【Technical Field】
The present invention relates to a novel compound exhibiting GLP-1 receptor
agonist activity, an isomer thereof, a pharmaceutically acceptable salt thereof, a
pharmaceutical composition including the compound, and a method of preparing the
compound.
10 【Background Art】
Glucagon-like peptide-1 (GLP-1) is a polypeptide hormone secreted from
intestinal L-cells after meals, and it may stimulate insulin secretion from pancreatic
islet β cells, thereby stabilizing postprandial blood sugar levels. The GLP-1 binds to
a GLP-1 receptor (GLP-1R). The GLP-1 receptor is a protein in the Class B receptor
15 subclass of G protein-conjugated receptors (GPCR) regulating important physiological
and pathophysiological processes. Its tertiary structure has not been identified, and
since the GLP-1 receptor has a unique binding manner of determining affinity by
binding the N-terminus thereof with a ligand, it is recognized as a drug target for which
it is very difficult to develop a low-molecule ligand.
20 Exogenous administration of GLP-1 normalizes a blood sugar level in a Type
2 diabetes patient. Since the effect of GLP-1 on reduction in a blood sugar level
varies according to a glucose concentration, the risk of hypoglycemia is greatly
reduced while the blood sugar level is regulated. In addition, GLP-1-based drugs
3
such as Byetta® and Bydureon BCise® (exenatide), Ozempic® (semaglutide),
Victoza® (liraglutide), Adlyxin® (lixisenatide); Tanzeum® (albiglutide) and
Trulicity® (dulaglutide) are GLP-1 receptor agonists, which have been successfully
sold in recent years, and it was identified that they provide blood sugar control which
is effective for treating a type 2 diabetes 5 patient in addition to providing weight loss
effects, preservation of a beta-cell function, and relief of hypertension, hypoglycemia
and/or hyperlipidemia.
However, since the above-described GLP-1 and GLP-1 receptor agonists may
lack sufficient oral bioavailability that is required for a peptide-based oral drug, there
10 is a need for a small-molecule agonist of the GLP-1 receptor with oral bioavailability.
【Disclosure of Invention】
【Technical Problem】
The present invention is directed to provide a novel compound having an
15 activity as a GLP-1 agonist.
In addition, the present invention is directed to provide a pharmaceutical
composition for preventing or treating a metabolic disease or neurodegenerative
disease, which contains the novel compound as an active ingredient.
20 【Solution to Problem】
The definition of each group used in the specification will be described in detail.
Unless specified otherwise, each group has the following definition.
The “halo” used herein may be fluoro, chloro, bromo or iodo.
4
The “alkyl” used herein refers to a linear or branched aliphatic saturated
hydrocarbon group, and specifically, may be C1-6 alkyl, C1-4 alkyl or C1-3 alkyl.
Examples of the alkyl may include methyl, ethyl, propyl, isopropyl, butyl, isobutyl,
sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, 1-ethylpropyl, hexyl, isohexyl, 1,1-
dimethylbutyl, 2,2-dimethylbutyl, 3,3 5 -dimethylbutyl or 2-ethylbutyl.
The “alkoxy” used herein refers to an oxygen group to which a single-bonded
linear or branched saturated hydrocarbon is bonded to, and may be specifically C1-6
alkoxy, C1-4 alkoxy or C1-3 alkoxy. Examples of the alkoxy may include methoxy,
ethoxy, propoxy, n-butoxy, tert-butoxy or 1-methylpropoxy.
10 The “cycloalkyl” used herein refers to a cyclic single-bonded saturated
hydrocarbon group, and is specifically C3-8 cycloalkyl or C3-6 cycloalkyl depending on
the number of carbon atoms. Examples of the cycloalkyl may include cyclopropyl,
cyclobutyl, cyclopentyl or cyclohexyl.
The “heterocycloalkyl” used herein refers to a cyclic single-bonded saturated
15 hydrocarbon group including one or more heteroatoms such as N, O or S other than a
carbon atom as a ring member, and may be monocyclic or a fused polycyclic ring.
Specifically, the heterocycloalkyl may be 4- to 10-membered heterocycloalkyl, 4- to
7-membered heterocycloalkyl, or 4- to 6-membered heterocycloalkyl, which includes
one or more, and preferably, one to three types of heteroatoms selected from the group
20 consisting of N, O and S. Examples of heterocycloalkyl may include oxytanyl,
aziridine, pyrrolidine, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl,
tetrahydrofuranyl or tetrahydropyranyl.
5
The “aryl” used herein refers to an aromatic substituent having at least one ring,
which has a covalent pi electron system, and may be monocyclic or a fused polycyclic
ring (that is, rings each having adjacent pairs of carbon atoms). Specifically, such
aryl may be C4-10 aryl or C6-10 aryl depending on the number of carbon atoms included
5 in a ring, and for example, phenyl or naphthyl.
The “heteroaryl” used herein refers to an aromatic ring compound including
one or more heteroatoms such as N, O or S, other than a carbon atom as a ring member,
and may be monocyclic or a fused polycyclic ring. Specifically, the heteroaryl may
be a 4- to 10-membered heteroaryl, a 4- to 7-membered heteroaryl, or a 4- to 6-
10 membered heteroaryl having one or more, and preferably, one to three types of
heteroatoms selected from the group consisting of N, O and S. Examples of
heteroaryl may be furanyl, pyranyl, imidazoly, oxazolyl, isoxaazolyl, pyridyl,
pyrazinyl, pyrimidyl, pyridazinyl, oxadiazolyl, thiadiazolyl, tetrazolyl, triazinyl,
triazyl, or triazoyl, but the present invention is not limited thereto.
15 The “substituent” used herein may be one or more selected from the group
consisting of a halo group, a nitrile group and a C1-3 alkyl group.
Hereinafter, the present invention will be described in detail.
To achieve the above-described objects, the present invention provides a
20 compound represented by Formula 1 below, an isomer thereof, or a pharmaceutically
acceptable salt thereof:
[Formula 1]
6
In this formula,
A is -(CH2)m-, -O- or -N(Ra)-, wherein m is an integer ranging from 1 to 3, and
Ra is hydrogen or alkyl;
R1 is (cycloalkyl)alkyl, (heterocycloalkyl)alkyl, (5 aryl)alkyl or (heteroaryl)alkyl;
R2, R3 or R4 is each independently hydrogen, deuterium, halo, alkyl, alkoxy,
alkylamine or a nitrile group;
n is an integer ranging from 1 to 4, wherein when n is an integer of 2 or more,
each of R2, R3 and R4 may be the same or different from each other;
10 Z1, Z2, Z3, Z4, Z5, Z6 or Z7 each independently represents CH, CF, CCl, CBr,
CI or N;
wherein, the alkyl, alkoxy, alkylamine, cycloalkyl, heterocycloalkyl, aryl, or
heteroaryl is unsubstituted or substituted.
15 In an exemplary embodiment, A may be -CH2-, -O- or -N(Ra)-.
In an exemplary embodiment, Ra may be hydrogen or C1-3 alkyl.
In an exemplary embodiment, R1 may be (C3-8 cycloalkyl)C1-3 alkyl, (4- to 10-
membered heterocycloalkyl)C1-3 alkyl, (C6-10 aryl)alkyl or (4- to 10-membered
7
heteroaryl)C1-3 alkyl, wherein, the heterocycloalkyl or heteroaryl contains one to three
types of heteroatoms selected from the group consisting of N, O and S.
In an exemplary embodiment, R2, R3 or R4 is each independently hydrogen,
deuterium, F, Cl, Br, I, C1-3 alkyl, C1-3 alkoxy, C1-3 alkylamine or a nitrile group.
In an exemplary embodiment, n is 5 an integer ranging from 1 to 3, wherein,
when n is an integer of 2 or more, each of R2, R3 or R4 may be the same or different
from each other.
In an exemplary embodiment, Z1, Z2, Z3, Z4, Z5, Z6 or Z7 each may be
independently CH, CF or CCl.
10 In an exemplary embodiment, the alkyl, alkoxy, alkylamine, cycloalkyl,
heterocycloalkyl, aryl, or heteroaryl may be unsubstituted, or halo- or C1-3 alkylsubstituted.
In more exemplary embodiment, A may be -CH2- or -O-.
15 In more exemplary embodiment, R1 may be cyclopropylmethyl,
cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl, oxytanylmethyl,
tetrahydrofuranylmethyl, tetrahydropyranylmethyl, oxazolylmethyl, benzyl,
unsubstituted or propyl-substituted triazolylmethyl, or unsubstituted or ethylsubstituted
imidazolylmethyl.
20 In more exemplary embodiment, R2, R3 or R4 each is independently hydrogen,
deuterium, F, Cl, or a nitrile group.
In more exemplary embodiment, n is 2, and each of R2, R3 or R4 may be the
same or different from each other.
8
Representative examples of compounds of Formula 1 according to the present
invention may include the following compounds, but the present invention is not
limited thereto:
1] 2-(4-(6-((4-chloro-2-fluorobenzyl)oxy)pyridin-2-yl)benzyl)-1-
((tetrahydrofuran-2-yl)methyl)-1H-benzo[5 d]imidazole-6-carboxylic acid;
2] (S)-2-(4-(6-((4-chloro-2-fluorobenzyl)oxy)pyridin-2-yl)benzyl)-1-(oxetan-
2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid;
3] (S)-2-(4-(6-((4-cyano-2-fluorobenzyl)oxy)pyridin-2-yl)benzyl)-1-(oxetan-
2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid;
10 4] 2-(4-(6-((4-cyano-2-fluorobenzyl)oxy)pyridin-2-yl)benzyl)-1-((1-ethyl-1Himidazol-
5-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid;
5] 2-(4-(6-((4-cyano-2-fluorobenzyl)oxy)pyridin-2-yl)phenoxy)-1-((1-ethyl-
1H-imidazol-5-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid;
6] (S)-2-(4-(6-((4-cyano-2-fluorobenzyl)oxy)pyridin-2-yl)phenoxy)-1-
15 (oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid;
7] (S)-2-(4-(6-((4-chloro-2-fluorobenzyl)oxy)pyridin-2-yl)phenoxy)-1-
(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid;
8] 2-(4-(6-((4-chloro-2-fluorobenzyl)oxy)pyridin-2-yl)benzyl)-1-(oxazol-5-
ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid;
20 9] 2-(4-(6-((4-cyano-2-fluorobenzyl)oxy)pyridin-2-yl)phenoxy)-1-(oxazol-5-
ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid;
10] (S)-2-(4-(6-((4-chloro-2-fluorobenzyl)oxy)pyridin-2-yl)-2-fluorobenzyl)-
1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid;
9
11] 2-(4-(6-((4-chloro-2-fluorobenzyl)oxy)pyridin-2-yl)-2-fluorobenzyl)-1-
(oxazol-5-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid;
12] (S)-2-(4-(6-((4-chloro-2-fluorobenzyl)oxy)pyridin-2-yl)benzyl)-1-
((tetrahydrofuran-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid;
13] (R)-2-(4-(6-((4-chloro-2-fluorobenzyl)5 oxy)pyridin-2-yl)benzyl)-1-
((tetrahydrofuran-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid;
14] 2-(4-(6-((4-chloro-2-fluorobenzyl)oxy)pyridin-2-yl)benzyl)-1-
((tetrahydro-2H-pyran-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid;
15] (S)-2-(4-(6-((4-chloro-2-fluorobenzyl)oxy)pyridin-2-yl)-3-fluorobenzyl)-
10 1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid;
16] (S)-2-(4-(6-((2-fluoro-4-(trifluoromethyl)benzyl)oxy)pyridin-2-
yl)benzyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid;
17] (S)-2-(4-(6-((4-chloro-2-fluorobenzyl)oxy)pyridin-2-yl)-2-
fluorophenoxy)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid;
15 18] (S)-2-(2-chloro-4-(6-((4-chloro-2-fluorobenzyl)oxy)pyridin-2-
yl)phenoxy)-1-(oxetan-2-ylmethyl)-1H-benzo[d] imidazol-6-carboxylic acid;
19] (S)-2-(4-(6-((4-chloro-2-fluorobenzyl)oxy)pyridin-2-yl)-2,6-
difluorophenoxy)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid;
20] (S)-2-(4-(6-((4-chloro-2-fluorobenzyl)oxy)pyridin-2-yl)-3-
20 fluorophenoxy)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid;
21] 2-(4-(6-((2-fluoro-4-(trifluoromethyl)benzyl)oxy)pyridin-2-yl)benzyl)-1-
(oxazol-5-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid;
10
22] 2-(3-chloro-4-(6-((4-chloro-2-fluorobenzyl)oxy)pyridin-2-yl)benzyl)-1-
(oxazol-5-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid;
23] 2-(4-(6-((4-chloro-2-fluorobenzyl)oxy)pyridin-2-yl)-3-fluorobenzyl)-1-
(oxazol-5-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid;
24] 2-(4-(6-((4-chloro-2-fluorobenzyl)oxy)5 pyridin-2-yl)benzyl)-1-((4-propyl-
4H-1,2,4-triazol-3-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid;
25] 2-(4-(6-((2-fluoro-4-(trifluoromethyl)benzyl)oxy)pyridin-2-yl)benzyl)-1-
((4-propyl-4H-1,2,4-triazol-3-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid;
26] 2-(3-chloro-4-(6-((4-chloro-2-fluorobenzyl)oxy)pyridin-2-yl)benzyl)-1-
10 ((4-propyl-4H-1,2,4-triazol-3-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid;
27] 2-(4-(6-((4-chloro-2-fluorobenzyl)oxy)pyridin-2-yl)-3-fluorobenzyl)-1-
((4-propyl-4H-1,2,4-triazol-3-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid;
28] 2-(4-(6-((4-chloro-2-fluorobenzyl)oxy)pyridin-2-yl)phenoxy)-1-
((tetrahydrofuran-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid;
15 29] (S)-2-(4-(6-((2-fluoro-4-(trifluoromethyl)benzyl)oxy)pyridin-2-
yl)benzyl)-1-((tetrahydrofuran-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid;
30] (S)-2-(4-(6-((4-chloro-2-fluorobenzyl)oxy)pyridin-2-yl)-2-fluorobenzyl)-
1-((tetrahydrofuran-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid;
31] (S)-2-(4-(6-((4-chloro-2-fluorobenzyl)oxy)pyridin-2-yl)-2-
20 fluorophenoxy)-1-((tetrahydrofuran-2-yl)methyl)-1H-benzo[d]imidazole-6-
carboxylic acid;
11
32] (S)-2-(2-chloro-4-(6-((4-chloro-2-fluorobenzyl)oxy)pyridin-2-
yl)phenoxy)-1-((tetrahydrofuran-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic
acid;
33] (R)-2-(4-(6-((4-chloro-2-fluorobenzyl)oxy)pyridin-2-yl)benzyl)-1-
((tetrahydrofuran-3-yl)methyl)-1H-benzo[5 d]imidazole-6-carboxylic acid;
34] (S)-2-(3-chloro-4-(6-((4-chloro-2-fluorobenzyl)oxy)pyridin-2-yl)benzyl)-
1-((tetrahydrofuran-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid;
35] (S)-2-(4-(6-((4-chloro-2-fluorobenzyl)oxy)pyridin-2-yl)benzyl)-1-
((tetrahydrofuran-3-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid;
10 36] (S)-2-(4-(6-((2-fluoro-4-(trifluoromethyl)benzyl)oxy)pyridin-2-
yl)benzyl)-1-((tetrahydrofuran-3-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid;
and
37] (S)-2-(3-chloro-4-(6-((4-chloro-2-fluorobenzyl)oxy)pyridin-2-yl)benzyl)-
1-((tetrahydrofuran-3-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid.
15 The compounds included in the category of the Formula 1 described above may
exhibit excellent GLP-1 receptor agonist activity, and thus, they exhibit a
hypoglycemic effect and a positive effect on pancreatic beta cells so that they can be
effectively used to treat various metabolic diseases.
Meanwhile, the compound represented by Formula 1 may have an asymmetric
20 carbon center, and when it has an asymmetric carbon center, it may be present as an
optical isomer, a partial optical isomer or a racemate thereof, and all types of isomers,
including these, may be included in the category of the compounds according to one
embodiment of the present invention. It is obvious that any type of isomer is also
12
included in the category of the compounds of one embodiment. Hereinafter, the term
“isomer” used herein may refer to the generic term for different compounds having the
same molecular formula, the “optical isomer” may refer to the generic term for all
stereoisomers that may exist for the compounds of one embodiment, including the
5 same geometric isomers.
In the compound represented by Formula 1 according to one embodiment, it is
understood that each substituent may be attached to a chiral center of the carbon atom.
In addition, any asymmetric carbon atom of the compound of one embodiment may be
present in any form of an (R)-, (S)- or (R, S)-configuration, and suitably, may be
10 present in an (R)- or (S)-configuration, which are separate forms. In addition, the
compound of one embodiment may be present in any form of possible isomers or
mixtures thereof, for example, any form of pure geometric isomers, diastereomers,
optical isomers, racemates, and mixtures thereof. In addition, when the compound
of one embodiment has a double bond, each substituent binding to a double bond may
15 be an E or Z configuration. In addition, when the compound of one embodiment
contains a disubstituted cycloalkyl, each substituent of the cycloalkyl may have a cis
or trans configuration.
Meanwhile, the term “pharmaceutically acceptable salt” used herein may be
the generic term for salts preferred in terms of pharmaceutical, biological or other
20 properties, which equivalently ensure the biological efficacy and properties of the
compound of Formula 1 according to one embodiment. Non-limiting examples of
the salt may include a salt to which an inorganic or organic base is added to the
compound of Formula 1, or an acid addition salt. Examples of an organic acid that
13
can form such an acid addition salt may include acetic acid, propionic acid, glycolic
acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid,
tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic
acid, ethanesulfonic acid, p-toluenesulfonic acid, or salicylic acid, and examples of an
inorganic acid may include hydrochloric 5 acid, hydrobromic acid, sulfuric acid, nitric
acid or phosphoric acid.
The pharmaceutically acceptable salt of the compound of the above-described
embodiment may be synthesized from a free base-type compound, or a basic or acidic
residue derived therefrom by a conventional chemical method. In addition, a second
10 pharmaceutically acceptable salt may be synthesized from a first pharmaceutically
acceptable salt. As a specific example, the acid addition salt of the compound of one
embodiment may be obtained by reacting the free base-type compound with a
stoichiometric amount of an appropriate acid. Here, the reaction may be performed
in water, an organic solvent or a mixture thereof, and specifically, in a non-aqueous
15 medium such as ether, ethyl acetate, ethanol, isopropanol or acetonitrile. In addition,
depending on the type of pharmaceutically acceptable salt, each type of salt may be
obtained by a conventional reaction well known to those of ordinary skill in the art.
Meanwhile, according to another embodiment of the present invention, a
pharmaceutical composition for preventing or treating a metabolic disease, which
20 includes a compound represented by Formula 1 described above, an isomer thereof or
a pharmaceutically acceptable salt thereof as an active ingredient is provided. As
described above, since compounds represented by Formula 1 according to the present
invention may exhibit a GLP-1 receptor (GLP-1R) activating activity, the
14
pharmaceutical composition containing such a compound may have an effective blood
sugar lowering action and a positive effect on pancreatic beta cells, and exhibit an
effect of improving lipid metabolism, which is a chronic cardiovascular risk factor,
and thus, they are effective in treating and/or preventing a disease associated with the
activity of GLP-1 receptor, for example, a 5 metabolic disease or neurodegenerative
disease. The metabolic disease may be a disease selected from the group consisting
of diabetes (preferably, type 2 diabetes), hypertension, hypoglycemia, hyperlipidemia
(dyslipidemia), atherosclerosis, coronary artery disease, cardiovascular disorders,
abnormal blood clotting, obesity, diabetic complications, diabetic retinopathy, liver
10 disease, hepatobiliary disease, fatty liver, alcoholic steatohepatitis, chronic kidney
disease, insulin resistance and impaired glucose tolerance. The neurodegenerative
disease may be a disease selected from the group consisting of Parkinson’s disease and
Alzheimer’s disease.
The pharmaceutical composition containing a compound represented by
15 Formula 1 described above, an isomer thereof or a pharmaceutically acceptable salt
thereof as an active ingredient may be used in the form of a conventional
pharmaceutical preparation. That is, the pharmaceutical composition may be
administered in various dosage forms such as oral or parenteral forms in actual clinical
administration, and may be suitably administered in an oral form. In addition, the
20 pharmaceutical composition may be formulated by further adding a pharmaceutically
acceptable diluent or excipient such as a conventional filler, thickener, binder, wetting
agent, disintegrant or surfactant depending on the dosage form.
15
A solid preparation for oral administration may be a tablet, a pill, powder, a
granule or a capsule, and the solid preparation may be provided by being mixed with
an active ingredient such as starch, calcium carbonate, sucrose, lactose or gelatin. In
addition, other than an excipient, a lubricant such as magnesium stearate or talc may
be used. In addition, a liquid preparation for 5 oral administration may be a suspension,
an oral liquid, an emulsion or a syrup, and the liquid preparation may contain various
excipients, for example, a wetting agent, a sweetening agent, a flavoring agent or a
preservative, in addition to a simple diluent such as water or a liquid paraffin. In
addition, a preparation for parenteral administration may be a sterilized aqueous
10 solution, a non-aqueous solvent, a suspension, an emulsion, a freeze-dried preparation
or a suppository. The parenteral preparation may include a non-aqueous solvent, and
as a suspending agent, propylene glycol, polyethylene glycol, a vegetable oil such as
olive oil, or an injectable ester such as ethyl oleate may be used. As a base for the
suppository, Witepsol, Macrogol, Tween 61, cacao butter, laurin or glycerogelatin may
15 be used.
Moreover, the compound represented by Formula 1 of the pharmaceutical
invention containing the present or pharmaceutically acceptable salt thereof as an
active ingredient, and an isomer composition thereof may exhibit an effective amount
in an administration range of approximately 0.1 to 1,000 mg. The composition may
20 be administered at various doses and in various ways, for example, once a day or
several times by dividing daily doses, depending on a patient’s body weight, age, sex,
health condition, a diet, administration time, an administration method, an excretion
rate and the severity of a disease.
16
The present invention also provides a method of preparing the composition
represented by Formula 1.
Hereinafter, to help understanding the present invention, the method of
preparing the compound represented by Formula 1 will be described based on
exemplary reaction schemes. However, 5 those of ordinary skill in the art to which the
present invention belongs may prepare the compound presented by Formula 1 by
various methods based on the structure of Formula 1, and these methods will be
construed as being included in the scope of the present invention. That is, the
compound represented by Formula 1 may be prepared by a combination of various
10 synthetic methods disclosed in the specification or in the related art, which will be
understood as being included in the scope of the present invention, and the method of
preparing the compound of Formula 1 is not limited to those to be described below.
In one exemplary embodiment, when A of the compound of Formula 1
15 according to the present invention is carbon, the compound of Formula 1 may be
prepared by a preparation method including the following steps:
1) reacting a compound of Formula 2 below with a compound of Formula 3
below in the presence of a palladium catalyst to obtain a compound of Formula 4 below;
2) reacting the compound of Formula 4 below obtained in step 1) with a
20 compound of Formula 5 below in the presence of a palladium catalyst, followed by
hydrolyzing the resulting reaction product to obtain a compound of Formula 6 below;
and
17
3) coupling the compound of Formula 6 below obtained in step 2) with a
compound of Formula 7 below, followed by condensing and hydrolyzing the resulting
reaction product to obtain the compound of Formula 1 below.
The bases used in steps 1) and 2) may be a material selected from the group
consisting of a C1-4 trialkylamine, diisopropylethylene 5 amine (DIPEA, Hunig's base),
pyridine, K2CO3, KOH, NaOH, Na2CO3, NaOAc, Ca(OH)2, NaHCO3, Cs2CO3 and
LiOH, which may be used alone or in combination thereof, and ligands used in steps
1) and 2) may be triarylphosphines, trialkylphosphines, biaryl (dialkyl)phosphines,
diphosphines, N-heterocyclic carbenes, cyclopentadienides, acetylacetonates,
10 diamines, bipyridines, pyridines, DIOP, DiPAMP, BINAP, chiraphos or the like, but is
not limited thereto.
The hydrolysis of step 2) may be performed using NaOH, KOH or LiOH at 0
to 80 ℃, 10 to 70 ℃, 20 to 60 ℃, room temperature or 50 ℃, but is not limited thereto.
In addition, the reaction may be performed through stirring for a suitable time, which
15 may be properly controlled.
The preparation method described above may be represented by Reaction
Scheme 1:
[Reaction Scheme 1]
18
In an exemplary embodiment, when A of the compound of Formula 1 according
to the present invention is oxygen, the compound of Formula 1 may be prepared by a
5 preparation method including the following steps:
1’) coupling a compound of Formula 4 below with a compound of Formula 8
below to obtain a compound of Formula 9 below; and
2’) conducting a substitution reaction of the compound of Formula 9 below
obtained in step 1’) with a compound of Formula 10 below in the presence of a base,
10 followed by hydrolyzing the resulting reaction product to obtain the compound of
Formula 1 below.
All of bases, ligands and hydrolysis conditions used in the preparation method
may be the same as those described in the preparation method used when A is carbon.
19
The preparation method described above may be represented by Reaction
Scheme 2 below.
[Reaction Scheme 2]
5
The compound of Formula 10 used in Reaction Scheme 2 may be prepared by
a preparation method, which includes:
a) conducting a cyclization reaction of the compound of Formula 6 below, and
then a substitution reaction with a benzyl halide to obtain a compound of Formula 11
10 below; and
b) conducting an oxidation reaction of the compound of Formula 11 obtained
in step a) to obtain the compound of Formula 10.
The cyclization reaction of step a) may be performed using a suitable coupling
agent. Examples of the coupling agent may include 1,1’-thiocarbonyldiimidzole
15 (TCDI), 1,1’-carbonyldiimidzole (CDI) or the like, but is not limited thereto. In
20
addition, the base used in step a) may be the same as described in the preparation
method used when A is carbon.
In addition, the oxidation reaction of step b) may be performed using a suitable
oxidant. Examples of the oxidant may include m-chloroperoxybenzoic acid (m-
CPBA), hydrogen 5 peroxide, potassium peroxymonosulfate, sodium periodate, sodium
percarbonate, potassium permanganate, ruthenium oxide or the like, but is not limited
thereto. The oxidant may be used in the presence of one or more additives, for
example, KF, KHCO3, NEt3, AcONa, or the like. Those of ordinary skill in the art
may recognize that an additive may be selected depending on the oxidant and reaction
10 conditions to be used.
The preparation method described above may be represented by Reaction
Scheme 3 below.
[Reaction Scheme 3]
15
21
In an exemplary embodiment, when A of the compound of Formula 1 is
nitrogen, the compound of Formula 1 may be prepared by a preparation method
including the following steps:
1”) coupling a compound of Formula 4 below with a compound of Formula 12
5 below to obtain a compound of Formula 13 below; and
2”) conducting a substitution reaction of the compound of Formula 13 below
obtained in step 1”) with a compound of Formula 14 in the presence of acid catalyst,
followed by hydrolyzing the resulting reaction product to obtain the compound of
Formula 1 below.
10 The preparation method described above may be represented by Reaction
Scheme 4 below.
[Reaction Scheme 4]
22
All of bases, ligands and hydrolysis conditions used in the preparation method
may be the same as those described in the preparation method used when A is carbon.
In addition, the acid catalyst used in step 2”) may be one selected from the
group consisting of acetic acid, sulfuric acid, paratoluenesulfonic acid, hydrochloric
acid, phosphoric 5 acid and nitric acid, but is not limited thereto.
In Reaction Schemes 1 to 4, m, n, Ra, R1, R2, R3, R4, Z1, Z2, Z3, Z4, Z5, Z6 and
Z7 are as defined in Formula 1;
R5 is alkyl; and
10 X is halo, and preferably, Cl, Br or I.
A compound not specifically described in the preparation method of the
specification is a known compound, or a compound that can be easily synthesized from
a known compound by a known synthetic method or a similar method thereto.
15 The compound of Formula 1 obtained through the above-described method
may be isolated or purified by various methods including recrystallization,
iontophoresis, silica gel column chromatography or ion exchange resin
chromatography from a reaction product.
As described above, the compounds according to the present invention, and
20 starting materials or intermediates for preparing the same may be synthesized by
various methods, and the methods should be construed as being included in the scope
of the present invention with respect to the preparation of the compound represented
by Formula 1.
【Advantageous Effects of Invention】
23
A novel compound according to the present invention is useful as an agent for
treating or preventing obesity or various metabolic diseases such as diabetes and
hyperlipidemia due to excellent GLP-1 agonist activity and an excellent DMPK profile.
【Mode for the Invention】
Herein after, the present invention will 5 be described in further detail with
reference to the following examples and experimental examples. However, the
following examples and experimental examples are only exemplary, and merely
provided to more easily understand the present invention, and the present invention is
not limited thereto.
10
In the examples, the following abbreviations are defined to represent the
following materials.
DMF: dimethylformamide
15 THF: tetrahydrofuran
TEA: triethylamine
EtOAc: ethyl acetate
MgSO4: magnesium sulfate
MPLC: Medium-Pressure Liquid Chromatography
20 Pd/C: palladium on carbon
AcOH: acetic acid
HCl: hydrochloric acid
CS2: carbon disulfide
NaH: sodium hydride
24
DCM: dichloromethane
mCPBA: 3-chloroperbenzoic acid
NaHCO3: sodium bicarbonate
t-BuOK: potassium tert-butoxide
5 Cs2CO3: cesium carbonate
K2CO3: potassium carbonate
BINAP: (2,2'-bis(diphenylphosphino)-1,1'-binaphthyl)
Pd2(dba)3: tris(dibenzylideneacetone)dipalladium
Fe: iron
10 NH4Cl: ammonium chloride
CDI: carbodiimidazole
DCE: 1,2-dichloroethane
POCl3: phosphoryl chloride
NaOH: sodium hydroxide
15 H2O: water
MeOH: methanol
HOBt: hydroxybenzotriazole
EDC: 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide
Dppf: 1,1'-bis(diphenylphosphino)ferrocene
20 Na2SO4: sodium sulfate
NMR: Nuclear Magnetic Resonance
HATU: (1-[bis(dimethylamino)methylidene]-1H-1,2,3-triazolo[4,5-
b]pyridinium 3-oxide hexafluoro phosphate
25
[Preparation Example 1: Preparation of 2-chloro-6-((4-chloro-2-
fluorobenzyl)oxy)pyridine]
2-chloro-6-((4-chloro-2-fluorobenzyl)oxy)pyridine
(4-chloro-2-fluorophenyl)5 methanol (1236 mg, 7 mmol) was dissolved in 10
mL of DMF, and NaH (60% dispersion in mineral oil, 420 mg, 10.5 mmol) was added
at 0 °C. After stirring at the same temperature for 10 minutes, 2,6-dichloropyridine
(1036 mg, 7 mmol) was added and then stirred for 2 hours at room temperature.
Water was added after the reaction, followed by extraction with EtOAc. An organic
10 layer was dried with Na2SO4, concentrated under reduced pressure and purified by
using MPLC, thereby obtaining 2-chloro-6-((4-chloro-2-fluorobenzyl)oxy)pyridine
(1.06 g, 4.21 mmol, 60%).

【CLAIMS】
【Claim 1】
A compound of Formula 1, an isomer or a pharmaceutically acceptable salt
thereof:
5 [Formula 1]
wherein,
A is -(CH2)m-, -O- or -N(Ra)-, wherein m is an integer ranging from 1 to 3, and
Ra is hydrogen or alkyl;
10 R1 is (cycloalkyl)alkyl, (heterocycloalkyl)alkyl, (aryl)alkyl or (heteroaryl)alkyl;
R2, R3 or R4 is each independently hydrogen, deuterium, halo, alkyl, alkoxy,
alkylamine or a nitrile group;
n is an integer ranging from 1 to 4, wherein when n is an integer of 2 or more,
each of R2, R3 and R4 may be the same or different from each other; and
15 Z1, Z2, Z3, Z4, Z5, Z6 or Z7 each independently represents CH, CF, CCl, CBr,
CI or N;
wherein the alkyl, alkoxy, alkylamine, cycloalkyl, heterocycloalkyl, aryl, or
heteroaryl is unsubstituted or substituted.
【Claim 2】
140
The compound, the isomer or the pharmaceutically acceptable salt thereof of
claim 1, wherein the A is -CH2-, -O- or -N(Ra)-, wherein the Ra is hydrogen or C1-3
alkyl.
【Claim 3】
The compound, the isomer or the pharmaceutically 5 acceptable salt thereof of
claim 1, wherein the R1 may be (C3-8 cycloalkyl)C1-3 alkyl, (4- to 10-membered
heterocycloalkyl)C1-3 alkyl, (C6-10 aryl)alkyl or (4- to 10-membered heteroaryl)C1-3
alkyl, wherein the heterocycloalkyl or heteroaryl is one containing 1 to 3 heteroatoms
selected from the group consisting of N, O and S; and
10 the R2, R3 or R4 is each independently hydrogen, deuterium, F, Cl, Br, I, C1-3
alkyl, C1-3 alkoxy, C1-3 alkylamine or a nitrile group, n is an integer ranging from 1 to
3, wherein when n is an integer of 2 or more, each of R2, R3 and R4 may be the same
or different from each other.
【Claim 4】
15 The compound, the isomer or the pharmaceutically acceptable salt thereof of
claim 1, wherein Z1, Z2, Z3, Z4, Z5, Z6 or Z7 is each independently CH, CF or CCl.
【Claim 5】
The compound, the isomer or the pharmaceutically acceptable salt thereof of
claim 1, wherein the R1 is cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl,
20 cyclohexylmethyl, oxetanylmethyl, tetrahydrofuranylmethyl,
tetrahydropyranylmethyl, oxazolylmethyl, benzyl, unsubstituted or propyl-substituted
triazolylmethyl, or unsubstituted or ethyl-substituted imidazolylmethyl.
【Claim 6】
141
The compound, the isomer or the pharmaceutically acceptable salt thereof of
claim 1, wherein the compound represented by Formula 1 is selected from the group
consisting of the following compounds:
1] 2-(4-(6-((4-chloro-2-fluorobenzyl)oxy)pyridin-2-yl)benzyl)-1-
((tetrahydrofuran-2-yl)methyl)-1H-benzo[5 d]imidazole-6-carboxylic acid;
2] (S)-2-(4-(6-((4-chloro-2-fluorobenzyl)oxy)pyridin-2-yl)benzyl)-1-(oxetan-
2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid;
3] (S)-2-(4-(6-((4-cyano-2-fluorobenzyl)oxy)pyridin-2-yl)benzyl)-1-(oxetan-
2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid;
10 4] 2-(4-(6-((4-cyano-2-fluorobenzyl)oxy)pyridin-2-yl)benzyl)-1-((1-ethyl-1Himidazol-
5-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid;
5] 2-(4-(6-((4-cyano-2-fluorobenzyl)oxy)pyridin-2-yl)phenoxy)-1-((1-ethyl-
1H-imidazol-5-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid;
6] (S)-2-(4-(6-((4-cyano-2-fluorobenzyl)oxy)pyridin-2-yl)phenoxy)-1-
15 (oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid;
7] (S)-2-(4-(6-((4-chloro-2-fluorobenzyl)oxy)pyridin-2-yl)phenoxy)-1-
(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid;
8] 2-(4-(6-((4-chloro-2-fluorobenzyl)oxy)pyridin-2-yl)benzyl)-1-(oxazol-5-
ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid;
20 9] 2-(4-(6-((4-cyano-2-fluorobenzyl)oxy)pyridin-2-yl)phenoxy)-1-(oxazol-5-
ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid;
10] (S)-2-(4-(6-((4-chloro-2-fluorobenzyl)oxy)pyridin-2-yl)-2-fluorobenzyl)-
1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid;
142
11] 2-(4-(6-((4-chloro-2-fluorobenzyl)oxy)pyridin-2-yl)-2-fluorobenzyl)-1-
(oxazol-5-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid;
12] (S)-2-(4-(6-((4-chloro-2-fluorobenzyl)oxy)pyridin-2-yl)benzyl)-1-
((tetrahydrofuran-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid;
13] (R)-2-(4-(6-((4-chloro-2-fluorobenzyl)5 oxy)pyridin-2-yl)benzyl)-1-
((tetrahydrofuran-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid;
14] 2-(4-(6-((4-chloro-2-fluorobenzyl)oxy)pyridin-2-yl)benzyl)-1-
((tetrahydro-2H- pyran-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid;
15] (S)-2-(4-(6-((4-chloro-2-fluorobenzyl)oxy)pyridin-2-yl)-3-fluorobenzyl)-
10 1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid;
16] (S)-2-(4-(6-((2-fluoro-4-(trifluoromethyl)benzyl)oxy)pyridin-2-
yl)benzyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid;
17] (S)-2-(4-(6-((4-chloro-2-fluorobenzyl)oxy)pyridin-2-yl)-2-
fluorophenoxy)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid;
15 18] (S)-2-(2-chloro-4-(6-((4-chloro-2-fluorobenzyl)oxy)pyridin-2-
yl)phenoxy)-1-(oxetan-2-ylmethyl)-1H-benzo[d] imidazol-6-carboxylic acid;
19] (S)-2-(4-(6-((4-chloro-2-fluorobenzyl)oxy)pyridin-2-yl)-2,6-
difluorophenoxy)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid;
20] (S)-2-(4-(6-((4-chloro-2-fluorobenzyl)oxy)pyridin-2-yl)-3-
20 fluorophenoxy)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid;
21] 2-(4-(6-((2-fluoro-4-(trifluoromethyl)benzyl)oxy)pyridin-2-yl)benzyl)-1-
(oxazol-5-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid;
143
22] 2-(3-chloro-4-(6-((4-chloro-2-fluorobenzyl)oxy)pyridin-2-yl)benzyl)-1-
(oxazol-5-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid;
23] 2-(4-(6-((4-chloro-2-fluorobenzyl)oxy)pyridin-2-yl)-3-fluorobenzyl)-1-
(oxazol-5-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid;
24] 2-(4-(6-((4-chloro-2-fluorobenzyl)oxy)5 pyridin-2-yl)benzyl)-1-((4-propyl-
4H-1,2,4-triazol-3-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid;
25] 2-(4-(6-((2-fluoro-4-(trifluoromethyl)benzyl)oxy)pyridin-2-yl)benzyl)-1-
((4-propyl-4H-1,2,4-triazol-3-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid;
26] 2-(3-chloro-4-(6-((4-chloro-2-fluorobenzyl)oxy)pyridin-2-yl)benzyl)-1-
10 ((4-propyl-4H-1,2,4-triazol-3-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid;
27] 2-(4-(6-((4-chloro-2-fluorobenzyl)oxy)pyridin-2-yl)-3-fluorobenzyl)-1-
((4-propyl-4H-1,2,4-triazol-3-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid;
28] 2-(4-(6-((4-chloro-2-fluorobenzyl)oxy)pyridin-2-yl)phenoxy)-1-
((tetrahydrofuran-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid;
15 29] (S)-2-(4-(6-((2-fluoro-4-(trifluoromethyl)benzyl)oxy)pyridin-2-
yl)benzyl)-1-((tetrahydrofuran-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid;
30] (S)-2-(4-(6-((4-chloro-2-fluorobenzyl)oxy)pyridin-2-yl)-2-fluorobenzyl)-
1-((tetrahydrofuran-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid;
31] (S)-2-(4-(6-((4-chloro-2-fluorobenzyl)oxy)pyridin-2-yl)-2-
20 fluorophenoxy)-1-((tetrahydrofuran-2-yl)methyl)-1H-benzo[d]imidazole-6-
carboxylic acid;
144
32] (S)-2-(2-chloro-4-(6-((4-chloro-2-fluorobenzyl)oxy)pyridin-2-
yl)phenoxy)-1-((tetrahydrofuran-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic
acid;
33] (R)-2-(4-(6-((4-chloro-2-fluorobenzyl)oxy)pyridin-2-yl)benzyl)-1-
((tetrahydrofuran-3-yl)methyl)-1H-benzo[5 d]imidazole-6-carboxylic acid;
34] (S)-2-(3-chloro-4-(6-((4-chloro-2-fluorobenzyl)oxy)pyridin-2-yl)benzyl)-
1-((tetrahydrofuran-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid;
35] (S)-2-(4-(6-((4-chloro-2-fluorobenzyl)oxy)pyridin-2-yl)benzyl)-1-
((tetrahydrofuran-3-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid;
10 36] (S)-2-(4-(6-((2-fluoro-4-(trifluoromethyl)benzyl)oxy)pyridin-2-
yl)benzyl)-1-((tetrahydrofuran-3-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid;
and
37] (S)-2-(3-chloro-4-(6-((4-chloro-2-fluorobenzyl)oxy)pyridin-2-yl)benzyl)-
1-((tetrahydrofuran-3-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid.
15 【Claim 7】
A pharmaceutical composition for preventing or treating a metabolic disease
or a neurodegenerative disease, comprising the compound of any one of claims 1 to 6,
or an isomer or a pharmaceutically acceptable salt thereof, and a pharmaceutically
acceptable excipient, diluent or carrier.
20 【Claim 8】
The pharmaceutical composition of claim 7, wherein the metabolic disease is
selected from the group consisting of diabetes, hypertension, hypoglycemia,
hyperlipidemia (dyslipidemia), atherosclerosis, coronary artery disease,
145
cardiovascular disorders, abnormal blood clotting, obesity, diabetic complications,
diabetic retinopathy, liver disease, hepatobiliary disease, fatty liver, alcoholic
steatohepatitis, chronic kidney disease, insulin resistance and impaired glucose
tolerance.
5 【Claim 9】
The pharmaceutical composition of claim 7, wherein the neurodegenerative
disease is selected from the group consisting of Parkinson’s disease and Alzheimer’s
disease.
【Claim 10】
10 A method of preparing a compound of Formula 1 below, comprising:
1) reacting a compound of Formula 2 below with a compound of Formula 3
below in the presence of a palladium catalyst to obtain a compound of Formula 4 below;
2) reacting the compound of Formula 4 below obtained in step 1) with a
compound of Formula 5 below in the presence of a palladium catalyst, followed by
15 hydrolyzing the resulting reaction product to obtain a compound of Formula 6 below;
and
3) coupling the compound of Formula 6 below obtained in step 2) with a
compound of Formula 7 below, followed by condensing and hydrolyzing the resulting
reaction product to obtain the compound of Formula 1 below:
20 [Formula 1]
146
[Formula 2]
[Formula 3]
5
[Formula 4]
[Formula 5]
X N X
1/) ;.....-
(R3)n
147
[Formula 6]
[Formula 7]
5 wherein,
A is carbon;
m, n, R1, R2, R3, R4, Z1, Z2, Z3, Z4, Z5, Z6 and Z7 are the same as defined in
claim 1;
R5 is alkyl; and
10 X is halo.
【Claim 11】
A method of preparing a compound of Formula 1 below, comprising:
1’) coupling a compound of Formula 4 below with a compound of Formula 8
below to obtain a compound of Formula 9 below; and
15 2’) conducting a substitution reaction of the compound of Formula 9 below
obtained in step 1’) with a compound of Formula 10 below in the presence of a base,
148
followed by hydrolyzing the resulting reaction product to obtain the compound of
Formula 1 below:
[Formula 1]
5 [Formula 4]
[Formula 8]
[Formula 9]
149
[Formula 10]
wherein,
5 A is oxygen;
n, R1, R2, R3, R4, Z1, Z2, Z3, Z4, Z5, Z6 and Z7 are the same as defined in claim
1; and
X is halo.
【Claim 12】
10 The method of claim 11, wherein the compound of Formula 10 is prepared by
a preparation method comprising following steps:
a) conducting a cyclization reaction of the compound of Formula 6 below, and
then a substitution reaction with a benzyl halide to obtain a compound of Formula 11
below; and
15 b) conducting an oxidation reaction of the compound of Formula 11 obtained
in step a) to obtain the compound of Formula 10;
150
[Formula 6]
[Formula 11]
5 【Claim 13】
A method of preparing a compound of Formula 1 below, comprising:
1”) coupling a compound of Formula 4 below with a compound of Formula 12
below to obtain a compound of Formula 13 below; and
2”) conducting a substitution reaction of the compound of Formula 13 below
10 obtained in step 1”) with a compound of Formula 14 in the presence of base, followed
by hydrolyzing the resulting reaction product to obtain the compound of Formula 1
below;
[Formula 1]
151
[Formula 4]
[Formula 12]
5 [Formula 13]
[Formula 14]
wherein,
10 A is nitrogen;
n, Ra, R1, R2, R3, Z1, Z2, Z3, Z4, Z5, Z6 and Z7 are the same as defined in claim
1; and
152
X is halo.