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

Azabicyclo alkyl derivatives as FXR agonist, and uses thereof Download PDF

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KR20220118267A
KR20220118267A KR1020210022197A KR20210022197A KR20220118267A KR 20220118267 A KR20220118267 A KR 20220118267A KR 1020210022197 A KR1020210022197 A KR 1020210022197A KR 20210022197 A KR20210022197 A KR 20210022197A KR 20220118267 A KR20220118267 A KR 20220118267A
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methyl
azabicyclo
cyclopropyl
octan
dichlorophenyl
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정원근
정희진
김학도
남은혜
양덕모
이혜미
박진영
이희진
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주식회사 보령
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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

FXR 작용제로서 아자바이사이클로알킬 유도체 화합물 및 이의 용도{Azabicyclo alkyl derivatives as FXR agonist, and uses thereof}Azabicycloalkyl derivatives as FXR agonists and uses thereof

본 발명은 FXR 작용제 활성을 갖는 아자바이사이클로알킬 유도체 화합물 및 이의 용도에 관한 것이다.The present invention relates to azabicycloalkyl derivative compounds having FXR agonist activity and uses thereof.

파네소이드 X 수용체(FXR, NR1H4)는 핵 수용체로 알려진 리간드 활성 전사인자(ligand-activated transcription factor) 군에 속하며, 간, 식도, 위, 십이지장, 소장, 결장, 신장 및 부신 등에서 발현되는 것으로 알려져 있다(Kuipers, F. et al., Rev. Endocrine Metab. Disorders, 2004, 5: 319-326). 또한, 케노데옥시콜산(chenodeoxycholic acid; CDCA)과 같은 담즙산 또는 이의 타우린 또는 글리신아미드 접합체는 FXR의 내인성 리간드이다. FXR은 담즙산과 결합시 활성화되고, 레티노이드 X 수용체(RXR)와 이종이량체 복합체를 형성함으로써 간 및 순환계에서 담즙산, 콜레스테롤, 트리글리세리드 및 지단백질의 항상성에 관여하는 유전자 등 다수의 유전자의 발현을 제어한다(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). 또한, FXR은 FGF15(Fibroblast growth factor 15)(설치류). 또는, FGF19(원숭이, 인간)의 발현을 상향 조절함으로써 주변분비(paracrine) 및 내분비(endocrine) 신호 전달에 관여하는 것으로 보인다(T. Inagaki et al., Cell Metab., 2005, 2(4), 217-225). 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).

한편, 오베티콜산(Obeticholic acid; 6-Et CDCA)은 내인성 CDCA보다 더 활성을 나타내는 FXR 작용제로서, 비알콜성 지방간 질환(NAFLD), 비알콜성 지방간염(NASH), 원발 담즙성 간경화(PBC)에 대한 임상 시험에서 일부 유효한 효과를 나타냈다(Mudaliar, s. et al., gastroenterology, 2013, 145: 574-582; Nevens, F. et al., J. Hepatol., 2014, 60: S525-S526). 그러나, 공지된 FXR 작용제들은 여전히 약력학적 또는 약동학적 특성에 단점을 가지므로, FXR에 작용 활성을 가져 FXR에 의해 매개되는 간 질환의 치료에 유용하게 활용될 수 있는 신규 화합물에 대한 미충족된 수요가 증대되고 있다.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: 319-326Kuipers, F. et al., Rev. Endocrine Metab. Disorders, 2004, 5: 319-326 Kalaany, N.Y. et al., Annu. Rev.Physiol., 2006, 68: 159-191Kalaany, N.Y. et al., Annu. Rev. Physiol., 2006, 68: 159-191 Calkin, A. C. et al., Nat. Rev.mol. Cell Biol., 2012, 13: 213-224Calkin, A. C. et al., Nat. Rev. mol. Cell Biol., 2012, 13: 213-224 T. Inagaki et al., Cell Metab., 2005, 2(4), 217-225T. Inagaki et al., Cell Metab., 2005, 2(4), 217-225 Mudaliar, s. et al., gastroenterology, 2013, 145: 574-582 Mudalia, s. et al., gastroenterology, 2013, 145: 574-582 Nevens, F. et al., J. Hepatol., 2014, 60: S525-S526Nevens, F. et al., J. Hepatol., 2014, 60: S525-S526

본 발명의 목적은 신규한 구조의 아자바이사이클로알킬 유도체 화합물, 이의 광학 이성질체, 또는 이의 약학적으로 허용 가능한 염을 제공하는 것이다.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.

본 발명의 다른 목적은 상기 아자바이사이클로알킬 유도체 화합물의 제조방법을 제공하는 것이다.Another object of the present invention is to provide a method for preparing the azabicycloalkyl derivative compound.

본 발명의 다른 목적은 상기 아자바이사이클로알킬 유도체 화합물의 의약용도를 제공하는 것으로서, 구체적으로 상기 아자바이사이클로알킬 유도체 화합물을 유효성분으로 포함하는 FXR에 의해 매개되는 간 질환의 치료 또는 예방용 약학적 조성물, 상기 화합물을 이용한 FXR에 의해 매개되는 간 질환의 치료 또는 예방 용도 또는 상기 화합물을 투여하는 단계를 포함하는 FXR에 의해 매개되는 간 질환의 치료 또는 예방 방법을 제공하는 것이다.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.

상기 목적을 달성하기 위하여, 본 발명자들이 연구 노력한 결과, 아래에서 언급하는 화학식 1로 표시되는 아자바이사이클로알킬 유도체 화합물들이 FXR 활성을 유도하는 것을 확인함으로써 본 발명을 완성하였다.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.

아자바이사이클로알킬 유도체 화합물Azabicycloalkyl derivative compounds

본 발명은 하기 화학식 1로 표시되는 화합물, 이의 광학 이성질체, 또는 이들의 약학적으로 허용가능한 염을 제공한다:The present invention provides a compound represented by the following formula (1), an optical isomer thereof, or a pharmaceutically acceptable salt thereof:

[화학식 1][Formula 1]

Figure pat00001
Figure pat00001

상기 화학식 1에서,In Formula 1,

m 및 n은 각각 독립적으로 0 또는 1이고;m and n are each independently 0 or 1;

고리 A는 아릴, 헤테로아릴, 또는 아무 것도 아니고(null) {여기서, 상기 아릴 또는 헤테로아릴의 하나 이상의 H는 -C1-4알킬, -C1-4시아노알킬, -C1-4아미노알킬, -C1-4하이드록시알킬, -C1-4할로알킬, -CN, -NR1R2, -OR3, 또는 할로로 치환될 수 있음};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};

고리 B는 아릴, 헤테로아릴, 사이클로알킬, 또는 헤테로사이클로알킬이고 {여기서, 상기 아릴 또는 헤테로아릴의 하나 이상의 H는 -C1-4알킬, -C1-4시아노알킬, -C1-4아미노알킬, -C1-4하이드록시알킬, -C1-4할로알킬, -CN, -NR1R2, -OR3, 또는 할로로 치환될 수 있고; 상기 사이클로알킬 또는 헤테로사이클로알킬의 하나 이상의 H는 -C1-4알킬 또는 -할로로 치환될 수 있음};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};

X는 -NH-, -O-, 또는 -S-이고;X is -NH-, -O-, or -S-;

L1은 -(CH2)a-, -C(=O)-, -C(=O)NH-, -S(=O)-, -S(=O)2-, 또는 아무 것도 아니고(null) {여기서, 상기 -(CH2)a-의 하나 이상의 H는 -C1-4알킬, -C1-4할로알킬, 또는 할로로 치환될 수 있음}; 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};

L2는 -(CH2)b-, -C(=O)-, -S(=O)-, 또는 -S(=O)2- 이고 {여기서, 상기 -(CH2)b-의 하나 이상의 H는 -C1-4알킬, -C1-4할로알킬, 또는 할로로 치환될 수 있음}; 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 및 b는 각각 독립적으로 1, 2, 3, 또는 4이고;a and b are each independently 1, 2, 3, or 4;

Y는 아릴 또는 헤테로아릴이고 {여기서, 상기 아릴 또는 헤테로아릴의 하나 이상의 H는 -H, -C1-4알킬, -C1-4할로알킬, -CN, -NR1R2, -OR3, 또는 -할로로 치환될 수 있음};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};

Z는 사이클로알킬 또는 헤테로사이클로알킬이고 {여기서, 상기 사이클로알킬 또는 헤테로사이클로알킬의 하나 이상의 H는 -H, -C1-4알킬, -C1-4할로알킬, -CN, -NR1R2, -OR3, 또는 -할로로 치환될 수 있음};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};

R1 및 R2는 각각 독립적으로 -H 또는 -C1-4알킬이고;R 1 and R 2 are each independently —H or —C 1-4 alkyl;

R3는 -H, -C1-4알킬이고, 또는 -C1-4할로알킬이다.R 3 is —H, —C 1-4 alkyl, or —C 1-4 haloalkyl.

또한, 본 발명의 구체예에 따르면, 상기 화학식 1로 표시되는 화합물이 하기 범위일 수 있다:In addition, according to an embodiment of the present invention, the compound represented by Formula 1 may be in the following range:

m 및 n은 각각 독립적으로 1이고;m and n are each independently 1;

고리 A는 아릴, 헤테로아릴, 또는 아무 것도 아니고(null) {여기서, 상기 아릴 또는 헤테로아릴의 하나 이상의 H는 -C1-4알킬, 또는 할로로 치환될 수 있음};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};

고리 B는 아릴, 헤테로아릴, 또는 헤테로사이클로알킬이고 {여기서, 상기 아릴 또는 헤테로아릴의 하나 이상의 H는 -C1-4알킬, -C1-4할로알킬, -CN, -OR3, 또는 할로로 치환될 수 있고; 상기 헤테로사이클로알킬의 하나 이상의 H는 -C1-4알킬 또는 -할로로 치환될 수 있음};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};

X는 -NH- 또는 -O-이고;X is -NH- or -O-;

L1은 -(CH2)a-, -C(=O)-, -C(=O)NH-, -S(=O)2-, 또는 아무 것도 아니고(null) {여기서, 상기 -(CH2)a-의 하나 이상의 H는 -C1-4알킬, -C1-4할로알킬, 또는 할로로 치환될 수 있음}; 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};

L2는 -(CH2)b- 또는 -C(=O)- 이고 {여기서, 상기 -(CH2)b-의 하나 이상의 H는 -C1-4알킬, -C1-4할로알킬, 또는 할로로 치환될 수 있음}; 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 및 b는 각각 독립적으로 1이고;a and b are each independently 1;

Y는 아릴이고 {여기서, 상기 아릴의 하나 이상의 H는 -H, -C1-4알킬, -NR1R2, -OR3, 또는 -할로로 치환될 수 있음};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};

Z는 사이클로알킬이고 {여기서, 상기 사이클로알킬의 하나 이상의 H는 -H, -C1-4알킬, -C1-4할로알킬, 또는 -할로로 치환될 수 있음};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};

R1 및 R2는 각각 독립적으로 -H 또는 -C1-4알킬이고;R 1 and R 2 are each independently —H or —C 1-4 alkyl;

R3는 -H, -C1-4알킬이고, 또는 -C1-4할로알킬이다.R 3 is —H, —C 1-4 alkyl, or —C 1-4 haloalkyl.

또한, 본 발명의 구체예에 따르면, 상기 화학식 1로 표시되는 화합물이 하기 범위일 수 있다:In addition, according to an embodiment of the present invention, the compound represented by Formula 1 may be in the following range:

상기 화학식 1로 표시되는 화합물은 하기 화학식 2로 표시되는 화합물이고;The compound represented by Formula 1 is a compound represented by Formula 2 below;

[화학식 2][Formula 2]

Figure pat00002
Figure pat00002

상기 화학식 2에서,In Formula 2,

고리 A는 6-10원 아릴, 5-6원 헤테로아릴, 또는 아무 것도 아니고(null) {여기서, 상기 5-6원 헤테로아릴은 고리 내에 N, O, 또는 S 원자 중 1 이상을 포함하고, 상기 6-10원 아릴 또는 5-6원 헤테로아릴의 하나 이상의 H는 -C1-4알킬 또는 할로로 치환될 수 있음};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};

고리 B는 6-10원 아릴, 5-10원 헤테로아릴, 또는 4-7원 헤테로사이클로알킬이고 {여기서, 상기 5-10원 헤테로아릴 및 4-7원 헤테로사이클로알킬은 고리 내에 N, O, 또는 S 원자 중 1 이상을 포함하고, 상기 6-10원 아릴 또는 5-10원 헤테로아릴의 하나 이상의 H는 -C1-4알킬, -C1-4할로알킬, -CN, -OR3, 또는 할로로 치환될 수 있고; 상기 4-7원 헤테로사이클로알킬의 하나 이상의 H는 -C1-4알킬 또는 -할로로 치환될 수 있음};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};

X는 -NH- 또는 -O-이고;X is -NH- or -O-;

L1은 -(CH2)a-, -C(=O)-, -C(=O)NH-, -S(=O)2-, 또는 아무 것도 아니고(null) {여기서, 상기 -(CH2)a-의 하나 이상의 H는 -C1-4알킬, -C1-4할로알킬, 또는 할로로 치환될 수 있음}; 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};

L2는 -(CH2)b- 또는 -C(=O)- 이고 {여기서, 상기 -(CH2)b-의 하나 이상의 H는 -C1-4알킬, -C1-4할로알킬, 또는 할로로 치환될 수 있음}; 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 및 b는 각각 독립적으로 1이고;a and b are each independently 1;

Y1 및 Y2는 각각 독립적으로 -H, -C1-4알킬, -NR1R2, -OR3, 또는 -할로이고;Y 1 and Y 2 are each independently —H, —C 1-4 alkyl, —NR 1 R 2 , —OR 3 , or —halo;

R1 및 R2는 각각 독립적으로 -H 또는 -C1-4알킬이고;R 1 and R 2 are each independently —H or —C 1-4 alkyl;

R3는 -H, -C1-4알킬이고, 또는 -C1-4할로알킬이다.R 3 is —H, —C 1-4 alkyl, or —C 1-4 haloalkyl.

본 발명의 구체예에 따르면, 상기 화학식 1로 표시되는 화합물이 하기에 기재된 화합물로 이루어진 군으로부터 선택된 것일 수 있다: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-사이클로프로필-3-(2,6-다이클로로페닐)아이소옥사졸-4-일)메틸)-8-아자바이사이클로[3.2.1]옥탄-3-일)옥시)메틸)벤조산;(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-사이클로프로필-3-(2,6-다이클로로페닐)아이소옥사졸-4-일)-메틸)-8-아자바이사이클로[3.2.1]옥탄-3-일)옥시)메틸)페닐)니코틴산;(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-사이클로프로필-3-(2,6-다이클로로페닐)아이소옥사졸-4-일)메틸)-8-아자바이사이클로[3.2.1]옥탄-3-일)옥시)메틸)-6-플루오로-[1,1'-바이페닐]-3-카르복실산;(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-사이클로프로필-3-(2,6-다이클로로페닐)아이소옥사졸-4-일)메틸)-8-아자바이사이클로[3.2.1]옥탄-3-일)옥시)메틸)-4-메틸-[1,1'-바이페닐]-3-카르복실산;(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-사이클로프로필-3-(2,6-다이클로로페닐)아이소옥사졸-4-일)메틸)-8-아자바이사이클로[3.2.1]옥탄-3-일)옥시)메틸)-6-메틸-[1,1'-바이페닐]-3-카르복실산;(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-사이클로프로필-3-(2,6-다이클로로페닐)아이소옥사졸-4-일)메틸)-8-아자바이사이클로[3.2.1]옥탄-3-일)옥시)메틸)-5-플루오로-[1,1'-바이페닐]-3-카르복실산;(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-클로로-4'-((((1R,3R,5S)-8-((5-사이클로프로필-3-(2,6-다이클로로페닐)아이소옥사졸-4-일)메틸)-8-아자바이사이클로[3.2.1]옥탄-3-일)옥시)메틸)-[1,1'-바이페닐]-3-카르복실산;(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-사이클로프로필-3-(2,6-다이클로로페닐)아이소옥사졸-4-일)메틸)-8-아자바이사이클로[3.2.1]옥탄-3-일)옥시)메틸)-2'-메틸-[1,1'-바이페닐]-4-카르복실산;(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-사이클로프로필-3-(2,6-다이클로로페닐)아이소옥사졸-4-일)메틸)-8-아자바이사이클로[3.2.1]옥탄-3-일)옥시)메틸)-2'-메틸-[1,1'-바이페닐]-3-카르복실산;(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-시아노-4'-((((1R,3R,5S)-8-((5-사이클로프로필-3-(2,6-다이클로로페닐)아이소옥사졸-4-일)메틸)-8-아자바이사이클로[3.2.1]옥탄-3-일)옥시)메틸)-[1,1'-바이페닐]-3-카르복실산;(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-사이클로프로필-3-(2,6-다이클로로페닐)아이소옥사졸-4-일)메틸)-8-아자바이사이클로[3.2.1]옥탄-3-일)옥시)메틸)-2-플루오로-[1,1'-바이페닐]-3-카르복실산;(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-사이클로프로필-3-(2,6-다이클로로페닐)아이소옥사졸-4-일)메틸)-8-아자바이사이클로[3.2.1]옥탄-3-일)옥시)메틸)피리딘-3-일)벤조산;(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-사이클로프로필-3-(2,6-다이클로로페닐)아이소옥사졸-4-일)메틸)-8-아자바이사이클로[3.2.1]옥탄-3-일)옥시)메틸)-2-메틸페닐)푸란-2-카르복실산;(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-사이클로프로필-3-(2,6-다이클로로페닐)아이소옥사졸-4-일)메틸)-8-아자바이사이클로[3.2.1]옥탄-3-일)옥시)메틸)-6-플루오로-5-메틸-[1,1'-바이페닐]-3-카르복실산;(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-사이클로프로필-3-(2-(트리플루오로메톡시)페닐)아이소옥사졸-4-일)메틸)-8-아자바이사이클로[3.2.1]옥탄-3-일)옥시)메틸)-2-메틸페닐)푸란-2-카르복실산;(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-사이클로프로필-3-(2,6-다이클로로페닐)아이소옥사졸-4-일)메틸)-8-아자바이사이클로[3.2.1]옥탄-3-일)옥시)메틸)피리딘-3-일)푸란-2-카르복실산;(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-사이클로프로필-3-(2,6-다이클로로페닐)아이소옥사졸-4-일)메틸)-8-아자바이사이클로[3.2.1]옥탄-3-일)옥시)메틸)피리딘-2-일)벤조산;(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-사이클로프로필-3-(2,6-다이클로로페닐)아이소옥사졸-4-일)메틸)-8-아자바이사이클로[3.2.1]옥탄-3-일)옥시)메틸)페닐)푸란-2-카르복실산;(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-사이클로프로필-3-(2,6-다이클로로페닐)아이소옥사졸-4-일)메틸)-8-아자바이사이클로[3.2.1]옥탄-3-일)옥시)메틸)페닐)푸란-2-카르복실산;(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-사이클로프로필-3-(2,6-다이클로로페닐)아이소옥사졸-4-일)메틸)-8-아자바이사이클로[3.2.1]옥탄-3-일)옥시)메틸)페닐)티오펜-2-카르복실산;(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-사이클로프로필-3-(2,6-다이클로로페닐)아이소옥사졸-4-일)메틸)-8-아자바이사이클로[3.2.1]옥탄-3-일)옥시)메틸)페닐)옥사졸-5-카르복실산;(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-사이클로프로필-3-(2,6-다이클로로페닐)아이소옥사졸-4-일)메틸)-8-아자바이사이클로[3.2.1]옥탄-3-일)옥시)메틸)페닐)-1-메틸-1H-피라졸-5-카르복실산;(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-사이클로프로필-3-(2,6-다이클로로페닐)아이소옥사졸-4-일)메틸)-8-아자바이사이클로[3.2.1]옥탄-3-일)옥시)메틸)-[1,1'-바이페닐]-2-카르복실산);(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-사이클로프로필-3-(2,6-다이클로로페닐)아이소옥사졸-4-일)메틸)-8-아자바이사이클로[3.2.1]옥탄-3-일)옥시)메틸)-[1,1'-바이페닐]-2-카르복실산;(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-사이클로프로필-3-(2,6-다이클로로페닐)아이소옥사졸-4-일)메틸)-8-아자바이사이클로[3.2.1]옥탄-3-일)옥시)메틸)-[1,1'-바이페닐]-4-카르복실산;(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-사이클로프로필-3-(2,6-다이클로로페닐)아이소옥사졸-4-일)메틸)-8-아자바이사이클로[3.2.1]옥탄-3-일)옥시)메틸)-[1,1'-바이페닐]-4-카르복실산;(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-사이클로프로필-3-(2,6-다이클로로 페닐)아이소옥사졸-4-일)메틸)-8-아자바이사이클로[3.2.1]옥탄-3-일)옥시)메틸)-4-플루오로-[1,1'-바이페닐]-3-카르복실산;(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-사이클로프로필-3-(2,6-다이클로로페닐)아이소옥사졸-4-일)메틸)-8-아자바이사이클로[3.2.1]옥탄-3-일)옥시)메틸)-3-플루오로-[1,1'-바이페닐]-4-카르복실산;(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-사이클로프로필-3-(2,6-다이클로로페닐)아이소옥사졸-4-일)메틸)-8-아자바이사이클로[3.2.1]옥탄-3-일)옥시)메틸)페닐)피리미딘-2-카르복실산;(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-사이클로프로필-3-(2,6-다이클로로페닐)아이소옥사졸-4-일)메틸)-8-아자바이사이클로[3.2.1]옥탄-3-일)옥시)메틸)-2-플루오로-[1,1'-바이페닐]-4-카르복실산;(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-사이클로프로필-3-(2,6-다이클로로페닐)아이소옥사졸-4-일)메틸)-8-아자바이사이클로[3.2.1]옥탄-3-일)옥시)메틸)-3'-플루오로-[1,1'-바이페닐]-4-카르복실산;(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-사이클로프로필-3-(2,6-다이클로로페닐)아이소옥사졸-4-일)메틸)-8-아자바이사이클로[3.2.1]옥탄-3-일)옥시)메틸)-[1,1'-바이페닐]-4-카르복실산;(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-사이클로프로필-3-(2,6-다이클로로페닐)아이소옥사졸-4-일)메틸)-8-아자바이사이클로[3.2.1]옥탄-3-일)옥시)메틸)-[1,1'-바이페닐]-3-카르복실산;(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-사이클로프로필-3-(2,6-다이클로로페닐)아이소옥사졸-4-일)메틸)-8-아자바이사이클로[3.2.1]옥탄-3-일)옥시)메틸)-[1,1'-바이페닐]-2-카르복실산;(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-사이클로프로필-3-(2,6-다이클로로페닐)아이소옥사졸-4-일)메틸)-8-아자바이사이클로[3.2.1]옥탄-3-일)옥시)메틸)-3'-플루오로-[1,1'-바이페닐]-2-카르복실산;(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-사이클로프로필-3-(2,6-다이클로로페닐)아이소옥사졸-4-일)메틸)-8-아자바이사이클로[3.2.1]옥탄-3-일)옥시)메틸)-3'-플루오로-[1,1'-바이페닐]-3-카르복실산;(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-사이클로프로필-3-(2,6-다이클로로페닐)아이소옥사졸-4-일)메틸)-8-아자바이사이클로[3.2.1]옥탄-3-일)옥시)메틸)-5-플루오로-[1,1'-바이페닐]-2-카르복실산;(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-클로로-4'-((((1R,3R,5S)-8-((5-사이클로 프로필-3-(2,6-다이클로로페닐)아이소옥사졸-4-일)메틸)-8-아자바이사이클로[3.2.1]옥탄-3-일)옥시)메틸)-[1,1'-바이페닐]-2-카르복실산;(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-클로로-4'-((((1R,3S,5S)-8-((5-사이클로프로필-3-(2,6-다이클로로페닐)아이소옥사졸-4-일)메틸)-8-아자바이사이클로[3.2.1]옥탄-3-일)옥시)메틸)-[1,1'-바이페닐]-2-카르복실산;(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-사이클로프로필-3-(2,6-다이클로로페닐)아이소옥사졸-4-일)메틸)-8-아자바이사이클로[3.2.1]옥탄-3-일)옥시)메틸)-3-(트리플루오로메틸)-[1,1'-바이페닐]-2-카르복실산;(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-사이클로프로필-3-(2,6-다이클로로페닐)아이소옥사졸-4-일)메틸)-8-아자바이사이클로[3.2.1]옥탄-3-일)옥시)메틸)-4-플루오로-[1,1'-바이페닐]-2-카르복실산;(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-사이클로프로필-3-(2,6-다이클로로페닐)아이소옥사졸-4-일)메틸)-8-아자바이사이클로[3.2.1]옥탄-3-일)옥시)메틸)페닐)아제티딘-3-카르복실산;(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-사이클로프로필-3-(2,6-다이클로로페닐)아이소옥사졸-4-일)메틸)-8-아자바이사이클로[3.2.1]옥탄-3-일)옥시)메틸)-3'-메틸-[1,1'-바이페닐]-2-카르복실산;(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-사이클로프로필-3-(2,6-다이클로로페닐)아이소옥사졸-4-일)메틸)-8-아자바이사이클로[3.2.1]옥탄-3-일)옥시)메틸)-[1,1'-바이페닐]-3-카르복실산;(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-사이클로프로필-3-(2,6-다이클로로페닐)아이소옥사졸-4-일)메틸)-8-아자바이사이클로[3.2.1]옥탄-3-일)옥시)메틸)-3'-메틸-[1,1'-바이페닐]-3-카르복실산;(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-사이클로프로필-3-(2,6-다이클로로페닐)아이소옥사졸-4-일)메틸)-8-아자바이사이클로[3.2.1]옥탄-3-일)옥시)메틸)-1-나프토산;(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-사이클로프로필-3-(2,6-다이클로로페닐)아이소옥사졸-4-일)메틸)-8-아자바이사이클로[3.2.1]옥탄-3-일)옥시)메틸)페닐)-1H-피롤-2-카르복실산;(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-사이클로프로필-3-(2,6-다이클로로페닐)아이소옥사졸-4-일)메틸)-8-아자바이사이클로[3.2.1]옥탄-3-일)옥시)메틸)피리딘-2-일)벤조산;(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-사이클로프로필-3-(2,6-다이클로로페닐)아이소옥사졸-4-일)메틸)-8-아자바이사이클로[3.2.1]옥탄-3-일)옥시)메틸)피리딘-2-일)벤조산;(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-사이클로프로필-3-(2,6-다이클로로페닐)아이소옥사졸-4-일)메틸)-8-아자바이사이클로[3.2.1]옥탄-3-일)옥시)메틸)페닐)니코틴산;(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-사이클로프로필-3-(2,6-다이클로로페닐)아이소옥사졸-4-일)메틸)-8-아자바이사이클로[3.2.1]옥탄-3-일)옥시)메틸)페닐)니코틴산;(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-사이클로프로필-3-(2,6-다이클로로페닐)아이소옥사졸-4-일)메틸)-8-아자바이사이클로[3.2.1]옥탄-3-일)옥시)메틸)페닐)아이소니코틴산;(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-사이클로프로필-3-(2,6-다이클로로페닐)아이소옥사졸-4-일)메틸)-8-아자바이사이클로[3.2.1]옥탄-3-일)옥시)메틸)페닐)푸란-2-카르복실산;(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-사이클로프로필-3-(2,6-다이클로로페닐)아이소옥사졸-4-일)메틸)-8-아자바이사이클로[3.2.1]옥탄-3-일)옥시)메틸)페닐)푸란-2-카르복실산;(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-사이클로프로필-3-(2,6-다이클로로페닐)아이소옥사졸-4-일)메틸)-8-아자바이사이클로[3.2.1]옥탄-3-일)옥시)메틸)페닐)피콜린산;(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-사이클로프로필-3-(2,6-다이클로로페닐)아이소옥사졸-4-일)메틸)-8-아자바이사이클로[3.2.1]옥탄-3-일)옥시)메틸)피리딘-2-일)푸란-2-카르복실산;(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-사이클로프로필-3-(2,6-다이클로로페닐)아이소옥사졸-4-일)메틸)-8-아자바이사이클로[3.2.1]옥탄-3-일)옥시)메틸)-3-플루오로페닐)푸란-2-카르복실산;(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-사이클로프로필-3-(2,6-다이클로로페닐)아이소옥사졸-4-일)메틸)-8-아자바이사이클로[3.2.1]옥탄-3-일)옥시)메틸)페닐)-2-메틸티오펜-3-카르복실산;(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-사이클로프로필-3-(2,6-다이클로로페닐)아이소옥사졸-4-일)메틸)-8-아자바이사이클로[3.2.1]옥탄-3-일)옥시)메틸)나프탈렌-1-일)푸란-2-카르복실산;(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-사이클로프로필-3-(2,6-다이클로로페닐)아이소옥사졸-4-일)메틸)-8-아자바이사이클로[3.2.1]옥탄-3-일)옥시)메틸)나프탈렌-1-일)벤조산;(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-사이클로프로필-3-(2,6-다이클로로페닐)아이소옥사졸-4-일)메틸)-8-아자바이사이클로[3.2.1]옥탄-3-일)옥시)메틸)-4-메톡시-[1,1'-바이페닐]-3-카르복실산;(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-사이클로프로필-3-(2,6-다이클로로페닐)아이소옥사졸-4-일)메틸)-8-아자바이사이클로[3.2.1]옥탄-3-일)옥시)메틸)-3-메틸페닐)푸란-2-카르복실산;(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-사이클로프로필-3-(2,6-다이클로로페닐)아이소옥사졸-4-일)메틸)-8-아자바이사이클로[3.2.1]옥탄-3-일)옥시)메틸)나프탈렌-1-일)푸란-2-카르복실산;(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-사이클로프로필-3-(2-(트리플루오로메톡시)페닐)아이소옥사졸-4-일)메틸)-8-아자바이사이클로[3.2.1]옥탄-3-일)옥시)메틸)-3-플루오로페닐)푸란-2-카르복실산;(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-사이클로프로필-3-(2,6-다이클로로페닐)아이소옥사졸-4-일)메틸)-8-아자바이사이클로[3.2.1]옥탄-3-일)옥시)플루오로메틸)-[1,1'-바이페닐]-3-카르복실산;(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-사이클로프로필-3-(2,6-다이클로로페닐)아이소옥사졸-4-일)메틸)-8-아자바이사이클로[3.2.1]옥탄-3-일)옥시)플루오로메틸)페닐)푸란-2-카르복실산;(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-사이클로프로필-3-(2,6-다이클로로페닐)아이소옥사졸-4-일)메틸)-8-아자바이사이클로[3.2.1]옥탄-3-일)아미노)벤조[d]티아졸-6-카르복실산;(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-사이클로프로필-3-(2,6-다이클로로페닐)아이소옥사졸-4-일)메틸)-8-아자바이사이클로[3.2.1]옥탄-3-일)아미노)벤조[d]티아졸-6-카르복실산;(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-사이클로프로필-3-(2,6-다이클로로페닐)아이소옥사졸-4-일)메틸)-8-아자바이사이클로[3.2.1]옥탄-3-일)아미노)-2-나프토산;(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-사이클로프로필-3-(2,6-다이클로로페닐)아이소옥사졸-4-일)메틸)-8-아자바이사이클로[3.2.1]옥탄-3-일)아미노)-[1,1'-바이페닐]-4-카르복실산 (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-사이클로프로필-3-(2,6-다이클로로페닐)아이소옥사졸-4-일)메틸)-8-아자바이사이클로[3.2.1]옥탄-3-일)아미노)메틸)-[1,1'-바이페닐]-2-카르복실산;(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-사이클로프로필-3-(2,6-다이클로로페닐)아이소옥사졸-4-일)메틸)-8-아자바이사이클로[3.2.1]옥탄-3-일)아미노)메틸)-[1,1'-바이페닐]-2-카르복실산;(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-사이클로프로필-3-(2,6-다이클로로페닐)아이소옥사졸-4-일)메틸)-8-아자바이사이클로[3.2.1]옥탄-3-일)설파모일)벤조산;(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-사이클로프로필-3-(2,6-다이클로로페닐)아이소옥사졸-4-일)메틸)-8-아자바이사이클로[3.2.1]옥탄-3-일) 설파모일)벤조산;(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-사이클로프로필-3-(2,6-다이클로로페닐)아이소옥사졸-4-일)메틸)-8-아자바이사이클로[3.2.1]옥탄-3-일)카르바모일)피리딘-3-일)벤조산;(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-사이클로프로필-3-(2,6-다이클로로페닐)아이소옥사졸-4-일)메틸)-8-아자바이사이클로[3.2.1]옥탄-3-일) 카르바모일)벤조산;(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-사이클로프로필-3-(2,6-다이클로로페닐)아이소옥사졸-4-일)메틸)-8-아자바이사이클로[3.2.1]옥탄-3-일)우레이도)-[1,1'-바이페닐]-4-카르복실산;(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-사이클로프로필-3-(2,6-다이클로로페닐)아이소옥사졸-4-일)메틸)-8-아자바이사이클로[3.2.1]옥탄-3-일)우레이도)벤조산;(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-사이클로프로필-3-(2,6-다이클로로페닐)아이소옥사졸-4-카르보닐)-8-아자바이사이클로[3.2.1]옥탄-3-일)옥시)메틸)-[1,1'-바이페닐]-4-카르복실산;(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-사이클로프로필-3-(2,6-다이클로로페닐)아이소옥사졸-4-카르보닐)-8-아자바이사이클로[3.2.1]옥탄-3-일)옥시)메틸)-[1,1'-바이페닐]-4-카르복실산;(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-사이클로프로필-3-(2,6-다이클로로페닐) 아이소옥사졸-4-카르보닐)-8-아자바이사이클로[3.2.1]옥탄-3-일)옥시)메틸)페닐)피리미딘-2-카르복실산;(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-사이클로프로필-3-(2,6-다이클로로페닐)아이소옥사졸-4-카르보닐)-8-아자바이사이클로[3.2.1]옥탄-3-일)옥시)메틸)-[1,1'-바이페닐]-2-카르복실산;(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-사이클로프로필-3-(2,6-다이클로로페닐)아이소옥사졸-4-카르보닐)-8-아자바이사이클로[3.2.1]옥탄-3-일)옥시)메틸)-4-플루오로-[1,1'-바이페닐]-3-카르복실산;(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-사이클로프로필-3-(2,6-다이클로로페닐)아이소옥사졸-4-카르보닐)-8-아자바이사이클로[3.2.1]옥탄-3-일)옥시)메틸)-3-플루오로-[1,1'-바이페닐]-4-카르복실산; 및(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-사이클로프로필-3-(2,6-다이클로로페닐)아이소옥사졸-4-카르보닐)-8-아자바이사이클로[3.2.1]옥탄-3-일)옥시)메틸)페닐)이소니코틴산.(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.

본 발명에 있어서, "알킬"은, 다른 기재가 없는 한, 직쇄 또는 분지쇄의 비고리형, 고리형 또는 이들이 결합된 포화 탄화수소를 의미할 수 있다. 예를 들어, "C1-4알킬"은 탄소 원자를 1 내지 4 개 포함하는 알킬을 의미할 수 있다. 비고리형 알킬은, 일 예로서, 메틸, 에틸, n-프로필, n-부틸, 아이소프로필, 2 급(sec)-부틸, 아이소부틸, 또는 3 급(tert)-부틸 등을 포함할 수 있으나, 이에 제한되지 않는다. 고리형 알킬은 본 명세서에서 "사이클로알킬"과 교환적으로 사용될 수 있으며, 일 예로서, 사이클로프로필, 사이클로부틸, 사이클로펜틸, 사이클로헥실, 사이클로헵틸, 또는 사이클로옥틸 등을 포함할 수 있으나, 이에 제한되지 않는다. 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

본 발명에 있어서, "알콕시"는 알킬 에터기로 -(O-알킬)을 의미할 수 있고, 여기서, 알킬은 상기에서 정의된 바와 같다. 예를 들어, "C1-4의 알콕시"는 C1-4의 알킬을 함유하는 알콕시, 즉, -(O-C1-4알킬)을 의미할 수 있으며, 일 예로서, 알콕시는 메톡시(methoxy), 에톡시(ethoxy), n-프로폭시(n-propoxy), 아이소프로폭시(isopropoxy), n-부톡시(n-butoxy), 아이소부톡시(isobutoxy), sec-부톡시(sec-butoxy), 또는 tert-부톡시(tert-butoxy) 등을 포함할 수 있으나, 이에 제한되는 것은 아니다.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.

본 발명에 있어서, "할로"는 F, Cl, Br, 또는 I일 수 있다.In the present invention, "halo" may be F, Cl, Br, or I.

본 발명에 있어서, "할로알킬"은 본원에 정의된 바와 같은 하나 이상의 할로로 치환된 탄소 원자를 갖는 직쇄 또는 분지쇄 알킬(탄화수소)을 의미할 수 있다. 상기 할로알킬의 예로는 하나 이상의 할로겐, 예를 들어 F, Cl, Br, 또는 I로 독립적으로 치환된 메틸, 에틸, 프로필, 아이소프로필, 아이소부틸 또는 n-부틸을 포함하나, 이에 한정되는 것은 아니다.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. .

본 발명에 있어서, "아미노알킬"은 아미노(NR'R")로 치환된 탄소 원자를 갖는 직쇄 또는 분지쇄 알킬(탄화수소)을 의미할 수 있다. 여기서, R' 및 R"은 각각 독립적으로 수소, 및 C1-4알킬로 이루어진 군으로부터 선택될 수 있으며, 상기 선택된 R'및 R"은 각각 독립적으로 치환되거나 비치환될 수 있다.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.

본 발명에 있어서, "시아노알킬"은 시아노(CN)로 치환된 탄소 원자를 갖는 직쇄 또는 분지쇄 알킬(탄화수소)을 의미할 수 있다. In the present invention, "cyanoalkyl" may mean a straight or branched chain alkyl (hydrocarbon) having a carbon atom substituted with cyano (CN).

본 발명에 있어서, "하이드록시알킬"은 하이드록시(OH)로 치환된 탄소 원자를 갖는 직쇄 또는 분지쇄 알킬(탄화수소)을 의미할 수 있다. In the present invention, "hydroxyalkyl" may mean a straight-chain or branched alkyl (hydrocarbon) having a carbon atom substituted with hydroxy (OH).

본 발명에 있어서, "헤테로사이클로알킬"은 고리를 형성하는 원자로 N, O 및 S로부터 선택된 1 내지 5 개의 헤테로 원자를 함유하는 고리를 의미할 수 있고, 포화 또는 부분적으로 불포화될 수 있다. 여기서, 불포화된 경우, 헤테로사이클로알켄으로 지칭될 수 있다. 달리 언급하지 않는 한, 헤테로사이클로알킬은 단일 고리이거나, 스파이로(spiro) 고리, 다리(bridged) 고리 또는 융합(fused) 고리와 같은 다중 고리일 수 있다. 또한, "3 내지 12원 헤테로사이클로알킬"은 고리를 형성하는 원자를 3 내지 12 개 포함하는 헤테로사이클로알킬을 의미할 수 있으며, 일 예로서, 헤테로사이클로알킬은 피롤리딘, 피페리딘, 이미다졸리딘, 피라졸리딘, 부티로락탐, 발레로락탐, 이미다졸리딘온, 하이단토인, 다이옥솔란, 프탈이미드, 피페리딘, 피리미딘-2,4(1H,3H)-다이온, 1,4-다이옥산, 모르폴린, 싸이오모르폴린, 싸이오모르폴린-S-옥사이드, 싸이오모르폴린-S,S-옥사이드, 피페라진, 피란, 피리돈, 3-피롤린, 싸이오오피란, 피론, 테트라하이드로퓨란, 테트라하이드로싸이오펜, 퀴누클리딘, 트로판, 2-아자스파이로[3.3]헵탄, (1R,5S)-3-아자바이사이클로[3.2.1]옥탄, (1s,4s)-2-아자바이사이클로[2.2.2]옥탄, 또는 (1R,4R)-2-옥사-5-아자바이사이클로[2.2.2]옥탄 등을 포함할 수 있으나, 이에 제한되는 것은 아니다.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.

본 발명에 있어서, "아렌"은 방향족 탄화수소 고리를 의미할 수 있다. 아렌은 단환식 아렌 또는 다환식 아렌일 수 있다. 아렌의 고리 형성 탄소수는 5 이상 30 이하, 5 이상 20 이하, 또는 5 이상 15 이하일 수 있다. 아렌의 예로는 벤젠, 나프탈렌, 플루오렌, 안트라센, 페난트렌, 터벤젠, 쿼터벤젠, 퀸크벤젠, 섹시벤젠, 트라이페닐렌, 피렌, 벤조 플루오란텐, 크리센 등을 예시할 수 있지만, 이들에 한정되지 않는다. 본 명세서에서 상기 "아렌"에서 수소 원자 하나를 제거한 잔기를 "아릴"로 지칭한다.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".

본 발명에 있어서, "헤테로아렌"은 이종 원소로 O, N, P, Si, 및 S 중 1 개 이상을 포함하는 방향족 고리일 수 있다. 헤테로아렌의 고리 형성 탄소수는 2 이상 30 이하 또는 2 이상 20 이하일 수 있다. 헤테로아렌은 단환식 헤테로아렌 또는 다환식 헤테로아렌일 수 있다. 다환식 헤테로아렌은 예를 들어, 2 환 또는 3 환 구조를 갖는 것일 수 있다. 헤테로아렌의 예로는 싸이오펜, 퓨린, 피롤, 피라졸, 이미다졸, 싸이아졸, 옥사졸, 아이소싸이아졸, 옥사다이아졸, 트라이아졸, 피리딘, 트라이아진, 아크리딜, 피리다진, 피라진, 퀴놀린, 퀴나졸린, 퀴녹살린, 페녹사진, 프탈라진, 피리미딘, 피리도 피리미딘, 피리도 피라진, 피라지노 피라진, 아이소퀴놀린, 인돌, 카바졸, 이미다조피리다진, 이미다조피리딘, 이미다조피리미딘, 피라졸로피리미딘, 이미다조피라진, 피라졸로피리딘, N-아릴카바졸, N-헤테로아릴카바졸, N-알킬카바졸, 벤조옥사졸, 벤조이미다졸, 벤조싸이아졸, 벤조카바졸, 벤조싸이오펜, 다이벤조싸이오펜, 싸이에노싸이오펜, 벤조퓨란, 페난트롤린, 아이소옥사졸, 옥사다이아졸, 싸이아다이아졸, 벤조싸이아졸, 테트라졸, 페노싸이아진, 다이벤조실롤, 다이벤조퓨란 등이 있으나, 이들에 한정되지 않는다. 본 명세서에서 상기 "헤테로아렌"에서 수소 원자 하나를 제거한 잔기를 "헤테로아릴"로 지칭한다.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".

본 발명에 있어서, 용어 "광학 이성질체(enantiomer)"는 동일한 화학식 또는 분자식을 가지지만 입체적으로 다른 본 발명의 화합물 또는 그것의 염을 의미한다. 이러한 각각의 광학 이성질체 및 그것의 혼합물들 역시 본 발명의 범위에 포함된다. 다른 설명이 없는 한, 비대칭 탄소 원자와 연결되는 실선 결합 (-)은 입체 중심의 절대적 배열을 나타내는 쐐기형 실선 결합

Figure pat00003
또는 쐐기형 점선 결합
Figure pat00004
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.
Figure pat00003
or wedge-dotted join
Figure pat00004
may include.

본 발명의 화학식 1의 화합물은 "약학적으로 허용가능한 염"의 형태로 존재할 수 있다. 염으로는 약학적으로 허용가능한 유리산(free acid)에 의해 형성된 산부가염이 유용하다. 본 발명의 용어 "약학적으로 허용가능한 염"이란 환자에게 비교적 비독성이고 무해한 유효작용을 갖는 농도로서 이 염에 기인한 부작용이 화학식 1로 표시되는 화합물의 이로운 효능을 저하시키지 않는 상기 화합물의 임의의 모든 유기산 또는 무기산 부가염을 의미한다.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

산부가염은 통상의 방법, 예를 들어 화합물을 과량의 산 수용액에 용해시키고, 이 염을 수혼화성 유기 용매, 예를 들어 메탄올, 에탄올, 아세톤 또는 아세토나이트릴을 사용하여 침전시켜서 제조한다. 동 몰량의 화합물 및 물 중의 산 또는 알코올을 가열하고, 이어서 상기 혼합물을 증발시켜 건조시키거나, 또는 석출된 염을 흡인 여과시킬 수 있다.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.

이때, 유리산으로는 유기산과 무기산을 사용할 수 있으며, 무기산으로는 염산, 인산, 황산, 또는 질산 등을 사용할 수 있고 유기산으로는 메테인설폰산, p-톨루엔설폰산, 아세트산, 트라이플루오로아세트산, 말레인산(maleic acid), 숙신산, 옥살산, 벤조산, 타르타르산, 푸마르산(fumaric acid), 만데르산, 프로피온산(propionic acid), 구연산(citric acid), 젖산(lactic acid), 글리콜산(glycollic acid), 글루콘산(gluconic acid), 갈락투론산, 글루탐산, 글루타르산(glutaric acid), 글루쿠론산(glucuronic acid), 아스파르트산, 아스코르브산, 카본산, 바닐릭산, 또는 아이오딘화수소산(hydroiodic acid) 등을 사용할 수 있다. 다만, 이들에 제한되지 않는다.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.

또한, 염기를 사용하여 약학적으로 허용가능한 금속염을 만들 수 있다. 알칼리 금속염 또는 알칼리 토금속염은, 예를 들어 화합물을 과량의 알칼리 금속 수산화물 또는 알칼리 토금속 수산화물 용액 중에 용해시키고, 비용해 화합물 염을 여과한 후 여액을 증발, 건조시켜 얻는다. 이때, 금속염으로는 특히 나트륨, 칼륨, 또는 칼슘염을 제조하는 것이 제약상 적합하나 이들에 제한되는 것은 아니다. 또한 이에 대응하는 은염은 알칼리 금속 또는 알칼리 토금속 염을 적당한 은염(예, 질산은)과 반응시켜 얻을 수 있다.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).

본 발명의 약학적으로 허용가능한 염은, 달리 지시되지 않는 한, 상기 화학식 1의 화합물에 존재할 수 있는 산성 또는 염기성 기의 염을 포함한다. 예를 들어, 약학적으로 허용가능한 염으로는 하이드록시기의 나트륨, 칼슘 및 칼륨염 등이 포함될 수 있고, 아미노기의 기타 약학적으로 허용가능한 염으로는 하이드로브롬화물, 황산염, 수소 황산염, 인산염, 수소 인산염, 이수소 인산염, 아세테이트, 숙시네이트, 시트레이트, 타르트레이트, 락테이트, 만델레이트, 메테인설포네이트(메실레이트), 및 p-톨루엔설포네이트(토실레이트) 염 등이 있으며, 당업계에 알려진 염의 제조방법을 통하여 제조될 수 있다.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.

아자바이사이클로알킬 유도체 화합물의 용도Use of Azabicycloalkyl Derivative Compounds

본 발명은 하기 화학식 1로 표시되는 화합물, 이의 광학 이성질체, 또는 이들의 약학적으로 허용가능한 염의 용도를 제공한다.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.

[화학식 1][Formula 1]

Figure pat00005
Figure pat00005

상기 화학식 1은 위에서 정의한 바와 같다.Formula 1 is as defined above.

본 발명의 화학식 1로 표시되는 화합물, 이의 광학 이성질체, 또는 이들의 약학적으로 허용가능한 염은 FXR 작용제 활성을 나타내므로, FXR에 의해 매개되는 간 질환에 대하여 치료 또는 예방에 유용하게 사용될 수 있다. 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.

본 발명에 있어서, 상기 FXR에 의해 매개되는 간 질환은 담즙 정체증, 간내 담즙 정체증, 에스트로겐-유발성 담즙 정체증, 약물-유발성 담즙 정체증, 임신시 담즙 정체증, 비경구 영양-관련 담즙 정체증, 원발성 담즙성 간경변(PBC), 원발성 경화성 담관염(PSC), 진행성 가족성 담즙 정체증(PFIC), 비알코올성 지방간 질환(NAFLD), 비알코올성 지방간염(NASH), 약물-유발성 담관 손상, 담석, 간경화, 알코올-유발성 간경변, 낭성 섬유증-관련 간질환(CFLD), 담관폐쇄, 담석증, 및 간 섬유증으로 이루어진 군으로부터 선택된 1 이상일 수 있다. 보다 구체적으로, 상기 FXR에 의해 매개되는 간 질환은 원발성 담즙성 간경변(PBC), 비알코올성 지방간 질환(NAFLD), 또는 비알코올성 지방간염(NASH)일 수 있다. 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).

본 발명의 상기 약학적 조성물은 상기 화학식 1로 표시되는 화합물, 이의 광학 이성질체, 또는 이들의 약학적으로 허용가능한 염 외에 동일 또는 유사한 약효를 나타내는 유효성분을 1 종 이상을 더 포함할 수 있다. 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.

또한 본 발명의 일 구체예에 따르면, 상기 화학식 1로 표시되는 화합물, 이의 광학 이성질체, 또는 이의 약학적으로 허용 가능한 염의 치료학적으로 유효한 양을, 이를 필요로 하는 대상(subject)에게 투여하는 단계를 포함하는, FXR에 의해 매개되는 간 질환을 치료 또는 예방하는 방법을 제공한다. 상기 대상(subject)은 인간을 포함하는 포유류일 수 있다.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.

본 발명에서 사용되는 "치료학적으로 유효한 양"이라는 용어는 FXR에 의해 매개되는 간 질환 의 치료 또는 예방에 유효한 상기 화학식 1로 표시되는 화합물의 양을 나타낸다. 구체적으로, "치료학적으로 유효한 양"은 의학적 치료에 적용 가능한 합리적인 수혜/위험 비율로 질환을 치료하기에 충분한 양을 의미하며, 유효 용량 수준은 개체 종류 및 중증도, 연령, 성별, 질병의 종류, 약물의 활성, 약물에 대한 민감도, 투여 시간, 투여 경로 및 배출 비율, 치료기간, 동시 사용되는 약물을 포함한 요소 및 기타 의학 분야에 잘 알려진 요소에 따라 결정될 수 있다. 본 발명의 약학적 조성물은 개별 치료제로 투여하거나 다른 치료제와 병용하여 투여될 수 있고 시판되는 치료제와는 순차적으로 또는 동시에 투여될 수 있다. 그리고 단일 또는 다중 투여될 수 있다. 상기 요소를 모두 고려하여 부작용없이 최소한의 양으로 최대 효과를 얻을 수 있는 양을 투여하는 것이 중요하며, 당업자에 의해 용이하게 결정될 수 있다. 본 발명의 약학적 조성물의 투여 용량은, 환자의 상태, 연령, 성별 및 합병증 등의 다양한 요인에 따라 전문가에 의해 결정될 수 있다. 본 발명의 약학적 조성물의 유효성분은 안전성이 우수하므로, 결정된 투여 용량 이상으로도 사용될 수 있다.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.

또한 본 발명의 일 구체예에 따르면, 본 발명은 FXR에 의해 매개되는 간 질환의 치료 또는 예방에 사용하기 위한 약제(medicament)의 제조에 사용하기 위한, 상기 화학식 1로 표시되는 화합물, 이의 광학 이성질체, 또는 이의 약학적으로 허용 가능한 염의 용도(use)를 제공한다. 약제의 제조를 위한 상기 화학식 1로 표시되는 화합물은 허용되는 보조제, 희석제, 담체 등을 혼합할 수 있으며, 기타 활성제제와 함께 복합 제제로 제조되어 활성 성분들의 상승 작용을 가질 수 있다.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.

본 발명의 용도, 조성물, 치료 방법에서 언급된 사항은 서로 모순되지 않는 한 동일하게 적용된다.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.

본 발명의 실시 형태는 여러가지 다른 형태로 변형될 수 있으며, 본 발명의 범위가 이하 설명하는 실시 형태로 한정되는 것은 아니다. 또한 본 발명의 실시 형태는 당해 기술분야에서 평균적인 지식을 가진 자에게 본 발명을 더욱 완전하게 설명하기 위해서 제공되는 것이다. 나아가, 명세서 전체에서 어떤 구성요소를 "포함"한다는 것은 특별히 반대되는 기재가 없는 한 다른 구성요소를 제외하는 것이 아니라 다른 구성요소를 더 포함할 수 있다는 것을 의미한다.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.

본 발명의 아자바이사이클로알킬 유도체 화합물은 FXR에 대해 우수한 작용 활성을 나타내므로, 상기 FXR에 의해 매개되는 간 질환의 치료제로 유용하게 사용될 수 있다.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.

이하, 본 발명을 제조예, 실시예 및 실험예에 의하여 상세히 설명한다. 단, 하기 제조예, 실시예 및 실험예는 본 발명을 예시하는 것일 뿐, 본 발명의 범위가 이에 한정되는 것은 아니다.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.

제조예 1: 4-((((1R,3R,5S)-8-((5-사이클로프로필-3-(2,6-다이클로로페닐)아이소옥사졸-4-일)메틸)-8-아자바이사이클로[3.2.1]옥탄-3-일)옥시)메틸)벤조산 (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)의 제조 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)

Figure pat00006
Figure pat00006

단계 1: tert-부틸 (1R,3R,5S)-3-((4-(메톡시카르보닐)벤질)옥시)-8-아자바이사이클로[3.2.1]옥탄-8-카르복실레이트 (tert-butyl (1R,3R,5S)-3-((4-(methoxycarbonyl)benzyl)oxy)-8-azabicyclo[3.2.1]octane-8-carboxylate)의 제조Step 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)

Figure pat00007
Figure pat00007

tert-부틸 (1R,3R,5S)-3-하이드록시-8-아자바이사이클로[3.2.1]옥탄-8-카르복실레이트에 THF 30 V을 넣고 18-크라운-6 1 당량, 메틸 4-(브로모메틸)벤조에이트 1.2 당량, KOtBu 2 당량을 넣고 상온에서 8 시간 동안 교반하였다. 반응 종결 후, 염화암모늄 포화 수용액과 EA를 이용하여 추출하였다. 황산마그네슘을 이용하여 건조시키고 셀라이트 필터하여 EA 용액을 제거 후, Prep-LC로 정제하여 생성물을 얻었다(60 % 수율).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).

단계 2: 메틸 4-((((1R,3R,5S)-8-아자바이사이클로[3.2.1]옥탄-3-일)옥시)메틸)벤조에이트 (methyl 4-((((1R,3R,5S)-8-azabicyclo[3.2.1]octan-3-yl)oxy)methyl)benzoate)의 제조Step 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)

Figure pat00008
Figure pat00008

단계 1에서 제조한 tert-부틸 (1R,3R,5S)-3-((4-(메톡시카르보닐)벤질)옥시)-8-아자바이사이클로[3.2.1]옥탄-8-카르복실레이트를 TFA(5 V)와 MC(10 V)에 녹이고, 밤새 상온에서 교반하였다. 반응 종결 후, MC 용매를 진공 회전농축기로 제거하였다. 따로 분리 과정 없이 바로 다음 반응을 진행하였다.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.

단계 3: 메틸 4-((((1R,3R,5S)-8-((5-사이클로프로필-3-(2,6-다이클로로페닐)아이소옥사졸-4-일)메틸)-8-아자바이사이클로[3.2.1]옥탄-3-일)옥시)메틸)벤조에이트 (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)의 제조Step 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)

Figure pat00009
Figure pat00009

단계 2에서 제조한 메틸 4-((((1R,3R,5S)-8-아자바이사이클로[3.2.1]옥탄-3-일)옥시)메틸)벤조에이트(1 당량), 4-(클로로메틸)-5-사이클로프로필-3-(2,6-다이클로로페닐)아이소옥사사졸(1.1 당량), CS2CO3(3 당량), NaI(1 당량), ACN 20 V에 녹인 후 60 ℃에서 밤새 가열하였다. 반응 종결 후, EA와 H2O를 이용하여 추출하였다. EA 층에 Na2SO4를 첨가하여 수분을 제거하고 EA를 날렸다. Prep-LC를 이용하여 분리하였다(80 % 수율).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).

단계 4: 4-((((1R,3R,5S)-8-((5-사이클로프로필-3-(2,6-다이클로로페닐)아이소옥사졸-4-일)메틸)-8-아자바이사이클로[3.2.1]옥탄-3-일)옥시)메틸)벤조산 (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)의 제조 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)

Figure pat00010
Figure pat00010

단계 3에서 제조한 메틸 4-((((1R,3R,5S)-8-((5-사이클로프로필-3-(2,6-다이클로로페닐)아이소옥사졸-4-일)메틸)-8-아자바이사이클로[3.2.1]옥탄-3-일)옥시)메틸)벤조에이트(1 당량), 1N KOH 수용액 10 V을 THF (10 V), 메탄올(10 V)에 녹인 후 50 ℃에서 밤새 교반하였다. EA, AcOH, 정제수로 추출하였다. EA층에 Na2SO4를 첨가하여 수분을 제거하고 EA를 날렸다. Prep-LC를 이용하여 분리하였다(70 % 수율).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).

<실시예 1-1><Example 1-1>

실시예 1-1에서는 제조예 1과 실질적으로 동일한 방법으로 화합물을 제조하였다.In Example 1-1, a compound was prepared in substantially the same manner as in Preparation Example 1.

실시예 1-1: 4-((((1R,3R,5S)-8-((5-사이클로프로필-3-(2,6-다이클로로페닐)아이소옥사졸-4-일)메틸)-8-아자바이사이클로[3.2.1]옥탄-3-일)옥시)메틸)벤조산 (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)의 제조Example 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)

Figure pat00011
Figure pat00011

1H-NMR(400MHz, 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) 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)

제조예 2: 4'-((((1R,3R,5S)-8-((5-사이클로프로필-3-(2,6-다이클로로페닐)아이소옥사졸-4-일)메틸)-8-아자바이사이클로[3.2.1]옥탄-3-일)옥시)메틸)-[1,1'-바이페닐]-2-카르복실산 (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)의 제조Preparation 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)

Figure pat00012
Figure pat00012

단계 1: tert-부틸 (1R,3R,5S)-3-((4-브로모벤질)옥시)-8-아자바이사이클로[3.2.1]옥탄-8-카르복실레이트 (tert-butyl (1R,3R,5S)-3-((4-bromobenzyl)oxy)-8-azabicyclo[3.2.1]octane-8-carboxylate)의 제조Step 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)

Figure pat00013
Figure pat00013

tert-부틸 (1R,3R,5S)-3-하이드록시-8-아자바이사이클로[3.2.1]옥탄-8-카르복실레이트 400 mg(1.0 당량), 18-크라운-6(1.5 당량)을 THF에 녹이고 상온에서 20 분 동안 교반해 주었다. 20 분 후 1-브로모-4-(브로모메틸)벤젠(1.5 당량)을 첨가해 준 다음 상온에서 밤새 교반해 주었다. 반응 종결 후, 염화암모늄 포화 수용액과 EA를 이용하여 추출하였다. 황산마그네슘을 이용하여 건조시키고 셀라이트 필터하여 EA 용액을 제거후 MPLC로 정제하여 목적 화합물을 수득하였다(697 mg).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).

단계 2: (1R,3R,5S)-3-((4-브로모벤질)옥시)-8-아자바이사이클로[3.2.1]옥탄 ((1R,3R,5S)-3-((4-bromobenzyl)oxy)-8-azabicyclo[3.2.1]octane)의 제조Step 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)

Figure pat00014
Figure pat00014

단계 1에서 제조한 tert-부틸 (1R,3R,5S)-3-((4-브로모벤질)옥시)-8-아자바이사이클로[3.2.1]옥탄-8-카르복실레이트 697 mg에 TFA 1 ml를 MC 2 ml에 녹이고, 밤새 상온에서 교반해 주었다. 반응 종결 후, MC 용매를 진공회전농축기로 제거하고, 따로 분리 과정 없이 바로 다음 반응을 진행하였다.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.

단계 3-1: 4-(((1R,3R,5S)-3-((4-브로모벤질)옥시)-8-아자바이사이클로[3.2.1]옥탄-8-일)메틸)-5-사이클로프로필-3-(2,6-다이클로로페닐)아이소옥사졸 (4-(((1R,3R,5S)-3-((4-bromobenzyl)oxy)-8-azabicyclo[3.2.1]octan-8-yl)methyl)-5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazole)의 제조Step 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)

Figure pat00015
Figure pat00015

단계 2에서 제조한 (1R,3R,5S)-3-((4-브로모벤질)옥시)-8-아자바이사이클로[3.2.1]옥탄(1 당량), 4-(브로모메틸)-5-사이클로프로필-3-(2,6-다이클로로페닐)아이소옥사졸(1.2 당량), CS2CO3(3 당량), NaI(1 당량), ACN 20 V에 녹인 후 60 ℃에서 밤새 가열하였다. 반응 종결 후, EA와 H2O을 이용하여 추출하였다. EA층에 Na2SO4를 첨가하여 수분을 제거하고 EA를 날렸다. Prep-LC를 이용하여 분리하였다(80 % 수율).(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).

단계 3-2: 4-(((1R,3R,5S)-3-((4-브로모벤질)옥시)-8-아자바이사이클로[3.2.1]옥탄-8-일)메틸)-5-사이클로프로필-3-(2-(트리플루오로메톡시)페닐)아이소옥사졸 (4-(((1R,3R,5S)-3-((4-bromobenzyl)oxy)-8-azabicyclo[3.2.1]octan-8-yl)methyl)-5-cyclopropyl-3-(2-(trifluoromethoxy)phenyl)isoxazole)의 제조Step 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)

Figure pat00016
Figure pat00016

단계 2에서 제조한 (1R,3R,5S)-3-((4-브로모벤질)옥시)-8-아자바이사이클로[3.2.1]옥탄(1 당량), 4-(클로로메틸)-5-사이클로프로필-3-(2-(트리플루오로메톡시)페닐)아이소옥사졸(1.2 당량), CS2CO3(3 당량), NaI(1 당량), ACN 20 V에 녹인 후 60 ℃에서 밤새 가열하였다. 반응 종결 후, EA와 H2O을 이용하여 추출하였다. EA층에 Na2SO4를 첨가하여 수분을 제거하고 EA를 날렸다. Prep-LC를 이용하여 분리하였다(80 % 수율).(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).

단계 4: 메틸 4'-((((1R,3R,5S)-8-((5-사이클로프로필-3-(2,6-다이클로로페닐)아이소옥사졸-4-일)메틸)-8-아자바이사이클로[3.2.1]옥탄-3-일)옥시)메틸)-[1,1'-바이페닐]-2-카르복실레이트 (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) 의 제조Step 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)

Figure pat00017
Figure pat00017

단계 3-1에서 제조한 4-(((1R,3R,5S)-3-((4-브로모벤질)옥시)-8-아자바이사이클로[3.2.1]옥탄-8-일)메틸)-5-사이클로프로필-3-(2,6-다이클로로페닐)아이소옥사졸 30 mg(1.0 당량)과 (2-(메톡시카르보닐)페닐)보론산(2.0 당량), 2 M K2CO3(과량), Pd 촉매(20 mol%)를 다이옥산 2 ml에 녹였다. 100 ℃에서 10 분 동안 마이크로웨이브 반응을 하였다. 반응 종결 후 증류수와 EA를 이용하여 추출하였다. 황산마그네슘을 이용하여 건조시키고 EA 용액을 제거한 후 Prep-LC로 정제하여 목적 화합물을 수득하였다 (19.3 mg).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).

단계 5: 4'-((((1R,3R,5S)-8-((5-사이클로프로필-3-(2,6-다이클로로페닐)아이소옥사졸-4-일)메틸)-8-아자바이사이클로[3.2.1]옥탄-3-일)옥시)메틸)-[1,1'-바이페닐]-2-카르복실산 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 의 제조Step 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

Figure pat00018
Figure pat00018

단계 4에서 제조한 메틸 4'-((((1R,3R,5S)-8-((5-사이클로프로필-3-(2,6-다이클로로페닐)아이소옥사졸-4-일)메틸)-8-아자바이사이클로[3.2.1]옥탄-3-일)옥시)메틸)-[1,1'-바이페닐]-3-카르복실레이트 19.3 mg에 과량의 1 M NaOH 수용액을 THF 1 ml, MeOH 1 ml에 녹이고 50 ℃에서 2 시간 동안 교반하였다. 반응 종결 후 1 N HCl 수용액으로 산성화를 해주고 증류수와 EA를 이용하여 추출하였다. 황산마그네슘을 이용하여 건조시키고 EA 용액을 제거한 후, Prep-LC로 정제하여 목적 화합물을 수득하였다(10 mg).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).

<실시예 2-1 내지 실시예 2-63><Examples 2-1 to 2-63>

실시예 2-1 내지 실시예 2-63에서는 제조예 2와 실질적으로 동일한 방법으로 화합물을 제조하였다.In Examples 2-1 to 2-63, compounds were prepared in substantially the same manner as in Preparation Example 2.

실시예 2-1: 2-(4-((((1R,3R,5S)-8-(5-사이클로프로필-3-(2,6-다이클로로페닐)아이소옥사졸-4-일)-메틸)-8-아자바이사이클로[3.2.1]옥탄-3-일)옥시)메틸)페닐)니코틴산 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 의 제조Example 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

Figure pat00019
Figure pat00019

1H-NMR(400MHz, CDCl3) 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) 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)

실시예 2-2: 4'-((((1R,3R,5S)-8-((5-사이클로프로필-3-(2,6-다이클로로페닐)아이소옥사졸-4-일)메틸)-8-아자바이사이클로[3.2.1]옥탄-3-일)옥시)메틸)-6-플루오로-[1,1'-바이페닐]-3-카르복실산 (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)의 제조Example 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)

Figure pat00020
Figure pat00020

1H-NMR(400MHz, CDCl3) 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) 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)

실시예 2-3: 4'-((((1R,3R,5S)-8-((5-사이클로프로필-3-(2,6-다이클로로페닐)아이소옥사졸-4-일)메틸)-8-아자바이사이클로[3.2.1]옥탄-3-일)옥시)메틸)-4-메틸-[1,1'-바이페닐]-3-카르복실산 (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)의 제조Example 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)

Figure pat00021
Figure pat00021

1H-NMR(400MHz, CDCl3) 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) 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)

실시예 2-4: 4'-((((1R,3R,5S)-8-((5-사이클로프로필-3-(2,6-다이클로로페닐)아이소옥사졸-4-일)메틸)-8-아자바이사이클로[3.2.1]옥탄-3-일)옥시)메틸)-6-메틸-[1,1'-바이페닐]-3-카르복실산 (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)의 제조Example 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)

Figure pat00022
Figure pat00022

1H-NMR(400MHz, CDCl3) 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) 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)

실시예 2-5: 4'-((((1R,3R,5S)-8-((5-사이클로프로필-3-(2,6-다이클로로페닐)아이소옥사졸-4-일)메틸)-8-아자바이사이클로[3.2.1]옥탄-3-일)옥시)메틸)-5-플루오로-[1,1'-바이페닐]-3-카르복실산 (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)의 제조Example 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)

Figure pat00023
Figure pat00023

1H-NMR(400MHz, CDCl3) 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) 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)

실시예 2-6: 4-클로로-4'-((((1R,3R,5S)-8-((5-사이클로프로필-3-(2,6-다이클로로페닐)아이소옥사졸-4-일)메틸)-8-아자바이사이클로[3.2.1]옥탄-3-일)옥시)메틸)-[1,1'-바이페닐]-3-카르복실산 (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)의 제조Example 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)

Figure pat00024
Figure pat00024

1H-NMR(400MHz, CDCl3) 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) 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)

실시예 2-7: 4'-((((1R,3R,5S)-8-((5-사이클로프로필-3-(2,6-다이클로로페닐)아이소옥사졸-4-일)메틸)-8-아자바이사이클로[3.2.1]옥탄-3-일)옥시)메틸)-2'-메틸-[1,1'-바이페닐]-4-카르복실산 (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)의 제조Example 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)

Figure pat00025
Figure pat00025

1H-NMR(400MHz, CDCl3) 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) 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)

실시예 2-8: 4'-((((1R,3R,5S)-8-((5-사이클로프로필-3-(2,6-다이클로로페닐)아이소옥사졸-4-일)메틸)-8-아자바이사이클로[3.2.1]옥탄-3-일)옥시)메틸)-2'-메틸-[1,1'-바이페닐]-3-카르복실산 (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)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)

Figure pat00026
Figure pat00026

1H-NMR(400MHz, CDCl3) 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) 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)

실시예 2-9: 5-시아노-4'-((((1R,3R,5S)-8-((5-사이클로프로필-3-(2,6-다이클로로페닐)아이소옥사졸-4-일)메틸)-8-아자바이사이클로[3.2.1]옥탄-3-일)옥시)메틸)-[1,1'-바이페닐]-3-카르복실산 (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)oxy)methyl)-[1,1'-biphenyl]-3-carboxylic acid)의 제조Example 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)

Figure pat00027
Figure pat00027

1H-NMR(400MHz, CDCl3) 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) 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)

실시예 2-10: 4'-((((1R,3R,5S)-8-((5-사이클로프로필-3-(2,6-다이클로로페닐)아이소옥사졸-4-일)메틸)-8-아자바이사이클로[3.2.1]옥탄-3-일)옥시)메틸)-2-플루오로-[1,1'-바이페닐]-3-카르복실산 (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)의 제조Example 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)

Figure pat00028
Figure pat00028

1H-NMR(400MHz, CDCl3) 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) 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)

실시예 2-11: 3-(6-((((1R,3R,5S)-8-((5-사이클로프로필-3-(2,6-다이클로로페닐)아이소옥사졸-4-일)메틸)-8-아자바이사이클로[3.2.1]옥탄-3-일)옥시)메틸)피리딘-3-일)벤조산 (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)의 제조Example 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

Figure pat00029
Figure pat00029

1H-NMR(400MHz, CDCl3) 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) 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)

실시예 2-12: 3-(4-((((1R,3R,5S)-8-((5-사이클로프로필-3-(2,6-다이클로로페닐)아이소옥사졸-4-일)메틸)-8-아자바이사이클로[3.2.1]옥탄-3-일)옥시)메틸)-2-메틸페닐)푸란-2-카르복실산 (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)의 제조Example 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)

Figure pat00030
Figure pat00030

1H-NMR(400MHz, 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) 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)

실시예 2-13: 4'-((((1R,3R,5S)-8-((5-사이클로프로필-3-(2,6-다이클로로페닐)아이소옥사졸-4-일)메틸)-8-아자바이사이클로[3.2.1]옥탄-3-일)옥시)메틸)-6-플루오로-5-메틸-[1,1'-바이페닐]-3-카르복실산 (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)의 제조Example 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)

Figure pat00031
Figure pat00031

1H-NMR(400MHz, 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) 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)

실시예 2-14: 3-(4-((((1R,3R,5S)-8-((5-사이클로프로필-3-(2-(트리플루오로메톡시)페닐)아이소옥사졸-4-일)메틸)-8-아자바이사이클로[3.2.1]옥탄-3-일)옥시)메틸)-2-메틸페닐)푸란-2-카르복실산 (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)의 제조Example 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)

제조예 2의 단계 3-2를 이용하여 제조할 수 있다. It can be prepared using step 3-2 of Preparation Example 2.

Figure pat00032
Figure pat00032

1H-NMR(400MHz, 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) 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)

실시예 2-15: 3-(6-((((1R,3R,5S)-8-((5-사이클로프로필-3-(2,6-다이클로로페닐)아이소옥사졸-4-일)메틸)-8-아자바이사이클로[3.2.1]옥탄-3-일)옥시)메틸)피리딘-3-일)푸란-2-카르복실산 (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)의 제조Example 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)

Figure pat00033
Figure pat00033

1H-NMR(400MHz, CDCl3) 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) 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)

실시예 2-16: 2-(6-((((1R,3R,5S)-8-((5-사이클로프로필-3-(2,6-다이클로로페닐)아이소옥사졸-4-일)메틸)-8-아자바이사이클로[3.2.1]옥탄-3-일)옥시)메틸)피리딘-2-일)벤조산 (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)의 제조Example 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

Figure pat00034
Figure pat00034

1H NMR (400 MHz, CDCl3) 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) 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)

실시예 2-17: 3-(4-((((1R,3R,5S)-8-((5-사이클로프로필-3-(2,6-다이클로로페닐)아이소옥사졸-4-일)메틸)-8-아자바이사이클로[3.2.1]옥탄-3-일)옥시)메틸)페닐)푸란-2-카르복실산 (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)의 제조Example 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)

Figure pat00035
Figure pat00035

1H 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) 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)

실시예 2-18: 3-(4-((((1R,3R,5S)-8-((5-사이클로프로필-3-(2,6-다이클로로페닐)아이소옥사졸-4-일)메틸)-8-아자바이사이클로[3.2.1]옥탄-3-일)옥시)메틸)페닐)푸란-2-카르복실산 (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)의 제조Example 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)

Figure pat00036
Figure pat00036

1H-NMR(400MHz, CDCl3) 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) 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)

실시예 2-19: 4-(4-((((1R,3R,5S)-8-((5-사이클로프로필-3-(2,6-다이클로로페닐)아이소옥사졸-4-일)메틸)-8-아자바이사이클로[3.2.1]옥탄-3-일)옥시)메틸)페닐)티오펜-2-카르복실산 (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)의 제조Example 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)

Figure pat00037
Figure pat00037

1H-NMR(400MHz, CDCl3) 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) 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)

실시예 2-20: 4-(4-((((1R,3R,5S)-8-((5-사이클로프로필-3-(2,6-다이클로로페닐)아이소옥사졸-4-일)메틸)-8-아자바이사이클로[3.2.1]옥탄-3-일)옥시)메틸)페닐)옥사졸-5-카르복실산 (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)의 제조Example 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)

Figure pat00038
Figure pat00038

1H-NMR(400MHz, CDCl3) 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) 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)

실시예 2-21: 4-(4-((((1R,3R,5S)-8-((5-사이클로프로필-3-(2,6-다이클로로페닐)아이소옥사졸-4-일)메틸)-8-아자바이사이클로[3.2.1]옥탄-3-일)옥시)메틸)페닐)-1-메틸-1H-피라졸-5-카르복실산 (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)의 제조Example 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)

Figure pat00039
Figure pat00039

1H-NMR(400MHz, CDCl3) 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) 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)

실시예 2-22: 3-(N-((1R,3R,5S)-8-((5-사이클로프로필-3-(2,6-다이클로로페닐)아이소옥사졸-4-일)메틸)-8-아자바이사이클로[3.2.1]옥탄-3-일)옥시)메틸)-[1,1'-바이페닐]-2-카르복실산) (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)의 제조Example 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)

Figure pat00040
Figure pat00040

1H-NMR(400MHz, 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) 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)

실시예 2-23: 4'-((((1R,3S,5S)-8-((5-사이클로프로필-3-(2,6-다이클로로페닐)아이소옥사졸-4-일)메틸)-8-아자바이사이클로[3.2.1]옥탄-3-일)옥시)메틸)-[1,1'-바이페닐]-2-카르복실산 (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)의 제조Example 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)

Figure pat00041
Figure pat00041

1H-NMR(400MHz, 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) 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)

실시예 2-24: 4'-((((1R,3R,5S)-8-((5-사이클로프로필-3-(2,6-다이클로로페닐)아이소옥사졸-4-일)메틸)-8-아자바이사이클로[3.2.1]옥탄-3-일)옥시)메틸)-[1,1'-바이페닐]-4-카르복실산 (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)의 제조Example 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)

Figure pat00042
Figure pat00042

1H-NMR(400MHz, 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) 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)

실시예 2-25: 4'-((((1R,3S,5S)-8-((5-사이클로프로필-3-(2,6-다이클로로페닐)아이소옥사졸-4-일)메틸)-8-아자바이사이클로[3.2.1]옥탄-3-일)옥시)메틸)-[1,1'-바이페닐]-4-카르복실산 (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)의 제조Example 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)

Figure pat00043
Figure pat00043

1H-NMR(400MHz, 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) 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)

실시예 2-26: 4'-((((1R,3R,5S)-8-((5-사이클로프로필-3-(2,6-다이클로로페닐)아이소옥사졸-4-일)메틸)-8-아자바이사이클로[3.2.1]옥탄-3-일)옥시)메틸)-4-플루오로-[1,1'-바이페닐]-3-카르복실산 (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)의 제조Example 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)

Figure pat00044
Figure pat00044

1H-NMR(400MHz, 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) 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)

실시예 2-27: 4'-((((1R,3R,5S)-8-((5-사이클로프로필-3-(2,6-다이클로로페닐)아이소옥사졸-4-일)메틸)-8-아자바이사이클로[3.2.1]옥탄-3-일)옥시)메틸)-3-플루오로-[1,1'-바이페닐]-4-카르복실산 (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)의 제조Example 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)

Figure pat00045
Figure pat00045

1H-NMR(400MHz, 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) 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)

실시예 2-28: 5-(4-((((1R,3R,5S)-8-((5-사이클로프로필-3-(2,6-다이클로로페닐)아이소옥사졸-4-일)메틸)-8-아자바이사이클로[3.2.1]옥탄-3-일)옥시)메틸)페닐)피리미딘-2-카르복실산 (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)의 제조Example 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)

Figure pat00046
Figure pat00046

1H-NMR(400MHz, 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) 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)

실시예 2-29: 4'-((((1R,3R,5S)-8-((5-사이클로프로필-3-(2,6-다이클로로페닐)아이소옥사졸-4-일)메틸)-8-아자바이사이클로[3.2.1]옥탄-3-일)옥시)메틸)-2-플루오로-[1,1'-바이페닐]-4-카르복실산 (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)의 제조Example 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)

Figure pat00047
Figure pat00047

1H-NMR(400MHz, 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) 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)

실시예 2-30: 4'-((((1R,3R,5S)-8-((5-사이클로프로필-3-(2,6-다이클로로페닐)아이소옥사졸-4-일)메틸)-8-아자바이사이클로[3.2.1]옥탄-3-일)옥시)메틸)-3'-플루오로-[1,1'-바이페닐]-4-카르복실산 (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)의 제조Example 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)

Figure pat00048
Figure pat00048

1H-NMR(400MHz, 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) 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)

실시예 2-31: 3'-((((1R,3R,5S)-8-((5-사이클로프로필-3-(2,6-다이클로로페닐)아이소옥사졸-4-일)메틸)-8-아자바이사이클로[3.2.1]옥탄-3-일)옥시)메틸)-[1,1'-바이페닐]-4-카르복실산 (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)의 제조Example 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)

Figure pat00049
Figure pat00049

1H-NMR(400MHz, 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) 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)

실시예 2-32: 3'-((((1R,3R,5S)-8-((5-사이클로프로필-3-(2,6-다이클로로페닐)아이소옥사졸-4-일)메틸)-8-아자바이사이클로[3.2.1]옥탄-3-일)옥시)메틸)-[1,1'-바이페닐]-3-카르복실산 (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)의 제조Example 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)

Figure pat00050
Figure pat00050

1H-NMR(400MHz, 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) 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)

실시예 2-33: 3'-((((1R,3R,5S)-8-((5-사이클로프로필-3-(2,6-다이클로로페닐)아이소옥사졸-4-일)메틸)-8-아자바이사이클로[3.2.1]옥탄-3-일)옥시)메틸)-[1,1'-바이페닐]-2-카르복실산 (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)의 제조Example 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)

Figure pat00051
Figure pat00051

1H-NMR(400MHz, 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) 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)

실시예 2-34: 4'-((((1R,3R,5S)-8-((5-사이클로프로필-3-(2,6-다이클로로페닐)아이소옥사졸-4-일)메틸)-8-아자바이사이클로[3.2.1]옥탄-3-일)옥시)메틸)-3'-플루오로-[1,1'-바이페닐]-2-카르복실산 (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)의 제조Example 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)

Figure pat00052
Figure pat00052

1H-NMR(400MHz, 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) 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)

실시예 2-35: 4'-((((1R,3R,5S)-8-((5-사이클로프로필-3-(2,6-다이클로로페닐)아이소옥사졸-4-일)메틸)-8-아자바이사이클로[3.2.1]옥탄-3-일)옥시)메틸)-3'-플루오로-[1,1'-바이페닐]-3-카르복실산 (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)의 제조Example 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)

Figure pat00053
Figure pat00053

1H-NMR(400MHz, 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) 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)

실시예 2-36: 4'-((((1R,3R,5S)-8-((5-사이클로프로필-3-(2,6-다이클로로페닐)아이소옥사졸-4-일)메틸)-8-아자바이사이클로[3.2.1]옥탄-3-일)옥시)메틸)-5-플루오로-[1,1'-바이페닐]-2-카르복실산 (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)의 제조Example 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)

Figure pat00054
Figure pat00054

1H-NMR(400MHz, 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) 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)

실시예 2-37: 5-클로로-4'-((((1R,3R,5S)-8-((5-사이클로프로필-3-(2,6-다이클로로페닐)아이소옥사졸-4-일)메틸)-8-아자바이사이클로[3.2.1]옥탄-3-일)옥시)메틸)-[1,1'-바이페닐]-2-카르복실산 (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)의 제조Example 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)

Figure pat00055
Figure pat00055

1H-NMR(400MHz, 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) 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)

실시예 2-38: 5-클로로-4'-((((1R,3S,5S)-8-((5-사이클로프로필-3-(2,6-다이클로로페닐)아이소옥사졸-4-일)메틸)-8-아자바이사이클로[3.2.1]옥탄-3-일)옥시)메틸)-[1,1'-바이페닐]-2-카르복실산 (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)의 제조Example 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)

Figure pat00056
Figure pat00056

1H-NMR(400MHz, 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) 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)

실시예 2-39: 4'-((((1R,3R,5S)-8-((5-사이클로프로필-3-(2,6-다이클로로페닐)아이소옥사졸-4-일)메틸)-8-아자바이사이클로[3.2.1]옥탄-3-일)옥시)메틸)-3-(트리플루오로메틸)-[1,1'-바이페닐]-2-카르복실산 (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)의 제조Example 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)

Figure pat00057
Figure pat00057

1H-NMR(400MHz, 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) 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)

실시예 2-40: 4'-((((1R,3R,5S)-8-((5-사이클로프로필-3-(2,6-다이클로로페닐)아이소옥사졸-4-일)메틸)-8-아자바이사이클로[3.2.1]옥탄-3-일)옥시)메틸)-4-플루오로-[1,1'-바이페닐]-2-카르복실산 (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)의 제조Example 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)

Figure pat00058
Figure pat00058

1H-NMR(400MHz, 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) 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)

실시예 2-41: 1-(4-((((1R,3R,5S)-8-((5-사이클로프로필-3-(2,6-다이클로로페닐)아이소옥사졸-4-일)메틸)-8-아자바이사이클로[3.2.1]옥탄-3-일)옥시)메틸)페닐)아제티딘-3-카르복실산 (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)의 제조Example 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)

Figure pat00059
Figure pat00059

1H-NMR(400MHz, 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) 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)

실시예 2-42: 4'-((((1R,3R,5S)-8-((5-사이클로프로필-3-(2,6-다이클로로페닐)아이소옥사졸-4-일)메틸)-8-아자바이사이클로[3.2.1]옥탄-3-일)옥시)메틸)-3'-메틸-[1,1'-바이페닐]-2-카르복실산 (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)의 제조Example 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)

Figure pat00060
Figure pat00060

1H-NMR(400MHz, 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) 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)

실시예 2-43: 4'-((((1R,3R,5S)-8-((5-사이클로프로필-3-(2,6-다이클로로페닐)아이소옥사졸-4-일)메틸)-8-아자바이사이클로[3.2.1]옥탄-3-일)옥시)메틸)-[1,1'-바이페닐]-3-카르복실산 (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)의 제조Example 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)

Figure pat00061
Figure pat00061

1H-NMR(400MHz, 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) 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)

실시예 2-44: 4'-((((1R,3R,5S)-8-((5-사이클로프로필-3-(2,6-다이클로로페닐)아이소옥사졸-4-일)메틸)-8-아자바이사이클로[3.2.1]옥탄-3-일)옥시)메틸)-3'-메틸-[1,1'-바이페닐]-3-카르복실산 (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)의 제조Example 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)

Figure pat00062
Figure pat00062

1H-NMR(400MHz, 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) 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)

실시예 2-45: 4-((((1R,3R,5S)-8-((5-사이클로프로필-3-(2,6-다이클로로페닐)아이소옥사졸-4-일)메틸)-8-아자바이사이클로[3.2.1]옥탄-3-일)옥시)메틸)-1-나프토산 (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)의 제조Example 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)

Figure pat00063
Figure pat00063

1H-NMR(400MHz, 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) 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 )

실시예 2-46: 1-(4-((((1R,3R,5S)-8-((5-사이클로프로필-3-(2,6-다이클로로페닐)아이소옥사졸-4-일)메틸)-8-아자바이사이클로[3.2.1]옥탄-3-일)옥시)메틸)페닐)-1H-피롤-2-카르복실산 (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)의 제조Example 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)

Figure pat00064
Figure pat00064

1H-NMR(400MHz, 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) 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)

실시예 2-47: 2-(5-((((1R,3R,5S)-8-((5-사이클로프로필-3-(2,6-다이클로로페닐)아이소옥사졸-4-일)메틸)-8-아자바이사이클로[3.2.1]옥탄-3-일)옥시)메틸)피리딘-2-일)벤조산 (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)의 제조Example 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

Figure pat00065
Figure pat00065

1H-NMR(400MHz, 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) 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)

실시예 2-48: 3-(5-((((1R,3R,5S)-8-((5-사이클로프로필-3-(2,6-다이클로로페닐)아이소옥사졸-4-일)메틸)-8-아자바이사이클로[3.2.1]옥탄-3-일)옥시)메틸)피리딘-2-일)벤조산 (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)의 제조Example 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

Figure pat00066
Figure pat00066

1H-NMR(400MHz, 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) 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)

실시예 2-49: 2-(4-((((1R,3R,5S)-8-((5-사이클로프로필-3-(2,6-다이클로로페닐)아이소옥사졸-4-일)메틸)-8-아자바이사이클로[3.2.1]옥탄-3-일)옥시)메틸)페닐)니코틴산 (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)의 제조Example 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)

Figure pat00067
Figure pat00067

1H-NMR(400MHz, 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) 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)

실시예 2-50: 6-(4-((((1R,3R,5S)-8-((5-사이클로프로필-3-(2,6-다이클로로페닐)아이소옥사졸-4-일)메틸)-8-아자바이사이클로[3.2.1]옥탄-3-일)옥시)메틸)페닐)니코틴산 (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)의 제조Example 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)

Figure pat00068
Figure pat00068

1H-NMR(400MHz, 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) 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)

실시예 2-51: 2-(4-((((1R,3R,5S)-8-((5-사이클로프로필-3-(2,6-다이클로로페닐)아이소옥사졸-4-일)메틸)-8-아자바이사이클로[3.2.1]옥탄-3-일)옥시)메틸)페닐)아이소니코틴산 (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)의 제조Example 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)

Figure pat00069
Figure pat00069

1H-NMR(400MHz, 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) 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)

실시예 2-52: 3-(4-((((1R,3R,5S)-8-((5-사이클로프로필-3-(2,6-다이클로로페닐)아이소옥사졸-4-일)메틸)-8-아자바이사이클로[3.2.1]옥탄-3-일)옥시)메틸)페닐)푸란-2-카르복실산 (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)의 제조Example 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)

Figure pat00070
Figure pat00070

1H-NMR(400MHz, 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) 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)

실시예 2-53: 5-(4-((((1R,3R,5S)-8-((5-사이클로프로필-3-(2,6-다이클로로페닐)아이소옥사졸-4-일)메틸)-8-아자바이사이클로[3.2.1]옥탄-3-일)옥시)메틸)페닐)푸란-2-카르복실산 (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)의 제조Example 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)

Figure pat00071
Figure pat00071

1H-NMR(400MHz, 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) 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)

실시예 2-54: 6-(4-((((1R,3R,5S)-8-((5-사이클로프로필-3-(2,6-다이클로로페닐)아이소옥사졸-4-일)메틸)-8-아자바이사이클로[3.2.1]옥탄-3-일)옥시)메틸)페닐)피콜린산 (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)의 제조Example 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)

Figure pat00072
Figure pat00072

1H-NMR(400MHz, 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) 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)

실시예 2-55: 3-(5-((((1R,3R,5S)-8-((5-사이클로프로필-3-(2,6-다이클로로페닐)아이소옥사졸-4-일)메틸)-8-아자바이사이클로[3.2.1]옥탄-3-일)옥시)메틸)피리딘-2-일)푸란-2-카르복실산 (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)의 제조Example 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)

Figure pat00073
Figure pat00073

1H-NMR(400MHz, 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) 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)

실시예 2-56: 3-(4-((((1R,3R,5S)-8-((5-사이클로프로필-3-(2,6-다이클로로페닐)아이소옥사졸-4-일)메틸)-8-아자바이사이클로[3.2.1]옥탄-3-일)옥시)메틸)-3-플루오로페닐)푸란-2-카르복실산 (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)의 제조Example 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)

Figure pat00074
Figure pat00074

1H-NMR(400MHz, 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) 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)

실시예 2-57: 5-(4-((((1R,3R,5S)-8-((5-사이클로프로필-3-(2,6-다이클로로페닐)아이소옥사졸-4-일)메틸)-8-아자바이사이클로[3.2.1]옥탄-3-일)옥시)메틸)페닐)-2-메틸티오펜-3-카르복실산 (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)의 제조Example 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)

Figure pat00075
Figure pat00075

1H-NMR(400MHz, 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) 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)

실시예 2-58: 3-(4-((((1R,3R,5S)-8-((5-사이클로프로필-3-(2,6-다이클로로페닐)아이소옥사졸-4-일)메틸)-8-아자바이사이클로[3.2.1]옥탄-3-일)옥시)메틸)나프탈렌-1-일)푸란-2-카르복실산 (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)의 제조Example 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)

Figure pat00076
Figure pat00076

1H-NMR(400MHz, 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) 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)

실시예 2-59: 3-(4-((((1R,3R,5S)-8-((5-사이클로프로필-3-(2,6-다이클로로페닐)아이소옥사졸-4-일)메틸)-8-아자바이사이클로[3.2.1]옥탄-3-일)옥시)메틸)나프탈렌-1-일)벤조산 (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)의 제조Example 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

Figure pat00077
Figure pat00077

1H-NMR(400MHz, 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) 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)

실시예 2-60: 4'-((((1R,3R,5S)-8-((5-사이클로프로필-3-(2,6-다이클로로페닐)아이소옥사졸-4-일)메틸)-8-아자바이사이클로[3.2.1]옥탄-3-일)옥시)메틸)-4-메톡시-[1,1'-바이페닐]-3-카르복실산 (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)의 제조Example 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)

Figure pat00078
Figure pat00078

1H-NMR(400MHz, 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) 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)

실시예 2-61: 3-(4-((((1R,3R,5S)-8-((5-사이클로프로필-3-(2,6-다이클로로페닐)아이소옥사졸-4-일)메틸)-8-아자바이사이클로[3.2.1]옥탄-3-일)옥시)메틸)-3-메틸페닐)푸란-2-카르복실산 (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)의 제조Example 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)

Figure pat00079
Figure pat00079

1H-NMR(400MHz, 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) 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)

실시예 2-62: 3-(4-((((1R,3R,5S)-8-((5-사이클로프로필-3-(2,6-다이클로로페닐)아이소옥사졸-4-일)메틸)-8-아자바이사이클로[3.2.1]옥탄-3-일)옥시)메틸)나프탈렌-1-일)푸란-2-카르복실산 (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)의 제조Example 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)

Figure pat00080
Figure pat00080

1H-NMR(400MHz, 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) 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)

실시예 2-63: 3-(4-((((1R,3R,5S)-8-((5-사이클로프로필-3-(2-(트리플루오로메톡시)페닐)아이소옥사졸-4-일)메틸)-8-아자바이사이클로[3.2.1]옥탄-3-일)옥시)메틸)-3-플루오로페닐)푸란-2-카르복실산 (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)의 제조Example 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)

제조예 2의 단계 3-2 를 이용하여 제조하였다. It was prepared using step 3-2 of Preparation Example 2.

Figure pat00081
Figure pat00081

1H-NMR(400MHz, 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) 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)

제조예 3: 4'-((((1R,3R,5S)-8-((5-사이클로프로필-3-(2,6-다이클로로페닐)아이소옥사졸-4-일)메틸)-8-아자바이사이클로[3.2.1]옥탄-3-일)옥시)플루오로메틸)-[1,1'-바이페닐]-3-카르복실산 (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)의 제조Preparation 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)

Figure pat00082
Figure pat00082

단계 1: 4-(((1R,3R,5S)-3-((4-브로모페닐)플루오로메톡시)-8-아자바이사이클로[3.2.1]옥탄-8-일)메틸)-5-사이클로프로필-3-(2,6-다이클로로페닐)아이소옥사졸 (4-(((1R,3R,5S)-3-((4-bromophenyl)fluoromethoxy)-8-azabicyclo[3.2.1]octan-8-yl)methyl)-5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazole)의 제조Step 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)

Figure pat00083
Figure pat00083

microwave vial 에 출발물질(1.0 당량), 1-브로모-4-(브로모플루오로 메틸)벤젠(1.5 당량), Cs2CO3(2 당량)를 아세토나이트릴 2 ml에 녹인 후 90 ℃에서 밤새 가열하였다. 반응 종결 후, EA와 정제수를 이용하여 추출하였다. EA층에 Na2SO4를 첨가하여 수분을 제거하고 EA를 제거하였다. MPLC를 이용하여 EA/Hx 용매 조건에서 컬럼분리하였다.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.

단계 2: 메틸 4'-((((1R,3R,5S)-8-((5-사이클로프로필-3-(2,6-다이클로로페닐)아이소옥사졸-4-일)메틸)-8-아자바이사이클로[3.2.1]옥탄-3-일)옥시)플루오로메틸)-[1,1'-바이페닐]-3-카르복실레이트 (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)의 제조Step 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

Figure pat00084
Figure pat00084

microwave vial에 단계 1에서 제조한 4-(((1R,3R,5S)-3-((4-브로모페닐)플루오로메톡시)-8-아자바이사이클로[3.2.1]옥탄-8-일)메틸)-5-사이클로프로필-3-(2,6-다이클로로페닐)아이소옥사졸 (1.0 당량), 3-(메톡시카르보닐)페닐) 보론산(1.5 당량), 2M K2CO3 수용액(2.0 당량), Pd 촉매(10 mol%)를 다이옥산(2 mL)에 녹인 후 microwave를 사용하여 180 ℃에서 30 분 동안 반응하였다. 반응 종결 후, EA와 brine solution을 이용하여 추출하였다. EA층에 Na2SO4를 첨가하여 수분을 제거하고 EA를 제거하였다. Prep-LC를 이용하여 분리하였다.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.

단계 3: 4 '-((((1R,3R,5S)-8-((5-사이클로프로필-3-(2,6-다이클로로페닐)아이소옥사졸-4-일)메틸)-8-아자바이사이클로[3.2.1]옥탄-3-일)옥시)플루오로메틸)-[1,1'-바이페닐]-3-카르복실산 (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)의 제조Step 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)

Figure pat00085
Figure pat00085

단계 1에서 제조한 메틸 4'-((((1R,3R,5S)-8-((5-사이클로프로필-3-(2,6-다이클로로페닐)아이소옥사졸-4-일)메틸)-8-아자바이사이클로[3.2.1]옥탄-3-일)옥시)플루오로메틸)-[1,1'-바이페닐]-3-카르복실레이트(1 당량), 1N KOH 수용액 2 ml을 THF 2 ml, 메탄올 1 ml에 녹인 후 50 ℃ 에서 밤새 교반하였다. EA/AcOH 를 사용하여 산성화하고, 정제수로 추출하였다. EA층에 Na2SO4를 첨가하여 수분을 제거하고 EA를 제거하였다. Prep-LC를 이용하여 분리하였다.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.

<실시예 3-1 내지 실시예 3-2><Examples 3-1 to 3-2>

실시예 3-1 내지 실시예 3-2에서는 제조예 3과 실질적으로 동일한 방법으로 화합물을 제조하였다.In Examples 3-1 to 3-2, compounds were prepared in substantially the same manner as in Preparation Example 3.

실시예 3-1: 4'-((((1R,3R,5S)-8-((5-사이클로프로필-3-(2,6-다이클로로페닐)아이소옥사졸-4-일)메틸)-8-아자바이사이클로[3.2.1]옥탄-3-일)옥시)플루오로메틸)-[1,1'-바이페닐]-3-카르복실산 (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)의 제조 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)

Figure pat00086
Figure pat00086

1H-NMR(400MHz, CDCl3) δ ppm 1.08-2.18 (12H, m), 3.30-3.48 (4H, m), 5.21 (1H, s), 7.33-8.35 (11H, m) 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)

실시예 3-2: 3-(4-((((1R,3R,5S)-8-((5-사이클로프로필-3-(2,6-다이클로로페닐)아이소옥사졸-4-일)메틸)-8-아자바이사이클로[3.2.1]옥탄-3-일)옥시)플루오로메틸)페닐)푸란-2-카르복실산 (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)의 제조Example 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)

Figure pat00087
Figure pat00087

1H-NMR(400MHz, 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) 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)

제조예 4. 6-(((1R,3R,5S)-8-((5-사이클로프로필-3-(2,6-다이클로로페닐)아이소옥사졸-4-일)메틸)-8-아자바이사이클로[3.2.1]옥탄-3-일)아미노)-2-나프토산 (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)의 제조Preparation 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)

Figure pat00088
Figure pat00088

단계 1. 메틸 6-(((1R,3R,5S)-8-((5-사이클로프로필-3-(2,6-다이클로로페닐)아이소옥사졸-4-일)메틸)-8-아자바이사이클로[3.2.1]옥탄-3-일)아미노)-2-나프토에이트) (methyl 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-naphthoate)의 제조Step 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)

Figure pat00089
Figure pat00089

상기 반응식의 출발물질(1 당량), 메틸 6-브로모-2-나프토에이트(1.5 당량), Pd(OAc)2(0.1 당량), 2,2'-비스(디페닐포스피노)-1,1'-비나프틸:BINAP(0.1 당량), Cs2CO3(3 당량) 를 톨루엔에 녹인 후 130 ℃에서 밤새 가열하였다. 반응 종결 후, EA와 brine solution을 이용하여 추출하였다. EA층에 Na2SO4를 첨가하여 수분을 제거하고 EA를 제거하였다. MPLC에서 EA/Hx 조건에서 컬럼 분리하였다.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.

단계 2: 6-(((1R,3R,5S)-8-((5-사이클로프로필-3-(2,6-다이클로로페닐)아이소옥사졸-4-일)메틸)-8-아자바이사이클로[3.2.1]옥탄-3-일)아미노)-2-나프토산 (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)의 제조Step 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)

Figure pat00090
Figure pat00090

단계 1에서 제조한 메틸 6-(((1R,3R,5S)-8-((5-사이클로프로필-3-(2,6-다이클로로페닐)아이소옥사졸-4-일)메틸)-8-아자바이사이클로[3.2.1]옥탄-3-일)아미노)-2-나프토에이트) (1 당량), 1N KOH 수용액 2 ml을 THF 2 ml, methanol 1 ml에 녹인 후 50 ℃에서 밤새 교반하였다. EA, AcOH, 정제수로 추출하였다. EA층에 Na2SO4를 첨가하여 수분을 제거하고 EA를 제거하였다. Prep-LC를 이용하여 분리하였다.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.

<실시예 4-1 내지 실시예 4-3><Examples 4-1 to 4-3>

실시예 4-1 내지 실시예 4-3에서는 제조예 4와 실질적으로 동일한 방법으로 화합물을 제조하였다.In Examples 4-1 to 4-3, compounds were prepared in substantially the same manner as in Preparation Example 4.

실시예 4-1: 2-(((1R,3R,5S)-8-((5-사이클로프로필-3-(2,6-다이클로로페닐)아이소옥사졸-4-일)메틸)-8-아자바이사이클로[3.2.1]옥탄-3-일)아미노)벤조[d]티아졸-6-카르복실산 (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)의 제조Example 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)

Figure pat00091
Figure pat00091

1H-NMR(400MHz, 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) 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)

실시예 4-2: 2-(((1R,3R,5S)-8-((5-사이클로프로필-3-(2,6-다이클로로페닐)아이소옥사졸-4-일)메틸)-8-아자바이사이클로[3.2.1]옥탄-3-일)아미노)벤조[d]티아졸-6-카르복실산 (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)의 제조Example 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)

Figure pat00092
Figure pat00092

1H-NMR(400MHz, 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) 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)

실시예 4-3: 6-(((1R,3R,5S)-8-((5-사이클로프로필-3-(2,6-다이클로로페닐)아이소옥사졸-4-일)메틸)-8-아자바이사이클로[3.2.1]옥탄-3-일)아미노)-2-나프토산 (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)의 제조Example 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)

Figure pat00093
Figure pat00093

1H-NMR(400MHz, 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) 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)

제조예 5: 3'-(((1R,3R,5S)-8-((5-사이클로프로필-3-(2,6-다이클로로페닐)아이소옥사졸-4-일)메틸)-8-아자바이사이클로[3.2.1]옥탄-3-일)아미노)-[1,1'-바이페닐]-4-카르복실산 (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)의 제조Preparation 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)

Figure pat00094
Figure pat00094

단계 1: tert-부틸 (1R,3R,5S)-3-((4'-(메톡시카르보닐)-[1,1'-바이페닐]-3-일)아미노)-8-아자바이사이클로[3.2.1]옥탄-8-카복실레이트 (tert-butyl (1R,3R,5S)-3-((4'-(methoxycarbonyl)-[1,1'-biphenyl]-3-yl)amino)-8-azabicyclo[3.2.1]octane-8-carboxylate)의 제조Step 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)

Figure pat00095
Figure pat00095

상기 반응식의 출발물질(1 당량), 메틸 3'-브로모-[1,1'-바이페닐]-4-카르복실레이트(1.5 당량), Pd(OAc)2(0.1 당량), 2,2'-비스(디페닐포스피노)-1,1'-비나프틸(0.1 당량), Cs2CO3(3 당량)를 톨루엔에 녹인 후 130 ℃에서 밤새 가열하였다. 반응 종결 후, EA와 brine solution을 이용하여 추출하였다. EA층에 Na2SO4를 첨가하여 수분을 제거하고 EA를 날렸다. MPLC에서 EA/Hx 조건에서 컬럼 분리하였다.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.

단계 2:Step 2: 메틸 3'-(((1R,3R,5S)-8-아자바이사이클로[3.2.1]옥탄-3-일)아미노)-[1,1'-바이페닐]-4-카르복실레이트의 제조Preparation of methyl 3'-(((1R,3R,5S)-8-azabicyclo[3.2.1]octan-3-yl)amino)-[1,1'-biphenyl]-4-carboxylate

Figure pat00096
Figure pat00096

단계 1에서 제조한 tert-부틸 (1R,3R,5S)-3-((4'-(메톡시카르보닐)-[1,1'-바이페닐]-3-일)아미노)-8-아자바이사이클로[3.2.1]옥탄-8-카복실레이트 (1 당량)를 CH2Cl2 2 ml에 녹였다. 트리플루오로 아세트산 2 ml를 넣었다. 상온에서 밤새 교반하였다. 반응 종결 후, 농축하였다. Vacuum 하였다.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.

단계 3: 메틸 3'-(((1R,3R,5S)-8-((5-사이클로프로필-3-(2,6-다이클로로페닐)아이소옥사졸-4-일)메틸)-8-아자바이사이클로[3.2.1]옥탄-3-일)아미노)-[1,1'-바이페닐]-4-카르복실레이트 (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)의 제조Step 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

Figure pat00097
Figure pat00097

메틸 3'-(((1R,3R,5S)-8-아자바이사이클로[3.2.1]옥탄-3-일)아미노)-[1,1'-바이페닐]-4-카르복실레이트(1 당량)과 4-(클로로메틸)-5-사이클로프로필-3-(2,6-다이클로로페닐)아이소옥사졸(1.1 당량)과 N,N-다이아이소프로필아민(2.5 당량)를 다이메틸아세트아마이드(DMA) 2 ml에 녹인 후 85 ℃에서 밤새 가열하였다. 반응 종결 후, EA와 brine solution을 이용하여 추출하였다. EA층에 Na2SO4를 첨가하여 수분을 제거하고 EA를 날렸다. Prep-LC를 이용하여 분리하였다.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.

단계 4: 3'-(((1R,3R,5S)-8-((5-사이클로프로필-3-(2,6-다이클로로페닐)아이소옥사졸-4-일)메틸)-8-아자바이사이클로[3.2.1]옥탄-3-일)아미노)-[1,1'-바이페닐]-4-카르복실산 (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)의 제조Step 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)

Figure pat00098
Figure pat00098

단계 3에서 제조한 메틸 3'-(((1R,3R,5S)-8-((5-사이클로프로필-3-(2,6-다이클로로페닐)아이소옥사졸-4-일)메틸)-8-아자바이사이클로[3.2.1]옥탄-3-일)아미노)-[1,1'-바이페닐]-4-카르복실레이트(1 당량), 1N KOH 수용액 2 ml을 THF 2 ml, 메탄올 1 ml에 녹인 후 50 ℃에서 밤새 교반하였다. EA, AcOH, 정제수로 추출하였다. EA층에 Na2SO4를 첨가하여 수분을 제거하고 EA를 날렸다. Prep-LC를 이용하여 분리하였다.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.

실시예 5-1: 3'-(((1R,3R,5S)-8-((5-사이클로프로필-3-(2,6-다이클로로페닐)아이소옥사졸-4-일)메틸)-8-아자바이사이클로[3.2.1]옥탄-3-일)아미노)-[1,1'-바이페닐]-4-카르복실산 (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)의 제조Example 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)

Figure pat00099
Figure pat00099

제조예 5와 실질적으로 동일한 방법으로 화합물을 제조하였다.A compound was prepared in substantially the same manner as in Preparation Example 5.

1H-NMR(400MHz, CDCl3) 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) 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)

제조예 6. 4'-((((1R,3R,5S)-8-((5-사이클로프로필-3-(2,6-다이클로로페닐)아이소옥사졸-4-일)메틸)-8-아자바이사이클로[3.2.1]옥탄-3-일)아미노)메틸)-[1,1'-바이페닐]-2-카르복실산 (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)의 제조Preparation 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)

Figure pat00100
Figure pat00100

단계 1. tert-부틸 ((1R,3R,5S)-8-((5-사이클로프로필-3-(2,6-다이클로로페닐)아이소옥사졸-4-일)메틸)-8-아자바이사이클로[3.2.1]옥탄-3-일)카바메이트 (tert-butyl ((1R,3R,5S)-8-((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)methyl)-8-azabicyclo[3.2.1]octan-3-yl)carbamate)의 제조Step 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)

Figure pat00101
Figure pat00101

tert-부틸 ((1R,3R,5S)-8-아자바이사이클로[3.2.1]옥탄-3-일)카르바메이트(1 당량), 4-(클로로메틸)-5-사이클로프로필-3-(2,6-다이클로로페닐)아이소옥사졸(1.1 당량), N,N-다이아이소프로필아민(2.5 당량)를 다이메틸아세트아마이드 2 ml에 녹인 후 85 ℃에서 밤새 가열하였다. 반응 종결 후, EA와 brine solution을 이용하여 추출하였다. EA층에 Na2SO4를 첨가하여 수분을 제거하고 EA를 날렸다. Prep-LC를 이용하여 분리하였다.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.

단계 2. (1R,3R,5S)-8-((5-사이클로프로필-3-(2,6-다이클로로페닐)아이소옥사졸-4-일)메틸)-8-아자바이사이클로[3.2.1]옥탄-3-아민 ((1R,3R,5S)-8-((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)methyl)-8-azabicyclo [3.2.1]octan-3-amine)의 제조Step 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)

Figure pat00102
Figure pat00102

단계 1에서 제조한 tert-부틸 ((1R,3R,5S)-8-((5-사이클로프로필-3-(2,6-다이클로로페닐)아이소옥사졸-4-일)메틸)-8-아자바이사이클로[3.2.1]옥탄-3-일)카바메이트(1 당량)를 다이클로로메탄 2 ml에 녹였다. 트리플루오로아세트산 2 ml를 넣었다. 상온에서 밤새 교반하였다. 반응 종결 후, 농축하였다. vacuum하였다.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.

단계 3. 메틸 4'-((((1R,3R,5S)-8-((5-사이클로프로필3-(2,6-다이클로로페닐)아이소옥사졸-4-일)메틸)-8-아자바이사이클로[3.2.1]옥탄-3-일)아미노)메틸)-[1,1'-바이페닐]-2-카르복실레이트 (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'-biphenyl]-2-carboxylate)의 제조Step 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)

Figure pat00103
Figure pat00103

단계 2에서 제조한 (1R,3R,5S)-8-((5-사이클로프로필-3-(2,6-다이클로로페닐)아이소옥사졸-4-일)메틸)-8-아자바이사이클로[3.2.1]옥탄-3-아민(1 당량), 메틸 4'-(브로모메틸)-[1,1'-바이페닐]-2-카르복실레이트(1.2 당량), Cs2CO3(2.5 당량)를 아세토나이트릴에 녹인 후 상온에서 밤새 교반하였다. 반응 종결 후, EA와 brine solution을 이용하여 추출하였다. EA층에 Na2SO4를 첨가하여 수분을 제거하고 EA를 날렸다. MPLC에서 MeOH/CHCl3 조건에서 컬럼 분리하였다.(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.

단계 4: 4'-((((1R, 3R, 5S)-8-((5-사이클로프로필-3-(2,6-다이클로로 페닐)아이소옥사졸-4-일)메틸)-8-아자바이사이클로[3.2.1]옥탄-3-일)아미노) 메틸)-[1,1'-바이페닐]-2-카르복실산 (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)의 제조Step 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)

Figure pat00104
Figure pat00104

단계 3에서 제조한 메틸 4'-((((1R,3R,5S)-8-((5-사이클로프로필3-(2,6-다이클로로페닐)아이소옥사졸-4-일)메틸)-8-아자바이사이클로[3.2.1]옥탄-3-일)아미노)메틸)-[1,1'-바이페닐]-2-카르복실레이트(1 당량), 1N KOH 수용액 2 ml을 THF 2 ml, 메탄올 1 ml에 녹인 후 50 ℃에서 밤새 교반하였다. EA, AcOH, 정제수로 추출하였다. EA층에 Na2SO4를 첨가하여 수분을 제거하고 EA를 날렸다. Prep-LC를 이용하여 분리하였다.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.

<실시예 6-1 내지 실시예 6-2><Examples 6-1 to 6-2>

실시예 6-1 내지 실시예 6-2에서는 제조예 6과 실질적으로 동일한 방법으로 화합물을 제조하였다.In Examples 6-1 to 6-2, compounds were prepared in substantially the same manner as in Preparation Example 6.

실시예 6-1: 4'-((((1R,3R,5S)-8-((5-사이클로프로필-3-(2,6-다이클로로페닐)아이소옥사졸-4-일)메틸)-8-아자바이사이클로[3.2.1]옥탄-3-일)아미노)메틸)-[1,1'-바이페닐]-2-카르복실산 (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)의 제조Example 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)

Figure pat00105
Figure pat00105

1H-NMR(400MHz, 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) 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)

실시예 6-2: 4'-((((1R,3S,5S)-8-((5-사이클로프로필-3-(2,6-다이클로로페닐)아이소옥사졸-4-일)메틸)-8-아자바이사이클로[3.2.1]옥탄-3-일)아미노)메틸)-[1,1'-바이페닐]-2-카르복실산 (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)의 제조Example 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)

Figure pat00106
Figure pat00106

1H-NMR(400MHz, 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) 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)

제조예 7: 3-(N-((1R,3R,5S)-8-((5-사이클로프로필-3-(2,6-다이클로로페닐)아이소옥사졸-4-일)메틸)-8-아자바이사이클로[3.2.1]옥탄-3-일)설파모일)벤조산 (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)의 제조Preparation 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)

Figure pat00107
Figure pat00107

단계 1. 메틸 3-(N-((1R,3R,5S)-8-((5-사이클로프로필-3-(2,6-다이클로로페닐)아이소옥사졸-4-일)메틸)-8-아자바이사이클로[3.2.1]옥탄-3-일)설파모일)벤조에이트 (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)의 제조Step 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)

Figure pat00108
Figure pat00108

(1R,3R,5S)-8-((5-사이클로프로필-3-(2,6-다이클로로페닐)아이소옥사졸-4-일)메틸)-8-아자바이사이클로[3.2.1]옥탄-3-아민(1 당량), 디메틸 2-(클로로설포닐)테레프탈레이트(1.1 당량), 트리에틸아민(2 당량)를 MC에 녹인 후 상온에서 밤새 교반하였다. 반응 종결 후, MC와 정제수로 추출하였다. MgSO4를 첨가하여 수분을 제거하고 MC를 제거하였다. MPLC를 이용하여 분리하였다.(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.

단계 2. 3-(N-((1R,3R,5S)-8-((5-사이클로프로필-3-(2,6-다이클로로페닐)아이소옥사졸-4-일)메틸)-8-아자바이사이클로[3.2.1]옥탄-3-일)설파모일)벤조산 (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)의 제조 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)

Figure pat00109
Figure pat00109

단계 1에서 제조한 메틸 3-(N-((1R,3R,5S)-8-((5-사이클로프로필-3-(2,6-다이클로로페닐)아이소옥사졸-4-일)메틸)-8-아자바이사이클로[3.2.1]옥탄-3-일)설파모일)벤조에이트(1 당량), 1N KOH 수용액 2ml을 THF 2ml, 메탄올 1ml에 녹인 후 50 ℃에서 밤새 교반하였다. 반응 종결 후, EA, AcOH, 정제수로 추출하였다. EA층에 Na2SO4를 첨가하여 수분을 제거하고 EA를 날렸다. Prep-LC를 이용하여 분리하였다.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.

<실시예 7-1 내지 실시예 7-2><Examples 7-1 to 7-2>

실시예 7-1 내지 실시예 7-2에서는 제조예 7과 실질적으로 동일한 방법으로 화합물을 제조하였다.In Examples 7-1 to 7-2, compounds were prepared in substantially the same manner as in Preparation Example 7.

실시예 7-1: 3-(N-((1R,3R,5S)-8-((5-사이클로프로필-3-(2,6-다이클로로페닐)아이소옥사졸-4-일)메틸)-8-아자바이사이클로[3.2.1]옥탄-3-일)설파모일)벤조산 (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)의 제조Example 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)

Figure pat00110
Figure pat00110

1H-NMR(400MHz, DMSO-d6) δ ppm 1.03-1.91 (12H, m), 2.31-2.86 (4H, m), 3.16 (2H, s), 7.44-8.32 (8H, m) 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)

실시예 7-2: 2-(N-((1R,3R,5S)-8-((5-사이클로프로필-3-(2,6-다이클로로페닐)아이소옥사졸-4-일)메틸)-8-아자바이사이클로[3.2.1]옥탄-3-일)설파모일)벤조산 (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)의 제조Example 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)

Figure pat00111
Figure pat00111

1H-NMR(400MHz, 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) 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)

제조예 8: 2-(6-(((1R,3R,5S)-8-((5-사이클로프로필-3-(2,6-다이디클로로페닐)아이소옥사졸-4-일)메틸)-8-아자바이사이클로[3.2.1]옥탄-3-일)카르바모일)피리딘-3-일)벤조산 (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)의 제조Preparation 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)

Figure pat00112
Figure pat00112

단계 1: tert-부틸 (1R,3R,5S)-3-(5-브로모피콜린아미도)-8-아자바이사이클로[3.2.1]옥탄-8-카르복실레이트 (tert-butyl (1R,3R,5S)-3-(5-bromopicolinamido)-8-azabicyclo[3.2.1]octane-8-carboxylate)의 제조Step 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)

Figure pat00113
Figure pat00113

tert-부틸 (1R,3R,5S)-3-아미노-8-아자바이사이클로[3.2.1]옥탄-8-카르복실레이트(1 당량), 5-브로모피콜산(1.3 당량)와 HOBt(1.1 당량), EDCI.HCl(1.15 당량) 넣고 TEA(3 당량)를 넣은 후 MC에 녹여서 상온에서 밤새 교반하였다. 반응 종결 후, MC와 정제수로 추출하였다. MgSO4를 첨가하여 수분을 제거하고 MC를 제거하였다. MPLC 를 이용하여 분리하였다.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.

단계 2: N-((1R,3R,5S)-8-아자바이사이클로[3.2.1]옥탄-3-일)-5-브로모피콜린아미드 (N-((1R,3R,5S)-8-azabicyclo[3.2.1]octan-3-yl)-5-bromopicolinamide)의 제조Step 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)

Figure pat00114
Figure pat00114

단계 1에서 제조한 tert-부틸 (1R,3R,5S)-3-(5-브로모피콜린아미도)-8-아자바이사이클로[3.2.1]옥탄-8-카르복실레이트 (1 당량)를 다이클로로메탄 2 ml에 녹였다. 트리플루오로아세트산 2 ml를 넣고, 상온에서 밤새 교반하였다. 반응 종결 후, 농축하고 vacuum 진공 건조하였다.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.

단계 3: 5-브로모-N-((1R,3R,5S)-8-((5-사이클로프로필-3-(2,6-다이클로로페닐)아이소옥사졸-4-일)메틸)-8-아자바이사이클로[3.2.1]옥탄-3-일)피콜린아미드 (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)의 제조Step 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)

Figure pat00115
Figure pat00115

단계 2에서 제조한 N-((1R,3R,5S)-8-아자바이사이클로[3.2.1]옥탄-3-일)-5-브로모피콜린아미드(1 당량)과 4-(클로로메틸)-5-사이클로프로필-3-(2,6-다이클로로페닐)아이소옥사졸 (1.1 당량)을 넣고 다이메틸아세트아마이드(2 ml)에 녹인 후 N,N-다이아이소프로필아민(2.5 아민)를 주입 하고 85 ℃에서 밤새 가열하였다. 반응 종결 후, EA와 brine solution을 이용하여 추출하였다. EA층에 Na2SO4를 첨가하여 수분을 제거하고 EA를 날렸다. Prep-LC를 이용하여 분리하였다.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.

단계 4: 메틸 2-(6-(((1R,3R,5S)-8-((5-사이클로프로필-3-(2,6-다이클로로페닐)아이소옥사졸-4-일)메틸)-8-아자바이사이클로[3.2.1]옥탄-3-일)카르바모일)피리딘-3-일)벤조에이트 (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)의 제조Step 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)

Figure pat00116
Figure pat00116

단계 3에서 제조한 5-브로모-N-((1R,3R,5S)-8-((5-사이클로프로필-3-(2,6-다이클로로페닐)아이소옥사졸-4-일)메틸)-8-아자바이사이클로[3.2.1] 옥탄-3-일)피콜린아미드(1 당량), 2-(메톡시카르보닐)페닐)보론산(1.5 당량), 2N K2CO3(3 당량), Pd(dppf)2Cl2(0.1 당량)를 다이옥산(2 ml)에 녹인 후 130 ℃에서 밤새 교반하였다. 반응 종결 후, EA와 brine solution을 이용하여 추출하였다. EA층에 Na2SO4를 첨가하여 수분을 제거하고 EA를 제거하였다. Prep-LC를 이용하여 분리하였다.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.

단계 5. 2-(6-(((1R,3R,5S)-8-((5-사이클로프로필-3-(2,6-다이클로로페닐)아이소옥사졸-4-일)메틸)-8-아자바이사이클로[3.2.1]옥탄-3-일)카르바모일)피리딘-3-일)벤조산 (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)의 제조Step 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)

Figure pat00117
Figure pat00117

단계 4에서 제조한 메틸 2-(6-(((1R,3R,5S)-8-((5-사이클로프로필-3-(2,6-다이클로로페닐)아이소옥사졸-4-일)메틸)-8-아자바이사이클로[3.2.1]옥탄-3-일)카르바모일)피리딘-3-일)벤조에이트(1 당량), 1N KOH 수용액 2 ml을 THF 2 ml : 메탄올 1 ml에 녹인 후 50 ℃에서 밤새 교반 하였다. 반응 종결 후, EA, AcOH, 정제수로 추출하였다. EA층에 Na2SO4를 첨가하여 수분을 제거하고 EA를 날렸다. Prep-LC를 이용하여 분리하였다.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.

<실시예 8-1 내지 실시예 8-2><Examples 8-1 to 8-2>

실시예 8-1 내지 실시예 8-2에서는 제조예 8과 실질적으로 동일한 방법으로 화합물을 제조하였다.In Examples 8-1 to 8-2, compounds were prepared in substantially the same manner as in Preparation Example 8.

실시예 8-1: 2-(6-(((1R,3R,5S)-8-((5-사이클로프로필-3-(2,6-다이클로로페닐)아이소옥사졸-4-일)메틸)-8-아자바이사이클로[3.2.1]옥탄-3-일)카르바모일)피리딘-3-일)벤조산 (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)의 제조Example 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)

Figure pat00118
Figure pat00118

1H-NMR(400MHz, CDCl3) 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) 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)

실시예 8-2: 4-(((1R,3R,5S)-8-((5-사이클로프로필-3-(2,6-다이클로로페닐)아이소옥사졸-4-일)메틸)-8-아자바이사이클로[3.2.1]옥탄-3-일)카르바모일)벤조산 (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)의 제조Example 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)

Figure pat00119
Figure pat00119

1H-NMR(400MHz, 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) 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)

제조예 9: 4'-(3-((1R,3R,5S)-8-((5-사이클로프로필-3-(2,6-다이클로로페닐)아이소옥사졸-4-일)메틸)-8-아자바이사이클로[3.2.1]옥탄-3-일)우레이도)-[1,1'-바이페닐]-4-카르복실산 (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)의 제조Preparation 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)

Figure pat00120
Figure pat00120

단계 1: 1-(4-브로모페닐)-3-((1R,3R,5S)-8-((5-사이클로프로필-3-(2,6-다이클로로페닐)아이소옥사졸-4-일)메틸)-8-아자바이사이클로[3.2.1]옥탄-3-일)우레아 (1-(4-bromophenyl)-3-((1R,3R,5S)-8-((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)methyl)-8-azabicyclo[3.2.1]octan-3-yl)urea)의 제조Step 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)

Figure pat00121
Figure pat00121

(1R,3R,5S)-8-((5-사이클로프로필-3-(2,6-다이클로로페닐)아이소옥사졸-4-일)메틸)-8-아자바이사이클로[3.2.1]옥탄-3-아민(1 당량), 1-브로모-4-이소시아네이토 벤젠(1.2 당량), TEA(2.5 당량)를 THF에 녹인 후 상온에서 밤새 교반하였다. 반응 종결 후, EA와 brine solution을 이용하여 추출하였다. EA층에 Na2SO4를 첨가하여 수분을 제거하고 EA를 제거하였다. MPLC를 이용하여 분리하였다.(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.

단계 2. 에틸 4'-(3-((1R,3R,5S)-8-((5-사이클로프로필-3-(2,6-다이클로로페닐)아이소옥사졸-4-일)메틸)-8-아자바이사이클로[3.2.1]옥탄-3-일)우레이도)-[1,1'-바이페닐]-4-카르복실레이트 (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)의 제조Step 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

Figure pat00122
Figure pat00122

단계 1에서 제조한 1-(4-브로모페닐)-3-((1R,3R,5S)-8-((5-사이클로프로-3-(2,6-다이클로로페닐)아이소옥사졸-4-일)메틸)-8-아자바이사이클로[3.2.1]옥탄-3-일)우레아(1 당량), (4-(에톡시카르보닐)페닐)보론산(1.5 당량), 2N K2CO3(3 당량), Pd(dppf)2Cl2(0.1 당량)를 다이옥산(2 ml)에 녹인 후 130 ℃에서 밤새 교반하였다. 반응 종결 후, EA와 brine solution을 이용하여 추출하였다. EA층에 Na2SO4를 첨가하여 수분을 제거하고 EA를 제거하였다. Prep-LC를 이용하여 분리하였다.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.

단계 3. 4'-(3-((1R,3R,5S)-8-((5-사이클로프로필-3-(2,6-다이클로로페닐)아이소옥사졸-4-일)메틸)-8-아자바이사이클로[3.2.1]옥탄-3-일)우레이도)-[1,1'-바이페닐]-4-카르복실산 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 acid의 제조Step 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

Figure pat00123
Figure pat00123

단계 2에서 제조한 에틸 4'-(3-((1R,3R,5S)-8-((5-사이클로프로필-3-(2,6-다이클로로페닐)아이소옥사졸-4-일)메틸)-8-아자바이사이클로[3.2.1]옥탄-3-일)우레이도)-[1,1'-바이페닐]-4-카르복실레이트(1 당량), 1N KOH 수용액 2 ml을 THF 2 ml, 메탄올 1 ml에 녹인 후 50 ℃에서 밤새 교반하였다. 반응 종결 후, EA, AcOH, 정제수로 추출하였다. EA층에 Na2SO4를 첨가하여 수분을 제거하고 EA를 제거하였다. Prep-LC를 이용하여 분리하였다.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.

<실시예 9-1 내지 실시예 9-2><Examples 9-1 to 9-2>

실시예 9-1 내지 실시예 9-2에서는 제조예 9와 실질적으로 동일한 방법으로 화합물을 제조하였다.In Examples 9-1 to 9-2, compounds were prepared in substantially the same manner as in Preparation Example 9.

실시예 9-1: 4'-(3-((1R,3R,5S)-8-((5-사이클로프로필-3-(2,6-다이클로로페닐)아이소옥사졸-4-일)메틸)-8-아자바이사이클로[3.2.1]옥탄-3-일)우레이도)-[1,1'-바이페닐]-4-카르복실산 (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)의 제조Example 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)

Figure pat00124
Figure pat00124

1H-NMR(400MHz, 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) 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)

실시예 9-2: 4-(3-((1R,3R,5S)-8-((5-사이클로프로필-3-(2,6-다이클로로페닐)아이소옥사졸-4-일)메틸)-8-아자바이사이클로[3.2.1]옥탄-3-일)우레이도)벤조산 (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)의 제조Example 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)

Figure pat00125
Figure pat00125

1H-NMR(400MHz, 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) 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)

제조예 10: 4'-((((1R,3R,5S)-8-(5-사이클로프로필-3-(2,6-다이클로로페닐)아이소옥사졸-4-카르보닐)-8-아자바이사이클로[3.2.1]옥탄-3-일)옥시)메틸)-[1,1'-바이페닐]-4-카르복실산 (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)의 제조Preparation 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)

Figure pat00126
Figure pat00126

단계 1: (1R,5S)-8-(5-사이클로프로필-3-(2,6-다이클로로페닐)아이소옥사졸-4-카르보닐)-8-아자바이사이클로[3.2.1]옥탄-3-온 (1R,5S)-8-(5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazole-4-carbonyl)-8-azabicyclo[3.2.1]octan-3-one)의 제조Step 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)

Figure pat00127
Figure pat00127

DMF에 5-사이클로프로필-3-(2,6-다이클로로페닐)아이소옥사졸-4-카르복실산(1.5 당량), (1S,5S)-8-아자바이사이클로[3.2.1]옥탄-3-온(1 당량), HATU(1.5 당량), DIPEA(3 당량)를 녹여 상온에서 밤새 교반하였다. 반응 종결 후, 1M NaOH를 과량 첨가하여 acid를 제거하고 MC를 이용하여 추출하였다. MC층을 황산마그네슘을 이용하여 건조한 후, 회전농축기를 이용하여 MC를 제거하고 생성물을 수득하였다(207.5 mg, 39% 수율).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).

단계 2: 5-사이클로프로필-3-(2,6-다이클로로페닐)아이소옥사졸-4-일)(1R,5S)-3-하이드록시-8-아자바이사이클로[3.2.1]옥탄-8-일)메탄온 (5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)((1R,5S)-3-hydroxy-8-azabicyclo[3.2.1]octan-8-yl)methanone 제조Step 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

Figure pat00128
Figure pat00128

단계 1에서 제조한 (1R,5S)-8-(5-사이클로프로필-3-(2,6-다이클로로페닐)아이소옥사졸-4-카르보닐)-8-아자바이사이클로[3.2.1]옥탄-3-온(1 당량)을 0 ℃에서 메탄올 5 ml에 NaBH4(1.2 당량)를 추가한 후, 상온에서 30분간 교반하였다. 반응 종결 후, 진공회전 농축기를 이용하여 메탄올을 제거하였다. EA와 1M HCl 용액을 이용하여 acidify하였다. 황산마그네슘을 이용하여 EA층을 건조시키고, 회전농축기를 이용하여 EA를 제거 후, MPLC로 분리하여 생성물, 즉 5-사이클로프로필-3-(2,6-다이클로로페닐)아이소옥사졸-4-일)(1R,3S,5S)-3-하이드록시-8-아자바이사이클로[3.2.1]옥탄-8-일)메탄온 ((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 % 수율) 및 5-사이클로프로필-3-(2,6-다이클로로페닐)아이소옥사졸-4-일)(1R,3R,5S)-3-하이드록시-8-아자바이사이클로[3.2.1]옥탄-8-일)메탄온 ((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 % 수율)를 수득하였다.(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.

단계 3-1: ((1R,3S,5S)-3-((4-브로모벤질)옥시)-8-아자바이사이클로[3.2.1]옥탄-8-일)(5-사이클로프로필-3-(2,6-다이클로로페닐)아이소옥사졸-4-일)메탄온 ((1R,3S,5S)-3-((4-bromobenzyl)oxy)-8-azabicyclo[3.2.1]octan-8-yl)(5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)methanone의 제조 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

Figure pat00129
Figure pat00129

단계 2에서 제조한 5-사이클로프로필-3-(2,6-다이클로로페닐)아이소옥사졸-4-일)(1R,3S,5S)-3-하이드록시-8-아자바이사이클로[3.2.1]옥탄-8-일)메탄온(1 당량)에, THF 3 ml, 18-크라운-6 에터(1.5 당량), KOtBu(2 당량)을 넣고 20분간 교반하였다. 여기에 1-브로모-4-(브로모메틸)벤젠(1.5 당량)을 넣고 4 시간 동안 교반하였다. 염화암모늄 포화 수용액과 EA를 사용하여 추출하였다. 황산마그네슘을 이용하여 건조시키고 회전농축기를 이용하여 EA 용액을 제거 후, MPLC로 정제하여 생성물을 얻었다(28% 수율).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).

단계 4-1: 4'-((((1R,3S,5S)-8-(5-사이클로프로필-3-(2,6-다이클로로페닐)아이소옥사졸-4-카르보닐)-8-아자바이사이클로[3.2.1]옥탄-3-일)옥시)메틸)[1,1'-바이페닐]-4-카르복실산 (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)의 제조Step 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)

Figure pat00130
Figure pat00130

단계 3-1에서 제조한 ((1R,3S,5S)-3-((4-브로모벤질)옥시)-8-아자바이사이클로[3.2.1]옥탄-8-일)(5-사이클로프로필-3-(2,6-다이클로로페닐)아이소옥사졸-4-일)메탄온(1 당량), 4-보로노벤조산(2 당량), Pd(amphos)Cl2(0.2 당량), DIPEA 0.1 ml(과량)를 THF 1ml: MeOH 1ml에 녹이고, 50 ℃에서 2 시간 동안 교반하였다. 반응 종결 후, 1N HCl과 EA로 추출하였다. 황산마그네슘을 이용하여 건조시키고 회전농축기를 이용하여 EA 용액을 제거 후, Prep-LC로 정제하여 생성물을 얻었다(40 % 수율). 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).

<실시예 10-1 내지 실시예 10-7><Examples 10-1 to 10-7>

실시예 10-1 내지 실시예 10-7에서는 제조예 10과 실질적으로 동일한 방법으로 화합물을 제조하였다. In Examples 10-1 to 10-7, compounds were prepared in substantially the same manner as in Preparation Example 10.

실시예 10-1: 4'-((((1R,3S,5S)-8-(5-사이클로프로필-3-(2,6-다이클로로페닐)아이소옥사졸-4-카르보닐)-8-아자바이사이클로[3.2.1]옥탄-3-일)옥시)메틸)-[1,1'-바이페닐]-4-카르복실산 (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)의 제조Example 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)

Figure pat00131
Figure pat00131

1H-NMR(400MHz, CDCl3) 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) 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)

실시예 10-2: 4'-((((1R,3R,5S)-8-(5-사이클로프로필-3-(2,6-다이클로로페닐)아이소옥사졸-4-카르보닐)-8-아자바이사이클로[3.2.1]옥탄-3-일)옥시)메틸)-[1,1'-바이페닐]-4-카르복실산 (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)의 제조Example 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)

제조예 10의 단계 2-2를 이용하여 제조할 수 있다. It can be prepared using step 2-2 of Preparation Example 10.

Figure pat00132
Figure pat00132

1H-NMR(400MHz, CDCl3) 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) 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)

실시예 10-3: 5-(4-((((1R,3R,5S)-8-(5-사이클로프로필-3-(2,6-다이클로로페닐)아이소옥사졸-4-카르보닐)-8-아자바이사이클로[3.2.1]옥탄-3-일)옥시)메틸)페닐)피리미딘-2-카르복실산 (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)의 제조Example 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)

Figure pat00133
Figure pat00133

1H-NMR(400MHz, CDCl3) 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) 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)

실시예 10-4: 4'-((((1R,3R,5S)-8-(5-사이클로프로필-3-(2,6-다이클로로페닐)아이소옥사졸-4-카르보닐)-8-아자바이사이클로[3.2.1]옥탄-3-일)옥시)메틸)-[1,1'-바이페닐]-2-카르복실산 (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)의 제조Example 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)

Figure pat00134
Figure pat00134

1H-NMR(400MHz, CDCl3) 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) 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)

실시예 10-5: 4'-((((1R,3R,5S)-8-(5-사이클로프로필-3-(2,6-다이클로로페닐)아이소옥사졸-4-카르보닐)-8-아자바이사이클로[3.2.1]옥탄-3-일)옥시)메틸)-4-플루오로-[1,1'-바이페닐]-3-카르복실산 (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)의 제조Example 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)

Figure pat00135
Figure pat00135

1H-NMR(400MHz, CDCl3) 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) 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)

실시예 10-6: 4'-((((1R,3R,5S)-8-(5-사이클로프로필-3-(2,6-다이클로로페닐)아이소옥사졸-4-카르보닐)-8-아자바이사이클로[3.2.1]옥탄-3-일)옥시)메틸)-3-플루오로-[1,1'-바이페닐]-4-카르복실산 (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)의 제조Example 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)

Figure pat00136
Figure pat00136

1H-NMR(400MHz, CDCl3) 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) 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)

실시예 10-7: 3-(4-((((1R,3R,5S)-8-(5-사이클로프로필-3-(2,6-다이클로로페닐)아이소옥사졸-4-카르보닐)-8-아자바이사이클로[3.2.1]옥탄-3-일)옥시)메틸)페닐)이소니코틴산 (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)의 제조Example 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)

Figure pat00137
Figure pat00137

1H-NMR(400MHz, CDCl3) 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) 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)

실험예: 본 발명의 FXR 작용제 활성 평가(cofactor assay)Experimental Example: FXR agonist activity evaluation (cofactor assay) of the present invention

본 발명의 화합물들은 LanthaScreen™ TR-FRET FXR Coactivator Assay kit를 사용하여 cofactor recruitment 여부를 확인하였다. 화합물 10uM, FL-SRC2-2 500nM, TB anti-GST 5nM, FXR-LBD-GST 5nM 로 실온에서 1시간 동안 반응시켰다. 그 후 Excitation 340nm, Emission 520과 495nm로 Flexstation을 사용하여 reading하였다. Emission 파장값을 520/495로 계산한 뒤 대조약물(control)인 tropifexor 또는 INT-747 대비　% 로 표기하였다. 그 결과는 하기 표 1에 나타내었다.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.

[표 1][Table 1]

Figure pat00138
Figure pat00138

Figure pat00139
Figure pat00139

Claims (6)

하기 화학식 1로 표시되는 화합물, 이의 광학 이성질체, 또는 이의 약학적으로 허용가능한 염:
[화학식 1]
Figure pat00140

상기 화학식 1에서,
m 및 n은 각각 독립적으로 0 또는 1이고;
고리 A는 아릴, 헤테로아릴, 또는 아무 것도 아니고(null) {여기서, 상기 아릴 또는 헤테로아릴의 하나 이상의 H는 -C1-4알킬, -C1-4시아노알킬, -C1-4아미노알킬, -C1-4하이드록시알킬, -C1-4할로알킬, -CN, -NR1R2, -OR3, 또는 할로로 치환될 수 있음};
고리 B는 아릴, 헤테로아릴, 사이클로알킬, 또는 헤테로사이클로알킬이고 {여기서, 상기 아릴 또는 헤테로아릴의 하나 이상의 H는 -C1-4알킬, -C1-4시아노알킬, -C1-4아미노알킬, -C1-4하이드록시알킬, -C1-4할로알킬, -CN, -NR1R2, -OR3, 또는 할로로 치환될 수 있고; 상기 사이클로알킬 또는 헤테로사이클로알킬의 하나 이상의 H는 -C1-4알킬 또는 -할로로 치환될 수 있음};
X는 -NH-, -O-, 또는 -S-이고;
L1은 -(CH2)a-, -C(=O)-, -C(=O)NH-, -S(=O)-, -S(=O)2-, 또는 아무 것도 아니고(null) {여기서, 상기 -(CH2)a-의 하나 이상의 H는 -C1-4알킬, -C1-4할로알킬, 또는 할로로 치환될 수 있음};
L2는 -(CH2)b-, -C(=O)-, -S(=O)-, 또는 -S(=O)2- 이고 {여기서, 상기 -(CH2)b-의 하나 이상의 H는 -C1-4알킬, -C1-4할로알킬, 또는 할로로 치환될 수 있음};
a 및 b는 각각 독립적으로 1, 2, 3, 또는 4이고;
Y는 아릴 또는 헤테로아릴이고 {여기서, 상기 아릴 또는 헤테로아릴의 하나 이상의 H는 -H, -C1-4알킬, -C1-4할로알킬, -CN, -NR1R2, -OR3, 또는 -할로로 치환될 수 있음};
Z는 사이클로알킬 또는 헤테로사이클로알킬이고 {여기서, 상기 사이클로알킬 또는 헤테로사이클로알킬의 하나 이상의 H는 -H, -C1-4알킬, -C1-4할로알킬, -CN, -NR1R2, -OR3, 또는 -할로로 치환될 수 있음};
R1 및 R2는 각각 독립적으로 -H 또는 -C1-4알킬이고;
R3는 -H, -C1-4알킬이고, 또는 -C1-4할로알킬이다.A compound represented by the following formula (1), an optical isomer thereof, or a pharmaceutically acceptable salt thereof:
[Formula 1]
Figure pat00140

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. 제 1 항에 있어서,
m 및 n은 각각 독립적으로 1이고;
고리 A는 아릴, 헤테로아릴, 또는 아무 것도 아니고(null) {여기서, 상기 아릴 또는 헤테로아릴의 하나 이상의 H는 -C1-4알킬, 또는 할로로 치환될 수 있음};
고리 B는 아릴, 헤테로아릴, 또는 헤테로사이클로알킬이고 {여기서, 상기 아릴 또는 헤테로아릴의 하나 이상의 H는 -C1-4알킬, -C1-4할로알킬, -CN, -OR3, 또는 할로로 치환될 수 있고; 상기 헤테로사이클로알킬의 하나 이상의 H는 -C1-4알킬 또는 -할로로 치환될 수 있음};
X는 -NH- 또는 -O-이고;
L1은 -(CH2)a-, -C(=O)-, -C(=O)NH-, -S(=O)2-, 또는 아무 것도 아니고(null) {여기서, 상기 -(CH2)a-의 하나 이상의 H는 -C1-4알킬, -C1-4할로알킬, 또는 할로로 치환될 수 있음};
L2는 -(CH2)b- 또는 -C(=O)- 이고 {여기서, 상기 -(CH2)b-의 하나 이상의 H는 -C1-4알킬, -C1-4할로알킬, 또는 할로로 치환될 수 있음};
a 및 b는 각각 독립적으로 1이고;
Y는 아릴이고 {여기서, 상기 아릴의 하나 이상의 H는 -H, -C1-4알킬, -NR1R2, -OR3, 또는 -할로로 치환될 수 있음};
Z는 사이클로알킬이고 {여기서, 상기 사이클로알킬의 하나 이상의 H는 -H, -C1-4알킬, -C1-4할로알킬, 또는 -할로로 치환될 수 있음};
R1 및 R2는 각각 독립적으로 -H 또는 -C1-4알킬이고;
R3는 -H, -C1-4알킬이고, 또는 -C1-4할로알킬인;
화학식 1로 표시되는 화합물, 이의 광학 이성질체, 또는 이의 약학적으로 허용가능한 염.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. 제 2 항에 있어서,
상기 화학식 1로 표시되는 화합물은 하기 화학식 2로 표시되는 화합물이고;
[화학식 2]
Figure pat00141

상기 화학식 2에서,
고리 A는 6-10원 아릴, 5-6원 헤테로아릴, 또는 아무 것도 아니고(null) {여기서, 상기 5-6원 헤테로아릴은 고리 내에 N, O, 또는 S 원자 중 1 이상을 포함하고, 상기 6-10원 아릴 또는 5-6원 헤테로아릴의 하나 이상의 H는 -C1-4알킬 또는 할로로 치환될 수 있음};
고리 B는 6-10원 아릴, 5-10원 헤테로아릴, 또는 4-7원 헤테로사이클로알킬이고 {여기서, 상기 5-10원 헤테로아릴 및 4-7원 헤테로사이클로알킬은 고리 내에 N, O, 또는 S 원자 중 1 이상을 포함하고, 상기 6-10원 아릴 또는 5-10원 헤테로아릴의 하나 이상의 H는 -C1-4알킬, -C1-4할로알킬, -CN, -OR3, 또는 할로로 치환될 수 있고; 상기 4-7원 헤테로사이클로알킬의 하나 이상의 H는 -C1-4알킬 또는 -할로로 치환될 수 있음};
X는 -NH- 또는 -O-이고;
L1은 -(CH2)a-, -C(=O)-, -C(=O)NH-, -S(=O)2-, 또는 아무 것도 아니고(null) {여기서, 상기 -(CH2)a-의 하나 이상의 H는 -C1-4알킬, -C1-4할로알킬, 또는 할로로 치환될 수 있음};
L2는 -(CH2)b- 또는 -C(=O)- 이고 {여기서, 상기 -(CH2)b-의 하나 이상의 H는 -C1-4알킬, -C1-4할로알킬, 또는 할로로 치환될 수 있음};
a 및 b는 각각 독립적으로 1이고;
Y1 및 Y2는 각각 독립적으로 -H, -C1-4알킬, -NR1R2, -OR3, 또는 -할로이고;
R1 및 R2는 각각 독립적으로 -H 또는 -C1-4알킬이고;
R3는 -H, -C1-4알킬이고, 또는 -C1-4할로알킬인;
화학식 1로 표시되는 화합물, 이의 광학 이성질체, 또는 이의 약학적으로 허용가능한 염.3. The method of claim 2,
The compound represented by Formula 1 is a compound represented by Formula 2 below;
[Formula 2]
Figure pat00141

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. 제 1 항에 있어서,
상기 화학식 1로 표시되는 화합물이 하기 화합물로 이루어진 군으로부터 선택된 것인, 화합물, 이의 광학 이성질체, 또는 이의 약학적으로 허용 가능한 염:
(1-1) 4-((((1R,3R,5S)-8-((5-사이클로프로필-3-(2,6-다이클로로페닐)아이소옥사졸-4-일)메틸)-8-아자바이사이클로[3.2.1]옥탄-3-일)옥시)메틸)벤조산;
(2-1) 2-(4-((((1R,3R,5S)-8-(5-사이클로프로필-3-(2,6-다이클로로페닐)아이소옥사졸-4-일)-메틸)-8-아자바이사이클로[3.2.1]옥탄-3-일)옥시)메틸)페닐)니코틴산;
(2-2) 4'-((((1R,3R,5S)-8-((5-사이클로프로필-3-(2,6-다이클로로페닐)아이소옥사졸-4-일)메틸)-8-아자바이사이클로[3.2.1]옥탄-3-일)옥시)메틸)-6-플루오로-[1,1'-바이페닐]-3-카르복실산;
(2-3) 4'-((((1R,3R,5S)-8-((5-사이클로프로필-3-(2,6-다이클로로페닐)아이소옥사졸-4-일)메틸)-8-아자바이사이클로[3.2.1]옥탄-3-일)옥시)메틸)-4-메틸-[1,1'-바이페닐]-3-카르복실산;
(2-4) 4'-((((1R,3R,5S)-8-((5-사이클로프로필-3-(2,6-다이클로로페닐)아이소옥사졸-4-일)메틸)-8-아자바이사이클로[3.2.1]옥탄-3-일)옥시)메틸)-6-메틸-[1,1'-바이페닐]-3-카르복실산;
(2-5) 4'-((((1R,3R,5S)-8-((5-사이클로프로필-3-(2,6-다이클로로페닐)아이소옥사졸-4-일)메틸)-8-아자바이사이클로[3.2.1]옥탄-3-일)옥시)메틸)-5-플루오로-[1,1'-바이페닐]-3-카르복실산;
(2-6) 4-클로로-4'-((((1R,3R,5S)-8-((5-사이클로프로필-3-(2,6-다이클로로페닐)아이소옥사졸-4-일)메틸)-8-아자바이사이클로[3.2.1]옥탄-3-일)옥시)메틸)-[1,1'-바이페닐]-3-카르복실산;
(2-7) 4'-((((1R,3R,5S)-8-((5-사이클로프로필-3-(2,6-다이클로로페닐)아이소옥사졸-4-일)메틸)-8-아자바이사이클로[3.2.1]옥탄-3-일)옥시)메틸)-2'-메틸-[1,1'-바이페닐]-4-카르복실산;
(2-8) 4'-((((1R,3R,5S)-8-((5-사이클로프로필-3-(2,6-다이클로로페닐)아이소옥사졸-4-일)메틸)-8-아자바이사이클로[3.2.1]옥탄-3-일)옥시)메틸)-2'-메틸-[1,1'-바이페닐]-3-카르복실산;
(2-9) 5-시아노-4'-((((1R,3R,5S)-8-((5-사이클로프로필-3-(2,6-다이클로로페닐)아이소옥사졸-4-일)메틸)-8-아자바이사이클로[3.2.1]옥탄-3-일)옥시)메틸)-[1,1'-바이페닐]-3-카르복실산;
(2-10) 4'-((((1R,3R,5S)-8-((5-사이클로프로필-3-(2,6-다이클로로페닐)아이소옥사졸-4-일)메틸)-8-아자바이사이클로[3.2.1]옥탄-3-일)옥시)메틸)-2-플루오로-[1,1'-바이페닐]-3-카르복실산;
(2-11) 3-(6-((((1R,3R,5S)-8-((5-사이클로프로필-3-(2,6-다이클로로페닐)아이소옥사졸-4-일)메틸)-8-아자바이사이클로[3.2.1]옥탄-3-일)옥시)메틸)피리딘-3-일)벤조산;
(2-12) 3-(4-((((1R,3R,5S)-8-((5-사이클로프로필-3-(2,6-다이클로로페닐)아이소옥사졸-4-일)메틸)-8-아자바이사이클로[3.2.1]옥탄-3-일)옥시)메틸)-2-메틸페닐)푸란-2-카르복실산;
(2-13) 4'-((((1R,3R,5S)-8-((5-사이클로프로필-3-(2,6-다이클로로페닐)아이소옥사졸-4-일)메틸)-8-아자바이사이클로[3.2.1]옥탄-3-일)옥시)메틸)-6-플루오로-5-메틸-[1,1'-바이페닐]-3-카르복실산;
(2-14) 3-(4-((((1R,3R,5S)-8-((5-사이클로프로필-3-(2-(트리플루오로메톡시)페닐)아이소옥사졸-4-일)메틸)-8-아자바이사이클로[3.2.1]옥탄-3-일)옥시)메틸)-2-메틸페닐)푸란-2-카르복실산;
(2-15) 3-(6-((((1R,3R,5S)-8-((5-사이클로프로필-3-(2,6-다이클로로페닐)아이소옥사졸-4-일)메틸)-8-아자바이사이클로[3.2.1]옥탄-3-일)옥시)메틸)피리딘-3-일)푸란-2-카르복실산;
(2-16) 2-(6-((((1R,3R,5S)-8-((5-사이클로프로필-3-(2,6-다이클로로페닐)아이소옥사졸-4-일)메틸)-8-아자바이사이클로[3.2.1]옥탄-3-일)옥시)메틸)피리딘-2-일)벤조산;
(2-17) 3-(4-((((1R,3R,5S)-8-((5-사이클로프로필-3-(2,6-다이클로로페닐)아이소옥사졸-4-일)메틸)-8-아자바이사이클로[3.2.1]옥탄-3-일)옥시)메틸)페닐)푸란-2-카르복실산;
(2-18) 3-(4-((((1R,3R,5S)-8-((5-사이클로프로필-3-(2,6-다이클로로페닐)아이소옥사졸-4-일)메틸)-8-아자바이사이클로[3.2.1]옥탄-3-일)옥시)메틸)페닐)푸란-2-카르복실산;
(2-19) 4-(4-((((1R,3R,5S)-8-((5-사이클로프로필-3-(2,6-다이클로로페닐)아이소옥사졸-4-일)메틸)-8-아자바이사이클로[3.2.1]옥탄-3-일)옥시)메틸)페닐)티오펜-2-카르복실산;
(2-20) 4-(4-((((1R,3R,5S)-8-((5-사이클로프로필-3-(2,6-다이클로로페닐)아이소옥사졸-4-일)메틸)-8-아자바이사이클로[3.2.1]옥탄-3-일)옥시)메틸)페닐)옥사졸-5-카르복실산;
(2-21) 4-(4-((((1R,3R,5S)-8-((5-사이클로프로필-3-(2,6-다이클로로페닐)아이소옥사졸-4-일)메틸)-8-아자바이사이클로[3.2.1]옥탄-3-일)옥시)메틸)페닐)-1-메틸-1H-피라졸-5-카르복실산;
(2-22) 3-(N-((1R,3R,5S)-8-((5-사이클로프로필-3-(2,6-다이클로로페닐)아이소옥사졸-4-일)메틸)-8-아자바이사이클로[3.2.1]옥탄-3-일)옥시)메틸)-[1,1'-바이페닐]-2-카르복실산);
(2-23) 4'-((((1R,3S,5S)-8-((5-사이클로프로필-3-(2,6-다이클로로페닐)아이소옥사졸-4-일)메틸)-8-아자바이사이클로[3.2.1]옥탄-3-일)옥시)메틸)-[1,1'-바이페닐]-2-카르복실산;
(2-24) 4'-((((1R,3R,5S)-8-((5-사이클로프로필-3-(2,6-다이클로로페닐)아이소옥사졸-4-일)메틸)-8-아자바이사이클로[3.2.1]옥탄-3-일)옥시)메틸)-[1,1'-바이페닐]-4-카르복실산;
(2-25) 4'-((((1R,3S,5S)-8-((5-사이클로프로필-3-(2,6-다이클로로페닐)아이소옥사졸-4-일)메틸)-8-아자바이사이클로[3.2.1]옥탄-3-일)옥시)메틸)-[1,1'-바이페닐]-4-카르복실산;
(2-26) 4'-((((1R,3R,5S)-8-((5-사이클로프로필-3-(2,6-다이클로로페닐)아이소옥사졸-4-일)메틸)-8-아자바이사이클로[3.2.1]옥탄-3-일)옥시)메틸)-4-플루오로-[1,1'-바이페닐]-3-카르복실산;
(2-27) 4'-((((1R,3R,5S)-8-((5-사이클로프로필-3-(2,6-다이클로로페닐)아이소옥사졸-4-일)메틸)-8-아자바이사이클로[3.2.1]옥탄-3-일)옥시)메틸)-3-플루오로-[1,1'-바이페닐]-4-카르복실산;
(2-28) 5-(4-((((1R,3R,5S)-8-((5-사이클로프로필-3-(2,6-다이클로로페닐)아이소옥사졸-4-일)메틸)-8-아자바이사이클로[3.2.1]옥탄-3-일)옥시)메틸)페닐)피리미딘-2-카르복실산;
(2-29) 4'-((((1R,3R,5S)-8-((5-사이클로프로필-3-(2,6-다이클로로페닐)아이소옥사졸-4-일)메틸)-8-아자바이사이클로[3.2.1]옥탄-3-일)옥시)메틸)-2-플루오로-[1,1'-바이페닐]-4-카르복실산;
(2-30) 4'-((((1R,3R,5S)-8-((5-사이클로프로필-3-(2,6-다이클로로페닐)아이소옥사졸-4-일)메틸)-8-아자바이사이클로[3.2.1]옥탄-3-일)옥시)메틸)-3'-플루오로-[1,1'-바이페닐]-4-카르복실산;
(2-31) 3'-((((1R,3R,5S)-8-((5-사이클로프로필-3-(2,6-다이클로로페닐)아이소옥사졸-4-일)메틸)-8-아자바이사이클로[3.2.1]옥탄-3-일)옥시)메틸)-[1,1'-바이페닐]-4-카르복실산;
(2-32) 3'-((((1R,3R,5S)-8-((5-사이클로프로필-3-(2,6-다이클로로페닐)아이소옥사졸-4-일)메틸)-8-아자바이사이클로[3.2.1]옥탄-3-일)옥시)메틸)-[1,1'-바이페닐]-3-카르복실산;
(2-33) 3'-((((1R,3R,5S)-8-((5-사이클로프로필-3-(2,6-다이클로로페닐)아이소옥사졸-4-일)메틸)-8-아자바이사이클로[3.2.1]옥탄-3-일)옥시)메틸)-[1,1'-바이페닐]-2-카르복실산;
(2-34) 4'-((((1R,3R,5S)-8-((5-사이클로프로필-3-(2,6-다이클로로페닐)아이소옥사졸-4-일)메틸)-8-아자바이사이클로[3.2.1]옥탄-3-일)옥시)메틸)-3'-플루오로-[1,1'-바이페닐]-2-카르복실산;
(2-35) 4'-((((1R,3R,5S)-8-((5-사이클로프로필-3-(2,6-다이클로로페닐)아이소옥사졸-4-일)메틸)-8-아자바이사이클로[3.2.1]옥탄-3-일)옥시)메틸)-3'-플루오로-[1,1'-바이페닐]-3-카르복실산;
(2-36) 4'-((((1R,3R,5S)-8-((5-사이클로프로필-3-(2,6-다이클로로페닐)아이소옥사졸-4-일)메틸)-8-아자바이사이클로[3.2.1]옥탄-3-일)옥시)메틸)-5-플루오로-[1,1'-바이페닐]-2-카르복실산;
(2-37) 5-클로로-4'-((((1R,3R,5S)-8-((5-사이클로프로필-3-(2,6-다이클로로페닐)아이소옥사졸-4-일)메틸)-8-아자바이사이클로[3.2.1]옥탄-3-일)옥시)메틸)-[1,1'-바이페닐]-2-카르복실산;
(2-38) 5-클로로-4'-((((1R,3S,5S)-8-((5-사이클로프로필-3-(2,6-다이클로로페닐)아이소옥사졸-4-일)메틸)-8-아자바이사이클로[3.2.1]옥탄-3-일)옥시)메틸)-[1,1'-바이페닐]-2-카르복실산;
(2-39) 4'-((((1R,3R,5S)-8-((5-사이클로프로필-3-(2,6-다이클로로페닐)아이소옥사졸-4-일)메틸)-8-아자바이사이클로[3.2.1]옥탄-3-일)옥시)메틸)-3-(트리플루오로메틸)-[1,1'-바이페닐]-2-카르복실산;
(2-40) 4'-((((1R,3R,5S)-8-((5-사이클로프로필-3-(2,6-다이클로로페닐)아이소옥사졸-4-일)메틸)-8-아자바이사이클로[3.2.1]옥탄-3-일)옥시)메틸)-4-플루오로-[1,1'-바이페닐]-2-카르복실산;
(2-41) 1-(4-((((1R,3R,5S)-8-((5-사이클로프로필-3-(2,6-다이클로로페닐)아이소옥사졸-4-일)메틸)-8-아자바이사이클로[3.2.1]옥탄-3-일)옥시)메틸)페닐)아제티딘-3-카르복실산;
(2-42) 4'-((((1R,3R,5S)-8-((5-사이클로프로필-3-(2,6-다이클로로페닐)아이소옥사졸-4-일)메틸)-8-아자바이사이클로[3.2.1]옥탄-3-일)옥시)메틸)-3'-메틸-[1,1'-바이페닐]-2-카르복실산;
(2-43) 4'-((((1R,3R,5S)-8-((5-사이클로프로필-3-(2,6-다이클로로페닐)아이소옥사졸-4-일)메틸)-8-아자바이사이클로[3.2.1]옥탄-3-일)옥시)메틸)-[1,1'-바이페닐]-3-카르복실산;
(2-44) 4'-((((1R,3R,5S)-8-((5-사이클로프로필-3-(2,6-다이클로로페닐)아이소옥사졸-4-일)메틸)-8-아자바이사이클로[3.2.1]옥탄-3-일)옥시)메틸)-3'-메틸-[1,1'-바이페닐]-3-카르복실산;
(2-45) 4-((((1R,3R,5S)-8-((5-사이클로프로필-3-(2,6-다이클로로페닐)아이소옥사졸-4-일)메틸)-8-아자바이사이클로[3.2.1]옥탄-3-일)옥시)메틸)-1-나프토산;
(2-46) 1-(4-((((1R,3R,5S)-8-((5-사이클로프로필-3-(2,6-다이클로로페닐)아이소옥사졸-4-일)메틸)-8-아자바이사이클로[3.2.1]옥탄-3-일)옥시)메틸)페닐)-1H-피롤-2-카르복실산;
(2-47) 2-(5-((((1R,3R,5S)-8-((5-사이클로프로필-3-(2,6-다이클로로페닐)아이소옥사졸-4-일)메틸)-8-아자바이사이클로[3.2.1]옥탄-3-일)옥시)메틸)피리딘-2-일)벤조산;
(2-48) 3-(5-((((1R,3R,5S)-8-((5-사이클로프로필-3-(2,6-다이클로로페닐)아이소옥사졸-4-일)메틸)-8-아자바이사이클로[3.2.1]옥탄-3-일)옥시)메틸)피리딘-2-일)벤조산;
(2-49) 2-(4-((((1R,3R,5S)-8-((5-사이클로프로필-3-(2,6-다이클로로페닐)아이소옥사졸-4-일)메틸)-8-아자바이사이클로[3.2.1]옥탄-3-일)옥시)메틸)페닐)니코틴산;
(2-50) 6-(4-((((1R,3R,5S)-8-((5-사이클로프로필-3-(2,6-다이클로로페닐)아이소옥사졸-4-일)메틸)-8-아자바이사이클로[3.2.1]옥탄-3-일)옥시)메틸)페닐)니코틴산;
(2-51) 2-(4-((((1R,3R,5S)-8-((5-사이클로프로필-3-(2,6-다이클로로페닐)아이소옥사졸-4-일)메틸)-8-아자바이사이클로[3.2.1]옥탄-3-일)옥시)메틸)페닐)아이소니코틴산;
(2-52) 3-(4-((((1R,3R,5S)-8-((5-사이클로프로필-3-(2,6-다이클로로페닐)아이소옥사졸-4-일)메틸)-8-아자바이사이클로[3.2.1]옥탄-3-일)옥시)메틸)페닐)푸란-2-카르복실산;
(2-53) 5-(4-((((1R,3R,5S)-8-((5-사이클로프로필-3-(2,6-다이클로로페닐)아이소옥사졸-4-일)메틸)-8-아자바이사이클로[3.2.1]옥탄-3-일)옥시)메틸)페닐)푸란-2-카르복실산;
(2-54) 6-(4-((((1R,3R,5S)-8-((5-사이클로프로필-3-(2,6-다이클로로페닐)아이소옥사졸-4-일)메틸)-8-아자바이사이클로[3.2.1]옥탄-3-일)옥시)메틸)페닐)피콜린산;
(2-55) 3-(5-((((1R,3R,5S)-8-((5-사이클로프로필-3-(2,6-다이클로로페닐)아이소옥사졸-4-일)메틸)-8-아자바이사이클로[3.2.1]옥탄-3-일)옥시)메틸)피리딘-2-일)푸란-2-카르복실산;
(2-56) 3-(4-((((1R,3R,5S)-8-((5-사이클로프로필-3-(2,6-다이클로로페닐)아이소옥사졸-4-일)메틸)-8-아자바이사이클로[3.2.1]옥탄-3-일)옥시)메틸)-3-플루오로페닐)푸란-2-카르복실산;
(2-57) 5-(4-((((1R,3R,5S)-8-((5-사이클로프로필-3-(2,6-다이클로로페닐)아이소옥사졸-4-일)메틸)-8-아자바이사이클로[3.2.1]옥탄-3-일)옥시)메틸)페닐)-2-메틸티오펜-3-카르복실산;
(2-58) 3-(4-((((1R,3R,5S)-8-((5-사이클로프로필-3-(2,6-다이클로로페닐)아이소옥사졸-4-일)메틸)-8-아자바이사이클로[3.2.1]옥탄-3-일)옥시)메틸)나프탈렌-1-일)푸란-2-카르복실산;
(2-59) 3-(4-((((1R,3R,5S)-8-((5-사이클로프로필-3-(2,6-다이클로로페닐)아이소옥사졸-4-일)메틸)-8-아자바이사이클로[3.2.1]옥탄-3-일)옥시)메틸)나프탈렌-1-일)벤조산;
(2-60) 4'-((((1R,3R,5S)-8-((5-사이클로프로필-3-(2,6-다이클로로페닐)아이소옥사졸-4-일)메틸)-8-아자바이사이클로[3.2.1]옥탄-3-일)옥시)메틸)-4-메톡시-[1,1'-바이페닐]-3-카르복실산;
(2-61) 3-(4-((((1R,3R,5S)-8-((5-사이클로프로필-3-(2,6-다이클로로페닐)아이소옥사졸-4-일)메틸)-8-아자바이사이클로[3.2.1]옥탄-3-일)옥시)메틸)-3-메틸페닐)푸란-2-카르복실산;
(2-62) 3-(4-((((1R,3R,5S)-8-((5-사이클로프로필-3-(2,6-다이클로로페닐)아이소옥사졸-4-일)메틸)-8-아자바이사이클로[3.2.1]옥탄-3-일)옥시)메틸)나프탈렌-1-일)푸란-2-카르복실산;
(2-63) 3-(4-((((1R,3R,5S)-8-((5-사이클로프로필-3-(2-(트리플루오로메톡시)페닐)아이소옥사졸-4-일)메틸)-8-아자바이사이클로[3.2.1]옥탄-3-일)옥시)메틸)-3-플루오로페닐)푸란-2-카르복실산;
(3-1) 4'-((((1R,3R,5S)-8-((5-사이클로프로필-3-(2,6-다이클로로페닐)아이소옥사졸-4-일)메틸)-8-아자바이사이클로[3.2.1]옥탄-3-일)옥시)플루오로메틸)-[1,1'-바이페닐]-3-카르복실산;
(3-2) 3-(4-((((1R,3R,5S)-8-((5-사이클로프로필-3-(2,6-다이클로로페닐)아이소옥사졸-4-일)메틸)-8-아자바이사이클로[3.2.1]옥탄-3-일)옥시)플루오로메틸)페닐)푸란-2-카르복실산;
(4-1) 2-(((1R,3R,5S)-8-((5-사이클로프로필-3-(2,6-다이클로로페닐)아이소옥사졸-4-일)메틸)-8-아자바이사이클로[3.2.1]옥탄-3-일)아미노)벤조[d]티아졸-6-카르복실산;
(4-2) 2-(((1R,3R,5S)-8-((5-사이클로프로필-3-(2,6-다이클로로페닐)아이소옥사졸-4-일)메틸)-8-아자바이사이클로[3.2.1]옥탄-3-일)아미노)벤조[d]티아졸-6-카르복실산;
(4-3) 6-(((1R,3R,5S)-8-((5-사이클로프로필-3-(2,6-다이클로로페닐)아이소옥사졸-4-일)메틸)-8-아자바이사이클로[3.2.1]옥탄-3-일)아미노)-2-나프토산;
(5-1) 3'-(((1R,3R,5S)-8-((5-사이클로프로필-3-(2,6-다이클로로페닐)아이소옥사졸-4-일)메틸)-8-아자바이사이클로[3.2.1]옥탄-3-일)아미노)-[1,1'-바이페닐]-4-카르복실산
(6-1) 4'-((((1R,3R,5S)-8-((5-사이클로프로필-3-(2,6-다이클로로페닐)아이소옥사졸-4-일)메틸)-8-아자바이사이클로[3.2.1]옥탄-3-일)아미노)메틸)-[1,1'-바이페닐]-2-카르복실산;
(6-2) 4'-((((1R,3S,5S)-8-((5-사이클로프로필-3-(2,6-다이클로로페닐)아이소옥사졸-4-일)메틸)-8-아자바이사이클로[3.2.1]옥탄-3-일)아미노)메틸)-[1,1'-바이페닐]-2-카르복실산;
(7-1) 3-(N-((1R,3R,5S)-8-((5-사이클로프로필-3-(2,6-다이클로로페닐)아이소옥사졸-4-일)메틸)-8-아자바이사이클로[3.2.1]옥탄-3-일)설파모일)벤조산;
(7-2) 2-(N-((1R,3R,5S)-8-((5-사이클로프로필-3-(2,6-다이클로로페닐)아이소옥사졸-4-일)메틸)-8-아자바이사이클로[3.2.1]옥탄-3-일) 설파모일)벤조산;
(8-1) 2-(6-(((1R,3R,5S)-8-((5-사이클로프로필-3-(2,6-다이클로로페닐)아이소옥사졸-4-일)메틸)-8-아자바이사이클로[3.2.1]옥탄-3-일)카르바모일)피리딘-3-일)벤조산;
(8-2) 4-(((1R,3R,5S)-8-((5-사이클로프로필-3-(2,6-다이클로로페닐)아이소옥사졸-4-일)메틸)-8-아자바이사이클로[3.2.1]옥탄-3-일) 카르바모일)벤조산;
(9-1) 4'-(3-((1R,3R,5S)-8-((5-사이클로프로필-3-(2,6-다이클로로페닐)아이소옥사졸-4-일)메틸)-8-아자바이사이클로[3.2.1]옥탄-3-일)우레이도)-[1,1'-바이페닐]-4-카르복실산;
(9-2) 4-(3-((1R,3R,5S)-8-((5-사이클로프로필-3-(2,6-다이클로로페닐)아이소옥사졸-4-일)메틸)-8-아자바이사이클로[3.2.1]옥탄-3-일)우레이도)벤조산;
(10-1) 4'-((((1R,3S,5S)-8-(5-사이클로프로필-3-(2,6-다이클로로페닐)아이소옥사졸-4-카르보닐)-8-아자바이사이클로[3.2.1]옥탄-3-일)옥시)메틸)-[1,1'-바이페닐]-4-카르복실산;
(10-2) 4'-((((1R,3R,5S)-8-(5-사이클로프로필-3-(2,6-다이클로로페닐)아이소옥사졸-4-카르보닐)-8-아자바이사이클로[3.2.1]옥탄-3-일)옥시)메틸)-[1,1'-바이페닐]-4-카르복실산;
(10-3) 5-(4-((((1R,3R,5S)-8-(5-사이클로프로필-3-(2,6-다이클로로페닐) 아이소옥사졸-4-카르보닐)-8-아자바이사이클로[3.2.1]옥탄-3-일)옥시)메틸)페닐)피리미딘-2-카르복실산;
(10-4) 4'-((((1R,3R,5S)-8-(5-사이클로프로필-3-(2,6-다이클로로페닐)아이소옥사졸-4-카르보닐)-8-아자바이사이클로[3.2.1]옥탄-3-일)옥시)메틸)-[1,1'-바이페닐]-2-카르복실산;
(10-5) 4'-((((1R,3R,5S)-8-(5-사이클로프로필-3-(2,6-다이클로로페닐)아이소옥사졸-4-카르보닐)-8-아자바이사이클로[3.2.1]옥탄-3-일)옥시)메틸)-4-플루오로-[1,1'-바이페닐]-3-카르복실산;
(10-6) 4'-((((1R,3R,5S)-8-(5-사이클로프로필-3-(2,6-다이클로로페닐)아이소옥사졸-4-카르보닐)-8-아자바이사이클로[3.2.1]옥탄-3-일)옥시)메틸)-3-플루오로-[1,1'-바이페닐]-4-카르복실산; 및
(10-7) 3-(4-((((1R,3R,5S)-8-(5-사이클로프로필-3-(2,6-다이클로로페닐)아이소옥사졸-4-카르보닐)-8-아자바이사이클로[3.2.1]옥탄-3-일)옥시)메틸)페닐)이소니코틴산.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. 제 1 항 내지 제 4 항 중 어느 하나의 항에 따른 화합물, 이의 광학 이성질체, 또는 이의 약학적으로 허용 가능한 염을 유효성분으로 함유하는, FXR에 의해 매개되는 간 질환의 예방 또는 치료용 약학적 조성물.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. . 제 5 항에 있어서,
상기 FXR에 의해 매개되는 간 질환은 담즙 정체증, 간내 담즙 정체증, 에스트로겐-유발성 담즙 정체증, 약물-유발성 담즙 정체증, 임신시 담즙 정체증, 비경구 영양-관련 담즙 정체증, 원발성 담즙성 간경변(PBC), 원발성 경화성 담관염(PSC), 진행성 가족성 담즙 정체증(PFIC), 비알코올성 지방간 질환(NAFLD), 비알코올성 지방간염(NASH), 약물-유발성 담관 손상, 담석, 간경화, 알코올-유발성 간경변, 낭성 섬유증-관련 간질환(CFLD), 담관폐쇄, 담석증, 및 간 섬유증으로 이루어진 군으로부터 선택된 1 이상인 약학적 조성물.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.
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Non-Patent Citations (6)

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

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