KR20220118267A - Azabicyclo alkyl derivatives as FXR agonist, and uses thereof - Google Patents

Abstract

The present invention relates to an azabicycloalkyl derivative compound, and uses thereof. Since the azabicycloalkyl derivative compound of the present invention exhibits excellent action activity on FXR, it can be usefully used as a therapeutic agent for liver diseases mediated by the FXR.

Description

Azabicycloalkyl derivatives as FXR agonists and uses thereof

The present invention relates to azabicycloalkyl derivative compounds having FXR agonist activity and uses thereof.

Farnesoid X receptor (FXR, NR1H4) belongs to a group of ligand-activated transcription factors known as nuclear receptors, and is known to be expressed in the liver, esophagus, stomach, duodenum, small intestine, colon, kidney and adrenal gland. (Kuipers, F. et al., Rev. Endocrine Metab. Disorders, 2004, 5: 319-326). In addition, bile acids such as chenodeoxycholic acid (CDCA) or their taurine or glycinamide conjugates are endogenous ligands of FXR. FXR is activated upon binding to bile acids and forms a heterodimeric complex with the retinoid X receptor (RXR), thereby controlling the expression of a number of genes, including those involved in the homeostasis of bile acids, cholesterol, triglycerides, and lipoproteins in the liver and circulatory system ( Kalaany, N.Y. et al., Annu. Rev. Physiol., 2006, 68: 159-191; Calkin, A. C. et al., Nat. Rev. mol. Cell Biol., 2012, 13: 213-224). In addition, FXR is Fibroblast growth factor 15 (FGF15) (rodent). Alternatively, it appears to be involved in paracrine and endocrine signaling by up-regulating the expression of FGF19 (monkey, human) (T. Inagaki et al., Cell Metab., 2005, 2(4), 217-225).

On the other hand, obeticholic acid (6-Et CDCA) is an FXR agonist that exhibits more activity than endogenous CDCA, in non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), and primary biliary cirrhosis (PBC). ) showed some effective effects in clinical trials for (Mudaliar, s. et al., gastroenterology, 2013, 145: 574-582; Nevens, F. et al., J. Hepatol., 2014, 60: S525-S526) ). However, since known FXR agonists still have shortcomings in pharmacodynamic or pharmacokinetic properties, there is an unmet need for novel compounds that have agonistic activity on FXR and can be usefully utilized in the treatment of liver diseases mediated by FXR. is increasing

Kuipers, F. et al., Rev. Endocrine Metab. Disorders, 2004, 5: 319-326 Kalaany, N.Y. et al., Annu. Rev. Physiol., 2006, 68: 159-191 Calkin, A. C. et al., Nat. Rev. mol. Cell Biol., 2012, 13: 213-224 T. Inagaki et al., Cell Metab., 2005, 2(4), 217-225 Mudalia, s. et al., gastroenterology, 2013, 145: 574-582 Nevens, F. et al., J. Hepatol., 2014, 60: S525-S526

An object of the present invention is to provide an azabicycloalkyl derivative compound having a novel structure, an optical isomer thereof, or a pharmaceutically acceptable salt thereof.

Another object of the present invention is to provide a method for preparing the azabicycloalkyl derivative compound.

Another object of the present invention is to provide a pharmaceutical use of the azabicycloalkyl derivative compound, specifically for the treatment or prevention of FXR-mediated liver disease comprising the azabicycloalkyl derivative compound as an active ingredient. To provide a composition, use for treating or preventing a liver disease mediated by FXR using the compound, or a method for treating or preventing a liver disease mediated by FXR, comprising administering the compound.

In order to achieve the above object, as a result of research efforts of the present inventors, the present invention was completed by confirming that the azabicycloalkyl derivative compounds represented by Chemical Formula 1 mentioned below induce FXR activity.

Azabicycloalkyl derivative compounds

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

[Formula 1]

In Formula 1,

m and n are each independently 0 or 1;

ring A is aryl, heteroaryl, or null {wherein at least one H of the aryl or heteroaryl is -C _1-4 alkyl, -C _1-4 cyanoalkyl, -C _1-4 amino may be substituted with alkyl, —C _1-4 hydroxyalkyl, —C _1-4 haloalkyl, —CN, —NR ₁ R ₂ , —OR ₃ , or halo};

Ring B is aryl, heteroaryl, cycloalkyl, or heterocycloalkyl {wherein at least one H of the aryl or heteroaryl is -C _1-4 alkyl, -C _1-4 cyanoalkyl, -C _1-4 may be substituted with aminoalkyl, —C _1-4 hydroxyalkyl, —C _1-4 haloalkyl, —CN, —NR ₁ R ₂ , —OR ₃ , or halo; one or more H of said cycloalkyl or heterocycloalkyl may be substituted with -C _1-4 alkyl or -halo};

X is -NH-, -O-, or -S-;

L ₁ is -(CH ₂ ) _a -, -C(=O)-, -C(=O)NH-, -S(=O)-, -S(=O) ₂ -, or nothing ( null) {wherein, one or more H of -(CH ₂ ) _a - may be substituted with -C _1-4 alkyl, -C _1-4 haloalkyl, or halo};

L ₂ is -(CH ₂ ) _b -, -C(=O)-, -S(=O)-, or -S(=O) ₂ -, {herein, one of the -(CH ₂ ) _b - or more H may be substituted with -C _1-4 alkyl, -C _1-4 haloalkyl, or halo};

a and b are each independently 1, 2, 3, or 4;

Y is aryl or heteroaryl {wherein at least one H of said aryl or heteroaryl is -H, -C _1-4 alkyl, -C _1-4 haloalkyl, -CN, -NR ₁ R ₂ , -OR ₃ , or - may be substituted with halo};

Z is cycloalkyl or heterocycloalkyl {wherein at least one H of said cycloalkyl or heterocycloalkyl is -H, -C _1-4 alkyl, -C _1-4 haloalkyl, -CN, -NR ₁ R ₂ , -OR ₃ , or -halo};

R ₁ and R ₂ are each independently —H or —C _1-4 alkyl;

R ₃ is —H, —C _1-4 alkyl, or —C _1-4 haloalkyl.

In addition, according to an embodiment of the present invention, the compound represented by Formula 1 may be in the following range:

m and n are each independently 1;

ring A is aryl, heteroaryl, or null {wherein one or more H of the aryl or heteroaryl may be substituted with -C _1-4 alkyl, or halo};

Ring B is aryl, heteroaryl, or heterocycloalkyl {wherein at least one H of the aryl or heteroaryl is -C _1-4 alkyl, -C _1-4 haloalkyl, -CN, -OR ₃ , or halo may be substituted with; one or more H of said heterocycloalkyl may be substituted with -C _1-4 alkyl or -halo};

X is -NH- or -O-;

L ₁ is -(CH ₂ ) _a -, -C(=O)-, -C(=O)NH-, -S(=O) ₂ -, or nothing (null) {wherein the -( CH ₂ ) one or more H of _a — may be substituted with —C _1-4 alkyl, —C _1-4 haloalkyl, or halo};

L ₂ is -(CH ₂ ) _b - or -C(=O)-, wherein at least one H of -(CH ₂ ) _b - is -C _1-4 alkyl, -C _1-4 haloalkyl, or may be substituted with halo};

a and b are each independently 1;

Y is aryl, wherein one or more H of said aryl may be substituted with -H, -C _1-4 alkyl, -NR ₁ R ₂ , -OR ₃ , or -halo};

Z is cycloalkyl, wherein one or more H of said cycloalkyl may be substituted with -H, -C _1-4 alkyl, -C _1-4 haloalkyl, or -halo};

R ₁ and R ₂ are each independently —H or —C _1-4 alkyl;

R ₃ is —H, —C _1-4 alkyl, or —C _1-4 haloalkyl.

In addition, according to an embodiment of the present invention, the compound represented by Formula 1 may be in the following range:

The compound represented by Formula 1 is a compound represented by Formula 2 below;

[Formula 2]

In Formula 2,

ring A is 6-10 membered aryl, 5-6 membered heteroaryl, or null, wherein said 5-6 membered heteroaryl contains one or more of N, O, or S atoms in the ring; at least one H of said 6-10 membered aryl or 5-6 membered heteroaryl may be substituted with -C _1-4 alkyl or halo};

Ring B is 6-10 membered aryl, 5-10 membered heteroaryl, or 4-7 membered heterocycloalkyl, wherein said 5-10 membered heteroaryl and 4-7 membered heterocycloalkyl are N, O, or at least one of the S atoms, wherein at least one H of the 6-10 membered aryl or 5-10 membered heteroaryl is -C _1-4 alkyl, -C _1-4 haloalkyl, -CN, -OR ₃ , or halo; one or more H of said 4-7 membered heterocycloalkyl may be substituted with -C _1-4 alkyl or -halo};

X is -NH- or -O-;

L ₁ is -(CH ₂ ) _a -, -C(=O)-, -C(=O)NH-, -S(=O) ₂ -, or nothing (null) {wherein the -( CH ₂ ) one or more H of _a — may be substituted with —C _1-4 alkyl, —C _1-4 haloalkyl, or halo};

L ₂ is -(CH ₂ ) _b - or -C(=O)-, wherein at least one H of -(CH ₂ ) _b - is -C _1-4 alkyl, -C _1-4 haloalkyl, or may be substituted with halo};

a and b are each independently 1;

Y ₁ and Y ₂ are each independently —H, —C _1-4 alkyl, —NR ₁ R ₂ , —OR ₃ , or —halo;

R ₁ and R ₂ are each independently —H or —C _1-4 alkyl;

R ₃ is —H, —C _1-4 alkyl, or —C _1-4 haloalkyl.

According to an embodiment of the present invention, the compound represented by Formula 1 may be selected from the group consisting of the compounds described below:

(1-1) 4-((((1R,3R,5S)-8-((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)methyl)-8 -azabicyclo[3.2.1]octan-3-yl)oxy)methyl)benzoic acid;

(2-1) 2-(4-((((1R,3R,5S)-8-(5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)-methyl )-8-azabicyclo[3.2.1]octan-3-yl)oxy)methyl)phenyl)nicotinic acid;

(2-2) 4'-((((1R,3R,5S)-8-((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)methyl)- 8-azabicyclo[3.2.1]octan-3-yl)oxy)methyl)-6-fluoro-[1,1′-biphenyl]-3-carboxylic acid;

(2-3) 4'-((((1R,3R,5S)-8-((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)methyl)- 8-azabicyclo[3.2.1]octan-3-yl)oxy)methyl)-4-methyl-[1,1′-biphenyl]-3-carboxylic acid;

(2-4) 4'-((((1R,3R,5S)-8-((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)methyl)- 8-azabicyclo[3.2.1]octan-3-yl)oxy)methyl)-6-methyl-[1,1′-biphenyl]-3-carboxylic acid;

(2-5) 4'-((((1R,3R,5S)-8-((5-cyclopropyl-3-(2,6-dichlorophenyl)isooxazol-4-yl)methyl)- 8-azabicyclo[3.2.1]octan-3-yl)oxy)methyl)-5-fluoro-[1,1′-biphenyl]-3-carboxylic acid;

(2-6) 4-chloro-4'-((((1R,3R,5S)-8-((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl )methyl)-8-azabicyclo[3.2.1]octan-3-yl)oxy)methyl)-[1,1′-biphenyl]-3-carboxylic acid;

(2-7) 4'-((((1R,3R,5S)-8-((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)methyl)- 8-azabicyclo[3.2.1]octan-3-yl)oxy)methyl)-2′-methyl-[1,1′-biphenyl]-4-carboxylic acid;

(2-8) 4'-((((1R,3R,5S)-8-((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)methyl)- 8-azabicyclo[3.2.1]octan-3-yl)oxy)methyl)-2′-methyl-[1,1′-biphenyl]-3-carboxylic acid;

(2-9) 5-cyano-4'-((((1R,3R,5S)-8-((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazole-4- yl)methyl)-8-azabicyclo[3.2.1]octan-3-yl)oxy)methyl)-[1,1′-biphenyl]-3-carboxylic acid;

(2-10) 4'-((((1R,3R,5S)-8-((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)methyl)- 8-azabicyclo[3.2.1]octan-3-yl)oxy)methyl)-2-fluoro-[1,1′-biphenyl]-3-carboxylic acid;

(2-11) 3-(6-((((1R,3R,5S)-8-((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)methyl) )-8-azabicyclo[3.2.1]octan-3-yl)oxy)methyl)pyridin-3-yl)benzoic acid;

(2-12) 3-(4-((((1R,3R,5S)-8-((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)methyl) )-8-azabicyclo[3.2.1]octan-3-yl)oxy)methyl)-2-methylphenyl)furan-2-carboxylic acid;

(2-13) 4'-((((1R,3R,5S)-8-((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)methyl)- 8-azabicyclo[3.2.1]octan-3-yl)oxy)methyl)-6-fluoro-5-methyl-[1,1′-biphenyl]-3-carboxylic acid;

(2-14) 3-(4-((((1R,3R,5S)-8-((5-cyclopropyl-3-(2-(trifluoromethoxy)phenyl)isoxazol-4-yl) )methyl)-8-azabicyclo[3.2.1]octan-3-yl)oxy)methyl)-2-methylphenyl)furan-2-carboxylic acid;

(2-15) 3-(6-((((1R,3R,5S)-8-((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)methyl) )-8-azabicyclo[3.2.1]octan-3-yl)oxy)methyl)pyridin-3-yl)furan-2-carboxylic acid;

(2-16) 2-(6-((((1R,3R,5S)-8-((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)methyl) )-8-azabicyclo[3.2.1]octan-3-yl)oxy)methyl)pyridin-2-yl)benzoic acid;

(2-17) 3-(4-((((1R,3R,5S)-8-((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)methyl) )-8-azabicyclo[3.2.1]octan-3-yl)oxy)methyl)phenyl)furan-2-carboxylic acid;

(2-18) 3-(4-((((1R,3R,5S)-8-((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)methyl) )-8-azabicyclo[3.2.1]octan-3-yl)oxy)methyl)phenyl)furan-2-carboxylic acid;

(2-19) 4-(4-((((1R,3R,5S)-8-((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)methyl) )-8-azabicyclo[3.2.1]octan-3-yl)oxy)methyl)phenyl)thiophene-2-carboxylic acid;

(2-20) 4-(4-((((1R,3R,5S)-8-((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)methyl) )-8-azabicyclo[3.2.1]octan-3-yl)oxy)methyl)phenyl)oxazole-5-carboxylic acid;

(2-21) 4-(4-((((1R,3R,5S)-8-((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)methyl )-8-azabicyclo[3.2.1]octan-3-yl)oxy)methyl)phenyl)-1-methyl-1H-pyrazole-5-carboxylic acid;

(2-22) 3-(N-((1R,3R,5S)-8-((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)methyl)- 8-azabicyclo[3.2.1]octan-3-yl)oxy)methyl)-[1,1′-biphenyl]-2-carboxylic acid);

(2-23) 4'-((((1R,3S,5S)-8-((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)methyl)- 8-azabicyclo[3.2.1]octan-3-yl)oxy)methyl)-[1,1′-biphenyl]-2-carboxylic acid;

(2-24) 4'-((((1R,3R,5S)-8-((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)methyl)- 8-azabicyclo[3.2.1]octan-3-yl)oxy)methyl)-[1,1′-biphenyl]-4-carboxylic acid;

(2-25) 4'-((((1R,3S,5S)-8-((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)methyl)- 8-azabicyclo[3.2.1]octan-3-yl)oxy)methyl)-[1,1′-biphenyl]-4-carboxylic acid;

(2-26) 4'-((((1R,3R,5S)-8-((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)methyl)- 8-azabicyclo[3.2.1]octan-3-yl)oxy)methyl)-4-fluoro-[1,1′-biphenyl]-3-carboxylic acid;

(2-27) 4'-((((1R,3R,5S)-8-((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)methyl)- 8-azabicyclo[3.2.1]octan-3-yl)oxy)methyl)-3-fluoro-[1,1′-biphenyl]-4-carboxylic acid;

(2-28) 5-(4-((((1R,3R,5S)-8-((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)methyl )-8-azabicyclo[3.2.1]octan-3-yl)oxy)methyl)phenyl)pyrimidine-2-carboxylic acid;

(2-29) 4'-((((1R,3R,5S)-8-((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)methyl)-8-azabicyclo [3.2.1]octan-3-yl)oxy)methyl)-2-fluoro-[1,1′-biphenyl]-4-carboxylic acid;

(2-30) 4'-((((1R,3R,5S)-8-((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)methyl)- 8-azabicyclo[3.2.1]octan-3-yl)oxy)methyl)-3′-fluoro-[1,1′-biphenyl]-4-carboxylic acid;

(2-31) 3'-((((1R,3R,5S)-8-((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)methyl)- 8-azabicyclo[3.2.1]octan-3-yl)oxy)methyl)-[1,1′-biphenyl]-4-carboxylic acid;

(2-32) 3'-((((1R,3R,5S)-8-((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)methyl)- 8-azabicyclo[3.2.1]octan-3-yl)oxy)methyl)-[1,1′-biphenyl]-3-carboxylic acid;

(2-33) 3'-((((1R,3R,5S)-8-((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)methyl)- 8-azabicyclo[3.2.1]octan-3-yl)oxy)methyl)-[1,1′-biphenyl]-2-carboxylic acid;

(2-34) 4'-((((1R,3R,5S)-8-((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)methyl)- 8-azabicyclo[3.2.1]octan-3-yl)oxy)methyl)-3′-fluoro-[1,1′-biphenyl]-2-carboxylic acid;

(2-35) 4'-((((1R,3R,5S)-8-((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)methyl)- 8-azabicyclo[3.2.1]octan-3-yl)oxy)methyl)-3′-fluoro-[1,1′-biphenyl]-3-carboxylic acid;

(2-36) 4'-((((1R,3R,5S)-8-((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)methyl)- 8-azabicyclo[3.2.1]octan-3-yl)oxy)methyl)-5-fluoro-[1,1′-biphenyl]-2-carboxylic acid;

(2-37) 5-chloro-4'-((((1R,3R,5S)-8-((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl) )methyl)-8-azabicyclo[3.2.1]octan-3-yl)oxy)methyl)-[1,1′-biphenyl]-2-carboxylic acid;

(2-38) 5-chloro-4'-((((1R,3S,5S)-8-((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl) )methyl)-8-azabicyclo[3.2.1]octan-3-yl)oxy)methyl)-[1,1′-biphenyl]-2-carboxylic acid;

(2-39) 4'-((((1R,3R,5S)-8-((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)methyl)- 8-azabicyclo[3.2.1]octan-3-yl)oxy)methyl)-3-(trifluoromethyl)-[1,1′-biphenyl]-2-carboxylic acid;

(2-40) 4'-((((1R,3R,5S)-8-((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)methyl)- 8-azabicyclo[3.2.1]octan-3-yl)oxy)methyl)-4-fluoro-[1,1′-biphenyl]-2-carboxylic acid;

(2-41) 1-(4-((((1R,3R,5S)-8-((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)methyl) )-8-azabicyclo[3.2.1]octan-3-yl)oxy)methyl)phenyl)azetidine-3-carboxylic acid;

(2-42) 4'-((((1R,3R,5S)-8-((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)methyl)- 8-azabicyclo[3.2.1]octan-3-yl)oxy)methyl)-3′-methyl-[1,1′-biphenyl]-2-carboxylic acid;

(2-43) 4'-((((1R,3R,5S)-8-((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)methyl)- 8-azabicyclo[3.2.1]octan-3-yl)oxy)methyl)-[1,1′-biphenyl]-3-carboxylic acid;

(2-44) 4'-((((1R,3R,5S)-8-((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)methyl)- 8-azabicyclo[3.2.1]octan-3-yl)oxy)methyl)-3′-methyl-[1,1′-biphenyl]-3-carboxylic acid;

(2-45) 4-((((1R,3R,5S)-8-((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)methyl)-8 -azabicyclo[3.2.1]octan-3-yl)oxy)methyl)-1-naphthoic acid;

(2-46) 1-(4-((((1R,3R,5S)-8-((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)methyl )-8-azabicyclo[3.2.1]octan-3-yl)oxy)methyl)phenyl)-1H-pyrrole-2-carboxylic acid;

(2-47) 2-(5-((((1R,3R,5S)-8-((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)methyl )-8-azabicyclo[3.2.1]octan-3-yl)oxy)methyl)pyridin-2-yl)benzoic acid;

(2-48) 3-(5-((((1R,3R,5S)-8-((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)methyl )-8-azabicyclo[3.2.1]octan-3-yl)oxy)methyl)pyridin-2-yl)benzoic acid;

(2-49) 2-(4-((((1R,3R,5S)-8-((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)methyl) )-8-azabicyclo[3.2.1]octan-3-yl)oxy)methyl)phenyl)nicotinic acid;

(2-50) 6-(4-((((1R,3R,5S)-8-((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)methyl) )-8-azabicyclo[3.2.1]octan-3-yl)oxy)methyl)phenyl)nicotinic acid;

(2-51) 2-(4-((((1R,3R,5S)-8-((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)methyl )-8-azabicyclo[3.2.1]octan-3-yl)oxy)methyl)phenyl)isonicotinic acid;

(2-52) 3-(4-((((1R,3R,5S)-8-((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)methyl )-8-azabicyclo[3.2.1]octan-3-yl)oxy)methyl)phenyl)furan-2-carboxylic acid;

(2-53) 5-(4-((((1R,3R,5S)-8-((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)methyl) )-8-azabicyclo[3.2.1]octan-3-yl)oxy)methyl)phenyl)furan-2-carboxylic acid;

(2-54) 6-(4-((((1R,3R,5S)-8-((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)methyl) )-8-azabicyclo[3.2.1]octan-3-yl)oxy)methyl)phenyl)picolinic acid;

(2-55) 3-(5-((((1R,3R,5S)-8-((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)methyl )-8-azabicyclo[3.2.1]octan-3-yl)oxy)methyl)pyridin-2-yl)furan-2-carboxylic acid;

(2-56) 3-(4-((((1R,3R,5S)-8-((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)methyl )-8-azabicyclo[3.2.1]octan-3-yl)oxy)methyl)-3-fluorophenyl)furan-2-carboxylic acid;

(2-57) 5-(4-((((1R,3R,5S)-8-((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)methyl )-8-azabicyclo[3.2.1]octan-3-yl)oxy)methyl)phenyl)-2-methylthiophene-3-carboxylic acid;

(2-58) 3-(4-((((1R,3R,5S)-8-((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)methyl )-8-azabicyclo[3.2.1]octan-3-yl)oxy)methyl)naphthalen-1-yl)furan-2-carboxylic acid;

(2-59) 3-(4-((((1R,3R,5S)-8-((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)methyl) )-8-azabicyclo[3.2.1]octan-3-yl)oxy)methyl)naphthalen-1-yl)benzoic acid;

(2-60) 4'-((((1R,3R,5S)-8-((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)methyl)- 8-azabicyclo[3.2.1]octan-3-yl)oxy)methyl)-4-methoxy-[1,1′-biphenyl]-3-carboxylic acid;

(2-61) 3-(4-((((1R,3R,5S)-8-((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)methyl) )-8-azabicyclo[3.2.1]octan-3-yl)oxy)methyl)-3-methylphenyl)furan-2-carboxylic acid;

(2-62) 3-(4-((((1R,3R,5S)-8-((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)methyl )-8-azabicyclo[3.2.1]octan-3-yl)oxy)methyl)naphthalen-1-yl)furan-2-carboxylic acid;

(2-63) 3-(4-((((1R,3R,5S)-8-((5-cyclopropyl-3-(2-(trifluoromethoxy)phenyl)isoxazol-4-yl) )methyl)-8-azabicyclo[3.2.1]octan-3-yl)oxy)methyl)-3-fluorophenyl)furan-2-carboxylic acid;

(3-1) 4'-((((1R,3R,5S)-8-((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)methyl)- 8-azabicyclo[3.2.1]octan-3-yl)oxy)fluoromethyl)-[1,1′-biphenyl]-3-carboxylic acid;

(3-2) 3-(4-((((1R,3R,5S)-8-((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)methyl) )-8-azabicyclo[3.2.1]octan-3-yl)oxy)fluoromethyl)phenyl)furan-2-carboxylic acid;

(4-1) 2-(((1R,3R,5S)-8-((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)methyl)-8- azabicyclo[3.2.1]octan-3-yl)amino)benzo[d]thiazole-6-carboxylic acid;

(4-2) 2-(((1R,3R,5S)-8-((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)methyl)-8- azabicyclo[3.2.1]octan-3-yl)amino)benzo[d]thiazole-6-carboxylic acid;

(4-3) 6-(((1R,3R,5S)-8-((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)methyl)-8- azabicyclo[3.2.1]octan-3-yl)amino)-2-naphthoic acid;

(5-1) 3'-(((1R,3R,5S)-8-((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)methyl)-8 -azabicyclo[3.2.1]octan-3-yl)amino)-[1,1'-biphenyl]-4-carboxylic acid

(6-1) 4'-((((1R,3R,5S)-8-((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)methyl)- 8-azabicyclo[3.2.1]octan-3-yl)amino)methyl)-[1,1′-biphenyl]-2-carboxylic acid;

(6-2) 4'-((((1R,3S,5S)-8-((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)methyl)- 8-azabicyclo[3.2.1]octan-3-yl)amino)methyl)-[1,1′-biphenyl]-2-carboxylic acid;

(7-1) 3-(N-((1R,3R,5S)-8-((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)methyl)- 8-azabicyclo[3.2.1]octan-3-yl)sulfamoyl)benzoic acid;

(7-2) 2-(N-((1R,3R,5S)-8-((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)methyl)- 8-azabicyclo[3.2.1]octan-3-yl)sulfamoyl)benzoic acid;

(8-1) 2-(6-(((1R,3R,5S)-8-((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)methyl) -8-azabicyclo[3.2.1]octan-3-yl)carbamoyl)pyridin-3-yl)benzoic acid;

(8-2) 4-(((1R,3R,5S)-8-((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)methyl)-8- azabicyclo[3.2.1]octan-3-yl)carbamoyl)benzoic acid;

(9-1) 4'-(3-((1R,3R,5S)-8-((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)methyl) -8-azabicyclo[3.2.1]octan-3-yl)ureido)-[1,1'-biphenyl]-4-carboxylic acid;

(9-2) 4-(3-((1R,3R,5S)-8-((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)methyl)- 8-azabicyclo[3.2.1]octan-3-yl)ureido)benzoic acid;

(10-1) 4'-((((1R,3S,5S)-8-(5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazole-4-carbonyl)-8- azabicyclo[3.2.1]octan-3-yl)oxy)methyl)-[1,1′-biphenyl]-4-carboxylic acid;

(10-2) 4'-((((1R,3R,5S)-8-(5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazole-4-carbonyl)-8- azabicyclo[3.2.1]octan-3-yl)oxy)methyl)-[1,1′-biphenyl]-4-carboxylic acid;

(10-3) 5-(4-((((1R,3R,5S)-8-(5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazole-4-carbonyl)- 8-azabicyclo[3.2.1]octan-3-yl)oxy)methyl)phenyl)pyrimidine-2-carboxylic acid;

(10-4) 4'-((((1R,3R,5S)-8-(5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazole-4-carbonyl)-8- azabicyclo[3.2.1]octan-3-yl)oxy)methyl)-[1,1′-biphenyl]-2-carboxylic acid;

(10-5) 4'-((((1R,3R,5S)-8-(5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazole-4-carbonyl)-8- azabicyclo[3.2.1]octan-3-yl)oxy)methyl)-4-fluoro-[1,1′-biphenyl]-3-carboxylic acid;

(10-6) 4'-((((1R,3R,5S)-8-(5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazole-4-carbonyl)-8- azabicyclo[3.2.1]octan-3-yl)oxy)methyl)-3-fluoro-[1,1′-biphenyl]-4-carboxylic acid; and

(10-7) 3-(4-((((1R,3R,5S)-8-(5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazole-4-carbonyl)- 8-azabicyclo[3.2.1]octan-3-yl)oxy)methyl)phenyl)isonicotinic acid.

In the present invention, unless otherwise specified, "alkyl" may mean a straight or branched acyclic, cyclic, or saturated hydrocarbon to which they are bonded. For example, "C _1-4 alkyl" can mean an alkyl containing 1 to 4 carbon atoms. Acyclic alkyl may include, as an example, methyl, ethyl, n -propyl, n -butyl, isopropyl, sec -butyl, isobutyl, or tert -butyl, etc., It is not limited thereto. Cyclic alkyl may be used interchangeably with “cycloalkyl” herein, and may include, as an example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, or cyclooctyl, but is limited thereto. doesn't happen

In the present invention, "alkoxy" may mean -(O-alkyl) as an alkyl ether group, wherein alkyl is as defined above. For example, "C _1-4 alkoxy" may mean alkoxy containing C _1-4 alkyl, that is, -(OC _1-4 alkyl), and for example, alkoxy is methoxy ), ethoxy, n -propoxy, isopropoxy, n - butoxy , isobutoxy , sec -butoxy ), or tert - butoxy , etc., but is not limited thereto.

In the present invention, "halo" may be F, Cl, Br, or I.

As used herein, "haloalkyl" may mean a straight or branched chain alkyl (hydrocarbon) having one or more halo-substituted carbon atoms as defined herein. Examples of such haloalkyl include, but are not limited to, methyl, ethyl, propyl, isopropyl, isobutyl or n -butyl independently substituted with one or more halogens, such as F, Cl, Br, or I. .

In the present invention, "aminoalkyl" may mean a straight or branched chain alkyl (hydrocarbon) having a carbon atom substituted with amino (NR'R"), wherein R' and R" are each independently hydrogen , and may be selected from the group consisting of C _1-4 alkyl, wherein the selected R' and R" may be each independently substituted or unsubstituted.

In the present invention, "cyanoalkyl" may mean a straight or branched chain alkyl (hydrocarbon) having a carbon atom substituted with cyano (CN).

In the present invention, "hydroxyalkyl" may mean a straight-chain or branched alkyl (hydrocarbon) having a carbon atom substituted with hydroxy (OH).

In the present invention, "heterocycloalkyl" may mean a ring containing 1 to 5 heteroatoms selected from N, O and S as atoms forming the ring, and may be saturated or partially unsaturated. Here, when unsaturated, it may be referred to as a heterocycloalkene. Unless otherwise stated, a heterocycloalkyl may be a single ring or multiple rings such as a spiro ring, a bridged ring or a fused ring. In addition, "3 to 12 membered heterocycloalkyl" may mean a heterocycloalkyl containing 3 to 12 atoms forming a ring, for example, heterocycloalkyl is pyrrolidine, piperidine, imi Dazolidine, pyrazolidine, butyrolactam, valerolactam, imidazolidinone, hydantoin, dioxolane, phthalimide, piperidine, pyrimidine-2,4( 1H , 3H )- Dione, 1,4-dioxane, morpholine, thiomorpholine, thiomorpholine- S -oxide, thiomorpholine- S , S -oxide, piperazine, pyran, pyridone, 3-pyrroline, Thiopyran , pyrone, tetrahydrofuran, tetrahydrothiophene, quinuclidine, tropane, 2-azaspiro[3.3]heptane, (1R, 5S )-3-azabicyclo[3.2.1] octane, (1 s ,4 s )-2-azabicyclo[2.2.2]octane, or (1 R ,4 R )-2-oxa-5-azabicyclo[2.2.2]octane, etc. However, the present invention is not limited thereto.

In the present invention, "arene" may mean an aromatic hydrocarbon ring. The arene may be a monocyclic arene or a polycyclic arene. The ring carbon number of arene may be 5 or more and 30 or less, 5 or more and 20 or less, or 5 or more and 15 or less. Examples of arenes include benzene, naphthalene, fluorene, anthracene, phenanthrene, terbenzene, quaterbenzene, quinkbenzene, sexbenzene, triphenylene, pyrene, benzofluoranthene, chrysene, etc. not limited In the present specification, the residue in which one hydrogen atom is removed from the "arene" is referred to as "aryl".

In the present invention, "heteroarene" may be an aromatic ring containing at least one of O, N, P, Si, and S as a heterogeneous element. The number of ring carbon atoms of heteroarene may be 2 or more and 30 or less, or 2 or more and 20 or less. The heteroarene may be a monocyclic heteroarene or a polycyclic heteroarene. The polycyclic heteroarene may have, for example, a two- or three-ring structure. Examples of heteroarenes include thiophene, purine, pyrrole, pyrazole, imidazole, thiazole, oxazole, isothiazole, oxadiazole, triazole, pyridine, triazine, acridyl, pyridazine, pyrazine, quinoline , quinazoline, quinoxaline, phenoxazine, phthalazine, pyrimidine, pyridopyrimidine, pyridopyrazine, pyrazinopyrazine, isoquinoline, indole, carbazole, imidazopyridazine, imidazopyridine, imidazopyr Limidine, pyrazolopyrimidine, imidazopyrazine, pyrazolopyridine, N -arylcarbazole, N -heteroarylcarbazole, N -alkylcarbazole, benzoxazole, benzoimidazole, benzothiazole, benzocarbazole , benzothiophene, dibenzothiophene, thienothiophene, benzofuran, phenanthroline, isoxazole, oxadiazole, thiadiazole, benzothiazole, tetrazole, phenothiazine, dibenzosyl roll, dibenzofuran, and the like, but is not limited thereto. In the present specification, the residue in which one hydrogen atom is removed from the "heteroarene" is referred to as "heteroaryl".

또는 쐐기형 점선 결합

을 포함할 수 있다.In the present invention, the term "enantiomer" means a compound of the present invention or a salt thereof having the same chemical formula or molecular formula but sterically different. Each of these optical isomers and mixtures thereof are also included within the scope of the present invention. Unless otherwise noted, a solid line bond (-) connecting an asymmetric carbon atom is a wedge-shaped solid line bond indicating the absolute configuration of the stereocenter.

or wedge-dotted join

may include.

The compound of Formula 1 of the present invention may exist in the form of a "pharmaceutically acceptable salt". As the salt, an acid addition salt formed with a pharmaceutically acceptable free acid is useful. As used herein, the term "pharmaceutically acceptable salt" refers to a concentration of a compound having an effective action relatively non-toxic and harmless to a patient, and any side effects resulting from the salt do not reduce the beneficial efficacy of the compound represented by the formula (1). Any organic or inorganic acid addition salt of

Acid addition salts are prepared by conventional methods, for example by dissolving the compound in an aqueous solution of an excess of acid and precipitating the salt using a water-miscible organic solvent such as methanol, ethanol, acetone or acetonitrile. Equal molar amounts of the compound and the acid or alcohol in water may be heated, and then the mixture may be evaporated to dryness, or the precipitated salt may be filtered off with suction.

In this case, an organic acid and an inorganic acid may be used as the free acid, and hydrochloric acid, phosphoric acid, sulfuric acid, or nitric acid may be used as the inorganic acid, and the organic acid may be methanesulfonic acid, p -toluenesulfonic acid, acetic acid, trifluoroacetic acid, Maleic acid, succinic acid, oxalic acid, benzoic acid, tartaric acid, fumaric acid, manderic acid, propionic acid, citric acid, lactic acid, glycolic acid, glycolic acid, glue Conic acid, galacturonic acid, glutamic acid, glutaric acid, glucuronic acid, aspartic acid, ascorbic acid, carbonic acid, vanillic acid, or hydroiodic acid, etc. can be used However, the present invention is not limited thereto.

In addition, bases can be used to prepare pharmaceutically acceptable metal salts. The alkali metal salt or alkaline earth metal salt is obtained, for example, by dissolving the compound in an excess alkali metal hydroxide or alkaline earth metal hydroxide solution, filtering the undissolved compound salt, and then evaporating and drying the filtrate. In this case, it is pharmaceutically suitable to prepare a sodium, potassium, or calcium salt as the metal salt, but is not limited thereto. Also, the corresponding silver salt can be obtained by reacting an alkali metal or alkaline earth metal salt with a suitable silver salt (eg, silver nitrate).

The pharmaceutically acceptable salts of the present invention include salts of acidic or basic groups that may be present in the compound of Formula 1, unless otherwise indicated. For example, pharmaceutically acceptable salts may include sodium, calcium and potassium salts of a hydroxyl group, and other pharmaceutically acceptable salts of an amino group include hydrobromide, sulfate, hydrogen sulfate, phosphate, hydrogen phosphate, dihydrogen phosphate, acetate, succinate, citrate, tartrate, lactate, mandelate, methanesulfonate (mesylate), and p -toluenesulfonate (tosylate) salts; It can be prepared through a method for preparing a known salt.

Use of Azabicycloalkyl Derivative Compounds

The present invention provides the use of a compound represented by the following formula (1), an optical isomer thereof, or a pharmaceutically acceptable salt thereof.

[Formula 1]

Formula 1 is as defined above.

Since the compound represented by Formula 1 of the present invention, its optical isomer, or a pharmaceutically acceptable salt thereof exhibits FXR agonist activity, it can be usefully used for treatment or prevention of FXR-mediated liver disease.

In the present invention, the liver disease mediated by FXR is cholestasis, intrahepatic cholestasis, estrogen-induced cholestasis, drug-induced cholestasis, cholestasis in pregnancy, parenteral nutrition-related Cholestasis, primary biliary cirrhosis (PBC), primary sclerosing cholangitis (PSC), progressive familial cholestasis (PFIC), nonalcoholic fatty liver disease (NAFLD), nonalcoholic steatohepatitis (NASH), drug-induced bile ducts It may be at least one selected from the group consisting of injury, gallstones, cirrhosis, alcohol-induced cirrhosis, cystic fibrosis-associated liver disease (CFLD), bile duct obstruction, cholelithiasis, and liver fibrosis. More specifically, the liver disease mediated by FXR may be primary biliary cirrhosis (PBC), nonalcoholic fatty liver disease (NAFLD), or nonalcoholic steatohepatitis (NASH).

The pharmaceutical composition of the present invention may further include one or more active ingredients exhibiting the same or similar efficacy in addition to the compound represented by Formula 1, an optical isomer thereof, or a pharmaceutically acceptable salt thereof.

Also, according to one embodiment of the present invention, the step of administering to a subject in need thereof a therapeutically effective amount of the compound represented by Formula 1, an optical isomer thereof, or a pharmaceutically acceptable salt thereof It provides a method of treating or preventing a liver disease mediated by FXR, comprising: The subject may be a mammal including a human.

As used herein, the term "therapeutically effective amount" refers to an amount of the compound represented by Formula 1 effective for the treatment or prevention of FXR-mediated liver disease. Specifically, "therapeutically effective amount" means an amount sufficient to treat a disease at a reasonable benefit/risk ratio applicable to medical treatment, and effective dose level includes the subject type and severity, age, sex, type of disease, The activity of the drug, the sensitivity to the drug, the time of administration, the route of administration and the rate of excretion, the duration of treatment, factors including concurrently used drugs, and other factors well known in the medical field may be determined. The pharmaceutical composition of the present invention may be administered as an individual therapeutic agent or may be administered in combination with other therapeutic agents, and may be administered sequentially or simultaneously with commercially available therapeutic agents. and may be administered single or multiple. Taking all of the above factors into consideration, it is important to administer an amount that can obtain the maximum effect with a minimum amount without side effects, and can be easily determined by those skilled in the art. The dosage of the pharmaceutical composition of the present invention may be determined by an expert according to various factors such as the patient's condition, age, sex, and complications. Since the active ingredient of the pharmaceutical composition of the present invention is excellent in safety, it can be used at a dose higher than the determined dosage.

Also, according to one embodiment of the present invention, the present invention provides a compound represented by Formula 1, an optical isomer thereof, for use in the preparation of a medicament for use in the treatment or prevention of FXR-mediated liver disease , or a pharmaceutically acceptable salt thereof. The compound represented by Formula 1 for the manufacture of a drug may be mixed with an acceptable adjuvant, diluent, carrier, etc., and may have a synergistic action of the active ingredients by being prepared as a complex formulation together with other active agents.

Matters mentioned in the uses, compositions, and methods of treatment of the present invention are equally applicable as long as they do not contradict each other.

Embodiments of the present invention may be modified in various other forms, and the scope of the present invention is not limited to the embodiments described below. In addition, the embodiment of the present invention is provided in order to more completely explain the present invention to those of ordinary skill in the art. Furthermore, "including" a certain element throughout the specification means that other elements may be further included, rather than excluding other elements, unless otherwise stated.

Since the azabicycloalkyl derivative compound of the present invention exhibits excellent agonistic activity against FXR, it can be usefully used as a therapeutic agent for liver disease mediated by FXR.

Hereinafter, the present invention will be described in detail with reference to Preparation Examples, Examples and Experimental Examples. However, the following Preparation Examples, Examples and Experimental Examples are merely illustrative of the present invention, and the scope of the present invention is not limited thereto.

Preparation 1: 4-((((1R,3R,5S)-8-((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)methyl)-8- Azabicyclo[3.2.1]octan-3-yl)oxy)methyl)benzoic acid (4-((((1R,3R,5S)-8-((5-cyclopropyl-3-(2,6-dichlorophenyl) Preparation of isoxazol-4-yl)methyl)-8-azabicyclo[3.2.1]octan-3-yl)oxy)methyl)benzoic acid)

Step 1: tert-Butyl (1R,3R,5S)-3-((4-(methoxycarbonyl)benzyl)oxy)-8-azabicyclo[3.2.1]octane-8-carboxylate (tert Preparation of -butyl (1R,3R,5S)-3-((4-(methoxycarbonyl)benzyl)oxy)-8-azabicyclo[3.2.1]octane-8-carboxylate)

tert-Butyl (1R,3R,5S)-3-hydroxy-8-azabicyclo[3.2.1]octane-8-carboxylate in 30 V of THF, 18-crown-6 1 equivalent, methyl 4- 1.2 equivalents of (bromomethyl)benzoate and 2 equivalents of KOtBu were added and stirred at room temperature for 8 hours. After completion of the reaction, extraction was performed using a saturated aqueous solution of ammonium chloride and EA. After drying over magnesium sulfate and filtering with celite to remove the EA solution, the product was purified by Prep-LC (60% yield).

Step 2: Methyl 4-((((1R,3R,5S)-8-azabicyclo[3.2.1]octan-3-yl)oxy)methyl)benzoate (methyl 4-((((1R,3R) Preparation of ,5S)-8-azabicyclo[3.2.1]octan-3-yl)oxy)methyl)benzoate)

tert-Butyl (1R,3R,5S)-3-((4-(methoxycarbonyl)benzyl)oxy)-8-azabicyclo[3.2.1]octane-8-carboxylate prepared in step 1 was dissolved in TFA (5 V) and MC (10 V), and stirred at room temperature overnight. After completion of the reaction, the MC solvent was removed with a vacuum rotary concentrator. The next reaction was carried out immediately without a separate separation process.

Step 3: Methyl 4-((((1R,3R,5S)-8-((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)methyl)-8- Azabicyclo[3.2.1]octan-3-yl)oxy)methyl)benzoate (methyl 4-((((1R,3R,5S)-8-((5-cyclopropyl-3-(2,6-) Preparation of dichlorophenyl)isoxazol-4-yl)methyl)-8-azabicyclo[3.2.1]octan-3-yl)oxy)methyl)benzoate)

methyl 4-((((1R,3R,5S)-8-azabicyclo[3.2.1]octan-3-yl)oxy)methyl)benzoate (1 eq), 4-(chloro Methyl)-5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazole (1.1 eq.), CS ₂ CO ₃ (3 eq.), NaI (1 eq.), ACN After dissolving in 20 V, 60 ℃ heated overnight. After completion of the reaction, extraction was performed using EA and H ₂ O. Moisture was removed by adding Na ₂ SO ₄ to the EA layer and the EA was blown off. Separated using Prep-LC (80 % yield).

Step 4: 4-((((1R,3R,5S)-8-((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)methyl)-8-aza Bicyclo[3.2.1]octan-3-yl)oxy)methyl)benzoic acid (4-((((1R,3R,5S)-8-((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol) Preparation of -4-yl)methyl)-8-azabicyclo[3.2.1]octan-3-yl)oxy)methyl)benzoic acid)

Methyl 4-((((1R,3R,5S)-8-((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)methyl)- prepared in step 3 8-azabicyclo [3.2.1] octan-3-yl) oxy) methyl) benzoate (1 equivalent), 10 V of 1N aqueous KOH solution were dissolved in THF (10 V) and methanol (10 V) and then 50 Stir overnight at °C. Extracted with EA, AcOH, and purified water. Na ₂ SO ₄ was added to the EA layer to remove moisture and EA was blown away. It was isolated using Prep-LC (70 % yield).

<Example 1-1>

In Example 1-1, a compound was prepared in substantially the same manner as in Preparation Example 1.

Example 1-1: 4-((((1R,3R,5S)-8-((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)methyl)- 8-azabicyclo[3.2.1]octan-3-yl)oxy)methyl)benzoic acid (4-((((1R,3R,5S)-8-((5-cyclopropyl-3-(2,6-) Preparation of dichlorophenyl)isoxazol-4-yl)methyl)-8-azabicyclo[3.2.1]octan-3-yl)oxy)methyl)benzoic acid)

¹ H-NMR (400 MHz, MeOD) δ ppm 1.05-1.80 (2H, d), 1.22-1.33 (3H, m), 1.68-1.78 (4H, m), 1.96-2.03 (2H, d), 2.13-2.35 (1H, m), 3.12-3.64 (6H, m), 4.34 (2H, s), 7.10-7.14 (7H, m)

Preparation 2: 4'-((((1R,3R,5S)-8-((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)methyl)-8 -azabicyclo[3.2.1]octan-3-yl)oxy)methyl)-[1,1'-biphenyl]-2-carboxylic acid (4'-((((1R,3R,5S)- 8-((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)methyl)-8-azabicyclo[3.2.1]octan-3-yl)oxy)methyl)-[1,1' Preparation of -biphenyl]-2-carboxylic acid)

Step 1: tert-Butyl (1R,3R,5S)-3-((4-bromobenzyl)oxy)-8-azabicyclo[3.2.1]octane-8-carboxylate (tert-butyl (1R) Preparation of ,3R,5S)-3-((4-bromobenzyl)oxy)-8-azabicyclo[3.2.1]octane-8-carboxylate)

400 mg (1.0 equiv) of tert-butyl (1R,3R,5S)-3-hydroxy-8-azabicyclo[3.2.1]octane-8-carboxylate, 18-crown-6 (1.5 equiv) It was dissolved in THF and stirred at room temperature for 20 minutes. After 20 minutes, 1-bromo-4-(bromomethyl)benzene (1.5 equivalents) was added, followed by stirring at room temperature overnight. After completion of the reaction, extraction was performed using a saturated aqueous solution of ammonium chloride and EA. After drying over magnesium sulfate and filtering with celite to remove the EA solution, the product was purified by MPLC to obtain the target compound (697 mg).

Step 2: (1R,3R,5S)-3-((4-bromobenzyl)oxy)-8-azabicyclo[3.2.1]octane ((1R,3R,5S)-3-((4- Preparation of bromobenzyl)oxy)-8-azabicyclo[3.2.1]octane)

TFA in 697 mg of tert-butyl (1R,3R,5S)-3-((4-bromobenzyl)oxy)-8-azabicyclo[3.2.1]octane-8-carboxylate prepared in step 1 1 ml was dissolved in 2 ml of MC, and stirred at room temperature overnight. After completion of the reaction, the MC solvent was removed with a vacuum rotary concentrator, and the next reaction proceeded without a separate separation process.

Step 3-1: 4-(((1R,3R,5S)-3-((4-bromobenzyl)oxy)-8-azabicyclo[3.2.1]octan-8-yl)methyl)-5 -Cyclopropyl-3-(2,6-dichlorophenyl)isoxazole (4-(((1R,3R,5S)-3-((4-bromobenzyl)oxy)-8-azabicyclo[3.2.1] Preparation of octan-8-yl)methyl)-5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazole)

(1R,3R,5S)-3-((4-bromobenzyl)oxy)-8-azabicyclo[3.2.1]octane (1 eq), 4-(bromomethyl)- prepared in step 2 5-cyclopropyl-3- (2,6-dichlorophenyl) isoxazole (1.2 eq.), CS ₂ CO ₃ (3 eq.), NaI (1 eq.), ACN After dissolving in 20 V, heated at 60 ° C overnight did. After completion of the reaction, extraction was performed using EA and H ₂ O. Na ₂ SO ₄ was added to the EA layer to remove moisture and EA was blown away. Separated using Prep-LC (80 % yield).

Step 3-2: 4-(((1R,3R,5S)-3-((4-bromobenzyl)oxy)-8-azabicyclo[3.2.1]octan-8-yl)methyl)-5 -Cyclopropyl-3-(2-(trifluoromethoxy)phenyl)isoxazole (4-(((1R,3R,5S)-3-((4-bromobenzyl)oxy)-8-azabicyclo[3.2. Preparation of 1]octan-8-yl)methyl)-5-cyclopropyl-3-(2-(trifluoromethoxy)phenyl)isoxazole)

(1R,3R,5S)-3-((4-bromobenzyl)oxy)-8-azabicyclo[3.2.1]octane (1 eq), 4-(chloromethyl)-5 prepared in step 2 -Cyclopropyl-3-(2-(trifluoromethoxy)phenyl)isoxazole (1.2 equiv.), CS ₂ CO ₃ (3 equiv), NaI (1 equiv.), ACN After dissolving in 20 V at 60 ° C overnight heated. After completion of the reaction, extraction was performed using EA and H ₂ O. Na ₂ SO ₄ was added to the EA layer to remove moisture and EA was blown away. Separated using Prep-LC (80 % yield).

Step 4: Methyl 4'-((((1R,3R,5S)-8-((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)methyl)-8 -azabicyclo[3.2.1]octan-3-yl)oxy)methyl)-[1,1'-biphenyl]-2-carboxylate (methyl 4'-((((1R,3R,5S) -8-((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)methyl)-8-azabicyclo[3.2.1]octan-3-yl)oxy)methyl)-[1,1 Preparation of '-biphenyl]-2-carboxylate)

4-(((1R,3R,5S)-3-((4-bromobenzyl)oxy)-8-azabicyclo[3.2.1]octan-8-yl)methyl) prepared in step 3-1 -5-cyclopropyl-3- (2,6-dichlorophenyl) isoxazole 30 mg (1.0 equiv) and (2- (methoxycarbonyl) phenyl) boronic acid (2.0 equiv), 2 MK ₂ CO ₃ (excess), Pd catalyst (20 mol%) was dissolved in 2 ml of dioxane. Microwave reaction was performed at 100 °C for 10 minutes. After completion of the reaction, it was extracted using distilled water and EA. After drying using magnesium sulfate, removing the EA solution, and purification by Prep-LC, the target compound was obtained (19.3 mg).

Step 5: 4'-((((1R,3R,5S)-8-((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)methyl)-8- Azabicyclo[3.2.1]octan-3-yl)oxy)methyl)-[1,1′-biphenyl]-2-carboxylic acid 4′-((((1R,3R,5S)-8- ((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)methyl)-8-azabicyclo[3.2.1]octan-3-yl)oxy)methyl)-[1,1'-biphenyl ]-2-carboxylic acid production

Methyl 4'-((((1R,3R,5S)-8-((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)methyl) prepared in step 4 -8-azabicyclo[3.2.1]octan-3-yl)oxy)methyl)-[1,1'-biphenyl]-3-carboxylate 19.3 mg of an excess of 1 M aqueous NaOH solution in 1 ml of THF , was dissolved in 1 ml of MeOH and stirred at 50 °C for 2 hours. After completion of the reaction, the mixture was acidified with 1 N HCl aqueous solution and extracted using distilled water and EA. After drying using magnesium sulfate, removing the EA solution, and purification by Prep-LC, the target compound was obtained (10 mg).

<Examples 2-1 to 2-63>

In Examples 2-1 to 2-63, compounds were prepared in substantially the same manner as in Preparation Example 2.

Example 2-1: 2-(4-((((1R,3R,5S)-8-(5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)- methyl)-8-azabicyclo[3.2.1]octan-3-yl)oxy)methyl)phenyl)nicotinic acid 2-(4-((((1R,3R,5S)-8-((5-cyclopropyl-) Preparation of 3-(2,6-dichlorophenyl)isoxazol-4-yl)-methyl)-8-azabicyclo[3.2.1]octan-3-yl)oxy)methyl)phenyl)nicotinic acid

¹ H-NMR (400 MHz, CDCl ₃ ) δ ppm 1.19-2.28 (13H, m), 3.64 (1H, s), 4.04 (1H, br), 4.50 (2H, s), 4.55 (1H, br), 7.29 -8.81 (10H, m)

Example 2-2: 4'-((((1R,3R,5S)-8-((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)methyl) -8-azabicyclo[3.2.1]octan-3-yl)oxy)methyl)-6-fluoro-[1,1'-biphenyl]-3-carboxylic acid (4'-(((((() 1R,3R,5S)-8-((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)methyl)-8-azabicyclo[3.2.1]octan-3-yl)oxy)methyl Preparation of )-6-fluoro-[1,1'-biphenyl]-3-carboxylic acid)

¹ H-NMR (400 MHz, CDCl ₃ ) δ ppm 1.00-2.72 (13H, m), 3.48 (1H, s), 3.66 (2H, s), 3.93 (2H, s), 4.47 (2H, s), 7.10 -8.06 (10H, m)

Example 2-3: 4'-((((1R,3R,5S)-8-((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)methyl) -8-azabicyclo[3.2.1]octan-3-yl)oxy)methyl)-4-methyl-[1,1′-biphenyl]-3-carboxylic acid (4′-((((1R) ,3R,5S)-8-((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)methyl)-8-azabicyclo[3.2.1]octan-3-yl)oxy)methyl) Preparation of -4-methyl-[1,1'-biphenyl]-3-carboxylic acid)

¹ H-NMR (400 MHz, CDCl ₃ ) δ ppm 1.04-2.60 (16H, m), 3.48-3.53 (3H, m), 3.73 (2H, s), 4.44 (2H, s), 7.23-8.07 (10H, m)

Example 2-4: 4'-((((1R,3R,5S)-8-((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)methyl) -8-azabicyclo[3.2.1]octan-3-yl)oxy)methyl)-6-methyl-[1,1′-biphenyl]-3-carboxylic acid (4′-((((1R) ,3R,5S)-8-((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)methyl)-8-azabicyclo[3.2.1]octan-3-yl)oxy)methyl) Preparation of -6-methyl-[1,1'-biphenyl]-3-carboxylic acid)

¹ H-NMR (400 MHz, CDCl ₃ ) δ ppm 1.02-2.62 (16H, m), 3.55 (3H, br), 3.79 (2H, s), 4.46 (2H, s), 7.28-7.91 (10H, m)

Example 2-5: 4'-((((1R,3R,5S)-8-((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)methyl) -8-azabicyclo[3.2.1]octan-3-yl)oxy)methyl)-5-fluoro-[1,1'-biphenyl]-3-carboxylic acid (4'-((((( 1R,3R,5S)-8-((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)methyl)-8-azabicyclo[3.2.1]octan-3-yl)oxy)methyl Preparation of )-5-fluoro-[1,1'-biphenyl]-3-carboxylic acid)

¹ H-NMR (400 MHz, CDCl ₃ ) δ ppm 1.18-2.72 (13H, m), 3.66 (1H, br), 3.81 (2H,br), 4.00 (2H, s), 4.47 (2H, s), 7.30 -8.03 (10H, m)

Example 2-6: 4-chloro-4'-((((1R,3R,5S)-8-((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazole-4- yl)methyl)-8-azabicyclo[3.2.1]octan-3-yl)oxy)methyl)-[1,1'-biphenyl]-3-carboxylic acid (4-chloro-4'-( (((1R,3R,5S)-8-((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)methyl)-8-azabicyclo[3.2.1]octan-3-yl) Preparation of oxy)methyl)-[1,1'-biphenyl]-3-carboxylic acid)

¹ H-NMR (400 MHz, CDCl ₃ ) δ ppm 1.25-3.14 (13H, m), 3.70 (1H, br), 3.88 (2H, br), 4.06 (2H, s), 4.45 (2H, s), 7.28 -7.98 (10H, m)

Example 2-7: 4'-((((1R,3R,5S)-8-((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)methyl) -8-azabicyclo[3.2.1]octan-3-yl)oxy)methyl)-2′-methyl-[1,1′-biphenyl]-4-carboxylic acid (4′-(((((() 1R,3R,5S)-8-((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)methyl)-8-azabicyclo[3.2.1]octan-3-yl)oxy)methyl Preparation of )-2'-methyl-[1,1'-biphenyl]-4-carboxylic acid)

¹ H-NMR (400 MHz, CDCl ₃ ) δ ppm 1.25-2.16 (12H, m), 2.25 (3H, s), 2.54 (1H, s), 3.45 (2H, s), 3.60 (1H, s), 3.66 (2H, s), 4.42 (2H, s), 7.14-8.09 (10H, m)

Example 2-8: 4'-((((1R,3R,5S)-8-((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)methyl) -8-azabicyclo[3.2.1]octan-3-yl)oxy)methyl)-2′-methyl-[1,1′-biphenyl]-3-carboxylic acid (4′-(((((() 1R,3R,5S)-8-((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)methyl)-8-azabicyclo[3.2.1]octan-3-yl)oxy)methyl )-2'-methyl-[1,1'-biphenyl]-3-carboxylic acid)

¹ H-NMR (400 MHz, CDCl ₃ ) δ ppm 1.04-2.21 (12H, m), 2.23 (3H, s), 2.61-2.66 (1H, m), 3.52 (1H, s), 3.57 (2H, br) , 3.85 (2H, s), 4.43 (2H, s), 7.09-7.98 (10H, m)

Example 2-9: 5-cyano-4'-((((1R,3R,5S)-8-((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazole-4 -yl)methyl)-8-azabicyclo[3.2.1]octan-3-yl)oxy)methyl)-[1,1'-biphenyl]-3-carboxylic acid (5-cyano-4'- ((((1R,3R,5S)-8-((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)methyl)-8-azabicyclo[3.2.1]octan-3-yl Preparation of )oxy)methyl)-[1,1'-biphenyl]-3-carboxylic acid)

¹ H-NMR (400 MHz, CDCl ₃ ) δ ppm 0.94-2.74 (13H, m), 3.48 (1H, br), 3.83 (2H, br), 4.09 (2H, s), 4.48 (2H, s), 7.30 -8.36 (10H, m)

Example 2-10: 4'-((((1R,3R,5S)-8-((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)methyl) -8-azabicyclo[3.2.1]octan-3-yl)oxy)methyl)-2-fluoro-[1,1′-biphenyl]-3-carboxylic acid (4′-((((( 1R,3R,5S)-8-((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)methyl)-8-azabicyclo[3.2.1]octan-3-yl)oxy)methyl Preparation of )-2-fluoro-[1,1'-biphenyl]-3-carboxylic acid)

¹ H-NMR (400 MHz, CDCl ₃ ) δ ppm 1.09-2.78 (13H, m), 3.57 (1H, br), 3.67 (2H, br), 3.92 (2H, s), 4.44 (2H, s), 7.11 -7.72 (10H, m)

Example 2-11: 3-(6-((((1R,3R,5S)-8-((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl) methyl)-8-azabicyclo[3.2.1]octan-3-yl)oxy)methyl)pyridin-3-yl)benzoic acid (3-(6-((((1R,3R,5S)-8-( (5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)methyl)-8-azabicyclo[3.2.1]octan-3-yl)oxy)methyl)pyridin-3-yl)benzoic acid) manufacture of

¹ H-NMR (400 MHz, CDCl ₃ ) δ ppm 1.00-2.28 (13H, m), 2.94 (2H, s), 3.19 (2H, s), 3.48 (1H, br), 4.22 (2H, s), 6.68 -8.30 (10H, m)

Example 2-12: 3-(4-((((1R,3R,5S)-8-((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl) methyl)-8-azabicyclo[3.2.1]octan-3-yl)oxy)methyl)-2-methylphenyl)furan-2-carboxylic acid (3-(4-((((1R,3R,5S) )-8-((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)methyl)-8-azabicyclo[3.2.1]octan-3-yl)oxy)methyl)-2-methylphenyl ) Preparation of furan-2-carboxylic acid)

¹ H-NMR (400 MHz, MeOD) δ ppm 1.15-2.44 (16H, m), 3.15 (2H, br), 3.47 (2H, br), 4.36 (2H, s), 4.60 (1H, s), 6.38- 7.55 (8H, m)

Example 2-13: 4'-((((1R,3R,5S)-8-((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)methyl) -8-azabicyclo[3.2.1]octan-3-yl)oxy)methyl)-6-fluoro-5-methyl-[1,1'-biphenyl]-3-carboxylic acid (4'- ((((1R,3R,5S)-8-((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)methyl)-8-azabicyclo[3.2.1]octan-3-yl Preparation of )oxy)methyl)-6-fluoro-5-methyl-[1,1'-biphenyl]-3-carboxylic acid)

¹ H-NMR (400 MHz, MeOD) δ ppm 1.22-2.63 (16H, m), 3.74 (1H, br), 3.85 (2H, br), 4.11 (2H, s), 4.54 (2H, s), 7.11 8.06 (9H, m)

Example 2-14: 3-(4-((((1R,3R,5S)-8-((5-cyclopropyl-3-(2-(trifluoromethoxy)phenyl)isoxazole-4- yl)methyl)-8-azabicyclo[3.2.1]octan-3-yl)oxy)methyl)-2-methylphenyl)furan-2-carboxylic acid (3-(4-((((1R,3R) ,5S)-8-((5-cyclopropyl-3-(2-(trifluoromethoxy)phenyl)isoxazol-4-yl)methyl)-8-azabicyclo[3.2.1]octan-3-yl)oxy)methyl)- Preparation of 2-methylphenyl)furan-2-carboxylic acid)

It can be prepared using step 3-2 of Preparation Example 2.

¹ H-NMR (400 MHz, MeOD) δ ppm 1.12-2.37 (16H, m), 2.98 (2H, br), 3.39 (2H, br), 3.44-3.46 (1H, m), 4.35 (2H, s), 6.36-7.68 (9H, m)

Example 2-15: 3-(6-((((1R,3R,5S)-8-((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl) methyl)-8-azabicyclo[3.2.1]octan-3-yl)oxy)methyl)pyridin-3-yl)furan-2-carboxylic acid (3-(6-((((1R,3R, 5S)-8-((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)methyl)-8-azabicyclo[3.2.1]octan-3-yl)oxy)methyl)pyridin-3 -yl) furan-2-carboxylic acid)

¹ H-NMR (400 MHz, CDCl ₃ ) δ ppm 0.93-2.22 (13H, m), 2.88 (2H, br), 3.13-3.27 (3H, br), 4.20 (2H, s), 5.97-8.43 (9H, m)

Example 2-16: 2-(6-((((1R,3R,5S)-8-((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl) methyl)-8-azabicyclo[3.2.1]octan-3-yl)oxy)methyl)pyridin-2-yl)benzoic acid (2-(6-((((1R,3R,5S)-8-( (5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)methyl)-8-azabicyclo[3.2.1]octan-3-yl)oxy)methyl)pyridin-2-yl)benzoic acid) manufacture of

¹ H NMR (400 MHz, CDCl ₃ ) δ ppm 1.32 (m, 4H), 1.73 (m, 2H), 2.27-2.36 (m, 6H), 2.56 (m, 1H), 3.82 (d, 3H), 4.11 (s, 2H), 4.66 (s, 2H), 7.53-7.99 (m, 8H), 8.01 (m, 2H)

Example 2-17: 3-(4-((((1R,3R,5S)-8-((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl) methyl)-8-azabicyclo[3.2.1]octan-3-yl)oxy)methyl)phenyl)furan-2-carboxylic acid (3-(4-((((1R,3R,5S)-8) -((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)methyl)-8-azabicyclo[3.2.1]octan-3-yl)oxy)methyl)phenyl)furan-2-carboxylic acid)

¹ H NMR (400 MHz, MeOD) δ ppm 1.25 (m, 4H), 1.73 (m, 2H), 2.01 (m, 4H), 2.21 (m, 2H), 2.45 (m, 1H), 3.58 (m, 3H), 3.87 (s, 2H), 4.45 (s, 2H), 6.62 (s, 1H), 7.26 (d, 2H), 7.55-7.62 (m, 6H)

Example 2-18: 3-(4-((((1R,3R,5S)-8-((5-cyclopropyl-3-(2,6-dichlorophenyl)isooxazol-4-yl) methyl)-8-azabicyclo[3.2.1]octan-3-yl)oxy)methyl)phenyl)furan-2-carboxylic acid (3-(4-((((1R,3R,5S)-8) -((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)methyl)-8-azabicyclo[3.2.1]octan-3-yl)oxy)methyl)phenyl)furan-2-carboxylic acid)

¹ H-NMR (400 MHz, CDCl ₃ ) δ ppm 0.99-1.44 (9H, m), 1.65-1.68 (2H, m), 2.25-2.29 (3H, m), 3.08-3.74 (6H, m), 4.42 ( 2H, s), 6.52-7.57 (10H, m)

Example 2-19: 4-(4-((((1R,3R,5S)-8-((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl) methyl)-8-azabicyclo[3.2.1]octan-3-yl)oxy)methyl)phenyl)thiophene-2-carboxylic acid (4-(4-((((1R,3R,5S)- 8-((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)methyl)-8-azabicyclo[3.2.1]octan-3-yl)oxy)methyl)phenyl)thiophene-2- carboxylic acid)

¹ H-NMR (400 MHz, CDCl ₃ ) δ ppm 1.03-1.08 (2H, m), 1.21-1.25 (2H, m), 1.39-1.42 (2H, m), 1.91-2.40 (6H, m), 2.72 2.79 (1H, m), 3.56-3.71 (3H, m), 3.95 (2H, s), 4.42 (2H, s), 7.23-7.84 (9H, m)

Example 2-20: 4-(4-((((1R,3R,5S)-8-((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl) methyl)-8-azabicyclo[3.2.1]octan-3-yl)oxy)methyl)phenyl)oxazole-5-carboxylic acid (4-(4-((((1R,3R,5S)- 8-((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)methyl)-8-azabicyclo[3.2.1]octan-3-yl)oxy)methyl)phenyl)oxazole-5- carboxylic acid)

¹ H-NMR (400 MHz, CDCl ₃ ) δ ppm 1.04-1.25 (5H, m), 1.72-1.73 (4H, m), 1.96-2.00 (2H, m), 2.20-2.27 (1H, m), 2.97- 2.98 (2H, m), 3.32 (2H, s), 3.44-3.47 (1H, m), 4.39 (2H, s), 7.24-7.94 (8H, m), 8.88 (1H, s)

Example 2-21: 4-(4-((((1R,3R,5S)-8-((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl) methyl)-8-azabicyclo[3.2.1]octan-3-yl)oxy)methyl)phenyl)-1-methyl-1H-pyrazole-5-carboxylic acid (4-(4-((((() 1R,3R,5S)-8-((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)methyl)-8-azabicyclo[3.2.1]octan-3-yl)oxy)methyl Preparation of )phenyl)-1-methyl-1H-pyrazole-5-carboxylic acid)

¹ H-NMR (400 MHz, CDCl ₃ ) δ ppm 1.08-1.28 (4H, m), 1.62-2.21 (6H, m), 2.69-2.76 (1H, m), 3.30-3.34 (2H, m), 3.90 ( 2H, s), 4.19 (3H, s), 4.33 (2H, s), 7.11-7.55 (8H, m), 9.46 (1H, s)

Example 2-22: 3-(N-((1R,3R,5S)-8-((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)methyl) -8-azabicyclo[3.2.1]octan-3-yl)oxy)methyl)-[1,1'-biphenyl]-2-carboxylic acid) (4'-((((1R,3R, 5S)-8-((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)methyl)-8-azabicyclo[3.2.1]octan-3-yl)oxy)methyl)-[1 Preparation of ,1'-biphenyl]-2-carboxylic acid)

¹ H-NMR (400 MHz, MeOD) δ ppm 1.31-1.36 (4H, m), 2.17-2.53 (9H, m) 3.76 (1H, br), 3.93 (2H, s), 4.12 (2H, s), 4.55 -4.56 (d, 2H), 7.34-7.72 (10H, m)

Example 2-23: 4'-((((1R,3S,5S)-8-((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)methyl) -8-azabicyclo[3.2.1]octan-3-yl)oxy)methyl)-[1,1'-biphenyl]-2-carboxylic acid (4'-((((1R,3S,5S) )-8-((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)methyl)-8-azabicyclo[3.2.1]octan-3-yl)oxy)methyl)-[1, Preparation of 1'-biphenyl]-2-carboxylic acid)

¹ H-NMR (400 MHz, MeOD) δ ppm 1.31-1.37 (4H, m), 2.15-2.60 (9H, m) 3.76 (1H, br), 3.93 (2H, s), 4.15 (2H, s), 4.52 -4.54 (d, 2H), 7.34-7.82 (10H, m)

Example 2-24: 4'-((((1R,3R,5S)-8-((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)methyl) -8-azabicyclo[3.2.1]octan-3-yl)oxy)methyl)-[1,1'-biphenyl]-4-carboxylic acid (4'-((((1R,3R,5S) )-8-((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)methyl)-8-azabicyclo[3.2.1]octan-3-yl)oxy)methyl)-[1, Preparation of 1'-biphenyl]-4-carboxylic acid)

¹ H-NMR (400 MHz, MeOD) δ ppm 1.04-1.05 (2H, d), 1.22-1.23 (3H, m), 1.68-1.78 (4H, m), 1.96-2.03 (2H, d), 2.12-2.35 (1H, m), 3.12-3.64 (6H, m), 4.34 (2H, s), 7.12-7.16 (11H, m), 7.88-7.90 (2H, d)

Example 2-25: 4'-((((1R,3S,5S)-8-((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)methyl) -8-azabicyclo[3.2.1]octan-3-yl)oxy)methyl)-[1,1'-biphenyl]-4-carboxylic acid (4'-((((1R,3S,5S) )-8-((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)methyl)-8-azabicyclo [3.2.1]octan-3-yl)oxy)methyl)-[1, Preparation of 1'-biphenyl]-4-carboxylic acid)

¹ H-NMR (400 MHz, MeOD) δ ppm 1.08-1.82 (13H, m), 2.41 (1H, m), 3.22-3.44 (4H, m), 3.63-3.66 (1H, m), 4.59 (1H, br ), 7.32-7.68 (10H, m), 8.17 (1H, d)

Example 2-26: 4'-((((1R,3R,5S)-8-((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)methyl) -8-azabicyclo[3.2.1]octan-3-yl)oxy)methyl)-4-fluoro-[1,1′-biphenyl]-3-carboxylic acid (4′-(((((() 1R,3R,5S)-8-((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)methyl)-8-azabicyclo[3.2.1]octan-3-yl)oxy)methyl Preparation of )-4-fluoro-[1,1'-biphenyl]-3-carboxylic acid)

¹ H-NMR (400 MHz, MeOD) δ ppm 1.20-1.45 (7H, m), 2.03 (2H, d), 2.33 (2H, d), 3.65-4.12 (7H, m), 4.59 (1H, br), 7.13-7.68 (10H, m), 8.17 (1H, d)

Example 2-27: 4'-((((1R,3R,5S)-8-((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)methyl) -8-azabicyclo[3.2.1]octan-3-yl)oxy)methyl)-3-fluoro-[1,1′-biphenyl]-4-carboxylic acid (4′-(((((() 1R,3R,5S)-8-((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)methyl)-8-azabicyclo[3.2.1]octan-3-yl)oxy)methyl Preparation of )-3-fluoro-[1,1'-biphenyl]-4-carboxylic acid)

¹ H-NMR (400 MHz, MeOD) δ ppm 1.3-1.45 (7H, m), 2.13 (2H, d), 2.32 (2H, d), 3.85-4.12 (6H, m), 4.59 (2H, s), 7.35-7.68 (10H, m), 8.17 (1H, m)

Example 2-28: 5-(4-((((1R,3R,5S)-8-((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl) methyl)-8-azabicyclo[3.2.1]octan-3-yl)oxy)methyl)phenyl)pyrimidine-2-carboxylic acid (5-(4-((((1R,3R,5S)- 8-((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)methyl)-8-azabicyclo[3.2.1]octan-3-yl)oxy)methyl)phenyl)pyrimidine-2- carboxylic acid)

¹ H-NMR (400 MHz, MeOD) δ ppm 1.30-1.36 (4H, m), 1.76-1.79 (2H, d), 2.26-2.55 (7H, m), 3.61 (2H, s), 3.79-3.90 (3H) , m) 4.12 (2H, s), 4.61 (1H, s), 7.54-7.82 (8H, m), 9.24 (1H, s)

Example 2-29: 4'-((((1R,3R,5S)-8-((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)methyl) -8-azabicyclo[3.2.1]octan-3-yl)oxy)methyl)-2-fluoro-[1,1′-biphenyl]-4-carboxylic acid (4′-((((( 1R,3R,5S)-8-((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)methyl)-8-azabicyclo[3.2.1]octan-3-yl)oxy)methyl Preparation of )-2-fluoro-[1,1'-biphenyl]-4-carboxylic acid)

¹ H-NMR (400 MHz, MeOD) δ ppm 1.34-1.36 (4H, m), 1.75-1.78 (2H, d), 2.27-2.56 (7H, m), 3.61 (1H, s), 3.89 (2H, s) ) 4.12 (2H, s), 4.58 (2H, s), 7.44-7.82 (11H, m)

Example 2-30: 4'-((((1R,3R,5S)-8-((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)methyl) -8-azabicyclo[3.2.1]octan-3-yl)oxy)methyl)-3′-fluoro-[1,1′-biphenyl]-4-carboxylic acid (4′-(((( (1R,3R,5S)-8-((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)methyl)-8-azabicyclo[3.2.1]octan-3-yl)oxy) Preparation of methyl)-3'-fluoro-[1,1'-biphenyl]-4-carboxylic acid)

¹ H-NMR (400 MHz, MeOD) δ ppm 1.30-2.25 (12H, m), 3.09-3.13 (2H, d), 3.46 (2H, d), 3.82-3.97 (3H, m), 4.47-4.52 (2H) , d), 7.65-7.67 (9H, m), 8.18 (1H, d)

Example 2-31: 3'-((((1R,3R,5S)-8-((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)methyl) -8-azabicyclo[3.2.1]octan-3-yl)oxy)methyl)-[1,1'-biphenyl]-4-carboxylic acid (3'-((((1R,3R,5S) )-8-((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)methyl)-8-azabicyclo [3.2.1]octan-3-yl)oxy)methyl)-[1, Preparation of 1'-biphenyl]-4-carboxylic acid)

¹ H-NMR (400 MHz, MeOD) δ ppm 1.08-1.82 (13H, m), 2.41 (1H, m), 3.22-3.44 (4H, m), 3.63-3.66 (1H, m), 4.59 (1H, br ), 7.32-7.68 (10H, m), 8.17 (1H, d)

Example 2-32: 3'-((((1R,3R,5S)-8-((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)methyl) -8-azabicyclo[3.2.1]octan-3-yl)oxy)methyl)-[1,1'-biphenyl]-3-carboxylic acid (3'-((((1R,3R,5S) )-8-((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)methyl)-8-azabicyclo[3.2.1]octan-3-yl)oxy)methyl)-[1, Preparation of 1'-biphenyl]-3-carboxylic acid)

¹ H-NMR (400 MHz, MeOD) δ ppm 1.08-1.82 (13H, m), 2.41 (1H, m), 3.22-3.44 (4H, m), 3.63-3.66 (1H, m), 4.59 (1H, br ), 7.32-7.68 (10H, m), 8.17 (1H, d)

Example 2-33: 3'-((((1R,3R,5S)-8-((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)methyl) -8-azabicyclo[3.2.1]octan-3-yl)oxy)methyl)-[1,1'-biphenyl]-2-carboxylic acid (3'-((((1R,3R,5S) )-8-((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)methyl)-8-azabicyclo[3.2.1]octan-3-yl)oxy)methyl)-[1, Preparation of 1'-biphenyl]-2-carboxylic acid)

¹ H-NMR (400 MHz, MeOD) δ ppm 1.08-1.82 (13H, m), 2.41 (1H, m), 3.22-3.44 (4H, m), 3.63-3.66 (1H, m), 4.59 (1H, br ), 7.32-7.68 (10H, m), 8.17 (1H, d)

Example 2-34: 4'-((((1R,3R,5S)-8-((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)methyl) -8-azabicyclo[3.2.1]octan-3-yl)oxy)methyl)-3′-fluoro-[1,1′-biphenyl]-2-carboxylic acid (4′-(((( (1R,3R,5S)-8-((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)methyl)-8-azabicyclo[3.2.1]octan-3-yl)oxy) Preparation of methyl)-3'-fluoro-[1,1'-biphenyl]-2-carboxylic acid)

¹ H-NMR (400 MHz, MeOD) δ ppm 1.33-1.35 (6H, m), 1.74 (2H, d), 2.25-2.36 (5H, m), 3.23 (2H, q), 3.72-3.88 (3H, m) ), 4.11 (2H,d), 4.57 (2H, d), 7.07-7.68 (10H, m), 8.05 (1H, d)

Example 2-35: 4'-((((1R,3R,5S)-8-((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)methyl) -8-azabicyclo[3.2.1]octan-3-yl)oxy)methyl)-3′-fluoro-[1,1′-biphenyl]-3-carboxylic acid (4′-(((( (1R,3R,5S)-8-((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)methyl)-8-azabicyclo[3.2.1]octan-3-yl)oxy) Preparation of methyl)-3'-fluoro-[1,1'-biphenyl]-3-carboxylic acid)

¹ H-NMR (400 MHz, MeOD) δ ppm 1.32 (4H, d), 1.76 (2H, d), 2.20-2.34 (6H, m), 3.77-3.84 (3H, m), 4.12 (2H, d), 4.56 (2H, d), 7.49-7.90 (7H, m), 8.04-8.27 (2H, d), 8.32 (1H, d)

Example 2-36: 4'-((((1R,3R,5S)-8-((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)methyl) -8-azabicyclo[3.2.1]octan-3-yl)oxy)methyl)-5-fluoro-[1,1'-biphenyl]-2-carboxylic acid (4'-((((( 1R,3R,5S)-8-((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)methyl)-8-azabicyclo[3.2.1]octan-3-yl)oxy)methyl Preparation of )-5-fluoro-[1,1'-biphenyl]-2-carboxylic acid)

¹ H-NMR (400 MHz, MeOD) δ ppm 1.32 (4H, m), 1.76 (2H, d), 2.12-2.55 (7H, m), 3.61-3.78 (3H, m), 4.06 (2H, d), 4.35 (2H, s), 7.07-7.16 (2H, m), 7.33-7.39 (4H, m), 7.61-7.68 (4H, m)

Example 2-37: 5-chloro-4'-((((1R,3R,5S)-8-((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazole-4- yl)methyl)-8-azabicyclo[3.2.1]octan-3-yl)oxy)methyl)-[1,1'-biphenyl]-2-carboxylic acid (5-chloro-4'-( (((1R,3R,5S)-8-((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)methyl)-8-azabicyclo[3.2.1]octan-3-yl) Preparation of oxy)methyl)-[1,1'-biphenyl]-2-carboxylic acid)

¹ H-NMR (400 MHz, MeOD) δ ppm 1.31 (4H, m), 1.76 (2H, d), 2.15-2.57 (7H, m), 3.61 (1H, s), 3.75 (2H, s), 4.05 ( 2H, s), 4.51 (2H, s), 7.33-7.41 (6H, m), 7.60-7.67 (4H, m)

Example 2-38: 5-chloro-4'-((((1R,3S,5S)-8-((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazole-4- yl)methyl)-8-azabicyclo[3.2.1]octan-3-yl)oxy)methyl)-[1,1'-biphenyl]-2-carboxylic acid (5-chloro-4'-( (((1R,3S,5S)-8-((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)methyl)-8-azabicyclo[3.2.1]octan-3-yl) Preparation of oxy)methyl)-[1,1'-biphenyl]-2-carboxylic acid)

¹ H-NMR (400 MHz, MeOD) δ ppm 1.34 (4H, m), 1.79 (2H, d), 2.03-2.53 (7H, m), 3.72-3.84 (3H, m), 4.10 (2H, s), 4.54 (2H, s), 7.36 (4H, m), 7.45 (1H, d), 7.64-7.77 (5H, m)

Example 2-39: 4'-((((1R,3R,5S)-8-((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)methyl) -8-azabicyclo[3.2.1]octan-3-yl)oxy)methyl)-3-(trifluoromethyl)-[1,1'-biphenyl]-2-carboxylic acid (4'- ((((1R,3R,5S)-8-((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)methyl)-8-azabicyclo[3.2.1]octan-3-yl Preparation of )oxy)methyl)-3-(trifluoromethyl)-[1,1'-biphenyl]-2-carboxylic acid)

¹ H-NMR (400 MHz, MeOD) δ ppm 1.16-1.30 (5H, m), 1.37 (2H, d), 1.67-1.70 (4H, m), 2.03-2.53 (7H, m), 2.55-2.58 (1H) , m), 3.65-3.69 (2H, m), 4.02 (2H, s), 4.49 (3H, s), 7.36-7.76 (8H, m)

Example 2-40: 4'-((((1R,3R,5S)-8-((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)methyl) -8-azabicyclo[3.2.1]octan-3-yl)oxy)methyl)-4-fluoro-[1,1′-biphenyl]-2-carboxylic acid (4′-((((( 1R,3R,5S)-8-((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)methyl)-8-azabicyclo[3.2.1]octan-3-yl)oxy)methyl Preparation of )-4-fluoro-[1,1'-biphenyl]-2-carboxylic acid)

¹ H-NMR (400 MHz, MeOD) δ ppm 1.34 (4H, m), 1.79 (3H, m), 2.03-2.53 (8H, m), 3.73-4.13 (4H, m), 4.54 (2H, s), 7.27-7.67 (9H, m)

Example 2-41: 1-(4-((((1R,3R,5S)-8-((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl) methyl)-8-azabicyclo[3.2.1]octan-3-yl)oxy)methyl)phenyl)azetidine-3-carboxylic acid (1-(4-((((1R,3R,5S)- 8-((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)methyl)-8-azabicyclo [3.2.1]octan-3-yl)oxy)methyl)phenyl)azetidine-3- carboxylic acid)

¹ H-NMR (400 MHz, MeOH) δ ppm 1.16-1.19 (4H, m), 1.72-1.78 (8H, m), 2.37-2.41 (1H, m), 3.08 (2H, s), 3.41-3.61 (4H) , m), 3.89-4.04 (4H, m), 4.29 (2H, s), 6.45-6.47 (2H, d), 7.10-7.12 (2H, d), 7.49-7.56 (3H, m)

Example 2-42: 4'-((((1R,3R,5S)-8-((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)methyl) -8-azabicyclo[3.2.1]octan-3-yl)oxy)methyl)-3′-methyl-[1,1′-biphenyl]-2-carboxylic acid (4′-(((((() 1R,3R,5S)-8-((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)methyl)-8-azabicyclo[3.2.1]octan-3-yl)oxy)methyl Preparation of )-3'-methyl-[1,1'-biphenyl]-2-carboxylic acid)

¹ H-NMR (400 MHz, MeOH) δ ppm 1.24-1.34 (5H, m), 1.77-1.79 (2H, m), 2.17-2.53 (6H, m), 3.73 (1H, s), 3.83 (2H, s) ), 4.09-4.15 (3H, m), 4.54 (2H, s), 7.18-7.69 (10H, m)

Example 2-43: 4'-((((1R,3R,5S)-8-((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)methyl) -8-azabicyclo[3.2.1]octan-3-yl)oxy)methyl)-[1,1'-biphenyl]-3-carboxylic acid (4'-((((1R,3R,5S) )-8-((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)methyl)-8-azabicyclo[3.2.1]octan-3-yl)oxy)methyl)-[1, Preparation of 1'-biphenyl]-3-carboxylic acid)

¹ H-NMR (400 MHz, MeOD) δ ppm 1.18-1.82 (13H, m), 2.41 (1H, m), 3.12-3.35 (4H, m), 3.63-3.67 (1H, m), 4.48 (1H, br) ), 7.32-7.68 (10H, m), 8.15 (1H, d)

Example 2-44: 4'-((((1R,3R,5S)-8-((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)methyl) -8-azabicyclo[3.2.1]octan-3-yl)oxy)methyl)-3′-methyl-[1,1′-biphenyl]-3-carboxylic acid (4′-(((((() 1R,3R,5S)-8-((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)methyl)-8-azabicyclo[3.2.1]octan-3-yl)oxy)methyl Preparation of )-3'-methyl-[1,1'-biphenyl]-3-carboxylic acid)

¹ H-NMR (400 MHz, MeOD) δ ppm 1.21-1.26 (5H, m), 1.77-2.53 (11H, m), 3.58 (3H, s), 3.83 (2H, s), 4.48 (2H, s), 4.54 (1H, s), 7.36-7.54 (6H, m), 7.57 (1H, d), 7.75 (1H, d), 8.23 (1H, s)

Example 2-45: 4-((((1R,3R,5S)-8-((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)methyl)- 8-azabicyclo[3.2.1]octan-3-yl)oxy)methyl)-1-naphthoic acid (4-((((1R,3R,5S)-8-((5-cyclopropyl-3-( Preparation of 2,6-dichlorophenyl)isoxazol-4-yl)methyl)-8-azabicyclo[3.2.1]octan-3-yl)oxy)methyl)-1-naphthoic acid)

¹ H-NMR (400 MHz, MeOD) δ ppm 1.20-1.26 (5H, m), 1.82-2.48 (10H, m), 3.58 (2H, s), 4.48 (2H, s), 7.36-7.54 (9H, m )

Example 2-46: 1-(4-((((1R,3R,5S)-8-((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl) methyl)-8-azabicyclo[3.2.1]octan-3-yl)oxy)methyl)phenyl)-1H-pyrrole-2-carboxylic acid (1-(4-((((1R,3R,5S) )-8-((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)methyl)-8-azabicyclo[3.2.1]octan-3-yl)oxy)methyl)phenyl)-1H Preparation of -pyrrole-2-carboxylic acid)

¹ H-NMR (400 MHz, MeOD) δ ppm 1.20-1.21 (4H, m), 1.77-2.43 (8H, m), 3.19 (2H, s), 3.50-3.51 (3H, m), 4.48 (2H, s) ), 6.70 (1H, s), 7.19 (1H, s), 7.42-7.57 (8H, m), 7.76 (1H, s)

Example 2-47: 2-(5-((((1R,3R,5S)-8-((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl) methyl)-8-azabicyclo[3.2.1]octan-3-yl)oxy)methyl)pyridin-2-yl)benzoic acid (2-(5-((((1R,3R,5S)-8-( (5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)methyl)-8-azabicyclo[3.2.1]octan-3-yl)oxy)methyl)pyridin-2-yl)benzoic acid) manufacture of

¹ H-NMR (400 MHz, MeOD) δ ppm 1.31-1.37 (5H, m), 1.78-1.82 (2H, m), 2.34-2.37 (5H, m), 2.65-2.67 (2H, m), 3.91-3.94 (3H, m), 4.15 (2H, s), 4.79 (2H, s), 7.19 (1H, s), 7.59-7.97 (6H, m), 8.26-8.28 (1H, d), 8.50-8.52 (1H) , d), 8.74 (1H, s)

Example 2-48: 3-(5-((((1R,3R,5S)-8-((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl) methyl)-8-azabicyclo[3.2.1]octan-3-yl)oxy)methyl)pyridin-2-yl)benzoic acid (3-(5-((((1R,3R,5S)-8-( (5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)methyl)-8-azabicyclo[3.2.1]octan-3-yl)oxy)methyl)pyridin-2-yl)benzoic acid) manufacture of

¹ H-NMR (400 MHz, MeOD) δ ppm 1.30-1.37 (4H, m), 1.77-1.79 (2H, m), 2.33-2.37 (4H, m), 2.61-2.64 (1H, m), 3.91-3.94 (2H, m), 4.15 (1H, s), 4.81 (2H, s), 7.63-7.84 (3H, m), 8.28-8.20 (1H, d), 8.34-8.40 (3H, m), 8.69-8.61 (2H, m), 8.74 (1H, s)

Example 2-49: 2-(4-((((1R,3R,5S)-8-((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl) methyl)-8-azabicyclo[3.2.1]octan-3-yl)oxy)methyl)phenyl)nicotinic acid (2-(4-((((1R,3R,5S)-8-((5-cyclopropyl) Preparation of -3-(2,6-dichlorophenyl)isoxazol-4-yl)methyl)-8-azabicyclo[3.2.1]octan-3-yl)oxy)methyl)phenyl)nicotinic acid)

¹ H-NMR (400 MHz, MeOD) δ ppm 1.31-1.32 (4H, m), 1.73-1.76 (2H, m), 2.00-2.31 (6H, m), 2.52-2.54 (2H, m), 3.63-3.75 (3H, m), 4.05 (2H, s), 4.51-4.53 (2H, s), 7.37-7.68 (7H, m), 7.93-7.95 (1H, d), 8.54-8.55 (1H, d)

Example 2-50: 6-(4-((((1R,3R,5S)-8-((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl) methyl)-8-azabicyclo[3.2.1]octan-3-yl)oxy)methyl)phenyl)nicotinic acid (6-(4-((((1R,3R,5S)-8-((5-cyclopropyl) Preparation of -3-(2,6-dichlorophenyl)isoxazol-4-yl)methyl)-8-azabicyclo[3.2.1]octan-3-yl)oxy)methyl)phenyl)nicotinic acid)

¹ H-NMR (400 MHz, MeOD) δ ppm 1.26-1.28 (4H, m), 1.80-2.46 (10H, m), 3.50-3.81 (4H, m), 4.54 (2H, s), 4.62 (2H, s) ), 7.46-7.71 (6H, m), 8.56 (1H, s), 8.84 (1H, d), 9.01 (1H, s)

Example 2-51: 2-(4-((((1R,3R,5S)-8-((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl) methyl)-8-azabicyclo[3.2.1]octan-3-yl)oxy)methyl)phenyl)isonicotinic acid (2-(4-((((1R,3R,5S)-8-((5-) Preparation of cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)methyl)-8-azabicyclo[3.2.1]octan-3-yl)oxy)methyl)phenyl)isonicotinic acid)

¹ H-NMR (400 MHz, MeOD) δ ppm 1.25-1.28 (4H, m), 1.80-2.44 (9H, m), 3.50-3.63 (3H, m), 4.54-4.62 (4H, m), 7.44-7.80 (5H, m), 7.95 (2H, d), 8.27 (1H, s), 8.65 (1H, d)

Example 2-52: 3-(4-((((1R,3R,5S)-8-((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl) methyl)-8-azabicyclo[3.2.1]octan-3-yl)oxy)methyl)phenyl)furan-2-carboxylic acid (3-(4-((((1R,3R,5S)-8) -((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)methyl)-8-azabicyclo[3.2.1]octan-3-yl)oxy)methyl)phenyl)furan-2-carboxylic acid)

¹ H-NMR (400 MHz, MeOD) δ ppm 1.16-1.18 (4H, m), 1.66-2.01 (8H, m), 2.33-2.36 (1H, m), 2.99 (2H, s), 3.34 (1H, m) ), 4.41 (2H, s), 6.61 (1H, s), 7.26-7.28 (2H, d), 7.48-7.64 (7H, m)

Example 2-53: 5-(4-((((1R,3R,5S)-8-((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl) methyl)-8-azabicyclo[3.2.1]octan-3-yl)oxy)methyl)phenyl)furan-2-carboxylic acid (5-(4-((((1R,3R,5S)-8) -((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)methyl)-8-azabicyclo[3.2.1]octan-3-yl)oxy)methyl)phenyl)furan-2-carboxylic acid)

¹ H-NMR (400 MHz, MeOD) δ ppm 1.14-1.78 (4H, m), 1.70-1.98 (7H, m), 2.38 (1H, m), 3.00 (2H, s), 3.44-3.45 (1H, m) ), 4.29 (2H, s), 4.62 (3H, s), 6.73 (2H, d), 7.11 (2H, d), 7.49-7.53 (3H, m)

Example 2-54: 6-(4-((((1R,3R,5S)-8-((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl) methyl)-8-azabicyclo[3.2.1]octan-3-yl)oxy)methyl)phenyl)picolinic acid (6-(4-((((1R,3R,5S)-8-((5) Preparation of -cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)methyl)-8-azabicyclo[3.2.1]octan-3-yl)oxy)methyl)phenyl)picolinic acid)

¹ H-NMR (400 MHz, MeOD) δ ppm 1.15-1.18 (4H, m), 1.72-2.05 (7H, m), 2.33-2.39 (1H, m), 3.03 (2H, s), 3.52 (1H, m) ), 4.49 (2H, s), 7.43-7.55 (5H, m), 7.86 (1H, d), 7.95 (2H, d), 8.35 (1H, d), 9.14 (1H, s)

Example 2-55: 3-(5-((((1R,3R,5S)-8-((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl) methyl)-8-azabicyclo[3.2.1]octan-3-yl)oxy)methyl)pyridin-2-yl)furan-2-carboxylic acid (3-(5-((((1R,3R, 5S)-8-((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)methyl)-8-azabicyclo[3.2.1]octan-3-yl)oxy)methyl)pyridin-2 -yl) furan-2-carboxylic acid)

¹ H-NMR (400 MHz, MeOD) δ ppm 1.15-1.18 (4H, m), 1.57-1.99 (9H, m), 2.36-2.39 (1H, m), 3.03 (2H, s), 3.53 (1H, m) ), 4.48 (2H, s), 6.83 (1H, s), 7.48-7.56 (4H, m), 7.71-7.74 (1H, dd), 8.15 (1H, d), 8.35 (1H, d)

Example 2-56: 3-(4-((((1R,3R,5S)-8-((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl) methyl)-8-azabicyclo[3.2.1]octan-3-yl)oxy)methyl)-3-fluorophenyl)furan-2-carboxylic acid (3-(4-((((1R,3R) ,5S)-8-((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)methyl)-8-azabicyclo[3.2.1]octan-3-yl)oxy)methyl)-3 Preparation of -fluorophenyl)furan-2-carboxylic acid)

¹ H-NMR (400 MHz, MeOD) δ ppm 1.15-1.18 (4H, m), 1.73-1.99 (8H, m), 2.36-2.38 (1H, m), 3.03 (2H, s), 3.51 (1H, m) ), 4.45 (2H, s), 6.36 (1H, s), 7.36-7.56 (7H, m)

Example 2-57: 5-(4-((((1R,3R,5S)-8-((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl) methyl)-8-azabicyclo[3.2.1]octan-3-yl)oxy)methyl)phenyl)-2-methylthiophene-3-carboxylic acid (5-(4-((((1R,3R) ,5S)-8-((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)methyl)-8-azabicyclo[3.2.1]octan-3-yl)oxy)methyl)phenyl) Preparation of -2-methylthiophene-3-carboxylic acid)

¹ H-NMR (400 MHz, MeOD) δ ppm 1.14-1.18 (4H, m), 1.72-2.03 (8H, m), 2.37-2.40 (1H, m), 2.70 (3H, s), 3.02 (2H, s) ), 3.48-3.50 (1H, m), 4.41 (2H, s), 7.28-7.54 (8H, m)

Example 2-58: 3-(4-((((1R,3R,5S)-8-((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl) methyl)-8-azabicyclo[3.2.1]octan-3-yl)oxy)methyl)naphthalen-1-yl)furan-2-carboxylic acid (3-(4-((((1R,3R, 5S)-8-((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)methyl)-8-azabicyclo[3.2.1]octan-3-yl)oxy)methyl)naphthalen-1 -yl) furan-2-carboxylic acid)

¹ H-NMR (400 MHz, MeOD) δ ppm 1.14-1.18 (4H, m), 1.72-2.03 (8H, m), 2.36-2.38 (1H, m), 3.03 (2H, s), 3.60 (1H, m) ), 4.92-4.95 (2H, m), 6.53 (1H, s), 7.41-7.54 (7H, m), 7.64 (2H, s), 7.86 (1H, d), 8.12 (1H, d)

Example 2-59: 3-(4-((((1R,3R,5S)-8-((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl) methyl)-8-azabicyclo[3.2.1]octan-3-yl)oxy)methyl)naphthalen-1-yl)benzoic acid (3-(4-((((1R,3R,5S)-8-( (5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)methyl)-8-azabicyclo[3.2.1]octan-3-yl)oxy)methyl)naphthalen-1-yl)benzoic acid) manufacture of

¹ H-NMR (400 MHz, MeOD) δ ppm 1.14-1.18 (4H, m), 1.74-2.04 (8H, m), 2.36-2.40 (1H, m), 3.03 (2H, s), 3.64 (1H, m) ), 4.92-4.95 (2H, m), 7.38-7.55 (9H, m), 7.88 (1H, d), 7.86 (1H, d), 8.12-8.14 (3H, m)

Example 2-60: 4'-((((1R,3R,5S)-8-((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)methyl) -8-azabicyclo[3.2.1]octan-3-yl)oxy)methyl)-4-methoxy-[1,1'-biphenyl]-3-carboxylic acid (4'-((((( 1R,3R,5S)-8-((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)methyl)-8-azabicyclo[3.2.1]octan-3-yl)oxy)methyl Preparation of )-4-methoxy-[1,1'-biphenyl]-3-carboxylic acid)

¹ H-NMR (400 MHz, MeOD) δ ppm 1.16-1.18 (4H, m), 1.74-2.02 (8H, m), 2.36-2.38 (1H, m), 3.02 (2H, s), 3.51 (1H, m) ), 4.43 (2H, s), 7.05 (1H, d), 7.34 (2H, d), 7.49-7.56 (6H, m), 7.69 (1H, s)

Example 2-61: 3-(4-((((1R,3R,5S)-8-((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl) methyl)-8-azabicyclo[3.2.1]octan-3-yl)oxy)methyl)-3-methylphenyl)furan-2-carboxylic acid (3-(4-((((1R,3R,5S) )-8-((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)methyl)-8-azabicyclo[3.2.1]octan-3-yl)oxy)methyl)-3-methylphenyl ) Preparation of furan-2-carboxylic acid)

¹ H-NMR (400 MHz, MeOD) δ ppm 1.14-1.16 (4H, m), 1.68-1.99 (8H, m), 2.36-2.38 (1H, m), 2.97 (2H, s), 3.40-3.49 (3H) , m), 4.39 (2H, s), 6.58 (1H, d), 7.25 (1H, d), 7.44-7.50 (5H, m), 7.61-7.69 (2H, m)

Example 2-62: 3-(4-((((1R,3R,5S)-8-((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl) methyl)-8-azabicyclo[3.2.1]octan-3-yl)oxy)methyl)naphthalen-1-yl)furan-2-carboxylic acid (3-(4-((((1R,3R, 5S)-8-((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)methyl)-8-azabicyclo[3.2.1] octan-3-yl)oxy)methyl)naphthalen-1 -yl) furan-2-carboxylic acid)

¹ H-NMR (400 MHz, MeOD) δ ppm 1.14-1.16 (4H, m), 1.70-2.03 (9H, m), 2.33-2.36 (1H, m), 2.99 (2H, s), 3.60-3.61 (1H) , m), 6.53 (1H, d), 7.40-7.67 (10H, m), 7.86 (1H, d), 8.12 (1H, d)

Example 2-63: 3-(4-((((1R,3R,5S)-8-((5-cyclopropyl-3-(2-(trifluoromethoxy)phenyl)isoxazole-4- yl)methyl)-8-azabicyclo[3.2.1]octan-3-yl)oxy)methyl)-3-fluorophenyl)furan-2-carboxylic acid (3-(4-((((1R) ,3R,5S)-8-((5-cyclopropyl-3-(2-(trifluoromethoxy)phenyl)isoxazol-4-yl)methyl)-8-azabicyclo[3.2.1]octan-3-yl)oxy)methyl Preparation of )-3-fluorophenyl)furan-2-carboxylic acid)

It was prepared using step 3-2 of Preparation Example 2.

¹ H-NMR (400 MHz, MeOD) δ ppm 1.14-1.16 (4H, m), 1.69-2.00 (8H, m), 2.33-2.36 (1H, m), 3.00 (2H, s), 3.42-3.56 (3H) , m), 4.45 (2H, s), 6.34 (1H, s), 7.35-7.69 (8H, m)

Preparation 3: 4'-((((1R,3R,5S)-8-((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)methyl)-8 -azabicyclo[3.2.1]octan-3-yl)oxy)fluoromethyl)-[1,1'-biphenyl]-3-carboxylic acid (4'-((((1R,3R,5S) )-8-((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)methyl)-8-azabicyclo[3.2.1]octan-3-yl)oxy)fluoromethyl)-[1, Preparation of 1'-biphenyl]-3-carboxylic acid)

Step 1: 4-(((1R,3R,5S)-3-((4-bromophenyl)fluoromethoxy)-8-azabicyclo[3.2.1]octan-8-yl)methyl)-5 -Cyclopropyl-3-(2,6-dichlorophenyl)isoxazole (4-(((1R,3R,5S)-3-((4-bromophenyl)fluoromethoxy)-8-azabicyclo[3.2.1] Preparation of octan-8-yl)methyl)-5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazole)

In a microwave vial, the starting material (1.0 equiv.), 1-bromo-4- (bromofluoromethyl) benzene (1.5 equiv.), Cs ₂ CO ₃ (2 equiv.) was dissolved in 2 ml of acetonitrile and then at 90 ° C. Heated overnight. After completion of the reaction, extraction was performed using EA and purified water. Na ₂ SO ₄ was added to the EA layer to remove moisture and EA was removed. Column separation was performed under EA/Hx solvent conditions using MPLC.

Step 2: Methyl 4'-((((1R,3R,5S)-8-((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)methyl)-8 -azabicyclo[3.2.1]octan-3-yl)oxy)fluoromethyl)-[1,1'-biphenyl]-3-carboxylate (methyl 4'-((((1R,3R, 5S)-8-((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)methyl)-8-azabicyclo[3.2.1]octan-3-yl)oxy)fluoromethyl)-[1 ,1'-biphenyl]-3-carboxylate) preparation

4-(((1R,3R,5S)-3-((4-bromophenyl)fluoromethoxy)-8-azabicyclo[3.2.1]octan-8-yl prepared in step 1 in a microwave vial )methyl)-5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazole (1.0 equiv.), 3-(methoxycarbonyl)phenyl) boronic acid (1.5 equiv), 2M K ₂ CO ₃ An aqueous solution (2.0 equivalents) and a Pd catalyst (10 mol%) were dissolved in dioxane (2 mL), and then reacted at 180° C. for 30 minutes using a microwave. After completion of the reaction, extraction was performed using EA and brine solution. Na ₂ SO ₄ was added to the EA layer to remove moisture and EA was removed. Separated using Prep-LC.

Step 3: 4 '-((((1R,3R,5S)-8-((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)methyl)-8- Azabicyclo[3.2.1]octan-3-yl)oxy)fluoromethyl)-[1,1′-biphenyl]-3-carboxylic acid (4′-((((1R,3R,5S) -8-((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)methyl)-8-azabicyclo [3.2.1]octan-3-yl)oxy)fluoromethyl)-[1,1 Preparation of '-biphenyl]-3-carboxylic acid)

Methyl 4'-((((1R,3R,5S)-8-((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)methyl) prepared in step 1 -8-azabicyclo[3.2.1]octan-3-yl)oxy)fluoromethyl)-[1,1'-biphenyl]-3-carboxylate (1 equiv), 2 ml of 1N KOH aqueous solution 50 after dissolving in 2 ml of THF and 1 ml of methanol Stir overnight at °C. Acidified with EA/AcOH and extracted with purified water. Na ₂ SO ₄ was added to the EA layer to remove moisture and EA was removed. Separated using Prep-LC.

<Examples 3-1 to 3-2>

In Examples 3-1 to 3-2, compounds were prepared in substantially the same manner as in Preparation Example 3.

Example 3-1: 4'-((((1R,3R,5S)-8-((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)methyl) -8-azabicyclo[3.2.1]octan-3-yl)oxy)fluoromethyl)-[1,1′-biphenyl]-3-carboxylic acid (4′-((((1R,3R) ,5S)-8-((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)methyl)-8-azabicyclo[3.2.1]octan-3-yl)oxy)fluoromethyl)-[ Preparation of 1,1'-biphenyl]-3-carboxylic acid)

¹ H-NMR (400 MHz, CDCl ₃ ) δ ppm 1.08-2.18 (12H, m), 3.30-3.48 (4H, m), 5.21 (1H, s), 7.33-8.35 (11H, m)

Example 3-2: 3-(4-((((1R,3R,5S)-8-((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl) methyl)-8-azabicyclo[3.2.1]octan-3-yl)oxy)fluoromethyl)phenyl)furan-2-carboxylic acid (3-(4-((((1R,3R,5S) -8-((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)methyl)-8-azabicyclo[3.2.1]octan-3-yl)oxy)fluoromethyl)phenyl)furan-2 -carboxylic acid)

¹ H-NMR (400 MHz, MeOD) δ ppm 1.15-1.17 (4H, m), 1.70-2.03 (8H, m), 2.34-2.41 (1H, m), 3.09-3.13 (2H, m), 3.38 (2H) , s), 6.65 (1H, s), 7.46-7.95 (8H, m)

Preparation Example 4. 6-(((1R,3R,5S)-8-((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)methyl)-8-aza Bicyclo[3.2.1]octan-3-yl)amino)-2-naphthoic acid (6-(((1R,3R,5S)-8-((5-cyclopropyl-3-(2,6-dichlorophenyl) Preparation of isoxazol-4-yl)methyl)-8-azabicyclo[3.2.1]octan-3-yl)amino)-2-naphthoic acid)

Step 1. Methyl 6-(((1R,3R,5S)-8-((5-cyclopropyl-3-(2,6-dichlorophenyl)isooxazol-4-yl)methyl)-8-aza Bicyclo[3.2.1]octan-3-yl)amino)-2-naphthoate) (methyl 6-(((1R,3R,5S)-8-((5-cyclopropyl-3-(2,6) Preparation of -dichlorophenyl)isoxazol-4-yl)methyl)-8-azabicyclo[3.2.1]octan-3-yl)amino)-2-naphthoate)

Starting material of the above scheme (1 equiv), methyl 6-bromo-2-naphthoate (1.5 equiv), Pd(OAc) ₂ (0.1 equiv), 2,2'-bis(diphenylphosphino)-1 ,1'-binaphthyl:BINAP (0.1 eq.), Cs ₂ CO ₃ (3 eq.) was dissolved in toluene and heated at 130 °C overnight. After completion of the reaction, extraction was performed using EA and brine solution. Na ₂ SO ₄ was added to the EA layer to remove moisture and EA was removed. In MPLC, column separation was performed under EA/Hx conditions.

Step 2: 6-(((1R,3R,5S)-8-((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)methyl)-8-azabi Cyclo[3.2.1]octan-3-yl)amino)-2-naphthoic acid (6-(((1R,3R,5S)-8-((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol) Preparation of -4-yl)methyl)-8-azabicyclo[3.2.1]octan-3-yl)amino)-2-naphthoic acid)

Methyl 6-(((1R,3R,5S)-8-((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)methyl)-8 prepared in step 1 -Azabicyclo[3.2.1]octan-3-yl)amino)-2-naphthoate) (1 equivalent), 2 ml of 1N aqueous KOH solution was dissolved in 2 ml of THF and 1 ml of methanol, and then 50 Stir overnight at °C. Extracted with EA, AcOH, and purified water. Na ₂ SO ₄ was added to the EA layer to remove moisture and EA was removed. Separated using Prep-LC.

<Examples 4-1 to 4-3>

In Examples 4-1 to 4-3, compounds were prepared in substantially the same manner as in Preparation Example 4.

Example 4-1: 2-(((1R,3R,5S)-8-((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)methyl)-8 -azabicyclo[3.2.1]octan-3-yl)amino)benzo[d]thiazole-6-carboxylic acid (2-(((1R,3R,5S)-8-((5-cyclopropyl-) Preparation of 3-(2,6-dichlorophenyl)isoxazol-4-yl)methyl)-8-azabicyclo[3.2.1]octan-3-yl)amino)benzo[d]thiazole-6-carboxylic acid)

¹ H-NMR (400 MHz, MeOD) δ ppm 1.16-1.18 (4H, m), 1.80-2.03 (8H, m), 2.36-2.43 (1H, m), 3.14 (2H, bs), 3.43 (2H, s) ), 3.86-3.91 (1H, m), 7.41-8.22 (6H, m)

Example 4-2: 2-(((1R,3R,5S)-8-((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)methyl)-8 -azabicyclo[3.2.1]octan-3-yl)amino)benzo[d]thiazole-6-carboxylic acid (2-(((1R,3R,5S)-8-((5-cyclopropyl-) Preparation of 3-(2,6-dichlorophenyl)isoxazol-4-yl)methyl)-8-azabicyclo[3.2.1]octan-3-yl)amino)benzo[d]thiazole-6-carboxylic acid)

¹ H-NMR (400 MHz, MeOD) δ ppm 1.20-1.21 (4H, m), 1.85-2.12 (8H, m), 2.41-2.44 (1H, m), 3.29 (2H, bs), 3.57 (2H, s) ), 3.90-3.93 (1H, m), 7.43-8.24 (6H, m)

Example 4-3: 6-(((1R,3R,5S)-8-((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)methyl)-8 -azabicyclo[3.2.1]octan-3-yl)amino)-2-naphthoic acid (6-(((1R,3R,5S)-8-((5-cyclopropyl-3-(2,6-) Preparation of dichlorophenyl)isoxazol-4-yl)methyl)-8-azabicyclo[3.2.1]octan-3-yl)amino)-2-naphthoic acid)

¹ H-NMR (400 MHz, MeOD) δ ppm 1.16-1.18 (4H, m), 1.70-2.06 (9H, m), 2.37-2.44 (1H, m), 3.14-3.53 (5H, m), 6.57-8.34 (9H, m)

Preparation 5: 3'-(((1R,3R,5S)-8-((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)methyl)-8- Azabicyclo[3.2.1]octan-3-yl)amino)-[1,1′-biphenyl]-4-carboxylic acid (3′-(((1R,3R,5S)-8-(( 5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)methyl)-8-azabicyclo[3.2.1]octan-3-yl)amino)-[1,1'-biphenyl]-4- carboxylic acid)

Step 1: tert-Butyl (1R,3R,5S)-3-((4′-(methoxycarbonyl)-[1,1′-biphenyl]-3-yl)amino)-8-azabicyclo [3.2.1]octane-8-carboxylate (tert-butyl (1R,3R,5S)-3-((4'-(methoxycarbonyl)-[1,1'-biphenyl]-3-yl)amino)- Preparation of 8-azabicyclo[3.2.1]octane-8-carboxylate)

Starting material of the above scheme (1 equiv), methyl 3'-bromo-[1,1'-biphenyl]-4-carboxylate (1.5 equiv), Pd(OAc) ₂ (0.1 equiv), 2,2 '-Bis(diphenylphosphino)-1,1'-binaphthyl (0.1 eq.) and Cs ₂ CO ₃ (3 eq.) were dissolved in toluene and heated at 130° C. overnight. After completion of the reaction, extraction was performed using EA and brine solution. Na ₂ SO ₄ was added to the EA layer to remove moisture and EA was blown away. In MPLC, column separation was performed under EA/Hx conditions.

Step 2: Preparation of methyl 3'-(((1R,3R,5S)-8-azabicyclo[3.2.1]octan-3-yl)amino)-[1,1'-biphenyl]-4-carboxylate

tert-Butyl (1R,3R,5S)-3-((4′-(methoxycarbonyl)-[1,1′-biphenyl]-3-yl)amino)-8-aza prepared in step 1 Bicyclo[3.2.1]octane-8-carboxylate (1 eq) was dissolved in 2 ml of CH ₂ Cl ₂ . 2 ml of trifluoroacetic acid were added. The mixture was stirred at room temperature overnight. After completion of the reaction, it was concentrated. Vacuumed.

Step 3: Methyl 3'-(((1R,3R,5S)-8-((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)methyl)-8- Azabicyclo[3.2.1]octan-3-yl)amino)-[1,1'-biphenyl]-4-carboxylate (methyl 3'-(((1R,3R,5S)-8-( (5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)methyl)-8-azabicyclo[3.2.1]octan-3-yl)amino)-[1,1'-biphenyl]-4 -carboxylate) preparation

Methyl 3′-(((1R,3R,5S)-8-azabicyclo[3.2.1]octan-3-yl)amino)-[1,1′-biphenyl]-4-carboxylate (1 equiv) and 4-(chloromethyl)-5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazole (1.1 equiv.) and N,N-diisopropylamine (2.5 equiv) with dimethylacet After dissolving in 2 ml of amide (DMA), it was heated at 85 °C overnight. After completion of the reaction, extraction was performed using EA and brine solution. Na ₂ SO ₄ was added to the EA layer to remove moisture and EA was blown away. Separated using Prep-LC.

Step 4: 3'-(((1R,3R,5S)-8-((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)methyl)-8-aza Bicyclo[3.2.1]octan-3-yl)amino)-[1,1′-biphenyl]-4-carboxylic acid (3′-(((1R,3R,5S)-8-((5) -cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)methyl)-8-azabicyclo[3.2.1]octan-3-yl)amino)-[1,1'-biphenyl]-4-carboxylic acid)

Methyl 3'-(((1R,3R,5S)-8-((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)methyl)- prepared in step 3 8-azabicyclo[3.2.1]octan-3-yl)amino)-[1,1'-biphenyl]-4-carboxylate (1 equivalent), 2 ml of 1N aqueous KOH solution was mixed with 2 ml of THF, methanol 50 after dissolving in 1 ml Stir overnight at °C. Extracted with EA, AcOH, and purified water. Na ₂ SO ₄ was added to the EA layer to remove moisture and EA was blown away. Separated using Prep-LC.

Example 5-1: 3'-(((1R,3R,5S)-8-((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)methyl)- 8-azabicyclo[3.2.1]octan-3-yl)amino)-[1,1'-biphenyl]-4-carboxylic acid (3'-(((1R,3R,5S)-8- ((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)methyl)-8-azabicyclo[3.2.1]octan-3-yl)amino)-[1,1'-biphenyl]- 4-carboxylic acid)

A compound was prepared in substantially the same manner as in Preparation Example 5.

¹ H-NMR (400 MHz, CDCl ₃ ) δ ppm 0.81-1.30 (10H, m), 2.31-2.36 (2H, m), 3.22-3.65 (6H, m), 6.58-8.12 (12H, m)

Preparation 6. 4'-((((1R,3R,5S)-8-((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)methyl)-8 -azabicyclo[3.2.1]octan-3-yl)amino)methyl)-[1,1'-biphenyl]-2-carboxylic acid (4'-((((1R,3R,5S)- 8-((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)methyl)-8-azabicyclo [3.2.1]octan-3-yl)amino)methyl)-[1,1' Preparation of -biphenyl]-2-carboxylic acid)

Step 1. tert-Butyl ((1R,3R,5S)-8-((5-cyclopropyl-3-(2,6-dichlorophenyl)isooxazol-4-yl)methyl)-8-azabi Cyclo[3.2.1]octan-3-yl)carbamate (tert-butyl ((1R,3R,5S)-8-((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl) Preparation of methyl)-8-azabicyclo[3.2.1]octan-3-yl)carbamate)

tert-Butyl ((1R,3R,5S)-8-azabicyclo[3.2.1]octan-3-yl)carbamate (1 eq), 4-(chloromethyl)-5-cyclopropyl-3- (2,6-dichlorophenyl)isoxazole (1.1 equivalents) and N,N-diisopropylamine (2.5 equivalents) were dissolved in 2 ml of dimethylacetamide and heated at 85° C. overnight. After completion of the reaction, extraction was performed using EA and brine solution. Na ₂ SO ₄ was added to the EA layer to remove moisture and EA was blown away. Separated using Prep-LC.

Step 2. (1R,3R,5S)-8-((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)methyl)-8-azabicyclo[3.2. 1]octan-3-amine ((1R,3R,5S)-8-((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)methyl)-8-azabicyclo [3.2.1] octan-3-amine)

tert-Butyl ((1R,3R,5S)-8-((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)methyl)-8- prepared in step 1 Azabicyclo[3.2.1]octan-3-yl)carbamate (1 eq) was dissolved in 2 ml of dichloromethane. 2 ml of trifluoroacetic acid was added. The mixture was stirred at room temperature overnight. After completion of the reaction, it was concentrated. vacuumed.

Step 3. Methyl 4'-((((1R,3R,5S)-8-((5-cyclopropyl3-(2,6-dichlorophenyl)isoxazol-4-yl)methyl)-8- Azabicyclo[3.2.1]octan-3-yl)amino)methyl)-[1,1'-biphenyl]-2-carboxylate (methyl 4'-((((1R,3R,5S)- 8-((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)methyl)-8-aza bicyclo[3.2.1]octan-3-yl)amino)methyl)-[1,1 Preparation of '-biphenyl]-2-carboxylate)

(1R,3R,5S)-8-((5-cyclopropyl-3-(2,6-dichlorophenyl)isooxazol-4-yl)methyl)-8-azabicyclo[ 3.2.1] octane-3-amine (1 equiv), methyl 4'-(bromomethyl)-[1,1'-biphenyl]-2-carboxylate (1.2 equiv), Cs ₂ CO ₃ (2.5 equivalent) was dissolved in acetonitrile and stirred at room temperature overnight. After completion of the reaction, extraction was performed using EA and brine solution. Na ₂ SO ₄ was added to the EA layer to remove moisture and EA was blown away. In MPLC, column separation was performed under MeOH/CHCl ₃ conditions.

Step 4: 4'-((((1R, 3R, 5S)-8-((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)methyl)-8- Azabicyclo[3.2.1]octan-3-yl)amino)methyl)-[1,1′-biphenyl]-2-carboxylic acid (4′-((((1R,3R,5S)-8 -((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)methyl)-8-azabicyclo [3.2.1]octan-3-yl)amino)methyl)-[1,1'- biphenyl]-2-carboxylic acid)

Methyl 4'-((((1R,3R,5S)-8-((5-cyclopropyl3-(2,6-dichlorophenyl)isoxazol-4-yl)methyl)- prepared in step 3 8-azabicyclo[3.2.1]octan-3-yl)amino)methyl)-[1,1'-biphenyl]-2-carboxylate (1 equiv), 2 ml of 1N aqueous KOH solution is mixed with 2 ml of THF , after dissolving in 1 ml of methanol 50 Stir overnight at °C. Extracted with EA, AcOH, and purified water. Na ₂ SO ₄ was added to the EA layer to remove moisture and EA was blown away. Separated using Prep-LC.

<Examples 6-1 to 6-2>

In Examples 6-1 to 6-2, compounds were prepared in substantially the same manner as in Preparation Example 6.

Example 6-1: 4'-((((1R,3R,5S)-8-((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)methyl) -8-azabicyclo[3.2.1]octan-3-yl)amino)methyl)-[1,1'-biphenyl]-2-carboxylic acid (4'-((((1R,3R,5S) )-8-((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)methyl)-8-azabicyclo[3.2.1]octan-3-yl)amino)methyl)-[1, Preparation of 1'-biphenyl]-2-carboxylic acid)

¹ H-NMR (400 MHz, MeOD) δ ppm 1.16-2.33 (9H, m), 2.49-3.34 (7H, m), 4.06-4.12 (3H, m), 7.34-7.90 (11H, m)

Example 6-2: 4'-((((1R,3S,5S)-8-((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)methyl) -8-azabicyclo[3.2.1]octan-3-yl)amino)methyl)-[1,1'-biphenyl]-2-carboxylic acid (4'-((((1R,3S,5S) )-8-((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)methyl)-8-azabicyclo[3.2.1]octan-3-yl)amino)methyl)-[1, Preparation of 1'-biphenyl]-2-carboxylic acid)

¹ H-NMR (400 MHz, MeOD) δ ppm 1.16-2.47 (16H, m), 2.91-2.97 (1H, m), 4.06 (2H, s), 7.34-7.77 (11H, m)

Preparation 7: 3-(N-((1R,3R,5S)-8-((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)methyl)-8 -azabicyclo[3.2.1]octan-3-yl)sulfamoyl)benzoic acid (3-(N-((1R,3R,5S)-8-((5-cyclopropyl-3-(2,6-dichlorophenyl) Preparation of )isoxazol-4-yl)methyl)-8-azabicyclo[3.2.1]octan-3-yl)sulfamoyl)benzoic acid)

Step 1. Methyl 3-(N-((1R,3R,5S)-8-((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)methyl)-8 -azabicyclo[3.2.1]octan-3-yl)sulfamoyl)benzoate (methyl 3-(N-((1R,3R,5S)-8-((5-cyclopropyl-3-(2,6) Preparation of -dichlorophenyl)isoxazol-4-yl)methyl)-8-azabicyclo[3.2.1]octan-3-yl)sulfamoyl)benzoate)

(1R,3R,5S)-8-((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)methyl)-8-azabicyclo[3.2.1]octane -3-amine (1 eq.), dimethyl 2-(chlorosulfonyl)terephthalate (1.1 eq.), and triethylamine (2 eq.) were dissolved in MC and stirred at room temperature overnight. After completion of the reaction, extraction was performed with MC and purified water. MgSO4 was added to remove moisture and MC was removed. Separated using MPLC.

Step 2. 3-(N-((1R,3R,5S)-8-((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)methyl)-8- Azabicyclo[3.2.1]octan-3-yl)sulfamoyl)benzoic acid (3-(N-((1R,3R,5S)-8-((5-cyclopropyl-3-(2,6-dichlorophenyl) Preparation of isoxazol-4-yl)methyl)-8-azabicyclo[3.2.1]octan-3-yl)sulfamoyl)benzoic acid)

Methyl 3-(N-((1R,3R,5S)-8-((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)methyl) prepared in step 1 -8-azabicyclo[3.2.1]octan-3-yl)sulfamoyl)benzoate (1 equivalent) and 2ml of 1N aqueous KOH solution were dissolved in 2ml of THF and 1ml of methanol, and then 50 Stir overnight at °C. After completion of the reaction, extraction was performed with EA, AcOH, and purified water. Na ₂ SO ₄ was added to the EA layer to remove moisture and EA was blown away. Separated using Prep-LC.

<Examples 7-1 to 7-2>

In Examples 7-1 to 7-2, compounds were prepared in substantially the same manner as in Preparation Example 7.

Example 7-1: 3-(N-((1R,3R,5S)-8-((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)methyl) -8-azabicyclo[3.2.1]octan-3-yl)sulfamoyl)benzoic acid (3-(N-((1R,3R,5S)-8-((5-cyclopropyl-3-(2,6) Preparation of -dichlorophenyl)isoxazol-4-yl)methyl)-8-azabicyclo[3.2.1]octan-3-yl)sulfamoyl)benzoic acid)

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ ppm 1.03-1.91 (12H, m), 2.31-2.86 (4H, m), 3.16 (2H, s), 7.44-8.32 (8H, m)

Example 7-2: 2-(N-((1R,3R,5S)-8-((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)methyl) -8-azabicyclo[3.2.1]octan-3-yl)sulfamoyl)benzoic acid (2-(N-((1R,3R,5S)-8-((5-cyclopropyl-3-(2,6) Preparation of -dichlorophenyl)isoxazol-4-yl)methyl)-8-azabicyclo[3.2.1]octan-3-yl)sulfamoyl)benzoic acid)

¹ H-NMR (400 MHz, MeOD) δ ppm 1.28-1.34 (4H, m), 1.84-2.57 (7H, m), 3.23-3.26 (1H, m), 3.61-4.23 (4H, m), 7.49-8.01 (7H, m), 9.02 (1H, s)

Preparation 8: 2-(6-(((1R,3R,5S)-8-((5-cyclopropyl-3-(2,6-didichlorophenyl)isoxazol-4-yl)methyl)- 8-azabicyclo[3.2.1]octan-3-yl)carbamoyl)pyridin-3-yl)benzoic acid (2-(6-(((1R,3R,5S)-8-((5-cyclopropyl) Preparation of -3-(2,6-dichlorophenyl)isoxazol-4-yl)methyl)-8-azabicyclo[3.2.1]octan-3-yl)carbamoyl)pyridin-3-yl)benzoic acid)

Step 1: tert-Butyl (1R,3R,5S)-3-(5-bromopicolinamido)-8-azabicyclo[3.2.1]octane-8-carboxylate (tert-butyl (1R, Preparation of 3R,5S)-3-(5-bromopicolinamido)-8-azabicyclo[3.2.1]octane-8-carboxylate)

tert-Butyl (1R,3R,5S)-3-amino-8-azabicyclo[3.2.1]octane-8-carboxylate (1 eq), 5-bromopicholic acid (1.3 eq) and HOBt (1.1 equiv), EDCI.HCl (1.15 equiv), TEA (3 equiv) was added, dissolved in MC, and stirred at room temperature overnight. After completion of the reaction, extraction was performed with MC and purified water. MgSO4 was added to remove moisture and MC was removed. It was separated using MPLC.

Step 2: N-((1R,3R,5S)-8-azabicyclo[3.2.1]octan-3-yl)-5-bromopicolinamide (N-((1R,3R,5S)-8 Preparation of -azabicyclo[3.2.1]octan-3-yl)-5-bromopicolinamide)

tert-Butyl (1R,3R,5S)-3-(5-bromopicolinamido)-8-azabicyclo[3.2.1]octane-8-carboxylate (1 equivalent) prepared in step 1 It was dissolved in 2 ml of dichloromethane. 2 ml of trifluoroacetic acid was added, and the mixture was stirred at room temperature overnight. After completion of the reaction, it was concentrated and vacuum dried.

Step 3: 5-Bromo-N-((1R,3R,5S)-8-((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)methyl)- 8-azabicyclo[3.2.1]octan-3-yl)picolinamide (5-bromo-N-((1R,3R,5S)-8-((5-cyclopropyl-3-(2,6-) Preparation of dichlorophenyl)isoxazol-4-yl)methyl)-8-azabicyclo[3.2.1]octan-3-yl)picolinamide)

N-((1R,3R,5S)-8-azabicyclo[3.2.1]octan-3-yl)-5-bromopicolinamide (1 eq) and 4-(chloromethyl) prepared in step 2 -5-Cyclopropyl-3-(2,6-dichlorophenyl)isoxazole (1.1 equivalents) was added and dissolved in dimethylacetamide (2 ml), and then N,N-diisopropylamine (2.5 amine) was added. It was injected and heated at 85 °C overnight. After completion of the reaction, extraction was performed using EA and brine solution. Na ₂ SO ₄ was added to the EA layer to remove moisture and EA was blown away. Separated using Prep-LC.

Step 4: Methyl 2-(6-(((1R,3R,5S)-8-((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)methyl)- 8-azabicyclo[3.2.1]octan-3-yl)carbamoyl)pyridin-3-yl)benzoate (methyl 2-(6-(((1R,3R,5S)-8-((5) Preparation of -cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)methyl)-8-azabicyclo[3.2.1]octan-3-yl)carbamoyl)pyridin-3-yl)benzoate)

5-bromo-N-((1R,3R,5S)-8-((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)methyl prepared in step 3 )-8-azabicyclo[3.2.1] octan-3-yl)picolinamide (1 eq.), 2-(methoxycarbonyl)phenyl)boronic acid (1.5 eq.), 2N K ₂ CO ₃ (3 equivalent), Pd(dppf) ₂ Cl ₂ (0.1 equivalent) was dissolved in dioxane (2 ml) and stirred at 130° C. overnight. After completion of the reaction, extraction was performed using EA and brine solution. Na ₂ SO ₄ was added to the EA layer to remove moisture and EA was removed. Separated using Prep-LC.

Step 5. 2-(6-(((1R,3R,5S)-8-((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)methyl)-8 -azabicyclo[3.2.1]octan-3-yl)carbamoyl)pyridin-3-yl)benzoic acid (2-(6-(((1R,3R,5S)-8-((5-cyclopropyl-) Preparation of 3-(2,6-dichlorophenyl)isoxazol-4-yl)methyl)-8-azabicyclo[3.2.1]octan-3-yl)carbamoyl)pyridin-3-yl)benzoic acid)

Methyl 2-(6-(((1R,3R,5S)-8-((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)methyl prepared in step 4) )-8-azabicyclo[3.2.1]octan-3-yl)carbamoyl)pyridin-3-yl)benzoate (1 equivalent), 2 ml of 1N KOH aqueous solution were dissolved in 2 ml of THF: 1 ml of methanol after 50 Stir overnight at °C. After completion of the reaction, extraction was performed with EA, AcOH, and purified water. Na ₂ SO ₄ was added to the EA layer to remove moisture and EA was blown away. Separated using Prep-LC.

<Examples 8-1 to 8-2>

In Examples 8-1 to 8-2, compounds were prepared in substantially the same manner as in Preparation Example 8.

Example 8-1: 2-(6-(((1R,3R,5S)-8-((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)methyl )-8-azabicyclo[3.2.1]octan-3-yl)carbamoyl)pyridin-3-yl)benzoic acid (2-(6-(((1R,3R,5S)-8-((5) Preparation of -cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)methyl)-8-azabicyclo[3.2.1]octan-3-yl)carbamoyl)pyridin-3-yl)benzoic acid)

¹ H-NMR (400 MHz, CDCl ₃ ) δ ppm 0.81-1.70 (10H, m), 2.26-3.25 (6H, m), 3.89-4.38 (2H, m), 7.13-8.44 (10H, m)

Example 8-2: 4-(((1R,3R,5S)-8-((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)methyl)-8 -azabicyclo[3.2.1]octan-3-yl)carbamoyl)benzoic acid (4-(((1R,3R,5S)-8-((5-cyclopropyl-3-(2,6-dichlorophenyl) Preparation of isoxazol-4-yl)methyl)-8-azabicyclo[3.2.1]octan-3-yl)carbamoyl)benzoic acid)

¹ H-NMR (400 MHz, MeOD) δ ppm 1.15-1.17 (4H, m), 1.70-2.42 (5H, m), 3.10-3.44 (5H, m), 3.86-3.90 (1H, m), 5.88-5.95 (1H, m), 7.46-7.99 (7H, m)

Preparation 9: 4'-(3-((1R,3R,5S)-8-((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)methyl)- 8-azabicyclo[3.2.1]octan-3-yl)ureido)-[1,1'-biphenyl]-4-carboxylic acid (4'-(3-((1R,3R,5S) -8-((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)methyl)-8-azabicyclo[3.2.1]octan-3-yl)ureido)-[1,1'- biphenyl]-4-carboxylic acid)

Step 1: 1-(4-Bromophenyl)-3-((1R,3R,5S)-8-((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazole-4- yl)methyl)-8-azabicyclo[3.2.1]octan-3-yl)urea (1-(4-bromophenyl)-3-((1R,3R,5S)-8-((5-cyclopropyl- Preparation of 3-(2,6-dichlorophenyl)isoxazol-4-yl)methyl)-8-azabicyclo[3.2.1]octan-3-yl)urea)

(1R,3R,5S)-8-((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)methyl)-8-azabicyclo[3.2.1]octane -3-amine (1 eq.), 1-bromo-4-isocyanatobenzene (1.2 eq.), and TEA (2.5 eq.) were dissolved in THF and stirred at room temperature overnight. After completion of the reaction, extraction was performed using EA and brine solution. Na ₂ SO ₄ was added to the EA layer to remove moisture and EA was removed. Separated using MPLC.

Step 2. Ethyl 4'-(3-((1R,3R,5S)-8-((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)methyl)- 8-azabicyclo[3.2.1]octan-3-yl)ureido)-[1,1'-biphenyl]-4-carboxylate (ethyl 4'-(3-((1R,3R,5S) )-8-((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)methyl)-8-azabicyclo[3.2.1]octan-3-yl)ureido)-[1,1' -biphenyl]-4-carboxylate) preparation

1-(4-bromophenyl)-3-((1R,3R,5S)-8-((5-cycloprop-3-(2,6-dichlorophenyl)isoxazole- prepared in step 1) 4-yl)methyl)-8-azabicyclo[3.2.1]octan-3-yl)urea (1 equiv), (4-(ethoxycarbonyl)phenyl)boronic acid (1.5 equiv), 2N K ₂ CO ₃ (3 equivalents), Pd(dppf) ₂ Cl ₂ (0.1 equivalents) was dissolved in dioxane (2 ml) and stirred at 130° C. overnight. After completion of the reaction, extraction was performed using EA and brine solution. Na ₂ SO ₄ was added to the EA layer to remove moisture and EA was removed. Separated using Prep-LC.

Step 3. 4'-(3-((1R,3R,5S)-8-((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)methyl)-8 -azabicyclo[3.2.1]octan-3-yl)ureido)-[1,1'-biphenyl]-4-carboxylic acid 4'-(3-((1R,3R,5S)-8 -((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)methyl)-8-azabicyclo[3.2.1]octan-3-yl)ureido)-[1,1'-biphenyl] Preparation of -4-carboxylic acid

Ethyl 4'-(3-((1R,3R,5S)-8-((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)methyl prepared in step 2 )-8-azabicyclo[3.2.1]octan-3-yl)ureido)-[1,1'-biphenyl]-4-carboxylate (1 equivalent), 1N KOH aqueous solution 2 ml THF 2 ml, after dissolving in 1 ml of methanol 50 Stir overnight at °C. After completion of the reaction, extraction was performed with EA, AcOH, and purified water. Na ₂ SO ₄ was added to the EA layer to remove moisture and EA was removed. Separated using Prep-LC.

<Examples 9-1 to 9-2>

In Examples 9-1 to 9-2, compounds were prepared in substantially the same manner as in Preparation Example 9.

Example 9-1: 4'-(3-((1R,3R,5S)-8-((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)methyl )-8-azabicyclo[3.2.1]octan-3-yl)ureido)-[1,1'-biphenyl]-4-carboxylic acid (4'-(3-((1R,3R, 5S)-8-((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)methyl)-8-azabicyclo[3.2.1]octan-3-yl)ureido)-[1,1 Preparation of '-biphenyl]-4-carboxylic acid)

¹ H-NMR (400 MHz, MeOD) δ ppm 1.12-1.27 (4H, m), 1.58-1.94 (7H, m), 2.33-2.37 (1H, m), 3.06-3.11 (2H, bs), 3.32 (2H) , s), 3.81-3.83 (1H, m), 5.99-6.00 (1H, m), 7.46-7.99 (11H, m)

Example 9-2: 4-(3-((1R,3R,5S)-8-((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)methyl) -8-azabicyclo[3.2.1]octan-3-yl)ureido)benzoic acid (4-(3-((1R,3R,5S)-8-((5-cyclopropyl-3-(2,6) Preparation of -dichlorophenyl)isoxazol-4-yl)methyl)-8-azabicyclo[3.2.1]octan-3-yl)ureido)benzoic acid)

¹ H-NMR (400 MHz, MeOD) δ ppm 1.15-1.17 (4H, m), 1.59-1.62 (2H, m), 1.86-2.01 (6H, m), 2.35-2.42 (1H, m), 3.16 (2H) , bs), 3.46 (2H, s), 3.74-3.77 (1H, m), 7.41-7.89 (7H, m)

Preparation 10: 4'-((((1R,3R,5S)-8-(5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazole-4-carbonyl)-8-aza Bicyclo[3.2.1]octan-3-yl)oxy)methyl)-[1,1′-biphenyl]-4-carboxylic acid (4′-((((1R,3R,5S)-8- (5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazole-4-carbonyl)-8-azabicyclo[3.2.1]octan-3-yl)oxy)methyl)-[1,1'-biphenyl]-4 -carboxylic acid)

Step 1: (1R,5S)-8-(5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazole-4-carbonyl)-8-azabicyclo[3.2.1]octane- Preparation of 3-one (1R,5S)-8-(5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazole-4-carbonyl)-8-azabicyclo[3.2.1]octan-3-one)

5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazole-4-carboxylic acid (1.5 equiv) in DMF, (1S,5S)-8-azabicyclo[3.2.1]octane- 3-one (1 eq.), HATU (1.5 eq.), and DIPEA (3 eq.) were dissolved and stirred at room temperature overnight. After completion of the reaction, 1M NaOH was added in excess to remove acid, and extraction was performed using MC. After drying the MC layer using magnesium sulfate, MC was removed using a rotary concentrator to obtain a product (207.5 mg, 39% yield).

Step 2: 5-Cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)(1R,5S)-3-hydroxy-8-azabicyclo[3.2.1]octane- 8-yl)methanone (5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)((1R,5S)-3-hydroxy-8-azabicyclo[3.2.1]octan-8-yl )methanone manufacturing

(1R,5S)-8-(5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazole-4-carbonyl)-8-azabicyclo[3.2.1] prepared in step 1 Octan-3-one (1 equivalent) was added to 5 ml of methanol at 0 ° C. NaBH ₄ (1.2 equivalents), followed by stirring at room temperature for 30 minutes. After completion of the reaction, methanol was removed using a vacuum rotary concentrator. Acidification was carried out using EA and 1M HCl solution. The EA layer was dried using magnesium sulfate, the EA was removed using a rotary concentrator, and the product was separated by MPLC, that is, 5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazole-4- yl)(1R,3S,5S)-3-hydroxy-8-azabicyclo[3.2.1]octan-8-yl)methanone ((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol- 4-yl)((1R,3S,5S)-3-hydroxy-8-azabicyclo[3.2.1]octan-8-yl)methanone)(2-1) 61 mg (22% yield) and 5-cyclopropyl -3-(2,6-dichlorophenyl)isoxazol-4-yl)(1R,3R,5S)-3-hydroxy-8-azabicyclo[3.2.1]octan-8-yl)methane One ((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)((1R,3R,5S)-3-hydroxy-8-azabicyclo[3.2.1]octan-8-yl)methanone ) (2-2) 80 mg (28 % yield) was obtained.

Step 3-1: ((1R,3S,5S)-3-((4-bromobenzyl)oxy)-8-azabicyclo[3.2.1]octan-8-yl)(5-cyclopropyl-3 -(2,6-dichlorophenyl)isoxazol-4-yl)methanone ((1R,3S,5S)-3-((4-bromobenzyl)oxy)-8-azabicyclo[3.2.1]octan- Preparation of 8-yl) (5-cyclopropyl-3- (2,6-dichlorophenyl) isoxazol-4-yl) methanone

5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)(1R,3S,5S)-3-hydroxy-8-azabicyclo[3.2. 1] Octan-8-yl)methanone (1 equiv), 3 ml of THF, 18-crown-6 ether (1.5 equiv), and KO ^t Bu (2 equiv) were added and stirred for 20 minutes. Here, 1-bromo-4-(bromomethyl)benzene (1.5 equivalents) was added and stirred for 4 hours. It was extracted using a saturated aqueous solution of ammonium chloride and EA. After drying using magnesium sulfate and removing the EA solution using a rotary concentrator, the product was purified by MPLC (28% yield).

Step 4-1: 4'-((((1R,3S,5S)-8-(5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazole-4-carbonyl)-8- Azabicyclo[3.2.1]octan-3-yl)oxy)methyl)[1,1′-biphenyl]-4-carboxylic acid (4′-((((1R,3s,5S)-8- (5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazole-4-carbonyl)-8-azabicyclo[3.2.1]octan-3-yl)oxy)methyl)-[1,1'-biphenyl]-4 -carboxylic acid)

Prepared in step 3-1 ((1R,3S,5S)-3-((4-bromobenzyl)oxy)-8-azabicyclo[3.2.1]octan-8-yl)(5-cyclopropyl -3-(2,6-dichlorophenyl)isooxazol-4-yl)methanone (1 equiv), 4-boronobenzoic acid (2 equiv), Pd(amphos)Cl ₂ (0.2 equiv), DIPEA 0.1 ml (excess) was dissolved in 1 ml of THF: 1 ml of MeOH, and stirred at 50° C. for 2 hours. After completion of the reaction, extraction was performed with 1N HCl and EA. After drying using magnesium sulfate and removing the EA solution using a rotary concentrator, the product was purified by Prep-LC (40% yield).

<Examples 10-1 to 10-7>

In Examples 10-1 to 10-7, compounds were prepared in substantially the same manner as in Preparation Example 10.

Example 10-1: 4'-((((1R,3S,5S)-8-(5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazole-4-carbonyl)-8 -azabicyclo[3.2.1]octan-3-yl)oxy)methyl)-[1,1'-biphenyl]-4-carboxylic acid (4'-((((1R,3S,5S)- 8-(5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazole-4-carbonyl)-8-azabicyclo[3.2.1]octan-3-yl)oxy)methyl)-[1,1'-biphenyl] -4-carboxylic acid)

¹ H-NMR (400 MHz, CDCl ₃ ) δ ppm 1.19-2.35 (13H, m), 3.79-3.85 (1H, m), 4.13 (1H, br), 4.53 (2H, s), 4.70 (1H, br) , 7.30-8.17 (11H, m)

Example 10-2: 4'-((((1R,3R,5S)-8-(5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazole-4-carbonyl)-8 -azabicyclo[3.2.1]octan-3-yl)oxy)methyl)-[1,1'-biphenyl]-4-carboxylic acid (4'-((((1R,3R,5S)- 8-(5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazole-4-carbonyl)-8-azabicyclo[3.2.1]octan-3-yl)oxy)methyl)-[1,1'-biphenyl] -4-carboxylic acid)

It can be prepared using step 2-2 of Preparation Example 10.

¹ H-NMR (400 MHz, CDCl ₃ ) δ ppm 1.19-2.30 (13H, m), 3.70 (1H, s), 4.10 (1H, br), 4.51 (2H, s), 4.62 (1H, br), 7.30 -8.18 (11H, m)

Example 10-3: 5-(4-((((1R,3R,5S)-8-(5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazole-4-carbonyl) -8-azabicyclo[3.2.1]octan-3-yl)oxy)methyl)phenyl)pyrimidine-2-carboxylic acid (5-(4-((((1R,3R,5S)-8- Preparation of (5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazole-4-carbonyl)-8-azabicyclo[3.2.1]octan-3-yl)oxy)methyl)phenyl)pyrimidine-2-carboxylic acid)

¹ H-NMR (400 MHz, CDCl ₃ ) δ ppm 1.19-2.30 (13H, m), 3.71 (1H, s), 4.10 (1H, br), 4.54 (2H, s), 4.60 (1H, br), 7.30 -9.17 (9H, m)

Example 10-4: 4'-((((1R,3R,5S)-8-(5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazole-4-carbonyl)-8 -azabicyclo[3.2.1]octan-3-yl)oxy)methyl)-[1,1'-biphenyl]-2-carboxylic acid (4'-((((1R,3R,5S)- 8-(5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazole-4-carbonyl)-8-azabicyclo[3.2.1]octan-3-yl)oxy)methyl)-[1,1'-biphenyl] -2-carboxylic acid)

¹ H-NMR (400 MHz, CDCl ₃ ) δ ppm 1.18-2.33 (13H, m), 3.68 (1H, s), 4.06 (1H, br), 4.49 (2H, s), 4.59 (1H, br), 7.26 -7.94 (11H, m)

Example 10-5: 4'-((((1R,3R,5S)-8-(5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazole-4-carbonyl)-8 -azabicyclo[3.2.1]octan-3-yl)oxy)methyl)-4-fluoro-[1,1′-biphenyl]-3-carboxylic acid (4′-((((1R, 3R,5S)-8-(5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazole-4-carbonyl)-8-azabicyclo[3.2.1]octan-3-yl)oxy)methyl)-4-fluoro Preparation of -[1,1'-biphenyl]-3-carboxylic acid)

¹ H-NMR (400 MHz, CDCl ₃ ) δ ppm 1.19-2.30 (13H, m), 3.69 (1H, s), 4.10 (1H, br), 4.50 (2H, s), 4.61 (1H, br), 7.22 -8.23 (10H, m)

Example 10-6: 4'-((((1R,3R,5S)-8-(5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazole-4-carbonyl)-8 -azabicyclo[3.2.1]octan-3-yl)oxy)methyl)-3-fluoro-[1,1′-biphenyl]-4-carboxylic acid (4′-((((1R, 3R,5S)-8-(5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazole-4-carbonyl)-8-azabicyclo[3.2.1]octan-3-yl)oxy)methyl)-3-fluoro Preparation of -[1,1'-biphenyl]-4-carboxylic acid)

¹ H-NMR (400 MHz, CDCl ₃ ) δ ppm 1.18-2.28 (13H, m), 3.67 (1H, s), 4.06 (1H, br), 4.49 (3H, m), 7.30-8.70 (10H, m)

Example 10-7: 3-(4-((((1R,3R,5S)-8-(5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazole-4-carbonyl) -8-azabicyclo[3.2.1]octan-3-yl)oxy)methyl)phenyl)isonicotinic acid (3-(4-((((1R,3R,5S)-8-(5-cyclopropyl-3) Preparation of -(2,6-dichlorophenyl)isoxazole-4-carbonyl)-8-azabicyclo[3.2.1]octan-3-yl)oxy)methyl)phenyl)isonicotinic acid)

¹ H-NMR (400 MHz, CDCl ₃ ) δ ppm 1.20-2.30 (13H, m), 3.70 (1H, s), 4.08 (1H, br), 4.51 (2H, s), 4.61 (1H, br), 7.30 -8.10 (10H, m)

Experimental Example: FXR agonist activity evaluation (cofactor assay) of the present invention

The compounds of the present invention were confirmed whether cofactor recruitment was performed using LanthaScreen™ TR-FRET FXR Coactivator Assay kit. Compound 10uM, FL-SRC2-2 500nM, TB anti-GST 5nM, FXR-LBD-GST 5nM was reacted at room temperature for 1 hour. Then, excitation 340 nm, emission 520 and 495 nm were read using a Flexstation. After calculating the emission wavelength value as 520/495, it was expressed as 　% compared to the control drug tropifexor or INT-747. The results are shown in Table 1 below.

[Table 1]

Claims (6)

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

In Formula 1,
m and n are each independently 0 or 1;
ring A is aryl, heteroaryl, or null {wherein at least one H of the aryl or heteroaryl is -C _1-4 alkyl, -C _1-4 cyanoalkyl, -C _1-4 amino may be substituted with alkyl, —C _1-4 hydroxyalkyl, —C _1-4 haloalkyl, —CN, —NR ₁ R ₂ , —OR ₃ , or halo};
Ring B is aryl, heteroaryl, cycloalkyl, or heterocycloalkyl {wherein at least one H of the aryl or heteroaryl is -C _1-4 alkyl, -C _1-4 cyanoalkyl, -C _1-4 may be substituted with aminoalkyl, —C _1-4 hydroxyalkyl, —C _1-4 haloalkyl, —CN, —NR ₁ R ₂ , —OR ₃ , or halo; one or more H of said cycloalkyl or heterocycloalkyl may be substituted with -C _1-4 alkyl or -halo};
X is -NH-, -O-, or -S-;
L ₁ is -(CH ₂ ) _a -, -C(=O)-, -C(=O)NH-, -S(=O)-, -S(=O) ₂ -, or nothing ( null) {wherein, one or more H of -(CH ₂ ) _a - may be substituted with -C _1-4 alkyl, -C _1-4 haloalkyl, or halo};
L ₂ is -(CH ₂ ) _b -, -C(=O)-, -S(=O)-, or -S(=O) ₂ -, {herein, one of the -(CH ₂ ) _b - or more H may be substituted with -C _1-4 alkyl, -C _1-4 haloalkyl, or halo};
a and b are each independently 1, 2, 3, or 4;
Y is aryl or heteroaryl {wherein at least one H of said aryl or heteroaryl is -H, -C _1-4 alkyl, -C _1-4 haloalkyl, -CN, -NR ₁ R ₂ , -OR ₃ , or - may be substituted with halo};
Z is cycloalkyl or heterocycloalkyl {wherein at least one H of said cycloalkyl or heterocycloalkyl is -H, -C _1-4 alkyl, -C _1-4 haloalkyl, -CN, -NR ₁ R ₂ , -OR ₃ , or -halo};
R ₁ and R ₂ are each independently —H or —C _1-4 alkyl;
R ₃ is —H, —C _1-4 alkyl, or —C _1-4 haloalkyl. The method of claim 1,
m and n are each independently 1;
ring A is aryl, heteroaryl, or null {wherein one or more H of the aryl or heteroaryl may be substituted with -C _1-4 alkyl, or halo};
Ring B is aryl, heteroaryl, or heterocycloalkyl {wherein at least one H of the aryl or heteroaryl is -C _1-4 alkyl, -C _1-4 haloalkyl, -CN, -OR ₃ , or halo may be substituted with; one or more H of said heterocycloalkyl may be substituted with -C _1-4 alkyl or -halo};
X is -NH- or -O-;
L ₁ is -(CH ₂ ) _a -, -C(=O)-, -C(=O)NH-, -S(=O) ₂ -, or nothing (null) {wherein the -( CH ₂ ) one or more H of _a — may be substituted with —C _1-4 alkyl, —C _1-4 haloalkyl, or halo};
L ₂ is -(CH ₂ ) _b - or -C(=O)-, wherein at least one H of -(CH ₂ ) _b - is -C _1-4 alkyl, -C _1-4 haloalkyl, or may be substituted with halo};
a and b are each independently 1;
Y is aryl, wherein one or more H of said aryl may be substituted with -H, -C _1-4 alkyl, -NR ₁ R ₂ , -OR ₃ , or -halo};
Z is cycloalkyl, wherein one or more H of said cycloalkyl may be substituted with -H, -C _1-4 alkyl, -C _1-4 haloalkyl, or -halo};
R ₁ and R ₂ are each independently —H or —C _1-4 alkyl;
R ₃ is —H, —C _1-4 alkyl, or —C _1-4 haloalkyl;
A compound represented by Formula 1, an optical isomer thereof, or a pharmaceutically acceptable salt thereof. 3. The method of claim 2,
The compound represented by Formula 1 is a compound represented by Formula 2 below;
[Formula 2]

In Formula 2,
ring A is 6-10 membered aryl, 5-6 membered heteroaryl, or null, wherein said 5-6 membered heteroaryl contains one or more of N, O, or S atoms in the ring; at least one H of said 6-10 membered aryl or 5-6 membered heteroaryl may be substituted with -C _1-4 alkyl or halo};
Ring B is 6-10 membered aryl, 5-10 membered heteroaryl, or 4-7 membered heterocycloalkyl, wherein said 5-10 membered heteroaryl and 4-7 membered heterocycloalkyl are N, O, or at least one of the S atoms, wherein at least one H of the 6-10 membered aryl or 5-10 membered heteroaryl is -C _1-4 alkyl, -C _1-4 haloalkyl, -CN, -OR ₃ , or halo; one or more H of said 4-7 membered heterocycloalkyl may be substituted with -C _1-4 alkyl or -halo};
X is -NH- or -O-;
L ₁ is -(CH ₂ ) _a -, -C(=O)-, -C(=O)NH-, -S(=O) ₂ -, or nothing (null) {wherein the -( CH ₂ ) one or more H of _a — may be substituted with —C _1-4 alkyl, —C _1-4 haloalkyl, or halo};
L ₂ is -(CH ₂ ) _b - or -C(=O)-, wherein at least one H of -(CH ₂ ) _b - is -C _1-4 alkyl, -C _1-4 haloalkyl, or may be substituted with halo};
a and b are each independently 1;
Y ₁ and Y ₂ are each independently —H, —C _1-4 alkyl, —NR ₁ R ₂ , —OR ₃ , or —halo;
R ₁ and R ₂ are each independently —H or —C _1-4 alkyl;
R ₃ is —H, —C _1-4 alkyl, or —C _1-4 haloalkyl;
A compound represented by Formula 1, an optical isomer thereof, or a pharmaceutically acceptable salt thereof. The method of claim 1,
The compound represented by Formula 1 is selected from the group consisting of the following compounds, a compound, an optical isomer thereof, or a pharmaceutically acceptable salt thereof:
(1-1) 4-((((1R,3R,5S)-8-((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)methyl)-8 -azabicyclo[3.2.1]octan-3-yl)oxy)methyl)benzoic acid;
(2-1) 2-(4-((((1R,3R,5S)-8-(5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)-methyl )-8-azabicyclo[3.2.1]octan-3-yl)oxy)methyl)phenyl)nicotinic acid;
(2-2) 4'-((((1R,3R,5S)-8-((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)methyl)- 8-azabicyclo[3.2.1]octan-3-yl)oxy)methyl)-6-fluoro-[1,1′-biphenyl]-3-carboxylic acid;
(2-3) 4'-((((1R,3R,5S)-8-((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)methyl)- 8-azabicyclo[3.2.1]octan-3-yl)oxy)methyl)-4-methyl-[1,1′-biphenyl]-3-carboxylic acid;
(2-4) 4'-((((1R,3R,5S)-8-((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)methyl)- 8-azabicyclo[3.2.1]octan-3-yl)oxy)methyl)-6-methyl-[1,1′-biphenyl]-3-carboxylic acid;
(2-5) 4'-((((1R,3R,5S)-8-((5-cyclopropyl-3-(2,6-dichlorophenyl)isooxazol-4-yl)methyl)- 8-azabicyclo[3.2.1]octan-3-yl)oxy)methyl)-5-fluoro-[1,1′-biphenyl]-3-carboxylic acid;
(2-6) 4-chloro-4'-((((1R,3R,5S)-8-((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl )methyl)-8-azabicyclo[3.2.1]octan-3-yl)oxy)methyl)-[1,1′-biphenyl]-3-carboxylic acid;
(2-7) 4'-((((1R,3R,5S)-8-((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)methyl)- 8-azabicyclo[3.2.1]octan-3-yl)oxy)methyl)-2′-methyl-[1,1′-biphenyl]-4-carboxylic acid;
(2-8) 4'-((((1R,3R,5S)-8-((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)methyl)- 8-azabicyclo[3.2.1]octan-3-yl)oxy)methyl)-2′-methyl-[1,1′-biphenyl]-3-carboxylic acid;
(2-9) 5-cyano-4'-((((1R,3R,5S)-8-((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazole-4- yl)methyl)-8-azabicyclo[3.2.1]octan-3-yl)oxy)methyl)-[1,1′-biphenyl]-3-carboxylic acid;
(2-10) 4'-((((1R,3R,5S)-8-((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)methyl)- 8-azabicyclo[3.2.1]octan-3-yl)oxy)methyl)-2-fluoro-[1,1′-biphenyl]-3-carboxylic acid;
(2-11) 3-(6-((((1R,3R,5S)-8-((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)methyl) )-8-azabicyclo[3.2.1]octan-3-yl)oxy)methyl)pyridin-3-yl)benzoic acid;
(2-12) 3-(4-((((1R,3R,5S)-8-((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)methyl) )-8-azabicyclo[3.2.1]octan-3-yl)oxy)methyl)-2-methylphenyl)furan-2-carboxylic acid;
(2-13) 4'-((((1R,3R,5S)-8-((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)methyl)- 8-azabicyclo[3.2.1]octan-3-yl)oxy)methyl)-6-fluoro-5-methyl-[1,1′-biphenyl]-3-carboxylic acid;
(2-14) 3-(4-((((1R,3R,5S)-8-((5-cyclopropyl-3-(2-(trifluoromethoxy)phenyl)isoxazol-4-yl) )methyl)-8-azabicyclo[3.2.1]octan-3-yl)oxy)methyl)-2-methylphenyl)furan-2-carboxylic acid;
(2-15) 3-(6-((((1R,3R,5S)-8-((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)methyl) )-8-azabicyclo[3.2.1]octan-3-yl)oxy)methyl)pyridin-3-yl)furan-2-carboxylic acid;
(2-16) 2-(6-((((1R,3R,5S)-8-((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)methyl) )-8-azabicyclo[3.2.1]octan-3-yl)oxy)methyl)pyridin-2-yl)benzoic acid;
(2-17) 3-(4-((((1R,3R,5S)-8-((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)methyl) )-8-azabicyclo[3.2.1]octan-3-yl)oxy)methyl)phenyl)furan-2-carboxylic acid;
(2-18) 3-(4-((((1R,3R,5S)-8-((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)methyl) )-8-azabicyclo[3.2.1]octan-3-yl)oxy)methyl)phenyl)furan-2-carboxylic acid;
(2-19) 4-(4-((((1R,3R,5S)-8-((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)methyl) )-8-azabicyclo[3.2.1]octan-3-yl)oxy)methyl)phenyl)thiophene-2-carboxylic acid;
(2-20) 4-(4-((((1R,3R,5S)-8-((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)methyl) )-8-azabicyclo[3.2.1]octan-3-yl)oxy)methyl)phenyl)oxazole-5-carboxylic acid;
(2-21) 4-(4-((((1R,3R,5S)-8-((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)methyl )-8-azabicyclo[3.2.1]octan-3-yl)oxy)methyl)phenyl)-1-methyl-1H-pyrazole-5-carboxylic acid;
(2-22) 3-(N-((1R,3R,5S)-8-((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)methyl)- 8-azabicyclo[3.2.1]octan-3-yl)oxy)methyl)-[1,1′-biphenyl]-2-carboxylic acid);
(2-23) 4'-((((1R,3S,5S)-8-((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)methyl)- 8-azabicyclo[3.2.1]octan-3-yl)oxy)methyl)-[1,1′-biphenyl]-2-carboxylic acid;
(2-24) 4'-((((1R,3R,5S)-8-((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)methyl)- 8-azabicyclo[3.2.1]octan-3-yl)oxy)methyl)-[1,1′-biphenyl]-4-carboxylic acid;
(2-25) 4'-((((1R,3S,5S)-8-((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)methyl)- 8-azabicyclo[3.2.1]octan-3-yl)oxy)methyl)-[1,1′-biphenyl]-4-carboxylic acid;
(2-26) 4'-((((1R,3R,5S)-8-((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)methyl)- 8-azabicyclo[3.2.1]octan-3-yl)oxy)methyl)-4-fluoro-[1,1′-biphenyl]-3-carboxylic acid;
(2-27) 4'-((((1R,3R,5S)-8-((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)methyl)- 8-azabicyclo[3.2.1]octan-3-yl)oxy)methyl)-3-fluoro-[1,1′-biphenyl]-4-carboxylic acid;
(2-28) 5-(4-((((1R,3R,5S)-8-((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)methyl )-8-azabicyclo[3.2.1]octan-3-yl)oxy)methyl)phenyl)pyrimidine-2-carboxylic acid;
(2-29) 4'-((((1R,3R,5S)-8-((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)methyl)- 8-azabicyclo[3.2.1]octan-3-yl)oxy)methyl)-2-fluoro-[1,1′-biphenyl]-4-carboxylic acid;
(2-30) 4'-((((1R,3R,5S)-8-((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)methyl)- 8-azabicyclo[3.2.1]octan-3-yl)oxy)methyl)-3′-fluoro-[1,1′-biphenyl]-4-carboxylic acid;
(2-31) 3'-((((1R,3R,5S)-8-((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)methyl)- 8-azabicyclo[3.2.1]octan-3-yl)oxy)methyl)-[1,1′-biphenyl]-4-carboxylic acid;
(2-32) 3'-((((1R,3R,5S)-8-((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)methyl)- 8-azabicyclo[3.2.1]octan-3-yl)oxy)methyl)-[1,1′-biphenyl]-3-carboxylic acid;
(2-33) 3'-((((1R,3R,5S)-8-((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)methyl)- 8-azabicyclo[3.2.1]octan-3-yl)oxy)methyl)-[1,1′-biphenyl]-2-carboxylic acid;
(2-34) 4'-((((1R,3R,5S)-8-((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)methyl)- 8-azabicyclo[3.2.1]octan-3-yl)oxy)methyl)-3′-fluoro-[1,1′-biphenyl]-2-carboxylic acid;
(2-35) 4'-((((1R,3R,5S)-8-((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)methyl)- 8-azabicyclo[3.2.1]octan-3-yl)oxy)methyl)-3′-fluoro-[1,1′-biphenyl]-3-carboxylic acid;
(2-36) 4'-((((1R,3R,5S)-8-((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)methyl)- 8-azabicyclo[3.2.1]octan-3-yl)oxy)methyl)-5-fluoro-[1,1′-biphenyl]-2-carboxylic acid;
(2-37) 5-chloro-4'-((((1R,3R,5S)-8-((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl) )methyl)-8-azabicyclo[3.2.1]octan-3-yl)oxy)methyl)-[1,1′-biphenyl]-2-carboxylic acid;
(2-38) 5-chloro-4'-((((1R,3S,5S)-8-((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl) )methyl)-8-azabicyclo[3.2.1]octan-3-yl)oxy)methyl)-[1,1′-biphenyl]-2-carboxylic acid;
(2-39) 4'-((((1R,3R,5S)-8-((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)methyl)- 8-azabicyclo[3.2.1]octan-3-yl)oxy)methyl)-3-(trifluoromethyl)-[1,1′-biphenyl]-2-carboxylic acid;
(2-40) 4'-((((1R,3R,5S)-8-((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)methyl)- 8-azabicyclo[3.2.1]octan-3-yl)oxy)methyl)-4-fluoro-[1,1′-biphenyl]-2-carboxylic acid;
(2-41) 1-(4-((((1R,3R,5S)-8-((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)methyl) )-8-azabicyclo[3.2.1]octan-3-yl)oxy)methyl)phenyl)azetidine-3-carboxylic acid;
(2-42) 4'-((((1R,3R,5S)-8-((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)methyl)- 8-azabicyclo[3.2.1]octan-3-yl)oxy)methyl)-3′-methyl-[1,1′-biphenyl]-2-carboxylic acid;
(2-43) 4'-((((1R,3R,5S)-8-((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)methyl)- 8-azabicyclo[3.2.1]octan-3-yl)oxy)methyl)-[1,1′-biphenyl]-3-carboxylic acid;
(2-44) 4'-((((1R,3R,5S)-8-((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)methyl)- 8-azabicyclo[3.2.1]octan-3-yl)oxy)methyl)-3′-methyl-[1,1′-biphenyl]-3-carboxylic acid;
(2-45) 4-((((1R,3R,5S)-8-((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)methyl)-8 -azabicyclo[3.2.1]octan-3-yl)oxy)methyl)-1-naphthoic acid;
(2-46) 1-(4-((((1R,3R,5S)-8-((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)methyl )-8-azabicyclo[3.2.1]octan-3-yl)oxy)methyl)phenyl)-1H-pyrrole-2-carboxylic acid;
(2-47) 2-(5-((((1R,3R,5S)-8-((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)methyl )-8-azabicyclo[3.2.1]octan-3-yl)oxy)methyl)pyridin-2-yl)benzoic acid;
(2-48) 3-(5-((((1R,3R,5S)-8-((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)methyl )-8-azabicyclo[3.2.1]octan-3-yl)oxy)methyl)pyridin-2-yl)benzoic acid;
(2-49) 2-(4-((((1R,3R,5S)-8-((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)methyl) )-8-azabicyclo[3.2.1]octan-3-yl)oxy)methyl)phenyl)nicotinic acid;
(2-50) 6-(4-((((1R,3R,5S)-8-((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)methyl) )-8-azabicyclo[3.2.1]octan-3-yl)oxy)methyl)phenyl)nicotinic acid;
(2-51) 2-(4-((((1R,3R,5S)-8-((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)methyl )-8-azabicyclo[3.2.1]octan-3-yl)oxy)methyl)phenyl)isonicotinic acid;
(2-52) 3-(4-((((1R,3R,5S)-8-((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)methyl )-8-azabicyclo[3.2.1]octan-3-yl)oxy)methyl)phenyl)furan-2-carboxylic acid;
(2-53) 5-(4-((((1R,3R,5S)-8-((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)methyl) )-8-azabicyclo[3.2.1]octan-3-yl)oxy)methyl)phenyl)furan-2-carboxylic acid;
(2-54) 6-(4-((((1R,3R,5S)-8-((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)methyl) )-8-azabicyclo[3.2.1]octan-3-yl)oxy)methyl)phenyl)picolinic acid;
(2-55) 3-(5-((((1R,3R,5S)-8-((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)methyl )-8-azabicyclo[3.2.1]octan-3-yl)oxy)methyl)pyridin-2-yl)furan-2-carboxylic acid;
(2-56) 3-(4-((((1R,3R,5S)-8-((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)methyl )-8-azabicyclo[3.2.1]octan-3-yl)oxy)methyl)-3-fluorophenyl)furan-2-carboxylic acid;
(2-57) 5-(4-((((1R,3R,5S)-8-((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)methyl )-8-azabicyclo[3.2.1]octan-3-yl)oxy)methyl)phenyl)-2-methylthiophene-3-carboxylic acid;
(2-58) 3-(4-((((1R,3R,5S)-8-((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)methyl )-8-azabicyclo[3.2.1]octan-3-yl)oxy)methyl)naphthalen-1-yl)furan-2-carboxylic acid;
(2-59) 3-(4-((((1R,3R,5S)-8-((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)methyl) )-8-azabicyclo[3.2.1]octan-3-yl)oxy)methyl)naphthalen-1-yl)benzoic acid;
(2-60) 4'-((((1R,3R,5S)-8-((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)methyl)- 8-azabicyclo[3.2.1]octan-3-yl)oxy)methyl)-4-methoxy-[1,1′-biphenyl]-3-carboxylic acid;
(2-61) 3-(4-((((1R,3R,5S)-8-((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)methyl) )-8-azabicyclo[3.2.1]octan-3-yl)oxy)methyl)-3-methylphenyl)furan-2-carboxylic acid;
(2-62) 3-(4-((((1R,3R,5S)-8-((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)methyl )-8-azabicyclo[3.2.1]octan-3-yl)oxy)methyl)naphthalen-1-yl)furan-2-carboxylic acid;
(2-63) 3-(4-((((1R,3R,5S)-8-((5-cyclopropyl-3-(2-(trifluoromethoxy)phenyl)isoxazol-4-yl) )methyl)-8-azabicyclo[3.2.1]octan-3-yl)oxy)methyl)-3-fluorophenyl)furan-2-carboxylic acid;
(3-1) 4'-((((1R,3R,5S)-8-((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)methyl)- 8-azabicyclo[3.2.1]octan-3-yl)oxy)fluoromethyl)-[1,1′-biphenyl]-3-carboxylic acid;
(3-2) 3-(4-((((1R,3R,5S)-8-((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)methyl) )-8-azabicyclo[3.2.1]octan-3-yl)oxy)fluoromethyl)phenyl)furan-2-carboxylic acid;
(4-1) 2-(((1R,3R,5S)-8-((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)methyl)-8- azabicyclo[3.2.1]octan-3-yl)amino)benzo[d]thiazole-6-carboxylic acid;
(4-2) 2-(((1R,3R,5S)-8-((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)methyl)-8- azabicyclo[3.2.1]octan-3-yl)amino)benzo[d]thiazole-6-carboxylic acid;
(4-3) 6-(((1R,3R,5S)-8-((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)methyl)-8- azabicyclo[3.2.1]octan-3-yl)amino)-2-naphthoic acid;
(5-1) 3'-(((1R,3R,5S)-8-((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)methyl)-8 -azabicyclo[3.2.1]octan-3-yl)amino)-[1,1'-biphenyl]-4-carboxylic acid
(6-1) 4'-((((1R,3R,5S)-8-((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)methyl)- 8-azabicyclo[3.2.1]octan-3-yl)amino)methyl)-[1,1′-biphenyl]-2-carboxylic acid;
(6-2) 4'-((((1R,3S,5S)-8-((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)methyl)- 8-azabicyclo[3.2.1]octan-3-yl)amino)methyl)-[1,1′-biphenyl]-2-carboxylic acid;
(7-1) 3-(N-((1R,3R,5S)-8-((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)methyl)- 8-azabicyclo[3.2.1]octan-3-yl)sulfamoyl)benzoic acid;
(7-2) 2-(N-((1R,3R,5S)-8-((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)methyl)- 8-azabicyclo[3.2.1]octan-3-yl)sulfamoyl)benzoic acid;
(8-1) 2-(6-(((1R,3R,5S)-8-((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)methyl) -8-azabicyclo[3.2.1]octan-3-yl)carbamoyl)pyridin-3-yl)benzoic acid;
(8-2) 4-(((1R,3R,5S)-8-((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)methyl)-8- azabicyclo[3.2.1]octan-3-yl)carbamoyl)benzoic acid;
(9-1) 4'-(3-((1R,3R,5S)-8-((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)methyl) -8-azabicyclo[3.2.1]octan-3-yl)ureido)-[1,1'-biphenyl]-4-carboxylic acid;
(9-2) 4-(3-((1R,3R,5S)-8-((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)methyl)- 8-azabicyclo[3.2.1]octan-3-yl)ureido)benzoic acid;
(10-1) 4'-((((1R,3S,5S)-8-(5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazole-4-carbonyl)-8- azabicyclo[3.2.1]octan-3-yl)oxy)methyl)-[1,1′-biphenyl]-4-carboxylic acid;
(10-2) 4'-((((1R,3R,5S)-8-(5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazole-4-carbonyl)-8- azabicyclo[3.2.1]octan-3-yl)oxy)methyl)-[1,1′-biphenyl]-4-carboxylic acid;
(10-3) 5-(4-((((1R,3R,5S)-8-(5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazole-4-carbonyl)- 8-azabicyclo[3.2.1]octan-3-yl)oxy)methyl)phenyl)pyrimidine-2-carboxylic acid;
(10-4) 4'-((((1R,3R,5S)-8-(5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazole-4-carbonyl)-8- azabicyclo[3.2.1]octan-3-yl)oxy)methyl)-[1,1′-biphenyl]-2-carboxylic acid;
(10-5) 4'-((((1R,3R,5S)-8-(5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazole-4-carbonyl)-8- azabicyclo[3.2.1]octan-3-yl)oxy)methyl)-4-fluoro-[1,1′-biphenyl]-3-carboxylic acid;
(10-6) 4'-((((1R,3R,5S)-8-(5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazole-4-carbonyl)-8- azabicyclo[3.2.1]octan-3-yl)oxy)methyl)-3-fluoro-[1,1′-biphenyl]-4-carboxylic acid; and
(10-7) 3-(4-((((1R,3R,5S)-8-(5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazole-4-carbonyl)- 8-azabicyclo[3.2.1]octan-3-yl)oxy)methyl)phenyl)isonicotinic acid. A pharmaceutical composition for preventing or treating liver disease mediated by FXR, comprising the compound according to any one of claims 1 to 4, an optical isomer thereof, or a pharmaceutically acceptable salt thereof as an active ingredient. . 6. The method of claim 5,
The FXR mediated liver disease is cholestasis, intrahepatic cholestasis, estrogen-induced cholestasis, drug-induced cholestasis, cholestasis in pregnancy, parenteral nutrition-related cholestasis, primary Biliary cirrhosis (PBC), primary sclerosing cholangitis (PSC), progressive familial cholestasis (PFIC), nonalcoholic fatty liver disease (NAFLD), nonalcoholic steatohepatitis (NASH), drug-induced bile duct damage, gallstones, cirrhosis , alcohol-induced cirrhosis, cystic fibrosis-associated liver disease (CFLD), bile duct obstruction, cholelithiasis, and at least one pharmaceutical composition selected from the group consisting of liver fibrosis.