KR20210059584A - Glp-1 receptor agonist and use thereof - Google Patents

Abstract

The present invention provides a novel compound represented by chemical formula 1, an optical isomer, or a pharmaceutically acceptable salt thereof. The novel compound according to the present invention exhibits excellent activity as an agonist for a GLP-1 receptor compound. The present invention can provide an oral fast-acting formulation of an excess extract having improved bioavailability by improving solubility and dissolution rate, and a method for manufacturing the same.

Description

GLP-1 receptor agonist and uses thereof {GLP-1 RECEPTOR AGONIST AND USE THEREOF}

Provided herein are novel GLP-1R agonist compounds, methods of making such compounds, and uses of such compounds.

Insulin is a peptide secreted from the beta cells of the pancreas and plays a very important role in regulating blood sugar in the body. Diabetes is a metabolic disease in which the concentration of glucose in the blood increases due to insufficient secretion of insulin or the normal functioning. A case in which blood sugar rises due to the inability to secrete insulin from the pancreas is referred to as type 1 diabetes, and administration of insulin is required to treat it.

On the other hand, a case in which the blood sugar in the body cannot be controlled and rises due to insufficient insulin secretion or the secreted insulin not working properly is called type 2 diabetes, and treatment is performed using an oral hypoglycemic agent containing a chemical substance as a main component.

It is well known through large-scale clinical studies that strict blood sugar control close to normal blood sugar in diabetes treatment is important for preventing various complications arising from diabetes.

As a candidate compound that can lower blood sugar by stimulating the secretion of insulin strongly, there is a hormone called glucagon like peptide-1 (GLP-1). GLP-1 was first discovered in 1985 as an incretin hormone secreted by L-cells in the ileum and colon. GLP-1 increases insulin secretion by increasing a receptor called GLP-1R (Glucagon like peptide-1 Receptor). GLP-1R is secreted by stimulation by absorbed nutrients or blood sugar levels. Diabetes treatment using GLP-1 has the advantage that hypoglycemia does not occur because insulin is secreted depending on the glucose concentration. In addition, it is known that this hormone has the effect of lowering the movement of the upper digestive system and suppressing appetite, and may proliferate the existing beta cells of the pancreas.

With this characteristic, it is applied as a treatment method for type 2 diabetes, but it was a candidate compound that had many obstacles in developing it as a drug because the half-life in blood was only 2 minutes. In order to overcome the shortcomings of GLP-1, which has been a problem due to its short action time, it is a GLP-1 analog and a DPP-₃ inhibitor that is resistant to an enzyme called Dipeptidyl Peptidase IV (DPP-IV) that destroys GLP-1 in the blood. Therapies have been developed in two ways (Oh, SJ "Glucagon-like Peptide-1 Analogue and Dipeptidyl Peptidase-IV Inhibitors" Journal of the Korean Endocrine Society Vol. 21(6), pp. 437-447, 2006; Holst, JJ " Glucagon like peptide 1: a newly discovered gastrointestinal hormone" Gastroenterology Vol. 107, pp. 1848-1855, 1994).

Among insulin-secreting peptides other than GLP-1, exendin is a peptide found in the salivary secretions of the Mexican bead lizard and the American poison lizard, endogenous reptiles of Arizona and North Mexico. Exendin-3 is present in the salivary secretions of Heroderma horridum , and Exendin-4 is present in the salivary secretions of Heloderma suspectum , and has high homology with the GLP-1 sequence. (Goke et al., J. Biol. Chem. Vo1. 268, pp. 19650-19655, 1993). Pharmacological research reports state that exendin-4 can act on the GLP-1 receptor on certain insulin-secreting cells, on scattered staphylococcus cells from the pancreas of guinea pigs and gastric parietal cells, and these peptides stimulate somatostatin release. And was reported to inhibit gastrin release in the separated stomach.

Recently, research is being conducted to discover an agent (agonist) that activates GLP-1R and use it as a candidate substance for diabetes treatment.

Recently, in Korea, it has been reported that DA-15864, a new low-molecular compound capable of selectively stimulating the GLP-1 receptor in humans and rats, is a GLP-1 receptor agonist that can be administered orally to treat diabetes and obesity (Moon, H.-S. et al., "The development of non-peptide glucagon-like peptide 1 receptor agonist for the treatment of type 2 diabetes" Arch. Pharm. Res. Vol. 34(7), pp. 1041-1043, 2011).

In the present invention, novel agonist compounds having an excellent effect of increasing the activity of the GLP-1 receptor were screened from various candidate substances, and it was confirmed that these compounds exhibited excellent activity as an agonist to the GLP-1 receptor compound.

The present invention relates to a compound represented by the following formula (1), an optical isomer thereof, or a pharmaceutically acceptable salt thereof:

[Formula 1]

In Formula 1,

R ₁ is substituted or provided with -C(=O)R _a, -S(=O) ₂ R _a , -(C ₁ -C ₃ alkyl)OH, -CN, and -(C ₁ -C _{4 alkyl)} It is any one selected from the group consisting of cyclic tetrazolyl;

R _a is one selected from the group consisting of -OH, -O-(C ₁ -C ₄ alkyl) and -NR _a1 R _a2;

R _a1 and R _a2 are each independently any one selected from the group consisting of hydrogen, -OH, -(C ₁ -C ₄ alkyl) and -(C ₁ -C ₄ alkyl)C(=O)OH;

Y ₁ and Y ₂ are each independently -CH- or -N-;

R ₂ is a substituted or unsubstituted C ₆ ~C ₁₂ aryl, a substituted or unsubstituted C ₅ ~C ₁₂ heteroaryl, a substituted or unsubstituted C ₃ ~C ₈ heterocycloalkyl, a substituted or unsubstituted C ₃ ~ C ₈ cycloalkyl, and any one selected from the group consisting of -C(=O)R _b , wherein substituted, aryl, heteroaryl, heterocycloalkyl and cycloalkyl are at least one or more -OH, -(C ₁ -C ₄ alkyl), halogen, or -CN;

R _b is -(C ₁ -C ₄ alkyl) or -NR _b1 R _b2 ;

R _b1 and R _b2 are each independently hydrogen or -(C ₁ -C ₄ alkyl);

Q ₁ and Q ₂ is carbon or nitrogen, each independently, where, if Q ₁ is nitrogen, Q ₂ is carbon, if Q ₂ is nitrogen, Q ₁ is carbon;

,

,

또는

이고;A ₁ is

,

,

or

ego;

은 적어도 하나의 질소를 함유하는 치환되거나 비치환된 C₃～C₈ 헤테로시클로알킬, 또는 적어도 하나의 질소를 함유하는 치환되거나 비치환된 C₃～C₁₂ 헤테로바이시클로알킬이고 (여기서, 치환된, 헤테로시클로알킬 및 헤테로바이시클로알킬은 적어도 하나 이상의 -OH, -(C₁-C₄알킬), 할로겐, 또는 -CN으로의 치환이며);

Is a substituted or unsubstituted C ₃ to C ₈ heterocycloalkyl containing at least one nitrogen, or a substituted or unsubstituted C ₃ to C ₁₂ heterobicycloalkyl containing at least one nitrogen, wherein , Heterocycloalkyl and heterobicycloalkyl are substituted with at least one -OH, -(C ₁ -C ₄ alkyl), halogen, or -CN);

R` is hydrogen, or -(C ₁ -C ₄ alkyl);

X is -CR _c -or -N-;

R _c is any one selected from the group consisting of -H, halogen, -CN, -OH, -O-(C ₁ -C ₄ alkyl), -NH ₂ , -NO ₂ and -C ₁ -C _{4 haloalkyl} ego;

W ₁ is -CR _d -or -N-;

W ₂ is -CR _e -or -N-;

W ₃ is -CR _f -or -N-;

R _d to R _f are each independently -H, halogen, -CN, -OH, -O-(C ₁ -C ₄ alkyl), -NH ₂ , -NO ₂ and -C ₁ -C ₄ haloalkyl Is any one selected from the group;

L is any one selected from the group consisting of -O-, -S- and -NR _{g -;}

R _g is -H or -(C ₁ -C ₄ alkyl);

,

및

로 이루어지는 군에서 선택되는 어느 하나이고; A ₂ is

,

And

It is any one selected from the group consisting of;

Z ₁ is -CR _h -or -N-;

Z ₂ is -CR _i -or -N-;

Z ₃ is -CR _j -or -N-;

Z ₄ is -CR _k -or -N-;

Z ₅ is -CR ₁ -or -N-;

R _h to R _l are each independently -H, halogen, -CN, -OH, -O-(C ₁ -C ₄ alkyl), -NH ₂ , -NO ₂ and -C ₁ -C ₄ haloalkyl Is any one selected from the group;

R ₃ and R ₄ are each independently -H, halogen, -CN, -OH, -O-(C ₁ -C ₄ alkyl), -NH ₂ , -NO ₂ and -C ₁ -C ₄ haloalkyl Is any one selected from the group; And

n is an integer of 1 or 2.

In another embodiment of the present invention, the compound represented by Formula 1, an optical isomer thereof, or a pharmaceutically acceptable salt thereof is preferably a compound represented by Formula 2, an optical isomer thereof, or a pharmaceutically acceptable salt thereof. to be:

[Formula 2]

In Chemical Formula 2,

R ₁ is substituted or provided with -C(=O)R _a, -S(=O) ₂ R _a , -(C ₁ -C ₃ alkyl)OH, -CN, and -(C ₁ -C _{4 alkyl)} It is any one selected from the group consisting of cyclic tetrazolyl;

R _a is one selected from the group consisting of -OH, -O-(C ₁ -C ₄ alkyl), and -NR _a1 R _a2;

R _a1 and R _a2 are each independently any one selected from the group consisting of hydrogen, -OH, -(C ₁ -C ₄ alkyl), and -(C ₁ -C _{4 alkyl)C(=O)OH} ;

Y ₁ and Y ₂ are each independently -CH- or -N-;

R ₂ is a substituted or unsubstituted C ₆ ~C ₁₂ aryl, a substituted or unsubstituted C ₅ ~C ₁₂ heteroaryl, a substituted or unsubstituted C ₃ ~C ₈ heterocycloalkyl, a substituted or unsubstituted C ₃ ~ C ₈ cycloalkyl, and any one selected from the group consisting of -C(=O)R _b , wherein substituted, aryl, heteroaryl, heterocycloalkyl and cycloalkyl are at least one or more -OH, -(C ₁ -C ₄ alkyl), halogen, or -CN;

R _b is -(C ₁ -C ₄ alkyl) or -NR _b1 R _b2 ;

R _b1 and R _b2 are each independently hydrogen or -(C ₁ -C ₄ alkyl);

,

,

또는

이고;A ₁ is

,

,

or

ego;

은 적어도 하나의 질소를 함유하는 치환되거나 비치환된 C₃～C₈ 헤테로시클로알킬, 또는 적어도 하나의 질소를 함유하는 치환되거나 비치환된 C₃～C₁₂ 헤테로바이시클로알킬이고 (여기서, 치환된, 헤테로시클로알킬 및 헤테로바이시클로알킬은 적어도 하나 이상의 -OH, -(C₁-C₄알킬), 할로겐, 또는 -CN으로의 치환이며);

Is a substituted or unsubstituted C ₃ to C ₈ heterocycloalkyl containing at least one nitrogen, or a substituted or unsubstituted C ₃ to C ₁₂ heterobicycloalkyl containing at least one nitrogen, wherein , Heterocycloalkyl and heterobicycloalkyl are substituted with at least one -OH, -(C ₁ -C ₄ alkyl), halogen, or -CN);

R` is hydrogen, or -(C ₁ -C ₄ alkyl);

X is -CR _c -or -N-;

R _c is any one selected from the group consisting of -H, halogen, -CN, -OH, -O-(C ₁ -C ₄ alkyl), -NH ₂ , -NO ₂ and -C ₁ -C _{4 haloalkyl} ego;

W ₁ is -CR _d -or -N-;

W ₂ is -CR _e -or -N-;

W ₃ is -CR _f -or -N-;

R _d to R _f are each independently -H, halogen, -CN, -OH, -O-(C ₁ -C ₄ alkyl), -NH ₂ , -NO ₂ and -C ₁ -C ₄ haloalkyl Is any one selected from the group;

L is any one selected from the group consisting of -O-, -S- and -NR _{g -;}

R _g is -H or -(C ₁ -C ₄ alkyl);

,

및

로 이루어지는 군에서 선택되는 어느 하나이고; A ₂ is

,

And

It is any one selected from the group consisting of;

Z ₁ is -CR _h -or -N-;

Z ₂ is -CR _i -or -N-;

Z ₃ is -CR _j -or -N-;

Z ₄ is -CR _k -or -N-;

Z ₅ is -CR ₁ -or -N-;

R _h to R _l are each independently -H, halogen, -CN, -OH, -O-(C ₁ -C ₄ alkyl), -NH ₂ , -NO ₂ and -C ₁ -C ₄ haloalkyl Is any one selected from the group;

R ₃ and R ₄ are each independently -H, halogen, -CN, -OH, -O-(C ₁ -C ₄ alkyl), -NH ₂ , -NO ₂ and -C ₁ -C ₄ haloalkyl Is any one selected from the group; And

n is an integer of 1 or 2.

In another embodiment of the present invention, preferably the compound represented by Formula 1, an optical isomer thereof, or a pharmaceutically acceptable salt thereof is a compound represented by Formula 3, an optical isomer thereof, or a pharmaceutically acceptable salt thereof. to be:

[Formula 3]

In Chemical Formula 3,

R ₁ is -C(=O)R _a ;

R _a is -OH or -O-(C ₁ -C ₄ alkyl);

Y ₁ and Y ₂ are each independently -CH- or -N-;

R ₂ is a substituted or unsubstituted C ₆ ~C ₁₂ aryl, a substituted or unsubstituted C ₅ ~C ₁₂ heteroaryl, a substituted or unsubstituted C ₃ ~C ₈ heterocycloalkyl, a substituted or unsubstituted C ₃ ~ C ₈ cycloalkyl, and any one selected from the group consisting of -C(=O)R _b , wherein substituted, aryl, heteroaryl, heterocycloalkyl and cycloalkyl are at least one or more -OH, -(C ₁ -C ₄ alkyl), halogen, or -CN;

R _b is -(C ₁ -C ₄ alkyl) or -NR _b1 R _b2 ;

R _b1 and R _b2 are each independently hydrogen or -(C ₁ -C ₄ alkyl);

,

,

또는

이고;A ₁ is

,

,

or

ego;

은 적어도 하나의 질소를 함유하는 치환되거나 비치환된 C₃～C₈ 헤테로시클로알킬, 적어도 하나의 질소를 함유하는 치환되거나 비치환된 C₃～C₁₂ 스파이로헤테로시클로알킬, 또는 적어도 하나의 질소를 함유하는 치환되거나 비치환된 C₃～C₁₂ 다리걸친 헤테로바이시클로알킬이고(여기서, 치환된, 헤테로시클로알킬, 스파이로헤테로시클로알킬 및 헤테로바이시클로알킬은 적어도 하나 이상의 -OH, -(C₁-C₄알킬), 할로겐, 또는 -CN으로의 치환이며);

Is a substituted or unsubstituted C ₃ to C ₈ heterocycloalkyl containing at least one nitrogen, a substituted or unsubstituted C ₃ to C ₁₂ spiroheterocycloalkyl containing at least one nitrogen, or at least one nitrogen Is a substituted or unsubstituted C ₃ to C ₁₂ bridged heterobicycloalkyl containing (wherein, substituted, heterocycloalkyl, spiroheterocycloalkyl and heterobicycloalkyl are at least one -OH, -(C ₁ -C ₄ alkyl), halogen, or -CN;

R` is hydrogen, or -(C ₁ -C ₄ alkyl);

X is -CR _c -or -N-;

R _c is any one selected from the group consisting of -H, halogen, -CN, -OH, -O-(C ₁ -C ₄ alkyl), -NH ₂ , -NO ₂ and -C ₁ -C _{4 haloalkyl} ego;

W ₁ is -CR _d -or -N-;

W ₂ is -CR _e -or -N-;

W ₃ is -CR _f -or -N-;

R _d to R _f are each independently -H, halogen, -CN, -OH, -O-(C ₁ -C ₄ alkyl), -NH ₂ , -NO ₂ and -C ₁ -C ₄ haloalkyl Is any one selected from the group;

Z ₁ is -CR _h -or -N-;

Z ₂ is -CR _i -or -N-;

Z ₃ is -CR _j -or -N-;

Z ₄ is -CR _k -or -N-; And

R _h to R _l are each independently -H, halogen, -CN, -OH, -O-(C ₁ -C ₄ alkyl), -NH ₂ , -NO ₂ and -C ₁ -C ₄ haloalkyl It is any one selected from the group.

In another embodiment of the present invention, when X is -N- and W ₁ , W ₂ or W ₃ are each -CR _d --CR _e -or -CR _f -, at least one of _{Z 1} to Z ₄ Is -N-, a compound represented by Formula 1, an optical isomer thereof, or a pharmaceutically acceptable salt thereof.

In another embodiment of the present invention, when X is -N-, _{at least one of W 1} , W ₂ and W ₃ is N, a compound represented by Formula 1, an optical isomer thereof, or a pharmaceutically acceptable salt thereof. to be.

In another embodiment of the present invention, X is -CR _c -, and W ₁ , W ₂ or W ₃ are each -CR _d --CR _e -or -CR _f -. Isomers or pharmaceutically acceptable salts thereof.

In another embodiment of the present invention, X is -CH-, and _{at least one of W 1} , W ₂ and W ₃ is -N-, an optical isomer thereof, or a pharmaceutically acceptable salt thereof. to be.

이며;In another embodiment of the present invention, A ₂ in Formula 1 is

Is;

At least one of Z ₁ to Z ₅ is -N-, which is a compound represented by Formula 1, an optical isomer thereof, or a pharmaceutically acceptable salt thereof.

Specifically, it relates to a compound represented by the following Formula 4, an optical isomer thereof, or a pharmaceutically acceptable salt thereof:

[Formula 4]

In Formula 4, Z ₁ is -CR _h -or -N-; Z ₂ is -CR _i -or -N-;

Z ₃ is -CR _j -or -N-; Z ₄ is -CR _k -or -N-; Z ₅ is -CR ₁ -or -N-; At least one of Z ₁ to Z ₅ is -N-, and L, X, W ₁ , W ₂ , W ₃ , A ₁ , R ₂ , Y ₁ , Y ₂ , and R ₁ are as previously defined in Formula 1 same.

가 적어도 하나의 -N-을 포함함으로써, 헤테로아릴을 구성한다. In the compound represented by Formula 4,

By including at least one -N-, a heteroaryl is formed.

Preferred embodiments satisfying the above Formula 4 include:

1-(oxazol-2-ylmethyl)-2-((4-(6-(pyridin-4-ylmethoxy)pyridin-2-yl)piperazin-1-yl)methyl)-1 H -benzo[ d ]imidazole-6-carboxylic acid;

1-(oxazol-2-ylmethyl)-2-((4-(6-(pyridin-2-ylmethoxy)pyridin-2-yl)piperazin-1-yl)methyl)-1 H -benzo[ d ]imidazole-6-carboxylic acid;

(S)-2-((4-(6-((5-chloro-3-fluoropyridin-2-yl)methoxy)pyridin-2-yl)piperazin-1-yl)methyl)-1- (Oxetan-2-ylmethyl)-1 H -benzo[ d ]imidazole-6-carboxylic acid;

(S)-2-((4-(6-((5-chloro-3-fluoropyridin-2-yl)methoxy)pyridin-2-yl)piperidin-1-yl)methyl)-1 -(Oxetan-2-ylmethyl)-1 H -benzo[ d ]imidazole-6-carboxylic acid;

(S)-2-((4-(6-((5-cyanopyridin-2-yl)methoxy)pyridin-2-yl)piperidin-1-yl)methyl)-1-(oxetane -2-ylmethyl)-1 H -benzo[ d ]imidazole-6-carboxylic acid;

1-(oxazol-2-ylmethyl)-2-((4-(6-(pyridin-3-ylmethoxy)pyridin-2-yl)piperazin-1-yl)methyl)-1 H -benzo[ d ]imidazole-6-carboxylic acid;

(S)-2-((4-(6-((5-cyanopyridin-2-yl)methoxy)pyridin-2-yl)piperazin-1-yl)methyl)-1-(oxetane- 2-ylmethyl)-1 H -benzo[ d ]imidazole-6-carboxylic acid;

(S)-2-((4-(3-((5-chloro-3-fluoropyridin-2-yl)methoxy)phenyl)piperidin-1-yl)methyl)-1-(oxetane -2-ylmethyl)-1 H -benzo[ d ]imidazole-6-carboxylic acid;

(S)-2-((4-(6-((5-cyanopyridin-2-yl)methoxy)pyrazin-2-yl)piperazin-1-yl)methyl)-1-(oxetane- 2-ylmethyl)-1 H -benzo[ d ]imidazole-6-carboxylic acid;

(S)-2-((4-(4-((5-cyanopyridin-2-yl)methoxy)pyrimidin-2-yl)piperidin-1-yl)methyl)-1-(oxy Cetan-2-ylmethyl)-1 H -benzo[ d ]imidazole-6-carboxylic acid;

(S)-2-((4-(3-((5-cyanopyridin-2-yl)methoxy)phenyl)piperazin-1-yl)methyl)-1-(oxetan-2-ylmethyl )-1 H -benzo[ d ]imidazole-6-carboxylic acid;

(S)-2-((4-(6-((5-cyanopyridin-2-yl)methoxy)pyridin-2-yl)piperazin-1-yl)methyl)-3-(oxetane- 2-ylmethyl)-3 H -imidazo[4,5-b]pyridin-5-carboxylic acid;

(S)-2-((4-(3-((5-cyanopyridin-2-yl)methoxy)phenyl)piperazin-1-yl)methyl)-3-(oxetan-2-ylmethyl ) -3 H - imidazo [4,5-b] pyridine-5-carboxylic acid;

(S)-2-((4-(6-((5-chloropyridin-2-yl)methoxy)pyridin-2-yl)piperazin-1-yl)methyl)-1-(oxetane-2 -Ylmethyl)-1 H -benzo[ d ]imidazole-6-carboxylic acid;

2-(((S)-4-(6-((5-cyanopyridin-2-yl)methoxy)pyridin-2-yl)-2-methylpiperazin-1-yl)methyl)-1- (((S)-oxetan-2-yl)methyl)-1 H -benzo[ d ]imidazole-6-carboxylic acid; And

2-(((S)-4-(6-((5-cyanopyridin-2-yl)methoxy)pyridin-2-yl)-2-methylpiperazin-1-yl)methyl)-3- (((S) - oxetan-2-yl) methyl) -3 H - imidazo [4,5-b] pyridine-5-carboxylic acid.

는Another embodiment of the present invention, in Formula 1 above

Is

,

또는

이며,

,

or

Is,

가

인 경우, W₁, W₂ 및 W₃ 중 적어도 하나는 -N-이며; A₂는

이며; Z₁ 은 -CR_h-이고; Z₂ 는 -CR_i-이고; Z₃ 는 -CR_j-이고; Z₄ 는 -CR_k-이고; Z₅ 는 -CR_l-인 것인, 화학식 1로 표시되는 화합물, 이의 광학 이성질체 또는 이의 약제학적으로 허용가능한 염이다.

end

In the case of, at least one of _{W 1} , W ₂ and W _{3 is -N-;} A ₂ is

Is; Z ₁ is -CR _h -; Z ₂ is -CR _i -; Z ₃ is -CR _j -; Z ₄ is -CR _k -; Z ₅ is -CR ₁ -, which is a compound represented by Formula 1, an optical isomer thereof, or a pharmaceutically acceptable salt thereof.

Specifically, it relates to a compound represented by the following Formula 5, an optical isomer thereof, or a pharmaceutically acceptable salt thereof:

[Formula 5]

는In Chemical Formula 5

Is

,

또는

이며,

,

or

Is,

R _c is any one selected from the group consisting of -H, halogen, -CN, -OH, -O-(C ₁ -C ₄ alkyl), -NH ₂ , -NO ₂ and -C ₁ -C _{4 haloalkyl} ego;

R _d to R _f are each independently -H, halogen, -CN, -OH, -O-(C ₁ -C ₄ alkyl), -NH ₂ , -NO ₂ and -C ₁ -C ₄ haloalkyl Is any one selected from the group;

W ₁ is -CR _d -or -N-; W ₂ is -CR _e -or -N-; W ₃ is -CR _f -or -N-;

가

인 경우, W₁, W₂ 및 W₃ 중 적어도 하나는 -N-이며;

end

In the case of, at least one of _{W 1} , W ₂ and W _{3 is -N-;}

R _h, R _i , R _j , R _k , R ₁ , L, A ₁ , R ₂ , Y ₁ , Y ₂ , and R ₁ are as previously defined in Formula 1.

는 페닐, 피라진, 또는 X=CH인 피리딘일 수 있다. In the compound represented by Formula 5,

May be phenyl, pyrazine, or pyridine where X=CH.

More specifically, the compound represented by Chemical Formula 5, an optical isomer thereof, or a pharmaceutically acceptable salt thereof may be any one selected from the group consisting of the following Chemical Formulas 5-1 to 5-3.

[Chemical Formula 5-1]

[Chemical Formula 5-2]

[Chemical Formula 5-3]

The groups defined in Chemical Formulas 5-1 to 5-3 are as defined in Chemical Formula 5.

Preferred embodiments satisfying the above formula (5) include:

2-((4-(4-((4-cyano-2-fluorobenzyl)oxy)pyridin-2-yl)piperazin-1-yl)methyl)-1-(oxazol-2-ylmethyl )-1 H -benzo[ d ]imidazole-6-carboxylic acid;

2-((4-(3-((4-cyano-2-fluorobenzyl)oxy)phenyl)piperazin-1-yl)methyl)-1-(oxazol-2-ylmethyl)-1 H -Benzo[ d ]imidazole-6-carboxylic acid;

2-((4-(5-((4-cyano-2-fluorobenzyl)oxy)pyridin-3-yl)piperazin-1-yl)methyl)-1-(oxazol-2-ylmethyl )-1 H -benzo[ d ]imidazole-6-carboxylic acid;

2-((4-(6-((4-cyano-2-fluorobenzyl)oxy)pyrazin-2-yl)piperazin-1-yl)methyl)-1-(oxazol-2-ylmethyl )-1 H -benzo[d]imidazole-6-carboxylic acid

2-((4-(2-((4-cyano-2-fluorobenzyl)oxy)pyridin-4-yl)piperazin-1-yl)methyl)-1-(oxazol-2-ylmethyl )-1 H -benzo[ d ]imidazole-6-carboxylic acid;

2-((4-(4-((4-cyano-2-fluorobenzyl)oxy)pyridin-2-yl)piperidin-1-yl)methyl)-1-(oxazol-2-yl Methyl)-1 H -benzo[ d ]imidazole-6-carboxylic acid;

2-((4-(2-((4-cyano-2-fluorobenzyl)oxy)pyridin-4-yl)piperidin-1-yl)methyl)-1-(oxazol-2-yl Methyl)-1 H -benzo[ d ]imidazole-6-carboxylic acid;

(S)-2-((4-(6-((4-cyano-2-fluorobenzyl)oxy)pyrazin-2-yl)piperazin-1-yl)methyl)-1-(oxetane- 2-ylmethyl)-1 H -benzo[ d ]imidazole-6-carboxylic acid;

(S)-2-((4-(3-((4-cyano-2-fluorobenzyl)oxy)phenyl)piperazin-1-yl)methyl)-1-(oxetan-2-ylmethyl )-1 H -benzo[ d ]imidazole-6-carboxylic acid;

2-((4-(3-((4-cyano-2-fluorobenzyl)oxy)phenyl)piperazin-1-yl)methyl)-1-((1-ethyl-1 H -imidazole- 5-yl)methyl)-1 H -benzo[ d ]imidazole-6-carboxylic acid;

(S)-2-((4-(3-((4-cyano-2-fluorobenzyl)oxy)phenyl)piperidin-1-yl)methyl)-1-(oxetan-2-yl Methyl)-1 H -benzo[ d ]imidazole-6-carboxylic acid;

(S)-2-((4-(6-((4-cyano-2-fluorobenzyl)oxy)pyrazin-2-yl)piperidin-1-yl)methyl)-1-(oxetane -2-ylmethyl)-1 H -benzo[ d ]imidazole-6-carboxylic acid;

(S)-2-((6-(3-((4-cyano-2-fluorobenzyl)oxy)phenyl)-2,6-diazaspiro[3.3]heptan-2-yl)methyl) -1-(oxetan-2-ylmethyl)-1 H -benzo[ d ]imidazole-6-carboxylic acid;

(S)-2-((4-(3-((4-cyano-2-fluorobenzyl)oxy)phenyl)piperazin-1-yl)methyl)-1-((tetrahydrofuran-2- Yl)methyl)-1 H -benzo[ d ]imidazole-6-carboxylic acid;

(S)-2-((4-(3-((4-cyano-2-fluorobenzyl)oxy)phenyl)piperidin-1-yl)methyl)-3-(oxetan-2-yl methyl) -3 H - imidazo [4,5-b] pyridine-5-carboxylic acid;

(S)-2-((4-(3-((4-cyano-2-fluorobenzyl)oxy)phenyl)-1,4-diazepan-1-yl)methyl)-1-(oxetane -2-ylmethyl)-1 H -benzo[ d ]imidazole-6-carboxylic acid;

(S)-2-((4-(3-((4-cyano-2-fluorobenzyl)oxy)phenyl)piperazin-1-yl)methyl)-3-(oxetan-2-ylmethyl ) -3 H - imidazo [4,5-b] pyridine-5-carboxylic acid;

2-((4-(3-((4-cyano-2-fluorobenzyl)oxy)phenyl)piperazin-1-yl)methyl)-1-((1-fluorocyclopropyl)methyl)- 1 H -benzo[ d ]imidazole-6-carboxylic acid;

(S)-2-((4-(5-((4-cyano-2-fluorobenzyl)oxy)-2-fluorophenyl)piperazin-1-yl)methyl)-1-(oxetane -2-ylmethyl)-1 H -benzo[ d ]imidazole-6-carboxylic acid;

(S)-2-((4-(6-((4-cyano-2-fluorobenzyl)oxy)pyrazin-2-yl)-1,4-diazepan-1-yl)methyl)-1 -(Oxetan-2-ylmethyl)-1 H -benzo[ d ]imidazole-6-carboxylic acid;

(S)-2-((4-((3-((4-cyano-2-fluorobenzyl)oxy)phenyl)amino)piperidin-1-yl)methyl)-1-(oxetane- 2-ylmethyl)-1 H -benzo[ d ]imidazole-6-carboxylic acid;

2-(((S)-3-((3-((4-cyano-2-fluorobenzyl)oxy)phenyl)amino)pyrrolidin-1-yl)methyl)-1-(((S )-Oxetan-2-yl)methyl)-1 H -benzo[ d ]imidazole-6-carboxylic acid;

(S)-2-((4-(6-((4-cyano-2-fluorobenzyl)oxy)pyrazin-2-yl)piperazin-1-yl)methyl)-3-(oxetane- 2-ylmethyl)-3 H -imidazo[4,5-b]pyridin-5-carboxylic acid;

2-((3-(3-((4-cyano-2-fluorobenzyl)oxy)phenyl)-3,6-diazabicyclo[3.1.1]heptan-6-yl)methyl)-1 -(((S)-oxetan-2-yl)methyl)-1 H -benzo[ d ]imidazole-6-carboxylic acid;

2-(((S)-4-(6-((4-cyano-2-fluorobenzyl)oxy)pyrazin-2-yl)-2-methylpiperazin-1-yl)methyl)-1- (((S)-oxetan-2-yl)methyl)-1 H -benzo[ d ]imidazole-6-carboxylic acid;

2-(((S)-4-(3-((4-cyano-2-fluorobenzyl)oxy)phenyl)-2-methylpiperazin-1-yl)methyl)-1-(((S )-Oxetan-2-yl)methyl)-1 H -benzo[ d ]imidazole-6-carboxylic acid; And

2-(((S)-4-(3-((4-cyano-2-fluorobenzyl)oxy)phenyl)-2-methylpiperazin-1-yl)methyl)-3-(((S )-Oxetan-2-yl)methyl)-3 H -imidazo[4,5-b]pyridin-5-carboxylic acid.

이고;

은 적어도 하나의 질소를 함유하는 치환되거나 비치환된 7원 또는 8원 헤테로시클로알킬, 적어도 하나의 질소를 함유하는 치환되거나 비치환된 C₃～C₁₂ 스파이로헤테로시클로알킬, 또는 적어도 하나의 질소를 함유하는 치환되거나 비치환된 C₃～C₁₂ 다리걸친 헤테로바이시클로알킬이고(여기서, 치환된, 헤테로시클로알킬, 스파이로헤테로시클로알킬 및 헤테로바이시클로알킬은 적어도 하나 이상의 -OH, -(C₁-C₄알킬), 할로겐, 또는 -CN으로의 치환이며);In another embodiment of the present invention, A ₁ in Formula 1 is

ego;

Is a substituted or unsubstituted 7 member containing at least one nitrogen Or 8-membered heterocycloalkyl, substituted or unsubstituted C ₃ to C ₁₂ spiroheterocycloalkyl containing at least one nitrogen, or substituted or unsubstituted C ₃ to C ₁₂ bridging containing at least one nitrogen Heterobicycloalkyl, wherein substituted, heterocycloalkyl, spiroheterocycloalkyl and heterobicycloalkyl are substituted with at least one -OH, -(C ₁ -C ₄ alkyl), halogen, or -CN Is);

는 W₂가 -CR_e-일 때, X, W₁, 및 W₃ 중 둘은 -N-이거나; X, W₁, W₂, 및 W₃ 중 하나는 -N-인 것이고;

Is when W ₂ is -CR _e -, two of X, W ₁ , and W ₃ are -N-; One of X, W ₁ , W ₂ , and W ₃ is -N-;

이며; Z₁ 은 -CR_h-이고; Z₂ 는 -CR_i-이고; Z₃ 는 -CR_j-이고; Z₄ 는 -CR_k-이고; Z₅ 는 -CR_l-인, 화학식 1로 표시되는 화합물, 이의 광학 이성질체 또는 이의 약제학적으로 허용가능한 염이다. A ₂ is

Is; Z ₁ is -CR _h -; Z ₂ is -CR _i -; Z ₃ is -CR _j -; Z ₄ is -CR _k -; Z ₅ is -CR ₁ -in, a compound represented by Formula 1, an optical isomer thereof, or a pharmaceutically acceptable salt thereof.

Specifically, it relates to a compound represented by the following Formula 6-1, an optical isomer thereof, or a pharmaceutically acceptable salt thereof:

[Chemical Formula 6-1]

이고;

은 적어도 하나의 질소를 함유하는 치환되거나 비치환된 7원 또는 8원 헤테로시클로알킬, 적어도 하나의 질소를 함유하는 치환되거나 비치환된 C₃～C₁₂ 스파이로헤테로시클로알킬, 또는 적어도 하나의 질소를 함유하는 치환되거나 비치환된 C₃～C₁₂ 다리걸친 헤테로바이시클로알킬이고(여기서, 치환된, 헤테로시클로알킬, 스파이로헤테로시클로알킬 및 헤테로바이시클로알킬은 적어도 하나 이상의 -OH, -(C₁-C₄알킬), 할로겐, 또는 -CN으로의 치환이며);In Formula 6-1, A ₁ is

ego;

Is a substituted or unsubstituted 7 member containing at least one nitrogen Or 8-membered heterocycloalkyl, substituted or unsubstituted C ₃ to C ₁₂ spiroheterocycloalkyl containing at least one nitrogen, or substituted or unsubstituted C ₃ to C ₁₂ bridging containing at least one nitrogen Heterobicycloalkyl, wherein substituted, heterocycloalkyl, spiroheterocycloalkyl and heterobicycloalkyl are substituted with at least one -OH, -(C ₁ -C ₄ alkyl), halogen, or -CN Is);

X is -CR _c -or -N-;

R _c is any one selected from the group consisting of -H, halogen, -CN, -OH, -O-(C ₁ -C ₄ alkyl), -NH ₂ , -NO ₂ and -C ₁ -C _{4 haloalkyl} ego;

W ₁ is -CR _d -or -N-;

W ₂ is -CR _e -or -N-;

W ₃ is -CR _f -or -N-;

R _d to R _f are each independently -H, halogen, -CN, -OH, -O-(C ₁ -C ₄ alkyl), -NH ₂ , -NO ₂ and -C ₁ -C ₄ haloalkyl Is any one selected from the group;

는 W₂가 -CR_e-일 때, X, W₁ 및 W₃ 중 둘은 -N-이거나; X, W₁, W₂ 및 W₃ 중 하나는 -N-인 것이고;

Is when W ₂ is -CR _e -, two of X, W ₁ and W ₃ are -N-; One of X, W ₁ , W ₂ and W ₃ is -N-;

R _h, R _i , R _j , R _k , R ₁ , L, A ₁ , R ₂ , Y ₁ , Y ₂ , and R ₁ are as previously defined in Formula 1.

Preferred embodiments satisfying the above Formula 6-1 include:

(S)-2-((4-(6-((4-cyano-2-fluorobenzyl)oxy)pyridin-2-yl)-1,4-diazepan-1-yl)methyl)-1 -(Oxetan-2-ylmethyl)-1 H -benzo[ d ]imidazole-6-carboxylic acid;

(S)-2-((6-(6-((4-cyano-2-fluorobenzyl)oxy)pyridin-2-yl)-2,6-diazaspiro[3.3]heptane-2- Yl)methyl)-1-(oxetan-2-ylmethyl)-1 H -benzo[ d ]imidazole-6-carboxylic acid;

(S)-2-((4-(4-((4-cyano-2-fluorobenzyl)oxy)pyrimidin-2-yl)-1,4-diazepan-1-yl)methyl)- 1-(oxetan-2-ylmethyl)-1 H -benzo[ d ]imidazole-6-carboxylic acid;

2-((3-(6-((4-cyano-2-fluorobenzyl)oxy)pyridin-2-yl)-3,6-diazabicyclo[3.1.1]heptan-6-yl) Methyl)-1-(((S)-oxetan-2-yl)methyl)-1 H -benzo[ d ]imidazole-6-carboxylic acid; And

2-((3-(6-((4-cyano-2-fluorobenzyl)oxy)pyridin-2-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl) Methyl)-1-(((S)-oxetan-2-yl)methyl)-1 H -benzo[ d ]imidazole-6-carboxylic acid.

,

, 또는

이고;In another embodiment of the present invention, A ₁ in Formula 1 is

,

, or

ego;

은 적어도 하나의 질소를 함유하는 치환되거나 비치환된 4 내지 7원 헤테로시클로알킬, 적어도 하나의 질소를 함유하는 치환되거나 비치환된 C₃～C₁₂ 스파이로헤테로시클로알킬, 또는 적어도 하나의 질소를 함유하는 치환되거나 비치환된 C₃～C₁₂ 다리걸친 헤테로바이시클로알킬이고(여기서, 치환된, 헤테로시클로알킬, 스파이로헤테로시클로알킬 및 헤테로바이시클로알킬은 적어도 하나 이상의 -OH, -(C₁-C₄알킬), 할로겐, 또는 -CN으로의 치환이며);

Is a substituted or unsubstituted 4-7 member containing at least one nitrogen Heterocycloalkyl, substituted or unsubstituted C ₃ to C ₁₂ spiroheterocycloalkyl containing at least one nitrogen, or substituted or unsubstituted C ₃ to C ₁₂ bridged heterobicyclo containing at least one nitrogen Alkyl, wherein substituted, heterocycloalkyl, spiroheterocycloalkyl and heterobicycloalkyl are substitution with at least one or more -OH, -(C ₁ -C ₄ alkyl), halogen, or -CN;

는 W₂가 -CR_e-일 때, X, W₁ 및 W₃ 중 둘은 -N-이거나; X, W₁, W₂, 및 W₃ 중 하나는 -N-인 것이고;

Is when W ₂ is -CR _e -, two of X, W ₁ and W ₃ are -N-; One of X, W ₁ , W ₂ , and W ₃ is -N-;

이며; A ₂ is

Is;

Z ₁ is -CR _h -; Z ₂ is -CR _i -; Z ₃ is -CR _j -; Z ₄ is -CR _k -; Z ₅ is -CR ₁ -in, a compound represented by Formula 1, an optical isomer thereof, or a pharmaceutically acceptable salt thereof.

Specifically, it relates to a compound represented by the following Formula 6-2, an optical isomer thereof, or a pharmaceutically acceptable salt thereof:

[Formula 6-2]

,

, 또는

이고;A ₁ is

,

, or

ego;

은 적어도 하나의 질소를 함유하는 치환되거나 비치환된 4 내지 7원 헤테로시클로알킬, 적어도 하나의 질소를 함유하는 치환되거나 비치환된 C₃～C₁₂ 스파이로헤테로시클로알킬, 또는 적어도 하나의 질소를 함유하는 치환되거나 비치환된 C₃～C₁₂ 다리걸친 헤테로바이시클로알킬이고(여기서, 치환된, 헤테로시클로알킬, 스파이로헤테로시클로알킬 및 헤테로바이시클로알킬은 적어도 하나 이상의 -OH, -(C₁-C₄알킬), 할로겐, 또는 -CN으로의 치환이며);

Is a substituted or unsubstituted 4-7 member containing at least one nitrogen Heterocycloalkyl, substituted or unsubstituted C ₃ to C ₁₂ spiroheterocycloalkyl containing at least one nitrogen, or substituted or unsubstituted C ₃ to C ₁₂ bridged heterobicyclo containing at least one nitrogen Alkyl, wherein substituted, heterocycloalkyl, spiroheterocycloalkyl and heterobicycloalkyl are substitution with at least one or more -OH, -(C ₁ -C ₄ alkyl), halogen, or -CN;

X is -CR _c -or -N-;

R _c is any one selected from the group consisting of -H, halogen, -CN, -OH, -O-(C ₁ -C ₄ alkyl), -NH ₂ , -NO ₂ and -C ₁ -C _{4 haloalkyl} ego;

W ₁ is -CR _d -or -N-;

W ₂ is -CR _e -or -N-;

W ₃ is -CR _f -or -N-;

R _d to R _f are each independently -H, halogen, -CN, -OH, -O-(C ₁ -C ₄ alkyl), -NH ₂ , -NO ₂ and -C ₁ -C ₄ haloalkyl Is any one selected from the group;

는 W₂가 -CR_e-일 때, X, W₁, 및 W₃ 중 둘은 -N-이거나; X, W₁, W₂ 및 W₃ 중 하나는 -N-인 것이고;

Is when W ₂ is -CR _e -, two of X, W ₁ , and W ₃ are -N-; One of X, W ₁ , W ₂ and W ₃ is -N-;

R _h, R _i , R _j , R _k , R ₁ , L, A ₁ , R ₂ , Y ₁ , Y ₂ , and R ₁ are as previously defined in Formula 1.

Preferred embodiments satisfying Formula 6-2 include:

2-((3-((6-((4-cyano-2-fluorobenzyl)oxy)pyridin-2-yl)amino)pyrrolidin-1-yl)methyl)-1-(((S )-Oxetan-2-yl)methyl)-1 H -benzo[ d ]imidazole-6-carboxylic acid;

(S)-2-((4-((6-((4-cyano-2-fluorobenzyl)oxy)pyridin-2-yl)amino)piperidin-1-yl)methyl)-1- (Oxetan-2-ylmethyl)-1 H -benzo[ d ]imidazole-6-carboxylic acid;

(S)-2-((3-((6-((4-cyano-2-fluorobenzyl)oxy)pyridin-2-yl)amino)azetidin-1-yl)methyl)-1-( Oxetan-2-ylmethyl)-1 H -benzo[ d ]imidazole-6-carboxylic acid;

2-(((S)-3-((6-((4-cyano-2-fluorobenzyl)oxy)pyridin-2-yl)amino)pyrrolidin-1-yl)methyl)-1- (((S)-oxetan-2-yl)methyl)-1 H -benzo[ d ]imidazole-6-carboxylic acid;

(S)-2-((4-((6-((4-cyano-2-fluorobenzyl)oxy)pyridin-2-yl)(methyl)amino)piperidin-1-yl)methyl) -1-(oxetan-2-ylmethyl)-1 H -benzo[ d ]imidazole-6-carboxylic acid; And

2-(((R)-3-((6-((4-cyano-2-fluorobenzyl)oxy)pyridin-2-yl)amino)pyrrolidin-1-yl)methyl)-1- (((S)-oxetan-2-yl)methyl)-1 H -benzo[ d ]imidazole-6-carboxylic acid.

이며,In another embodiment of the present invention, A ₁ is

Is,

은 1 또는 2 개의 질소를 함유하는 6원 헤테로시클로알킬이고;

Silver 6-membered containing 1 or 2 nitrogens Heterocycloalkyl;

는

Is

When W ₂ is -CR _e -, two of X, W ₁ , and W ₃ are -N-;

이며; A ₂ is

Is;

Z ₁ is -CR _h -;

Z ₂ is -CR _i -;

Z ₃ is -CR _j -;

Z ₄ is -CR _k -;

Z ₅ is -CR ₁ -in, a compound represented by Formula 1, an optical isomer thereof, or a pharmaceutically acceptable salt thereof.

Specifically, it relates to a compound represented by the following formula (7), an optical isomer thereof, or a pharmaceutically acceptable salt thereof:

[Formula 7]

이며,A ₁ is

Is,

은 1 또는 2 개의 질소를 함유하는 6원 헤테로시클로알킬이고;

Silver 6-membered containing 1 or 2 nitrogens Heterocycloalkyl;

X is -CR _c -or -N-;

R _c is any one selected from the group consisting of -H, halogen, -CN, -OH, -O-(C ₁ -C ₄ alkyl), -NH ₂ , -NO ₂ and -C ₁ -C _{4 haloalkyl} ego;

W ₁ is -CR _d -or -N-;

W ₃ is -CR _f -or -N-;

R _d to R _f are each independently -H, halogen, -CN, -OH, -O-(C ₁ -C ₄ alkyl), -NH ₂ , -NO ₂ and -C ₁ -C ₄ haloalkyl Is any one selected from the group;

R _h, R _i , R _j , R _k , R _l , L, R ₂ , Y ₁ , Y ₂ , and R ₁ are as previously defined in Formula 1.

Preferred embodiments satisfying the above formula (7) include:

2-((4-(4-((4-cyano-2-fluorobenzyl)oxy)pyrimidin-2-yl)piperazin-1-yl)methyl)-1-(oxazol-2-yl Methyl)-1 H -benzo[ d ]imidazole-6-carboxylic acid;

2-((4-(6-((4-cyano-2-fluorobenzyl)oxy)pyrimidin-4-yl)piperazin-1-yl)methyl)-1-(oxazol-2-yl Methyl)-1 H -benzo[ d ]imidazole-6-carboxylic acid;

2-((4-(4-((4-cyano-2-fluorobenzyl)oxy)pyrimidin-2-yl)piperidin-1-yl)methyl)-1-(oxazol-2- Ylmethyl)-1 H -benzo[ d ]imidazole-6-carboxylic acid;

(S)-2-((4-(4-((4-cyano-2-fluorobenzyl)oxy)pyrimidin-2-yl)piperidin-1-yl)methyl)-1-(oxy Cetan-2-ylmethyl)-1 H -benzo[ d ]imidazole-6-carboxylic acid; And

(S)-2-((4-(4-((4-cyano-2-fluorobenzyl)oxy)pyrimidin-2-yl)piperazin-1-yl)methyl)-1-(oxetane -2-ylmethyl)-1 H -benzo[ d ]imidazole-6-carboxylic acid.

이고;

는In another embodiment of the present invention, A ₁ is

ego;

Is

X and W ₁ are -N-;

W ₂ is -CR _e -;

W ₃ is -CR _f -;

R _f is any one selected from the group consisting of halogen, -CN, -OH, -O-(C ₁ -C ₄ alkyl), -NH ₂ , -NO ₂ and -C ₁ -C _{4 haloalkyl;}

이며; A ₂ is

Is;

Z ₁ is -CR _h -;

Z ₂ is -CR _i -;

Z ₃ is -CR _j -;

Z ₄ is -CR _k -;

Z ₅ is -CR ₁ -in, a compound represented by Formula 1, an optical isomer thereof, or a pharmaceutically acceptable salt thereof.

Specifically, it relates to a compound represented by the following Formula 8, an optical isomer thereof, or a pharmaceutically acceptable salt thereof:

[Formula 8]

In Formula 8, R _f is selected from the group consisting of halogen, -CN, -OH, -O-(C ₁ -C ₄ alkyl), -NH ₂ , -NO ₂ and -C ₁ -C _{4 haloalkyl} Any one;

R _e , R _h, R _i , R _j , R _k , R ₁ , L, R ₂ , Y ₁ , Y ₂ , and R ₁ are as previously defined in Formula 1.

Preferred embodiments satisfying Formula 8 include:

(S)-2-((4-(4-((4-cyano-2-fluorobenzyl)oxy)-5-fluoropyrimidin-2-yl)piperazin-1-yl)methyl)- 1-(oxetan-2-ylmethyl)-1 H -benzo[ d ]imidazole-6-carboxylic acid.

In another embodiment of the present invention, Y ₁ is -N-;

이고;A ₁ is

ego;

에서

in

X and W ₁ are -N-;

W ₂ is -CR _e -;

W ₃ is -CR _f -;

이며; A ₂ is

Is;

Z ₁ is-CR _h -;

Z ₂ is -CR _i -;

Z ₃ is -CR _j -;

Z ₄ is -CR _k -;

Z ₅ is -CR ₁ -in, a compound represented by Formula 1, an optical isomer thereof, or a pharmaceutically acceptable salt thereof.

Specifically, it relates to a compound represented by the following Formula 9, an optical isomer thereof, or a pharmaceutically acceptable salt thereof:

[Formula 9]

R _e , R _f , R _h, R _i , R _j , R _k , R ₁ , L, R ₂ , Y ₂ , and R ₁ are as previously defined in Formula 1.

Preferred embodiments satisfying Formula 9 include:

(S)-2-((4-(4-((4-cyano-2-fluorobenzyl)oxy)pyrimidin-2-yl)piperidin-1-yl)methyl)-3-(oxy Cetan-2-ylmethyl)-3 H -imidazo[4,5-b]pyridine-5-carboxylic acid.

Another embodiment of the present invention,

R ₁ is -C(=O)R _a ;

R _a is NR _a1 R _a2 ;

이고;A ₁ is

ego;

는

이고;

Is

ego;

이며; A ₂ is

Is;

Z ₁ is -CR _h -;

Z ₂ is -CR _i -;

Z ₃ is -CR _j -;

Z ₄ is -CR _k -;

Z ₅ is -CR ₁ -in, a compound represented by Formula 1, an optical isomer thereof, or a pharmaceutically acceptable salt thereof.

Specifically, it relates to a compound represented by the following Formula 10, an optical isomer thereof, or a pharmaceutically acceptable salt thereof:

[Formula 10]

R ₁ is -C(=O)R _a ;

R _a is NR _a1 R _a2 ;

R _h, R _i , R _j , R _k , R _l , L, R ₂ , Y ₁ and Y ₂ are as previously defined in Formula 1.

Preferred embodiments satisfying Formula 10 include:

(2-((4-(6-((4-cyano-2-fluorobenzyl)oxy)pyridin-2-yl)piperazin-1-yl)methyl)-1-(((S)-oxy Cetan-2-yl)methyl)-1 H -benzo[ d ]imidazole-6-carbonyl)-L-alanine.

Another embodiment of the present invention relates to a compound or a pharmaceutically acceptable salt thereof independently selected from one or any combination of the following:

2-((4-(4-((4-cyano-2-fluorobenzyl)oxy)pyrimidin-2-yl)piperazin-1-yl)methyl)-1-(oxazol-2-yl Methyl)-1 H -benzo[ d ]imidazole-6-carboxylic acid;

2-((4-(4-((4-cyano-2-fluorobenzyl)oxy)pyridin-2-yl)piperazin-1-yl)methyl)-1-(oxazol-2-ylmethyl )-1 H -benzo[ d ]imidazole-6-carboxylic acid;

1-(oxazol-2-ylmethyl)-2-((4-(6-(pyridin-4-ylmethoxy)pyridin-2-yl)piperazin-1-yl)methyl)-1 H -benzo[ d ]imidazole-6-carboxylic acid;

2-((4-(3-((4-cyano-2-fluorobenzyl)oxy)phenyl)piperazin-1-yl)methyl)-1-(oxazol-2-ylmethyl)-1 H -Benzo[ d ]imidazole-6-carboxylic acid;

2-((4-(5-((4-cyano-2-fluorobenzyl)oxy)pyridin-3-yl)piperazin-1-yl)methyl)-1-(oxazol-2-ylmethyl )-1 H -benzo[ d ]imidazole-6-carboxylic acid;

2-((4-(6-((4-cyano-2-fluorobenzyl)oxy)pyrazin-2-yl)piperazin-1-yl)methyl)-1-(oxazol-2-ylmethyl )-1 H -benzo[ d ]imidazole-6-carboxylic acid;

2-((4-(2-((4-cyano-2-fluorobenzyl)oxy)pyridin-4-yl)piperazin-1-yl)methyl)-1-(oxazol-2-ylmethyl )-1 H -benzo[ d ]imidazole-6-carboxylic acid;

1-(oxazol-2-ylmethyl)-2-((4-(6-(pyridin-2-ylmethoxy)pyridin-2-yl)piperazin-1-yl)methyl)-1 H -benzo[ d ]imidazole-6-carboxylic acid;

2-((4-(6-((4-cyano-2-fluorobenzyl)oxy)pyrimidin-4-yl)piperazin-1-yl)methyl)-1-(oxazol-2-yl Methyl)-1 H -benzo[ d ]imidazole-6-carboxylic acid;

2-((4-(4-((4-cyano-2-fluorobenzyl)oxy)pyridin-2-yl)piperidin-1-yl)methyl)-1-(oxazol-2-yl Methyl)-1 H -benzo[ d ]imidazole-6-carboxylic acid;

2-((4-(4-((4-cyano-2-fluorobenzyl)oxy)pyrimidin-2-yl)piperidin-1-yl)methyl)-1-(oxazol-2- Ylmethyl)-1 H -benzo[ d ]imidazole-6-carboxylic acid;

2-((4-(2-((4-cyano-2-fluorobenzyl)oxy)pyridin-4-yl)piperidin-1-yl)methyl)-1-(oxazol-2-yl Methyl)-1 H -benzo[ d ]imidazole-6-carboxylic acid;

(S)-2-((4-(6-((4-cyano-2-fluorobenzyl)oxy)pyrazin-2-yl)piperazin-1-yl)methyl)-1-(oxetane- 2-ylmethyl)-1 H -benzo[ d ]imidazole-6-carboxylic acid;

(S)-2-((4-(3-((4-cyano-2-fluorobenzyl)oxy)phenyl)piperazin-1-yl)methyl)-1-(oxetan-2-ylmethyl )-1 H -benzo[ d ]imidazole-6-carboxylic acid;

(S)-2-((4-(6-((5-chloro-3-fluoropyridin-2-yl)methoxy)pyridin-2-yl)piperazin-1-yl)methyl)-1- (Oxetan-2-ylmethyl)-1 H -benzo[ d ]imidazole-6-carboxylic acid;

2-((4-(3-((4-cyano-2-fluorobenzyl)oxy)phenyl)piperazin-1-yl)methyl)-1-((1-ethyl-1 H -imidazole- 5-yl)methyl)-1 H -benzo[ d ]imidazole-6-carboxylic acid;

(S)-2-((4-(6-((4-cyano-2-fluorobenzyl)oxy)pyridin-2-yl)-1,4-diazepan-1-yl)methyl)-1 -(Oxetan-2-ylmethyl)-1 H -benzo[ d ]imidazole-6-carboxylic acid;

(S)-2-((4-(4-((4-cyano-2-fluorobenzyl)oxy)pyrimidin-2-yl)piperidin-1-yl)methyl)-1-(oxy Cetan-2-ylmethyl)-1 H -benzo[ d ]imidazole-6-carboxylic acid;

(S)-2-((4-(6-((5-chloro-3-fluoropyridin-2-yl)methoxy)pyridin-2-yl)piperidin-1-yl)methyl)-1 -(Oxetan-2-ylmethyl)-1 H -benzo[ d ]imidazole-6-carboxylic acid;

(S)-2-((4-(6-((5-cyanopyridin-2-yl)methoxy)pyridin-2-yl)piperidin-1-yl)methyl)-1-(oxetane -2-ylmethyl)-1 H -benzo[ d ]imidazole-6-carboxylic acid;

(S)-2-((4-(3-((4-cyano-2-fluorobenzyl)oxy)phenyl)piperidin-1-yl)methyl)-1-(oxetan-2-yl Methyl)-1 H -benzo[ d ]imidazole-6-carboxylic acid;

(S)-2-((4-(4-((4-cyano-2-fluorobenzyl)oxy)pyrimidin-2-yl)piperazin-1-yl)methyl)-1-(oxetane -2-ylmethyl)-1 H -benzo[ d ]imidazole-6-carboxylic acid;

1-(oxazol-2-ylmethyl)-2-((4-(6-(pyridin-3-ylmethoxy)pyridin-2-yl)piperazin-1-yl)methyl)-1 H -benzo[ d ]imidazole-6-carboxylic acid;

(S)-2-((4-(6-((5-cyanopyridin-2-yl)methoxy)pyridin-2-yl)piperazin-1-yl)methyl)-1-(oxetane- 2-ylmethyl)-1 H -benzo[ d ]imidazole-6-carboxylic acid;

(S)-2-((4-(3-((5-chloro-3-fluoropyridin-2-yl)methoxy)phenyl)piperidin-1-yl)methyl)-1-(oxetane -2-ylmethyl)-1 H -benzo[ d ]imidazole-6-carboxylic acid;

(S)-2-((4-(6-((5-cyanopyridin-2-yl)methoxy)pyrazin-2-yl)piperazin-1-yl)methyl)-1-(oxetane- 2-ylmethyl)-1 H -benzo[ d ]imidazole-6-carboxylic acid;

(S)-2-((4-(4-((5-cyanopyridin-2-yl)methoxy)pyrimidin-2-yl)piperidin-1-yl)methyl)-1-(oxy Cetan-2-ylmethyl)-1 H -benzo[ d ]imidazole-6-carboxylic acid;

(S)-2-((4-(3-((5-cyanopyridin-2-yl)methoxy)phenyl)piperazin-1-yl)methyl)-1-(oxetan-2-ylmethyl )-1 H -benzo[ d ]imidazole-6-carboxylic acid;

(S)-2-((4-(6-((5-cyanopyridin-2-yl)methoxy)pyridin-2-yl)piperazin-1-yl)methyl)-3-(oxetane- 2-ylmethyl)-3 H -imidazo[4,5-b]pyridin-5-carboxylic acid;

(S)-2-((4-(3-((5-cyanopyridin-2-yl)methoxy)phenyl)piperazin-1-yl)methyl)-3-(oxetan-2-ylmethyl ) -3 H - imidazo [4,5-b] pyridine-5-carboxylic acid;

(S)-2-((4-(6-((5-chloropyridin-2-yl)methoxy)pyridin-2-yl)piperazin-1-yl)methyl)-1-(oxetane-2 -Ylmethyl)-1 H -benzo[ d ]imidazole-6-carboxylic acid;

2-(((S)-4-(6-((5-cyanopyridin-2-yl)methoxy)pyridin-2-yl)-2-methylpiperazin-1-yl)methyl)-1- (((S)-oxetan-2-yl)methyl)-1 H -benzo[ d ]imidazole-6-carboxylic acid;

2-(((S)-4-(6-((5-cyanopyridin-2-yl)methoxy)pyridin-2-yl)-2-methylpiperazin-1-yl)methyl)-3- (((S)-oxetan-2-yl)methyl)-3 H -imidazo[4,5-b]pyridin-5-carboxylic acid;

(S)-2-((4-(6-((4-cyano-2-fluorobenzyl)oxy)pyrazin-2-yl)piperidin-1-yl)methyl)-1-(oxetane -2-ylmethyl)-1 H -benzo[ d ]imidazole-6-carboxylic acid;

(S)-2-((6-(3-((4-cyano-2-fluorobenzyl)oxy)phenyl)-2,6-diazaspiro[3.3]heptan-2-yl)methyl) -1-(oxetan-2-ylmethyl)-1 H -benzo[ d ]imidazole-6-carboxylic acid;

(S)-2-((4-(3-((4-cyano-2-fluorobenzyl)oxy)phenyl)piperazin-1-yl)methyl)-1-((tetrahydrofuran-2- Yl)methyl)-1 H -benzo[ d ]imidazole-6-carboxylic acid;

(S)-2-((4-(3-((4-cyano-2-fluorobenzyl)oxy)phenyl)piperidin-1-yl)methyl)-3-(oxetan-2-yl methyl) -3 H - imidazo [4,5-b] pyridine-5-carboxylic acid;

(S)-2-((4-(3-((4-cyano-2-fluorobenzyl)oxy)phenyl)-1,4-diazepan-1-yl)methyl)-1-(oxetane -2-ylmethyl)-1 H -benzo[ d ]imidazole-6-carboxylic acid;

(S)-2-((4-(3-((4-cyano-2-fluorobenzyl)oxy)phenyl)piperazin-1-yl)methyl)-3-(oxetan-2-ylmethyl ) -3 H - imidazo [4,5-b] pyridine-5-carboxylic acid;

2-((4-(3-((4-cyano-2-fluorobenzyl)oxy)phenyl)piperazin-1-yl)methyl)-1-((1-fluorocyclopropyl)methyl)- 1 H -benzo[ d ]imidazole-6-carboxylic acid;

(S)-2-((4-(5-((4-cyano-2-fluorobenzyl)oxy)-2-fluorophenyl)piperazin-1-yl)methyl)-1-(oxetane -2-ylmethyl)-1 H -benzo[ d ]imidazole-6-carboxylic acid;

(S)-2-((4-(6-((4-cyano-2-fluorobenzyl)oxy)pyrazin-2-yl)-1,4-diazepan-1-yl)methyl)-1 -(Oxetan-2-ylmethyl)-1 H -benzo[ d ]imidazole-6-carboxylic acid;

(S)-2-((4-((3-((4-cyano-2-fluorobenzyl)oxy)phenyl)amino)piperidin-1-yl)methyl)-1-(oxetane- 2-ylmethyl)-1 H -benzo[ d ]imidazole-6-carboxylic acid;

2-(((S)-3-((3-((4-cyano-2-fluorobenzyl)oxy)phenyl)amino)pyrrolidin-1-yl)methyl)-1-(((S )-Oxetan-2-yl)methyl)-1 H -benzo[ d ]imidazole-6-carboxylic acid;

(S)-2-((4-(6-((4-cyano-2-fluorobenzyl)oxy)pyrazin-2-yl)piperazin-1-yl)methyl)-3-(oxetane- 2-ylmethyl)-3 H -imidazo[4,5-b]pyridin-5-carboxylic acid;

2-((3-(3-((4-cyano-2-fluorobenzyl)oxy)phenyl)-3,6-diazabicyclo[3.1.1]heptan-6-yl)methyl)-1 -(((S)-oxetan-2-yl)methyl)-1 H -benzo[ d ]imidazole-6-carboxylic acid;

2-(((S)-4-(6-((4-cyano-2-fluorobenzyl)oxy)pyrazin-2-yl)-2-methylpiperazin-1-yl)methyl)-1- (((S)-oxetan-2-yl)methyl)-1 H -benzo[ d ]imidazole-6-carboxylic acid;

2-(((S)-4-(3-((4-cyano-2-fluorobenzyl)oxy)phenyl)-2-methylpiperazin-1-yl)methyl)-1-(((S )-Oxetan-2-yl)methyl)-1 H -benzo[ d ]imidazole-6-carboxylic acid;

2-(((S)-4-(3-((4-cyano-2-fluorobenzyl)oxy)phenyl)-2-methylpiperazin-1-yl)methyl)-3-(((S )-Oxetan-2-yl)methyl)-3 H -imidazo[4,5-b]pyridin-5-carboxylic acid;

(S)-2-((6-(6-((4-cyano-2-fluorobenzyl)oxy)pyridin-2-yl)-2,6-diazaspiro[3.3]heptane-2- Yl)methyl)-1-(oxetan-2-ylmethyl)-1 H -benzo[ d ]imidazole-6-carboxylic acid;

(S)-2-((4-(4-((4-cyano-2-fluorobenzyl)oxy)pyrimidin-2-yl)-1,4-diazepan-1-yl)methyl)- 1-(oxetan-2-ylmethyl)-1 H -benzo[ d ]imidazole-6-carboxylic acid;

2-((3-(6-((4-cyano-2-fluorobenzyl)oxy)pyridin-2-yl)-3,6-diazabicyclo[3.1.1]heptan-6-yl) Methyl)-1-(((S)-oxetan-2-yl)methyl)-1 H -benzo[ d ]imidazole-6-carboxylic acid;

2-((3-(6-((4-cyano-2-fluorobenzyl)oxy)pyridin-2-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl) Methyl)-1-(((S)-oxetan-2-yl)methyl)-1 H -benzo[ d ]imidazole-6-carboxylic acid;

2-((3-((6-((4-cyano-2-fluorobenzyl)oxy)pyridin-2-yl)amino)pyrrolidin-1-yl)methyl)-1-(((S )-Oxetan-2-yl)methyl)-1 H -benzo[ d ]imidazole-6-carboxylic acid;

(S)-2-((4-((6-((4-cyano-2-fluorobenzyl)oxy)pyridin-2-yl)amino)piperidin-1-yl)methyl)-1- (Oxetan-2-ylmethyl)-1 H -benzo[ d ]imidazole-6-carboxylic acid;

(S)-2-((3-((6-((4-cyano-2-fluorobenzyl)oxy)pyridin-2-yl)amino)azetidin-1-yl)methyl)-1-( Oxetan-2-ylmethyl)-1 H -benzo[ d ]imidazole-6-carboxylic acid;

2-(((S)-3-((6-((4-cyano-2-fluorobenzyl)oxy)pyridin-2-yl)amino)pyrrolidin-1-yl)methyl)-1- (((S)-oxetan-2-yl)methyl)-1 H -benzo[ d ]imidazole-6-carboxylic acid;

(S)-2-((4-((6-((4-cyano-2-fluorobenzyl)oxy)pyridin-2-yl)(methyl)amino)piperidin-1-yl)methyl) -1-(oxetan-2-ylmethyl)-1 H -benzo[ d ]imidazole-6-carboxylic acid;

2-(((R)-3-((6-((4-cyano-2-fluorobenzyl)oxy)pyridin-2-yl)amino)pyrrolidin-1-yl)methyl)-1- (((S)-oxetan-2-yl)methyl)-1 H -benzo[ d ]imidazole-6-carboxylic acid;

(S)-2-((4-(4-((4-cyano-2-fluorobenzyl)oxy)-5-fluoropyrimidin-2-yl)piperazin-1-yl)methyl)- 1-(oxetan-2-ylmethyl)-1 H -benzo[ d ]imidazole-6-carboxylic acid;

(S)-2-((4-(4-((4-cyano-2-fluorobenzyl)oxy)pyrimidin-2-yl)piperidin-1-yl)methyl)-3-(oxy Cetan-2-ylmethyl)-3 H -imidazo[4,5-b]pyridin-5-carboxylic acid; And

(2-((4-(6-((4-cyano-2-fluorobenzyl)oxy)pyridin-2-yl)piperazin-1-yl)methyl)-1-(((S)-oxy Cetan-2-yl)methyl)-1 H -benzo[ d ]imidazole-6-carbonyl)-L-alanine.

In another embodiment of the invention, a compound of Formula 1, 2, 3, 4, 5, 6-1, 6-2, 7, 8, 9 or 10, as defined in any of the embodiments described herein, It provides a pharmaceutical composition comprising an optical isomer or a pharmaceutically acceptable salt thereof.

In another embodiment of the invention, a compound of Formula 1, 2, 3, 4, 5, 6-1, 6-2, 7, 8, 9, or 10 as defined in any of the embodiments described herein, It provides a pharmaceutical composition for preventing or treating metabolic diseases comprising an optical isomer thereof or a pharmaceutically acceptable salt thereof.

In another embodiment of the invention, a compound of Formula 1, 2, 3, 4, 5, 6-1, 6-2, 7, 8, 9 or 10, as defined in any of the embodiments described herein, It provides a GLP-1R agonist comprising an optical isomer or a pharmaceutically acceptable salt thereof.

The invention also includes the following embodiments:

For use as a medicament, a compound of Formulas 1, 2, 3, 4, 5, 6-1, 6-2, 7, 8, 9 or 10, or a pharmaceutical thereof, as defined in any of the embodiments described herein Salts acceptable as;

1, 2, 3, 4, 5, 6-1, 6-2, 7, 8, as defined in any of the embodiments described herein, for use in the prevention and/or treatment of metabolic diseases discussed herein. The compound of 9 or 10, or a pharmaceutically acceptable salt thereof;

A therapeutically effective amount of a compound of 1, 2, 3, 4, 5, 6-1, 6-2, 7, 8, 9 or 10, or a pharmaceutically acceptable salt thereof, as defined in any of the embodiments described herein. A method of treating the disease in an individual in need of prevention and/or treatment of a disease for which a GLP-1R agonist is prescribed, comprising administering to the individual;

1, 2, 3, 4, 5, 6-1, 6-2, 7 as defined in any of the embodiments described herein for the manufacture of a medicament for the treatment of a disease or condition for which a GLP-1R agonist is prescribed. , The use of a compound of 8, 9 or 10, or a pharmaceutically acceptable salt thereof;

1, 2, 3, 4, 5, 6-1, 6-2, 7, 8, as defined in any of the embodiments described herein, for use in the treatment of a disease or condition for which the GLP-1R agonist is prescribed The compound of 9 or 10, or a pharmaceutically acceptable salt thereof; or

1, 2, 3, 4, 5, 6-1, 6-2, 7, 8, 9 or as defined in any of the embodiments described herein for treating a disease or condition for which a GLP-1R agonist is prescribed A pharmaceutical composition comprising the compound of 10, or a pharmaceutically acceptable salt thereof.

All examples, or pharmaceutically acceptable salts thereof, may be claimed individually or together in groups in any combination with any number of each and all embodiments described herein.

The invention also provides 1, 2, 3, 4, 5, 6-1, 6-2, as defined in any of the embodiments described herein, for use in the treatment and/or prevention of metabolic diseases discussed herein. It relates to a pharmaceutical composition comprising a compound of 7, 8, 9 or 10, or a pharmaceutically acceptable salt thereof.

Specifically, metabolic diseases include, for example, diabetes (T1D and/or T2DM, such as pre-diabetes), idiopathic T1D (type 1b), latent autoimmune diabetes in adults (LADA), early onset T2DM (EOD), younger onset. Atypical diabetes (YOAD), adult onset diabetes in young (MODY), malnutrition-related diabetes, gestational diabetes, hyperglycemia, insulin resistance, hepatic insulin resistance, impaired glucose tolerance, diabetic neuropathy, diabetic nephropathy, kidney disease (e.g., Acute renal impairment, tubular dysfunction, pro-inflammatory changes to the proximal tubules), diabetic retinopathy, adipocyte dysfunction, visceral fat accumulation, sleep apnea, obesity (e.g., hypothalamic obesity and mono-genetic obesity) and related Concomitant diseases (e.g., osteoarthritis and urinary incontinence), eating disorders (e.g., binge eating syndrome, anorexia nervosa, and syndrome of obesity, such as Prader-Willi syndrome and Barde-Biedl syndrome) , Weight gain due to the use of other drugs (e.g., from the use of steroids and antipsychotics), excessive sugar intake, dyslipidemia (hyperlipidemia, hypertriglyceridemia, increased total cholesterol, high LDL cholesterol, and low HDL cholesterol) Including), hyperinsulinemia, NAFLD (including related diseases such as steatosis, NASH, fibrosis, cirrhosis, and hepatocellular carcinoma), cardiovascular disease, atherosclerosis (including coronary artery disease), peripheral vascular disease, hypertension, endothelial dysfunction, Vascular compliance disorder, congestive heart failure, myocardial infarction (e.g., necrosis and apoptosis), stroke, hemorrhagic stroke, ischemic stroke, traumatic brain injury, pulmonary hypertension, restenosis after angioplasty, intermittent claudication, postprandial lipidemia, metabolic acidosis , Ketosis, arthritis, osteoporosis, Parkinson's disease, left ventricular hypertrophy, peripheral arterial disease, vision loss, cataract, glomerular sclerosis, chronic renal failure, metabolic syndrome, syndrome X, premenstrual syndrome, angina, thrombosis, atherosclerosis, transient ischemic attack, Vascular restenosis, impaired glucose metabolism, fasting blood sugar Symptoms of the disorder, hyperuricemia, gout, erectile dysfunction, skin and connective tissue disorders, psoriasis, foot ulcers, ulcerative colitis, hyper-spore B lipoproteinemia, Alzheimer's disease, schizophrenia, cognitive impairment, inflammatory bowel disease, short bowel syndrome , Crohn's disease, colitis, irritable bowel syndrome prevention and/or treatment, polycystic ovary syndrome prevention or treatment, and addiction treatment (eg, alcohol and/or drug abuse).

The meanings of terms and symbols used herein are as follows:

The term "alkyl" as used herein means a straight or branched chain monovalent hydrocarbon group _{of the structural formula -C n} H _(2n+1). Non-limiting examples thereof include methyl, ethyl, propyl, isopropyl, butyl, 2-methyl-propyl, 1,1-dimethylethyl, pentyl and hexyl, and the like. For example, "C ₁ -C ₄ alkyl" may refer to alkyl such as methyl, ethyl, propyl, butyl, 2-methyl-propyl, isopropyl.

The term "C ₆ ~C ₁₂ aryl" as used herein refers to an aromatic hydrocarbon containing 6 or 12 carbon atoms. For example, monocyclic (eg, phenyl); It may refer to a ring system such as bicyclic (eg, indenyl, naphthalenyl, tetrahydronaphthyl, tetrahydroindenyl).

_{The term "C 5} ~C ₁₂ heteroaryl" as used herein refers to an aromatic hydrocarbon containing 5 to 12 carbon atoms in which at least one of the ring carbon atoms is replaced with a heteroatom selected from oxygen, nitrogen and sulfur. The heteroaryl group may be attached through a ring carbon atom or, if valency permits, through a ring nitrogen atom or the like. Heteroaryl groups include benzo condensed ring systems having 2 to 3 rings.

The term "C ₃ to C ₈ cycloalkyl" herein refers to a cyclic, monovalent hydrocarbon group of _{the structural formula -C n} H _(2n-1) containing 3 to 8 carbon atoms. Non-limiting examples thereof include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl.

The term "C ₃ to C ₈ heterocycloalkyl" herein refers to 3 to 8 carbons, in which at least one of the ring methylene groups (-CH ₂ -) is replaced with a group selected from -O-, -S- and nitrogen. It refers to a cycloalkyl group containing an atom. In this case, nitrogen may provide a point of attachment or may be substituted as provided within each embodiment.

The term "C ₃ ~C ₁₂ heterobicycloalkyl" as used herein is a non-aromatic 2-ring cyclic group, wherein the ring shares 1 to 2 atoms, wherein at least one ring is a heteroatom (O, S Or N). For the purposes of the present invention, the heterobicycloalkyl group includes a spiro group, a bridged bicyclic group, or a fused ring group unless otherwise indicated. Preferably, it includes a spiro group, a bridged bicyclic group.

As used herein, "unsubstituted" refers to a state that is not substituted with any substituent or is hydrogen. "Substituted aryl, heteroaryl, heterocycloalkyl and cycloalkyl" herein refers to at least one or more, ie, 1, 2, 3, 4, 5, 6 or more -OH, -(C ₁ -C ₄ alkyl) , Halogen, or -CN, and each of these substitutions may be independently made.

The term "C ₃ to C ₁₂ spiroheterocycloalkyl" as used herein is a non- containing at least two rings fused at a single carbon atom containing at least one hetero atom and containing 3 to 12 carbon atoms. It means an aromatic hydrocarbon moiety. That is, the "spyroheterocycloalkyl" refers to a polycyclic hydrocarbon containing one or more heteroatoms, which share an atom (referred to as a spyro atom) between monocyclic rings. They may contain one or more double bonds, but no atom of the ring has a fully conjugated pi-electron system.

As used herein, the term C ₃ to C ₁₂ bridged heterobicycloalkyl is a bridged multi-cyclic ring assembly, which is a bridged (bridged) containing at least one hetero atom, preferably one or more nitrogen atoms. ) Refers to a multi-annular ring assembly.

The term "halogen" as used herein refers to fluoride, chloride, bromide, or iodide.

The term “haloalkyl” as used herein refers to an alkyl group substituted with one or more halogens (eg fluoride, chloride, bromide, or iodide).

The following abbreviations described in the present invention represent the terms below.

Hal: halogen

PG: Saver

DMF: dimethylformamide

EA: ethyl acetate

DCM: dichloromethane

BINAP: 2,2`-bis(diphenylphosphino)-1,1`-binapthyl

TFA: Trifluoroacetic acid

TBD: Triazabicyclodecene

IPA: isopropyl alcohol

TEA: triethylamine

pTSA: para-toluenesulfonic acid

NaH: sodium hydride

Pd ₂ (dba) ₃ : Tris(dibenzylideneacetone)dipalladium(0)

K ₃ PO ₄ : Tripotassium phosphate

PCy ₃ : tricyclohexylphosphine

MeCN: acetonitrile

Me ₃ SnOH: trimethyltin hydroxide

THF: tetrahydrofuran

As used herein, the term "tetrazolyl" refers to a 5-membered heterocyclo compound containing 4 nitrogen atoms and 1 carbon atom. Non-limiting examples of unsubstituted tetrazolyl include:

A non-limiting example of substituted tetrazolyl is (C ₁ -C ₄ alkyl)tetrazolyl.

"은 적어도 하나의 질소를 함유하는 C₃∼C₈ 헤테로시클로알킬 또는 적어도 하나의 질소를 함유하는 C₃~C₁₂ 헤테로바이시클로알킬을 의미한다.Here the symbol "

"Refers to a C ₃ ~C ₈ alkyl heterocycloalkyl, or C ₃ ~ C ₁₂ heteroaryl bicycle containing at least one nitrogen containing at least one nitrogen.

"의 비제한적 예시는 하기를 포함한다: For example the symbol "

Non-limiting examples of "include:

"은 상기 기호 "

"에 부착된 물결선의 개수만큼 치환기의 부착지점이 존재하는 것을 의미한다. 예를 들어 기호 "

"의 비제한적 예시는 하기를 포함한다: Here the symbol "

"Silver above sign"

"It means that there are as many points of attachment of a substituent as many as the number of wavy lines attached to. For example, the symbol "

Non-limiting examples of "include:

"은 일단에 메틸기(-CH₂-)가 더 치환되어 있는 상태로 물결선이 부착된 것을 제외하고는 상기 기호 "

"와 동일한 의미를 갖는다.Here the symbol "

"Is the above symbol, except that a wavy line is attached in a state in which a methyl group (-CH _{2 -) is further substituted at one end"}

It has the same meaning as ".

"은 일단에 옥실기(-O-)가 더 치환되어 있는 상태로 물결선이 부착된 것을 제외하고는 상기 기호 "

"와 동일한 의미를 갖는다.Here the symbol "

"Is the above symbol, except that a wavy line is attached in a state in which an oxyl group (-O-) is further substituted at one end"

It has the same meaning as ".

"은 일단에 -NR'기가 더 치환되어 있는 상태로 물결선이 부착된 것을 제외하고는 상기 기호 "

"와 동일한 의미를 갖는다.Here the symbol "

"Is the above symbol, except that a wavy line is attached with a -NR' group further substituted at one end"

It has the same meaning as ".

In the present invention, a C ₃ ~ C ₁₂ heteroaryl bicycle containing at least one nitrogen-alkyl may be a heterocycloalkyl with C ₃ ~ C ₁₂ spy containing at least one nitrogen, containing at least one nitrogen In C ₃ to C ₁₂ spiroheterocycloalkyl, at least one ring atom is nitrogen and the remaining ring atoms are carbon. Nitrogen-containing spiroheterocycloalkyl may be classified as monospyroheterocycloalkyl, dispyroheterocycloalkyl, or polypyroheterocycloalkyl depending on the number of atoms constituting the ring. Non-limiting examples of spiroheterocycloalkyl comprising nitrogen include:

In the present invention, the C ₃ ~C ₁₂ heterobicycloalkyl containing at least one nitrogen may be a C ₃ ~C ₁₂ bridged heterobicycloalkyl containing at least one nitrogen, and at least one ring atom is nitrogen And the remaining ring atoms are carbon. Non-limiting examples of bridged heterobicycloalkyls comprising nitrogen include:

,

,

"은, 또 다른 기에 대한 치환기의 부착 지점을 나타낸다. Wavy lines in this application"

"Represents the point of attachment of a substituent to another group.

In Formula 1, R ₁ is -C(=O)R _a, -S(=O) ₂ R _a , -(C ₁ -C ₃ alkyl) OH, -CN and -(C ₁ -C ₄ alkyl) It is any one selected from the group consisting of substituted or unsubstituted tetrazolyl; R _a is one selected from the group consisting of -OH, -O-(C ₁ -C ₄ alkyl) and -NR _a1 R _a2; R _a1 and R _a2 are each independently any one selected from the group consisting of hydrogen, -OH, -(C ₁ -C ₄ alkyl) and -(C ₁ -C ₄ alkyl)C(=O)OH.

R ₁ is preferably -C(=O)OH, -C(=O)NH ₂ , -C(=O)NHOH, -S(=O) ₂ NH ₂ , -CN, -C(=O )NHCH(CH ₃ )C(=O)OH, -C(=O)NHCH ₂ C(=O)OH, -C(=O)NHCH ₂ C(=O)OH, -tetrazolyl and -CH ₂ It may be any one selected from the group consisting of OH.

In Formula 1, R ₂ is a substituted or unsubstituted C ₆ ~C ₁₂ aryl, a substituted or unsubstituted C ₅ ~C ₁₂ heteroaryl, a substituted or unsubstituted C ₃ ~C ₈ heterocycloalkyl, a substituted or unsubstituted Is any one selected from the group consisting of C ₃ ~C ₈ cycloalkyl, and -C(=O)R _b (wherein substituted, aryl, heteroaryl, heterocycloalkyl and cycloalkyl are at least one or more -OH , -(C ₁ -C ₄ alkyl), halogen, or substitution with -CN); R _b is -(C ₁ -C ₄ alkyl) or -NR _b1 R _b2 ,; R _b1 and R _b2 are each independently hydrogen or -(C ₁ -C ₄ alkyl). R ₂ is preferably substituted with oxazole, oxacyclobutane containing a chiral central carbon, C ₁ -C ₄ alkyl substituted or unsubstituted imidazole, C ₁ -C ₄ alkyl, halogen or CN, or It may be any one selected from the group consisting of unsubstituted C ₃ ~C ₈ cycloalkyl and -C(=O)R _b.

,

,

또는

이고;

은 적어도 하나의 질소를 함유하는 C₃~C₈ 헤테로시클로알킬 또는 적어도 하나의 질소를 함유하는 C₃~C₁₀ 스파이로헤테로시클로알킬이다.In Formula 1, A ₁ is

,

,

or

ego;

Is a C ₃ to C ₈ heterocycloalkyl containing at least one nitrogen or a C ₃ to C ₁₀ spiroheterocycloalkyl containing at least one nitrogen.

"은 바람직하게는 하기 화합물로 이루어진 군으로부터 선택되는 어느 하나일 수 있다:remind "

"May preferably be any one selected from the group consisting of the following compounds:

"은 바람직하게는 하기 화합물로 이루어진 군으로부터 선택되는 어느 하나일 수 있다. Above symbol "

"Is preferably any one selected from the group consisting of the following compounds.

"은 바람직하게는 하기 화합물로 이루어진 군으로부터 선택되는 어느 하나일 수 있다:Above symbol "

"May preferably be any one selected from the group consisting of the following compounds:

"은 바람직하게는 하기 화합물로 이루어진 군으로부터 선택되는 어느 하나일 수 있다:Above symbol "

"May preferably be any one selected from the group consisting of the following compounds:

,

"은 바람직하게는 하기 화합물로 이루어진 군으로부터 선택되는 어느 하나일 수 있다:Above symbol "

"May preferably be any one selected from the group consisting of the following compounds:

R` is hydrogen, or -(C <sub>1</sub> -C <sub>4</sub> alkyl). As a preferred example, R` may be -H or -CH ₃ .

,

및

로 이루어지는 군에서 선택되는 어느 하나이고; Z₁ 은 -CR_h- 또는 -N-이고; Z₂ 는 -CR_i- 또는 -N-이고; Z₃ 는 -CR_j- 또는 -N-이고; Z₄ 는 -CR_k- 또는 -N-이고; Z₅ 는 -CR_l- 또는 -N-이고; R_h 내지 R_l은 각각 독립적으로 -H, 할로겐, -CN, -OH, -O-(C₁-C₄알킬), -NH₂, -NO₂ 및 -C₁-C₄할로알킬로 이루어지는 군에서 선택되는 어느 하나이고; R₃ 및 R₄는 각각 독립적으로 -H, 할로겐, -CN, -OH, -O-(C₁-C₄알킬), -NH₂, -NO₂ 및 -C₁-C₄할로알킬로 이루어지는 군에서 선택되는 어느 하나이고; n는 1 또는 2의 정수이다.In Formula 2, A ₂ is

,

And

It is any one selected from the group consisting of; Z ₁ is -CR _h -or -N-; Z ₂ is -CR _i -or -N-; Z ₃ is -CR _j -or -N-; Z ₄ is -CR _k -or -N-; Z ₅ is -CR ₁ -or -N-; R _h to R _l are each independently -H, halogen, -CN, -OH, -O-(C ₁ -C ₄ alkyl), -NH ₂ , -NO ₂ and -C ₁ -C ₄ haloalkyl Is any one selected from the group; R ₃ and R ₄ are each independently -H, halogen, -CN, -OH, -O-(C ₁ -C ₄ alkyl), -NH ₂ , -NO ₂ and -C ₁ -C ₄ haloalkyl Is any one selected from the group; n is an integer of 1 or 2.

In Formula 1, A ₂ may preferably be any one selected from the group consisting of the following compounds:

The compounds and intermediates described below were named using the naming convention provided by ChemBioDraw Ultra. Its naming practices are generally consistent with the International Union for Pure and Applied Chemistry (IUPAC) recommendations for nomenclature of organic chemistry and CAS index rules, and that chemical names may have only parentheses, or may have parentheses and brackets. Will make sense. Stereochemical descriptions can also be placed in different locations within the name itself, depending on the naming convention. Those of skill in the art will be aware of these formatting crystal modifications and understand that they provide the same chemical structure.

Compounds of Formula 1, optical isomers thereof, or pharmaceutically acceptable salts thereof include acid addition salts and base addition salts.

Suitable acid addition salts are formed from acids that form non-toxic salts. Examples are acetate, adipate, aspartate, benzoate, besylate, bicarbonate/carbonate, bisulfate/sulfate, borate, camsylate, citrate, cyclamate, ediselate, esylate, formate, fuma Rate, glutenate, gluconate, glucuronate, hexafluorophosphate, hybenzate, hydrochloride/chloride, hydrobromide/bromide, hydroiodide/iodide, isethionate, lactate, Maleate, maleate, malonate, mesylate, methyl sulfate, naphthylate, 2-naphsylate, nicotinate, nitrate, orotate, oxalate, palmitate, pamoate, phosphate/hydrogen phosphate/i Hydrogen phosphate, pyroglutamate, saccharate, stearate, succinate, tannate, tartrate, tosylate, trifluoroacetate, 1,5-naphthalenedisulfonic acid and xinafoate salts.

Suitable base addition salts are formed from bases forming non-toxic salts. Examples are aluminum, arginine, benzathine, calcium, choline, diethylamine, bis(2-hydroxyethyl)amine (diolamine), glycine, lysine, magnesium, meglumine, 2-aminoethanol (olamine) ), potassium, sodium, 2-amino-2-(hydroxymethyl)propane-1,3-diol (tris or trimethamine), and zinc salts.

In addition, hemi salts of acids and bases, such as hemisulfate and hemicalcium salts, may be formed.

The compound of Formula 1, and pharmaceutically acceptable salts thereof, may exist in unsolvated and solvated forms. The term'solvate' herein is used to describe a molecular complex comprising a compound of Formula 1 or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable solvent molecules (eg, ethanol). The term'hydrate' is used when the solvent is water.

Multi-component complexes (in addition to salts and solvates) are also included within the scope of the present invention, wherein the drug and one or more other components are present in stoichiometric or non-stoichiometric amounts. Complexes of this type include inclusion compounds (drug-host inclusion complexes) and co-crystals. Co-crystals are typically defined as crystalline complexes of neutral molecular constituents that are bonded together through non-covalent interactions, but can also be complexes of neutral molecules with salts. Co-crystals can be prepared by melt crystallization, by recrystallization from a solvent, or by physically grinding the components together.

The compounds of the present invention may exist as solid state continuums ranging from completely amorphous to fully crystalline. The term'amorphous' refers to a state in which a material loses long-distance regularity at the molecular level and is capable of exhibiting the physical properties of a solid or liquid depending on temperature. Typically, the material does not provide a unique X-ray diffraction pattern and, while exhibiting the character of a solid, is more formally described as a liquid. Upon heating, a change from solid to liquid properties occurs, which is characterized by a change of state (typically secondary) ('glass transition'). The term'crystalline' refers to a solid phase in which the material has an internal structure that is regularly arranged at the molecular level and provides an X-ray diffraction pattern with defined peaks. The material will also exhibit the character of a liquid when heated sufficiently, but the change from solid to liquid is characterized by a phase change (typically primary) ('melting point').

Compounds of Formula 1 containing one or more asymmetric carbon atoms may exist as two or more stereoisomers. When structural isomers are inter-convertible through a low energy barrier, tautomeric isomerism or tautomerism can occur. This may, for example, take the form of proton tautomerism in compounds of formula 1 containing imino, keto, or oxime groups, or so-called valence tautomerism in compounds containing aromatic moieties. Consequently, a single compound may exhibit more than one type of isomerism.

Pharmaceutically acceptable salts of the compounds of formula 1 may also contain optically active or racemic counter-ions.

Conventional techniques for the preparation/isolation of individual enantiomers include chiral synthesis from suitable optically pure precursors, or racemates (or salts or derivatives) using, for example, chiral high pressure liquid chromatography (HPLC). Semibody). Alternatively, the racemate (or racemic precursor) is a suitable optically active compound, e.g., an alcohol, or a base or acid (e.g. 1-phenylethylamine) if the compound of formula 1 contains an acidic or basic moiety. Or tartaric acid). The resulting diastereomeric mixture can be separated by chromatography and/or fractional crystallization, and one or both of the diastereomers can be converted to the corresponding pure enantiomer(s) by means well known to those skilled in the art. have. Chiral compounds of formula 1 (and chiral precursors thereof) contain 0 to 50% by volume, typically 2% to 20% of isopropanol, and 0 to 5% by volume of alkylamine, typically 0.1% diethylamine. Chromatography on asymmetric resins, typically HPLC, using a mobile phase consisting of a hydrocarbon, typically heptane or hexane, can be obtained in enantiomeric-rich form. Concentration of the eluent gives an enriched mixture. Chiral chromatography using subcritical and supercritical fluids can be used. Chiral chromatography methods useful in some embodiments of the present invention are known in the art.

When any racemate crystallizes, two different types of crystals are possible. The first type is the aforementioned racemic compounds (true racemates) in which crystals of one homogeneous form are produced containing both enantiomers in equimolar amounts. The second type is a racemic mixture or conglomerate in which crystals of two forms, each comprising a single enantiomer, are produced in equimolar amounts. Although both crystal forms present in the racemic mixture have the same physical properties, they may have different physical properties compared to the true racemate. Racemic mixtures can be separated by conventional techniques known to those skilled in the art.

Reference to a compound of formula 1, preferably a compound of formula 2, formula 3, formula 4, formula 5, formula 6-1, formula 6-2, formula 7, formula 8, formula 9 and/or formula 10, The compound itself and its prodrugs are included. The present invention includes not only the compound of Formula 1, but also a pharmaceutically acceptable salt of the compound, and a pharmaceutically acceptable solvate of the compound and salt.

Dosing and dosage

Typically, the compounds of the present invention are administered in an amount effective to treat the symptoms described herein. The compounds of the present invention can be administered as the compound itself or, alternatively, as a pharmaceutically acceptable salt. For administration and dosage purposes, the compound itself or a pharmaceutically acceptable salt thereof will simply be referred to as the compound of the present invention.

The compounds of the present invention are administered by any suitable route, in the form of a pharmaceutical composition suitable for the route, and in a dosage effective for the intended treatment. The compounds of the present invention can be administered orally, rectal, vaginal, parenteral, or topically.

The compounds of the present invention can be preferably administered orally. Oral administration may involve swallowing the compound to enter the gastrointestinal tract, or buccal or sublingual administration may be used to allow the compound to enter the bloodstream directly from the oral cavity.

In another embodiment, the compounds of the present invention can also be administered directly to the bloodstream, muscle or internal organs. Suitable means for parenteral administration include intravenous, intraarterial, intraperitoneal, intrathecal, intraventricular, intraurethral, intrasternal, intracranial, intramuscular and subcutaneous. Devices suitable for parenteral administration include needle (including microneedle) syringes, needleless syringes, and infusion techniques.

In another embodiment, the compounds of the present invention may also be administered topically (ie, epidermal or transdermal) to the skin or mucous membranes. In another embodiment, the compounds of the present invention may also be administered intranasally or by inhalation. In another embodiment, the compounds of the present invention may be administered rectally or intravaginally. In another embodiment, the compounds of the present invention can also be administered directly to the eye or ear.

The compound of the present invention and/or the composition containing the compound may be administered according to the type, age, weight, sex, and medical condition of the patient; Severity of symptoms; Route of administration; And the activity of the particular compound employed. Thus, the dosage regimen can vary widely. In one embodiment, the total daily dose of a compound of the invention is typically from about 0.001 to about 100 mg/kg (i.e., mg of a compound of the invention per kg body weight) for the treatment of a given condition discussed herein. to be. In another embodiment, the total daily dose of the compound of the invention is about 0.01 to about 30 mg/kg, in another embodiment, about 0.03 to about 10 mg/kg, in another embodiment, about 0.1 to about It is 3 mg/kg. It is not uncommon for the administration of the compounds of the present invention to be repeated several times a day (typically up to 4 times). Multiple doses per day can typically be used to increase the total daily dose, if necessary.

In the case of oral administration, the composition may be provided in the form of tablets, capsules, liquids, etc. for symptom-related control of the dosage to a patient. Such medicaments typically contain from about 0.01 mg to about 500 mg of active ingredient.

Suitable subjects according to the invention include mammalian subjects. In one embodiment, humans are suitable subjects. Human subjects can be male or female and any stage of growth.

Pharmaceutical composition

In another embodiment, the invention includes pharmaceutical compositions.

The present invention provides a pharmaceutical composition for preventing and treating metabolic diseases comprising a compound represented by Formula 1, an optical isomer thereof, or a pharmaceutically acceptable salt thereof.

The pharmaceutical composition may contain the compound of the present invention together with a pharmaceutically acceptable carrier.

Other pharmacologically active ingredients may also be present. As used herein, "pharmaceutically acceptable carrier" includes any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents, and the like that are physiologically compatible. Examples of pharmaceutically acceptable carriers include one or more of water, saline, phosphate buffered saline, dextrose, glycerol, ethanol, as well as combinations thereof, and isotonic agents such as sugar, sodium chloride, Alternatively, polyalcohols such as mannitol or sorbitol may be included in the composition. Pharmaceutically acceptable ingredients (eg, wetting agents) or minor amounts of auxiliary ingredients (eg, wetting agents, emulsifying agents, preservatives or buffers) that enhance the shelf life or effectiveness of the antibody or antibody portion are included.

The composition of the present invention may be in various forms. This includes, for example, liquid, semi-solid and solid dosage forms, such as liquid solutions (eg, injectable and injectable solutions), dispersions or suspensions, tablets, pills, powders, liposomes and suppositories. The form depends on the intended mode of administration and therapeutic use.

Typical compositions are in the form of injectable and infusible solutions, such as compositions similar to those used for passive immunization of humans, generally with antibodies. One mode of administration is parenteral (eg, intravenous, subcutaneous, intraperitoneal, intramuscular). In another embodiment, the antibody is administered by intravenous infusion or injection. In another embodiment, the antibody is administered by intramuscular or subcutaneous injection.

Oral administration in solid dosage forms can be provided, for example, in hard or soft capsules, pills, cachets, lozenges or tablets, each containing a predetermined amount of one or more compounds of the invention. In another embodiment, oral administration may be in powder or granular form. In another embodiment, the oral dosage form is sublingual, eg, lozenge. In such solid dosage forms, the compound of formula 1 is usually combined with one or more excipients. The capsules or tablets may contain controlled release formulations. In the case of capsules, tablets and pills, the dosage form may also contain a buffering agent or may be prepared with an enteric coating.

In another embodiment, oral administration may be in a liquid dosage form. Liquid dosage forms for oral administration include, for example, pharmaceutically acceptable emulsions, solutions, suspensions, syrups, and elixirs containing inert diluents (eg, water) commonly used in the art. The composition may also contain excipients such as wetting agents, emulsifying agents, suspending agents, flavoring agents (eg sweetening agents), and/or fragrances.

In another embodiment, the invention includes parenteral dosage forms. “Parental administration” includes, for example, subcutaneous injection, intravenous injection, intraperitoneal injection, intramuscular injection, intrasternal injection, and infusion. Injectable preparations (ie, sterile injectable aqueous or oleaginous suspensions) can be formulated according to known techniques using suitable dispersing, wetting and/or suspending agents.

In another embodiment, the invention includes topical dosage forms. “Topical administration” includes transdermal administration, intraocular administration, or intranasal or inhalation administration, for example via a transdermal patch or iontophoretic device. Compositions for topical administration also include, for example, topical gels, sprays, ointments, and creams. Topical formulations may include compounds that enhance the absorption or penetration of the active ingredient through the skin or other affected area. When the compounds of the present invention are administered by transdermal devices, administration will be accomplished using reservoirs and patches of porous membrane type or solid matrix type. Typical formulations for this purpose include gels, hydrogels, lotions, solutions, creams, ointments, sprays, dressings, foams, films, skin patches, wafers, implants, sponges, fibers, bandages and microemulsions. Liposomes can also be used. Typical carriers include alcohol, water, mineral oil, liquid petrolatum, white petrolatum, glycerin, polyethylene glycol and propylene glycol. Penetration enhancers may be incorporated. See, for example, B. C. Finnin and T. M. Morgan, J. Pharm. Sci., vol. 88, pp. 955-958, 1999].

For intranasal administration or administration by inhalation, the active compounds of the invention are conveniently in the form of a solution or suspension from a pump spray container that is squeezed or pumped by the patient, or in a pressurized container or by the use of a suitable propellant. Delivered as an aerosol spray offering from a nebulizer. Formulations suitable for intranasal administration are typically in the form of a dry powder from a dry powder inhaler (alone; as a mixture, for example in the form of a dry blend with lactose; or mixed ingredients, for example mixed with a phospholipid, such as phosphatidylcholine. As particles), or with or without a suitable propellant (e.g. 1,1,1,2-tetrafluoroethane or 1,1,1,2,3,3,3-heptafluoropropane) , Pumps, sprays, atomizers (preferably nebulizers that use electrohydrodynamics to create fine mist), or as an aerosol spray from a nebulizer. For intranasal use, the powder may comprise a bioadhesive, for example chitosan or cyclodextrin.

In another embodiment, the invention includes rectal dosage forms. Such rectal dosage forms may be, for example, in the form of suppositories. Cocoa butter is a traditional suppository base, but a variety of alternatives can be used where appropriate.

Other carrier materials and modes of administration known in the pharmaceutical art may also be used. The pharmaceutical compositions of the present invention can be prepared by any well known pharmaceutical technique, such as effective formulation and administration procedures. These considerations for effective formulation and administration procedures are well known in the art and are described in standard textbooks.

Kit

Another aspect of the present invention is a compound of Formula 1, 2, 3, 4, 5, 6-1, 6-2, 7, 8, 9 or 10 or Formula 1, 2, 3, 4, 5 of the present invention. It provides a kit comprising a pharmaceutical composition comprising the compound of, 6-1, 6-2, 7, 8, 9 or 10. The kit may include a diagnostic agent or a therapeutic agent in addition to the compound of Formulas 1, 2, 3, 4, 5, 6-1, 6-2, 7, 8, 9 or 10 of the present invention or a pharmaceutical composition thereof. have. The kit also includes instructions for use in a method of diagnosis or treatment. In some embodiments, the kit includes a compound of Formulas 1, 2, 3, 4, 5, 6-1, 6-2, 7, 8, 9 or 10, or a pharmaceutical composition thereof and a diagnostic agent. In another embodiment, the kit comprises a compound of Formula 1, 2, 3, 4, 5, 6-1, 6-2, 7, 8, 9 or 10, or a pharmaceutical composition thereof.

In another embodiment, the invention includes kits suitable for use in performing the methods of treatment described herein. In one embodiment, the kit contains a first dosage form comprising an amount of one or more compounds of the invention sufficient to carry out the methods of the invention. In another embodiment, the kit comprises an amount of one or more compounds of the invention sufficient to carry out the methods of the invention, and a container for administration.

Produce

The schemes described below are intended to provide a general description of the methodology used in the preparation of the compounds of the present invention. Some of the compounds of the present invention may contain single or multiple chiral centers with stereochemical designations (R) or (S). Whether the material is enantiomer-enriched or racemate, it will be apparent to those skilled in the art that all synthetic transformations can be carried out in a similar manner. In addition, separation for the desired optically active material can be carried out at any desired point in a sequence using known methods as described herein and in the chemical literature.

In the following scheme, the variables Q ₁ , Q ₂ , X, Y ₁ , Y ₂ , Y ₃ , W ₁ , W ₂ , W ₃ , Z ₁ , Z ₂ , Z ₃ , Z ₄ , Z ₅ , R ₁ , R ₂ , R ₃ , R ₄ , R _a , R _b , R _c , R _d , R _e , R _f , R _g , R _h , R _i , R _j , R _k , R _l R _a1 , R _a2 , R _b1 , R _b2 are as described herein for compounds of Formulas 1, 2, 3, 4, 5, 6-1, 6-2, 7, 8, 9 or 10, unless otherwise stated.

The compounds of Formulas 1, 2, 3, 4, 5, 6-1, 6-2, 7, 8, 9 or 10 herein include the compounds of Examples prepared below. The compounds of the above examples may be prepared or prepared based on various methods described in the literature and common technical knowledge known to those skilled in the art based on two or more selected from the following intermediate compounds. The intermediate compound may be prepared or prepared based on various methods described in the literature and common technical knowledge known to those skilled in the art based on the compound of the following precursor.

Reaction Schemes 1 to 5 described below disclose a method of preparing a precursor of an intermediate used to prepare a compound of Formulas 1, 2, 3, 4, 5, 6-1, 6-2, 7, 8, 9 or 10. .

Scheme 1 below provides a method for preparing precursor 4.

The preparation of precursor 2 can be achieved by an alkylation method of precursor 1 and a compound in which halogen is appropriately substituted in the presence of a strong base, or through a Mitsunobu reaction with an appropriate alcohol.

Precursor 3 may be prepared by using Butvalk-Hartwick coupling between the precursor 2 and the ring into which the protecting group is introduced, in the presence of a palladium catalyst and a ligand complex, or by reacting in the presence of a base.

Precursor 4 can be prepared by removing the protecting group from precursor 3 through various methods described in the literature. In the following Scheme 1, the symbol "Hal" means a halogen element, and preferably includes chloride, bromide or iodine. The symbol "PG" means a protecting group, and preferably includes tertbutyl carbonate, carboxybenzyl, fluorenylmethyloxycarbonyl, and the like.

The method for synthesizing the compound according to the present invention using this Scheme 1 is specifically shown in Preparation Method 1 below.

[Scheme 1]

Preparation of the precursor 2 can also be prepared by the method of the following Scheme 2. In the presence of a strong base, it can be prepared by reacting precursor 5 with precursor 6.

The method for synthesizing the compound according to the present invention using Scheme 2 is specifically shown in Preparation Method 2 below.

[Scheme 2]

Scheme 3 below provides another method for preparing precursor 3. Precursor 8 can be prepared by using precursor 7, for example, a ring containing a double bond into which a protecting group is introduced, preferably a piperidine substituted boronic acid or boronate ester, and a Suzuki coupling. Precursor 9 is prepared in a hydrogen atmosphere of 1 to 6 atmospheres, using a preferred metal catalyst (e.g., palladium on carbon, Raney nickel, etc.), a protic solvent (e.g., methanol, etc.) or an aprotic solvent. It can be prepared by reduction under (for example, ethyl acetate, tetrahydrofuran, etc.). Alternatively, precursor 10 to which a protecting group is introduced from precursor 8 may be synthesized similarly to the method described above to obtain precursor 11. Precursor 9 can be obtained by removing the protecting group from precursor 11 by a suitable method that can be selected by a person skilled in the art.

Precursor 3 can be prepared in the presence of a strong base, by an alkylation method of a compound in which precursor 9 and a halogen are appropriately substituted, or through a Mitsunobu reaction with an appropriate alcohol.

The method for synthesizing the compound according to the present invention using Scheme 3 is specifically shown in Preparation Method 3 below.

[Scheme 3]

Scheme 4 provides a method of preparing precursor 15. _{Precursor 13 may be prepared by reacting precursor 12 with R 2} CH ₂ NH _{2 in} the presence of a base (eg, sodium carbonate, cesium carbonate, potassium carbonate, etc.). Preparation of precursor 14 is carried out in a hydrogen atmosphere, using a preferred metal catalyst (e.g., palladium on carbon, Raney nickel, etc.), a protic solvent (e.g., methanol, etc.) or an aprotic solvent (e.g., It can be prepared by reduction under ethyl acetate, tetrahydrofuran, etc.). Precursor 14 can be prepared as precursor 15 through various methods. Treatment with 2-chloroacetyl chloride under an aprotic solvent (eg, tetrahydrofuran, etc.), and heating to prepare the desired preparation. Alternatively, in an aprotic solvent (e.g. MeCN, THF, 1,4-dioxane), in the presence of an acidic catalyst (e.g. pTSA), 2-chloro-1,1,1,-trimethoxyethane It can be prepared by processing. Alternatively, it can be prepared by treating with chloroacetic anhydride in an aprotic solvent and heating.

The method for synthesizing the compound according to the present invention using Scheme 4 is specifically shown in Preparation Method 4 below.

[Scheme 4]

Scheme 5 below provides another method for preparing precursor 3. Precursor 1 in the presence of an appropriate base (e.g., sodium hydride, potassium carbonate, etc.) or an organic base (e.g., triethylamine, etc.) or a suitable basic precursor, a protic solvent (e.g., butanol, methanol, etc.) Etc.) or in a polar aprotic solvent (eg, DMF, DMSO, etc.), by reacting with an appropriately substituted and protected basic precursor, to prepare precursor 9.

Precursor 3 can be achieved in the presence of a strong base, by an alkylation method of precursor 9 and a compound in which halogen is suitably substituted, or through a Mitsunobu reaction with an appropriate alcohol. In this case, examples of compounds in which halogen is appropriately substituted are referred to as substituted benzyl bromide, substituted benzyl chloride, and the like, which can be obtained by reacting appropriately substituted benzyl alcohol with thionyl chloride.

The method for synthesizing the compound according to the present invention using Scheme 5 is specifically shown in Preparation Method 5 below.

[Scheme 5]

Scheme 6 below provides a method for preparing a compound according to the present invention. Precursor 16 in the presence of a suitable base (e.g., sodium hydride, potassium carbonate, etc.) or an organic base (e.g. triethylamine, etc.), a protic solvent (e.g., butanol, methanol, etc.) or polar In an aprotic solvent (eg, DMF, DMSO, etc.), precursor 17 may be prepared by reacting with precursor 4. From the material obtained under the above conditions, the compounds according to the present invention can be obtained using a well known hydrolysis method.

The method for synthesizing the compound according to the present invention using Scheme 6 is specifically shown in Preparation Methods A, B and C below.

[Scheme 6]

As a novel compound, the present invention exhibits excellent activity as an agonist against the GLP-1 receptor compound.

Hereinafter, a preferred embodiment is presented to aid the understanding of the present invention. However, the following examples are provided for easier understanding of the present invention, and the contents of the present invention are not limited by the examples.

The reagents and solvents mentioned below were purchased from Sigma-Aldrich, TCI, unless otherwise noted, HPLC was used by Waters' Alliance HPLC system, and the silica gel for column chromatography was used by Biotage's Flash purification system. ¹ HNMR data was measured using 400 MHz, and Mass Spectrum was used by Waters' Masslynx MS system.

^{The 1} H nuclear magnetic resonance (NMR) spectra were in all cases consistent with the proposed structure. Characteristic chemical shifts (δ) are in parts-per-million ( _{ppm) for residual proton signal in deuterated solvent (CDCl 3} : 7.27 ppm; CD ₂ HOD: 3.31 ppm; DMSO- d ₆ : 2.50 ppm). Are presented and reported as conventional abbreviations for the designation of major peaks: for example, s, singlet; d, doublet; t, triplet; q, quartet; m, multiplet; br, broad. ¹ H NMR spectra were obtained using an electric field intensity of 400 MHz, unless otherwise noted.

Synthesis example

Synthesis Example 1. Synthesis of Intermediates 1 to 53

Examples of the manufacturing process of Intermediates 1 to 53 using any one of Reaction Schemes 1 to 5 are described in detail below. Each of Preparation Methods 1 to 5 corresponds to an example of each of Schemes 1 to 5, and a person skilled in the art uses the synthesis method reactions of Schemes 1 to 5 and specific examples of Preparation Methods 1 to 5 to be commercially sold or synthesized as an intermediate 1 To 53 can be prepared.

(1) Preparation 1. Synthesis of Intermediate 1

1) Synthesis of 4-(((2-chloropyrimidin-4-yl)oxy)methyl)-3-fluorobenzonitrile

4-(bromomethyl)-3-fluorobenzonitrile (1.2 eq., 983.0 mg, 4.60 mmol) and 2-chloropyrimidin-4-ol (1.0 eq., 500 mg, 3.83 mmol), silver carbonate ( 1.2 eq., 1.27 g, 4.60 mmol) was dissolved in DMF and stirred at 90° C. overnight. The reaction solution was filtered through Celite, washed with brine, and extracted with EA. The organic layer was dried over anhydrous magnesium sulfate, filtered, concentrated, and purified by column chromatography to obtain 4-(((2-chloropyrimidin-4-yl)oxy)methyl)-3-fluorobenzonitrile as a white solid. (558.0 mg, 55%)

2) Synthesis of tert-butyl 4-(4-((4-cyano-2-fluorobenzyl)oxy)pyrimidin-2-yl)piperazine-1-carboxylate

4-(((2-chloropyrimidin-4-yl)oxy)methyl)-3-fluorobenzonitrile (1.0 eq., 272.0 mg, 1.03 mmol) and tert-butyl piperazine-1-carboxylate (1.2 eq., 230.0 mg, 1.24 mmol) and potassium carbonate (3.0 eq., 427.0 mg, 3.09 mmol) were dissolved in DMF (10.5 mL) and stirred at room temperature overnight. The reaction solution was washed with brine and extracted with EA. The organic layer was dried over anhydrous magnesium sulfate, filtered, concentrated, and purified by column chromatography to obtain tert-butyl 4-(4-((4-cyano-2-fluorobenzyl)oxy)pyrimidin-2-yl)piperazine. The -1-carboxylate was obtained as a white solid. (381.0 mg, 89.0%)

3) Synthesis of 3-fluoro-4-(((2-(piperazin-1-yl)pyrimidin-4-yl)oxy)methyl)benzonitrile

Tert-butyl 4-(4-((4-cyano-2-fluorobenzyl)oxy)pyrimidin-2-yl)piperazine-1-carboxylate (1.0 eq., 200.0 mg, 0.48 mmol) in DCM (10.0 mL) was dissolved, and TFA (2.5 mL) was added dropwise. After stirring at room temperature for 3 hours, it was concentrated, washed with a saturated aqueous sodium hydrogen carbonate solution, and extracted with EA. The organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated to obtain 3-fluoro-4-(((2-(piperazin-1-yl)pyrimidin-4-yl)oxy)methyl)benzonitrile as an intermediate 1 to white. It was obtained as a solid. (168.0 mg, 100%), (M+H) ⁺ : 314

(2) Preparation 2. Synthesis of Intermediate 2

1) Synthesis of 4-(((6-chloropyrimidin-4-yl)oxy)methyl)-3-fluorobenzonitrile

4,6-dichloropyrimidine (1.1 eq., 500.0 mg, 3.36 mmol) and 3-fluoro-4-(hydroxymethyl)benzonitrile (1.0 eq., 461.0 mg, 3.05 mmol) in anhydrous THF (15.0 mL) ), NaH (1.1 eq., 128.0 mg, 3.20 mmol) was added. After stirring at room temperature overnight, the reaction solution was washed with brine and extracted with EA. The organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated to obtain 4-(((6-chloropyrimidin-4-yl)oxy)methyl)-3-fluorobenzonitrile as a white solid without further purification. (844.0 mg, 100%)

2) Synthesis of tert-butyl 4-(6-((4-cyano-2-fluorobenzyl)oxy)pyrimidin-4-yl)piperazine-1-carboxylate

4-(((6-chloropyrimidin-4-yl)oxy)methyl)-3-fluorobenzonitrile (1.0 eq., 260.0 mg, 0.99 mmol) ether tert-butyl piperazine-1-carboxylate (1.2 eq., 220.0 mg, 1.18 mmol) and potassium carbonate (2.0 eq., 272.0 mg, 1.97 mmol) were dissolved in DMF (3.3 mL) and stirred at room temperature overnight. The reaction solution was washed with brine and extracted with EA. The organic layer was dried over anhydrous magnesium sulfate, filtered, concentrated, and purified by column chromatography to obtain tert-butyl 4-(6-((4-cyano-2-fluorobenzyl)oxy)pyrimidin-4-yl)piperazine. -1-carboxylate was obtained as a white solid. (327.0 mg, 80%)

3) Synthesis of (3-fluoro-4-(((6-(piperazin-1-yl)pyrimidin-4-yl)oxy)methyl)benzonitrile)

Tert-butyl 4-(6-((4-cyano-2-fluorobenzyl)oxy)pyrimidin-4-yl)piperazine-1-carboxylate (1.0 eq., 310.0 mg, 0.75 mmol) It was dissolved in DCM (15.0 mL), and TFA (3.0 mL) was added dropwise. After stirring at room temperature for 6 hours, it was concentrated, washed with a saturated aqueous sodium hydrogen carbonate solution, and extracted with EA. The organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated to obtain white 3-fluoro-4-(((6-(piperazin-1-yl)pyrimidin-4-yl)oxy)methyl)benzonitrile as intermediate 2. It was obtained as a solid. (243 mg, 100%), (M+H) ⁺ : 314

(3) Preparation 3. Synthesis of Intermediate 3

1) Synthesis of tert-butyl 4-hydroxy-3',6'-dihydro-[2,4'-bipyridin]-1'(2' H )-carboxylate

2-Chloropyridin-4-ol (1.0 eq., 500.0 mg, 3.86 mmol), tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2 -Yl-2-yl)-3,6-dihydropyridin-1( 2H )-carboxylate (1.2 eq., 1.43 g, 4.63 mmol), Pd ₂ (dba) ₃ (0.07 eq., 247.0 mg, 0.27 mmol), K ₃ PO ₄ (2.5 eq., 2.1 g, 9.7 mmol), PCy ₃ (0.1 eq., 151.0 mg, 0.5 mmol) in 1,4-dioxane (20.8 mL) and H ₂ O (2.0 mL ) To dissolve. After stirring under reflux at 95° C. overnight, the reaction solution was washed with brine and extracted with EA. The organic layer was dried over anhydrous magnesium sulfate, filtered, concentrated, and purified by silica chromatography to obtain tert-butyl 4-hydroxy-3',6'-dihydro-[2,4'-bipyridine]-1'(2' H )-carboxylate was obtained as a white solid. (796.0 mg, 74%)

2) Synthesis of tert-butyl 4-(4-hydroxypyridin-2-yl)piperidine-1-carboxylate

Tert-butyl 4-hydroxy-3',6'-dihydro-[2,4'-bipyridin]-1'(2' H )-carboxylate (1.0 eq., 788.0 mg. 1.92 mmol) and 10 % Palladium on carbon (1.5 eq., 315.0 mg, 2.96 mmol) is dissolved in methanol (19.0 mL). After stirring overnight under a hydrogen atmosphere, it was filtered through Celite and concentrated under reduced pressure to obtain tert-butyl 4-(4-hydroxypyridin-2-yl)piperidine-1-carboxylate beige solid. (740.0 mg, 93%)

3) Synthesis of tert-butyl 4-(4-((4-cyano-2-fluorobenzyl)oxy)pyridin-2-yl)piperidine-1-carboxylate

Tert-butyl 4-(4-hydroxypyridin-2-yl)piperidine-1-carboxylate (1.0 eq., 300.0 mg, 1.08 mmol), 4-(bromomethyl)-3-fluorobenzonitrile (1.1 eq., 242.0 mg, 1.13 mmol) and potassium carbonate (3.0 eq., 447.0 mg, 3.23 mmol) are dissolved in DMF (10.0 mL). After stirring at room temperature overnight, the reaction solution was washed with brine and extracted with EA. The organic layer was dried over anhydrous magnesium sulfate, filtered, concentrated, and purified by silica chromatography to obtain tert-butyl 4-(4-((4-cyano-2-fluorobenzyl)oxy)pyridin-2-yl)piperidine. The -1-carboxylate was obtained as a yellow oil. (361.0 mg, 81%)

4) Synthesis of (3-fluoro-4-(((2-(piperidin-4-yl)pyridin-4-yl)oxy)methyl)benzonitrile)

Tert-butyl 4-(4-((4-cyano-2-fluorobenzyl)oxy)pyridin-2-yl)piperidine-1-carboxylate (1.0 eq., 341.0 mg, 0.83 mmol) in DCM After dissolving in (16.0 mL), TFA (3.3 mL) was added dropwise. After stirring at room temperature for 4 hours, it was concentrated under reduced pressure, washed with saturated aqueous sodium hydrogen carbonate solution, and extracted with EA. The organic layer was dried over anhydrous magnesium sulfate, filtered, concentrated, and 3-fluoro-4-(((2-(piperidin-4-yl)pyridin-4-yl)oxy)methyl as an intermediate without separate purification. ) Benzonitrile was obtained as a yellow liquid. (242.0 mg, 94%), (M+H) ⁺ : 312

(4) Preparation 4. Synthesis of Intermediate 22

1) Synthesis of 1-fluorocyclopropane-1-carbonyl chloride

1-fluorocyclopropane-1-carboxylic acid (1.0 eq., 2.0 g, 19.7 mmol) was added to thionyl chloride (2.5 eq., 49.3 mmol) and stirred under reflux for 60 minutes. After concentration under reduced pressure, 1-fluorocyclopropane-1-carbonyl chloride was obtained as a liquid without further purification, and used in the next reaction.

28% aq. in THF (10 mL). After adding an ammonia solution (5 mL), the obtained 1-fluorocyclopropane-1-carbonyl chloride was gradually added dropwise at 0° C., followed by stirring in an open flask overnight. The white solid formed in the reaction solution was filtered, washed with ice cold water, and dried to obtain 1-fluorocyclopropane-1-carboxamide as a pale yellow solid. (275 mg, 13%). ¹ H NMR (400 MHz, DMSO-d ₆ ): δ 7.80 (s, 1H), 7.58 (s, 1H), 1.29-1.14 (m, 4H)

2) Synthesis of (1-fluorocyclopropyl) methanamine hydrochloride

After dissolving 1-fluorocyclopropane-1-carboxamide (1.0 eq., 270 mg, 2.62 mmol) in THF (5 mL), 1M BH ₃ THF solution (4.0 eq., 10.5 mL) was added at 0°C. Added dropwise. After stirring at 70° C. overnight, 10% HCl aqueous solution (2 mL) was slowly added dropwise at 0° C., followed by stirring at room temperature for 1 hour. This was concentrated under reduced pressure, washed with diethyl ether, basified to pH 10 with 10% NaOH aqueous solution, and extracted three times with diethyl ether. The organic layer was dried over anhydrous magnesium sulfate, concentrated under reduced pressure to about 5 mL, and then a 2N hydrochloric acid (ether) solution was added dropwise at 0°C, stirred at room temperature for 1 hour, concentrated under reduced pressure, and (1-fluorocyclopropyl) methane without separate purification. Amine hydrochloride was obtained as a pale green solid. (102 mg, 31%)

3) Synthesis of methyl 3-(((1-fluorocyclopropyl)methyl)amino)-4-nitrobenzoate

(1-fluorocyclopropyl)methanamine hydrochloride (1.0 eq., 100 mg, 0.80 mmol) and methyl 3-fluoro-4-nitrobenzoate (1,0 eq., 158 mg, 0.80 mmol) were added to ACN (3 mL), TEA (3.0 eq., 0.33 mL) was added dropwise. After stirring at 85° C. overnight, it was concentrated under reduced pressure and purified by column chromatography to obtain methyl 3-(((1-fluorocyclopropyl)methyl)amino)-4-nitrobenzoate as a white solid. (119 mg, 56%) 269 (M+H) ⁺

4) Synthesis of methyl 4-amino-3-(((1-fluorocyclopropyl)methyl)amino)benzoate

After dissolving methyl 6-(((1-fluorocyclopropyl)methyl)amino)-5-nitropicolinate (1.0 eq., 100 mg, 0.37 mmol) in THF (5 mL), Pd/C (3.0 eq ., 118mg, 1.11mmol) was added and stirred under a hydrogen atmosphere for 3 hours. This was filtered and concentrated under reduced pressure to obtain methyl 4-amino-3-(((1-fluorocyclopropyl)methyl)amino)benzoate as a white solid. (71 mg, 80%) 239 (M+H) ⁺

5) Synthesis of methyl 2-(chloromethyl)-1-((1-fluorocyclopropyl)methyl)-1 H -benzo[ d ]imidazole-6-carboxylate

Methyl 5-amino-6-(((1-fluorocyclopropyl)methyl)amino)picolinate (1.0 eq., 70 mg, 0.30 mmol) and 2-chloro-1,1,1-trimethoxyethane ( 1.05 eq., 0.04 mL, 0.32 mmol) was dissolved in ACN (3 mL), pTSA (0.05 eq., 3 mg) was added, stirred at 85° C. for 3 hours, concentrated under reduced pressure, and purified by column chromatography as Intermediate 22. Methyl 2-(chloromethyl)-1-((1-fluorocyclopropyl)methyl)-1 H -benzo[ d ]imidazole-6-carboxylate was obtained as a white solid. (89mg, 52%) 297 (M+H) ⁺ ; ¹ H NMR (400 MHz, CDCl ₃ ): δ 8.09 (s, 1H), 8.04 (dd, J =8.4 Hz, J =1.6 Hz, 1H), 7.82 (d, J = 5.2 Hz, 1H), 4.97 ( s, 2H), 4.74 (d, J = 20 Hz, 1H), 1.23 (d, J = 11.6 Hz, 2H), 0.97 (d, J = 7.2 Hz, 2H)

(5) Preparation 5. Synthesis of Intermediate 30

1) Synthesis of tert-butyl 4-(6-hydroxypyridin-2-yl)piperazine-1-carboxylate

6-chloropyridin-2-ol (1,0 eq., 2.0 g, 15.44 mmol) and tert-butyl piperazine-1-carboxylate (2.5 eq., 7.19 mmol) dissolved in n-butanol (16 mL) Then, the mixture was stirred under reflux for 3 days. Then, it was concentrated under reduced pressure and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated to obtain 4-(6-hydroxypyridin-2-yl)piperazine-1-carboxylate as a brown solid without further purification. (1.29 g, 38.1%)

2) Synthesis of tert-butyl 4-(6-((5-chloropyridin-2-yl)methoxy)pyridin-2-yl)piperazine-1-carboxylate

After dissolving 5-chloropyridin-2-yl)methanol (1,18 eq., 1.0 g, 6.97 mmol) in DCM (10 mL), SOCl ₂ (2.37 eq., 1.01 mL, 13.93 mmol) was slowly added dropwise. After stirring at room temperature for 3 hours, the reaction solution was concentrated under reduced pressure. After dissolving in ACN (40mL) in the concentrate, potassium carbonate (6.0 eq., 4.89 g, 35.28 mmol) was added, and after stirring for 10 minutes, tert-butyl 4-(6-hydroxypyridin-2-yl)piperazine- After adding 1-carboxylate (1.0eq., 1.29 g, 5.88 mmol), the mixture was stirred at room temperature overnight. The reaction solution was washed with brine and extracted with ethyl acetate (EA). The organic layer was dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography to obtain tert-butyl 4-(6-((5-chloropyridin-2-yl)methoxy)pyridin-2-yl)piperazin-1 -The carboxylate was obtained as a pale yellow solid. (2.60 g, 63.4%)

3) 1-(6-((5-chloropyridin-2-yl)methoxy)pyridin-2-yl)piperazine 2TFA salt synthesis

4-(6-((5-chloropyridin-2-yl)methoxy)pyridin-2-yl)piperazine-1-carboxylate (1,0 eq., 624 mg, 1.54 mmol) was added to DCM (5 mL ), TFA (5 mL) was added dropwise. After stirring at room temperature for 4 hours, concentration under reduced pressure and 1-(6-((5-chloropyridin-2-yl)methoxy)pyridin-2-yl)piperazine 2TFA salt as the 2TFA salt of Intermediate 30 without separate purification Obtained as a pale green solid. (623 mg, 80.1%)

(6) Synthesis of Intermediates 1-53

Intermediates 1 to 53 listed in Table 1 below were prepared using the same or similar procedure as described above, and using suitable commercially available starting materials, or using preparation methods well known to those skilled in the art.

Each intermediate number, the manufacturing method conditions used for the synthesis, and the mass results confirmed according to the synthesis are shown in Table 1 below.

[Table 1]

Synthesis Example 2. Synthesis of Examples 1 to 62

A method for synthesizing Example Compounds 1 to 62 using Scheme 6 is described in detail below. Preparations A, B, and C correspond to specific examples of Scheme 6. A person skilled in the art can synthesize the compounds of Examples 1 to 62 according to the present invention with reference to the synthesis method reaction of Scheme 6 and specific examples of Preparation Methods A, B, and C.

(1) Preparation A. Synthesis of Example 1

1) Methyl 2-((4-(4-((4-cyano-2-fluorobenzyl)oxy)pyrimidin-2-yl)piperazin-1-yl)methyl)-1-(oxazole- Synthesis of 2-ylmethyl)-1 H -benzo[ d ]imidazole-6-carboxylate

Intermediate A (Intermediate 1, 1.0 eq., 73.0 mg, 0.23 mmol) and Intermediate B (Intermediate 16, 1.0 eq., 72.0 mg, 0.23 mmol) and potassium carbonate (5.0 eq., 160.0 mg, 1.16 mmol) was dissolved in DMF (2.4 mL), followed by stirring at room temperature overnight. The reaction solution was washed with brine and extracted twice with 10% methanol:DCM. The organic layer was dried over anhydrous magnesium sulfate, filtered, concentrated, and recrystallized with EA to obtain methyl 2-((4-(4-((4-cyano-2-fluorobenzyl)oxy)pyrimidin-2-yl)piperazine. -1-yl)methyl)-1-(oxazol-2-ylmethyl)-1 H -benzo[ d ]imidazole-6-carboxylate was obtained as a white solid. (50.0 mg, 37%)

2) 　 Synthesis of the compound of Example 1

Methyl 2-((4-(4-((4-cyano-2-fluorobenzyl)oxy)pyrimidin-2-yl)piperazin-1-yl)methyl)-1-(oxazol-2- Monomethyl)-1 H -benzo[ d ]imidazole-6-carboxylate (1.0 eq., 45.0 mg, 0.077 mmol), lithium hydroxide monohydrate (10 eq., 32.0 mg, 0.77 mmol) was added to dioxane (5.0 mL) ), H ₂ O (0.9 mL) was added. After stirring at room temperature for 3 days , pH was adjusted to 4 with 1 N -HCl solution, and extracted three times with EA. The organic layer was dried over anhydrous magnesium sulfate, filtered, concentrated, and purified by column chromatography to obtain the compound 2-((4-(4-((4-cyano-2-fluorobenzyl)oxy)pyrimidine- 2-yl)piperazin-1-yl)methyl)-1-(oxazol-2-ylmethyl)-1 H -benzo[ d ]imidazole-6-carboxylic acid was obtained as a white solid. (25.0 mg, 57%)

(2) Preparation B. Synthesis of Example 18

1) methyl (S)-2-((4-(4-((4-cyano-2-fluorobenzyl)oxy)pyrimidin-2-yl)piperidin-1-yl)methyl)-1 Synthesis of -(oxetan-2-ylmethyl)-1 H -benzo[ d ]imidazole-6-carboxylate

Intermediate A (Intermediate 10, 1.0 eq., 100.0 mg, 0.32 mmol), Intermediate B (Intermediate 17, 1.0 eq., 95.0 mg, 0.32 mmol) and potassium carbonate (4.0 eq., 177.0 mg, 1.28 mmol) were added to MeCN (Intermediate 10, 1.0 eq., 100.0 mg, 0.32 mmol). 2.0 mL) and stirred at room temperature for 3 hours. _{After adding H 2} O (10.0 mL) to the reaction solution, it was extracted three times with EA. The organic layer was dried over anhydrous magnesium sulfate, filtered, concentrated, and purified by column chromatography to obtain methyl (S)-2-((4-(4-((4-cyano-2-fluorobenzyl)oxy)pyrimidine- 2-yl)piperidin-1-yl)methyl)-1-(oxetan-2-ylmethyl)-1 H -benzo[ d ]imidazole-6-carboxylate was obtained as a white solid. (95.0 mg, 52%)

2) Synthesis of Example 18

Methyl (S)-2-((4-(4-((4-cyano-2-fluorobenzyl)oxy)pyrimidin-2-yl)piperidin-1-yl)methyl)-1-( Oxetan-2-ylmethyl)-1 H -benzo[ d ]imidazole-6-carboxylate (1.0 eq, 90.0 mg, 0.16 mmol), TBD (2.2 eq, 49.0 mg, 0.35 mmol) was added to MeCN (1.5 mL ), H ₂ O (0.35 mL) was added. After stirring at room temperature for 19 hours , pH was adjusted to 6 with 1 N -HCl solution, and extracted three times with EA. The organic layer was dried over anhydrous magnesium sulfate, filtered, concentrated, and purified by column chromatography to obtain the compound (S)-2-((4-(4-((4-cyano-2-fluorobenzyl)oxy) of Example 18. ) pyrimidin-2-yl) piperidin-1-yl) methyl) -1- (oxetan-2-ylmethyl) -1 H - benzo [d] imidazole-6-carboxylic acid to give a white solid . (45.0 mg, 51%)

(3) Preparation C. Synthesis of Example 23

1) Methyl 2-((4-(4-((4-cyano-2-fluorobenzyl)oxy)pyrimidin-2-yl)piperazin-1-yl)methyl)-1-(oxazole- Synthesis of 2-ylmethyl)-1 H -benzo[ d ]imidazole-6-carboxylate

Intermediate A (Intermediate 14, 1.0 eq., 67.7 mg, 0.250 mmol), Intermediate B (Intermediate 16, 1.1 eq., 84.2 mg, 0.275 mmol) and potassium carbonate were dissolved in DMF (2.4 mL) and stirred at room temperature overnight. I did. The reaction solution was washed with brine and extracted twice with 10% methanol:DCM. The organic layer was dried over anhydrous magnesium sulfate, filtered, concentrated, and recrystallized with EA to obtain methyl 2-((4-(4-((4-cyano-2-fluorobenzyl)oxy)pyrimidin-2-yl)piperazine. -1-yl)methyl)-1-(oxazol-2-ylmethyl)-1 H -benzo[ d ]imidazole-6-carboxylate was obtained as a white solid. (50.0 mg, 37%)

2) Synthesis of Example 23

Methyl 1-(oxazol-2-ylmethyl)-2-((4-(6-(pyridin-3-ylmethoxy)pyridin-2-yl)piperazin-1-yl)methyl)-1 H -benzo [ d ]imidazole-6-carboxylate (1.0 eq., 45.0 mg, 0.083 mmol), Me ₃ SnOH (10.0 eq., 150.0 mg, 0.83 mmol) was dissolved in DCM (3.0 mL) and then 3 at 80 °C. After stirring for a day , the pH was adjusted to 5 with 1 N -HCl solution and extracted three times with IPA:chloroform (1:4). The organic layer was dried over anhydrous magnesium sulfate, filtered, concentrated, and purified by column chromatography to obtain the compound 1-(oxazol-2-ylmethyl)-2-((4-(6-(pyridin-3-ylmethyl)) of Example 23. ethoxy) pyridin-2-yl) piperazin-1-yl) methyl) -1 H - benzo [d] imidazole-6-carboxylic acid to give a pale brown solid. (8.0 mg, 18%)

(4) Synthesis of Examples 1 to 62

The compounds of Examples 1 to 62 listed in Table 2 below are prepared using the same or similar procedure as described above, and using appropriate commercially available starting materials, or prepared using preparation methods well known to those skilled in the art, Or prepared in a similar manner to the route described above for other intermediates. These compounds were purified using methods well known to those of skill in the art, which may include silica gel chromatography, HPLC, or recrystallization from the reaction mixture. The final compound could be isolated as a neutral substance or as an acid or base salt. The compound names, NMR data, and LC-MS data of the prepared examples are shown in Table 2 below.

[Table 2]

Experimental Example 1. Evaluation of cAMP-based activity against human GLP-1R

The GLP-1 receptor CHO-K1 cells used in the test were cells expressing the human GLP-1 receptor and were purchased from Genscript and used (Cat: M00451, Genscript). GLP-1 receptor CHO-K1 cells were supplied with F-12 medium containing 10% FBS and 1% antibiotic, and cultured in an incubator at _{37° C. 5% CO 2.} The medium was replaced at intervals of 2 to 3 days, and subculture was performed when the cells were about 70 to 80% of the dish.

The cAMP assay test was performed according to the optimized test method based on the protocol provided by the cAMP assay kit manufacturer (CISBIO). ^{Dispense GLP-1 receptor CHO-K1 cells at 6 x 10 3} cells/well/5 μL into a 96-well plate for cAMP measurement (low volume, white), and treat exendin-4 as a control material and derivatives at room temperature. Incubated for 7 minutes. For cAMP quantification, a standard solution of 0 to 712 nM of cAMP was prepared and dispensed according to the concentration suggested in the kit protocol. The cAMP-d ₂ conjugate and the anti-cAMP cryptate conjugate reagent were prepared by diluting each of the cAMP & cGMP conjugates and elution buffers at a ratio of 1:4, respectively, and 5 μL of each were treated in all wells. After incubation at room temperature for 1 hour, wavelengths of 665 nm and 620 nm were measured using a FlexStation 3 (Molecular Devices) instrument. After calculating the 665/620 ratio based on the measured 665 nm and 620 nm wavelength values, the cAMP change according to the treatment by concentration was quantified based on the standard curve. The cAMP stimulation rate was calculated by converting the maximum cAMP measurement value to 100% as the result of exendin-4 treatment in one test. The results are shown in Tables 3-1 and 3-2, respectively, according to Examples.

[Table 3-1]

[Table 3-2]

Claims (15)

A compound represented by the following Formula 1, an optical isomer thereof, or a pharmaceutically acceptable salt thereof:
[Formula 1]

In Formula 1,
R ₁ is unsubstituted or substituted with -C(=O)R _a, -S(=O) ₂ R _a , -(C ₁ -C ₃ alkyl) OH, -CN and -(C ₁ -C _{4 alkyl)} Is any one selected from the group consisting of tetrazolyl;
R _a is one selected from the group consisting of -OH, -O-(C ₁ -C ₄ alkyl) and -NR _a1 R _a2;
R _a1 and R _a2 are each independently any one selected from the group consisting of hydrogen, -OH, -(C ₁ -C ₄ alkyl) and -(C ₁ -C ₄ alkyl)C(=O)OH;
Y ₁ and Y ₂ are each independently -CH- or -N-;
R ₂ is a substituted or unsubstituted C ₆ ∼C ₁₂ aryl, a substituted or unsubstituted C ₅ ∼C ₁₂ heteroaryl, a substituted or unsubstituted C ₃ ∼C ₈ heterocycloalkyl, a substituted or unsubstituted C ₃ ∼ C ₈ cycloalkyl, and any one selected from the group consisting of -C(=O)R _b , wherein substituted, aryl, heteroaryl, heterocycloalkyl and cycloalkyl are at least one or more -OH, -(C ₁ -C ₄ alkyl), halogen, or -CN;
R _b is -(C ₁ -C ₄ alkyl) or -NR _b1 R _b2 ,;
R _b1 and R _b2 are each independently hydrogen or -(C ₁ -C ₄ alkyl);
Q ₁ and Q ₂ is carbon or nitrogen, each independently, where, if Q ₁ is nitrogen, Q ₂ is carbon, if Q ₂ is nitrogen, Q ₁ is carbon;
A ₁ is

,

,

or

ego;

Is a substituted or unsubstituted C ₃ to C ₈ heterocycloalkyl containing at least one nitrogen, or a substituted or unsubstituted C ₃ to C ₁₂ heterobicycloalkyl containing at least one nitrogen, wherein , Heterocycloalkyl and heterobicycloalkyl are substituted with at least one -OH, -(C ₁ -C ₄ alkyl), halogen, or -CN);
R` is hydrogen, or -(C ₁ -C ₄ alkyl);
X is -CR _c -or -N-;
R _c is any one selected from the group consisting of -H, halogen, -CN, -OH, -O-(C ₁ -C ₄ alkyl), -NH ₂ , -NO ₂ and -C ₁ -C _{4 haloalkyl} ego;
W ₁ is -CR _d -or -N-;
W ₂ is -CR _e -or -N-;
W ₃ is -CR _f -or -N-;
R _d to R _f are each independently -H, halogen, -CN, -OH, -O-(C ₁ -C ₄ alkyl), -NH ₂ , -NO ₂ and -C ₁ -C ₄ haloalkyl Is any one selected from the group;
L is any one selected from the group consisting of -O-, -S- and -NR _{g -;}
R _g is -H or -(C ₁ -C ₄ alkyl);
A ₂ is

,

And

It is any one selected from the group consisting of;
Z ₁ is -CR _h -or -N-;
Z ₂ is -CR _i -or -N-;
Z ₃ is -CR _j -or -N-;
Z ₄ is -CR _k -or -N-;
Z ₅ is -CR ₁ -or -N-;
R _h to R _l are each independently -H, halogen, -CN, -OH, -O-(C ₁ -C ₄ alkyl), -NH ₂ , -NO ₂ and -C ₁ -C ₄ haloalkyl Is any one selected from the group;
R ₃ and R ₄ are each independently -H, halogen, -CN, -OH, -O-(C ₁ -C ₄ alkyl), -NH ₂ , -NO ₂ and -C ₁ -C ₄ haloalkyl Is any one selected from the group; And
n is an integer of 1 or 2. The method of claim 1,
The compound represented by Formula 1 is a compound represented by Formula 1, an optical isomer thereof, or a pharmaceutically acceptable salt thereof, which is a compound represented by Formula 2 below:
[Formula 2]

In Chemical Formula 2,
R ₁ is substituted or provided with -C(=O)R _a, -S(=O) ₂ R _a , -(C ₁ -C ₃ alkyl)OH, -CN, and -(C ₁ -C _{4 alkyl)} It is any one selected from the group consisting of cyclic tetrazolyl;
R _a is one selected from the group consisting of -OH, -O-(C ₁ -C ₄ alkyl), and -NR _a1 R _a2;
R _a1 and R _a2 are each independently any one selected from the group consisting of hydrogen, -OH, -(C ₁ -C ₄ alkyl), and -(C ₁ -C _{4 alkyl)C(=O)OH} ;
Y ₁ and Y ₂ are each independently -CH- or -N-;
R ₂ is a substituted or unsubstituted C ₆ ∼C ₁₂ aryl, a substituted or unsubstituted C ₅ ∼C ₁₂ heteroaryl, a substituted or unsubstituted C ₃ ∼C ₈ heterocycloalkyl, a substituted or unsubstituted C ₃ ∼ C ₈ cycloalkyl, and any one selected from the group consisting of -C(=O)R _b , wherein substituted, aryl, heteroaryl, heterocycloalkyl and cycloalkyl are at least one or more -OH, -(C ₁ -C ₄ alkyl), halogen, or -CN;
R _b is -(C ₁ -C ₄ alkyl) or -NR _b1 R _b2 ,;
R _b1 and R _b2 are each independently hydrogen or -(C ₁ -C ₄ alkyl);
A ₁ is

,

,

or

ego;

Is a substituted or unsubstituted C ₃ to C ₈ heterocycloalkyl containing at least one nitrogen, or a substituted or unsubstituted C ₃ to C ₁₂ heterobicycloalkyl containing at least one nitrogen, wherein , Heterocycloalkyl and heterobicycloalkyl are substituted with at least one -OH, -(C ₁ -C ₄ alkyl), halogen, or -CN);
X is -CR _c -or -N-;
R _c is any one selected from the group consisting of -H, halogen, -CN, -OH, -O-(C ₁ -C ₄ alkyl), -NH ₂ , -NO ₂ and -C ₁ -C _{4 haloalkyl} ego;
W ₁ is -CR _d -or -N-;
W ₂ is -CR _e -or -N-;
W ₃ is -CR _f -or -N-;
R _d to R _f are each independently -H, halogen, -CN, -OH, -O-(C ₁ -C ₄ alkyl), -NH ₂ , -NO ₂ and -C ₁ -C ₄ haloalkyl Is any one selected from the group;
L is any one selected from the group consisting of -O-, -S- and -NR _{g -;}
R _g is -H or -(C ₁ -C ₄ alkyl);
A ₂ is

,

And

It is any one selected from the group consisting of;
Z ₁ is -CR _h -or -N-;
Z ₂ is -CR _i -or -N-;
Z ₃ is -CR _j -or -N-;
Z ₄ is -CR _k -or -N-;
Z ₅ is -CR ₁ -or -N-;
R _h to R _l are each independently -H, halogen, -CN, -OH, -O-(C ₁ -C ₄ alkyl), -NH ₂ , -NO ₂ and -C ₁ -C ₄ haloalkyl Is any one selected from the group;
R ₃ and R ₄ are each independently -H, halogen, -CN, -OH, -O-(C ₁ -C ₄ alkyl), -NH ₂ , -NO ₂ and -C ₁ -C ₄ haloalkyl Is any one selected from the group; And
n is an integer of 1 or 2. The method of claim 1,
The compound represented by Formula 1 is a compound represented by Formula 1, an optical isomer thereof, or a pharmaceutically acceptable salt thereof, which is a compound represented by Formula 3 below:
[Formula 3]

In Chemical Formula 3,
R ₁ is -C(=O)R _a ;
R _a is -OH or -O-(C ₁ -C ₄ alkyl);
Y ₁ and Y ₂ are each independently -CH- or -N-;
R ₂ is a substituted or unsubstituted C ₆ ∼C ₁₂ aryl, a substituted or unsubstituted C ₅ ∼C ₁₂ heteroaryl, a substituted or unsubstituted C ₃ ∼C ₈ heterocycloalkyl, a substituted or unsubstituted C ₃ ∼ C ₈ cycloalkyl, and any one selected from the group consisting of -C(=O)R _b , wherein substituted, aryl, heteroaryl, heterocycloalkyl and cycloalkyl are at least one or more -OH, -(C ₁ -C ₄ alkyl), halogen, or -CN;
R _b is -(C ₁ -C ₄ alkyl) or -NR _b1 R _b2 ,;
R _b1 and R _b2 are each independently hydrogen or -(C ₁ -C ₄ alkyl);
A ₁ is

,

,

or

ego;

Is a substituted or unsubstituted C ₃ to C ₈ heterocycloalkyl containing at least one nitrogen, a substituted or unsubstituted C ₃ to C ₁₂ spiroheterocycloalkyl containing at least one nitrogen, or at least one nitrogen Is a substituted or unsubstituted C ₃ to C ₁₂ bridged heterobicycloalkyl containing (wherein, substituted, heterocycloalkyl, spiroheterocycloalkyl and heterobicycloalkyl are at least one -OH, -(C ₁ -C ₄ alkyl), halogen, or -CN;
R` is hydrogen, or -(C ₁ -C ₄ alkyl);
X is -CR _c -or -N-;
R _c is any one selected from the group consisting of -H, halogen, -CN, -OH, -O-(C ₁ -C ₄ alkyl), -NH ₂ , -NO ₂ and -C ₁ -C _{4 haloalkyl} ego;
W ₁ is -CR _d -or -N-;
W ₂ is -CR _e -or -N-;
W ₃ is -CR _f -or -N-;
R _d to R _f are each independently -H, halogen, -CN, -OH, -O-(C ₁ -C ₄ alkyl), -NH ₂ , -NO ₂ and -C ₁ -C ₄ haloalkyl Is any one selected from the group;
Z ₁ is -CR _h -or -N-;
Z ₂ is -CR _i -or -N-;
Z ₃ is -CR _j -or -N-;
Z ₄ is -CR _k -or -N-;
R _h to R _l are each independently -H, halogen, -CN, -OH, -O-(C ₁ -C ₄ alkyl), -NH ₂ , -NO ₂ and -C ₁ -C ₄ haloalkyl It is any one selected from the group. The method of claim 1,
A ₂ is

Is;
At least one of Z ₁ to Z ₅ is -N-, a compound represented by Formula 1, an optical isomer thereof, or a pharmaceutically acceptable salt thereof. The method of claim 1,

Is

,

or

Is,

end

In the case of, at least one of _{W 1} , W ₂ and W _{3 is -N-;}
A ₂ is

Is;
Z ₁ is -CR _h -;
Z ₂ is -CR _i -;
Z ₃ is -CR _j -;
Z ₄ is -CR _k -;
Z ₅ is -CR ₁ -, a compound represented by Formula 1, an optical isomer thereof, or a pharmaceutically acceptable salt thereof. The method of claim 1,
A ₁ is

ego;

Is a substituted or unsubstituted 7 member containing at least one nitrogen Or 8-membered heterocycloalkyl, substituted or unsubstituted C ₃ to C ₁₂ spiroheterocycloalkyl containing at least one nitrogen, or substituted or unsubstituted C ₃ to C ₁₂ bridging containing at least one nitrogen Heterobicycloalkyl, wherein substituted, heterocycloalkyl, spiroheterocycloalkyl and heterobicycloalkyl are substituted with at least one -OH, -(C ₁ -C ₄ alkyl), halogen, or -CN Is);

Is
When W ₂ is -CR _e -, two of X, W ₁ , and W ₃ are -N-;
One of X, W ₁ , W ₂ , and W ₃ is -N-;
A ₂ is

Is;
Z ₁ is -CR _h -;
Z ₂ is -CR _i -;
Z ₃ is -CR _j -;
Z ₄ is -CR _k -;
Z ₅ is -CR ₁ -, a compound represented by Formula 1, an optical isomer thereof, or a pharmaceutically acceptable salt thereof. The method of claim 1,
A ₁ is

,

, or

ego;

Is a substituted or unsubstituted 4-7 member containing at least one nitrogen Heterocycloalkyl, substituted or unsubstituted C ₃ to C ₁₂ spiroheterocycloalkyl containing at least one nitrogen, or substituted or unsubstituted C ₃ to C ₁₂ bridged heterobicyclo containing at least one nitrogen Alkyl, wherein substituted, heterocycloalkyl, spiroheterocycloalkyl and heterobicycloalkyl are substitution with at least one or more -OH, -(C ₁ -C ₄ alkyl), halogen, or -CN;

Is
When W ₂ is -CR _e -, two of X, W ₁ , and W ₃ are -N-;
One of X, W ₁ , W ₂ , and W ₃ is -N-;
A ₂ is

Is;
Z ₁ is -CR _h -;
Z ₂ is -CR _i -;
Z ₃ is -CR _j -;
Z ₄ is -CR _k -;
Z ₅ is -CR ₁ -, a compound represented by Formula 1, an optical isomer thereof, or a pharmaceutically acceptable salt thereof. The method of claim 1,
A ₁ is

Is,

Silver 6-membered containing 1 or 2 nitrogens Heterocycloalkyl;

Is
When W ₂ is -CR _e -, two of X, W ₁ and W ₃ are -N-;
A ₂ is

Is;
Z ₁ is-CR _h -;
Z ₂ is -CR _i -;
Z ₃ is -CR _j -;
Z ₄ is -CR _k -;
Z ₅ is -CR ₁ -, a compound represented by Formula 1, an optical isomer thereof, or a pharmaceutically acceptable salt thereof. The method of claim 1,
A ₁ is

ego;

Is
X and W ₁ are -N-;
W ₂ is -CR _e -;
W ₃ is -CR _f -;
R _f is any one selected from the group consisting of halogen, -CN, -OH, -O-(C ₁ -C ₄ alkyl), -NH ₂ , -NO ₂ and -C ₁ -C _{4 haloalkyl;}
A ₂ is

Is;
Z ₁ is-CR _h -;
Z ₂ is -CR _i -;
Z ₃ is -CR _j -;
Z ₄ is -CR _k -;
Z ₅ is -CR ₁ -, a compound represented by Formula 1, an optical isomer thereof, or a pharmaceutically acceptable salt thereof. The method of claim 1,
Y1 is -N-;
A ₁ is

ego;

in
X and W ₁ are -N-;
W ₂ is -CR _e -;
W ₃ is -CR _f -;
A ₂ is

Is;
Z ₁ is-CR _h -;
Z ₂ is -CR _i -;
Z ₃ is -CR _j -;
Z ₄ is -CR _k -;
Z ₅ is -CR ₁ -, a compound represented by Formula 1, an optical isomer thereof, or a pharmaceutically acceptable salt thereof. The method of claim 1,
R1 is -C(=O)R _a ;
Ra is NR _a1 R _a2 ;
A ₁ is

ego;

Is

ego;
A ₂ is

Is;
Z ₁ is -CR _h -;
Z ₂ is -CR _i -;
Z ₃ is -CR _j -;
Z ₄ is -CR _k -;
Z ₅ is -CR ₁ -, a compound represented by Formula 1, an optical isomer thereof, or a pharmaceutically acceptable salt thereof. The compound of claim 1, wherein the compound represented by Formula 1 is any one selected from the group consisting of the following compounds, an optical isomer thereof, or a pharmaceutically acceptable salt thereof:
2-((4-(4-((4-cyano-2-fluorobenzyl)oxy)pyrimidin-2-yl)piperazin-1-yl)methyl)-1-(oxazol-2-yl Methyl)-1 H -benzo[ d ]imidazole-6-carboxylic acid;
2-((4-(4-((4-cyano-2-fluorobenzyl)oxy)pyridin-2-yl)piperazin-1-yl)methyl)-1-(oxazol-2-ylmethyl )-1 H -benzo[ d ]imidazole-6-carboxylic acid;
1-(oxazol-2-ylmethyl)-2-((4-(6-(pyridin-4-ylmethoxy)pyridin-2-yl)piperazin-1-yl)methyl)-1 H -benzo[ d ]imidazole-6-carboxylic acid;
2-((4-(3-((4-cyano-2-fluorobenzyl)oxy)phenyl)piperazin-1-yl)methyl)-1-(oxazol-2-ylmethyl)-1 H -Benzo[ d ]imidazole-6-carboxylic acid;
2-((4-(5-((4-cyano-2-fluorobenzyl)oxy)pyridin-3-yl)piperazin-1-yl)methyl)-1-(oxazol-2-ylmethyl )-1 H -benzo[ d ]imidazole-6-carboxylic acid;
2-((4-(6-((4-cyano-2-fluorobenzyl)oxy)pyrazin-2-yl)piperazin-1-yl)methyl)-1-(oxazol-2-ylmethyl )-1 H -benzo[ d ]imidazole-6-carboxylic acid;
2-((4-(2-((4-cyano-2-fluorobenzyl)oxy)pyridin-4-yl)piperazin-1-yl)methyl)-1-(oxazol-2-ylmethyl )-1 H -benzo[ d ]imidazole-6-carboxylic acid;
1-(oxazol-2-ylmethyl)-2-((4-(6-(pyridin-2-ylmethoxy)pyridin-2-yl)piperazin-1-yl)methyl)-1 H -benzo[ d ]imidazole-6-carboxylic acid;
2-((4-(6-((4-cyano-2-fluorobenzyl)oxy)pyrimidin-4-yl)piperazin-1-yl)methyl)-1-(oxazol-2-yl Methyl)-1 H -benzo[ d ]imidazole-6-carboxylic acid;
2-((4-(4-((4-cyano-2-fluorobenzyl)oxy)pyridin-2-yl)piperidin-1-yl)methyl)-1-(oxazol-2-yl Methyl)-1 H -benzo[ d ]imidazole-6-carboxylic acid;
2-((4-(4-((4-cyano-2-fluorobenzyl)oxy)pyrimidin-2-yl)piperidin-1-yl)methyl)-1-(oxazol-2- Ylmethyl)-1 H -benzo[ d ]imidazole-6-carboxylic acid;
2-((4-(2-((4-cyano-2-fluorobenzyl)oxy)pyridin-4-yl)piperidin-1-yl)methyl)-1-(oxazol-2-yl Methyl)-1 H -benzo[ d ]imidazole-6-carboxylic acid;
(S)-2-((4-(6-((4-cyano-2-fluorobenzyl)oxy)pyrazin-2-yl)piperazin-1-yl)methyl)-1-(oxetane- 2-ylmethyl)-1 H -benzo[ d ]imidazole-6-carboxylic acid;
(S)-2-((4-(3-((4-cyano-2-fluorobenzyl)oxy)phenyl)piperazin-1-yl)methyl)-1-(oxetan-2-ylmethyl )-1 H -benzo[ d ]imidazole-6-carboxylic acid;
(S)-2-((4-(6-((5-chloro-3-fluoropyridin-2-yl)methoxy)pyridin-2-yl)piperazin-1-yl)methyl)-1- (Oxetan-2-ylmethyl)-1 H -benzo[ d ]imidazole-6-carboxylic acid;
2-((4-(3-((4-cyano-2-fluorobenzyl)oxy)phenyl)piperazin-1-yl)methyl)-1-((1-ethyl-1 H -imidazole- 5-yl)methyl)-1 H -benzo[ d ]imidazole-6-carboxylic acid;
(S)-2-((4-(6-((4-cyano-2-fluorobenzyl)oxy)pyridin-2-yl)-1,4-diazepan-1-yl)methyl)-1 -(Oxetan-2-ylmethyl)-1 H -benzo[ d ]imidazole-6-carboxylic acid;
(S)-2-((4-(4-((4-cyano-2-fluorobenzyl)oxy)pyrimidin-2-yl)piperidin-1-yl)methyl)-1-(oxy Cetan-2-ylmethyl)-1 H -benzo[ d ]imidazole-6-carboxylic acid;
(S)-2-((4-(6-((5-chloro-3-fluoropyridin-2-yl)methoxy)pyridin-2-yl)piperidin-1-yl)methyl)-1 -(Oxetan-2-ylmethyl)-1 H -benzo[ d ]imidazole-6-carboxylic acid;
(S)-2-((4-(6-((5-cyanopyridin-2-yl)methoxy)pyridin-2-yl)piperidin-1-yl)methyl)-1-(oxetane -2-ylmethyl)-1 H -benzo[ d ]imidazole-6-carboxylic acid;
(S)-2-((4-(3-((4-cyano-2-fluorobenzyl)oxy)phenyl)piperidin-1-yl)methyl)-1-(oxetan-2-yl Methyl)-1 H -benzo[ d ]imidazole-6-carboxylic acid;
(S)-2-((4-(4-((4-cyano-2-fluorobenzyl)oxy)pyrimidin-2-yl)piperazin-1-yl)methyl)-1-(oxetane -2-ylmethyl)-1 H -benzo[ d ]imidazole-6-carboxylic acid;
1-(oxazol-2-ylmethyl)-2-((4-(6-(pyridin-3-ylmethoxy)pyridin-2-yl)piperazin-1-yl)methyl)-1 H -benzo[ d ]imidazole-6-carboxylic acid;
(S)-2-((4-(6-((5-cyanopyridin-2-yl)methoxy)pyridin-2-yl)piperazin-1-yl)methyl)-1-(oxetane- 2-ylmethyl)-1 H -benzo[ d ]imidazole-6-carboxylic acid;
(S)-2-((4-(3-((5-chloro-3-fluoropyridin-2-yl)methoxy)phenyl)piperidin-1-yl)methyl)-1-(oxetane -2-ylmethyl)-1 H -benzo[ d ]imidazole-6-carboxylic acid;
(S)-2-((4-(6-((5-cyanopyridin-2-yl)methoxy)pyrazin-2-yl)piperazin-1-yl)methyl)-1-(oxetane- 2-ylmethyl)-1 H -benzo[ d ]imidazole-6-carboxylic acid;
(S)-2-((4-(4-((5-cyanopyridin-2-yl)methoxy)pyrimidin-2-yl)piperidin-1-yl)methyl)-1-(oxy Cetan-2-ylmethyl)-1 H -benzo[ d ]imidazole-6-carboxylic acid;
(S)-2-((4-(3-((5-cyanopyridin-2-yl)methoxy)phenyl)piperazin-1-yl)methyl)-1-(oxetan-2-ylmethyl )-1 H -benzo[ d ]imidazole-6-carboxylic acid;
(S)-2-((4-(6-((5-cyanopyridin-2-yl)methoxy)pyridin-2-yl)piperazin-1-yl)methyl)-3-(oxetane- 2-ylmethyl)-3 H -imidazo[4,5-b]pyridin-5-carboxylic acid;
(S)-2-((4-(3-((5-cyanopyridin-2-yl)methoxy)phenyl)piperazin-1-yl)methyl)-3-(oxetan-2-ylmethyl ) -3 H - imidazo [4,5-b] pyridine-5-carboxylic acid;
(S)-2-((4-(6-((5-chloropyridin-2-yl)methoxy)pyridin-2-yl)piperazin-1-yl)methyl)-1-(oxetane-2 -Ylmethyl)-1 H -benzo[ d ]imidazole-6-carboxylic acid;
2-(((S)-4-(6-((5-cyanopyridin-2-yl)methoxy)pyridin-2-yl)-2-methylpiperazin-1-yl)methyl)-1- (((S)-oxetan-2-yl)methyl)-1 H -benzo[ d ]imidazole-6-carboxylic acid;
2-(((S)-4-(6-((5-cyanopyridin-2-yl)methoxy)pyridin-2-yl)-2-methylpiperazin-1-yl)methyl)-3- (((S)-oxetan-2-yl)methyl)-3 H -imidazo[4,5-b]pyridin-5-carboxylic acid;
(S)-2-((4-(6-((4-cyano-2-fluorobenzyl)oxy)pyrazin-2-yl)piperidin-1-yl)methyl)-1-(oxetane -2-ylmethyl)-1 H -benzo[ d ]imidazole-6-carboxylic acid;
(S)-2-((6-(3-((4-cyano-2-fluorobenzyl)oxy)phenyl)-2,6-diazaspiro[3.3]heptan-2-yl)methyl) -1-(oxetan-2-ylmethyl)-1 H -benzo[ d ]imidazole-6-carboxylic acid;
(S)-2-((4-(3-((4-cyano-2-fluorobenzyl)oxy)phenyl)piperazin-1-yl)methyl)-1-((tetrahydrofuran-2- Yl)methyl)-1 H -benzo[ d ]imidazole-6-carboxylic acid;
(S)-2-((4-(3-((4-cyano-2-fluorobenzyl)oxy)phenyl)piperidin-1-yl)methyl)-3-(oxetan-2-yl methyl) -3 H - imidazo [4,5-b] pyridine-5-carboxylic acid;
(S)-2-((4-(3-((4-cyano-2-fluorobenzyl)oxy)phenyl)-1,4-diazepan-1-yl)methyl)-1-(oxetane -2-ylmethyl)-1 H -benzo[ d ]imidazole-6-carboxylic acid;
(S)-2-((4-(3-((4-cyano-2-fluorobenzyl)oxy)phenyl)piperazin-1-yl)methyl)-3-(oxetan-2-ylmethyl ) -3 H - imidazo [4,5-b] pyridine-5-carboxylic acid;
2-((4-(3-((4-cyano-2-fluorobenzyl)oxy)phenyl)piperazin-1-yl)methyl)-1-((1-fluorocyclopropyl)methyl)- 1 H -benzo[ d ]imidazole-6-carboxylic acid;
(S)-2-((4-(5-((4-cyano-2-fluorobenzyl)oxy)-2-fluorophenyl)piperazin-1-yl)methyl)-1-(oxetane -2-ylmethyl)-1 H -benzo[ d ]imidazole-6-carboxylic acid;
(S)-2-((4-(6-((4-cyano-2-fluorobenzyl)oxy)pyrazin-2-yl)-1,4-diazepan-1-yl)methyl)-1 -(Oxetan-2-ylmethyl)-1 H -benzo[ d ]imidazole-6-carboxylic acid;
(S)-2-((4-((3-((4-cyano-2-fluorobenzyl)oxy)phenyl)amino)piperidin-1-yl)methyl)-1-(oxetane- 2-ylmethyl)-1 H -benzo[ d ]imidazole-6-carboxylic acid;
2-(((S)-3-((3-((4-cyano-2-fluorobenzyl)oxy)phenyl)amino)pyrrolidin-1-yl)methyl)-1-(((S )-Oxetan-2-yl)methyl)-1 H -benzo[ d ]imidazole-6-carboxylic acid;
(S)-2-((4-(6-((4-cyano-2-fluorobenzyl)oxy)pyrazin-2-yl)piperazin-1-yl)methyl)-3-(oxetane- 2-ylmethyl)-3 H -imidazo[4,5-b]pyridin-5-carboxylic acid;
2-((3-(3-((4-cyano-2-fluorobenzyl)oxy)phenyl)-3,6-diazabicyclo[3.1.1]heptan-6-yl)methyl)-1 -(((S)-oxetan-2-yl)methyl)-1 H -benzo[ d ]imidazole-6-carboxylic acid;
2-(((S)-4-(6-((4-cyano-2-fluorobenzyl)oxy)pyrazin-2-yl)-2-methylpiperazin-1-yl)methyl)-1- (((S)-oxetan-2-yl)methyl)-1 H -benzo[ d ]imidazole-6-carboxylic acid;
2-(((S)-4-(3-((4-cyano-2-fluorobenzyl)oxy)phenyl)-2-methylpiperazin-1-yl)methyl)-1-(((S )-Oxetan-2-yl)methyl)-1 H -benzo[ d ]imidazole-6-carboxylic acid;
2-(((S)-4-(3-((4-cyano-2-fluorobenzyl)oxy)phenyl)-2-methylpiperazin-1-yl)methyl)-3-(((S )-Oxetan-2-yl)methyl)-3 H -imidazo[4,5-b]pyridin-5-carboxylic acid;
(S)-2-((6-(6-((4-cyano-2-fluorobenzyl)oxy)pyridin-2-yl)-2,6-diazaspiro[3.3]heptane-2- Yl)methyl)-1-(oxetan-2-ylmethyl)-1 H -benzo[ d ]imidazole-6-carboxylic acid;
(S)-2-((4-(4-((4-cyano-2-fluorobenzyl)oxy)pyrimidin-2-yl)-1,4-diazepan-1-yl)methyl)- 1-(oxetan-2-ylmethyl)-1 H -benzo[ d ]imidazole-6-carboxylic acid;
2-((3-(6-((4-cyano-2-fluorobenzyl)oxy)pyridin-2-yl)-3,6-diazabicyclo[3.1.1]heptan-6-yl) Methyl)-1-(((S)-oxetan-2-yl)methyl)-1 H -benzo[ d ]imidazole-6-carboxylic acid;
2-((3-(6-((4-cyano-2-fluorobenzyl)oxy)pyridin-2-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl) Methyl)-1-(((S)-oxetan-2-yl)methyl)-1 H -benzo[ d ]imidazole-6-carboxylic acid;
2-((3-((6-((4-cyano-2-fluorobenzyl)oxy)pyridin-2-yl)amino)pyrrolidin-1-yl)methyl)-1-(((S )-Oxetan-2-yl)methyl)-1 H -benzo[ d ]imidazole-6-carboxylic acid;
(S)-2-((4-((6-((4-cyano-2-fluorobenzyl)oxy)pyridin-2-yl)amino)piperidin-1-yl)methyl)-1- (Oxetan-2-ylmethyl)-1 H -benzo[ d ]imidazole-6-carboxylic acid;
(S)-2-((3-((6-((4-cyano-2-fluorobenzyl)oxy)pyridin-2-yl)amino)azetidin-1-yl)methyl)-1-( Oxetan-2-ylmethyl)-1 H -benzo[ d ]imidazole-6-carboxylic acid;
2-(((S)-3-((6-((4-cyano-2-fluorobenzyl)oxy)pyridin-2-yl)amino)pyrrolidin-1-yl)methyl)-1- (((S)-oxetan-2-yl)methyl)-1 H -benzo[ d ]imidazole-6-carboxylic acid;
(S)-2-((4-((6-((4-cyano-2-fluorobenzyl)oxy)pyridin-2-yl)(methyl)amino)piperidin-1-yl)methyl) -1-(oxetan-2-ylmethyl)-1 H -benzo[ d ]imidazole-6-carboxylic acid;
2-(((R)-3-((6-((4-cyano-2-fluorobenzyl)oxy)pyridin-2-yl)amino)pyrrolidin-1-yl)methyl)-1- (((S)-oxetan-2-yl)methyl)-1 H -benzo[ d ]imidazole-6-carboxylic acid;
(S)-2-((4-(4-((4-cyano-2-fluorobenzyl)oxy)-5-fluoropyrimidin-2-yl)piperazin-1-yl)methyl)- 1-(oxetan-2-ylmethyl)-1 H -benzo[ d ]imidazole-6-carboxylic acid;
(S)-2-((4-(4-((4-cyano-2-fluorobenzyl)oxy)pyrimidin-2-yl)piperidin-1-yl)methyl)-3-(oxy Cetan-2-ylmethyl)-3 H -imidazo[4,5-b]pyridin-5-carboxylic acid; And
(2-((4-(6-((4-cyano-2-fluorobenzyl)oxy)pyridin-2-yl)piperazin-1-yl)methyl)-1-(((S)-oxy Cetan-2-yl)methyl)-1 H -benzo[ d ]imidazole-6-carbonyl)-L-alanine. A pharmaceutical composition comprising a compound according to any one of claims 1 to 12, an optical isomer thereof, or a pharmaceutically acceptable salt thereof. A pharmaceutical composition for preventing or treating metabolic diseases comprising the compound according to any one of claims 1 to 12, an optical isomer thereof, or a pharmaceutically acceptable salt thereof. A GLP-1R agonist comprising a compound according to any one of claims 1 to 12, an optical isomer thereof, or a pharmaceutically acceptable salt thereof.