-[tert-butyl(dimethyl)silyl]oxypropyl]phenyl]ethynyl]isoxazol-3- yl]methyl methanesulfonate (82 mg) in acetonitrile (0.91 mL) was added potassium carbonate (76 mg) and l-(lH-imidazol-2-yl)ethanol (21 mg). After stirring for 18 hours at 80 °C, the mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was purified with amino-type silica gel column chromatography (15-100 % EtOAc in n-hexane) to give the title compound (43 mg, 51 % yield) as pink oil.

MS (ESI) m/z : 466[M+l]⁺.

RT = 1.038 min.

LCMS condition : B.

Step -3)

3-{4-[(3-{[2-(l-Hydroxyethyl)- lH-imidazol- l-yl]methyl}- l,2-oxazol"5- yl)ethynyl]phenyl}propan- l"ol (Compound-53)

Compound-53

To a solution of l-[l-[[5-[2-[4-[3-[tert-butyl(dimethyl)silyl]oxypropyl]phenyl]ethynyl]isoxazol- 3-yl]methyl]imidazol-2-yl]ethanol (43 mg) in THF (1.0 mL) was added TBAF (0.28 mL, 1 mol/L solution in THF). After stirring for 5 hours at room temperature, the reaction was quenched with a saturated aqueous sodium bicarbonate and extracted with EtOAc. The organic layer was dried over MgSO-i, and concentrated in vacuo. The residue was purified with amino-type silica gel column chromatography (CHCI3) and OH-type silica gel column chromatography (60 % EtOAc in n-hexane and then 0-10% CHCI3 in MeOH) to give the title compound (13 mg, 40 % yield) as pink oil.

Ή-NMR, MS and LCMS retention time data of Compound-53 are shown in Table 3.

Preparation of Compound-54 and Compound-55

3-{4- [(3-{[2-(l-Hydroxyethyl)- lH-imidazol- l-yl]methyl}- l,2-oxazol-5- yl)ethynyl]phenyl}propan-l-ol (Compound-54: chiral)

3-{4-[(3-{[2-(l-Hydroxyethyl)-lH-imidazol-l-yl]methyl}-l,2-oxazol-5- yl)ethynyl]phenyl}propan-l-ol (Compound-55: chiral) Compound-54 Compound-55

(chiral) (chiral)

Compound-53 was separated with chiral SFC to afford the first eluting isomer (Compound- 54, 17 mg, > 99 % ee) and the second eluting isomer (Compound-55, 13 mg, > 99 % ee).

SFC separation condition:

Instrumentation: WATERS SFC30.

Column: DAICEL CHIRALPAK ΑΌΉ 20 x 250 mm, 5 pm.

Mobile phase: C0₂/MeOH = 70/30.

Flow rate: 30 mL/min.

Temperature: 40 °C.

Back pressure: 120 bar.

Detection: 254 nm.

Ή-NMR, MS and LCMS retention time data of Compound-54 are shown in Table 3.

Ή-NMR, MS and LCMS retention time data of Compound-55 are shown in Table 3.

Synthesis of Compound-62

l-{l-[(5-{[4-(Hydroxymethyl)phenyl]ethynyl}-l,2-oxazol-3-yl)methyl]-lH-imidazol-2-yl}ethan- l-ol

Compound-62 Step-1)

-{[2-(l-Hydroxyethyl)-lH-imidazol-l-yl]methyl}-l,2-oxazol-5-yl)ethynyl]benzaldehyde

To a stirred solution of l-[l-[(5-ethynylisoxazol-3-yl)methyl]imidazol-2-yl]ethanol (0.17 g) and 4-iodobenzaldehydeJa36 g) in DM K (1.5 mL) was added. TEA (3.8 mL). The flask was evacuated and backfilled with nitrogen followed by addition of Cul (30 mg) and Pd(PPli3)4 (0.13 g). After stirring overnight at room temperature, the reaction mixture was diluted with CHC and concentrated in vacuo onto ISOLUTE® HM^_N. The residue was purified with OH-type silica gel column chromatography (2-13 % MeOH in CHCI3) to give the title compound (0.29 g, quant.) as oil.

MS (ESI) m/z 322 [M+l]⁺.

RT = 0.859 min.

LCMS condition : A.

Step-2)

l-{l-[(5-{[4-(Hydroxymethyl)phenyl]ethynyl}-l,2-oxazol-3-yl)methyl]-lH-imidazol-2-yl}ethan- l-ol (Compound-62)

To a stirred solution of 4-[2-[3-[[2-(l-hydroxyethyl)imidazol-l-yl]methylJisoxazol-5- yl]ethynyl]benzaldehyde (40 mg) in MeOH (1.2 mL) was added NaBH₄ (4.7 mg) at 0 °C. After stirring for 2 hours at the same temperature, a precipitate was filtered and washed with MeOH to give the title compound (20 mg, 50 % yield) as pale green powder.

Ή-NMR, MS and LCMS retention time data of Compound-62 are shown in Table 3.

Synthesis of Compound-63

l-[l-({5-[(4-{[(Oxetan-3-yl)amino]methyl}phenyl)ethynyl]-l,2-oxazol-3-yl}methyl)-lH- imidazol-2-yl]ethan- l-ol

Step-1) l-[l-({5-[(4-{[(Oxetan-3-yl)amino]methyl}phenyl)ethynyl]-l,2-oxazol-3-yl}methyl)-lH- imidazol-2-yl]ethan-l-ol (Comopund-63)

To a stirred solution of ethyl l-[2-[tert- butoxycarbonyl(methyl)amino]ethylamino]cyclopropanecarboxylate (40 mg) in CHCI3 (1.2 niL) was added oxetan-3-amine (16 mg). After stirring for 3 hours at room temperature, NaBH(OAc)3 (53 mg) was added to the mixture. After stirring for 2 hours at room temperature, the reaction mixture was diluted with CHCI3 and MeOH. The resulting precipitate was filtered out and the filtrate was concentrated in vacuo onto ISOLUTE® HM- N. The residue was purified with amino-type silica gel preparative chromatography (10 % MeOH in CHCI3) to give the title compound (42 mg, 89 % yield) as colorless powder.

Ή-^'NMR, MS and LCMS retention time data of Compound-63 are shown in Table 3.

Synthesis of Compound-68

l-(l-{[5-({4-[(Morpholin-4-yl)methyl]phenyl}ethynyl)-l,2-oxazol-3-yl]methyl}-lH-imidazol-2- yl)ethan-l-ol

Compound-68

Step-1) l-(l-{[5-({4-[(Morpholin-4-yl)methyl]phenyl}ethynyl)-l,2-oxazol-3-yl]

imidazol"2-yl)ethan- l-ol (Compound-68)

Compound-68

To a solution of 4-[(4-bromophenyl)methyl]morpholine (83 mg) in DMF (1.6 mL) were added PdCl₂(PPh₃)2 (45 mg), Cul (12 mg), PPh₃ (34 mg), HMDS (0.10 mL) and TEA (0.45 mL) at room temperature. The mixture was stirred at 110 °C for 10 minutes. Then l-[l-[(5-ethynyl- l,2-oxazol-3-yl)methyl]imidazol-2-yl]ethanol (70 mg) in DMF (l mL) was added at the same temperature and the mixture was stirred for_ _ 3_hours_._ After cooling, the— mixture was concentrated in vacuo. The residue was purified with amino-type silica gel column chromatography (MeOH in CHCI3) to give a crude product, which was purified with preparative chromatography (10 % MeOH in CHCI3) to give the title compound (4.8 mg, 3.8% yield) as pale yellow gum.

Ή-NMR, MS and LCMS retention time data of Compound-68 are shown in Table 3. Preparation of Compound-75 and Compound-76

l-{l-[(5-{[4-(2-Hydroxyethoxy)phenyl]ethynyl}-l,2-oxazol-3-yl)methyl]-lH-imidazol"2- yl}ethan-l-ol (Compound-75- chiral, eutomer)

l-{l-[(5-{[4-(2-Hydroxyethoxy)phenyl]ethynyl}-l,2-oxazol-3-yl)methyl]-lH"imidazol-2- yl}ethan-l-ol (Compound- 76^: chiral, distomer)

Step- 1)

(chiral) (chiral)

Compound-74 (45 mg) was separated by chiral SFC to afford the first eluting isomer (Compound-75, 21 mg) and the second eluting isomer (Compound-76, 18 mg).

SFC separation condition:

Instrumentation: WATERS SFC30.

Column: DAICEL CHIRALPAK IA 20 x 250 mm, 5 pm.

Mobile phase: C0₂/MeOH = 70/30.

Flow rate: 30 mL/min.

Temperature: 40 °C.

Back pressure: 120 bar.

Detection: 254 nm.

Ή-NMR, MS and LCMS retention time data of Compound-75 are shown in Table 3.

Ή-NMR, MS and LCMS retention time data of Compound-76 are shown in Table 3. Synthesis of Compound-77 and Compound-78

2- [2-(l-Hydroxyethyl)-lH-imidazol-l-yl]-2-(5-{[4-(hydroxymethyl)phenyl]ethynyl}-l,2-oxazol-

3- yl)ethan-l-ol (Compound-77)

l-{l-[l-(5-{[4-(Hydroxymethyl)phenyl]ethynyl}-l,2-oxazol-3-yl)ethenyl]-lH-imidazol-2- yl}ethan-l-ol (Compound'78)

Step-1)

3-(2,2-Dimethyl-l,3-dioxolan-4-yl)-5"iodo-l,2-oxazole

To a solution of tributyl(ethynyl)stannane (0.66 mL) in THF (23 mL) were added TEA (0.81 mL) and a THF solution of (4Z)-N-hydroxy-2,2-dimethyl-l,3-dioxolane-4-carboximidoyl chloride (0.42 g). After stirring for 16 hours at room temperature, the reaction was quenched with water. The mixture was diluted with EtOAc followed by washing with water and brine. The organic phase was separated, dried over MgSO-i, and concentrated in vacuo to give a crude product which was used in the next step without further purification.

To a solution of the crude product in THF (23 mL) was added a THF solution of iodine (0.59 g). After stirring for 18 hours at room temperature, the reaction was quenched with an aqueous sodium thiosulfate until the brown color of iodine disappeared. The aqueous solution was extracted with EtOAc and the combined organic layer was dried over MgSC , filtered and concentrated in vacuo. The residue was purified with OH-type silica gel column chromatography (0-20 % EtOAc in n-hexane) to give the title compound (0.36 g, 52 % yield) as colorless oil.

MS (ESI) m/z : 296 [M+lh

RT = 1.021 min.

LCMS condition : B.

Step -2)

(4-{[3-(2,2-Dimethyl- l,3-dioxolan-4-yl)" l,2-oxazol-5-yl]ethynyl}phenyl)methanol

To a solution of 3-(2,2-dimethyl-l,3-dioxolan-4-yl)-5-iodo-isoxazole (0.28 g) and (4- ethynylphenyOmethanol (0.25 g) in acetonitrile (9.4 mL) were added Cul (0.11 g), SUPERSTABLE Pd(0) CATALYST, (0.60 g) and TEA (1.3 mL). The reaction mixture was stirred for 18 hours at room temperature. The resulting precipitate was filtered out and the filtrate was concentrated in vacuo. The residue was purified with amino-type silica gel column chromatography (20-65 % EtOAc in n-hexane) to give the title compound (0.22 g, 76 % yield) as yellow solid. MS (ESI) m/z : 300 [M+l]⁺.

RT = 0.960 min.

LCMS condition : B. Step -3)

l-(5-{[4-(Hydroxymethyl)phenyl]ethynyl}- l,2-oxazol"3-yl)ethane- l,2-diol

To a solution of [4-[2-[3-(2,2-dimethyl- l,3-dioxolan-4-yl)isoxazol-5- yl]ethynyl]phenyl]methanol (0.25 g,) in Me OH (4.0 niL) and water (l.O mL) was added TFA (0.50 mL). After stirring for 2.5 hours at 60 °C, the resulting mixture was concentrated in vacuo. The residue was purified with OH-type silica gel column chromatography (50- 100 % EtOAc in n-hexane) to give the title compound (0.13 g, 58 % yield) as colorless powder.

MS (ESI) m/z : 260 [M+l]⁺.

RT = 0.544 min.

LCMS condition : B.

Step-4)

2-{[Tert-butyl(diphenyl)silyl]oxy}- l-(5-{[4-({[tert-

hane- 1,2-diol (0.13 g) in DMF (2.4 mL) were added imidazole (0.16 g) and tert- butylchlorodiphenylsilane (0.26 mL). After stirring for 1 hour at 0 °C, the reaction was quenched with a saturated aqueous ammonium chloride and extracted with EtOAc. The organic layer was passed through a phase separator and concentrated in vacuo. The residue was purified with OH-type silica gel column chromatography (0-20 % EtOAc in n-hexane) to give the title compound (0.30 g, 83 % yield) as colorless oil.

Ή NMR (400 MHz, CHLOROFORM-d) δ ppm 1.08 (s, 9 H), 1.10 (s, 9 H), 3.01 (d, J=4.8 Hz, 1 H), 3.87 (dd, J=10.3, 6.7 Hz, 1 H), 4.00 (dd, J=10.3, 4.0 Hz, 1 H), 4.78 (s, 2 H), 4.96 - 5.03 (m, 1 H), 6.51 (s, 1 H), 7.33 - 7.48 (m, 14 H), 7.53 (d, J=8.2 Hz, 2 H), 7.60 - 7.71 (m, 8 H).

LCMS : not determined. Step -5)

2-{[Tert-butyl(diphenyl)silyl]oxy}- l-(5-{[4-({[tert- butyl(diphenyl)silyl]oxy}methyl)phenyl]ethynyl}-l,2-oxazol-3-yl)ethyl methanesulfonate BDPS

To an ice-cooled solution of 2-[tert-butyl(diphenyl)silyl]oxyl-[5-[2-[4-[[tert- butyl(diphenyl)silyl]oxymethyl]phenyl]ethynyl]isoxazol-3^_yl]ethanol (0.17 g) in CHCI3 (2.3 mL) were added TEA (94 μΐ_^) and methanesulfonyl chloride (32 μ . After stirring for 30 minutes at room temperature, the reaction was quenched with a saturated aqueous sodium bicarbonate and extracted with CHCI3. The organic layer was passed through a phase separator and concentrated in vacuo to give the title compound (0.19 g, quant.) as colorless oil.

Ή NMR (400 MHz, CHLOROFORM-d) δ ppm 1.07 (s, 9 H), 1.10 (s, 9 H), 3.03 (s, 3 H), 4.06 - 4.16 (m, 2 H), 4.79 (s, 2 H), 5.78 - 5.84 (m, 1 H), 6.55 (s, 1 H), 7.35 - 7.48 (m, 14 H), 7.53 (d, J=8.2 Hz, 2 H), 7.62^■ 7.70 (m, 8 H).

LCMS : not determined.

Step -6)

l-{l-[2-{[Tert-butyl(diphehyl)silyl]oxy}-l-(5-{[4-({[tert- butyl(diphenyl)silyl]oxy}methyl)phenyl]ethynyl}-l,2-oxazol-3^_yl)ethyl]-lH-imidazol-2- yl}ethan-l-one

To a solution of l-(lH"imidazol-2-yl)ethanone (26 mg) and [2-[tert"butyl(diphenyl)silyl]oxy-l- [5-[2-[4-[[tert-butyl(diphenyl)silyl]oxymethyl]phenyl]ethynyl]isoxazol-3-yl]ethyl]

methanesulfonate (0.18 g) in acetonitrile (2.3 mL) was added potassium carbonate (94 mg). After stirring for 22 hours at 80 °C, l-(lH-imidazol-2-yl)ethanone (26 mg) and potassium carbonate (94 mg) was added. The mixture was further stirred for 8 hours at 80°C. The reaction was quenched with water and extracted with CHCI3. The organic layer was passed through a phase separator and concentrated in vacuo. The residue was purified with OH- type silica gel column chromatography (O20 % EtOAc in n-hexane) to give the title compound (93 mg, 50 % yield) as colorless oil.

Ή NMR (400 MHz, CHLOROFORM-d) 8 ppm 0.96 (s, 9 H), 1.10 (s, 9 H), 2.68 (s, 3 H), 4.20 - 4.31 (m, 2 H), 4.78 (s, 2 H), 6.37 (s, 1 H), 6.97 - 7.04 (m, 1 H), 7.20 (s, 1 H), 7.33 (s, 1 H), 7.34^■ 7.54 (m, 20 H), 7.64^■ 7.71 (m, 4 H).

LCMS : not determined. Step -7)

l-{l-[2-{[Tert-butyl(diphenyl)silyl]oxy}-l-(5-{[4-({[tert- butyl(diphenyl)silyl]oxy}methyl)phenyl]ethynyl}-l,2-oxazol-3-yl)ethyl]-lH-imidazol-2- yl}ethan-l-ol

To an ice-cooled solution of l-[l-[2-[tert-butyl(diphenyl)silyl]oxy-l-[5-[2-[4-[[tert- butyl(diphenyl)silyl]oxymethyl]phenyl]ethynyl]isoxazol-3-yl]ethyl]imidazol-2-yl]ethanone (91 mg) in MeOH (2.2 mL) was added sodium borohydride (42 mg). After stirring for 20 minutes at 0 °C, the reaction was quenched with water and extracted with CHCI3. The organic layer was passed through a phase separator and concentrated in vacuo to give the title compound (90 mg, 99 % yield) as colorless powder.

Ή NMR (400 MHz, CHLOROFORM-d) 8 ppm 0.97 (s, 4.5 H), 1.00 (s, 4.5 H), 1.10 (s, 9 H), 1.65 (d, J=6.5 Hz, 1.5 H), 1.71 (d, J=6.5 Hz, 1.5 H), 2.19 (br d, J=6.0 Hz, 0.5 H), 2.55 (br d, J=6.6 Hz, 0.5 H), 4.15 - 4.24 (m, 1 H), 4.29 - 4.41 (m, 1 H), 4.78 (s, 2 H), 4.94 - 5.03 (m, 0.5 H), 5.06 - 5.14 (m, 0.5 H), 5.83 - 5.90 (m, 0.5 H), 5.93 - 5.99 (m, 0.5 H), 6.30 (s, 0.5 H), 6.31 (s, 0.5 H), 6.93 (d, J=1.3 Hz, 0.5 H), 7.03 (d, J=l.l Hz, 0.5 H), 7.04 - 7.05 (m, 0.5 H), 7.06 (d, J=1.3 Hz, 0.5 H), 7.32 - 7.53 (m, 18 H), 7.54 - 7.59 (m, 2 H), 7.64 - 7.70 (m, 4 H).

LCMS : not determined.

Step-8)

2-[2-(l-Hydroxyethyl)-lH-imidazol-l-yl]-2-(5-{[4-(hydroxymethyl)phenyl]ethynyl}-l,2-oxazol- 3-yl)ethan-l-ol (Compound-77) and

l-{l-[l-(5-{[4-(Hydroxymethyl)phenyl]ethynyl}-l,2-oxazol-3-yl)ethenyl]-lH-imidazol-2- yl}ethan-l-ol (Compound-78)

Compound-77 Compound-78 To a solution of l-[l-[2-[tert-butyl(diphenyl)silyl]oxyl-[5-[2-[4-[[tert- butyl(diphenyl)silyl]oxymethyl]phenyl]ethynyl]isoxazol-3-yl]ethyl]imidazol-2-yl]ethanol (90 mg) in THF (l.lmL) was added TBAF (0.33 mL, 1 mol L solution in THF). After stirring for 20 minutes at room temperature, the reaction was quenched with a saturated aqueous ammonium chloride and extracted with CHCI3. The organic layer was passed through a phase separator and concentrated in vacuo. The residue was purified with OH-type silica gel column chromatography (0-15 % MeOH in CHCI3) to give Compound-78 (11 mg, 31 % yield) as colorless solid and impurities. The crude material was re-purified with prep-HPLC and preparative chromatography (10% MeOH in CHCI3) to give Compound-77 (3.6 mg, 9.4 % yield) as colorless powder.

!H-NMR, MS and LCMS retention time data of Compound-77 are shown in Table 3.

Ή-NMR, MS and LCMS retention time data of Compound-78 are shown in Table 3.

Synthesis of Compound-82

2-Hydroxy-2-{l-[(4-{[4-(3-hydroxypropyl)phenyl]ethynyl}phenyl)methyl]-lH-imidazol-2- yl}propanoic acid formic acid salt

Step-1)

Ethyl {l-[(4-iodophenyl)methyl]- lH-imidazol-2-yl}(oxo)acetate

The title compound was obtained in the manner as with the "Synthesis of Compound- 10: step-1" using the corresponding materials,

MS (ESI) m/z 385 [M+l]⁺.

RT = 1.120 min.

LCMS condition : B.

Step-2)

ol-2-yl}propanoate

The title compound was obtained in the manner as with the "Synthesis of Compound- 15: step-1" using the corresponding materials.

MS (ESI) m/z 401 [M+l]⁺.

RT = 1.041 min.

LCMS condition : A. Step -3) 2-Hydroxy-2-{l-[(4-{[4-(3-hydroxypropyl)phenyl]ethynyl}phenyl)methyl]- 1H- imidazol-2-yl}propanoic acid formic acid salt (Compound-82)

Compound-82 was obtained in the manner as with the "Synthesis of Compound-68: step-1" and "Synthesis of Compound- 15: step-2" using the corresponding materials. Ή-NMR, MS and LCMS retention time data of Compound-82 are shown in Table 3. Synthesis of Compound-83

2-Hydroxy-2-{l-[(5-{[4-(3-hydroxypropyl)phenyl]ethynyl}-l,2-oxazol-3-yl)methyl]-lH- imidazol-2-yl}propanoic acid

Step-1)

Ethyl 2-(l"benzyl- lH"imidazol-2-yl)-2-hydroxypropanoate

The title compound was obtained in the manner as with the "Synthesis of Compound- 15· step-1" using the corresponding materials.

MS (ESI) m/z : 275 [M+l]⁺.

RT = 0.766 min.

LCMS condition : A.

Step-2)

Eth l 2-hydroxy-2-(lH-imidazol-2-yl)propanoate

To a stirred solution of ethyl 2-(l-benzylimidazol-2-yl)-2-hydroxy-propanoate (50 mg) in EtOH (1.8 mL) was added 7.5 wt% Pd/C (25 mg). The mixture was stirred under hydrogen atmosphere at room temperature for 30 minutes and at 70 °C for 30 minutes. The insoluble matter was filtered out and the filtrate was concentrated in vacuo to give the title compound (35 mg, quant.) as colorless powder.

Ή NMR (400 MHz, DMSOd6) δ ppm 1.15 (t, J=7.1 Hz, 3 H), 1.70 (s, 3 H), 4.00 - 4.19 (m, 2 H), 6.40 (br s, 1 H), 7.07 (s, 2 H), 12.89 (br s, 1 H).

LCMS : not determined.

Step -3)

2-Hydroxy-2-{l-[(5-{[4-(3-hydroxypropyl)phenyl]ethynyl}-l,2-oxazol-3-yl)

imidazol-2-yl}propanoic acid (Compound-83)

Compound-83 was obtained in the manner as with the "Synthesis of Compound-53^ step-2", "Synthesis of Compound-53: step-3" and "Synthesis of Compound- 15: step-2" using the corresponding materials.

Ή-NMR, MS and LCMS retention time data of Compound-83 are shown in Table 3. Synthesis of Compound-84

3-(2-{4-[(3-{[2-(l-Hydroxyethyl)-lH-imidazol-l-yl]methyl}-l,2-oxazol-5- yl)ethynyl]phenyl}ethyl)-4-(hydroxymethyl)-l,3-oxazolidin-2-one

Step-1)

Tert-butyl (2-{4-[(3-{[2-(l-hydroxyethyl)-lH-imidazol-l-yl]methyl}-l,2-oxazol-5- yl)ethynyl]phenyl}ethyl)oxetan-3-ylcarbamate

The title compound was obtained in the manner as with the "Synthesis of Compound-68" using the corresponding materials.

MS (ESI) m/z : 493 [M+l]⁺.

RT = 0.696 min.

LCMS condition : B.

Step -2)

3-(2-{4-[(3-{[2-(l-Hydroxyethyl)- lH-imidazol- l-yl]methyl}- l,2-oxazol-5- yl)ethynyl]phenyl}ethyl)-4-(hydroxymethyl)- l,3-oxazolidin-2-one (Compound-84)

To a stirred solution of tert-butyl (2-{4-[(3-{[2-(l-hydroxyethyl)-lH-imidazol-l-yl]methyl}- l,2- oxazol-5-yl)ethynyl]phenyl}ethyl)oxetan-3-ylcarbamate (20 mg) in CHCI3 (2.4 mL) was added TFA (O.6 mL). The mixture was stirred at room temperature for 30 minutes. The reaction was quenched with a saturated aqueous sodium bicarbonate and extracted with CHCI3. The organic layer was passed through a phase separator and concentrated in vacuo to give the title compound (18 mg, 99 % yield) as colorless powder.

Ή-NMR, MS and LCMS retention time data of Compound-84 are shown in Table 3.

Synthesis of Compound-89

l-{l-[(5-{[4-(2-Hydroxyethyl)phenyl]ethynyl}-l,2-oxazol-3-yl)methyl]- lH-imidazol-2-yl}ethan- l-ol

Step- 1)

3-{[2-(l-{[Tert-butyl(dimethyl)silyl]oxy}ethyl)- lH-imidazol- l-yl]methyl}-5-ethynyl-l,2-oxazole

To a stirred solution of l-{l-[(5-ethynyM,2-oxazol-3-yl)methyl]-lH-imidazol-2-yl}ethan-l-ol (Intermediate-4) (50 mg) in DMF (2.3 mL) were added imidazole (24 mg) and tert- butyldimethylsilyl chloride (42 mg). The mixture was stirred at room temperature for 2 hours. The reaction was quenched with water and extracted with EtOAc. The organic layer was washed with brine and dried over MgS04 and concentrated in vacuo. The residue was purified with OH-type silica gel column chromatography Xl-10 %-MeOH in -GHCI3-) to give the title compound (60 mg, 79 % yield) as pale yellow oil.

MS (ESI) m/z : 332 [M+l]⁺.

RT = 0.747 min.

LCMS Condition : B.

Step -2)

3-{[2-(l-{[Tert-butyl(dimethyl)silyl]oxy}ethyl)-lH-imidazol-l-yl]methyl}-5-{[4-(2-{[tert- butyl(dimethyl)silyl]oxy}ethyl)phenyl]ethynyl}-l,2-oxazole

The title compound was obtained in the manner as with the "Synthesis of Compound-68: step-1" using the corresponding materials.

MS (ESI) m/z : 566 [M+l]⁺.

RT = 1.287 min.

LCMS condition : B.

Step -3)

1- {l-[(5-{[4-(2-Hydroxyethyl)phenyl]ethynyl}-l,2-oxazol-3-yl)methyl]-lH-imidazol-2-yl}ethan- l-ol (Compound-89) and

2- {4-[(3-{[2-(l-{[tert-butyl(dimethyl)silyl]oxy}ethyl)-lH-imidazol-l-yl]methyl}-l,2-oxazol-5- yl)ethynyl]phenyl}ethan- l-ol

To a stirred solution of 3-{[2-(l-{[Tert-butyl(dimethyl)silyl]oxy}ethyl)- lH-imidazoM- yl]methyl}-5-{[4-(2-{[tert-butyl(dimethyl)silyl]oxy}ethyl)phenyl]ethynyl}- 1,2-oxazole (75 mg) in THF (1.3 mL) was added 1 mol/L aqueous HC1 (1.3 mL). The mixture was stirred at room temperature for 1 hour. The reaction mixture was quenched with 1 mol/L aqueous NaOH (1.5 mL) and extracted with CHCI3. The organic layer was passed through a phase separator and concentrated in vacuo. The residue was purified with amino-type silica gel column chromatography (25-100 % EtOAc in n-hexane and then 10 % MeOH in CHCk) to give Compound-89 (l.O mg, 2.2 % yield) as colorless oil and 2-{4-[(3-{[2-(l-{[tert- butyl(dimethyl)silyl]oxy}ethyl)- lH-imidazol- l-yl]methyl}- l,2-oxazol"5- yl)ethynyl]phenyl}ethan-l-ol (Intermediate 89" 1, 61 mg) as a crude product of colorless oil. The deprotection position of the TBS group was determined from the Ή-NMR signal peak of the crude intermediate (aldehyde peak observed) in the next step (Synthesis of Compound- 90, step-1).

Ή-NMR, MS and LCMS retention time data of Compound-89 are shown in Table 3.

Intermediate 89-1:

MS (ESI) m/z : 452 [M+l]⁺.

RT = 1.223 min.

LCMS Condition : A.

Synthesis of Compound-90

l-(l-{[5-({4-[2-(Morpholin-4-yl)ethyl]phenyl}ethynyl)-l,2-oxazol-3-yl]methyl}-lH-imidazol-2- yl)ethan-l-ol

Step- 1)

4-(2-{4-[(3-{[2-(l-{[Tert-butyl(dimethyl)silyl]oxy}ethyl)- lH-imidazol- l-yl]methyl}- l,2-oxazol-5- yl)ethynyl]phenyl}ethyl)morpholine

To an ice- cooled solution of 2-{4-[(3-{[2-(l-{[Tert-butyl(dimethyl)silyl]oxy}ethyl)- lH-imidazol- l-yl]methyl}- l,2-o^zol-5-yl)ethyjiyl]phenyl}ethan" l"ol (Intermediate 89" 1, 60 mg) in CHCI3 (1.3 mL) were added sodium bicarbonate (33 mg) and Dess-Martin Periodinane (62 mg). The mixture was stirred at room temperature for 30 minutes. The reaction was quenched with a half-saturated aqueous sodium thiosulfate and extracted with CHCI3. The organic layer was passed through a phase separator and concentrated in vacuo to give a crude product as yellow amorphous. Ή-NMR measurement (CHROLOFORM-d) showed a signal peak at 6=9.77 ppm. The crude product was used in the next step without further purification.

To a stirred solution of the crude product in CHCI3 (1.3 mL) was added morpholine (14 μ∑) and NaBH(OAc)3 (37 mg). The mixture was stirred at room temperature for 17 hours. After addition of morpholine (58 μΌ and NaBH(OAc)3 (0.14 g), the mixture was stirred at room temperature for 1 hour. The reaction was quenched with a saturated aqueous sodium bicarbonate and extracted with CHCI3. The organic layer was passed through a phase separator and concentrated in vacuo. The residue was purified with amino-type silica gel column chromatography (O-IOO % EtOAc in n- hexane and then 10 % Me OH in CHCI3) to give the title compound (5.9 mg, 8.5 % yield) as colorless oil.

MS (ESI) m/z : 521 [M+l]⁺.

RT = 1.028 min.

LCMS Condition : A. Step -2)

l-(l-{[5-({4-[2-(Morpholin-4-yl)ethyl]phenyl}ethynyl)-l,2-oxazol-3-yl]methyl}- lH-imidazol-2- yl)ethan- l-ol (Compound-90)

To a stirred solution of 4-(2-{4-[(3-{[2-(l-{[Tert-butyl(dimethyl)silyl]oxy}ethyl)-lH-imidazol-l- yl]methyl}-l,2-oxazol-5-yl)ethynyl]phenyl}ethyl)morpholine (5.9 mg) in THF (l mL) was added 1 mol/L aqueous HC1 (l mL). The mixture was stirred at room temperature for 27 hours. The reaction mixture was quenched with 1 mol/L aqueous NaOH (l mL) and extracted with CHCI3. The organic layer was passed through a phase separator and concentrated in vacuo. The residue was purified with amino-type silica gel column chromatography (50-100 % EtOAc in n-hexane and then 10 % Me OH in CHCI3) to give the title compound (2.5 mg, 55 % yield) as colorless amorphous.

Ή-NMR and MS data of Compound-90 are shown in Table 3.

Synthesis of Compound-91

l-[l-({5-[4-(l-Aminocyclopropyl)buta-l,3-diyn-l-yl]-l,2-oxazol-3-yl}methyl)-lH-imidazol-2- l]ethan-l-ol

Step-1)

5-(Bromoethynyl)-3-{[2-(l-{[tert-butyl(dimethyl)silyl]oxy}ethyl)-lH-imidazol-l-yl]methyl}- 1,2-oxazole

To a cooled (0 °C) solution of methyl l-(2-trimethylsilylethoxymethyl)imidazole-4-carboxylate (67 mg) in acetone (l.l mL) were added silver trifluoroacetate (4.4 mg) and N- bromosuccinimide (41 mg) in portions. After stirring for 30 minutes at 0 °C, the reaction was quenched with a saturated aqueous sodium bicarbonate and extracted with EtOAc. The organic layer was washed with brine, dried over MgS04 and concentrated in vacuo. The residue was purified with OH-type silica gel column chromatography (25-80 % EtOAc in n- hexane) to give the title compound (74 mg, 91 % yield) as yellow oil.

MS (ESI) m/z : 410 [M+l]⁺.

RT = 0.842 min.

LCMS condition : B. Ste -2)

1 - [4- (3-{[2 - ( 1 -{[Tert-butyl(dime^

yl)buta- 1,3-diyn- l-yl]cyclopropan- 1-amine

To a cooled (0 °C) solution of-5 bromoethynyl)-3-{[2^

lH-imidazol-l-yl]methyl}-l,2-oxazole (74 mg), l-ethynylcyclopropan- 1-amine and 10% aqueous butylamine (1.5 mL) in THF (0.5 mL) were added dropwise a solution of copperG) chloride (1.3 mg) and hydroxylamine hydrochloride (3.1 mg) in 10% aqueous butylamine (0.20 mL). After stirring for 1 hour at 0 °C, the reaction was quenched with a half-saturated aqueous ammonium chloride and extracted with EtOAc. The organic layer was washed with brine, dried over MgS04 and concentrated in vacuo. The residue was purified with amino- type silica gel column chromatography (15"80 % EtOAc in n-hexane) to give the title compound (15 mg, 20 % yield) as yellow oil.

MS (ESI) m/z : 411 [M+l]⁺.

RT = 0.562 min.

LCMS condition : B.

Step -3)

l-[l-({5-[4-(l-Aminocyclopropyl)buta-l,3-diyn-l-yl]-l,2-oxazol-3-yl}methyl)-lH-imidazol-2- l]ethan-l-ol (Compound-9l)

^ ^ Compound-91

Compound-91 was obtained in the manner as with the "Synthesis of Compound-90: step-2" using the corresponding materials.

Ή-NMR, MS and LCMS retention time data of Compound-91 are shown in Table 3.

Synthesis of Compound-93

l-{5-Methyl-l-[(5-phenyl-l,2-oxazol-3-yl)methyl]-lH-imidazol-2-yl}ethan-l-ol

Compound-93

Step-1)

l-{4-methyl-l-[(5-phenyl-l,2-oxazol-3-yl)methyl]-lH-imidazol-2-yl}ethan-l-one (Intermediate 93-1) and

-l-{5-methyl-l-[(5-phen^^^ (Intermediate

Intermediate 93-1 Intermediate 93-:

To a solution of l-(4-methyl-lH-imidazol-2-yl)ethanone (58 mg) and 3-(bromomethyl)-5- phenyHsoxazole (0.11 g) in acetonitrile (4 mL) was added potassium carbonate (0.13 g). The reaction mixture was stirred for 3 days at room temperature. The reaction was quenched with water and extracted with CHCk. The organic layer was passed through a phase separator and concentrated in vacuo. The residue was purified with OH-type silica gel column chromatography (25"65 % EtOAc in n-Hexane) to give l-{4-methyl-l-[(5-phenyl-l,2- oxazol-3-yl)methyl]-lH-imidazol-2-yl}ethan-l-one (Intermediate 93- 1, 56 mg, 43 % yield) as colorless solid and a high-polar crude product. The crude product was purified with OH-type silica gel column chromatography (25^*75 % EtOAc in n-hexane) to give l-{5-methyl-l-[(5- phenyl-l,2-oxazol-3-yl)methyl]-lH-imidazol-2-yl}ethan-l-one (Intermediate 93-2, 31 mg, 24 % yield) as colorless solid. The chemical structure of both products were analyzed and determined by Ή-NMR NOE spectrum.

Intermediate 93-I:

MS (ESI) m/z : 282[M+l]⁺.

RT = 0.937 min.

LCMS condition : B

Intermediate 93-2:

MS (ESI) m/z : 282[M+l]⁺.

RT = 0.918 min.

LCMS condition : B. Step-2)

l-{5-Methyl-l-[(5-phenyl-l,2-oxazol-3-yl)methyl]-lH-imidazol-2-yl}ethan-l-ol (Compound-93)

ompoun -

Compound-93 was obtained in the manner as with the "Synthesis of Compound-2" using the corresponding materials.

Ή-NMR, MS and LCMS retention time data of Compound-93 are shown in Table 3.

Synthesis of Compound-94

4-{[3-({2- [(IS)- 1-h droxyethyl]- lH-imidazol- l-yl}methyl)- l,2-oxazol-5-yl]ethynyl}phenol

Step-1)

4-{[3-({2-[(lS)-l-hydroxyethyl]-lH-imidazol-l-yl}methyl)-l,2-oxazol-5-yl]ethynyl}phenol (Compound-94)

To a solution of 4-[2-[3-[[2-[(lS)-l-tetrahydropyran-2-yloxyethyl]imidazoM- yl]methyl]isoxazol-5-yl]ethynyl]phenol (30 mg) in CHC1₃ (0.76 mL) was added TFA (0.20 mL). The reaction mixture was stirred at room temperature for 30 minutes. After cooling to 0 °C, water was added and the mixture was adjusted to being basic by addition of 1 mol/L aqueous NaOH and then extracted with CHCI3. The organic extract was passed through a phase separator and concentrated in vacuo. The residue was purified with OH-type silica gel column chromatography (0-15 % MeOH in CHCI3) to give the title compound (5.0 mg, 21 % yield) as colorless amorphous.

Ή-NMR, MS and LCMS retention time data of Compound-94 are shown in Table 3. Synthesis of Compound-95

(2S)-3-(4-{[3-({2-[(lS)-l-Hydroxyethyl]-lH-imidazol-l-yl}methyl)-l,2-oxazol-5- yl] e thynyl}p henoxy)prop ane - 1 , 2 - diol

Step-1)

5-[(4-{[(4R)-2,2^dimethyl-l,3-dioxolan-4-yl]methoxy}phenyl)ethynyl]-3-[(2-{(lS)-l-[(oxan-2-

To a solution of 4-[2-[3-[[2-[(lS)-l"tetrahydropyran-2-yloxyethyl]imidazol-l- yl]methyl]isoxazol-5-yl]ethynyl]phenol (30 mg) and [(4S)-2,2-dimethyl-l,3-dioxolan-4- yl]methyl 4-methylbenzenesulfonate (26 mg) in DMF (0.76 mL) was added potassium carbonate (16 mg). The mixture was stirred at 100 °C for 1 hour. After cooling, the mixture was quenched with water and extracted with EtOAc. The organic extract was concentrated in vacuo. The residue was purified with OH-type silica gel column chromatography (10- 100 % EtOAc in n-hexane) to give the title compound (31 mg, 81 % yield) as colorless oil. MS (ESI) m/z : 508 [M+l]⁺.

RT = 0.808 min.

LCMS condition : B.

Step -2)

(2S)-3-(4-{[3-({2-[(lS)-l-hydroxyethyl]-lH-imidazol-l-yl}methyl)-l,2-oxazol-5- yl]ethynyl}phenoxy)propane-l,2"diol (Compound-95)

To a solution of 5-[2-[4-[[(4R)-2,2-dimethyl-l,3-dioxolan-4-yl]methoxy]phenyl]ethynyl]-3-[[2- [(lS)^_l-tetrahydropyran-2-yloxyethyl]imidazol-l-yl]methyl]isoxazole (20 mg) in MeOH (0.39 mL) and water (39 μΐ.) was added p-TsOH monohydrate (18 mg). After stirring at room temperature for 16_ho_urs, the mixture _was quenched with a saturated -aqueous sodium bicarbonate and extracted with CHCI3. The organic extract was passed through a phase separator and concentrated in vacuo. The residue was purified with OH-type silica gel column chromatography (5- 15 % MeOH in CHCI3) to give the title compound (12 mg, 78 % yield) as colorless amorphous.

Ή-NMR, MS and LCMS retention time data of Compound-95 are shown in Table 3.

Synthesis of Compound- 101

(S)-2-((4-(2-(3-((2-(l-hydroxyethyl)-lH-imidazol-l-yl)methyl)isoxazol-5- yl) vinyl)phenoxy) me thy l)p rop ane - 1 , 3 - diol

Step-1)

Ethyl 5-({4-[(2,2'dimethyl-l,3-dioxan-5-yl)methoxy]phenyl}ethynyl)-l,2-oxazole-3- carboxylate

The title compound was obtained in the manner as with the "Synthesis of Intermediate-8: step-1" using the corresponding materials. MS (ESI) m/z : 386[M+l]⁺.

RT = 1.252 min.

LCMS condition : B. Step-2) 2-({4-[2-{3-[(2-{(lS)-l-[(oxan-2-yl)oxy]ethyl}-lH-imidazol-l-yl)methyl]-l,2-oxazol-5- yl}ethenyl]phenoxy}methyl)propane-l,3^_diol

To a solution of ethyl 5-[2-[4-[(2,2-dimethyM,3-dioxan-5- yl)methoxy]phenyl]ethynyl]isoxazole-3-carboxylate (0.32 g) in EtOH (2.8 mL) was added NaBH4 (0.16 g) at 0 °C. After stirring for 2 hours at room temperature, the reaction was quenched with water. The aqueous layer was extracted with CHC . The organic layer was passed through a phase separator and concentrated in vacuo. The residue was purified with OH-type silica gel column chromatography (10-60 % EtOAc in n-hexane) to give a product, which was used in the next step without further purification.

To a solution of the product in THF (2.7 mL) were added 2-[(lS)-l-tetrahydropyran-2- yloxyethylMH-imidazole (0.30 g), TMAD (0.42 g), PBua (0.48 g) at 0 °C. After stirring for 2 hours at room temperature, the mixture was concentrated in vacuo. The residue was diluted with water and EtOAc, and extracted with EtOAc. The organic layer was dried over MgS04, and concentrated in vacuo. The residue was purified with OH-type silica gel column chromatography (5 % MeOH in CHCb) and then re-purified with prep-HPLC to give the title compound (42 mg, 10 % yield) as colorless solid.

MS (ESI) m/z : 484[M+l]⁺.

RT = 0.584 min.

LCMS condition : B.

Step -3)

(S)-2-((4-(2-(3-((2-(l-hydroxyethyl)-lH-imidazol-l-yl)methyl)isoxazol-5- yl)vinyl)phenoxy)methyl)propane- l,3-diol(Compound- 101)

Compound-101

Compound-101 was obtained in the manner as with the "Synthesis of Compound-94: step-l'^! using the corresponding materials.

Ή-NMR, MS and LCMS retention time data of Compound-101 are shown in Table 3. Synthesis of Compound- 102

(lS)-l-(l-{[5-({4-[(Piperidin-4-yl)oxy]phenyl}ethynyl)-l,2-oxazol-3-yl]methyl}-lH-imidazol-2- l)ethan-l-ol

Compound-102

Step-1)

5-((4-(Piperidin-4-yloxy)phenyl)ethynyl)-3-((2-((lS)-l-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)- -imidazol-l-yl)methyl)isoxazole

A round bottomed flask was charged with 5-Ethynyl-3-[(2-{(lS)-l-[(oxan-2-yl)oxy]ethyl}-lH- imidazol-l-yl)methyl]-l,2-oxazole (Intermediate-6, 48 mg), 4-(4-iodophenoxy)piperidine (40 mg), PdCl2(PPhs)2 (4.6 mg) and Cul (2.5 mg). The flask was evacuated and backfilled with nitrogen followed by addition of DMF (1.3 mL) and TEA (0.18 mL). The mixture was placed into a preheated oil bath (80 °C) and stirred for 1 hour. The reaction mixture was diluted with CHCI3 followed by washing with 10% aqueous ammonium hydroxide and brine. The organic phase was separated, dried over MgSC*4, and concentrated under reduced pressure. The residue was purified with amino-type silica gel chromatography (0-5 % MeOH in EtOAc) to give the title compound (40 mg, 64 % yield) as orange oil.

MS (ESI) m/z : 477 [M+l]⁺.

RT = 0.783 min.

LCMS condition : A. Step-2)

(lS)^-(l-{[5-({4-[(Piperidin-4-yl)oxy]phenyl}ethynyl)-l,2-oxazol-3 l]methyl} H-imidazol-2- yl)ethan-l-ol (Compound- 102)

Compound-102

To a solution of 5-((4-(Piperidin-4-yloxy)phenyl)ethynyl)-3-((2-((lS)-l-((tetrahydro-2H-pyran- 2-yl)oxy)ethyl)-lH-imidazol-l-yl)methyl)isoxazole (37 mg) in MeOH (0.78 mL) was added p- TsOH monohydrate (52 mg) at room temperature. After stirring for 1 hour, the reaction mixture was basified with 10% aqueous sodium carbonate and extracted with 10 % MeOH in CHCI3 three times. The combined organic layer was dried over MgS04, filtered and concentrated in vacuo. The residue was purified with amino-type silica gel chromatography (0"15 % MeOH in EtOAc) to give the title compound (20 mg, 66 % yield) as amorphous.

Ή-NMR, MS and LCMS retention time data of Compound-102 are shown in Table 3.

Synthesis of Compound- 103

(lS)-l-(l-{[5-({4-[(l-methylpiperidin-4-yl)oxy]phenyl}ethynyl)-l,2-oxazol-3-yl]

imidazol-2- l)ethan- l"ol

Compound-103

Step-1)

(lS)-l-(l-{[5-({4-[(l-methylpiperidin-4-yl)oxy]phenyl}ethynyl)-l,2-oxazol-3-yl]

imidazol-2-yl)ethan-l-ol (Compound-103)

To a solution of (lS)-l-(l-{[5-({4-[(piperidin-4-yl)oxy]phenyl}ethynyl)-l,2-oxazol-3-yl]methyl}- lH-imidazol-2-yDethan-l-ol (15 mg) in Me OH (0.38_.mL) was added 35% formaldehyde (8.8 μ at room temperature. After stirring for 1 hour, NaBH(OAc)3 (16 mg) was added and the resulting mixture was stirred for another 1 hour. The reaction was quenched with a half- saturated aqueous ammonium chloride and the resulting mixture was basified with a saturated aqueous sodium bicarbonate. The whole mixture was extracted three times with 5 % MeOH-CHCl3 and the combined organic layer was dried over MgSC , filtered, and concentrated in vacuo. The residue was triturated with EtOAc and the solid was collected by filtration to give the title compound (8.4 mg, 54 % yield) as colorless solid.

Ή-NMR, MS and LCMS retention time data of Compound" 103 are shown in Table 3.

Synthesis of Compound- 109

3-(4-{[3-({2-[(lS)-l-Hydroxyethyl]-lH-imidazol-l-yl}methyl)-l,2-oxazol-5- yl]eth nyl}phenoxy)propan- l"ol

Step-1)

5-{[4-(3-{[Tert-butyl(dimethyl)silyl]oxy}propoxy)phenyl]ethynyl}-3-[(2-{(lS)-l-[(oxan-2- yl)oxy] ethyl}- lH-imidazol" l-yl)methyl]- 1,2-oxazole

To a stirred solution of [5-[2-[4"[3-[tert- butyl(dimethyl)silyl]oxypropoxy]phenyl]ethynyl]isoxazol-3-yl]methanol (4 g) and 2-[(lS)-l- tetrahydropyran-2-yloxyethyl]-lH-imidazole (2.3 g) in THF (69 mL) was added TMAD (2.3 g). Tributylphosphine (3.3 mL) was added at 0 °C under nitrogen atmosphere and the mixture was stirred for 2 hours at room temperature. The reaction mixture was quenched by water and extracted three times with EtOAc. The organic layer was dried over MgS04 and concentrated in vacuo onto ISOLUTE® HM"N. The residue was purified with OH-type silica gel column chromatography (16-94 % EtOAc in n-hexane) to give the title compound (5.8 g, quant.) as colorless oil.

MS (ESI) m/z 566 [M+l]⁺. RT = 0.890 min.

LCMS condition : C.

Step 2)

3-[4-({3-[(2-{(lS)-l-[(Oxan-2-yl)oxy]ethyl}-lH-imidazol-l-yl)methyl]-l,2-oxazol-5- yl}ethynyl)phenoxy]propan- l"ol

To a stirred solution of tert"butyl-dimethyl-[3-[4-[2-[3-[[2-[(lS)-l-tetrahydropyran-2- yloxyethyl]imidazol-l-yl]methyl]isoxazol-5-yl]ethynyl]phenoxy]propoxy]silane (5.8 g) in THF (0.10 L) was added TBAF (12 mL, 1 mol/L solution in THF). After stirring for 2 hours at 0 °C, reaction mixture was concentrated in vacuo onto ISOLUTE® HM-N. The residue was purified with amino-type silica gel column chromatography (0^_3 % MeOH in CHC ) to give the title compound (4.9 g, quant.) as pale yellow oil.

MS (ESI) m/z 606 [M+l]⁺.

RT = 0.680 min.

LCMS condition : C.

Step -3) 3-(4-{[3-({2-[(lS)-l-Hydroxyethyl]-lH-imidazol-l-yl}methyl)-l,2-oxazol-5- yl]ethynyl}phenoxy)propan- l-ol (Compound- 109)

Compound-109

Compound- 109 was obtained in the manner as with the "Synthesis of Compound- 102: step-2" using the corresponding materials.

Ή-NMR, MS and LCMS retention time data of Compound-109 are shown in Table 3. Synthesis of Compound-110

(lS)-l-{l-[(5-{[4-(3-{[(3S)-Oxolan-3-yl]amino}propyl)phenyl]ethynyl}-l,2-oxazol-3-yl)methyl]- lH-imidazol-2-yl}ethan-l-ol Compound-110

Step-1) 3-[4-({3-[(2-{(lS)-l-[(oxan-2-yl)oxy]ethyl}-lH-imidazol-l-yl)methyl]-l,2-oxazol-5- yl}ethynyl)phenoxy]propyl 4-methylbenzene- 1-sulfonate

The title compound was obtained in the manner as with the "Synthesis of Intermediate-4 step -3" using the corresponding materials.

MS (ESI) m/z 606 [M+l]⁺.

RT = 0.680 min.

LCMS condition : C.

Step-2)

N-{3-[4-({3-[(2-{(lS)-l-[(oxan-2-yl)oxy]ethyl}-lH-imidazol-l-yl)methyl]-l,2-oxazol-5- l}ethynyl)phenoxy]propyl}oxetan-3-amine

To a stirred solution of 3-[4-[2-[3-[[2-[(lS)-l-tetrahydropyran-2-yloxyethyl]imidazol-l- yl]methyl]isoxazol-5-yl]ethynyl]phenoxy]propyl 4-methylbenzenesulfonate (0.15 g) in CHCI3 (2.5 mL) and acetonitrile (2.5 mL) were added oxetan-3-amine (54 mg), DIPEA (0.13 mL) and potassium carbonate (0.17 g). After stirring for overnight at 60 °C, the reaction mixture was quenched with water and extracted three times with CHCI3. 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 (CHCI3) to give the title compound (60 mg, 48 % yield) as colorless oil.

MS (ESI) m/z 507 [M+l]⁺.

RT = 0.782 min.

LCMS condition : A. Step -3)

(lS)-l-{l-[(5-{[4-(3-{[(3S) xolan-3-yl]amino}propyl)phenyl]ethynyl}-l,2-oxazol-3-yl) lH-imidazol-2-yl}ethan- l-ol (Compound- 110)

Compound- 109 was obtained in the manner as with the "Synthesis of Compound- 102: step-2" using the corresponding materials.

Ή-NMR, MS and LCMS retention time data of Compound- 110 are shown in Table 3.

Synthesis of Compound-131

(S) - 3 - (3- ((3- ((2 - ( 1 -hydroxyethyl) - lH-imidazol- 1 -yl)methyl)isoxazol-5- l)ethynyl)bicyclo[l.1. l]pentan- l-yl)propan- l-ol

Compound-131

Step-1)

3-(3-(((Tert-butyldiphenylsilyl)oxy)methyl)bicyclo[l.1. l]pentan- l-yl)propan- l-ol

~ OEt

EtCX .OEt

1 ) ~^p

O O

To a solution of triethyl phosphonoacetate (0.38 mL) in THF (16 mL) was added sodium hydride (88 mg) at 0 °C. After stirring for 30 minutes 3-(((tert- butyldiphenylsilyl)oxy)methyl)bicyclo[l.l.l]pentane-l-carbaldehyde (0.58 g), obtained by the method in WO2015/091741 page 80, in THF (7.2 mL) was added. The mixture was allowed to warm to room temperature and stirred for 30 minutes. The reaction mixture was quenched with acetic acid (0.12 mL) and water and extracted with EtOAc. The organic extract was concentrated in vacuo. The residue was purified with OH-type silica gel column chromatography (0^*30 % EtOAc in n-hexane) to give a crude material (0.59 g) which was used in the next step.

To a stirred solution of the crude material (0.59 g) in Me OH (23 mL) was added 10 wt% Pd/C (0.19 g). The mixture was stirred under hydrogen atmosphere at room temperature for 50 minutes. The insoluble matter was filtered out and the filtrate was concentrated in vacuo to give a crude material (0.58 g) which was used in the next step without further purification. To a solution of the crude material (0.58 g) in THF was added L1BH4 (63 mg) and the mixture was stirred for 2 hours at 65 °C. After addition of L1BH4 (30 mg), the mixture was further stirred at the same temperature for 1 hour. The reaction was quenched with a saturated aqueous ammonium chloride and extracted with EtOAc. The organic layer was washed with water and brine, dried over MgS04 and concentrated in vacuo. The-residue was purified with OH-type silica gel column chromatography (15-45 % EtOAc in n-hexane) to give the title compound (0.38 g, 61 % yield in 3 steps) as colorless oil.

iH NMR (400 MHz, CHLOROFORM-d) 8 ppm 0.96 - 1.17 (m, 13 H), 1.52 - 1.57 (m, 6 H), 3.51^■ 3.72 (m, 4 H), 7.27^■ 7.47 (m, 6 H), 7.55^■ 7.75 (m, 4 H).

MS (ESI/APCI) m/z : 417 [M+23]⁺.

MS condition : F.

Step -2)

(3- 3-(Trityloxy)propyl)bicyclo[l. l. l]pentan- l-yl)methanol

To a solution of 3-(3-(((Tert-butyldiphenylsilyl)oxy)methyl)bicyclo[l. l. l]pentan- l-yl)propan- l -ol

(84 mg) in CHCI3 (2.5 mL) were sequentially added 4-dimethylaminopyridine (2.2 mg), TEA (1.4 mg) and triphenylmethyl chloride (76 mg). After stirring for 19 hours at room temperature, the reaction was quenched with water and extracted with CHCI3. The organic extract was passed through a phase separator and concentrated in vacuo. The residue was purified with OH-type silica gel column chromatography (0- 15 % EtOAc in n-hexane) to give a crude material (138 mg) which was used in the next step.

To a solution of the crude material (43 mg) in THF (4.2 mL) was added TBAF (0.45 mL, 1 mol/L solution in THF). After stirring for 19 hours at room temperature, the reaction was quenched with water and extracted with EtOAc. The organic layer was dried over MgS04 and concentrated in vacuo. The residue was purified with OH-type silica gel column chromatography (20-45 % EtOAc in n-hexane) to give the title compound (69 mg, 80 % yield in 2 steps) as colorless oil.

Ή NMR (400 MHz, CHLOROFORM-d) 8 ppm 1.00 - 1.17 (m, 1 H), 1.51^■ 1.65 (m, 10 H), 3.04 (t, J=6.4 Hz, 2 H), 3.56 (d, J=5.9 Hz, 2 H), 7.20 - 7.49 (m, 15 H).

MS (ESI/APCI) m/z : 421 [M+23]⁺.

MS condition : F.

Step -3)

3-(3-(Trityloxy)propyl)bicyclo[l.l.l]pentane-l-carbaldehyde

To a solution of (3-(3-(trityloxy)propyl)bicyclo[l.l.l]pentan-l-yl)methanol (10 mg) in CHCI3 (0.40 mL) was added Dess-Martin Periodinane (12 mg) at 0 °C. After stirring for 90 minutes at 0 °C, the reaction was quenched with a saturated aqueous sodium thiosulfate and extracted with CHCI3. The organic extract was passed through a phase separator and concentrated in vacuo. The residue was purified with OH"type silica gel column chromatography (0"15 % EtOAc in n-hexane) to give the title compound (7.1 mg, 71 % yield) as colorless oil.

Ή NMR (400 MHz, CHLOROFORM-d) δ ppm 1.21 - 1.44 (m, 2 H), 1.55 - 1.61 (m, 2 H), 1.80 - 1.87 (m, 6 H), 3.00 - 3.10 (m, 2 H), 7.17 - 7.51 (m, 15 H), 9.54 (s, 1 H).

MS (ESI/APCI) m/z : 419 [M+23]⁺.

MS condition■¥.

(S)-3-(3-((3-((2-(l-hydroxyethyl)- lH-imidazol- l-yl)methyl)isoxazol-5- l)ethynyl)bicyclo[l.l.l]pentan-l-yl)propan-l-ol (Compound- 131)

Compound-131

Compound- 131 was obtained in the manner as with the "Synthesis of Compound- 135" using 3-(3-(trityloxy)propyl)bicyclo[l.l.l]pentane-l-carbaldehyde obtained by "Synthesis of Compound- 131: step -6" and the corresponding materials.

Ή-NMR, MS and LCMS retention time data of Compound- 131 are shown in Table 3. Synthesis of Compound- 135 and Compound-221

(lS)-l-{l-[(5-{[3-(Hydroxymethyl)bicyclo[l.l.l]pentan-l-yl]ethynyl}-l,2-oxazol-3-yl)methyl]- lH"imidazol-2- l}ethan- l"ol

Compound-135

(S,Z)-l-(l-((5-(2-(3-(hydroxymethyl)bicyclo[l.l.l]pentan-l-yl)vinyl)isoxazol-3-yl)methyl) imidazol-2-yl)ethanol

Compound-221

Step-l)

Tert-butyl((3-ethynylbicyclo[l.l.l]pentan-l-yl)methoxy)diphenylsilane

To a cooled (0 °C) solution of 3-(((tert-butyldiphenylsilyl)oxy)methyl)bicyclo[l.l.l]pentane-l- carbaldehyde (0.55 g) in MeOH (16 mL) were added potassium carbonate (0.43 g) and (1- diazo-2-oxopropyl) phosphonate (0.45 mL). After 40 minutes with stirring, the mixture was allowed to warm to room temperature and stirred for 19 hours. The reaction was quenched with a saturated aqueous sodium bicarbonate and extracted with EtOAc. The organic layer was washed with brine three times and concentrated in vacuo. The residue was charged onto ISOLUTE® HM-N and purified with OH-type silica gel column chromatography (0-30 % EtOAc in n-hexane) to give the title compound (0.41 g, 75 % yield) as colorless oil.

Ή NMR (400 MHz, CHLOROFORM-d) 8 ppm 1.04 (s, 9 H), 1.90 - 1.99 (m, 6 H), 2.09 (s, 1 H), 3.60 (s, 2 H), 7.32 - 7.48 (m, 6 H), 7.57 - 7.69 (m, 4 H).

LCMS : not determined.

Step-2)

(5-((3-(((tert-butyldiphenylsilyl)oxy)methyl)bicyclo[l.l.l]pentan-l-yl)ethynyl)isoxazol-3- y methanol (Intermediate 135-1)

(Z)-(5-(2-(3-(((tert-butyldiphenylsilyl)oxy)methyl)bicyclo[l.l.l]pentan-l-yl)vinyl)isoxazol-3- l)methanol (Intermediate 135-2)

Intermediate 135-1 Intermediate 135-2

To a solution of compound ethyl 5-iodoisoxazole-3-carboxylate (0.24 mg) and tert-butyl((3- ethynylbicyclo[l.l.l]pentan-l-yl)methoxy)diphenylsilane (0.31 g) in acetonitrile (5.3 mL) were added Cul (17 mg), SUPERSTABLE Pd(0) CATALYST (94-mg) and TEA (0.(50 mL) at room temperature. The reaction mixture was stirred at the same temperature for 30 minutes. 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 (l"21 % EtOAc in n-hexane) to give a crude material (0.41 g) which was used in the next step.

To a solution of the crude material (0.17 g) in EtOH (1.8 mL) and THF (l.8mL) was added NaBH4 (70 mg) in portions, while keeping the internal temperature below 5 °C. After stirring for 4 hours at 0 °C, a saturated aqueous sodium bicarbonate was added to the reaction mixture while keeping the internal temperature below 15 °C. The mixture was concentrated under reduced pressure and the resulting aqueous solution was extracted three times with CHCI3. The combined organic layer was washed with brine, dried over MgS04 and concentrated in vacuo. The residue was purified with OH-type silica gel column chromatography (25-80 % EtOAc in n-hexane) to give a 55:45 mixture (134 mg) of Intermediate 135-1 and Intermediate 135-2, which was re-purified with OH-type silica gel column chromatography (8"40 % EtOAc in CHCI3) to give the title Intermediate- 135-2 (13 mg, 8 % yield) as colorless oil. The remaining material (lOlmg, mixture of Intermediate 135^'- 1 and 135-2) was used in the next step.

Mixture of Intermediate 135-1 and 135-2:

Ή NMR (400 MHz, CHLOROFORM-d) 5 ppm 1.01 - 1.08 (m, 9 H), 1.88 (t, J=6.2 Hz, 1 H), 1.91 - 2.08 (m, 6 H), 3.60 - 3.67 (m, 2 H), 4.72 - 4.80 (m, 2 H), 5.94 (d, J=12.5 Hz, 0.45H), 6.17 - 6.22 (m, 0.90H), 6.39 (s, 0.55 H), 7.28 - 7.45 (m, 6 H), 7.60 - 7.68 (m, 4 H).

Intermediate 135-2:

Ή NMR (400 MHz, CHLOROFORM-d) δ ppm 1.05 (s, 9 H), 1.88 (t, J=6.2 Hz, 1 H), 1.91 - 1.96 (m, 6 H), 3.64 (s, 2 H), 4.77 (d, J=6.2 Hz, 2 H), 5.94 (d, J=12.6 Hz, 1 H), 6.17 - 6.22 (m, 2 H), 7.35 - 7.44 (m, 6 H), 7.62 - 7.67 (m, 4 H).

LCMS : not determined. Step -3)

(IS)- 1-{1- [(5-{[3-(hydroxymethyl)bicyclo[l.1. l]pentan- l-yl]ethynyl}- l,2-oxazol-3-yl)methyl]- lH-imidazol-2- l}ethan- l"ol (Compound- 135)

Compound- 135

(S,Z)-l-(l-((5-(2-(3-(hydroxymethyl)bicyclo[l.l.l]pentan- l-yl)vinyl)isoxazol-3-yl)

221)

Compound-221

Mixture of Intermediate 135-1 and 135-2 2) TsOH

Compound-135 Compound-221

Compound-135 and Compound-221 were obtained in the manner as with the "Synthesis of Intermediate-7", "Synthesis of Intermediate-8" and "Synthesis of Compound- 109" using the mixture of Intermediate 135-1 and Intermediate 135-2 and the corresponding materials, followed by the purification with chiral SFC. The first eluting isomer was identified as Compound-135 (8.5 mg) and the second eluting isomer as Compound-221 (10 mg). Cis-form of Compound-221 was determined by Ή-NMR NOE spectrum (correlation between two hydrogen atoms attached at the olefin carbon atoms).

SFC separation condition:

Instrumentation-' WATERS SFC30.

Column: DAICEL CHIRALPAK AD-H/SFC 20 x 250 mm, 5 pm.

Mobile phase: C0₂/MeOH = 80/20 (0-15 min), C0₂/MeOH = 60/40 (15-25 min). Flow rate: 30 mL/min.

Temperature: 40 °C.

Back pressure: 120 bar.

Detection: 210 - 300 nm.

Ή-NMR, MS and LCMS retention time data of Compound- 135 are shown in Table 3.

Ή-NMR, MS and LCMS retention time data of Compound-221 are shown in Table 3.

Synthesis of Compound-143

(lS)-l-(l-{[5-({4-[4-(2-hydroxyethyl)piperazin-l-yl]phenyl}ethynyl)-l,2-oxazol-3-yl]

-imidazol-2-yl)ethan- l^_ol

Step-1)

l-(2-{[Tert-butyl(dimethyl)silyl]oxy}ethyl)-4-(4-iodophenyl)piperazine

To a suspension of l-(4-iodophenyl)piperazine hydrochloride (4.4 g) in acetonitrile (90 mL) were added 2-bromoethoxytert-butyl-dimethyl-silane (3.9 g) and potassium carbonate (7.4 g) at room temperature. The reaction mixture was stirred at 80 °C for 19 hours. After cooling to room temperature, the insoluble matter was removed by filtration and the filtrate was concentrated in vacuo. The residue was purified with OH-type silica gel column chromatography (4-40% EtOAc in n-hexane) to give the title compound (4.6 g, 77 % yield) as colorless solid.

MS (ESI) m/z : 447 [M+l]⁺.

RT = 0.864 min.

LCMS condition : B.

Step -2)

l-(2-{[Tert-butyl(dimethyl)silyl]oxy}ethyl)-4-[4-({3-[(2-{(lS)-l-[(oxan-2-yl)oxy]ethyl}-lH- imidazol-l-yl)methyl]-l,2-oxazol-5-yl}ethynyl)phenyl]piperazine

A mixture of l-(2-{[tert-butyl(dimethyl)silyl]oxy}ethyl)-4-(4-iodophenyl)piperazine (0.35 g), CS2CO3 (0.66 g), XPhos (0.11 g) and PdClaiCHaCN^ (20 mg) in acetonitrile (9 mL) was stirred at room temperature for 0.5 hours, then Intermediate-6 (0.47 g) in acetonitrile (4.1 mL) was added into the mixture, which was stirred at 80 °C for 2.5 hours. After cooling, the mixture was passed through a NH-type silica gel which was sandwiched between Celite® and washed with acetonitrile. The filtrate was concentrated in vacuo. The residue was purified with NH-type silica gel column chromatography (10- 100% EtOAc in n-hexane) to give the title compound (0.28 g, 58 % yield) as pale yellow oil.

MS (ESI) m/z : 620 [M+l]⁺.

RT = 0.987 min.

LCMS condition : A. Step-3)

(lS)"l-(l-{[5-({4"[4-(2-hydroxyethyl)piperazin-l-yl]phenyl}ethynyl)-l,2-oxazol-3-yl]methyl}- l -imidazol"2-yl)ethan- l-ol (Compound- 143)

To a solution of l-(2-{[tert-butyl(dimethyl)silyl]oxy}ethyl)-4-[4-({3-[(2-{(lS)-l-[(oxan-2- yl)oxy]ethyl}-lH-imidazol-l-yl)methyl]-l,2-oxazol-5-yl}ethynyl)phenyl]piperazine (0.28 g) in THF (4.5 mL) was added 1 mol/L TBAF in THF (0.90 mL) at 0°C. After stirring for 15 minutes at 0°C, the mixture was stirred for 2 hours at room temperature and concentrated in vacuo. The residue was purified with OH-type silica gel column chromatography (O-IO % MeOH in CHCI3) to give the desilylated compound, which was dissolved in MeOH (8 mL) and water (0.8 mL) and then p-TsOH monohydrate (0.34 g) was added. The reaction mixture was stirred at room temperature for 19 hours. After cooling, saturated aqueous sodium bicarbonate and CHCI3 were added. The bHayer was separated and the aqueous layer was extracted with 10% MeOH in CHCI3. The combined organic extracts were passed through a phase separator and concentrated in vacuo. The residue was purified with NH-type silica gel column chromatography (0"6% MeOH in CHCI3) to give the title compound (0.18 g, 95 % yield) as pale yellow solid.

Ή-NMR, MS and LCMS retention time data of Compound- 143 are shown in Table 3.

Synthesis of Compound-145

(lS)-l-[l-({5-[(4-{l-[(Oxetan-3-yl)amino]ethyl}phenyl)ethynyl]-l,2-oxazol-3-yl}methyl)-lH- imidazol-2- l]ethan- l-ol

Step-1)

N-(l-(4-((3-((2-((lS)-l-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-lH-imidazol-l- l)methyl)isoxazol-5-yl)ethynyl)phenyl)ethyl)oxetan-3-amine

To a stirred solution of l-[4-({3-[(2-{(lS)-l-[(oxan;2-yl)oxy]ethyl}-lH-imidazol-l-yl)methyl]- l,2-oxazol-5-yl}ethynyl)phenyl]ethan-l-one (32 mg) in MeOH (2.0 mL) were added oxetan-3" amine (17 mg), acetic acid (0.20 mL) and borane-2-picoline complex (24 mg). The mixture was stirred at room temperature for 2.5 hours. After addition of oxetan-3-amine (17 mg) and borane-2-picoline complex (24 mg), the mixture was stirred overnight. The reaction was concentrated in vacuo, quenched with a saturated aqueous sodium bicarbonate and extracted with CHCI3. The organic layer was passed through a phase separator and concentrated in vacuo. The residue was purified with amino-type silica gel column chromatography (25-100 % EtOAc in n-hexane) to give the title compound (30 mg, 83 % yield) as a colorless oil.

MS (ESI) m/z : 477 [M+l]⁺.

RT = 0.728 min. LCMS condition : A.

Step-2)

(lS)-l-[l-({5-[(4-{l-[(Oxetan-3-yDamino]ethyl}phenyl)ethynyl]-l,2-oxazol-3-yl}

imidazol-2-yl]ethan- l-ol (Com ound- 145)

Compound- 145 was obtained in the manner as with the "Synthesis of Compound- 102: step-2" using the corresponding materials.

Ή-NMR, MS and LCMS retention time data of Compound- 145 are shown in Table 3. Synthesis of Compound-147

(lS)-l-{l-[(5-{[4-(piperazin-l-yl)phenyl]ethynyl}-l,2-oxazol-3-yl)methyl]-lH-imidazol-2- yl}ethan-l-ol

Step-1)

-Trifluoro- 1- [4-(4"iodophenyl)piperazin- l-yl]ethan- 1-one

To a solution of l-(4-iodophenyl)piperazine (0.13 g) in CHCI3 (l.l mL) were sequentially added pyridine (0.084 mL) and trifluoroacetic anhydride (O.ll mL) at 0 °C. After stirring for 30 minutes, the reaction mixture was concentrated in vacuo onto ISOLUTE® HM-N. The residue was purified with OH type silica gel column chromatography (10-50 % EtOAc in n- hexane) to give the title compound (0.13 g, 79 % yield) as a colorless oil.

MS (ESI) m/z 385 [M+l]⁺.

RT = 1.203 min. LCMS condition : B.

Step-2)

(lS)-l-(l-{[5-({4-[4-(trifluoroacetyl)piperazin-l-yl]phenyl}ethynyl)-l,2-oxazol-3-yl]

lH-imidazol"2- l)ethyl acetate

To a solution of 2,2,2-trifluoro-l"[4-(4-iodophenyl)piperazin-l-yl]ethanone (0.14 g)in DMF(2 mL) were added Pd(PPhs)4 (41 mg), Cul (3.3 mg), and TEA (0.49mL) at room temperature under nitrogen atmosphere. After being stirred at 65 °C for 5 minutes,^' [(1S)"1^_[1^_[(5- ethynylisoxazol-3-yl)methyl]imidazol-2-yl]ethyl] acetate (0.12 g) in DMF (1.5 mL) was added at the same temperature. After being stirred for 30 minutes at 65 °C, the reaction mixture was cooled to room temperature, and added brine. The mixture was extracted with EtOAc- toluene (l^' l). The organic layer was washed with brine, dried over MgSC*4, and concentrated in vacuo onto ISOLUTE® HM^_N. The residue was purified with NH-type silica gel column chromatography (50-100% EtOAc in n-hexane) to give the title compound (0.18 g, 98% yield) as a colorless oil.

MS (ESI) m/z : 516 [M+l]⁺.

RT = 0.800 min.

LCMS condition : B.

Step -3)

(IS)- l-{l- [(5-{[4-(piperazhv l-yl)phenyl]ethynyl}- l,2-oxazol-3-yl)methyl]- lH-imidazol-2- l}ethan-l-ol (Compound- 147)

To a solution of [(lS)-l-[l-[[5-[2-[4-[4-(2,2,2-trifluoroacetyl)piperazin-l- yl]phenyl]ethynyl]isoxazol-3-yl]methyl]imidazol-2-yl]ethyl] acetate (0.18 g) in THF (1.7 mL) and MeOH (0.86 mL) was added 1 mol/L aqueous NaOH (1.7 mL) at room temperature. After stirring overnight at room temperature, 20% aqueous K2CO3 was added. The mixture was extracted with CHCh-MeOH (10: l) and concentrated in vacuo onto ISOLUTE® HM-N. The residue was purified with NH-type silica gel column chromatography (0-10% MeOH in CHCI3) to give the title compound (O.ll g, 88% yield) as a colorless solid.

Ή-NMR, MS and LCMS retention time data of Compound- 147 are shown in Table 3.

Synthesis of Compound- 154

3-(4-(3-((2-(l-hydroxyethyl)- lH-imidazol- l-yl)methyl)benzo[d]isoxazol-6-yl)phenyl)propan- 1- ol

Compound-154

Step-1)

-(l-((6-Bromobenzo[d]isoxazol-3-yl)methyl)-lH"imidazol-2-yl)ethanone

To a solution of 6-bromo-3-(bromomethyl)-l,2-benzoxazole (55 mg) in acetonitrile (0.9 mL) were added potassium carbonate (78 mg) and l-(lH-imidazol-2-yl)ethanone (22 mg). After stirring for 2 hours at 80 °C, the reaction was filtered and the filtrate was concentrated in vacuo. The residue was purified with OH-type silica gel column chromatography (5^_60 % EtOAc in n-hexane) to give the title compound (54 mg, 89 % yield) as colorless solid.

MS (ESI) m/z : 320[M+l]⁺.

RT = 0.936 min.

LCMS Condition : B.

3-(4-(3-((2-(l-hydroxyethyl)-lH-imidazol-l-yl)methyl)benzo[d]isoxazol-6-yl)phenyl)propan-l- ol (Compound-154)

Compound-154

The title was obtained in the manner as with the "Synthesis of Compound-28" using l-(l-((6- bromobenzo[d]isoxazol-3-yl)methyl)-lH-imidazol-2-yl)ethanone and the corresponding materials.

Ή-NMR, MS and LCMS retention time data of Compound- 154 are shown in Table 3. Synthesis of Compound- 157

4-(4-{[3-(l-hydroxy-2-{2-[(lS)-l-hydroxyethyl]-lH-imidazol-l-yl}ethyl)-l,2-oxazol-5- yl]ethynyl}phenoxy)butan- l"ol

Compound-157

Step-1)

l-(5-((4-(4-((Tetrahydro-2H-pyran-2-yl)oxy)butoxy)phenyl)ethynyl)isoxazol-3-yl)-2-(2-((lS)-l- ((tetrahydro-2H -pyran-2-yl)oxy)ethyl)-lH"imidazol-l-yl)ethanol

To an ice-cooled solution of 2"[(lS)-l-tetrahydropyran-2-yloxyethyl]-lH-imidazole (36 mg) in DMF (2.5 mL) was added sodium hydride (9.9 mg). After stirring for 30 minutes at 0°C was added a DMF (2.5 mL) solution of [2-[tert-butyl(diphenyl)silyl]oxy-l-[5-[2-[4-(4- tetrahydropyran-2-yloxybutoxy)phenyl]ethynyl]isoxazol^_3-yl]ethyl] 4- methylbenzenesulfonate (98 mg), prepared in the manner as with the "Synthesis of Compound-77: step- 1 to step-5" using the corresponding materials. After stirring for 30 minutes at 50 °C, the reaction was quenched with a saturated aqueous ammonium chloride and extracted with EtOAc. The organic layer was washed with water and brine, passed through a phase separator and concentrated in vacuo. The residue was purified with OH- type silica gel column chromatography (30-50 % EtOAc in n-hexane and then 0-5 % MeOH in CHCI3) to give the title compound (31 mg, 43 % yield) as pale yellow oil.

MS (ESI) m/z : 580 [M+l]⁺.

RT = 0.895 min.

LCMS Condition : B.

Step-2)

4-(4-{[3-(l-Hydroxy-2-{2-[(lS)- l-hydroxyethyl]- lH-imidazol-l-yl}ethyl)- l,2-oxazol-5- yl]ethynyl}phenoxy)butan- l-ol (Compound- 157)

The title compound was obtained in the manner as with the "Synthesis of Compound- 102 step-2" using the corresponding materials.

Ή-NMR, MS and LCMS retention time data of Compound- 157 are shown in Table 3. Synthesis of Compound- 160

2-[(4-{[3-(3-Hydroxy-l-{2-[(lS)- l-hydroxyethyl]- lH-imidazol- l-yl}propyl)- l,2-oxazol-5- yl] ethy nyl}phenoxy) methyl] p ropane -1,3- diol

Step-1)

N-{(E)-[(4S)-2-phenyl"l,3-dioxan-4-yl]methylidene}hydroxylamine

1) Dess-martin Periodinane

2) NH₂OH hydrochlolide

To a solution of ((4S)-2-phenyl-l,3-dioxan-4-yDmethanol (1.7 g) in CHCI3 (18 mL) was added Dess-Martin Periodinane (4.1 g) at 0 °C. The reaction mixture was allowed to warm to room temperature and stirred for_1.5 hours. After-addition of Dess-Martin Periodinane (2.0 g), the- mixture was further stirred at the same temperature for 1 hour. The reaction was quenched with a saturated aqueous sodium thiosulfate and extracted with CHCI3. The organic extract was passed through a phase separator and concentrated in vacuo. The residue was used in the next step without further purification.

The crude material was dissolved in MeOH (18 mL). Hydroxylamine hydrochloride (0.62 g) and potassium carbonate (0.61 g) were added to the solution. The mixture was stirred at room temperature for 16 hours and concentrated in vacuo. The residue was purified with OH-type silica gel column chromatography (10-40 % EtOAc in n-hexane) to give the title compound (0.98 g, 53 % yield) as colorless oil.

MS (ESI) m/z : 208 [M+l]⁺.

RT = 0.768 min and 0.831 min (Diastereomer were observed as a separate peak).

LCMS condition : B.

Step-2)

5-iodo-3-((4S)-2-phenyl-l,3-dioxan-4-yl)isoxazole

To a solution of N-{(E)-[(4S)-2-phenyl-l,3-dioxan-4-yl]methylidene}hydroxylamine (0.98 g) in DMF (4.7 mL) was added N-chlorosuccinimide (0.69 g). After stirring at room temperature for 30 minutes, water and diethyl ether were added into the mixture and separated. The organic layer was washed with water and brine, passed through a phase separator and concentrated in vacuo to give a crude residue (l.l g), which was used in the next step without further purification.

To a solution of tributyl(ethynyl)stannane (2.0 g) in THF (13 mL) was added a solution of TEA (2.2 mL) and the crude residue (l.l g) in THE After stirring at room temperature for 16 hours, the reaction was quenched with water and extracted with EtOAc. The organic extract was washed with brine, dried over MgS04 and concentrated in vacuo. The residue was used in the next step without further purification.

After the residue was dissolved in THF (30 mL), iodine (1.6 g) in THF solution was added to the solution and the mixture was stirred at room temperature for 1 hour. After cooling to 0 °C temperature, the reaction was quenched with an aqueous sodium hydrosulfite and extracted with EtOAc. The organic extract was dried over Na2S04 and concentrated in vacuo. The residue was purified with OH-type silica gel column chromatography (0-20 % EtOAc in n:hexane)_and amino-type silica ..gel- column chromatography (0-20 % EtOAc in n-hexane) to give the title compound (0.22 g, 14 % yield) as pale yellow oil.

MS (ESI) m/z : 380 [M+23]⁺.

RT = 1.132 min.

LCMS condition : B.

Step -3)

-diol

To a solution of 5-iodo-3-((4S)-2-phenyl-l,3-dioxan-4-yl)isoxazole (0.21 g) in Me OH (8 mL) and water (2 mL) was added TFA (l mL). The reaction mixture was stirred at room temperature for 1 hour. After cooling to 0 °C, the mixture was adjusted to being basic by addition of lmol/L aqueous NaOH and then concentrated in vacuo. The residue was purified with OH-type silica gel column chromatography (10-50 % EtOAc in Hexane) to give the title compound (0.11 g, 71 % yield) as colorless oil.

MS (ESI) m/z : 270 [M+l]⁺.

RT = 0.452 min.

LCMS condition : B.

Step-4)

(S)-3-((tert-butyldiphenylsilyl)oxy)-l-(5-iodoisoxazol-3-yl)propan-l-ol

To a solution of (S)-l-(5-iodoisoxazol-3-yl)propane-l,3-diol (0.11 g) in DMF (2.1 mL) was added imidazole (0.14 g) and tert-butylchlorodiphenylsilane (0.13 g) at 0 °C. After stirring for 2 hours at the same temperature, the reaction was quenched with a saturated aqueous ammonium chloride and extracted with EtOAc. The organic layer was passed through a phase separator and concentrated in vacuo. The residue was purified with OH-type silica gel column chromatography (0-10 % EtOAc in n-hexane) to give the title compound (0.18 g, 85 % yield) as colorless oil.

MS (ESI) m/z : 530 [M+23]⁺.

RT = 1.454 min.

LCMS condition : B.

Step -5)

(S)-3-((tert-butyldiphenylsilyl)oxy)-l-(5-((4-((2,2-dimethyl-l,3-dioxan-5- l)methoxy)phenyl)ethynyl)isoxazol-3-yl)propan-l-ol

The title compound was obtained in the manner as with the "Synthesis of Intermediated step-1" using the corresponding materials.

Ή NMR (400 MHz, CHLOROFORM-d) δ ppm 1.07 (s, 9 H), 1.43 (s, 3 H), 1.48 (s, 3 H), 2.08 - 2.16 (m, 3 H), 3.80 - 3.99 (m, 4 H), 4.07 - 4.17 (m, 4 H), 5.16 - 5.22 (m, 1 H), 6.53 (s, 1 H), 6.92 (d, J=8.7 Hz, 2 H), 7.37 - 7.48 (m, 6 H), 7.51 (d, J=8.7 Hz, 2 H), 7.67 (t, J=6.5 Hz, 4 H).

LCMS : not determined.

Step-6)

(S)-3-((tert-butyldiphenylsilyl)oxy)-l-(5-((4-((2,2-dimethyl-l,3-dioxan-5- yl)methoxy)phenyl)ethynyl)isoxazol"3-yl)propyl 4-methylbenzenesulfonate

The title compound was obtained in the manner as with the "Synthesis of Intermediated step -3" using the corresponding materials.

Ή NMR (400 MHz, CHLOROFORM-d) δ ppm 1.02 (s, 9 H), 1.43 (s, 3 H), 1.48 (s, 3 H), 2.06 - 2.15 (m, 2 H), 2.15 - 2.24 (m, 1 H), 2.38 (s, 3 H), 3.54^■ 3.64 (m, 1 H), 3.64^■ 3.74 (m, 1 H), 3.87 (d, J=4.7 Hz, 1 H), 3.90 (d, J=4.7 Hz, 1 H), 4.07 - 4.18 (m, 4 H), 5.89 (t, J=7.0 Hz, 1 H), 6.28 (s, 1 H), 6.93 (d, J=8.8 Hz, 2 H), 7.20 - 7.25 (m, 2 H), 7.33 - 7.45 (m, 6 H), 7.49 (d, J=8.8 Hz, 2 H), 7.55^■ 7.65 (m, 4 H), 7.72 (d, J=8.2 Hz, 2 H).

LCMS : not determined.

Step -7)

3-((lR)-3-((tert-butyldiphenylsilyl)oxy)- l-(2-((lS)- l-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)- IH-imidazol- l-yl)propyl)-5-((4-((2,2-dimethyl- l,3-dioxan-5- yl)methoxy)phenyl)ethynyl)isoxazole (Intermediate 160- l) and

3-(5-((4-((2,2-dimethyl- l,3-dioxan-5-yl)methoxy)phenyl)ethynyl)isoxazol-3-yl)-3-(2-((lS)- l- ((tetrahydro-2H-pyran-2-yl)oxy)ethyl)- IH-imidazol- l-yl)propan- l"ol (Intermediate 160-2)

The title compounds were obtained in the manner as with the "Synthesis of Intermediated step-4" using the corresponding materials.

Intermediate 160- V-

Ή NMR (400 MHz, CHLOROFORM-d) δ ppm 1.04 (s, 9 H), 1.30 - 1.92 (m, 6 H), 1.42 (s, 3 H),

1.48 (s, 3 H), 1.64 (d, J=6.6 Hz, 3 H), 2.07 - 2.15 (m, 1 H), 2.34 - 2.47 (m, 1 H), 2.54 - 2.66 (m,

1 H), 3.34 - 4.17 (m, 10 H), 4.70 (br s, 1 H), 4.87 (q, J=6.6 Hz, 1 H), 6.20 - 6.27 (m, 2 H), 6.86 -

7.05 (m, 4 H), 7.32 - 7.45 (m, 6 H), 7.48 (d, J=8.6 Hz, 2 H), 7.56 - 7.66 (m, 4 H).

LCMS : not determined.

Intermediate 160-2:

MS (ESI) m/z : 566 [M+l]⁺.

RT = 0.793 min.

LCMS condition : B.

Step-8) 2- [(4-{[3-(3-Hydroxy l-{2- [(IS)- 1-hydroxyethyl]- IH-imidazol- l-yl}propyl)- l,2-oxazol-5- yl]ethynyl}phenoxy)methyl]propane-l,3-diol (Compound- 160)

Compound- 160 was obtained in the manner as with the "Synthesis of Compound- 102: step-2" using Intermediate 16Q-2 and corresponding materials.

Ή-NMR, MS and LCMS retention time data of Compound" 160 are shown in Table 3.

Synthesis of Compound- 166

(lS)-l-{l-[(5-{[4-(2-methoxyoxolan-2-yl)phenyl]ethynyl}-l,2-oxazol-3-yl)methyl]-lH-imidazol- 2-yl}ethan-l-ol

Step-1)

(lS)-l-{l-[(5-{[4-(2-methoxyoxolan-2-yl)phenyl]ethynyl}-l,2-oxazol-3-yl)methyl]-lH-imidazol- 2-yl}ethan-l-ol (Compound- 166)

To a solution of 4-hydroxy-l-[4-({3-[(2-{(lS)-l-[(oxan-2-yl)oxy]ethyl}-lH-imidazol-l- yl)methyl]-l,2-oxazol-5-yl}ethynyl)phenyl]butan- l-one in MeOH (1.4 mL) was added p-TsOH monohydrate (96 mg) at room temperature. After stirring overnight, the reaction mixture was basified with 20% aqueous potassium carbonate and extracted with 10 % MeOH in CHCI3. The organic layer was passed through a phase separator and concentrated in vacuo. The residue was purified with amino-type silica gel column chromatography (50 % EtOAc in n-hexane and then 0-10 % Me OH in CHCk) to give the title compound (24 mg, 43 % yield) pale yellow amorphous.

^!H-NMR and MS data of Compound- 166 are shown in Table 3. Synthesis of Compound-176

1 - {l - [(4- {Trans- 3- [4- (hydroxymethyl)phenyl] cyclobutyl}phenyl)methyl] - lH-imidazol-2 - yl}ethan-l-ol

Step 1)

(4-(3-(4-(((Tert-butyldimethylsilyl)oxy)methyl)phenyl)cyclobutyl)phenyl)methanol

To a stirred solution of ethyl 4-[3-[4-[[tert- butyl(dimethyl)silyl]oxymethyl]phenyl]cyclobutyl]benzoate (0.20 g) in MeOH (0.94 mL) and THF (9.4 mL) was added 3 mol/L lithium tetrahydroborate in THF (1.6 mL) at 0 °C. After stirring for 2 hours at 0 °C, the reaction mixture was quenched with water and extracted three times 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 (2-18% in EtOAc in n-hexane) to give the title compound (0.21 g, quant.) as colorless oil.

MS (ESI) m/z 405 [M+23]⁺.

RT = 1.228 min.

LCMS condition : C. Step 2)

l-(l-(4-(3-(4-(((Tert-butyldimethylsilyl)oxy)methyl)phenyl)cyclobutyl)benzyl)- lH-imidazol-2- yl)ethanone

The title compound was obtained in the manner as with the "Synthesis of Intermediated step-1" using the corresponding materials.

MS (ESI) m/z 475 [M+l]⁺.

RT = 1.238 min.

LCMS condition : C.

Step 3)

l^_(l^_(4-(3-(4-(((Tert-butyldimethylsilyl)oxy)methyl)phenyl)cyclobutyl)benzyl)-lH-imidazol-2- yDethanol

The title compound was obtained in the manner as with the "Synthesis of Compound-2: step- 1" using the corresponding materials.

MS (ESI) m/z 477 [M+l]⁺.

RT = 0.792 min.

LCMS condition : C.

Step 4)

l-{l-[(4-{Trans-3-[4-(hydroxymethyl)phenyl]cyclobutyl}phenyl)methyl]-lH"imidazol-2- yl}ethan-l-ol (Compound- 176)

Compound-176

To a stirred solution of l-[l-[[4-[3-[4-[[tert- butyl(dimethyl)silyl]oxymethyl]phenyl]cyclobutyl]phenyl]methyl]imidazol-2-yl]ethanol (0.15 g) in THF was added TBAF (0.47 mL, 1 mol/L solution in THF). After stirred for 1 hour at 0 °C, the reaction mixture was quenched with water and extracted three times with CHCI3. The organic layer was concentrated in vacuo and the residue was purified with prep-HPLC to give Compound-176 (15 mg as mixture of isomers [cis/trans=l/3], 13 % yield) as colorless powder and its cis isomer, l-{l-[(4-{cis-3-[4- (hydroxymethyl)phenyl]cyclobutyl}phenyl)methyl]-lH-imidazol-2-yl}ethan-l-ol (50 mg, 44% yield), as colorless powder. The cis isomer was identified by Ή-NMR NOESY spectrum (correlation from beta proton of cyclobutyl to two protons of each phenyl ring).

Ή-NMR, MS and LCMS retention time data of Compound- 176 are shown in Table 3. Synthesis of Compound- 177

4-Hydroxy-l-(4-{[3-({2-[(lS)-l-hydroxyethyl]-lH-imidazol-l-yl}methyl)-l,2-oxazol-5- l]ethynyl}phenyl)butan- 1-one

Compound-177

Step-1)

(S)-4-(4-((3-((2-(l-hydroxyethyl)-lH-imidazol-l-yl)methyl)isoxazol-5-yl)ethynyl)phenyl)-4- oxobutyl pivalate

The title compound was obtained in the manner as with the "Synthesis of Compound- 102 step-2" using the corresponding materials.

MS (ESI) m/z : 464 [M+l]⁺.

RT = 0.767 min.

LCMS condition : B.

Step-2)

4-Hydroxy-l-(4-{[3-({2-[(lS)-l-hydroxyethyl]-lH-imidazol-l-yl}methyl)-l,2-oxazol-5- l]ethynyl}phenyl)butan-l-one (Compound-177)

To a stirred solution of (S)-4-(4-((3-((2-(l-Hydroxyethyl)-lH-imidazol-l-yl)methyl)isoxazol-5- yl)ethynyl)phenyl)-4-oxobutyl pivalate (49 mg) in MeOH (1 mL) and THF (l mL) was added 1 mol/L aqueous NaOH (l mL). The mixture was stirred for 2 hours at room temperature and for 1 hour at 40°C. The reaction was quenched with 20% aqueous potassium carbonate and extracted with 10 % MeOH in CHCI3. The organic layer was passed through a phase separator and concentrated in vacuo. The residue was purified with amino-type silica gel column chromatography (EtOAc and then 0-10 % MeOH in CHCI3) to give the title compound (22 mg, 56 % yield) as colorless solid.

Ή-NMR, MS and LCMS retention time data of Compound- 177 are shown in Table 3.

Synthesis of Compound- 179

3-(4-{2-[3-({2-[(lS)-l-hydroxyethyl]-lH-imidazol-l-yl}methyl)-l,2-oxazol-5- yl]ethyl}phenoxy)propan- l"ol

Step-1)

3-(4-(2-(3-((2-((lS)-p((tetrahydro-2H-pyran-2 l)oxy)ethyl)-lH-imidazol-l-yl)methyl)isoxazol- 5-yl)ethyl)phenoxy)propan-l-ol

To a solution of 3-[4-({3-[(2-{(lS)-l-[(oxan-2-yDoxy]ethyl}-lH-imidazol-l-yl)methyl]-l,2- oxazol-5-yl}ethynyl)phenoxy]propan-l-ol (48 mg) in EtOH (l mL) and THF (0.5 mL) was added 5 % Pd/C (5 mg) at room temperature. The mixture was stirred under hydrogen atmosphore for 30 minutes. The insoluble matter was removed by filtration through Celite® and washed with CHCI3. The filtrate was concentrated in vacuo. The residue was purified with amino-type preparative chromatography (2.5 % MeOH in CHCI3) to give the title compound (15 mg, 32 % yield) as pale yellow oil.

MS (ESI) m/z : 456[M+l]⁺.

RT = 0.609 min.

LCMS condition : B.

Step -2)

4-Hydroxyl-(4-{[3-({2-[(lS)-l-hydroxyethyl]-lH-imidazol-l-yl}methyl)-l,2-oxazol-5- yl]ethynyl}phenyl)butan-l-one (Compound- 179)

Compound-179

The title compound was obtained in the manner as with the "Synthesis of Compound- 102 step-2" using the corresponding materials. Ή-NMR, MS and LCMS retention time data of Compound- 179 are shown in Table 3.

Synthesis of Compound- 181

2-((4-((3-((R)-3-amino- l-(2-((S)- 1-hydroxyethyl)- lH-imidazol- l-yl)propyl)isoxazol-5" yl)ethynyl)phenoxy)methyl)propane- 1,3-diol

Step-1)

(3R)-3-(5-((4-((2,2-dimethyl-l,3-dioxan-5-yl)methoxy)phenyl)ethynyl)isoxazol-3-yl)-3-(2-((lS)- l-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)- lH-imidazol- l-yl)propan- l"ol

To a solution of 3-((lR)-3-((tert-butyldiphenylsilyl)oxy)-l-(2-((lS)-l-((tetrahydro-2H-pyran-2- yl)oxy)ethyl)- lH-imidazol- l-yl)propyl)-5-((4-((2,2-dimethyl- l,3"dioxan-5- yl)methoxy)phenyl)ethynyl)isoxazole (95 mg) in THF (1.2 mL) was added TBAF (0.24 mL, 1 mol/L solution in THF). After stirring at room temperature for 2 hours, the reaction was quenched with water and extracted with CHCI3. The organic extract was passed through a phase separator and concentrated in vacuo. The residue was purified with amino-type silica gel column chromatography (60-100 % EtOAc in n-hexane) to give the title compound (42 mg, 62 % yield) as colorless oil.

MS (ESI) m/z : 566 [M+l]⁺.

RT = 0.776 min.

LCMS condition : B. Step -2)

2-((3R)-3-(5-((4-((2,2-dimethyl-l,3-dioxan-5-yl)methoxy)phenyl)ethynyl)isoxazol-3-yl)-3-(2- ((lS)-l-((tetrah dro-2H^yran-2-yl)oxy)ethyl)-lH midazol-l-yl)propyl)isoindoline-l,3-dione

To a solution of (3R)-3-(5-((4-((2,2-dimethyl-l,3-dioxan-5-yl)methoxy)phenyl)ethynyl)isoxazol- 3-yl)-3-(2-((lS)-l-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-lH-imidazol-l-yl)propan-l-ol (40 mg) in THF (0.24 mL) were added phthalimide (16 mg), PPh₃ (37 mg) and DEAD (64 uL) at room temperature. After stirring for 2 hours at the same temperature, the reaction solution was concentrated in vacuo. The residue was purified with OH-type silica gel column chromatography (10-100 % EtOAc in n-hexane) to give the title compound (49 mg, 99 % yield) as colorless oil.

MS (ESI) m/z : 695 [M+l]⁺.

RT = 0.950 min.

LCMS condition : B.

Step -3)

(3R)-3-(5-((4-((2,2-dimethyl-l,3-dioxan-5-yl)methoxy)phenyl)ethynyl)isoxazol-3-yl)-3-(2-((lS)- l-((tetrah dro-2H -pyran^_2-yl)oxy)ethyl)- lH-imidazol- l-yl)propan- 1-amine

To a solution of 2-((3R)-3-(5-((4-((2,2-dimethyM,3-dioxan-5- yl)methoxy)phenyl)ethynyl)isoxazol-3-yl)-3-(2-((lS)-l-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)- lH-imidazol-l-yl)propyl)isoindoline-l,3-dione (47 mg) in EtOH (l mL) was added hydrazine hydrate (9.9 uL) at room temperature. The mixture was stirred at 60 °C for 2 hours. After cooling to room temperature, the insoluble matter was removed by filtration and washed with EtOH, and the filtrate was concentrated in vacuo. The residue was purified with amino-type silica gel column chromatography (CHCI3) to give the title compound (37 mg, 96 % yield) as colorless oil.

MS (ESI) m/z : 565 [M+l]⁺.

RT = 0.576 min.

LCMS condition : B.

Step-4) 2-((4-((3-((R)-3-amino- l-(2-((S)- 1-hydroxyethyl)- lH-imidazol- l-yl)propyl)isoxazol-5- yl)ethynyl)phenoxy)methyl)propane- 1,3-diol (Compound- 181)

The title compound was obtained in the manner as with the "Synthesis of Compound- 102: step-2" using the corresponding materials.

Ή-NMR, MS and LCMS retention time data of Compound- 181 are shown in Table 3.

Synthesis of Compound- 184 and Compound- 185

3-(4-{[3-(l-{2-[(lS)- 1-hydroxyethyl]- lH-imidazol- l-yl}ethyl)- l,2-oxazol"5- yl]ethynyl}phenoxy)propan-l-ol (Single diasterepmer, low polar : Compound- 184)

3-(4-{[3-(l-{2-[(lS)-l-hydroxyethyl]-lH-imidazol-l-yl}ethyl)-l,2-oxazol-5- yl]ethynyl}phenoxy)propan-l-ol (Single diastereomer, high polar : Compound- 185)

(first eluding isomer) (second eluding somer)

Step-l) 5-((4-(3-((Tert-butyldimethylsilyl)oxy)propoxy)phenyl)ethynyl)isoxazole-3- carbaldehyde

To an ice-cooled solution of [5-[2-[4-[3-[tert- butyl(dimethyl)silyl]oxypropoxy]phenyl]ethynyl]isoxazol-3-yl]methanol (0.30 g) in CHCI3 (3.9 mL) were added sodium bicarbonate (0.20 g) and Dess-Martin Periodinane (0.36 g). After stirring for 30 minutes at room temperature, the reaction was quenched with a saturated aqueous sodium thiosulfate and extracted with CHCI3. The organic layer was passed through a phase separator and concentrated in vacuo. The residue was purified with OH-type silica gel column chromatography (5-30 % EtOAc in n-hexane) to give the title compound (0.25 g, 84 % yield) as colorless oil.

Ή NMR (400 MHz, CHLOROFORM-d) δ ppm 0.04 (s, 6 H), 0.89 (s, 9 H), 1.96 - 2.04 (m, 2 H), 3.80 (t, J=5.9 Hz, 2 H), 4.11 (t, J=6.2 Hz, 2 H), 6.78 (s, 1 H), 6.92 (d, J=8.8 Hz, 2 H), 7.52 (d, J=8.8 Hz, 2 H), 10.16 (s, 1 H).

LCMS : not determined. Step-2)

l-(5-((4-(3-((Tert-butyldimethylsilyl)oxy)propoxy)phenyl)ethynyl)isoxazol-3-yl)ethanol

To an ice-cooled solution of 5-[2-[4-[3-[tert- butyl(dimethyl)silyl]oxypropoxy]phenyl]ethynyl]isoxazole-3-carbaldehyde (O.IO g) in THF (1.3 mL) was added 3 mol/L methylmagnesium bromide (0.43 mL) in THF. After stirring for 30 minutes at room temperature, the reaction was quenched with a saturated aqueous ammonium chloride and extracted with CHCI3. The organic layer was passed through a phase separator and concentrated in vacuo. The residue was purified with OH-type silica gel column chromatography (5-40 % EtOAc in n-hexane) to give the title compound (81 mg, 78 % yield) as colorless oil.

Ή NMR (400 MHz, CHLOROFORM-d) δ ppm 0.04 (s, 6 H), 0.89 (s, 9 H), 1.58 (d, J=6.6 Hz, 3 H), 1.95 - 2.03 (m, 2 H), 2.13 (d, J=4.6 Hz, 1 H), 3.80 (t, J=5.9 Hz, 2 H), 4.10 (t, J=6.2 Hz, 2 H), 5.02 - 5.11 (m, 1 H), 6.47 (s, 1 H), 6.90 (d, J=8.7 Hz, 2 H), 7.49 (d, J=8.7 Hz, 2 H).

LCMS : not determined. Step -3)

l-(5-((4-(3-((tert-butyldimethylsilyl)oxy)propoxy)phenyl)ethynyl)isoxazol-3-yl)ethyl 4- methylbenzenesulfonate

The title compound was obtained in the manner as with the "Synthesis of-Intermediate-4: step -2" using the corresponding materials.

Ή NMR (400 MHz, CHLOROFORM-d) δ ppm 0.04 (s, 6 H), 0.89 (s, 9 H), 1.65 (d, J=6.6 Hz, 3 H), 1.99 (quin, J=6.0 Hz, 2 H), 2.43 (s, 3 H), 3.80 (t, J=6.0 Hz, 2 H), 4.10 (t, J=6.0 Hz, 2 H), 5.69 (q, J=6.6 Hz, 1 H), 6.33 (s, 1 H), 6.90 (d, J=8.7 Hz, 2 H), 7.31 (d, J=8.0 Hz, 2 H), 7.47 (d, J=8.7 Hz, 2 H), 7.76 (d, J=8.0 Hz, 2 H).

LCMS : not determined.

Step-4)

5-((4-(3-((tert-butyldimethylsilyl)oxy)propoxy)phenyl)ethynyl)-3-(l-(2-((lS)-l-((tetrahydro- 2H-pyran-2-yl)oxy)ethyl)-lH"imidazol-l-yl)ethyl)isoxazole

To an ice-cooled solution of 2-[(lS)-l-tetrahydropyran-2-yloxyethyl]-lH-imidazole (28 mg) in DMF (1.9 mL) was added sodium hydride (7.6 mg) and the mixture was stirred for 30 minutes at 0 °C. After addition of the solution of l"[5-[2-[4-[3-[tert- butyl(dimethyl)silyl]oxypropoxy]phenyl]ethynyl]isoxazol"3-yl]ethyl 4- methylbenzenesulfonate (53 mg) in DMF (1.9 mL), the mixture was stirred for 30 minutes at 50 °C. The reaction mixture was allowed to cool to room temperature, quenched with a saturated aqueous ammonium chloride and extracted with EtOAc. The organic layer was washed with brine, passed through a phase separator and concentrated in vacuo. The residue was purified with OH-type silica gel column chromatography (0-3 % MeOH in CHCI3) to give the title compound (45 mg, 80 % yield) as pale yellow oil.

MS (ESI) m/z : 580 [M+l]⁺.

RT = 1.189 min.

LCMS condition : B.

Step -5)

3-(4-{[3-(l-{2-[(lS)-l-hydroxyethyl]-lH-imidazol-l-yl}ethyl)-l,2-oxazol-5- yl]ethynyl}phenoxy)propan-l-ol (Single diastereomer, First eluding isomer : Compound- 184) 3-(4-{[3-(l-{2-[(lS)-l-hydroxyethyl]-lH-imidazol-l-yl}ethyl)-l,2-oxazol-5- yl]ethynyl}phenoxy)propa^l-ol_(SJngle^iastereome _second eluding isomer ^Compound

First eluding isomer Second eluding isomer

To a solution of tert-butyl-dimethyl-[3-[4-[2-[3-[l-[2-[(lS)-l-tetrahydropyran-2- yloxyethyl]imidazol-l-yl]ethyl]isoxazol-5-yl]ethynyl]phenoxy]propoxy]silane (62 mg) in THF

(1.0 mL) was added 1 mol/L hydrochloric acid (l.O mL). After stirring for 1.5 hours at room temperature, the reaction was quenched with 20% aqueous potassium carbonate solution and extracted with CHCI3 at three times. The organic layer was passed through a phase separator and concentrated in vacuo. The residue was purified with OH-type silica gel column chromatography (0-10 % MeOH in CHCI3) to give a pale yellow powder (31 mg), which was separated with prep-HPLC to afford the first eluding isomer (Compound-184, 11 mg, colorless powder, 98 % ee) and the second eluding isomer (Compound-185, 13 mg, colorless powder, 93 % ee).

HPLC separation condition :

Instrumentation: GILSON Preparative HPLC System.

Column: DAICEL CHIRALPAK OJ-H 20 x 250 mm, 5 μηι.

Mobile phase : EtOH/Hex = 30/70.

Flow rate: 10 mL/min.

Detection: 254 nm.^!H-NMR data of Compound- 184 is shown in Table 3.

!H-NMR data of Compound- 185 is shown in Table 3.

Synthesis of Compound- 186

l-(4-{[3-({2-[(lS)- 1-hydroxyethyl]- lH-imidazol- l-yl}methyl)- l,2-oxazol-5- l]ethynyl}phenyl)butane-l,4-diol

Compound-186

Step- 1) 4-Hydroxy-4-(4-((3-((2-((lS)- l-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)- lH-imidazol- 1- yl)methyl)isoxazol-5-yl)ethynyl)phenyl)butyl pivalate

The title compound was obtained in the manner as with the "Synthesis of Compounds step 1" using the corresponding materials.

MS (ESI) m/z : 550 [M+l]⁺.

RT = 0.831 min.

LCMS condition : B.

Step-2) l-(4-{[3-({2- [(IS)- 1-hydroxyethyl]- lH-imidazol-l-yl}methyl)-l,2-oxazol-5 yl]ethynyl}phenyl)butane-l,4-diol (Compound-186)

Compound-186

The title compound was obtained in the manner as with the "Synthesis of Compound- 177: step-1 and step-2" using the corresponding materials.

Ή-NMR, MS and LCMS retention time data of Compound-186 are shown in Table 3. Synthesis of Compound- 192

6-{[3-({2-[(lS)-l-hydroxyethyl]-lH-imidazol-l-y methyl)-l,2-oxazol-5-yl]ethynyl}-3-(3- hy droxyprop oxy)pyridin- 2 -ol

Compound-192

Step-1)

2-Bromo-3-(3-((tert-butyldimethylsilyl)oxy)propoxy)-6-iodopyridine

To a solution of 2-bromo-6-iodo-pyridin-3-ol (0.50 g) in acetonitrile (8.3 mL) were added potassium carbonate (0.69 g) and (3-bromopropoxy)-tert-butyldimethylsilane (0.77 mL) at room temperature. After stirring for 16 hours at 70 °C, the mixture was allowed to cool to room temperature, quenched with water and stirred, and extracted with EtOAc. The organic extract was concentrated in vacuo. The residue was purified with OH-type silica gel column chromatography (0"10 % EtOAc in n-hexane) to give the title compound (0.54 g, 70 % yield) as colorless oil.

MS (ESI) m/z : 472 [M+l]⁺.

RT = 1.207 min.

LCMS condition : C.

Step -2)

3-(3-((Tert-but ldimethylsilyl)oxy)propoxy)-6-iodo-2-((4-methoxybenzyl)oxy)pyridine

To a solution of 4-methoxybenzyl alcohol (0.16 mL) in DMF (1.3 mL) was added sodium hydride (30 mg) at 0 °C. After stirring for 10 minutes at room temperature, 3-[(2"bromo-6- iodo-3-pyridyl)oxy]propoxy-tert-butyl-dimethyl-silane (0.30 g) in DMF (1.3 mL) was added. The mixture was allowed to warm to 65 °C and stirred for 1.5 hours. Water was added and the mixture was stirred and extracted with EtOAc. The organic extract was concentrated in vacuo. The residue was purified with OH-type silica gel column chromatography (0 - 70 % EtOAc in n-hexane) to give the title compound (97 mg, 29 % yield) as colorless oil.

iH NMR (400 MHz, CHLOROFORM-d) δ ppm 0.00 (s, 6 H), 0.85 (s, 9 H), 1.96 (quin, J=6.0 Hz, 2 H), 3.75 (t, J=6.0 Hz, 2 H), 3.80 (s, 3 H), 4.04 (t, J=6.0 Hz, 2 H), 5.33 (s, 2 H), 6.75 (d, J=7.9 Hz, 1 H), 6.88 (d, J=8.6 Hz, 2 H), 7.18 (d, J=7.9 Hz, 1 H), 7.42 (d, J=8.6 Hz, 2 H).

Step -3)

5-((5-(3-((Tert-butyldimethylsilyl)oxy)propoxy)-6-((4-methoxybenzyl)oxy)pyridin-2- yl)ethynyl)-3-((2-((lS)- l-((tetrahydra-2H-py^^

yl)methyl)isoxazole

The title compound was obtained in the manner as with the "Synthesis of Compound- 102: step- 1" using the corresponding materials.

MS (ESI) m/z : 703 [M+l]⁺.

RT = 1.191 min.

LCMS condition : B.

Step -4)

6-{[3-({2- [(IS)- 1-hydroxyethyl]- lH-imidazol- l-yl}methyl)- l,2-oxazol-5-yl]ethynyl}-3-(3- hydroxypropoxy)pyridin-2-ol (Compound- 192)

Compound-192

To a solution of tert-butyl- [3- [[2- [(4-methoxyphenyl)methoxy]-6-[2- [3- [[2- [(lS)- l- te trahydropyran - 2 -yloxyethyl] imidazol- 1 -yl] methyl] isoxazol- 5 -yl] ethy nyl] - 3 - pyridyl]oxy]propoxy]-dimethyl-silane (94 mg) in CHCb (2 mL) was added TFA (l mL) and the reaction mixture was stirred at room temperature for 1 hours. After cooling to 0 °C, the mixture was adjusted to being basic by addition of 1 mol/L aqueous NaOH and then passed through Diaion HP-20® resin. The organic phase was concentrated in vacuo. The residue was purified with amino-type silica gel column chromatography (0-15 % MeOH in CHCb) to give the title compound (30 mg, 58 % yield) as pale yellow powder.

Ή-NMR, MS and LCMS retention time data of Compound- 192 are shown in Table 3.

Synthesis of Compound-193

3-(4-{[3-({2- [(lSH-hydroxyethylHH^

l]ethynyl}phenoxy)propyl 4-(methanesulfonyl)piperazine-l-carboxylate

Step-1)

3-(4-((3-((2-((lS)-l-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-lH-imidazol-l-yl)methyl)isoxazol-5- yl)ethynyl)phenoxy) ropyl 4-(methylsulfonyl)piperazine-l-carboxylate

3-[4-[2-[3-[[2-[(lS)-l-tetrahydropyran-2-yloxyethyl]imidazol-l-yl]methyl]isoxazol-5- yl]ethynyl]phenoxy]propyl 4-methylbenzenesulfonate (50 mg) in dimethyl sulfoxide (0.8mL) were added 1-methylsulfonylpiperazine (41 mg) and cesium carbonate (0.14 g). After stirring for 2 hours at 60 °C, the reaction mixture was quenched with water and extracted with EtOAc. The organic layer was passed through a phase separator and concentrated in vacuo onto ISOLUTE® HM-N. The residue was purified with NH-type silica gel column chromatography (20-100 % EtOAc in n-hexane) to give the title compound (35 mg, 66 % yield) as colorless gum.

MS (ESI) m/z : 642[M+l]⁺.

RT = 1.081 min.

LCMS condition : A.

Step-2)

3-(4-{[3-({2- [(IS)- l-hydroxyethyl]- lH-imidazol- l-yl}methyl)- l,2-oxazol-5- yl]ethynyl}phenoxy)propyl 4-(methanesulfonyl)piperazine- 1-carboxylate (Compound- 193)

The title compound was obtained in the manner as with the "Synthesis of Compound- 102 step-1" using the corresponding materials.

Ή-NMR, MS and LCMS retention time data of Compound- 193 are shown in Table 3. Synthesis of Compound-210

N-(3-{2-[(lS)-l-hydroxyethyl]-lH-imidazol-l-yl}-3-[5-({4-[3-hydroxy-2- (hydroxymethyl)propoxy]phenyl}ethynyl)-l,2-oxazol-3-yl]propyl)methanesulfonamide

Step-1)

2-(3-(5-((4-((2,2-Dimethyl-l,3-dioxan-5-yl)methoxy)phenyl)ethynyl)isoxazol-3-yl)-3-(2-((lS)-l- ((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-lH-imidazol-l-yl)propyl)isoindoline-l,3-dione

r

The title compound was obtained in the manner as with the "Synthesis of Compound- 181 step -2" using the corresponding materials.

MS (ESI) m/z : 695 [M+lK

RT = 0.947 min.

LCMS condition : B.

Step -2)

3-(5-((4-((2,2-Dimethyl- l,3-dioxan-5-yl)methoxy)phenyl)ethynyl)isoxazol-3-yl)-3-(2-((lS)- l- tetrahydro-2H-pyran-2-yl)oxy)ethyl)- IH-imidazol" l-yl)propan- 1-amine

The title compound was obtained in the manner as with the "Synthesis of Compound- 18V step-3" using the corresponding materials.

MS (ESI) m/z : 565 [M+l]⁺.

RT = 0.573 min.

LCMS condition : B.

Step-3)

N-(3-(5-((4-((2,2-dimethyl- l,3-dioxan-5-yl)methoxy)phenyl)ethynyl)isoxazol-3-yl)-3-(2-((lS)- l- ((tetrahydro-2H-pyran-2-yl)oxy)ethyl)- lH-imidazol- l-yl)propyl)methanesulfonamide

To a solution of 3-[5-[2-[4-[(2,2-dimethyl-l,3-dioxan-5-yl)methoxy]phenyl]ethynyl]isoxazol-3- yl]-3-[2-[(lS)-l-tetrahydropyran-2-yloxyethyl]imidazoM-yl]propan-l-amine (20 mg) in CHC (0.35 mL) were added TEA (25 uL) and methanes.ulfon.yl .-chloride -(5.5 ^L)_^After- stirring at room temperature for 30 minutes, the reaction mixture was quenched with water and extracted with CHCb. The organic extract was passed through a phase separator and concentrated in vacuo. The residue was purified with amino-type silica gel column chromatography (10· 100 % EtOAc in n-hexane) to give the title compound (22 mg, 95 % yield) as colorless oil.

MS (ESI) m/z : 643 [M+l]⁺.

RT = 0.795 min.

LCMS condition : B.

Step -4)

N-(3-{2-[(lS)-l-hydroxyethyl]-lH-imidazol-l-yl}-3-[5-({4-[3-hydroxy-2-

(hydroxymethyl)propoxy]phenyl}ethynyl)-l,2-oxazol-3-yl]propyl)methanesulfonamide

(Compound-210)

The title compound was obtained in the manner as with the "Synthesis of Compound- 102: step -2" using the corresponding materials.

Ή-NMR, MS and LCMS retention time data of Compound-210 are shown in Table 3.

Synthesis of Compound-222

N-(3-{2-[(lS)-l-hydroxyethyl]-lH-imidazol-l-yl}-3-[5-({4-[3-hydroxy-2- (hydroxymethyl)propoxy]phenyl}ethynyl)-l,2-oxazol-3-yl]propyl)acetamide

Step-1)

N-(3-(5-((4-((2,2-dimethyhl,3-dioxan-5-yl)methoxy)phenyl)ethynyl)isoxazol-3-yl)-3-(2-((lS)-l- ((tetrahydro-2H^■pyran-2-yl)oxy)eth l)- lH-imidazol- l- l) ro l)acetamide

To a solution of 3-[5-[2-[4-[(2,2-dimethyl-l,3-dioxan-5^_yl)methoxy]phenyl]ethynyl]isoxazol-3- yl]-3-[2-[(lS)-l-tetrahydropyran-2-yloxyethyl]imidazol-l-yl]propan-l-amine (20 mg) in CHCI3 (0.35 niL) were added TEA (25 μ and acetyl chloride (5.1 μΐ,). After stirring at room temperature for 30 minutes, the reaction mixture was quenched with water and extracted with CHCI3. The organic extract was passed through a phase separator and concentrated in vacuo. The residue was purified with amino-type silica gel column chromatography (10- 100 % EtOAc in n-hexane) to give the title compound (16 mg, 76 % yield) as colorless oil. MS (ESI) m/z : 607 [M+l]⁺.

RT = 0.764 min.

LCMS condition : B.

Step-2)

N-(3-{2-[(lS)-l-hydroxyethyl]-lH-imidazol-l-yl}-3-[5-({4-[3-hydroxy-2- (hydroxymethyl)propoxy]phenyl}ethynyl)- l,2-oxazol-3-yl]propyl)acetamide (Compound-222)

The title compound was obtained in the manner as with the "Synthesis of Compound- 102 ; step -2" using the corresponding materials.

^!H-NMR, MS and LCMS retention time data of Compound-222 are shown in Table 3.

Synthesis of Compound-224

-l-(l-{3-[5-(4-bromophenyl)-l,2-oxazol-3-yl]propyl}-lH-imidazol-2-yl)ethan-l-ol

Step-1)

-[5-(4-Bromophenyl)-l,2-oxazol-3-yl]propan-l-ol

To a solution of 3-[5-(4-bromophenyl)isoxazol-3-yl]propanoic acid (0.51 g) in THF (10 mL) was added 1 mol/L borane-THF complex (6.0 mL) at 0 °C. The reaction mixture was stirred at room temperature. After stirring for 24 hours, borane-THF (6.0 mL) was added and the mixture was stirred for additional 22 hours. After cooling to 0 °C, MeOH was added until no fume appeared. The mixture was concentrated in vacuo and the residue was purified with OH-type silica gel column chromatography (MeOH in CHCb) to give the title compound (Ο.34 g, 71 % yield) as colorless oil.

MS (ESI) m/z : 282 [M+l]⁺.

RT = 0.946 min.

LCMS condition : B.

Step-2)

3-[5-(4-Bromophenyl)-l,2-oxazol-3-yl]propyl 4-methylbenzene-l-sulfonate

To a solution of 3-[5-(4-bromophenyl)-l,2-oxazol-3-yl]propan-l-ol (75 mg) in CHCb (5.3 mL) were added TsCl (66 mg), trimethylamine hydrochloride (13 mg) and TEA (0.074 mL). After stirring for 2 hours at room temperature, water was added to the reaction mixture and the solution was extracted with CHCb. The organic extract was washed with brine, dried over MgS04 and concentrated in vacuo to give the title compound (0.14 g) as crude product, which was used in the next step without further purification.

MS (ESI) m/z : 436 [M+l]⁺.

RT = 1.201 min.

LCMS condition : B. -(4-Bromophenyl)-3-[3-(2-{(lS)-l-[(oxan-2-yl)oxy]ethyl}-lH-imidazol-l-yl)piOpyl]-l,2-oxazole

To a mixture of the 2-[(lS)-l-tetrahydropyran-2-yloxyethyl]-lH-imidazole (0.13 g) and sodium hydride (26 mg) in DMF (6.4 mL) was added the crude material obtained in the Step-2 (0.14 g) at room temperature. After stirring for 10 minutes at 70 °C, water was added to the reaction mixture and the solution was extracted with EtOAc. The organic extract was washed with brine, dried over MgS04 and concentrated in vacuo. The residue was purified with NH-type silica gel column chromatography (50- 100% EtOAc in n-hexane) to give the title compound (0.16 g) as crude product, which was used in the next step without further purification.

MS (ESI) m/z : 460 [M+l]⁺.

RT = 0.655 min.

LCMS condition : B.

Step-4)

(lS)-l-(l-{3-[5-(4-bromophenyl)-l,2-oxazol-3-yl]pi-opyl}-lH-imidazol-2-yl)ethan-l-ol

(Compound-224)

Compound-224

The title compound was obtained in the manner as with the "Synthesis of Compound- 102: step-2" using the corresponding materials.

Ή-NMR, MS and LCMS retention time data of Compoundl47 are shown in Table 3.

Synthesis of Compound-230

(lS)-l-[l-({5-[(4-{[(3S)-l-(2-hydroxyethyl)pyrrolidin-3-yl]oxy}phenyl)ethynyl]-l,2-oxazol-3- l}methyl)-lH-imidazol-2-yl]ethan-l-ol

Compound-230

Step-1)

(3S) - 1 - (2- {[tert-but l(dimethyl)silyl] oxy}ethyl) - 3- (4-iodophenoxy)pyrrolidine

^tbs—

The title compound was obtained in the - manner as with the "Syjnthesis of In¹termediate-6: step-1" using the corresponding materials.

MS (ESI) m/z : 448 [M+l]⁺.

RT = 0.880 min.

LCMS condition · B.

Step-2)

5-[(4-{[(3S)-l-(2-{[tert-butyl(dimethyl)silyl]oxy}ethyl)pyrrolidin-3-yl]oxy}phenyl)ethynyl]-3- [(2-{(lS)- l-[(oxan-2-yl)oxy]ethyl}- lH-imidazol- l-yl)meth l]- 1,2-oxazole

The title compound was obtained in the manner as with the "Synthesis of Compound- 102: step-1" using the corresponding materials.

MS (ESI) m/z : 621 [M+l]⁺.

RT = 0.830 min.

LCMS condition : B.

Step -3)

(lS)-l-[l-({5-[(4-{[(3S)-l-(2-hydroxyethyl)pyrrolidin-3-yl]oxy}phenyl)ethynyl]-l,2-oxazol-3- yl}methyl)- lH-imidazol-2-yl]ethan- l"ol (Compound-230)

Compound-230

The title compound was obtained in the manner as with the "Synthesis of Compound- 102 ste -2" using the corresponding materials.

Ή-NMR, MS and LCMS retention time data of Compound-230 are shown in Table 3. Synthesis of Compound-237

3-(4-{[3-({2-[(lS)-l-aminoethyl]-lH-imidazol-l-yl}methyl)-l,2-oxazol-5- l]ethynyl}phenoxy)propan- l"ol dihydrochloride

Step-1)

Tert-butyl [(lS)-l-(lH-imidazol-2-yl)ethyl]carbamate

To a solution of tert-butyl N-[(lS)"l-methyl-2-oxo-ethyl]carbamate (0.31 g) in Me OH (3.5 mL) was added 28% aqueous ammonia (0.49 mL) and 8.8 mol/L glyoxal (0.39 mL) successively. The mixture was stirred for 4 days at room temperature and evaporated. The residue was charged onto ISOLUTE® HM-N and purified with OH-type silica gel column chromatography (O10 % MeOH in CHCls) to give the title compound (0.24 g, 65 % yield, 55%ee) as brown oil.

MS (ESI) m/z : 212 [M+l]⁺.

RT = 0.422 min.

LCMS condition : A.

The chiral analysis was done by following SFC systems.

UPLC : WATERS ACQUITY UPC2.

Chiral Column : DAICEL CHIRALPAK ΑΥΉ 4.6x250 mm.

Mobile phase : MeOH/CO2=20/80.

Flow Rate : 3 ml/min.

Temp. : 40 °C.

Time: 10 min.

Sample concentration: lmg/mL in MeOH.

The racemic compound has retention time of 1.22 and 2.03 min while the title compound has retention time of 2.03 min.

Step-2)

Tert-butyl [(lS)-l-{l-[(5"{[4-(3-{[tert-butyl(dimethyl)silyl]oxy}propoxy)phenyl]ethynyl}-l,2- oxazol-3- l meth l -lH-imidazol-2- l eth l carbamate

To a solution of tert-butyl [(lS)-l-(lH-imidazol-2-yl)ethyl]carbamate (22 mg) in DMF (1.4 mL) was added sodium hydride (4.2 mg) at 0 °C. After stirring for 30 minutes, Intermediate- 14 (47 mg) in DMF (1.4 mL) was added. The mixture was allowed to warm to room temperature and stirred for 2.5 hours. The reaction mixture was quenched with AcOH (7.5 pL) and a saturated aqueous ammonium chloride and extracted with EtOAc. The organic extract was concentrated in vacuo. The residue was purified with amino-type silica gel column chromatography (34-100 % EtOAc in n-hexane) to give the title compound (39 mg, 78 % yield) as colorless oil.

MS (ESI) m/z : 581 [M+l]⁺.

RT = 0.860 min.

LCMS condition : C. Step -3)

Tert-butyl [(lS)-l-{l-[(5-{[4-(3-hydroxypropoxy)phenyl]ethynyl}-l,2-oxazol-3-yl)methyl]-lH- imidazol- 2 - l}e thy 1] carbamate

The title compound was obtained in the manner as with the "Synthesis of Compound-53: step-3" using the corresponding materials.

MS (ESI) m/z : 467 [M+l]⁺.

RT = 0.446 min.

LCMS condition : C.

Step -4)

3-(4-{[3-({2-[(lS)-l-aminoethyl]-lH-imidazol-l-yl}methyl)-l,2-oxazol-5- l]ethynyl}phenoxy)propan-l-ol dihydrochloride (Compound-237)

To a solution of tert-butyl [(lS)-l-{l-[(5-{[4-(3-hydroxypropoxy)phenyl]ethynyl}-l,2-oxazol-3- yl)methyl]-lH-imidazol-2-yl}ethyl]carbamate (4.5 mg) in l,4"dioxane (0.50 mL) was added 4 mol/L HC1 in 1,4-dioxane (0.50 mL) at room temperature and stirred for 0.5 hours and concentrated in vacuo. The residue was triturated with EtOAc and IPE .The solid was collected by filtration to give the title compound (2.6 mg, 61 % yield) as colorless solid.

Ή-NMR, MS and LCMS retention time data of Compound-237 are shown in Table 3.

Synthesis of Compound-243

3-[3-(4-{[3-({2-[(lS)-l-hydroxyethyl]-lH-imidazol-l-yl}methyl)-l,2-oxazol-5- yl]ethynyl}phenoxy)azetidin- l-yl]propane- 1,2-diol

Step-1)

To a suspension of 3-(4-iodophenoxy)azetidine (0.20 g) in 2-propanol (3.6 mL) was added tert- butyldimethylsilyl glycidyl ether (0.15 g) at room temperature. The mixture was heated to 80 °C for 5 hours and then allowed to cool to room temperature. The reaction mixture was concentrated and the residue was purified_by OH-type jgilica gel column-chromatography- (0- 10 % MeOH in CHCI3) to give the title compound (0.15 g, 45 % yield) as colorless oil.

MS (ESI) m/z : 464 [M+l]⁺.

RT = 0.835 min.

LCMS condition : B.

Step -2)

3-[3-(4-{[3-({2-[(lS)-l-hydroxyethyl]-lH-imidazol-l-yl}methyl)-l,2-oxazol-5- l]ethynyl}phenoxy)azetidin- l-yl]propane- 1,2-diol (Compound-243)

Compound-243

The title compound was obtained in the manner as with the "Synthesis of Compound-230^" step-2 and step-3" using the corresponding materials.

Ή-NMR, MS and LCMS retention time data of Compound-243 are shown in Table 3.

Synthesis of Compound-245

5-({6-[3-({2-[(lS)-l-hydroxyethyl]-lH-imidazol-l-yl}methyl)-l,2-oxazol-5-yl]naphthalen-2- yl}oxy)pentan- l-ol

Compound-245

Step-1)

-[(6-Bromonaphthalen-2-yl)oxy]pentyl}oxy)(tert-butyl)dimethylsilane

To a solution of 6-bromonaphthalen-2-ol (0.50 g), 5-[tert-butyl(dimethyl)silyl]oxypentan-l-ol (0.98 g) in THF (4.5 mL) and toluene (4.5 niL) were added DIAD (2.4 mL, 1.9 M solution in toluene) and PPh3 (1.2 g). After stirring for 5 hours at 80 °C, the reaction mixture was concentrated in vacuo. The resulting residue was diluted with 25% EtOAc in /rhexane and the insoluble matters were filtered out. The filtrate was concentrated in vacuo. The residue was charged onto ISOLUTE® HM-N and purified by OH-type silica gel column chromatography (2-8 % EtOAc in /2-hexane) to give the title compound (0.95 g, 100% yield) as colorless oil.

Ή NMR (400 MHz, CHLOROFORM-d) δ ppm 0.06 (s, 6 H), 0.90 (s, 9 H), 1.49^■ 1.65 (m, 4 H), 1.87 (quin, J=6.9 Hz, 2 H), 3.65 (t, J=6.2 Hz, 2 H), 4.06 (t, J=6.5 Hz, 2 H), 7.08 (d, J=2.2 Hz, 1 H), 7.15 (dd, J=8.9, 2.4 Hz, 1 H), 7.46^■ 7.51 (m, 1 H), 7.55^■ 7.66 (m, 2 H), 7.90 (d, J=1.5 Hz, 1 H).

Step -2)

5-{[6-(4,4,5,5-Tetrameth M,3,2-dioxaborolan-2-yl)naphthalen-2-yl]oxy}pentan-l-ol

A round bottomed flask was charged with 5-[(6-bromo-2-naphthyl)oxy]pentoxytert-butyl- dimethyl-silane (0.40 g), potassium acetate (0.23 g), bis(pinacolato)diboron (0.36 g), and DMSO (4.7mL). The flask was evacuated and backfilled with nitrogen followed by addition of PdCb(dppf) (21 mg). After stirring for 7 hours at 100 °C, to the reaction mixture was added PdC idppf) (21 mg) and the reaction mixture was stirred for 1 hour at the same temperature. After cooling, the reaction mixture was diluted with EtOAc followed by washing with brine twice. The organic layer was dried over MgS04 and concentrated in vacuo. The residue was purified by OH-type silica gel column chromatography (25-50 % EtOAc in /rhexane) to give the title compound (0.26 g, 68% yield) as pale yellow oil.

MS (ESI) m/z : 357 [M+l]⁺.

RT = 1.266 min.

LCMS condition : B.

Step -3)

5-[(6-{3-[(2-{(lS)-l-[(oxan-2-yl)oxy]ethyl}-lH-imidazol-l-yl)methyl]-l,2-oxazol-5- yl}naphthalen-2-yl)oxy]pentan- l"ol

To a solution of 5-iodp-3-[[2-[(lS)-l-tetrahydropyran-2-yloxyethyl]imidazol-l- yl] methyl] isoxazole (49 mg) and 5-[[6-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-2- naphthyl]oxy]pentan-l-ol (43 mg) in 1,4-dioxane (1.2 mL) and H2O (0.12 mL) were added potassium carbonate (50 mg) and Pd(PP 113)4 (28 mg). The flask was evacuated and backfilled with nitrogen and then the reaction mixture was stirred overnight at 70 °C. After addition of total amount (42 mg) of Pd(PPh3)4 in two portions, the mixture was stirred for additional 50 hours at 70 °C. After cooling, the reaction mixture was filtered through a pad of Celite® and NH-type silica gel, and concentrated in vacuo. The residue was purified by NH-type silica gel column chromatography (25-100 % EtOAc in a-hexane and then 10-20% MeOH in

CHCI3) to give the title compound (7.0 mg, 11% yield).

MS (ESI) m/z : 506 [M+l]⁺.

RT = 0.735 min.

LCMS condition : B. Step-4)

5-({6-[3-({2-[(lS)-l-hydroxyethyl]-lH-imidazol-l-yl}methyl)-l,2-oxazol-5-yl]naphthalen-2- yl}oxy)pentan- l-ol (Compound-245)

Compound-245

Compound-245 was obtained in the manner as with the "Synthesis of Compound- 102: step-2" using the corresponding materials.

Ή-NMR, MS and LCMS retention time data of Compound-245 are shown in Table 3. Synthesis of Compound-252

3-(4-{[6-({2-[(lS)-l-hydroxyethyl]-lH-imidazol-l-yl}methyl)pyridin-3- yl]ethynyl}phenoxy)propan- l'ol

Step-1)

(5-{[4-(3-{[Tert'butyl(dimethyl)silyl]oxy}propoxy)phenyl]ethynyl}pyridin-2-yl)methanol

To a suspension of tert-butyl-[3-(4-ethynylphenoxy)propoxy]-dimethyl-silane (0.16 g) and (5- bromo-2-pyridyl)methanol (0.10 g) in THF (5 mL) were added PdCl₂(PPh₃)2 (15 mg), Cul (2.0 mg), PPI13 (42 mg) and TEA (0.21 mL). The resulting mixture was stirred overnight at room temperature. The reaction mixture was poured into water and extracted three times with EtOAc. The combined organic layer was washed with water, dried over MgSCk, and concentrated in vacuo. The residue was purified by OH-type silica gel column chromatography (20-80 % EtOAc in n-hexane) to give the title compound (0.14 g, 46 % yield) as yellow solid.

Ή NMR (600 MHz, CHLOROFORM-d) 8 ppm 0.05 (s, 6 H), 0.89 (s, 9 H), 1.97 - 2.02 (m, 2 H), 3.79 - 3.82 (m, 2 H), 4.08 - 4.11 (m, 2 H), 4.76 - 4.80 (m, 2 H), 6.87 - 6.92 (m, 2 H), 7.22 - 7.25 (m, 1 H), 7.45 - 7.49 (m, 2 H), 7.77^■ 7.80 (m, 1 H), 8.68 - 8.70 (m, 1 H).

Step -2)

3-(4-{[6-({2-[(lS)-l-hydroxyethyl]-lH-imidazol-l-yl}methyl)pyridin-3- yl]ethynyl}phenoxy)propan-l-ol (Compound-252)

To a solution of (5-{[4-(3"{[tert-butyl(dimethyl)silyl]oxy}propoxy)phenyl]ethynyl}pyridin-2- yDmethanol (0.13 g) and Intermediated (96 mg) in THF (5.2 mL) were added TMAD (0.14 g) and tributylphosphine (0.16 g) at 0 °C. The resulting mixture was allowed to warm to room temperature and stirred for 2 hours. The reaction mixture was diluted with EtOAc followed by washing with water. The organic layer was dried over MgSC*4 and concentrated in vacuo. The residue was roughly purified by OH-type silica gel column chromatography (0"10 % MeOH in CHC1₃) to give a colorless oil. The oil was dissolved in THF (33 mL) followed by addition of 1 mol/L aqueous HC1 (33 mL). After stirring for 4 hours, the reaction mixture was basified with aqueous potassium carbonate and concentrated to remove excess THF. The resulting aqueous solution was extracted with chloroform and the organic layer was dried over MgS04. The crude product, obtained after concentration, was purified by NH-type silica gel column chromatography (O-IO % MeOH in CHCI3) to give the title compound (61 mg, 49 % yield) as pale grey solid.

^!H-NMR, MS and LCMS retention time data of Compound-252 are shown in Table 3.

Synthesis of Compound-257

(lS)-l-(l-{[5-({4-[trans-2-(aminomethyl)cyclopropyl]phenyl}ethynyl)-l,2-oxazol-3-yl]methyl}- -imidazol-2-yl)ethan-l-ol

Compound-257

Step-1) thyl trans-2-(4"iodophenyl)cyclopropane- 1-carboxylate

To a solution of trimethylsulfoxonium iodide (0.95 g) in dimethyl sulfoxide (12 niL) were added sodium hydride (0.17 g) and ethyl (E)-3-(4-iodophenyl)prop-2-enoate (1.0 g). The reaction mixture was stirred at room temperature for 2 hours, quenched with water and extracted with EtOAc. The organic extract was washed with brine, dried over MgS04 and concentrated in vacuo. The residue was purified with OH-type silica gel column chromatography (0-50% EtOAc in n-hexane) to give the title compound (0.55 g, 53% yield) as colorless solid.

Ή NMR (400 MHz, CHLOROFORM-d) δ ppm 1.23 - 1.32 (m, 3 H), 1.56^■ 1.64 (m, 2 H), 1.81 1.91 (m, 1 H), 2.41 - 2.50 (m, 1 H), 4.17 (q, J=7.1 Hz, 2 H), 6.85 (br d, J=8.2 Hz, 2 H), 7.59 (b d, J=8.2 Hz, 2 H).

Step -2)

To a solution of ethyl trans-2-(4-iodophenyl)cyclopropanecarboxylate (0.87 g) in THF (4.0 mL) was added lithium borohydride (0.18 g). The reaction mixture was stirred at room temperature for 1 hour, quenched with 1 mol/L aqueous HCl and extracted with CHCI3. The organic extract was washed with brine, dried over MgSC and concentrated in vacuo. The residue was purified with OH-type silica gel column chromatography (50- 100% EtOAc in n- hexane) to give the title compound (0.73 g, 97% yield) as colorless oil.

iH NMR (400 MHz, CHLOROFORM-d) 8 ppm 0.86 - 1.00 (m, 2 H), 1.34 - 1.49 (m, 2 H), 3.62 (br d, J=6.5 Hz, 2 H), 6.82 (d, J=8.3 Hz, 2 H), 7.56 (d, J=8.3 Hz, 2 H).

idophenyl)cyclopropyl]methyl}-lH-isoindole-l,3(2H)-dione

To a solution of [trans-2-(4-iodophenyl)cyclopropyl]methanol (l.l g) in THF (15 mL) were added phthalimide (0.89 g), PPhs (2.1 g) and 2.2 mol L DEAD in toluene (3.6 mL). The reaction mixture was stirred at room temperature for 1 hour and concentrated in vacuo. The residue was purified with OH-type silica gel column chromatography (2050% EtOAc in n- hexane) to give the title compound (l.l g, 68% yield) as colorless solid.

Ή NMR (400 MHz, CHLOROFORM-d) δ ppm 0.89 - 0.98 (m, 1 H), 1.05 - 1.13 (m, 1 H), 1.44 - 1.52 (m, 1 H), 1.95 - 2.02 (m, 1 H), 3.59 - 3.68 (m, 1 H), 3.73^■ 3.81 (m, 1 H), 6.76 (d, J=8.3 Hz, 2 H), 7.52 (d, J=8.3 Hz, 2 H), 7.68 - 7.75 (m, 2 H), 7.81 - 7.88 (m, 2 H).

Step-4)

■ [Trans - 2 - (4- iodophenyOcyclop ropy 1] methanamine

To a solution of 2-[[trans-2-(4-iodophenyl)cyclopropyl]methyl]isoindoline-l,3-dione (l.l g) in EtOH (3.0 mL) was added hydrazine hydrate (0.41 g). The reaction mixture was stirred at 65 °C for 2 hours and filtered through a pad of Celite®. The filtrate was poured into water and extracted with CHCb. The organic extract was washed with brine, dried over MgSC-4 and concentrated in vacuo. The residue was purified with NH-type silica gel column chromatography (0-10% MeOH in EtOAc) to give the title compound (0.75 g, quant.) as colorless oil.

Ή NMR (400 MHz, CHLOROFORM-d) δ ppm 0.82^■ 0.92 (m, 2 H), 1.17^■ 1.29 (m, 1 H), 1.62^■ 1.71 (m, 1 H), 2.64^■ 2.78 (m, 2 H), 6.81 (d, J=8.3 Hz, 2 H), 7.55 (d, J=8.3 Hz, 2 H).

Step-5)

2,2,2-Trifluoro-N-{[trans-2-(4-iodophenyl)cyclopropyl]methyl}acetamide

To a solution of [trans-2-(4-iodophenyl)cyclopropyl]methanamine (0.75 g) in MeOH (10 mL) were added ethyl trifluoroacetate (0.78 g) and TEA (l.l mL). The reaction mixture was stirred at room temperature for 1 hour and concentrated in vacuo to give the title compound (0.93 g, 92% yield) as powder.

MS (ESI) m/z : 370 [M+l]⁺.

RT = 1.065 min.

LCMS condition : B.

Step -6)

2,2,2-Trifluoro-N-({trans-2-[4-({3-[(2-{(lS)-l-[(oxan-2 l)oxy]ethyl}-lH-imidazol-l-yl)methyl]- l,2-oxazol-5-yl}ethynyl)phenyl]cyclopropyl}methyl)acetamide

The title compound was obtained in the manner as with the "Synthesis of Compound-62 step-1" using the corresponding materials.

MS (ESI) m/z : 543 [M+l]⁺.

RT = 0.687 min.

LCMS condition : B.

Step-7)

l-{Trans-2-[4-({3-[(2-{(lS)-l-[(oxan-2-yl)oxy]ethyl}-lH-imidazol-l-yl)methyl]-l,2-oxazol-5-

To a solution of 2,2,2-trifluoro-N-[[trans-2-[4-[2-[3-[[2-[(lS)-l-tetrahydropyran-2- yloxyethyl]imidazol-l-yl]methyl]isoxazol-5-yl]ethynyl]phenyl]cyclopropyl]methyl]acetamide (0.17 g) in MeOH (8.0 mL) was added 20% aqueous potassium carbonate (4.0 mL). The reaction mixture was stirred at room temperature for 3 hours, poured into saturated aqueous sodium bicarbonate and extracted with CHCI3. The organic extract was washed with brine, dried over MgSC"4 and concentrated in vacuo to give the title compound (0.14 g, 99% yield) as oil.

MS (ESI) m/z : 447 [M+l]⁺.

RT = 0.224 min.

LCMS condition : A.

Step -8)

(lS)-l-(l-{[5-({4-[trans-2-(aminomethyl)cyclopropyl]phenyl}ethynyl)-l,2-oxazol-3-yl]methyl}- -imidazol-2-yl)ethan-l-ol (Compound-257)

Compound-257

The title compound was obtained in the manner as with the "Synthesis of Compound- 102: ste -2" using the corresponding materials.

Ή-NMR, MS and LCMS retention time data of Compound-257 are shown in Table 3.

Synthesis of Compound-264

(3R)-4-[3-(4-{[3-({2-[(lS)- l-hydroxyethyl]- lH-imidazol- l-yl}methyl)- l,2-oxazol-5- l] ethynyljp henoxy) azetidin- 1 -yl]butane^■ 1 , 3 - diol

Compound-264

Step- 1)

3-(4-Iodo henox )-l-{ -2- hen l- l,3-dioxan-4-yl]methyl}azetidine

To a stirred solution of ethyl 3-(4-iodophenoxy)azetidine (0.20 g) in CHCI3 (1.2 niL) were added (4R)-2-phenyl-l,3-dioxane-4-carbaldehyde (0.20 g), NaBH(OAc)₃ (53 mg) and AcOH (0.20 mL) at room temperature. The mixture was stirred at the same temperature for 30 minutes, and then 10 minutes at 50 °C. The mixture was allowed to cool to room temperature and quenched with a saturated aqueous sodium bicarbonate and extracted with CHCI3. The organic layer was passed through a phase separator and concentrated in vacuo. The residue was purified with amino-type silica gel column chromatography (20"70 % EtOAc in n-hexane) to give the title compound (0.31 g, 93 % yield) as colorless oil.

MS (ESI) m/z : 452 [M+l]⁺.

RT = 0.704 min.

LCMS condition : B.

Step -2)

3-[(2-{(lS)-l-[(oxan-2-yl)oxy]ethyl}- lH-imidazol-l-yl)methyl]-5-({4-[(l-{[(4R)-2-phenyl-l,3- dioxan-4-yl]methyl}azetidin-3-yl)oxy]phenyl}ethynyl)- l,2-oxazole

The title compound was obtained in the manner as with the "Synthesis of Compound-62: step-1" using the corresponding materials

MS (ESI) m/z : 625 [M+l]⁺.

RT = 0.560 min.

LCMS condition : B.

Ste -3)

(3R)-4- [3·(4·{[3-({2- [(IS)- 1-hydroxyethyl]- lH-imidazol- l-yl}methyl)- 1,

yl]ethynyl}phenoxy)azetidin- l-yl]butane- 1,3-diol (Compound-264)

To a solution of 3-[(2-{(lS)-l-[(oxan-2-yl)oxy]ethyl}-lH-imidazol-l-yl)methyl]-5-({4-[(l-{[(4R)- 2-phenyl-l,3-dioxan-4-yl]methyl}azetidin-3-yl)oxy]phenyl}ethynyl)-l,2-oxazole (0.10 g) in MeOH (1.3 mL) and 1,4-dioxane (0.30 mL) was added 4 mol/L HC1 in 1,4-dioxane (1.0 mL) at room temperature and stirred for 1 hours and concentrated in vacuo. The residue was basified with 10% aqueous potassium carbonate and extracted with 10 % MeOH in CHC three times. The combined organic layer was dried over MgS04, filtered and concentrated in vacuo. The residue was purified with amino-type silica gel chromatography (0"15 % MeOH in CHCI3) to give the title compound (45 mg, 59 % yield) as orange amorphus.

Ή-NMR, MS and LCMS retention time data of Compound-264 are shown in Table 3.

Synthesis of Compound-266

2-{[4-(4-{[3-({2-[(lS)-l-hydroxyethyl]-lH-imidazol-l-yl}methyl)-l,2-oxazol-5- yl]ethynyl}phenoxy)piperidin-l-yl]methyl}propane- 1,3-diol

Compound-266

Step-1)

l-[(2,2-Dimethyi ,3-dioxan-5-yl)methyl]-4-[4-({3-[(2-{(lS)-l-[(oxan-2-yl)oxy]ethyl}-lH- imidazol- l-yl)methyl]- l,2-oxazol-5-yl}ethynyl)phenoxy]piperidine

To a solution of 5-((4-(piperidin-4-yloxy)phenyl)ethynyl)-3"((2-((lS)-l-((tetrahydro-2H-pyran- 2-yl)oxy)ethyl)-lH-imidazol-l-yl)methyl)isoxazole (65 mg) in CHCI3 (1.4 mL) were added 2,2- dimethyM,3-dioxane-5-carbaldehyde (30 mg) and acetic acid (0.039 mL) at room temperature. The mixture was stirred for 1 hour and then NaBH(OAc)3 (43 mg) was added at room temperature. The mixture was stirred at the same temperature for 2 hours and then stirred at 55 °C for 22 hours. After cooling, saturated aqueous sodium bicarbonate was added and the bHayer was separated. The organic extract was passed through a phase separator and concentrated in vacuo. The residue was purified with NH-type silica gel column chromatography (50-75% EtOAc in n-hexane) to give the title compound (18 mg, 22% yield) as pale yellow oil.

MS (ESI) m/_Z : 605 [M+l]⁺.

RT = 0.874 min.

LCMS condition : A.

Step-2)

2-{[4-(4-{[3-({2-[(lS)-l-hydroxyethyl]-lH-imidazol-l-yl}methyl)-l,2-oxazol-5-

Compound-266 The title compound was obtained in the manner as with the "Synthesis of Compound- 102: step -2" using the corresponding materials.

Ή-NMR, MS and LCMS retention time data of Compound-266 are shown in Table 3.

Synthesis of Compound-267

(2S)-l-[(2-aminoethyl)amino]-3-(4-{[3-({2-[(lS)-l-hydroxyethyl]-lH-imidazol-l-yl}n

-oxazol-5-yl]ethynyl}phenoxy)propan-2-ol

Step-1)

(lS)-l-[l-({5-[(4-{[(2S)-oxiran-2-yl]methoxy}phenyl)ethynyl]-l,2-oxazol-3-yl}methyl)-lH- imidazol-2- l ethan-l-ol

The title compound was obtained in the manner as with the "Synthesis of Compound- 102: step-l" using the corresponding materials.

MS (ESI) m/z : 366 [M+l]⁺.

RT = 0.531 min.

LCMS condition : B.

Step-2)

(2S)-l-[(2-aminoethyl)amino]-3-(4-{[3-({2-[(lS)-l-hydroxyethyl]-lH-imidazol-l-yl}methyl)-l,2- oxazol-5-yl]ethynyl}phenoxy)propan-2-ol (Compound-267)

To a suspension of (lS)-l-[l-({5-[(4-{[(2S)-oxiran-2-yl]methoxy}phenyl)ethynyl]-l,2-oxazol-3- yl}methyl)-lH-imidazol-2-yl]ethan-l-ol (14 mg) in EtOH (0.13 mL) was added ethylenediamine (3.5 mg). The resulting mixture was heated to 80 °C for 1 hour and then concentrated under reduced pressure. The residue was purified by OH-type silica gel column chromatography (0"10 % MeOH in CHCI3 containing 1% NH4OH) to give the title compound (10 mg, 61 % yield) as pale yellow solid.

^!H-NMR, MS and LCMS retention time data of Compound-267 are shown in Table 3.

Synthesis of Compound-269

3-{3-[4-({3-[(lR)-2-amino-l-{2-[(lS)-l-hydroxyethyl]-lH-imidazol-l-yl}ethyl]- l,2-oxazol-5- yl}ethynyl)phenoxy]azetidin- l-yl}propan- l-ol

Compound-269

Step-1)

Methyl (2R)-3-[(tert-butoxycarbonyl)amino]-2-(2-{(lS)-l-[(oxan-2-yl)oxy]ethyl}-lH-imidazol- l- l)propanoate

To a solution of (2S)-2-tetrahydropyran-2-yloxypropanal (7.5 g) in MeOH (80 mL) were added glyoxal (4.2 mL) and methyl (2R)-2-amino-3-hydroxy-propanoate (8.0 g) in MeOH (40 mL) at room temperature. After stirring for 10 minutes, ammonium acetate (2.8 g) was added into the reaction mixture, which was stirred for additional 3 days and concentrated in vacuo. The residue was purified with OH-type silica gel column chromatography (10-100% EtOAc in n-hexane) to give the title compound (4.4 g, 30 % yield) as yellow amorphous. MS (ESI) m/z : 398 [M+lh

RT = 0.559 min.

LCMS condition : B. Step-2)

Tert-butyl [(2R,3E)-3-(hydroxyimino)-2-(2-{(lS)-l-[(oxan-2-yDoxy]ethyl}-lH-imidazol-l- yl)propyl]carbamate

To a solution of methyl (2R)-3-(tert-butoxycarbonylamino)-2-[2-[(lS)-l-tetrahydropyran-2- yloxyethyl]imidazoM-yl]propanoate (4.4 g) in toluene (55 mL) was added dropwise DIBAL (44 mL, 1.0 M solution in toluene) while keeping the internal temperature below -70 °C. The reaction mixture was stirred for 15 minutes and then the reaction was quenched by adding MeOH (50 mL) while keeping the internal temperature below -67 °C. To the reaction mixture were added a 50 wt% aqueous potassium sodium tartrate (100 mL) and EtOAc (50 mL) and the solution was allowed to warm to room temperature and stirred for 3 hours. The layers were separated and the aqueous layer was extracted with EtOAc. The combined organic layer was dried over Na2S04 and concentrated in vacuo to give a crude material (4.3 g). To this crude material dissolved in MeOH (55 mL) and water (55 mL) were added hydroxylamine hydrochloride (0.84 g) and potassium carbonate (0.76 g). The reaction mixture was stirred for 16 hours and then the reaction mixture was concentrated and extracted with CHCI3. The organic extract was passed through a phase separator and concentrated in vacuo. The residue was purified with OH-type silica gel column chromatography (10-100 % EtOAc in n-hexane) to give the title compound (3.2 g, 76 % yield) as colorless amorphous.

MS (ESI) m/z : 383 [M+lh

RT = 0.478 min.

LCMS condition : B. Step-3)

Tert-butyl [(2R)-2-(5-iodo-l,2-oxazol-3-yl)-2-(2-{(lS)-l-[(oxan-2-yl)oxy]ethyl}-lH-imidazol-l- yl)ethyl] carbamate

To a solution of tert-butyl N-[(2R,3E)-3-hydroxyimino-2-[2-[(lS)-l-tetrahydropyran-2- yloxyethyl]imidazol-l-yl]propyl]carbamate (3.2 g) in EtOAc (83 mL) were added

tributyl(ethynyl)stannane (4.8 mL), NaHC03 (2.1 g) and water (8.3 mL) at room

temperature. After stirring for 10 minutes, N-chlorosuccinimide (2.2 g) was added-into the reaction mixture in portions, which was stirred for additional 1 hour. The mixture was diluted with EtOAc followed by washing with a saturated aqueous sodium bicarbonate and brine. The organic layer was dried over MgS04, filtered, and concentrated in vacuo to give the title compound as a crude material.

To this crude material dissolved in THF (20 mL) was added iodine (5.3 g) in THF (22 mL) at 0 °C. The reaction mixture was stirred for 1 hour and then the reaction was quenched with saturated aqueous sodium thiosulfate and staturated aqueous sodium bicarbonate and EtOAc. The layers were separated and the aqueous layer was extracted with EtOAc. The combined organic layer was dried over Na2S04 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 (1.7 g, 38 % yield) as pale yellow amorphous.

MS (ESI) m/z : 533 [M+l]⁺.

RT = 0.712 min.

LCMS condition : B.

Step-4)

Tert-butyl [(2R)-2-{5-[(4-{[l-(3-{[tert-butyl(dimethyl)silyl]oxy}propyl)azetidin-3- yl]oxy}phenyl)ethynyl]-l,2-oxazol-3-yl}-2-(2-{(lS)-l-[(oxan-2-yl)oxy]ethyl}-lH-imidazol-l- yl)ethyl] carbamate

To a solution of (lR)-3-[tert-butyl(diphenyl)silyl]oxy-l-(5-iodoisoxazol-3-yl)propan-l-ol (0.14 g) and l-ethynyl-4-[3-[(4-methoxyphenyl)methoxy]propoxy]benzene (0.18 g) in acetonitrile (2.6 mL) were added SUPERSTABLE Pd(0) CATALYST (28 mg), Cul (5.0 mg), TEA (0.18 mL) at room temperature. The reaction mixture was stirred for 2 hours and then the reaction mixture was added staturated aqueous sodium bicarbonate and EtOAc. The layers were separated and the aqueous layer was extracted with EtOAc. The combined organic layer was dried over Na2SC"4 and concentrated in vacuo. The residue was purified with NH^_ type silica gel column chromatography (10-100 % EtOAc in n-hexane) to give the title compound (0.16 g, 80 % yield) as pale yellow amorphous.

MS (ESI) m/z : 750 [M+l]⁺.

RT = 0.787 min.

LCMS condition : B. Step-5)

3-{3-[4-({3-[(lR)-2-amino-l-{2-[(lS)-l-hydroxyethyl]-lH-imidazol-l-yl}ethyl]-l,2-oxazol-5- yl}ethynyl)phenoxy]azetidin- l-yl}propan- l"ol (Compound-269)

Compound-269

To a solution of tert-butyl N-[(2R)-2-[5-[2-[4-[l-[3-[tert- butyl(dimethyl)silyl]ox^ropyl]azetidin-3-yl]oxyphenyl]ethynyl]isoxazol-3-yl]-2-[2-[(lS)-l- tetrahydropyran-2-yloxyethyl]imidazoM-yl]ethyl]carbamate (0.16 g) in l,4"dioxane (0.50 mL) and MeOH (0.20 mL) was added 4 mol/L HC1 in 1,4-dioxane (1.0 mL) at room

temperature and stirred for 1 hour. The reaction mixture was evaporated and this obtained residue was diluted with staturated aqueous sodium bicarbonate and CHC . The layers were separated and the aqueous layer was extracted with CHCI3. The organic extract was passed through a phase separator and concentrated in vacuo. The residue was purified with NH-type silica gel column chromatography (5- 10 % MeOH in CHCb) to give the title compound (66 mg, 69 % yield) as yellow amorphous.

Ή-NMR, MS and LCMS retention time data of Compound-269 are shown in Table 3.

Synthesis of Compound-276

(2S)-2-hydroxy-l-(4-{4-[3-({2-[(lS)-l-hydroxyethyl]-lH-imidazol-l-yl}methyl)-l,2-oxazol-5- yl]phenyl}piperidin-l-yl)propan-l-one

Step-1)

(2S)-2-hydroxy-l-(4-{4-[3-({2-[(lS)-l-hydroxyethyl]-lH-imidazol-l-yl}methyl)-l,2-oxazol-5- yl]phenyl}piperidin-l-yl)propan-l-one (Compound-276)

Compound-276

To a stirred solution of (lS)-l-[l-[[5-[4-(4-piperidyl)phenyl]isoxazol-3-yl]methyl]imidazol-2- yl]ethanol (30 mg) in DMF (l mL) were added HATU (39 mg), DIPEA (30 uL) and L-(+)- lactic acid (9.2 mg). The mixture was stirred for 5 hours at room temperature. The reaction mixture was poured into 20% aqueous potassium carbonate and extracted with EtOAc. The organic layer was washed twice with 20% aqueous potassium carbonate, dried over MgSC*4 and concentrated in vacuo. The residue was purified with NH-type preparative chromatography (CHCls MeOH = 15/1) to give the title compound (27mg, 75% yield) as colorless amorphous.

Ή-NMR, MS and LCMS retention time data of Compound-276 are shown in Table 3. Synthesis of Compound-281 (lS) -(l-{[5-({4-[(azetidin-3-yl)(hydroxy)methyl]phenyl}ethynyl)-l,2-oxazol-3-yl]methyl}-lH- imidazol- 2-yl)ethan- 1 -ol

Compound-281 Step-1)

Tert-butyl 3-[methoxy(methyl)carbamoyl]azetidine- 1-carboxylate

To a solution of l-tert-butoxycarbonylazetidine-3-carboxylic acid (1.0 g) in DMF (25 mL) were added Ν,Ο dime thy Ihydroxylamine hydrochloride (0.51 g), HATU (2.3 g), and DIPEA (2.6 mL). After stirring for 1 hour at room temperature, the reaction mixture was diluted with brine and extracted with EtOAc twice. The combined organic layer was washed with brine twice, dried over MgS04, and concentrated in vacuo. The residue was purified with OH-type silica gel column chromatography (25-55% EtOAc in /rhexane) to give the title compound (1.3 g, quant.) as colorless oil.

MS (ESI) m/z : 267 [M+l]⁺.

RT = 0.771 min.

LCMS condition : B.

Step -2)

Tert-butyl 3-(4-iodobenzoyl)azetidine^_l^_carboxylate

A three-necked flask was charged with 1,4-diiodobenzene (0.41 g) and diethyl ether (11 mL). The flask was evacuated and backfilled with nitrogen gas. To the solution was added n-BuLi (0.46 mL, 2.65 mol/L solution in n-hexane) dropwise at -78 °C and the reaction mixture was stirred for 1 hour at the same temperature. The solution of tert-butyl 3-

[methoxy(methyl)carbamoyl]azetidine-l-carboxylate (0.30 g) in diethyl ether (1.5 mL) was added dropwise to the mixture at -78 °C and the reaction was stirred for 2 hours. The reaction was allowed to warm to room temperature and stirred for 30 minutes. After cooling to 0 °C, the reaction was quenched with saturated aqueous ammonium chloride and extracted with EtOAc. The organic layer was washed with brine, dried over MgSC , and concentrated in vacuo. The residue was purified with OH-type silica gel column

chromatography (10"60% EtOAc in /rhexane) to give the title compound (34 mg, 7.2% yield) as yellow oil.

MS (ESI) m/z : 410 [M+l]⁺.

RT = 1.230 min.

LCMS condition : B.

Step -3)

Tert-butyl 3-[4-({3-[(2-{(lS)-l-[(oxan-2-yDoxy]ethyl}-lH-imidazol-l-yl)methyl]-l,2-oxazol-5- yl}ethy ny benzoyl] azetidine - 1 - carboxylate

To a stirred solution of tert-butyl 3-(4-iodobenzoyl)azetidine-l-carboxylate (34 mg) in DMF (1.0 mL) were added TEA (0.12 mL), Pd(PPh₃)₄ (10 mg), and Cul (1.7 mg). The flask was evacuated and backfilled with nitrogen. The mixture was heated to 65 °C for 5 minutes. The solution of 5-ethynyl-3-[[2-[(lS)-l-tetrahydropyran-2-yloxyethyl]imidazol-l- yl] methyl] isoxazole (29 mg) in DMF (0.50 mL) was added dropwise to the mixture above at 65 °C and stirred 30 minutes. After cooling, the reaction mixture was poured into water and extracted with EtOAc. The organic layer was washed with brine, dried over MgS04, and concentrated in vacuo. The residue was purified with NH-type silica gel column

chromatography (25"75% EtOAc in /rhexane) to give the title compound (53 mg, quant.) as colorless gum.

MS (ESI) m/z : 561 [M+l]⁺.

RT = 0.848 min.

LCMS condition : B.

Step-4)

Tert-butyl 3-{hydroxy[4-({3-[(2-{(lS)-l-[(oxan-2-yl)oxy]ethyl}-lH-imidazol-l-yl)methyl]-l,2- oxazol-5-yl}ethynyl)phenyl]methyl}azetidine-l-carboxylate

The title compound was obtained in the manner as with the "Synthesis of Compound-2: step- 1" using the corresponding materials.

MS (ESI) m/z : 563 [M+l]⁺.

RT = 0.766 min.

LCMS condition : B.

Step -5)

(lS)-l-(l-{[5-({4-[(azetidin-3-yl)(hydroxy)methyl]phenyl}ethynyl)-l,2-oxazol-3-yl]methyl}-lH- imidazol-2-yl)ethan-l-ol (Compound-281)

The title compound was obtained in the manner as with the "Synthesis of Compound-94 step-1" using the corresponding materials.

Ή-NMR, MS and LCMS retention time data of Compound-281 are shown in Table 3. Synthesis of Compound-283

(lS)-l-{l-[(5-{[4-(trans-2-{[(2-hydroxyethyl)amino]methyl}cyclopropyl)phenyl]ethynyl}-l,2- oxazol-3-yl)methyl]-lH-imidazol-2-yl}ethan-l-ol

Compound-283

Step-1)

N-(2-{[tert-butyl(dimethyl)silyl]oxy}ethyl)-2,2,2-trifluoro-N-{[t:

iodophenyl)cyclopropyl]methyl}acetamide

To a solution of 2,2,2-trifluoro-N-[[trans-2-(4-iodophenyl)cyclopropyl]methyl]acetamide (0.10 g) in DMF (2.7 mL) was added 2-bromoethoxy-tert-butyl-dimethyl-silane (71 mg) and CS2CO3 (0.18 g) at room temperature. After being stirred for 1 hour, the reaction mixture was heated to 65 °C. After being stirred for 2 hours at the same temperature, additional 2- bromoethoxy-tert-butyl-dimethyl-silane (36 mg) was added. Then the reaction mixture was stirred at 65 °C for 16 Jiours. After cooling, the reaction mixture was -added -saturated aqueous NH4CI and extracted with EtOAc. The combined organic layer was dried over MgS04, concentrated in vacuo onto ISOLUTE® HM-N. The residue was purified with OH- type silica gel column chromatography (5- 10 % EtOAc in n-hexane) to give the title compound (0.12 g, 84% yield) as a colorless oil.

Ή NMR (400 MHz, CHLOROFORM-d) δ ppm 0.02 - 0.12 (m, 6 H), 0.84 - 0.93 (m, 9 H), 0.93 - 1.09 (m, 2 H), 1.22 - 1.42 (m, 1 H), 1.79 - 1.92 (m, 1 H), 3.34 - 3.96 (m, 6 H), 6.76 - 6.83 (m, 2 H), 7.54 - 7.60 (m, 2 H).

Step -2)

2-{[Tert-butyl(dimethyl)silyl]oxy}-N-{[trans-2-(4-iodophenyl)cyclopropyl]methyl}ethan-l- amine

To a solution of N-[2-[tert-butyl(dimethyl)silyl]oxyethyl]-2,2,2-trifluoro-N-[[trans-2-(4- iodophenyl)cyclopropyl]methyl]acetamide (0.12 g) in MeOH (2.3 mL) was added K2CO3 (0.31 g) at room temperature. After being stirred for 30 minutes, 1 mol/L aqueous NaOH (3.0 mL) was added, and stirred for 1 hour. Then the reaction mixture was warmed to 65 °C, and stirred for 3.5 hours. After cooling, the reaction mixture was extracted with CHCI3. The organic layer was concentrated in vacuo onto ISOLUTE® HM-N. The residue was purified with NH-type silica gel column chromatography (0-5% MeOH in CHCI3) to give the title compound (35 mg, 36% yield) as a colorless oil.

Ή NMR (400 MHz, METHANOL- d4) δ ppm 0.07 (s, 6 H), 0.85 - 0.99 (m, 10 H), 1.19 - 1.40 (m, 2 H), 1.70 - 1.78 (m, 1 H), 2.57 (dd, J=12.4, 7.4 Hz, 1 H), 2.68 - 2.81 (m, 3 H), 3.75 (t, J=5.4 Hz, 2 H), 6.87 (d, J=8.3 Hz, 2 H), 7.55 (d, J=8.3 Hz, 2 H). Step- 3)

(lS)-l-{l (5-{[4-(trans-2-{[(2-hydroxyethyl)amino]methyl}cyclopropyl)phenyl]ethynyl}-l,2-

Compound-283

The title compound was obtained in the manner as with the "Synthesis of Compound-62: step-1" and "Synthesis of Compound- 102 |_step^2!' using the corresponding-materials- Ή-NMR, MS and LCMS retention time data of Compound-283 are shown in Table 3.

Synthesis of Compound-286

3-(4-{[2-({2-[(lS)-l-hydroxyethyl]-lH-imidazol-l-yl}methyl)-l,3-oxazol-5- yl]ethynyl}phenoxy)propan- l-ol

To a solution of 5-[tert-butyl(diphenyl)silyl]oxypentane-l,2-diol (5.0 g) in CHCI3 (70 mL) were added TEA (14 g) and pivaloyl chloride (3.4 g) at 0 °C. The reaction mixture was stirred for 2 hours at room temperature. The reaction was quenched with a saturated aqueous sodium bicarbonate and extracted with CHCI3. The organic layer was passed through a phase separator and concentrated in vacuo. The resiude was purified by OH-type silica gel column chromatography (0-20 % EtOAc in /rHexane) to give the title compound (4.5 g, 73 % yield) as colorless oil.

MS (ESI/APCI dual) m/z : 443 [M+l]⁺.

Step-2)

To a solution of 5-{[tert-butyl(diphenyl)silyl]oxy}-2-hydroxypentyl 2,2-dimethylpropanoate (4.5 g) in CHC1₃ (51 mL) were added TEA (3.1 g), DMAP (0.13 g), and tert-butyldimethylsilyl trifluoromethanesulfonate (4.0 g) at 0 °C. After stirring for 15 minutes, the reaction mixture was poured into saturated sodium bicarbonate and extracted with CHC . The organic layer was passed through a phase separator and_^ concentrated in vacuo. The residue was purified by OH-type silica gel column chromatography (0-5 % EtOAc in /rHexane) to give the title compound (4.9 g, 86 % yield) as colorless oil.

MS (ESI/APCI dual) m/z : 557 [M+lK

Step -3)

2-{[Tert-but l(dimethyl)silyl]oxy}-5-{[tert-butyl(diphenyl)silyl]oxy}pentan-l-ol

To a solution of 2-{[tert-butyl(dimethyl)silyl]oxy}-5-{[tert"butyl(diphenyl)silyl]oxy}pentyl 2,2- dimethylpropanoate (4.8 g) in toluene (43 mL) was added drop wise DIBAL (26 mL, 1.0 mol/L solution in toluene) at -78 °C. The reaction mixture was stirred for 1 hour and then the reaction was quenched by adding MeOH. After the resulting mixture was allowed to warm to room temperature, aqueous Rochelle salt and EtOAc were added and the resulting biphasic mixture was stirred for 5 hours. The layers were separated and the aqueous layer was extracted with EtOAc. The combined organic layer was passed through a phase separator and concentrated in vacuo. The residue was purified by OH-type silica gel column chromatography (0-20 % EtOAc in /2-Hexane) to give the title compound (3.8 g, 92 % yield) as colorless oil.

MS (ESI/APCI dual) m/z : 473 [M+l]⁺.

Step -4)

N-[(lE)-2-{[tert-butyl(dimethyl)silyl]oxy}-5-{[tert- buty l(diphe nyl) silyl] oxy}p entylidene] hydroxy lamine

To a solution of 2-{[tert-butyl(dimethyl)silyl]oxy}-5-{[tert-butyl(diphenyl)silyl]oxy}pentan-l-ol (0.20 g) in CHCls (2.1 mL) were added trichloroisocyanuric acid (0.11 g) and TEMPO (6.7 mg) at 0 °C, and the resulting mixture was stirred for 15 minutes. The reaction was quenched with saturated aqueous thiosulfate and staturated aqueous sodium bicarbonate. The phases were separated and the aqueous phase was extracted with CHCb. The combined organic layer was passed through a phase separator and concentrated under reduced pressure to give pale yellow oil, which was used in next step without further purication. The crude material obtained above was dissolved in MeOH (2.0 mL) and water followed by addition of hydroxylamine hydrochloride (88 mg) and potassium carbonate (0.21 g) at room temperature. The resulting suspension was stirred for 15 minutes and then acetonitrile (5.0 mL) was added to get the clear solution. After stirring for_another 30 minutes, the reaction mixture was concentrated and the residue was partitioned between CHCb and water. The organic layer was passed through a phase separator and concentrated in vacuo. The residue was purified by OH-type silica gel column chromatography (0-20 % EtOAc in /2-Hexane) to give the title compound (0.19 g, 94 % yield) as colorless oil.

MS (ESI/APCI dual) m/z : 486 [M+l]⁺.

Step -5)

(lZ)-2-{[tert-butyl(dimethyl)silyl]oxy}-5-{[tert-butyl(diphenyl)silyl]oxy}-N- h droxypentanimidoyl chloride

N-[(lE)-2-{[tert-butyl(dimethyl)silyl]oxy}-5-{[tert- butyl(diphenyl)silyl]oxy}pentylidene]hydroxylamine (0.16 g) in DMF (l.O mL) was added N- chlorosuccinimide (48 mg) at room temperature. After stirring for 1 hour, the mixture was diluted with diethyl ether followed by washing with water and brine. The organic layer was passed throught a phase separator and concentrated under reduced pressure to give the title compound (0.16 g, 94% yield) as colorless oil, which was used in next step without further purification.

Ή NMR (400 MHz, CHLOROFORM-d) δ ppm 0.04 (s, 3 H), 0.06 (s, 3 H), 0.88 (s, 9 H), 1.04 (s, 9 H), 1.43 - 1.68 (m, 2 H), 1.72^■ 1.88 (m, 2 H), 3.67 (t, J=7.1 Hz, 2 H), 4.42 (t, J=7.1 Hz, 1 H), 7.35 - 7.44 (m, 6 H), 7.63 - 7.68 (m, 4 H).

Step-6)

3-(2,2,3,3, 11, 11-Hexamethyl- 10, 10-diphenyl-4,9-dioxa-3, 10-disiladodecan-5-yl)-5-iodo- 1,2- oxazole OTBDPS

The title compound was obtained in the manner as with the "Synthesis of Compound-77 and Compound-78: step-1" using the corresponding materials

MS (ESI/APCI dual) m/z : 636 [M+l]⁺.

Step -7)

5-({4-[(2,2-Dimethyl-l,3-dioxan-5-yl)methoxy]phenyl}ethynyl)-3-(2,2,3,3,ll,ll-hexamethyl- 10,10-diphenyl-4,9-dioxa-3,10-disiladodecan-5-yl)-l,2-oxazole

The title compound was obtained in the manner as with the "Synthesis of Compound-77 and Compound-78: step-2" using the corresponding materials.

Ή NMR (400 MHz, CHLOROFORM-d) δ ppm -0.04 (s, 3 H), 0.07 (s, 3 H), 0.88 (s, 9 H), 1.04 (s, 9 H), 1.42 (s, 3 H), 1.48 (s, 3 H), 1.55 - 1.66 (m, 2 H), 1.74 - 1.92 (m, 2 H), 2.08 - 2.15 (m, 1 H), 3.66 (t, J=6.2 Hz, 2 H), 3.84 - 3.91 (m, 2 H), 4.08 - 4.16 (m, 4 H), 4.89 (t, J=6.2 Hz, 1 H), 6.42 (s, 1 H), 6.92 (d, J=8.6 Hz, 2 H), 7.34 - 7.44 (m, 6 H), 7.50 (d, J=8.6 Hz, 2 H), 7.64 (m, 4 H).

Step-8)

l-[5-({4-[(2,2-Dimethyl-l,3-dioxan-5-yl)methoxy]phenyl}ethynyl)-l,2-oxazol-3-yl]butane-l,4- diol

To a cooled (0 °C) solution of 5-({4-[(2,2-dimethyl-l,3-dioxan-5-yl)methoxy]phenyl}ethynyl)-3- (2,2,3,3, 11, 11-hexamethyl- 10, 10-diphenyl-4,9-dioxa-3, 10-disiladodecan-5-yl)- 1,2-oxazole (0.49 g) in THF (3.3 mL) was added dropwise TBAF (1.6 mL, 1 mol/L solution in THF). After stirring for 1 hour at room temperature, the mixture was poured into saturated aqueous ammonium chloride and extracted with EtOAc. The combined organic layer was washed with brine, passed through a phase separator, and concentrated in vacuo. The residue was purified by OH-type silica gel column chromatography (0-5 % MeOH in CHCI3) to give the title compound (0.25 g, 96 % yield) as colorless solid.

MS (ESI) m/z : 402 [M+l]⁺.

RT = 0.917 min.

LCMS condition : B.

Step -9)

4-{[Tert-butyl(dimethyl)silyl]oxy}- l-[5-({4-[(2,2-dimethyl-l,3-dioxan-5-

To a cooled (0 °C) solution of l-[5-({4-[(2,2-dimethyl- l,3-dioxan-5- yl)methoxy]phenyl}ethynyl)- l,2-oxazol-3-yl]butane- l,4-diol (0.25 g) in DMF (3.1 mL) were added imidazole (0.21 g) and TBSCl (O. IO g). After stirring for 1.5 hours at 0 °C, the reaction mixture was poured into saturated aqueous ammonium chloride and extracted with ethyl acetate. The combined organic layer was washed with water and brine, passed through a phase separator, and concentrated in vacuo. The residue was purified by OH-type silica gel column chromatography (5"50 % EtOAc in /rhexane) to give the title compound (0.31 g, 97 % yield) as colorless solid.

MS (ESI) m/z : 516 [M+l]⁺.

RT = 1.47 min.

LCMS condition : B.

Step- 10)

3-(4-{[2-({2-[(lS)- l-hydroxyethyl]- lH-imidazol- l-yl}methyl)-l,3-oxazol-5- yl]ethynyl}phenoxy)propan- l-ol (Compound-286)

The title compound was obtained in the manner as with the "Synthesis of Compound- 160: step-6"8" using the corresponding materials. Ή-NMR, MS and LCMS retention time data of Compound-286 are shown in Table 3. Synthesis of Compound-287

(S)-3-(4-((2-((2-(l-hydroxyethyl)-lH-imidazol-l-yl)methyl)oxazol-5- l)ethynyl)phenoxy)propan-l-ol

Compound-287

Step-1)

2-{[(Oxan-2- l)ox ]methyl}-l,3^_oxazole

To a solution of oxazol-2-ylmethanol (1.5 g) in CHCk (50 mL) were added 3,4-dihydro-2H- pyran (1.4 g) and pyridinium p-toluenesulfonate (0.38 g) at room temperature. The reaction mixture was heated to 70 °C for 1.5 hours and then stirred overnight at room temperature.

The mixture was poured into saturated aqueous sodium bicarbonate and extracted with CHCk. The organic layer was dried over MgS04 and concentrated in vacuo. The residue was purified by OH'type silica gel column chromatography (10-90 % EtOAc in n-hexane) to give the title compound (2.0 g, 74% yield) as pale yellow oil.

MS (ESI) m/z : 184 [M+l]⁺.

RT = 0.634 min.

LCMS condition : B.

Step-2)

l)oxy]methyl}-l,3^_oxazole

To a solution of 2-{[(oxan-2-yl)oxy]methylM,3-oxazole (1.0 g) in THF (27 mL) was added n- BuLi (2.2 mL, 2.6 mol/L solution in n-hexane) at -78 °C. After stirring for 20 minutes, the mixture was warmed to -40 °C and stirred for 105 minutes. The mixture was cooled to -78 °C and then a solution of iodine (1.8 g) in THF (2 mL) was added dropwise. After addition was completed, the mixture was diluted with EtOAc and 10% aqueous sodium thiosulfate. The resulting biphasic mixture was brought to room temperature and the layers were separated. The organic layer was washed with brine, dried over MgS04, and concentrated in vacuo. The residue was purified by OH-type silica gel column chromatography (20-80 % EtOAc in n- hexane) to give the title compound (90 mg, 5% yield) as yellow oil.

MS (ESI) m/z : 310 [M+l]⁺.

RT = 0.921 min.

LCMS condition : B. Step-3)

(5Todo- l,3-oxazol-2-yl)methanol

A solution of 5-iodo-2-{[(oxan-2-yl)oxy]methyl}-l,3-oxazole (88 mg) in 1 mol/L aqueous HC1

(2.9 mL) was stirred for 1 hour at room temperature. The mixture was basified with 1 mol/L aqueous NaOH and the resulting mixture was extracted with EtOAc. The organic layer was dried over MgS04 and concentrated in vacuo. The residue was purified by OH-type silica gel column chromatography (10-60 % EtOAc in /2-hexane) to give the title compound (31 mg,

48% yield) as colorless solid.

MS (ESI) m/z : 226 [M+l]⁺.

RT = 0.479 min.

LCMS condition : B.

Step -4)

(5-{[4-(3-{[Tert-butyl(dimethyl)silyl]oxy}propoxy)phenyl]ethynyl}-l,3-oxazol-2-yl)methanol

The title compound was obtained in the manner as with the "Synthesis of Compound-62: step-1" using the corresponding materials.

MS (ESI) m/z : 388 [M+l]⁺.

RT = 1.083 min.

LCMS condition : C. Step -5)

(S)-3-(4-((2-((2-(l-hydroxyethyl)- lH-imidazol-l-yl)methyl)oxazol-5- yl)ethynyl)phenoxy)propan-l-ol (Compound-287)

Compound-287

Compound-287 was obtained in the manner as with the "Synthesis of Intermediated step-3- 4" and "Synthesis of Compound- 192: step 4" using the corresponding materials.

Ή-NMR, MS and LCMS retention time data of Compound-287 are shown in Table 3.

Synthesis of Compound-288

3-({[trans-2-(4-{[3-({2-[(lS)-l-hydroxyethyl]-lH-imidazol-l-yl}methyl)-l,2-oxazol-5- yl]ethynyl}phenyl)cyclopropyl]methyl}amino)propane- 1,2-diol

Compound-288 Step-1)

5-({[Tert-butyl(dimethyl)silyl]oxy}methyl)-3-{[trans-2-(4-iodophenyl)cyclopropyl]methyl}-l,3-

To a solution of 2,2,2-trifluoro-N-[[trans-2-(4-iodophenyl)cyclopropyl]methyl]acetamide (0.15 g) in DMF (4.1 mL) were added tert-butyl-dimethyl-(oxiran-2-ylmethoxy)silane (0.38 g) and CS2CO3 (0.26 g) at room temperature. After being stirred at room temperature for 1 hour, the reaction mixture was heated to 65 °C for 1 hour, and heated to 80 °C for 1 hour. After cooling, the reaction mixture was poured into water, and extracted with EtOAc. The combined organic layer was washed with brine, dried over Na2S04, and concentrated in vacuo onto ISOLUTE® HM-N. The residue was purified with OH-type silica gel column chromatography (20-100 % EtOAc in n-hexane) to give the title compound (68 mg, 34% yield) as colorless oil.

Ή NMR (400 MHz, CHLOROFORM-d) δ ppm 0.02 - 0.12 (m, 6 H), 0.82 - 0.92 (m, 9 H), 0.94 - 1.01 (m, 2 H), 1.18 - 1.29 (m, 1 H), 1.72 - 1.81 (m, 1 H), 2.45 - 4.62 (m, 7 H), 6.73 - 6.84 (m, 2 H), 7.49 - 7.62 (m, 2 H).

Step-2)

5-({[Tert-butyl(dimethyl)silyl]oxy}methyl)-3-({trans-2-[4-({3-[(2-{(lS)-l-[(oxan-2-yl)oxy]ethyl}- lH-imidazol- l-yl)methyl]- l,2-oxazol-5-yl}ethynyl)phenyl]cyclopropyl}methyl)- 1,3-oxazolidin- 2-one

The title compound was obtained in the manner as with the "Synthesis of Compound-62 step-1" using the corresponding materials.

MS (ESI) m/z : 661 [M+l]⁺.

RT = 0.733, 0.744 min.

LCMS condition : C.

Step-3)

3-{[Trans-2-(4-{[3-({2-[(lS)- 1-hydroxyethyl] - lH-imidazol- l-yl}methyl)- l,2-oxazol"5- yl]ethynyl}phenyl)cyclopropyl]methyl}-5-(hydroxymethyl)-l,3-oxazolidin-2-one

The title compound was obtained in the manner as with the "Synthesis of Compound- 102: step-2" using the corresponding materials.

MS (ESI) m/z : 463 [M+l]⁺. RT = 0.489 min.

LCMS condition : B.

Step-4)

3-({[Trans-2-(4-{[3-({2-[(lS)-l-hydroxyethyl]-lH-imidazol-l-yl}methyl)-l,2-oxazol-5- l]ethynyl}phenyl)cyclopropyl]methyl}amino)pi-opane-l,2-diol (Compound-288)

Compound-288

To a solution of 3-[[trans-2-[4-[2-[3-[[2-[(lS)-l-hydroxyethyl]imidazol"l-yl]methyl]isoxazol-5- yl]ethynyl]phenyl]cyclopropyl]methyl]-5-(hydroxymethyl)oxazolidin-2-one (16 mg) in MeOH (l.O mL) was added 1 mol/L aqueous NaOH (1.0 mL) and stirred overnight at room temperature. Then the reaction mixture was heated to 65 °C for 8 hours. After cooling, the reaction mixture was extracted with CHCI3, concentrated in vacuo onto ISOLUTE® HM-N. The residue was purified by NH-type silica gel column chromatography (0^_10 % MeOH in CHCI3) to give the title compound (8.0 mg, 53% yield) as a pale yellow solid.

Ή-NMR, MS and LCMS retention time data of Compound-288 are shown in Table 3.

Synthesis of Compound-290

(lS)-l-(l-{[5-({4-[(3-methylazetidin-3-yl)oxy]phenyl}ethynyl)-l,2-oxazol-3-yl]

imidazol"2-yl)ethan- l-ol

Compound-290

Step-1)

Tert-butyl 3-(4-iodophenoxy)-3-methylazetidine- 1-carboxylate

To a solution of tert-butyl 3-hydroxy3-methyl-azetidine- 1-carboxylate (0.52 g) in DMF (6.0 mL) was added sodium hydride (0.13 g) at 0 °C. After stirring at the same temperature for 30 minutes, l-fluoro"4-iodo-benzene (0.32 mL) was added into the mixture, which was stirred at room temperature for 30 minutes and then stirred at 85 °C for 19 hours. After cooling, water and EtOAc were added carefully. The brlayer was separated and the aqueous layer was extracted with EtOAc. The combined organic extracts were washed with brine, dried over MgS04 and concentrated in vacuo. The residue was purified with OH-type silica gel column chromatography (12- 100% EtOAc in n-hexane) to give the title compound (24 mg, 2.2% yield) as pale yellow oil.

Ή NMR (400 MHz, CHLOROFORM-d) δ ppm 1.44 (s, 9 H), 1.64 (s, 3 H), 3.92 (d, J=8.9 Hz, 2 H), 4.17 (d, J=8.9 Hz, 2 H), 6.48 (d, J=8.6 Hz, 2 H), 7.55 (d, J=8.6 Hz, 2 H).

Step-2)

Tert-butyl 3-methyl-3-[4-({3-[(2-{(lS)-l-[(oxan-2-yl)oxy]ethyl}-lH-imidazol-l-yDmethyl]-l,2- oxazol-5-yl}ethynyl)phenoxy]azetidine-l-carboxylate

The title compound was obtained in the manner as with the "Synthesis of Compound-62: step-1" using the corresponding materials.

MS (ESI) m/z : 563 [M+l]⁺.

RT = 0.902 min.

LCMS condition : B.

Step -3)

(lS)-l-(l-{[5-({4-[(3-methylazetidin-3-yl)oxy]phenyl}ethynyl)-l,2-oxazol-3-yl]methyl}-lH- imidazol-2- l)ethan-l-ol (Compound"290)

The title compound was obtained in the manner as with the "Synthesis of Compound-94: step-1" using the corresponding materials.

Ή-NMR, MS and LCMS retention time data of Compound-290 are shown in Table 3.

Synthesis of Compound-292

(lS)-l-(l-{[5-({4-[(azetidin-3-yl)(difluoro)methyl]phenyl}ethynyl)-l,2-oxazol-3-yl]methyl}-lH- imidazol"2-yl)ethan- l"ol

Step-1)

Tert-butyl 3- [difluoro(4-iodophenyl)methyl]azetidine- 1-carboxylate

To a solution of tert-butyl 3-(4-iodobenzoyl)azetidine- 1-carboxylate (0.12 g) in CHCI3 (1.0 mL) was added bis(2-methoxyethyl)aminosulfur trifluoride (0.15 mL). The reaction mixture was stirred for 16 hours at 50 °C and then allowd to cool to room temperature. After stirring for 2 days, the reaction was poured into saturated aqueous sodium bicarbonate at 0 °C and extracted with CHCI3 twice. The organic layer was passed through a phase separator and concentrated in vacuo. The residue was purified with OH-type silica gel column chromatography (10-25% EtOAc in /rhexane) to give the title compound (46 mg, 36% yield) as colorless oil.

Ή NMR (400 MHz, CHLOROFORM-d) 8 ppm 1.44 (s, 9 H), 3.08 - 3.27 (m, 1 H), 3.87 - 4.05 (m, 4 H), 7.15 - 7.23 (m, 2 H), 7.75 - 7.84 (m, 2 H).

Step -2)

(lS)-l-(l-{[5-({4-[(azetidin-3-yl)(difluoro)methyl]phenyl}ethynyl)-l,2-oxazol-3-yl]

imidazol-2-yl)ethan-l-ol (Compound-292)

Compound-292

The title compound was obtained in the manner as with the "Synthesis of Compound-281: step-3 and Step-5" using the corresponding materials.

Ή-NMR, MS and LCMS retention time data of Compound-292 are shown in Table 3. Synthesis of Compound- 301

(lS)-l-[l-({5-[(4-{trans-2-[(l,4-oxazepan-4-yl)methyl]cyclopropyl}phenyl)ethynyl]-l,2-oxazol- -yl}methyl)-lH-imidazol-2-yl]ethan-l-ol

Compound-301

Step-l)

Trans-2-(4-iodophenyl)cyclopropane-l-carbaldehyde

To a solution of [trans-2-(4-iodophenyl)cyclopropyl]methanol (0.11 g) in CHCb (4.0 mL) was added Dess-Martin Periodinane (0.21 g) at 0 °C. The reaction mixture was stirred at room temperature for 40 minutes. After cooling to 0°C, saturated aqueous NaHCOe was added into the mixture. The bHayer was separated and the aqueous layer was extracted with CHCI3. The combined organic extracts were passed through a phase separator and concentrated in vacuo. The residue was purified with OH-type silica gel column chromatography (12-100% EtOAc in n-hexane) to give the title compound (97 mg, 90% yield) as colorless oil.

Ή NMR (400 MHz, CHLOROFORM-d) 8 ppm 1.43 - 1.53 (m, 1 H), 1.73 (dt, J=9.3, 4.9 Hz, 1 H), 2.14 (dq, J=8.4, 4.3 Hz, 1 H), 2.49 - 2.62 (m, 1 H), 6.86 (d, J=7.9 Hz, 2 H), 7.61 (d, J=7.9 Hz, 2 H), 9.35 (d, J=4.3 Hz, 1 H).

idophenyl)cyclopropyl]methyl}-l,4-oxazepane

To a solution of 1,4-oxazepane hydrochloride (43 mg) in CHCI3 (3.0 mL) were added acetic acid (0.024 mL) and trans-2-(4-iodophenyl)cyclopropane"l-carbaldehyde (77 mg) in CHCI3 (2.0 mL) at room temperature. After stirring for 1 hour, NaBH(OAc)3 (0.12 g) was added and the reaction mixture was stirred at the same temperature for 4 days. After cooling, saturated aqueous sodium bicarbonate was added. The bHayer was separated and the aqueous layer was extracted with CHCb twice. The combined organic extracts were passed through a phase separator and concentrated in vacuo. The residue was purified with NH- type silica gel column chromatography (12-100% EtOAc in n-hexane) to give the title compound (58 mg, 57% yield) as colorless oil.

MS (ESI) m/z : 358 [M+l]⁺.

RT = 0.530 min.

LCMS condition : B.

Step -3)

(lS)-l-[l-({5-[(4-{trans-2-[(l,4-oxazepan-4-yl)methyl]cyclopropyl}phenyl)ethynyl]-l,2-oxazol- -yl}methyl)-lH-imidazol-2-yl]ethan-l-ol (Compound-301)

Compound-301

The title compound was obtained in the manner as with the "Synthesis of Compound-62: step-1" and "Synthesis of Compound- 102: step-2" using the corresponding materials.

Ή-NMR, MS and LCMS retention time data of Compound-301 are shown in Table 3.

Synthesis of Compound-305

(lS)-l-(l-{[5-({4-[l-(hydroxymethyl)cyclopropyl]phenyl}ethynyl)-l,2-oxazol-3-yl]methyl}-lH-

Step-1)

{l-[4-({3-[(2-{(lS)-l-[(oxan-2-yl)oxy]ethyl}-lH-imidazol-l-yl)methyl]-l,2-oxazol-5- yl}ethynyl)phenyl]cyclopropyl}methanol

lntermediate-6

In a microwave vial, [l-(4-bromophenyl)cyclopropyl]methanol (50 mg),

bis(acetonitrile)dichloropalladiumdl) (5.7 mg), XPhos (32 mg), and CS2CO3 (0.19 g) was suspended in DMF (0.4 mL). After stirring for 10 minutes, a solution of Intermediate -6 (80 mg) in DMF (0.70 mL) was added and the resulting mixture was irradiated in a microwave reactor at 120 "C for 30 miniutes. The reaction mixture was diluted with. EtOAc-filtered— through a pad of Celite®, and concentrated in vacuo. The residue was purified by NH-type silica gel column chromatography (0"8 % MeC-H-CHCle) to give the title compound (8.3 mg, 8% yield) as pale yellow oil.

MS (ESI) m/z : 448 [M+l]⁺.

RT = 0.673 min.

LCMS condition : B.

Step-2)

(lS)-l-(l-{[5-({4-[l-(hydroxymethyl)cyclopropyl]phenyl}ethynyl)-l,2-oxazol-3-yl]methyl}- lH- imidazol-2-yl)ethan-l-ol (Compound-305)

Compound-305 was obtained in the manner as with the "Synthesis of Compound- 102: step-2" using the corresponding materials.

Ή-NMR, MS and LCMS retention time data of Compound-305 are shown in Table 3. Synthesis of Compound-308

(lS)-l-[l-({5-[3-(4-bromophenyl)cyclobutyl]-l,2-oxazol-3-yl}methyl)-lH-imidazol-2-yl]ethan-l- ol

Compound-308 Step-1)

3- 4-Bromophenyl)-N-methoxy-N-methylcyclobutane-l-carboxamide

To a solution of 3-(4-bromophenyl)cyclobutanecarboxylic acid (0.54 g) in DMF (11 mL) were added Ν,Ο-dimethylhydroxylamine hydrochloride (0.51 g), HATU (0.97 g), and DIPEA (1.1 mL). After stirring for 1 hour at room temperature, the reaction mixture was diluted with brine and extracted with EtOAc twice. The combined organic layer was washed with brine twice, dried over MgS04, and concentrated in vacuo. The residue was purified with OH type silica gel column chromatography (25-40% EtOAc in zrhexane) to give the title compound (0.56 g, 89 % yield) as colorless oil.

MS (ESI) m/z : 298 [M+l]⁺.

RT = 0.867 min.

LCMS condition : C.

Step-2)

l-[Trans-3-(4-bromophenyl)cyclobutyl]ethan-l-one and

1 - [cis- 3" (4-bromophenyl)cyclobutyl] ethan- 1 -one

To a solution of 3-(4-bromophenyl)-N-methoxy-N-methylcyclobutane-l-carboxamide (0.57 g) in THF (11 mL) was added dropwise methylmagnesium bromide (0.82 mL, 3.0 mol/L solution in diethyl ether) at 0 °C. After stirring for 1 hour at the same temperature, the reaction was quenched with AcOH (0.14 mL) and saturated aqueous ammonium chloride and extracted twice with EtOAc. The combined organic layer was washed with brine, dried over MgS04 and concentrated in vacuo. The residue was purified with OH-type silica gel column chromatography (6"38 % EtOAc in n-hexane) to give to give l-[trans-3-(4- bromophenyl)cyclobutyl]ethan-l"one (0.14 g, 28 % yield) as colorless oil and l-[cis-3-(4- bromophenyl)cyclobutyl]ethan-l-one (0.31 g, 66 % yield) as colorless oil.

l-[Trans-3-(4-bromophenyl)cyclobutyl]ethan-l"one :

Ή NMR (400 MHz, CHLOROFORM-d) 8 ppm 2.18 (s, 3 H), 2.23^■ 2.41 (m, 2 H), 2.56 - 2.75 (m, 2 H), 3.19 - 3.32 (m, 1 H), 3.43^■ 3.61 (m, 1 H), 7.09 (d, J=8.1 Hz, 2 H), 7.43 (d, J=8.1 Hz, 2 H).

l-[Cis-3-(4-bromophenyl)cyclobutyl]ethan-l-one : Ή NMR (400 MHz, CHLOROFORM-d) δ ppm 2.11 (s, 3 H), 2.21 - 2.36 (m, 2 H), 2.46 - 2.63 (m, 2 H), 3.16^■ 3.28 (m, 1 H), 3.31 - 3.54 (m, 1 H), 7.07 (d, J=8.2 Hz, 2 H), 7.41 (d, J=8.2 Hz, 2 H).

Each structure was determined by Ή-NMR NOE spectrum (correlation between three hydrogen atoms attached at the cyclobutyl carbon atoms). In l-[trans-3-(4- bromophenyl)cyclobutyl]ethan-l-one, NOE signals between Hi and ¾, and H3 and H4 were observed, respectively. In l-[cis-3-(4-bromophenyl)cyclobutyl]ethan-l-one NOE signals beween H5 and Ηβ , Ηβ and He, and H5 and ¾ were observed, respectively.

Step -3)

Ethyl 4- [3-(4-bromophenyl)cyclobutyl] -2,4-dioxobutanoate

To a solution of l-[trans-3-(4-bromophenyl)cyclobutyl]ethan-l-one (0.14 g) and in EtOH (4.1 mL) were added diethyl oxalate (0.29 mL) and sodium ethoxide (0.82 mL, ca. 20% solution in ethanol) at room temperature. The mixture was stirred for 1 hour at 70°C and allowed to cool to room temperature. After cooling to 0 °C, the reaction was quenched with AcOH (0.12 mL) and saturated aqueous ammonium chloride and extracted with EtOAc. The combined organic layer was washed with brine (30 mL), dried over MgS04 and concentrated in vacuo. The residue was purified with OH-type silica gel column chromatography (10-50 % EtOAc in n-hexane) to give to give the title compound (0.34 g, 99 % yield) as colorless oil.

Ή NMR (400 MHz, CHLOROFORM-d) δ ppm 1.38 (t, J=7.2 Hz, 3 H), 2.31 - 2.47 (m, 3 H), 2.58 - 2.68 (m, 2 H), 2.68 - 2.77 (m, 1 H), 3.20 - 3.37 (m, 1 H), 3.37 - 3.55 (m, 1 H), 4.36 (q, J=7.2 Hz, 2 H), 7.08 - 7.13 (m, 2 H), 7.40 - 7.47 (m, 2 H).

Step -4)

Ethyl 5-[3-(4-bromophenyl)cyclobutyl]-l,2-oxazole-3-carboxylate

To a solution of ethyl 4-[3-(4-bromophenyl)cyclobutyl]-2,4-dioxobutanoate (0.14 g) and in EtOH (4.1 mL) was added hydroxylamine hydrochloride (88 mg) at room temperature. The mixture was stirred for 0.5 hour at 90°C and allowed to cool to room temperature. The reaction was concentrated in vacuo, quenched with a saturated aqueous sodium bicarbonate and extracted with CHCI3. The organic layer was passed through a phase separator and concentrated in vacuo. The residue was purified with OH-type silica gel column chromatography (I'll % EtOAc in n-hexane) to give the title compound (0.22 g, 73 % yield) as a colorless oil.

Ή NMR (400 MHz, CHLOROFORM-d) 8 ppm 1.37 - 1.46 (m, 3 H), 2.34 - 2.44 (m, 2 H), 2.79 - 2.88 (m, 2 H), 3.45 - 3.76 (m, 2 H), 4.44 (q, J=7.4 Hz, 2 H), 6.45 (s, 1 H), 7.08^■ 7.18 (m, 2 H), 7.44 (d, J=7.9 Hz, 2 H).

Step -5)

■ [3^■ (4· Bromop heny Ocyclobuty 1] -1,2- oxazol- 3 -yl}methanol

To a solution of ethyl 5-[3-(4-bromophenyl)cyclobutyl]-l,2-oxazole'3-carboxylate (0.21 g) in THF (5.9 mDwas added L1BH4 (43 mg) and the mixture was stirred for 2 hours at room temperature. The reaction was quenched with a saturated aqueous ammonium chloride and extracted with EtOAc. The organic layer was washed with water and brine, dried over MgS04 and concentrated in vacuo. The residue was purified with OH-type silica gel column chromatography (20-60 % EtOAc in n-hexane) to give the title compound (0.10 g, 57 % yield) as colorless oil.

MS (ESI) m/z : 308 [M+l]⁺.

RT = 0.819 min.

LCMS condition : C.

Step -6)

(lS)-l-[l-({5-[3-(4-bromophenyl)cyclobutyl]-l,2-oxazol-3-yl}methyl)-lH-imidazol-2-yl]ethan-l- ol

Compound-308)

Compound-308 The title compound was obtained in the manner as with the "Synthesis of Intermediated step-3-4 and Compound-102: step-2" using the corresponding materials.

^!H-NMR, MS and LCMS retention time data of Compound-308 are shown in Table 3. Synthesis of Compound-309

(lS)-l-[l-({5-[(4-{[trans-2-(hydroxymethyl)cyclopropyl]oxy}phenyl)ethynyl]-l,2-oxazol-3-

Step-1)

Ethyl trans-2-(4-iodophenoxy)cyclopropane-l-carboxylate and

ethyl cis-2-(4-iodo henoxy)cyclo ro ane- 1-carbox late

To a cooled (O °C) suspension of l'iodo-4-vinyloxy "benzene (0.39 g) and rhodium (II) acetate dimer dihydrate (76 mg) in diethyl ether (10 mL) was added ethyl diazoacetate (0.29 mL) in portions under nitrogen atmosphore and the reaction mixture was stirred for 6 hour stirring at room temperature. After addtion of rhodium (II) acetate dimer dihydrate (76 mg) and ethyl diazoacetate (0.29 mL) were added and the mixture was further stirred for 4 days. The reaction mixture was quenched with half- saturated brine and extracted with EtOAc. The organic layer was washed with saturated aqueous sodium bicarbonate, dried over MgS04 and and concentrated in vacuo onto ISOLUTE® HM-N. The residue was purified twice with OH-type silica gel column chromatography (5-35 % EtOAc in n-hexane and 0"15 % EtOAc in n-hexane) to give ethyl trans-2-(4-iodophenoxy)cyclopropane- 1-carboxylate (low polar component, light yellow oil, 0.13 g, 24% yield) and ethyl cis-2-(4-iodophenoxy)cyclopropane- 1-carboxylate (high polar component, colorless oil, 74 mg, 14% yield).

Ethyl trans-2-(4"iodophenoxy)cyclopropane- 1-carboxylate :

Ή NMR (600 MHz, CHLOROFORM-d) 8 ppm 1.29 (t, J=7.2 Hz, 3 H), 1.36 - 1.43 (m, 1 H), 1.50 (q, J=6.5 Hz, 1 H), 1.89 - 1.96 (m, 1 H), 3.97 - 4.09 (m, 1 H), 4.13 - 4.23 (m, 2 H), 6.75 (d, J=8.8 Hz, 2 H), 7.57 (d, J=8.8 Hz, 2 H)

Ethyl cis-2-(4-iodophenoxy)cyclopropane- 1-carboxylate :

Ή NMR (600 MHz, CHLOROFORM-d) 5 ppm 1.07 (t, J=7.0 Hz, 3 H), 1.28 - 1.35 (m, 1 H), 1.74 (td, J=6.6, 4.5 Hz, 1 H), 1.94 - 2.06 (m, 1 H), 3.96 (td, J=6.6, 4.5 Hz, 1 H), 4.00 (q, J=7.0 Hz, 2 H), 6.81 (d, J=9.1 Hz, 2 H), 7.55 (d, J=9.1 Hz, 2 H)

Each structure was determined by Ή-NMR NOE spectrum (correlation between three hydrogen atoms attached at the cyclpropyl carbon atoms). In ethyl trans-2-(4- iodophenoxy)cyclopropane-l-carboxylate NOE signals between Hi and H2 ,and H3 and H4 were observed, respectively. In ethyl cis-2-(4-iodophenoxy)cyclopropane-l-carboxylate NOE signals beween H5 and Ηβ ,Ηβ and He, and H5 and He were observed, respectively.

Step-2)

trans trans

To a cooled (O °C) solution of ethyl trans-2-(4-iodophenoxy)cyclopropane-l-carboxylate (0.12 g) in THF (2 mL) was added L1BH4 (24 mg) and the reaction mixture was stirred overnight at room temperature. The reaction was quenched with a saturated aqueous sodium bicarbonate and extracted 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 (25-75 % EtOAc in n-hexane) to give the title compound (77 mg, 73 % yield) as colorless syrup.

MS (ESI/APCI) m/z : 308 [M+18(NH4)]⁺, 325[M+35(C1)]\

Step -3)

(lS)-l-[l-({5-[(4-{[trans-2-(hydroxymethyl)cyclopropyl]oxy}phenyl)ethynyl]-l,2-oxazol-3- yl}methyl)-lH-imidazol-2-yl]ethan-l-ol (Compound-309)

Compound 309 was obtained in the manner as with the "Synthesis of Compound- 102: step-1 and step-2" using the corresponding materials.

Ή-NMR, MS and LCMS retention time data of Compound- 309 are shown in Table 3.

Synthesis of Compound-315

(lS)-l-(l-{[5-({4-[(trans-2-aminocyclopropyl)oxy]phenyl}ethynyl)-l,2-oxazol-3-yl]

imidazol-2-yl)ethan- l"ol

trans Compound-315 Step-1)

Trans-2-(4-iodophenoxy)cyclopropane-l-carboxylic id

To a solution of ethyl trans-2"(4-iodophenoxy)cyclopropanecarboxylate (0.46 g) in THF (2.3 mL) and MeOH (2.3 niL) was added 1 mol/L aqueous NaOH (4.2 mL) at room temperature. After being stirred for 42 hours, the reaction mixture was neutralized with 1 mol/L aqueous HCl (to pH 3~4), and extracted with CHCI3. The combined organic layer was washed with brine, dried over MgS04, and concentrated to give the title compound (0.44 g) as a crude product (pale yellow amorphous). The residue was used in the next step without further purification.

MS (ESI) m/z : 303 [M-l]^'.

RT = 1.033 min.

LCMS condition : B.

Step-2) '

Tert-butyl [trans-2-(4-iodo henoxy)cyclo ro yl]carbamate

trans trans

To a suspension of the crude material obtained in the Step-1 (0.42 g) in tert-butyl alcohol (10 mL) was sequentially added TEA (0.39 mL) and DPPA (0.47 mL) at room temperature. The mixture was heated to 95 °C for 1 hour. After cooling, saturated aqueous sodium bicarbonate was added to the reaction mixture and extracted with CHCI3. The organic layer was dried over MgS04 and concentrated in vacuo onto ISOLUTE® HM-N. The residue was purified by OH-type silica gel column chromatography (10-100 % EtOAc imrhexane) to give the title compound (O.ll g, 21% yield) as a colorless solid.

Ή NMR (400 MHz, CHLOROFORM-d) 8 ppm 0.99 - 1.09 (m, 1 H), 1.13 - 1.22 (m, 1 H), 1.46 (s, 9 H), 2.77 - 2.91 (m, 1 H), 3.60 - 3.75 (m, 1 H), 4.41 - 4.80 (m, 1 H), 6.82 - 6.97 (m, 2 H), 7.46 - 7.66 (m, 2 H).

Step -3)

(lS)-l-(l-{[5-({4-[(trans-2-aminocyclopropyl)oxy]phenyl}ethynyl)-l,2-oxazol-3"yl]

imidazol-2-yl)ethan-l-ol (Compound-315)

Compound-315

The title compound was obtained in the manner as with the "Synthesis of Compound-62 step-1" and "Synthesis of Compound-264: step-3" using the corresponding materials.

Ή-NMR, MS and LCMS retention time data of Compound-315 are shown in Table 3.

Synthesis of Compound- 317

3-(4-{[5-({2- [(IS)- 1-hydroxyethyl]- lH-imidazol- l-yl}methyl)furan-3- l]ethynyl}phenoxy)propan- l-ol

ompoun -

Step-1)

Methyl 4-{[4-(3-{[tert-butyl(dimethyl)silyl]oxy}propoxy)phenyl]ethynyl}furan-2-carboxylate

To a stirred solution of methyl 4-bromofuran-2-carboxylate (52 mg) in butyl acetate (2.6 mL) were added Cul (4.8 mg), PdCl₂(PPh₃)2 (8.9 mg) and TEA (0.18 mL). The mixture was stirred at 60 °C for 10 minutes. Then tert-butyl(3-(4-ethynylphenoxy)propoxy)dimethylsilane (88 mg) in butyl acetate (1 mL) was added at the same temperature and the mixture was stirred for 3 hours. After cooling, the insoluble matter was removed by filtration through Celite® and washed with EtOAc. The filtrate was concentrated in vacuo onto ISOLUTE® HM-N. The residue was purified with OH-type silica gel column chromatography (1-30 % EtOAc in /2-Hexane) to give the title compound (0.10 g, 95 % yield) as pale yellow oil.

Ή NMR (400 MHz, CHLOROFORM-d) 8 ppm 0.04 (s, 6 H), 0.89 (s, 9 H), 1.95^■ 2.05 (m, 2 H), 3.80 (t, J=5.7 Hz, 2 H), 3.91 (s, 3 H), 4.09 (br t, J=6.1 Hz, 2 H), 6.65 (d, J≡3.3 Hz, 1 H), 6.88 (d, J=8.3 Hz, 2 H), 7.16^■ 7.20 (m, 1 H), 7.46 (d, J=8.3 Hz, 2 H).

Step -2)

(4- [4-(3-{[Tert-butyl(dimethyl)silyl]oxy}propoxy)phenyl]ethynyl}furan-2-yl)methanol

To a solution of methyl 4-{[4^_(3-{[tert-butyl(dimethyl)silyl]oxy}propoxy)phenyl]ethynyl}furan-

2- carboxylate(50 mg) in toluene (0.58 mL) was added dropwise DIBAL (0.35 mL, 1.0 mol/L solution in toluene) at -40 °C. The reaction mixture was stirred for 1.5 hours and then the reaction was quenched by adding MeOH. After the resulting mixture was allowed to warm to room temperature, aqueous Rochelle salt and EtOAc were added and the resulting biphasic mixture was stirred for 1 hour. The layers were separated and the aqueous layer was extracted with EtOAc. The organic layer was washed with water and brine, dried over MgS04 and concentrated in vacuo. The residue was purified by OH-type silica gel column chromatography (15-50 % EtOAc in zr Hexane) to give the title compound (34 mg, 76 % yield) as colorless oil.

Ή NMR (400 MHz, CHLOROFORM-d) δ ppm 0.04 (s, 6 H), 0.89 (s, 9 H), 1.73 (t, J=6.3 Hz, 1 H), 1.95 - 2.04 (m, 2 H), 3.80 (t, J=5.6 Hz, 2 H), 4.08 (t, J=6.2 Hz, 2 H), 4.59 - 4.70 (m, 2 H), 6.32 (d, J=2.9 Hz, 1 H), 6.56 (d, J=2.9 Hz, 1 H), 6.87 (d, J=8.3 Hz, 2 H), 7.44 (d, J=8.3 Hz, 2 H).

Step-3)

3- (4-{[5-({2-[(lS)-l-hydroxyethyl]-lH-imidazol-l-yl}methyl)furan-3- yl]ethynyl}phenoxy)propan- l"ol (Compound-317)

The title compound was obtained in the manner as with the "Synthesis of Intermediated step-3-4 and Compound- 102: step-2" using the corresponding materials.

Ή-NMR, MS and LCMS retention time data of Compound-315 are shown in Table 3.

Synthesis of Compound-319

Ethyl trans-2-(4-{[3-({2-[(lS)-l-hydroxyethyl]-lH-imidazol-l-yl}methyl)-l,2-oxazol-5- e

Step-1)

Ethyl trans-2-(4-{[3-({2-[(lS)-l-hydroxyethyl]-lH-imidazol-l-yl}methyl)-l,2-oxazol-5- yl]ethynyl}phenyl)cyclopropane- 1-carboxylate (Compound-319)

The title compound was obtained in the manner as with the "Synthesis of Compound-62: step-1" and "Synthesis of Compound- 102: step-2" using the corresponding materials.

Ή-NMR, MS and LCMS retention time data of Compound-319 are shown in Table 3.

Synthesis of Compound-320

Trans-2-(4-{[3-({2-[(lS)- 1-hydroxyethyl]- lH-imidazol- l-yl}methyl)- l,2-oxazol-5- yl]ethynyl}phenyl)cyclopropane- 1-carboxylic acid

Compound-320

To a solution of ethyl trans-2-[4-[2-[3^_[[2-[(lS)-l-hydroxyethyl]imidazoM-yl]methyl]isoxazol^_ 5-yl]ethynyl]phenyl]cyclopropanecarboxylate (50 mg) in MeOH (10 mL) and THF (10 niL) was added 1 mol/L aqueous NaOH (20 mL). The reaction mixture was stirred at room temperature for 2 hours, adjusted to pH 6 by addition of 1 mol L aqueous HCl and concentrated in vacuo. The residue was suspended with 10% MeOH in CHCI3 and the insoluble matter was removed by filtration. The filtrate was concentrated in vacuo and the residue was purified with PoraPak Rxn RP 20cc (acetonitrile in water) to give the title compound (47 mg, quant.) as colorless amorphous.

Ή-NMR, MS and LCMS retention time data of Compound-320 are shown in Table 3.

Synthesis of Compound-322

(lS)- l-[l-({5-[(4-{[trans-2-(aminomethyl)cyclopropyl]oxy}phenyl)ethynyl]- l,2-oxazol-3-

odophenoxy)cyclopropyl]methyl}- lH-isoindole- l,3(2H)-dione

To a mixture of trans-2-(4-iodophenoxy)cyclopropylmethanol (50 mg), phthalimide (28 mg), and PPI13 (54 mg) in toluene (0.57 mL) was added di-2-methoxyethyl azodicarboxylate (48 mg). The mixture was stirred at room temperature for 1 hour. The mixture was washed with water and the organic layer was separated. The aqueous layer was extracted with EtOAc. The organic layer was washed with brine, dried over MgSC , and concentrated in vacuo onto JSOLXITE® HM:N. The_residue-was-purified-by OH-type -silica gel- column chromatography (10-100 % EtOAc in n-hexane) to give the title compound (46 mg, 61% yield) as a colorless oil. Ή NMR (400 MHz, CHLOROFORM-d) δ ppm 0.87 - 0.95 (m, 1 H), 0.95 - 1.02 (m, 1 H), 1.54^■ 1.68 (m, 1 H), 3.52^■ 3.63 (m, 1 H), 3.70 - 3.82 (m, 2 H), 6.68 - 6.76 (m, 2 H), 7.40^■ 7.49 (m, 2 H), 7.71 - 7.79 (m, 2 H), 7.83 - 7.93 (m, 2 H).

Step-2)

2-({Trans-2-[4-({3-[(2-{(lS)-l-[(oxan-2-yl)oxy]ethyl}-lH-imidazol-l-yl)methyl]-l,2-oxazol-5- yl}ethynyl)phenoxy]cyclopropyl}methyl)-lH-isoindole-l,3(2H)-dione

The title compound was obtained in the manner as with the "Synthesis of Compound-62: step-1" using the corresponding materials.

MS (ESI) m/z : 593 [M+l]⁺.

RT = 0.905 min.

LCMS condition : B.

Step -3)

l-{Trans-2-[4-({3-[(2-{(lS)-l-[(oxan-2-yl)oxy]ethyl}-lH-imidazol-l-yl)methyl]-l,2-oxazol-5- yl}ethyny l)p henoxy] cyclop ropyllmethanamine

0 trans

To a solution of 2-[[trans-2-[4-[2-[3-[[2-[(lS)-l-tetrahydropyran-2-yloxyethyl]imidazol-l" yl]methyl]isoxazol-5-yl]ethynyl]phenoxy]cyclopropyl]methyl]isoindoline-l,3-dione (55 mg) in EtOH (0.93 mL) was added hydrazine hydrate (0.014 mL) at room temperature. After being stirred at room temperature for 16 hours, the resulting precipitate was removed by filtration and the filtrate was concentrated in vacuo onto ISOLUTE® HM-N. The residue was purified with NH-type silica gel column chromatography (EtOAc to 5% MeOH in CHCI3) to give the title compound (29 mg, 67% yield) as a colorless oil.

MS (ESI) m/z : 463 [M+l]⁺.

RT = 0.797 min.

LCMS condition : A.

Ste -3)

(lS)-l-[l-({5-[(4-{[trans-2-(aminomethyl)cyclopropyl]oxy}phenyl)ethynyl]-l,2-oxazol-3-

The title compound was obtained in the manner as with the "Synthesis of Compound- 102 step-2" using the corresponding materials.

Ή-NMR, MS and LCMS retention time data of Compound-322 are shown in Table 3. Synthesis of Compound-323

, N-(2-aminoethyl)-trans-2-(4-{[3-({2- [(IS)- 1-hydroxyethyl]- lH-imidazol- l-yl}methyl)- 1,2- oxazol- 5 -yl] ethy nyl}p heny Ocyclopropane - 1 - carboxamide

Step-1)

N-(2-aminoethyl)-trans-2-(4-{[3-({2-[(lS) -hydroxyethyl] H-imidazol-l-yl}methyl)-l,2- oxazol-5-yl]ethynyl}phenyl)cyclopropane-l-carboxamide (Compound-323)

Compound-323

To a mixture of trans-2-[4-[2-[3-[[2-[(lS)-l-hydroxyethyl]imidazoM-yl]methyl]isoxazol-5- yl]ethynyl]phenyl]cyclopropanecarboxylic acid (43 mg), tert-butyl N-(2- aminoethyDcarbamate (27 mg) and HATU (64 mg) in DMF (2.3 mL) was added TEA (0.047 mL). The reaction mixture was stirred at room temperature for 1 hour, poured into water and extracted with EtOAc. The organic extract was washed with brine, dried over MgS04 and concentrated in vacuo. The residue was purified with NH-type silica gel column chromatography (0"10 % MeOH in CHCls) to give a crude material (42 mg) as colorless amorphous, which was dissolved in CHCI3 (2.0 mL) and TFA (2.0 mL) was added. The reaction mixture was stirred at room temperature for 1 hour and concentrated in vacuo. The residue was partitioned between 20% aqueous potassium carbonate and 10% MeOH in CHCI3. The organic layer was washed with brine, dried over MgS04 and concentrated in vacuo. The residue was purified with NH-type silica gel column chromatography (O-IO % MeOH in CHCI3) to give the title compound (30 mg, 65% yield) as colorless amorphous. Ή-NMR, MS and LCMS retention time data of Compound-323 are shown in Table 3.

Synthesis of Compound-330

(lS)-l-{l-[(lR)-2-amino-l-{5-[(4-{[(lS,2S)-2-aminocyclopropyl]methoxy}phenyl)ethynyl]-l,2- oxazol-3-yl}ethyl]-lH-imidazol-2-yl}ethan-l-ol

Step-1)

(2 S) - 2 - [(4 - iodophenoxy) methyl] oxirane

To a suspension of 4-iodophenol (5.0 g) and (R)-(-)-epichlorohydrin (3.2 g) in water (10 n L) were added NaOH (0.91 g), pottasium carbonate (6.3 g) and tetrabutylammonium bromide (0.64 mL). The reaction mixture was stirred for 15 minutes at 100 °C under microwave irradiation, quenched with water and extracted with EtOAc. The organic layer was concentrated in vacuo and the obtained residue was purified twice with NH-type silica gel column chromatography (10-25 % EtOAc in n-hexane and 0-15 % EtOAc in n-hexane) to give the title compound (2.8 g, 44% yield) as white powder. The absolute stereochemisry was confirmed by X-ray crystal structure analysis.

Ή NMR (600 MHz, CHLOROFORM-d) δ ppm 2.75 (dd, J=5.0, 2.9 Hz, 1 H), 2.91 (dd, J=5.0, 4.1 Hz, 1 H), 3.30 - 3.38 (m, 1 H), 3.92 (dd, J=11.0, 5.8 Hz, 1 H), 4.21 (dd, J=11.0, 3.1 Hz, 1 H), 6.69 - 6.73 (m, 2 H), 7.52 - 7.60 (m, 2 H).

Step-2)

Ethyl (lS,2S)-2-[(4-iodophenoxy)methyl]cyclopropane-l-carboxylate

To a cooled (0 °C) solution of triethyl phosphonoacetate (8.3 mL) in toluene (50 mL) was added 60% sodium hydrite (0.84 g) in portions. After strring for 10 minutes (2S)"2-[(4- iodophenoxy)methyl]oxirane (5.8 g) in toluene (20 mL) was added dropwise to a cooled (0 Ό reaction mixture under nitrogen atmosphore. The mixture was stirred for 30 minutes at room temperature and 6.5 hours at 105 "C. After cooled to room tempeture the reaction mixture was quenched with a saturated aqueous ammonium chloride and extracted with EtOAc. The organic layer was concentrated in vacuo onto ISOLUTE® HM-N and the obtained residue was purified with OH-type silica gel column chromatography (10"100 % EtOAc in n-hexane) to give the title compound (1.3 g, 18 % yield) as colorless oil.

MS (ESI) m/z : 347 [M+l]⁺, 369 [M+23]⁺.

RT = 1.243 min.

LCMS condition : B.

Step -3)

(lS,2S)-2-[(4-iodophenoxy)methyl]cyclopropane-l-carboxylic acid

To a solution of ethyl (lS,2S)-2-[(4-iodophenoxy)methyl]cyclopropanecarboxylate (1.3 g) in THF (5 mL) was added MeOH (5mL) , water (10 mL) and NaOH (0.45 g) and the reaction mixture was stirred overnight at room temperature. The mixture was acidified with aqueous HC1 and evaporated in vacuo. The obtained residue was suspended in water and stirred for 2 hours. The preticipates were filtered, gathered and dried in vacuo to give the title compound (1.2 g, 98 % yield) as colorless solid. The absolute stereochemisry of was confirmed by X-ray crystal structure analysis.

MS (ESI) m/z : 317 [M-l] .

RT = 1.010 min.

LCMS condition : B.

Step-4)

arbamate

A solution of (lS,2S)-2-[(4-iodophenoxy)methyl]cyclopropanecarboxylic acid (1.2 g) in acetone (37 mL) was cooled by salt-mixed ice bath and TEA (0.72 mL) and ethyl chloroformate (0.49 mL) were added. The mixture was stirred for 75 minutes at the same temperature. Sodium azide (0.43 g) in water (8 mL) was added and the mixture was further stirred for 30 minutes at the same temperature. The mixture was quenched with iced water (10 mL) and extractred with toluene. The organic layer was washed with brine, dried over MgS04 and evapolated in vacuo until the solvent volume decreased to about 20 mL. The obtained solution was stirred for 1 hour at 90 °C. Tert-butyl alcohol (10 mL) was added and the reaction mixture was stirred overnight at 80 °C. The reaction mixture was evaporated in vacuo onto ISOLUTE® HM-N and the obtained residue was purified with OH-type silica gel column chromatography (15-100 % EtOAc in n- hexane and 2- 15 % MeOH in CHCls) to give the title compound (0.50 g, 35 % yield) as colorless solid.

MS (ESI) m/z : 412 [M+l]⁺.

RT = 1.234 min.

LCMS condition : B.

Step -5)

Tert-butyl {(lS,2S)-2-[(4-ethynylphenoxy)methyl]cyclopropyl}carbamate

The title compound was obtained in the manner as with the "Synthesis of Intermediate -17" using the corresponding materials.

MS (ESI) m/z : 310 [M+l]⁺.

RT = 1.122 min.

LCMS condition : B.

Step -6)

(lS)-l-{l-[(lR)-2-amino-l-{5-[(4-{[(lS,2S)-2-aminocyclopropyl]methoxy}phenyl)ethynyl]-l,2- oxazol-3-yl}ethyl]-lH-imidazol-2-yl}ethan-l-ol (Compound-330)

The title compound was obtained in the manner as with the "Synthesis of Compound-269" using the corresponding materials.

Ή-NMR, MS and LCMS retention time data of Compound-330 are shown in Table 3.

Synthesis of Compound-333

(lS)-l-{l-[(5-{[4-({(lR,2R)-2-[(2-aminoethyl)amino]cyclopropyl}methoxy)phenyl]ethynyl}-l,2-

Step-1)

Tert-butyl [2-({2-[(4-{[3-({2-[(lS)-l-hydroxyethyl]-lH-imidazol-l-yl}methyl)-l,2-oxazol-5- yl]ethynyl}phenoxy)methyl]cyclopropyl}amino)ethyl]carbamate

To a solution of tert-butyl N-[2-[[trans-2-[[4-[2-[3-[[2-[(lS)- l-hydroxyethyl]imidazol- l- yl]methyl]isoxazol-5-yl]ethynylJphenoxy]methyl]cyclopropyl]amino]ethyl]carbamate (23 mg) in CHCI3 (2 niL) were added a solution of tert-butyl N-(2-oxoethyl)carbamate (27 mg) in CHCI3 (1.6 mL), AcOH (39 pL), and NaBH(OAc)₃ (0.11 g) at room temperature. After being stirred for 20 minutes, additional NaBH(OAc)3 (0.11 g) was added. After being stirred for 1 hour, the reaction was quenched with satrated aqueous sodium bicarbonate at 0 °C. The reaction mixture was extracted with CHCI3 for three times and the combined organic layer was concentrated in vacuo onto ISOLUTE® HM-N. The residue was purified with NH-type silica gel column chromatography (0-10% MeOH in EtOAc and then 0- 10% MeOH in CHCI3) to give the title compound (23 mg, 25% yield) as a colorless oil.

MS (ESI) m/z : 522 [M+l]⁺.

RT = 0.775 min.

LCMS condition : A.

Step -2)

(lS)- l-{l-[(5-{[4-({(lR,2R)-2-[(2-aminoethyl)amino]cyclopropyl}methoxy)phenyl]ethynyl}- l,2- oxazol-3- l)methyl]- lH-imidazol-2-yl}ethan- l"ol (Compound-333)

Compound-333

The title compound was obtained in the manner as with the "Synthesis of Compound-264: step-3" using the corresponding materials.

Ή-NMR, MS and LCMS retention time data of Compound-333 are shown in Table 3. Synthesis of Compound-334

3- [3-(4-{[5-({2-[(lS)- l-hydroxyethyl]- lH-imidazol- l-yl}methyl)- l,2-oxazol-3- yl]ethynyl}phenoxy)azetidin- l-yl]propan- l"ol

Compound-334

Step-1)

3- Tri(propan-2-yl)silyl]prop-2-ynal

To a solution of ethynyl(triisopropyl)silane (2.0 g) in diethyl ether (7.3 n L) was added dropwise n^_BuLi (4.8 mL, 2.6 mol/L solution in n-hexane) at -78 °C. The mixture was stirred for 20 minutes at -78 °C and then stirred for 45 minutes at room temperature. The mixture was re-cooled to -78 °C followed by addition of DMF (1.0 mL). After stirring for 10 minutes, the reaction mixture was brought to room temperature and stirred for 1 hour. The mixture was poured into 10% aqueous KH2PO4 and diethyl ether, and the resulting biphasic mixture was vigorously stirred for 15 minutes. The layers were separated and the aqueous layer was extracted twice with diethyl ether. The combined organic layer was dried over MgS04, filtered, and concentrated under reduced pressure to give the title compound (2.7 g) as pale yellow oil, which was used in next step without further purification.

Ή NMR (400 MHz, CHLOROFORM-d) δ ppm 1.08 - 1.23 (m, 21 H), 9.21 (s, 1 H).

Step-2)

-{(lE)-3-[tri(propan-2-yl)silyl]prop-2-yn-l-ylidene}hydroxylamine

To a solution of 3-[tri(propan-2-yl)silyl]prop-2-ynal (11 mmol) in MeOH (44 mL) were sequentially added sodium bicarbonate (0.92 g) and hydroxylamine hydrochloride (0.76 g) at room temperature. After stirring for 1 hour, the mixture was concentrated to half volume to remove excess MeOH. The resulting solution was poured into water and the mixture was extracted three times with diethyl ether. The combined organic layer was washed with brine, dried over MgSC , and concentrated under reduced pressure to give the title compound (2.5 g, 99% yield) as pale yellow oil.

MS (ESI) m/z : 226 [M+l]⁺.

RT = 1.389, 1.426 min. (E- and Z- mixture)

LCMS condition : B.

Step -3)

(3-{[Tri(propan-2-yl)silyl]ethynyl}-l,2-oxazol-5-yl)methanol

To a solution of N-{(lE)-3-[tri(propan-2-yl)silyl]prop-2-yn-l-ylidene}hydroxylamine (0.30 g) and propargyl alcohol (0.75 g) in CHCI3 (1.3 mL) was bis(trifluoroacetoxy)iodobenzene (0.86 g) in portions at room temperature. Upon completion of the addition, the reaction mixture was stirred for another 15 minutes at room temperature. 1 mol/L aqueous sodium thiosulfate, saturated aqueous sodium bicarbonate, and EtOAc were added to the mixture and the resulting biphasic mixture was vigorously stirred for 15 minutes. The layers were separated and the aqueous layer was extracted twice with EtOAc. The combined organic layer was washed with brine, dried over MgS04, and concentrated in vacuo. The residue was purified by OH-type silica gel column chromatography (15-80 % EtOAc in zrhexane) to give the title compound (0.29 g, 78 % yield) as pale yellow oil.

MS (ESI) m/z : 280 [M+l]⁺.

RT = 1.084 min.

LCMS condition : C. Step-4)

5-[(2-{(lS)-l-[(oxan-2-yl)oxy]ethyl}-lH-imidazol-l-yl)methyl]-3-{[tri(propan-2- yl)silyl]ethynyl}- 1,2-oxazole

The title compound was obtained in the manner as with the "Synthesis of Intermediate-6 step-1" using the corresponding materials.

MS (ESI) m/z : 458 [M+l]⁺. RT = 1.111 min.

LCMS condition : B.

Step -5)

-Ethynyl-5-[(2-{(lS)-l-[(oxan-2-yl)oxy]ethyl}-lH-imidazol-l-yl)methyl]-l,2-oxazole

The title compound was obtained in the manner as with the "Synthesis of Intermediate-6: step-2" using the corresponding materials

MS (ESI) m/z : 302 [M+l]⁺.

RT = 0.383 min.

LCMS condition : B.

Step -6)

3-[3-(4-{[5-({2-[(lS)-l-hydroxyethyl]-lH-imidazol-l-yl}methyl)-l,2-oxazol-3- yl]ethynyl}phenoxy)azetidin-l-yl]propan-l-ol Compound-334)

Compound-334

Compound-334 was obtained in the manner as with the "Synthesis of Compound- 102: step-1- 2" using Intermediate- 16 and corresponding materials.

Ή-NMR, MS and LCMS retention time data of Compound-334 are shown in Table 3.

Synthesis of Compound-341

(lS)-l-{l-[(5-{[5-(methoxymethyl)furan-3-yl]ethynyl}-l,2-oxazol-3-yl)methyl]-lH-imidazol-2- yl}ethan-l-ol

5-{[5-(Methoxymethyl)furan-3 l]ethynyl}-3-[(2-{(lS)- l-[(oxan-2 l)oxy]ethyl}-lH-imidazol- l- yOmethyl]- 1,2-oxazole

To a solution of 5-iodo-3-[(2-{(lS)- l-[(oxan-2-yl)oxy]ethyl}-lH-imidazol- l-yl)methyl]-l,2- oxazole(34 mg) in acetonitrile (0.85 n L) were added Cul (1.6 mg), SUPERSTABLE Pd (0) CATALYST (8.9 mg) and TEA (59 pL) at room temperature. After stirring for 5 minutes, 4- ethynyl-2-(methoxymethyl)furan (34 mg) in acetonitrile (1.0 ml,) was added dropwise to the reaction mixture and stirred at the same temperature for 30 minutes. The insoluble matter was removed by filtration through Celite® and washed with EtOAc. The filtrate was concentrated in vacuo. The residue was purified with amino-type silica gel column chromatography (20- 100 % EtOAc in n-hexane) to give the title compound (19 mg, 55 % yield) as pale yellow oil.

MS (ESI) m/z : 412 [M+l]⁺.

RT = 0.648 min.

LCMS condition : B.

Step -2)

(lS)- l-{l-[(5-{[5-(methoxymethyl)furan-3-yl]ethynyl}- l,2-oxazol-3-yl)methyl]-lH-imidazol-2- yl}ethan-l-ol

Compound-341

The title compound was obtained in the manner as with the "Synthesis of Compound- 102: step-2" using the corresponding materials.

Ή-NMR, MS and LCMS retention time data of Compound-341 are shown in Table 3.

Synthesis of Compound- 348

(lS)- l-(l-{(lR)-2-amino-l-[5-({4-[4-(2-hydroxyethyl)piperazin-l-yl]phenyl}ethynyl)- l,2- oxazol-3-yl]ethyl}- lH-imidazol-2-yl)ethan- l"ol

HO^" ompoun -

Step-1)

(1S) 1-{1- [(lR)-2-amino- l-(5-iodo- l,2-oxazol-3-yl)ethyl] - lH-imidazol-2-yl}ethan- l-ol

To a solution of 3-[3-[4-[2-[3-[[2-[(lS)-l-hydroxyethyl]imidazol-l-yl]-(3- pyridyl)methyl]isoxazol-5-yl]ethynyl]phenoxy]azetidin-l-yl]propan-l-ol [(0.25 g,) in CHCI3 (4.0 mL) and water (l.O mL) was added TFA (0.50 mL). After stirring for 1 hour at room temperature, the resulting mixture was concentrated in vacuo. The residue was purified with amino-type silica gel column chromatography (1-13 % MeOH in CHCI3) to give the title compound (31 mg, quant.) as pale yellow oil.

MS (ESI) m/z : 349 [M+l]⁺.

RT = 0.190 min.

LCMS condition : AB.

Step-2)

2,2,2-Trifluoro-N-[(2R)-2-{2-[(lS)-l-hydroxyethyl]-lH-imidazol-l-yl}-2-(5-iodo-l,2-oxazol-3- l) ethyl] acetamide

To a solution of (lS)-l-{l-[(lR)-2-amino-l-(5-iodo-l,2-oxazol-3-yDethyl]-lH-imidazol-2- yl}ethan-l-ol (31 mg) in MeOH (l.O mL) were sequentially added TEA (62 μθ and trifluoroacetic anhydride (21 pL) at 0 °C. After stirring for 1 hour, the reaction mixture was concentrated in vacuo to give the title compound (39 mg, quant.) as colorless oil and impurities. MS (ESI) m/z : 445 [M+l]⁺.

RT = 0.714 min.

LCMS condition : A.

Step-3)

N-[(2R)-2-{2-[(lS)-l-{[tert-butyl(dimethyl)silyl]oxy}ethyl]-lH-imidazol-l l}-2-(5-^

oxazol^■ 3 -yOethyl] -2,2, 2 - trifluoroacetamide

To a solution of 2,2,2-trifluoro-N-[(2R)-2-{2-[(lS)-l-hydroxyethyl]-lH-imidazol-l-yl}-2-(5-iodo- l,2-oxazol-3-yl)ethyl]acetamide (39 mg) in DMF (0.40 mL) were added imidazole (14 mg) and

TBSCl (21 mg) at room temperature. The reaction mixture was stirred at the same temperature for 2 hours and and concentrated in vacuo. The residue was purified with NH- type silica gel column chromatography (10-100% EtOAc in n-hexane) to give the title compound (29 mg, 59% yield) as colorless amorphous.

MS (ESI) m/z : 559 [M+l]⁺.

RT = 0.862 min.

LCMS condition : B.

Step -4)

l-(2-{[Tert-but l(dimethyl)silyl]oxy}ethyl)-4- -ethynylphenyl)piperazine

The title compound was obtained in the manner as with the "Synthesis of Intermediate- 17" using the corresponding materials.

MS (ESI) m/z : 345 [M+l]⁺.

RT = 0.795 min.

LCMS condition : B.

Step -5)

N-{(2R)-2-{2-[(lS)-l-{[tert-butyl(dimethyl)silyl]oxy}ethyl]-lH-imidazol-l-yl}-2-[5-({4-[4-(2- {[tert-butyl(dimethyl)silyl]oxy}ethyl)piperazin-l-yl]phenyl}ethynyl)-l,2-oxazol-3-yl]ethyl}- ■ trifluoroacetamide

The title compound was obtained in the manner as with the "Synthesis of Compound-341: step-1" using the corresponding materials.

MS (ESI) m/z : 775 [M+l]⁺.

RT = 0.866 min.

LCMS condition : B. Step-6)

2,2,2-Trifluoro-N-{(2R)-2-{2-[(lS)-l-hydroxyethyl]-lH-imidazol-l-yl}-2-[5-({4-[4-(2- hydroxyethyl)piperazin-l-yl]phenyl}ethynyl)-l,2-oxazol-3-yl]ethyl}acetamide

The title compound was obtained in the manner as with the "Synthesis of Compound-53: step -3" using the corresponding materials.

MS (ESI) m/z : 547 [M+l]⁺.

RT = 0.643 min.

LCMS condition : A.

Step -7)

(lS)-l-(l-{(lR)-2-amino-l-[5-({4-[4-(2-hydroxyethyl)piperazin-l-yl]phenyl}ethynyl)-l,2-oxazol- 3-yl]ethyl}-lH-imidazol-2-yl)ethan-l-ol (Compound- 348)

Compound-348

To a solution of

[4-(2"hydroxyethyl)piperazin- l-yl]phenyl}ethynyl)- l,2-oxazol-3-yl]ethyl}acetamide (8.6 mg) in MeOH (0.43 mL) was added 20% aqueous K2CO3 (0.11 g) at room temperature and stirred for 6 hours. The reaction mixture was extracted with CHCk'MeOH (10: l) and concentrated in vacuo onto ISOLUTE® HM-N. The residue was purified with NH-type silica gel column chromatography (0"10% MeOH in CHCI3) to give a crude product, which was re-purified with amino-type preparative chromatography (5 % MeOH in CHCI3) to give the title compound (2.7 mg, 37% yield) as pale yellow solid.

Ή-NMR, MS and LCMS retention time data of Compound-348 are shown in Table 3. Synthesis of Compound-354

(lS)-l-(l-{(lR)-2-amino-l-[5-({4-[(2-aminocyclopropyl)methyl]phenyl}ethynyl)-l,2-oxazol-3- yl]ethyl}-lH-imidazol-2-yl)ethan-l-ol

Compound-354

Step-1)

Ethyl trans-2- [(4-bromophenyl)methyl]cyclopropane- 1-carboxylate

To a solution of triethyl phosphonoacetate (1.2 mL) in toluene (6.0 mL) was added sodium hydride (0.12 g) at 0 °C and the mixture was stirred at the same temperature for 15 minutes. Then 2-[(4-bromophenyl)methyl]oxirane (0.62 g) in toluene (3.0 mL) was added and the mixture was stirred at room temperature for 15 minutes and then 105 °C for 6 hours. Then, sodium hydride (0.12 g) was further added and the mixture was stirred at the same temperature for 16 hours. After cooling to 0°C, saturated aqueous ammonium chloride and EtOAc were added into the mixture. The brlayer was separated and the aqueous layer was extracted with EtOAc. The combined organic extracts were washed with brine, dried over MgS04 and concentrated in vacuo. The residue was purified with NH-type silica gel column chromatography (3-30% EtOAc in n-hexane) to give the title compound (0.69 g, 84% yield) as colorless oil.

Ή NMR (400 MHz, CHLOROFORM-d) 8 ppm 0.77 - 0.86 (m, 1 H), 1.20 - 1.29 (m, 4 H), 1.50 (dt, J=8.3, 4.3 Hz, 1 H), 1.59 - 1.70 (m, 1 H), 2.49 - 2.59 (m, 1 H), 2.63 - 2.74 (m, 1 H), 4.11 (q, J=7.1 Hz, 2 H), 7.09 (d, J=8.2 Hz, 2 H), 7.42 (d, J=8.2 Hz, 2 H).

Step -2)

oxylic acid

To a solution of ethyl trans-2- [(4-bromophenyl)methyl]cyclopropane-l-carboxylate (0.33 g) in THF (2.0 mL), Me OH (2.0 mL) and water (4.0 mL) was added NaOH (0.14 g) at room temperature. The reaction mixture was stirred at the same temperature for 3days. After cooling, the reaction mixture was adjusted to pH 5 by addition of aqueous HC1. The obtained white suspension was concentrated in vacuo until one-third volume and extracted with 10% MeOH in CHCI3 twice. The combined organic extracts were passed through a phase separator and concentrated in vacuo to give the title product (0.29 g, 98 % yield) as pale white oil. The relative configuration was confirmed by 2D-NMR and Nuclear Overhauser Effect (NOE).

Ή NMR (400 MHz, CHLOROFORM-d) δ ppm 0.78 - 0.97 (m, 2 H), 1.27 - 1.37 (m, 1 H), 1.51 (dt, J=8.3, 4.2 Hz, 1 H), 1.64 - 1.78 (m, 1 H), 2.54 - 2.71 (m, 1 H), 7.08 (d, J=8.2 Hz, 2 H), 7.42 (br d, J=8.2 Hz, 2 H).

Step -3)

opyl}carbamate

The title compound was obtained in the manner as with the "Synthesis of Compound-330: step-4" using the corresponding materials.

Ή NMR (400 MHz, CHLOROFORM-d) 8 ppm 0.59 - 0.68 (m, 1 H), 0.69 - 0.77 (m, 1 H), 1.05 - 1.17 (m, 1 H), 1.44 (s, 9 H), 2.32 - 2.46 (m, 2 H), 2.80 (br dd, J=14.7, 6.2 Hz, 1 H), 4.66 (br s, 1 H), 7.12 (br d, J=8.2 Hz, 2 H), 7.41 (d, J=8.2 Hz, 2 H).

Step-4)

(lS)-l-(l-{(lR)-2-amino-l-[5-({4-[(trans-2-aminocyclopropyl)methyl]phenyl}ethynyl)-l,2-

Compound-354

The title compound was obtained in the manner as with the "Synthesis of Compound-330" using the corresponding materials.

^!H-NMR, MS and LCMS retention time data of Compound-354 are shown in Table 3.

Synthesis of Compound-355

3-[3-(4-{[5-(2-Amino-l-{2-[(lS)-l-hydroxyethyl]-lH-imidazol-l-yl}ethyl)-l,2-oxazol-3- l]ethynyl}phenoxy)azetidin- l-yl]propan- l"ol

Compound-355

Step-1)

Tert-but l [2-(2-{(lS)-l-[(oxan-2-yl)oxy]ethyl}-lH-imidazol-l-yl)but-3-yn-l-yl]carbamate

To a solution of tert-butyl N-[(2R)-3-oxo-2-[2-[(lS)-l-tetrahydropyran-2-yloxyethyl]imidazol- l-yl]propyl]carbamate (0.23 mg) in MeOH (6.9 mL) was added potassium carbonate (0.13 g). Dimethyl (l-diazo-2-oxopropyl)phosphonate (0.18 mL) was added dropwise to the reaction mixture at 0 °C. The reaction was allowed to warm to room temperature and stirred overnight. The reaction was diluted with saturated aqueous sodium bicarbonate and extracted with EtOAc twice. The organic layer was washed with brine, dried over MgSC , and concentrated in vacuo. The residue was charged onto ISOLUTE® HM-N and purified by OH-type silica gel column chromatography (50-100 % EtOAc in 2-hexane) to give the title compound (0.16 g, 72% yield) as pale yellow oil.

MS (ESI) m/z : 364 [M+l]⁺.

RT = 0.556 min.

LCMS condition : B.

Step-2)

Tert-butyl [2-{2-[(lS)-l-hydroxyethyl]-lH-imidazol-l-yl}-2-(3-{[tri(propan-2-yl)silyl]ethynyl}- l,2-oxazol-5-yl)ethyl]carbamate

To a solution of tert-butyl N-[2-[2-[(lS)-l-tetrahydropyran-2-yloxyethyl]imidazol-l-yl]but-3- ynyl] carbamate (63 mg) and [bis(trifluoroacetoxy)iodo]benzene (56 mg) in chloroform (0.20 mL) was added a solution of (E)-3-(triisopropylsilyl)propiolaldehyde oxime (20 mg) in CHCI3 (l mL) dropwise. The reaction mixture was stirred for 20 minutes at room temperature. Then [bis(trifluoroacetoxy)iodo]benzene (56 mg) and (E)-3-(triisopropylsilyl)propiolaldehyde oxime (20 mg) in CHCI3 (l mL) were added twice every 20 minutes. The mixture was stirred overnight at room temperature. Saturated aqueous sodium thiosulfate, saturated aqueous sodium bicarbonate and EtOAc were added to the reaction and the resulting mixture was vigorously stirred for 15 minutes. The layers were separated and the aqueous layer was extracted with EtOAc. The combined organic layer was dried over MgS04, and concentrated in vacuo. The residue was charged onto ISOLUTE® HM-N and purified by OH-type silica gel column chromatography (50-100 % EtOAc in /rhexane) to give the title compound (70 mg, 80% yield), in which the tetrahydropyranyl group was deprotected, as a crude material.

MS (ESI) m/z : 503 [M+l]⁺.

RT = 1.018 min.

LCMS condition : B.

Step -3)

Tert-butyl [2-{2-[(lS)-l-{[tert-butyl(dimethyl)silyl]oxy}ethyl]-lH-imidazol-l-yl}-2-(3-ethynyl- 1,2- oxazol- 5 -yl)ethyl] carbamate

To a solution of the above crude material including tert-butyl [2-{2-[(lS)-l"hydroxyethyl]-lH- imidazol- l-yl}"2'(3-{[tri(propan-2-yl)silyl]ethynyl}- l,2-oxazol^_5-yl)ethyl]carbamate (0.12 g) in THF (1.6 mL) was added TBAF (0.25 mL, 1 M solution in THF) at 0 °C and the reaction mixture was stirred for 20 minutes at the same temperature. The reaction was quenched with saturated aqueous ammonium chloride and extracted with EtOAc. The organic layer was washed with saturated aqueous ammonium chloride^ water, - and- brine-, dried over MgS04, and concentrated in vacuo. The residue was charged onto ISOLUTE® HM-N and purified by OH-type silica gel column chromatography (50-100 % EtOAc in /2-hexane and then 0-10% MeOH in EtOAc) to give a yellow gum (82 mg), which was used for the next reaction without further purification.

To a solution of the yellow gum (79 mg) in DMF (l mL) were added imidazole (23 mg) and TBSCl (45 mg), and the reaction mixture was stirred for 1 hour at room temperature. After addition of imidazole (23 mg) and TBSCl (45 mg), the reaction was stirred for 2 hours at the same temperature. The reaction was diluted with EtOAc and washed with water three times. The organic layer was dried over MgS04 and concentrated in vacuo. The combined organic layer was dried over MgS04, and concentrated in vacuo. The residue was charged onto ISOLUTE® HM-N and purified by OH'type silica gel column chromatography (50-100 % EtOAc in n-hexane) to give the title compound (76 mg, 72% yield) as pale yellow gum.

MS (ESI) m/z : 461 [M+l]⁺.

RT = 0.884 min.

LCMS condition : B.

Step-4)

3-[3-(4-{[5-(2-Amino-l-{2-[(lS)-l-hydroxyethyl]-lH-imidazol-l-yl}ethyl)-l,2-oxazol-3- yl]ethynyl}phenoxy)azetidin-l- l] ro an-l-ol (Com ound-355)

Compound-355

Compound-355 were obtained in the manner as with the "Synthesis of Compound-28 step- 3 and Compound-269: step-6" using the corresponding materials.^!H-NMR, MS and LCMS retention time data of Compound-355 are shown in Table 3.

Synthesis of Compound-356

(lS)-l-[l-({5-[(4-iodo henyl)ethynyl]-l,2-oxazol-3-yl}methyl)-lH-imidazol-2-yl]ethan-l-ol

Compound-356

Step-1)

(lS)-l-[l-({5-[(4-iodophenyl)ethynyl]-l,2-oxazol-3-yl}methyl)-lH-imidazol-2-yl]ethan-l-ol (Com ound-356)

To a solution of tert-butyl-[(lS)-l-[l-[[5-[2-(4"iodophenyl)ethynyl]isoxazol-3- yl]methyl]imidazol-2-yl]ethoxy]-dimethyl-silane (11 mg) in DMSO (0.3 mL) was added potassium fluoride (10 mg) and the mixture was stirred for 1.5 hours at room temperature. After addition of further potassium fluoride (10 mg) and DMSO (0.3 mL), the mixture was stirred for 5 hours at 60 °C and overnight at room temperature. The reaction mixture was quenched with 20% aqueous potassium carbonate and extracted with CHCI3. The organic layer was passed through a phase separator and concentrated in vacuo onto ISOLUTE® HM-N. The residue was purified with NH-type silica gel column chromatography (1-10 % MeOH in CHCI3) to give the title compound (6.8 mg, 80 % yield) as slightly blue solid. Ή-NMR, MS and LCMS retention time data of Compound-356 are shown in Table 3.

Synthesis of Compound-357

l-[4-(4-{[3-({2-[(lS)-l-hydroxyethyl]-lH-imidazol-l-yl}methyl)-l,2-oxazol-5- yl]ethynyl}phenyl)piperazin-l-yl]-3-methoxypropan-2-ol

Step-1)

l-Methoxy-3-{4-[4-({3 (2-{(lS)-l-[(oxan-2 l)oxy]ethyl}-lH-imidazol-l-yl)methyl]-l,2-oxazol- 5- l}ethynyl)phenyl]piperazin-l-yl}propan-2-ol

To a solution of 5-[2-(4-piperazin-l-ylphenyl)ethynyl]-3-[[2-[(lS)-l-tetrahydropyran-2- yloxyethyl]imidazol-l-yl]methyl]isoxazole (25 mg) in EtOH (0.50 mL) was added 2- (methoxymethyl)oxirane (0.024 mL) at room temperature. After stirring for 3 hours, 2- (methoxymethyl)oxirane (0.024 mL) was further added. The reaction mixture was stirred at the same temperature for additional 17 hours and concentrated in vacuo. The residue was purified with OH-type silica gel column chromatography (0"8% MeOH in CHCk) to give the title compound (21 mg, 71% yield) as yellow oil.

MS (ESI) m/z : 550 [M+l]⁺.

RT = 0.224 min.

LCMS condition : A.

Step -2)

l-[4-(4-{[3-({2-[(lS)-l-hydroxyethyl]-lH-imidazol-l-yl}methyl)-l,2-oxazol-5- yl]ethynyl}phenyl)piperazin- l-yl]-3-methoxypropan-2-ol (Compound^_357)

Compound-357

To a solution of l-methoxy-3-{4-[4-({3-[(2-{(lS)-l-[(oxan-2-yDoxy]ethyl}-lH-imidazoM- yl)methyl]-l,2-oxazol-5-yl}ethynyl)phenyl]piperazin-l-yl}propan-2"ol (21 mg) in MeOH (1.0 niL) and water (0.10 mL) was added p-TsOH monohydrate (29 mg) at room temperature. The reaction mixture was stirred at the same temperature for 24 hours. After cooling, saturated aqueous sodium bicarbonate and CHCk were added into the mixture. The bi-layer was separated and the aqueous layer was extracted with 10% MeOH in CHCI3. The combined organic extracts were passed through a phase separator and concentrated in vacuo. The residue was purified with NH-type silica gel column chromatography (0-4% MeOH in CHCI3) to give the title compound (12 mg, 67% yield) as pale yellow solid.

Ή-NMR, MS and LCMS retention time data of Compound-357 are shown in Table 3.

Synthesis of Compound-358

(3R)-4-[4-(4-{[3-({2-[(lS)- l-hydroxyethyl]- lH-imidazol- l-yl}methyl)- l,2-oxazol-5- yl]ethynyl}phenyl)piperazin- l-yl]butane- 1,3-diol

Step- 1)

-(4-Iodophenyl)-4-{[(4R)-2-phenyl- l,3-dioxan-4-yl]methyl}piperazine

To a suspension of l-(4-iodophenyl)piperazine hydrochloride (0.98 g) in CHCk (50 mL) and MeOH (5.0 mL) was added 1 mol/L aqueous NaOH (30 mL) at room temperature. The reaction mixture was stirred at the same temperature for 0.5 hours. The bi-layer was separated and the aqueous layer was extracted with 10% MeOH in CHCI3. The combined organic extracts were passed through a phase separator and concentrated in vacuo to give the free form. After dilution with THF (20 mL) and MeOH (6.0 mL), (4R)-2-phenyM,3- dioxane-4-carbaldehyde (0.23 g) and acetic acid (0.41 mL) were added and the mixture was stirred for 45 minutes. Then picoline borane (0.38 g) was added and the mixture was stirred at the same temperature for 16 hours. After cooling, CHCI3 and saturated aqueous sodium bicarbonate were added. The separated organic extract was passed through a phase separator and concentrated in vacuo. The residue was purified with OH-type silica gel column chromatography (5-60% EtOAc in n-hexane) to give the title compound (0.20 g) as crude product of white solid, which was used in next step without further purification.

MS (ESI) m/z : 465 [M+l]⁺.

RT = 0.574 min.

LCMS condition : B.

Step -2)

-4-[4-(4"iodophenyl)piperazin-l-yl]butane-l,3-diol hydrochloride

To a solution of l-(4-iodophenyl)-4-{[(4R)-2-phenyl-l,3"dioxan-4-yl]methyl}piperazine (0.20 g) in 1,4'dioxane (6.0 mL) and water (4.0 mL) was added 4 mol/L HC1 in 1,4-dioxane (10 mL) at room temperature. The reaction mixture was stirred at the same temperature for 22 hours. Then, 4 mol/L HC1 in 1,4-dioxane (10 mL) was further added and the mixture was additionally stirred for 5 hours. The mixture was concentrated in vacuo to give the title compound (0.20 g) as crude product of pale yellow solid, which was used in next step without further purification.

MS (ESI) m/z : 377 [M+l]⁺.

RT = 0.662 min.

LCMS condition : A. Step -3)

-4-[4-(4-iodophenyl)piperazin-l-yl]butane-l,3-diyl diacetate

To a solution of (3R)-4-[4-(4-iodophenyl)piperazin-l-yl]butane-l,3-diol hydrochloride (0.14 g) in THF (3.4 mL) were added TEA (0.28 mL) and acetic anhydride (0.096 mL) at 0 °C. The reaction mixture was stirred at room temperature for 16 hours. After cooling, the mixture was diluted with CHCI3 and quenched with saturated aqueous sodium bicarbonate. The bi- layer was separated and the aqueous layer was extracted with CHCI3. The combined organic extract was passed through a phase separator and concentrated in vacuo. The residue was purified with NH-type silica gel column chromatography (0-4% MeOH in CHCI3) to give the title compound (26 mg, 17% yield) as white solid.

MS (ESI) m/z : 461 [M+l]⁺.

RT = 0.881 min. LCMS condition : A.

Ste -4)

(3R)-4^4-(4-{[3-({2-[(lS) -(acetyloxy)ethyl]-lH-imidazol-l-yl}methyl)-l,2-oxazol-5- yl]ethynyl}phenyl)piperazin- l-yl]butane- 1,3-diyl diacet

A mixture of (3R)-4-[4-(4-iodophenyl)piperazin- l-yl]butane- 1,3-diyl diacetate (26 mg), cesium carbonate (48 mg), XPhos (8.1 mg) and PdCl2(CH3CN)2 (1.5 mg) in acetonitrile (0.50 mL) was stirred at room temperature for 0.5 hours, then (lS)-l-{l-[(5-ethynyl-l,2-oxazol-3-yl)methyl]- lH-imidazol-2-yl}ethyl acetate (29 mg) in acetonitrile (0.50 mL) was added into the mixture, which was stirred at 80 °C for 2.5 hours. After cooling, the mixture was passed through Celite® and NH-type silica gel pad and washed with acetonitrile. The filtrate was concentrated in vacuo. The residue was purified with NH-type silica gel column chromatography (25-80% EtOAc in n-hexane) to give the title compound (15 mg, 44% yield) as yellow oil.

MS (ESI) m/z : 592 [M+l]⁺.

RT = 0.700 min.

LCMS condition : A.

Step -5)

(3R)-4-[4-(4-{[3-({2-[(lS)-l-hydroxyethyl]-lH-imidazol-l-yl}methyl)-l,2-oxazol-5- l]ethynyl}phenyl)piperazin- l-yl]butane- 1,3-diol (Compound- 358)

Compound-358

To a solution of (3R)-4-[4-(4-{[3-({2-[(lS)-l-(acetyloxy)ethyl]-lH-imidazol-l-yl}methyl)-l,2- oxazol-5-yl]ethynyl}phenyl)piperazin-l-yl]butane- 1,3-diyl diacetate (15 mg) in THF (l.O mL) and MeOH (0.40 mL) was added 1 mol/L aqueous NaOH (0.38 mL) at room temperature. The reaction mixture was stirred at the same temperature for 3 hours and then diluted with CHCI3 and saturated aqueous sodium bicarbonate. The bi-layer was separated and the aqueous layer was extracted with 10% MeOH in CHCI3. The combined organic extracts were passed through a phase separator and concentrated in vacuo. The residue was purified with NH-type silica gel column chromatography (05% MeOH in CHCI3) to give the title compound (10 mg, 88% yield) as light yellow solid.

Ή-NMR, MS and LCMS retention time data of Compound-358 are shown in Table 3. Synthesis of Compound-359

l-[4-(4-{[3-({2-[(lS)-l-hydroxyethyl]-lH-imidazol-l-yl}methyl)-l,2-oxazol-5- yl]ethynyl}phenyl)piperazin-l-yl]propan-2-ol

Compound-359

Step-1)

l-[4-(4-{[3-({2-[(lS)-l-hydroxyethyl]-lH-imidazol-l-yl}methyl)-l,

l]ethynyl}phenyl)piperazin-l-yl]propan-2-ol (Compound-359)

A microwave vial was charged with (lS)-l-[l-[[5-[2-(4-piperazin-l-ylphenyl)ethynyl]isoxazol- 3-yl]methyl]imidazol-2-yl]ethanol (30 mg), MeOH (l mL), and propylene oxide (0.028 niL). The vial was sealed with a Teflon® cap. After being stirred at room temperature for 1 hour, additional propylene oxide (0.028 mL) was added and the mixture was irradiated in a microwave reactor at 50 °C for 30 minutes. The mixture was concentrated in vacuo onto ISOLUTE® HM-N. The residue was purified with NH-type silica gel column chromatography (0-10% MeOH in CHCI3) to give the title compound (25 mg, 73% yield) as a colorless solid.

Ή-NMR, MS and LCMS retention time data of Compound-359 are shown in Table 3. Synthesis of Compound-360

(lS)-l-(l-{[5-({4-[4-(2-methoxyethyl)piperazin-l-yl]phenyl}ethynyl)-l,2-oxazol-3-yl]methyl}- lH-imidazol-2- l)ethan- l-ol

Compound-:

Step-1)

l-(4-{[3-({2-[(lS)- l-{[tert-butyl(dimethy^

5 -yl] ethynyljp henyl)^■ 4- (2- methoxyethy pip erazine

To a solution of tert-butyl-[(lS)-l-[l-[[5-[2-(4-iodophenyl)ethynyl]isoxazol-3- yl]methyl]imidazol-2-yl]ethoxy]-dimethyl-silane (50 mg), l-(2-methoxyethyl)piperazine (27 mg), Pd2(dba)3 (4.3 mg), 2-dicyclohexylphosphino-2'-(NjV-dimethylamino)biphenyl (3.7 mg) in toluene (l mL) was added sodium tert-butoxide (18 mg). The reaction mixture was evacuated, backfilled with nitrogen, and stirred for 5.5 hours at 60 °C. After cooling, the reaction was diluted with aqueous sodium bicarbonate and extracted with CHC . The organic layer was dried over MgS04 and concentrated in vacuo onto ISOLUTE® HM-N. The residue was purified with NH-type silica gel column chromatography (25-65% EtOAc in nr hexane) to give the title compound (39 mg, 75% yield) as pale yellow amorphous.

MS (ESI) m/z : 550 [M+l]⁺.

RT = 0.597 min.

LCMS condition : B.

Step -2)

(lS)-l-(l-{[5-({4-[4-(2-methoxyethyl)piperazin-l-yl]phenyl}ethynyl)-l,2-oxazol-3-yl]methyl}- -imidazol-2-yl)ethan-l-ol (Compound-360)

To a solution of tert-butyl-[(lS)-l-[l-[[5-[2-[4-[4-(2-methoxyethyl)piperazin-l- yl]phenyl]ethynyl]isoxazol-3-yl]methyl]imidazol-2-yl]ethoxy]-dimethyl-silane (38 mg) in THF (0.70 niL) was added 1 mol/L TBAF in THF (0.089 mL). The reaction mixture was stirred at room temperature for 0.5 hours, quenched with 20% aqueous potassium carbonate and extracted with 10% MeOH in CHC . The organic extract was passed through a phase separator and concentrated in vacuo. The residue was purified with NH-type silica gel column chromatography (50% EtOAc in n- hexane and 0"5% MeOH in CHCI3) to give the title compound (24 mg, 80% yield) as pale yellow solid.

Ή-NMR, MS and LCMS retention time data of Compound- 359 are shown in Table 3.

Synthesis of Compound-364

(lS)-l-[l-({5-[(4-{4-[(oxetan-3-yl)methyl]piperazin-l-yl}phenyl)ethynyl]-l,2-oxazol-3- yl}methyl)- lH"imidazol-2-yl]ethan- l-ol

Compound-:

Step-1)

(lS)-l-[l-({5-[(4-{4-[(oxetan-3-yl)methyl]piperazin-l-yl}phenyl)ethynyl]-l,2-oxazol-3- yl}methyl)- lH-imidazol-2-yl]ethan- l-ol (Compound-364)

To a solution of (lS)-l-[l-[[5-[2-(4-piperazin-l-ylphenyl)ethynyl]isoxazol-3- yl]methyl]imidazol-2-yl]ethanol (20 mg) in acetonitrile (0.5 mL) and DMF (0.5 mL) were added oxetan-3-ylmethyl 4-methylbenzenesulfonate (15 mg) in acetonitrile (0.5 mL) and K2CO3 (11 mg) at room temperature. The reaction mixture was heated to 50 °C for 1 hour, and heated to 80 °C for 9 hours. Oxetan-3-ylmethyl 4-methylbenzenesulfonate (15 mg) in acetonitrile (0.5 mL) was added and the mixture was stirred for 1 hour. Sodium iodide (15 mg) was added the mixture was stirred for additional 1.5 hours. After cooling, the mixture was quenched by water and extracted with CHC -MeOH. The combined organic layer was concentrated in vacuo onto ISOLUTE® HM-N. The residue was purified with NH-type silica gel column chromatography (5-10 % EtOAc in hexane) and preparative thin layer chromatography (5 % EtOAc in hexane) to give the title compound (8.3 mg, 35% yield) as colorless solid.

Ή-NMR, MS and LCMS retention time data of Compound-364 are shown in Table 3.

Compounds-3, 6, 7, 8 and 9 were obtained in the manner as with the "Synthesis of Compound-2" using the corresponding materials.

Compounds- 17 and 18 were obtained in the manner as with the "Synthesis of Compound- 16" using the corresponding materials,

Compounds-20, 21, 22, 23 and 24 were obtained in the manner as with the "Synthesis of Compound- 19" using the corresponding materials.

Compounds-26 and 80 were obtained in the manner as with the "Synthesis of Compound-25" using the corresponding materials.

Compounds-29 and 30 were obtained in the manner as with the "Synthesis of Compound-28" using the corresponding materials.

Compounds-32 and 33 were obtained in the manner as with the "Synthesis of Compound-31" using the corresponding materials.

Compounds-36, 37, 38, 39, 40, 41 and 42 were obtained in the manner as with the "Synthesis of Compound-35" using the corresponding materials.

Compounds-44, 45, 46, 47, 48 and 49 were obtained in the manner as with the "Synthesis of Compound-43" using the corresponding materials.

Compounds-51 and 52 were obtained in the manner as with the "Synthesis of Compound-50" using the corresponding materials.

Comopunds-56, 57, 58, 59, 60, 61 and 116 were obtained in the manner as with the "Synthesis of Compound-53" using the corresponding materials.

Compounds-64, 65, 66, 67, 115 and 178 were obtained in the manner as with the "Synthesis of Compound-63" using the corresponding materials.

Comopunds-69, 70, 71, 72, 73 and 74 were obtained in the manner as with' the "Synthesis of Compound-68" using the corresponding materials.

Compounds-79 and 81 were obtained in the manner as with the "Synthesis of Intermediate 8" and "Synthesis of Comopund-53" using the corresponding materials.

Compound-85 was obtained in the manner as with the "Synthesis of Compound-84" using the corresponding materials.

Compounds-87 and 88 were obtained in the manner as with the "Synthesis of Compound-86" using the corresponding materials.

Compound-92 was obtained in the manner as with the "Synthesis of Compound-91" using the corresponding materials.

Compounds-96, 97, 98, 99, 100, 119, 124, 126, 144 and 149 were obtained in the manner as with the "Synthesis of Compound-95" using the corresponding materials.

Compounds- 104, 105, 106, 107, 108, 117, 118, 121, 122, 123, 125, 127, 128, 129, 130, 132, 133, 134, 136, 137, 138, 139, 140, 141, 142, 143, 146, 147, 148, 150, 151, 152, 153, 155, 156, 158, 159, 161, 162, 163, 164, 165, 167, 170, 171, 172, 173, 180, 183, 187, 188, 191, 197, 198, 199, 200, 204, 205, 209, 214, 215, 218, 219, 220, 223, 228, 231, 235, 241, 246, 251, 255, 262, 280, 291, 295, 297 and 312 were obtained in the manner as with the "Synthesis of Compound- 102" using the corresponding materials.

Compounds- 168 was obtained in the manner as with the "Synthesis of Compound- 103" using the corresponding materials.

Compounds- 114 232, 260, 271, 272, 273 and 339 were obtained in the manner as with the "Synthesis of Compound- 109" using the corresponding materials.

Compounds- 1, 111, 112, 113, 120, 169, 175, 182, 189, 190, 195, 196, 201, 202, 203, 207, 208, 212, 213, 216 and 217 , 225, 226, 227, 233, 234, 236, 238, 239, 240, 242, 250 and 353 were obtained in the manner as with the "Synthesis of Compound- 110" using the corresponding materials.

Compound-211 was obtained in the manner as with the "Synthesis of Compound-160" using the corresponding materials.

Compounds- 174, 194 and 206 were obtained in the manner as with the "Synthesis of Compound- 193" using the corresponding materials.

Compounds-229, 247, 261, 277, 284, 289, 310, 314 and 316 were obtained in the manner as with the "Synthesis of Compound-230" using the corresponding materials.

Compound-313 was obtained in the manner as with the "Synthesis of Compound-240" using the corresponding materials.

Compounds-248, 249, 258 and 259 were obtained in the manner as with the "Synthesis of Compound-243" using the corresponding materials.

Compound-253 was obtained in the manner as with the "Synthesis of Compound-252" using the corresponding materials.

Compounds-263 and 270 were obtained in the manner as with the "Synthesis of Compound- 264" using the corresponding materials.

Compound-254 was obtained in the manner as with the "Synthesis of Compound-266" using the corresponding materials.

Compound-268 was obtained in the manner as with the "Synthesis of Compound-267" using the corresponding materials.

Compounds-256, 282, 293, 294, 299, 303, 306, 307, 321, 326, 329, 335, 336, 338, 340, 342, 343, 344, 345, 346, 347, 349, 350 and 370 were obtained in the manner as with the "Synthesis of Compound-269" using the corresponding materials.

Compounds-302 and 304 were obtained in the manner as with the "Synthesis of Compound - 301" using the corresponding materials.

Compounds-244, 285, 296, 351 and 352 were obtained in the manner as with the "Synthesis of Compound-305" using the corresponding materials.

Compounds-311 was obtained in the manner as with the "Synthesis of Compound-309" using the corresponding materials.

Compounds-327 was obtained in the manner as with the "Synthesis of Compound-315" using the corresponding materials.

Compounds-331 was obtained in the manner as with the "Synthesis of Compound-322" using the corresponding materials.

Compounds-324 was obtained in the manner as with the "Synthesis of Compound-323" using the corresponding materials.

Compounds-332 was obtained in the manner as with the "Synthesis of Compound-330" using the corresponding materials.

Compounds-274, 275, 278, 359, 361 and 362 were obtained in the manner as with the "Synthesis of Compound-359" using the corresponding materials.

Compounds-363, 365, 366, 367, 368 and 369 were obtained in the manner as with the "Synthesis of Compound-360" using the corresponding materials.

Compound-298 was obtained in the manner as with the "Synthesis of Compounds-210 and 300" using the corresponding materials.

Compound-300 was obtained in the manner as with the "Synthesis of Compounds- 160 and 181" using the corresponding materials.

Compound-279 was obtained in the manner as with the "Synthesis of Compounds-230 and 264" using the corresponding materials.

Compound-328 was obtained in the manner as with the "Synthesis of Compounds- 102, 264 and 310" using the corresponding materials.

Compound-337 was obtained in the manner as with the "Synthesis of Compounds- 102 and 330" using the corresponding materials.

Compounds- 165 and 318 were obtained in the manner as with the "Synthesis of Intermediate- 14 and Compounds- 102" using the corresponding materials.

Table 3 shows the list of Example Compounds. Compound ID number, chemical structures, Ή-NMR data, MS data and LCMS retention time (minutes) data are shown. Table 3. List of Example Compounds

: 285

(ESI) : 269

:

:

:

: 0.499

(A)

:

:

:

:

0.629 (B)

: 0.366

:

:

:

:

:

:

0.487 (A)

:

:

:

Chemical names of the Example Compounds in Table 3 are follows.

Compound- l: (lS)-l-{l-[(5-{[4-(4-aminobutoxy)phenyl]ethynyl}-l,2-oxazol-3-yl)methyl]-lH- imidazol-2-yl}ethan- l-ol

Compound-2: l-{l-[3-(4-Chlorophenyl)propyl]-lH-imidazol-2-yl}ethan-l-ol

Compound-3: l-{l-[4-(4"Chlorophenyl)butyl]-lH-imidazol-2-yl}ethan-l-ol

Compound-4: (lR)-l-{l-[4-(4-Chlorophenyl)butyl]"lH-imidazol-2-yl}ethan-l-ol

Compound-5: (lS)-l-{l-[4-(4-Chlorophenyl)butyl]-lH-imidazol-2-yl}ethan-l-ol

Compounds l-{l-[2-(4-Bromophenoxy)ethyl]-lH-imidazol-2-yl}ethan-l-ol

Compound-7: l-{l-[3-(4-Bromophenyl)propyl]-lH-imidazol-2-yl}ethan-l-ol

Compound-8: l-{l-[4-(4-Bromophenyl)butyl]-lH-imidazol-2-yl}ethan-l-ol

Compound-9: l-{l-[4-([l,l'-Biphenyl]-4-yl)butyl]-lH-imidazol-2-yl}ethan-l-ol

Compound- 10: {l-[3-(4-Chlorophenyl)propyl]-lH-imidazol-2-yl}(hydroxy)acetic acid Compound- 11: 2-{l-[3-(4-Chlorophenyl)propyl]-lH-imidazol-2-yl}-2-hydroxyacetamide Compound- 12: Amino{l-[3-(4-chlorophenyl)propyl]-lH-imidazol-2-yl}acetic acid

Compound- 13: l-{l-[3-(4-Chlorophenyl)propyl]-lH-imidazol-2-yl}ethan-l-amine

Compound- 14: 2-{l-[3-(4-Chlorophenyl)propyl]-lH-imidazol-2-yl}alanine

Compound- 15: 2-{l-[3-(4-Chlorophenyl)propyl]-lH-imidazol-2-yl}-2-hydroxypropanoic acid Compound- 16: l-{l-[3-(4-Chlorophenyl)propyl]-lH-imidazol-2-yl}propan-l-ol

Compound- 17: l-{l-[3-(4-Chlorophenyl)propyl]-lH-imidazol-2-yl}butan-l-ol

Compound- 18: {l-[3-(4-Chlorophenyl)propyl]-lH-imidazol-2-yl}(cyclopropyl)methanol Compound- 19: l-(l-{[4-(Phenylethynyl)phenyl]methyl}-lH-imidazol-2-yl)ethan-l-ol Compound-20: l-(l-{3-[4-(Phenylethynyl)phenyl]propyl}-lH-imidazol-2-yl)ethan-l-ol Compound"2i: l-(l-{4-[4-(Phenylethynyl)phenyl]butyl}-lH-imidazol-2-yl)ethan-l-ol Compound-22: 1- 1 - {[3- (Phenylethynyl)phenyl] methyl} - lH-imidazol-2-yl)ethan- 1 -ol

Compound-23: 1- l-{2-[4-(Phenylethynyl)phenyl]ethyl}-lH-imidazol-2-yl)ethan-l-ol

Compound-24: 3- 4-[(4-{[2-(l-Hydroxyethyl)-lH-imidazol-l- yl]methyl}phenyl. ethynyl]phenyl}propan-l-ol

Compound 25 1- l-[3-(4-Chlorophenyl)propyl]-lH-imidazol-2-yl}-2,2,2-trifluoroethan-l-ol

Compound 26 1- l-[3-(4-Chlorophenyl)propyl]-lH-imidazol-2-yl}-2,2-difluoroethan-l-ol

Compound 27 1- l-f3-(4-Chlorophenyl)propyl]-5-methyl-lH"imidazol-2-yl}ethan-l-ol

Compound 28 1- l-[2-([l,l'-Biphenyl]-4-yl)ethyl]-lH-imidazol-2-yl}ethan-l-ol

Compound 29 1- l-t3-([l,r-Biphenyl]-4-yl)propyl]-lH-imidazol-2-yl}ethan-l-ol

Compound 30 1- l-[([l,l'-Biphenyl]-4-yDmethyl]-lH-imidazol-2-yl}ethan-l-ol

Compound 31 1- l-[(4-Bromo-3-methylphenyl)methyl]-lH-imidazol-2-yl}ethan-l-ol

Compound 32 1- l-{[3-(4"Fluorophenyl)-l,2-oxazol-5-yl]methyl}-lH-imidazol-2-yl)ethan-l-ol

Compound 33 1- [l,r-Biphenyl]-4-yl)-2-[2-(l-hydroxyethyl)-lH-imidazol-l-yl]ethan-l-one

Compound 34 1- [l,r-Biphenyl]-4-yl)-2-[2-(l-hydroxyethyl)-lH-imidazol-l-yl]ethan-l-ol

Compound 35 1- l-[(5-Phenyl-l,3-thiazol-2-yl)methyl]-lH-imidazol-2-yl}ethan-l-ol

Compound 36 1- l-[(5-Phenyl-l,2,4-oxadiazol-3-yl)methyl]-lH-imidazol-2-yl}ethan-l-ol

Compound 37 1- 1- [(3-Benzyl- l,2,4-oxadiazol-5-yl)methyl]- lH-imidazol-2-yl}ethan- l"ol

Compound 38 1- l-[(2-Phenyl-l,3-thiazol-4-yl)methyl]-lH-imidazol-2-yl}ethan-l-ol

Compound 39 1- l-[(l-Phenyl-lH-pyrazol-3-yl)methyl]-lH-imidazol-2-yl}ethan-l-ol

Compound 40 1- l-[(l-Phenyl-lH-pyrazol-4-yl)methyl]-lH-imidazol-2-yl}ethan-l-ol

Compound 41 1- l-[(2-Phenyl-2H-l,2_>3-triazol-4-yl)methyl]-lH-imidazol-2-yl}ethan-l-ol

Compound- 42 1- l-{[3-(4-Fluorophenyl)-lH-pyrazol-5-yl]methyl}-lH-imidazol-2-yl)ethan-l- ol

Compound- 43 1- l-[(5-Phenyl-l,2-oxazol-3-yl)methyl]-lH-imidazol-2-yl}ethan-l-ol

Compound" 44 1- l-[(l-Methyl-5-phenyl-lH-pyrazol-3-yl)methyl]-lH-imidazol-2-yl}ethan-l-ol

Compound- 45 1- l-[(l-Phenyl-lH-l,2,3-triazol-4-yl)methyl]-lH-imidazol-2-yl}ethan-l-ol

Compound- 46 1- l-{[5-(Naphthalen-2-yl)-l,2-oxazol-3-yl]methyl}-lH-imidazol-2-yl)ethan-l- ol

Compound"47 l-{[5-(Thiophen-2-yl)-l,2-oxazol-3-yl]methyl}-lH-imidazol-2-yl)ethan-l-ol Compound-48 l-{[5-(Furan-2-yl)-l,2-oxazol-3-yl]methyl}-lH-imidazol-2-yl)ethan-l-ol Compound-49 l-{[5-(Prop-l-yn-l-yl)-l,2-oxazol-3-yl]methyl}-lH-imidazol-2-yl)ethan-l-ol Compound-50 4- [(2 -Fluoro-4- {[2 - ( 1 -hydroxyethyl) - lH-imidazol" 1 - yl]methyl}phenyl, ethynyl]phenyl}propan-l-ol

Compound"5i: 3 4-[(4-{[2-(l-Hydroxyethyl)- lH-imidazol-l-yl]methyl}-2- methylphenyl)ethynyl]phenyl}propan- l'ol

Compound-52: 3-[4-(5-{[2-(l-Hydroxyethyl)- lH-imidazol'l-yl]methyl}pyrimidin-2- yl)phenyl]propan-l-ol Compound-53: 3-{4-[(3-{[2-(l-Hydroxyethyl)- lH-imidazol-l-yl]methyl}- l,2-oxazol-5- yl)ethynyl]phenyl}propan- l"ol

Compound-54: 3-(4-{[3-({2- [(IS)- 1-hydroxyethyl]- IH-imidazol- l-yl}methyl)- l,2-oxazol-5- yl]ethynyl}phenyl)propan- l"ol

Compound-55: 3-(4-{[3-({2-[(lR)- l-hydroxyethyl]- lH-imidazol- l-yl}methyl)-l,2-oxazol-5- yl]ethynyl}phenyl)propan- l"ol

Compound-56: l-(l-{[5-(Phenylethynyl)- l,2-oxazol-3-yl]methyl}- lH-imidazol-2-yl)ethan- l-ol Compound-57: 3-[4-(3-{[2-(l-Hydroxyethyl)- lH-imidazol-l-yl]methyl}-l,2-oxazol-5- yl)phenyl]propan- l-ol

Compound-58: 3-{3-[(3-{[2-(l-Hydroxyethyl)- lH-imidazol-l-yl]methyl}- l,2-oxazol-5- yl)ethynyl]phenyl}propan- l-ol

Compound-59: 3-[4-(2-{[2-(l-Hydroxyethyl)- lH-imidazol-l-yl]methyl}pyrimidin-5- yl)phenyl]propan- l-ol

Compound-60: 3-[4-(6-{[2-(l-Hydroxyethyl)- lH-imidazol-l-yl]methyl}pyridazin-3- yl)phenyl]propan- l-ol

Compound-6l: 5-(3-{[2-(l-Hydroxyethyl)-lH-imidazol- l-yl]methyl}- l,2-oxazol-5-yl)pent-4-yn- l-ol

Compound-62: l-{l-[(5-{[4-(Hydroxymethyl)phenyl]ethynyl}-l,2-oxazol-3-yl)methyl]- lH- imidazol-2-yl}ethan- l-ol

Compound-63: l-[l-({5-[(4-{[(Oxetan-3-yl)amino]methyl}phenyl)ethynyl]-l,2-oxazol-3- yl}methyl)- lH-imidazol-2-yl]ethan-l-ol

Compound-64: l-{l-[(5-{[4-({[(3S)-Oxolan-3-yl]amino}methyl)phenyl]ethynyl}- l,2-oxazol-3- yl)methyl]- lH-imidazol-2-yl}ethan-l-ol

Compound-65: l-{l-[(5-{[4-({[l-(Hydroxymethyl)cyclopropyl]amino}methyl)phenyl]ethynyl}- l,2-oxazol-3-yl)methyl]- lH-imidazol-2-yl}ethan-l-ol

Compound-66: l-(l-{[5-({4-[(Piperidin-l-yl)methyl]phenyl}ethynyl)- l,2-oxazol-3-yl]methyl}- lH-imidazol-2-yl)ethan-l-ol

Compound-67: l-(l-{[5-({4-[(2-Oxa-6-azaspiro[3.3]heptan-6-yl)methyl]phenyl}ethynyl)- l,2- oxazol-3-yl]methyl}- lH-imidazol-2-yl)ethan- l-ol

Compound-68: l-(l-{[5-({4-[(Morpholin-4-yl)methyl]phenyl}ethynyl)-l,2-oxazol-3-yl]methyl}- lH-imidazol-2-yl)ethan- l-ol

Compound-69: l-(l-{[5-({4-[2-(Morpholin-4-yl)ethoxy]phenyl}ethynyl)-l,2-oxazol-3- yl]methyl}- lH-imidazol-2-yl)ethan- l-ol

Compound-70: 2-({4-[(3-{[2-(l-Hydroxyethyl)- lH-imidazol-l-yl]methyl}- l,2-oxazol-5- yl)ethynyl]phenoxy}methyl)propane-l,3-diol

Compound-7i: l-(l-{[5-({4-[3-(Morpholin-4-yl)propoxy]phenyl}ethynyl)- l,2-oxazol-3- yl]methyl}- lH-imidazol-2-yl)ethan- l-ol Compound-72: l-(l-{[5-({6-[2-(Morpholin-4-yl)ethoxy]pyridin-3-yl}ethynyl)-l,2-oxazol-3- yllmethyl}- lH-imidazol"2-yl)ethan- l"ol

Compound-73: l-[l-({5-[(l-Methyl- lH-pyrazol-4-yl)ethynyl]- l,2-oxazol-3-yl}methyl)- lH- imidazol-2-yl]ethan- l'ol

Compound-74: l-{l-[(5-{[4-(2-Hydroxyethoxy)phenyl]ethynyl}- l,2-oxazol-3-yl)methyl]-lH- imidazol-2-yl}ethan-l-ol

Compound-75: (lS)- l-{l-[(5-{[4-(2-hydroxyethoxy)phenyl]ethynyl}- l,2-oxazol-3-yl)methyl]- lH-imidazol-2-yl}ethan- l"ol

Compound-76: (lR)- l-{l-[(5-{[4-(2-hydroxyethoxy)phenyl]ethynyl}- l,2-oxazol-3-yl)methyl]- lH-imidazol-2-yl}ethan-l-ol

Compound-77: 2-[2-(l-Hydroxyethyl)- lH-imidazol-l-yl]-2-(5-{[4- (hydroxymethyl)phenyl]ethynyl}-l,2-oxazol-3-yl)ethan-l-ol

Compound-78: l-{l-[l-(5-{[4-(Hydroxymethyl)phenyl]ethynyl}- l,2-oxazol-3-yl)ethenyl]- lH- imidazol-2-yl}ethan- l-ol

Compound-79: l-(l-{[4-Methyl-5-(phenylethynyl)-l,2-oxazol-3-yl]methyl}- lH-imidazol-2- yl)ethan- l-ol

Compound-80: 3-{4-[(3-{[2-(2,2-Difluoro-l-hydroxyethyl)- lH-imidazol- l-yl]methyl}-l,2- oxazol-5-yl)ethynyl]phenyl}propan- l-ol

Compound-8i: l-(l-{[5-(Phenylethynyl)- lH-imidazol-2-yl]methyl}- lH-imidazol-2-yl)ethan- l- ol

Compound-82: 2-Hydroxy-2-{l-[(4-{[4-(3-hydroxypropyl)phenyl]ethynyl}phenyl)methyl]-lH- imidazol-2-yl}propanoic acid --formic acid (l/l)

Compound-83: 2-Hydroxy-2-{l-[(5-{[4-(3-hydroxypropyl)phenyl]ethynyl}- l,2-oxazol-3- yl)methyl]- lH-imidazol-2-yl}propanoic acid

Compound-84: 3-(2-{4-[(3-{[2-(l-Hydroxyethyl)- lH"imidazol- l-yl]methyl}- l,2-oxazol-5- yl)ethynyl]phenyl}ethyl)-4-(hydroxymethyl)-l,3-oxazolidin-2-one

Compound-85: 3-(3-{4-[(3-{[2-(l-Hydroxyethyl)- lH-imidazol- l-yl]methyl}-l,2-oxazol-5- yl)ethynyl]phenyl}propyl)-4-(hydroxymethyl)- l,3-oxazolidin-2-one

Compound-86: l-(l-{[5-(Pyridin-2-yl)- l,2-oxazol-3-yl]methyl}-lH-imidazol-2-yl)ethan- l-ol Compound-87: l-(l-{[5-(5-Bromothiophen-2-yl)- l,2-oxazol-3-yl]methyl}- lH-imidazol-2- yl)ethan- l-ol

Compound-88: l-(l-{[5-(2,3-Dihydro- l,4-benzodioxin-6-yl)-l,2-oxazol-3-yl]methyl}- lH- imidazol-2-yl)ethan- l-ol

Compound-89: l-{l-[(5-{[4-(2-Hydroxyethyl)phenyl]ethynyl}- l,2-oxazol-3-yl)methyl]- lH- imidazol-2-yl}ethan- l-ol

Compound-90: l-(l-{[5-({4-[2-(Morpholin-4-yl)ethyl]phenyl}ethynyl)- l,2-oxazol-3-yl]methyl}- lH-imidazol"2-yl)ethan- l-ol Compound-91: l-[l-({5-[4-(l"Aminocyclopropyl)buta-l,3-diyn-l-yl]-l,2-oxazol-3-yl}methyl)- lH-imidazol-2-yl]ethan- l"ol

Compound-92: 7-(3-((2-(l-hydroxyethyl)-lH-imidazol-l-yl)methyl)isoxazol-5-yl)hepta-4,6- diyn-l-ol

Compound-93: l-{5-Methyl-l-[(5-phenyl-l,2-oxazol-3-yl)methyl]-lH-imidazol-2-yl}ethan-l-ol Compound-94: 4-{[3-({2-[(lS)-l-Hydroxyethyl]-lH-imidazol-l-yl}methyl)-l,2-oxazol-5- yl]ethynyl}phenol

Compound-95: (2S)-3-(4-{[3-({2-[(lS)-l-Hydroxyethyl]-lH-imidazol-l-yl}methyl)-l,2-oxazol-5- yl]ethynyl}phenoxy)propane- l,2"diol

Compound-96: (2R)-4-(4'{[3-({2-[(lS)- l-Hydroxyethyl]-lH-imidazol-l-yl}methyl)- l,2-oxazol-5- y 1] e thy nyl}phenoxy)butane - 1 , 2 - diol

Compound-97: (3R)-4-(4-{[3-({2-[(lS)-l-Hydroxyethyl]-lH-imidazol-l-yl}methyl)-l,2-oxazol-5- yl] e thynyl}phenoxy)butane - 1 , 3 - diol

Compound-98: 2-[2-(4-{[3-({2-[(lS)-l-Hydroxyethyl]-lH-imidazol-l-yl}methyl)-l,2-oxazol-5- y 1] ethynyl}phenoxy)ethy l]p rop ane - 1 , 3 - diol

Compound-99: 2-[(4-{[3-({2-[(lS)-l-Hydroxyethyl]-lH-imidazol-l-yl}methyl)-l,2-oxazol-5- y 1] ethyny l}phenoxy) methyl] - 2 - me thy lp rop ane - 1 , 3 -diol

Compound- lOO: (2R)-2-Amino-3-(4-{[3-({2- [(IS)- 1-hydroxyethyl]- lH-imidazol- l-yl}methyl)- l,2-oxazol-5-yl]ethynyl}phenoxy)propan-l-ol

Compound- lOl: (S)-2-((4-(2-(3-((2-(l-hydroxyethyl)-lH-imidazol-l-yl)methyl)isoxazol-5- yl)vinyl)phenoxy)methyl)propane - 1 , 3"diol

Compound- 102: (IS)- l-(l-{[5-({4-[(Piperidin-4-yl)oxy]phenyl}ethynyl)-l,2-oxazol-3-yl]methyl}- lH"imidazol-2-yl)ethan-l-ol

Compound- 103: (lS)-l-(l-{[5-({4-[(l-Methylpiperidin-4-yl)oxy]phenyl}ethynyl)-l,2-oxazol"3- yl]methyl}-lH-imidazol-2-yl)ethan-l-ol

Compound- 104: (IS)- [(5-{[2-(Hydroxymethyl)-2,3-dihydro- lH-inden-5-yl]ethynyl}- 1,2· oxazol-3-yl)methyl]-lH-imidazol-2-yl}ethan-l-ol hydrochloride

Compound- 105: 2-[(4-{[3-({2" KlS) - 1-Hydroxyethyl]- lH-imidazol- l-yl}methyl)- l,2-oxazol-5- yl] ethyny l}p henoxy) me thyl]p ropane - 1 , 3 - diol

Compound-106: (lS)-l-{l-[(5-{[4-(2-{[(3S)-Oxolan-3-yl]amino}ethyl)phenyl]ethynyl}-l,2- oxazol-3-yl)methyl]-lH-imidazol-2-yl}ethan-l-ol

Compound- 107: 4-(4-{[3-({2" KlS)- 1-Hydroxyethyl] -lH-imidazol-l-yl}methyl)-l,2-oxazol-5- yl]ethynyl}phenoxy)butan- l-ol

Compound-108: 2-[(4-{[3-({2-[(lS)-l-Hydroxyethyl]-lH-imidazol-l-yl}methyl)-l,2-oxazol-5- yl]ethynyl}phenyl)methoxy]propane-l,3-diol

Compound- IO9: 3-(4-{[3-({2-[(lS)-l-Hydroxyethyl]-lH-imidazol-l-yl}methyl)-l,2-oxazol-5- yl]ethynyl}phenoxy)propan- l-ol Compound- 110: (lS)-l-[l"({5-[(4-{3-[(Oxetan-3-yl)amino]propoxy}phenyl)ethynyl]-l,2-oxazol- 3-yl}methyl)- lH-imidazol-2-yl]ethan- l-ol

Compound-Ill: (lS)-l"[l-({5-[(4-{3-[(2,2-Difluoroethyl)amino]propoxy}phenyl)ethynyl]-l,2- oxazol-3-yl}methyl)- lH-imidazol-2-yl]ethan- l-ol

Compound-112: (lS)-l-{l-[(5-{[4-(3-{[(3S)-Oxolan-3-yl]amino}propyl)phenyl]ethynyl}-l,2- oxazol-3-yl)methyl]-lH-imidazol-2-yl}ethan-l-ol

Compound- 113: (lS)-l-(l-{[5-({4-[3-(Morpholin-4-yl)propyl]phenyl}ethynyl)-l,2-oxazol-3- yl]methyl}- lH-imidazol-2-yl)ethan- l-ol

Compound- 114: 2-(4-{[3-({2-[(lS)- l-Hydroxyethyl]-lH-imidazol-l-yl}methyl)-l,2-oxazol-5- yl]ethynyl}phenyl)-2-methylpropan-l-ol

Compound- 115: (lS)-l-{l-[(5-{[2-({[(3S)-Oxolan-3-yl]amino}methyl)-2,3-dihydro-lH-inden-5- yl]ethynyl}-l,2-oxazol-3-yl)methyl]-lH-imidazol-2-yl}ethan-l-ol

Compound-116: (lS)-l-[l-({5-[(l,2,3,4-tetrahydroisoquinolin-6-yl)ethynyl]-l,2-oxazol-3- yl}methyl)-lH-imidazol-2-yl]ethan-l-ol

Compound-117: (lS)-l-[l-({5-[(5-ethoxypyridin-2-yl)ethynyl]-l,2-oxazol-3-yl}methyl)-lH- imidazol- 2 -yl] ethan - 1 - ol

Compound-118: (lS)-l-[l-({5-[(2-ethoxypyrimidin-5-yl)ethynyl]-l,2-oxazol-3-yl}methyl)-lH- imidazol- 2 -yl] ethan - 1 - ol

Compound- 119: 2- [(4-{[3-({2- [(IS) - 1-hydroxyethyl]- IH-imidazol- l-yl}methyl) - l,2-oxazol-5- y 1] e thy nyl}p henoxy) methyl] - 2 - (hydroxymethyl)p rop ane - 1 , 3 -diol

Compound- 120: i- [3-(4-{[3-({2- [(IS) - 1-hydroxyethyl]- IH-imidazol- l-yl}methyl)- l,2-oxazol-5- y 1] ethy nyl}p henoxy)p ropyl] azetidin - 3 -ol

Compound- 121: (lS)-l-(l-{[5-({4-[3-(2,2-difluoropyrrolidin-l-yl)propoxy]phenyl}ethynyl)"l,2- oxazol-3-yl]methyl}- lH-imidazol-2-yl)ethan- l-ol

Compound- 122: (lS)-l-{l-[(5-{[2-(2-hydroxyethyl)-l,2,3,4-tetrahydroisoquinolin-6- yl]ethynyl}-l,2-oxazol-3-yl)methyl]-lH-imidazol-2-yl}ethan-l-ol

Compound- 123: (IS)- l-(l-{[5-({4- [3-(pyrrolidin- l-yl)propoxy]phenyl}ethynyl)- l,2-oxazol"3- yl]methyl}-lH-imidazol-2-yl)ethan-l-ol

Compound- 124: 2-[(2-fluoro-4-{[3-({2-[(lS) - 1-hydroxyethyl] - IH-imidazol- l-yl}methyl)- 1,2- oxazol-5-yl]ethynyl}phenoxy)methyl]propane-l,3-diol

Compound-125: 4-{[3-({2-[(lS)-l-hydroxyethyl]-lH-imidazol-l-yl}methyl)-l,2-oxazol-5- yl]ethynyl}benzene- 1-sulfonamide

Compound- 126: 2-[(4-{[3-({2-[(lS)-l-hydroxyethyl]-lH-imidazol-l-yl}methyl)-l,2-oxazol-5- yl] ethy nyl} - 2 - methylp henoxy) methy l]prop ane - 1 , 3- diol

Compound- 127: (lS)-l"(l-{[5-({4-[(2-hydroxyethoxy)methyl]phenyI}ethynyl)-l,2-oxazol-3- yUmethyl}- lH-imidazol-2-yl)ethan- l-ol Compound-128: 4'-{[3-({2-[(lS)-l-hydroxyethyl]- lH-imidazol-l-yl}methyl)-l,2-oxazol-5- y 1] e thynyl} [ 1 , 1 ' -bip henyl]^■ 4- ol

Compound- 129: l-(4-{[3-({2 - [(IS) - 1-hydroxyethyl]- ΙΗ-imidazol· l-yl}methyl)- l,2-oxazol-5- yl] ethynyl}benzene - 1 -sulfonyl)azetidin- 3"ol

Compound-130: (lS)-l-(l-{[5-({4'-[3-(morpholin-4-yl)propoxy][l,r-biphenyl]-4-yl}ethynyl)-l,2- oxazol-3-yl]methyl}-lH-imidazol-2-yl)ethan-l-ol

Compound-131: (S)-3-(3-((3-((2-(l-hydroxyethyl)-lH-imidazol-l-yl)methyl)isoxazol-5- yl)ethynyl)bicyclo[l .1. ljpentan- 1 -yl)propan- 1 -ol

Compound-132: (lS)-l-[l-({5-[(2,3-dihydro-l,4-benzodioxin-6-yl)ethynyl]-l,2-oxazol-3- yl}methyl)-lH-imidazol-2-yl]ethan-l-ol

Compound- 133: l-(4-{[3-({2- [(IS)- 1-hydroxyethyl]- lH-imidazol- l-yl}methyl)- l,2-oxazol-5- yl]ethynyl}phenyl)ethan-l-one

Compound-134: (lS)-l-{l-[(5-{[4-(l-hydroxyethyl)phenyl]ethynyl}-l,2-oxazol-3-yl)methyl]-lH- imidazol-2-yl}ethan-l-ol

Compound- 135: (IS)- l-{l-[(5-{[3-(hydroxymethyl)bicyclo[l.1. l]pentan- l-yl]ethynyl}- 1,2- oxazol"3-yl)methyl]- lH-imidazol-2-yl}ethan- l-ol

Compound-136: (lS)-l-[l-({5-[(4-methylphenyl)ethynyl]-l,2-oxazol-3-yl}methyl)-lH-imidazol- 2-yl]ethan-l-ol hydrochloride

Compound-137: (lS)-l-[l-({5-[(3-fluoro-4-methylphenyl)ethynyl]-l,2-oxazol-3-yl}methyl)-lH- imidazol-2-yl]ethan-l-ol hydrochloride

Compound-138: (lS)-l-{l-[(5-{[4-(trifluoromethyl)phenyl]ethynyl}-l,2-oxazol-3-yl)methyl]- lH-imidazol-2-yl}ethan- l-ol hydrochloride

Compound-139: (lS)-l-{l-[(5-{[4-(piperidin-4-yl)phenyl]ethynyl}-l,2-oxazol-3-yl)methyl]-lH- imidazol-2-yl}ethan-l-ol dihydrochloride

Compound- 140: (IS)- Hi- [(5-{[4-(propan-2-yl)phenyl]ethynyl}- l,2-oxazol-3-yl)methyl]- 1H- imidazol"2-yl}ethan- l-ol hydrochloride

Compound-141: (lS)-l-[l-({5-[(4-tert-butylphenyl)ethynyl]-l,2-oxazol-3-yl}methyl)-lH- imidazol-2-yl]ethan- l-ol hydrochloride

Compound-142: (4-{[3-({2-[(lS)-l-hydroxyethyl]-lH-imidazol-l-yl}methyl)-l,2-oxazol-5- yl]ethynyl}phenyl)(morpholin-4-yl)methanone

Compound-143: (lS)-l-(l-{[5-({4-[4-(2-hydroxyethyl)piperazin-l-yl]phenyl}ethynyl)-l,2- oxazol"3-yl]methyl}-lH-imidazol-2-yl)ethan-l-ol

Compound-144: 2-[(3-Fluoro-4-{[3-({2-[(lS)-l-hydroxyethyl]-lH-imidazol-l-yl}methyl)-l,2- oxazol-5-yl]ethynyl}phenoxy)methyl]propane- 1,3-diol

Compound-145: (lS)-l-[l-({5-[(4-{l-[(oxetan-3-yl)amino]ethyl}phenyl)ethynyl]-l,2-oxazol"3- yl}methyl)-lH-imidazol-2-yl]ethan-l-ol Compound-146: 2-Amino-2-[(4-{[3-({2-[(lS)-l-hydroxyethyl]-lH-imidazol-l-yl}methyl)-l,2- oxazol- 5 -yl] ethy nyl}p henoxy) methyllp ropane^■ 1 , 3- diol

Compound- 147: (lS)- Hi- [(5-{[4-(piperazhr l-yl)phenyl]ethynyl}- l,2-oxazol-3-yl)methyl]- 1H- imidazol- 2 -yllethan- 1 - ol

Compound- 148: Methyl trans-2-((4-((3-((2-((S) - 1-hydroxyethyl)- lH-imidazol- 1- yl)methyl)isoxazol-5-yl)ethynyl)phenoxy)methyl)cyclopropanecarboxylate

Compound- 149: (lS)-l-{l-[(5-{[3-fluoro-4-(2-hydroxyethoxy)phenyl]ethynyl}-l,2-oxazol-3- yl)methyl]-lH-imidazol-2-yl}ethan-l-ol

Compound- 150: (IS)- l-{l-[(5-{[4-(piperidine-l-sulfonyl)phenyl]ethynyl}-l,2-oxazol-3- yl)methyl]-lH-imidazol-2-yl}ethan-l-ol

Compound- 151: (lS)-l-{l-[(5-{[4-(l-aminocyclopropyl)phenyl]ethynyl}-l,2-oxazol-3- yl)methyl]- lH-imidazol-2-yl}ethan- l"ol

Compound-152: 4-{[3-({2-[(lS)-l-hydroxyethyl]-lH-imidazol-l-yl}methyl)-l,2-oxazol-5- yl]ethynyl}benzamide

Compound-153: N-(2-hydroxyethyl)-4-{[3-({2-[(lS)-l-hydroxyethyl]-lH-imidazol-l-yl}methyl)- l,2-oxazol-5-yl]ethynyl}benzamide

Compound- 154: 3-(4-(3-((2-(l-Hydroxyethyl)-lH-imidazol-l-yl)methyl)b enzo [d] isoxazol- 6 - yl)phenyl)propan- l-ol

Compound-155: (lS)-l-(l-{[5-({4-[l-(2-hydroxyethoxy)ethyl]phenyl}ethynyl)-l,2-oxazol-3- yl]methyl}-lH-imidazol-2-yl)ethan-l-ol

Compound- 156: 2-Hydroxy l-(5-{[3-({2- [(IS) - 1-hydroxyethyl]- lH-imidazol- l-yl}methyl)- 1,2- oxazol"5-yl]ethynyl}- l,3-dihydro-2H-isoindol-2-yl)ethan- 1-one

Compound-157: 4-(4-{[3-(l-Hydroxy-2-{2-[(lS)-l-hydroxyethyl]-lH-imidazol-l-yl}ethyl)-l,2- oxazol- 5 -yl] ethy nyl}p he noxy)butan- 1 -ol

Compound-158: 2-[(2,6-Difluoro-4-{[3-({2-[(lS)-l-hydroxyethyl]-lH-imidazol-l-yl}methyl)-l,2- oxazol- 5 -yl] e thy nyl}p he noxy) methyl]p rop ane - 1 , 3- diol

Compound- 159: 5-(4-{[3-({2" [(IS)- 1-hydroxyethyl]- lH-imidazol- l-yl}methyl) - l,2-oxazol-5- yl]ethynyl}phenoxy)pentan- l-ol

Compound- 160: 2-[(4-{[3-(3-Hydroxy-l-{2-[(lS)-l-hydroxyethyl]-lH-imidazol-l-yl}propyl)-l,2- oxazol- 5 -yl] ethy nyl}p he noxy) methyl]p rop ane - 1 , 3 "diol

Compound- 161: l-[(2S)-2-hydroxy-3-(4-{[3-({2-[(lS)-l-hydroxyethyl]-lH-imidazol-l- yl}methyl)-l,2-oxazol-5-yl]ethynyl}phenoxy)propyl]azetidin-3-ol

Compound- 162: (2S)- 1- (4- {[3 - ({2 - [(IS) - 1-hydroxyethyl] - lH-imidazol- l-yl}methyl)- 1,2-oxazol- 5-yl]ethynyl}phenoxy)-3-[(oxetan-3-yl)amino]propan-2-ol

Compound- 163: (2S) - l-amino-3-(4-{[3-({2- KlS) - 1-hydroxyethyl]- lH-imidazol- 1-yOmethyD" 1,2- oxazol- 5 -yl] ethynyl}phenoxy)prop an- 2 - ol Compound- 164: Methyl 5-{[3-({2- [(IS)- 1-hydroxyethyl]- IH-imidazol- l-yl}methyl)- 1,2'oxazol- 5 -yl] ethynyl} -2,3- dihydro- 1H -indene - 2 - carboxylate

Compound- 165: 5-{[3-({2- [(IS)- 1-hydroxyethyl] - IH-imidazol- l-yl}methyl)- l,2-oxazol-5- yl]ethynyl}-2,3-dihydro-lH"indene-2-carboxylic acid--formic acid (l/l)

Compound- 166: (lS)-l-{l-[(5-{[4-(2-methoxyoxolan-2-yl)phenyl]ethynyl}-l,2-oxazol-3- yl)methyl]- lH-imidazol-2-yl}ethan- l-ol

Compound-167: 3-[4-(4-{[3-({2-[(lS)-l-hydroxyethyl]-lH-imidazol-l-yl}methyl)-l,2-oxazol-5- yl]ethynyl}phenyl)piperazin- l-yl]propan- l^_ol

Compound-168: (lS)-l-(l-{[5-({4-[(l-methylazetidin-3-yl)oxy]phenyl}ethynyl)-l,2-oxazol"3- yllmethyl}- lH-imidazol-2-yl)ethan- l-ol

Compound- 169: (lS)-l-{l-[(5-{[4-({5-[(oxetan-3-yl)amino]pentyl}oxy)phenyl]ethynyl}-l,2- oxazol-3-yl)methyl]-lH-imidazol-2-yl}ethan-l-ol

Compound-170: (lS)-l-(l-{[5-({4-[2-(2-hydroxyethoxy)ethoxy]phenyl}ethynyl)-l,2-oxazol-3- yl]methyl}- lH-imidazol-2-yl)ethan- l-ol

Compound-171: (lS)-l-[l-({5-[(2,3-dihydro[l,4]dioxino[2,3-c]pyridin-7-yl)ethynyl]-l,2-oxazol- 3-yl}methyl)-lH-imidazol-2-yl]ethan-l-ol

Compound- 172: (lS)-l-{l-[(5-{[2-(hydroxymethyl)-2,3-dihydro-l,4-benzodioxin-6-yl]ethynyl}- l,2-oxazol-3-yl)methyl]-lH-imidazol-2-yl}ethan-l-ol

Compound- 173: (2R)-2 -amino-3-(4-{[3-({2- [(IS)- 1-hydroxyethyl] - IH-imidazol- l-yl}methyl)- l,2-oxazol-5-yl]ethynyl}phenoxy)propan- l-ol

Compound- 174: 3-(4-{[3-({2- [(IS)- 1-hydroxyethyl]- IH-imidazol- l-yl}methyl)- l,2-oxazol-5- yl]ethynyl}phenoxy)propyl [l-(hydroxymethyl)cyclopropyl]carbamate

Compound- 175: (lS)-l-{l-[(5-{[4-(3-aminopropoxy)phenyl]ethynyl}-l,2-oxazol-3-yl)methyl]- lH-imidazol-2-yl}ethan- l-ol

Compound- 176: l-{l-[(4-{Trans-3-[4-(hydroxymethyl)phenyl]cyclobutyl}phenyl)methyl]-lH- imidazol-2-yl}ethan- l-ol

Compound-177: 4-Hydroxyl-(4-{[3-({2-[(lS)-l-hydroxyethyl]-lH-imidazol-l-yl}methyl)-l,2- oxazol- 5 -yl] ethy ny l}p henyl)butan- 1 - one

Compound-178: (lS)-l-[l-({5-[(3-fluoro-4-{3-[(oxetan-3-yl)amino]propoxy}phenyl)ethynyl]-l,2- oxazol-3-yl}methyl)- lH-imidazol"2-yl]ethan- l-ol

Compound-179: 3-(4-{2-[3-({2-[(lS)-l-hydroxyethyl]-lH-imidazol-l-yl}methyl)-l,2-oxazol"5- yl]ethyl}phenoxy)propan- l-ol

Compound- 180: (lS)-l-{l-[(5-{[5-(2-hydroxyethoxy)pyridin-2-yl]ethynyl}-l,2-oxazol-3- yl)methyl]- lH-imidazol-2-yl}ethan- l-ol

Compound- 181: 2-((4-((3-((R)-3-amino- l-(2-((S) - 1-hydroxyethyl)- IH-imidazol- 1·

yl)propyl)isoxazol-5-yl)ethynyl)phenoxy)methyl)propane-l,3-diol Compound- 182: 2-{[3-(4-{[3-({2- [(IS) - l-hydroxyethyl]- IH-imidazol- 1-yDmethyl) - l,2-oxazol-5- yl] ethy nyl}p henoxy)p ropy 1] amino}prop ane - 1 , 3- diol

Compound-183: l-[4-(4-{[3-({2-[(lS)-l-hydroxyethyl]-lH-imidazol-l-yl}methyl)-l,2-oxazol-5- yl]ethynyl}phenyl)piperazin- l-yl]ethan- 1-one

Compound-184: 3-(4-{[3-(l-{2-[(lS)-l-hydroxyethyl]-lH-imidazol-l-yl}ethyl)-l,2-oxazol-5- yl]ethynyl}phenoxy)propan- l"ol

Compound- 185: 3-(4-{[3-(l-{2- [(IS)- l-hydroxyethyl]- IH-imidazol- l-yl}ethyl)- l,2-oxazol-5- yl]ethynyl}phenoxy)propan- l-ol

Compound- 186: l-(4-{[3-({2- [(IS) - l-hydroxyethyl]- IH-imidazol- l-yl}methyl)- l,2-oxazol-5- yl]ethynyl}phenyl)butane-l,4-diol

Compound- 187: (2R)-2 -amino"4-(4-{[3-({2- [(IS)- l-hydroxyethyl] - IH-imidazol- l-yl}methyl)- 1 , 2 - oxazol- 5 -yl] ethynyllp henoxy)butan^_ 1 - ol

Compound- 188: 2-[4-(4-{[3-({2- [(IS)- l-hydroxyethyl]- IH-imidazol- l-yl}methyl)- l,2-oxazol-5- yl]ethynyl}phenyl)piperazin- l-yl]propane- 1,3-diol

Compound-189: (lS)-l-[l-({5-[(4-{4-[(oxetan-3-yl)amino]butoxy}phenyl)ethynyl]-l,2-oxazol-3- yljmethyl)- lH-imidazol"2-yl]ethan- l-ol

Compound- 190: 2,2'-{[3-(4-{[3-({2- [(IS)- l-hydroxyethyl] -IH-imidazol- l-yl}methyl)- 1,2-oxazol- 5-yl]ethynyl}phenoxy)propyl]azanediyl}di(ethan-l-ol)

Compound- 191: 4"Hydroxy- 1- [4-(4-{[3-({2- [(IS)- l-hydroxyethyl]- IH-imidazol- l-yl}methyl)- l,2-oxazol-5-yl]ethynyl}phenyl)piperazin-l-yl]butan-l-one

Compound-192: 6"{[3-({2-[(lS)-l-hydroxyethyl]-lH-imidazol-l-yl}methyl)-l,2-oxazol-5- yl]ethynyl}-3-(3-hydroxypropoxy)pyridin-2-ol

Compound-193: 3-(4-{[3-({2-[(lS)-l-hydroxyethyl]-lH-imidazol-l-yl}methyl)-l,2-oxazol-5- yl]ethynyl}phenoxy)propyl 4-(methanesulfonyl)piperazine-l-carboxylate

Compound- 194: 3-(4-{[3-({2-[(lS)-l-hydroxyethyl]-lH-imidazol-l-yl}methyl)-l,2-oxazol-5- yl]ethynyl}phenoxy)propyl 4-methylpiperazine- 1-carboxylate

Compound- 195: (IS)- l-(l-{[5-({4- [3-(4-methylpiperazin- l-yl)propoxy]phenyl}ethynyl)- 1,2- oxazol"3-yl]methyl}- lH-imidazol-2-yl)ethan- l-ol

Compound-196: (lS)-l-[l-({5-[(4-{3-[(2-hydroxyethyl)(oxetan-3- yl)amino]propoxy}pheny0ethynyl]-l,2-oxazol-3-yl}methyl)-lH-imidazol-2-yl]ethan-l-ol

Compound-197: (lS)-l-[l-({5-[(4-{[l-(2-hydroxyethyl)azetidin-3-yl]oxy}phenyl)ethynyl]-l,2- oxazol"3-yl}methyl)- lH-imidazol-2-yl]ethan- l-ol

Compound- 198: (lS)-l-(l-{[5-({4-[2-(2-aminoethoxy)ethoxy]phenyl}ethynyl)-l,2-oxazol-3- yl]methyl}- lH-imidazol-2-yl)ethan- l-ol

Compound- 199: (lS)-l-{l-[(5-{[4-(azetidin-3-yl)phenyl]ethynyl}-l,2-oxazol-3-yl)methyl]-lH- imidazol"2-yl}ethan- l-ol Compound-200: (lS)-l-{l-[(5-{[4-(2-{2-[(oxetan-3-yDamino]ethoxy}ethoxy)phenyl]ethynyl}- l,2-oxazol-3-yl)methyl]- lH-imidazol-2-yl}ethan- l"ol

Compound-201: (lS)-l-[l-({5-[(4-{3-[ethyl(2-hydroxyethyl)amino]propoxy}phenyl)ethynyl]- l,2-oxazol^_3-yl}methyl)-lH-imidazol'2-yl]ethan-l-ol

Compound-202: 2-{[3-(4-{[3-({2-[(lS)-l-hydroxyethyl]-lH-imidazol-l-yl}methyl)-l,2-oxazol-5- yl] ethyny l}p henoxy)p ropyl] aminolp rop an- 1 -ol

Compound-203: l-{[3-(4-{[3-({2-[(lS)-l-hydroxyethyl]-lH-imidazol-l-yl}methyl)-l,2-oxazol-5- yl] ethyny l}p henoxy)p ropyl] amino}p rop an- 2 -ol

Compound-204: (lS)-l-(l-{[5-({4-[l-(2-hydroxyethyl)piperidin-4-yl]phenyl}ethynyl)-l,2- oxazol-3-yl]methyl}-lH-imidazol-2-yl)ethan-l-ol

Compound-205: (lS)-l-(l-{[5-({4-[3-(2-hydroxyethoxy)propoxy]phenyl}ethynyl)-l,2-oxazol-3- yl]methyl}-lH-imidazol-2-yl)ethan-l-ol

Compound-206: 3-(4-{[3-({2-[(lS)-l-hydroxyethyl]-lH-imidazol-l-yl}methyl)-l,2-oxazol-5- yl]ethynyl}phenoxy)propyl 3-hydroxyazetidine- 1-carboxylate

Compound-207: (lS)-l-[l-({5-[(4-{3-[(2-aminoethyl)amino]propoxy}phenyl)ethynyl]-l,2- oxazol-3-yl}methyl)- lH-imidazol-2-yl]ethan- l"ol

Compound-208: N²-[3-(4-{[3-({2-[(lS)-l-hydroxyethyl]-lH-imidazol-l-yl}methyl)-l,2-oxazol-5- yl] ethyny l}p henoxy)p ropyl] glycinamide

Compound-209: 4-[4-(4-{[3-({2-[(lS)-l-hydroxyethyl]-lH-imidazol-l-yl}methyl)-l,2-oxazol-5- yl]ethynyl}phenyl)piperazin-l-yl]butan-l-ol

Compound-210: N-(3-{2-[(lS)-l-hydroxyethyl]-lH-imidazol-l-yl}-3-[5-({4-[3-hydroxy-2- (hydroxymethyl)propoxy]phenyl}ethynyl)-l,2-oxazol-3-yl]propyl)methanesulfonamide Compound-211: 2-{[4-({3-[(lS)-3-hydroxy-l-{2-[(lS)-l-hydroxyethyl]-lH-imidazol-l- yl}propyl]-l,2-oxazol-5-yl}ethynyl)phenoxy]methyl}propane-l,3-diol

Compound-212: (lS)-l-(l-{[5-({4-[3-(ethylamino)propoxy]phenyl}ethynyl)-l,2-oxazol-3- yl]methyl}- lH-imidazol-2-yl)ethan- l-ol

Compound-213: (lS)-l-[l-({5-[(4-{3-[(2-hydroxyethyl)amino]propoxy}phenyl)ethynyl]-l,2- oxazol-3-yl}methyl)-lH-imidazol-2-yl]ethan-l-ol

Compound-214: (lS)-l-(l-{[5-({4-[(l-methylpiperidin-4-yl)methoxy]phenyl}ethynyl)-l,2- oxazol-3-yl]methyl}-lH"imidazol-2-yl)ethan-l-ol

Compound-215: (lS)-l-{l-[(5-{[4-(4-methylpiperazin-l-yl)phenyl]ethynyl}-l,2-oxazol-3- y methyl]- lH-imidazol-2-yl}ethan- l-ol

Compound-216: (lS)-l-(l-{[5-({4-[3-(2-aminoethoxy)propoxy]phenyl}ethynyl)-l,2-oxazol-3- yl]methyl}-lH-imidazol^_2-yl)ethan-l"ol

Compound-217: (2R)-2^■amino-3-[3-(4-{[3-({2-[(lS)-l-hydroxyethyl]-lH-imidazol-l-yl}methyl)- l,2-oxazol-5-yl]ethynyl}phenoxy)propoxy]propan-l-ol Compound-218: (lS)-l-{l-[(5-{[4-(3-aminobutoxy)phenyl]ethynyl}-l,2-oxazol-3-yl)methyl]-lH- imidazol-2-yl}ethan- l"ol

Compound-219: (lS)-l-{l-[(5-{[4-(3-aminopropoxy)-2-fluorophenyl]ethynyl}-l,2-oxazol-3- yl)methyl]-lH"imidazol-2-yl}ethan-l-ol

Compound-220: 2-[(4-{[3-({2-[(lS)-l-hydroxyethyl]-lH-imidazol-l-yl}methyl)- l,2-oxazol-5- yl]ethynyl}phenoxy)methyl]-3-[(oxetan-3-yl)amino]propan-l-ol

Compound-221: (S,Z)-l-(l-((5-(2-(3-(hydroxymethyl)bicyclo[l.l.l]pentan-l-yl)vinyl)isoxazol- 3-yl)methyl)-lH-imidazol-2-yl)ethanol

Compound-222: N-(3-{2-[(lS)-l-hydroxyethyl]-lH-imidazol-l-yl}-3-[5-({4-[3-hydroxy-2- (hydroxymethyl)propoxy]phenyl}ethynyl)-l,2-oxazol-3-yl]piOpyl)acetamide

Compound-223: (lS)-l-(l-{[5-({4-[(azetidin-3-yl)oxy]phenyl}ethynyl)-l,2-oxazol-3-yl]methyl}- lH-imidazol-2-yl)ethan- l-ol

Compound-224: (lS)-l-(l-{3-[5-(4-bromophenyl)-l,2-oxazol-3-yl]propyl}-lH-imidazol-2- yl)ethan-l-ol

Compound-225: (lS)-l-[l-({5-[(4-{3-[(3-aminopropyl)amino]propoxy}phenyl)ethynyl]-l,2- oxazol-3-yl}methyl)-lH-imidazol-2-yl]ethan-l-ol

Compound-226: (lS)-l-{l-[(5-{[4-({5-[(2-aminoethyl)amino]pentyl}oxy)phenyl]ethynyl}-l,2- oxazol-3-yl)methyl]-lH-imidazol-2-yl}ethan- l-ol

Compound-227: (lS)-l-(l-{[5-({4-[3-(piperazin-l-yl)propoxy]phenyl}ethynyl)-l,2-oxazol-3- yl]methyl}-lH-imidazol-2-yl)ethan-l-ol

Compound-228: (lS)-l-[l-({5-[(4-{[(3S)-l-methylpyrrolidin-3-yl]oxy}phenyl)ethynyl]-l,2- oxazol-3-yl}methyl)- lH-imidazol-2-yl]ethan- l-ol

Compound-229: (lS)-l-[l-({5-[(4-{[(3S,5S)-5-(hydroxymethyl)-l-methylpyrrolidin-3- yl]oxy}phenyl)ethynyl]-l,2-oxazol-3-yl}methyl)-lH-imidazol-2-yl]ethan-l-ol

Compound-230: (lS)-l-[l-({5-[(4-{[(3S)-l-(2-hydroxyethyl)pyrrolidin-3-yl]oxy}phenyl)ethynyl]- l,2-oxazol-3-yl}methyl)- lH-imidazol-2-yl]ethan- l-ol

Compound-231: 3-[3-(4-{[3-({2-[(lS)-l-hydroxyethyl]-lH-imidazol-l-yl}methyl)-l,2-oxazol-5- yl]ethynyl}phenoxy)azetidin- l-yl]propan- l-ol

Compound-232: (lS)-l-(l-{2-[([l, r-biphenyl]-4-yl)oxy]ethyl}-lH-imidazol-2-yl)ethan-l-ol Compound-233: N2-[3-(4-{[3-({2-[(lS)-l-hydroxyethyl]-lH-imidazol-l-yl}methyl)-l,2-oxazol-5- yl]ethynyl}phenoxy)propyl]-L-serinamide

Compound-234: (lS)-l-[l-({5-[(4-{3-[(azetidin-3-yl)amino]propoxy}phenyl)ethynyl]-l,2-oxazol- 3-yl}methyl) - lH-imidazol" 2 -yl]ethan- 1 -ol

Compound-235: (lS)-l-[l-({5-[(4-{[l-(2-hydroxyethyl)azetidin-3-yl]methoxy}phenyl)ethynyl]- l,2-oxazol-3-yl}methyl)- lH-imidazol-2-yl]ethan- l-ol

Compound-236: 2-{[3-(4-{[3-({2-[(lS)-l-hydroxyethyl]-lH-imidazol-l-yl}methyl)-l,2-oxazol-5- yl] e thy nyl}p henoxy)p ropy 1] amino}ethane - 1 - sulfonamide Compound-237: 3-(4-{[3-({2-[(lS)-l-aminoethyl]-lH-imidazol-l-yl}methyl)-l,2-oxazol-5- yl]ethynyl}phenoxy)propan- l-ol dihydrochloride

Compound-238: (lS)-l-[l-({5-[(4-{3-[(2-aminoethyl)(ethyl)amino]propoxy}phenyl)ethynyl]-l,2- oxazol-3-yl}methyl)- lH-imidazol-2-yl]ethan- l-ol

Compound-239: 3-{[3-(4-{[3-({2-[(lS)-l-hydroxyethyl]-lH-imidazol-l-yl}methyl)-l,2-oxazol-5- yl] ethynyllp henoxy)p ropyl] amino}^■ L- alanine

Compound-240: (lS)-l-{l-[(5-{[4-({5-[(3-aminopropyl)amino]pentyl}oxy)phenyl]ethynyl}-l,2- oxazol-3-yl)methyl]-lH-imidazol-2-yl}ethan-l-ol

Compound-241: (lS)-l-(l-{[5-({4"[4-(2-aminoethyl)piperazin-l-yl]phenyl}ethynyl)-l,2-oxazol- 3-yUmethyl}- lH-imidazol-2-yDethan- l ol

Compound-242: 3-Amino-N2-[3-(4-{[3-({2-[(lS)-l-hydroxyethyl]-lH-imidazol-l-yl}methyl)- l,2-oxazol-5-yl]ethynyl}phenoxy)propyl]-L-alaninamide trihydrochloride

Compound-243: 3-[3-(4-{[3-({2-[(lS)-l-hydroxyethyl]-lH-imidazol-l-yl}methyl)-l,2-oxazol-5- yl]ethynyl}phenoxy)azetidin- l-yl]propane- 1,2-diol

Compound-244: (lS)-l-{l-[(5-{[2-(hydroxymethyl)-2,3-dihydro-l,4-benzodioxin-6-yl]ethynyl}- l,2-oxazol-3-yl)methyl]- lH-imidazol-2-yl}ethan- l-ol

Compound-245: 5-({6-[3-({2-[(lS)-l-hydroxyethyl]-lH-imidazol-l-yl}methyl)-l,2-oxazol-5- yl]naphthalen-2-yl}oxy)pentan-l-ol

Compound-246: (lS)-l"(l-{[5-({4-[trans-2-(hydroxymethyl)cyclopropyl]phenyl}ethynyl)-l,2- oxazol-3-yl]methyl}- lH-imidazol-2-yl)ethan- l-ol

Compound-247: (lS)-l-(l-{[5-({4-[(2-azaspiro[3.3]heptan-6-yl)oxy]phenyl}ethynyl)-l,2-oxazol- 3 -yl] methyl} - 1H - imidazol- 2 -yl)ethan- 1 - ol

Compound-248: (2R)-3-[4-(4-{[3-({2-[(lS)-l-hydroxyethyl]-lH-imidazol-l-yl}methyl)-l,2- oxazol-5-yl]ethynyl}phenoxy)piperidin- l-yl]propane- 1,2-diol

Compound-249: (2S)-3-[4-(4-{[3-({2-[(lS)-l-hydroxyethyl]-lH-imidazol-l-yl}methyl)-l,2- oxazol-5-yl]ethynyl}phenoxy)piperidin- l-yl]propane- 1,2-diol

Compound-250: 3-Amino-N-[3-(4-{[3-({2-[(lS)-l-hydroxyethyl]-lH-imidazol-l-yl}methyl)-l₎2- oxazol-5-yl]ethynyl}phenoxy)propyl]-L-alanine

Compound-251: 2-Amino-2-({[5-(4-{[3-({2-[(lS)-l-hydroxyethyl]-lH-imidazol-l-yl}methyl)-l,2- oxazol-5-yl]ethynyl}phenoxy)pentyl]amino}methyl)propane-l,3-diol

Compound-252: 3-(4-{[6-({2-[(lS)-l-hydroxyethyl]-lH-imidazol-l-yl}methyl)pyridin-3- yl]ethynyl}phenoxy)propan- l-ol

Compound-253: 3-(4-{[2-({2-[(lS)-l-hydroxyethyl]-lH-imidazol-l-yl}methyl)-l,3-thiazol-5- yl]ethynyl}phenoxy)propan- l-ol

Compound-254: 2-{[3-(4-{[3-({2-[(lS)-l-hydroxyethyl]- lH-imidazol-l-yl}methyl)-l,2-oxazol-5- yl]ethynyl}phenoxy)azetidin- l-yl]methyl}propane- 1,3-diol Compound-255: 2 (4-{[3-({2-[(lR) -hydroxyethyl] H-imidazol-l-yl}metliyl)-l,2-oxazol-5- yl]ethynyl}phenoxy)methyl]propane-l,3-diol

Compound-256: 3-{3-[4-({3-[(lS)-2-hydroxy-l-{2-[(lS)-l-hydroxyethyl]-lH-imidazol-l- yl}ethyl]-l,2-oxazol-5-yl}ethynyl)phenoxy]azetidin-l-yl}propan-l-ol

Compound-257: (lS)-l-(l-{[5-({4-[trans-2-(aminomethyl)cyclopropyl]phenyl}ethynyl)-l,2- oxazol- 3 -yl] methyl}- lH-imidazol-2-yl)ethan- l-ol

Compound-258: (2R)-3-[3-(4-{[3-({2-[(lS)-l-hydroxyethyl]-lH-imidazol-l-yl}methyl)-l,2- oxazol-5-yl]ethynyl}phenoxy)azetidin- l-yl]propane- 1,2-diol

Compound-259: (2S)-3-[3-(4-{[3-({2-[(lS)-l-hydroxyethyl]-lH-imidazol-l-yl}methyl)-l,2- oxazol-5-yl]ethynyl}phenoxy)azetidin- l-yl]propane- l,2"diol

Compound-260: (lS)-l-(l-{[5-([l,r-biphenyl]-4-yl)-l,2-oxazol-3-yl]methyl}-lH-imidazol-2- yl)ethan-l-ol

Compound-26l: 2-Amino-2-[3-(4-{[3-({2-[(lS)-l-hydroxyethyl]-lH-imidazol-l-yl}methyl)-l,2- oxazol-5-yl]ethynyl}phenoxy)propyl]propane- 1,3-diol

Compound-262: (lS)-l-{l-[(5-{[4-(hydroxymethyl)phenyl]ethynyl}-l,2-oxazol-3-yl)methyl]-lH- imidazol- 2 -yllethan- 1 - ol

Compound-263: 2-Amino-2-{[4-(4-{[3-({2-[(lS)-l-hydroxyethyl]-lH-imidazol-l-yl}methyl)-l,2- oxazol-5-yl]ethynyl}phenyl)piperazin-l-yl]methyl}propane-l,3-diol

Compound-264: (3R)-4-[3-(4-{[3-({2-[(lS)-l-hydroxyethyl]-lH-imidazol-l-yl}methyl)-l,2- oxazol-5-yl]ethynyl}phenoxy)azetidin-l-yl]butane-l,3-diol

Compound-265: (lS)-l-[l-({5-[(4-{[l-(2-hydroxyethyl)piperidin-4-yl]oxy}phenyl)ethynyl]-l,2- oxazol- 3-yl}methyl) - lH-imidazol-2 -yl]ethan- l-ol

Compound-266: 2-{[4-(4-{[3-({2-[(lS)-l-hydroxyethyl]-lH-imidazol-l-yl}methyl)-l,2-oxazol-5- yl]ethynyl}phenoxy)piperidin- l-yl]methyl}propane- 1,3-diol

Compound-267: (2S)-l-[(2-aminoethyl)amino]-3-(4-{[3-({2-[(lS)-l-hydroxyethyl]-lH-imidazol- l-yl}methyl)- l,2-oxazol-5-yl]ethynyl}phenoxy)propan-2-ol

Compound-268: 2-{[(2S)-2-hydroxy-3-(4-{[3-({2-[(lS)-l-hydroxyethyl]-lH-imidazol-l- yllmethyl) - 1 , 2 -oxazol- 5 -yl] ethyny l}p henoxy)p ropy 1] amino} - 2 - (hydroxymethyl)prop ane -1,3- diol

Compound-269: 3-{3-[4-({3-[(lR)-2-amino-l-{2-[(lS)-l-hydroxyethyl]-lH-imidazol-l-yl}ethyl]- l,2-oxazol-5-yl}ethynyl)phenoxy]azetidin- l-yl}propan- l-ol

Compound-270: 2-[3-(4-{[3-({2-[(lS)-l-hydroxyethyl]-lH-imidazol-l-yl}methyl)-l,2-oxazol-5- yl]ethynyl}phenoxy)azetidin-l-yl]propane- 1,3-diol

Compound-271: (lS)-l-(l-{[5-(4-cyclohexylphenyl)-l,2-oxazol-3-yl]methyl}-lH-imidazol-2- yl)ethan-l-ol

Compound-272: (lS)-l-{l-[(5-{4'-[(azetidin-3-yl)oxy][l,r-biphenyl]-4-yl}-l,2-oxazol-3- yl)methyl]-lH-imidazol-2-yl}ethan-l-ol Compound-273: (lS)-l-[l-({5-[4-(piperidin-4-yl)phenyl]-l,2-oxazol-3-yl}methyl)-lH-imidazol-

2- yl]ethan-l-ol

Compound-274: (2R)-3-(4-{4-[3-({2-[(lS)-l-hydroxyethyl]-lH-imidazol-l-yl}methyl)-l,2- oxazol-5-yl]phenyl}piperidin- l-yl)propane- 1,2-diol

Compound-275: l-(4-{4-[3-({2-[(lS)-l-hydroxyethyl]-lH-imidazol-l-yl}methyl)-l,2-oxazol-5- yl]phenyl}piperidin-l-yl)-3-methoxypropan-2-ol

Compound-276: (2S)-2-hydroxy-l-(4-{4-[3-({2-[(lS)-l-hydroxyethyl]-lH-imidazol-l- yl}methyl)-l,2-oxazol-5-yl]phenyl}piperidin-l-yl)propan-l-one

Compound-277: (lS)-l-[l-({5-[(4-{[(3S,5S)-5-(hydroxymethyl)pyrrolidin-3- yl]oxy}phenyl)ethynyl]-l,2'Oxazol-3'yl}methyl)-lH-imidazol-2-yl]ethan-l-ol

Compound-278: 3-[3-({4'-[3-({2-[(lS)-l-hydroxyethyl]-lH-imidazol-l-yl}methyl)-l,2-oxazol-5- yl][l,l'-biphenyl]-4-yl}oxy)azetidin-l-yl]propane- 1,2-diol

Compound-279: (lS)-l-[l-({5-[(4-{[2-(2-hydroxyethyl)-2-azaspiro[3.3]heptan-6- yl]oxy}phenyl)ethynyl]-l,2-oxazol-3-yl}methyl)-lH-imidazol"2-yl]ethan-l-ol

Compound-280: 3-(4-{[3-({2-[(lS)-l-hydroxyethyl]-lH-imidazoM-yl}methyl)-l,2-oxazol-5- yl]ethynyl}phenyl)azetidin-3-ol

Compound-281: (lS)-l-(l-{[5"({4-[(azetidin-3-yl)(hydroxy)methyl]phenyl}ethynyl)-l,2-oxazol-

3- yl]methyl}-lH-imidazol-2-yl)ethan-l-ol

Compound-282: (lS)-l-(l-{(lR)"2-amino-l-[5-({4-[trans-2- (hydroxymethyl)cyclopropyl]phenyl}ethynyl)-l,2-oxazol-3-yl]ethyl}-lH-imidazol-2-yl)ethan-l- ol

Compound-283: (lS)"l-{l-[(5-{[4-(trans-2-{[(2- hydroxyethyl)amino]methyl}cyclopropyl)phenyl]ethynyl}-l,2-oxazol-3-yl)methyl]-lH- imidazol-2-yl}ethan- l"ol

Compound-284: (3S,5S)-5-[(4-{[3-({2-[(lS)-l-hydroxyethyl]-lH-imidazol-l-yl}methyl)-l,2- oxazol-5-yl]ethynyl}phenoxy)methyl]pyrrolidin-3-ol

Compound-285: (lS)-l-(l-{[5-({4-[(azetidin-3-yl)methyl]phenyl}ethynyl)-l,2-oxazol-3- yl]methyl}- lH-imidazol-2-yl)ethan- l-ol

Compound-286: 2-[(4-{[3-(4-Hydroxy-l-{2-[(lS)-l-hydroxyethyl]-lH-imidazol-l-yl}butyl)-l,2- oxazol-5-yl]ethynyl}phenoxy)methyl]propane-l,3-diol

Compound-287: (S)-3-(4-((2-((2-(l-hydroxyethyl)- lH-imidazol- l-yl)methyl)oxazol-5- yl)ethynyl)phenoxy)propan- l-ol

Compound-288: 3-({[trans-2-(4-{[3-({2-[(lS)-l-hydroxyethyl]-lH-imidazol-l-yl}methyl)-l,2- oxazol- 5 -yl] ethy ny l}p heny cyclop ropyl] methyl}amino)prop ane - 1 , 2 - diol

Compound-289: (lS)-l-[l-({5-[(4-{[(3R)-l-(2-hydroxyethyl)pyrrolidin-3- yl]oxy}phenyl)ethynyl]- l,2-oxazol-3-yl}methyl)- lH-imidazol-2-yl]ethan- l-ol Compound-290: (lS)-l-(l-{[5-({4-[(3-methylazetidin-3-yl)oxy]phenyl}ethynyl)-l,2-oxazol-3- yl]methyl}-lH-imidazol-2-yl)ethan-l-ol

Compound-291: (lS)-l-(l-{[5-({4-[(trans-2-aminocyclopropyl)methoxy]phenyl}ethynyl)"l,2- oxazol- 3 -yl] methyl}- lH-imidazol-2-yl)ethan- l-ol

Compound-292: (lS)-l-(l-{[5-({4-[(azetidin-3-yl)(difluoro)methyl]phenyl}ethynyl)-l,2-oxazol- 3-yl]methyl}-lH-imidazol-2-yl)ethan-l-ol

Compound-293: 3-{3-[4-({3-[(lR)-2-amino-l-{2-[(lS)-l"hydroxyethyl]-lH-imidazol-l- yljpropyl]- l,2-oxazol-5-yl}ethynyl)phenoxy]azetidin- l-yl}propan- l-ol

Compound-294: 2-Amino-2-((4-((3-(2^■amino- l-(2-((S)- 1-hydroxyethyl)- lH-imidazol- 1- yl)ethyl)isoxazol- -yl)ethynyl)phenoxy)methyl)propane- l,3-diol

Compound-295: (lS)-l-{l-[(5-{[4-(trans-2-aminocyclopropyl)phenyl]ethynyl}-l,2-oxazol-3- yl)methyl]-lH-imidazol-2-yl}ethan-l-ol

Compound-296: (lS)-l-(l-{[5-({4-[3-(hydroxymethyl)cyclobutyl]phenyl}ethynyl)-l,2-oxazol-3- yl] methyl} - lH-imidazol-2-yl)ethan- l-ol

Compound-297: (lS)-l-{l-[(5-{[6-(cyclohexyloxy)pyridazin-3-yl]ethynyl}-l,2-oxazol-3- yl)methyl] - lH-imidazol-2-yl}ethan- l-ol

Compound-298: N-(4-{2-[(lS)-l-hydroxyethyl]-lH-imidazol-l-yl}-4-[5-({4-[3-hydroxy-2- (hydroxymethyl)propoxy]phenyl}ethynyl)- l,2-oxazol-3-yl]butyl)methanesulfonamide

Compound-299: 3-{3-[4-({3-[(lR,2S)-2-amino-l-{2-[(lS)-l-hydroxyethyl]-lH-imidazol-l- yl}propyl]- l,2-oxazol-5-yl}ethynyl)phenoxy]azetidin- l-yl}propan- l-ol

Compound-300: 2-[(4-{[3-(4-amino-l-{2-[(lS)-l-hydroxyethyl]-lH-imidazol-l-yl}butyl)-l,2- oxazol-5-yl]ethynyl}phenoxy)methyl]propane-l,3-diol

Compound-301: (lS)-l-[l-({5-[(4-{trans-2-[(l,4-oxazepan-4- yl)methyl]cyclopropyl}phenyl)ethynyl]-l,2-oxazol-3-yl}methyl)-lH-imidazol-2-yl]ethan-l-ol Compound-302: (lS)-l-[l-({5-[(4-{trans"2-

[(cyclopropylamino)methyl]cyclopropyl}phenyl)ethynyl]-l,2-oxazol-3-yl}methyl)-lH-imidazol- 2-yl]ethan-l-ol

Compound-303: (2S)-2-[5-({4-[(trans-2-aminocyclopropyl)methoxy]phenyl}ethynyl)-l,2- oxazol-3-yl]-2-{2- [(IS)- 1-hydroxyethyl]- lH-imidazol- l-yl}ethan- l-ol

Compound-304: (lS)-l-(l-{[5-({4-[trans-2-({[(3S)-oxolan-3- yl]amino}methyl)cyclopropyl]phenyl}ethynyl)-l,2-oxazol-3-yl]methyl}-lH-imidazol-2- yl)ethan-l-ol

Compound-305: (lS)-l-(l-{[5-({4-[l-(hydroxymethyl)cyclopropyl]phenyl}ethynyl)-l,2-oxazol-3- yljmethyl}- lH-imidazol-2-yl)ethan- l-ol

Compound-306: 3-{3-[4-({3-[(lR)-l-{2-[(lS)-l-hydroxyethyl]- lH-imidazol-l-yl}-2- methylpropyl]-l,2-oxazol-5-yl}ethynyl)phenoxy]azetidin-l-yl}propan-l-ol Compound-307: 4-({3 (lR)-2-amino -{2-[(lS)-l-hydroxyethyl] H-imidazol-l-yl}ethyl]-l,2- oxazol-5-yl}ethynyl)phenol

Compound-308: (lS)-l-[l-({5-[3-(4-bromophenyl)cyclobutyl]-l,2-oxazol-3-yl}methyl)-lH- imidazol-2-yl]ethan- l"ol

Compound-309: (lS)-l-[l-({5-[(4-{[trans-2-(hydroxymethyl)cyclopropyl]oxy}phenyl)ethynyl]- l,2-oxazol-3-yl}methyl)-lH-imidazol-2-yl]ethan-l-ol

Compound-310: (lS)-l-(l-{[5-({4-[(l-aminocyclopropyl)methoxy]phenyl}ethynyl)-l,2-oxazol-3- yl]methyl}- lH-imidazol-2-yl)ethan- l-ol

Compound-311: (lS)-l-[l-({5-[(4-{[cis-2-(hydroxymethyl)cyclopropyl]oxy}phenyl)ethynyl]-l,2- oxazol-3-yl}methyl)-lH-imidazol-2-yl]ethan-l-ol

Compound-312: (lS)"l-(l-{[5-({4-[trans-2-(2-hydroxyethyl)cyclopropyl]phenyl}ethynyl)-l,2- oxazol-3-yl] methyl}- lH-imidazol-2-yl)ethan- l-ol

Compound-313: (lS)-l-{l-[(5-{[4-(trans-2-{2-[(2- aminoethyl)amino]ethyl}cyclopropyl)phenyl]ethynyl}-l,2-oxazol-3-yl)methyl]-lH-imidazol-2- yl}ethan-l-ol

Compound-314: (lS)-l-[l-({5-[(4-{[(lS,5S)-3-azabicyclo[3.1.0]hexan-l- yl]methoxy}phenyl)ethynyl]- l,2-oxazol-3-yl}methyl)- lH-imidazol"2-yl]ethan- l-ol

Compound-315: (lS)-l-(l-{[5-({4-[(trans-2-aminocyclopropyl)oxy]phenyl}ethynyl)-l,2-oxazol- 3-yl]methyl}- lH-imidazol-2-yl)ethan- l-ol

Compound-316: (lS)-l-[l-({5-[(4-{[(lR,5S,6r)-3-azabicyclo[3.1.0]hexan-6- yl]methoxy}phenyl)ethynyl]-l,2-oxazol-3-yl}methyl)-lH-imidazol-2-yl]ethan-l-ol

Compound-317: 3-(4-{[5-({2-[(lS)-l-hydroxyethyl]-lH-imidazol-l-yl}methyl)furan-3- yl]ethynyl}phenoxy)propan- l-ol

Compound-318: (lS)-l-[l-({5-[(4-{[l-(2"hydroxyethyl)azetidin-2-yl]methoxy}phenyl)ethynyl]- l,2-oxazol-3-yl}methyl)-lH-imidazol-2-yl]ethan-l-ol

Compound-319: Ethyl trans-2-(4-{[3-({2-[(lS)-l-hydroxyethyl]-lH-imidazol-l-yl}methyl)-l,2- oxazol- 5 -yl] ethynyl}p henyl)cycloprop ane - 1 - carboxylate

Compound-320: 2-(4-{[3-({2-[(lS)-l-hydroxyethyl]-lH-imidazol-l-yl}methyl)-l,2-oxazol-5- yl]ethynyl}phenyl)cyclopropane- 1-carboxylic acid

Compound-321: (lS)-l-(l-{(lR)-2-amino-l-[5-({4-[(2- aminocyclopropyl)methoxy]phenyl}ethynyl)-l,2-oxazol-3-yl]ethyl}-lH-imidazol-2-yl)ethan-l- ol

Compound-322: (lS)-l-[l-({5-[(4-{[trans-2-(aminomethyl)cyclopropyl]oxy}phenyl)ethynyl]-l,2- oxazol- 3 -yl}methyl) - lH-imidazol"2-yl]ethan- l-ol

Compound-323: N-(2-aminoethyl)-trans-2-(4-{[3-({2-[(lS)-l-hydroxyethyl]-lH-imidazol-l- yl}methyl)-l,2-oxazol-5-yl]ethynyl}phenyl)cyclopropane-l-carboxamide Compound-324: rans-2-(4-{[3-({2-[(lS)- l-hydroxyethyl]- lH-imidazol- l-yl}methyl)- l,2-oxazol- 5-yl]ethynyl}phenyl)cyclopropane- 1-carboxamide

Compound-325: (lS)- l-(l-{[5-({4-[(trans-2-{[(2- aminoethyl)amino]methyl}cyclopropyl)oxy]phenyl}ethynyl)- l,2-oxazol-3-yl]methyl}-lH- imidazol-2-yl)ethan-l-ol

Compound-326: 3-{3-[4-({3-[(lR)- l-{2-[(lS)- l-hydroxyethyl]- lH-imidazol- l-yl}propyl]-l,2- oxazol-5-yl}ethynyl)phenoxy]azetidin- l-yl}propan- l-ol

Compound -32 T- (lS)" l-(l-{[5-({4-[(cis-2-aminocyclopropyl)oxy]phenyl}ethynyl)- l,2-oxazol-3- yl]methyl}- lH-imidazol-2-yl)ethan- l-ol

Compound-328: (lS)- l-{l-[(5-{[4-({l-[(2- aminoethyl)amino]cyclopropyl}methoxy)phenyl]ethynyl}- l,2-oxazol-3-yl)methyl]-lH- imidazol-2-yl}ethan- l-ol

Compound-329: 3-{3-[4-({3-[(lS,2S)-2-hydroxy- l-{2-[(lS)- l-hydroxyethyl]- lH-imidazol-l- yl}propyl]- l,2-oxazol-5-yl}ethynyl)phenoxy]azetidin- l-yl}propan- l-ol

Compound-330: (lS)- l-{l-[(lR)-2-amino-l-{5-[(4-{[(lS,2S)-2- aminocyclopropyl]methoxy}phenyl)ethynyl]- l,2-oxazol-3-yl}ethyl]- lH-imidazol-2-yl}ethan- l- ol

Compound-331: (lS)- l-[l-({5-[(4-{[trans-2-

(aminomethyl)cyclopropyl]methoxy}phenyl)ethynyl] - l,2-oxazol-3-yl}methyl)" lH-imidazol-2- yl]ethan- l-ol

Compound-332: (lS)- l-{l-[(lR)-2-amino-l-{5-[(4-{[(lR,2R)-2- aminocyclopropyl]methoxy}phenyl)ethynyl]- l,2-oxazol"3-yl}ethyl]- lH-imidazol-2-yl}ethan- 1- ol

Compound-333: (lS)-l-{l-[(5-{[4-({(lR,2R)-2-[(2- aminoethyl)amino]cyclopropyl}methoxy)phenyl]ethynyl}- l,2-oxazol-3-yl)methyl]- 1H- imidazol-2-yl}ethan-l-ol

Compound-334: 3-[3-(4-{[5-({2-[(lS)-l-hydroxyethyl]- lH-imidazol- l-yl}methyl)- l,2-oxazol-3- yl]ethynyl}phenoxy)azetidin- l-yl]propan- l-ol

Compound-335: (lS)- l-(l-{(lR)-2-amino- l-[5-({4-[(l- aminocyclopropyl)methoxy]phenyl}ethynyl)- l,2-oxazol-3-yl]ethyl}-lH-imidazol-2-yl)ethan-l- ol

Compound-336: 2-Amino-2-{[4-({3-[(lR)- l-{2-[(lS)- l-hydroxyethyl]- lH-imidazol- l-yl}propyl]- 1 , 2 -oxazol- 5 -yl}ethynyl)p henoxy] methyllprop ane - 1 , 3 - diol

Compound-337: (lS)- l-[l-({5-[(4-{[(lS,2S)-2-amino-2- methylcyclopropyl]methoxy}phenyl)ethynyl]- l,2-oxazol-3-yl}methyl)- lH-imidazol-2-yl]ethan- l-ol Compound-338: (lS)-l-{l-[(lR)"2-amino-l-(5-{[4-({5-[(2- aminoethyl)amino]pentyl}oxy)phenyl]ethynyl}-l,2-oxazol-3-yl)ethyl]-lH-imidazol-2-yl}ethan-

1- ol

Compound-339: (lS)-l-(l-{[5-(4-fluorophenyl)-l,2-oxazol-3-yl]methyl}-lH-imidazol-2- yl)ethan-l-ol

Compound-340: (2S)-2-[5-({4-[(l-aminocyclopropyl)methoxy]phenyl}ethynyl)-l,2-oxazol-3-yl]-

2- {2-[(lS)-l-hydroxyethyl]-lH-imidazol-l-yl}ethan-l-ol

Compound-341: (lS)-l-{l-[(5-{[5-(methoxymethyl)furan-3-yl]ethynyl}-l,2-oxazol-3-yDmethyl]- lH-imidazol-2-yl}ethan- l-ol

Compound-342: (lS)-l-{l-[(lR)-2-amino-l- (4-{[(lS,2S)-2-amino-2- methylcyclopropyl]methoxy}phenyl)ethynyl]- l,2-oxazol-3-yl}ethyl]- lH-imidazol-2-yl}ethan- 1- ol

Compound-343: (lS)-l-(l-{(lR)-2-amino-l-[5-({4-[(trans-2- aminocyclopropyl)oxy]phenyl}ethynyl)- l,2-oxazol-3-yl]ethyl}- lH-imidazol-2-yl)ethan- l-ol Compound-344: (2S)-2-[5-({4-[(trans-2-aminocyclopropyl)oxy]phenyl}ethynyl)-l,2-oxazol-3- yl] -2- {2- [( IS) - 1 -hydroxyethyl] - lH-imidazol- 1 -yDethan- l-ol

Compound-345: (2S)-2-{2-[(lS)-l-hydroxyethyl]-lH-imidazol-l-yl}-2-[5-({4-[4-(2- hydroxyethyl)piperazin-l-yl]phenyl}ethynyl)-l,2-oxazol-3-yl]ethan-l-ol

Compound-346: (lS)-l-{l-[(lR)-2-amino-l-{5-[(4-{[l-(2-hydroxyethyl)azetidin-3- yl]oxy}phenyl)ethynyl]-l,2-oxazol-3-yl}ethyl]-lH-imidazol-2-yl}ethan-l-ol

Compound-347: (2S)-2-{5-[(4-{[l-(2-hydroxyethyl)azetidin-3-yl]oxy}phenyl)ethynyl]-l,2- oxazol-3-yl}-2-{2-[(lS)-l-hydroxyethyl]-lH-imidazol-l-yl}ethan-l-ol

Compound-348: (lS)-l-(l-{(lR)-2-amino-l-[5-({4-[4-(2-hydroxyethyl)piperazin-l- yl]phenyl}ethynyl)-l,2-oxazol-3-yl]ethyl}-lH-imidazol-2-yl)ethan-l-ol

Compound-349: (lS) -(l-{(lR)-2-amino-l-[5-({4-[(trans-3- aminocyclobutyl)oxy]phenyl}ethynyl)- l,2-oxazol"3-yl]ethyl}- lH-imidazol-2-yl)ethan- l-ol Compound-350: (lS)-l-{l-[(lR)-2-amino-l-{5-[(4-{3-[(oxetan-3- yl)amino]propoxy}phenyl)ethynyl]- l,2-oxazol-3-yl}ethyl]- lH-imidazol-2-yl}ethan- l-ol

Compound-351: (lS)-l-[l-({5-[(4-{4-[(l-aminocyclopropyl)methyl]piperazin-l- yl}phenyl)ethynyl]-l,2-oxazol-3-yl}methyl)-lH-imidazol-2-yl]ethan-l-ol

Compound-352: (l-Aminocyclopropyl)[4-(4-{[3-({2-[(lS)-l-hydroxyethyl]-lH-imidazol-l- yl}me thyl) - 1 , 2 - oxazol- 5 -yl] ethynyl}phenyl)p iperazin- 1 -yl] methanone

Compound-353: (lS)-l-{l-[(5-{[4-(3-{[(3S)-oxolan-3-yl]amino}propoxy)phenyl]ethynyl}-l,2- oxazol-3-yl)methyl]- lH-imidazol-2-yl}ethan- l-ol

Compound-354: (lS)-l-(l-{(lR)-2-amino-l-[5-({4-[(trans-2- aminocyclopropyl)methyl]phenyl}ethynyl)- 1, 2 -oxazol- 3 -yl] ethyl}- lH-imidazol-2-yl)ethan- l-ol Compound-355: 3-[3-(4-{[5-(2-Amino-l-{2-[(lS)-l-hydroxyethyl]-lH-imidazol-l-yl}ethyl)-l,2- oxazol-3-yl]ethynyl}phenoxy)azetidin-l-yl]propan-l-ol

Compound- 356: (lS)-l-[l-({5-[(4-iodophenyl)ethynyl]-l,2-oxazol-3-yl}methyl)-lH-imidazol-2- yl]ethan-l-ol

Compound-357: l-[4-(4-{[3-({2-[(lS)-l-hydroxyethyl]-lH-imidazol-l-yl}methyl)-l,2-oxazol-5- yl]ethynyl}phenyl)piperazin-l-yl]-3-methoxypropan-2-ol

Compound-358: (3R)-4-[4-(4-{[3-({2-[(lS)-l-hydroxyethyl]-lH-imidazol-l-yl}methyl)-l,2- oxazol-5-yl]ethynyl}phenyl)piperazin-l-yl]butane-l,3-diol

Compound-359: l-[4-(4-{[3-({2-[(lS)-l-hydroxyethyl]-lH-imidazol-l-yl}methyl)-l,2-oxazol-5- yl]ethynyl}phenyl)piperazin-l-yl]propan-2-ol

Compound-360: (lS)-l-(l-{[5-({4-[4-(2-methoxyethyl)piperazin-l-yl]phenyl}ethynyl)-l,2- oxazol- 3-yl] methyl}- lH-imidazol-2 -yOethan - 1 -ol

Compound-361: 1, 1, l-Trifluoro-3- [4-(4-{[3-({2"[(lS) - 1-hydroxyethyl]- lH-imidazol- 1- yl}methyl)-l,2-oxazol-5-yl]ethynyl}phenyl)piperazin-l-yl]propan-2-ol

Compound-362: l-[4-(4-{[3-({2- [(IS)- 1-hydroxyethyl] -lH-imidazol- l-yl}methyl)- l,2-oxazol"5- yl]ethynyl}phenyl)piperazin- l-yl]-2-methylpropan-2-ol

Compound"363: (lS)-l-{l-[(5-{[4-(4-cyclopropylpiperazin-l-yl)phenyl]ethynyl}-l,2-oxazol-3- yl)methyl]-lH-imidazol-2-yl}ethan-l-ol

Compound-364: (lS)-l-[l-({5-[(4-{4-[(oxetan-3-yl)methyl]piperazin-l-yl}phenyl)ethynyl]-l,2- oxazol-3-yl}methyl)- lH-imidazol-2-yl]ethan- l-ol

Compound-365: (S)-l-(l-((5-((4-(4-ethylpiperazin-l-yl)phenyl)ethynyl)isoxazol-3-yl)methyl)- lH-imidazol-2-yl)ethanol

Compound-366: l-((R)-4-(4-((3-((2-((S)- 1-hydroxyethyl)- lH-imidazol-l-yl)methyl)isoxazol-5- yl)ethynyl)phenyl)-2-methylpiperazin- l-yl)propan-2-ol

Compound-367: (S)-l-(l-((5-((4-(4-(2-morpholinoethyl)piperazin-l-yl)phenyl)ethynyl)isoxazol- 3-yl)methyl)-lH-imidazol-2-yl)ethanol

Compound-368: (S)-2-(4-(4-((3-((2-(l-hydroxyethyl) - lH-imidazol- l-yl)methyl)isoxazol-5- yl)ethy ny l)p henyl)p ip erazin- 1 -yl) - 1 - morp holinoe thanone

Compound-369: l-((S)-4-(4-((3-((2-((S)-l-hydroxyethyl)-lH-imidazol-l-yl)methyl)isoxazol-5- yl)ethynyl)phenyl)-2-methylpiperazin- l-yl)propan-2-ol

Compound-370: 4-(4-((3-((R)-2-amino- l-(2-((S) - 1-hydroxyethyl)- lH-imidazol- 1- yl)ethyl)isoxazol-5-yl)ethynyl)phenoxy)butan- l-ol Test Examples

The following pharmacological tests were conducted to verify the action of inventive compounds.

Test l: Evaluation of the inhibitory activities on Pseudomonas aeruginosa LpxC enzyme

Inhibitory activities on P.aeruginosa LpxC enzyme of compounds were evaluated using Method A (fluorescamine method) or Method B (LCMS method). Method B was particularly applied in-the ease where a compound eontaining-a-primary-amino group was examined at^" micromolar or the higher concentration because the primary amino group of the compound may interfere with the detection system of Method A. In other cases Method A was applied for the measurement of inhibitory activities. (Method A) Fluorescamine method

To assay the activity of LpxC enzyme of P. aeruginosa, LpxC was reacted with its substrate UDP-3 -((R)-3-hydroxydecanoyl)-N-acetylglucosamine and the amount of the reaction product was determined by quantifying the primary amino group present in it. 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-3-0-((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 ZnCb. To terminate the reaction, 1.0 mg/mL fluorescamine in a LI mixture of acetonitrile and dimethylformamide and sodium phosphate buffer (pH 8.0) were added. The amount of the reaction product was measured at excitation and fluorescence wavelengths of 390 nm and 495 nm, respectively. 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 that suppressed the formation of the reaction product 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-A. Table 4-A Inhibitory activities IC50 (μΜ) on P. aeruginosa LpxC enzyme (Method A).

Compound ICso (μΜ) Compound ICso (μΜ)

1 0.0085 37 68

2 10 38 50

3 0.95 39 92

4 5.0 40 22

5 0.52 41 30

6 20 42 20

7^■ 5.3 43 0.88

8 0.67 44 20

9 0.27 45 7.0

10 16 46 0.10

11 42 47 3÷2

15 10 48 5.4

16 22 49 23

17 65 50 0.082

18 97 51 0.21

19 0.57 52 6.1

20 0.16 53 0.0090

21 0.69 54 0.0040

22 7,1 55 1.4

23 2.4 56 0.048

24 0.098 57 0.86

25 23 58 0.065 .

26 7.8 59 5.3

27 32 60 80

28 10 61 13

29 0.13 62 0.16

30 3.9 63 0.082

31 44 64 0.15

32 1.5 65 0.35

33 23 66 0.25

34 16 67 0.10

35 7.8 68 0.18

36 8.0 69 0.015 Table 4-A (continued)

Compound ICso (μΜ) Compound ICso (μΜ)

70 0.011 103 0.0082

71 0.013 104 0.0072

72 0.10 105 0.0041

73 0.89 106 0.014

74 0.014 107 0.0026

75 0.010 108 0.021

76 1.1 109 0.0024

77 0.032 110 0.0046

78 5.0 111 0.0027

79 5.6 112 0.010

80 0.023 113 0.0038

81 34 114 0.054

82 3.2 115 0.0093

83 1.6 116 0.061

84 0.031 117 0.032

85 0.023 118 0.31

86 24 119 0.024

87 0.32 120 0.0057

88 0.16 121 0.0027

89 0.035 122 0.041

90 0.033 123 0.011

91 1.0 124 0.0076

92 0.74 125 0.063

93 4.6 126 0.0041

94 0.025 127 0.014

95 0.0072 128 0.012

96 0.0042 129 0.091

97 0.0051 130 0.0029

98 0.0039 131 0.0097

99 0.0051 132 0.0055

100 0.017 133 0.015

101 0.41 134 0.021

102 0.012 135 0.13 Table 4Ά (Continued)

Compound ICso (μΜ) Compound ICso (μΜ)

136 0.0082 169 0.0042

137 0.0087 170 0.0077

138 0.022 171 0.12

139 0.044 172 0.028

140 0.015 173 0.027

141 0.045 174 0.0057

142 0.91 175 0.015

143 0.013 176 1.1

144 0.0057 177 0.011

145 0.10 178 0.0069

146 0.020 179 0.030

147 0.041 180 0.15

148 0.0047 181 0.033

149 0.015 182 0.0097

150 0.086 183 0.018

151 0.053 184 0.17

152 0.047 185 0.0020

153 0.063 186 0.038

154 1.4 187 0.020

155 0.091 188 0.015

156 0.049 189 0.0064

157 0.15 190 0.0099

158 0.011 191 0.019

159 0.0022 192 3.0

160 0.019 193 0.0045

161 0.031 194 0.0043

162 0.040 195 0.0056

163 0.034 196 0.0046

164 0.0064 197 0.0044

165 0.074 198 0.015

166 0.039 199 0.15

167 0.011 200 0.016

168 0.015 201 0.0065 Table 4-A (Continued)

Compound ICso (μΜ) Compound ICso (μΜ)

202 0.0077 235 0.0081

203 0.012 236 0.0051

204 0.030 237 0.013

205 0.0031 238 0.0049

206 0.0036 239 0.018

207 0.0070 240 0.0014

208 0.0065 241 0.013

209 0.013 242 0.011

210 0.013 243 0.014

211 0.89 244 0.0053

212 0.017 245 <0.0030

213 0.012 246 0.0017

214 0.0044 247 0.0046

215 0.011 248 0.0042

216 0.0069 249 0.0048

217 0.0063 250 0.0090

218 0.015 251 0.0048

219 0.0080 252 0.058

220 0.045 253 0.029

221 77 254 0.0029

222 0.015 255 0.41

223 0.017 256 0.0059

224 0.34 257 0.011

225 0.0051 258 0.0045

226 0.0045 259 0.0062

227 <0.0030 260 0.010

228 0.011 261 0.0050

229 0.013 262 0.030

230 0.0060 263 0.0094

231 0.0040 264 0.0050

232 0.15 265 0.0041

233 0.0044 266 0.0047

234 0.0050 267 0.0089 Table 4-A (Continued)

Compound ICso (μΜ) Compound ICso (μΜ)

268 0.0077 302 0.0039

269 0.0052 303 0.0036

270 0.0040 304 0.0044

271 0.027 305 0.045

272 ND 306 0.012

273 1.0 307 0.015

274 0.68 308 0.034

275 0.51 309 0.0031

276 0.33 310 0.0058

277 0.0085 311 0.0025

278 0.0035 312 0.0017

279 0.0025 313 0.0052

280 0.031 314 0.0086

281 0.062 315 0.0054

282 0.0017 316 0.0065

283 0.0065 317 0.36

284 0.017 318 0.0065

285 0.034 319 0.0018

^■ 286 0.0078 320 0.014

287 1.1 321 0.0053

288 0.0071 322 0.0078

289 0.0041 323 0.0031

290 0.024 324 0.0030

291 0.0042 325 0.0047

292 0.041 326 0.0052

293 0.022 327 0.014

295 0.0091 328 0.0081

296 0.0023 329 0.0098

297 0.052 330 0.0034

298 0.0093 331 0.0082

299 0.0096 332 0.0054

300 ND 333 0.0047

301 0.0093 334 0.0049 Table 4-A (Continued)

Compound ICso (μΜ)

335 0.0037

336 0.0075

337 0.0021

338 0.0018

339 0.37

340 0.0025

341 0.085

342 0.0056

343 0.0047

344 0.0024

345 0.0065

346 0.0049

347 0.0052

348 0.0096

349 0.0095

350 0.0049

351 0.0042

352 0.0089

(Method B) LC/MS method

To assay the activity of P. aeruginosa LpxC enzyme, LpxC was reacted with its substrate UDP-3-0-((R)-3-hydroxydecanoyl)-N-acetylglucosamine. The amounts of the substrate and the reacted product were determined by a liquid chromatographytandem 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-3-0-((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 ZnC . To terminate the reaction, acetonitrile containing 25 pmol/L of UDP-GlcNAc as an internal standard was added. The mixture was centrifuged and the supernatant was injected into LC/MS/MS. The samples were separated with Inertsil Amide (3.0 μπι, 50 mm x 2.1 mm I.D., GLScience, Japan). The mobile phase was 8 mmol/L ammonium acetate containing 72% acetonitrile and the flow rate was 0.2mL/min. MS/MS detection of each component was performed using a TSQ Quantum system with an electrospray interface (ThermoFisher Scientific, USA) in a 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 that suppressed the formation of the reaction product 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^_B.

Table 4-B Inhibitory activities IC50 (μΜ) on P. aeruginosa LpxC enzyme (Method B).

Compound IC50 (μΜ)

12 23

13 15

14 49 Test 2- Evaluation of the inhibitory activities on Escherichia coli LpxC enzyme

Inhibitory activities on E. coli LpxC enzyme of compounds were evaluated using Method A (fluorescamine method) or Method B (LC/MS method). Method B was particularly applied in the case where a compound containing a primary amino group was examined because the primary amino group of the compound may interfere with the detection system of Method A. In other cases Method A was applied for the measurement of inhibitory activities.

(Method A) Fluorescamine method

- ^Fo-assay the activity of-LpxG^enzyme of Er coli^~LpxG was reacted with its substrate L^'DP-3- 0-((R)-3-hydroxymyristoyl)-N-acetylglucosamine and the amount of the reaction product was determined by quantifying the primary amino group present in it. Specifically, 3.1 nmol/L of E. coli LpxC enzyme was mixed with 20 pmol/L of UDP-3 -((R)-3- hydroxymyristoyl)-N-acetylglucosamine (Alberta Research Council) and the mixture was incubated at room temperature for 120 minutes. The reaction was performed in 40 mmol/L of 2-(N-morpholino)ethanesulfonic acid buffer solution (pH 6.5) supplemented with 0.02% (v/v) Brij 35, 80 pmol/L of dithiothreitol and 25 nmol/L of ZnC . To terminate the reaction, 1.0 mg/mL fluorescamine in a 1 1 mixture of acetonitrile and dimethylformamide and sodium phosphate buffer (pH 8.0) were added. The amount of the reaction product was measured at excitation and fluorescence wavelengths of 390 nm and 495 nm, respectively. An inhibition curve was constructed for each test compound by performin the aforementioned reaction at varying concentrations of the test compound. From this inhibition curve, the concentration of the test compound that suppressed the formation of the reaction product by 50% was determined as the IC50 of the test compound, which was an index for the inhibitory activity on E. coli LpxC enzyme. Geometric means of IC50 values from two independent tests for various test compounds are shown in Table 5\A.

Table 5-A Inhibitory activities IC50 (μΜ) on E. coli LpxC enzyme (Method A).

ND : not determined

(Method B) LC/MS method

To assay the activity of E. coli LpxC enzyme, LpxC was reacted with its substrate UDP-3 - ((R)-3-hydroxymyristoyl)-N-acetylglucosamine. The amounts of the substrate and the reacted product were determined by liquid chromatography-tandem mass spectrometry (LC/MS/MS). Specifically, 3.1 nmol/L of E. coli LpxG enzyme was mixed with 20 pmol L of UDP-3 -((R)-3-hydroxymyristoyl)-N-acetylglucosamine (Alberta Research Council) and the mixture was incubated at room temperature for 120 minutes. The reaction was performed in 40 mmol/L of 2-(N-morpholino)ethanesulfonic acid buffer solution (pH 6.5) supplemented with 0.02% (v/v) Brij 35, 80 pmol/L of dithiothreitol and 25 nmol/L of ZnCb. To terminate the reaction, acetonitrile containing 25 pmol/L of UDP-N-acetylglucosamine as an internal standard was added. The mixture was centrifuged and the supernatant was injected into LC/MS/MS. The samples were separated with Inertsil Amide (3.0 μπι, 50 mm x 2.1 mm I.D., GLScience, Japan). The mobile phase was 8 mmol/L ammonium acetate containing 72% acetonitrile and the flow rate was 0.2 mL/min. MS/MS detection of each component was performed using a TSQ Quantum system with an electrospray interface (ThermoFisher Scientific, USA) in a 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 that suppressed the formation of the reaction product by 50% was determined as the IC50 of the test compound, which was an index for the inhibitory activity on E. coli LpxC enzyme. Geometric means of ICso values from two independent tests for various test compounds are shown in Table 5-B.

Table 5"B Inhibitory activities ICso (μΜ) on E. coli LpxC enzyme (Method B).

ND : not determined Test 3: Evaluation of antimicrobial activities

Minimum inhibitory concentration (MIC) was determined using the following broth microdilution method according to the Clinical and Laboratory Standards Institute guidelines. The bacteria used were Pseudomonas aeruginosa strain ATCC27853, Klebsiella pneumoniae strain ATCC 13883 and Escherichia coli strain ATCC25922. Prior to testing, these strains were cultured overnight at 35°C on Heart Infusion Agar plates. Bacterial cells of the above strains were inoculated in 100 pL of cation-adjusted Mueller-Hinton broth medium containing serially diluted test compounds so that each well contained approximately 5 x 10⁵ CFU/mL. All bacterial strains were incubated for 18 h at 35°C. A minimum drug concentration at which no cell growth was visible to the naked eye was designated as MIC. The test results for representative compounds are shown in Table 6.

Table 6 MIC ^g/mL), antibacterial activities against P. aeruginosa, E. coli and K. pneumoniae.

Compound P. aeruginosa E. coli K. pneumoniae

ATCC27853 ATCC25922 ATCC 13883

1 4 NT 8

5 > 128 64 NT

9 > 8 > 8 NT

19 > 16 > 16 NT

20 > 16 2 NT

21 > 4 > 4 NT

24 > 64 8 NT

29 > 64 16 NT

46 > 32 32 NT

47 > 128 > 128 NT

49 > 128 > 128 NT

50 > 8 4 NT

51 > 32 16 NT

53 64 2 4

54 32 0.5 2

55 > 128 > 128 NT

56 > 128 16 32

57 > 128 > 128 NT

58 > 128 64 NT > 128 > 128 NT

> 64 64 NT

> 128 16 32

> 128 16 64

> 64 8 32

> 128 64 64

> 64 64 64

> 64 8 32

64 2 4

16 4 NT

32 2 4

64 4 8

64 2 4

> 128 128 NT

> 64 > 64 NT

> 128 > 128 NT

> 128 16 NT

> 128 > 128 NT

> 128 32 NT

128 8 NT

> 128 4 NT

> 128 2 NT

> 128 64 NT

> 128 64 NT

64 4 NT

8 4 8

16 2 2

16 2 8

8 1 2

8 2 8

8 16 64

> 128 128 NT

16 16 32

16 4 8

> 128 8 NT

8 2 4 106 32 16 NT

107 8 0.25 0.5

108 32 16 NT

109 16 0.5 1

110 16 1 1

111 16 0.25 0.5

112 64 16 32

113 32 1 2

114 > 128 8 NT 115 128 16 NT

116 > 128 32 NT

117 > 128 4^' NT

119 8 16 > 16

120 8 8 16

121 > 16 1 NT

122 128 32 NT

123 32 8 NT

124 32 4 NT

125 128 128 NT

126 32 4 NT

127 64 4 NT

128 > 8 ND NT

129 > 64 32 NT

130 > 2 > 2 NT

131 32 NT 32

132 32 2 NT

133 > 64 2 NT

134 128 4 NT

135 128 NT > 128

136 64 2 NT

137 64 4 NT

138 > 16 16 NT

139 64 64 NT

142 > 128 128 NT

143 8 0.5 1

144 8 2 4 145 > 128 32 NT

146 4 16 64

147 8 8 16

148 > 16 0.5 NT

149 128 4 NT

151 > 32 4 NT

152 > 128 128 NT

153 > 128 128 NT

155 > 64 16 NT

156 > 128 64 NT

157 > 128 64 NT

158 64 8 NT

159 8 0.25 0.5

160 8 8 16

161 16 64 > 128

162 16 8 16

163 16 16 64

164 > 32 2 NT

165 64 128 NT

166 64 2 NT

167 16 1 2

168 16 4 NT

169 16 0.5 NT

170 32 ND NT

171 > 128 8 NT

172 > 128 4 NT

173 4 ND 64

174 32 1 NT

175 4 4 8

177 128 NT 16

178 32 NT 8

179 > 128 NT 64

180 > 128 NT 128

181 4 NT 128

182 16 NT 64

183 > 16 NT 2 184 > 64 NT > 64

185 16 NT 1

186 64 NT 32

187 8 NT 64

188 16 NT 8

189 32 NT 1

190 16 NT 16

191 128 NT 8

193 > 4 NT > 4

194 32 NT 2

195 16 NT 4

196 32 NT 4

197 4 4 4

198 16 NT 16

199 64 NT 64

200 64 NT 4

'201 32 NT 16

202 16 NT 16

203 16 NT 16

204 64 NT 16

205 16 NT 2

206 > 32 NT 2

207 2 NT 32

208 8 NT 8

209 32 NT 4

210 16 NT 64

211 > 128 NT > 128

212 32 NT 128

213 32 NT 64

214 16 NT 8

215 > 32 NT 2

216 8 NT 8

217 8 NT 16

218 8 NT 32

219 8 .NT 32

220 32 NT > 128 222 32 NT 128

223 8 NT 16

224 > 128 NT 128

225 8 NT 64

226 1 NT 4

227 8 NT 16

228 16 NT 16

229 16 NT 32

230 8 NT ' 8

231 .4 NT 8

232 > 8 NT > 8

233 8 NT 8

234 8 NT 32

235 16 NT 32

236 8 NT 16

237 16 NT 64

238 8 NT 32

239 64 NT > 128

240 2 NT 16

241 16 NT 32

242 8 NT 32

243 2 NT 8

244 32 NT 4

245 > 16 0.5 0.5

246 4 0.25 0.5

247 4 NT 32

248 4 NT 8

249 4 NT ND

250 64 NT 64

251 8 NT 16

252 > 128 NT 16

253 > 64 NT 8

254 8 NT 16

255 > 128 NT > 128

256 4 NT 16

257_. 4 NT 16 258 4 NT 16

259 4 NT 16

260 > 4 NT > 4

261 4 NT 32

262 64 NT 16

263 16 NT 32

264 4 NT 8

265 4 NT 8

266 8 NT 8

267 8 NT > 64

268 8 NT > 128

269 2 NT 32

270 4 NT 8

271 > 16 NT > 16

272 > 16 NT 8

273 > 128 NT > 128

274 > 128 NT > 128

275 > 128 NT > 128

276 > 128 NT > 128

277 8 NT 64

278 16 NT 4

279 8 NT 8

280 32 NT > 128

281 > 128 NT > 128

282 2 NT 8

283 8 NT 64

284 8 NT 64

285 128 NT 128

286 16 NT 32

287 > 128 NT 64

288 8 NT 128

289 8 NT 8

290 32 NT 32

291 4 NT 8

292 > 64 NT > 64

293 8 NT 32 294 4 64 128

295 4 NT ND

296 16 0.5 1

297 > 16 NT 8

298 8 NT 32

299 4 NT 16

300 32 NT > 128

301 32 NT 8

302 16 NT 4

303 2 NT 64

304 8 NT 8

305 > 64 NT 4

306 16 NT 8

307 8 NT 128

308 > 32 NT > 32

309 32 0.5 1

310 8 2 2

311 16 0.5 0.5

312 4 0.12 0.25

313 1 NT 8

314 8 NT 32

315 8 1 1

316 8 NT 32

317 > 64 NT 32

318 16 NT 16

319 8 0.25 0.5

320 4 NT 8

321 1 NT 64

322 8 NT 64

323 4 NT 64

324 8 NT 4

325 4 NT 16

326 8 2 2

327 16 NT 8

328 8 NT 32

329 4 NT 16 330 1 NT 32

331 8 NT 32

332 1 NT 64

333 4 NT 16

334 8 NT 16

335 2 NT 16

336 16 NT 64

337 8 NT 8

338 8 NT 64

339 > 128 NT 128

340 8 NT 8

341 > 128 NT 16

342 4 NT 64

343 1 4 4

344 2 2 2

345 8 NT 4

346 1 NT 16

347 2 NT 16

348 2 2 4

349 2 NT 32

350 4 NT 8

351 32 2 4

352 > 64 NT 8

353 16 NT 8

354 8 16 32

355 4 16 32

356 > 16 1 4

357 16 1 2

358 8 1 2

359 16 0.5 1

360 16 0.25 0.5

361 > 16 2 2

362 > 8 0.5 2

363 > 4 0.25 0.5

364 16 1 2

365 > 16 0.5 2 366 64 1 2

367 16 1 2

368 32 4 4

369 64 2 2

370 4 0.5 2

NT : not tested, ND : not determined

INDUSTRIAL APPLICABILITY The present invention enables providing novel compounds that inhibit LpxC or pharmaceutically acceptable salts thereof, as well as new pharmaceutical drugs comprising those compounds or pharmaceutically acceptable salts thereof, that exhibit antimicrobial activity against gram-negative bacteria including multi-drug resistant strains and that are useful in the treatment of bacterial infections.

Claims

Claims

[Claim l] A compound represented by the following general formula [l] or a pharmaceutically acceptable salt thereof

wherein

Z represents a hydroxyl group or an amino group,

R¹ represents a hydrogen atom, a Ci 4 alkyl group, a Ci-4 haloalkyl group or a cyclopropyl group,

R² represents a hydrogen atom, -COOH or -CONH2, provided that R¹ and R² are not a hydrogen atom at the same time,

R³ represents a hydrogen atom or a Ci-4 alkyl group,

R⁴ represents a hydrogen atom, a Ci-4 alkyl group, a Ci-4 hydroxyalkyl group or a C1-4 aminoalkyl group (the amino group of the C1-4 aminoalkyl group may be substituted with a

C2 4 alkanoyl group or a C1-4 alkylsulfonyl group),

R⁵ represents a hydrogen atom,

R⁴ and R⁵ may form a Ci-4 alkylidene group together,

L¹ represents a bond, a Ci-4 alkylene group (the Ci-4 alkylene group may be substituted with a hydroxyl group), -OCH2 - or -C(=0) -,

A¹ represents a divalent 5-membered heteroaromatic group, a 1,4-divalent 6-membered heteroaromatic group, a 1,4-phenylene group (the divalent 5-membered heteroaromatic group, the 1,4-divalent 6-membered heteroaromatic group and the 1,4-phenylene group may be substituted with 1 to 3 substituents which are the same or different and are selected from "a halogen atom and a Ci-4 alkyl group") or a benzoisoxazolylene group,

L² represents -C≡C-, -C≡C-G≡C-, -CH=CH-, a Ci alkylene group, 1,3-cyclobutylene group or a bond,

W¹ represents W²-A²-, a Ci 8 alkyl group (the Ci-8 alkyl group may be substituted with a hydroxyl group), a chlorine atom or a bromine atom,

A² represents a divalent 5-membered heteroaromatic group, a 1,4-divalent 6-membered heteroaromatic group, a 1,4-phenylene group or a divalent group selected from the following

(the divalent 5-membered heteroaromatic group, the 1,4-divalent 6-membered

heteroaromatic group, the 1,4-phenylene group and the divalent group selected from the formula [2Λ] may be substituted with-l -to 3 substituents which-are the same or different- and are selected from "a halogen atom, a hydroxyl group, a Ci-4 alkyl group and a Ci-4 hydroxyalkyl group"),

G represents N or CH,

W² represents Re-Χΐΐ-, Re-Xi-Yi-Xn-_Κ6-χ2-γ2-χΐ-γΐ-χιι_ Q-χι- Q-X12-YI_XII__OR

Q_X12__Y2-X1-Y1-X11-_OR Q_Y3_X12_Y2-X1-Y1-X11-_j

Y¹ represents -(CH₂)mO- -NR⁷-, -SO2-, -C(=0)- or -NR⁷C(=0)- wherein m is 0 to 3,

Y2 represents -0(CH₂)n- -NR⁷(CH₂)n- -NHC(=0)0-, -C(=0)0- or -OC(=0)- wherein each n is 0 to 3,

Y³ represents -NR⁷-,

X^I and X² are the same or different and each represent a Ci-e alkylene group or a C3-9 cycloalkylene group (the Ci 8 alkylene group and the C3-9 cycloalkylene group may be substituted with 1 to 3 substituents which are the same or different and are selected from "a halogen atom, a hydroxyl group or an amino group"),

X^II and X¹² are the same or different and each represent a Ci-8 alkylene group (the Ci-e alkylene group may be substituted with 1 to 3 substituents which are the same or different and are selected from "a halogen atom, a hydroxyl group and an amino group"), a C3 9 cycloalkylene group, or a bond,

R⁶ represents a hydrogen atom, a halogen atom, a hydroxyl group, a C1-4 hydroxyalkyl group, an amino group, a C1-4 aminoalkyl group, a carbamoyl group, -SO2NH2, or -COOR⁷,

R⁷ represents a hydrogen atom, C1-4 hydroxyalkyl group or a Ci-4 alkyl group,

and Q represents a nitrogen-containing 4- to 7-membered saturated heterocyclic group wherein the ring-constituting atoms may optionally contain 1 or 2 oxygen or sulfur atoms, or an oxygen-containing 4- to 7-membered saturated heterocyclic group (the nitrogen- containing 4- to 7-membered saturated heterocyclic group and the oxygen-containing 4- to 7- membered saturated heterocyclic group may be substituted with 1 or 2 oxo groups and may be substituted with 1 to 3 substituents which are the same or different and are selected from "a halogen atom, a hydroxyl group, C 1-4 alkyl group, Ci-4 alkoxy group, a Ci -8 hydroxyalkyl group or a Ci -4 alkylsulfonyl group"), and

* indicates the site of attachment of a moiety.

[Claim 2] A compound represented by the following general formula [l] or a pharmaceutically acceptable salt thereof

wherein

Z represents a hydroxyl group or an amino group,

R¹ represents a hydrogen atom, a Ci-4 alkyl group, a C1-4 haloalkyl group or a cyclopropyl group,

R² represents a hydrogen atom, -COOH or -CONH2, provided that R¹ and R² are not a hydrogen atom at the same time,

R³ represents a hydrogen atom or a Ci-4 alkyl group,

R⁴ represents a hydrogen atom, a C1-4 alkyl group, a C1-4 hydroxyalkyl group or a Ci-4 aminoalkyl group (the amino group of the Ci 4 aminoalkyl group may be substituted with a C2-4 alkanoyl group or a C1-4 alkylsulfonyl group),

R⁵ represents a hydrogen atom,

R⁴ and R⁵ may form a C1-4 alkylidene group together,

L¹ represents a bond, a Ci 4 alkylene group (the Ci 4 alkylene group may be substituted with a hydroxyl group), -OCH2 - or -C(=0) -,

A¹ represents a divalent 5-membered heteroaromatic group, a 1,4-divalent 6-membered heteroaromatic group, a 1,4-phenylene group (the divalent 5-membered heteroaromatic group, the 1,4-divalent 6-membered heteroaromatic group and the 1,4-phenylene group may be substituted with 1 to 3 substituents which are the same or different and are selected from "a halogen atom and a C1-4 alkyl group") or a benzoisoxazolylene group, L² represents -C≡ C- -C≡ C-C≡ C- -CH=CH- a C1-4 alkylene group, 1,3- cyclobutylene group or a bond,

W¹ represents W²-A²-, a Ci-8 alkyl group (the Ci-8 alkyl group may be substituted with a hydroxyl group), a chlorine atom or a bromine atom,

A² represents a divalent 5-membered heteroaromatic group, a 1,4-divalent 6-membered heteroaromatic group, a 1,4-phenylene group or a divalent group selected from the

divalent 5-membered heteroaromatic group, the 1,4-divalent 6-membered heteroaromatic group, the 1,4-phenylene group and the divalent group selected from the formula [2] may be substituted with 1 to 3 substituents which are the same or different and are selected from "a halogen atom, a hydroxyl group, a Ci-4 alkyl group and a Ci-4 hydroxy alky 1 group"),

G represents N or CH,

W² represents R6-X"- Re-Χ^ΐ-γ^ΐ-Χ"-, R6-X²-Y²-Xi-Yi-Xii- Q-Χΐ- Q-Xi2-Yi-Xii- or <¾-Χΐ2-Υ2-χΐ-γΐ-χπ-

Yⁱ represents -0-, -NR⁷-, -SO2-, -C(=0)- or -NR C(=0)-,

Y² represents -0 -, -NR⁷ - or -0C(=0)-,

X^I and X² are the same or different and each represent a Ci-8 alkylene group, a C3 9 cycloalkylene group (the Ci-8 alkylene group and the C3-9 cycloalkylene group may be substituted with 1 to 3 substituents which are the same or different and are selected from "a halogen atom, a hydroxyl group or an amino group"),

X^II and X¹² are the same or different and each represent a Ci-8 alkylene group (the Ci-e alkylene group may be substituted with 1 to 3 substituents which are the same or different and are selected from "a halogen atom, a hydroxyl group and an amino group"), a C3-9 cycloalkylene group, or a bond,

R⁶ represents a hydrogen atom, a halogen atom, a hydroxyl group, an amino group, a carbamoyl group, -SO2NH2, or -COOR⁷,

R⁷ represents a hydrogen atom, C1-4 hydroxyalkyl group or a Ci-4 alkyl group, and Q represents a nitrogen-containing 4- to 7-membered saturated heterocyclic group wherein the ring-constituting atoms may optionally contain 1 or 2 oxygen or sulfur atoms, or an oxygen-containing 4- to 7-membered saturated heterocyclic group (the nitrogen-containing 4- to 7-membered saturated heterocyclic group and the oxygen- containing 4- to 7-membered saturated heterocyclic group may be substituted with 1 or 2 oxo groups and may be substituted with 1 to 3 substituents which are the same or different and are selected from "a halogen atom, a hydroxyl group, a C1-4 alkyl group, a Ci 4 alkoxy group, a C 1-4 hydroxy alkyl group or a C 1-4 alky lsulfonyl group"), and

* indicates the site of attachment of a moiety.

[Claim 3] The compound or the pharmaceutically acceptable salt thereof, according to claim 1 or 2, wherein R² is a hydrogen atom.

[Claim 4] The compound or the pharmaceutically acceptable salt thereof, according to any one of claims 1 to 3, wherein R¹ is a methyl group, an ethyl group, a difluoromethyl group or a trifluoromethyl group.

[Claim 5] The compound or the pharmaceutically acceptable salt thereof, according to claim 4, wherein R¹ is a methyl group.

[Claim 6] The compound or the pharmaceutically acceptable salt thereof, according to any one of claims 1 to 5, wherein Z is a hydroxyl group.

[Claim 7] The compound or the pharmaceutically acceptable salt thereof, according to any one of claims 1 to 6, wherein R³ is a hydrogen atom.

[Claim 8] The compound or the pharmaceutically acceptable salt thereof, according to any one of claims 1 to 7, wherein R⁴ is a hydrogen atom, a C1 4 hydroxyalkyl group or a Ci-4 aminoalkyl group and R⁵ is a hydrogen atom.

[Claim 9] The compound or the pharmaceutically acceptable salt thereof, according to any one of claims 1 to 8, wherein A¹ is a divalent group selected from the following formula [3],

[3]

where R^A1, R^A2, R^A3, R^A4, R^A5 and R^A6 are the same or different and each represent a hydrogen atom, halogen atom or a methyl group.

[Claim 10] The compound or the pharmaceutically acceptable salt thereof, according to claim 9, w nt group represented by the following formula [4]

[Claim 11] The compound or the pharmaceutically acceptable salt thereof, according to any one of claims 1 to 10, wherein L¹ is a bond.

[Claim 12] The compound or the pharmaceutically acceptable salt thereof, according to any one of claims 1 to 11, wherein L² is -C≡C-, a 1,3-cyclobutylene group or a bond.

[Claim 13] The compound or the pharmaceutically acceptable salt thereof, according to claim 12, wherein L² is -C≡C-.

[Claim 14] The compound or the pharmaceutically acceptable salt thereof, according to any one of claims 1 to 13, wherein W¹ is W²-A²-.

[Claim 15] The compound or the pharmaceutically acceptable salt thereof, according to amy one of claims 1 to 14, wherein A² is a divalent group selected from the following formula [5]

wherein the above formula [5] may be substituted by 1 to 3 substituents which are the same or different and are selected from "a halogen atom, a hydroxyl group, a Ci-4 alkyl group and a Ci-4 hydroxyalkyl group".

[Claim 16] The compound or the pharmaceutically acceptable salt thereof, according to claim 15, wherein A² is a 1,4-phenylene group wherein the 1,4-phenylene group may be substituted by 1 to 3 substituents which are the same or different and are selected from "a halogen atom, a hydroxyl group, a Ci-4 alkyl group and a Ci-4 hydroxyalkyl group".

[Claim 17] The compound or the pharmaceutically acceptable salt thereof, according to any one of claims 1 to 16, wherein W² is_. R6-X"- or Rs-Χ^ΐ-Υ¹-, R6-X²-Y²-Xⁱ-Yⁱ- or Q-X^-Y¹- wherein Y¹ represents -0-, Y² represents -O- or -NR⁷ wherein R⁷ represents a hydrogen atom, Ci-4 hydroxyalkyl group or a Ci 4 alkyl group, X¹ and X² are the same or different and each represent a Ci-8 alkylene group (the Ci-8 alkylene group may be substituted with 1 to 3 hydroxyl groups), X¹¹ and X¹² are the same or different and each represent a Ci -8 alkylene group (the Ci-8 alkylene group may be substituted with 1 to 3 hydroxyl groups) or a bond, R⁶ is a hydroxyl group, an amino group a carbamoyl group, and Q represents a nitrogen-containing 4- to 7-membered saturated heterocyclic group wherein the nitrogen-containing 4- to 7-membered saturated heterocyclic group may be substituted with 1 to 3 substituents which are the same or different and are selected from a hydroxyl group and a Ci-4 hydroxyalkyl group.

[Claim 18] The compound or the pharmaceutically acceptable salt thereof, according to any one of claims 1 to 16, wherein W² is R^X^!-Y¹- wherein Y¹ represents -(CH2)mO-, m is 0 to 3, X¹ represents a C3-6 cycloalkyl group and R⁶ represents an amino group or a Ci-4 aminoalkyl group.

[Claim 19] The compound or the pharmaceutically acceptable salt thereof, according to any one of claims 1 to 15, wherein A² is the following formula

W² is R⁶-Xⁿ-, R^X^!-Y^!-X¹¹-, wherein Y¹ represents -0-, X¹ represents a Ci s alkylene group (the Ci-8 alkylene group may be substituted with 1 to 3 hydroxyl groups), X¹¹ represents a Ci-8 alkylene group (the Ci-8 alkylene group may be substituted with 1 to 3 hydroxyl groups) and R⁶ is a hydrogen or a hydroxyl group.

[Claim 20]- -A— pharmaceutical— composition -comprising the compound or^"the pharmaceutically acceptable salt thereof according to any one of claims 1 to 19.

[Claim 21] An LpxC inhibitor comprising the compound or the pharmaceutically acceptable salt thereof according to any one of claims 1 to 19.

[Claim 22] An antimicrobial agent comprising the compound or the pharmaceutically acceptable salt thereof according to any one of claims 1 to 19.