# Patent

## Title
Tricyclic compound and use thereof

## Abstract

The present invention relates to: a compound selected from the group consisting of a tricyclic compound having the structure of formula I, a pharmaceutically acceptable salt, an isomer, a solvate and a precursor thereof; and a use thereof. The compound effectively controls GPR40, and thus, can be effectively used for the prophylaxis or treatment of diseases associated with GPR40, for example, diabetes and many other diseases.

## Background
FIELD OF THE INVENTION
The present invention relates to a novel tricyclic compound, and a use thereof, and, more particularly to, a tricyclic compound having a structure of Formula I, and a use of the compound for preventing or treating various diseases including diabetes.
BACKGROUND OF THE INVENTION
Diabetes is a progressive debilitating disease that causes various microvascular and macrovascular complications and morbidity. Type II diabetes mellitus that is the most common type of diabetes is characterized by an increase in insulin resistance associated with inappropriate secretion of insulin after compensatory hyperinsulinemia. Free fatty acids (FFAs) are generally known to have an influence on secretion of insulin from β cells by promoting glucose-stimulated insulin secretion (GSIS), and regulate the release of insulin when G protein-coupled receptors (GPRs) expressed in the β cells respond to a change in blood sugar levels (see Nature, 2003, vol. 422, pp. 173-176). Among these, GPR40 (also known as a fatty acid receptor 1 (FFAR1)) is a membrane-bound FFA receptor that is preferentially expressed in pancreatic islets and particularly β cells to mediate heavy- and long-chain fatty acid-induced insulin secretion. It is known that compounds regulating the expression of GPR40 may be used to exhibit an incretin effect so as to promote GSIS, and may also be combined with a wide range of anti-diabetic drugs to treat diabetes, etc. Further, it is known that the compounds regulating the expression of GPR40 may be used to treat various diseases such as impaired glucose tolerance, ketosis, acidosis, diabetic neuropathy, diabetic nephropathy, diabetic retinopathy, macular edema, hyperlipidemia, genital disorders, skin diseases, arthropathia, osteopenia, arteriosclerosis, thrombotic diseases, dyspepsia, memory and learning difficulties, depression, manic depression, schizophrenia, attention-deficit hyperactivity disorder (ADHD), visual impairments, appetite dysregulation (for example, hyperorexia), obesity, hypoglycemia, hypertension, edemas, insulin resistance, labile diabetes, lipoatrophia, insulin allergies, insulinoma, lipotoxicity, pancreatic fatigue, hyperinsulinemia, cancers (for example, breast cancer), metabolic syndromes, immune diseases (for example, immunodeficiency), inflammatory diseases (for example, enteritis, arthritis, allergies), multiple sclerosis, acute renal failure, and the like, in addition to the diabetes.
There are a large number of reported compounds that have an ability to modulate a GPR40 receptor and are useful as drugs for preventing or treating diabetes. For example, WO 2004/106276 and WO 2005/051890 disclose compounds having an ability to modulate a GPR40 receptor. In recent years, WO 2008/001931, WO 2008/130514, and WO 2012/010413 disclose compounds that have an ability to modulate a GPR40 receptor and are useful as drugs for preventing or treating diabetes.
Although efforts to search for compounds modulating a GPR40 receptor have continued as described above, novel compounds having excellent efficacy are still required.
SUMMARY OF THE INVENTION
Therefore, it is an aspect of the present invention to provide a novel tricyclic compound.
It is another aspect of the present invention to provide a pharmaceutical use of the tricyclic compound.
To achieve the above goals, the present invention provides a compound selected from the group consisting of a tricyclic compound represented by the following Formula I, and a pharmaceutically acceptable salt, isomer, solvate and precursor thereof.




In Formula I, V, W, X, Y, Z, Ar, R1, R2, R3, R4, R5, R6, R7, n, and o are as defined in this disclosure.
According to another aspect, the present invention provides a use of a compound selected from the group consisting of the tricyclic compound of Formula I, and the pharmaceutically acceptable salt, isomer, solvate and precursor thereof, for the manufacture of a medicament for preventing or treating various diseases associated with GRP40, for example, diseases selected from the group consisting of diabetes, impaired glucose tolerance, ketosis, acidosis, diabetic neuropathy, diabetic nephropathy, diabetic retinopathy, macular edema, hyperlipidemia, genital disorders, skin diseases, arthropathia, osteopenia, arteriosclerosis, thrombotic diseases, dyspepsia, memory and learning difficulties, depression, manic depression, schizophrenia, attention-deficit hyperactivity disorder, visual impairments, appetite dysregulation, obesity, hypoglycemia, hypertension, edemas, insulin resistance, labile diabetes, lipoatrophia, insulin allergies, insulinoma, lipotoxicity, pancreatic fatigue, hyperinsulinemia, cancers, metabolic syndromes, immune diseases, inflammatory diseases, multiple sclerosis and acute renal failure.
Also, the present invention provides a pharmaceutical composition for preventing or treating various diseases associated with GRP40, which includes a compound selected from the group consisting of the tricyclic compound of Formula I, and the pharmaceutically acceptable salt, isomer, solvate and precursor thereof, and a pharmaceutically acceptable carrier.
Further, the present invention provides a method of preventing or treating various diseases associated with GRP40 in a mammal, which includes administering a compound selected from the group consisting of the tricyclic compound of Formula I, and the pharmaceutically acceptable salt, isomer, solvate and precursor thereof to the mammal.


DETAILED DESCRIPTION OF THE INVENTION
Hereinafter, the terms used in the present invention will be defined.
The term “halogen” used in the present invention encompasses fluoro, chloro, bromo, and iodo.
The term “alkyl” or “alkylene” used in the present invention encompasses a branched or linear saturated aliphatic hydrocarbon group having a specified number of carbon atoms. For example, the term “C1-6 alkyl” refers to an alkyl group having 1 to 6 carbon atoms. Specific examples of the alkyl group include methyl (Me), ethyl (Et), propyl (for example, n-propyl, and isopropyl), butyl (for example, n-butyl, isobutyl, and t-butyl), and pentyl (for example, n-pentyl, isopentyl, and neopentyl), but are not limited thereto.
The term “alkoxy” used in the present invention refers to an —O-alkyl group. The term “C1-6 alkoxy” includes C1, C2, C3, C4, C5, and C6 alkoxy groups. Specific examples of the alkoxy group include methoxy, ethoxy, propoxy (for example, n-propoxy, and isopropoxy), and t-butoxy, but are not limited thereto. Similarly, the term “alkylthio” used in the present invention includes an alkyl group having a specified number of carbon atoms, which is attached through a sulfur bridge, for example an —S-methyl group, and an —S-ethyl group.
The term “amino” used in the present invention includes a mono- or di-C1-6 alkyl-amino group (for example, methylamino, ethylamino, propylamino, dimethylamino, and diethylamino), a mono- or di-C6-14 aryl-amino group (for example, phenylamino, diphenylamino, 1-naphthylamino, and 2-naphthylamino), a mono- or di-C7-16 aralkyl-amino group (for example, benzylamino, and phenethylamino), an N—C1-6 alkyl-N—C6-14 aryl-amino group (for example, N-methyl-N-phenylamino, and N-ethyl-N-phenylamino), and an N—C1-6 alkyl-N—C7-16 aralkyl-amino group (for example, N-methyl-N-benzylamino, and N-ethyl-N-benzylamino), but the present invention is not limited thereto.
The term “acyl” used in the present invention includes a formyl group, a carboxyl group, a carbamoyl group, a C1-6 alkyl-carbonyl group, a C1-6 alkoxy-carbonyl group, a C3-8 cycloalkyl-carbonyl group, a C6-14 aryl-carbonyl group, a C7-16 aralkyl-carbonyl group, a C6-14 aryloxy-carbonyl group, a C7-16 aralkyloxy-carbonyl group, a mono- or di-C1-6 alkylcarbamoyl group, a mono- or di-C6-14 aryl-carbamoyl group, a C3-8 cycloalkyl-carbamoyl group, a C7-16 aralkyl-carbamoyl group, a nitrogen-containing heterocyclyl-carbonyl group, a thiocarbamoyl group, and a mono- or di-C1-6 alkyl-phosphono group, but is not limited thereto.
The phrase “substituted or unsubstituted” is used in the present invention to refer to a compound that is unsubstituted or substituted with 1 to 3 substituents selected from the following examples. For example, the substituted compound refers to a compound that may be substituted with at least one substituent selected from the group consisting of a 4- to 7-membered heterocyclyl containing 1 to 4 heteroelements selected from the group consisting of N, O, S, S(═O), and S(═O)2 (which may be also substituted with 1 to 3 substituents selected from the group consisting of a halogenated C1-6 alkyl group, a hydroxyl group, and a C1-6 alkoxy-carbonyl group, preferably 1 to 3 substituents selected from the group consisting of pyridyl, thiazolyl, pyrrolidinyl, oxopyrrolidinyl, tetrahydropyranyl, tetrahydrothiopyranyl, 1-oxidotetrahydrothiopyranyl, 1,1-dioxidotetrahydrothiopyranyl, and oxetanyl), a C3-8 cycloalkyl, a hydroxy, a halogenated C1-6 alkoxy, an amino, a mono- or di-C1-6 alkyl-amino, an N—C1-6 alkyl-N—C1-6 alkyl-carbonyl-amino, a C7-16 aralkyloxy, a C1-6 alkylthio, a C1-6 alkylsulfinyl, a C1-6 alkylsulfonyl, and a mono- or di-C1-6 alkyl-phosphono.
The term “carbocyclyl” used in the present invention includes a radical group of any stable 3-, 4-, 5-, 6-, 7- or 8-membered monocyclic or bicyclic rings, or 7-, 8-, 9- or 10-membered bicyclic rings, which may be saturated, unsaturated, partially unsaturated, or aromatic. Examples of such a carbocyclyl include cyclopropyl, cyclobutyl, cyclobutenyl, cyclopentyl, cyclopentenyl, cyclohexyl, cycloheptenyl, cycloheptyl, cycloheptenyl, adamantyl, cyclooctyl, cyclooctenyl, cyclooctadienyl, fluorenyl, phenyl, naphthyl, indanyl, and adamantyl, but are not limited thereto. Unless stated otherwise, the preferred carbocyclyl is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, or naphthyl. When the “carbocyclyl” is used, the carbocyclyl includes an “aryl” group. The “aryl” group, for example, refers to a monocyclic or bicyclic aromatic hydrocarbon group including phenyl and naphthyl. The term “bicyclic carbocycle” refers to a stable 9- or 10-membered carbocyclyl group which contains two fused rings and is composed of carbon atoms. In the two fused rings, a first ring is a benzo ring fused to a second ring; and the second ring is a saturated, unsaturated, or partially unsaturated 5- or 6-membered carbon ring. The bicyclic carbocyclyl group may be attached to a pendant group through any carbon atom generating a stable structure.
Unless stated otherwise, the term “heterocyclyl” used in the present invention, for example, includes a 5- to 14-membered (monocyclic, bicyclic or tricyclic) heterocyclyl containing one or two or more (i.e., 1 to 4) heteroelements selected from the group consisting of N, O, S, S(═O), and S(═O)2 as a ring-forming element in addition to the carbon atom, preferably (i) a 5- to 14-membered (preferably 5- to 10-membered) aromatic heterocyclyl, and (ii) a 5- to 10-membered non-aromatic heterocyclyl, and the like. Among these, a 5- or 6-membered aromatic heterocyclyl is preferred. Examples of the aromatic heterocyclyl may include thienyl, furyl, pyridyl, thiazolyl, oxazolyl, pyrazinyl, pyrimidinyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, pyridazinyl, isothiazolyl, isoxazolyl, indolyl, 2-benzothiazolyl, 2-benzoxazolyl, benzimidazolyl, benzo[b]thienyl, benzo[b]furanyl, quinolyl, and isoquinolyl, but are not limited thereto. Examples of the non-aromatic heterocyclyl may include pyrrolidinyl, oxazolidinyl, imidazolinyl, pyperidinyl, pyperazinyl, morpholinyl, thiomorpholinyl, 1,1-dioxidotetrahydro-2H-thiopyranyl, and tetrahydropyranyl, but are not limited thereto.
The phrase “pharmaceutically acceptable” is used in the present invention to refer to a compound, a material, a composition, and/or a dosage form which is/are suitable for being used in contact with tissues of humans and animals without causing excessive toxicity, irritation, an allergic reaction, and/or other problems or complications within the scope of fair medical judgment, and has a balance of reasonable benefit-to-risk ratios.
The present invention provides a compound selected from the group consisting of a tricyclic compound represented by the following Formula I, and a pharmaceutically acceptable salt, isomer, solvate and precursor thereof:




wherein
V and W are each independently ═C(R14)—, or ═N—;
X is —CH2—, —O—, —O—CH2—O—, —S—, —C(═O)—, —S(═O)—, —S(═O)2—, or —NR15—;
Y is a C1-6 alkylene;
Z is —O—, —S—, —C(═O)—, —S(═O)—, —S(═O)2—, or —NR15—;
Ar is one of the following substituents (a) to (c),




wherein A is —CH2—, —CF2—, —O—, —NR15—, —S—, —S(═O)—, —S(═O)2—, —C(═O)—, or —CH(OR15)—;
B is a C1-3 alkylene;
R1 is hydrogen, a halogen, hydroxy, amino, nitro, cyano, a C1-6 alkyl, a C1-10 alkoxy, a C1-6 alkylthio, acyl, a C1-6 alkylsulfonyloxy, a C3-12 carbocyclyl, a C3-12 carbocyclyloxy, a C3-12 carbocyclylsulfonyloxy, a 5- to 14-membered heterocyclyl, a 5- to 14-membered heterocyclyloxy, or a 5- to 14-membered heterocyclylsulfonyloxy;
R2, R3, R4, R5, R6, and R7 are each independently hydrogen, a halogen, amino, cyano, a C1-6 alkyl, a C1-6 alkoxy, a C1-6 alkylthio, acyl, a C3-12 carbocyclyl, or a 5- to 14-membered heterocyclyl;
R8 is hydrogen, a halogen, hydroxy, amino, nitro, cyano, a C1-6 alkyl, a C1-6 alkoxy, or a C1-6 alkylthio;
R9 and R10 are each independently hydrogen, a halogen, hydroxy, a C1-6 alkyl, or a C1-6 alkoxy;
R11 is hydroxy, amino, or a C1-6 alkoxy;
R12 is hydrogen, a C1-6 alkyl, a C2-6 akenyl, a C2-6 alkynyl, a C1-6 alkoxy, a C1-6 alkoxy-C1-6 alkyl, a C3-12 carbocyclyl, or a 5- to 14-membered heterocyclyl;
R13 is hydrogen, or a C1-6 alkyl;
R14 is hydrogen, a halogen, amino, —CF3, nitro, cyano, a C1-6 alkyl, a C1-6 alkoxy, a C1-6 alkylthio, acyl, a C3-12 carbocyclyl, or a 5- to 14-membered heterocyclyl;
R15 is hydrogen, or a C1-6 alkyl; and
n, o, and p are each independently 0, 1, 2, or 3;
provided that the alkylene, the alkyl, the akenyl, the alkynyl, the alkoxy, the alkylthio, the amino, the acyl, the alkylsulfonyloxy, the carbocyclyl, the carbocyclyloxy, the carbocyclylsulfonyloxy, the heterocyclyl, the heterocyclyloxy, and the heterocyclylsulfonyloxy may each independently be substituted with at least one substituent selected from the group consisting of a 4- to 7-membered heterocyclyl (unsubstituted or substituted with 1 to 3 substituents selected from the group consisting of hydroxy, a halogenated C1-6 alkyl, and a C1-6 alkoxy-carbonyl), a C3-8 cycloalkyl, hydroxy, a C1-6 alkoxy, a halogenated C1-6 alkoxy, amino, a mono- or di-C1-6 alkyl-amino, an N—C1-6 alkyl-N—C1-6 alkyl-carbonyl-amino, a C7-16 aralkyloxy, a C1-6 alkylthio, a C1-6 alkylsulfinyl, a C1-6 alkylsulfonyl, and a mono- or di-C1-6 alkyl-phosphono; and
the heterocyclyl contains 1 to 4 heteroelements selected from the group consisting of N, O, S, S(═O), and S(═O)2.
According to one preferred embodiment, in the compound of Formula I:
V and W are each independently ═C(R14)—, or ═N—;
X is —CH2—, —O—, —O—CH2—O—, —S—, or —NR15—;
Y is a C1-3 alkylene;
Z is —O—, —S—, or —NR15—, provided that Z is substituted at the 2nd or 3rd carbon atom of Ar;
Ar is one of the substituents (a) to (c);
A is —CH2—, —CF2—, —O—, or —NR15—;
B is a C1-2 alkylene;
R1 is hydrogen, a halogen, hydroxy, amino, nitro, cyano, a C1-6 alkyl, a C1-10 alkoxy, a C1-6 alkylthio, acyl, a C1-6 alkylsulfonyloxy, a C3-12 carbocyclyl, a C3-12 carbocyclyloxy, a C3-12 carbocyclylsulfonyloxy, a 5- to 14-membered heterocyclyl, a 5- to 14-membered heterocyclyloxy, or a 5- to 14-membered heterocyclylsulfonyloxy;
R2 is hydrogen, a halogen, amino, cyano, a C1-6 alkyl, a C1-6 alkoxy, a C1-6 alkylthio, a C3-12 carbocyclyl, or a 5- to 14-membered heterocyclyl;
R3, R4, R5, and R6 are each independently hydrogen, a halogen, amino, a C1-6 alkyl, or a C1-6 alkoxy;
R7 is hydrogen, a halogen, amino, cyano, a C1-6 alkyl, a C1-6 alkoxy, a C1-6 alkylthio, a C3-12 carbocyclyl, or a 5- to 14-membered heterocyclyl;
R8 is hydrogen, a halogen, amino, a C1-6 alkyl, or a C1-6 alkoxy;
R9 and R10 are each independently hydrogen, a halogen, hydroxy, a C1-6 alkyl, or a C1-6 alkoxy;
R11 is hydroxy, or a C1-6 alkoxy;
R12 is hydrogen, a C1-6 alkyl, a C2-6 akenyl, a C2-6 alkynyl, a C1-6 alkoxy, a C1-6 alkoxy-C1-6 alkyl, a C3-12 carbocyclyl, or a 5- to 14-membered heterocyclyl;
R13 is hydrogen, or a C1-6 alkyl;
R14 is hydrogen, a halogen, amino, —CF3, a C1-6 alkyl, a C1-6 alkoxy, acyl, a C3-12 carbocyclyl, or a 5- to 14-membered heterocyclyl;
R15 is hydrogen, or a C1-6 alkyl; and
n, o, and p are each independently 0, 1, or 2;
provided that the alkylene, the alkyl, the alkynyl, the alkoxy, the alkylthio, the amino, the acyl, the alkylsulfonyloxy, the carbocyclyl, the carbocyclyloxy, the carbocyclylsulfonyloxy, the heterocyclyl, and the heterocyclyloxy may each independently substituted with at least one substituent selected from the group consisting of a 4- to 7-membered heterocyclyl (unsubstituted or substituted with 1 to 3 substituents selected from the group consisting of hydroxy, a halogenated C1-6 alkyl, and a C1-6 alkoxy-carbonyl), a C3-8 cycloalkyl, hydroxy, a C1-6 alkoxy, a halogenated C1-6 alkoxy, amino, a mono- or di-C1-6 alkyl-amino, an N—C1-6 alkyl-N—C1-6 alkyl-carbonyl-amino, a C7-16 aralkyloxy, a C1-6 alkylthio, a C1-6 alkylsulfinyl, a C1-6 alkylsulfonyl, and a mono- or di-C1-6 alkyl-phosphono; and
the heterocyclyl contains 1 to 4 heteroelements selected from the group consisting of N, O, S, S(═O), and S(═O)2.
According to another preferred embodiment, in the compound of Formula I:
V and W are each independently ═C(R14)—, or ═N—;
X is —CH2—, —O—CH2—O—, —O—, —S—, or —NR15—;
Y is a C1-3 alkylene;
Z is —O—, —S—, or —NR15—, provided that Z is substituted at the 2nd or 3rd carbon atom of Ar;
Ar is one of the substituents (a) to (c);
A is —CH2—, —CF2—, —O—, or —NR15—;
B is a C1-2 alkylene;
R1 is hydrogen, a halogen, hydroxy, amino, a C1-6 alkyl, a C1-10 alkoxy, acyl, a C1-6 alkylsulfonyloxy, a C3-12 carbocyclyloxy, a 5- to 14-membered heterocyclyl, or a 5- to 14-membered heterocyclyloxy;
R2, R3, R4, R5, R6, R7, and R8 are each independently hydrogen, a halogen, amino, a C1-6 alkyl, or a C1-6 alkoxy;
R9 and R10 are each independently hydrogen, or a halogen;
R11 is hydroxy, or a C1-6 alkoxy;
R12 is hydrogen, a C1-6 alkyl, a C2-6 akenyl, a C2-6 alkynyl, a C1-6 alkoxy, a C1-6 alkoxy-C1-6 alkyl, a C3-12 carbocyclyl, or a 5- to 14-membered heterocyclyl;
R13 is hydrogen;
R14 is hydrogen, a halogen, amino, a C1-6 alkyl, a C1-6 alkoxy, or acyl;
R15 is hydrogen, methyl, ethyl, or isopropyl; and
n, o, and p are each independently 0, 1, or 2;
provided that the alkylene, the alkyl, the alkynyl, the alkoxy, the amino, the acyl, the alkylsulfonyloxy, the carbocyclyloxy, the heterocyclyl, and the heterocyclyloxy may each independently be substituted with at least one substituent selected from the group consisting of a 4- to 7-membered heterocyclyl (unsubstituted or substituted with 1 to 3 substituents selected from the group consisting of hydroxy, a halogenated C1-6 alkyl, and a C1-6 alkoxy-carbonyl), a C3-8 cycloalkyl, hydroxy, a C1-6 alkoxy, a halogenated C1-6 alkoxy, amino, a mono- or di-C1-6 alkyl-amino, an N—C1-6 alkyl-N—C1-6 alkyl-carbonyl-amino, a C7-16 aralkyloxy, a C1-6 alkylthio, a C1-6 alkylsulfinyl, a C1-6 alkylsulfonyl, and a mono- or di-C1-6 alkyl-phosphono; and
the heterocyclyl contains 1 to 4 heteroelements selected from the group consisting of N, O, S, S(═O), and S(═O)2.
According to still another preferred embodiment, in the compound of Formula I:
V and W are each independently ═CH—, or ═N—;
X is —CH2—, —O—, —O—CH2—O—, or —N(CH2CH3)—;
Y is methylene;
Z is —O— or —NH—, provided that Z is substituted at the 2nd or 3rd carbon atom of Ar;
Ar is one of the substituents (a) to (c);
A is —O—;
B is methylene;
R1 is methylsulfonylpropoxy, ethylsulfonylpropoxy, ethoxyethoxy, morpholino, morpholinoethoxy, tetrahydrofuranyloxy,




R2 is hydrogen, or methyl;
R3, R4, R5, and R6 are each independently hydrogen, or methyl;
R7 and R8 are each independently hydrogen, or fluoro;
R9 and R10 are hydrogen;
R11 is hydroxy;
R12 is hydrogen, methyl, propyl, cyclopropyl, ethoxymethyl, ethynyl, —CH═CH—CH3, —C≡C—CH3, fluorophenyl, or methyloxazolyl;
R13 is hydrogen;
n and o are each independently 0, 1, or 2; and
p may be 0 or 1.
Specific examples of the preferred compounds according to the present invention are as described below:

    (1) 2-((3S)-6-((11-methyl-9-(3-(methylsulfonyl)propoxy)-6,7-dihydro-5H-dibenzo[a,c][7]annulen-4-yl)methoxy)-2,3-dihydrobenzofuran-3-yl)acetic acid;
    (2) (1S,2S)-2-(4-((9-(3-(methylsulfonyl)propoxy)-6,7-dihydrodibenzo[b,d]oxepin-2-yl)methoxy)phenyl)cyclopropanecarboxylic acid;
    (3) (1S,2S)-2-(4-(((9-(2-ethoxyethoxy)-6,7-dihydrodibenzo[b,d]oxepin-2-yl)methyl)amino)phenyl)cyclopropanecarboxylic acid;
    (4) (1S,2S)-2-(4-(((9-(3-(methylsulfonyl)propoxy)-6,7-dihydrodibenzo[b,d]oxepin-2-yl)methyl)amino)phenyl)cyclopropanecarboxylic acid;
    (5) (S)-2-(6-((9-(3-(methylsulfonyl)propoxy)-6,7-dihydro-5H-dibenzo[a,c][7]annulen-2-yl)methoxy)-2,3-dihydrobenzofuran-3-yl)acetic acid;
    (6) (1S,2S)-2-(4-(((9-(3-(methylsulfonyl)propoxy)-6,7-dihydro-5H-dibenzo[a,c][7]annulen-2-yl)methyl)amino)phenyl)cyclopropanecarboxylic acid;
    (7) 2-((3S)-6-((11-methyl-9-(3-(methylsulfonyl)propoxy)-6,7-dihydro-5H-dibenzo[a,c][7]annulen-2-yl)methoxy)-2,3-dihydrobenzofuran-3-yl)acetic acid;
    (8) (1R,2R)-2-(4-(((10-methyl-8-(3-(methylsulfonyl)propoxy)-6H-benzo[c]chromen-4-yl)methyl)amino)phenyl)cyclopropanecarboxylic acid;
    (9) (1S,2S)-2-(4-(((10-methyl-8-(3-(methylsulfonyl)propoxy)-6H-benzo[c]chromen-2-yl)methyl)amino)phenyl)cyclopropanecarboxylic acid;
    (10) (S)-2-(6-((5-methyl-7-(3-(methylsulfonyl)propoxy)-9,10-dihydrophenanthren-1-yl)methoxy)-2,3-dihydrobenzofuran-3-yl)acetic acid;
    (11) (S)-2-(6-((5-methyl-7-(3-(methylsulfonyl)propoxy)-9,10-dihydrophenanthren-3-yl)methoxy)-2,3-dihydrobenzofuran-3-yl)acetic acid;
    (12) (S)-2-(6-((7-(2-ethoxyethoxy)-5-methyl-9,10-dihydrophenanthren-3-yl)methoxy)-2,3-dihydrobenzofuran-3-yl)acetic acid;
    (13) 2-((3S)-6-((11-methyl-9-(3-(methylsulfonyl)propoxy)-6,7-dihydrodibenzo[b,d]oxepin-4-yl)methoxy)-2,3-dihydrobenzofuran-3-yl)acetic acid;
    (14) 2-((3S)-6-((11-methyl-9-(3-(methylsulfonyl)propoxy)-6,7-dihydrodibenzo[b,d]oxepin-2-yl)methoxy)-2,3-dihydrobenzofuran-3-yl)acetic acid;
    (15) (1S,2S)-2-(4-(((11-methyl-9-(3-(methylsulfonyl)propoxy)-6,7-dihydrodibenzo[b,d]oxepin-2-yl)methyl)amino)phenyl)cyclopropanecarboxylic acid;
    (16) (1S,2S)-2-(4-(((8-(2-ethoxyethoxy)-10-methyl-6H-benzo[c]chromen-2-yl)methyl)amino)phenyl)cyclopropanecarboxylic acid;
    (17) (S)-2-(6-((8-(2-ethoxyethoxy)-10-methyl-6H-benzo[c]chromen-2-yl)methoxy)-2,3-dihydrobenzofuran-3-yl)acetic acid;
    (18) (1S,2S)-2-(4-(((9-(3-(methylsulfonyl)propoxy)-5,7-dihydrodibenzo[c,e]oxepin-2-yl)methyl)amino)phenyl)cyclopropanecarboxylic acid;
    (19) (1S,2S)-2-(4-(((11-methyl-9-(3-(methylsulfonyl)propoxy)-5,7-dihydrodibenzo[c,e]oxepin-4-yl)methyl)amino)phenyl)cyclopropanecarboxylic acid;
    (20) (S)-2-(6-((9-(3-(methylsulfonyl)propoxy)-5,7-dihydrodibenzo[c,e]oxepin-2-yl)methoxy)-2,3-dihydrobenzofuran-3-yl)acetic acid;
    (21) (1S,2S)-2-(4-(((3-(3-(methylsulfonyl)propoxy)-6,7-dihydrodibenzo[b,d]oxepin-10-yl)methyl)amino)phenyl)cyclopropanecarboxylic acid;
    (22) (1S,2S)-2-(4-(((9-(2-ethoxyethoxy)-5,7-dihydrodibenzo[c,e]oxepin-2-yl)methyl)amino)phenyl)cyclopropanecarboxylic acid;
    (23) (S)-2-(6-((9-(2-ethoxyethoxy)-5,7-dihydrodibenzo[c,e]oxepin-2-yl)methoxy)-2,3-dihydrobenzofuran-3-yl)acetic acid;
    (24) (1S,2S)-2-(4-((9-(3-(methylsulfonyl)propoxy)-5,7-dihydrodibenzo[c,e]oxepin-2-yl)methoxy)phenyl)cyclopropanecarboxylic acid;
    (25) (1S,2S)-2-(4-((9-(3-(methylsulfonyl)propoxy)-6,7-dihydro-5H-dibenzo[a,c][7]annulen-2-yl)methoxy)phenyl)cyclopropanecarboxylic acid;
    (26) (S)-2-(6-((10-methyl-8-(3-(methylsulfonyl)propoxy)-6H-benzo[c]chromen-2-yl)methoxy)-2,3-dihydrobenzofuran-3-yl)acetic acid;
    (27) (S)-2-(6-((9-(2-ethoxyethoxy)-6,7-dihydro-5H-dibenzo[a,c][7]annulen-2-yl)methoxy)-2,3-dihydrobenzofuran-3-yl)acetic acid;
    (28) (1S,2S)-2-(4-(((9-(2-ethoxyethoxy)-6,7-dihydro-5H-dibenzo[a,c][7]annulen-2-yl)methyl)amino)phenyl)cyclopropanecarboxylic acid;
    (29) (1S,2S)-2-(4-(((11-methyl-9-(3-(methylsulfonyl)propoxy)-6,7-dihydro-5H-dibenzo[a,c][7]annulen-2-yl)methyl)amino)phenyl)cyclopropanecarboxylic acid;
    (30) (1S,2S)-2-(4-((10-methyl-8-(3-(methylsulfonyl)propoxy)-6H-benzo[c]chromen-2-yl)methoxy)phenyl)cyclopropanecarboxylic acid;
    (31) (1S,2S)-2-(4-((5-methyl-7-(3-(methylsulfonyl)propoxy)-9,10-dihydrophenanthren-3-yl)methoxy)phenyl)cyclopropanecarboxylic acid;
    (32) (S)-2-(6-((9-(3-(methylsulfonyl)propoxy)-6,7-dihydrodibenzo[b,d]oxepin-2-yl)methoxy)-2,3-dihydrobenzofuran-3-yl)acetic acid;
    (33) 2-((3S)-6-((11-methyl-9-(3-(methylsulfonyl)propoxy)-5,7-dihydrodibenzo[c,e]oxepin-2-yl)methoxy)-2,3-dihydrobenzofuran-3-yl)acetic acid;
    (34) (1S,2S)-2-(4-(((11-methyl-9-(3-(methylsulfonyl)propoxy)-5,7-dihydrodibenzo[c,e]oxepin-2-yl)methyl)amino)phenyl)cyclopropanecarboxylic acid;
    (35) 2-((3S)-6-((9-(2-ethoxyethoxy)-11-methyl-6,7-dihydro-5H-dibenzo[a,c][7]annulen-2-yl)methoxy)-2,3-dihydrobenzofuran-3-yl)acetic acid;
    (36) 2-((3S)-6-((9-((1,1-dioxidotetrahydro-2H-thiopyran-4-yl)oxy)-11-methyl-6,7-dihydrodibenzo[b,d]oxepin-2-yl)methoxy)-2,3-dihydrobenzofuran-3-yl)acetic acid;
    (37) 2-((3S)-6-((9-(2-(1,1-dioxidothiomorpholino)ethoxy)-11-methyl-6,7-dihydrodibenzo[b,d]oxepin-2-yl)methoxy)-2,3-dihydrobenzofuran-3-yl)acetic acid;
    (38) 2-((3S)-6-((9-(3-(ethylsulfonyl)propoxy)-11-methyl-6,7-dihydrodibenzo[b,d]oxepin-2-yl) methoxy)-2,3-dihydrobenzofuran-3-yl)acetic acid;
    (39) (1S,2S)-2-(4-((11-methyl-9-(3-(methylsulfonyl)propoxy)-6,7-dihydrodibenzo[b,d]oxepin-2-yl)methoxy)phenyl)cyclopropanecarboxylic acid;
    (40) (1S,2S)-2-(2-fluoro-4-((11-methyl-9-(3-(methylsulfonyl)propoxy)-6,7-dihydrodibenzo[b,d]oxepin-2-yl)methoxy)phenyl)cyclopropanecarboxylic acid;
    (41) (1S,2S)-2-(4-((9-(3-(ethylsulfonyl)propoxy)-11-methyl-6,7-dihydrodibenzo[b,d]oxepin-2-yl)methoxy)-2-fluorophenyl)cyclopropanecarboxylic acid;
    (42) (S)-2-(6-((3-(3-(methylsulfonyl)propoxy)-6,7-dihydrodibenzo[b,d]oxepin-10-yl)methoxy)-2,3-dihydrobenzofuran-3-yl)acetic acid;
    (43)


(S)-2-(6-((6,6-dimethyl-9-(3-(methylsulfonyl)propoxy)-6,7-dihydrodibenzo[b,d]oxepin-2-yl)methoxy)-2,3-dihydrobenzofuran-3-yl)acetic acid;

    (44) (S)-2-(6-((5-ethyl-9-(3-(methylsulfonyl)propoxy)-6,7-dihydro-5H-dibenzo[b,d]azepin-2-yl)methoxy)-2,3-dihydrobenzofuran-3-yl)acetic acid;
    (45) (1S,2S)-2-(4-((5-ethyl-9-(3-(methylsulfonyl)propoxy)-6,7-dihydro-5H-dibenzo[b,d]azepin-2-yl)methoxy)phenyl)cyclopropanecarboxylic acid;
    (46) 2-((3S)-6-((9-((4-hydroxy-1,1-dioxidotetrahydro-2H-thiopyran-4-yl)methoxy)-11-methyl-6,7-dihydrodibenzo[b,d]oxepin-2-yl)methoxy)-2,3-dihydrobenzofuran-3-yl)acetic acid;
    (47) 2-((3S)-6-((9-((1,1-dioxidotetrahydro-2H-thiopyran-4-yl)methoxy)-11-methyl-6,7-dihydrodibenzo[b,d]oxepin-2-yl)methoxy)-2,3-dihydrobenzofuran-3-yl)acetic acid;
    (48) (1S,2S)-2-(4-((9-((1,1-dioxidotetrahydro-2H-thiopyran-4-yl)oxy)-11-methyl-6,7-dihydrodibenzo[b,d]oxepin-2-yl)methoxy)phenyl)cyclopropanecarboxylic acid;
    (49) (1S,2S)-2-(4-((9-(3-(ethylsulfonyl)propoxy)-11-methyl-6,7-dihydrodibenzo[b,d]oxepin-2-yl)methoxy)phenyl)cyclopropanecarboxylic acid;
    (50) (1S,2S)-2-(4-((9-((1,1-dioxidotetrahydro-2H-thiopyran-4-yl)oxy)-11-methyl-6,7-dihydrodibenzo[b,d]oxepin-2-yl)methoxy)-2-fluorophenyl)cyclopropanecarboxylic acid;
    (51) (1S,2S)-2-{2-fluoro-4-[9-(4-hydroxy-1,1-dioxido-hexahydro-thiopyran-4-ylmethoxy)-11-methyl-6,7-dihydro-5-oxa-dibenzo[a,c]cyclohepten-2-ylmethoxy]-phenyl}-cyclopropanecarboxylic acid;
    (52) (1S,2S)-2-(4-(((9-((1,1-dioxidotetrahydro-2H-thiopyran-4-yl)oxy)-11-methyl-6,7-dihydrodibenzo[b,d]oxepin-2-yl)methyl)amino)-2-fluorophenyl)cyclopropanecarboxylic acid;
    (53) (1S,2S)-2-(4-(((9-(3-(ethylsulfonyl)propoxy)-11-methyl-6,7-dihydrodibenzo[b,d]oxepin-2-yl)methyl)amino)-2-fluorophenyl)cyclopropanecarboxylic acid;
    (54) 2-((3S)-6-((6,6,11-trimethyl-9-(3-(methylsulfonyl)propoxy)-6,7-dihydrodibenzo[b,d]oxepin-2-yl)methoxy)-2,3-dihydrobenzofuran-3-yl)acetic acid;
    (55) 2-((3S)-6-((9-((1,1-dioxidotetrahydro-2H-thiopyran-4-yl)oxy)-11-methyl-6,7-dihydro-5H-dibenzo[a,c][7]annulen-2-yl)methoxy)-2,3-dihydrobenzofuran-3-yl)acetic acid;
    (56) 2-((3S)-6-((9-((4-hydroxy-1,1-dioxidotetrahydro-2H-thiopyran-4-yl)methoxy)-11-methyl-6,7-dihydro-5H-dibenzo[a,c][7]annulen-2-yl)methoxy)-2,3-dihydrobenzofuran-3-yl)acetic acid;
    (57) 2-((3S)-6-((9-(3-(ethylsulfonyl)propoxy)-11-methyl-6,7-dihydro-5H-dibenzo[a,c][7]annulen-2-yl)methoxy)-2,3-dihydrobenzofuran-3-yl)acetic acid;
    (58) (1S,2S)-2-(4-4H-methyl-9-(3-(methylsulfonyl)propoxy)-6,7-dihydro-5H-dibenzo[a,c][7]annulen-2-yl)methoxy)phenyl)cyclopropanecarboxylic acid;
    (59) (1S,2S)-2-(4-((9-((1,1-dioxidotetrahydro-2H-thiopyran-4-yl)oxy)-11-methyl-6,7-dihydro-5H-dibenzo[a,c][7]annulen-2-yl)methoxy)phenyl)cyclopropanecarboxylic acid;
    (60) (1S,2S)-2-(4-((9-((4-hydroxy-1,1-dioxidotetrahydro-2H-thiopyran-4-yl)methoxy)-11-methyl-6,7-dihydro-5H-dibenzo[a,c][7]annulen-2-yl)methoxy)phenyl)cyclopropanecarboxylic acid;
    (61) (1S,2S)-2-(4-((9-(3-(ethylsulfonyl)propoxy)-11-methyl-6,7-dihydro-5H-dibenzo[a,c][7]annulen-2-yl)methoxy)phenyl)cyclopropanecarboxylic acid;
    (62) (1S,2S)-2-(2-fluoro-4-((9-((4-hydroxy-1,1-dioxidotetrahydro-2H-thiopyran-4-yl)methoxy)-11-methyl-6,7-dihydro-5H-dibenzo[a,c][7]annulen-2-yl)methoxy)phenyl)cyclopropanecarboxylic acid;
    (63) (1S,2S)-2-(2-fluoro-4-(((9-((4-hydroxy-1,1-dioxidotetrahydro-2H-thiopyran-4-yl)methoxy)-11-methyl-6,7-dihydro-5H-dibenzo[a,c][7]annulen-2-yl)methyl)amino)phenyl)cyclopropanecarboxylic acid;
    (64) (S)-2-(6-((9-((1,1-dioxidotetrahydro-2H-thiopyran-4-yl)oxy)-6,7-dihydro-5H-dibenzo[a,c][7]annulen-2-yl)methoxy)-2,3-dihydrobenzofuran-3-yl)acetic acid;
    (65) (S)-2-(6-((9-((4-hydroxy-1,1-dioxidotetrahydro-2H-thiopyran-4-yl)methoxy)-6,7-dihydro-5H-dibenzo[a,c][7]annulen-2-yl)methoxy)-2,3-dihydrobenzofuran-3-yl)acetic acid;
    (66) (S)-2-(6-((9-(3-(ethylsulfonyl)propoxy)-6,7-dihydro-5H-dibenzo[a,c][7]annulen-2-yl)methoxy)-2,3-dihydrobenzofuran-3-yl)acetic acid;
    (67) (1S,2S)-2-(4-((9-((1,1-dioxidotetrahydro-2H-thiopyran-4-yl)oxy)-6,7-dihydro-5H-dibenzo[a,c][7]annulen-2-yl)methoxy)phenyl)cyclopropanecarboxylic acid;
    (68) (1S,2S)-2-(4-((9-((4-hydroxy-1,1-dioxidotetrahydro-2H-thiopyran-4-yl)methoxy)-6,7-dihydro-5H-dibenzo[a,c][7]annulen-2-yl)methoxy)phenyl)cyclopropanecarboxylic acid;
    (69) (1S,2S)-2-(4-((9-(3-(ethylsulfonyl)propoxy)-6,7-dihydro-5H-dibenzo[a,c][7]annulen-2-yl) methoxy)phenyl)cyclopropanecarboxylic acid;
    (70) (1S,2S)-2-(4-(((9-((1,1-dioxidotetrahydro-2H-thiopyran-4-yl)oxy)-6,7-dihydro-5H-dibenzo[a,c][7]annulen-2-yl)methyl)amino)phenyl)cyclopropanecarboxylic acid;
    (71) (1S,2S)-2-(4-(((9-((4-hydroxy-1,1-dioxidotetrahydro-2H-thiopyran-4-yl)methoxy)-6,7-dihydro-5H-dibenzo[a,c][7]annulen-2-yl)methyl)amino)phenyl)cyclopropanecarboxylic acid;
    (72) (1S,2S)-2-(4-(((9-(3-(ethylsulfonyl)propoxy)-6,7-dihydro-5H-dibenzo[a,c][7]annulen-2-yl)methyl)amino)phenyl)cyclopropanecarboxylic acid;
    (73) (1S,2S)-2-(4-(((9-((1,1-dioxidotetrahydro-2H-thiopyran-4-yl)oxy)-11-methyl-6,7-dihydrodibenzo[b,d]oxepin-2-yl)methyl)amino)phenyl)cyclopropanecarboxylic acid;
    (74) (1S,2S)-2-(4-(((9-(3-(ethylsulfonyl)propoxy)-11-methyl-6,7-dihydro-5H-dibenzo[a,c][7]annulen-2-yl)methyl)amino)phenyl)cyclopropanecarboxylic acid;
    (75) (1S,2S)-2-(4-(((9-((1,1-dioxidotetrahydro-2H-thiopyran-4-yl)methoxy)-11-methyl-6,7-dihydro-5H-dibenzo[a,c][7]annulen-2-yl)methyl)amino)phenyl)cyclopropanecarboxylic acid;
    (76) (1S,2S)-2-(4-(((9-((1,1-dioxidotetrahydro-2H-thiopyran-4-yl)oxy)-11-methyl-6,7-dihydro-5H-dibenzo[a,c][7]annulen-2-yl)methyl)amino)phenyl)cyclopropanecarboxylic acid;
    (77) (1S,2S)-2-(4-(((9-((4-hydroxy-1,1-dioxidotetrahydro-2H-thiopyran-4-yl)methoxy)-11-methyl-6,7-dihydro-5H-dibenzo[a,c][7]annulen-2-yl)methyl)amino)phenyl)cyclopropanecarboxylic acid;
    (78) (1S,2S)-2-(4-(((9-((1,1-dioxidotetrahydro-2H-thiopyran-4-yl)methoxy)-6,7-dihydro-5H-dibenzo[a,c][7]annulen-2-yl)methyl)amino)phenyl)cyclopropanecarboxylic acid;
    (79) 2-((S)-6-(((R)-6-methyl-9-(3-(methylsulfonyl)propoxy)-6,7-dihydrodibenzo[b,d]oxepin-2-yl)methoxy)-2,3-dihydrobenzofuran-3-yl)acetic acid;
    (80) (S)-2-(6-((9-(3-(methylsulfonyl)propoxy)dibenzo[d,f][1,3]dioxepin-2-yl)methoxy)-2,3-dihydrobenzofuran-3-yl)acetic acid;
    (81) 2-((3S)-6-((1-methyl-3-morpholino-6,7-dihydro-5H-benzo[3,4]cyclohepta[1,2-d]pyrimidin-10-yl)methoxy)-2,3-dihydrobenzofuran-3-yl)acetic acid;
    (82) (S)-2-(6-(((9-(3-(methylsulfonyl)propoxy)-6,7-dihydro-5H-dibenzo[a,c][7]annulen-2-yl)methyl)amino)-2,3-dihydrobenzofuran-3-yl)acetic acid;
    (83) (S)-2-(6-(((9-((1,1-dioxidotetrahydro-2H-thiopyran-4-yl)methoxy)-6,7-dihydro-5H-dibenzo[a,c][7]annulen-2-yl)methyl)amino)-2,3-dihydrobenzofuran-3-yl)acetic acid;
    (84) (S)-2-(6-((9-((1,1-dioxidotetrahydro-2H-thiopyran-4-yl)methoxy)-6,7-dihydro-5H-dibenzo[a,c][7]annulen-2-yl)methoxy)-2,3-dihydrobenzofuran-3-yl)acetic acid;
    (85) (S)-2-(6-((9-((1,1-dioxidotetrahydro-2H-thiopyran-4-yl)methoxy)-3-fluoro-6,7-dihydro-5H-dibenzo[a,c][7]annulen-2-yl)methoxy)-2,3-dihydrobenzofuran-3-yl)acetic acid;
    (86) (1S,2S)-2-(4-(((9-((1,1-dioxidotetrahydro-2H-thiopyran-4-yl)methoxy)-3-fluoro-6,7-dihydro-5H-dibenzo[a,c][7]annulen-2-yl)methyl)amino)phenyl)cyclopropanecarboxylic acid;
    (87) (1S,2S)-2-(4-(((9-(3-(ethylsulfonyl)propoxy)-11-methyl-6,7-dihydrodibenzo[b,d]oxepin-2-yl)methyl)amino)phenyl)cyclopropanecarboxylic acid;
    (88) 2-((3S)-6-((9-(2-ethoxyethoxy)-11-methyl-6,7-dihydrodibenzo[b,d]oxepin-2-yl)methoxy)-2,3-dihydrobenzofuran-3-yl)acetic acid;
    (89) (1S,2S)-2-(4-((1-methyl-3-morpholino-6,7-dihydro-5H-benzo[3,4]cyclohepta[1,2-d]pyrimidin-10-yl)methoxy)phenyl)cyclopropanecarboxylic acid;
    (90) 2-((3S)-6-((1-methyl-3-(3-(methylsulfonyl)propoxy)-6,7-dihydro-5H-benzo[3,4]cyclohepta[1,2-d]pyrimidin-10-yl)methoxy)-2,3-dihydrobenzofuran-3-yl)acetic acid;
    (91) (S)-2-(6-(((9-(2-ethoxyethoxy)-6,7-dihydro-5H-dibenzo[a,c][7]annulen-2-yl)methyl)amino)-2,3-dihydrobenzofuran-3-yl)acetic acid;
    (92) (S)-2-(6-(((9-(3-(ethylsulfonyl)propoxy)-6,7-dihydro-5H-dibenzo[a,c][7]annulen-2-yl)methyl)amino)-2,3-dihydrobenzofuran-3-yl)acetic acid;
    (93) (S)-2-(6-((9-((4-methyl-1,1-dioxidotetrahydro-2H-thiopyran-4-yl)methoxy)-6,7-dihydro-5H-dibenzo[a,c][7]annulen-2-yl)methoxy)-2,3-dihydrobenzofuran-3-yl)acetic acid;
    (94) (1S,2S)-2-(4-(((9-((4-methyl-1,1-dioxidotetrahydro-2H-thiopyran-4-yl)methoxy)-6,7-dihydro-5H-dibenzo[a,c][7]annulen-2-yl)methyl)amino)phenyl)cyclopropanecarboxylic acid;
    (95) (S)-2-(6-((3-fluoro-9-((4-methyl-1,1-dioxidotetrahydro-2H-thiopyran-4-yl)methoxy)-6,7-dihydro-5H-dibenzo[a,c][7]annulen-2-yl)methoxy)-2,3-dihydrobenzofuran-3-yl)acetic acid;
    (96) (S)-2-(6-((3-fluoro-9-(3-(methylsulfonyl)propoxy)-6,7-dihydro-5H-dibenzo[a,c][7]annulen-2-yl)methoxy)-2,3-dihydrobenzofuran-3-yl)acetic acid;
    (97) (S)-2-(6-((9-(3-(ethylsulfonyl)propoxy)-3-fluoro-6,7-dihydro-5H-dibenzo[a,c][7]annulen-2-yl)methoxy)-2,3-dihydrobenzofuran-3-yl)acetic acid;
    (98) (S)-2-(6-((9-((1,1-dioxidotetrahydro-2H-thiopyran-4-yl)oxy)-3-fluoro-6,7-dihydro-5H-dibenzo[a,c][7]annulen-2-yl)methoxy)-2,3-dihydrobenzofuran-3-yl)acetic acid;
    (99) (S)-2-(6-((3-fluoro-9-((4-hydroxy-1,1-dioxidotetrahydro-2H-thiopyran-4-yl)methoxy)-6,7-dihydro-5H-dibenzo[a,c][7]annulen-2-yl)methoxy)-2,3-dihydrobenzofuran-3-yl)acetic acid;
    (100) (1S,2S)-2-(4-((9-((1,1-dioxidotetrahydro-2H-thiopyran-4-yl)oxy)-3-fluoro-6,7-dihydro-5H-dibenzo[a,c][7]annulen-2-yl)methoxy)phenyl)cyclopropanecarboxylic acid;
    (101) (1S,2S)-2-(4-((3-fluoro-9-((4-hydroxy-1,1-dioxidotetrahydro-2H-thiopyran-4-yl)methoxy)-6,7-dihydro-5H-dibenzo[a,c][7]annulen-2-yl)methoxy)phenyl)cyclopropanecarboxylic acid;
    (102) (1S,2S)-2-(4-((3-fluoro-9-(3-(methylsulfonyl)propoxy)-6,7-dihydro-5H-dibenzo[a,c][7]annulen-2-yl)methoxy)phenyl)cyclopropanecarboxylic acid;
    (103) (1S,2S)-2-(4-((9-((1,1-dioxidotetrahydro-2H-thiopyran-4-yl)methoxy)-3-fluoro-6,7-dihydro-5H-dibenzo[a,c][7]annulen-2-yl)methoxy)phenyl)cyclopropanecarboxylic acid;
    (104) (1S,2S)-2-(4-(((3-fluoro-9-(3-(methylsulfonyl)propoxy)-6,7-dihydro-5H-dibenzo[a,c][7]annulen-2-yl)methyl)amino)phenyl)cyclopropanecarboxylic acid;
    (105) (1S,2S)-2-(4-(((9-(3-(ethylsulfonyl)propoxy)-3-fluoro-6,7-dihydro-5H-dibenzo[a,c][7]annulen-2-yl)methyl)amino)phenyl)cyclopropanecarboxylic acid;
    (106) 2-((S)-6-((3-fluoro-9-(((R)-tetrahydrofuran-3-yl)oxy)-6,7-dihydro-5H-dibenzo[a,c][7]annulen-2-yl)methoxy)-2,3-dihydrobenzofuran-3-yl)acetic acid;
    (107) (S)-2-(6-((3-fluoro-9-(2-morpholinoethoxy)-6,7-dihydro-5H-dibenzo[a,c][7]annulen-2-yl) methoxy)-2,3-dihydrobenzofuran-3-yl)acetic acid;
    (108) (S)-3-(4-((9-(3-(methylsulfonyl)propoxy)-6,7-dihydro-5H-dibenzo[a,c][7]annulen-2-yl)methoxy)phenyl)hex-4-ynoic acid;
    (109) (S)-3-(4-((9-((1,1-dioxidotetrahydro-2H-thiopyran-4-yl)methoxy)-6,7-dihydro-5H-dibenzo[a,c][7]annulen-2-yl)methoxy)phenyl)hex-4-ynoic acid;
    (110) (S)-3-(4-((9-((1,1-dioxidotetrahydro-2H-thiopyran-4-yl)oxy)-6,7-dihydro-5H-dibenzo[a,c][7]annulen-2-yl)methoxy)phenyl)hex-4-ynoic acid;
    (111) (S)-3-(4-((9-(3-(ethylsulfonyl)propoxy)-6,7-dihydro-5H-dibenzo[a,c][7]annulen-2-yl)methoxy)phenyl)hex-4-ynoic acid;
    (112) (S)-3-(4-((9-((1,1-dioxidotetrahydro-2H-thiopyran-4-yl)methoxy)-3-fluoro-6,7-dihydro-5H-dibenzo[a,c][7]annulen-2-yl)methoxy)phenyl)hex-4-ynoic acid;
    (113) (S)-3-(4-((9-((1,1-dioxidotetrahydro-2H-thiopyran-4-yl)methoxy)-6,7-dihydrodibenzo[b,d]oxepin-2-yl)methoxy)phenyl)hex-4-ynoic acid;
    (114) (S)-3-(4-((3-((1,1-dioxidotetrahydro-2H-thiopyran-4-yl)methoxy)-6,7-dihydro-5H-benzo[3,4]cyclohepta[1,2-b]pyridin-10-yl)methoxy)phenyl)hex-4-ynoic acid;
    (115) (R)-3-cyclopropyl-3-(3-((9-((1,1-dioxidotetrahydro-2H-thiopyran-4-yl)methoxy)-6,7-dihydro-5H-dibenzo[a,c][7]annulen-2-yl)methoxy)phenyl)propanoic acid;
    (116) 3-cyclopropyl-3-(4-((9-((1,1-dioxidotetrahydro-2H-thiopyran-4-yl)methoxy)-6,7-dihydro-5H-dibenzo[a,c][7]annulen-2-yl)methoxy)phenyl)propanoic acid;
    (117) (S)-3-(4-((9-((1,1-dioxidotetrahydro-2H-thiopyran-4-yl)methoxy)-6,7-dihydro-5H-dibenzo[a,c][7]annulen-2-yl)methoxy)phenyl)hexanoic acid;
    (118) (R,Z)-3-(4-((9-((1,1-dioxidotetrahydro-2H-thiopyran-4-yl)methoxy)-6,7-dihydro-5H-dibenzo[a,c][7]annulen-2-yl)methoxy)phenyl)hex-4-enoic acid;
    (119) (S)-3-(4-((9-((1,1-dioxidotetrahydro-2H-thiopyran-4-yl)methoxy)-6,7-dihydro-5H-dibenzo[a,c][7]annulen-2-yl)methoxy)phenyl)-3-(5-methylisoxazol-3-yl)propanoic acid;
    (120) (S)-3-(4-((9-((1,1-dioxidotetrahydro-2H-thiopyran-4-yl)methoxy)-6,7-dihydro-5H-dibenzo[a,c][7]annulen-2-yl)methoxy)phenyl)-3-(isoxazol-3-yl)propanoic acid;
    (121) 3-(4-((9-((1,1-dioxidotetrahydro-2H-thiopyran-4-yl)methoxy)-6,7-dihydro-5H-dibenzo[a,c][7]annulen-2-yl)methoxy)phenyl)-3-(3-methylisoxazol-5-yl)propanoic acid;
    (122) (S)-3-(4-((3-(3-(methylsulfonyl)propoxy)-6,7-dihydro-5H-benzo[3,4]cyclohepta[1,2-b]pyridin-10-yl)methoxy)phenyl)hex-4-ynoic acid;
    (123) (S)-3-(4-((3-(3-(ethylsulfonyl)propoxy)-6,7-dihydro-5H-benzo[3,4]cyclohepta[1,2-b]pyridin-10-yl)methoxy)phenyl)hex-4-ynoic acid;
    (124) (S)-3-(4-((3-((1,1-dioxidotetrahydro-2H-thiopyran-4-yl)oxy)-6,7-dihydro-5H-benzo[3,4]cyclohepta[1,2-b]pyridin-10-yl)methoxy)phenyl)hex-4-ynoic acid;
    (125) (S)-3-(4-((5-methyl-7-(3-(methylsulfonyl)propoxy)-9,10-dihydrophenanthren-3-yl)methoxy)phenyl)hex-4-ynoic acid;
    (126) (S)-3-(4-((7-(2-ethoxyethoxy)-5-methyl-9,10-dihydrophenanthren-3-yl)methoxy)phenyl)hex-4-ynoic acid;
    (127) (S)-3-(4-((5-methyl-7-(3-(methylsulfonyl)propoxy)-9,10-dihydrophenanthren-1-yl)methoxy)phenyl)hex-4-ynoic acid;
    (128) (S)-3-(4-((11-methyl-9-(3-(methylsulfonyl)propoxy)-6,7-dihydro-5H-dibenzo[a,c][7]annulen-2-yl)methoxy)phenyl)hex-4-ynoic acid;
    (129) (S)-3-(4-((9-(3-(methylsulfonyl)propoxy)dibenzo[d,f][1,3]dioxepin-2-yl)methoxy)phenyl)hex-4-ynoic acid;
    (130) (S)-3-(4-((6,6-dimethyl-9-(3-(methylsulfonyl)propoxy)-6,7-dihydrodibenzo[b,d]oxepin-2-yl)methoxy)phenyl)hex-4-ynoic acid;
    (131) (S)-3-(4-((1-methyl-3-(3-(methylsulfonyl)propoxy)-6,7-dihydro-5H-benzo[3,4]cyclohepta[1,2-d]pyrimidin-10-yl)methoxy)phenyl)hex-4-ynoic acid;
    (132) (S)-3-(4-((9-((1,1-dioxidotetrahydro-2H-thiopyran-4-yl)methoxy)-6,7-dihydro-5H-dibenzo[a,c][7]annulen-2-yl)methoxy)phenyl)butanoic acid;
    (133) (R)-3-(4-((9-((1,1-dioxidotetrahydro-2H-thiopyran-4-yl)methoxy)-6,7-dihydro-5H-dibenzo[a,c][7]annulen-2-yl)methoxy)phenyl)butanoic acid;
    (134) (S)-3-(4-((9-((1,1-dioxidotetrahydro-2H-thiopyran-4-yl)methoxy)-6,7-dihydro-5H-dibenzo[a,c][7]annulen-2-yl)methoxy)phenyl)-4-ethoxybutanoic acid;
    (135) (S)-3-(4-(((9-(3-(methylsulfonyl)propoxy)-6,7-dihydro-5H-dibenzo[a,c][7]annulen-2-yl)methyl)amino)phenyl)hex-4-ynoic acid;
    (136) (S)-3-(4-(((9-((1,1-dioxidotetrahydro-2H-thiopyran-4-yl)methoxy)-6,7-dihydro-5H-dibenzo[a,c][7]annulen-2-yl)methyl)amino)phenyl)hex-4-ynoic acid;
    (137) 3-(4-((9-((1,1-dioxidotetrahydro-2H-thiopyran-4-yl)methoxy)-6,7-dihydro-5H-dibenzo[a,c][7]annulen-2-yl)methoxy)phenyl)-3-(4-fluorophenyl)propanoic acid;
    (138) (S)-3-(4-((11-methyl-9-(((R)-tetrahydrofuran-3-yl)oxy)-6,7-dihydro-5H-dibenzo[a,c][7]annulen-2-yl)methoxy)phenyl)hex-4-ynoic acid;
    (139) (R)-3-(4-((9-((1,1-dioxidotetrahydro-2H-thiopyran-4-yl)methoxy)-6,7-dihydro-5H-dibenzo[a,c][7]annulen-2-yl)methoxy)phenyl)pent-4-ynoic acid;
    (140) (S)-3-(4-((5-ethyl-9-(((R)-tetrahydrofuran-3-yl)oxy)-6,7-dihydro-5H-dibenzo[b,d]azepin-2-yl)methoxy)phenyl)hex-4-ynoic acid;
    (141) sodium (1S,2S)-2-(4-(((9-(3-(methylsulfonyl)propoxy)-6,7-dihydro-5H-dibenzo[a,c][7]annulen-2-yl)methyl)amino)phenyl)cyclopropanecarboxylate;
    (142) sodium 2-((3S)-6-((11-methyl-9-(3-(methyl sulfonyl)propoxy)-6,7-dihydro-5H-dibenzo[a,c][7]annulen-2-yl)methoxy)-2,3-dihydrobenzofuran-3-ylacetate;
    (143) sodium (1S,2S)-2-(4-((11-methyl-9-(3-(methyl sulfonyl)propoxy)-6,7-dihydrodibenzo[b,d]oxepin-2-yl)methoxy)phenyl)cyclopropanecarboxylate;
    (144) sodium (1S,2S)-2-(4-((9-(3-(ethylsulfonyl)propoxy)-11-methyl-6,7-dihydro-5H-dibenzo[a,c][7]annulen-2-yl)methoxy)phenyl)cyclopropanecarboxylate;
    (145) sodium (S)-2-(6-(((9-(3-(methylsulfonyl)propoxy)-6,7-dihydro-5H-dibenzo[a,c][7]annulen-2-yl)methyl)amino)-2,3-dihydrobenzofuran-3-ylacetate;
    (146) sodium (S)-3-(4-((9-(3-(methyl sulfonyl)propoxy)-6,7-dihydro-5H-dibenzo[a,c][7]annulen-2-yl)methoxy)phenyl)hex-4-ynoate; and
    (147) sodium (S)-3-(4-((9-((1,1-dioxidotetrahydro-2H-thiopyran-4-yl)methoxy)-6,7-dihydro-5H-dibenzo[a,c][7]annulen-2-yl)methoxy)phenyl)hex-4-ynoate.


The present invention includes a pharmaceutically acceptable salt, isomer, solvate and precursor of the compound of Formula I.
The term “pharmaceutically acceptable salt” used in the present invention refers to a derivative obtained by converting a parent compound into a salt thereof by using an acid or base. Examples of the pharmaceutically acceptable salt include an inorganic or organic acid salt containing a basic moiety, for example, an amine; an alkali or organic salt containing an acidic moiety, for example, carboxylic acid, but are not limited thereto. For example, the pharmaceutically acceptable salt includes a conventional non-toxic salt, or a quaternary ammonium salt of a parent compound, which is formed from a non-toxic inorganic or organic acid. For example, such a conventional non-toxic salt includes salts derived from inorganic acids, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, sulfamic acid, phosphoric acid, and nitric acid; and salts prepared from organic acids, for example, acetic acid, propionic acid, succinic acid, glycolic acid, stearic acid, lactic acid, malic acid, tartaric acid, citric acid, ascorbic acid, pamoic acid, maleic acid, hydroxymaleic acid, phenylacetic acid, glutamic acid, benzoic acid, salicylic acid, sulfanilic acid, 2-acetoxybenzoic acid, fumaric acid, toluenesulfonic acid, methanesulfonic acid, ethane disulfonic acid, oxalic acid, isethionic acid, etc.
The pharmaceutically acceptable salt according to the present invention may be prepared from a parent compound containing a basic or acidic moiety by using a conventional chemical reaction. Generally, such a salt may be prepared by allowing the compound in the form of a free acid or base to react with a stoichiometric amount of a base or acid in water, an organic solvent, or a mixture thereof (generally, a non-aqueous medium such as ether, ethyl acetate, ethanol, isopropanol, or acetonitrile is preferred).
Also, the compound of Formula I may have a structure in which hydrogen atoms of carboxyl groups (—COOH) contained in the compound are replaced by alkaline metals (Li, Na, K, etc.) through an ionic bond thereto. Such an ionic salt compound may also be in the form of a pharmaceutically acceptable salt of the compound of Formula I, which is encompassed in the scope of the present invention.
Also, the compound of Formula I may include one or more unsymmetrically substituted carbon atoms, and may be isolated in an optically active or racemic form. Therefore, the compound of Formula I particularly includes all chiral, diastereomeric, racemic, and geometrically isomeric forms of the compound of Formula I. A method of preparing and isolating such an optically active form is widely known in the relevant art. For example, a mixture of stereoisomers may be isolated by isolation of a racemic form, by normal-phase chromatography, reversed-phase chromatography or chiral chromatography, by a standard technique including salt formation and recrystallization, etc., or by chiral synthesis from a chiral starting material or chiral synthesis using synthesis of a target chiral center.
Further, the compound of Formula I may be in the form of a solvate. A solvate refers to a physical aggregation of the compound according to the present invention and one or more solvent molecules (regardless of an organic or inorganic solvent). The physical aggregation includes a hydrogen bond. In a certain case, for example, when one or more solvent molecules are incorporated into a crystal lattice of a crystalline solid, it is possible to isolate a solvate. The solvent molecules may be present in the solvate in a regular arrangement and/or an irregular arrangement. The solvate may include either a stoichiometric or nonstoichiometric amount of the solvent molecules. The term “solvate” includes both a solution-phase solvate and a solvate that can be isolated. The exemplary solvate includes a hydrate, an ethanolate, a methanolate, and an isopropanolate, but is not limited thereto. A solvation method is generally known in the art.
Also, the compound of Formula I may be in the form of a precursor. Any compound that may be converted in vivo to provide a physiologically active agent (i.e., the compound of Formula I) is a prodrug which falls within the scope of the present invention. Various types of prodrugs and methods of preparing same are widely known in the art.
Compounds containing a carboxyl group may form a physiologically hydrolyzable ester which functions as a prodrug that generates the compound of Formula I by means of hydrolysis in vivo. Preferably, since in many cases, the hydrolysis generally occurs under the influence of digestive enzymes, such a prodrug is orally administered. When the ester itself is active, or the hydrolysis occurs in blood, the prodrug may be used for parenteral administration. Examples of the physiologically hydrolyzable ester of the compound of Formula I include a C1-6 alkyl, a C1-6 alkylbenzyl, 4-methoxybenzyl, indanyl, phthalyl, methoxymethyl, a C1-6 alkanoyloxy-C1-6 alkyl (for example, acetoxymethyl, pivaloyloxymethyl, or propionyloxymethyl), a C1-6 alkoxycarbonyloxy-C1-6 alkyl (for example, methoxycarbonyl-oxymethyl, ethoxycarbonyloxymethyl, glycyloxymethyl, phenylglycyloxymethyl, or (5-methyl-2-oxo-1,3-dioxolen-4-yl)-methyl), and other widely known physiologically hydrolyzable esters, such as those used in penicillin and cephalosporin industries. Such an ester may be prepared by conventional techniques known in the art.
The compounds according to the present invention may be prepared by using the methods as described below or methods in the working examples, or other known methods, methods apparent to those skilled in the art, or modified methods thereof. Unless particularly stated otherwise, respective symbols of the compounds in the following schemes are as defined above.
Compounds Ia, Ia′, Ib, Ib′, Ic, and Ic′ may be prepared by using the following Scheme 1 or 2, or a method similar to Scheme 1 or 2.








In Schemes 1 and 2, L is a leaving group, or a hydroxyl group, and Y1=O is in the form of a ketone or aldehyde of Y.
For example, the compound Ia may be synthesized under a binding reaction of intermediates II and IIIa in the presence of a proper base (for example, sodium hydride, potassium carbonate, cesium carbonate, etc.) when L is a leaving group, and may be synthesized under a Mitsunobu reaction when L is a hydroxyl group. Also, the compound Ia may be synthesized under a reductive amination reaction of intermediates II′ and IIIa in the presence of a proper reducing agent (for example, sodium cyanoborohydride, sodium triacetoxyborohydride, sodium borohydride, etc.). When imine products as intermediates may be stably isolated from a reaction system, the compound Ia may be synthesized under a separate reduction reaction after the corresponding imine products are obtained.
When R′′ in compound Ia, Ib, or Ic is not hydroxy, the compound Ia, Ib, or Ic may be hydrolyzed in the presence of a proper acid or base to synthesize compound Ia′, Ib′ or Ic′ containing a carboxyl group.
The intermediates II and II′ in Scheme 1 may be prepared by the following Scheme 3, or methods similar to Scheme 3. In some cases, the intermediates II and II′ may be prepared by means of various known synthesis methods in accordance with the characteristics of the types of the backbone or substituent. In terms of a preparation technique, it may also be effective to substitute a functional group with a proper protective group, that is, a group that may be readily converted into the corresponding functional group, during the steps in which starting materials or intermediates are prepared, depending on the types of the functional groups. Thereafter, the protective group may be optionally removed to provide a desired compound.
The intermediate II of Scheme 1 may be prepared under an intramolecular cyclization reaction in the presence of a proper base as shown in Step 3, and may be prepared also under a Suzuki reaction as shown in Step 3′, when necessary.
Meanwhile, the intermediate II′ may be prepared by oxidizing the intermediate II with a proper oxidizing agent (for example, a manganese oxide, a Des s-Martin reagent (1,1,1-triacetoxy-1,1-dihydro-1,2-benziodoxol-3(1H)-one), etc.).




In Scheme 3, L, L1, L2, and L3 represent leaving groups.
The intermediates IV and IV′ in Scheme 3 may be prepared under a Suzuki reaction or methods similar to the Suzuki reaction, as shown in the following Scheme 4.




Also, the intermediates V and V′ in Scheme 3 may be prepared under a binding reaction in the presence of a proper base, as shown in the following Scheme 5.




The compounds according to the present invention prepared thus are isolated and purified in a free state, or as salts thereof by performing a salt forming treatment using a conventional method. The isolation/purification is performed by means of conventional chemical processes such as extraction, concentration, distillation, removal, crystallization, filtration, recrystallization, various chromatographies, etc.
Various isomers may be isolated by a conventional method using a difference in physicochemical properties between the isomers. For example, a racemic mixture may be separated into optically pure isomers by using a racemic resolution method, for example, by preparing using a diastereomeric salt with a typical optically-active acid such as tartaric acid to optically resolve the racemic mixture, or various chromatographies. Also, the resulting diastereomeric mixture may be separated, for example, by fractional crystallization or various chromatographies. In addition, the optically active compound may also be prepared by using a proper optically-active starting material.
When the compound of Formula I includes a stereoisomer, both the respective isomers and mixtures of the respective isomers fall under the scope of the present invention. Also, the compound of Formula I may be a hydrate, or a non-hydrate.
The compound of Formula I may be labeled with an isotope (for example, 3H, 14C, 35S), etc.
The compound selected from the group consisting of the tricyclic compound of Formula I according to the present invention or the pharmaceutically acceptable salt, isomer, solvate and precursor thereof has an ability to modulate GPR40 receptor functions (GPR40 receptor agonist activity and GPR40 receptor antagonist activity), particularly, GPR40 receptor agonist activity, and exhibits low toxicity and fewer side effects (for example, acute toxicity, chronic toxicity, genetic toxicity, developmental toxicity, cardiotoxicity, drug interactions, and carcinogenicity). Therefore, the compounds according to the present invention are useful as a stable GPR40 receptor modulator, preferably a GPR40 agonist.
The compound according to the present invention, or a pharmaceutical composition comprising the compound has an excellent ability to modulate GPR40 receptor functions in mammals (for example, mice, rats, hamsters, rabbits, cats, dogs, cattle, sheep, monkeys, humans, etc.), and is useful as a medicament for modulating the physiological functions in which the GPR40 receptor takes part, or a medicament for preventing or treating diseases in which the GPR40 receptor takes part.
Specifically, the compound according to the present invention, or the pharmaceutical composition comprising the compound is useful as an insulin secretion modulator (preferably an insulin secretagogue), a hypoglycemic agent, and a pancreatic β cell protective agent.
Also, the compound according to one exemplary embodiment of the present invention, or the pharmaceutical composition including the compound is useful as a medicament for preventing or treating diseases such as diabetes, impaired glucose tolerance, ketosis, acidosis, diabetic neuropathy, diabetic nephropathy, diabetic retinopathy, macular edema, hyperlipidemia, genital disorders, skin diseases, arthropathia, osteopenia, arteriosclerosis, thrombotic diseases, dyspepsia, memory and learning difficulties, depression, manic depression, schizophrenia, attention-deficit hyperactivity disorder, visual impairments, appetite dysregulation (for example, hyperorexia), obesity, hypoglycemia, hypertension, edemas, insulin resistance, labile diabetes, lipoatrophia, insulin allergies, insulinoma, lipotoxicity, pancreatic fatigue, hyperinsulinemia, cancers (for example, breast cancer), metabolic syndromes, immune diseases (for example, immunodeficiency), inflammatory diseases (for example, enteritis, arthritis, and allergy), multiple sclerosis, acute renal failure, etc.; particularly diseases such as diabetes, impaired glucose tolerance, ketosis, acidosis, diabetic neuropathy, diabetic nephropathy, diabetic retinopathy, macular edema, hyperlipidemia, genital disorders, skin diseases, arthropathia, osteopenia, arteriosclerosis, thrombotic diseases, dyspepsia, memory and learning difficulties, etc.
Here, the diabetes may include type I diabetes mellitus, type II diabetes mellitus, and gestational diabetes. Also, the hyperlipidemia may include hypertriglyceridemia, hypercholesteremia, hyper-HDL-cholesterolemia, postprandial hyperlipidemia, etc.
According to one exemplary embodiment, the compound of the present invention, or the pharmaceutical composition comprising the compound may be used to prevent or treat type II diabetes mellitus.
The compound according to the present invention may be used in combination with other drugs. Examples of such other drugs that may be used in combination with the compound according to the present invention may include an anti-diabetic agent, an anti-diabetic complication agent, an anti-hyperlipidemic agent, an anti-hypertensive agent, an anti-obesity agent, a diuretic agent, a chemotherapeutic agent, an immunotherapeutic agent, an anti-inflammatory drug, an anti-thrombotic agent, a therapeutic agent for osteoporosis, vitamins, anti-dementia drug, a therapeutic agent for urinary incontinence or urinary frequency, an anti-dysuria agent, etc., but are not limited thereto.
The pharmaceutical composition comprising the compound according to the present invention may be prepared by using a pharmaceutically acceptable carrier, an excipient, and the like, generally used in the relevant art in accordance with a conventional preparation method.
The pharmaceutical composition according to the present invention may be prepared into various types of formulations, and administered. A route of administration of the formulation may include oral administration by a tablet, a pill, a capsule, a granule, a powder, a solution, and the like, or parenteral administration by an intraarticular, intravenous or intramuscular injection, a suppository, eye drops, an oculentum, a liquid for transcutaneous use, an ointment, an adhesive for transcutaneous use, a transmucosal liquid, a transmucosal adhesive, an inhalant, etc.
Examples of a solid formulation for oral administration according to the present invention may include a tablet, a pill, a powder, a granule, etc. Such a formulation is prepared by mixing at least one or two or more active ingredients with at least one pharmacologically inert excipient, for example, lactose, mannitol, glucose, hydroxypropyl cellulose, microcrystalline cellulose, starch, polyvinyl pyrrolidone, and/or magnesium aluminium metasilicate. The formulation may include a pharmacologically inert additive, for example, a lubricant such as magnesium stearate, a disintegrating agent such as carboxymethyl starch sodium, a stabilizing agent, a solubilizing aid, etc. The tablet or the pill may be coated with a sugar coating, or coated with a film made of a gastric juice-soluble material or an enteric material.
Examples of a liquid formulation for oral administration according to the present invention may include an emulsion, a solution, a suspension, a syrup, or an elixir. In this case, the liquid formulation may comprise a conventional inert diluent, for example, purified water or ethanol. In addition, the liquid formulation may comprise a solubilizing agent, a wetting agent, an auxiliary agent such as a suspension, a sweetening agent, a flavoring agent, an aromatic, a preservative, etc.
An injection for parenteral administration includes an aseptic aqueous or non-aqueous solution, suspension or emulsion. For example, injectable distilled water, or a saline solution is included as an aqueous solvent. For example, a non-aqueous solvent may be propylene glycol, polyethylene glycol, a vegetable oil such as olive oil, an alcohol such as ethanol, or Polysorbate 80. Such a composition may further comprise an isotonic agent, a preservative, a wetting agent, an emulsifying agent, a dispersing agent, a stabilizing agent, or a solubilizing aid. These components may, for example, be sterilized by filtration using a bacteria retaining filter, blending of a disinfectant, or irradiation. Also, these components may also be used to prepare an aseptic solid composition, and may be dissolved or suspended in sterile water or an aseptic injectable solvent before use.
Hereinafter, the present invention will be described in further detail with reference to exemplary embodiments thereof.
However, it should be understood that the detailed description herein is given by way of illustration of the present invention only, and is not intended to limit the scope of the present invention. Unless stated otherwise, the abbreviations and chemical symbols used in the following examples have conventional meanings as commonly understood by one of ordinary skill in the art. Unless stated otherwise, the compounds disclosed herein are prepared, isolated and identified by using schemes disclosed herein, and other methods.
Example 1
Preparation of 2-((3S)-6-((11-methyl-9-(3-(methylsulfonyl)propoxy)-6,7-dihydro-5H-dibenzo[a,c][7]annulen-4-yl)methoxy)-2,3-dihydrobenzofuran-3-yl)acetic acid
<1-1> Preparation of 2-(3-methoxy-5-methylphenyl)acetaldehyde




Dess-Martin periodinane (3.25 g, 7.65 mmol) was slowly added to a solution of 2-(3-methoxy-5-methylphenyl)ethanol (prepared according to the method disclosed in the document [Australian Journal of Chemistry, 1999, vol. 52, #11, pp. 1093-1108]; 1.06 g, 6.37 mmol) in dichloromethane (60 mL) at 0° C., and stirred at ambient temperature for 30 minutes. The resulting mixture was diluted with dichloromethane, and washed with a 1 N NaOH aqueous solution and water. An organic layer was dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified using silica gel chromatography to obtain the title compound (pale yellow oil, 749 mg, 4.56 mmol, and 72% yield).
1H NMR (300 MHz, CDCl3) δ 9.72 (t, 1H), 6.65 (d, 2H), 6.56 (s, 1H), 3.79 (s, 3H), 3.61 (d, 2H), 2.33 (s, 3H).
<1-2> Preparation of (2-bromo-6-(methoxycarbonyl)benzyl)triphenylphosphonium bromide




Triphenylphosphine (3.58 g, 13.64 mmol) was added to a solution of methyl 3-bromo-2-(bromomethyl)benzoate (prepared according to the method disclosed in the document [U.S. Pat. No. 6,518,257 B1]; 4.2 g, 13.64 mmol) in toluene (100 mL), and stirred at 95° C. for 15 hours. The resulting compound was cooled to ambient temperature, diluted with hexane (100 mL), and then stirred at ambient temperature for 10 minutes or more. The mixture was filtered, and washed with hexane. Then, the resulting solid was dried in a vacuum to obtain the title compound (white solid, 7.0 g, 12.27 mmol, and 90% yield).
1H NMR (300 MHz, CDCl3) δ 7.88-7.74 (m, 5H), 7.71-7.52 (m, 12H), 7.35 (td, 1H), 5.58 (d, 2H), 3.59 (s, 3H).
<1-3> Preparation of methyl 3-bromo-2-(3-(3-methoxy-5-methylphenyl)prop-1-en-1-yl)benzoate




The compound (1.57 g, 9.56 mmol) obtained in <1-1> was dissolved in dichloromethane (57 mL) and THF (38 mL), and the compound (5.45 g, 9.56 mmol) obtained in <1-2> was added thereto. Subsequently, K2CO3 (3.97 g, 28.7 mmol) and 18-Crown-6 (505 mg, 1.91 mmol) were added. The mixture was stirred at 70° C. for 1 hour, and the compound (1.09 g, 1.91 mmol) obtained in <1-2> was then added, and stirred for 4 hours. The mixture was cooled to room temperature, and diluted with a saturated EtOAc and NH4Cl aqueous solution. Layers were separated, and an organic layer was dried over magnesium sulfate, filtered, and then concentrated under reduced pressure. The residue was purified using silica gel chromatography to obtain the title compound (an E/Z mixture, colorless oil, 1.11 g, and 31% yield).
E form: 1H NMR (300 MHz, CDCl3) δ 7.67 (dd, 1H), 7.54 (dd, 1H), 7.13 (t, 1H), 6.66-6.58 (m, 4H), 5.82 (dt, 1H), 3.80 (d, 3H), 3.67 (d, 3H), 3.50 (d, 2H), 2.32 (t, 3H).
Z form: 1H NMR (300 MHz, CDCl3) δ 7.76 (ddd, 2H), 7.22 (m, 1H), 6.62-6.49 (m, 4H), 5.93 (dt, 1H), 3.82 (d, 3H), 3.75 (s, 3H), 3.08 (d, 2H), 2.27 (t, 3H).
<1-4> Preparation of methyl 2-(3-(3-methoxy-5-methylphenyl)propyl)benzoate




The compound (1.5 g, 3.99 mmol) obtained in <1-3> was dissolved in EtOAc (15 mL), and 10% Pd/C (1.5 g, 1.40 mmol) was added thereto, and stirred for 5 hours under hydrogen gas. The reaction mixture was filtered through Celite, and the filtrate was concentrated under reduced pressure. The residue was purified using silica gel chromatography to obtain the title compound (colorless oil, 984 mg, and 83% yield).
1H NMR (600 MHz, CDCl3) δ 7.86 (d, 1H), 7.41 (t, 1H), 7.28-7.21 (m, 2H), 6.62 (s, 1H), 6.55 (d, 2H), 3.85 (s, 3H), 3.78 (s, 3H), 3.02-2.96 (m, 2H), 2.66-2.60 (m, 2H), 2.30 (s, 3H), 1.96-1.87 (m, 2H).
<1-5> Preparation of methyl 2-(3-(2-bromo-5-methoxy-3-methylphenyl)propyl)benzoate




The compound (980 mg, 3.29 mmol) obtained in <1-4> was dissolved in CH3CN (30 mL), and N-bromosuccinimide (585 mg, 3.29 mmol) was added thereto, and stirred at ambient temperature for 3 hours. The resulting compound was concentrated under reduced pressure, and the residue was purified using silica gel chromatography to obtain the title compound (colorless oil, 1.2 g, and 97% yield).
1H NMR (300 MHz, CDCl3) δ 7.86 (dd, 1H), 7.41 (m, 1H), 7.30-7.20 (m, 2H), 6.64 (s, 2H), 3.87 (s, 3H), 3.76 (s, 3H), 3.10-2.98 (m, 2H), 2.86-2.74 (m, 2H), 2.38 (s, 3H), 1.99-1.84 (m, 2H).
<1-6> Preparation of methyl 9-methoxy-11-methyl-6,7-dihydro-5H-dibenzo[a,c][7]annulen-4-carboxylate




The compound (500 mg, 1.32 mmol) obtained in <1-5>, tricyclohexylphosphine tetrafluoroborate (137 mg, 0.370 mmol), and K2CO3 (365 mg, 2.64 mmol) were mixed with N,N-dimethylacetamide (4 mL), and palladium (II) acetate (42 mg, 0.185 mmol) was added thereto, replaced with nitrogen, and stirred at 150° C. for 15 hours. The mixture was cooled to room temperature, diluted with EtOAc, and washed with a saturated NH4Cl aqueous solution and saline. Thereafter, the mixture was dried over sodium sulfate, and concentrated under reduced pressure. Then, the residue was purified using silica gel chromatography to obtain the title compound (colorless oil, 43 mg, and 11% yield).
1H NMR (300 MHz, CDCl3) δ 7.77-7.66 (m, 1H), 7.42-7.28 (m, 2H), 6.75 (d, 1H), 6.65 (d, 1H), 3.92 (s, 3H), 3.84 (s, 3H), 3.30-3.21 (m, 1H), 2.47 (m, 1H), 2.30 (s, 3H), 2.24-1.95 (m, 4H).
<1-7> Preparation of methyl 9-hydroxy-11-methyl-6,7-dihydro-5H-dibenzo[a,c][7]annulen-4-carboxylate




The compound (147 mg, 0.5 mmol) obtained in <1-6> was dissolved in dichloromethane (5 mL), and boron tribromide (a 1 M dichloromethane solution, 1 mL, 1 mmol) was slowly added thereto at 0° C., slowly heated, and stirred at ambient temperature for 3 hours. The reaction mixture was diluted with methanol (2 mL) and dichloromethane (15 mL), and washed with a saturated NH4Cl aqueous solution. An organic layer was dried over sodium sulfate, and concentrated under reduced pressure. Then, the residue was purified using silica gel chromatography to obtain the title compound (white foam, 93 mg, and 66% yield).
1H NMR (300 MHz, CDCl3) δ 7.73 (dd, 1H), 7.40-7.28 (m, 2H), 6.69 (d, 1H), 6.58 (d, 1H), 4.67 (s, 1H), 3.92 (s, 3H), 3.30-3.19 (m, 1H), 2.49-2.37 (m, 1H), 2.25 (s, 3H), 2.23-2.10 (m, 3H), 2.05-1.95 (m, 1H).
<1-8> Preparation of methyl 11-methyl-9-(3-(methylsulfonyl)propoxy)-6,7-dihydro-5H-dibenzo[a,c][7]annulen-4-carboxylate




The compound (90 mg, 0.318 mmol) obtained in <1-7> was dissolved in DMF (4 mL), and 3-(methylsulfonyl)propyl 4-methylbenzenesulfonate (112 mg, 0.383 mmol) and K2CO3 (66 mg, 0.478 mmol) were added thereto, and stirred at 90° C. for 15 hours. The reaction mixture was cooled to room temperature, diluted with EtOAc, and then washed with a saturated NH4Cl aqueous solution and saline. An organic layer was dried over sodium sulfate, and concentrated under reduced pressure. Then, the residue was purified using silica gel chromatography to obtain the title compound (white foam, 124 mg, and 97% yield).
1H NMR (300 MHz, CDCl3) δ 7.73 (dd, 1H), 7.40-7.27 (m, 2H), 6.74 (d, 1H), 6.63 (d, 1H), 4.15 (m, 2H), 3.92 (s, 3H), 3.27 (m, 2H), 2.97 (s, 3H), 2.55-2.28 (m, 4H), 2.27 (s, 3H), 2.18 (m, 3H), 2.01 (m, 1H).
<1-9> Preparation of (11-methyl-9-(3-(methylsulfonyl)propoxy)-6,7-dihydro-5H-dibenzo[a,c][7]annulen-4-yl)methanol




The compound (122 mg, 0.303 mmol) obtained in <1-8> was dissolved in THF (4 mL), and LiAlH4 (a 1 M THF solution, 455 μL, and 0.455 mmol) was slowly added thereto at 0° C. The reaction mixture was heated slowly, and stirred at ambient temperature for 1 hour. The mixture was diluted with dichloromethane and a saturated sodium sulfate aqueous solution, and layers were separated. An organic layer was dried over MgSO4, and concentrated under reduced pressure. Then, the residue was purified using silica gel chromatography to obtain the title compound (white foam, 100 mg, and 88% yield).
1H NMR (300 MHz, CDCl3) δ 7.34-7.17 (m, 3H), 6.73 (d, 1H), 6.62 (d, 1H), 4.78 (s, 2H), 4.20-4.12 (m, 2H), 3.34-3.22 (m, 2H), 2.97 (s, 3H), 2.87 (dd, 1H), 2.49-2.30 (m, 2H), 2.29 (s, 3H), 2.25-2.04 (m, 2H), 1.67 (br s, 1H).
<1-10> Preparation of methyl 2-((3S)-6-((11-methyl-9-(3-(methylsulfonyl)propoxy)-6,7-dihydro-5H-dibenzo[a,c][7]annulen-4-yl)methoxy)-2,3-dihydrobenzofuran-3-yl)acetate




The compound (100 mg, 0.267 mmol) obtained in <1-9>, (S)-methyl 2-(6-hydroxy-2,3-dihydrobenzofuran-3-yl)acetate (prepared according to the method disclosed in the document [WO 2008/001931]; 56 mg, 0.267 mmol), and tributylphosphine (100 μL, 0.4 mmol) were dissolved in THF (3.6 mL), and 1,1′-(azodicarbonyl)dipiperidine (101 mg, 0.4 mmol) was slowly added thereto, and stirred at ambient temperature for 2 hours. The mixture was concentrated, and purified using silica gel chromatography to obtain the title compound (white foam, 126 mg, and 84% yield).
1H NMR (600 MHz, CDCl3) δ 7.36 (dd, 1H), 7.29-7.23 (m, 2H), 7.06 (d, 1H), 6.73 (d, 1H), 6.63 (d, 1H), 6.53 (dd, 1H), 6.51 (d, 1H), 5.08 (d, 1H), 5.00 (d, 1H), 4.77 (t, 1H), 4.28 (dd, 1H), 4.15 (t, 2H), 3.87-3.78 (m, 1H), 3.72 (s, 3H), 3.31-3.25 (m, 2H), 2.97 (s, 3H), 2.80-2.75 (m, 1H), 2.75-2.71 (m, 2H), 2.58 (dd, 1H), 2.44 (dd, 1H), 2.40-2.33 (m, 2H), 2.30 (s, 3H), 2.22 (ddt, 2H), 2.09 (m, 1H), 1.99 (m, 1H).
<1-11> Preparation of 2-((3S)-6-((11-methyl-9-(3-(methylsulfonyl)propoxy)-6,7-dihydro-5H-dibenzo[a,c][7]annulen-4-yl)methoxy)-2,3-dihydrobenzofuran-3-yl)acetic acid




The compound (126 mg, 0.223 mmol) obtained in <1-10> was dissolved in methanol (2.4 mL) and THF (1.2 mL), and 2 N NaOH (330 μL, 0.66 mmol) was added thereto, and stirred at 75° C. for 2 hours. The mixture was cooled to ambient temperature, and water was added to the mixture to adjust a pH value of a 1 N citric acid aqueous solution to pH 5. The mixture was extracted with dichloromethane, dried over sodium sulfate, and concentrated under reduced pressure. Then, the residue was purified using silica gel chromatography to obtain the title compound (white foam, 112 mg, and 91% yield).
MS m/z 549 [M−H]−.
1H NMR (600 MHz, CDCl3) δ 7.36 (dd, 1H), 7.29-7.23 (m, 2H), 7.10 (d, 1H), 6.74 (d, 1H), 6.63 (d, 1H), 6.55 (dd, 1H), 6.52 (d, 1H), 5.08 (d, 1H), 5.00 (d, 1H), 4.78 (t, 1H), 4.31 (dd, 1H), 4.14 (t, 2H), 3.88-3.79 (m, 1H), 3.31-3.25 (m, 2H), 2.97 (s, 3H), 2.83 (dd, 1H), 2.74 (dd, 1H), 2.64 (dd, 1H), 2.44 (dd, 1H), 2.41-2.33 (m, 2H), 2.30 (s, 3H), 2.22 (ddt, 2H), 2.09 (m, 1H), 1.99 (m, 1H).
Example 2
Preparation of (1S,2S)-2-(4-((9-(3-(methylsulfonyl)propoxy)-6,7-dihydrodibenzo[b,d]oxepin-2-yl)methoxy)phenyl)cyclopropanecarboxylic acid
<2-1> Preparation of 2-(3-methoxy-phenyl)-ethanol




(3-Methoxy-phenyl)-acetic acid methyl ester (2.5 g, 13.9 mmol) was dissolved in EtOH/H2O (40/10 mL), and CaCl2 (1.5 g, 13.9 mmol) was added thereto. Thereafter, when the solids were completely dissolved, NaBH4 (1.1 g, 27.8 mmol) was slowly added. The resulting mixture was stirred for 1 hour and a half, and water and 2 N HCl were added to be adjusted to pH 3 to 4, and then concentrated. The mixture was diluted with water, and extracted with dichloromethane. An organic layer was dried over sodium sulfate, and concentrated under reduced pressure. Then, the residue was purified using silica gel chromatography to obtain the title compound (colorless oil, 1.44 g, and 68% yield).
1H NMR (300 MHz, CDCl3) δ 7.24 (t, 1H), 6.78-6.84 (m, 3H), 3.85 (m, 2H), 3.79 (s, 3H), 2.85 (t, 2H), 1.52 (br s, 1H).
<2-2> Preparation of 2-(2-bromo-5-methoxy-phenyl)-ethanol




The compound (1.44 g, 9.46 mmol) obtained in <2-1> was dissolved in CH3CN (26 mL), N-bromosuccinimide (1.68 g, 9.46 mmol) was added thereto, and stirred for 1 hour. The reaction mixture was concentrated under reduced pressure, and then purified using silica gel chromatography to obtain the title compound (pale brown oil, 2.1 g, and 96% yield).
1H NMR (300 MHz, CDCl3) δ 7.43 (d, 1H), 6.83 (d, 1H), 6.67 (dd, 1H), 3.88 (q, 2H), 3.79 (s, 3H), 2.99 (t, 2H), 1.41 (t, 1H).
<2-3> Preparation of 4-hydroxy-benzoic acid methyl ester




4-Hydroxy-benzoic acid (10 g, 72.4 mmol) was dissolved in methanol (130 mL), and sulfuric acid (1.9 mL) was added thereto, and stirred for 4 hours under reflux. The reaction mixture was concentrated, diluted with water, and extracted with EtOAc. An organic layer was washed with saline, dried over sodium sulfate, and concentrated under reduced pressure. Then, the residue was purified using silica gel chromatography to obtain the title compound (white solid, 11.01 g, and 99% yield).
1H NMR (300 MHz, CDCl3) δ 7.95 (d, 2H), 6.87 (d, 2H), 3.89 (s, 3H).
<2-4> Preparation of 3-bromo-4-hydroxy-benzoic acid methyl ester




The compound (5 g, 32.9 mmol) obtained in <2-3> was dissolved in dichloromethane (350 mL), and a solution obtained by dissolving Br2 (1.7 mL, 32.9 mmol) in dichloromethane (50 mL) was slowly added thereto at 0° C., and stirred at ambient temperature for 1 hour. The mixture was stirred at ambient temperature for another 5 hours, and water and a Na2S2O3 aqueous solution were added thereto. The mixture was extracted with dichloromethane, washed with saline, dried over sodium sulfate, and then concentrated under reduced pressure. The residue was purified using silica gel chromatography to obtain the title compound (white solid, 6.18 g, and 81% yield).
1H NMR (300 MHz, CDCl3) δ 8.19 (d, 1H), 7.92 (dd, 1H), 7.05 (d, 1H), 5.93 (s, 1H), 3.89 (s, 3H).
<2-5> Preparation of 3-bromo-4-methoxymethoxy-benzoic acid methyl ester




The compound (3 g, 13.0 mmol) obtained in <2-4> was dissolved in acetone (25 mL), and K2CO3 (2.3 g, 16.9 mmol) and chloro-methoxy-methane (1.2 mL, 15.6 mmol) were added thereto, and stirred at ambient temperature. After 3 hours, the mixture was filtered, and concentrated. Then, the residue was purified using silica gel chromatography to obtain the title compound (colorless oil, 3.25 g, and 91% yield).
1H NMR (300 MHz, CDCl3) δ 8.24 (d, 1H), 7.94 (dd, 1H), 7.17 (d, 1H), 5.31 (s, 2H), 3.90 (s, 3H), 3.52 (s, 3H).
<2-6> Preparation of 4-methoxymethoxy-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzoic acid methyl ester




The compound (3.2 g, 11.6 mmol) obtained in <2-5>, and bis(pinacolato)diboron (4.4 g, 17.4 mmol) were dissolved in 1,4-dioxane (60 mL), and potassium acetate (3.4 g, 34.8 mmol), and a complex (473 mg, 0.58 mmol) of [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium (II) with dichloromethane were added thereto, and then replaced with nitrogen. The mixture was stirred at 90° C. for 22 hours, cooled to ambient temperature, and then diluted with saline. The mixture was extracted with EtOAc, dried over magnesium sulfate, filtered through silica gel, and then concentrated under reduced pressure. The residue was purified using silica gel chromatography to obtain the title compound (colorless oil, 2.79 g, and 75% yield).
1H NMR (300 MHz, CDCl3) δ 8.35 (d, 1H), 8.06 (dd, 1H), 7.05 (d, 1H), 5.26 (s, 2H), 3.89 (s, 3H), 3.51 (s, 3H), 1.36 (s, 12H).
<2-7> Preparation of 2′-(2-hydroxy-ethyl)-4′-methoxy-6-methoxymethoxy-biphenyl-3-carboxylic acid methyl ester




The compound (1.67 g, 7.2 mmol) obtained in <2-2>, the compound (2.5 g, 7.8 mmol) obtained in <2-6>, and K2CO3 (3.4 g, 34.8 mmol) were dissolved in 1,4-dioxane (26 mL), and a complex (294 mg, 0.36 mmol) of [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium (II) with dichloromethane was added thereto, and replaced with nitrogen. The reaction mixture was stirred at 90° C. for 14 hours, cooled to ambient temperature, and then diluted with saline. The mixture was extracted with EtOAc, dried over magnesium sulfate, and concentrated under reduced pressure. Then, the residue was purified using silica gel chromatography to obtain the title compound (oil, 2.4 g, and 96% yield).
1H NMR (300 MHz, CDCl3) δ 8.01 (dd, 1H), 7.84 (d, 1H), 7.22 (d, 1H), 7.09 (d, 1H), 6.89 (d, 1H), 6.82 (dd, 1H), 5.14 (s, 2H), 3.88 (s, 3H), 3.85 (s, 3H), 3.66 (q, 2H), 3.37 (s, 3H), 2.73 (m, 2H), 1.37 (t, 1H).
<2-8> Preparation of 6-hydroxy-2′-(2-hydroxy-ethyl)-4′-methoxy-biphenyl-3-carboxylic acid methyl ester




The compound (2.4 g, 6.9 mmol) obtained in <2-7> was dissolved in methanol (60 mL), and p-TsOH.H2O (4.0 g, 20.8 mmol) was added thereto, and stirred at ambient temperature. After 30 minutes, p-TsOH.H2O (2.0 g, 10.4 mmol) was added, stirred for 14 hours, and then concentrated. The mixture was diluted with water and dichloromethane, and basified with a saturated NaHCO3 aqueous solution, and extraction was then performed. An organic layer was dried over sodium sulfate, and concentrated under reduced pressure. Then, the residue was purified using silica gel chromatography to obtain the title compound (white solid, 1.50 g, and 72% yield).
1H NMR (300 MHz, CDCl3) δ 7.98 (dd, 1H), 7.81 (d, 1H), 7.14 (d, 1H), 7.01 (d, 1H), 6.94 (d, 1H), 6.88 (dd, 1H), 6.00 (br s, 1H), 3.88 (s, 3H), 3.86 (s, 3H), 3.79 (t, 2H), 2.70 (m, 2H), 1.50 (br s, 1H).
<2-9> Preparation of 6-hydroxy-4′-methoxy-2′-[2-(toluene-4-sulfonyloxy)-ethyl]-biphenyl-3-carboxylic acid methyl ester




The compound (1.5 g, 4.96 mmol) obtained in <2-8> was dissolved in dichloromethane (60 mL), pyridine (2.0 mL, 24.8 mmol) was added thereto to dissolve solids, and p-TsCl (1.4 g, 7.44 mmol) was added at 0° C. The mixture was slowly heated, stirred at ambient temperature for 16 hours, and diluted with water, and extraction was then performed. An organic layer was dried over sodium sulfate, and concentrated under reduced pressure. Then, the residue was purified using silica gel chromatography to obtain the title compound (white solid, 2.23 g, and 98% yield).
1H NMR (300 MHz, CDCl3) δ 7.95 (dd, 1H), 7.70 (d, 1H), 7.61 (d, 1H), 7.26 (d, 1H), 7.11 (d, 1H), 6.96 (d, 1H), 6.90 (d, 1H), 6.86 (dd, 1H), 5.23 (s, 1H), 4.00 (t, 2H), 3.88 (s, 3H), 3.84 (s, 3H), 2.78 (m, 2H), 2.43 (s, 3H).
<2-10> Preparation of 9-methoxy-6,7-dihydro-5-oxa-dibenzo[a,c]cycloheptene-2-carboxylic acid methyl ester




The compound (2.23 g, 4.88 mmol) obtained in <2-9> was dissolved in DMF (60 mL), and K2CO3 (2.0 g, 14.65 mmol) was added thereto, and stirred at 90° C. for 1 hour and 30 minutes. The mixture was diluted with water and saline, filtered, and then washed with water. The resulting solids were dried at 35° C. in a vacuum to obtain the title compound (white solid, 1.26 g, and 91% yield).
1H NMR (300 MHz, CDCl3) δ 8.09 (d, 1H), 7.96 (dd, 1H), 7.43 (d, 1H), 7.14 (d, 1H), 6.94 (dd, 1H), 6.83 (d, 1H), 4.62 (t, 2H), 3.92 (s, 3H), 3.86 (s, 3H), 2.81 (t, 2H).
<2-11> Preparation of 9-hydroxy-6,7-dihydro-5-oxa-dibenzo[a,c]cycloheptene-2-carboxylic acid methyl ester




The title compound (white solid, 852.2 mg, and 77% yield) was obtained from the compound obtained in <2-10> according to the procedure described in <1-7>.
1H NMR (300 MHz, CDCl3) δ 8.08 (d, 1H), 7.96 (dd, 1H), 7.36 (d, 1H), 7.14 (d, 1H), 6.86 (dd, 1H), 6.78 (d, 1H), 5.18 (s, 1H), 4.61 (t, 2H), 3.93 (s, 3H), 2.78 (t, 2H).
<2-12> Preparation of 9-(3-methanesulfonyl-propoxy)-6,7-dihydro-5-oxa-dibenzo[a,c]cycloheptene-2-carboxylic acid methyl ester




The title compound (colorless oil, 396.7 mg, >100% yield) was obtained from the compound obtained in <2-11> according to the procedure described in <1-8>.
1H NMR (300 MHz, CDCl3) δ 8.08 (d, 1H), 7.97 (dd, 1H), 7.42 (d, 1H), 7.14 (d, 1H), 6.91 (dd, 1H), 6.83 (d, 1H), 4.61 (t, 2H), 4.18 (t, 2H), 3.92 (s, 3H), 3.29 (t, 2H), 2.97 (s, 3H), 2.80 (t, 2H), 2.38 (m, 2H).
<2-13> Preparation of [9-(3-methanesulfonyl-propoxy)-6,7-dihydro-5-oxa-dibenzo[a,c]cyclohepten-2-yl]-methanol




The title compound (colorless oil, 294.7 mg, and 86% yield) was obtained from the compound obtained in <2-12> according to the procedure described in <1-9>.
1H NMR (300 MHz, CDCl3) δ 7.39 (d, 1H), 7.37 (dd, 1H), 7.29 (dd, 1H), 7.11 (d, 1H), 6.89 (dd, 1H), 6.83 (d, 1H), 4.72 (d, 2H), 4.55 (t, 2H), 4.16 (t, 2H), 3.28 (t, 2H), 2.97 (s, 3H), 2.77 (t, 2H), 2.37 (m, 2H), 1.75 (br t, 1H).
<2-14> Preparation of (1S,2S)-2-(4-acetoxy-phenyl)-cyclopropanecarboxylic acid ethyl ester




Chloroform (10 mL) was replaced with argon, and (CuOTf)2-toluene (39.8 mg, 0.077 mmol), and (2R)-4-tert-butyl-2-{1-[(4R)-4-tert-butyl-4,5-dihydro-1,3-oxazol-2-yl]-1-methylethyl}-4,5-dihydro-1,3-oxazole (45.3 mg, 0.154 mmol) were added, and stirred for 1 hour and 10 minutes. Acetic acid 4-vinyl-phenyl ester (2.5 g, 15.4 mmol) was dissolved in chloroform (10 mL), and replaced with argon, and the prepared solution was then added thereto. Diazo-acetic acid ethyl ester (2.1 mL, 17.0 mmol) was dissolved in chloroform (30 mL), replaced with argon, and then slowly added to the mixture over 3 hours. The reaction mixture was filtered through silica gel, washed with EtOAc/dichloromethane (1/9 ratio), concentrated under reduced pressure, and then purified using silica gel chromatography to obtain the title compound (colorless oil, 3.6 g, and 94% yield).
<2-15> Preparation of (1S,2S)-2-(4-hydroxy-phenyl)-cyclopropanecarboxylic acid ethyl ester




The compound (2.6 g, 10.47 mmol) obtained in <2-14> was dissolved in MeOH/H2O (80/20 mL), and NH4OAc (6.46 g, 83.78 mmol) was added thereto, and stirred for 3 hours 30 minutes under reflux. The reaction mixture was cooled to ambient temperature, and concentrated. Thereafter, the reaction mixture was diluted with water, and extracted with EtOAc, and an organic layer was then washed with saline. Subsequently, the organic layer was dried over magnesium sulfate, and concentrated under reduced pressure. Then, the residue was purified using silica gel chromatography to obtain the title compound (colorless oil, 1.77 g, 80% yield, and 97% ee).
1H NMR (300 MHz, CDCl3) δ 7.00 (d, 2H), 6.74 (d, 2H), 4.85 (br s, 1H), 4.16 (q, 2H), 2.47 (m, 1H), 1.81 (m, 1H), 1.55 (m, 1H), 1.28 (t, 3H), 1.24 (m, 1H).
<2-16> Preparation of (1S,2S)-ethyl 2-(4-((9-(3-(methylsulfonyl)propoxy)-6,7-dihydrodibenzo[b,d]oxepin-2-yl)methoxy)phenyl)cyclopropanecarboxylate




The compound (88.8 mg, 0.25 mmol) obtained in <2-13>, the compound (50.5 mg, 0.25 mmol) obtained in <2-15>, and PPh3 (96.5 mg, 0.37 mmol) were dissolved in THF (2 mL), and diethyl azodicarboxylate (a 40% toluene solution, 0.17 mL, 0.37 mmol) was slowly added thereto, and stirred for 3 hours 30 minutes. The reaction mixture was concentrated under reduced pressure, and then purified using silica gel chromatography to obtain the title compound (oil, 99.4 mg, and 74% yield).
1H NMR (300 MHz, CDCl3) δ 7.43 (d, 1H), 7.37 (d, 1H), 7.34 (dd, 1H), 7.13 (d, 1H), 7.04 (d, 2H), 6.91 (d, 2H), 6.89 (dd, 1H), 6.83 (d, 1H), 5.05 (s, 2H), 4.56 (t, 2H), 4.18 (t, 2H), 4.15 (q, 2H), 3.28 (t, 2H), 2.97 (s, 3H), 2.78 (t, 2H), 2.47 (m, 1H), 2.37 (m, 2H), 1.82 (m, 1H), 1.55 (m, 1H), 1.26 (t, 3H), 1.24 (m, 1H).
<2-17> Preparation of (1S,2S)-2-(4-((9-(3-(methylsulfonyl)propoxy)-6,7-dihydrodibenzo[b,d]oxepin-2-yl)methoxy)phenyl)cyclopropanecarboxylic acid




The title compound (white solid, 74.5 mg, 79% yield) was obtained from the compound obtained in <2-16> according to the procedure described in <1-11>.
MS m/z 521 [M−H]−.
1H NMR (300 MHz, CDCl3) δ 7.42 (d, 1H), 7.37 (d, 1H), 7.34 (dd, 1H), 7.13 (d, 1H), 7.05 (d, 2H), 6.91 (d, 2H), 6.90 (dd, 1H), 5.05 (t, 2H), 4.56 (t, 2H), 4.17 (t, 2H), 3.28 (t, 2H), 2.97 (s, 3H), 2.78 (t, 2H), 2.56 (m, 1H), 2.37 (m, 2H), 1.84 (m, 1H), 1.62 (m, 1H), 1.35 (m, 1H).
Example 3
Preparation of (1S,2S)-2-(4-(((9-(2-ethoxyethoxy)-6,7-dihydrodibenzo[b,d]oxepin-2-yl)methyl)amino)phenyl)cyclopropanecarboxylic acid
<3-1> Preparation of methyl 9-(2-ethoxyethoxy)-6,7-dihydrodibenzo[b,d]oxepin-2-carboxylate




The compound (100 mg, 0.37 mmol) obtained in <2-11>, and K2CO3 (61 mg, 0.44 mmol) were dissolved in DMF (1.5 mL), and KI (12 mg, 74 μmol) and 2-chloroethyl ethyl ether (62 μL, 0.56 mmol) were sequentially added to the suspension solution, and then stirred at 80° C. for 18 hours. The mixture was diluted with EtOAc, and washed with a saturated NH4Cl aqueous solution. An organic layer was dried over sodium sulfate, and concentrated under reduced pressure. Then, the residue was purified using silica gel chromatography to obtain the title compound (colorless oil, 94 mg, and 73% yield).
1H NMR (600 MHz, CDCl3) δ 8.09 (d, 1H), 7.96 (dd, 1H), 7.42 (d, 1H), 7.14 (d, 1H), 6.96 (dd, 1H), 6.88 (d, 1H), 4.61 (t, 2H), 4.18 (t, 2H), 3.92 (s, 3H), 3.82 (t, 2H), 3.63 (q, 2H), 2.80 (t, 2H), 1.26 (t, 3H).
<3-2> Preparation of (9-(2-ethoxyethoxy)-6,7-dihydrodibenzo[b,d]oxepin-2-yl)methanol




The compound (90 mg, 0.26 mmol) obtained in <3-1> was dissolved in THF (5 mL), and LiAlH4 (0.53 mL, 0.53 mmol) was slowly added thereto at 0° C., and then stirred at room temperature for 1 hour. The reaction mixture was cooled to 0° C., and diluted with a saturated sodium sulfate aqueous solution. Layers were separated, and an organic layer was dried over sodium sulfate, concentrated under reduced pressure, and then purified using silica gel chromatography to obtain the title compound (colorless oil, 80 mg, and 97% yield).
1H NMR (600 MHz, CDCl3) δ 7.38-7.39 (m, 1H), 7.37 (s, 1H), 7.29 (dd, 1H), 7.11 (d, 1H), 6.94 (dd, 1H), 6.88 (d, 1H), 4.73 (d, 2H), 4.55 (t, 2H), 4.18 (t, 2H), 3.82 (t, 2H), 3.63 (q, 2H), 2.77 (t, 2H), 1.67 (t, 1H), 1.26 (t, 3H).
<3-3> Preparation of 9-(2-ethoxyethoxy)-6,7-dihydrodibenzo[b,d]oxepin-2-carbaldehyde




The compound (80 mg, 0.25 mmol) obtained in <3-2> was dissolved in CH3CN (4 mL), and MnO2 (110 mg, 1.27 mmol) was added thereto, and then stirred at 60° C. for 70 minutes. The reaction mixture was filtered through Celite, concentrated under reduced pressure, and then purified using silica gel chromatography to obtain the title compound (colorless oil, 79 mg, and 100% yield).
1H NMR (600 MHz, CDCl3) δ 10.01 (s, 1H), 7.92 (d, 1H), 7.81 (dd, 1H), 7.43 (d, 1H), 7.23 (d, 1H), 6.97 (dd, 1H), 6.89 (d, 1H), 4.64 (t, 2H), 4.19 (q, 2H), 3.83 (t, 2H), 3.63 (q, 2H), 2.83 (t, 2H), 1.26 (t, 3H).
<3-4> Preparation of (1S,2S)-ethyl 2-(4-(((9-(2-ethoxyethoxy)-6,7-dihydrodibenzo[b,d]oxepin-2-yl)methyl)amino)phenyl)cyclopropanecarboxylate




The compound (79 mg, 0.25 mmol) obtained in <3-3>, and a (1S,2S)-2-(4-amino-phenyl)-cyclopropanecarboxylic acid ethyl ester (prepared according to the method disclosed in the document [Bioorganic & Medicinal Chemistry, 2006, pp. 1840-1845]; 52 mg, 0.25 mmol) were dissolved in dichloromethane (3 mL), and AcOH (29 μL, 0.51 mmol) was added thereto, and stirred at room temperature for 1 hour. The mixture was cooled to 0° C., and Na(OAc)3BH (107 mg, 0.51 mmol) was slowly added. The mixture was stirred at room temperature for 2 hours, and then diluted with water. Layers were separated, and an organic layer was dried over sodium sulfate, concentrated under reduced pressure, and then purified using silica gel chromatography to obtain the title compound (colorless foam, 121 mg, and 95% yield).
1H NMR (600 MHz, CDCl3) δ 7.36 (d, 1H), 7.34 (d, 1H), 7.25-7.27 (m, 1H), 7.08 (d, 1H), 6.90-6.94 (m, 3H), 6.88 (d, 1H), 6.57-6.62 (m, 2H), 4.54 (t, 2H), 4.32 (s, 2H), 4.13-4.18 (m, 4H), 4.00 (br, 1H), 3.81 (t, 2H), 3.63 (q, 2H), 2.76 (t, 2H), 2.42-2.45 (m, 1H), 1.77-1.80 (m, 1H), 1.50-1.53 (m, 1H), 1.24-1.28 (m, 6H), 1.21-1.23 (m, 1H).
<3-5> Preparation of (1S,2S)-2-(4-(((9-(2-ethoxyethoxy)-6,7-dihydrodibenzo[b,d]oxepin-2-yl)methyl)amino)phenyl)cyclopropanecarboxylic acid




The compound (121 mg, 0.24 mmol) obtained in <3-4> was dissolved in THF (1.5 mL) and MeOH (3 mL), and 2 N NaOH (0.36 mL, 0.72 mmol) was added thereto, and then stirred at 80° C. for 2 hours. The mixture was diluted with a 0.5 M citric acid aqueous solution until the pH value reached approximately pH 3 to 4. Layers were extracted, and an organic layer was dried over sodium sulfate, concentrated under reduced pressure, and then purified using silica gel chromatography to obtain the title compound (colorless foam, 100 mg, and 88% yield).
MS m/z 472 [M−H]−.
1H NMR (600 MHz, CDCl3) δ 7.36 (d, 1H), 7.34 (d, 1H), 7.25-7.27 (m, 1H), 7.08 (d, 1H), 6.92-6.96 (m, 3H), 6.88 (d, 1H), 6.58-6.60 (m, 2H), 4.54 (t, 2H), 4.32 (s, 2H), 4.17 (t, 2H), 3.82 (t, 2H), 3.63 (q, 2H), 2.76 (t, 2H), 2.50-2.53 (m, 1H), 1.77-1.80 (m, 1H), 1.56-1.59 (m, 1H), 1.31-1.34 (m, 1H), 1.26 (t, 3H).
Example 4
Preparation of (1S,2S)-2-(4-(((9-(3-(methylsulfonyl)propoxy)-6,7-dihydrodibenzo[b,d]oxepin-2-yl)methyl)amino)phenyl)cyclopropanecarboxylic acid
<4-1> Preparation of 9-(3-(methylsulfonyl)propoxy)-6,7-dihydrodibenzo[b,d]oxepin-2-carbaldehyde




The title compound (white solid, 103.4 mg, and 99% yield) was obtained from the compound obtained in <2-13> according to the procedure described in <3-3>.
1H NMR (300 MHz, CDCl3) δ 10.01 (s, 1H), 7.92 (d, 1H), 7.82 (dd, 1H), 7.43 (d, 1H), 7.23 (d, 1H), 6.93 (dd, 1H), 6.84 (d, 1H), 4.65 (t, 2H), 4.19 (t, 2H), 3.29 (t, 2H), 2.98 (s, 3H), 2.84 (t, 2H), 2.39 (m, 2H).
<4-2> Preparation of (1S,2S)-ethyl 2-(4-(((9-(3-(methylsulfonyl)propoxy)-6,7-dihydrodibenzo[b,d]oxepin-2-yl)methyl)amino)phenyl)cyclopropanecarboxylate




The title compound (oil, 150.2 mg, and 94% yield) was obtained from the compound obtained in <4-1> according to the procedure described in <3-4>.
1H NMR (300 MHz, CDCl3) δ 7.35 (d, 1H), 7.33 (d, 1H), 7.27 (dd, 1H), 7.07 (d, 1H), 6.93 (d, 2H), 6.87 (dd, 1H), 6.82 (d, 1H), 6.57 (d, 2H), 4.53 (t, 2H), 4.31 (s, 2H), 4.15 (t, 2H), 4.14 (q, 2H), 4.00 (br s, 1H), 3.27 (t, 2H), 2.96 (s, 3H), 2.76 (t, 2H), 2.32-2.46 (m, 3H), 1.77 (m, 1H), 1.50 (m, 1H), 1.26 (t, 3H), 1.21 (m, 1H).
<4-3> Preparation of (1S,2S)-2-(4-(((9-(3-(methylsulfonyl)propoxy)-6,7-dihydrodibenzo[b,d]oxepin-2-yl)methyl)amino)phenyl)cyclopropanecarboxylic acid




The title compound (white solid, 68.9 mg, and 49% yield) was obtained from the compound obtained in <4-2> according to the procedure described in <3-5>.
MS m/z 520 [M−H]−.
1H NMR (300 MHz, CDCl3) δ 7.35 (d, 1H), 7.34 (d, 1H), 7.27 (dd, 1H), 7.08 (d, 1H), 6.94 (d, 2H), 6.88 (dd, 1H), 6.83 (d, 1H), 6.58 (d, 2H), 4.55 (t, 2H), 4.33 (s, 2H), 4.16 (t, 2H), 3.28 (t, 2H), 2.97 (s, 3H), 2.77 (t, 2H), 2.52 (m, 1H), 2.38 (m, 2H), 1.79 (m, 1H), 1.58 (m, 1H), 1.32 (m, 1H).
Example 5
Preparation of (S)-2-(6-((9-(3-(methylsulfonyl)propoxy)-6,7-dihydro-5H-dibenzo[a,c][7]annulen-2-yl) methoxy)-2,3-dihydrobenzofuran-3-yl)acetic acid
<5-1> Preparation of (2-bromo-4-(methoxycarbonyl)benzyl)triphenylphosphonium bromide




The title compound (white solid, 4.95 g, and 92% yield) was obtained from methyl 3-bromo-4-(bromomethyl)benzoate (prepared according to the method disclosed in the document [Journal of the American Chemical Society, 2002, vol. 124, #50, pp. 14993-15000]; 2.90 g, 9.42 mmol) according to the procedure described in <1-2>.
1H NMR (300 MHz, CDCl3) δ 8.04 (s, 1H), 7.84-7.62 (m, 17H), 5.90 (d, 2H), 3.90 (s, 3H).
<5-2> Preparation of methyl 3-bromo-4-(3-(3-methoxyphenyl)prop-1-en-1-yl)benzoate




The title compound (an E/Z mixture, light yellow oil, 3.13 g, and 84% yield) was obtained from the compound obtained in <5-1>, and 2-(3-methoxyphenyl)acetaldehyde according to the procedure described in <1-3>.
E form: 1H NMR (300 MHz, CDCl3) δ 8.21 (d, 1H), 7.88 (dd, 1H), 7.54 (d, 1H), 7.23 (d, 1H), 6.90-6.73 (m, 4H), 6.41 (dt, 1H), 3.91 (s, 3H), 3.81 (s, 3H), 3.59 (d, 2H).
Z form: 1H NMR (300 MHz, CDCl3) δ 8.28 (d, 1H), 7.94 (dd, 1H), 7.38 (d, 1H), 7.21 (d, 1H), 6.90-6.73 (m, 3H), 6.63 (d, 1H), 6.05 (dt, 1H), 3.93 (s, 3H), 3.80 (s, 3H), 3.49 (d, 2H).
<5-3> Preparation of methyl 3-bromo-4-(3-(3-methoxyphenyl)propyl)benzoate




The compound (3.13 g, 8.67 mmol) obtained in <5-2> was dissolved in EtOAc (30 mL), and 10% Pd/C (600 mg, 0.56 mmol) was added thereto, and stirred for 2 hours under hydrogen flow. The reaction mixture was filtered through Celite, and washed with EtOAc, and the filtrate was then concentrated under reduced pressure. The residue was purified using silica gel chromatography to obtain the title compound (colorless oil, 2.39 g, and 76% yield).
1H NMR (300 MHz, CDCl3) δ 8.20 (d, 1H), 7.88 (dd, 1H), 7.27 (d, 1H), 7.24-7.18 (m, 1H), 6.80 (d, 1H), 6.76-6.73 (m, 2H), 3.91 (s, 3H), 3.80 (s, 3H), 2.81 (t, 2H), 2.68 (t, 2H), 2.01-1.91 (m, 2H).
<5-4> Preparation of methyl 4-(3-(3-methoxyphenyl)propyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate




The compound (2.39 g, 6.58 mmol) obtained in <5-3> was dissolved in DMF (30 mL), and bis(pinacolato)diboron (2.01 g, 7.90 mmol) and KOAc (1.94 g, 19.74 mmol) were added thereto, and replaced with nitrogen. Thereafter, [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium (269 mg, 0.33 mmol) was added, and stirred at 100° C. for 10 hours. The reaction mixture was cooled to room temperature, and water was added. The resulting mixture was extracted with EtOAc. An organic layer was washed with saline, dried over sodium sulfate, filtered, and then concentrated under reduced pressure. The residue was purified using silica gel chromatography to obtain the title compound (colorless oil, 1.88 g, and 70% yield).
1H NMR (300 MHz, CDCl3) δ 8.42 (d, 1H), 7.99 (dd, 1H), 7.23 (d, 1H), 7.22-7.16 (m, 1H), 6.78 (d, 1H), 6.73-6.71 (m, 2H), 3.90 (s, 3H), 3.79 (s, 3H), 2.98 (t, 2H), 2.65 (t, 2H), 1.93-1.83 (m, 2H), 1.34 (s, 12H).
<5-5> Preparation of methyl 4-(3-(2-bromo-5-methoxyphenyl)propyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate




The compound (1.87 g, 4.56 mmol) obtained in <5-4> was dissolved in acetonitrile (30 mL), and N-bromosuccinimide (0.81 g, 4.56 mmol) was added thereto at 0° C., warmed to room temperature, and stirred for 3 hours. The reaction mixture was concentrated under reduced pressure, and water was added. Then, the mixture was extracted with dichloromethane. An organic layer was dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified using silica gel chromatography to obtain the title compound (colorless oil, 1.96 g, and 88% yield).
1H NMR (300 MHz, CDCl3) δ 8.43 (d, 1H), 8.00 (dd, 1H), 7.39 (d, 1H), 7.27 (d, 1H), 6.74 (d, 1H), 6.61 (dd, 1H), 3.90 (s, 3H), 3.76 (s, 3H), 3.03 (t, 2H), 2.74 (t, 2H), 1.93-1.83 (m, 2H), 1.34 (s, 12H).
<5-6> Preparation of methyl 9-methoxy-6,7-dihydro-5H-dibenzo[a,c][7]annulen-2-carboxylate




The compound (1.82 g, 3.72 mmol) obtained in <5-5> was dissolved in 1,4-dioxane (25 mL), and K2CO3 (1.54 g, 11.16 mmol) was added thereto, and replaced with nitrogen. Thereafter, PdCl2(dppf) (152 mg, 0.19 mmol) was added, and stirred at 95° C. for 16 hours. The reaction mixture was cooled to room temperature, and a saturated NH4Cl aqueous solution was added. Then, the mixture was extracted with EtOAc. An organic layer was washed with saline, dried over sodium sulfate, filtered, and then concentrated under reduced pressure. The residue was purified using silica gel chromatography to obtain the title compound (colorless oil, 695 mg, and 66% yield).
1H NMR (300 MHz, CDCl3) δ 8.02 (d, 1H), 7.92 (dd, 1H), 7.35 (d, 1H), 7.29 (d, 1H), 6.89 (dd, 1H), 6.81 (d, 1H), 3.93 (s, 3H), 3.86 (s, 3H), 2.55 (t, 2H), 2.46 (t, 2H), 2.25-2.16 (m, 2H).
<5-7> Preparation of methyl 9-hydroxy-6,7-dihydro-5H-dibenzo[a,c][7]annulen-2-carboxylate




The compound (685 mg, 2.43 mmol) obtained in <5-6> was dissolved in dichloromethane (25 mL), and BBr3 (a 1 M dichloromethane solution, 4.85 mL, 4.85 mmol) was slowly added thereto at 0° C., warmed to room temperature, and stirred for 1 hour. Methanol and water were sequentially added to the reaction mixture at 0° C., and then extracted with dichloromethane. An organic layer was dried over sodium sulfate, filtered, and then concentrated under reduced pressure. The residue was purified using silica gel chromatography to obtain the title compound (colorless foam, 643 mg, and 99% yield).
1H NMR (300 MHz, CDCl3) δ 8.01 (d, 1H), 7.92 (dd, 1H), 7.29 (d, 2H), 6.83 (dd, 1H), 6.75 (d, 1H), 5.08 (s, 1H), 3.93 (s, 3H), 2.54 (t, 2H), 2.43 (t, 2H), 2.24-2.14 (m, 2H).
<5-8> Preparation of methyl 9-(3-(methylsulfonyl)propoxy)-6,7-dihydro-5H-dibenzo[a,c][7]annulen-2-carboxylate




The title compound (white solid, 424 mg, and 98% yield) was obtained from the compound obtained in <5-7> according to the procedure described in <1-8>.
1H NMR (300 MHz, CDCl3) δ 8.01 (d, 1H), 7.93 (dd, 1H), 7.35 (d, 1H), 7.30 (d, 1H), 6.87 (dd, 1H), 6.80 (d, 1H), 4.17 (t, 2H), 3.93 (s, 3H), 3.29 (t, 2H), 2.98 (s, 3H), 2.54 (t, 2H), 2.46 (t, 2H), 2.43-2.34 (m, 2H), 2.25-2.16 (m, 2H).
<5-9> Preparation of (9-(3-(methylsulfonyl)propoxy)-6,7-dihydro-5H-dibenzo[a,c][7]annulen-2-yl)methanol




The title compound (white solid, 338 mg, and 87% yield) was obtained from the compound obtained in <5-8> according to the procedure described in <1-9>.
1H NMR (300 MHz, CDCl3) δ 7.34 (d, 1H), 7.32 (d, 1H), 7.29-7.21 (m, 2H), 6.85 (dd, 1H), 6.79 (d, 1H), 4.74 (d, 2H), 4.17 (t, 2H), 3.29 (t, 2H), 2.97 (s, 3H), 2.49 (t, 2H), 2.46 (t, 2H), 2.42-2.33 (m, 2H), 2.22-2.13 (m, 2H), 1.65 (t, 1H).
<5-10> Preparation of (S)-methyl 2-(6-((9-(3-(methylsulfonyl)propoxy)-6,7-dihydro-5H-dibenzo[a,c][7]annulen-2-yl)methoxy)-2,3-dihydrobenzofuran-3-yl)acetate




The title compound (white foam, 103 mg, and 84% yield) was obtained from the compound obtained in <5-9> according to the procedure described in <1-10>.
1H NMR (300 MHz, CDCl3) δ 7.38 (d, 1H), 7.31 (d, 2H), 7.23 (d, 1H), 7.03 (d, 1H), 6.85 (dd, 1H), 6.79 (d, 1H), 6.53-6.48 (m, 2H), 5.04 (s, 2H), 4.76 (t, 1H), 4.27 (dd, 1H), 4.17 (t, 2H), 3.86-3.76 (m, 1H), 3.72 (s, 3H), 3.29 (t, 2H), 2.97 (s, 3H), 2.76 (dd, 1H), 2.56 (dd, 1H), 2.50 (t, 2H), 2.47 (t, 2H), 2.42-2.33 (m, 2H), 2.22-2.13 (m, 2H).
<5-11> Preparation of (S)-2-(6-((9-(3-(methylsulfonyl)propoxy)-6,7-dihydro-5H-dibenzo[a,c][7]annulen-2-yl)methoxy)-2,3-dihydrobenzofuran-3-yl)acetic acid




The title compound (white foam, 81 mg, and 83% yield) was obtained from the compound obtained in <5-10> according to the procedure described in <1-11>.
MS m/z 535 [M−H]−.
1H NMR (300 MHz, CDCl3) δ 7.38 (d, 1H), 7.31 (d, 2H), 7.23 (d, 1H), 7.07 (d, 1H), 6.85 (dd, 1H), 6.79 (d, 1H), 6.54-6.49 (m, 2H), 5.04 (s, 2H), 4.77 (t, 1H), 4.29 (dd, 1H), 4.16 (t, 2H), 3.87-3.77 (m, 1H), 3.29 (t, 2H), 2.97 (s, 3H), 2.82 (dd, 1H), 2.62 (dd, 1H), 2.50 (t, 2H), 2.47 (t, 2H), 2.42-2.33 (m, 2H), 2.22-2.13 (m, 2H).
Example 6
Preparation of (1S,2S)-2-(4-(((9-(3-(methylsulfonyl)propoxy)-6,7-dihydro-5H-dibenzo[a,c][7]annulen-2-yl)methyl)amino)phenyl)cyclopropanecarboxylic acid
<6-1> Preparation of 9-(3-(methylsulfonyl)propoxy)-6,7-dihydro-5H-dibenzo[a,c][7]annulen-2-carbaldehyde




The title compound (white solid, 80 mg, and 89% yield) was obtained from the compound obtained in <5-9> according to the procedure described in <3-3>.
1H NMR (300 MHz, CDCl3) δ 10.05 (s, 1H), 7.84 (d, 1H), 7.78 (dd, 1H), 7.40 (d, 1H), 7.35 (d, 1H), 6.89 (dd, 1H), 6.81 (d, 1H), 4.18 (t, 2H), 3.30 (t, 2H), 2.98 (s, 3H), 2.57 (t, 2H), 2.47 (t, 2H), 2.43-2.34 (m, 2H), 2.27-2.18 (m, 2H).
<6-2> Preparation of (1S,2S)-ethyl2-(4-(((9-(3-(methylsulfonyl)propoxy)-6,7-dihydro-5H-dibenzo[a,c][7]annulen-2-yl)methyl)amino)phenyl)cyclopropanecarboxylate




The title compound (white foam, 115 mg, and 97% yield) was obtained from the compound obtained in <6-1> according to the procedure described in <3-4>.
1H NMR (300 MHz, CDCl3) δ 7.32 (d, 1H), 7.29-7.18 (m, 3H), 6.93 (d, 2H), 6.84 (dd, 1H), 6.79 (d, 1H), 6.59 (d, 2H), 4.33 (s, 2H), 4.16 (t, 2H), 4.15 (q, 2H), 4.01 (s, 1H), 3.29 (t, 2H), 2.97 (s, 3H), 2.48 (t, 2H), 2.46 (t, 2H), 2.44-2.33 (m, 3H), 2.21-2.12 (m, 2H), 1.81-1.75 (m, 1H), 1.53-1.48 (m, 1H), 1.27 (t, 3H), 1.24-1.19 (m, 1H).
<6-3> Preparation of (1S,2S)-2-(4-(((9-(3-(methylsulfonyl)propoxy)-6,7-dihydro-5H-dibenzo[a,c][7]annulen-2-yl)methyl)amino)phenyl)cyclopropanecarboxylic acid




The title compound (white solid, 82 mg, and 77% yield) was obtained from the compound obtained in <6-2> according to the procedure described in <3-5>.
MS m/z 518 [M−H]−.
1H NMR (300 MHz, CDCl3) δ ppm 7.31 (s, 1H), 7.28-7.17 (m, 3H), 6.94 (d, 2H), 6.84 (dd, 1H), 6.78 (d, 1H), 6.58 (d, 2H), 4.33 (s, 2H), 4.16 (t, 2H), 3.28 (t, 2H), 2.97 (s, 3H), 2.55-2.49 (m, 1H), 2.48 (t, 2H), 2.46 (t, 2H), 2.41-2.32 (m, 2H), 2.21-2.12 (m, 2H), 1.81-1.76 (m, 1H), 1.60-1.54 (m, 1H), 1.35-1.24 (m, 2H).
Example 7
Preparation of 2-((3S)-6-((11-methyl-9-(3-(methylsulfonyl)propoxy)-6,7-dihydro-5H-dibenzo[a,c][7]annulen-2-yl)methoxy)-2,3-dihydrobenzofuran-3-yl)acetic acid
<7-1> Preparation of methyl 3-bromo-4-(3-(3-methoxy-5-methylphenyl)prop-1-en-1-yl)benzoate




The title compound (E/Z mixture, colorless oil, 3.04 g, and 94% yield) was obtained from the compound obtained in <5-1> and the compound obtained in <1-1>, according to the procedure described in <1-3>.
E form: 1H NMR (300 MHz, CDCl3) δ 8.21 (d, 1H), 7.88 (ddd, 1H), 7.55 (d, 1H), 6.84 (d, 1H), 6.67-6.54 (m, 3H), 6.40 (dt, 1H), 3.91 (s, 3H), 3.79 (s, 3H), 3.55 (d, 2H), 2.32 (s, 3H).
Z form: 1H NMR (300 MHz, CDCl3) δ 8.28 (d, 1H), 7.93 (dd, 1H), 7.39 (d, 1H), 6.67-6.54 (m, 4H), 6.04 (dt, 1H), 3.93 (s, 3H), 3.78 (s, 3H), 3.45 (d, 2H), 2.31 (s, 3H).
<7-2> Preparation of methyl 3-bromo-4-(3-(3-methoxy-5-methylphenyl)propyl)benzoate




The title compound (colorless oil, 2.68 g, and 88% yield) was obtained from the compound obtained in <7-1> according to the procedure described in <5-3>.
1H NMR (300 MHz, CDCl3) δ 8.20 (d, 1H), 7.88 (dd, 1H), 7.27 (d, 1H), 6.62 (s, 1H), 6.56 (s, 2H), 3.91 (s, 3H), 3.78 (s, 3H), 2.81 (t, 2H), 2.64 (t, 2H), 2.31 (s, 3H), 2.00-1.89 (m, 2H).
<7-3> Preparation of methyl 4-(3-(3-methoxy-5-methylphenyl)propyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate




The title compound (colorless oil, 1.21 g, and 40% yield) was obtained from the compound obtained in <7-2> according to the procedure described in <5-4>.
1H NMR (300 MHz, CDCl3) δ 8.42 (d, 1H), 7.99 (dd, 1H), 7.23 (d, 1H), 6.60 (s, 1H), 6.54 (s, 2H), 3.90 (s, 3H), 3.77 (s, 3H), 2.98 (t, 2H), 2.61 (t, 2H), 2.29 (s, 3H), 1.92-1.81 (m, 2H), 1.34 (s, 12H).
<7-4> Preparation of methyl 4-(3-(2-bromo-5-methoxy-3-methylphenyl)propyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate




The title compound (colorless oil, 1.36 g, and 96% yield) was obtained from the compound obtained in <7-3> according to the procedure described in <5-5>.
1H NMR (300 MHz, CDCl3) δ 8.42 (d, 1H), 8.00 (dd, 1H), 7.27 (d, 1H), 6.65 (d, 1H), 6.59 (d, 1H), 3.90 (s, 3H), 3.75 (s, 3H), 3.03 (t, 2H), 2.78 (t, 2H), 2.38 (s, 3H), 1.93-1.83 (m, 2H), 1.34 (s, 12H).
<7-5> Preparation of methyl 9-methoxy-11-methyl-6,7-dihydro-5H-dibenzo[a,c][7]annulen-2-carboxylate




The title compound (colorless oil, 283 mg, and 35% yield) was obtained from the compound obtained in <7-4> according to the procedure described in <5-6>.
1H NMR (300 MHz, CDCl3) δ 7.95 (d, 1H), 7.91 (dd, 1H), 7.30 (d, 1H), 6.76 (d, 1H), 6.65 (d, 1H), 3.91 (s, 3H), 3.84 (s, 3H), 2.60-2.52 (m, 1H), 2.49-2.35 (m, 2H), 2.31 (s, 3H), 2.28-2.17 (m, 1H), 2.12-1.98 (m, 2H).
<7-6> Preparation of methyl 9-hydroxy-11-methyl-6,7-dihydro-5H-dibenzo[a,c][7]annulen-2-carboxylate




The title compound (white foam, 345 mg, and 97% yield) was obtained from the compound obtained in <7-5> according to the procedure described in <5-7>.
1H NMR (300 MHz, CDCl3) δ 7.94 (d, 1H), 7.91 (dd, 1H), 7.30 (d, 1H), 6.70 (d, 1H), 6.58 (d, 1H), 4.79 (s, 1H), 3.91 (s, 3H), 2.59-2.53 (m, 1H), 2.46-2.35 (m, 2H), 2.27 (s, 3H), 2.25-2.14 (m, 1H), 2.10-1.99 (m, 2H).
<7-7> Preparation of methyl 11-methyl-9-(3-(methylsulfonyl)propoxy)-6,7-dihydro-5H-dibenzo[a,c][7]annulen-2-carboxylate




The title compound (white foam, 285 mg, and 93% yield) was obtained from the compound obtained in <7-6> according to the procedure described in <1-8>.
1H NMR (300 MHz, CDCl3) δ 7.93-7.90 (m, 2H), 7.30 (d, 1H), 6.74 (d, 1H), 6.63 (d, 1H), 4.16 (t, 2H), 3.91 (s, 3H), 3.29 (t, 2H), 2.97 (s, 3H), 2.60-2.54 (m, 1H), 2.47-2.32 (m, 4H), 2.30 (s, 3H), 2.27-2.16 (m, 1H), 2.09-2.00 (m, 2H).
<7-8> Preparation of 11-methyl-9-(3-(methylsulfonyl)propoxy)-6,7-dihydro-5H-dibenzo[a,c][7]annulen-2-yl)methanol




The title compound (white foam, 212 mg, and 81% yield) was obtained from the compound obtained in <7-7> according to the procedure described in <1-9>.
1H NMR (300 MHz, CDCl3) δ 7.24 (s, 2H), 7.23 (s, 1H), 6.73 (d, 1H), 6.62 (d, 1H), 4.71 (d, 2H), 4.15 (t, 2H), 3.28 (t, 2H), 2.97 (s, 3H), 2.54-2.43 (m, 1H), 2.42-2.31 (m, 4H), 2.30 (s, 3H), 2.26-2.19 (m, 1H), 2.06-1.97 (m, 2H), 1.62 (t, 1H).
<7-9> Preparation of methyl 2-((3S)-6-((11-methyl-9-(3-(methylsulfonyl)propoxy)-6,7-dihydro-5H-dibenzo[a,c][7]annulen-2-yl)methoxy)-2,3-dihydrobenzofuran-3-yl)acetate




The title compound (white foam, 59 mg, and 36.3% yield) was obtained from the compound obtained in <7-8> according to the procedure described in <1-10>.
1H NMR (600 MHz, CDCl3) δ ppm 7.31-7.26 (m, 2H), 7.25-7.21 (m, 1H), 7.02 (d, 1H), 6.71 (d, 1H), 6.62 (d, 1H), 6.49 (dt, 1H), 6.47-6.45 (m, 1H), 5.04 (s, 2H), 4.75 (t, 1H), 4.28-4.23 (m, 1H), 4.14 (t, 2H), 3.84-3.76 (m, 1H), 3.71 (s, 3H), 3.30-3.24 (m, 2H), 2.97 (s, 3H), 2.74 (dd, 1H), 2.55 (dd, 1H), 2.53-2.48 (m, 1H), 2.45-2.39 (m, 1H), 2.39-2.32 (m, 3H), 2.31-2.25 (m, 1H), 2.24 (s, 3H), 2.06-1.98 (m, 2H).
<7-10> Preparation of 2-((3S)-6-((11-methyl-9-(3-(methylsulfonyl)propoxy)-6,7-dihydro-5H-dibenzo[a,c][7]annulen-2-yl)methoxy)-2,3-dihydrobenzofuran-3-yl)acetic acid




The title compound (white foam, 27 mg, and 47% yield) was obtained from the compound obtained in <7-9> according to the procedure described in <1-11>.
MS m/z 549 [M−H]−.
1H NMR (600 MHz, CDCl3) δ ppm 7.31-7.26 (m, 2H), 7.25-7.21 (m, 1H), 7.05 (d, 1H), 6.71 (d, 1H), 6.62 (d, 1H), 6.50 (dt, 1H), 6.47-6.45 (m, 1H), 5.04 (s, 2H), 4.76 (t, 1H), 4.31-4.25 (m, 1H), 4.14 (t, 2H), 3.86-3.76 (m, 1H), 3.31-3.22 (m, 2H), 2.97 (s, 3H), 2.82 (dd, 2H), 2.61 (dd, 1H), 2.54-2.48 (m, 1H), 2.45-2.39 (m, 1H), 2.38-2.33 (m, 3H), 2.32-2.25 (m, 1H), 2.24 (s, 3H), 2.04-1.97 (m, 2H).
Example 8
Preparation of (1R,2R)-2-(4-(((10-methyl-8-(3-(methylsulfonyl)propoxy)-6H-benzo[c]chromen-4-yl)methyl)amino)phenyl)cyclopropanecarboxylic acid
<8-1> Preparation of methyl 2-((2-bromo-5-methoxy-3-methylbenzyl)oxy)benzoate




2-Bromo-1-(bromomethyl)-5-methoxy-3-methylbenzene (prepared according to the method disclosed in the document [Journal of Organic Chemistry, 1994, vol. 59, #16, pp. 4473-4481]; 2.50 g, 8.50 mmol) was dissolved in DMF (25 mL), and K2CO3 (2.35 g, 17.01 mmol) and methyl 2-hydroxybenzoate (1.42 g, 9.35 mmol) were added thereto, and stirred at 65° C. for 15 hours. The reaction mixture was cooled to room temperature, and a saturated NH4Cl aqueous solution was added. Then, the resulting mixture was extracted with EtOAc. An organic layer was washed with saline, dried over sodium sulfate, filtered, and then concentrated under reduced pressure. The residue was purified using silica gel chromatography to obtain the title compound (white solid, 2.71 g, and 87% yield).
1H NMR (300 MHz, CDCl3) δ 7.86 (dd, 1H), 7.47 (ddd, 1H), 7.35 (d, 1H), 7.04 (d, 1H), 7.02 (t, 1H), 6.77 (d, 1H), 5.18 (s, 2H), 3.92 (s, 3H), 3.82 (s, 3H), 2.41 (s, 3H).
<8-2> Preparation of methyl 8-methoxy-10-methyl-6H-benzo[c]chromen-4-carboxylate




The compound (2.70 g, 7.39 mmol) obtained in <8-1>, PCy3-HBF4 (381 mg, 1.04 mmol), and K2CO3 (2.04 g, 14.79 mmol) were suspended in DMA (25 mL), and then replaced with nitrogen. Pd(OAc)2 (116 mg, 0.52 mmol) was added thereto, and stirred at 135° C. for 16 hours. The reaction mixture was cooled to room temperature, and a saturated NH4Cl aqueous solution was added. The resulting mixture was extracted with EtOAc. An organic layer was washed with saline, dried over sodium sulfate, filtered, and then concentrated under reduced pressure. The residue was purified using silica gel chromatography to obtain the title compound (light yellow oil, 1.85 g, and 88% yield).
1H NMR (300 MHz, CDCl3) δ 7.82 (dd, 1H), 7.68 (dd, 1H), 7.08 (t, 1H), 6.79 (d, 1H), 6.62 (d, 1H), 4.99 (s, 2H), 3.92 (s, 3H), 3.83 (s, 3H), 2.59 (s, 3H).
<8-3> Preparation of methyl 2′-(bromomethyl)-2,4′-dihydroxy-6′-methyl-[1,1′-biphenyl]-3-carboxylate




The compound (1.84 g, 6.47 mmol) obtained in <8-2> was dissolved in dichloromethane (25 mL), and BBr3 (a 1 M dichloromethane solution, 19.4 mL, 19.4 mmol) was slowly added thereto at 0° C., warmed to room temperature, and then stirred for 1 hour. Distilled water and a 1 N HCl aqueous solution were sequentially added to the reaction mixture at 0° C., and extracted with 5% methanol/dichloromethane. An organic layer was dried over sodium sulfate, filtered, and then concentrated under reduced pressure. The residue was purified using silica gel chromatography to obtain the title compound (white foam, 1.55 g, and 68% yield).
1H NMR (300 MHz, CDCl3) δ 11.02 (s, 1H), 7.93 (dd, 1H), 7.41 (dd, 1H), 7.00 (t, 1H), 6.85 (d, 1H), 6.75 (d, 1H), 4.86 (s, 1H), 4.30 (d, 1H), 4.07 (d, 1H), 3.98 (s, 3H), 2.01 (s, 3H).
<8-4> Preparation of methyl 10-methyl-8-(3-(methylsulfonyl)propoxy)-6H-benzo[c]chromen-4-carboxylate




The compound (800 mg, 2.28 mmol) obtained in <8-3> was dissolved in DMF (10 mL), and K2CO3 (945 mg, 6.83 mmol) was added, and stirred at room temperature for 1 hour. 3-(Methylsulfonyl)propyl 4-methylbenzenesulfonate (799 mg, 2.73 mmol) was added thereto, and stirred at 90° C. for 15 hours. The reaction mixture was cooled to room temperature, and a saturated NH4Cl aqueous solution was then added, and extracted with EtOAc. An organic layer was washed with saline, dried over sodium sulfate, filtered, and then concentrated under reduced pressure. The residue was purified using silica gel chromatography to obtain the title compound (white foam, 848 mg, and 95% yield).
1H NMR (300 MHz, CDCl3) δ 7.82 (dd, 1H), 7.69 (dd, 1H), 7.09 (t, 1H), 6.77 (d, 1H), 6.61 (d, 1H), 4.98 (s, 2H), 4.15 (t, 2H), 3.92 (s, 3H), 3.27 (t, 2H), 2.97 (s, 3H), 2.58 (s, 3H), 2.41-2.32 (m, 2H).
<8-5> Preparation of 10-methyl-8-(3-(methylsulfonyl)propoxy)-6H-benzo[c]chromen-4-yl)methanol




The compound (840 mg, 2.15 mmol) obtained in <8-4> was suspended in THF (25 mL), and LiAlH4 (a 1 M THF solution, 3.23 mL, 3.23 mmol) was added at 0° C., warmed to room temperature, and then stirred for 2 hours. A saturated sodium sulfate aqueous solution was added to the reaction mixture at 0° C., and water was added. The resulting mixture was extracted with dichloromethane. An organic layer was dried over sodium sulfate, filtered, and then concentrated under reduced pressure. The residue was purified using silica gel chromatography to obtain the title compound (white foam, 652 mg, and 84% yield).
1H NMR (300 MHz, CDCl3) δ 7.67 (dd, 1H), 7.23 (dd, 1H), 7.06 (t, 1H), 6.77 (d, 1H), 6.61 (d, 1H), 4.96 (s, 2H), 4.76 (d, 2H), 4.15 (t, 2H), 3.27 (t, 2H), 2.97 (s, 3H), 2.61 (s, 3H), 2.41-2.32 (m, 2H), 2.21 (t, 1H).
<8-6> Preparation of 10-methyl-8-(3-(methylsulfonyl)propoxy)-6H-benzo[c]chromen-4-carbaldehyde




The title compound (white foam, 90.2 mg, and 91% yield) was obtained from the compound obtained in <8-5> according to the procedure described in <3-3>.
<8-7> Preparation of (1R,2R)-ethyl 2-(4-(((10-methyl-8-(3-(methylsulfonyl)propoxy)-6H-benzo[c]chromen-4-yl)methyl)amino)phenyl)cyclopropanecarboxylate




The title compound (white foam, 125.7 mg, and 91% yield) was obtained from the compound obtained in <8-6> according to the procedure described in <3-4>.
1H NMR (300 MHz, CDCl3) δ 7.63 (d, 1H), 7.23 (d, 1H), 7.01 (t, 1H), 6.92 (d, 2H), 6.77 (s, 1H), 6.60 (d, 3H), 4.94 (s, 2H), 4.37 (s, 2H), 4.15 (dt, 4H), 3.32-3.20 (m, 2H), 2.97 (s, 3H), 2.60 (s, 3H), 2.39 (s, 3H), 1.83-1.72 (m, 1H), 1.54-1.44 (m, 1H), 1.26 (t, 4H).
<8-8> Preparation of (1R,2R)-2-(4-(((10-methyl-8-(3-(methylsulfonyl)propoxy)-6H-benzo[c]chromen-4-yl)methyl)amino)phenyl)cyclopropanecarboxylic acid




The title compound (reddish brown foam, 57.5 mg, and 48% yield) was obtained from the compound obtained in <8-7> according to the procedure described in <3-5>.
MS m/z 520 [M−H]−.
1H NMR (300 MHz, CDCl3) δ 7.62 (d, 1H), 7.23 (d, 1H), 7.01 (t, 1H), 6.93 (d, 2H), 6.76 (s, 1H), 6.60 (d, 3H), 4.94 (s, 2H), 4.37 (s, 2H), 4.15 (t, 2H), 3.33-3.20 (m, 2H), 2.97 (s, 3H), 2.60 (s, 3H), 2.50 (s, 1H), 2.44-2.29 (m, 2H), 1.77 (dd, 1H), 1.62-1.50 (m, 1H), 1.30 (d, 1H).
Example 9
Preparation of (1S,2S)-2-(4-(((10-methyl-8-(3-(methylsulfonyl)propoxy)-6H-benzo[c]chromen-2-yl)methyl)amino)phenyl)cyclopropanecarboxylic acid
<9-1> Preparation of methyl 2-((2-bromo-5-methoxy-3-methylbenzyl)oxy)benzoate




The title compound (white solid, 2.85 g, and 92% yield) was obtained from 2-bromo-1-(bromomethyl)-5-methoxy-3-methylbenzene and methyl 4-hydroxybenzoate according to the procedure described in <8-1>.
1H NMR (300 MHz, CDCl3) δ 8.00 (d, 2H), 7.00 (d, 2H), 6.93 (d, 1H), 6.78 (d, 1H), 5.17 (s, 2H), 3.89 (s, 3H), 3.77 (s, 3H), 2.42 (s, 3H).
<9-2> Preparation of methyl 8-methoxy-10-methyl-6H-benzo[c]chromen-2-carboxylate




The title compound (light yellow solid, 1.99 g, and 91% yield) was obtained from the compound obtained in <9-1> according to the procedure described in <8-2>.
1H NMR (300 MHz, CDCl3) δ 8.45 (d, 1H), 7.89 (dd, 1H), 7.06 (d, 1H), 6.80 (d, 1H), 6.61 (d, 1H), 4.99 (s, 2H), 3.92 (s, 3H), 3.84 (s, 3H), 2.66 (s, 3H).
<9-3> Preparation of 2′-(bromomethyl)-4′,6-dihydroxy-6′-methyl-[1,1′-biphenyl]-3-carboxylic acid




The compound (1.98 g, 6.96 mmol) obtained in <9-2> was dissolved in dichloromethane (25 mL), and BBr3 (a 1 M dichloromethane solution, 20.9 mL, 20.9 mmol) was slowly added at 0° C., warmed to room temperature, and then stirred for 3 hours. Water and a 1 N HCl aqueous solution were sequentially added to the reaction mixture at 0° C., and extracted with 10% methanol/dichloromethane. An organic layer was dried over sodium sulfate, filtered, and then concentrated under reduced pressure. The residue was purified using silica gel chromatography to obtain the title compound (light yellow foam, 1.64 g, and 70% yield).
1H NMR (300 MHz, DMSO-d6) δ 10.14 (s, 1H), 9.45 (s, 1H), 7.82 (dd, 1H), 7.60 (d, 1H), 7.00 (d, 1H), 6.77 (d, 1H), 6.67 (d, 1H), 4.40 (d, 1H), 4.05 (d, 1H), 1.88 (s, 3H).
<9-4> Preparation of methyl 2′-(bromomethyl)-4′,6-dihydroxy-6′-methyl-[1,1′-biphenyl]-3-carboxylate




The compound (1.40 g, 4.15 mmol) obtained in <9-3> was dissolved in methanol (20 mL), and SOCl2 (0.6 mL, 8.30 mmol) was slowly added at 0° C., and stirred at 70° C. for 1 hour under reflux. The reaction mixture was neutralized by slowly adding a saturated NaHCO3 aqueous solution to the reaction mixture at 0° C., and then extracted with dichloromethane. An organic layer was dried over sodium sulfate, filtered, and then concentrated under reduced pressure. The residue was purified using silica gel chromatography to obtain the title compound (white solid, 0.92 g, and 63% yield).
1H NMR (300 MHz, CDCl3) δ 8.03 (dd, 1H), 7.81 (d, 1H), 7.06 (d, 1H), 6.90 (d, 1H), 6.79 (d, 1H), 5.55 (s, 1H), 5.18 (s, 1H), 4.21 (d, 1H), 4.09 (d, 1H), 3.90 (s, 3H), 1.97 (s, 3H).
<9-5> Preparation of methyl 2-(10-methyl-8-(3-(methylsulfonyl)propoxy)-6H-benzo[c]chromen-2-yl)acetate




The title compound (white solid, 520 mg, and 99% yield) was obtained from the compound obtained in <9-4> according to the procedure described in <8-4>.
1H NMR (300 MHz, CDCl3) δ 8.45 (d, 1H), 7.89 (dd, 1H), 7.06 (d, 1H), 6.79 (d, 1H), 6.60 (d, 1H), 4.98 (s, 2H), 4.16 (t, 2H), 3.92 (s, 3H), 3.27 (t, 2H), 2.97 (s, 3H), 2.66 (s, 3H), 2.42-2.33 (m, 2H).
<9-6> Preparation of (10-methyl-8-(3-(methylsulfonyl)propoxy)-6H-benzo[c]chromen-2-yl)methanol




The title compound (white solid, 436 mg, and 82% yield) was obtained from the compound obtained in <9-5> according to the procedure described in <8-5>.
1H NMR (300 MHz, CDCl3) δ 7.73 (d, 1H), 7.21 (dd, 1H), 7.04 (d, 1H), 6.77 (d, 1H), 6.60 (d, 1H), 4.92 (s, 2H), 4.70 (d, 2H), 4.15 (t, 2H), 3.27 (t, 2H), 2.97 (s, 3H), 2.63 (s, 3H), 2.41-2.32 (m, 2H), 1.66 (t, 1H).
<9-7> Preparation of 8-(3-methanesulfonyl-propoxy)-10-methyl-6H-benzo[c]chromen-2-carbaldehyde




The title compound (white solid, 95.2 mg, and 96% yield) was obtained from the compound obtained in <9-6> according to the procedure described in <3-3>.
1H NMR (300 MHz, CDCl3) δ 9.95 (s, 1H), 8.25 (d, 1H), 7.72 (dd, 1H), 7.14 (d, 1H), 6.79 (d, 1H), 6.60 (d, 1H), 5.01 (s, 2H), 4.16 (t, 2H), 3.26 (t, 2H), 2.97 (s, 3H), 2.66 (s, 3H), 2.37 (m, 2H).
<9-8> Preparation of (1S,2S)-ethyl 2-(4-(((10-methyl-8-(3-(methylsulfonyl)propoxy)-6H-benzo[c]chromen-2-yl)methyl)amino)phenyl)cyclopropanecarboxylate




The title compound (white solid, 126.9 mg, and impure) was obtained from the compound obtained in <9-7> according to the procedure described in <3-4>.
1H NMR (300 MHz, CDCl3) δ 8.26 (1H, d), 7.74 (dd, 1H), 7.11-7.18 (m, 5H), 6.79 (d, 1H), 6.61 (d, 1H), 4.98 (s, 2H), 4.11-4.22 (m, 6H), 3.27 (t, 2H), 2.97 (s, 3H), 2.69 (s, 3H), 2.54 (m, 1H), 2.37 (m, 2H), 1.91 (m, 1H), 1.62 (m, 1H), 1.32 (m, 1H), 1.30 (t, 3H).
<9-9> Preparation of (1S,2S)-2-(4-(((10-methyl-8-(3-(methylsulfonyl)propoxy)-6H-benzo[c]chromen-2-yl)methyl)amino)phenyl)cyclopropanecarboxylic acid




The title compound (white solid, 21.7 mg, and 18% yield) was obtained from the compound obtained in <9-8> according to the procedure described in <3-5>.
MS m/z 520 [M−H]−.
1H NMR (300 MHz, CDCl3) δ 7.67 (d, 1H), 7.17 (dd, 1H), 7.01 (d, 1H), 6.94 (d, 2H), 6.73 (d, 1H), 6.60 (d, 1H), 6.59 (d, 2H), 4.90 (s, 2H), 4.32 (s, 2H), 4.14 (t, 2H), 3.26 (t, 2H), 2.96 (s, 3H), 2.52 (m, 1H), 2.49 (s, 3H), 2.36 (m, 2H), 1.78 (m, 1H), 1.57 (m, 1H), 1.32 (m, 1H).
Example 10
Preparation of (S)-2-(6-((5-methyl-7-(3-(methylsulfonyl)propoxy)-9,10-dihydrophenanthren-1-yl)methoxy)-2,3-dihydrobenzofuran-3-yl)acetic acid
<10-1> Preparation of (3-methoxy-5-methylbenzyl)triphenylphosphonium bromide




1-(Bromomethyl)-3-methoxy-5-methylbenzene (prepared according to the method disclosed in the document [Australian Journal of Chemistry, 1999, vol. 52, pp. 1093-1108]; 2.3 g, 10.46 mmol), and PPh3 (2.74 g, 10.46 mmol) were added to toluene (70 mL), and stirred at 95° C. for 16 hours. The reaction mixture was cooled to ambient temperature, and hexane was added, and stirred for 10 minutes. Thereafter, the resulting mixture was filtered, and washed with hexane. Then, the mixture was dried in a vacuum to obtain the title compound (white solid, 3.75 g, and 75% yield).
1H NMR (300 MHz, CDCl3) δ 7.84-7.57 (m, 15H), 6.57 (s, 2H), 6.34 (s, 1H), 5.28 (d, 2H), 3.53 (s, 2H), 2.07 (s, 3H).
<10-2> Preparation of methyl 2-(3-methoxy-5-methylstyryl)benzoate




K2CO3 (3.80 g, 27.46 mmol) and 18-Crown-6 (484 mg, 1.83 mmol) were added to a mixture including the compound (4.37 g, 9.15 mmol) obtained in <10-1>, methyl 2-formylbenzoate (1.50 g, 9.15 mmol), THF (92 mL), and dichloromethane (69 mL), and stirred for 3 hours under reflux. The reaction mixture was cooled to ambient temperature, and a saturated NH4Cl aqueous solution was then added. Thereafter, the mixture was extracted with EtOAc, and an organic layer was then dried over magnesium sulfate. Then, the filtrate was concentrated under reduced pressure. The residue was purified using silica gel chromatography to obtain the title compound (colorless oil, 2.58 g, approximately 100% yield, and an E/Z mixture).
Z-form: 1H NMR (300 MHz, CDCl3) δ 8.02-7.97 (m, 1H), 7.36-7.23 (m, 3H), 7.04 (d, 1H), 6.58 (d, 1H), 6.53-6.49 (m, 2H), 6.35 (s, 1H), 3.90 (s, 3H), 3.52 (s, 3H), 2.18 (s, 3H).
E-Form: 1H NMR (300 MHz, CDCl3) δ 7.95 (d, 1H), 7.95-7.90 (m, 1H), 7.70 (m, 1H), 7.51 (m, 1H), 7.36-7.28 (m, 1H), 6.99 (m, 1H), 6.95 (d, 1H), 6.89 (s, 1H), 6.66 (s, 1H), 3.93 (s, 3H), 3.83 (s, 3H), 2.36 (s, 3H).
<10-3> Preparation of methyl 2-(3-methoxy-5-methylphenethyl)benzoate




The compound (2.65 g, 9.38 mmol) obtained in <10-2> was dissolved in EtOAc (90 mL), and Pd/C (265 mg, based on 10% by weight of a dried product) was added thereto, and stirred for 1 hour under a hydrogen atmosphere. The reaction mixture was filtered through Celite, and washed with EtOAc. The filtrate was concentrated under reduced pressure, and dried in a vacuum to obtain the title compound (yellow oil, 2.43 g, and 91% yield).
1H NMR (300 MHz, CDCl3) δ 7.90 (dd, 1H), 7.41 (td, 1H), 7.32-7.17 (m, 2H), 6.65 (s, 1H), 6.57 (s, 2H), 3.91 (s, 3H), 3.77 (s, 3H), 3.23 (m, 2H), 2.83 (m, 2H), 2.31 (s, 3H).
<10-4> Preparation of methyl 2-(2-bromo-5-methoxy-3-methylphenethyl)benzoate




The compound (2.43 g, 8.54 mmol) obtained in <10-3> was dissolved in CH3CN (85 mL), and N-bromosuccinimide (1.60 g, 8.97 mmol) was added thereto, and then stirred at ambient temperature for 1 hour. The reaction mixture was concentrated under reduced pressure, and the residue was purified using silica gel chromatography to obtain the title compound (white solid, 2.87 g, and 92% yield).
1H NMR (300 MHz, CDCl3) δ 7.89 (dd, 1H), 7.42 (td, 1H), 7.33-7.20 (m, 2H), 6.67 (d, 1H), 6.60 (d, 1H), 3.90 (s, 3H), 3.82 (s, 3H), 3.24 (m, 2H), 3.03 (m, 2H), 2.41 (s, 3H).
<10-5> Preparation of methyl 7-methoxy-5-methyl-9,10-dihydrophenanthren-1-carboxylate




The compound (2.87 g, 7.90 mmol) obtained in <10-4> was dissolved in N,N-dimethylacetamide (26 mL), and tricyclohexylphosphine tetrafluoroborate (407 mg, 1.10 mmol) and K2CO3 (2.18 g, 15.80 mmol) were added thereto, and replaced with nitrogen. Thereafter, palladium (II) acetate (124 mg, 0.55 mmol) was added, and stirred at 135° C. for 15 hours. The reaction mixture was cooled to ambient temperature, and a saturated NH4Cl aqueous solution and water were added. Subsequently, the mixture was extracted with EtOAc, and an organic layer was washed with saline. The organic layer was dried over magnesium sulfate, filtered, and then concentrated. The resulting residue was purified using silica gel chromatography to obtain the title compound (colorless oil, 1.18 g, and 53% yield).
1H NMR (300 MHz, CDCl3) δ 7.70 (m, 2H), 7.30 (t, 1H), 6.73 (d, 1H), 6.69 (d, 1H), 3.92 (s, 3H), 3.84 (s, 3H), 3.08 (m, 2H), 2.68 (m, 2H), 2.55 (s, 3H).
<10-6> Preparation of methyl 7-hydroxy-5-methyl-9,10-dihydrophenanthren-1-carboxylate




The compound (1.06 g, 3.75 mmol) obtained in <10-5> was dissolved in dichloromethane (37 mL), and boron tribromide (a 1M MC solution, 7.5 mL, 7.50 mmol) was slowly added dropwise thereto at 0° C., and stirred for 1 hour and 40 minutes. The mixture was warmed to ambient temperature, and stirred for another 20 minutes, and methanol was then added at 0° C. Water was added to the reaction mixture, and the mixture was extracted with dichloromethane, and dried over magnesium sulfate. The filtrate was concentrated under reduced pressure, and purified using silica gel chromatography to obtain the title compound (white foam, 944 mg, and 94% yield).
1H NMR (300 MHz, CDCl3) δ 7.70 (m, 2H), 7.29 (t, 1H), 6.67 (d, 1H), 6.62 (d, 1H), 4.69 (s, 1H), 3.92 (s, 3H), 3.07 (m, 2H), 2.64 (m, 2H), 2.52 (s, 3H).
<10-7> Preparation of methyl 5-methyl-7-(3-(methylsulfonyl)propoxy)-9,10-dihydrophenanthren-1-carboxylate




The compound (white foam, 284 mg, and 98% yield) was obtained from the compound obtained in <10-6> according to the procedure described in <1-8>.
1H NMR (300 MHz, CDCl3) δ 7.70 (td, 2H), 7.30 (t, 1H), 6.72 (d, 1H), 6.67 (d, 1H), 4.15 (t, 2H), 3.92 (s, 3H), 3.27 (m, 2H), 3.08 (m, 2H), 2.97 (s, 3H), 2.67 (m, 2H), 2.54 (s, 3H), 2.37 (m, 1H).
<10-8> Preparation of (5-methyl-7-(3-(methylsulfonyl)propoxy)-9,10-dihydrophenanthren-1-yl)methanol




The title compound (white foam, 215 mg, and 82% yield) was obtained from the compound obtained in <10-7> according to the procedure described in <1-9>.
1H NMR (300 MHz, CDCl3) δ 7.56 (m, 1H), 7.33-7.21 (m, 2H), 6.71 (d, 1H), 6.67 (d, 1H), 4.79 (d, 2H), 4.15 (t, 2H), 3.27 (m, 2H), 2.97 (s, 3H), 2.86-2.68 (m, 4H), 2.57 (s, 3H), 2.44-2.28 (m, 2H), 1.55 (t, 1H).
<10-9> Preparation of (S)-methyl 2-(6-((5-methyl-7-(3-(methylsulfonyl)propoxy)-9,10-dihydrophenanthren-1-yl)methoxy)-2,3-dihydrobenzofuran-3-yl)acetate




The title compound (white foam, 89 mg, and 79% yield) was obtained from the compound obtained in <10-8> according to the procedure described in <1-10>.
1H NMR (300 MHz, CDCl3) δ 7.59 (dd, 1H), 7.34-7.23 (m, 2H), 7.08 (d, 1H), 6.71 (d, 1H), 6.66 (d, 1H), 6.51 (m, 2H), 5.06 (s, 2H), 4.77 (t, 1H), 4.28 (dd, 1H), 4.15 (t, 2H), 3.81 (m, 1H), 3.27 (m, 2H), 2.97 (s, 3H), 2.84-2.69 (m, 5H), 2.59 (m, 4H), 2.36 (m, 2H).
<10-10> Preparation of (S)-2-(6-((5-methyl-7-(3-(methylsulfonyl)propoxy)-9,10-dihydrophenanthren-1-yl)methoxy)-2,3-dihydrobenzofuran-3-yl)acetic acid




The title compound (white foam, 84 mg, and 99% yield) was obtained from the compound obtained in <10-9> according to the procedure described in <1-11>.
MS m/z 535 [M−H]−.
1H NMR (300 MHz, CDCl3) δ 7.59 (dd, 1H), 7.35-7.21 (m, 2H), 7.08 (d, 1H), 6.75 (d, 1H), 6.62 (d, 1H), 6.58-6.46 (m, 2H), 5.06 (s, 2H), 4.78 (t, 1H), 4.30 (dd, 1H), 4.14 (t, 2H), 3.88-3.77 (m, 1H), 3.33-3.21 (m, 2H), 2.97 (s, 3H), 2.87-2.62 (m, 5H), 2.57 (s, 3H), 2.36 (m, 2H).
Example 11
Preparation of (S)-2-(6-((5-methyl-7-(3-(methylsulfonyl)propoxy)-9,10-dihydrophenanthren-3-yl)methoxy)-2,3-dihydrobenzofuran-3-yl)acetic acid
<11-1> Preparation of methyl 4-(3-methoxy-5-methylstyryl)benzoate




The title compound (white solid, 1.70 g, 96% yield, and an E/Z mixture) was obtained from the compound obtained in <10-1> and methyl 4-formylbenzoate, according to the procedure described in <10-2>.
Z-form: 1H NMR (300 MHz, CDCl3) δ 8.02 (d, 2H), 7.55 (d, 2H), 7.15 (d, 2H), 6.96 (s, 1H), 6.88 (s, 1H), 6.68 (s, 1H), 3.93 (s, 3H), 3.84 (s, 3H), 2.36 (s, 3H).
E-form: 1H NMR (300 MHz, CDCl3) δ 7.89 (d, 2H), 7.32 (d, 2H), 6.72-6.52 (m, 5H), 3.89 (s, 3H), 3.62 (s, 3H), 2.24 (s, 3H).
<11-2> Preparation of methyl 4-(3-methoxy-5-methylphenethyl)benzoate




The title compound (colorless oil, 1.70 g, and 99% yield) was obtained from the compound obtained in <11-1> according to the procedure described in <10-3>.
1H NMR (300 MHz, CDCl3) δ 7.95 (d, 2H), 7.24 (d, 2H), 6.60 (s, 1H), 6.57 (s, 1H), 6.51 (s, 1H), 3.90 (s, 3H), 3.76 (s, 3H), 3.02-2.79 (m, 4H), 2.30 (s, 3H).
<11-3> Preparation of methyl 4-(2-bromo-5-methoxy-3-methylphenethyl)benzoate




The title compound (colorless oil, 1.86 g, and 85% yield) was obtained from the compound obtained in <11-2> according to the procedure described in <10-4>.
1H NMR (300 MHz, CDCl3) δ 7.96 (d, 2H), 7.29 (d, 2H), 6.68 (d, 1H) 6.60 (d, 1H), 3.91 (s, 3H), 3.72 (s, 3H), 3.09-2.89 (m, 4H), 2.41 (s, 3H).
<11-4> Preparation of methyl 7-methoxy-5-methyl-9,10-dihydrophenanthren-3-carboxylate




The title compound (colorless oil, 1.23 g, and 86% yield) was obtained from the compound obtained in <11-3> according to the procedure described in <10-5>.
1H NMR (300 MHz, CDCl3) δ 8.30 (d, 1H), 7.84 (dd, 1H), 7.31 (d, 1H), 6.75 (d, 1H), 6.68 (d, 1H), 3.93 (s, 3H), 3.84 (s, 3H), 2.84-2.70 (m, 4H), 2.64 (s, 3H).
<11-5> Preparation of methyl 7-hydroxy-5-methyl-9,10-dihydrophenanthren-3-carboxylate




The title compound (white solid, 768 mg, and 66% yield) was obtained from the compound obtained in <11-4> according to the procedure described in <10-6>.
1H NMR (300 MHz, CDCl3) δ 8.28 (d, 1H), 7.84 (dd, 1H), 7.31 (m, 1H), 6.69 (d, 1H), 6.62 (d, 1H), 4.78 (s, 1H), 3.93 (s, 3H), 2.84-2.65 (m, 4H), 2.60 (s, 3H).
<11-6> Preparation of methyl 5-methyl-7-(3-(methylsulfonyl)propoxy)-9,10-dihydrophenanthren-3-carboxylate




The title compound (white solid, 266 mg, and 92% yield) was obtained from the compound obtained in <11-5> according to the procedure described in <1-8>.
1H NMR (300 MHz, CDCl3) δ 8.29 (d, 1H), 7.85 (dd, 1H), 7.32 (d, 1H), 6.73 (d, 1H), 6.67 (d, 1H), 4.15 (t, 2H), 3.93 (s, 2H), 3.28 (m, 2H), 2.97 (s, 3H), 2.76 (m, 2H), 2.36 (m, 2H).
<11-7> Preparation of (5-methyl-7-(3-(methylsulfonyl)propoxy)-9,10-dihydrophenanthren-3-yl)methanol




The title compound (white solid, 194 mg, and 79% yield) was obtained from the compound obtained in <11-6> according to the procedure described in <1-9>.
1H NMR (300 MHz, CDCl3) δ 7.61 (d, 1H), 7.30-7.13 (m, 2H), 6.74 (d, 1H), 6.63 (d, 1H), 4.72 (d, 2H), 4.15 (t, 2H), 3.33-3.21 (m, 2H), 2.97 (s, 3H), 2.73 (s, 4H), 2.61 (s, 3H), 2.36 (m, 2H), 1.62 (t, 1H).
<11-8> Preparation of (S)-methyl 2-(6-((5-methyl-7-(3-(methylsulfonyl)propoxy)-9,10-dihydrophenanthren-3-yl)methoxy)-2,3-dihydrobenzofuran-3-yl)acetate




The title compound (colorless oil, 115 mg, and 80% yield) was obtained from the compound obtained in <11-7> according to the procedure described in <1-10>.
1H NMR (300 MHz, CDCl3) δ 7.62 (s, 1H), 7.31-7.19 (m, 2H), 7.03 (d, 1H), 6.72 (d, 1H), 6.62 (d, 1H), 6.55-6.44 (m, 2H), 5.04 (s, 2H), 4.75 (t, 1H), 4.26 (dd, 1H), 4.14 (t, 2H), 3.81 (m, 1H), 3.72 (s, 3H), 3.33-3.21 (m, 2H), 2.96 (s, 3H), 2.82-2.68 (m, 5H), 2.60-2.51 (m, 4H), 2.41-2.30 (m, 2H).
<11-9> Preparation of (S)-2-(6-((5-methyl-7-(3-(methylsulfonyl)propoxy)-9,10-dihydrophenanthren-3-yl)methoxy)-2,3-dihydrobenzofuran-3-yl)acetic acid




The title compound (white solid, 101 mg, and 92% yield) was obtained from the compound obtained in <11-8> according to the procedure described in <1-11>.
MS m/z 535 [M−H]−.
1H NMR (300 MHz, CDCl3) δ 7.62 (s, 1H), 7.31-7.16 (m, 2H), 7.06 (d, 1H), 6.73 (d, 1H), 6.62 (d, 1H), 6.56-6.45 (m, 2H), 5.05 (s, 2H), 4.76 (t, 1H), 4.29 (dd, 1H), 4.14 (t, 2H), 3.81 (t, 1H), 3.33-3.21 (m, 2H), 2.96 (s, 3H), 2.85-2.77 (m, 1H), 2.73 (s, 3H), 2.66-2.57 (m, 1H), 2.55 (s, 3H), 2.40-2.31 (m, 2H).
Example 12
Preparation of (S)-2-(6-((7-(2-ethoxyethoxy)-5-methyl-9,10-dihydrophenanthren-3-yl)methoxy)-2,3-dihydrobenzofuran-3-yl)acetic acid
<12-1> Preparation of methyl 7-(2-ethoxyethoxy)-5-methyl-9,10-dihydrophenanthren-3-carboxylate




The title compound (yellow oil, 410 mg, and approximately 100% yield) was obtained from the compound obtained in <11-5> according to the procedure described in <3-1>.
1H NMR (300 MHz, CDCl3) δ 8.29 (d, 1H), 7.84 (dd, 1H), 7.31 (d, 1H), 6.77 (d, 1H), 6.71 (d, 1H), 4.16 (t, 2H), 3.92 (s, 3H), 3.81 (t, 2H), 3.62 (q, 2H), 2.76 (m, 4H), 2.62 (s, 3H), 1.26 (t, 3H).
<12-2> Preparation of (7-(2-ethoxyethoxy)-5-methyl-9,10-dihydrophenanthren-3-yl)methanol




The title compound (white solid, 332 mg, and 95% yield) was obtained from the compound obtained in <12-1> according to the procedure described in <3-2>.
1H NMR (300 MHz, CDCl3) δ 7.61 (s, 1H), 7.26-7.15 (m, 2H), 6.79 (d, 1H), 6.67 (d, 1H), 4.71 (s, 2H), 4.15 (t, 2H), 3.80 (t, 2H), 3.62 (q, 2H), 2.72 (s, 4H), 2.61 (s, 3H), 1.25 (t, 3H).
<12-3> Preparation of (S)-methyl 2-(6-((7-(2-ethoxyethoxy)-5-methyl-9,10-dihydrophenanthren-3-yl)methoxy)-2,3-dihydrobenzofuran-3-yl)acetate




The title compound (colorless oil, 135 mg, and 84% yield) was obtained from the compound obtained in <12-2> according to the procedure described in <1-10>.
1H NMR (300 MHz, CDCl3) δ 7.62 (s, 1H), 7.30-7.15 (m, 2H), 7.02 (d, 1H), 6.77 (d, 1H), 6.66 (d, 1H), 6.55-6.44 (m, 2H), 5.04 (s, 2H), 4.75 (t, 1H), 4.26 (dd, 1H), 4.15 (t, 2H), 3.85-3.75 (m, 3H), 3.71 (s, 3H), 3.61 (q, 2H), 2.82-2.68 (m, 5H), 2.63-2.47 (m, 4H), 1.25 (t, 3H).
<12-4> Preparation of (S)-2-(6-((7-(2-ethoxyethoxy)-5-methyl-9,10-dihydrophenanthren-3-yl)methoxy)-2,3-dihydrobenzofuran-3-yl)acetic acid




The title compound (white foam, 93 mg, and 77% yield) was obtained from the compound obtained in <12-3> according to the procedure described in <1-11>.
MS m/z 487 [M−H]−.
1H NMR (300 MHz, CDCl3) δ 7.74 (d, 1H), 7.23 (dd, 1H), 7.05 (m, 2H), 6.80 (d, 1H), 6.63 (d, 1H), 6.56-6.45 (m, 2H), 5.02 (s, 2H), 4.92 (s, 2H), 4.76 (t, 1H), 4.29 (dd, 1H), 4.15 (t, 2H), 3.89-3.73 (m, 3H), 3.62 (q, 2H), 2.81 (dd, 1H), 2.69-2.57 (m, 1H), 2.57 (s, 3H), 1.25 (t, 3H).
Example 13
Preparation of 2-((3S)-6-((11-methyl-9-(3-(methylsulfonyl)propoxy)-6,7-dihydrodibenzo[b,d]oxepin-4-yl)methoxy)-2,3-dihydrobenzofuran-3-yl)acetic acid
<13-1> Preparation of methyl 3-bromo-2-(3-methoxy-5-methylphenethoxy)benzoate




2-(3-Methoxy-5-methylphenyl)ethanol (prepared according to the method disclosed in the document [Australian Journal of Chemistry, 1999, vol. 52, pp. 1093-1108]; 113 mg, 0.68 mmol), and methyl 3-bromo-2-hydroxybenzoate (see the document [Organic and Biomolecular Chemistry, 2004, vol. 2, pp. 963-964]; 157 mg, 0.68 mmol) were dissolved in THF (7 mL), PPh3 (267 mg, 1.02 mmol) was added thereto, and diethyl azodicarboxylate (40% toluene solution, 0.46 mL, 1.02 mmol) was slowly added dropwise. The reaction mixture was stirred at ambient temperature for 2 hours, concentrated under reduced pressure, and then purified using silica gel chromatography to obtain the title compound (yellow oil, 253 mg, and 98% yield).
1H NMR (300 MHz, CDCl3) δ 7.73 (td, 2H), 7.03 (t, 1H), 6.72 (s, 1H), 6.67 (s, 1H), 6.59 (s, 1H), 4.22 (t, 2H), 3.85 (s, 3H), 3.79 (s, 3H), 3.14 (t, 2H), 2.31 (s, 3H).
<13-2> Preparation of methyl 2-(3-methoxy-5-methylphenethoxy)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate




The compound (248 mg, 0.65 mmol) obtained in <13-1>, and bis(pinacolato)diboron (249 mg, 0.98 mmol) were dissolved in 1,4-dioxane (7 mL), and KOAc (193 mg, 1.96 mmol) was added thereto, and replaced with nitrogen. Thereafter, a complex (27 mg, 0.033 mmol) of [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium (II) with dichloromethane was added, and reacted at 90° C. for 15 hours. The reaction mixture was cooled to ambient temperature, filtered through Celite, and then washed with EtOAc. The filtrate was concentrated under reduced pressure, and then purified using silica gel chromatography to obtain the title compound (colorless oil, 131 mg, and a mixture including the compound obtained in <13-2> and bis(pinacolato)diboron at a ratio of 1.0:0.17).
1H NMR (300 MHz, CDCl3) δ 7.92-7.80 (m, 2H), 7.15 (t, 1H), 6.69 (s, 1H), 6.63 (s, 1H), 6.58 (s, 1H), 4.16 (t, 2H), 3.82 (s, 3H), 3.78 (s, 3H), 3.13 (t, 2H), 2.30 (s, 3H), 1.37 (s, 12H).
<13-3> Preparation of methyl 2-(2-bromo-5-methoxy-3-methylphenethoxy)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate




The compound (126 mg; a mixture including the compound obtained in <13-2> and bis(pinacolato)diboron at a ratio of 1.0:0.17) obtained in <13-2> was dissolved in acetonitrile (5 mL), and N-bromosuccinimide (48 mg, 0.26 mmol) was added thereto, and stirred at ambient temperature for 2 hours. The reaction mixture was concentrated under reduced pressure, and purified using silica gel chromatography to obtain the title compound (colorless oil, 109 mg, and 81% yield).
1H NMR (300 MHz, CDCl3) δ 7.86 (m, 2H), 7.15 (t, 1H), 6.80 (d, 1H), 6.68 (d, 1H), 4.20 (t, 2H), 3.83 (s, 3H), 3.77 (s, 3H), 3.33 (t, 2H), 2.39 (s, 3H), 1.36 (s, 12H).
<13-4> Preparation of methyl 9-methoxy-11-methyl-6,7-dihydrodibenzo[b,d]oxepin-4-carboxylate




The compound (106 mg, 0.21 mmol) obtained in <13-3> was dissolved in 1,4-dioxane (4 mL), and K2CO3 (87 mg, 0.63 mmol) was added thereto, and replaced with nitrogen. Thereafter, [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium (II) (15 mg, 0.021 mmol) was added, and stirred at 100° C. for 15 hours. The reaction mixture was cooled to ambient temperature, and water was added. Then, the mixture was extracted with EtOAc. An organic layer was collected, and dried over magnesium sulfate. Subsequently, the filtrate was concentrated under reduced pressure, and purified using silica gel chromatography to obtain the title compound (colorless oil, 8 mg, and 13% yield).
1H NMR (300 MHz, CDCl3) δ 7.72 (dd, 1H), 7.44 (dd, 1H), 7.22 (t, 1H), 6.79 (d, 1H), 6.71 (d, 1H), 4.70 (m, 1H), 4.44 (ddd, 1H), 3.92 (s, 3H), 3.84 (s, 3H), 2.84 (td, 1H), 2.54 (dd, 1H), 2.34 (s, 3H).
<13-5> Preparation of methyl 2′-(2-bromoethyl)-2,4′-dihydroxy-6′-methyl-[1,1′-biphenyl]-3-carboxylate




The compound (8 mg, 0.027 mmol) obtained in <13-4> was dissolved in dichloromethane (2 mL), and boron tribromide (a 1 M MC solution, 54 mL, 0.053 mmol) was slowly added dropwise thereto at 0° C., and stirred at the same temperature for 1 hour and 20 minutes. Thereafter, methanol (0.2 mL) was added at 0° C. Water was added to the reaction mixture, and the mixture was extracted with dichloromethane, and extracted with 5% methanol/dichloromethane again. Then, an organic layer was dried over magnesium sulfate. The filtrate was concentrated under reduced pressure to obtain the title compound (colorless oil, 10 mg, and approximately 100% yield), which was used for the next reaction without any additional purification.
1H NMR (300 MHz, CDCl3) δ 11.00 (s, 1H), 7.91 (dd, 1H), 7.31-7.21 (m, 1H), 6.97 (t, 1H), 6.70 (d, 1H), 6.67 (d, 1H), 4.65 (s, 1H), 3.99 (s, 3H), 3.35 (m, 2H), 2.95-2.78 (m, 2H), 1.98 (s, 3H).
<13-6> Preparation of methyl 11-methyl-9-(3-(methylsulfonyl)propoxy)-6,7-dihydrodibenzo[b,d]oxepin-4-carboxylate




The compound (11 mg, 0.03 mmol) obtained in <13-5> was dissolved in DMF (2 mL), and K2CO3 (6 mg, 0.045 mmol) was added thereto, and stirred at ambient temperature for 3 hours. 3-(Methylsulfonyl)propyl 4-methylbenzenesulfonate (11 mg, 0.036 mmol) was added to the reaction mixture, stirred at 90° C. for 16 hours, and then cooled to ambient temperature. The mixture was concentrated under reduced pressure, and purified using silica gel chromatography to obtain the title compound (colorless oil, 10 mg, and 82% yield).
1H NMR (300 MHz, CDCl3) δ 7.73 (dd, 1H), 7.44 (dd, 1H), 7.23 (t, 1H), 6.77 (d, 1H), 6.69 (d, 1H), 4.69 (dd, 1H), 4.43 (ddd, 1H), 4.16 (t, 2H), 3.92 (s, 3H), 3.28 (m, 2H), 2.97 (s, 3H), 2.83 (td, 1H), 2.41-2.30 (m, 2H), 2.33 (s, 3H).
<13-7> Preparation of (11-methyl-9-(3-(methyl sulfonyl)propoxy)-6,7-dihydrodibenzo[b,d]oxepin-4-yl)methanol




The title compound (colorless oil, 7 mg, and 75% yield) was obtained from the compound obtained in <13-6> according to the procedure described in <1-9>.
1H NMR (300 MHz, CDCl3) δ 7.34 (dd, 1H), 7.26 (dd, 1H), 7.22 (t, 1H), 6.78 (d, 1H), 6.69 (d, 1H), 4.89 (dd, 1H), 4.64 (dd, 1H), 4.56-4.36 (m, 2H), 4.16 (t, 2H), 3.28 (m, 2H), 2.97 (s, 3H), 2.85 (td, 1H), 2.52 (dd, 1H), 2.44-2.29 (m, 2H), 2.35 (s, 3H), 2.22 (dd, 1H).
<13-8> Preparation of methyl 2-((3S)-6-((11-methyl-9-(3-(methylsulfonyl)propoxy)-6,7-dihydrodibenzo[b,d]oxepin-4-yl)methoxy)-2,3-dihydrobenzofuran-3-yl)acetate




The title compound (colorless oil, 7 mg, and 93% yield) was obtained from the compound obtained in <13-7> according to the procedure described in <1-10>.
1H NMR (300 MHz, CDCl3) δ 7.45 (dd, 1H), 7.29 (dd, 1H), 7.21 (t, 1H), 7.05 (d, 1H), 6.78 (d, 1H), 6.69 (d, 1H), 6.59-6.48 (m, 2H), 5.20 (d, 1H), 4.99 (d, 1H), 4.77 (t, 1H), 4.53-4.36 (m, 2H), 4.28 (dd, 1H), 4.16 (t, 2H), 3.82 (m, 1H), 3.72 (s, 3H), 3.28 (m, 2H), 2.97 (s, 3H), 2.87 (td, 1H), 2.77 (dd, 1H), 2.65-2.47 (m, 2H), 2.41-2.32 (m, 2H), 2.36 (s, 3H).
<13-9> Preparation of 2-((3S)-6-((11-methyl-9-(3-(methylsulfonyl)propoxy)-6,7-dihydrodibenzo[b,d]oxepin-4-yl)methoxy)-2,3-dihydrobenzofuran-3-yl)acetic acid




The title compound (white foam, 7 mg, and 72% yield) was obtained from the compound obtained in <13-8> according to the procedure described in <1-11>.
MS m/z 551 [M−H]−.
1H NMR (300 MHz, CDCl3) δ 7.45 (dd, 1H), 7.29 (dd, 1H), 7.21 (t, 1H), 7.08 (d, 1H), 6.78 (d, 1H), 6.69 (d, 1H), 6.60-6.48 (m, 2H), 5.20 (d, 1H), 5.00 (d, 1H), 4.78 (t, 1H), 4.53-4.36 (m, 2H), 4.31 (dd, 1H), 4.16 (t, 2H), 3.82 (m, 1H), 3.28 (m, 2H), 2.97 (s, 3H), 2.92-2.76 (m, 2H), 2.71-2.47 (m, 2H), 2.41-2.31 (m, 2H), 2.36 (s, 3H).
Example 14
Preparation of 2-((3S)-6-((11-methyl-9-(3-(methylsulfonyl)propoxy)-6,7-dihydrodibenzo[b,d]oxepin-2-yl)methoxy)-2,3-dihydrobenzofuran-3-yl)acetic acid
<14-1> Preparation of 3-bromo-4-[2-(3-methoxy-5-methyl-phenyl)-ethoxy]-benzoic acidmethyl ester




2-(3-Methoxy-5-methyl-phenyl)-ethanol (prepared according to the method disclosed in the document [Australian Journal of Chemistry, 1999, vol. 52, pp. 1093-1108]; 1.9 g, 11.6 mmol), the compound (2.7 g, 11.6 mmol) obtained in <2-4>, and PPh3 (4.6 g, 17.4 mmol) were dissolved in THF (85 mL), and diethyl azodicarboxylate (40% toluene solution, 7.9 mL, 17.4 mmol) was slowly added thereto. After 2 hours, the reaction mixture was concentrated, and purified using silica gel chromatography to obtain the title compound (colorless oil, 4.18 g, and 95% yield).
1H NMR (300 MHz, CDCl3) δ 8.22 (d, 1H), 7.93 (dd, 1H), 6.86 (d, 1H), 6.76 (s, 1H), 6.71 (s, 1H), 6.62 (s, 1H), 4.25 (t, 2H), 3.89 (s, 3H), 3.80 (s, 3H), 3.11 (t, 2H), 2.32 (s, 3H).
<14-2> Preparation of 4-[2-(3-methoxy-5-methyl-phenyl)-ethoxy]-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzoic acidmethyl ester




The compound (4.18 g, 11.0 mmol) obtained in <14-1>, and bis(pinacolato)diboron (4.2 g, 16.5 mmol) were dissolved in DMF (60 mL), and potassium acetate (3.2 g, 33 mmol), and a complex of [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium (II) with dichloromethane were added thereto, and replaced with argon. The reaction mixture was stirred at 100° C. for 20 hours, cooled to ambient temperature, and then diluted with saline. The mixture was extracted with EtOAc, and an organic layer was washed with saline. The organic layer was dried over magnesium sulfate, and concentrated under reduced pressure. Then, the residue was purified using silica gel chromatography to obtain the title compound (oil, 6.1 g, >100% yield).
1H NMR (300 MHz, CDCl3) δ 8.30 (d, 1H), 8.04 (dd, 1H), 6.82 (d, 1H), 6.72 (s, 1H), 6.70 (s, 1H), 6.59 (s, 1H), 4.21 (t, 2H), 3.87 (s, 3H), 3.77 (s, 3H), 3.08 (t, 2H), 2.31 (s, 3H), 1.36 (s, 12H).
<14-3> Preparation of 4-[2-(2-bromo-5-methoxy-3-methyl-phenyl)-ethoxy]-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzoic acidmethyl ester




The compound (6.1 g, 11.0 mmol) obtained in <14-2> was dissolved in CH3CN (70 mL), and NBS (1.9 g, 11.0 mmol) was added thereto, and stirred for 2 hours. The reaction mixture was concentrated under reduced pressure, recrystallized from EtOAc/hexane (a mixture including EtOAc and hexane at a ratio of approximately 1:1), and then filtered. The filtrate was concentrated under reduced pressure, and the residue was purified using silica gel chromatography to obtain the title compound (oil, 6.48 g, >100% yield).
1H NMR (300 MHz, CDCl3) δ 8.30 (d, 1H), 8.05 (dd, 1H), 6.86 (d, 1H), 6.85 (d, 1H), 6.69 (d, 1H), 6.59 (s, 1H), 4.25 (t, 2H), 3.87 (s, 3H), 3.74 (s, 3H), 3.27 (t, 2H), 2.40 (s, 3H), 1.36 (s, 12H).
<14-4> Preparation of 9-methoxy-11-methyl-6,7-dihydro-5-oxa-dibenzo[a,c]cycloheptene-2-carboxylic acid methyl ester




The compound (6.48 g, 11.0 mmol) obtained in <14-3>, and K2CO3 (4.5 g, 33.0 mmol) were dissolved in 1,4-dioxane (70 mL), and a complex (718 mg, 0.88 mmol) of [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium (II) with dichloromethane was added thereto, and replaced with argon. The resulting mixture was stirred at 100° C. for 17 hours, and the reaction mixture was then cooled to ambient temperature, and diluted with water. The mixture was extracted with EtOAc, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified using silica gel chromatography to obtain the title compound (white solid, 2.4 g, and 96% yield).
1H NMR (300 MHz, CDCl3) δ 8.03 (d, 1H), 7.97 (dd, 1H), 7.17 (d, 1H), 6.80 (d, 1H), 6.69 (d, 1H), 4.45-4.53 (m, 2H), 3.91 (s, 3H), 3.85 (s, 3H), 2.82 (m, 1H), 2.52 (m, 1H), 2.38 (s, 3H).
<14-5> Preparation of methyl 9-hydroxy-11-methyl-6,7-dihydrodibenzo[b,d]oxepin-2-carboxylate




The compound (300 mg, 1.01 mmol) obtained in <14-4> was dissolved in dichloromethane (10 mL), and boron tribromide (a 1 M dichloromethane solution, 2.0 mL, 2.01 mmol) was slowly added dropwise thereto at 0° C., and stirred at the same temperature for 3 hours. Thereafter, methanol (4 mL) was added dropwise at 0° C., and water was added. The reaction mixture was extracted with 5% methanol/dichloromethane (40 mL), and an organic layer was then dried over magnesium sulfate. The filtrate was concentrated under reduced pressure, and then purified using silica gel chromatography to obtain the title compound (white solid, 119 mg, and 42% yield).
1H NMR (300 MHz, CDCl3) δ 8.02 (d, 1H), 7.97 (dd, 1H), 7.18 (d, 1H), 6.73 (d, 1H), 6.63 (d, 1H), 4.47 (m, 2H), 3.92 (s, 3H), 2.80 (td, 1H), 2.49 (m, 1H), 2.34 (s, 3H).
<14-6> Preparation of methyl 11-methyl-9-(3-(methylsulfonyl)propoxy)-6,7-dihydrodibenzo[b,d]oxepin-2-carboxylate




The title compound (white solid, 169 mg, and 63% yield) was obtained from the compound obtained in <14-5> according to the procedure described in <1-8>.
1H NMR (300 MHz, CDCl3) δ 8.02 (d, 1H), 7.98 (dd, 1H), 7.18 (d, 1H), 6.79 (d, 1H), 6.68 (d, 1H), 4.47 (m, 2H), 4.16 (t, 2H), 3.92 (s, 3H), 3.28 (m, 2H), 2.97 (s, 3H), 2.82 (td, 1H), 2.52 (dd, 1H), 2.42-2.33 (m, 2H), 2.37 (s, 3H).
<14-7> Preparation of (11-methyl-9-(3-(methylsulfonyl)propoxy)-6,7-dihydrodibenzo[b,d]oxepin-2-yl)methanol




The title compound (white foam, 266 mg, and 85% yield) was obtained from the compound obtained in <14-6> according to the procedure described in <1-9>.
1H NMR (300 MHz, CDCl3) δ 7.33-7.27 (m, 2H), 7.14 (dd, 1H), 6.77 (d, 1H), 6.68 (d, 1H), 4.71 (d, 2H), 4.41 (m, 2H), 4.15 (t, 2H), 3.27 (m, 2H), 2.97 (s, 3H), 2.81 (m, 1H), 2.52-2.45 (m, 2H), 2.42-2.31 (m, 2H), 2.37 (s, 3H), 1.64 (t, 1H).
<14-8> Preparation of methyl 2-((3S)-6-((11-methyl-9-(3-(methylsulfonyl)propoxy)-6,7-dihydrodibenzo[b,d]oxepin-2-yl)methoxy)-2,3-dihydrobenzofuran-3-yl)acetate




The title compound (white foam, 126 mg, and 84% yield) was obtained from the compound obtained in <14-7> according to the procedure described in <1-10>.
1H NMR (300 MHz, CDCl3) δ 7.36-7.31 (m, 2H), 7.15 (m, 1H), 7.03 (d, 1H), 6.76 (d, 1H), 6.68 (d, 1H), 6.48 (m, 2H), 5.04 (s, 2H), 4.75 (t, 1H), 4.41 (m, 2H), 4.26 (dd, 1H), 4.14 (t, 2H), 3.81 (m, 1H), 3.72 (s, 3H), 3.27 (m, 3H), 2.97 (s, 3H), 2.77 (m, 2H), 2.61-2.45 (m, 2H), 2.36 (m, 2H), 2.31 (s, 3H).
<14-9> Preparation of 2-((3S)-6-((11-methyl-9-(3-(methylsulfonyl)propoxy)-6,7-dihydrodibenzo[b,d]oxepin-2-yl)methoxy)-2,3-dihydrobenzofuran-3-yl)acetic acid




The title compound (white foam, 116 mg, and 98% yield) was obtained from the compound obtained in <14-8> according to the procedure described in <1-11>.
MS m/z 551 [M−H]−.
1H NMR (300 MHz, CDCl3) δ 7.36-7.31 (m, 2H), 7.18-7.03 (m, 2H), 6.76 (d, 1H), 6.68 (d, 1H), 6.49 (m, 2H), 5.04 (s, 2H), 4.76 (t, 1H), 4.42 (m, 2H), 4.29 (dd, 1H), 4.15 (t, 2H), 3.81 (m, 1H), 3.28 (m, 2H), 2.97 (s, 3H), 2.91-2.77 (m, 2H), 2.67-2.45 (m, 2H), 2.36 (m, 2H), 2.31 (s, 3H).
Example 15
Preparation of (1S,2S)-2-(4-(((11-methyl-9-(3-(methylsulfonyl)propoxy)-6,7-dihydrodibenzo[b,d]oxepin-2-yl)methyl)amino)phenyl)cyclopropanecarboxylic acid
<15-1> Preparation of 11-methyl-9-(3-(methylsulfonyl)propoxy)-6,7-dihydrodibenzo[b,d]oxepin-2-carbaldehyde




The title compound (colorless oil, 109 mg, and approximately 100% yield) was obtained from the compound obtained in <14-7> according to the procedure described in <3-3>.
1H NMR (300 MHz, CDCl3) δ 10.01 (s, 1H), 7.88-7.78 (m, 2H), 7.28 (m, 1H), 6.80 (d, 1H), 6.69 (d, 1H), 5.30 (s, 1H), 4.57-4.45 (m, 2H), 4.17 (t, 2H), 3.28 (m, 2H), 2.98 (s, 3H), 2.84 (td, 1H), 2.54 (m, 1H), 2.46-2.30 (m, 2H), 2.37 (s, 3H).
<15-2> Preparation of (1S,2S)-ethyl 2-(4-(((11-methyl-9-(3-(methylsulfonyl)propoxy)-6,7-dihydrodibenzo[b,d]oxepin-2-yl)methyl)amino)phenyl)cyclopropanecarboxylate




The title compound (white foam, 138 mg, and 96% yield) was obtained from the compound obtained in <15-1> according to the procedure described in <3-4>.
1H NMR (300 MHz, CDCl3) δ 7.31-7.23 (m, 2H), 7.11 (m, 1H), 6.93 (m, 2H), 6.75 (d, 1H), 6.67 (d, 1H), 6.62-6.52 (m, 2H), 4.45-4.37 (m, 2H), 4.34 (s, 2H), 4.22-4.11 (m, 4H), 4.03 (s, 1H), 3.27 (m, 2H), 2.97 (s, 3H), 2.82 (m, 1H), 2.54-2.30 (m, 4H), 2.26 (s, 3H), 1.78 (m, 1H), 1.52 (m, 1H), 1.33-1.16 (m, 1H), 1.27 (t, 3H).
<15-3> Preparation of (1S,2S)-2-(4-(((11-methyl-9-(3-(methylsulfonyl)propoxy)-6,7-dihydrodibenzo[b,d]oxepin-2-yl)methyl)amino)phenyl)cyclopropanecarboxylic acid




The title compound (white foam, 126 mg, and 97% yield) was obtained from the compound obtained in <15-2> according to the procedure described in <3-5>.
MS m/z 534 [M−H]−.
1H NMR (300 MHz, CDCl3) δ 7.28-7.24 (m, 2H), 7.11 (m, 1H), 6.93 (m, 2H), 6.74 (d, 1H), 6.61 (d, 1H), 6.57 (m, 2H), 4.40 (m, 2H), 4.34 (s, 2H), 4.14 (t, 2H), 3.27 (m, 2H), 2.96 (s, 3H), 2.81 (m, 1H), 2.50 (m, 2H), 2.36 (m, 2H), 2.25 (s, 3H), 1.77 (m, 1H), 1.57 (dt, 1H), 1.33 (m, 1H).
Example 16
Preparation of (1S,2S)-2-(4-(((8-(2-ethoxyethoxy)-10-methyl-6H-benzo[c]chromen-2-yl)methyl)amino)phenyl)cyclopropanecarboxylic acid
<16-1> Preparation of methyl 8-(2-ethoxyethoxy)-10-methyl-6H-benzo[c]chromen-2-carboxylate




The compound (180 mg, 0.51 mmol) obtained in <9-4> was dissolved in DMF (5 mL), and Cs2CO3 (500 mg, 1.54 mmol) was added thereto, and then stirred at ambient temperature for 1 hour. 2-Chloroethyl ethyl ether (67 mL, 0.61 mmol) was added to the mixture, and stirred at 90° C. for 15 hours. The reaction mixture was diluted with EtOAc, and then washed with a saturated NH4Cl aqueous solution. An aqueous layer was extracted with EtOAc again, and an organic layer was then dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified using silica gel chromatography to obtain the title compound (white solid, 100 mg, and 57% yield).
1H NMR (300 MHz, CDCl3) δ 8.45 (d, 1H), 7.88 (dd, 1H), 7.05 (d, 1H), 6.83 (d, 1H), 6.64 (d, 1H), 4.98 (s, 2H), 4.18-4.13 (m, 2H), 3.92 (s, 3H), 3.83-3.78 (m, 2H), 3.62 (q, 2H), 2.65 (s, 3H), 1.25 (t, 3H).
<16-2> Preparation of (8-(2-ethoxyethoxy)-10-methyl-6H-benzo[c]chromen-2-yl)methanol




The title compound (light yellow oil, 207 mg, and 99% yield) was obtained from the compound obtained in <16-1> according to the procedure described in <3-2>.
<16-3> Preparation of 8-(2-ethoxyethoxy)-10-methyl-6H-benzo[c]chromen-2-carbaldehyde




The title compound (light yellow oil, 207 mg, and 99% yield) was obtained from the compound obtained in <16-2> according to the procedure described in <3-3>.
1H NMR (300 MHz, CDCl3) δ 9.96 (s, 1H), 8.26 (d, 1H), 7.73 (dd, 1H), 7.15 (d, 1H), 6.85 (d, 1H), 6.65 (d, 1H), 5.01 (s, 2H), 4.19-4.14 (m, 2H), 3.84-3.78 (m, 2H), 3.62 (q, 2H), 2.66 (s, 3H), 1.26 (t, 3H).
<16-4> Preparation of (1S,2S)-ethyl 2-(4-(((8-(2-ethoxyethoxy)-10-methyl-6H-benzo[c]chromen-2-yl)methyl)amino)phenyl)cyclopropanecarboxylate




The title compound (light yellow oil, 137 mg, and 99% yield) was obtained from the compound obtained in <16-3> according to the procedure described in <3-4>.
1H NMR (300 MHz, CDCl3) δ 7.67 (d, 1H), 7.16 (dd, 1H), 7.00 (d, 1H), 6.93 (d, 2H), 6.78 (d, 1H), 6.63 (d, 1H), 6.59 (d, 2H), 4.90 (s, 2H), 4.31 (s, 2H), 4.15 (q, 2H) 4.11 (q, 2H), 4.00 (s, 1H), 3.82-3.77 (m, 2H), 3.61 (q, 2H), 2.50 (s, 3H), 2.48-2.39 (m, 1H), 1.81-1.73 (m, 1H), 1.51 (dt, 1H), 1.27 (t, 3H), 1.27-1.18 (m, 1H), 1.25 (t, 3H).
<16-5> Preparation of (1S,2S)-2-(4-(((8-(2-ethoxyethoxy)-10-methyl-6H-benzo[c]chromen-2-yl)methyl)amino)phenyl)cyclopropanecarboxylic acid)




The title compound (light yellow foam, 64 mg, and 50% yield) was obtained from the compound obtained in <16-4> according to the procedure described in <3-5>.
MS m/z 472 [M−H]−.
1H NMR (300 MHz, CDCl3) δ 7.68 (d, 1H), 7.16 (dd, 1H), 7.00 (d, 1H), 6.94 (d, 2H), 6.78 (d, 1H), 6.63 (d, 1H), 6.59 (d, 2H), 4.91 (s, 2H), 4.31 (s, 2H), 4.17-4.12 (m, 2H), 3.82-3.77 (m, 2H), 3.61 (q, 2H), 2.57-2.50 (m, 1H), 2.50 (s, 3H), 1.82-1.74 (m, 1H), 1.58 (dt, 1H), 1.37-1.28 (m, 1H), 1.25 (t, 3H).
Example 17
Preparation of (S)-2-(6-((8-(2-ethoxyethoxy)-10-methyl-6H-benzo[c]chromen-2-yl)methoxy)-2,3-dihydrobenzofuran-3-yl)acetic acid
<17-1> Preparation of (S)-methyl 2-(6-((8-(2-ethoxyethoxy)-10-methyl-6H-benzo[c]chromen-2-yl)methoxy)-2,3-dihydrobenzofuran-3-yl)acetate




The title compound (colorless oil, 113 mg, and 83% yield) was obtained from the compound obtained in <16-2> according to the procedure described in <1-10>.
1H NMR (300 MHz, CDCl3) δ 7.74 (d, 1H), 7.22 (dd, 1H), 7.03 (m, 2H), 6.79 (d, 1H), 6.63 (d, 1H), 6.54-6.46 (m, 2H), 5.01 (s, 2H), 4.91 (s, 2H), 4.75 (t, 1H), 4.26 (dd, 1H), 4.14 (t, 2H), 3.79 (m, 3H), 3.72 (s, 3H), 3.61 (q, 2H), 2.75 (m, 1H), 2.62-2.50 (m, 1H), 2.56 (s, 3H), 1.25 (t, 3H).
<17-2> Preparation of (S)-2-(6-((8-(2-ethoxyethoxy)-10-methyl-6H-benzo[c]chromen-2-yl)methoxy)-2,3-dihydrobenzofuran-3-yl)acetic acid




The title compound (white foam, 98 mg, and 89% yield) was obtained from the compound obtained in <17-1> according to the procedure described in <1-11>.
MS m/z 489 [M−H]−.
1H NMR (300 MHz, CDCl3) δ 7.74 (d, 1H), 7.23 (dd, 1H), 7.05 (t, 2H), 6.80 (d, 1H), 6.63 (d, 1H), 6.55-6.46 (m, 2H), 5.02 (s, 2H), 4.92 (s, 2H), 4.76 (t, 1H), 4.29 (dd, 1H), 4.15 (m, 2H), 3.80 (m, 3H), 3.61 (q, 2H), 2.81 (m, 1H), 2.68-2.51 (m, 1H), 2.57 (s, 3H), 1.25 (t, 3H).
Example 18
Preparation of (1S,2S)-2-(4-(((9-(3-(methylsulfonyl)propoxy)-5,7-dihydrodibenzo[c,e]oxepin-2-yl)methyl)amino)phenyl)cyclopropanecarboxylic acid
<18-1> Preparation of (2-bromo-5-(methoxymethoxy)phenyl)methanol




(3-(Methoxymethoxy)phenyl)methanol (prepared according to the method disclosed in the document [Journal of Organic Chemistry, 2006, vol. 71, #9, pp. 3650-3652]; 3.45 g, 20.5 mmol) was dissolved in CH3CN (51.25 mL), and N-bromosuccinimide (4.01 g, 22.55 mmol) was added thereto, and stirred at ambient temperature for 1 hour. The mixture was concentrated, diluted with dichloromethane, and then filtered. The filtrate was purified using silica gel chromatography to obtain the title compound (white solid, 4.63 g, and 91% yield).
1H NMR (300 MHz, CDCl3) δ 7.43 (d, 1H), 7.20 (d, 1H), 6.86 (dd, 1H), 5.17 (s, 2H), 4.71 (d, 2H), 3.47 (s, 3H), 1.97 (t, 1H).
<18-2> Preparation of methyl 4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate




Methyl 3-bromo-4-methylbenzoate (3 mL, 19.2 mmol) was dissolved in 1,4-dioxane (96 mL), and bis(pinacolato)diboron (7.31 g, 28.2 mmol), potassium acetate (5.65 g, 57.6 mmol), and Pd(dppf)Cl2 (2.8 g, 3.84 mmol) were added thereto. The resulting mixture was replaced with argon, and stirred at 90° C. for 16 hours. The mixture was cooled to room temperature, and water was added. Then, the mixture was extracted with EtOAc. An organic layer was dried over magnesium sulfate, concentrated, and then purified using silica gel chromatography to obtain the title compound (off-white solid, 4.46 g, and 84% yield).
1H NMR (300 MHz, CDCl3) δ 8.40 (d, 1H), 7.97 (dd, 1H), 7.23 (d, 1H), 3.94-3.87 (m, 3H), 2.58 (s, 3H), 1.35 (d, 12H).
<18-3> Preparation of methyl 4-(bromomethyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate




Methyl 4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate (1.15 g, 4.16 mmol) was dissolved in ACN (27.7 mL), and N-bromosuccinimide (888 mg, 4.99 mmol) and AIBN (13.6 mg, 0.083 mmol) were added thereto, and then stirred at 90° C. for 4 hours. The mixture was concentrated, diluted with dichloromethane, and then filtered. The filtrate was concentrated, and then purified using silica gel chromatography to obtain the title compound (colorless oil, 1.4 g, and 95% yield).
1H NMR (300 MHz, CDCl3) δ 8.46 (d, 1H), 8.06 (dd, 1H), 7.46 (d, 1H), 4.91 (s, 2H), 3.92 (s, 3H), 1.37 (d, 12H).
<18-4> Preparation of methyl 4-(((2-bromo-5-(methoxymethoxy)benzyl)oxy)methyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate




The compound (973.5 mg, 3.94 mmol) obtained in <18-1> was dissolved in DMF (13.1 mL), and NaH (315.2 mg, 7.88 mmol) was slowly added thereto, and stirred for 5 minutes. Meanwhile, the compound (1.4 g, 3.94 mmol) obtained in <18-3> was dissolved in DMF (5 mL), and this solution was slowly added to the mixture, and then stirred at ambient temperature for 3 hours. Water was slowly added to the mixture at 0° C., and saline and EtOAc were added. Then, the resulting mixture was filtered. An organic layer was washed with saline, dried over magnesium sulfate, concentrated, and then purified using silica gel chromatography to obtain the title compound (white solid, 851.1 mg, and 42% yield).
1H NMR (300 MHz, CDCl3) δ 8.46 (d, 1H), 8.11 (dd, 1H), 7.66 (d, 1H), 7.42 (d, 1H), 7.25 (s, 1H), 6.86 (dd, 1H), 5.15 (s, 2H), 4.95 (s, 2H), 4.63 (s, 2H), 3.92 (s, 3H), 3.46 (s, 3H), 1.34 (s, 12H).
<18-5> Preparation of methyl 9-(methoxymethoxy)-5,7-dihydrodibenzo[c,e]oxepin-2-carboxylate




The compound (851 mg, 1.63 mmol) obtained in <18-4> was dissolved in 1,4-dioxane (15 mL), and replaced with argon. K2CO3 (675.8 mg, 4.89 mmol) and [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium (II) (59.6 mg, 0.082 mmol) were sequentially added thereto, and then replaced with argon. The mixture was stirred at 90° C. for 18 hours. The mixture was cooled to room temperature, filtered through Celite, and then washed with dichloromethane. The filtrate was concentrated, and then purified using silica gel chromatography to obtain the title compound (white solid, 265.3 mg, and 52% yield).
1H NMR (300 MHz, CDCl3) δ 8.19 (d, 1H), 8.04 (dd, 1H), 7.57-7.45 (m, 2H), 7.20 (dd, 1H), 7.14 (d, 1H), 5.25 (s, 2H), 4.40 (s, 2H), 4.33 (s, 2H), 3.96 (s, 3H), 3.52 (s, 3H).
<18-6> Preparation of methyl 9-hydroxy-5,7-dihydrodibenzo[c,e]oxepin-2-carboxylate




The compound (195.3 mg, 0.62 mmol) obtained in <18-5> was dissolved in methanol (6.2 mL), and p-TsOH.H2O (353.8 mg, 1.86 mmol) was added thereto, and then stirred at ambient temperature for 16 hours. A NaHCO3 aqueous solution was added to the mixture to adjust the pH value of the mixture to approximately pH 8. Then, the mixture was extracted with dichloromethane. An organic layer was collected, dried over magnesium sulfate, concentrated, and then purified using silica gel chromatography to obtain the title compound (white solid, 136 mg, and 81% yield).
1H NMR (300 MHz, CDCl3) δ 8.18 (d, 1H), 8.04 (dd, 1H), 7.50 (dd, 2H), 7.00 (dd, 1H), 6.94 (d, 1H), 5.13 (s, 1H), 4.40 (s, 2H), 4.31 (s, 2H), 3.96 (s, 3H).
<18-7> Preparation of methyl 9-(3-(methylsulfonyl)propoxy)-5,7-dihydrodibenzo[c,e]oxepin-2-carboxylate




According to the procedures as described in <1-8>, the compound obtained in <18-6> was used to prepare the title compound (white solid, 487.9 mg, 74% yield).
1H NMR (300 MHz, CDCl3) δ 8.18 (d, 1H), 8.04 (dd, 1H), 7.52 (dd, 2H), 7.04 (dd, 1H), 6.98 (d, 1H), 4.39 (s, 2H), 4.32 (s, 2H), 4.21 (t, 2H), 3.96 (s, 3H), 3.35-3.24 (m, 2H), 2.98 (s, 3H), 2.42 (dd, 2H).
<18-8> Preparation of (9-(3-(methylsulfonyl)propoxy)-5,7-dihydrodibenzo[c,e]oxepin-2-yl)methanol




According to the procedures as described in <1-9>, the compound obtained in <18-7> was used to prepare the title compound (white solid, 417 mg, 92% yield).
1H NMR (300 MHz, CDCl3) δ 7.51 (d, 2H), 7.41 (t, 2H), 7.02 (d, 1H), 6.97 (s, 1H), 4.81 (d, 2H), 4.33 (d, 4H), 4.19 (t, 2H), 3.36-3.17 (m, 2H), 2.98 (s, 3H), 2.49-2.27 (m, 2H), 1.77 (t, 1H).
<18-9> Preparation of 9-(3-(methylsulfonyl)propoxy)-5,7-dihydrodibenzo[c,e]oxepin-2-carbaldehyde




According to the procedures as described in <3-3>, the compound obtained in <18-8> was used to prepare the title compound (white solid, 63.3 mg, 83% yield).
1H NMR (300 MHz, CDCl3) δ 10.12 (s, 1H), 8.02 (d, 1H), 7.89 (dd, 1H), 7.57 (dd, 2H), 7.06 (dd, 1H), 6.99 (d, 1H), 4.41 (s, 2H), 4.34 (s, 2H), 4.21 (t, 2H), 3.36-3.23 (m, 2H), 2.99 (s, 3H), 2.42 (d, 2H).
<18-10> Preparation of (1S,2S)-ethyl 2-(4-(((9-(3-(methylsulfonyl)propoxy)-5,7-dihydrodibenzo[c,e]oxepin-2-yl)methyl)amino)phenyl)cyclopropanecarboxylate




According to the procedures as described in <3-4>, the compound obtained in <18-9> was used to prepare the title compound (off-white foam, 83.8 mg, 85% yield).
1H NMR (300 MHz, CDCl3) δ 7.50 (s, 1H), 7.46 (d, 1H), 7.38 (s, 2H), 7.00 (d, 1H), 6.98-6.90 (m, 3H), 6.59 (d, 2H), 4.40 (s, 2H), 4.34 (s, 2H), 4.31 (s, 2H), 4.23-4.10 (m, 4H), 3.35-3.24 (m, 2H), 2.98 (s, 3H), 2.42 (m, 3H), 1.79 (m, 1H), 1.53-1.47 (m, 1H), 1.25 (m, 4H).
<18-11> Preparation of (1S,2S)-2-(4-(((9-(3-(methylsulfonyl)propoxy)-5,7-dihydrodibenzo[c,e]oxepin-2-yl)methyl)amino)phenyl)cyclopropanecarboxylic acid




According to the procedures as described in <3-5>, the compound obtained in <18-10> was used to prepare the title compound (white solid, 42.7 mg, 55% yield).
MS m/z 520 [M−H]−.
1H NMR (300 MHz, CDCl3) δ 7.49 (s, 1H), 7.46 (d, 1H), 7.38 (s, 2H), 7.05-6.98 (m, 1H), 6.98-6.90 (m, 3H), 6.60 (d, 2H), 4.40 (s, 2H), 4.34 (s, 2H), 4.32 (s, 2H), 4.19 (t, 2H), 3.35-3.23 (m, 2H), 2.99 (s, 3H), 2.46 (m, 1H), 2.43-2.32 (m, 2H), 1.75 (m, 1H), 1.53 (m, 1H), 1.20 (d, 1H).
Example 19
Preparation of (1S,2S)-2-(4-(((11-methyl-9-(3-(methylsulfonyl)propoxy)-5,7-dihydrodibenzo[c,e]oxepin-4-yl)methyl)amino)phenyl)cyclopropanecarboxylic acid
<19-1> Preparation of 4-bromo-3-(bromomethyl)-5-methylphenol




2-Bromo-1-(bromomethyl)-5-methoxy-3-methylbenzene (prepared in accordance with the reference [Chemistry—A European Journal, 2004, vol. 10, #16, p. 3931-3935]; 6.6 g, 22.5 mmol) was dissolved in dichloromethane (34 mL), and BBr3 (34 mL, 34 mmol) was slowly added to the mixture at 0° C. The reaction mixture was stirred at room temperature for 3 hours, and methanol was added to the mixture at 0° C. The mixture was washed with water, and the organic layer was dried over sodium sulfate and concentrated. The residue was purified to obtain the title compound (light yellow solid, 6.0 g, 95% yield).
1H NMR (300 MHz, CDCl3) δ 6.80 (d, 1H), 6.72 (d, 1H), 4.69 (s, 1H), 4.57 (s, 2H), 2.39 (s, 3H).
<19-2> Preparation of 2-bromo-1-(bromomethyl)-5-(methoxymethoxy)-3-methylbenzene




The compound obtained in <19-1> (6 g, 21.4 mmol) was dissolved in acetone (70 mL), which was then added with methyl chloromethyl ether (MOMCl, 2.4 mL, 32.1 mmol) and K2CO3 (4.8 g, 34.2 mmol). The reaction mixture thus obtained was stirred at room temperature for 2 hours and filtered. The filtered K2CO3 solid was washed with hexane, concentrated and purified by silica gel chromatography to obtain the title compound (colorless oil, 6.2 g, 89% yield).
1H NMR (300 MHz, CDCl3) δ 6.99 (d, 1H), 6.92 (d, 1H), 5.15 (s, 2H), 4.60 (s, 2H), 3.47 (s, 3H), 2.41 (s, 3H).
<19-3> Preparation of (2-bromo-5-(methoxymethoxy)-3-methylphenyl)methanol




The compound obtained in <19-2> (6.2 g, 19.1 mmol) was dissolved in 1,4-dioxane (50 mL) and water (50 mL), which was then added with CaCO3 (8.6 g, 86.0 mmol), followed by stirring for 18 hours at 100° C. The reaction mixture thus obtained was filtered, and the residue was diluted with EtOAc, washed with water, dried over sodium sulfate, and concentrated. The concentrates were purified by silica gel chromatography to obtain the title compound (white solid, 4.8 g, 96% yield).
1H NMR (300 MHz, CDCl3) δ 7.04 (d, 1H), 6.89 (d, 1H), 5.16 (s, 2H), 4.72 (d, 2H), 3.47 (s, 3H), 2.39 (s, 3H), 2.02 (t, 1H).
<19-4> Preparation of methyl 2-(bromomethyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2-yl)benzoate




Methyl 2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2-yl)benzoate (prepared in accordance with the reference [EP 2011788 A1]; 2.0 g, 7.1 mmol) was dissolved in CH3CN (40 mL), which was then added with AIBN (23 mg, 0.14 mmol) and N-bromosuccinimide (1.5 g, 8.5 mmol), followed by stirring for 3 hours at 90° C. The reaction mixture thus obtained was concentrated, and purified by silica gel chromatography to obtain the title compound (colorless oil, 2.2 g, 87% yield).
1H NMR (300 MHz, CDCl3) δ 7.97-7.93 (m, 2H), 7.34 (t, 1H), 5.43 (s, 2H), 3.95 (s, 3H), 1.39 (s, 12H).
<19-5> Preparation of methyl 2-(((2-bromo-5-(methoxymethoxy)-3-methylbenzyl)oxy)methyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2-yl)benzoate




According to the procedures as described in <18-4>, the compounds obtained in <19-3> and <19-4> were used to prepare the title compound (colorless oil, 320 mg, 69% yield).
1H NMR (300 MHz, CDCl3) δ 7.82 (m, 2H), 7.34 (t, 1H), 7.04 (d, 1H), 6.85 (d, 1H), 5.17 (s, 2H), 5.14 (s, 2H), 4.57 (s, 2H), 3.86 (s, 3H), 3.44 (s, 3H), 2.38 (s, 3H), 1.30 (s, 12H).
<19-6> Preparation of methyl 9-(methoxymethoxy)-11-methyl-5,7-dihydrodibenzo[c,e]oxepin-4-carboxylate




According to the procedures as described in <18-5>, the compound obtained in <19-5> was used to prepare the title compound (colorless oil, 63 mg, 32% yield).
1H NMR (300 MHz, CDCl3) δ 7.88 (dd, 1H), 7.54 (dd, 1H), 7.46 (t, 1H), 7.04 (d, 1H), 6.96 (d, 1H), 5.41 (d, 1H), 5.24 (q, 2H), 4.43 (d, 1H), 4.00-3.84 (m, 5H), 3.52 (s, 3H), 2.38 (s, 3H).
<19-7> Preparation of methyl 9-hydroxy-11-methyl-5,7-dihydrodibenzo[c,e]oxepin-4-carboxylate




According to the procedures as described in <18-6>, the compound obtained in <19-6> was used to prepare the title compound (white solid, 53 mg, 97% yield).
1H NMR (300 MHz, CDCl3) δ 7.88 (dd, 1H), 7.55 (dd, 1H), 7.47 (t, 1H), 6.87 (d, 1H), 6.77 (d, 1H), 5.79 (s, 1H), 5.46 (d, 1H), 4.40 (d, 1H), 4.00 (d, 1H), 3.96 (m, 4H), 2.36 (s, 3H).
<19-8> Preparation of methyl 11-methyl-9-(3-(methylsulfonyl)propoxy)-5,7-dihydrodibenzo[c,e]oxepin-4-carboxylate




According to the procedures as described in <1-8>, the compound obtained in <19-7> was used to prepare the title compound (white solid, 66 mg, 85% yield).
1H NMR (300 MHz, CDCl3) δ 7.87 (dd, 1H), 7.53 (dd, 1H), 7.46 (t, 1H), 6.89 (d, 1H), 6.80 (d, 1H), 5.41 (d, 1H), 4.41 (d, 1H), 4.17 (t, 2H), 4.02-3.84 (m, 5H), 3.28 (m, 2H), 2.97 (s, 3H), 2.58-2.33 (m, 5H).
<19-9> Preparation of (11-methyl-9-(3-(methylsulfonyl)propoxy)-5,7-dihydrodibenzo[c,e]oxepin-4-yl)methanol




According to the procedures as described in <1-9>, the compound obtained in <19-8> was used to prepare the title compound (white solid, 47 mg, 77% yield).
1H NMR (300 MHz, CDCl3) δ 7.48-7.31 (m, 3H), 6.89 (d, 1H), 6.80 (d, 1H), 4.97-4.79 (m, 3H), 4.38 (d, 1H), 4.18 (t, 2H), 3.97 (d, 1H), 3.93 (d, 1H), 3.35-3.21 (m, 2H), 2.98 (s, 3H), 2.47-2.29 (m, 5H), 1.86 (dd, 1H).
<19-10> Preparation of 11-methyl-9-(3-(methylsulfonyl)propoxy)-5,7-dihydrodibenzo[c,e]oxepin-4-carbaldehyde




According to the procedures as described in <3-3>, the compound obtained in <19-9> was used to prepare the title compound (white solid, 40 mg, 85% yield).
1H NMR (300 MHz, CDCl3) δ 10.45 (s, 1H), 7.93 (dd, 1H), 7.69-7.56 (m, 2H), 6.92 (d, 1H), 6.82 (d, 1H), 5.58 (d, 1H), 4.43 (d, 1H), 4.19 (t, 2H), 3.96 (t, 2H), 3.34-3.23 (m, 2H), 2.98 (s, 3H), 2.49-2.33 (m, 5H).
<19-11> Preparation of (1S,2S)-ethyl 2-(4-(((11-methyl-9-(3-(methylsulfonyl)propoxy)-5,7-dihydrodibenzo[c,e]oxepin-4-yl)methyl)amino)phenyl)cyclopropanecarboxylate




According to the procedures as described in <3-4>, the compound obtained in <19-10> was used to prepare the title compound (white solid, 51 mg, 85% yield).
1H NMR (300 MHz, CDCl3) δ 7.44-7.31 (m, 3H), 6.96 (d, 2H), 6.89 (d, 1H), 6.80 (d, 1H), 6.63 (d, 2H), 4.79 (d, 1H), 4.42 (dt, 3H), 4.25-4.04 (m, 6H), 4.00-3.88 (m, 2H), 3.33-3.22 (m, 2H), 2.98 (s, 3H), 2.50-2.31 (m, 6H), 1.86-1.75 (m, 1H), 1.63-1.46 (m, 2H), 1.31-1.18 (m, 6H).
<19-12> Preparation of (1S,2S)-2-(4-(((11-methyl-9-(3-(methylsulfonyl)propoxy)-5,7-dihydrodibenzo[c,e]oxepin-4-yl)methyl)amino)phenyl)cyclopropanecarboxylic acid




According to the procedures as described in <3-5>, the compound obtained in <19-11> was used to prepare the title compound (white solid, 27 mg, 57% yield).
MS m/z 534 [M−H]−.
1H NMR (600 MHz, CDCl3) δ 7.42-7.33 (m, 3H), 6.96 (d, 2H), 6.88 (d, 1H), 6.79 (d, 1H), 6.64-6.60 (m, 2H), 4.78 (d, 1H), 4.45 (d, 1H), 4.40 (q, 2H), 4.20-4.14 (m, 2H), 3.96 (d, 1H), 3.92 (d, 1H), 3.30-3.25 (m, 2H), 2.97 (s, 3H), 2.54-2.49 (m, 1H), 2.42 (s, 3H), 2.40-2.34 (m, 2H), 1.81-1.77 (m, 1H), 1.57 (dt, 1H), 1.35-1.31 (m, 1H).
Example 20
Preparation of (S)-2-(6-((9-(3-(methylsulfonyl)propoxy)-5,7-dihydrodibenzo[c,e]oxepin-2-yl)methoxy)-2,3-dihydrobenzofuran-3-yl)acetic acid
<20-1> Preparation of (S)-methyl 2-(6-((9-(3-(methylsulfonyl)propoxy)-5,7-dihydrodibenzo[c,e]oxepin-2-yl)methoxy)-2,3-dihydrobenzofuran-3-yl)acetate




According to the procedures as described in <1-10>, the compound obtained in <18-8> was used to prepare the title compound (off-white foam, 130.1 mg, 87% yield).
1H NMR (300 MHz, CDCl3) δ 7.56 (s, 1H), 7.50 (d, 1H), 7.43 (d, 2H), 7.03 (dd, 2H), 6.97 (d, 1H), 6.51 (dt, 2H), 5.10 (s, 2H), 4.76 (t, 1H), 4.36 (s, 2H), 4.32 (s, 2H), 4.27 (dd, 1H), 4.20 (t, 2H), 3.79 (s, 1H), 3.72 (s, 3H), 3.35-3.23 (m, 2H), 2.98 (s, 3H), 2.76 (dd, 1H), 2.57 (dd, 1H), 2.47-2.32 (m, 2H).
<20-2> Preparation of (S)-2-(6-((9-(3-(methylsulfonyl)propoxy)-5,7-dihydrodibenzo[c,e]oxepin-2-yl)methoxy)-2,3-dihydrobenzofuran-3-yl)acetic acid




According to the procedures as described in <1-11>, the compound obtained in <20-1> was used to prepare the title compound (white solid, 70.2 mg, 55% yield).
MS m/z 537 [M−H]−.
1H NMR (300 MHz, DMSO-d6) δ 7.60 (s, 1H), 7.53 (d, 1H), 7.47 (d, 2H), 7.12 (d, 3H), 6.51 (d, 2H), 5.14 (s, 2H), 4.69 (t, 1H), 4.21 (dd, 7H), 3.68 (s, 1H), 3.30-3.23 (m, 2H), 3.04 (s, 3H), 2.79-2.61 (m, 2H), 2.18 (s, 2H).
Example 21
Preparation of (1S,2S)-2-(4-(((3-(3-(methylsulfonyl)propoxy)-6,7-dihydrodibenzo[b,d]oxepin-10-yl)methyl)amino)phenyl)cyclopropanecarboxylic acid
<21-1> Preparation of methyl 3-bromo-4-(2-methoxy-2-oxoethyl)benzoate




Methyl 3-bromo-4-(cyanomethyl)benzoate (prepared in accordance with the reference [European Journal of Organic Chemistry. 2009, 2, p. 223-237]; 1.82 g, 7.16 mmol) was dissolved in methanol (30 mL), which was then slowly added with sulfuric acid (6 mL) at 0° C., followed by stirring for 12 hours at 100° C. Subsequently, the mixture was further added with sulfuric acid (3 mL), and stirred for 5 hours at 100° C. The reaction mixture thus obtained was cooled to room temperature, added with water at 0° C., and stirred for 1 hour. The solid thus produced was filtered, washed with water, and then dried in vacuo for 1 hour at 45° C. and for 15 hours at room temperature to obtain the title compound (yellow solid, 1.76 g, 85% yield).
1H NMR (300 MHz, CDCl3) δ 8.25 (d, 1H), 7.95 (d, 1H), 7.37 (d, 1H), 3.92 (s, 3H), 3.85 (s, 2H), 3.73 (s, 3H)
<21-2> Preparation of methyl 3-bromo-4-(2-hydroxyethyl)benzoate




The compound obtained in <21-1> (1.44 g, 5.02 mmol) was dissolved in dichloromethane (50 mL), which was then slowly added with DIBAL-H (1M dichloromethane solution, 7.5 mL, 7.52 mmol) at −78° C., followed by stirring for 2.5 hours at the same temperature. The reaction mixture was added with a mixture of methanol and water (1:1, 8 mL) and then with a saturated sodium potassium tartrate solution (50 mL), followed by stirring for 1 hour at room temperature. The reaction mixture was diluted dichloromethane, and the aqueous layer was further diluted with dichloromethane one more time. The organic layer was washed with brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was added with methanol (50 mL), cooled to 0° C., added with NaBH4 (474 mg, 12.5 mmol), and stirred at room temperature for 2 hours. The reaction mixture thus obtained was added with water, diluted with EtOAc and water, and the layers thus formed were separated. The organic layer was dried over magnesium sulfate, concentrated, and purified by silica gel chromatography to obtain the title compound (yellow oil, 331 mg, 25% yield).
1H NMR (300 MHz, CDCl3) δ 8.23 (d, 1H), 7.91 (dd, 1H), 7.36 (d, 1H), 3.94-3.90 (m, 2H), 3.92 (s, 3H), 3.08 (t, 2H)
<21-3> Preparation of 2-(4-(benzyloxy)-2-methoxyphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane




According to the procedures as described in <2-6>, 4-(benzyloxy)-1-bromo-2-methoxybenzene (prepared in accordance with the reference [US 2001/7873 A1]) was used to prepare the title compound (colorless oil, 1.32 g, 66% yield).
1H NMR (300 MHz, CDCl3) δ 7.64 (d, 1H), 7.50-7.31 (m, 5H), 6.55 (dd, 1H), 6.49 (d, 1H), 5.08 (s, 2H), 3.80 (s, 3H), 1.33 (s, 12H)
<21-4> Preparation of methyl 4′-(benzyloxy)-6-(2-hydroxyethyl)-2′-methoxy-[1,1′-biphenyl]-3-carboxylate




According to the procedures as described in <2-7>, the compound obtained in <21-3> was used to prepare the title compound (yellow oil, 638 mg, 96% yield).
1H NMR (300 MHz, CDCl3) δ 7.97 (dd, 1H), 7.85 (d, 1H), 7.50-7.35 (m, 6H), 7.04 (d, 1H), 6.65-6.60 (m, 2H), 5.11 (s, 2H), 3.89 (s, 3H), 3.70 (s, 3H), 3.70-3.67 (m, 2H), 2.76-2.82 (m, 2H).
<21-5> Preparation of methyl 4′-hydroxy-6-(2-hydroxyethyl)-2′-methoxy-[1,1′-biphenyl]-3-carboxylate




The compound obtained in <21-4> (598 mg, 1.52 mmol) was dissolved in dichloromethane (15 mL), which was then added with BBr3 (1M heptane solution, 1.8 mL, 1.82 mmol) −78° C. After 30 minutes, the reaction mixture was added with methanol (5 mL), slowly heated to room temperature, added with water, and neutralized with a saturated NaHCO3 aqueous solution. The mixture was extracted with dichloromethane, and then the organic layer was dried over magnesium sulfate, concentrated, and purified by silica gel chromatography to obtain the title compound (white foam, 331 mg, 72% yield).
1H NMR (300 MHz, CDCl3) δ 7.97 (dd, 1H), 7.84 (d, 1H), 7.41 (s, 1H), 6.97 (d, 1H), 6.50-6.44 (m, 2H), 5.11 (s, 1H), 3.89 (s, 3H), 3.70 (s, 3H), 3.68-3.73 (m, 2H), 2.82-2.77 (m, 2H)
<21-6> Preparation of methyl 6-(2-hydroxyethyl)-2′-methoxy-4′-(3-(methylsulfonyl)propoxy)-[1,1′-biphenyl]-3-carboxylate




The compound obtained in <21-5> (300 mg, 0.99 mmol) was dissolved in DMF (5 mL), added with 3-(methylsulfonyl)propyl 4-methylbenzenesulfonate (318 mg, 1.09 mmol) and Cs2CO3 (354 mg, 1.09 mmol), and then stirred at 50° C. for 1 hour. The reaction mixture was filtered and washed with EtOAc. The filtrate was concentrated and purified by silica gel chromatography to obtain the title compound (white solid, 411 mg, 73% yield).
1H NMR (300 MHz, CDCl3) δ 7.97 (dd, 1H), 7.83 (d, 1H), 7.39 (d, 1H), 7.04 (d, 1H), 6.55-6.51 (m, 2H), 4.17 (t, 2H), 3.89 (s, 3H), 3.72 (s, 3H), 3.72-3.67 (m, 2H), 3.32-3.27 (m, 2H), 2.99 (s, 3H), 2.80-2.75 (m, 2H), 2.43-2.36 (m, 2H).
<21-7> Preparation of methyl 2′-hydroxy-6-(2-hydroxyethyl)-4′-(3-(methylsulfonyl)propoxy)-[1,1′-biphenyl]-3-carboxylate




The compound obtained in <21-6> (157 mg, 0.28 mmol) was dissolved in dichloromethane (4 mL), which was then added with BBr3 (1M dichloromethane solution, 0.69 mmol, 0.70 mL) at 0° C., and stirred for 2 hours. The reaction mixture was added with methanol (2 mL), slowly heated to room temperature, added with water, and neutralized with a saturated NaHCO3 aqueous solution. The mixture was extracted with dichloromethane, and the organic layer was dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel chromatography to obtain the title compound (milky oil, 23.5 mg, 20% yield).
1H NMR (300 MHz, CDCl3) δ 8.03 (dd, 1H), 7.89 (d, 1H), 7.46 (d, 1H), 6.98 (d, 1H), 6.55-6.52 (m, 2H), 4.13 (t, 2H), 3.90 (s, 3H), 3.85-3.80 (m, 2H), 3.30-3.25 (m, 2H), 2.97 (s, 3H), 2.85-2.77 (m, 2H), 2.41-2.32 (m, 2H).
<21-8> Preparation of methyl 2′-hydroxy-4′-(3-(methylsulfonyl)propoxy)-6-(2-(tosyloxy)ethyl)-[1,1′-biphenyl]-3-carboxylate




According to the procedures as described in <2-9>, the compound obtained in Example <21-7> was used to prepare the title compound (white solid, 63.5 mg, 79% yield).
1H NMR (300 MHz, CDCl3) δ 7.96 (dd, 1H), 7.87 (d, 1H), 7.61 (d, 2H), 7.34 (d, 1H), 7.27-7.25 (m, 2H), 6.85 (d, 1H), 6.52-6.48 (m, 2H), 4.14 (t, 2H), 4.05 (t, 2H), 3.91 (s, 3H), 3.31-3.25 (m, 2H), 2.98 (s, 3H), 2.93-2.87 (m, 2H), 2.43 (s, 3H), 2.40-2.33 (m, 2H)
<21-9> Preparation of methyl 3-(3-(methylsulfonyl)propoxy)-6,7-dihydrodibenzo[b,d]oxepin-10-carboxylate




According to the procedures as described in <2-10>, the compound obtained in <21-8> was used to prepare the title compound (white solid, 26 mg, 59% yield).
1H NMR (300 MHz, CDCl3) δ 8.07 (d, 1H), 7.96 (dd, 1H), 7.38 (d, 1H), 7.34 (d, 1H), 6.81 (dd, 1H), 6.69 (d, 1H), 4.58 (t, 2H), 4.16 (t, 2H), 3.93 (s, 3H), 3.31-3.25 (m, 2H), 2.98 (s, 3H), 2.87 (t, 2H), 2.43-2.33 (m, 2H).
<21-10> Preparation of (3-(3-(methylsulfonyl)propoxy)-6,7-dihydrodibenzo[b,d]oxepin-10-yl)methanol




According to the procedures as described in <1-9>, the compound obtained in <21-9> was used to prepare the title compound (light yellow oil, 26 mg, 99% yield).
<21-11> Preparation of 3-(3-(methylsulfonyl)propoxy)-6,7-dihydrodibenzo[b,d]oxepin-10-carbaldehyde




According to the procedures as described in <3-3>, the compound obtained in <21-10> was used to prepare the title compound (light yellow oil, 19 mg, 73% yield).
1H NMR (300 MHz, CDCl3) δ 10.06 (s, 1H), 7.90 (d, 1H), 7.80 (dd, 1H), 7.44 (d, 1H), 7.39 (d, 1H), 6.82 (dd, 1H), 6.71 (d, 1H), 4.60 (t, 2H), 4.17 (t, 2H), 3.31-3.26 (m, 2H), 2.98 (s, 3H), 2.90 (t, 2H), 2.43-2.34 (m, 2H).
<21-12> Preparation of (1S,2S)-ethyl 2-(4-(((3-(3-(methylsulfonyl)propoxy)-6,7-dihydrodibenzo[b,d]oxepin-10-yl)methyl)amino)phenyl)cyclopropanecarboxylate




According to the procedures as described in <3-4>, the compound obtained in <21-11> was used to prepare the title compound (light yellow oil, 15 mg, 51% yield).
1H NMR (300 MHz, CDCl3) δ 7.38 (d, 1H), 7.32-7.21 (m, 3H), 6.94 (d, 2H), 6.77 (dd, 1H), 6.68 (d, 1H), 6.58 (d, 2H), 4.56 (t, 2H), 4.35 (s, 2H), 4.19-4.11 (m, 4H), 3.31-3.24 (m, 2H), 2.97 (s, 3H), 2.80 (t, 2H), 2.45-2.34 (m, 3H), 1.82-1.75 (m, 1H), 1.54-1.47 (m, 1H), 1.27 (t, 3H), 1.28-1.21 (m, 1H)
<21-13> Preparation of (1S,2S)-2-(4-(((3-(3-(methylsulfonyl)propoxy)-6,7-dihydrodibenzo[b,d]oxepin-10-yl)methyl)amino)phenyl)cyclopropanecarboxylic acid




According to the procedures as described in <3-5>, the compound obtained in <21-12> was used to prepare the title compound (white solid, 12 mg, 85% yield).
MS m/z 520 [M−H]−
1H NMR (300 MHz, CDCl3) δ 7.38-7.37 (m, 1H), 7.31-7.21 (m, 3H), 6.94 (d, 2H), 6.77 (dd, 1H), 6.68 (d, 1H), 6.58 (d, 2H), 4.56 (t, 2H), 4.34 (s, 2H), 4.14 (t, 2H), 3.30-3.24 (m, 2H), 2.97 (s, 3H), 2.80 (t, 2H), 2.55-2.48 (m, 1H), 2.41-2.32 (m, 2H), 1.82-1.75 (m, 1H), 1.61-1.54 (m, 1H), 1.37-1.25 (m, 1H)
Example 22
Preparation of (1S,2S)-2-(4-(((9-(2-ethoxyethoxy)-5,7-dihydrodibenzo[c,e]oxepin-2-yl)methyl)amino)phenyl)cyclopropanecarboxylic acid
<22-1> Preparation of methyl 9-(2-ethoxyethoxy)-5,7-dihydrodibenzo[c,e]oxepin-2-carboxylate




The compound obtained in <18-6> (180 mg, 0.66 mmol) was dissolved in DMF (6 mL), added with 2-chloroethyl ethyl ether (80 mL, 0.73 mmol) and Cs2CO3 (238 mg, 0.73 mmol), and stirred at 90° C. for 15 hours. The reaction mixture was diluted with EtOAc and washed with a saturated NH4Cl aqueous solution. The aqueous layer was further diluted with EtOAc one more time, and the organic layer was dried over magnesium sulfate and concentrated. The residue was purified by silica gel chromatography to obtain the title compound (white solid, 229 mg, 100% yield).
1H NMR (300 MHz, CDCl3) δ 8.18 (d, 1H), 8.03 (dd, 1H), 7.53 (d, 1H), 7.48 (d, 1H), 7.09 (dd, 1H), 7.02 (d, 1H), 4.38 (s, 2H), 4.32 (s, 2H), 4.22-4.19 (m, 2H), 3.96 (s, 3H), 3.85-3.82 (m, 2H), 3.63 (q, 2H), 1.27 (t, 3H)
<22-2> Preparation of (9-(2-ethoxyethoxy)-5,7-dihydrodibenzo[c,e]oxepin-2-yl)methanol




According to the procedures as described in <3-2>, the compound obtained in <22-1> was used to prepare the title compound (light yellow oil, 207 mg, 99% yield).
1H NMR (300 MHz, CDCl3) δ 7.52 (m, 1H), 7.49 (d, 1H), 7.43-7.35 (m, 2H), 7.06 (dd, 1H), 7.01 (d, 1H), 4.80 (d, 2H), 4.35 (s, 2H), 4.31 (s, 2H), 4.22-4.17 (m, 2H), 3.86-3.81 (m, 2H), 3.63 (q, 2H), 1.75 (t, 1H), 1.26 (t, 3H)
<22-3> Preparation of 9-(2-ethoxyethoxy)-5,7-dihydrodibenzo[c,e]oxepin-2-carbaldehyde




According to the procedures as described in <3-3>, the compound obtained in <22-2> was used to prepare the title compound (light yellow oil, 89 mg, 89% yield).
1H NMR (300 MHz, CDCl3) δ 10.12 (s, 1H), 8.02 (d, 1H), 7.88 (dd, 1H), 7.59 (d, 1H), 7.54 (d, 1H), 7.10 (dd, 1H), 7.03 (d, 1H), 4.40 (s, 2H), 4.34 (s, 2H), 4.24-4.19 (m, 2H), 3.87-3.82 (m, 2H), 3.63 (q, 2H), 1.27 (t, 3H)
<22-4> Preparation of (1S,2S)-ethyl 2-(4-(((9-(2-ethoxyethoxy)-5,7-dihydrodibenzo[c,e]oxepin-2-yl)methyl)amino)phenyl)cyclopropanecarboxylate




According to the procedures as described in <3-4>, the compound obtained in <22-3> was used to prepare the title compound (light yellow oil, 140 mg, 97% yield).
1H NMR (300 MHz, CDCl3) δ 7.50 (m, 1H), 7.45 (d, 1H), 7.37 (m, 2H), 7.05 (dd, 1H), 7.00 (d, 1H), 6.94 (d, 2H), 6.59 (d, 2H), 4.40 (s, 2H), 4.34 (s, 2H), 4.32 (s, 2H), 4.22-4.17 (m, 2H), 4.15 (q, 2H), 3.86-3.80 (m, 2H), 3.63 (q, 2H), 2.47-2.40 (m, 1H), 1.82-1.74 (m, 1H), 1.51 (dt, 1H), 1.27 (t, 3H), 1.26 (t, 3H), 1.26-1.19 (m, 1H)
<22-5> Preparation of (1S,2S)-2-(4-(((9-(2-ethoxyethoxy)-5,7-dihydrodibenzo[c,e]oxepin-2-yl)methyl)amino)phenyl)cyclopropanecarboxylic acid




According to the procedures as described in <3-5>, the compound obtained in <22-4> was used to prepare the title compound (light yellow foam, 67 mg, 50% yield).
MS m/z 472 [M−H]−
1H NMR (300 MHz, CDCl3) δ 7.50 (m, 1H), 7.44 (d, 1H), 7.38-7.35 (m, 2H), 7.05 (dd, 1H), 7.00 (d, 1H), 6.95 (d, 2H), 6.59 (d, 2H), 4.40 (s, 2H), 4.34 (s, 2H), 4.31 (s, 2H), 4.22-4.17 (m, 2H), 3.85-3.70 (m, 2H), 3.63 (q, 2H), 2.56-2.47 (m, 1H), 1.83-1.75 (m, 1H), 1.58 (dt, 1H), 1.37-1.26 (m, 1H), 1.26 (t, 3H).
Example 23
Preparation of (S)-2-(6-((9-(2-ethoxyethoxy)-5,7-dihydrodibenzo[c,e]oxepin-2-yl)methoxy)-2,3-dihydrobenzofuran-3-yl)acetic acid
<23-1> Preparation of (S)-methyl 2-(6-((9-(2-ethoxyethoxy)-5,7-dihydrodibenzo[c,e]oxepin-2-yl)methoxy)-2,3-dihydrobenzofuran-3-yl)acetate




According to the procedures as described in <1-10>, the compound obtained in <22-2> was used to prepare the title compound (white solid, 114 mg, 72% yield).
1H NMR (300 MHz, CDCl3) δ 7.56 (m, 1H), 7.48 (d, 1H), 7.41-7.42 (m, 2H), 7.09-7.00 (m, 3H), 6.55-6.48 (m, 2H), 5.10 (s, 2H), 4.76 (t, 1H), 4.35 (s, 2H), 4.32 (s, 2H), 4.27 (dd, 1H), 4.23-4.17 (m, 2H), 3.86-3.81 (m, 3H), 3.72 (s, 3H), 3.63 (q, 2H), 2.76 (dd, 1H), 2.56 (dd, 1H), 1.26 (t, 3H)
<23-2> Preparation of (S)-2-(6-((9-(2-ethoxyethoxy)-5,7-dihydrodibenzo[c,e]oxepin-2-yl)methoxy)-2,3-dihydrobenzofuran-3-yl)acetic acid




According to the procedures as described in <1-11>, the compound obtained in <23-1> was used to prepare the title compound (white solid, 99 mg, 100% yield).
MS m/z 489 [M−H]−
1H NMR (300 MHz, CDCl3) δ 7.56 (m, 1H), 7.48 (d, 1H), 7.42 (m, 2H), 7.09-7.04 (m, 2H), 7.01 (d, 1H), 6.53 (dd, 1H), 6.50 (d, 1H), 5.10 (s, 2H), 4.77 (t, 1H), 4.36 (s, 2H), 4.33 (s, 2H), 4.30 (dd, 1H), 4.22-4.18 (m, 2H), 3.85-3.79 (m, 3H), 3.63 (q, 2H), 2.82 (dd, 1H), 2.63 (dd, 1H), 1.26 (t, 3H).
Example 24
Preparation of (1S,2S)-2-(4-((9-(3-(methylsulfonyl)propoxy)-5,7-dihydrodibenzo[c,e]oxepin-2-yl)methoxy)phenyl)cyclopropanecarboxylic acid
<24-1> Preparation of (1S,2S)-ethyl 2-(4-((9-(3-(methylsulfonyl)propoxy)-5,7-dihydrodibenzo[c,e]oxepin-2-yl)methoxy)phenyl)cyclopropanecarboxylate




According to the procedures as described in <2-16>, the compound obtained in <18-8> was used to prepare the title compound (light yellow oil, 143 mg, 99% yield).
1H NMR (300 MHz, CDCl3) δ 7.56 (m, 1H), 7.50 (d, 1H), 7.43 (m, 2H), 7.04 (d, 2H), 7.02 (dd, 1H), 6.97 (d, 1H), 6.92 (d, 2H), 5.13 (s, 2H), 4.36 (s, 2H), 4.32 (s, 2H), 4.18 (t, 2H), 4.12 (q, 2H), 3.29 (t, 2H), 2.98 (s, 3H), 2.53-2.43 (m, 1H), 2.43-2.34 (m, 2H), 1.87-1.79 (m, 1H), 1.56 (dt, 1H), 1.30-1.23 (m, 1H), 1.28 (t, 3H)
<24-2> Preparation of (1S,2S)-2-(4-((9-(3-(methylsulfonyl)propoxy)-5,7-dihydrodibenzo[c,e]oxepin-2-yl)methoxy)phenyl)cyclopropanecarboxylic acid




According to the procedures as described in <1-11>, the compound obtained in <24-1> was used to prepare the title compound (white foam, 104 mg, 78% yield).
MS m/z 521 [M−H]−
1H NMR (300 MHz, CDCl3) δ 7.56 (m, 1H), 7.49 (d, 1H), 7.43 (d, 2H), 7.06 (d, 2H), 7.02 (dd, 1H), 6.97 (d, 1H), 6.93 (d, 2H), 5.13 (s, 2H), 4.36 (s, 2H), 4.33 (s, 2H), 4.20 (t, 2H), 3.33-3.26 (m, 2H), 2.98 (s, 3H), 2.61-2.52 (m, 1H), 2.45-2.34 (m, 2H), 1.88-1.80 (m, 1H), 1.63 (dt, 1H), 1.40-1.32 (m, 1H)
Example 25
Preparation of (1S,2S)-2-(4-((9-(3-(methylsulfonyl)propoxy)-6,7-dihydro-5H-dibenzo[a,c][7]annulen-2-yl)methoxy)phenyl)cyclopropanecarboxylic acid
<25-1> Preparation of (1S,2S)-ethyl 2-(4-((9-(3-(methylsulfonyl)propoxy)-6,7-dihydro-5H-dibenzo[a,c][7]annulen-2-yl)methoxy)phenyl)cyclopropanecarboxylate




According to the procedures as described in <2-16>, the compound obtained in <5-9> was used to prepare the title compound (light yellow oil, 111 mg, 87% yield).
1H NMR (300 MHz, CDCl3) δ 7.39 (d, 1H), 7.32 (d, 2H), 7.24 (d, 1H), 7.05 (d, 2H), 6.92 (d, 2H), 6.86 (dd, 1H), 6.81 (d, 1H), 5.07 (s, 2H), 4.17 (q, 2H), 4.17 (t, 2H), 3.33-3.26 (m, 2H), 2.98 (s, 3H), 2.54-2.44 (m, 5H), 2.44-2.33 (m, 2H), 2.24-2.15 (m, 2H), 1.87-1.79 (m, 1H), 1.56 (dt, 1H), 1.30-1.23 (m 1H), 1.29 (t, 3H)
<25-2> Preparation of (1S,2S)-2-(4-((9-(3-(methylsulfonyl)propoxy)-6,7-dihydro-5H-dibenzo[a,c][7]annulen-2-yl)methoxy)phenyl)cyclopropanecarboxylic acid




According to the procedures as described in <1-11>, the compound obtained in <25-1> was used to prepare the title compound (white foam, 88.3 mg, 86% yield).
MS m/z 519 [M−H]−
1H NMR (300 MHz, CDCl3) δ 7.38 (d, 1H), 7.31 (dd, 1H), 7.30 (d, 1H), 7.24 (d, 1H), 7.05 (d, 2H), 6.92 (d, 2H), 6.85 (dd, 1H), 6.79 (d, 1H), 5.07 (s, 2H), 4.17 (t, 2H), 3.32-3.25 (m, 2H), 2.97 (s, 3H), 2.61-2.53 (m, 1H), 2.53-2.43 (m, 4H), 2.42-2.32 (m, 2H), 2.23-2.14 (m, 2H), 1.88-1.80 (m, 1H), 1.66 (dt, 1H), 1.40-1.32 (m, 1H)
Example 26
Preparation of (S)-2-(6-((10-methyl-8-(3-(methylsulfonyl)propoxy)-6H-benzo[c]chromen-2-yl)methoxy)-2,3-dihydrobenzofuran-3-yl)acetic acid
<26-1> Preparation of (S)-methyl 2-(6-((10-methyl-8-(3-(methylsulfonyl)propoxy)-6H-benzo[c]chromen-2-yl)methoxy)-2,3-dihydrobenzofuran-3-yl)acetate




According to the procedures as described in <1-10>, the compound obtained in <9-6> was used to prepare the title compound (colorless oil, 89 mg, 58% yield).
1H NMR (600 MHz, CDCl3) δ 7.75 (d, 1H), 7.24 (dd, 1H), 7.04 (t, 1H), 6.75 (d, 1H), 6.59 (d, 1H), 6.51 (dd, 1H), 6.48 (d, 1H), 5.02 (s, 2H), 4.92 (s, 2H), 4.75 (t, 1H), 4.27 (dd, 1H), 4.14 (t, 2H), 3.79-3.83 (m, 1H), 3.72 (s, 3H), 3.25-3.28 (m, 2H), 2.97 (s, 3H), 2.75 (dd, 1H), 2.54-2.58 (m, 4H), 2.35-2.38 (m, 2H).
<26-2> Preparation of (S)-2-(6-((10-methyl-8-(3-(methylsulfonyl)propoxy)-6H-benzo[c]chromen-2-yl)methoxy)-2,3-dihydrobenzofuran-3-yl)acetic acid




According to the procedures as described in <1-11>, the compound obtained in <26-1> was used to prepare the title compound (colorless foam, 43 mg, 50% yield).
MS m/z 537 [M−H]−.
1H NMR (600 MHz, CDCl3) δ ppm 7.75 (d, 1H), 7.24 (dd, 1H), 7.04-7.08 (m, 2H), 6.75 (d, 1H), 6.59 (d, 1H), 6.52 (dd, 1H), 6.49 (d, 1H), 5.02 (s, 2H), 4.92 (s, 2H), 4.77 (t, 1H), 4.29 (dd, 1H), 4.14 (t, 2H), 3.80-3.83 (m, 1H), 3.26 (t, 2H), 2.97 (s, 3H), 2.81 (dd, 1H), 2.63 (dd, 1H), 2.57 (s, 3H), 2.34-2.38 (m, 2H).
Example 27
Preparation of (S)-2-(6-((9-(2-ethoxyethoxy)-6,7-dihydro-5H-dibenzo[a,c][7]annulen-2-yl)methoxy)-2,3-dihydrobenzofuran-3-yl)acetic acid
<27-1> Preparation of methyl 9-(2-ethoxyethoxy)-6,7-dihydro-5H-dibenzo[a,c][7]annulene-2-carboxylate




According to the procedures as described in <3-1>, the compound obtained in <5-7> was used to prepare the title compound (colorless oil, 210 mg, 87% yield).
1H NMR (600 MHz, CDCl3) δ 8.01 (d, 1H), 7.91 (dd, 1H), 7.33 (d, 1H), 7.29 (d, 1H), 6.91 (dd, 1H), 6.85 (d, 1H), 4.18 (t, 2H), 3.92 (s, 3H), 3.83 (t, 2H), 3.63 (q, 2H), 2.53 (t, 2H), 2.45 (t, 2H), 2.71-2.21 (m, 2H), 1.26 (t, 3H).
<27-2> Preparation of (9-(2-ethoxyethoxy)-6,7-dihydro-5H-dibenzo[a,c][7]annulen-2-yl)methanol




According to the procedures as described in <3-2>, the compound obtained in <27-1> was used to prepare the title compound (white solid, 171 mg, 88% yield).
1H NMR (600 MHz, CDCl3) δ 7.34 (d, 1H), 7.30 (d, 1H), 7.25-7.27 (m, 1H), 7.22 (d, 1H), 6.88 (dd, 1H), 6.84 (d, 1H), 4.74 (d, 2H), 4.17 (t, 2H), 3.82 (t, 2H), 3.63 (q, 2H), 2.44-2.59 (m, 4H), 2.14-2.19 (m, 2H), 1.66 (t, 1H), 1.26 (t, 3H)
<27-3> Preparation of (S)-methyl 2-(6-((9-(2-ethoxyethoxy)-6,7-dihydro-5H-dibenzo[a,c][7]annulen-2-yl)methoxy)-2,3-dihydrobenzofuran-3-yl)acetate




According to the procedures as described in <1-10>, the compound obtained in <27-2> was used to prepare the title compound (white solid, 102 mg, 71% yield).
1H NMR (600 MHz, CDCl3) δ 7.38 (d, 1H), 7.29-7.31 (m, 2H), 7.23 (d, 1H), 7.03 (d, 1H), 6.89 (dd, 1H), 6.84 (d, 1H), 6.51 (dd, 1H), 6.49 (d, 1H), 5.04 (s, 2H), 4.73-4.77 (m, 1H), 4.25-4.28 (m, 1H), 4.17 (t, 2H), 3.78-3.83 (m, 3H), 3.72 (s, 3H), 3.63 (q, 2H), 2.76 (dd, 1H), 2.57 (dd, 1H), 2.45-2.50 (m, 4H), 2.14-2.19 (m, 2H), 1.25 (t, 3H).
<27-4> Preparation of (S)-2-(6-((9-(2-ethoxyethoxy)-6,7-dihydro-5H-dibenzo[a,c][7]annulen-2-yl)methoxy)-2,3-dihydrobenzofuran-3-yl)acetic acid




According to the procedures as described in <1-11>, the compound obtained in <27-3> was used to prepare the title compound (white foam, 82 mg, 84% yield).
MS m/z 487 [M−H]−.
1H NMR (600 MHz, CDCl3) δ 7.38 (d, 1H), 7.29-7.31 (m, 2H), 7.23 (d, 1H), 7.05-7.7 (m, 1H), 6.89 (dd, 1H), 6.84 (d, 1H), 6.53 (dd, 1H), 6.49 (d, 1H), 5.04 (s, 2H), 4.77 (t, 1H), 4.29 (dd, 1H), 4.17 (t, 2H), 3.80-3.83 (m, 3H), 3.62 (q, 2H), 2.81 (dd, 1H), 2.63 (dd, 1H), 2.45-2.50 (m, 4H), 2.15-2.18 (m, 2H), 1.26 (t, 3H).
Example 28
Preparation of (1S,2S)-2-(4-(((9-(2-ethoxyethoxy)-6,7-dihydro-5H-dibenzo[a,c][7]annulen-2-yl)methyl)amino)phenyl)cyclopropanecarboxylic acid
<28-1> Preparation of 9-(2-ethoxyethoxy)-6,7-dihydro-5H-dibenzo[a,c][7]annulene-2-carbaldehyde




According to the procedures as described in <3-3>, the compound obtained in <27-2> was used to prepare the title compound (colorless oil, 78 mg, 98% yield).
1H NMR (600 MHz, CDCl3) δ 10.04 (s, 1H), 7.84 (d, 1H), 7.77 (dd, 1H), 7.39 (d, 1H), 7.34 (d, 1H), 6.93 (dd, 1H), 6.86 (d, 1H), 4.19 (t, 2H), 3.83 (t, 2H), 3.64 (q, 2H), 2.57 (t, 2H), 2.46 (t, 2H), 2.19-2.24 (m, 2H), 1.27 (t, 3H).
<28-2> Preparation of (1S,2S)-ethyl 2-(4-(((9-(2-ethoxyethoxy)-6,7-dihydro-5H-dibenzo[a,c][7]annulen-2-yl)methyl)amino)phenyl)cyclopropanecarboxylate




According to the procedures as described in <3-4>, the compound obtained in <28-1> was used to prepare the title compound (white foam, 108 mg, 88% yield).
1H NMR (600 MHz, CDCl3) δ 7.33 (d, 1H), 7.26-7.27 (m, 1H), 7.23-7.24 (m, 1H), 7.19 (d, 1H), 6.93-6.94 (m, 2H), 6.88 (dd, 1H), 6.84 (d, 1H), 6.58-6.59 (m, 2H), 4.33 (s, 2H), 4.13-4.18 (m, 4H), 4.00 (br, 1H), 3.82 (t, 2H), 3.63 (q, 2H), 2.43-2.48 (m, 5H), 2.14-2.18 (m, 2H), 1.77-1.79 (m, 1H), 1.49-1.52 (m, 1H), 1.24-1.28 (m, 6H), 1.21-1.23 (m, 1H).
<28-3> Preparation of (1S,2S)-2-(4-(((9-(2-ethoxyethoxy)-6,7-dihydro-5H-dibenzo[a,c][7]annulen-2-yl)methyl)amino)phenyl)cyclopropanecarboxylic acid




According to the procedures as described in <3-5>, the compound obtained in <28-2> was used to prepare the title compound (white foam, 94 mg, 94% yield).
MS m/z 470 [M−H]−.
1H NMR (600 MHz, CDCl3) δ ppm 7.32 (s, 1H), 7.23-7.27 (m, 2H), 7.19 (d, 1H), 6.94 (d, 2H), 6.88 (dd, 1H), 6.84 (d, 1H), 6.59 (d, 2H), 4.33 (s, 2H), 4.17 (t, 2H), 3.82 (t, 2H), 3.63 (q, 2H), 2.50-2.53 (m, 1H), 2.44-2.49 (m, 4H), 2.13-2.18 (m, 2H), 1.77-1.80 (m, 1H), 1.56-1.59 (m, 1H), 1.31-1.34 (m, 1H), 1.26 (t, 3H).
Example 29
Preparation of (1S,2S)-2-(4-(((11-methyl-9-(3-(methylsulfonyl)propoxy)-6,7-dihydro-5H-dibenzo[a,c][7]annulen-2-yl)methyl)amino)phenyl)cyclopropanecarboxylic acid
<29-1> Preparation of 11-methyl-9-(3-(methylsulfonyl)propoxy)-6,7-dihydro-5H-dibenzo[a,c][7]annulene-2-carb aldehyde




According to the procedures as described in <3-3>, the compound obtained in <7-8> was used to prepare the title compound (colorless oil, 100 mg, 100% yield).
1H NMR (600 MHz, CDCl3) δ 10.02 (s, 1H), 7.76-7.77 (m, 2H), 7.40 (d, 1H), 6.75 (d, 1H), 6.64 (d, 1H), 4.16 (t, 2H), 3.28-3.30 (m, 2H), 2.59-2.62 (m, 1H), 2.36-2.45 (m, 4H), 2.31 (s, 3H), 2.19-2.22 (m, 1H), 2.05-2.10 (m, 2H).
<29-2> Preparation of (1S,2S)-ethyl 2-(4-(((11-methyl-9-(3-(methylsulfonyl)propoxy)-6,7-dihydro-5H-dibenzo[a,c][7]annulen-2-yl)methyl)amino)phenyl)cyclopropanecarboxylate




According to the procedures as described in <3-4>, the compound obtained in <29-1> was used to prepare the title compound (white foam, 116 mg, 79% yield).
1H NMR (600 MHz, CDCl3) δ 7.17-7.22 (m, 3H), 6.91 (d, 2H), 6.69 (d, 1H), 6.61 (d, 1H), 6.56 (d, 2H), 4.32 (s, 2H), 4.12-4.16 (m, 4H), 4.00 (br, 1H), 3.25-3.28 (m, 2H), 2.97 (s, 3H), 2.46-2.50 (m, 1H), 2.39-2.43 (m, 2H), 2.20-2.37 (m, 4H), 2.18 (s, 3H), 1.98-2.03 (m, 2H), 1.74-1.77 (m, 1H), 1.48-1.51 (m, 1H), 1.26 (t, 3H), 1.19-1.22 (m, 1H).
<29-3> Preparation of (1S,2S)-2-(4-(((11-methyl-9-(3-(methylsulfonyl)propoxy)-6,7-dihydro-5H-dibenzo[a,c][7]annulen-2-yl)methyl)amino)phenyl)cyclopropanecarboxylic acid




According to the procedures as described in <3-5>, the compound obtained in <29-2> was used to prepare the title compound (white foam, 100 mg, 89% yield).
MS m/z 532 [M−H]−
1H NMR (600 MHz, CDCl3) δ 7.15-7.19 (m, 3H), 6.87-6.88 (m, 2H), 6.67-6.68 (m, 1H), 6.59-6.60 (m, 1H), 6.51-6.52 (m, 1H), 4.28 (s, 2H), 4.10-4.12 (m, 2H), 3.25 (m, 2H), 2.94 (s, 3H), 2.45-2.49 (m, 2H), 2.38-2.41 (m, 1H), 2.29-2.35 (m, 4H), 2.18-2.23 (m, 1H), 2.16 (s, 3H), 1.97-2.01 (m, 2H), 1.73-1.75 (m, 1H), 1.52-1.54 (m, 1H).
Example 30
Preparation of (1S,2S)-2-(4-((10-methyl-8-(3-(methylsulfonyl)propoxy)-6H-benzo[c]chromen-2-yl)methoxy)phenyl)cyclopropanecarboxylic acid
<30-1> Preparation of (1S,2S)-ethyl 2-(4-((10-methyl-8-(3-(methylsulfonyl)propoxy)-6H-benzo[c]chromen-2-yl)methoxy)phenyl)cyclopropanecarboxylate




According to the procedures as described in <2-16>, the compound obtained in <9-6> was used to prepare the title compound (white foam, 132 mg, 87% yield).
1H NMR (600 MHz, CDCl3) δ 7.74 (d, 1H), 7.24 (dd, 1H), 7.02-7.05 (m, 3H), 6.89-6.92 (m, 2H), 6.75 (d, 1H), 6.59 (d, 1H), 5.04 (s, 2H), 4.92 (s, 2H), 4.12-4.18 (m, 4H), 3.25-3.27 (m, 2H), 2.96 (s, 3H), 2.56 (s, 3H), 2.46-2.50 (m, 1H), 2.34-2.38 (m, 2H), 1.80-1.83 (m, 1H), 1.54-1.57 (m, 1H), 1.23-1.29 (m, 4H).
<30-2> Preparation of (1S,2S)-2-(4-((10-methyl-8-(3-(methylsulfonyl)propoxy)-6H-benzo[c]chromen-2-yl)methoxy)phenyl)cyclopropanecarboxylic acid




According to the procedures as described in <1-11>, the compound obtained in <30-1> was used to prepare the title compound (white solid, 105 mg, 84% yield).
MS m/z 521 [M−H]−
1H NMR (600 MHz, CDCl3) δ 7.73 (d, 1H), 7.23 (dd, 1H), 7.02-7.05 (m, 3H), 6.89-6.92 (m, 2H), 6.47 (d, 1H), 6.58 (d, 1H), 5.03 (s, 2H), 4.91 (s, 2H), 4.13 (t, 2H), 3.24-3.27 (m, 2H), 2.96 (s, 3H), 2.54-2.57 (m, 4H), 2.33-2.37 (m, 2H), 1.80-1.83 (m, 1H), 1.59-1.63 (m, 1H), 1.33-1.36 (m, 1H).
Example 31
Preparation of (1S,2S)-2-(4-((5-methyl-7-(3-(methylsulfonyl)propoxy)-9,10-dihydrophenanthren-3-yl) methoxy)phenyl)cyclopropanecarboxylic acid
<31-1> Preparation of (1S,2S)-ethyl 2-(4-((5-methyl-7-(3-(methylsulfonyl)propoxy)-9,10-dihydrophenanthren-3-yl)methoxy)phenyl)cyclopropanecarboxylate




According to the procedures as described in <2-16>, the compound obtained in <11-7> was used to prepare the title compound (white foam, 93 mg, 76% yield).
1H NMR (600 MHz, CDCl3) δ 7.62 (d, 1H), 7.25-7.27 (m, 1H), 7.21 (dd, 1H), 7.02-7.03 (m, 2H), 6.90-6.92 (m, 2H), 6.69 (d, 1H), 6.66 (d, 1H), 5.07 (s, 2H), 4.13-4.18 (m, 4H), 3.25-3.28 (m, 2H), 2.96 (s, 3H), 2.72 (s, 4H), 2.54 (s, 3H), 2.46-2.48 (m, 2H), 2.34-2.37 (m, 1H), 1.80-1.83 (m, 1H), 1.53-1.56 (m, 1H), 1.23-1.29 (m, 4H).
<31-2> Preparation of (1S,2S)-2-(4-((5-methyl-7-(3-(methylsulfonyl)propoxy)-9,10-dihydrophenanthren-3-yl)methoxy)phenyl)cyclopropanecarboxylic acid




According to the procedures as described in <1-11>, the compound obtained in <31-1> was used to prepare the title compound (white solid, 73 mg, 85% yield).
MS m/z 519 [M−H]−
1H NMR (600 MHz, CDCl3) δ 7.62 (d, 1H), 7.25-7.27 (m, 1H), 7.22 (dd, 1H), 7.03-7.05 (m, 2H), 6.90-6.92 (m, 2H), 6.69 (d, 1H), 6.66 (d, 1H), 5.07 (s, 2H), 4.14 (t, 2H), 3.25-3.28 (m, 2H), 2.96 (s, 3H), 2.73 (s, 4H), 2.54-2.57 (m, 4H), 2.33-2.38 (m, 2H), 1.81-1.84 (m, 1H), 1.60-1.63 (m, 1H), 1.33-1.36 (m, 1H).
Example 32
Preparation of (S)-2-(6-((9-(3-(methylsulfonyl)propoxy)-6,7-dihydrodibenzo[b,d]oxepin-2-yl)methoxy)-2,3-dihydrobenzofuran-3-yl)acetic acid
<32-1> Preparation of (S)-methyl 2-(6-((9-(3-(methylsulfonyl)propoxy)-6,7-dihydrodibenzo[b,d]oxepin-2-yl)methoxy)-2,3-dihydrobenzofuran-3-yl)acetate




According to the procedures as described in <1-10>, the compound obtained in <2-13> was used to prepare the title compound (white foam, 112 mg, 83% yield).
1H NMR (600 MHz, CDCl3) δ 7.42 (d, 1H), 7.38 (d, 1H), 7.34 (dd, 1H), 7.12 (d, 1H), 7.04 (dd, 1H), 6.89 (dd, 1H), 6.83 (d, 1H), 6.51 (dd, 1H), 6.48 (d, 1H), 5.03 (s, 2H), 4.76 (t, 1H), 4.56 (t, 2H), 4.27 (dd, 1H), 4.17 (t, 2H), 3.79-3.84 (m, 1H), 3.72 (s, 3H), 3.27-3.29 (m, 2H), 2.97 (s, 3H), 2.74-2.79 (m, 3H), 2.54-2.59 (m, 1H), 2.35-2.40 (m, 2H).
<32-2> Preparation of (S)-2-(6-((9-(3-(methylsulfonyl)propoxy)-6,7-dihydrodibenzo[b,d]oxepin-2-yl)methoxy)-2,3-dihydrobenzofuran-3-yl)acetic acid




According to the procedures as described in <1-11>, the compound obtained in <32-1> was used to prepare the title compound (white foam, 90 mg, 84% yield).
MS m/z 537 [M−H]−
1H NMR (600 MHz, CDCl3) δ 7.42 (d, 1H), 7.38 (d, 1H), 7.34 (dd, 1H), 7.13 (d, 1H), 7.07 (d, 1H), 6.89 (dd, 1H), 6.83 (d, 1H), 6.52 (dd, 1H), 6.49 (d, 1H), 5.03 (s, 2H), 4.77 (t, 1H), 4.56 (t, 2H), 4.30 (dd, 1H), 4.17 (t, 2H), 3.79-3.84 (m, 1H), 3.27-3.29 (m, 2H), 2.97 (s, 3H), 2.77-2.83 (m, 3H), 2.61-2.65 (m, 1H), 2.35-2.40 (m, 2H).
Example 33
Preparation of 2-((3S)-6-((11-methyl-9-(3-(methylsulfonyl)propoxy)-5,7-dihydrodibenzo[c,e]oxepin-2-yl)methoxy)-2,3-dihydrobenzofuran-3-yl)acetic acid
<33-1> Preparation of methyl 4-(bromomethyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2-yl)benzoate




According to the procedures as described in <1-4>, methyl 4-(bromomethyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2-yl)benzoate (prepared in accordance with the reference [Chemical Communications (Cambridge, United Kingdom), 2012, vol. 48, #34, p. 4115-4117]) was used to prepare the title compound (white solid, 3.0 g, 92% yield).
1H NMR (300 MHz, CDCl3) δ 8.46 (d, 1H), 8.06 (dd, 1H), 7.46 (d, 1H), 4.91 (s, 2H), 3.93 (s, 3H), 1.38 (s, 12H).
<33-2> Preparation of methyl 4-(((2-bromo-5-(methoxymethoxy)-3-methylbenzyl)oxy)methyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2-yl)benzoate




According to the procedures as described in <18-4>, the compounds obtained in <19-3> and <33-1> were used to prepare the title compound (white solid, 1.75 g, 47% yield).
1H NMR (300 MHz, CDCl3) δ 8.46 (d, 1H), 8.10 (dd, 1H), 7.67 (d, 1H), 7.11 (d, 1H), 6.89 (d, 1H), 5.15 (s, 2H), 4.96 (s, 2H), 4.64 (s, 2H), 3.92 (s, 3H), 3.46 (s, 3H), 2.39 (s, 3H), 1.34 (s, 13H).
<33-3> Preparation of methyl 9-(methoxymethoxy)-11-methyl-5,7-dihydrodibenzo[c,e]oxepin-2-carboxylate




According to the procedures as described in <18-5>, the compound obtained in <33-2> was used to prepare the title compound (colorless oil, 246 mg, 23% yield).
1H NMR (300 MHz, CDCl3) δ 8.12 (d, 1H), 8.03 (dd, 1H), 7.50 (d, 1H), 7.05 (d, 1H), 6.96 (d, 1H), 5.23 (q, 2H), 4.51 (d, 1H), 4.41 (d, 1H), 4.16 (d, 1H), 3.97 (d, 1H), 3.94 (s, 3H), 3.51 (s, 3H), 2.43 (s, 3H).
<33-4> Preparation of methyl 9-hydroxy-11-methyl-5,7-dihydrodibenzo[c,e]oxepin-2-carboxylate




According to the procedures as described in <18-6>, the compound obtained in <33-3> was used to prepare the title compound (white solid, 187 mg, 88% yield).
1H NMR (300 MHz, CDCl3) δ 8.12 (d, 1H), 8.04 (dd, 1H), 7.51 (d, 1H), 6.88 (d, 1H), 6.78 (d, 1H), 5.81 (s, 1H), 4.55 (d, 1H), 4.38 (d, 1H), 4.20 (d, 1H), 3.98 (d, 1H), 3.95 (s, 3H), 2.41 (s, 3H).
<33-5> Preparation of methyl 11-methyl-9-(3-(methylsulfonyl)propoxy)-5,7-dihydrodibenzo[c,e]oxepin-2-carboxylate




According to the procedures as described in <1-8>, the compound obtained in <33-4> was used to prepare the title compound (white solid, 217 mg, 82% yield).
1H NMR (300 MHz, CDCl3) δ 8.11 (d, 1H), 8.03 (dd, 1H), 7.50 (d, 1H), 6.90 (d, 1H), 6.81 (d, 1H), 4.51 (d, 1H), 4.39 (d, 1H), 4.20-4.11 (m, 3H), 3.98 (d, 1H), 3.95 (s, 3H), 3.36-3.22 (m, 2H), 2.98 (s, 3H), 2.50-2.33 (m, 5H).
<33-6> Preparation of (11-methyl-9-(3-(methylsulfonyl)propoxy)-5,7-dihydrodibenzo[c,e]oxepin-2-yl)methanol




According to the procedures as described in <1-9>, the compound obtained in <33-5> was used to prepare the title compound (white solid, 171 mg, 85% yield).
1H NMR (300 MHz, CDCl3) δ 7.46-7.34 (m, 3H), 6.89 (d, 1H), 6.80 (d, 1H), 4.78 (d, 2H), 4.47 (d, 1H), 4.37 (d, 1H), 4.18 (t, 2H), 4.12 (d, 1H), 4.00 (d, 1H), 3.28 (dd, 2H), 2.98 (s, 3H), 2.47-2.32 (m, 5H), 1.71 (t, 1H).
<33-7> Preparation of methyl 2-((3S)-6-((11-methyl-9-(3-(methylsulfonyl)propoxy)-5,7-dihydrodibenzo[c,e]oxepin-2-yl) methoxy)-2,3-dihydrobenzofuran-3-yl)acetate




According to the procedures as described in <1-10>, the compound obtained in <33-6> was used to prepare the title compound (white solid, 25 mg, 20% yield).
1H NMR (300 MHz, CDCl3) δ 7.51-7.37 (m, 3H), 7.03 (d, 1H), 6.87 (d, 1H), 6.80 (d, 1H), 6.54-6.43 (m, 2H), 5.10 (s, 2H), 4.75 (t, 1H), 4.48 (d, 1H), 4.37 (d, 1H), 4.27 (dd, 1H), 4.19-4.09 (m, 4H), 4.01 (d, 1H), 3.86-3.76 (m, 1H), 3.74 (d, 3H), 3.34-3.22 (m, 2H), 2.98 (s, 3H), 2.75 (dd, 1H), 2.56 (dd, 1H), 2.46-2.28 (m, 5H), 2.04 (s, 1H), 1.26 (t, 2H).
<33-8> Preparation of 2-((3S)-6-((11-methyl-9-(3-(methylsulfonyl)propoxy)-5,7-dihydrodibenzo[c,e]oxepin-2-yl) methoxy)-2,3-dihydrobenzofuran-3-yl)acetic acid




According to the procedures as described in <1-11>, the compound obtained in <33-7> was used to prepare the title compound (white solid, 11 mg, 46% yield).
MS m/z 551 [M−H]−.
1H NMR (600 MHz, CDCl3) δ 7.46-7.41 (m, 2H), 7.39 (dd, 1H), 7.05 (d, 1H), 6.86 (d, 1H), 6.78 (d, 1H), 6.49 (ddd, 1H), 6.46 (t, 1H), 5.10 (s, 2H), 4.75 (t, 1H), 4.47 (d, 1H), 4.37 (d, 1H), 4.28 (ddd, 1H), 4.16 (t, 2H), 4.11 (dd, 1H), 4.00 (d, 1H), 3.85-3.75 (m, 1H), 3.30-3.24 (m, 2H), 2.96 (s, 3H), 2.79 (dd, 1H), 2.61 (dd, 1H), 2.40-2.33 (m, 5H).
Example 34
(1S,2S)-2-(4-(((11-methyl-9-(3-(methylsulfonyl)propoxy)-5,7-dihydrodibenzo[c,e]oxepin-2-yl)methyl)amino)phenyl)cyclopropanecarboxylic acid
<34-1> Preparation of 11-methyl-9-(3-(methylsulfonyl)propoxy)-5,7-dihydrodibenzo[c,e]oxepin-2-carbaldehyde




According to the procedures as described in <3-3>, the compound obtained in <33-6> was used to prepare the title compound (white solid, 57 mg, 67% yield).
1H NMR (300 MHz, CDCl3) δ 10.10 (s, 1H), 7.94 (d, 1H), 7.88 (dd, 1H), 7.61 (d, 1H), 6.92 (d, 1H), 6.82 (d, 1H), 4.54 (d, 1H), 4.41 (d, 1H), 4.23-4.10 (m, 3H), 3.99 (d, 1H), 3.36-3.23 (m, 2H), 2.98 (s, 3H), 2.49-2.30 (m, 5H).
<34-2> Preparation of (1S,2S)-ethyl 2-(4-(((11-methyl-9-(3-(methylsulfonyl)propoxy)-5,7-dihydrodibenzo[c,e]oxepin-2-yl)methyl)amino)phenyl)cyclopropanecarboxylate




According to the procedures as described in <3-4>, the compound obtained in <34-1> was used prepare the title compound (white solid, 67 mg, 78% yield).
1H NMR (300 MHz, CDCl3) δ 7.42-7.30 (m, 3H), 6.92 (d, 2H), 6.85 (d, 1H), 6.78 (d, 1H), 6.57 (d, 2H), 4.46 (d, 1H), 4.40 (s, 2H), 4.36 (d, 1H), 4.23-4.05 (m, 6H), 3.99 (d, 1H), 3.27 (dd, 2H), 2.97 (s, 3H), 2.49-2.31 (m, 3H), 2.29 (s, 3H), 1.84-1.72 (m, 1H), 1.55-1.46 (m, 1H), 1.32-1.16 (m, 4H).
<34-3> Preparation of (1S,2S)-2-(4-(((11-methyl-9-(3-(methylsulfonyl)propoxy)-5,7-dihydrodibenzo[c,e]oxepin-2-yl)methyl)amino)phenyl)cyclopropanecarboxylic acid




According to the procedures as described in <3-5>, the compound obtained in <34-2> was used to prepare the title compound (white solid, 11 mg, 46% yield).
MS m/z 534 [M−H]−.
1H NMR (600 MHz, CDCl3) δ 7.38 (d, 4H), 7.33 (dd, 2H), 6.92 (d, 4H), 6.84 (d, 2H), 6.77 (d, 2H), 6.59-6.54 (m, 4H), 4.45 (d, 2H), 4.40 (s, 4H), 4.35 (d, 2H), 4.15 (t, 4H), 4.09 (d, 2H), 3.98 (d, 2H), 3.30-3.23 (m, 4H), 2.96 (s, 6H), 2.52-2.48 (m, 2H), 2.38-2.35 (m, 4H), 2.27 (s, 6H), 1.78-1.75 (m, 2H), 1.56 (dt, 3H), 1.34-1.28 (m, 3H), 1.28-1.23 (m, 3H).
Example 35
Preparation of 2-((3S)-6-((9-(2-ethoxyethoxy)-11-methyl-6,7-dihydro-5H-dibenzo[a,c][7]annulen-2-yl)methoxy)-2,3-dihydrobenzofuran-3-yl)acetic acid
<35-1> Preparation of methyl 9-(2-ethoxyethoxy)-11-methyl-6,7-dihydro-5H-dibenzo[a,c][7]annulene-2-carboxylate




According to the procedures as described in <3-1>, the compound obtained in <7-6> was used prepare the title compound (colorless oil, 67 mg, 86% yield).
1H NMR (300 MHz, CDCl3) δ 7.94 (d, 1H), 7.91 (dd, 1H), 7.29 (d, 1H), 6.78 (d, 1H), 6.68 (d, 1H), 4.16 (dd, 2H), 3.91 (s, 3H), 3.82 (dd, 2H), 3.63 (q, 2H), 2.61-2.14 (m, 7H), 2.08-1.98 (m, 2H), 1.26 (t, 3H).
<35-2> Preparation of (9-(2-ethoxyethoxy)-11-methyl-6,7-dihydro-5H-dibenzo[a,c][7]annulen-2-yl)methanol




According to the procedures as described in <3-2>, the compound obtained in <35-1> was used to prepare the title compound (colorless oil, 59 mg, 88% yield).
1H NMR (300 MHz, CDCl3) δ 7.25-7.20 (m, 3H), 6.77 (d, 1H), 6.67 (d, 1H), 4.70 (s, 2H), 4.16 (dd, 2H), 3.81 (dd, 2H), 3.62 (q, 2H), 2.53-2.18 (m, 7H), 2.04-1.96 (m, 2H), 1.26 (t, 3H).
<35-3> Preparation of methyl 2-((3S)-6-((9-(2-ethoxyethoxy)-11-methyl-6,7-dihydro-5H-dibenzo[a,c][7]annulen-2-yl)methoxy)-2,3-dihydrobenzofuran-3-yl)acetate




According to the procedures as described in <1-10>, the compound obtained in <35-2> was used to prepare the title compound (colorless oil, 80 mg, 93% yield).
1H NMR (300 MHz, CDCl3) δ 7.32-7.18 (m, 4H), 7.02 (d, 1H), 6.76 (d, 1H), 6.67 (d, 1H), 6.48 (dd, 2H), 5.04 (s, 2H), 4.75 (t, 1H), 4.26 (dd, 1H), 4.16 (t, 2H), 3.88-3.75 (m, 3H), 3.71 (s, 3H), 3.62 (q, 2H), 2.75 (dd, 1H), 2.59-2.24 (m, 7H), 2.04-1.98 (m, 2H), 1.26 (t, 4H).
<35-4> Preparation of 2-((3S)-6-((9-(2-ethoxyethoxy)-11-methyl-6,7-dihydro-5H-dibenzo[a,c][7]annulen-2-yl)methoxy)-2,3-dihydrobenzofuran-3-yl)acetic acid




According to the procedures as described in <1-11>, the compound obtained in <35-3> was used to prepare the title compound (white solid, 56 mg, 71% yield).
MS m/z 501 [M−H]−.
1H NMR (600 MHz, CDCl3) δ 7.29-7.25 (m, 2H), 7.22 (d, 1H), 7.04 (d, 1H), 6.75 (d, 1H), 6.66 (d, 1H), 6.52-6.48 (m, 1H), 6.46 (d, 1H), 5.03 (s, 2H), 4.75 (t, 1H), 4.32-4.24 (m, 1H), 4.17-4.13 (m, 2H), 3.83-3.77 (m, 3H), 3.61 (q, 2H), 2.79 (dd, 1H), 2.60 (dd, 1H), 2.48 (ddd, 1H), 2.44-2.37 (m, 1H), 2.38-2.31 (m, 1H), 2.31-2.24 (m, 1H), 2.23 (d, 3H), 2.05-1.95 (m, 2H), 1.24 (t, 4H).
Example 36
Preparation of 2-((3S)-6-((9-((1,1-dioxidotetrahydro-2H-thiopyran-4-yl)oxy)-11-methyl-6,7-dihydrodibenzo[b,d]oxepin-2-yl)methoxy)-2,3-dihydrobenzofuran-3-yl)acetic acid
<36-1> Preparation of methyl 11-methyl-9-((tetrahydro-2H-thiopyran-4-yl)oxy)-6,7-dihydrodibenzo[b,d]oxepin-2-carboxylate




The compound obtained in <14-5> (80 mg, 0.28 mmol), tetrahydro-2H-thiopyran-4-ol (33.1 mg, 0.28 mmol) and triphenylphosphine (110.2 mg, 0.42 mmol) were dissolved in THF (2.5 mL), which was then slowly added with diethyl azodicarboxylate (DEAD, 191 μL, 0.42 mmol) and stirred at room temperature for 19 hours. The resulting mixture was concentrated and purified by silica gel chromatography to obtain the title compound (white solid, 33.7 mg, 31% yield).
1H NMR (300 MHz, CDCl3) δ 8.02 (d, 1H), 7.97 (dd, 1H), 7.18 (d, 1H), 6.79 (d, 1H), 6.67 (d, 1H), 4.50-4.38 (m, 3H), 3.91 (s, 3H), 3.00-2.92 (m, 2H), 2.87-2.76 (m, 1H), 2.63-2.47 (m, 3H), 2.36 (s, 3H), 2.27-2.17 (m, 2H), 2.12-2.01 (m, 2H)
<36-2> Preparation of methyl 9-((1,1-dioxidotetrahydro-2H-thiopyran-4-yl)oxy)-11-methyl-6,7-dihydrodibenzo[b,d]oxepin-2-carboxylate




The compound obtained in <36-1> (71.1 mg, 0.18 mmol) was dissolved in dichloromethane (3 mL), which was then added with m-CPBA (87.4 mg, 0.39 mmol) at 0° C. After 20 minutes, the reaction mixture was stirred at room temperature for 30 minutes. The mixture was added with an aqeuous Na2S2O3 solution, diluted with dichloromethane and a saturated sodium sulfate aqueous solution, and the layers thus formed were separated. The aqueous layer was extracted with dichloromethane 2 times, and the organic layer was dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by silica gel chromatography to obtain the title compound (colorless oil, 94.4 mg, 99% yield).
1H NMR (300 MHz, CDCl3) δ 8.01 (d, 1H), 7.96 (dd, 1H), 7.16 (d, 1H), 6.77 (d, 1H), 6.67 (d, 1H), 4.71 (m, 1H), 4.50-4.45 (m, 2H), 3.92 (s, 3H), 3.50-3.39 (m, 2H), 2.95 (m, 2H), 2.88-2.77 (m, 1H), 2.52 (m, 3H), 2.40 (m, 2H), 2.37 (s, 3H)
<36-3> Preparation of 4-((2-(hydroxymethyl)-11-methyl-6,7-dihydrodibenzo[b,d]oxepin-9-yl)oxy)tetrahydro-2H-thiopyran 1,1-dioxide




According to the procedures as described in <1-9>, the compound obtained in <36-2> was used to prepare the title compound (colorless oil, 87.0 mg, 99% yield).
1H NMR (300 MHz, CDCl3) δ 7.32 (s, 1H), 7.27 (d, 1H), 7.13 (d, 1H), 6.80 (d, 1H), 6.71 (d, 1H), 4.71 (m, 3H), 4.43-4.39 (m, 2H), 3.49-3.43 (m, 2H), 2.94 (m, 2H), 2.87-2.76 (m, 1H), 2.54-2.42 (m, 3H), 2.38 (m, 2H), 2.37 (s, 3H), 1.78 (t, 1H)
<36-4> Preparation of methyl 2-((3S)-6-((9-((1,1-dioxidotetrahydro-2H-thiopyran-4-yl)oxy)-11-methyl-6,7-dihydrodibenzo[b,d]oxepin-2-yl)methoxy)-2,3-dihydrobenzofuran-3-ylacetate




According to the procedures as described in <1-10>, the compound obtained in <36-3> was used to prepare the title compound (colorless oil, 114.4 mg, 88% yield).
1H NMR (300 MHz, CDCl3) δ 7.34 (m, 2H), 7.15 (d, 1H), 7.02 (d, 1H), 6.79 (d, 1H), 6.71 (d, 1H), 6.48 (m, 2H), 5.04 (s, 2H), 4.75 (t, 1H), 4.70 (m, 1H), 4.41 (m, 2H), 4.26 (dd, 1H), 3.81 (m, 1H), 3.72 (s, 3H), 3.44 (m, 2H), 2.94 (m, 2H), 2.87-2.70 (m, 2H), 2.60-2.47 (m, 4H), 2.38 (m, 2H), 2.31 (s, 3H).
<36-5> Preparation of 2-((3S)-6-((9-((1,1-dioxidotetrahydro-2H-thiopyran-4-yl)oxy)-11-methyl-6,7-dihydrodibenzo[b,d]oxepin-2-yl)methoxy)-2,3-dihydrobenzofuran-3-yl)acetic acid




According to the procedures as described in <1-11>, the compound obtained in <36-4> was used to prepare the title compound (white foam, 93.3 mg, 83% yield).
MS m/z 563 [M−H]−.
1H NMR (600 MHz, CDCl3) δ 7.35 (m, 2H), 7.17 (d, 1H), 7.07 (d, 1H), 6.80 (d, 1H), 6.72 (d, 1H), 6.54-6.48 (m, 2H), 5.05 (s, 2H), 4.77 (t, 1H), 4.71 (m, 1H), 4.42 (m, 2H), 4.29 (dd, 1H), 3.82 (m, 1H), 3.45 (m, 2H), 2.96 (m, 2H), 2.84 (m, 1H), 2.79 (d, 1H), 2.62 (dd, 1H), 2.55-2.49 (m, 3H), 2.39 (m, 2H), 2.32 (s, 3H).
Example 37
Preparation of 2-((3S)-6-((9-(2-(1,1-dioxidothiomorpholino)ethoxy)-11-methyl-6,7-dihydrodibenzo[b,d]oxepin-2-yl)methoxy)-2,3-dihydrobenzofuran-3-yl)acetic acid
<37-1> Preparation of methyl 9-(2-(1,1-dioxidothiomorpholino)ethoxy)-11-methyl-6,7-dihydrodibenzo[b,d]oxepin-2-carboxylate




The compound obtained in <14-5> (80 mg, 0.28 mmol), 4-(2-hydroxyethyl)thiomorpholine 1,1-dioxide (50.4 mg, 0.28 mmol) and triphenylphosphine (110.2 mg, 0.42 mmol) were dissolved in THF (2.5 mL), which was then slowly added with diethyl azodicarboxylate (DEAD, 191 μL, 0.42 mmol) and stirred at room temperature for 19 hours. The resulting mixture was concentrated and purified by silica gel chromatography to obtain the title compound (white solid, 57.5 mg, 46% yield).
1H NMR (300 MHz, CDCl3) δ 8.02 (d, 1H), 7.97 (dd, 1H), 7.18 (d, 1H), 6.79 (d, 1H), 6.67 (d, 1H), 4.49-4.44 (m, 2H), 4.27 (t, 2H), 3.90 (s, 3H), 3.17 (m, 4H), 3.08 (m, 4H), 3.00 (t, 2H), 2.80 (m, 1H), 2.50 (m, 1H), 2.36 (s, 3H)
<37-2> Preparation of 4-(2-((2-(hydroxymethyl)-11-methyl-6,7-dihydrodibenzo[b,d]oxepin-9-yl)oxy)ethyl)thiomorpholine 1,1-dioxide




According to the procedures as described in <1-9>, the compound obtained in <37-1> was used to prepare the title compound (white foam, 93.6 mg, 75% yield).
1H NMR (300 MHz, CDCl3) δ 7.31 (s, 1H), 7.29 (dd, 1H), 7.14 (d, 1H), 6.77 (d, 1H), 6.68 (d, 1H), 4.71 (d, 1H), 4.40 (m, 2H), 4.14 (t, 2H), 3.18 (m, 4H), 3.09 (m, 4H), 3.01 (t, 2H), 2.81 (m, 1H), 2.48 (m, 1H), 2.38 (s, 3H), 1.65 (s, 1H).
<37-3> Preparation of methyl 2-((3S)-6-((9-(2-(1,1-dioxidothiomorpholino)ethoxy)-11-methyl-6,7-dihydrodibenzo[b,d]oxepin-2-yl)methoxy)-2,3-dihydrobenzofuran-3-ylacetate




According to the procedures as described in <1-10>, the compound obtained in <37-2> was used to prepare the title compound (colorless oil, 120.2 mg, 88% yield).
1H NMR (300 MHz, CDCl3) δ 7.34-7.32 (m, 2H), 7.15 (d, 1H), 7.02 (d, 1H), 6.76 (d, 1H), 6.66 (d, 1H), 6.51-6.46 (m, 2H), 5.03 (s, 2H), 4.75 (t, 1H), 4.41 (m, 2H), 4.26 (dd, 1H), 4.13 (t, 2H), 3.80 (m, 1H), 3.72 (s, 3H), 3.18 (m, 4H), 3.08 (m, 4H), 3.00 (t, 2H), 2.83 (m, 1H), 2.74 (dd, 1H), 2.54 (dd, 1H), 2.48 (dd, 1H), 2.32 (s, 3H).
<37-4> Preparation of 2-((3S)-6-((9-(2-(1,1-dioxidothiomorpholino)ethoxy)-11-methyl-6,7-dihydrodibenzo[b,d]oxepin-2-yl)methoxy)-2,3-dihydrobenzofuran-3-yl)acetic acid




According to the procedures as described in <1-11>, the compound obtained in <37-3> was used to prepare the title compound (white foam, 81.1 mg, 68% yield).
MS m/z 592 [M−H]−.
1H NMR (600 MHz, CDCl3) δ 7.35-7.33 (m, 2H), 7.16 (d, 1H), 7.06 (d, 1H), 6.76 (d, 1H), 6.68 (d, 1H), 6.52-6.47 (m, 2H), 5.04 (s, 2H), 4.77 (t, 1H), 4.41 (m, 2H), 4.29 (dd, 1H), 4.14 (t, 2H), 3.80 (m, 1H), 3.20 (m, 4H), 3.11 (m, 4H), 3.02 (t, 2H), 2.87 (m, 1H), 2.80 (dd, 1H), 2.61 (dd, 1H), 2.49 (dd, 1H), 2.32 (s, 3H).
Example 38
Preparation of 2-((3S)-6-((9-(3-(ethylsulfonyl)propoxy)-11-methyl-6,7-dihydrodibenzo[b,d]oxepin-2-yl)methoxy)-2,3-dihydrobenzofuran-3-yl)acetic acid
<38-1> Preparation of methyl 9-(3-(ethylsulfonyl)propoxy)-11-methyl-6,7-dihydrodibenzo[b,d]oxepin-2-carboxylate




A solution of the compound obtained in <14-5> (160 mg, 0.56 mmol) and 1-chloro-3-(ethylsulfonyl)propane (prepared in accordance with the reference [US 2009/270355 A1]; 162 mg, 0.95 mmol) in DMF (1.87 mL) was added with K2CO3 (201 mg, 1.46 mmol) and KI (19 mg, 0.112 mmol), followed by stirring for 5 hours at 90° C. The reaction mixture was cooled to room temperature and extracted with EtOAc. The organic layer was collected and dried over MgSO4. The resulting filtrate was concentrated under reduced pressure and purified by silica gel chromatography to obtain the title compound (yellow oil, 165 mg, 70% yield).
1H NMR (300 MHz, CDCl3) δ 8.02 (d, 1H), 7.98 (dd, 2H), 7.18 (d, 1H), 6.78 (d, 1H), 6.68 (d, 1H), 4.54-4.38 (m, 2H), 4.16 (t, 2H), 3.92 (s, 3H), 3.27-3.16 (m, 2H), 3.06 (q, 2H), 2.87-2.74 (m, 1H), 2.57-2.30 (m, 6H), 1.46 (t, 3H).
<38-2> Preparation of (9-(3-(ethylsulfonyl)propoxy)-11-methyl-6,7-dihydrodibenzo[b,d]oxepin-2-yl)methanol




According to the procedures as described in <1-9>, the compound obtained in <38-1> was used to prepare the title compound (colorless oil, 129 mg, 84% yield).
1H NMR (300 MHz, CDCl3) δ 7.33-7.26 (m, 2H), 7.14 (d, 1H), 6.77 (d, 1H), 6.69 (d, 1H), 4.72 (d, 2H), 4.44-4.36 (m, 2H), 4.15 (t, 2H), 3.28-3.15 (m, 2H), 3.05 (q, 2H), 2.80 (m, 1H), 2.49 (m, 1H), 2.41-2.29 (m, 5H), 1.64 (t, 1H), 1.45 (t, 3H).
<38-3> Preparation of methyl 2-((3S)-6-((9-(3-(ethylsulfonyl)propoxy)-11-methyl-6,7-dihydrodibenzo[b,d]oxepin-2-yl) methoxy)-2,3-dihydrobenzofuran-3-ylacetate




According to the procedures as described in <1-10>, the compound obtained in <38-2> was used to prepare the title compound (white foam, 58.7 mg, 56% yield).
1H NMR (300 MHz, CDCl3) δ 7.37-7.29 (m, 2H), 7.15 (d, 1H), 7.03 (d, 1H), 6.76 (d, 1H), 6.68 (d, 1H), 6.52-6.42 (m, 2H), 5.04 (s, 2H), 4.75 (t, 1H), 4.49-4.35 (m, 2H), 4.27 (dd, 1H), 4.15 (t, 2H), 3.81 (m, 1H), 3.72 (s, 3H), 3.27-3.14 (m, 2H), 3.05 (q, 2H), 2.83 (m, 1H), 2.75 (dd, 1H), 2.63-2.42 (m, 2H), 2.36 (m, 2H), 2.31 (s, 3H), 1.45 (t, 3H).
<38-4> Preparation of 2-((3S)-6-((9-(3-(ethylsulfonyl)propoxy)-11-methyl-6,7-dihydrodibenzo[b,d]oxepin-2-yl) methoxy)-2,3-dihydrobenzofuran-3-yl)acetic acid




According to the procedures as described in <1-11>, the compound obtained in <38-3> was used to prepare the title compound (white foam, 49.2 mg, 87% yield).
MS m/z 565 [M−H]−.
1H NMR (300 MHz, CDCl3) δ 7.37-7.30 (m, 2H), 7.15 (d, 1H), 7.06 (d, 1H), 6.76 (d, 1H), 6.68 (d, 1H), 6.54-6.44 (m, 2H), 5.04 (s, 2H), 4.77 (t, 1H), 4.46-4.36 (m, 2H), 4.29 (dd, 1H), 4.15 (t, 2H), 3.81 (m, 1H), 3.27-3.16 (m, 2H), 3.05 (q, 2H), 2.92-2.75 (m, 2H), 2.62 (dd, 1H), 2.51 (m, 1H), 2.36 (m, 2H), 2.31 (s, 3H), 1.45 (t, 3H).
Example 39
Preparation of (1S,2S)-2-(4-((11-methyl-9-(3-(methylsulfonyl)propoxy)-6,7-dihydrodibenzo[b,d]oxepin-2-yl)methoxy)phenyl)cyclopropanecarboxylic acid
<39-1> Preparation of (1S,2S)-ethyl 2-(4-((11-methyl-9-(3-(methylsulfonyl)propoxy)-6,7-dihydrodibenzo[b,d]oxepin-2-yl)methoxy)phenyl)cyclopropanecarboxylate




According to the procedures as described in <2-16>, the compound obtained in <14-7> was used to prepare the title compound (white foam, 66 mg, 45% yield).
1H NMR (300 MHz, CDCl3) δ 7.37-7.31 (m, 2H), 7.15 (d, 1H), 7.03 (d, 2H), 6.89 (d, 2H), 6.76 (d, 1H), 6.68 (d, 1H), 5.06 (s, 2H), 4.45-4.37 (m, 2H), 4.22-4.09 (m, 4H), 3.28 (m, 2H), 2.97 (s, 3H), 2.92-2.74 (m, 1H), 2.55-2.33 (m, 4H), 2.31 (s, 3H), 1.82 (m, 1H), 1.55 (m, 1H), 1.28 (t, 3H), 1.25 (m, 1H).
<39-2> Preparation of (1S,2S)-2-(4-((11-methyl-9-(3-(methylsulfonyl)propoxy)-6,7-dihydrodibenzo[b,d]oxepin-2-yl)methoxy)phenyl)cyclopropanecarboxylic acid




According to the procedures as described in <1-11>, the compound obtained in <39-1> was used to prepare the title compound (white foam, 54.6 mg, 85% yield).
MS m/z 535 [M−H]−.
1H NMR (300 MHz, CDCl3) δ 7.37-7.31 (m, 2H), 7.16 (d, 1H), 7.05 (d, 2H), 6.90 (d, 2H), 6.76 (d, 1H), 6.68 (d, 1H), 5.06 (s, 2H), 4.46-4.37 (m, 2H), 4.15 (t, 2H), 3.34-3.22 (m, 2H), 2.97 (s, 3H), 2.91-2.74 (m, 1H), 2.61-2.32 (m, 4H), 2.31 (s, 3H), 1.91-1.78 (m, 1H), 1.60 (m, 1H), 1.42-1.32 (m, 1H).
Example 40
Preparation of (1S,2S)-2-(2-fluoro-4-((11-methyl-9-(3-(methylsulfonyl)propoxy)-6,7-dihydrodibenzo[b,d]oxepin-2-yl)methoxy)phenyl)cyclopropanecarboxylic acid
<40-1> Preparation of (1S,2S)-ethyl 2-(2-fluoro-4-((11-methyl-9-(3-(methylsulfonyl)propoxy)-6,7-dihydrodibenzo[b,d]oxepin-2-yl)methoxy)phenyl)cyclopropanecarboxylate




The compound obtained in <14-7> (98.9 mg, 0.26 mmol), (1S,2S)-ethyl 2-(2-fluoro-4-hydroxyphenyl)cyclopropanecarboxylate (56 mg, 0.267 mmol) and tributylphosphine (97.4 μL, 0.39 mmol) were dissolved in THF (1.73 mL), which was then slowly added with 1,1′-(azodicarbonyl)dipiperidine) (98.4 mg, 0.39 mmol) and stirred at room temperature for 1.5 hours. The mixture thus obtained was concentrated and purified by silica gel chromatography to obtain the title compound (yellow foam, 122.2 mg, 81% yield).
1H NMR (300 MHz, CDCl3) δ 7.37-7.29 (m, 2H), 7.16 (d, 1H), 6.87 (d, 1H), 6.77 (d, 1H), 6.71-6.62 (m, 3H), 5.04 (s, 2H), 4.49-4.36 (m, 2H), 4.23-4.08 (m, 4H), 3.32-3.20 (m, 2H), 2.97 (s, 3H), 2.82 (m, 1H), 2.61-2.44 (m, 2H), 2.43-2.33 (m, 2H), 2.31 (s, 3H), 1.91-1.78 (m, 1H), 1.60-1.49 (m, 1H), 1.33-1.23 (m, 4H).
<40-2> Preparation of (1S,2S)-2-(2-fluoro-4-((11-methyl-9-(3-(methylsulfonyl)propoxy)-6,7-dihydrodibenzo[b,d]oxepin-2-yl)methoxy)phenyl)cyclopropanecarboxylic acid




According to the procedures as described in <1-11>, the compound obtained in <40-1> was used to prepare the title compound (white foam, 119.7 mg, 102% yield).
MS m/z 553 [M−H]−.
1H NMR (300 MHz, CDCl3) δ 7.37-7.29 (m, 2H), 7.16 (d, 1H), 6.88 (d, 1H), 6.77 (d, 1H), 6.71-6.64 (m, 3H), 5.05 (s, 2H), 4.49-4.35 (m, 2H), 4.15 (t, 2H), 3.33-3.21 (m, 2H), 2.97 (s, 3H), 2.83 (m, 1H), 2.62 (m, 1H), 2.50 (m, 1H), 2.38 (m, 2H), 2.31 (s, 3H), 1.91-1.80 (m, 1H), 1.68-1.56 (m, 1H), 1.40 (m, 1H).
Example 41
Preparation of (1S,2S)-2-(4-((9-(3-(ethylsulfonyl)propoxy)-11-methyl-6,7-dihydrodibenzo[b,d]oxepin-2-yl)methoxy)-2-fluorophenyl)cyclopropanecarboxylic acid
<41-1> Preparation of (1S,2S)-ethyl 2-(4-((9-(3-(ethylsulfonyl)propoxy)-11-methyl-6,7-dihydrodibenzo[b,d]oxepin-2-yl)methoxy)-2-fluorophenyl)cyclopropanecarboxylate




According to the procedures as described in <40-1>, the compound obtained in <38-2> was used to prepare the title compound (off-white foam, 81.9 mg, 91.5% yield).
1H NMR (300 MHz, CDCl3) δ 7.37-7.29 (m, 2H), 7.16 (d, 1H), 6.88 (d, 1H), 6.77 (d, 1H), 6.72-6.62 (m, 3H), 5.04 (s, 2H), 4.45-4.39 (m, 2H), 4.25-4.06 (m, 4H), 3.27-3.14 (m, 2H), 3.05 (q, 2H), 2.82 (m, 1H), 2.62-2.44 (m, 2H), 2.43-2.32 (m, 2H), 2.31 (s, 3H), 1.91-1.80 (m, 1H), 1.60-1.50 (m, 1H), 1.45 (t, 3H), 1.27 (m, 4H).
<41-2> Preparation of (1S,2S)-2-(4-((9-(3-(ethylsulfonyl)propoxy)-11-methyl-6,7-dihydrodibenzo[b,d]oxepin-2-yl)methoxy)-2-fluorophenyl)cyclopropanecarboxylic acid




According to the procedures as described in <1-11>, the compound obtained in <41-1> was used to prepare the title compound (white foam, 56.5 mg, 71% yield).
MS m/z 567 [M−H]−.
1H NMR (300 MHz, CDCl3) δ 7.35-7.30 (m, 2H), 7.16 (d, 1H), 6.88 (d, 1H), 6.76 (d, 1H), 6.71-6.65 (m, 3H), 5.05 (s, 2H), 4.47-4.37 (m, 2H), 4.14 (t, 2H), 3.26-3.15 (m, 2H), 3.05 (q, 2H), 2.91-2.75 (m, 1H), 2.64 (m, 1H), 2.52 (m, 1H), 2.34 (m, 2H), 2.31 (s, 3H), 1.85 (m, 1H), 1.67-1.56 (m, 1H), 1.45 (t, 3H), 1.41-1.33 (m, 1H).
Example 42
Preparation of (S)-2-(6-((3-(3-(methylsulfonyl)propoxy)-6,7-dihydrodibenzo[b,d]oxepin-10-yl)methoxy)-2,3-dihydrobenzofuran-3-yl)acetic acid
<42-1> Preparation of (S)-methyl 2-(6-((3-(3-(methylsulfonyl)propoxy)-6,7-dihydrodibenzo[b,d]oxepin-10-yl)methoxy)-2,3-dihydrobenzofuran-3-ylacetate




According to the procedures as described in <1-10>, the compound obtained in <21-10> was used to prepare the title compound (white solid, 42 mg, 65.5% yield).
1H NMR (300 MHz, CDCl3) δ 7.44 (s, 1H), 7.38-7.28 (m, 3H), 7.03 (d, 1H), 6.78 (dd, 1H), 6.69 (d, 1H), 6.56-6.43 (m, 2H), 5.05 (s, 2H), 4.76 (t, 1H), 4.57 (t, 2H), 4.27 (dd, 1H), 4.15 (t, 2H), 3.93-3.75 (m, 1H), 3.72 (s, 3H), 3.38-3.18 (m, 2H), 2.97 (s, 3H), 2.82 (t, 2H), 2.76 (dd, 1H), 2.56 (dd, 1H), 2.47-2.27 (m, 2H).
<42-2> Preparation of (S)-2-(6-((3-(3-(methylsulfonyl)propoxy)-6,7-dihydrodibenzo[b,d]oxepin-10-yl)methoxy)-2,3-dihydrobenzofuran-3-yl)acetic acid




According to the procedures as described in <1-11>, the compound obtained in <42-1> was used to prepare the title compound (white solid, 32 mg, 78.2% yield).
MS m/z 537 [M−H]−.
1H NMR (300 MHz, CDCl3) δ 7.44 (s, 1H), 7.36-7.27 (m, 3H), 7.07 (d, 1H), 6.78 (dd, 1H), 6.69 (d, 1H), 6.54-6.46 (m, 2H), 5.06 (s, 2H), 4.77 (t, 1H), 4.56 (t, 2H), 4.29 (dd, 1H), 4.15 (t, 2H), 3.89-3.75 (m, 1H), 3.28 (m, 2H), 2.97 (s, 3H), 2.87-2.75 (m, 3H), 2.62 (dd, 1H), 2.37 (m, 2H).
Example 43
Preparation of (S)-2-(6-((6,6-dimethyl-9-(3-(methylsulfonyl)propoxy)-6,7-dihydrodibenzo[b,d]oxepin-2-yl)methoxy)-2,3-dihydrobenzofuran-3-yl)acetic acid
<43-1> Preparation of 1-(2-bromo-5-methoxyphenyl)-2-methylpropan-2-ol




A solution of 1-(3-methoxyphenyl)-2-methylpropan-2-ol (prepared in accordance with the reference [Bioorg. Med. Chem. Lett., 2012, vol. 22, p. 1130-1135]; 1.98 g, 10.98 mmol) in CH3CN (50 mL) was added with N-bromosuccinimide (1.95 g, 10.98 mmol) and stirred at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure and purified by silica gel chromatography to obtain the title compound (yellow oil, 1.826 g, 64% yield).
1H NMR (300 MHz, CDCl3) δ 7.45 (d, 1H), 6.91 (d, 1H), 6.68 (dd, 1H), 3.79 (s, 3H), 2.97 (s, 2H), 1.29 (s, 6H).
<43-2> Preparation of methyl 2′-(2-hydroxy-2-methylpropyl)-4′-methoxy-2-(methoxymethoxy)-[1,1′-biphenyl]-4-carboxylate




A solution of the compounds obtained in <43-1> (1.63 g, 6.301 mmol) and <2-6> (2.03 g, 6.301 mmol) in 1,4-dioxane (30 mL) was added with K2CO3 (2.61 g, 18.903 mmol) and substituted with nitrogen. The mixture was added with Pd(dppf)Cl2.MC (257 mg, 0.315 mmol) and allowed to react at 90° C. for 13 hours. The reaction mixture was cooled to room temperature, added with distilled water and brine, and then extracted with EtOAc. The organic layer was dried over MgSO4, concentrated under reduced pressure, and purified by silica gel chromatography to obtain the title compound (yellow oil, 2.25 g, 96% yield).
1H NMR (300 MHz, CDCl3) δ 8.00 (dd, 1H), 7.85 (d, 1H), 7.22 (d, 1H), 7.11 (d, 1H), 6.97 (d, 1H), 6.85 (dd, 1H), 5.21-5.07 (m, 2H), 3.88 (s, 3H), 3.85 (s, 3H), 3.38 (s, 2H), 2.88-2.55 (m, 2H), 1.03 (s, 3H), 0.99 (s, 3H).
<43-3> Preparation of methyl 2-hydroxy-2′-(2-hydroxy-2-methylpropyl)-4′-methoxy-[1,1′-biphenyl]-4-carboxylate




A solution of the compound obtained in <43-2> (2.24 g, 6.780 mmol) in MeOH (35 mL) was added with p-toluenesulfonic acid monohydrate (3.87 g, 20.341 mmol) and stirred at room temperature for 19 hours. The reaction mixture was added with distilled water and neutralized by adding a saturated NaHCO3 aqueous solution. The organic layer extracted with CH2Cl2 was collected, dried over MgSO4, concentrated under reduced pressure, and purified by silica gel chromatography to obtain the title compound (yellow foam, 1.35 g, 68% yield).
1H NMR (300 MHz, CDCl3) δ 7.94 (dd, 1H), 7.79 (d, 1H), 7.14 (d, 1H), 7.00 (d, 1H), 6.97 (d, 1H), 6.89 (dd, 1H), 6.40 (br s, 1H), 3.87 (s, 3H), 3.85 (s, 3H), 2.85-2.52 (m, 2H), 1.12 (s, 6H).
<43-4> Preparation of methyl 9-methoxy-6,6-dimethyl-6,7-dihydrodibenzo[b,d]oxepin-2-carboxylate




A solution of the compound <43-3> (1.35 g, 4.086 mmol) in THF (40 mL) was consecutively added with PBu3 (1.5 mL, 6.129 mmol) and 1,1′-(azodicarbonyl)dipiperidine (1.547 g, 6.129 mmol), and then stirred at room temperature for 1.5 hours. The reaction mixture was concentrated under reduced pressure and purified by silica gel chromatography to obtain the title compound (white foam, 767 mg, 60% yield).
1H NMR (300 MHz, CDCl3) δ 8.11 (d, 1H), 7.96 (dd, 1H), 7.44 (d, 1H), 7.07 (d, 1H), 6.94 (dd, 1H), 6.80 (d, 1H), 3.92 (s, 3H), 3.87 (s, 3H), 2.59 (s, 2H), 1.42 (s, 6H).
<43-5> Preparation of methyl 9-hydroxy-6,6-dimethyl-6,7-dihydrodibenzo[b,d]oxepin-2-carboxylate




To a solution of the compound obtained in <43-4> (784 mg, 2.510 mmol) in CH2Cl2 (20 mL) at 0° C. was slowly added dropwise BBr3 (1.0M CH2Cl2 solution, 4.4 mL, 4.380 mmol). At the same temperature, the mixture was stirred for 2.5 hours and slowly added dropwise with MeOH. Then, the mixture was added with distilled water, extracted with CH2Cl2, and the organic layer was collected and dried over MgSO4. The filtrate was concentrated under reduced pressure and purified by silica gel chromatography to obtain the title compound (white foam, 377 mg, 50% yield).
1H NMR (300 MHz, CDCl3) δ 8.11 (d, 1H), 7.96 (dd, 1H), 7.37 (d, 1H), 7.07 (d, 1H), 6.87 (dd, 1H), 6.75 (d, 1H), 5.11 (s, 1H), 3.93 (s, 3H), 2.56 (s, 2H), 1.42 (s, 6H).
<43-6> Preparation of methyl 6,6-dimethyl-9-(3-(methylsulfonyl)propoxy)-6,7-dihydrodibenzo[b,d]oxepin-2-carboxylate




According to the procedures as described in <1-8>, the compound obtained in <43-5> was used to prepare the title compound (colorless oil, 137 mg, 88% yield).
1H NMR (300 MHz, CDCl3) δ 8.10 (d, 1H), 7.97 (dd, 1H), 7.44 (d, 1H), 7.07 (d, 1H), 6.92 (dd, 1H), 6.78 (d, 1H), 4.18 (t, 2H), 3.92 (s, 3H), 3.34-3.21 (m, 2H), 2.97 (s, 3H), 2.58 (s, 2H), 2.45-2.30 (m, 2H), 1.42 (s, 6H).
<43-7> Preparation of (6,6-dimethyl-9-(3-(methyl sulfonyl)propoxy)-6,7-dihydrodibenzo[b,d]oxepin-2-yl)methanol




According to the procedures as described in <1-9>, the compound obtained in <43-6> was used to prepare the title compound (white foam, 105 mg, 83% yield).
1H NMR (300 MHz, CDCl3) δ 7.40 (s, 1H), 7.38 (d, 1H), 7.27 (d, 1H), 7.02 (d, 1H), 6.88 (dd, 1H), 6.77 (d, 1H), 4.71 (d, 2H), 4.14 (t, 2H), 3.34-3.19 (m, 2H), 2.95 (s, 3H), 2.55 (s, 2H), 2.46-2.23 (m, 2H), 1.91 (t, 1H), 1.40 (s, 6H).
<43-8> Preparation of (S)-methyl 2-(6-((6,6-dimethyl-9-(3-(methylsulfonyl)propoxy)-6,7-dihydrodibenzo[b,d]oxepin-2-yl)methoxy)-2,3-dihydrobenzofuran-3-ylacetate




According to the procedures as described in <1-10>, the compound obtained in <43-7> was used to prepare the title compound (colorless oil, 141 mg, 90% yield).
1H NMR (300 MHz, CDCl3) δ 7.44 (d, 1H), 7.39 (d, 1H), 7.33 (dd, 1H), 7.04 (dd, 2H), 6.89 (dd, 1H), 6.78 (d, 1H), 6.57-6.41 (m, 2H), 5.02 (s, 2H), 4.76 (t, 1H), 4.27 (dd, 1H), 4.17 (t, 2H), 3.91-3.75 (m, 1H), 3.72 (s, 3H), 3.39-3.20 (m, 2H), 2.97 (d, 3H), 2.76 (dd, 1H), 2.65-2.47 (m, 3H), 2.47-2.27 (m, 2H), 1.41 (s, 6H).
<43-9> Preparation of (S)-2-(6-((6,6-dimethyl-9-(3-(methylsulfonyl)propoxy)-6,7-dihydrodibenzo[b,d]oxepin-2-yl)methoxy)-2,3-dihydrobenzofuran-3-yl)acetic acid




According to the procedures as described in <1-11>, the compound obtained in <43-8> was used to prepare the title compound (white foam, 126 mg, 92% yield).
MS m/z 565 [M−H]−.
1H NMR (300 MHz, CDCl3) δ 7.44 (d, 1H), 7.39 (d, 1H), 7.33 (dd, 1H), 7.09-7.02 (m, 2H), 6.89 (dd, 1H), 6.78 (d, 2H), 6.56-6.42 (m, 2H), 5.03 (s, 2H), 4.77 (t, 1H), 4.30 (dd, 1H), 4.17 (t, 2H), 3.82 (m, 1H), 3.36-3.21 (m, 2H), 2.97 (s, 3H), 2.82 (dd, 1H), 2.63 (dd, 1H), 2.57 (s, 2H), 2.45-2.29 (m, 2H), 1.41 (s, 6H).
Example 44
Preparation of (S)-2-(6-((5-ethyl-9-(3-(methylsulfonyl)propoxy)-6,7-dihydro-5H-dibenzo[b,d]azepin-2-yl)methoxy)-2,3-dihydrobenzofuran-3-yl)acetic acid
<44-1> Preparation of ethyl 3-bromo-4-nitrobenzoate




Ethyl 4-amino-3-bromobenzoate (prepared in accordance with the reference [Journal of the American Chemical Society, 2002, vol. 124, p. 5350-5364]; 2.20 g, 9.01 mmol) was dissolved in CF3CO2H (40 mL), which was then added with hydrogen peroxide (5.67 mL, 30% aqueous solution, 50.0 mmol) and stirred for 15 hours at 60° C. The reaction mixture was concentrated, diluted with EtOAc, washed with 2N NaOH aqueous solution, NaHCO3 aqueous solution and brine. The organic layer was dried over magnesium sulfate, concentrated under reduced pressure. The residue thus obtained was purified by silica gel chromatography to obtain the title compound (pale yellow solid, 1.94 g, 79% yield).
1H NMR (600 MHz, CDCl3) δ 8.39 (s, 1H), 8.10 (d, 1H), 7.85 (d, 1H), 4.44 (q, 2H), 1.43 (t, 3H).
<44-2> Preparation of ethyl 4-nitro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaboran-2-yl)benzoate




The compound obtained in <44-1> (820 mg, 2.99 mmol) and bis(pinacolato)diboron (1.14 g, 4.49 mmol) were dissolved in 1,4-dioxane (16 mL). The mixture was added with potassium acetate (881 mg, 8.89 mmol) and [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) complex with dichloromethane (122 mg, 0.15 mmol), and then substituted with nitrogen. The mixture was stirred at 90° C. for 15 hours, cooled to room temperature and diluted with brine. Then, the mixture was extracted with EtOAc, dried over magnesium sulfate, filtered and concentrated under reduced pressure. The residue thus obtained was purified by silica gel chromatography to obtain the title compound (pale yellow solid, 610 mg, 64% yield).
1H NMR (600 MHz, CDCl3) δδ8.21-8.18 (m, 3H), 4.44 (q, 2H), 1.44 (s, 12H), 1.42 (t, 3H).
<44-3> Preparation of ethyl 2′-(2-hydroxyethyl)-4′-methoxy-2-nitro-[1,1′-biphenyl]-4-carboxylate




The compound obtained in <44-2> (432 mg, 1.87 mmol) and the compound obtained in <2-2> (600 mg, 1.87 mmol) were dissolved in 1,4-dioxane (8 mL), which was then added with K2CO3 (775 g, 5.61 mmol) and substituted with nitrogen. Subsequently, the mixture was added with [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) complex with dichloromethane (76 mg, 0.093 mmol) and stirred at 90° C. for 15 hours. The reaction mixture was cooled room temperature, added with a saturated NH4Cl aqueous solution, and extracted with EtOAc. The organic layer was washed with brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. The filtrate thus obtained was purified by silica gel chromatography to obtain the title compound (pale brown oil, 379 mg, 59% yield).
1H NMR (600 MHz, CDCl3) δ 8.16 (d, 1H), 8.04 (s, 1H), 7.94 (d, 1H), 7.03 (d, 1H), 6.92 (s, 1H), 6.82 (dd, 1H), 4.44-4.40 (m, 2H), 3.85 (s, 3H), 3.70 (q, 2H), 2.81-2.76 (m, 1H), 2.69-2.65 (m, 1H), 1.47 (t, 1H), 1.41 (t, 3H).
<44-4> Preparation of ethyl 2′-(2-bromoethyl)-4′-methoxy-2-nitro-[1,1′-biphenyl]-4-carboxylate




The compound obtained in <44-3> (370 mg, 1.07 mmol) was dissolved in dichloromethane (5 mL), which was then added with triphenylphosphine (463 mg, 1.77 mmol), pyridine (0.51 mL, 6.21 mmol), and tetrabromomethane (532 mg, 1.61 mmol) at 0° C. The reaction mixture was stirred at room temperature for 5 hours, concentrated under reduced pressure and purified by silica gel chromatography to obtain the title compound (pale yellow oil, 405 mg, 93% yield).
1H NMR (600 MHz, CDCl3) δ 8.18 (d, 1H), 8.04 (s, 1H), 7.96 (d, 1H), 7.03 (d, 1H), 6.89 (s, 1H), 6.83 (dd, 1H), 4.45-4.41 (m, 2H), 3.85 (s, 3H), 3.42 (t, 2H), 3.07-3.03 (m, 1H), 2.93-2.88 (m, 1H), 1.41 (t, 3H).
<44-5> Preparation of ethyl 9-methoxy-6,7-dihydro-5H-dibenzo[b,d]azepin-2-carboxylate




The compound obtained in <44-4> (400 mg, 0.98 mmol) was dissolved in methanol (5 mL), which was then added with 10% Pd/C (40 mg, 0.38 mmol) and stirred under a hydrogen atmosphere for 15 hours. The reaction mixture was filtered through Celite, washed with EtOAc, and the resulting filtrate was concentrated under reduced pressure. The residue thus obtained was purified by silica gel chromatography to obtain the title compound (white foam, 179 mg, 61% yield).
1H NMR (600 MHz, CDCl3) δ 8.04 (s, 1H), 7.79 (d, 1H), 7.43 (d, 1H), 6.90 (d, 1H), 6.74 (d, 1H), 6.68 (d, 1H), 4.36 (q, 2H), 3.85 (s, 3H), 3.80 (t, 2H), 2.89 (t, 2H), 1.38 (t, 3H).
<44-6> Preparation of ethyl 5-ethyl-9-methoxy-6,7-dihydro-5H-dibenzo[b,d]azepin-2-carboxylate




The compound obtained in <44-5> (35 mg, 0.118 mmol) was dissolved in DMF (1 mL), which was then slowly added with NaH (7.06 mg, 0.177 mmol) at 0° C. and stirred for 30 minutes. The mixture thus obtained was slowly added with iodoethane (14 μL, 0.177 mmol) and stirred at room temperature for 3 hours. The reaction mixture was added with water at 0° C. and extracted with EtOAc. The organic layer was dried over magnesium sulfate, and the resulting filtrate was concentrated under reduced pressure. The residue thus obtained was purified by silica gel chromatography to obtain the title compound (colorless oil, 19 mg, 50% yield).
1H NMR (600 MHz, CDCl3) δ 7.96-7.93 (m, 2H), 7.34 (d, 1H), 7.01 (d, 1H), 6.90 (d, 1H), 6.79 (d, 1H), 4.36 (q, 2H), 3.86 (s, 1H), 3.54 (t, 2H), 3.17 (q, 2H), 2.72 (t, 2H), 1.38 (t, 3H), 1.09 (t, 3H).
<44-7> Preparation of ethyl 5-ethyl-9-hydroxy-6,7-dihydro-5H-dibenzo[b,d]azepin-2-carboxylate




According to the procedures as described in <1-7>, the compound obtained in <44-6> was used to prepare the title compound (white foam, 90 mg, 42% yield).
1H NMR (600 MHz, CDCl3) δ 7.96-7.93 (m, 2H), 7.28 (d, 1H), 7.01 (d, 1H), 6.83 (d, 1H), 6.73 (d, 1H), 5.01 (s, 1H), 4.38 (q, 2H), 3.53 (t, 2H), 3.17 (q, 2H), 2.69 (t, 2H), 1.39 (t, 3H), 1.10 (t, 3H).
<44-8> Preparation of ethyl 5-ethyl-9-(3-(methylsulfonyl)propoxy)-6,7-dihydro-5H-dibenzo[b,d]azepin-2-carboxylate




According to the procedures as described in <1-8>, the compound obtained in <44-7> was used to prepare the title compound (white foam, 329 mg, 85% yield).
1H NMR (600 MHz, CDCl3) δ 7.95-7.93 (m, 2H), 7.34-7.32 (m, 1H), 7.02 (d, 1H), 6.87 (dd, 1H), 6.77 (d, 1H), 4.37 (q, 1H), 4.17 (t, 2H), 3.55-3.52 (m, 2H), 3.29 (t, 2H), 3.17 (q, 2H), 2.97 (s, 3H), 2.72 (t, 2H), 2.37-2.35 (m, 2H), 1.38 (t, 3H), 1.09 (t, 3H).
<44-9> Preparation of (5-ethyl-9-(3-(methylsulfonyl)propoxy)-6,7-dihydro-5H-dibenzo[b,d]azepin-2-yl)methanol




According to the procedures as described in <1-9>, the compound obtained in <44-8> was used to prepare the title compound (white foam, 229 mg, 80% yield).
1H NMR (600 MHz, CDCl3) δ 7.31-7.29 (m, 3H), 7.04 (d, 1H), 6.86 (dd, 1H), 6.78 (d, 1H), 4.68 (d, 2H), 4.16 (t, 2H), 4.43 (t, 2H), 3.28 (t, 2H), 3.10 (q, 2H), 2.97 (s, 3H), 2.65 (t, 2H), 2.39-2.36 (m, 2H), 1.61 (t, 1H), 1.04 (t, 3H).
<44-10> Preparation of (S)-methyl 2-(6-((5-ethyl-9-(3-(methylsulfonyl)propoxy)-6,7-dihydro-5H-dibenzo[b,d]azepin-2-yl)methoxy)-2,3-dihydrobenzofuran-3-ylacetate




According to the procedures as described in <1-10>, the compound obtained in <44-9> was used to prepare the title compound (white foam, 33 mg, 22% yield).
1H NMR (600 MHz, CDCl3) δ 7.34-7.32 (m, 2H), 7.29 (d, 1H), 7.03 (d, 1H), 6.85 (dd, 1H), 6.77 (d, 1H), 6.50 (d, 1H), 6.48 (s, 1H), 4.98 (s, 2H), 4.75 (t, 2H), 4.26 (dd, 1H), 4.14 (t, 2H), 3.83-3.78 (m, 1H), 3.71 (s, 3H), 3.42 (t, 2H), 3.27 (t, 2H), 3.09 (q, 2H), 2.97 (s, 3H), 2.75 (dd, 1H), 2.65 (t, 2H), 2.55 (dd, 1H), 2.38-2.33 (m, 2H), 1.03 (t, 3H).
<44-11> Preparation of (S)-2-(6-((5-ethyl-9-(3-(methylsulfonyl)propoxy)-6,7-dihydro-5H-dibenzo[b,d]azepin-2-yl)methoxy)-2,3-dihydrobenzofuran-3-yl)acetic acid




According to the procedures as described in <1-11>, the compound obtained in <44-10> was used to prepare the title compound (white foam, 58 mg, 92% yield).
MS m/z 565 [M−H]−.
1H NMR (600 MHz, CDCl3) δ 7.35-7.34 (m, 2H), 7.30 (d, 1H), 7.05 (d, 2H), 6.85 (dd, 1H), 6.78 (d, 1H), 6.52 (d, 1H), 6.50 (s, 1H), 4.99 (s, 2H), 4.77 (t, 2H), 4.29 (dd, 1H), 4.16 (t, 2H), 3.83-3.80 (m, 1H), 3.45 (s, 3H), 3.28 (t, 2H), 3.10 (q, 2H), 2.97 (s, 3H), 2.80 (dd, 1H), 2.66 (t, 2H), 2.60 (dd, 1H), 2.39-2.35 (m, 2H), 1.75-1.70 (m, 1H), 1.57-1.53 (m, 1H), 1.43-1.39 (m, 1H), 1.04 (t, 3H).
Example 45
Preparation of (1S,2S)-2-(4-((5-ethyl-9-(3-(methylsulfonyl)propoxy)-6,7-dihydro-5H-dibenzo[b,d]azepin-2-yl)methoxy)phenyl)cyclopropanecarboxylic acid
<45-1> Preparation of (1S,2S)-ethyl 2-(4-((5-ethyl-9-(3-(methylsulfonyl)propoxy)-6,7-dihydro-5H-dibenzo[b,d]azepin-2-yl)methoxy)phenyl)cyclopropanecarboxylate




According to the procedures as described in <2-16>, the compound obtained in <44-9> was used to prepare the title compound (white foam, 98 mg, 55% yield).
1H NMR (600 MHz, CDCl3) δ 7.35-7.34 (m, 2H), 7.30 (d, 1H), 7.04 (d, 3H), 6.91 (d, 2H), 6.85 (dd, 1H), 6.79 (d, 1H), 5.01 (s, 2H), 4.18-4.14 (m, 4H), 3.42 (t, 2H), 3.28 (t, 2H), 3.09 (q, 2H), 2.97 (s, 3H), 2.66 (t, 2H), 2.50-2.46 (m, 1H), 2.39-2.35 (m, 2H), 1.84-1.81 (m, 1H), 1.57-1.54 (m, 2H), 1.29-1.25 (m, 5H), 1.04 (t, 3H).
<45-2> Preparation of (1S,2S)-2-(4-((5-ethyl-9-(3-(methylsulfonyl)propoxy)-6,7-dihydro-5H-dibenzo[b,d]azepin-2-yl)methoxy)phenyl)cyclopropanecarboxylic acid




According to the procedures as described in <1-11>, the compound obtained in <45-1> was used to prepare the title compound (white foam, 69 mg, 77% yield).
MS m/z 549 [M−H]−.
1H NMR (600 MHz, CDCl3) δ 7.34-7.33 (m, 2H), 7.28 (d, 1H), 7.05-7.02 (m, 3H), 6.92 (d, 2H), 6.84 (dd, 1H), 6.78 (d, 1H), 5.01 (s, 2H), 4.14 (t, 4H), 3.42 (t, 2H), 3.27 (t, 2H), 3.08 (q, 2H), 2.96 (s, 3H), 2.66 (t, 2H), 2.57-2.54 (m, 1H), 2.38-2.33 (m, 2H), 1.84-1.81 (m, 1H), 1.62-1.59 (m, 1H), 1.36-1.33 (m, 1H), 1.03 (t, 3H).
Example 46
Preparation of 2-((3S)-6-((9-((4-hydroxy-1,1-dioxidotetrahydro-2H-thiopyran-4-yl)methoxy)-11-methyl-6,7-dihydrodibenzo[b,d]oxepin-2-yl)methoxy)-2,3-dihydrobenzofuran-3-yl)acetic acid
<46-1> Preparation of methyl 9-((4-hydroxytetrahydro-2H-thiopyran-4-yl)methoxy)-11-methyl-6,7-dihydrodibenzo[b,d]oxepin-2-carboxylate




The compound obtained in <14-5> (105.6 mg, 0.37 mmol) was dissolved in DMF (4 mL), which was then added with 1-oxa-6-thiaspiro[2.5]octane 6,6-dioxide (49.3 mg, 0.38 mmol) and K2CO3 (77 mg, 0.56 mmol), followed by stirring at 90° C. for 12 hours. The reaction mixture was cooled to room temperature, diluted with EtOAc, and washed with a saturated NH4Cl aqueous solution and brine. The organic layer was dried over Na2SO4, concentrated under reduced pressure, and the residue thus obtained was purified by silica gel chromatography to obtain the title compound (colorless oil, 50.7 mg, 33% yield).
1H NMR (300 MHz, CDCl3) δ 8.05 (d, 1H), 7.98 (dd, 1H), 7.18 (d, 1H), 6.81 (d, 1H), 6.70 (d, 1H), 4.52-4.42 (m, 2H), 3.92 (s, 3H), 3.82 (s, 2H), 3.11 (m, 2H), 2.88-2.72 (m, 1H), 2.50 (m, 3H), 2.37 (s, 3H), 2.10 (m, 2H), 1.84 (m, 2H)
<46-2> Preparation of methyl 9-((4-hydroxy-1,1-dioxidotetrahydro-2H-thiopyran-4-yl)methoxy)-11-methyl-6,7-dihydrodibenzo[b,d]oxepin-2-carboxylate




According to the procedures as described in <36-2>, the compound obtained in <46-1> was used to prepare the title compound (white foam, 84.6 mg, 92% yield).
1H NMR (300 MHz, CDCl3) δ 8.02 (d, 1H), 7.99 (dd, 1H), 7.19 (d, 1H), 6.81 (d, 1H), 6.70 (d, 1H), 4.50-4.45 (m, 2H), 3.92 (s, 3H), 3.91 (s, 2H), 3.50 (m, 2H), 2.96 (m, 2H), 2.83 (m, 1H), 2.52 (m, 1H), 2.38 (s, 3H), 2.27 (m, 4H)
<46-3> Preparation of 4-hydroxy-4-(((2-(hydroxymethyl)-11-methyl-6,7-dihydrodibenzo[b,d]oxepin-9-yl)oxy)methyl)tetrahydro-2H-thiopyran 1,1-dioxide




According to the procedures as described in <1-9>, the compound obtained in <46-2> was used to prepare the title compound (white foam, 83.9 mg, 106% yield).
1H NMR (300 MHz, CDCl3) δ 7.32 (d, 1H), 7.30 (dd, 1H), 7.14 (d, 1H), 6.79 (d, 1H), 6.71 (d, 1H), 4.71 (d, 2H), 4.40 (m, 2H), 3.90 (s, 2H), 3.55-3.45 (m, 2H), 2.96 (m, 2H), 2.88-2.77 (m, 1H), 2.48 (m, 1H), 2.38 (s, 3H), 2.28 (m, 4H), 1.68 (t, 1H)
<46-4> Preparation of methyl 2-((3S)-6-((9-((4-hydroxy-1,1-dioxidotetrahydro-2H-thiopyran-4-yl)methoxy)-11-methyl-6,7-dihydrodibenzo[b,d]oxepin-2-yl)methoxy)-2,3-dihydrobenzofuran-3-ylacetate




According to the procedures as described in <1-10>, the compound obtained in <46-3> was used to prepare the title compound (colorless oil, 45.2 mg, 69% yield).
1H NMR (300 MHz, CDCl3) δ 7.35 (dd, 1H), 7.33 (d, 1H), 7.15 (d, 1H), 7.02 (d, 1H), 6.78 (d, 1H), 6.70 (d, 1H), 6.48 (dd, 1H), 6.46 (d, 1H), 5.04 (s, 2H), 4.75 (t, 1H), 4.41 (m, 2H), 4.26 (dd, 1H), 3.90 (s, 2H), 3.81 (m, 1H), 3.72 (s, 3H), 3.55-3.45 (m, 2H), 2.95 (m, 2H), 2.84 (m, 1H), 2.75 (dd, 1H), 2.55 (dd, 1H), 2.49 (m, 1H), 2.32 (s, 3H), 2.26 (m, 4H).
<46-5> Preparation of 2-((3S)-6-((9-((4-hydroxy-1,1-dioxidotetrahydro-2H-thiopyran-4-yl)methoxy)-11-methyl-6,7-dihydrodibenzo[b,d]oxepin-2-yl)methoxy)-2,3-dihydrobenzofuran-3-yl)acetic acid




According to the procedures as described in <1-11>, the compound obtained in <46-4> was used to prepare the title compound (white foam, 20.1 mg, 46% yield).
MS m/z 593 [M−H]−.
1H NMR (600 MHz, CDCl3) δ 7.34 (dd, 1H), 7.33 (d, 1H), 7.15 (d, 1H), 7.06 (d, 1H), 6.78 (d, 1H), 6.70 (d, 1H), 6.49 (dd, 1H), 6.46 (d, 1H), 5.04 (s, 2H), 4.77 (t, 1H), 4.41 (m, 2H), 4.29 (dd, 1H), 3.90 (s, 2H), 3.79 (m, 1H), 3.55-3.44 (m, 2H), 2.95 (m, 2H), 2.85 (m, 1H), 2.80 (dd, 1H), 2.61 (dd, 1H), 2.49 (m, 1H), 2.32 (s, 3H), 2.26 (m, 4H)
Example 47
Preparation of 2-((3S)-6-((9-((1,1-dioxidotetrahydro-2H-thiopyran-4-yl)methoxy)-11-methyl-6,7-dihydrodibenzo[b,d]oxepin-2-yl)methoxy)-2,3-dihydrobenzofuran-3-yl)acetic acid
<47-1> Preparation of methyl 9-((1,1-dioxidotetrahydro-2H-thiopyran-4-yl)methoxy)-11-methyl-6,7-dihydrodibenzo[b,d]oxepin-2-carboxylate




A solution of the compound obtained in <14-5> (80 mg, 0.28 mmol) and (1,1-dioxidotetrahydro-2H-thiopyran-4-yl)methyl 4-methylbenzenesulfonate (prepared in accordance with the reference [Bioorganic and Medicinal Chemistry Letters, 2011, vol. 21, p. 1748-1753]; 108 mg, 0.34 mmol) in DMF (1 mL) was added with K2CO3 (50 mg, 0.36 mmol), followed by stirring at 90° C. for 14 hours. The reaction mixture was cooled to room temperature, added with distilled water, and extracted with EtOAc. The organic layer was dried over MgSO4. The filtrate thus obtained was concentrated under reduced pressure and purified by silica gel chromatography (white foam, 133 mg, 110% yield).
1H NMR (300 MHz, CDCl3) δ 8.05-7.96 (m, 2H), 7.18 (d, 1H), 6.78 (d, 1H), 6.67 (d, 1H), 4.55-4.43 (m, 2H), 3.94-3.86 (m, 4H), 3.21-2.98 (m, 4H), 2.81 (m, 1H), 2.51 (m, 1H), 2.37 (s, 3H), 2.36-2.26 (m, 2H), 2.18-2.01 (m, 3H).
<47-2> Preparation of 4-(((2-(hydroxymethyl)-11-methyl-6,7-dihydrodibenzo[b,d]oxepin-9-yl)oxy)methyl)tetrahydro-2H-thiopyran 1,1-dioxide




According to the procedures as described in <1-9>, the compound obtained in <47-1> was used to prepare the title compound (white foam, 57.3 mg, 51% yield).
1H NMR (300 MHz, CDCl3) δ 7.34-7.28 (m, 2H), 7.14 (d, 1H), 6.76 (d, 1H), 6.68 (d, 1H), 5.30 (s, 2H), 4.72 (d, 2H), 4.46-4.37 (m, 2H), 3.92 (d, 2H), 3.21-2.98 (m, 4H), 2.81 (m, 1H), 2.49 (m, 1H), 2.38 (s, 3H), 2.36-2.27 (m, 2H), 2.13-1.96 (m, 3H), 1.64 (t, 1H).
<47-3> Preparation of methyl 2-((3S)-6-((9-((1,1-dioxidotetrahydro-2H-thiopyran-4-yl)methoxy)-11-methyl-6,7-dihydrodibenzo[b,d]oxepin-2-yl)methoxy)-2,3-dihydrobenzofuran-3-ylacetate




According to the procedures as described in <1-10>, the compound obtained in <47-2> was used to prepare the title compound (white foam, 71 mg, 85% yield).
1H NMR (300 MHz, CDCl3) δ 7.37-7.31 (m, 2H), 7.15 (d, 1H), 7.03 (d, 1H), 6.75 (d, 1H), 6.68 (d, 1H), 6.51-6.45 (m, 2H), 5.04 (s, 2H), 4.76 (t, 1H), 4.49-4.36 (m, 2H), 4.27 (dd, 1H), 3.90 (d, 2H), 3.81 (m, 1H), 3.72 (s, 3H), 3.22-2.98 (m, 4H), 2.83 (m, 1H), 2.75 (dd, 1H), 2.62-2.44 (m, 2H), 2.38-2.25 (m, 5H), 2.14-1.96 (m, 3H).
<47-4> Preparation of 2-((3S)-6-((9-((1,1-dioxidotetrahydro-2H-thiopyran-4-yl)methoxy)-11-methyl-6,7-dihydrodibenzo[b,d]oxepin-2-yl)methoxy)-2,3-dihydrobenzofuran-3-yl)acetic acid




According to the procedures as described in <1-11>, the compound obtained in <47-3> was used to prepare the title compound (white foam, 47.9 mg, 69% yield).
MS m/z 577 [M−H]−.
1H NMR (300 MHz, CDCl3) δ 7.37-7.30 (m, 2H), 7.15 (d, 1H), 7.06 (d, 1H), 6.75 (d, 1H), 6.68 (d, 1H), 6.53-6.44 (m, 2H), 5.04 (s, 2H), 4.76 (t, 1H), 4.46-4.35 (m, 2H), 4.29 (d, 1H), 3.91 (d, 2H), 3.81 (m, 1H), 3.20-2.95 (m, 4H), 2.94-2.73 (m, 2H), 2.62 (dd, 1H), 2.48 (m, 1H), 2.38-2.23 (m, 5H), 2.13-1.95 (m, 3H).
Example 48
Preparation of (1S,2S)-2-(4-((9-((1,1-dioxidotetrahydro-2H-thiopyran-4-yl)oxy)-11-methyl-6,7-dihydrodibenzo[b,d]oxepin-2-yl)methoxy)phenyl)cyclopropanecarboxylic acid
<48-1> Preparation of (1S,2S)-ethyl 2-(4-((9-((1,1-dioxidotetrahydro-2H-thiopyran-4-yl)oxy)-11-methyl-6,7-dihydrodibenzo[b,d]oxepin-2-yl)methoxy)phenyl)cyclopropanecarboxylate




According to the procedures as described in <2-16>, the compound obtained in <36-3> was used to prepare the title compound (white foam, 42.0 mg, 52% yield).
1H NMR (300 MHz, CDCl3) δ 7.38-7.32 (m, 2H), 7.16 (d, 1H), 7.03 (d, 2H), 6.89 (d, 2H), 6.79 (d, 1H), 6.72 (d, 1H), 5.06 (s, 2H), 4.70 (m, 1H), 4.46-4.37 (m, 2H), 4.16 (q, 2H), 3.45 (m, 2H), 3.01-2.74 (m, 3H), 2.60-2.26 (m, 9H), 1.82 (m, 1H), 1.56 (m, 1H), 1.33-1.20 (m, 4H).
<48-2> Preparation of (1S,2S)-2-(4-((9-((1,1-dioxidotetrahydro-2H-thiopyran-4-yl)oxy)-11-methyl-6,7-dihydrodibenzo[b,d]oxepin-2-yl)methoxy)phenyl)cyclopropanecarboxylic acid




According to the procedures as described in <1-11>, the compound obtained in <48-1> was used to prepare the title compound (white foam, 36.6 mg, 91% yield).
MS m/z 571 [M+Na]+.
1H NMR (300 MHz, CDCl3) δ 7.38-7.31 (m, 2H), 7.16 (d, 1H), 7.05 (d, 2H), 6.90 (d, 2H), 6.80 (d, 1H), 6.72 (d, 1H), 5.07 (s, 2H), 4.70 (m, 1H), 4.42 (m, 2H), 3.44 (m, 2H), 3.00-2.75 (m, 3H), 2.61-2.27 (m, 9H), 1.83 (m, 1H), 1.69-1.56 (m, 1H), 1.36 (m, 1H).
Example 49
Preparation of (1S,2S)-2-(4-((9-(3-(ethylsulfonyl)propoxy)-11-methyl-6,7-dihydrodibenzo[b,d]oxepin-2-yl)methoxy)phenyl)cyclopropanecarboxylic acid
<49-1> Preparation of (1S,2S)-ethyl 2-(4-((9-(3-(ethylsulfonyl)propoxy)-11-methyl-6,7-dihydrodibenzo[b,d]oxepin-2-yl)methoxy)phenyl)cyclopropanecarboxylate




According to the procedures as described in <2-16>, the compound obtained in <38-2> was used to prepare the title compound (white foam, 105.8 mg, 76% yield).
1H NMR (300 MHz, CDCl3) δ 7.37-7.31 (m, 2H), 7.15 (d, 1H), 7.03 (d, 2H), 6.89 (d, 2H), 6.76 (d, 1H), 6.68 (d, 1H), 5.06 (s, 2H), 4.41 (d, 2H), 4.21-4.06 (m, 4H), 3.27-3.14 (m, 2H), 3.05 (q, 2H), 2.82 (m, 1H), 2.53-2.43 (m, 2H), 2.40-2.28 (m, 5H) 1.87-1.76 (m, 1H), 1.61-1.49 (m, 1H), 1.44 (t, 3H), 1.32-1.19 (m, 4H).
<49-2> Preparation of (1S,2S)-2-(4-((9-(3-(ethylsulfonyl)propoxy)-11-methyl-6,7-dihydrodibenzo[b,d]oxepin-2-yl)methoxy)phenyl)cyclopropanecarboxylic acid




According to the procedures as described in <1-11>, the compound obtained in <49-1> was used to prepare the title compound (white foam, 85.8 mg, 92% yield).
MS m/z 573 [M+Na]+.
1H NMR (300 MHz, CDCl3) δ 7.39-7.30 (m, 2H), 7.15 (d, 1H), 7.04 (d, 2H), 6.90 (d, 2H), 6.76 (d, 1H), 6.68 (d, 1H), 5.06 (s, 2H), 4.41 (m, 2H), 4.14 (q, 2H), 3.26-3.13 (m, 2H), 3.05 (q, 2H), 2.82 (m, 1H), 2.63-2.43 (m, 2H), 2.43-2.25 (m, 5H), 1.89-1.76 (m, 1H), 1.69-1.56 (m, 1H), 1.44 (t, 3H), 1.35 (m, 1H).
Example 50
Preparation of (1S,2S)-2-(4-((9-((1,1-dioxidotetrahydro-2H-thiopyran-4-yl)oxy)-11-methyl-6,7-dihydrodibenzo[b,d]oxepin-2-yl)methoxy)-2-fluorophenyl)cyclopropanecarboxylic acid
<50-1> Preparation of (1S,2S)-ethyl 2-(4-((9-((1,1-dioxidotetrahydro-2H-thiopyran-4-yl)oxy)-11-methyl-6,7-dihydrodibenzo[b,d]oxepin-2-yl)methoxy)-2-fluorophenyl)cyclopropanecarboxylate




According to the procedures as described in <40-1>, the compound obtained in <36-3> was used to prepare the title compound (white foam, 38.2 mg, 76% yield).
1H NMR (300 MHz, CDCl3) δ 7.37-7.31 (m, 2H), 7.17 (d, 1H), 6.88 (d, 1H), 6.80 (d, 1H), 6.72 (d, 1H), 6.70-6.63 (m, 2H), 5.05 (s, 2H), 4.69 (m, 1H), 4.42 (m, 2H), 4.16 (q, 2H), 3.45 (m, 2H), 3.01-2.78 (m, 3H), 2.60-2.27 (m, 9H), 1.84 (m, 1H), 1.60-1.51 (m, 1H), 1.33-1.22 (m, 3H).
<50-2> Preparation of (1S,2S)-2-(4-((9-((1,1-dioxidotetrahydro-2H-thiopyran-4-yl)oxy)-11-methyl-6,7-dihydrodibenzo[b,d]oxepin-2-yl)methoxy)-2-fluorophenyl)cyclopropanecarboxylic acid




According to the procedures as described in <1-11>, the compound obtained in <50-1> was used to prepare the title compound (white foam, 31.9 mg, 88% yield).
MS m/z 565 [M−H]−.
1H NMR (300 MHz, CDCl3) δ 7.37-7.30 (m, 2H), 7.17 (d, 1H), 6.88 (d, 1H), 6.80 (d, 1H), 6.72 (d, 1H), 6.74-6.64 (m, 2H), 5.05 (s, 2H), 4.70 (m, 1H), 4.42 (m, 2H), 3.44 (m, 2H), 2.95 (m, 2H), 2.90-2.76 (m, 1H), 2.68-2.59 (m, 1H), 2.57-2.26 (m, 8H), 1.85 (m, 1H), 1.61 (m, 1H), 1.37 (m, 1H).
Example 51
Preparation of (1S,2S)-2-{2-fluoro-4-[9-(4-hydroxy-1,1-dioxido-hexahydro-thiopyran-4-ylmethoxy)-11-methyl-6,7-dihydro-5-oxa-dibenzo[a,c]cyclohepten-2-ylmethoxy]-phenyl}-cyclopropanecarboxylic acid
<51-1> Preparation of (1S,2S)-ethyl 2-{2-fluoro-4-[9-(4-hydroxy-1,1-dioxido-hexahydro-thiopyran-4-ylmethoxy)-11-methyl-6,7-dihydro-5-oxa-dibenzo[a,c]cyclohepten-2-ylmethoxyl]-phenyl}-cyclopropanecarboxylate




According to the procedures as described in <40-1>, the compound obtained in <46-3> was used to prepare the title compound (colorless oil, 16.3 mg, 28% yield).
1H NMR (300 MHz, CDCl3) δ 7.34 (dd, 1H), 7.32 (d, 1H), 7.16 (d, 1H), 7.02 (d, 1H), 6.88 (t, 1H), 6.79 (d, 1H), 6.70 (m, 2H), 6.65 (m, 1H), 5.05 (s, 2H), 4.42 (m, 2H), 4.12 (q, 2H), 3.91 (s, 2H), 3.49 (m, 2H), 2.96 (m, 2H), 2.85 (m, 1H), 2.56 (m, 1H), 2.50 (m, 1H), 2.31 (s, 3H), 2.27 (m, 4H), 1.85 (m, 1H), 1.29 (t, 3H), 1.25 (m, 1H).
<51-2> Preparation of (1S,2S)-2-{2-fluoro-4-[9-(4-hydroxy-1,1-dioxido-hexahydro-thiopyran-4-ylmethoxy)-11-methyl-6,7-dihydro-5-oxa-dibenzo[a,c]cyclohepten-2-ylmethoxyl]-phenyl}-cyclopropanecarboxylic acid




According to the procedures as described in <1-11>, the compound obtained in <51-1> was used to prepare the title compound (white foam, 3.9 mg, 25% yield).
MS m/z 595 [M−H]−.
1H NMR (300 MHz, CDCl3) δ 7.34 (dd, 1H), 7.32 (d, 1H), 7.16 (d, 1H), 7.02 (d, 1H), 6.89 (t, 1H), 6.79 (d, 1H), 6.70 (m, 2H), 6.65 (m, 1H), 5.05 (s, 2H), 4.42 (m, 2H), 3.90 (s, 2H), 3.49 (m, 2H), 2.96 (m, 2H), 2.84 (m, 1H), 2.49 (m, 1H), 2.31 (s, 3H), 2.27 (m, 4H), 1.85 (m, 1H), 1.57 (m, 1H), 1.37 (m, 1H).
Example 52
Preparation of (1S,2S)-2-(4-(((9-((1,1-dioxidotetrahydro-2H-thiopyran-4-yl)oxy)-11-methyl-6,7-dihydrodibenzo[b,d]oxepin-2-yl)methyl)amino)-2-fluorophenyl)cyclopropanecarboxylic acid
<52-1> Preparation of 9-((1,1-dioxidotetrahydro-2H-thiopyran-4-yl)oxy)-11-methyl-6,7-dihydrodibenzo[b,d]oxepin-2-carbaldehyde




According to the procedures as described in <3-3>, the compound obtained in <36-3> was used to prepare the title compound (white foam, 31.9 mg, 88% yield).
1H NMR (300 MHz, CDCl3) δ 10.01 (s, 1H), 7.89-7.77 (m, 2H), 7.29 (d, 1H), 6.84 (s, 1H), 6.73 (d, 1H), 4.72 (m, 1H), 4.58-4.41 (m, 2H), 4.12 (q, 5H), 3.42 (m, 2H), 2.96 (m, 2H), 2.91-2.75 (m, 1H), 2.51 (m, 2H), 2.46-2.32 (m, 2H), 2.38 (s, 3H).
<52-2> Preparation of (1S,2S)-ethyl 2-(4-(((9-((1,1-dioxidotetrahydro-2H-thiopyran-4-yl)oxy)-11-methyl-6,7-dihydrodibenzo[b,d]oxepin-2-yl)methyl)amino)-2-fluorophenyl)cyclopropanecarboxylate




The compound obtained in <52-1> (25 mg, 0.065 mmol) and (1S,2S)-ethyl 2-(4-amino-2-fluorophenyl)cyclopropanecarboxylate (14.5 mg, 0.065 mmol) were dissolved in dichloromethane (1 mL), which was then added with AcOH (7.44 μL, 0.13 mmol) and slowly added with Na(OAc)3BH (27.5 mg, 0.13 mmol) while stirring. The mixture thus obtained was stirred at room temperature for 17 hours, and then diluted with water and CH2Cl2. The layers thus formed were separated, and the organic layer was dried over sodium sulfate, concentrated under reduced pressure, and purified by silica gel chromatography to obtain the title compound (white foam, 29.6 mg, 77% yield).
1H NMR (300 MHz, CDCl3) δ 7.29-7.22 (m, 2H), 7.12 (d, 1H), 6.79 (d, 1H), 6.74 (d, 1H), 6.71 (d, 1H), 6.35-6.26 (m, 2H), 4.69 (m, 1H), 4.40 (m, 2H), 4.31 (d, 2H), 4.16 (q, 2H), 3.43 (m, 2H), 2.94 (m, 2H), 2.88-2.72 (m, 1H), 2.58-2.29 (m, 6H), 2.26 (s, 3H), 1.78 (s, 1H), 1.51 (m, 1H), 1.33-1.18 (m, 4H).
<52-3> Preparation of (1S,2S)-2-(4-(((9-((1,1-dioxidotetrahydro-2H-thiopyran-4-yl)oxy)-11-methyl-6,7-dihydrodibenzo[m]oxepin-2-yl)methyl)amino)-2-fluorophenyl)cyclopropanecarboxylic acid




According to the procedures as described in <1-11>, the compound obtained in <52-2> was used to prepare the title compound (white foam, 23.2 mg, 82% yield).
MS m/z 564 [M−H]−.
1H NMR (300 MHz, CDCl3) δ 7.29-7.22 (m, 2H), 7.13 (d, 1H), 6.83-6.73 (m, 2H), 6.71 (d, 1H), 6.38-6.23 (m, 2H), 4.69 (m, 1H), 4.41 (m, 2H), 4.33 (s, 2H), 3.43 (m, 2H), 2.95 (m, 2H), 2.82 (m, 1H), 2.65-2.30 (m, 6H), 2.26 (s, 3H), 1.78 (m, 1H), 1.58 (m, 1H), 1.37 (m, 1H).
Example 53
Preparation of (1S,2S)-2-(4-(((9-(3-(ethylsulfonyl)propoxy)-11-methyl-6,7-dihydrodibenzo[b,d]oxepin-2-yl)methyl)amino)-2-fluorophenyl)cyclopropanecarboxylic acid
<53-1> Preparation of 9-(3-(ethylsulfonyl)propoxy)-11-methyl-6,7-dihydrodibenzo[b,d]oxepin-2-carbaldehyde




According to the procedures as described in <3-3>, the compound obtained in <38-2> was used to prepare the title compound (white foam, 86.3 mg, 97% yield).
1H NMR (300 MHz, CDCl3) δ 10.01 (s, 1H), 7.87-7.79 (m, 2H), 7.28 (d, 1H), 6.80 (d, 1H), 6.69 (d, 1H), 4.58-4.43 (m, 2H), 4.17 (t, 2H), 3.28-3.15 (m, 2H), 3.06 (q, 2H), 2.82 (m, 1H), 2.55 (m, 1H), 2.42-2.30 (m, 2H), 2.37 (s, 3H), 1.45 (t, 3H).
<53-2> Preparation of (1S,2S)-ethyl 2-(4-(((9-(3-(ethylsulfonyl)propoxy)-11-methyl-6,7-dihydrodibenzo[b,d]oxepin-2-yl)methyl)amino)-2-fluorophenyl)cyclopropanecarboxylate




According to the procedures as described in <52-2>, the compound obtained in <53-1> was used to prepare the title compound (white foam, 96.0 mg, 73% yield).
1H NMR (300 MHz, CDCl3) δ 7.28-7.20 (m, 2H), 7.15-7.07 (m, 1H), 6.79-6.71 (m, 2H), 6.67 (d, 1H), 6.37-6.24 (m, 2H), 4.40 (m, 2H), 4.31 (d, 2H), 4.24-4.04 (m, 4H), 3.27-3.14 (m, 2H), 3.04 (q, 2H), 2.81 (m, 1H), 2.55-2.43 (m, 2H), 2.42-2.29 (m, 2H), 2.26 (s, 3H), 1.86-1.73 (m, 1H), 1.51 (m, 1H), 1.44 (t, 3H), 1.34-1.17 (m, 4H).
<53-3> Preparation of (1S,2S)-2-(4-(((9-(3-(ethylsulfonyl)propoxy)-11-methyl-6,7-dihydrodibenzo[b,d]oxepin-2-yl)methyl)amino)-2-fluorophenyl)cyclopropanecarboxylic acid




According to the procedures as described in <1-11>, the compound obtained in <53-2> was used to prepare the title compound (white foam, 79.8 mg, 88% yield).
MS m/z 566 [M−H]−.
1H NMR (300 MHz, CDCl3) δ 7.28-7.22 (m, 2H), 7.12 (d, 1H), 6.82-6.72 (m, 2H), 6.68 (d, 1H), 6.36-6.27 (m, 2H), 4.40 (m, 2H), 4.32 (s, 2H), 4.13 (t, 2H), 3.27-3.15 (m, 2H), 3.05 (q, 2H), 2.80 (m, 1H), 2.59 (m, 1H), 2.49 (m, 1H), 2.34 (m, 2H), 2.26 (s, 3H), 1.79 (m, 1H), 1.63-1.51 (m, 1H), 1.44 (t, 3H), 1.36 (m, 1H).
Example 54
Preparation of 2-((3S)-6-((6,6,11-trimethyl-9-(3-(methylsulfonyl)propoxy)-6,7-dihydrodibenzo[b,d]oxepin-2-yl)methoxy)-2,3-dihydrobenzofuran-3-yl)acetic acid
<54-1> Preparation of methyl 2-(3-methoxy-5-methylphenyl)acetate




A solution of 2-(3-methoxy-5-methylphenyl)acetonitrile (prepared in accordance with the reference [Australian Journal of Chemistry, 1999, vol. 52, #11, p. 1093-1108]; 8.80 g, 54.591 mmol) in MeOH (150 mL) was slowly added dropwise with sulfuric acid (50 mL) and refluxed for 15 hours. The reaction mixture was cooled to room temperature, added with distilled water, and extracted with CH2Cl2. The organic layer was collected, dried over MgSO4, and the filtrate thus obtained was concentrated under reduced pressure and purified by silica gel chromatography to obtain the title compound (colorless oil, 8.26 g, 78% yield).
1H NMR (300 MHz, CDCl3) δ 6.69 (s, 1H), 6.63 (s, 1H), 3.78 (s, 3H), 3.69 (s, 3H), 3.56 (s, 2H), 2.31 (s, 3H).
<54-2> Preparation of 1-(3-methoxy-5-methylphenyl)-2-methylpropan-2-ol




To a solution of the compound obtained <54-1> (9.66 g, 49.735 mmol) in THF (160 mL) 0° C. was added dropwise MeMgBr (3.0M Et2O solution, 57 mL, 169.902 mmol). The mixture was heated to room temperature and stirred for 4.5 hours. Then, the mixture slowly added with a saturated NH4Cl aqueous solution at 0° C. The reaction mixture thus obtained was added with EtOAc, a saturated NH4Cl aqueous solution and distilled water, and the layers thus formed were separated. The aqueous layer was extracted with EtOAc one more time, and the organic layer was collected and dried over MgSO4. The filtrate was concentrated under reduced pressure and purified by silica gel chromatography to obtain the title compound (yellow oil, 9.07 g, 94% yield).
1H NMR (300 MHz, CDCl3) δ 6.66-6.59 (m, 2H), 6.57 (s, 1H), 3.79 (d, 3H), 2.70 (s, 2H), 2.32 (s, 3H), 1.43 (s, 1H), 1.24 (s, 6H).
<54-3> Preparation of 1-(2-bromo-5-methoxy-3-methylphenyl)-2-methylpropan-2-ol




According to the procedures as described in <43-1>, the compound obtained in <54-2> was used to prepare the title compound (yellow oil, 11.93 g, 98% yield).
1H NMR (600 MHz, CDCl3) δ 6.74 (d, 1H), 6.70 (d, 1H), 3.76 (s, 3H), 3.03 (s, 2H), 2.40 (s, 3H), 1.54 (d, 1H), 1.28 (s, 6H).
<54-4> Preparation of methyl 2′-(2-hydroxy-2-methylpropyl)-4′-methoxy-2-(methoxymethoxy)-6′-methyl-[1,1′-biphenyl]-4-carboxylate




A mixed solution of the compounds obtained in <54-3> (1 g, 3.661 mmol) and <2-6> (1.77 g, 5.491 mmol) in toluene (23 mL) and distilled water (2.3 mL) was added with K3PO4 (301 mg, 0.732 mmol) and substituted with nitrogen. The mixture was added with Pd(OAc)2 (82 mg, 0.366 mmol) and stirred at 100° C. for 18 hours. The reaction mixture thus obtained was cooled to room temperature, added with distilled water and brine, and then extracted with EtOAc. The organic layer was collected and dried over MgSO4. The filtrate was concentrated under reduced pressure and purified by silica gel chromatography to obtain the title compound (yellow oil, 388 mg, 27% yield).
1H NMR (300 MHz, CDCl3) δ 8.02 (dd, 1H), 7.75 (d, 1H), 7.25 (d, 1H), 6.83 (d, 1H), 6.74 (d, 1H), 5.17-5.09 (m, 1H), 3.88 (s, 3H), 3.84 (s, 3H), 3.39 (s, 3H), 2.70-2.50 (m, 1H), 1.99 (s, 3H), 1.07 (s, 3H), 1.04 (s, 3H).
<54-5> Preparation of methyl 2-hydroxy-2′-(2-hydroxy-2-methylpropyl)-4′-methoxy-6′-methyl-[1,1′-biphenyl]-4-carboxylate




According to the procedures as described in <43-3>, the compound obtained in <54-4> was used to prepare the title compound (yellow oil, 301 mg, 83% yield).
1H NMR (300 MHz, CDCl3) δ 7.98 (dd, 1H), 7.71 (d, 1H), 7.02 (d, 1H), 6.86 (d, 1H), 6.78 (d, 1H), 6.03 (br s, 1H), 3.88 (s, 3H), 3.85 (s, 3H), 2.70 (d, 1H), 2.49 (d, 1H), 1.98 (s, 3H), 1.17 (s, 3H), 1.13 (s, 3H).
<54-6> Preparation of methyl 9-methoxy-6,6,11-trimethyl-6,7-dihydrodibenzo[b,d]oxepin-2-carboxylate




According to the procedures as described in <43-4>, the compound obtained in <54-5> was used to prepare the title compound (colorless oil, 82 mg, 29% yield).
1H NMR (300 MHz, CDCl3) δ 8.05 (d, 1H), 7.96 (dd, 1H), 7.09 (d, 1H), 6.80 (d, 1H), 6.64 (d, 1H), 3.92 (s, 3H), 3.85 (s, 3H), 2.60 (d, 1H), 2.39 (s, 3H), 2.35 (d, 1H), 1.38 (s, 3H), 1.33 (s, 3H).
<54-7> Preparation of methyl 9-hydroxy-6,6,11-trimethyl-6,7-dihydrobenzo[b,d]oxepin-2-carboxylate




According to the procedures as described in <43-5>, the compound obtained in <54-6> was used to prepare the title compound (colorless oil, 52 mg, 72% yield).
1H NMR (300 MHz, CDCl3) δ 8.04 (d, 1H), 7.96 (dd, 1H), 7.09 (dd, 1H), 6.73 (d, 1H), 6.58 (d, 1H), 5.03 (s, 1H), 3.92 (s, 3H), 2.57 (d, 1H), 2.34 (s, 3H), 2.32 (d, 1H), 1.37 (s, 3H), 1.33 (s, 3H).
<54-8> Preparation of methyl 6,6,11-trimethyl-9-(3-(methylsulfonyl)propoxy)-6,7-dihydrodibenzo[b,d]oxepin-2-carboxylate




According to the procedures as described in <1-8>, the compound obtained in <54-7> was used to prepare the title compound (colorless oil, 71 mg, 99% yield).
1H NMR (300 MHz, CDCl3) δ 8.04 (d, 1H), 7.97 (dd, 1H), 7.09 (d, 1H), 6.78 (d, 1H), 6.62 (d, 1H), 4.16 (t, 2H), 3.92 (s, 3H), 3.29 (m, 2H), 2.98 (s, 3H), 2.59 (d, 1H), 2.45-2.28 (m, 6H), 1.38 (d, 3H), 1.33 (d, 3H).
<54-9> Preparation of (6,6,11-trimethyl-9-(3-(methylsulfonyl)propoxy)-6,7-dihydrodibenzo[b,d]oxepin-2-yl)methanol




According to the procedures as described in <1-9>, the compound obtained in <54-8> was used to prepare the title compound (colorless oil, 60 mg, 90% yield).
1H NMR (300 MHz, CDCl3) δ 7.32 (d, 1H), 7.27 (d, 1H), 7.04 (d, 1H), 6.76 (d, 1H), 6.61 (d, 1H), 4.70 (s, 2H), 4.15 (t, 2H), 3.37-3.18 (m, 2H), 2.96 (s, 3H), 2.59 (d, 1H), 2.40-2.28 (m, 6H), 1.36 (s, 3H), 1.30 (s, 3H).
<54-10> Preparation of methyl 2-((3S)-6-((6,6,11-trimethyl-9-(3-(methylsulfonyl)propoxy)-6,7-dihydrodibenzo[b,d]oxepin-2-yl)methoxy)-2,3-dihydrobenzofuran-3-ylacetate




According to the procedures as described in <1-10>, the compound obtained in <54-9> was used to prepare the title compound (colorless oil, 68 mg, 77% yield).
1H NMR (300 MHz, CDCl3) δ 7.36 (d, 1H), 7.32 (dd, 1H), 7.09-6.99 (m, 2H), 6.75 (d, 1H), 6.61 (d, 1H), 6.53-6.45 (m, 2H), 5.03 (s, 2H), 4.76 (t, 1H), 4.35-4.23 (m, 1H), 4.15 (t, 2H), 3.87-3.75 (m, 1H), 3.72 (s, 3H), 3.34-3.21 (m, 2H), 2.97 (s, 3H), 2.75 (m, 1H), 2.68-2.50 (m, 2H), 2.42-2.23 (m, 6H), 1.37 (s, 3H), 1.31 (s, 3H).
<54-11> Preparation of 2-((3S)-6-((6,6,11-trimethyl-9-(3-(methylsulfonyl)propoxy)-6,7-dihydrodibenzo[b,d]oxepin-2-yl)methoxy)-2,3-dihydrobenzofuran-3-yl)acetic acid




According to the procedures as described in <1-11>, the compound obtained in <54-10> was used to prepare the title compound (white foam, 57 mg, 86% yield).
MS m/z 579 [M−H]−.
1H NMR (300 MHz, CDCl3) δ 7.35 (d, 1H), 7.31 (dd, 1H), 7.06 (dd, 2H), 6.75 (d, 1H), 6.61 (d, 1H), 6.54-6.45 (m, 2H), 5.03 (s, 2H), 4.77 (t, 1H), 4.29 (dd, 1H), 4.15 (t, 2H), 3.90-3.75 (m, 1H), 3.34-3.22 (m, 2H), 2.97 (s, 3H), 2.82 (dd, 1H), 2.68-2.56 (m, 2H), 2.44-2.25 (m, 6H), 1.37 (s, 3H), 1.30 (s, 3H).
Example 55
Preparation of 2-((3S)-6-((9-((1,1-dioxidotetrahydro-2H-thiopyran-4-yl)oxy)-11-methyl-6,7-dihydro-5H-dibenzo[a,c][7]annulen-2-yl)methoxy)-2,3-dihydrobenzofuran-3-yl)acetic acid
<55-1> Preparation of methyl 9-((1,1-dioxidotetrahydro-2H-thiopyran-4-yl)oxy)-11-methyl-6,7-dihydro-5H-dibenzo[a,c][7]annulene-2-carboxylate




A solution of the compound obtained in <7-6> (180 mg, 0.638 mmol) and 1,1-dioxidotetrahydro-2H-thiopyran-4-yl 4-methylbenzenesulfonate (388 mg, 1.275 mmol) in DMF (3.2 mL) was added with K2CO3 (176 mg, 1.275 mmol), followed by stirring at 90° C. for 14 hours. The reaction mixture was cooled to room temperature, added with a saturated NH4Cl aqueous solution and distilled water, and then extracted with EtOAc. The organic layer was dried over MgSO4. The filtrate was concentrated under reduced pressure and purified by silica gel chromatography to obtain the title compound (white foam, 213 mg, 81% yield).
1H NMR (300 MHz, CDCl3) δ 7.96-7.89 (m, 2H), 7.31 (d, 1H), 6.78 (d, 1H), 6.67 (d, 1H), 4.70 (m, 1H), 3.92 (s, 3H), 3.46 (t, 2H), 3.03-2.89 (m, 2H), 2.65-2.14 (m, 11H), 2.05 (m, 2H).
<55-2> Preparation of 4-((10-(hydroxymethyl)-1-methyl-6,7-dihydro-5H-dibenzo[a,c][7]annulen-3-yl)oxy)tetrahydro-2H-thiopyran 1,1-dioxide




According to the procedures as described in <1-9>, the compound obtained in <55-1> was used to prepare the title compound (colorless oil, 158 mg, 80% yield).
1H NMR (300 MHz, CDCl3) δ 7.29-7.20 (m, 3H), 6.77 (d, 1H), 6.66 (d, 1H), 4.70 (m, 3H), 3.46 (t, 2H), 2.95 (m, 2H), 2.59-2.17 (m, 11H), 2.11-1.95 (m, 2H), 1.76 (br s, 1H).
<55-3> Preparation of methyl 2-((3S)-6-((9-((1,1-dioxidotetrahydro-2H-thiopyran-4-yl)oxy)-11-methyl-6,7-dihydro-5H-dibenzo[a,c][7]annulen-2-yl)methoxy)-2,3-dihydrobenzofuran-3-ylacetate




According to the procedures as described in <1-10>, the compound obtained in <55-2> was used to prepare the title compound (white foam, 103 mg, 88% yield).
1H NMR (300 MHz, CDCl3) δ 7.35-7.19 (m, 3H), 7.02 (d, 1H), 6.75 (d, 1H), 6.66 (d, 1H), 6.54-6.42 (m, 2H), 5.04 (s, 2H), 4.75 (t, 1H), 4.69 (m, 1H), 4.26 (dd, 1H), 3.87-3.74 (m, 1H), 3.72 (s, 3H), 3.46 (t, 2H), 2.95 (m, 2H), 2.75 (dd, 1H), 2.62-2.28 (m, 9H), 2.24 (s, 3H), 2.05 (m, 2H).
<55-4> Preparation of 2-((3S)-6-((9-((1,1-dioxidotetrahydro-2H-thiopyran-4-yl)oxy)-11-methyl-6,7-dihydro-5H-dibenzo[a,c][7]annulen-2-yl)methoxy)-2,3-dihydrobenzofuran-3-yl)acetic acid




According to the procedures as described in <1-11>, the compound obtained in <55-3> was used to prepare the title compound (white foam, 84 mg, 84% yield).
MS m/z 561 [M−H]−.
1H NMR (300 MHz, CDCl3) δ 7.33-7.20 (m, 3H), 7.06 (d, 1H), 6.75 (d, 1H), 6.66 (d, 1H), 6.54-6.43 (m, 2H), 5.05 (s, 2H), 4.76 (t, 1H), 4.69 (m, 1H), 4.29 (dd, 1H), 3.81 (m, 1H), 3.46 (t, 2H), 3.03-2.89 (m, 2H), 2.81 (dd, 1H), 2.62 (dd, 1H), 2.57-2.28 (m, 8H), 2.24 (s, 3H), 2.04 (m, 2H).
Example 56
Preparation of 2-((3S)-6-((9-((4-hydroxy-1,1-dioxidotetrahydro-2H-thiopyran-4-yl)methoxy)-11-methyl-6,7-dihydro-5H-dibenzo[a,c][7]annulen-2-yl)methoxy)-2,3-dihydrobenzofuran-3-yl) acetic acid
<56-1> Preparation of methyl 9-((4-hydroxytetrahydro-2H-thiopyran-4-yl)methoxy)-11-methyl-6,7-dihydro-5H-dibenzo[a,c][7]annulene-2-carboxylate




A solution of the compound obtained in <7-6> (240 mg, 0.850 mmol) and 1-oxa-6-thiaspiro[2.5]octane (prepared in accordance with the reference [WO 2005/63729 A1]; 363 mg, 2.787 mmol) in DMF (4.3 mL) was added with K2CO3 (235 mg, 1.700 mmol) and KI (28 mg, 0.170 mmol), followed by stirring at 90° C. for 15 hours. The reaction mixture was cooled to room temperature, added with a saturated NH4Cl aqueous solution and distilled water, and extracted with EtOAc. The organic layer was collected, washed with brine and dried over MgSO4. The filtrate was concentrated under reduced pressure and purified by silica gel chromatography to obtain the title compound (white foam, 317 mg, 90% yield).
1H NMR (300 MHz, CDCl3) δ 7.95-7.88 (m, 2H), 7.30 (d, 1H), 6.77 (d, 1H), 6.66 (d, 1H), 3.91 (d, 3H), 3.82 (s, 2H), 3.21-3.02 (m, 2H), 2.63-2.33 (m, 5H), 2.31 (s, 3H), 2.28-2.18 (m, 1H), 2.17 (s, 1H), 2.16-1.96 (m, 4H), 1.91-1.76 (m, 2H).
<56-2> Preparation of methyl 9-((4-hydroxy-1,1-dioxidotetrahydro-2H-thiopyran-4-yl)methoxy)-11-methyl-6,7-dihydro-5H-dibenzo[a,c][7]annulen-2-carboxylate




A solution of the compound obtained in <56-1> (314 mg, 0.761 mmol) in CH2Cl2 (8 mL) was added with MCPBA (<77%, 358 mg, 1.598 mmol) at 0° C., and then stirred at the same temperature for 2 hours. The mixture was slowly added dropwise with a saturated Na2S2O3 aqueous solution at 0° C. and then added with distilled water. The reaction mixture was added with a saturated NaHCO3 aqueous solution so that the pH was adjusted to 8, and then extracted with CH2Cl2. The organic layer was collected, dried over MgSO4, and then the filtrate thus obtained was concentrated under reduced pressure and silica gel chromatography to obtain the title compound (white foam, 338 mg,  ̃100% yield).
1H NMR (300 MHz, CDCl3) δ 7.99-7.88 (m, 2H), 7.31 (d, 1H), 6.77 (d, 1H), 6.65 (d, 1H), 3.91 (s, 3H), 3.61-3.40 (m, 2H), 3.06-2.87 (m, 2H), 2.58 (m, 1H), 2.52-2.16 (m, 11H), 2.11-1.99 (m, 2H).
<56-3> Preparation of 4-hydroxy-4-(((10-(hydroxymethyl)-1-methyl-6,7-dihydro-5H-dibenzo[a,c][7]annulen-3-yl)oxy)methyl)tetrahydro-2H-thiopyran 1,1-dioxide




According to the procedures as described in <1-9>, the compound obtained in <56-2> was used to prepare the title compound (white foam, 288 mg, 92% yield).
1H NMR (300 MHz, CDCl3) δ 7.28-7.21 (m, 3H), 6.75 (d, 1H), 6.65 (d, 1H), 4.72 (d, 2H), 3.90 (s, 2H), 3.57-3.42 (m, 2H), 3.05-2.86 (m, 2H), 2.60-2.18 (m, 12H), 2.08-1.96 (m, 2H), 1.63 (t, 1H).
<56-4> Preparation of methyl 2-((3S)-6-((9-((4-hydroxy-1,1-dioxidotetrahydro-2H-thiopyran-4-yl)methoxy)-11-methyl-6,7-dihydro-5H-dibenzo[a,c][7]annulen-2-yl)methoxy)-2,3-dihydrobenzofuran-3-ylacetate




According to the procedures as described in <1-10>, the compound obtained in <56-3> was used to prepare the title compound (white foam, 86 mg, 84% yield).
1H NMR (300 MHz, CDCl3) δ 7.34-7.20 (m, 3H), 7.02 (d, 1H), 6.74 (d, 1H), 6.65 (d, 1H), 6.52-6.42 (m, 2H), 5.04 (s, 2H), 4.75 (t, 1H), 4.26 (dd, 1H), 3.90 (s, 2H), 3.86-3.75 (m, 1H), 3.72 (s, 3H), 3.59-3.41 (m, 2H), 2.96 (m, 2H), 2.75 (dd, 1H), 2.62-2.37 (m, 4H), 2.37-2.16 (m, 9H), 2.08-1.96 (m, 2H).
<56-5> Preparation of 2-((3S)-6-((9-((4-hydroxy-1,1-dioxidotetrahydro-2H-thiopyran-4-yl)methoxy)-11-methyl-6,7-dihydro-5H-dibenzo[a,c][7]annulen-2-yl)methoxy)-2,3-dihydrobenzofuran-3-yl)acetic acid




According to the procedures as described in <1-11>, the compound obtained in <56-4> was used to prepare the title compound (white foam, 49 mg, 58% yield).
MS m/z 591 [M−H]−.
1H NMR (300 MHz, CDCl3) δ 7.33-7.20 (m, 3H), 7.05 (d, 1H), 6.74 (d, 1H), 6.65 (d, 1H), 6.55-6.42 (m, 2H), 5.05 (s, 2H), 4.76 (t, 1H), 4.29 (dd, 1H), 3.90 (s, 2H), 3.81 (m, 1H), 3.60-3.40 (m, 2H), 3.03-2.89 (m, 2H), 2.81 (dd, 1H), 2.62 (dd, 1H), 2.57-2.17 (m, 11H), 2.05 (m, 2H).
Example 57
Preparation of 2-((3S)-6-((9-(3-(ethylsulfonyl)propoxy)-11-methyl-6,7-dihydro-5H-dibenzo[a,c][7]annulen-2-yl)methoxy)-2,3-dihydrobenzofuran-3-yl)acetic acid
<57-1> Preparation of methyl 9-(3-(ethylsulfonyl)propoxy)-11-methyl-6,7-dihydro-5H-dibenzo[a,c][7]annulene-2-carboxylate




The compound obtained in <7-6> (130 mg, 0.46 mmol) was in DMF (5 mL), which was added with 1-chloro-3-(ethylsulfonyl)propane (143 mg, 0.84 mmol), K2CO3 (371 mg, 1.38 mmol) and KI (30 mg, 0.18 mmol), followed by stirring at 90° C. for 7 hours. The reaction mixture was cooled to room temperature, diluted with EtOAc and a saturated ammonium chloride aqueous solution, followed by extraction. The organic layer was dried over sodium sulfate, concentrated under reduced pressure, and the residue thus obtained was purified by silica gel chromatography to obtain the title compound (colorless oil, 172 mg, 90% yield).
1H NMR (300 MHz, CDCl3) δ 7.93-7.90 (m, 2H), 7.30 (d, 1H), 6.74 (d, 1H), 6.63 (d, 1H), 4.15 (t, 2H), 3.91 (s, 3H), 3.22 (dd, 2H), 3.06 (q, 2H), 2.60-2.16 (m, 6H), 2.30 (s, 3H), 2.09-1.97 (m, 2H), 1.45 (t, 3H).
<57-2> Preparation of (9-(3-(ethylsulfonyl)propoxy)-11-methyl-6,7-dihydro-5H-dibenzo[a,c][7]annulen-2-yl)methanol




According to the procedures as described in <1-9>, the compound obtained in <57-1> was used to prepare the title compound (white foam, 138 mg, 86% yield).
1H NMR (300 MHz, CDCl3) δ 7.27-7.23 (m, 3H), 6.73 (d, 1H), 6.62 (d, 1H), 4.71 (d, 2H), 4.15 (t, 2H), 3.21 (dd, 2H), 3.05 (q, 2H), 2.54-2.19 (m, 6H), 2.30 (s, 3H), 2.05-1.96 (m, 2H), 1.61 (t, 1H), 1.45 (t, 3H).
<57-3> Preparation of methyl 2-((3S)-6-((9-(3-(ethylsulfonyl)propoxy)-11-methyl-6,7-dihydro-5H-dibenzo[a,c][7]annulen-2-yl)methoxy)-2,3-dihydrobenzofuran-3-ylacetate




According to the procedures as described in <1-10>, the compound obtained in <57-2> was used to prepare the title compound (white foam, 83 mg, 86% yield).
1H NMR (300 MHz, CDCl3) δ 7.30-7.22 (m, 3H), 7.02 (d, 1H), 6.72 (d, 1H), 6.62 (d, 1H), 6.51-6.45 (m, 2H), 5.04 (s, 2H), 4.75 (t, 1H), 4.26 (dd, 1H), 4.14 (t, 2H), 3.84-3.77 (m, 1H), 3.72 (s, 3H), 3.22 (dd, 2H), 3.05 (q, 2H), 2.75 (dd, 1H), 2.60-2.21 (m, 7H), 2.24 (s, 3H), 2.07-1.95 (m, 2H), 1.45 (t, 3H).
<57-4> Preparation of 2-((3S)-6-((9-(3-(ethylsulfonyl)propoxy)-11-methyl-6,7-dihydro-5H-dibenzo[a,c][7]annulen-2-yl)methoxy)-2,3-dihydrobenzofuran-3-yl)acetic acid




According to the procedures as described in <1-11>, the compound obtained in <57-3> was used to prepare the title compound (white foam, 53 mg, 67% yield).
MS m/z 563 [M−H]−.
1H NMR (300 MHz, CDCl3) δ 7.30-7.22 (m, 3H), 7.05 (d, 1H), 6.72 (d, 1H), 6.62 (d, 1H), 6.52-6.47 (m, 2H), 5.05 (s, 2H), 4.76 (t, 1H), 4.28 (dd, 1H), 4.14 (t, 2H), 3.84-3.78 (m, 1H), 3.21 (dd, 2H), 3.05 (q, 2H), 2.81 (dd, 1H), 2.61 (dd, 1H), 2.53-2.21 (m, 6H), 2.24 (s, 3H), 2.07-1.96 (m, 2H), 1.44 (t, 3H).
Example 58
Preparation of (1S,2S)-2-(4-((1-methyl-9-(3-(methylsulfonyl)propoxy)-6,7-dihydro-5H-dibenzo[a,c][7]annulen-2-yl)methoxy)phenyl)cyclopropanecarboxylic acid
<58-1> Preparation of (1S,2S)-ethyl 2-(4-((11-methyl-9-(3-(methylsulfonyl)propoxy)-6,7-dihydro-5H-dibenzo[a,c][7]annulen-2-yl)methoxy)phenyl)cyclopropanecarboxylate




According to the procedures as described in <2-16>, the compound obtained in <7-8> was used to prepare the title compound (white foam, 77 mg, 79% yield).
1H NMR (300 MHz, CDCl3) δ 7.30-7.22 (m, 3H), 7.02 (d, 2H), 6.89 (d, 2H), 6.72 (d, 1H), 6.62 (d, 1H), 5.06 (s, 2H), 4.20-4.11 (m, 4H), 3.28 (dd, 2H), 2.97 (s, 3H), 2.54-2.20 (m, 7H), 2.24 (s, 3H), 2.07-1.96 (m, 2H), 1.84-1.78 (m, 1H), 1.58-1.52 (m, 1H), 1.28 (t, 3H), 1.27-1.21 (m, 1H).
<58-2> Preparation of (1S,2S)-2-(4-((11-methyl-9-(3-(methylsulfonyl)propoxy)-6,7-dihydro-5H-dibenzo[a,c][7]annulen-2-yl)methoxy)phenyl)cyclopropanecarboxylic acid




According to the procedures as described in <1-11>, the compound obtained in <58-1> was used to prepare the title compound (white foam, 54 mg, 76% yield).
MS m/z 533 [M−H]−.
1H NMR (300 MHz, CDCl3) δ 7.30-7.22 (m, 3H), 7.03 (d, 2H), 6.90 (d, 2H), 6.72 (d, 1H), 6.62 (d, 1H), 5.07 (s, 2H), 4.14 (t, 2H), 3.28 (dd, 2H), 2.97 (s, 3H), 2.59-2.21 (m, 7H), 2.23 (s, 3H), 2.07-1.96 (m, 2H), 1.85-1.79 (m, 1H), 1.64-1.58 (m, 1H), 1.38-1.32 (m, 1H).
Example 59
Preparation of (1S,2S)-2-(4-((9-((1,1-dioxidotetrahydro-2H-thiopyran-4-yl)oxy)-11-methyl-6,7-dihydro-5H-dibenzo[a,c][7]annulen-2-yl)methoxy)phenyl)cyclopropanecarboxylic acid
<59-1> Preparation of (1S,2S)-ethyl 2-(4-((9-((1,1-dioxidotetrahydro-2H-thiopyran-4-yl)oxy)-11-methyl-6,7-dihydro-5H-dibenzo[a,c][7]annulen-2-yl)methoxy)phenyl)cyclopropanecarboxylate




According to the procedures as described in <2-16>, the compound obtained in <55-2> was used to prepare the title compound (white foam, 97 mg, 82% yield).
1H NMR (300 MHz, CDCl3) δ 7.35-7.21 (m, 3H), 7.03 (m, 2H), 6.94-6.84 (m, 2H), 6.75 (d, 1H), 6.66 (d, 1H), 5.07 (s, 2H), 4.69 (m, 1H), 4.16 (q, 2H), 3.46 (t, 2H), 3.03-2.88 (m, 2H), 2.61-2.27 (m, 9H), 2.24 (s, 3H), 2.12-1.94 (m, 2H), 1.81 (m, 1H), 1.61-1.49 (m, 1H), 1.32-1.21 (m, 4H).
<59-2> Preparation of (1S,2S)-2-(4-((9-((1,1-dioxidotetrahydro-2H-thiopyran-4-yl)oxy)-11-methyl-6,7-dihydro-5H-dibenzo[a,c][7]annulen-2-yl)methoxy)phenyl)cyclopropanecarboxylic acid




According to the procedures as described in <1-11>, the compound obtained in <59-1> was used to prepare the title compound (white foam, 82 mg, 89% yield).
MS m/z 545 [M−H]−.
1H NMR (300 MHz, CDCl3) δ 7.34-7.20 (m, 3H), 7.07-6.99 (m, 2H), 6.94-6.85 (m, 2H), 6.75 (d, 1H), 6.66 (d, 1H), 5.07 (s, 2H), 4.69 (m, 1H), 3.46 (t, 2H), 3.03-2.87 (m, 2H), 2.61-2.27 (m, 9H), 2.23 (s, 3H), 2.11-1.96 (m, 2H), 1.81 (m, 1H), 1.62 (m, 1H), 1.35 (m, 1H).
Example 60
Preparation of (1S,2S)-2-(4-((9-((4-hydroxy-1,1-dioxidotetrahydro-2H-thiopyran-4-yl)methoxy)-11-methyl-6,7-dihydro-5H-dibenzo[a,c][7]annulen-2-yl)methoxy)phenyl)cyclopropanecarboxylic acid
<60-1> Preparation of (1S,2S)-ethyl 2-(4-((9-((4-hydroxy-1,1-dioxidotetrahydro-2H-thiopyran-4-yl)methoxy)-11-methyl-6,7-dihydro-5H-dibenzo[a,c][7]annulen-2-yl)methoxy)phenyl)cyclopropanecarboxylate




According to the procedures as described in <1-10>, the compound obtained in <56-3> was used to prepare the title compound (colorless oil, 84 mg, 83% yield).
1H NMR (300 MHz, CDCl3) δ 7.33-7.20 (m, 3H), 7.06-6.96 (m, 2H), 6.93-6.83 (m, 2H), 6.74 (d, 1H), 6.65 (d, 1H), 5.06 (s, 2H), 4.14 (q, 2H), 3.90 (s, 2H), 3.58-3.38 (m, 2H), 3.07-2.85 (m, 2H), 2.59-2.16 (m, 13H), 2.05 (m, 2H), 1.89-1.76 (m, 1H), 1.58-1.50 (m, 2H), 1.27 (m, 4H).
<60-2> Preparation of (1S,2S)-2-(4-((9-((4-hydroxy-1,1-dioxidotetrahydro-2H-thiopyran-4-yl)methoxy)-11-methyl-6,7-dihydro-5H-dibenzo[a,c][7]annulen-2-yl)methoxy)phenyl)cyclopropanecarboxylic acid




According to the procedures as described in <1-11>, the compound obtained in <60-1> was used to prepare the title compound (white foam, 47 mg, 59% yield).
MS m/z 575 [M−H]−.
1H NMR (300 MHz, CDCl3) δ 7.34-7.20 (m, 3H), 7.10-6.96 (m, 2H), 6.95-6.82 (m, 2H), 6.74 (d, 1H), 6.65 (d, 1H), 5.07 (s, 2H), 3.90 (s, 2H), 3.60-3.36 (m, 2H), 3.05-2.86 (m, 2H), 2.63-2.16 (m, 12H), 2.03 (m, 2H), 1.82 (m, 1H), 1.62 (m, 1H), 1.35 (m, 1H).
Example 61
Preparation of (1S,2S)-2-(4-((9-(3-(ethylsulfonyl)propoxy)-11-methyl-6,7-dihydro-5H-dibenzo[a,c][7]annulen-2-yl)methoxy)phenyl)cyclopropanecarboxylic acid
<61-1> Preparation of (1S,2S)-ethyl 2-(4-((9-(3-(ethylsulfonyl)propoxy)-11-methyl-6,7-dihydro-5H-dibenzo[a,c][7]annulen-2-yl)methoxy)phenyl)cyclopropanecarboxylate




According to the procedures as described in <2-16>, the compound obtained in <57-2> was used to prepare the title compound (white foam, 89 mg, 86% yield).
1H NMR (300 MHz, CDCl3) δ 7.30-7.22 (m, 3H), 7.02 (d, 2H), 6.89 (d, 2H), 6.72 (d, 1H), 6.62 (d, 1H), 5.06 (s, 2H), 4.20-4.13 (m, 4H), 3.21 (dd, 2H), 3.05 (q, 2H), 2.53-2.21 (m, 7H), 2.24 (s, 3H), 2.07-1.97 (m, 2H), 1.84-1.78 (m, 1H), 1.58-1.52 (m, 1H), 1.45 (t, 3H), 1.28 (t, 3H), 1.27-1.21 (m, 1H).
<61-2> Preparation of (1S,2S)-2-(4-((9-(3-(ethylsulfonyl)propoxy)-11-methyl-6,7-dihydro-5H-dibenzo[a,c][7]annulen-2-yl)methoxy)phenyl)cyclopropanecarboxylic acid




According to the procedures as described in <1-11>, the compound obtained in <61-1> was used to prepare the title compound (white foam, 59 mg, 72% yield).
MS m/z 547 [M−H]−.
1H NMR (300 MHz, CDCl3) δ 7.30-7.22 (m, 3H), 7.03 (d, 2H), 6.90 (d, 2H), 6.72 (d, 1H), 6.62 (d, 1H), 5.07 (s, 2H), 4.14 (t, 2H), 3.21 (dd, 2H), 3.05 (q, 2H), 2.59-2.21 (m, 7H), 2.23 (s, 3H), 2.07-1.96 (m, 2H), 1.85-1.79 (m, 1H), 1.65-1.58 (m, 1H), 1.45 (t, 3H), 1.38-1.32 (m, 1H).
Example 62
Preparation of (1S,2S)-2-(2-fluoro-4-((9-((4-hydroxy-1,1-dioxidotetrahydro-2H-thiopyran-4-yl)methoxy)-11-methyl-6,7-dihydro-5H-dibenzo[a,c][7]annulen-2-yl)methoxy)phenyl)cyclopropanecarboxylic acid
<62-1> Preparation of (1S,2S)-ethyl 2-(2-fluoro-4-((9-((4-hydroxy-1,1-dioxidotetrahydro-2H-thiopyran-4-yl)methoxy)-11-methyl-6,7-dihydro-5H-dibenzo[a,c][7]annulen-2-yl)methoxy)phenyl)cyclopropanecarboxylate




According to the procedures as described in <40-1>, the compound obtained in <56-3> was used to prepare the title compound (colorless oil, 85 mg, 81% yield).
1H NMR (300 MHz, CDCl3) δ 7.33-7.20 (m, 3H), 6.87 (t, 1H), 6.74 (d, 1H), 6.71-6.60 (m, 3H), 5.05 (s, 2H), 4.23-4.06 (q, 2H), 3.90 (s, 2H), 3.50 (m, 2H), 3.03-2.87 (m, 2H), 2.64-2.17 (m, 13H), 2.05 (m, 2H), 1.85 (m, 1H), 1.54 (m, 1H), 1.35-1.20 (m, 4H).
<62-2> Preparation of (1S,2S)-2-(2-fluoro-4-((9-((4-hydroxy-1,1-dioxidotetrahydro-2H-thiopyran-4-yl)methoxy)-11-methyl-6,7-dihydro-5H-dibenzo[a,c][7]annulen-2-yl)methoxy)phenyl)cyclopropanecarboxylic acid




According to the procedures as described in <1-11>, the compound obtained in <62-1> was used to prepare the title compound (white foam, 39 mg, 48% yield).
MS m/z 593 [M−H]−.
1H NMR (300 MHz, CDCl3) δ 7.33-7.20 (m, 3H), 6.88 (t, 1H), 6.75 (d, 1H), 6.71-6.60 (m, 3H), 5.06 (s, 2H), 3.90 (s, 2H), 3.48 (m, 2H), 2.96 (m, 2H), 2.64 (m, 1H), 2.58-2.15 (m, 11H), 2.03 (m, 2H), 1.90-1.79 (m, 1H), 1.62 (m, 1H), 1.44-1.31 (m, 1H).
Example 63
Preparation of (1S,2S)-2-(2-fluoro-4-(((9-((4-hydroxy-1,1-dioxidotetrahydro-2H-thiopyran-4-yl)methoxy)-11-methyl-6,7-dihydro-5H-dibenzo[a,c][7]annulen-2-yl)methyl)amino)phenyl)cyclopropanecarboxylic acid
<63-1> Preparation of 9-((4-hydroxy-1,1-dioxidotetrahydro-2H-thiopyran-4-yl)methoxy)-11-methyl-6,7-dihydro-5H-dibenzo[a,c][7]annulen-2-carbaldehyde




According to the procedures as described in <3-3>, the compound obtained in <56-3> was used to prepare the title compound (colorless oil, 72 mg,  ̃100% yield).
1H NMR (300 MHz, CDCl3) δ 10.02 (s, 1H), 7.86-7.67 (m, 2H), 7.42 (d, 1H), 6.78 (d, 1H), 6.67 (d, 1H), 3.92 (s, 2H), 3.62-3.41 (m, 2H), 3.06-2.88 (m, 2H), 2.69-2.05 (m, 14H).
<63-2> Preparation of (1S,2S)-ethyl 2-(2-fluoro-4-(((9-((4-hydroxy-1,1-dioxidotetrahydro-2H-thiopyran-4-yl)methoxy)-11-methyl-6,7-dihydro-5H-dibenzo[a,c][7]annulen-2-yl)methyl)amino)phenyl)cyclopropanecarboxylate




According to the procedures as described in <52-2>, the compound obtained in <63-1> was used to prepare the title compound (colorless oil, 97 mg, 90% yield).
1H NMR (300 MHz, CDCl3) δ 7.23-7.14 (m, 3H), 6.80-6.68 (m, 2H), 6.64 (d, 1H), 6.37-6.22 (m, 2H), 4.32 (s, 2H), 4.14 (q, 2H), 3.89 (s, 2H), 3.58-3.36 (m, 2H), 3.04-2.85 (m, 2H), 2.58-2.22 (m, 10H), 2.20 (s, 3H), 2.05 (m, 2H), 1.79 (m, 1H), 1.50 (m, 1H), 1.27 (m, 4H).
<63-3> Preparation of (1S,2S)-2-(2-fluoro-4-(((9-((4-hydroxy-1,1-dioxidotetrahydro-2H-thiopyran-4-yl)methoxy)-11-methyl-6,7-dihydro-5H-dibenzo[a,c][7]annulen-2-yl)methyl)amino)phenyl)cyclopropanecarboxylic acid




According to the procedures as described in <1-11>, the compound obtained in <63-2> was used to prepare the title compound (white foam, 69 mg, 74% yield).
MS m/z 592 [M−H]−.
1H NMR (300 MHz, CDCl3) δ 7.23-7.13 (m, 3H), 6.81-6.68 (m, 2H), 6.64 (d, 1H), 6.30 (m, 2H), 4.33 (s, 2H), 3.89 (s, 2H), 3.59-3.39 (m, 2H), 2.96 (m, 2H), 2.65-2.13 (m, 12H), 2.03 (d, 2H), 1.84-1.74 (m, 1H), 1.57 (m, 1H), 1.35 (m, 1H).
Example 64
Preparation of (S)-2-(6-((9-((1,1-dioxidotetrahydro-2H-thiopyran-4-yl)oxy)-6,7-dihydro-5H-dibenzo[a,c][7]annulen-2-yl)methoxy)-2,3-dihydrobenzofuran-3-yl)acetic acid
<64-1> Preparation of methyl 9-((1,1-dioxidotetrahydro-2H-thiopyran-4-yl)oxy)-6,7-dihydro-5H-dibenzo[a,c][7]annulen-2-carboxylate




According to the procedures as described in <55-1>, the compound obtained in <5-7> was used to prepare the title compound (colorless oil, 467 mg, 131% yield).
1H NMR (300 MHz, CDCl3) δ 8.01 (d, 1H), 7.94 (dd, 1H), 7.34 (d, 1H), 7.29 (d, 1H), 6.89 (dd, 1H), 6.83 (d, 1H), 4.72 (s, 1H), 3.93 (s, 3H), 3.53-3.41 (m, 2H), 2.90 (m, 2H), 2.59-2.30 (m, 8H), 2.22 (m, 2H).
<64-2> Preparation of 4-((10-(hydroxymethyl)-6,7-dihydro-5H-dibenzo[a,c][7]annulen-3-yl)oxy)tetrahydro-2H-thiopyran 1,1-dioxide




According to the procedures as described in <1-9>, the compound obtained in <64-1> was used to prepare the title compound (white foam, 329.5 mg, 87% yield).
1H NMR (300 MHz, CDCl3) δ 7.38-7.20 (m, 3H), 6.89 (dd, 1H), 6.83 (d, 1H), 4.73 (m, 3H), 3.58-3.37 (m, 2H), 2.96 (m, 2H), 2.47 (m, 8H), 2.19 (m, 2H), 1.69 (t, 1H).
<64-3> Preparation of (S)-methyl 2-(6-((9-((1,1-dioxidotetrahydro-2H-thiopyran-4-yl)oxy)-6,7-dihydro-5H-dibenzo[a,c][7]annulen-2-yl)methoxy)-2,3-dihydrobenzofuran-3-ylacetate




According to the procedures as described in <1-10>, the compound obtained in <64-2> was used to prepare the title compound (yellow foam, 140.5 mg, 83% yield).
1H NMR (300 MHz, CDCl3) δ=7.39-7.30 (m, 3H), 7.24 (d, 1H), 7.04 (d, 1H), 6.88 (dd, 1H), 6.83 (d, 1H), 6.55-6.44 (m, 2H), 5.04 (s, 2H), 4.76 (t, 1H), 4.71 (br s, 1H), 4.27 (dd, 1H), 3.81 (m, 1H), 3.72 (s, 3H), 3.53-3.38 (m, 2H), 2.96 (m, 2H), 2.76 (dd, 1H), 2.63-2.24 (m, 9H), 2.18 (m, 2H).
<64-4> Preparation of (S)-2-(6-((9-((1,1-dioxidotetrahydro-2H-thiopyran-4-yl)oxy)-6,7-dihydro-5H-dibenzo[a,c][7]annulen-2-yl)methoxy)-2,3-dihydrobenzofuran-3-yl)acetic acid




According to the procedures as described in <1-11>, the compound obtained in <64-3> (white foam, 51.4 mg, 38% yield).
MS m/z 547 [M−H]−.
1H NMR (300 MHz, DMSO-d6) δ=7.36 (s, 1H), 7.34-7.24 (m, 3H), 7.11 (d, 1H), 7.05-6.94 (m, 2H), 6.53-6.42 (m, 2H), 5.07 (s, 2H), 4.77 (m, 1H), 4.68 (t, 1H), 4.19 (m, 1H), 3.68 (m, 1H), 3.21 (t, 4H), 2.70 (dd, 1H), 2.56-2.46 (m, 1H), 2.45-2.32 (m, 4H), 2.32-2.17 (m, 4H), 2.12 (m, 2H).
Example 65
Preparation of (S)-2-(6-((9-((4-hydroxy-1,1-dioxidotetrahydro-2H-thiopyran-4-yl)methoxy)-6,7-dihydro-5H-dibenzo[a,c][7]annulen-2-yl)methoxy)-2,3-dihydrobenzofuran-3-yl)acetic acid
<65-1> Preparation of methyl 9-((4-hydroxytetrahydro-2H-thiopyran-4-yl)methoxy)-6,7-dihydro-5H-dibenzo[a,c][7]annulen-2-carboxylate




According to the procedures as described in <56-1>, the compound obtained in <5-7> was used to prepare the title compound (white foam, 290 mg, 81% yield).
1H NMR (300 MHz, CDCl3) δ 8.01 (d, 1H), 7.93 (dd, 1H), 7.35 (d, 1H), 7.30 (d, 1H), 6.89 (dd, 1H), 6.82 (d, 1H), 3.93 (s, 3H), 3.84 (s, 2H), 3.20-3.03 (m, 2H), 2.61-2.40 (m, 6H), 2.27-2.07 (m, 5H), 1.92-1.77 (m, 2H).
<65-2> Preparation of methyl 9-((4-hydroxy-1,1-dioxidotetrahydro-2H-thiopyran-4-yl)methoxy)-6,7-dihydro-5H-dibenzo[a,c][7]annulene-2-carboxylate




According to the procedures as described in <56-2>, the compound obtained in <65-1> was used to prepare the title compound (white foam, 292 mg, 94% yield).
1H NMR (300 MHz, CDCl3) δ 8.01 (d, 1H), 7.94 (dd, 1H), 7.37 (d, 1H), 7.31 (d, 1H), 6.89 (dd, 1H), 6.83 (d, 1H), 3.93 (s, 3H), 3.51 (m, 2H), 2.97 (m, 2H), 2.55 (t, 2H), 2.50-2.42 (m, 3iH), 2.36-2.16 (m, 6H).
<65-3> Preparation of 4-hydroxy-4-(((10-(hydroxymethyl)-6,7-dihydro-5H-dibenzo[a,c][7]annulen-3-yl)oxy)methyl)tetrahydro-2H-thiopyran 1,1-dioxide




According to the procedures as described in <1-9>, the compound obtained in <65-2> was used to prepare the title compound (white foam, 256 mg, 94% yield).
1H NMR (300 MHz, CDCl3) δ 7.37-7.20 (m, 4H), 6.87 (dd, 1H), 6.82 (d, 1H), 4.74 (d, 2H), 3.92 (s, 2H), 3.58-3.41 (m, 2H), 3.03-2.87 (m, 2H), 2.55-2.40 (m, 5H), 2.35-2.11 (m, 6H), 1.67 (t, 1H).
<65-4> Preparation of (S)-methyl 2-(6-((9-((4-hydroxy-1,1-dioxidotetrahydro-2H-thiopyran-4-yl)methoxy)-6,7-dihydro-5H-dibenzo[a,c][7]annulen-2-yl)methoxy)-2,3-dihydrobenzofuran-3-ylacetate




According to the procedures as described in <1-10>, the compound obtained in <65-3> was used to prepare the title compound (colorless oil, 103 mg, 88% yield).
1H NMR (300 MHz, CDCl3) δ 7.41-7.28 (m, 3H), 7.24 (d, 1H), 7.03 (d, 1H), 6.87 (dd, 1H), 6.82 (d, 1H), 6.56-6.44 (m, 2H), 5.04 (s, 2H), 4.76 (t, 1H), 4.27 (dd, 1H), 3.92 (s, 2H), 3.87-3.76 (m, 1H), 3.72 (s, 3H), 3.59-3.40 (m, 2H), 2.96 (m, 2H), 2.76 (dd, 1H), 2.64-2.39 (m, 6H), 2.36-2.09 (m, 6H).
<65-5> Preparation of (S)-2-(6-((9-((4-hydroxy-1,1-dioxidotetrahydro-2H-thiopyran-4-yl)methoxy)-6,7-dihydro-5H-dibenzo[a,c][7]annulen-2-yl)methoxy)-2,3-dihydrobenzofuran-3-yl)acetic acid




According to the procedures as described in <1-11>, the compound obtained in <65-4> was used to prepare the title compound (white foam, 57 mg, 57% yield).
MS m/z 577 [M−H]−.
1H NMR (300 MHz, CDCl3) δ 7.40-7.20 (m, 4H), 7.07 (d, 1H), 6.87 (dd, 1H), 6.82 (d, 1H), 6.57-6.46 (m, 2H), 5.05 (s, 2H), 4.77 (t, 1H), 4.30 (dd, 1H), 3.92 (s, 2H), 3.82 (m, 1H), 3.59-3.42 (m, 2H), 2.97 (m, 2H), 2.82 (dd, 1H), 2.63 (dd, 1H), 2.49 (m, 4H), 2.35-2.12 (m, 6H).
Example 66
Preparation of (S)-2-(6-((9-(3-(ethylsulfonyl)propoxy)-6,7-dihydro-5H-dibenzo[a,c][7]annulen-2-yl)methoxy)-2,3-dihydrobenzofuran-3-yl)acetic acid
<66-1> Preparation of methyl 9-(3-(ethylsulfonyl)propoxy)-6,7-dihydro-5H-dibenzo[a,c][7]annulen-2-carboxylate




The compound obtained in <5-7> (240 mg, 0.89 mmol) was dissolved in DMF (5 mL), which was then added with 1-chloro-3-(ethylsulfonyl)propane (306 mg, 1.79 mmol) and K2CO3 (371 mg, 2.68 mmol), followed by stirring at 90° C. for 3 hours. The reaction mixture was cooled to room temperature, diluted with EtOAc and water, followed by extraction. The aqueous layer was extracted with EtOAc one more time. The organic layer was dried over sodium sulfate and concentrated under reduced pressure, and the residue thus obtained was purified by silica gel chromatography to obtain the title compound (white foam, 390 mg, 108% yield), which was used in the next step.
<66-2> Preparation of (9-(3-(ethylsulfonyl)propoxy)-6,7-dihydro-5H-dibenzo[a,c][7]annulen-2-yl)methanol




According to the procedures as described in <1-9>, the compound obtained in <66-1> was used to prepare the title compound (white foam, 275 mg, 82% yield).
1H NMR (600 MHz, CDCl3) δ 7.34 (d, 1H), 7.31 (d, 1H), 7.27 (d, 1H), 7.22 (d, 1H), 6.85 (dd, 1H), 6.79 (d, 1H), 4.73 (d, 2H), 4.16 (t, 2H), 3.23 (m, 2H), 3.05 (q, 2H), 2.49 (t, 2H), 2.46 (t, 2H), 2.39-2.35 (m, 2H), 2.17 (m, 2H), 1.65 (t, 1H), 1.45 (t, 3H).
<66-3> Preparation of (S)-methyl 2-(6-((9-(3-(ethylsulfonyl)propoxy)-6,7-dihydro-5H-dibenzo[a,c][7]annulen-2-yl)methoxy)-2,3-dihydrobenzofuran-3-ylacetate




According to the procedures as described in <1-10>, the compound obtained in <66-2> was used to prepare the title compound (white foam, 92 mg, 68% yield), which was used in the next step.
<66-4> Preparation of (S)-2-(6-((9-(3-(ethylsulfonyl)propoxy)-6,7-dihydro-5H-dibenzo[a,c][7]annulen-2-yl)methoxy)-2,3-dihydrobenzofuran-3-yl)acetic acid




According to the procedures as described in <1-11>, the compound obtained in <66-3> was used to prepare the title compound (white foam, 41 mg, 45% yield).
MS m/z 549 [M−H]−.
1H NMR (600 MHz, CDCl3) δ 7.38 (d, 1H), 7.31 (m, 2H), 7.23 (d, 1H), 7.06 (d, 1H), 6.85 (dd, 1H), 6.79 (d, 1H), 6.52 (dd, 2H), 6.49 (d, 1H), 5.04 (s, 2H), 4.77 (t, 1H), 4.29 (dd, 1H), 4.16 (t, 2H), 3.82 (m, 1H), 3.23 (m, 2H), 3.05 (q, 2H), 2.82 (dd, 1H), 2.63 (dd, 1H), 2.48 (m, 4H), 2.39-2.34 (m, 2H), 2.17 (m, 2H), 1.45 (t, 3H).
Example 67
Preparation of (1S,2S)-2-(4-((9-((1,1-dioxidotetrahydro-2H-thiopyran-4-yl)oxy)-6,7-dihydro-5H-dibenzo[a,c][7]annulen-2-yl)methoxy)phenyl)cyclopropanecarboxylic acid
<67-1> Preparation of (1S,2S)-ethyl 2-(4-((9-((1,1-dioxidotetrahydro-2H-thiopyran-4-yl)oxy)-6,7-dihydro-5H-dibenzo[a,c][7]annulen-2-yl)methoxy)phenyl)cyclopropanecarboxylate




According to the procedures as described in <2-16>, the compound obtained in <64-2> was used to prepare the title compound (yellow oil, 106.3 mg, 68% yield).
1H NMR (300 MHz, CDCl3) δ 7.38 (s, 1H), 7.33 (d, 2H), 7.25 (d, 1H), 7.04 (d, 2H), 6.94-6.81 (m, 4H), 5.07 (s, 2H), 4.71 (br s, 1H), 4.17 (q, 2H), 3.54-3.35 (m, 2H), 2.96 (m, 2H), 2.58-2.26 (m, 9H), 2.19 (m, 2H), 1.87-1.77 (m, 1H), 1.58-1.50 (m, 1H), 1.33-1.17 (m, 4H).
<67-2> Preparation of (1S,2S)-2-(4-((9-((1,1-dioxidotetrahydro-2H-thiopyran-4-yl)oxy)-6,7-dihydro-5H-dibenzo[a,c][7]annulen-2-yl)methoxy)phenyl)cyclopropanecarboxylic acid




According to the procedures as described in <1-11>, the compound obtained in <67-1> was used to prepare the title compound (white foam, 55.8 mg, 58% yield).
MS m/z 531 [M−H]−.
1H NMR (300 MHz, CDCl3) δ 7.41-7.21 (m, 4H), 7.05 (d, 2H), 6.97-6.81 (m, 4H), 5.07 (s, 2H), 4.71 (br s, 1H), 3.46 (m, 2H), 2.96 (m, 2H), 2.66-2.31 (m, 9H), 2.19 (m, 2H), 1.88-1.78 (m, 1H), 1.63 (dd, 1H), 1.42-1.30 (m, 1H).
Example 68
Preparation of (1S,2S)-2-(4-((9-((4-hydroxy-1,1-dioxidotetrahydro-2H-thiopyran-4-yl)methoxy)-6,7-dihydro-5H-dibenzo[a,c][7]annulen-2-yl)methoxy)phenyl)cyclopropanecarboxylic acid
<68-1> Preparation of (1S,2S)-ethyl 2-(4-((9-((4-hydroxy-1,1-dioxidotetrahydro-2H-thiopyran-4-yl)methoxy)-6,7-dihydro-5H-dibenzo[a,c][7]annulen-2-yl)methoxy)phenyl)cyclopropanecarboxylate




According to the procedures as described in <2-16>, the compound obtained in <65-3> was used to prepare the title compound (white foam, 99 mg, 84% yield).
1H NMR (300 MHz, CDCl3) δ 7.42-7.28 (m, 3H), 7.24 (d, 1H), 7.07-6.97 (m, 2H), 6.96-6.89 (m, 2H), 6.87 (dd, 1H), 6.82 (d, 1H), 5.06 (s, 2H), 4.14 (q, 2H), 3.92 (s, 2H), 3.63-3.38 (m, 2H), 3.07-2.85 (m, 2H), 2.60-2.38 (m, 6H), 2.39-2.10 (m, 6H), 1.82 (m, 1H), 1.67-1.51 (m, 2H), 1.33-1.20 (m, 4H).
<68-2> Preparation of (1S,2S)-2-(4-((9-((4-hydroxy-1,1-dioxidotetrahydro-2H-thiopyran-4-yl)methoxy)-6,7-dihydro-5H-dibenzo[a,c][7]annulen-2-yl)methoxy)phenyl)cyclopropanecarboxylic acid




According to the procedures as described in <1-11>, the compound obtained in <68-1> was used to prepare the title compound (white foam, 67 mg, 71% yield).
MS m/z 561 [M−H]−.
1H NMR (300 MHz, CDCl3) δ 7.41-7.29 (m, 3H), 7.26 (d, 1H), 7.09-7.01 (m, 2H), 6.92 (m, 2H), 6.87 (dd, 1H), 6.82 (d, 1H), 5.07 (s, 2H), 3.92 (s, 2H), 3.58-3.40 (m, 2H), 2.96 (m, 2H), 2.63-2.41 (m, 5H), 2.36-2.11 (m, 6H), 1.83 (m, 1H), 1.62 (m, 1H), 1.36 (m, 1H).
Example 69
Preparation of (1S,2S)-2-(4-((9-(3-(ethylsulfonyl)propoxy)-6,7-dihydro-5H-dibenzo[a,c][7]annulen-2-yl)methoxy)phenyl)cyclopropanecarboxylic acid
<69-1> Preparation of (1S,2S)-ethyl 2-(4-((9-(3-(ethylsulfonyl)propoxy)-6,7-dihydro-5H-dibenzo[a,c][7]annulen-2-yl)methoxy)phenyl)cyclopropanecarboxylate




According to the procedures as described in <2-16>, the compound obtained in <66-2> was used to prepare the title compound (white foam, 108 mg, 80% yield).
1H NMR (300 MHz, CDCl3) δ 7.38 (d, 1H), 7.30 (m, 2H), 7.23 (d, 1H), 7.04 (d, 2H), 6.91 (d, 2H), 6.85 (dd, 1H), 6.79 (d, 1H), 5.06 (s, 2H), 4.16 (m, 4H), 3.22 (m, 2H), 3.06 (q, 2H), 2.47 (m, 4H), 2.37 (m, 2H), 2.17 (m, 2H), 1.82 (m, 1H), 1.56 (m, 1H), 1.45 (t, 2H), 1.27 (t, 2H), 1.26 (m, 1H)
<69-2> Preparation of (1S,2S)-2-(4-((9-(3-(ethylsulfonyl)propoxy)-6,7-dihydro-5H-dibenzo[a,c][7]annulen-2-yl) methoxy)phenyl)cyclopropanecarboxylic acid




According to the procedures as described in <1-11>, the compound obtained in <69-1> was used to prepare the title compound (white foam, 79 mg, 76% yield).
MS m/z 533 [M−H]−
1H NMR (600 MHz, CDCl3) δ 7.37 (d, 1H), 7.30 (dd, 1H), 7.29 (d, 1H), 7.23 (d, 1H), 7.04 (d, 2H), 6.91 (d, 2H), 6.84 (dd, 1H), 6.78 (d, 1H), 5.06 (s, 2H), 4.15 (t, 2H), 3.22 (m, 2H), 3.05 (q, 2H), 2.57-2.54 (m, 1H), 2.50-2.44 (m, 4H), 2.37-2.34 (m, 2H), 2.17 (m, 2H), 1.82 (m, 1H), 1.61 (m, 1H), 1.44 (t, 3H), 1.36-1.33 (m, 1H)
Example 70
Preparation of (1S,2S)-2-(4-(((9-((1,1-dioxidotetrahydro-2H-thiopyran-4-yl)oxy)-6,7-dihydro-5H-dibenzo[a,c][7]annulen-2-yl)methyl)amino)phenyl)cyclopropanecarboxylic acid
<70-1> Preparation of 9-((1,1-dioxidotetrahydro-2H-thiopyran-4-yl)oxy)-6,7-dihydro-5H-dibenzo[a,c][7]annulene-2-carbaldehyde




According to the procedures as described in <3-3>, the compound obtained in <64-2> was used to prepare the title compound (white solid, 55.4 mg, 50% yield).
1H NMR (300 MHz, CDCl3) δ 10.05 (s, 1H), 7.84 (s, 1H), 7.79 (d, 1H), 7.41 (d, 1H), 7.37 (d, 1H), 6.92 (dd, 1H), 6.85 (d, 1H), 4.73 (m, 1H), 3.47 (m, 2H), 2.97 (m, 2H), 2.66-2.32 (m, 8H), 2.23 (m, 2H).
<70-2> Preparation of (1S,2S)-ethyl 2-(4-(((9-((1,1-dioxidotetrahydro-2H-thiopyran-4-yl)oxy)-6,7-dihydro-5H-dibenzo[a,c][7]annulen-2-yl)methyl)amino)phenyl)cyclopropanecarboxylate




According to the procedures as described in <3-4>, the compound obtained in <70-1> was used to prepare the title compound (white foam, 109.6 mg, 98% yield).
1H NMR (300 MHz, CDCl3) δ 7.34-7.23 (m, 3H), 7.20 (d, 1H), 6.93 (d, 2H), 6.87 (dd, 1H), 6.83 (d, 1H), 6.58 (d, 2H), 4.70 (br s, 1H), 4.34 (s, 2H), 4.14 (q, 2H), 4.03 (br s, 1H), 3.46 (m, 2H), 2.96 (m, 2H), 2.59-2.31 (m, 9H), 2.25-2.11 (m, 2H), 1.78 (m, 1H), 1.55-1.46 (m, 1H), 1.31-1.16 (m, 4H).
<70-3> Preparation of (1S,2S)-2-(4-(((9-((1,1-dioxidotetrahydro-2H-thiopyran-4-yl)oxy)-6,7-dihydro-5H-dibenzo[a,c][7]annulen-2-yl)methyl)amino)phenyl)cyclopropanecarboxylic acid




According to the procedures as described in <1-11>, the compound obtained in <70-2> was used to prepare the title compound (white foam, 92.2 mg, 84.5% yield).
MS m/z 530 [M−H]−.
1H NMR (300 MHz, CDCl3) δ 7.34-7.24 (m, 3H), 7.20 (d, 1H), 6.94 (d, 2H), 6.87 (dd, 1H), 6.83 (d, 1H), 6.59 (d, 2H), 4.70 (br s, 1H), 4.34 (s, 2H), 3.53-3.37 (m, 2H), 2.96 (m, 2H), 2.58-2.31 (m, 9H), 2.17 (m, 2H), 1.83-1.73 (m, 1H), 1.58 (m, 1H), 1.33 (m, 1H).
Example 71
Preparation of (1S,2S)-2-(4-(((9-((4-hydroxy-1,1-dioxidotetrahydro-2H-thiopyran-4-yl)methoxy)-6,7-dihydro-5H-dibenzo[a,c][7]annulen-2-yl)methyl)amino)phenyl)cyclopropanecarboxylic acid
<71-1> Preparation of 9-((4-hydroxy-1,1-dioxidotetrahydro-2H-thiopyran-4-yl)methoxy)-6,7-dihydro-5H-dibenzo[a,c][7]annulene-2-carbaldehyde




According to the procedures as described in <3-3>, the compound obtained in <65-3> was used to prepare the title compound (colorless oil, 83 mg, 92% yield).
1H NMR (300 MHz, CDCl3) δ 10.04 (s, 1H), 7.84 (d, 1H), 7.78 (dd, 1H), 7.41 (d, 1H), 7.36 (d, 1H), 6.91 (dd, 1H), 6.84 (d, 1H), 3.93 (s, 2H), 3.51 (m, 2H), 2.97 (m, 2H), 2.64 (s, 1H), 2.57 (t, 2H), 2.47 (t, 2H), 2.36-2.15 (m, 6H).
<71-2> Preparation of (1S,2S)-ethyl 2-(4-(((9-((4-hydroxy-1,1-dioxidotetrahydro-2H-thiopyran-4-yl)methoxy)-6,7-dihydro-5H-dibenzo[a,c][7]annulen-2-yl)methyl)amino)phenyl)cyclopropanecarboxylate




According to the procedures as described in <3-4>, the compound obtained in <71-1> was used to prepare the title compound (white foam, 100 mg, 82% yield).
1H NMR (300 MHz, CDCl3) δ 7.36-7.16 (m, 4H), 6.99-6.90 (m, 2H), 6.86 (dd, 1H), 6.82 (d, 1H), 6.63-6.53 (m, 2H), 4.34 (s, 2H), 4.14 (q, 2H), 4.02 (br s, 1H), 3.91 (s, 2H), 3.60-3.40 (m, 2H), 3.03-2.87 (m, 2H), 2.55-2.38 (m, 6H), 2.36-2.11 (m, 6H), 2.05 (s, 2H), 1.83-1.72 (m, 1H), 1.55-1.44 (m, 1H), 1.34-1.18 (m, 4H).
<71-3> Preparation of (1S,2S)-2-(4-(((9-((4-hydroxy-1,1-dioxidotetrahydro-2H-thiopyran-4-yl)methoxy)-6,7-dihydro-5H-dibenzo[a,c][7]annulen-2-yl)methyl)amino)phenyl)cyclopropanecarboxylic acid




According to the procedures as described in <1-11>, the compound obtained in <71-2> was used to prepare the title compound (white foam, 68 mg, 71% yield).
MS m/z 560 [M−H]−.
1H NMR (300 MHz, CDCl3) δ 7.35-7.23 (m, 3H), 7.20 (d, 1H), 6.94 (m, 2H), 6.86 (dd, 1H), 6.81 (d, 1H), 6.59 (m, 2H), 4.34 (s, 2H), 3.91 (d, 2H), 3.62-3.38 (m, 2H), 2.96 (m, 2H), 2.61-2.38 (m, 5H), 2.36-2.09 (m, 6H), 1.78 (m, 1H), 1.58 (m, 1H), 1.39-1.28 (m, 1H).
Example 72
Preparation of (1S,2S)-2-(4-(((9-(3-(ethylsulfonyl)propoxy)-6,7-dihydro-5H-dibenzo[a,c][7]annulen-2-yl)methyl)amino)phenyl)cyclopropanecarboxylic acid
<72-1> Preparation of 9-(3-(ethylsulfonyl)propoxy)-6,7-dihydro-5H-dibenzo[a,c][7]annulene-2-carbaldehyde




According to the procedures as described in <3-3>, the compound obtained in <66-2> was used to prepare the title compound (white solid, 82 mg, 91% yield).
1H NMR (300 MHz, CDCl3) δ 10.05 (s, 1H), 7.84 (d, 1H), 7.78 (dd, 1H), 7.40 (d, 1H), 7.35 (d, 1H), 6.89 (dd, 1H), 6.81 (d, 1H), 4.18 (t, 2H), 3.28 (t, 2H), 3.06 (q, 2H), 2.57 (t, 2H), 2.47 (t, 2H), 2.42-2.34 (m, 2H), 2.25 (m, 2H), 1.45 (t, 3H).
<72-2> Preparation of (1S,2S)-ethyl 2-(4-(((9-(3-(ethylsulfonyl)propoxy)-6,7-dihydro-5H-dibenzo[a,c][7]annulen-2-yl)methyl)amino)phenyl)cyclopropanecarboxylate




According to the procedures as described in <3-4>, the compound obtained in <72-1> was used to prepare the title compound (white solid, 122 mg, 100% yield).
1H NMR (300 MHz, CDCl3) δ 7.32 (d, 1H), 7.29-7.24 (m, 2H), 7.19 (d, 1H), 6.93 (d, 2H), 6.84 (dd, 1H), 6.78 (d, 1H), 6.58 (d, 2H), 4.33 (s, 2H), 4.16 (t, 2H), 4.15 (q, 2H), 3.22 (dd, 2H), 3.05 (q, 2H), 2.46 (m, 4H), 2.36 (m, 2H), 2.17 (m, 2H), 1.77 (m, 1H), 1.81-1.75 (m, 1H), 1.53 (m, 1H), 1.45 (t, 3H), 1.27 (t, 3H), 1.23 (m, 1H).
<72-3> Preparation of (1S,2S)-2-(4-(((9-(3-(ethylsulfonyl)propoxy)-6,7-dihydro-5H-dibenzo[a,c][7]annulen-2-yl)methyl)amino)phenyl)cyclopropanecarboxylic acid




According to the procedures as described in <3-5>, the compound obtained in <72-2> was used to prepare the title compound (white foam, 105 mg, 91% yield).
MS m/z 532 [M−H]−.
1H NMR (600 MHz, CDCl3) δ 7.31 (d, 1H), 7.26 (d, 1H), 7.23 (dd, 1H), 7.18 (d, 1H), 6.93 (d, 2H), 6.82 (dd, 1H), 6.78 (d, 1H), 6.58 (d, 2H), 4.32 (s, 2H), 4.15 (t, 2H), 3.21 (dd, 2H), 3.04 (q, 2H), 2.51-2.49 (m, 1H), 2.46 (m, 4H), 2.37-2.33 (m, 2H), 2.16 (m, 2H), 1.77 (m, 1H), 1.57 (m, 1H), 1.43 (t, 3H), 1.34-1.30 (m, 1H).
Example 73
Preparation of (1S,2S)-2-(4-(((9-((1,1-dioxidotetrahydro-2H-thiopyran-4-yl)oxy)-11-methyl-6,7-dihydrodibenzo[b,d]oxepin-2-yl)methyl)amino)phenyl)cyclopropanecarboxylic acid
<73-1> Preparation of (1S,2S)-ethyl 2-(4-(((9-((1,1-dioxidotetrahydro-2H-thiopyran-4-yl)oxy)-11-methyl-6,7-dihydrodibenzo[b,d]oxepin-2-yl)methyl)amino)phenyl)cyclopropanecarboxylate




According to the procedures as described in <3-4>, the compound obtained in <52-1> (white foam, 54.6 mg, 95% yield).
1H NMR (300 MHz, CDCl3) δ 7.31-7.24 (m, 2H), 7.12 (d, 1H), 6.93 (d, 2H), 6.78 (d, 1H), 6.71 (d, 1H), 6.57 (d, 2H), 4.69 (br s, 1H), 4.41 (m, 2H), 4.34 (s, 2H), 4.15 (q, 2H), 4.05 (br s, 1H), 3.43 (m, 2H), 2.95 (m, 2H), 2.89-2.73 (m, 1H), 2.58-2.30 (m, 6H), 2.26 (s, 3H), 1.76 (m, 1H), 1.55-1.47 (m, 1H), 1.32-1.17 (m, 4H).
<73-2> Preparation of (1S,2S)-2-(4-(((9-((1,1-dioxidotetrahydro-2H-thiopyran-4-yl)oxy)-11-methyl-6,7-dihydrodibenzo[b,d]oxepin-2-yl)methyl)amino)phenyl)cyclopropanecarboxylic acid




According to the procedures as described in <1-11>, the compound obtained in <73-1> was used to prepare the title compound (white foam, 45.2 mg, 87% yield).
MS m/z 570 [M+Na]+.
1H NMR (300 MHz, CDCl3) δ 7.31-7.23 (m, 2H), 7.12 (d, 1H), 6.93 (d, 2H), 6.78 (d, 1H), 6.71 (d, 1H), 6.57 (d, 2H), 4.69 (br s, 1H), 4.41 (m, 2H), 4.34 (s, 2H), 3.43 (m, 2H), 2.95 (m, 2H), 2.82 (m, 1H), 2.58-2.30 (m, 6H), 2.25 (s, 3H), 1.76 (m, 1H), 1.59 (m, 1H), 1.33 (m, 1H).
Example 74
Preparation of (1S,2S)-2-(4-(((9-(3-(ethylsulfonyl)propoxy)-11-methyl-6,7-dihydro-5H-dibenzo[a,c][7]annulen-2-yl)methyl)amino)phenyl)cyclopropanecarboxylic acid
<74-1> Preparation of 9-(3-(ethylsulfonyl)propoxy)-11-methyl-6,7-dihydro-5H-dibenzo[a,c][7]annulene-2-carbaldehyde




According to the procedures as described in <3-3>, the compound obtained in <57-2> was used to prepare the title compound (colorless oil, 124 mg,  ̃100% yield).
1H NMR (300 MHz, CDCl3) δ 10.02 (s, 1H), 7.81-7.69 (m, 2H), 7.45-7.34 (m, 1H), 6.76 (d, 1H), 6.65 (d, 1H), 5.51 (s, 1H), 4.16 (t, 2H), 3.31-3.16 (m, 2H), 3.07 (q, 2H), 2.61 (m, 1H), 2.53-1.96 (m, 10H), 1.45 (t, 3H).
<74-2> Preparation of (1S,2S)-ethyl 2-(4-(((9-(3-(ethylsulfonyl)propoxy)-11-methyl-6,7-dihydro-5H-dibenzo[a,c][7]annulen-2-yl)methyl)amino)phenyl)cyclopropanecarboxylate




According to the procedures as described in <3-4>, the compound obtained in <74-1> was used to prepare the title compound (white foam, 142 mg, 77% yield).
1H NMR (300 MHz, CDCl3) δ 7.25-7.15 (m, 3H), 6.96-6.85 (m, 2H), 6.70 (d, 1H), 6.62 (d, 1H), 6.60-6.49 (m, 2H), 4.33 (s, 2H), 4.20-4.00 (m, 5H), 3.27-3.15 (m, 2H), 3.05 (q, 2H), 2.55-2.14 (m, 9H), 2.08-1.94 (m, 2H), 1.77 (m, 1H), 1.51 (m, 1H), 1.44 (t, 3H), 1.32-1.15 (m, 4H).
<74-3> Preparation of (1S,2S)-2-(4-(((9-(3-(ethylsulfonyl)propoxy)-11-methyl-6,7-dihydro-5H-dibenzo[a,c][7]annulen-2-yl)methyl)amino)phenyl)cyclopropanecarboxylic acid




According to the procedures as described in <1-11>, the compound obtained in <74-2> was used to prepare the title compound (white foam, 125 mg, 93% yield).
MS m/z 546 [M−H]−.
1H NMR (300 MHz, CDCl3) δ 7.25-7.15 (m, 3H), 6.97-6.87 (m, 2H), 6.70 (d, 1H), 6.62 (d, 1H), 6.60-6.51 (m, 2H), 4.33 (s, 2H), 4.12 (t, 2H), 3.26-3.15 (m, 2H), 3.05 (q, 2H), 2.56-2.21 (m, 7H), 2.19 (s, 3H), 2.03 (m, 3H), 1.82-1.73 (m, 1H), 1.57 (m, 1H), 1.44 (t, 3H), 1.37-1.29 (m, 1H).
Example 75
Preparation of (1S,2S)-2-(4-(((9-((1,1-dioxidotetrahydro-2H-thiopyran-4-yl)methoxy)-11-methyl-6,7-dihydro-5H-dibenzo[a,c][7]annulen-2-yl)methyl)amino)phenyl)cyclopropanecarboxylic acid
<75-1> Preparation of methyl 9-((1,1-dioxidotetrahydro-2H-thiopyran-4-yl)methoxy)-11-methyl-6,7-dihydro-5H-dibenzo[a,c][7]annulene-2-carboxylate




According to the procedures as described in <47-1>, the compound obtained in <7-6> was used to prepare the title compound (colorless oil, 143 mg, 94% yield).
1H NMR (300 MHz, CDCl3) δ 7.96-7.88 (m, 2H), 7.31 (d, 1H), 6.74 (d, 1H), 6.63 (d, 1H), 3.96-3.86 (m, 5H), 3.23-2.97 (m, 4H), 2.63-2.52 (m, 1H), 2.52-2.16 (m, 8H), 2.14-1.97 (m, 5H).
<75-2> Preparation of 4-(((10-(hydroxymethyl)-1-methyl-6,7-dihydro-5H-dibenzo[a,c][7]annulen-3-yl)oxy)methyl)tetrahydro-2H-thiopyran 1,1-dioxide




According to the procedures as described in <1-9>, the compound obtained in <75-1> was used to prepare the title compound (colorless oil, 121 mg, 91% yield).
1H NMR (300 MHz, CDCl3) δ 7.28-7.20 (m, 3H), 6.72 (d, 1H), 6.62 (d, 1H), 4.71 (d, 2H), 3.90 (d, 2H), 3.22-2.94 (m, 4H), 2.58-2.19 (m, 9H), 2.15-1.93 (m, 5H), 1.68 (t, 1H).
<75-3> Preparation of 9-((1,1-dioxidotetrahydro-2H-thiopyran-4-yl)methoxy)-11-methyl-6,7-dihydro-5H-dibenzo[a,c][7]annulene-2-carbaldehyde




According to the procedures as described in <3-3>, the compound obtained in <75-2> was used to prepare the title compound (white foam, 100 mg, 83% yield).
1H NMR (300 MHz, CDCl3) δ 10.02 (s, 1H), 7.81-7.70 (m, 2H), 7.46-7.35 (m, 1H), 6.75 (d, 1H), 6.64 (d, 1H), 3.91 (d, 2H), 3.25-2.93 (m, 4H), 2.61 (m, 1H), 2.55-2.16 (m, 8H), 2.16-2.00 (m, 5H).
<75-4> Preparation of (1S,2S)-ethyl 2-(4-(((9-((1,1-dioxidotetrahydro-2H-thiopyran-4-yl)methoxy)-11-methyl-6,7-dihydro-5H-dibenzo[a,c][7]annulen-2-yl)methyl)amino)phenyl)cyclopropanecarboxylate




According to the procedures as described in <3-4>, the compound obtained in <75-3> was used to prepare the title compound (colorless oil, 130 mg, 88% yield).
1H NMR (300 MHz, CDCl3) δ 7.25-7.16 (m, 3H), 6.95-6.87 (m, 2H), 6.69 (d, 1H), 6.61 (d, 1H), 6.59-6.51 (m, 2H), 4.33 (s, 2H), 4.14 (q, 2H), 4.03 (br s, 1H), 3.89 (d, 2H), 3.20-2.95 (m, 4H), 2.56-2.22 (m, 7H), 2.20 (s, 3H), 2.12-1.95 (m, 5H), 1.76 (m, 1H), 1.50 (m, 1H), 1.30-1.18 (m, 4H).
<75-5> Preparation of (1S,2S)-2-(4-(((9-((1,1-dioxidotetrahydro-2H-thiopyran-4-yl)methoxy)-11-methyl-6,7-dihydro-5H-dibenzo[a,c][7]annulen-2-yl)methyl)amino)phenyl)cyclopropanecarboxylic acid




According to the procedures as described in <1-11>, the compound obtained in <75-4> was used to prepare the title compound (yellow foam, 99 mg, 80% yield).
MS m/z 558 [M−H]−.
1H NMR (300 MHz, CDCl3) δ 7.25-7.15 (m, 3H), 6.95-6.87 (m, 2H), 6.69 (d, 1H), 6.61 (d, 1H), 6.60-6.50 (m, 2H), 4.33 (s, 2H), 3.89 (d, 2H), 3.20-2.95 (m, 4H), 2.59-2.21 (m, 7H), 2.19 (s, 3H), 2.10-1.95 (m, 5H), 1.75 (m, 1H), 1.57 (m, 1H), 1.39-1.30 (m, 1H).
Example 76
Preparation of (1S,2S)-2-(4-(((9-((1,1-dioxidotetrahydro-2H-thiopyran-4-yl)oxy)-11-methyl-6,7-dihydro-5H-dibenzo[a,c][7]annulen-2-yl)methyl)amino)phenyl)cyclopropanecarboxylic acid
<76-1> Preparation of 9-((1,1-dioxidotetrahydro-2H-thiopyran-4-yl)oxy)-11-methyl-6,7-dihydro-5H-dibenzo[a,c][7]annulene-2-carbaldehyde




According to the procedures as described in <3-3>, the compound obtained in <55-2> was used to prepare the title compound (white foam, 112 mg, 96% yield).
1H NMR (300 MHz, CDCl3) δ 10.02 (s, 1H), 7.80-7.72 (m, 2H), 7.42 (d, 1H), 6.80 (d, 1H), 6.68 (d, 1H), 4.72 (m, 1H), 3.46 (t, 2H), 2.96 (m, 2H), 2.68-2.34 (m, 7H), 2.31 (s, 3H), 2.29-2.00 (m, 3H).
<76-2> Preparation of (1S,2S)-ethyl 2-(4-(((9-((1,1-dioxidotetrahydro-2H-thiopyran-4-yl)oxy)-11-methyl-6,7-dihydro-5H-dibenzo[a,c][7]annulen-2-yl)methyl)amino)phenyl)cyclopropanecarboxylate




According to the procedures as described in <3-4>, the compound obtained in <76-1> was used to prepare the title compound (white foam, 139 mg, 83% yield).
1H NMR (300 MHz, CDCl3) δ 7.26-7.15 (m, 3H), 6.98-6.87 (m, 2H), 6.74 (d, 1H), 6.65 (d, 1H), 6.61-6.50 (m, 2H), 4.68 (m, 1H), 4.33 (s, 2H), 4.14 (q, 2H), 4.03 (s, 1H), 3.45 (t, 2H), 3.04-2.84 (m, 2H), 2.59-2.13 (m, 12H), 2.05 (m, 2H), 1.82-1.72 (m, 1H), 1.51 (m, 1H), 1.32-1.17 (m, 4H).
<76-3> Preparation of (1S,2S)-2-(4-(((9-((1,1-dioxidotetrahydro-2H-thiopyran-4-yl)oxy)-11-methyl-6,7-dihydro-5H-dibenzo[a,c][7]annulen-2-yl)methyl)amino)phenyl)cyclopropanecarboxylic acid




According to the procedures as described in <1-11>, the compound obtained in <76-2> was used to prepare the title compound (white foam, 120 mg, 91% yield).
MS m/z 544 [M−H]−.
1H NMR (300 MHz, CDCl3) δ 7.25-7.17 (m, 3H), 6.98-6.84 (m, 2H), 6.74 (d, 1H), 6.65 (d, 1H), 6.60-6.48 (m, 2H), 4.68 (m, 1H), 4.34 (s, 2H), 3.45 (t, 2H), 3.04-2.84 (m, 2H), 2.55-2.20 (m, 9H), 2.18 (s, 3H), 2.05 (m, 2H), 1.85-1.68 (m, 1H), 1.57 (m, 1H), 1.39-1.29 (m, 1H).
Example 77
Preparation of (1S,2S)-2-(4-(((9-((4-hydroxy-1,1-dioxidotetrahydro-2H-thiopyran-4-yl)methoxy)-11-methyl-6,7-dihydro-5H-dibenzo[a,c][7]annulen-2-yl)methyl)amino)phenyl)cyclopropanecarboxylic acid
<77-1> Preparation of (1S,2S)-ethyl 2-(4-(((9-((4-hydroxy-1,1-dioxidotetrahydro-2H-thiopyran-4-yl)methoxy)-11-methyl-6,7-dihydro-5H-dibenzo[a,c][7]annulen-2-yl)methyl)amino)phenyl)cyclopropanecarboxylate




According to the procedures as described in <3-4>, the compound obtained in <63-1> was used to prepare the title compound (colorless oil, 76 mg, 90% yield).
1H NMR (300 MHz, CDCl3) δ 7.25-7.17 (m, 3H), 6.96-6.86 (m, 2H), 6.73 (d, 1H), 6.64 (d, 1H), 6.59-6.50 (m, 2H), 4.33 (s, 2H), 4.15 (q, 2H), 4.05 (br s, 1H), 3.89 (s, 2H), 3.61-3.39 (m, 2H), 3.03-2.85 (m, 2H), 2.58-2.13 (m, 12H), 2.02 (m, 2H), 1.84-1.72 (m, 1H), 1.51 (m, 1H), 1.35-1.17 (m, 4H).
<77-2> Preparation of (1S,2S)-2-(4-(((9-((4-hydroxy-1,1-dioxidotetrahydro-2H-thiopyran-4-yl)methoxy)-11-methyl-6,7-dihydro-5H-dibenzo[a,c][7]annulen-2-yl)methyl)amino)phenyl)cyclopropanecarboxylic acid




According to the procedures as described in <1-11>, the compound obtained in <77-1> was used to prepare the title compound (yellow foam, 48 mg, 66% yield).
MS m/z 574 [M−H]−.
1H NMR (300 MHz, CDCl3) δ 7.25-7.17 (m, 3H), 6.92 (m, 2H), 6.72 (d, 1H), 6.64 (d, 1H), 6.60-6.51 (m, 2H), 4.34 (s, 2H), 3.89 (s, 2H), 3.57-3.38 (m, 2H), 2.95 (m, 2H), 2.58-2.21 (m, 9H), 2.18 (s, 3H), 2.00 (m, 2H), 1.76 (m, 1H), 1.57 (m, 1H), 1.39-1.29 (m, 1H).
Example 78
Preparation of (1S,2S)-2-(4-(((9-((1,1-dioxidotetrahydro-2H-thiopyran-4-yl)methoxy)-6,7-dihydro-5H-dibenzo[a,c][7]annulen-2-yl)methyl)amino)phenyl)cyclopropanecarboxylic acid
<78-1> Preparation of methyl 9-((1,1-dioxidotetrahydro-2H-thiopyran-4-yl)methoxy)-6,7-dihydro-5H-dibenzo[a,c][7]annulene-2-carboxylate




According to the procedures as described in <47-1>, the compound obtained in <5-7> was used to prepare the title compound (white foam, 130.4 mg, 105% yield).
1H NMR (300 MHz, CDCl3) δ 8.01 (d, 1H), 7.93 (dd, 1H), 7.35 (d, 1H), 7.30 (d, 1H), 6.86 (dd, 1H), 6.79 (d, 1H), 3.93 (s, 5H), 3.26-2.96 (m, 4H), 2.55 (t, 2H), 2.46 (t, 2H), 2.31 (m, 2H), 2.27-2.14 (m, 2H), 2.13-2.05 (m, 3H).
<78-2> Preparation of 4-(((10-(hydroxymethyl)-6,7-dihydro-5H-dibenzo[a,c][7]annulen-3-yl)oxy)methyl)tetrahydro-2H-thiopyran 1,1-dioxide




According to the procedures as described in <1-9>, the compound obtained in <78-1> was used to prepare the title compound (white solid, 70.7 mg, 68% yield).
1H NMR (300 MHz, CDCl3) δ 7.37-7.19 (m, 3H), 6.84 (dd, 1H), 6.79 (d, 1H), 4.74 (d, 2H), 3.92 (d, 2H), 3.26-2.92 (m, 4H), 2.48 (m, 4H), 2.33 (m, 2H), 2.24-1.96 (m, 5H), 1.68 (t, 1H).
<78-3> Preparation of 9-((1,1-dioxidotetrahydro-2H-thiopyran-4-yl)methoxy)-6,7-dihydro-5H-dibenzo[a,c][7]annulene-2-carbaldehyde




According to the procedures as described in <3-3>, the compound obtained in <78-2> was used to prepare the title compound (white foam, 95.8 mg, 89% yield).
1H NMR (300 MHz, CDCl3) δ 10.05 (s, 1H), 7.84 (d, 1H), 7.78 (dd, 1H), 7.40 (d, 1H), 7.35 (d, 1H), 6.88 (dd, 1H), 6.81 (d, 1H), 3.93 (d, 2H), 3.24-2.95 (m, 4H), 2.58 (t, 2H), 2.48 (t, 2H), 2.32 (m, 2H), 2.24 (m, 2H), 2.15-1.96 (m, 3H).
<78-4> Preparation of (1S,2S)-ethyl 2-(4-(((9-((1,1-dioxidotetrahydro-2H-thiopyran-4-yl)methoxy)-6,7-dihydro-5H-dibenzo[a,c][7]annulen-2-yl)methyl)amino)phenyl)cyclopropanecarboxylate




According to the procedures as described in <3-4>, the compound obtained in <78-3> was used to prepare the title compound (white foam, 124.8 mg, 87% yield).
1H NMR (300 MHz, CDCl3) δ 7.34-7.22 (m, 3H), 7.19 (d, 1H), 6.93 (d, 2H), 6.83 (dd, 1H), 6.78 (d, 1H), 6.59 (d, 2H), 4.33 (s, 2H), 4.14 (q, 2H), 4.02 (s, 1H), 3.91 (d, 2H), 3.20-2.98 (m, 4H), 2.54-2.38 (m, 5H), 2.31 (m, 2H), 2.23-2.12 (m, 2H), 2.13-1.96 (m, 3H), 1.84-1.73 (m, 1H), 1.55-1.45 (m, 1H), 1.33-1.17 (m, 4H).
<78-5> Preparation of (1S,2S)-2-(4-(((9-((1,1-dioxidotetrahydro-2H-thiopyran-4-yl)methoxy)-6,7-dihydro-5H-dibenzo[a,c][7]annulen-2-yl)methyl)amino)phenyl)cyclopropanecarboxylic acid




According to the procedures as described in <1-11>, the compound obtained in <78-4> was used to prepare the title compound (white foam, 129.3 mg, 108% yield).
MS m/z 544 [M−H]−.
1H NMR (300 MHz, CDCl3) δ 7.34-7.17 (m, 4H), 6.94 (d, 2H), 6.84 (dd, 1H), 6.79 (d, 1H), 6.60 (d, 2H), 4.34 (s, 2H), 3.91 (d, 2H), 3.21-2.96 (m, 4H), 2.57-2.39 (m, 5H), 2.30 (m, 2H), 2.24-2.13 (m, 2H), 2.12-1.98 (m, 3H), 1.78 (m, 1H), 1.63-1.52 (m, 1H), 1.33 (m, 1H).
Example 79
Preparation of 2-((S)-6-(((R)-6-methyl-9-(3-(methylsulfonyl)propoxy)-6,7-dihydrodibenzo[b,d]oxepin-2-yl)methoxy)-2,3-dihydrobenzofuran-3-yl)acetic acid
<79-1> Preparation of 1-(benzyloxy)-3-bromobenzene




A solution of 3-bromophenol (3 g, 17.34 mmol) in acetone (100 mL) was added with benzyl bromide (2.2 mL, 19.07 mmol) and K2CO3 (7.0 g, 52.02 mmol), and the resulting mixture was refluxed for 15 hours. The reaction mixture was cooled to room temperature, filtered, and washed with acetone. The filtrate was concentrated and purified by silica gel chromatography to obtain the title compound (white solid, 5.1 g, 100% yield).
1H NMR (300 MHz, CDCl3) δ 7.50-7.30 (m, 5H), 7.20-7.01 (m, 3H), 6.98-6.80 (m, 1H), 5.05 (s, 2H).
<79-2> Preparation of (S)-1-(3-(benzyloxy)phenyl)propan-2-ol




A solution of the compound obtained in <79-1> (3.37 g, 12.8 mmol) in THF (100 mL) was cooled to −78° C., slowly added with n-BuLi (1.6M hexene solution, 8.4 mL, 13.44 mmol), and stirred for 20 minutes. The reaction mixture was added with (S)-(−)propylene oxide (985 L, 14.08 mmol) and BF3.Et2O (2.3 mL, 19.2 mmol), followed by stirring at the same temperature for 1.5 hours. The mixture was added with a saturated NH4Cl aqueous solution, slowly heated to room temperature, and then extracted with EtOAc two times. The organic layer was dried over MgSO4, concentrated, and purified by silica gel chromatography to obtain the title compound (colorless oil, 2.3 g, 74.6% yield).
1H NMR (300 MHz, CDCl3) δ 7.52-7.29 (m, 5H), 7.25-7.18 (m, 1H), 6.91-6.75 (m, 3H), 5.06 (s, 2H), 4.01 (m, 1H), 2.77 (dd, 1H), 2.66 (dd, 1H), 1.51 (d, 1H), 1.24 (d, 3H).
<79-3> Preparation of (S)-1-(5-(benzyloxy)-2-bromophenyl)propan-2-ol




A solution of the compound obtained in <79-2> (2.2 g, 9.07 mmol) in acetonitrile (90 mL) was cooled to 0° C., added with NBS (1.6 g, 9.07 mmol) and stirred at room temperature for 4 hours. The reaction mixture was concentrated and purified by silica gel chromatography to obtain the title compound (white solid, 2.48 g, 85.1% yield).
1H NMR (300 MHz, CDCl3) δ 7.49-7.28 (m, 5H), 6.90 (d, 1H), 6.74 (dd, 1H), 5.04 (s, 2H), 4.12 (m, 1H), 2.92 (dd, 1H), 2.78 (dd, 1H), 1.47 (d, 1H), 1.27 (d, 3H).
<79-4> Preparation of (S)-methyl 4′-(benzyloxy)-2′-(2-hydroxypropyl)-6-(methoxymethoxy)-[1,1′-biphenyl]-3-carboxylate




A solution of the compound obtained in <79-3> (2.00 g, 6.22 mmol) in 1,4-dioxane (50 mL) was added with methyl 4-(methoxymethoxy)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaboran-2-yl)benzoate (1.67 g, 5.18 mmol), Pd(dppf)Cl2 (211 mg, 0.259 mmol) and K2CO3 (2.15 g, 15.4 mmol), and then stirred at 90° C. for 15 hours. The reaction mixture was filtered through Celite and washed with ethyl acetate (EA). The filtrate was concentrated and purified by silica gel chromatography to obtain the title compound (brown oil, 1.84 g, 81.7% yield).
1H NMR (300 MHz, CDCl3) δ 8.01 (dd, 1H), 7.84 (s, 1H), 7.50-7.30 (m, 5H), 7.23 (d, 1H), 7.09 (d, 1H), 6.97 (d, 1H), 6.91 (dd, 1H), 5.22-5.04 (m, 4H), 3.88 (s, 3H), 3.81 (br s, 1H), 3.37 (s, 3H), 2.74-2.48 (m, 2H), 1.92 (s, 1H), 1.03 (d, 3H).
<79-5> Preparation of (S)-methyl 4′-(benzyloxy)-6-hydroxy-2′-(2-hydroxypropyl)-[1,1′-biphenyl]-3-carboxylate




A solution of the compound obtained in <79-4> (268 mg, 0.614 mmol) in MeOH (6 mL) was added with p-TsOH.H2O (350 mg, 1.84 mmol) and stirred at 50° C. for 2 hours. The reaction mixture was cooled to room temperature, diluted with distilled water, and neutralized with a saturated NaHCO3 aqueous solution. The aqueous layer was extracted with CH2Cl2 two times, and the organic layer was collected, dried over MgSO4, and purified by silica gel chromatography to obtain the title compound (yellow oil, 225 mg, 93.3% yield).
1H NMR (300 MHz, CDCl3) δ 7.98 (dd, 1H), 7.86-7.74 (m, 1H), 7.50-7.30 (m, 5H), 7.14 (d, 1H), 7.06-6.93 (m, 3H), 5.12 (s, 2H), 4.07 (m, 1H), 3.88 (s, 3H), 2.74-2.42 (m, 4H), 1.20 (d, 3H).
<79-6> Preparation of (R)-methyl 9-(benzyloxy)-6-methyl-6,7-dihydrodibenzo[b,d]oxepin-2-carboxylate




A solution of the compound obtained in <79-5> (225 mg, 0.573 mmol) in THF (5 mL) was added with PBu3 (0.021 mL, 0.860 mmol) and ADD (217 mg, 0.860 mmol), and then stirred at room temperature for 3 hours. The reaction mixture was concentrated and purified by silica gel chromatography to obtain the title compound (pale yellow oil, 150 mg, 69.9% yield).
1H NMR (300 MHz, CDCl3) δ 8.10 (d, 1H), 7.96 (dd, 1H), 7.52-7.30 (m, 6H), 7.12 (d, 1H), 7.01 (dd, 1H), 6.91 (d, 1H), 5.13 (s, 2H), 4.97-4.78 (m, 1H), 3.92 (s, 3H), 2.82 (dd, 1H), 2.52 (dd, 1H), 1.39 (d, 3H).
<79-7> Preparation of (R)-methyl 9-hydroxy-6-methyl-6,7-dihydrodibenzo[b,d]oxepin-2-carboxylate




A solution of the compound obtained in <79-6> (153 mg, 0.408 mmol) in MeOH (4 mL) was added with Pd—C (30 mg) and stirred under a hydrogen atmosphere for 15 hours. The reaction mixture was filtered through Celite and washed with EA. The filtrate thus obtained was concentrated and purified by silica gel chromatography to obtain the title compound (yellow oil, 114 mg, 98.2% yield).
1H NMR (300 MHz, CDCl3) δ 8.09 (d, 1H), 7.96 (dd, 1H), 7.38 (d, 1H), 7.12 (d, 1H), 6.87 (dd, 1H), 6.77 (d, 1H), 4.98 (s, 1H), 4.95-4.79 (m, 1H), 3.93 (s, 3H), 2.80 (dd, 1H), 2.50 (dd, 1H), 1.40 (d, 3H).
<79-8> Preparation of (R)-methyl 6-methyl-9-(3-(methylsulfonyl)propoxy)-6,7-dihydrodibenzo[b,d]oxepin-2-carboxylate




According to the procedures as described in <1-8>, the compound obtained in <79-7> was used to prepare the title compound (white solid, 204 mg, 99.0% yield).
1H NMR (300 MHz, CDCl3) δ 8.09 (d, 1H), 7.97 (dd, 1H), 7.43 (d, 1H), 7.12 (d, 1H), 6.92 (dd, 1H), 6.81 (d, 1H), 4.88 (m, 1H), 4.18 (t, 2H), 3.93 (s, 3H), 3.40-3.21 (m, 2H), 2.98 (s, 3H), 2.82 (dd, 1H), 2.52 (dd, 1H), 2.45-2.32 (m, 2H), 1.40 (d, 3H).
<79-9> Preparation of (R)-(6-methyl-9-(3-(methylsulfonyl)propoxy)-6,7-dihydrodibenzo[b,d]oxepin-2-yl)methanol




According to the procedures as described in <1-9>, the compound obtained in <79-8> was used to prepare the title compound (pale yellow oil, 142 mg, 76.3% yield).
1H NMR (300 MHz, CDCl3) δ 7.43-7.36 (m, 2H), 7.29 (dd, 1H), 7.08 (d, 1H), 6.90 (d, 1H), 6.81 (d, 1H), 4.88-4.77 (m, 1H), 4.73 (d, 2H), 4.17 (t, 2H), 3.40-3.16 (m, 2H), 2.98 (s, 3H), 2.80 (dd, 1H), 2.49 (dd, 1H), 2.44-2.28 (m, 2H), 1.69 (t, 1H), 1.38 (d, 3H).
<79-10> Preparation of methyl 2-((S)-6-(((R)-6-methyl-9-(3-(methylsulfonyl)propoxy)-6,7-dihydrodibenzo[b,d]oxepin-2-yl)methoxy)-2,3-dihydrobenzofuran-3-ylacetate




According to the procedures as described in <1-10>, the compound obtained in <79-9> was used to prepare the title compound (white foam, 126 mg, 69.2% yield).
1H NMR (300 MHz, CDCl3) δ 7.45-7.30 (m, 1H), 7.12-7.01 (m, 2H), 6.90 (dd, 1H), 6.81 (d, 1H), 6.54-6.45 (m, 2H), 5.03 (s, 2H), 4.89-4.71 (m, 3H), 4.27 (dd, 1H), 4.17 (t, 2H), 4.01-3.75 (m, 2H), 3.72 (s, 3H), 3.28 (m, 2H), 2.97 (s, 3H), 2.85-2.71 (m, 2H), 2.63-2.44 (m, 1H), i2.44-2.31 (m, 2H), 1.38 (d, 3H).
<79-11> Preparation of 2-((S)-6-(((R)-6-methyl-9-(3-(methylsulfonyl)propoxy)-6,7-dihydrodibenzo[b,d]oxepin-2-yl)methoxy)-2,3-dihydrobenzofuran-3-yl)acetic acid




According to the procedures as described in <1-11>, the compound obtained in <79-10> was used to prepare the title compound (white foam, 129 mg, 88.0% yield).
MS m/z 551 [M−H]−.
1H NMR (300 MHz, CDCl3) δ 7.43 (d, 1H), 7.38 (d, 1H), 7.34 (dd, 1H), 7.16-7.01 (m, 2H), 6.90 (dd, 1H), 6.81 (d, 1H), 6.58-6.45 (m, 2H), 5.03 (s, 2H), 4.89-4.71 (m, 2H), 4.30 (dd, 1H), 4.17 (t, 2H), 3.82 (m, 1H), 3.43-3.18 (m, 2H), 2.97 (s, 3H), 2.82 (m, 2H), 2.62 (dd, 1H), 2.51 (dd, 1H), 2.45-2.28 (m, 2H), 1.38 (d, 3H).
Example 80
Preparation of (S)-2-(6-((9-(3-(methylsulfonyl)propoxy)dibenzo[d,f][1,3]dioxepin-2-yl)methoxy)-2,3-dihydrobenzofuran-3-yl)acetic acid
<80-1> Preparation of methyl 4′-(benzyloxy)-2′,6-bis(methoxymethoxy)-[1,1′-biphenyl]-3-carboxylate




A solution of 4-(benzyloxy)-1-bromo-2-(methoxymethoxy)benzene (prepared in accordance with the reference [Synthesis, 1999, #6, p. 1017-1021]; 4.82 g, 14.921 mmol) and the compound obtained in <2-6> (4.37 g, 13.564 mmol) in 1,4-dioxane (70 mL) was added with K2CO3 (5.62 g, 40.693 mmol) and substituted with nitrogen. The reaction mixture was added with Pd(dppf)Cl2.MC (554 mg, 0.678 mmol) and stirred at 100° C. for 13 hours. The reaction mixture was cooled to room temperature, filtered through Celite, and washed with CH2Cl2. The filtrate thus obtained was concentrated under reduced pressure and purified by silica gel chromatography to obtain the title compound (yellow oil, 2.61 g, 44% yield).
1H NMR (300 MHz, CDCl3) δ 7.98 (dd, 1H), 7.94 (d, 1H), 7.50-7.31 (m, 5H), 7.23 (d, 1H), 7.15 (d, 1H), 6.91 (d, 1H), 6.70 (dd, 1H), 5.15 (s, 2H), 5.09 (s, 2H), 5.05 (s, 2H), 3.88 (d, 3H), 3.39 (d, 3H), 3.34 (d, 3H).
<80-2> Preparation of methyl 4′-(benzyloxy)-2′,6-dihydroxy-[1,1′-biphenyl]-3-carboxylate




According to the procedures as described in <43-3>, the compound obtained in <80-1> was used to prepare the title compound (white foam, 1.99 g, 95% yield).
1H NMR (300 MHz, CDCl3) δ 8.00 (dd, 1H), 7.96 (d, 1H), 7.49-7.31 (m, 5H), 7.17 (d, 1H), 7.06 (d, 1H), 6.72 (dd, 1H), 6.67 (d, 1H), 5.96 (br s, 1H), 5.43 (br s, 1H), 5.10 (s, 2H), 3.89 (d, 2H).
<80-3> Preparation of methyl 9-(benzyloxy)dibenzo[d,f][1,3]dioxepin-2-carboxylate




A mixed solution of the compound obtained in <80-2> (1.99 g, 5.680 mmol), K2CO3 (4.71 g, 34.079 mmol) and NaI (426 mg, 2.840 mmol) in DMF (20 mL) was added with dibromoethane (1.2 mL, 17.040 mmol) and stirred 80° C. for 13 hours. The reaction mixture was diluted with EtOAc, consecutively washed with distilled water, a saturated NH4Cl aqueous solution and brine, and then dried over MgSO4. The filtrate was concentrated under reduced pressure and purified by silica gel chromatography to obtain the title compound (white solid, 1.68 g, 82% yield).
1H NMR (300 MHz, CDCl3) δ 8.43 (d, 1H), 7.88 (dd, 1H), 7.76 (d, 1H), 7.49-7.30 (m, 5H), 7.12 (d, 1H), 6.88 (dd, 1H), 6.74 (d, 1H), 5.57 (s, 2H), 5.10 (s, 2H), 3.93 (s, 3H).
<80-4> Preparation of methyl 9-hydroxydibenzo[d,f][1,3]dioxepin-2-carboxylate




A solution of the compound obtained in <80-3> (1.68 g, 4.636 mmol) in CH2Cl2 (25 mL) and MeOH (25 mL) was added with Pd/C (10 wt % loading dry basis, 340 mg) and stirred under a hydrogen atmosphere for 3 hours. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure, diluted with CH2Cl2, stirred for 10 minutes, and then filtered. The solid thus obtained was dried in vacuo to obtain the title compound (white solid, 1.12 g, 89% yield).
1H NMR (300 MHz, CDCl3) δ 8.41 (d, 1H), 7.86 (dd, 1H), 7.69 (d, 1H), 7.11 (dd, 1H), 6.74 (dd, 1H), 6.61 (dd, 1H), 5.56 (d, 2H), 3.94 (d, 3H).
<80-5> Preparation of methyl 9-(3-(methylsulfonyl)propoxy)dibenzo[d,f][1,3]dioxepin-2-carboxylate




According to the procedures as described in <1-8>, the compound obtained in <80-4> was used to prepare the title compound (white solid, 442 mg,  ̃100% yield).
1H NMR (300 MHz, CDCl3) δ 8.42 (d, 1H), 7.89 (dd, 1H), 7.76 (d, 1H), 7.13 (d, 1H), 6.78 (dd, 1H), 6.65 (d, 1H), 5.57 (s, 2H), 4.15 (t, 2H), 3.94 (s, 3H), 3.34-3.23 (m, 2H), 2.98 (s, 3H), 2.46-2.29 (m, 2H).
<80-6> Preparation of (9-(3-(methylsulfonyl)propoxy)dibenzo[d,f][1,3]dioxepin-2-yl)methanol




According to the procedures as described in <1-9>, the compound obtained in <80-5> was used to prepare the title compound (white solid, 353 mg, 88% yield).
1H NMR (300 MHz, CDCl3) δ 7.72-7.60 (m, 2H), 7.25 (dd, 1H), 7.11 (d, 1H), 6.76 (dd, 1H), 6.66 (d, 1H), 5.57 (s, 2H), 4.73 (d, 2H), 4.15 (t, 2H), 3.39-3.19 (m, 2H), 2.97 (s, 3H), 2.45-2.30 (m, 2H), 1.68 (t, 1H).
<80-7> Preparation of (S)-methyl 2-(6-((9-(3-(methylsulfonyl)propoxy)dibenzo[d,f][1,3]dioxepin-2-yl)methoxy)-2,3-dihydrobenzofuran-3-ylacetate




According to the procedures as described in <1-10>, the compound obtained in <80-6> was used to prepare the title compound (white solid, 137 mg, 87% yield).
1H NMR (300 MHz, CDCl3) δ 7.69 (d, 1H), 7.63 (d, 1H), 7.29 (dd, 1H), 7.12 (d, 1H), 7.04 (d, 1H), 6.76 (dd, 1H), 6.65 (d, 1H), 6.54-6.45 (m, 2H), 5.57 (s, 2H), 5.02 (s, 2H), 4.76 (t, 1H), 4.34-4.22 (dd, 1H), 4.14 (t, 2H), 3.82 (m, 1H), 3.72 (s, 3H), 3.34-3.20 (m, 2H), 2.97 (s, 3H), 2.76 (dd, 1H), 2.57 (dd, 1H), 2.43-2.32 (m, 2H).
<80-8> Preparation of (S)-2-(6-((9-(3-(methylsulfonyl)propoxy)dibenzo[d,f][1,3]dioxepin-2-yl)methoxy)-2,3-dihydrobenzofuran-3-yl)acetic acid




According to the procedures as described in <1-11>, the compound obtained in <80-7> was used to prepare the title compound (white solid, 114 mg, 90% yield).
MS m/z 539 [M−H]−.
1H NMR (300 MHz, CDCl3) δ 7.69 (d, 1H), 7.63 (d, 1H), 7.29 (dd, 1H), 7.12 (d, 1H), 7.08 (d, 1H), 6.76 (dd, 1H), 6.65 (d, 1H), 6.57-6.43 (m, 2H), 5.57 (s, 2H), 5.03 (s, 2H), 4.78 (t, 1H), 4.30 (dd, 1H), 4.14 (t, 2H), 3.83 (m, 1H), 3.34-3.19 (m, 2H), 2.97 (s, 3H), 2.82 (dd, 1H), 2.63 (dd, 1H), 2.45-2.30 (m, 2H).
Example 81
Preparation of 2-((3S)-6-((1-methyl-3-morpholino-6,7-dihydro-5H-benzo[3,4]cyclohepta[1,2-d]pyrimidin-10-yl)methoxy)-2,3-dihydrobenzofuran-3-yl)acetic acid
<81-1> Preparation of 4-allyl-2-chloro-6-methylpyrimidine




2,4-dichloro-6-methylpyrimidine (10 g, 60.350 mmol), 2-allyl-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (11.5 mL, 61.350 mmol), K3PO4 (26.0 g, 122.699 mmol), THF (240 mL), distilled water (30 mL) were substituted with nitrogen for a few minutes while stirring. The mixture was added with Pd(PPh3)2Cl2 (2.15 g, 3.067 mmol) and allowed to react at 80° C. for 17 hours. The reaction mixture was cooled to room temperature and added with EtOAc and distilled water. The organic layer was separated and the aqueous layer was extracted with EtOAc one more time. The organic layer was collected, dried over MgSO4, and the filtrate thus obtained was concentrated under reduced pressure and purified by silica gel chromatography to obtain the title compound (yellow oil, 5.93 g, 57% yield).
1H NMR (300 MHz, CDCl3) δ 7.00 (s, 1H), 6.06-5.90 (m, 1H), 5.26-5.14 (m, 2H), 3.51 (m, 2H), 2.51 (s, 3H).
<81-2> Preparation of methyl 3-bromo-4-(3-(2-chloro-6-methylpyrimidin-4-yl)propyl)benzoate




A solution of the compound obtained in <81-1> (5.02 g, 29.771 mmol) in THF (35 mL) was added with 9-BBN (0.5M THF solution, 65.5 mL, 32.748 mmol) and stirred at room temperature for 2.5 hours. The mixture was added with DMF (100 mL), methyl 3-bromo-4-iodobenzoate (11.17 g, 32.748 mmol) and K2CO3 (12.34 g, 89.313 mmol), and then substituted with nitrogen for a few minutes. Then, the mixture was added with Pd(dppf)Cl2.MC (1.22 g, 1.489 mmol) and allowed to react at 100° C. for 16 hours. After cooled to room temperature, the reaction mixture was added with distilled water and brine, and then extracted with EtOAc. The organic layer was collected and dried over MgSO4. The filtrate thus obtained was concentrated under reduced pressure and purified by silica gel chromatography to obtain the title compound (yellow oil, 5.38 g, 47% yield).
1H NMR (300 MHz, CDCl3) δ 8.20 (d, 1H), 7.90 (dd, 1H), 7.29 (d, 1H), 6.98 (s, 1H), 3.92 (s, 3H), 2.90-2.74 (m, 4H), 2.50 (s, 3H), 2.17-1.99 (m, 2H).
<81-3> Preparation of methyl 3-bromo-4-(3-(6-methyl-2-morpholinopyrimidin-4-yl)propyl)benzoate




Methyl 3-bromo-4-(3-(2-chloro-6-methylpyrimidin-4-yl)propyl)benzoate obtained in <81-2> (500 mg, 1.30 mmol) was dissolved in CH3CN (5 mL), which was then added with morpholine (228 μL, 2.60 mmol) and i-Pr2NEt (340 μL, 1.95 mmol), followed by stirring at 60° C. for 1 hour. The mixture was added with morpholine (228 μL, 2.60 mmol) and further added with morpholine (228 μL, 2.60 mmol) 13 hours thereafter. After 3 hours later, the reaction mixture was cooled to room temperature, diluted with EtOAc, and extracted with brine three times. The organic layer was dried over MgSO4, concentrated under reduced pressure, and the residue thus obtained was purified by silica gel chromatography to obtain the title compound (colorless solid, 519.9 mg, 92% yield).
1H NMR (300 MHz, CDCl3) δ 8.20 (d, 1H), 7.88 (dd, 1H), 7.29 (d, 1H), 6.30 (s, 1H), 3.91 (s, 3H), 3.78 (m, 8H), 2.83 (t, 2H), 2.61 (t, 2H), 2.30 (s, 3H), 2.03 (m, 2H)
<81-4> Preparation of methyl 4-(3-(6-methyl-2-morpholinopyrimidin-4-yl)propyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaboran-2-yl)benzoate




According to the procedures as described in <5-4>, the compound obtained in <81-3> was used to prepare the title compound (pale green oil, 508.4 mg, 88% yield).
1H NMR (300 MHz, CDCl3) δ 8.43 (d, 1H), 7.99 (dd, 1H), 7.24 (d, 1H), 6.27 (s, 1H), 3.91 (s, 3H), 3.77 (m, 8H), 2.99 (t, 2H), 2.58 (t, 2H), 2.29 (s, 3H), 1.94 (m, 2H), 1.35 (s, 12H)
<81-5> Preparation of methyl 4-(3-(5-bromo-6-methyl-2-morpholinopyrimidin-4-yl)propyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaboran-2-yl)benzoate




According to the procedures as described in <5-5>, the compound obtained in <81-4> was used to prepare the title compound (colorless oil, 528.2 mg, 89% yield).
1H NMR (300 MHz, CDCl3) δ 8.43 (d, 1H), 7.99 (dd, 1H), 7.27 (d, 1H), 3.90 (s, 3H), 3.74 (m, 8H), 3.03 (t, 2H), 2.80 (t, 2H), 2.44 (s, 3H), 1.96 (m, 2H), 1.34 (s, 12H)
<81-6> Preparation of methyl 1-methyl-3-morpholino-6,7-dihydro-5H-benzo[3,4]cyclohepta[1,2-d]pyrimidine-10-carboxylate




According to the procedures as described in <5-6>, the compound obtained in <81-5> was used to prepare the title compound (colorless oil, 104.8 mg, 32% yield).
1H NMR (300 MHz, CDCl3) δ 7.95 (dd, 1H), 7.76 (d, 1H), 7.36 (d, 1H), 3.89 (s, 3H), 3.71 (m, 8H), 2.61-2.39 (m, 6H), 2.40 (s, 3H), 1.81 (m, 2H)
<81-7> Preparation of (1-methyl-3-morpholino-6,7-dihydro-5H-benzo[3,4]cyclohepta[1,2-d]pyrimidin-10-yl)methanol




According to the procedures as described in <1-9>, the compound obtained in <81-6> was used to prepare the title compound (colorless oil, 88.2 mg, 90% yield).
1H NMR (300 MHz, CDCl3) δ 7.13-7.30 (m, 3H), 4.71 (d, 2H), 3.88-3.74 (m, 8H), 2.66-2.34 (m, 4H), 2.37 (s, 3H), 2.25-2.01 (m, 2H)
<81-8> Preparation of methyl 2-((3S)-6-((9-((4-hydroxy-1,1-dioxidotetrahydro-2H-thiopyran-4-yl)methoxy)-11-methyl-6,7-dihydrodibenzo[b,d]oxepin-2-yl)methoxy)-2,3-dihydrobenzofuran-3-ylacetate




According to the procedures as described in <1-10>, the compound obtained in <81-7> was used to prepare the title compound (colorless oil, 84.5 mg, 61% yield).
1H NMR (300 MHz, CDCl3) δ 7.32-7.19 (m, 3H), 7.02 (d, 1H), 6.51-6.46 (m, 2H), 5.05 (s, 2H), 4.75 (t, 1H), 4.26 (dd, 1H), 3.88-3.74 (m, 9H), 3.72 (s, 3H), 2.74 (dd, 1H), 2.61-2.32 (m, 5H), 2.30 (s, 3H), 2.25-2.02 (m, 2H)
<81-9> Preparation of 2-((3S)-6-((1-methyl-3-morpholino-6,7-dihydro-5H-benzo[3,4]cyclohepta[1,2-d]pyrimidin-10-yl)methoxy)-2,3-dihydrobenzofuran-3-yl)acetic acid




According to the procedures as described in <1-11>, the compound obtained in <81-8> was used to prepare the title compound (white foam, 76.4 mg, 95% yield).
MS m/z 502 [M+H].
1H NMR (300 MHz, CDCl3) δ 7.32-7.21 (m, 3H), 7.05 (d, 1H), 6.52-6.46 (m, 2H), 5.05 (s, 2H), 4.76 (t, 1H), 4.28 (dd, 1H), 3.74-3.87 (m, 9H), 2.79 (dd, 1H), 2.65-2.36 (m, 5H), 2.30 (s, 3H), 2.25-2.02 (m, 2H)
Example 82
Preparation of (S)-2-(6-(((9-(3-(methylsulfonyl)propoxy)-6,7-dihydro-5H-dibenzo[a,c][7]annulen-2-yl)methyl)amino)-2,3-dihydrobenzofuran-3-yl)acetic acid
<82-1> Preparation of (S)-methyl 2-(6-(((9-(3-(methylsulfonyl)propoxy)-6,7-dihydro-5H-dibenzo[a,c][7]annulen-2-yl)methyl)amino)-2,3-dihydrobenzofuran-3-ylacetate




A solution of the compound obtained in <6-1> (80 mg, 0.223 mmol) and (S)-methyl 2-(6-amino-2,3-dihydrobenzofuran-3-ylacetate (prepared in accordance with the reference [WO 2010/143733 A1]; 46 mg, 0.223 mmol) in CH2Cl2 (2 mL) was added with AcOH (0.03 mL, 0.446 mmol), stirred at room temperature for 20 minutes, added with NaBH (OAc)3 (95 mg, 0.446 mmol), and further stirred for 3.5 hours. The reaction mixture was added with distilled water, extracted with CH2Cl2, and the organic layer was collected and dried over MgSO4. The filtrate thus obtained was concentrated under reduced pressure and purified by silica gel chromatography to obtain the title compound (white foam, 124 mg, >100% yield).
1H NMR (300 MHz, CDCl3) δ 7.34-7.21 (m, 3H), 7.19 (d, 1H), 6.93 (d, 1H), 6.84 (dd, 1H), 6.79 (d, 1H), 6.22-6.10 (m, 2H), 4.70 (t, 1H), 4.31 (s, 2H), 4.26-4.00 (m, 4H), 3.76 (m, 1H), 3.71 (s, 3H), 3.35-3.21 (m, 2H), 2.97 (s, 3H), 2.73 (dd, 1H), 2.59-2.42 (m, 5H), 2.42-2.30 (m, 2H), 2.18 (m, 2H).
<82-2> Preparation of (S)-2-(6-(((9-(3-(methylsulfonyl)propoxy)-6,7-dihydro-5H-dibenzo[a,c][7]annulen-2-yl)methyl)amino)-2,3-dihydrobenzofuran-3-yl)acetic acid




According to the procedures as described in <1-11>, the compound obtained in <82-1> was used to prepare the title compound (yellow foam, 102 mg, 84% yield).
MS m/z 534 [M−H]−.
1H NMR (300 MHz, CDCl3) δ 7.33-7.21 (m, 3H), 7.19 (d, 1H), 6.96 (d, 1H), 6.84 (dd, 1H), 6.79 (d, 1H), 6.24-6.11 (m, 2H), 4.72 (t, 1H), 4.32 (s, 2H), 4.24 (dd, 1H), 4.16 (t, 2H), 3.77 (m, 1H), 3.33-3.23 (m, 2H), 2.97 (s, 3H), 2.79 (dd, 1H), 2.59 (dd, 1H), 2.47 (m, 4H), 2.37 (m, 2H), 2.17 (m, 2H).
Example 83
Preparation of (S)-2-(6-(((9-((1,1-dioxidotetrahydro-2H-thiopyran-4-yl)methoxy)-6,7-dihydro-5H-dibenzo[a,c][7]annulen-2-yl)methyl)amino)-2,3-dihydrobenzofuran-3-yl)acetic acid
<83-1> Preparation of (S)-methyl 2-(6-(((9-((1,1-dioxidotetrahydro-2H-thiopyran-4-yl)methoxy)-6,7-dihydro-5H-dibenzo[a,c][7]annulen-2-yl)methyl)amino)-2,3-dihydrobenzofuran-3-ylacetate




According to the procedures as described in <82-1>, the compound obtained in <78-3> was used to prepare the title compound (off-white foam, 164.1 mg, 109% yield).
1H NMR (300 MHz, CDCl3) δ=7.34-7.23 (m, 3H), 7.19 (d, 1H), 6.93 (d, 1H), 6.83 (dd, 1H), 6.78 (d, 1H), 6.21-6.13 (m, 2H), 4.71 (t, 1H), 4.31 (s, 2H), 4.22 (dd, 1H), 4.07 (br s, 1H), 3.91 (d, 2H), 3.77 (m, 1H), 3.71 (s, 3H), 3.21-2.96 (m, 4H), 2.73 (dd, 1H), 2.58-2.39 (m, 5H), 2.31 (m, 2H), 2.24-2.13 (m, 2H), 2.12-1.95 (m, 3H).
<83-2> Preparation of (S)-2-(6-(((9-((1,1-dioxidotetrahydro-2H-thiopyran-4-yl)methoxy)-6,7-dihydro-5H-dibenzo[a,c][7]annulen-2-yl)methyl)amino)-2,3-dihydrobenzofuran-3-yl)acetic acid




According to the procedures as described in <1-11>, the compound obtained in <83-1> was used to prepare the title compound (off-white foam, 154.8 mg, 98% yield).
MS m/z 562 [M+H]+.
1H NMR (300 MHz, CDCl3) δ=7.34-7.23 (m, 3H), 7.19 (d, 1H), 6.97 (d, 1H), 6.83 (dd, 1H), 6.78 (d, 1H), 6.23-6.11 (m, 2H), 4.72 (t, 1H), 4.32 (s, 2H), 4.24 (dd, 1H), 3.92 (d, 2H), 3.77 (m, 1H), 3.21-2.97 (m, 4H), 2.79 (dd, 1H), 2.59 (dd, 1H), 2.48 (m, 4H), 2.31 (m, 2H), 2.18 (m, 2H), 2.13-1.97 (m, 3H).
Example 84
Preparation of (S)-2-(6-((9-((1,1-dioxidotetrahydro-2H-thiopyran-4-yl)methoxy)-6,7-dihydro-5H-dibenzo[a,c][7]annulen-2-yl)methoxy)-2,3-dihydrobenzofuran-3-yl)acetic acid
<84-1> Preparation of (S)-methyl 2-(6-((9-((1,1-dioxidotetrahydro-2H-thiopyran-4-yl)methoxy)-6,7-dihydro-5H-dibenzo[a,c][7]annulen-2-yl)methoxy)-2,3-dihydrobenzofuran-3-ylacetate




According to the procedures as described in <1-10>, the compound obtained in <84-2> was used to prepare the title compound (colorless oil, 190 mg, 104% yield).
1H NMR (300 MHz, CDCl3) δ 7.40-7.27 (m, 3H), 7.23 (d, 1H), 7.03 (dd, 1H), 6.84 (dd, 1H), 6.79 (d, 1H), 6.54-6.43 (m, 2H), 5.04 (s, 2H), 4.76 (t, 1H), 4.27 (dd, 1H), 3.91 (d, 2H), 3.80 (m, 1H), 3.72 (s, 3H), 3.24-2.93 (m, 4H), 2.76 (dd, 1H), 2.65-2.41 (m, 5H), 2.32 (m, 2H), 2.17 (m, 2H), 2.12-1.97 (m, 3H).
<84-2> Preparation of (S)-2-(6-((9-((1,1-dioxidotetrahydro-2H-thiopyran-4-yl)methoxy)-6,7-dihydro-5H-dibenzo[a,c][7]annulen-2-yl)methoxy)-2,3-dihydrobenzofuran-3-yl)acetic acid




According to the procedures as described in <1-11>, the compound obtained in <84-1> was used to prepare the title compound (white solid, 93 mg, 52% yield).
MS m/z 561 [M−H]−.
1H NMR (300 MHz, DMSO-d6) δ 7.37-7.22 (m, 4H), 7.11 (d, 1H), 6.95-6.87 (m, 2H), 6.51-6.45 (m, 2H), 5.07 (s, 2H), 4.68 (t, 1H), 4.19 (m, 1H), 3.93 (d, 2H), 3.67 (m, 1H), 3.27-3.00 (m, 4H), 2.70 (dd, 1H), 2.54-2.30 (m, 5H), 2.22-2.00 (m, 5H), 1.87-1.68 (m, 2H).
Example 85
Preparation of (S)-2-(6-((9-((1,1-dioxidotetrahydro-2H-thiopyran-4-yl)methoxy)-3-fluoro-6,7-dihydro-5H-dibenzo[a,c][7]annulen-2-yl)methoxy)-2,3-dihydrobenzofuran-3-yl)acetic acid
<85-1> Preparation of methyl 4-amino-5-bromo-2-fluorobenzoate




Methyl 4-amino-2-fluorobenzoate (prepared in accordance with the reference [Bioorganic and Medicinal Chemistry, 2009, vol. 17, p. 7042-7051]; 7.93 g, 46.9 mmol) was dissolved in CHCl3 (140 mL), added with N-bromosuccinimide (8.34 g, 46.9 mmol) at 0° C., and then stirred at room temperature for 1 hour. The reaction mixture was concentrated, and the residue thus obtained was purified by silica gel chromatography to obtain the title compound (white solid, 8.70 g, 75% yield).
1H NMR (600 MHz, CDCl3) δ 8.04 (d, 1H), 6.45 (d, 1H), 4.61 (br s, 2H), 3.88 (s, 3H).
<85-2> Preparation of methyl 5-bromo-2-fluoro-4-iodobenzoate




The compound obtained in <85-1> (8.7 g, 35.1 mmol) was dissolved in acetone, which was then added with 6N HCl aqueous solution (58.5 mL, 351 mmol) at 0° C. and stirred for 5 minutes. The reaction mixture was added with 3.5M NaNO2 aqueous solution (15 mL, 52.6 mmol) and stirred for 60 minutes. The reaction mixture was slowly added with 3.5M KI aqueous solution (20 mL, 70.1 mmol) and stirred for 2 hours. Then, the mixture was diluted with a saturated Na2S2O3 aqueous solution and extracted with EtOAc. The organic layer was washed with brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue thus obtained was purified by silica gel chromatography to obtain the title compound (white solid, 8.81 g, 70% yield).
1H NMR (600 MHz, CDCl3) δ 8.14 (d, 1H), 7.68 (d, 1H), 3.93 (s, 3H).
<85-3> Preparation of methyl 5-bromo-2-fluoro-4-(3-(3-methoxyphenyl)propyl)benzoate




1-Allyl-3-methoxybenzene (prepared in accordance with the reference [Journal of Organic Chemistry, 2013, vol. 78, p. 9772-9780]; 2.44 g, 16.5 mmol) was dissolved in THF (19 mL), slowly added with 9-BBN (0.5M THF solution, 39.5 mL, 19.8 mmol), and stirred at room temperature for 2 hours. The reaction mixture was added with the compound obtained in <88-2> (6.5 g, 18.1 mmol), K2CO3 (6.83 g, 49.3 mmol) and DMF (38 mL), and then substituted with nitrogen. Subsequently, the mixture was added with [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) complex with dichloromethane (672 mg, 0.823 mmol), and then stirred at 110° C. for 15 hours. The reaction mixture was cooled to room temperature, added with a saturated NH4Cl aqueous solution, and extracted with EtOAc. The organic layer was washed with brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue thus obtained was purified by silica gel chromatography to obtain the title compound (colorless oil, 3.49 g, 55% yield).
1H NMR (600 MHz, CDCl3) δ 8.09 (d, 1H), 7.21 (t, 1H), 7.00 (d, 1H), 6.79 (d, 1H), 6.76-6.74 (m, 2H), 3.92 (s, 3H), 3.80 (s, 3H), 2.76 (dd, 2H), 2.68 (t, 2H), 1.98-1.93 (m, 2H).
<85-4> Preparation of methyl 2-fluoro-4-(3-(3-methoxyphenyl)propyl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaboran-2-yl)benzoate




According to the procedures as described in <5-4>, the compound obtained in <85-3> was used to prepare the title compound (white foam, 5.02 g, 77% yield).
1H NMR (600 MHz, CDCl3) δ 8.34 (d, 1H), 7.20 (t, 1H), 6.93 (d, 1H), 6.77 (d, 1H), 6.74-6.72 (m, 2H), 3.91 (s, 3H), 3.79 (s, 3H), 2.96 (dd, 2H), 2.65 (t, 2H), 1.89-1.86 (m, 2H).
<85-5> Preparation of methyl 4-(3-(2-bromo-5-methoxyphenyl)propyl)-2-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaboran-2-yl)benzoate




According to the procedures as described in <5-5>, the compound obtained in <85-4> was used to prepare the title compound (white foam, 5.5 g, 93% yield).
1H NMR (600 MHz, CDCl3) δ 8.35 (d, 1H), 7.39 (d, 1H), 6.97 (d, 1H), 6.74 (d, 1H), 6.62 (dd, 2H), 3.91 (s, 3H), 3.77 (s, 3H), 3.00 (dd, 2H), 2.74 (t, 2H), 1.89-1.86 (m, 2H).
<85-6> Preparation of methyl 3-fluoro-9-methoxy-6,7-dihydro-5H-dibenzo[a,c][7]annulene-2-carboxylate




According to the procedures as described in <5-6>, the compound obtained in <85-5> was used to prepare the title compound (white foam, 1.89 g, 58% yield).
1H NMR (600 MHz, CDCl3) δ 7.89 (d, 1H), 7.30 (d, 1H), 7.02 (d, 1H), 6.88 (dd, 1H), 6.80 (d, 1H), 3.94 (s, 3H), 3.86 (s, 3H), 2.51 (t, 2H), 2.46 (t, 2H), 2.21-2.18 (m, 2H).
<85-7> Preparation of methyl 3-fluoro-9-hydroxy-6,7-dihydro-5H-dibenzo[a,c][7]annulene-2-carboxylate




According to the procedures as described in <5-7>, the compound obtained in <85-6> was used to prepare the title compound (white foam, 1.69 g, 94% yield).
1H NMR (600 MHz, CDCl3) δ 7.89 (d, 1H), 7.24 (d, 1H), 7.02 (d, 1H), 6.81 (dd, 1H), 6.74 (d, 1H), 4.98 (s, 1H), 3.94 (s, 3H), 2.51 (t, 2H), 2.43 (t, 2H), 2.22-2.15 (m, 2H).
<85-8> Preparation of methyl 9-((1,1-dioxidotetrahydro-2H-thiopyran-4-yl)methoxy)-3-fluoro-6,7-dihydro-5H-dibenzo[a,c][7]annulene-2-carboxylate




The compound obtained in <85-7> (80 mg, 0.279 mmol) was dissolved in DMF (1 mL), which was then added with (1,1-dioxidotetrahydro-2H-thiopyran-4-yl)methyl 4-methylbenzenesulfonate (prepared in accordance with the reference [Bioorganic and Medicinal Chemistry Letters, 2011, vol. 21, p. 1748-1753]; 133 mg, 0.419 mmol) and K2CO3 (58 mg, 0.419 mmol), and then stirred at 90° C. for 15 hours. The reaction mixture was cooled to room temperature, diluted with EtOAc, and washed with a saturated NH4Cl aqueous solution and brine. The organic layer was dried over sodium sulfate and concentrated under reduced pressure, and the residue thus obtained was purified by silica gel chromatography to obtain the title compound (white foam, 118 mg, 98% yield).
1H NMR (600 MHz, CDCl3) δ 7.89 (d, 1H), 7.30 (d, 1H), 7.03 (d, 1H), 6.85 (dd, 1H), 6.78 (d, 1H), 3.94 (s, 3H), 3.92 (d, 2H), 3.18-3.14 (m, 2H), 3.08-3.05 (m, 2H), 2.51 (t, 2H), 2.46 (t, 2H), 2.33-2.31 (m, 2H), 2.22-2.17 (m, 2H), 2.09-2.05 (m, 2H).
<85-9> Preparation of 4-(((9-fluoro-10-(hydroxymethyl)-6,7-dihydro-5H-dibenzo[a,c][7]annulen-3-yl)oxy)methyl)tetrahydro-2H-thiopyran 1,1-dioxide




According to the procedures as described in <1-9>, the compound obtained <85-8> was used to prepare the title compound (white foam, 103 mg, 95% yield).
1H NMR (600 MHz, CDCl3) δ 7.35 (d, 1H), 7.28 (d, 1H), 6.95 (d, 1H), 6.84 (dd, 1H), 6.78 (d, 1H), 4.79 (d, 2H), 3.92 (d, 2H), 3.18-3.13 (m, 2H), 3.08-3.03 (m, 2H), 2.48-2.44 (m, 4H), 2.34-2.30 (m, 2H), 2.19-2.14 (m, 2H), 2.10-2.04 (m, 2H), 1.83 (t, 1H).
<85-10> Preparation of (S)-methyl 2-(6-((9-((1,1-dioxidotetrahydro-2H-thiopyran-4-yl)methoxy)-3-fluoro-6,7-dihydro-5H-dibenzo[a,c][7]annulen-2-yl)methoxy)-2,3-dihydrobenzofuran-3-ylacetate




According to the procedures as described in <1-10>, the compound obtained in <85-9> was used to prepare the title compound (white foam, 139 mg, 92% yield).
1H NMR (600 MHz, CDCl3) δ 7.41 (d, 1H), 7.26 (d, 1H), 7.04 (d, 1H), 6.97 (d, 1H), 6.83 (dd, 1H), 6.77 (d, 1H), 6.51 (dd, 1H), 6.49 (d, 1H), 5.10 (s, 2H), 4.78 (t, 1H), 4.27 (dd, 1H), 3.90 (d, 2H), 3.83-3.80 (m, 1H), 3.72 (s, 3H), 3.17-3.14 (m, 2H), 3.07-3.03 (m, 2H), 2.75 (dd, 1H), 2.56 (dd, 1H), 2.48-2.44 (m, 4H), 2.34-2.30 (m, 2H), 2.19-2.14 (m, 2H), 2.09-2.04 (m, 2H).
<85-11> Preparation of (S)-2-(6-((9-((1,1-dioxidotetrahydro-2H-thiopyran-4-yl)methoxy)-3-fluoro-6,7-dihydro-5H-dibenzo[a,c][7]annulen-2-yl)methoxy)-2,3-dihydrobenzofuran-3-yl)acetic acid




According to the procedures as described in <1-11>, the compound obtained in <85-10> was used to prepare the title compound (white foam, 125 mg, 94% yield).
MS m/z 580 [M−H]−.
1H NMR (600 MHz, CDCl3) δ 7.41 (d, 1H), 7.25 (d, 1H), 7.07 (d, 1H), 6.97 (d, 1H), 6.83 (dd, 1H), 6.77 (d, 1H), 6.52 (dd, 1H), 6.49 (d, 1H), 5.10 (s, 2H), 4.77 (t, 1H), 4.29 (dd, 1H), 3.90 (d, 2H), 3.83-3.80 (m, 1H), 3.17-3.13 (m, 2H), 3.08-3.03 (m, 2H), 2.81 (dd, 1H), 2.62 (dd, 1H), 2.48-2.44 (m, 4H), 2.34-2.30 (m, 2H), 2.19-2.15 (m, 2H), 2.09-2.04 (m, 2H).
Example 86
Preparation of (1S,2S)-2-(4-(((9-((1,1-dioxidotetrahydro-2H-thiopyran-4-yl)methoxy)-3-fluoro-6,7-dihydro-5H-dibenzo[a,c][7]annulen-2-yl)methyl)amino)phenyl)cyclopropanecarboxylic acid
<86-1> Preparation of 9-((1,1-dioxidotetrahydro-2H-thiopyran-4-yl)methoxy)-3-fluoro-6,7-dihydro-5H-dibenzo[a,c][7]annulene-2-carbaldehyde




According to the procedures as described in <3-3>, the compound obtained in <85-9> was used to prepare the title compound (white foam, 89 mg, 88% yield).
1H NMR (600 MHz, CDCl3) δ 10.37 (s, 1H), 7.80 (d, 1H), 7.28 (d, 1H), 7.06 (d, 1H), 6.84 (dd, 1H), 6.77 (d, 1H), 4.79 (d, 2H), 3.90 (d, 2H), 3.17-3.13 (m, 2H), 3.08-3.03 (m, 2H), 2.53 (t, 2H), 2.45 (t, 2H), 2.34-2.30 (m, 2H), 2.22-2.16 (m, 2H), 2.80-2.03 (m, 2H), 1.83 (t, 1H).
<86-2> Preparation of (1S,2S)-ethyl 2-(4-(((9-((1,1-dioxidotetrahydro-2H-thiopyran-4-yl)methoxy)-3-fluoro-6,7-dihydro-5H-dibenzo[a,c][7]annulen-2-yl)methyl)amino)phenyl)cyclopropanecarboxylate




According to the procedures as described in <3-4>, the compound obtained in <86-1> was used to prepare the title compound (white foam, 121 mg, 95% yield).
1H NMR (600 MHz, CDCl3) δ 7.29 (d, 1H), 7.18 (d, 1H), 6.95-6.92 (m, 3H), 6.81 (dd, 1H), 6.76 (d, 1H), 6.60 (d, 2H), 4.39 (s, 2H), 4.15 (q, 2H), 4.02 (br s, 1H), 3.89 (d, 2H), 3.17-3.13 (m, 2H), 3.07-3.03 (m, 2H), 2.46-2.41 (m, 4H), 2.33-2.29 (m, 2H), 2.18-2.15 (m, 2H), 2.08-2.04 (m, 2H), 1.79-1.76 (m, 1H), 1.53-1.49 (m, 1H), 1.28-1.24 (m, 4H), 1.23-1.21 (m, 1H).
<86-3> Preparation of (1S,2S)-2-(4-(((9-((1,1-dioxidotetrahydro-2H-thiopyran-4-yl)methoxy)-3-fluoro-6,7-dihydro-5H-dibenzo[a,c][7]annulen-2-yl)methyl)amino)phenyl)cyclopropanecarboxylic acid




According to the procedures as described in <3-5>, the compound obtained in <86-2> was used to prepare the title compound (white foam, 98 mg, 86% yield).
MS m/z 563 [M−H]−.
1H NMR (600 MHz, CDCl3) δ 7.28 (d, 1H), 7.17 (d, 1H), 6.95-6.92 (m, 3H), 6.80 (dd, 1H), 6.76 (d, 1H), 6.59 (d, 2H), 4.39 (s, 2H), 3.90 (d, 2H), 3.16-3.13 (m, 2H), 3.07-3.02 (m, 2H), 2.52-2.48 (m, 1H), 2.46-2.42 (m, 4H), 2.33-2.29 (m, 2H), 2.18-2.15 (m, 2H), 2.08-2.04 (m, 2H), 1.79-1.76 (m, 1H), 1.58-1.55 (m, 1H), 1.33-1.30 (m, 1H).
Example 87
Preparation of (1S,2S)-2-(4-(((9-(3-(ethylsulfonyl)propoxy)-11-methyl-6,7-dihydrodibenzo[b,d]oxepin-2-yl)methyl)amino)phenyl)cyclopropanecarboxylic acid
<87-1> Preparation of (1S,2S)-ethyl 2-(4-(((9-(3-(ethylsulfonyl)propoxy)-11-methyl-6,7-dihydrodibenzo[b,d]oxepin-2-yl)methyl)amino)phenyl)cyclopropanecarboxylate




According to the procedures as described in <3-4>, the compound obtained in <53-1> was used to prepare the title compound (white foam, 89.6 mg, 103% yield) the compound obtained in.
1H NMR (300 MHz, CDCl3) δ 7.31-7.22 (m, 2H), 7.11 (d, 1H), 6.93 (d, 2H), 6.74 (d, 1H), 6.67 (d, 1H), 6.57 (d, 2H), 4.40 (m, 2H), 4.33 (s, 2H), 4.22-4.07 (m, 4H), 4.03 (br s, 1H), 3.26-3.14 (m, 2H), 3.05 (q, 2H), 2.80 (m, 1H), 2.54-2.29 (m, 4H), 2.26 (s, 3H), 1.82-1.73 (m, 1H), 1.52 (m, 1H), 1.44 (t, 3H), 1.32-1.17 (m, 4H).
<87-2> Preparation of (1S,2S)-2-(4-(((9-(3-(ethylsulfonyl)propoxy)-11-methyl-6,7-dihydrodibenzo[b,d]oxepin-2-yl)methyl)amino)phenyl)cyclopropanecarboxylic acid




According to the procedures as described in <1-11>, the compound obtained in <87-1> was used to prepare the title compound (white foam, 72.8 mg, 88% yield).
MS m/z 550 [M+H]+.
1H NMR (300 MHz, CDCl3) δ 7.31-7.22 (m, 2H), 7.11 (d, 1H), 6.93 (d, 2H), 6.74 (d, 1H), 6.67 (d, 1H), 6.57 (d, 2H), 4.40 (m, 2H), 4.34 (s, 2H), 4.13 (t, 2H), 3.28-3.14 (m, 2H), 3.05 (q, 2H), 2.81 (m, 1H), 2.56-2.42 (m, 2H), 2.42-2.28 (m, 2H), 2.25 (s, 3H), 1.76 (m, 1H), 1.58 (m, 1H), 1.44 (t, 3H), 1.38-1.30 (m, 1H).
Example 88
Preparation of 2-((3S)-6-((9-(2-ethoxyethoxy)-11-methyl-6,7-dihydrodibenzo[b,d]oxepin-2-yl)methoxy)-2,3-dihydrobenzofuran-3-yl)acetic acid
<88-1> Preparation of methyl 9-(2-ethoxyethoxy)-11-methyl-6,7-dihydrodibenzo[b,d]oxepin-2-carboxylate




According to the procedures as described in <3-1>, the compound obtained in <14-5> was used to prepare the title compound (yellow oil, 143 mg, >100% yield).
1H NMR (300 MHz, CDCl3) δ 8.02 (d, 1H), 7.97 (dd, 1H), 7.18 (d, 1H), 6.83 (d, 1H), 6.73 (d, 1H), 4.55-4.39 (m, 2H), 4.17 (t, 2H), 3.92 (s, 3H), 3.82 (m, 2H), 3.63 (q, 2H), 2.88-2.73 (m, 1H), 2.52 (m, 1H), 2.37 (s, 3H), 1.26 (t, 3H).
<88-2> Preparation of (9-(2-ethoxyethoxy)-11-methyl-6,7-dihydrodibenzo[b,d]oxepin-2-yl)methanol




According to the procedures as described in <1-9>, the compound obtained in <88-1> was used to prepare the title compound (colorless oil, 110 mg, 95% yield).
1H NMR (300 MHz, CDCl3) δ 7.34-7.27 (m, 2H), 7.13 (d, 1H), 6.82 (d, 1H), 6.73 (d, 1H), 4.71 (d, 2H), 4.41 (m, 2H), 4.16 (t, 2H), 3.86-3.76 (m, 2H), 3.62 (q, 2H), 2.81 (m, 1H), 2.53-2.43 (m, 1H), 2.37 (s, 3H), 1.67 (t, 1H), 1.26 (t, 3H).
<88-3> Preparation of methyl 2-((3S)-6-((9-(2-ethoxyethoxy)-11-methyl-6,7-dihydrodibenzo[b,d]oxepin-2-yl)methoxy)-2,3-dihydrobenzofuran-3-ylacetate




According to the procedures as described in <1-10>, the compound obtained in <88-2> was used to prepare the title compound (white foam, 129 mg, 77% yield).
1H NMR (300 MHz, CDCl3) δ 7.36-7.30 (m, 2H), 7.14 (d, 1H), 7.02 (d, 1H), 6.80 (d, 1H), 6.73 (d, 1H), 6.54-6.42 (m, 2H), 5.03 (s, 2H), 4.75 (t, 1H), 4.41 (m, 2H), 4.26 (dd, 1H), 4.16 (m, 2H), 3.81 (m, 3H), 3.72 (s, 3H), 3.62 (q, 2H), 2.91-2.68 (m, 2H), 2.63-2.41 (m, 2H), 2.31 (s, 3H), 1.26 (t, 3H).
<88-4> Preparation of 2-((3S)-6-((9-(2-ethoxyethoxy)-11-methyl-6,7-dihydrodibenzo[b,d]oxepin-2-yl)methoxy)-2,3-dihydrobenzofuran-3-yl)acetic acid




According to the procedures as described in <1-11>, the compound obtained in <88-3> was used to prepare the title compound (white foam, 121 mg, 96% yield).
MS m/z 503 [M−H]−.
1H NMR (300 MHz, CDCl3) δ 7.36-7.30 (m, 2H), 7.15 (d, 1H), 7.06 (d, 1H), 6.80 (d, 1H), 6.73 (d, 1H), 6.54-6.43 (m, 2H), 5.04 (s, 2H), 4.76 (t, 1H), 4.42 (m, 2H), 4.29 (dd, 1H), 4.20-4.12 (m, 2H), 3.81 (m, 3H), 3.62 (q, 2H), 2.90-2.75 (m, 2H), 2.61 (dd, 1H), 2.53-2.43 (m, 1H), 2.31 (s, 3H), 1.26 (t, 3H).
Example 89
Preparation of (1S,2S)-2-(4-((1-methyl-3-morpholino-6,7-dihydro-5H-benzo[3,4]cyclohepta[1,2-d]pyrimidin-10-yl)methoxy)phenyl)cyclopropanecarboxylic acid
<89-1> Preparation of (1S,2S)-ethyl 2-(4-((1-methyl-3-morpholino-6,7-dihydro-5H-benzo[3,4]cyclohepta[1,2-d]pyrimidin-10-yl)methoxy)phenyl)cyclopropanecarboxylate




According to the procedures as described in <2-16>, the compound obtained in <89-7> was used to prepare the title compound (white foam, 123 mg, 79% yield).
1H NMR (600 MHz, CDCl3) δ 7.28 (m, 1H), 7.25-7.23 (m, 2H), 7.01 (d, 2H), 6.87 (d, 2H), 5.05 (s, 2H), 4.15 (q, 2H), 3.85 (m, 4H), 3.77 (m, 4H), 2.58-2.54 (m, 1H), 2.52-2.37 (m, 4H), 2.28 (s, 3H), 2.23-2.15 (m, 1H), 2.11-2.05 (m, 1H), 1.80 (m, 1H), 1.54 (m, 1H), 1.26 (t, 3H), 1.24 (m, 1H)
<89-2> Preparation of (1S,2S)-2-(4-((1-methyl-3-morpholino-6,7-dihydro-5H-benzo[3,4]cyclohepta[1,2-d]pyrimidin-10-yl)methoxy)phenyl)cyclopropanecarboxylic acid




According to the procedures as described in <1-11>, the compound obtained in <89-1> was used to prepare the title compound (white foam, 71 mg, 71% yield).
MS m/z 484 [M−H]−
1H NMR (600 MHz, CDCl3) δ 7.28 (m, 1H), 7.25-7.23 (m, 2H), 7.03 (d, 2H), 6.88 (d, 2H), 5.06 (s, 2H), 3.85 (m, 4H), 3.78 (m, 4H), 2.58-2.49 (m, 3H), 2.46-2.37 (m, 2H), 2.28 (s, 3H), 2.23-2.16 (m, 1H), 2.11-2.05 (m, 1H), 1.81 (m, 1H), 1.60 (m, 1H), 1.33 (m, 1H)
Example 90
Preparation of 2-((3S)-6-((1-methyl-3-(3-(methylsulfonyl)propoxy)-6,7-dihydro-5H-benzo[3,4]cyclohepta[1,2-d]pyrimidin-10-yl)methoxy)-2,3-dihydrobenzofuran-3-yl)acetic acid
<90-1> Preparation of 4-chloro-N,N-bis(4-methoxybenzyl)-6-methylpyrimidine-2-amine




A solution of 4-chloro-6-methylpyrimidine-2-amine (10.0 g, 69.6 mmol) in DMF (200 mL) was added with NaH (60%, mineral oil dispersion, 7.24 g, 181 mmol), stirred for 15 minutes, added with 1-(chloromethyl)-4-methoxybenzene (24.6 mL, 181 mmol), and stirred at room temperature 2.5 hours. The mixture was slowly added with distilled water, further added with EtOAc, consecutively washed with distilled water and brine, and the organic layer thus obtained was dried over MgSO4. The filtrate was concentrated under reduced pressure and purified by silica gel chromatography (white solid, 19.6 g, 73% yield).
1H NMR (300 MHz, CDCl3) δ 7.21-7.12 (m, 4H), 6.87-6.79 (m, 4H), 6.44 (s, 1H), 4.74 (s, 4H), 3.80 (s, 6H), 2.31 (s, 3H).
<90-2> Preparation of 4-allyl-N,N-bis(4-methoxybenzyl)-6-methylpyrimidine-2-amine




According to the procedures as described in <81-1>, the compound obtained in <90-1> was used to prepare the title compound (colorless oil, 5.89 g, 42% yield).
1H NMR (300 MHz, CDCl3) δ 7.23-7.14 (m, 4H), 6.86-6.78 (m, 4H), 6.29 (s, 1H), 6.10-5.95 (m, 1H), 5.21-5.07 (m, 2H), 4.77 (s, 4H), 3.79 (d, 6H), 3.36-3.28 (m, 2H), 2.30 (s, 3H).
<90-3> Preparation of methyl 4-(3-(2-(bis(4-methoxybenzyl)amino)-6-methylpyrimidin-4-yl)propyl)-3-bromobenzoate




According to the procedures as described in <81-2>, the compound obtained in <90-2> was used to prepare the title compound (yellow solid, 5.78 g, 63% yield).
1H NMR (300 MHz, CDCl3) δ 8.18 (d, 1H), 7.83 (dd, 1H), 7.18 (m, 5H), 6.85-6.76 (m, 4H), 6.29 (s, 1H), 4.79 (s, 4H), 3.90 (s, 3H), 3.78 (s, 6H), 2.82-2.73 (m, 2H), 2.60 (t, 2H), 2.31 (s, 3H), 2.07-1.95 (m, 2H).
<90-4> Preparation of methyl 4-(3-(2-(bis(4-methoxybenzyl)amino)-6-methylpyrimidin-4-yl)propyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaboran-2-yl)benzoate




According to the procedures as described in <5-4>, the compound obtained in <90-3> was used to prepare the title compound (yellow oil, 3.38 g, 54% yield).
1H NMR (300 MHz, CDCl3) δ 8.41 (d, 1H), 7.96 (dd, 1H), 7.18 (m, 5H), 6.81 (m, 4H), 6.26 (s, 1H), 4.77 (s, 4H), 3.90 (s, 3H), 3.78 (s, 6H), 3.00-2.93 (m, 2H), 2.58 (t, 2H), 2.29 (s, 3H), 1.94 (m, 1H), 1.31 (s, 12H).
<90-5> Preparation of methyl 4-(3-(2-(bis(4-methoxybenzyl)amino)-5-bromo-6-methylpyrimidin-4-yl)propyl)-3-(4,4,5,5-tetramethyl-1,3,2-diboxaboran-2-yl)benzoate




According to the procedures as described in <5-5>, the compound obtained in <90-4> was used to prepare the title compound (yellow oil, 3.60 g, 95% yield).
1H NMR (300 MHz, CDCl3) δ 8.41 (d, 1H), 7.95 (dd, 1H), 7.20-7.10 (m, 5H), 6.90-6.75 (m, 4H), 4.73 (s, 4H), 3.89 (s, 3H), 3.77 (s, 6H), 3.04-2.94 (m, 2H), 2.85-2.74 (m, 2H), 2.46 (s, 3H), 1.95 (m, 2H), 1.30 (s, 12H).
<90-6> Preparation of methyl 3-(bis(4-methoxybenzyl)amino)-1-methyl-6,7-dihydro-5H-benzo[3,4]cyclohepta[1,2-d]pyrimidine-10-carboxylate




According to the procedures as described in <5-6>, the compound obtained in <90-5> was used to prepare the title compound (white foam, 453 mg, 18% yield).
1H NMR (300 MHz, CDCl3) δ 7.96 (d, 1H), 7.91 (dd, 1H), 7.32 (d, 1H), 7.26-7.21 (m, 4H), 6.89-6.83 (m, 4H), 4.83 (m, 4H), 3.93 (s, 3H), 3.81 (s, 6H), 2.71-2.48 (m, 3H), 2.39 (s, 3H), 2.36-2.03 (m, 3H).
<90-7> Preparation of methyl 3-amino-1-methyl-6,7-dihydro-5H-benzo[3,4]cyclohepta[1,2-d]pyrimidine-10-carboxylate




A solution of the compound obtained in <90-6> (347 mg, 0.663 mmol) in CH2Cl2 (7 mL) at 0° C. was consecutively added with TFA (7 mL) and H2SO4 (15 drops). After about 10 minutes, the mixture was heated to room temperature and stirred for 4.5 hours. The reaction mixture was concentrated under reduced pressure, and added with distilled water at 0° C. The mixture was added with NH4OH (pH 8-9), extracted with CH2Cl2, and the organic layer was collected and dried over MgSO4. The filtrate was concentrated under reduced pressure and purified by silica gel chromatography to obtain the title compound (white foam, 169 mg, 90% yield).
1H NMR (300 MHz, CDCl3) δ 7.99-7.88 (m, 2H), 7.38-7.29 (m, 1H), 5.06 (s, 2H), 3.93 (s, 3H), 2.66 (m, 1H), 2.56-2.42 (m, 2H), 2.38 (s, 3H), 2.37-2.07 (m, 3H).
<90-8> Preparation of methyl 3-hydroxy-1-methyl-6,7-dihydro-5H-benzo[3,4]cyclohepta[1,2-d]pyrimidine-10-carboxylate




A solution of the compound obtained in <90-7> (343 mg, 1.211 mmol) in acetic acid (8.4 mL) and distilled water (1.8 mL) at 60° C. was added dropwise with a solution of NaNO2 (125 mg, 1.816 mmol)/distilled water (1.8 mL) over a 20 minute period, and then stirred at the same temperature for 3 hours. The reaction mixture was cooled to room temperature, added with distilled water, and extracted with EtOAc. The organic layer was collected and dried over MgSO4. The filtrate thus obtained was concentrated under reduced pressure and purified by silica gel chromatography to obtain the title compound (yellow foam, 194 mg, 53% yield).
1H NMR (300 MHz, CDCl3) δ 7.99 (dd, 1H), 7.90 (s, 1H), 7.36 (d, 1H), 3.94 (s, 3H), 2.83-2.50 (m, 3H), 2.48 (s, 3H), 2.44-2.08 (m, 3H).
<90-9> Preparation of methyl 1-methyl-3-(3-(methylsulfonyl)propoxy)-6,7-dihydro-5H-benzo[3,4]cyclohepta[1,2-d]pyrimidine-10-carboxylate




According to the procedures as described in <1-8>, the compound obtained in <90-8> was used to prepare the title compound (yellow foam, 242 mg, 69% yield).
1H NMR (300 MHz, CDCl3) δ 7.99 (dd, 1H), 7.95 (d, 1H), 7.36 (d, 1H), 4.57 (m, 2H), 3.94 (s, 3H), 3.36-3.26 (m, 2H), 2.96 (s, 3H), 2.68 (m, 2H), 2.48 (s, 3H), 2.46-2.34 (m, 4H), 2.24 (m, 2H).
<90-10> Preparation of (1-methyl-3-(3-(methylsulfonyl)propoxy)-6,7-dihydro-5H-benzo[3,4]cyclohepta[1,2-d]pyrimidin-10-yl)methanol




According to the procedures as described in <1-9>, the compound obtained in <90-9> was used to prepare the title compound (white foam, 157 mg, 70% yield).
1H NMR (300 MHz, CDCl3) δ 7.35-7.23 (m, 3H), 4.75 (d, 2H), 4.56 (m, 2H), 3.37-3.25 (m, 2H), 2.96 (s, 3H), 2.63 (m, 2H), 2.48 (s, 3H), 2.45-2.31 (m, 4H), 2.19 (m, 2H), 1.79 (t, 1H).
<90-11> Preparation of methyl 2-((3S)-6-((1-methyl-3-(3-(methylsulfonyl)propoxy)-6,7-dihydro-5H-benzo[3,4]cyclohepta[1,2-d]pyrimidin-10-yl)methoxy)-2,3-dihydrobenzofuran-3-ylacetate




According to the procedures as described in <1-10>, the compound obtained in <90-10> was used to prepare the title compound (white foam, 131 mg, 87% yield).
1H NMR (300 MHz, CDCl3) δ 7.38-7.25 (m, 3H), 7.04 (d, 1H), 6.48 (m, 2H), 5.07 (s, 2H), 4.75 (t, 1H), 4.56 (t, 2H), 4.27 (dd, 1H), 3.81 (m, 1H), 3.72 (s, 3H), 3.39-3.24 (m, 2H), 2.96 (s, 3H), 2.75 (dd, 1H), 2.69-2.43 (m, 4H), 2.43-2.31 (m, 6H), 2.30-2.10 (m, 2H).
<90-12> Preparation of 2-((3S)-6-((1-methyl-3-(3-(methylsulfonyl)propoxy)-6,7-dihydro-5H-benzo[3,4]cyclohepta[1,2-d]pyrimidin-10-yl)methoxy)-2,3-dihydrobenzofuran-3-yl)acetic acid




According to the procedures as described in <1-11>, the compound obtained in <90-11> was used to prepare the title compound (white foam, 89 mg, 70% yield).
MS m/z 551 [M−H]−.
1H NMR (300 MHz, CDCl3) δ 7.38-7.27 (m, 3H), 7.07 (d, 1H), 6.54-6.41 (m, 2H), 5.07 (s, 2H), 4.77 (t, 1H), 4.55 (t, 2H), 4.34-4.23 (m, 1H), 3.82 (m, 1H), 3.40-3.25 (m, 2H), 2.96 (s, 3H), 2.80 (dd, 1H), 2.70-2.5 (m, 3H), 2.55-1.75 (m, 9H).
Example 91
Preparation of (S)-2-(6-(((9-(2-ethoxyethoxy)-6,7-dihydro-5H-dibenzo[a,c][7]annulen-2-yl)methyl)amino)-2,3-dihydrobenzofuran-3-yl)acetic acid
<91-1> Preparation of (S)-methyl 2-(6-(((9-(2-ethoxyethoxy)-6,7-dihydro-5H-dibenzo[a,c][7]annulen-2-yl)methyl)amino)-2,3-dihydrobenzofuran-3-ylacetate




According to the procedures as described in <82-1>, the compound obtained in <28-1> was used to prepare the title compound (yellow oil, 122.3 mg, 79% yield).
1H NMR (300 MHz, CDCl3) δ 7.34-7.21 (m, 3H), 7.18 (d, 1H), 6.93 (d, 1H), 6.88 (dd, 1H), 6.84 (d, 1H), 6.21-6.11 (m, 2H), 4.71 (t, 1H), 4.31 (s, 2H), 4.25-4.14 (m, 3H), 4.05 (br s, 1H), 3.85-3.73 (m, 3H), 3.71 (s, 3H), 3.62 (q, 2H), 2.73 (dd, 1H), 2.60-2.39 (m, 5H), 2.22-2.08 (m, 2H), 1.26 (t, 3H).
<91-2> Preparation of (S)-2-(6-(((9-(2-ethoxyethoxy)-6,7-dihydro-5H-dibenzo[a,c][7]annulen-2-yl)methyl)amino)-2,3-dihydrobenzofuran-3-yl)acetic acid




According to the procedures as described in <1-11>, the compound obtained <91-1> was used to prepare the title compound (off-white foam, 92.4 mg, 79% yield).
MS m/z 486 [M−H]−.
1H NMR (300 MHz, CDCl3) δ=7.34-7.21 (m, 3H), 7.18 (d, 1H), 6.96 (d, 1H), 6.87 (d, 1H), 6.84 (d, 1H), 6.22-6.12 (m, 2H), 4.72 (t, 1H), 4.31 (s, 2H), 4.24 (dd, 1H), 4.17 (t, 2H), 3.85-3.71 (m, 3H), 3.62 (q, 2H), 2.78 (dd, 1H), 2.58 (dd, 1H), 2.47 (m, 4H), 2.22-2.07 (m, 2H), 1.25 (t, 3H).
Example 92
Preparation of (S)-2-(6-(((9-(3-(ethylsulfonyl)propoxy)-6,7-dihydro-5H-dibenzo[a,c][7]annulen-2-yl)methyl)amino)-2,3-dihydrobenzofuran-3-yl)acetic acid
<92-1> Preparation of (S)-methyl 2-(6-(((9-(3-(ethylsulfonyl)propoxy)-6,7-dihydro-5H-dibenzo[a,c][7]annulen-2-yl)methyl)amino)-2,3-dihydrobenzofuran-3-ylacetate




According to the procedures as described in <82-1>, the compound obtained in <72-1> was used to prepare the title compound (white foam, 162 mg, 103% yield).
1H NMR (300 MHz, CDCl3) δ=7.34-7.22 (m, 3H), 7.19 (d, 1H), 6.93 (d, 1H), 6.83 (dd, 1H), 6.79 (d, 1H), 6.22-6.13 (m, 2H), 4.70 (t, 1H), 4.31 (s, 2H), 4.21 (dd, 1H), 4.16 (t, 2H), 4.09 (s, 1H), 3.76 (m, 1H), 3.70 (s, 3H), 3.28-3.16 (m, 2H), 3.05 (q, 2H), 2.73 (dd, 1H), 2.60-2.42 (m, 5H), 2.42-2.29 (m, 2H), 2.24-2.09 (m, 2H), 1.44 (t, 3H).
<92-2> Preparation of (S)-2-(6-(((9-(3-(ethylsulfonyl)propoxy)-6,7-dihydro-5H-dibenzo[a,c][7]annulen-2-yl)methyl)amino)-2,3-dihydrobenzofuran-3-yl)acetic acid




According to the procedures as described in <1-11>, the compound obtained in <92-1> was used to prepare the title compound (off-white foam, 150.4 mg, 94% yield).
MS m/z 548 [M−H]−.
1H NMR (300 MHz, CDCl3) δ=7.39-7.21 (m, 3H), 7.18 (d, 1H), 6.96 (d, 1H), 6.84 (dd, 1H), 6.78 (d, 1H), 6.23-6.10 (m, 2H), 4.71 (t, 1H), 4.31 (s, 2H), 4.28-4.19 (m, 1H), 4.15 (t, 2H), 3.76 (m, 1H), 3.28-3.16 (m, 2H), 3.05 (q, 2H), 2.75 (dd, 1H), 2.61 (dd, 1H), 2.47 (m, 4H), 2.41-2.28 (m, 2H), 2.24-2.08 (m, 2H), 1.44 (t, 3H).
Example 93
Preparation of (S)-2-(6-((9-((4-methyl-1,1-dioxidotetrahydro-2H-thiopyran-4-yl)methoxy)-6,7-dihydro-5H-dibenzo[a,c][7]annulen-2-yl)methoxy)-2,3-dihydrobenzofuran-3-yl)acetic acid
<93-1> Preparation of 4-methyltetrahydro-2H-thiopyran-4-carbonitrile




A solution of tetrahydro-2H-thiopyran-4-carbonitrile (1.27 g, 10.0 mmol) in THF (30 mL) was slowly added dropwise with LDA (2M THF/heptane solution, 6.5 mL, 13.0 mmol). After 30 minutes, the mixture was added with MeI (811 μL, 13.0 mmol) and stirred for 50 minutes. Then, the reaction mixture was slowly added with water, diluted with Et2O and brine, and extracted. The organic layer was dried over sodium sulfate, the filtrate thus obtained was concentrated under reduced pressure, and then the residue was purified by silica gel chromatography to obtain the title compound (colorless oil, 1.07 g, 76% yield).
1H NMR (300 MHz, CDCl3) δ 3.03-2.94 (m, 2H), 2.57 (m, 2H), 2.20 (m, 2H), 1.69-1.59 (m, 2H), 1.37 (s, 3H).
<93-2> Preparation of 4-methyltetrahydro-2H-thiopyran-4-carboxylic acid




A solution of the compound obtained in <93-1> (1.07 g, 7.58 mmol) in THF/H2O (14/7 mL) was added with NaOH (3.0 g, 75.8 mmol), stirred at 100° C. for 24 hours, and concentrated. The reaction mixture was diluted with Et2O and water, and then extracted. The aqueous layer was acidified to  ̃pH 1 by using concentrated hydrochloric acid and extracted with EtOAc. The organic layer was dried over sodium sulfate and concentrated under reduced pressure. The residue thus obtained was purified by silica gel chromatography to obtain the title compound (colorless oil, 992.2 mg, 82% yield).
1H NMR (300 MHz, CDCl3) δ 2.78-2.70 (m, 2H), 2.59-2.51 (m, 2H), 2.40-2.32 (m, 2H), 1.65-1.58 (m, 2H), 1.24 (s, 3H).
<93-3> Preparation of (4-methyltetrahydro-2H-thiopyran-4-yl)methanol




To a solution of the compound obtained in <93-2> (992 mg, 6.191 mmol) in THF (25 mL) was slowly added dropwise BH3.THF (1.0M THF solution, 7.4 mL, 7.429 mmol). The mixture was stirred at 70° C. for 2.5 hours, slowly added with distilled water at 0° C., and concentrated under reduced pressure. The concentrated reaction mixture was added with distilled water and 1M HCl aqueous solution (pH 3), and then extracted with CH2Cl2. The organic layer was collected and dried over MgSO4. The filtrate thus obtained was concentrated in vacuo to obtain the title compound (colorless oil, 856 mg, 95% yield).
1H NMR (300 MHz, CDCl3) δ 3.37 (d, 2H), 2.74 (m, 2H), 2.58-2.47 (m, 2H), 1.78-1.58 (m, 4H), 1.32 (t, 1H), 0.94 (s, 3H).
<93-4> Preparation of (4-methyltetrahydro-2H-thiopyran-4-yl)methyl 4-methylbenzenesulfonate




To a solution of the compound obtained in <93-3> (413 mg, 2.824 mmol) in CH2Cl2 (10 mL) at 0° C. was consecutively added with pyridine (5 mL) and m-toluenesulfonyl chloride (1.62 g, 8.472 mmol). After 10 minutes, the mixture was heated to room temperature, stirred for 4 hours, added with cold distilled water at 0° C., and extracted with EtOAc. The organic layer was collected, consecutively washed with 1M HCl aqueous solution, distilled water and brine, and then dried over MgSO4. The filtrate thus obtained was concentrated under reduced pressure reduced pressure and purified by silica gel chromatography to obtain the title compound (colorless oil, 733 mg, 86% yield).
1H NMR (300 MHz, CDCl3) δ 7.82-7.73 (m, 2H), 7.36 (m, 2H), 3.71 (s, 2H), 2.65 (m, 2H), 2.50-2.36 (m, 5H), 1.71-1.52 (m, 4H), 0.93 (s, 3H).
<93-5> Preparation of (4-methyl-1,1-dioxidotetrahydro-2H-thiopyran-4-yl)methyl 4-methylbenzenesulfonate




To a solution of the compound obtained in <93-4> (733 mg, 2.440 mmol) in CH2Cl2 (15 mL) at 0° C. was added MCPBA (>77%, 1.15 g, 5.123 mmol). The mixture was stirred at the same temperature for 2.5 hours. The reaction mixture was added with distilled water and a saturated NaHCO3 aqueous solution, and then extracted with CH2Cl2. The organic layer was collected, washed with brine and dried over MgSO4. The filtrate was concentrated under reduced pressure and recrystallized using CH2Cl2/hexane to obtain the title compound (white solid, 695 mg, 83% yield).
1H NMR (300 MHz, CDCl3) δ 7.85-7.71 (m, 2H), 7.45-7.30 (m, 2H), 3.79 (s, 2H), 3.05-2.84 (m, 2H), 2.47 (s, 3H), 2.09-1.94 (m, 2H), 1.91-1.79 (m, 2H), 1.08 (s, 3H).
<93-6> Preparation of methyl 9-((4-methyl-1,1-dioxidotetrahydro-2H-thiopyran-4-yl)methoxy)-6,7-dihydro-5H-dibenzo[a,c][7]annulene-2-carboxylate




A mixed solution of the compounds obtained in <5-7> (200 mg, 0.745 mmol) and <93-5> (372 mg, 1.118 mmol), K2CO3 (155 mg, 1.118 mmol) and KI (25 mg, 0.185 mmol) in DMF (4 mL) was stirred at 90° C. for 33 hours. The reaction mixture was cooled to room temperature, added with a saturated NH4Cl aqueous solution and distilled water, and extracted with EtOAc. The organic layer was collected, washed with brine, and dried over MgSO4. The filtrate was concentrated under reduced pressure and purified by silica gel chromatography to obtain the title compound (yellow foam, 162 mg, 51% yield).
1H NMR (300 MHz, CDCl3) δ 8.01 (d, 1H), 7.93 (dd, 1H), 7.35 (d, 1H), 7.30 (d, 1H), 6.88 (dd, 1H), 6.82 (d, 1H), 3.93 (d, 3H), 3.83 (s, 2H), 3.11 (m, 4H), 2.55 (t, 2H), 2.46 (t, 2H), 2.37-2.13 (m, 4H), 2.10-1.94 (m, 2H), 1.21 (s, 3H).
<93-7> Preparation of 4-(((10-(hydroxymethyl)-6,7-dihydro-5H-dibenzo[a,c][7]annulen-3-yl)oxy)methyl)-4-methyltetrahydro-2H-thiopyran 1,1-dioxide




According to the procedures as described in <1-9>, the compound obtained in <93-6> was used to prepare the title compound (white foam, 238 mg, 94% yield).
1H NMR (300 MHz, CDCl3) δ 7.36-7.20 (m, 4H), 6.86 (dd, 1H), 6.81 (d, 1H), 4.74 (d, 2H), 3.82 (s, 3H), 3.11 (m, 4H), 2.48 (q, 4H), 2.36-2.22 (m, 2H), 2.18 (m, 2H), 2.05 (m, 2H), 1.72 (t, 1H), 1.21 (s, 3H).
<93-8> Preparation of (S)-methyl 2-(6-((9-((4-methyl-1,1-dioxidotetrahydro-2H-thiopyran-4-yl)methoxy)-6,7-dihydro-5H-dibenzo[a,c][7]annulen-2-yl)methoxy)-2,3-dihydrobenzofuran-3-ylacetate




According to the procedures as described in <1-10>, the compound obtained in <93-7> was used to prepare the title compound (colorless oil, 159 mg, 90% yield).
1H NMR (300 MHz, CDCl3) δ 7.40-7.27 (m, 3H), 7.26 (d, 1H), 7.03 (d, 1H), 6.86 (dd, 1H), 6.81 (d, 1H), 6.55-6.43 (m, 2H), 5.04 (s, 2H), 4.76 (t, 1H), 4.27 (dd, 1H), 3.82 (m, 3H), 3.72 (s, 3H), 3.22-3.01 (m, 4H), 2.76 (dd, 1H), 2.63-2.40 (m, 5H), 2.35-2.10 (m, 4H), 2.11-1.94 (m, 2H), 1.21 (s, 3H).
<93-9> Preparation of (S)-2-(6-((9-((4-methyl-1,1-dioxidotetrahydro-2H-thiopyran-4-yl)methoxy)-6,7-dihydro-5H-dibenzo[a,c][7]annulen-2-yl)methoxy)-2,3-dihydrobenzofuran-3-yl)acetic acid




According to the procedures as described in <1-11>, the compound obtained in <93-8> was used to prepare the title compound (white foam, 114 mg, 73% yield).
MS m/z 575 [M−H]−.
1H NMR (300 MHz, CDCl3) δ 7.40-7.28 (m, 3H), 7.24 (d, 1H), 7.07 (d, 1H), 6.86 (dd, 1H), 6.81 (d, 1H), 6.55-6.45 (m, 2H), 5.05 (s, 2H), 4.77 (t, 1H), 4.30 (dd, 1H), 3.82 (m, 2H), 3.22-3.01 (m, 4H), 2.82 (dd, 1H), 2.62 (dd, 1H), 2.49 (m, 4H), 2.35-2.12 (m, 4H), 2.11-1.98 (m, 2H), 1.21 (s, 3H).
Example 94
Preparation of (1S,2S)-2-(4-(((9-((4-methyl-1,1-dioxidotetrahydro-2H-thiopyran-4-yl)methoxy)-6,7-dihydro-5H-dibenzo[a,c][7]annulen-2-yl)methyl)amino)phenyl)cyclopropanecarboxylic acid
<94-1> Preparation of 9-((4-methyl-1,1-dioxidotetrahydro-2H-thiopyran-4-yl)methoxy)-6,7-dihydro-5H-dibenzo[a,c][7]annulene-2-carbaldehyde




According to the procedures as described in <3-3>, the compound obtained in <93-7> was used to prepare the title compound (colorless oil, 101 mg, 87% yield).
1H NMR (300 MHz, CDCl3) δ 10.05 (s, 1H), 7.84 (d, 1H), 7.78 (dd, 1H), 7.40 (d, 1H), 7.36 (d, 1H), 6.90 (dd, 1H), 6.83 (d, 1H), 3.83 (s, 2H), 3.11 (m, 4H), 2.58 (t, 2H), 2.48 (t, 2H), 2.35-2.16 (m, 4H), 2.11-1.97 (m, 2H), 1.23 (s, 3H).
<94-2> Preparation of (1S,2S)-ethyl 2-(4-(((9-((4-methyl-1,1-dioxidotetrahydro-2H-thiopyran-4-yl)methoxy)-6,7-dihydro-5H-dibenzo[a,c][7]annulen-2-yl)methyl)amino)phenyl)cyclopropanecarboxylate




According to the procedures as described in <3-4>, the compound obtained in <94-1> was used to prepare the title compound (white foam, 192 mg, 130% yield).
1H NMR (300 MHz, CDCl3) δ 7.35-7.22 (m, 3H), 7.19 (d, 1H), 6.97-6.89 (m, 2H), 6.85 (dd, 1H), 6.81 (d, 1H), 6.63-6.52 (m, 2H), 4.33 (s, 2H), 4.16 (q, 2H), 4.02 (s, 1H), 3.81 (s, 2H), 3.10 (m, 4H), 2.56-2.37 (m, 5H), 2.35-2.11 (m, 4H), 2.05 (m, 2H), 1.78 (m, 1H), 1.51 (m, 1H), 1.26-1.20 (m, 4H), 1.20 (s, 3H).
<94-3> Preparation of (1S,2S)-2-(4-(((9-((4-methyl-1,1-dioxidotetrahydro-2H-thiopyran-4-yl)methoxy)-6,7-dihydro-5H-dibenzo[a,c][7]annulen-2-yl)methyl)amino)phenyl)cyclopropanecarboxylic acid




According to the procedures as described in <1-11>, the compound obtained in <94-2> was used to prepare the title compound (yellow foam, 108 mg, 59% yield).
MS m/z 558 [M−H]−.
1H NMR (300 MHz, CDCl3) δ 7.33-7.16 (m, 4H), 6.99-6.89 (m, 2H), 6.85 (dd, 1H), 6.81 (d, 1H), 6.64-6.54 (m, 2H), 4.34 (s, 2H), 3.82 (s, 2H), 3.10 (m, 4H), 2.56-2.40 (m, 5H), 2.35-2.11 (m, 4H), 2.04 (m, 2H), 1.84-1.74 (m, 1H), 1.58 (m, 1H), 1.33 (m, 1H), 1.20 (s, 3H).
Example 95
Preparation of (S)-2-(6-((3-fluoro-9-((4-methyl-1,1-dioxidotetrahydro-2H-thiopyran-4-yl)methoxy)-6,7-dihydro-5H-dibenzo[a,c][7]annulen-2-yl)methoxy)-2,3-dihydrobenzofuran-3-yl)acetic acid
<95-1> Preparation of methyl 3-fluoro-9-((4-methyl-1,1-dioxidotetrahydro-2H-thiopyran-4-yl)methoxy)-6,7-dihydro-5H-dibenzo[a,c][7]annulene-2-carboxylate




According to the procedures as described in <93-5>, the compound obtained in <85-7> was used to prepare the title compound (white foam, 155.8 mg, 61% yield).
1H NMR (300 MHz, CDCl3) δ 7.88 (d, 1H), 7.31 (d, 1H), 7.03 (d, 1H), 6.86 (d, 1H), 6.81 (d, 1H), 3.94 (s, 3H), 3.82 (s, 2H), 3.19-3.06 (m, 4H), 2.55-2.40 (m, 4H), 2.35-2.13 (m, 4H), 2.09-2.03 (m, 2H), 1.21 (s, 3H).
<95-2> Preparation of 4-(((9-fluoro-10-(hydroxymethyl)-6,7-dihydro-5H-dibenzo[a,c][7]annulen-3-yl)oxy)methyl)-4-methyltetrahydro-2H-thiopyran 1,1-dioxide




According to the procedures as described in <1-9>, the compound obtained in <95-1> was used to prepare the title compound (white foam, 131.2 mg, 90% yield).
1H NMR (300 MHz, CDCl3) δ 7.36 (d, 1H), 7.29 (d, 1H), 6.95 (d, 1H), 6.86 (dd, 1H), 6.81 (d, 1H), 4.80 (d, 2H), 3.82 (s, 2H), 3.20-3.01 (m, 4H), 2.51-2.39 (m, 4H), 2.35-2.22 (m, 2H), 2.22-2.11 (m, 2H), 2.10-2.02 (m, 2H), 1.80 (t, 1H), 1.21 (s, 3H).
<95-3> Preparation of (S)-methyl 2-(6-((3-fluoro-9-((4-methyl-1,1-dioxidotetrahydro-2H-thiopyran-4-yl)methoxy)-6,7-dihydro-5H-dibenzo[a,c][7]annulen-2-yl)methoxy)-2,3-dihydrobenzofuran-3-ylacetate




According to the procedures as described in <1-10>, the compound obtained in <95-2> was used to prepare the title compound (yellow foam, 193.5 mg, 102% yield).
1H NMR (300 MHz, CDCl3) δ=7.38 (d, 1H), 7.27 (d, 1H), 7.04 (d, 1H), 6.97 (d, 1H), 6.85 (dd, 1H), 6.80 (d, 1H), 6.54-6.47 (m, 2H), 5.10 (s, 2H), 4.76 (t, 1H), 4.27 (dd, 1H), 3.88-3.74 (m, 3H), 3.71 (s, 3H), 3.67 (m, 2H), 3.19-3.01 (m, 4H), 2.76 (dd, 1H), 2.56 (dd, 1H), 2.51-2.40 (m, 4H), 2.28 (m, 2H), 2.19 (m, 2H), 2.09-1.96 (m, 2H), 1.21 (s, 3H).
<95-4> Preparation of (S)-2-(6-((3-fluoro-9-((4-methyl-1,1-dioxidotetrahydro-2H-thiopyran-4-yl)methoxy)-6,7-dihydro-5H-dibenzo[a,c][7]annulen-2-yl)methoxy)-2,3-dihydrobenzofuran-3-yl)acetic acid




According to the procedures as described in <1-11>, the compound obtained in <95-3> was used to prepare the title compound (white foam, 63.3 mg, 34% yield).
MS m/z 617 [M+Na]+.
1H NMR (300 MHz, CDCl3) δ=7.42 (d, 1H), 7.26 (d, 1H), 7.08 (d, 1H), 6.97 (d, 1H), 6.85 (dd, 1H), 6.80 (d, 1H), 6.57-6.46 (m, 2H), 5.10 (s, 2H), 4.77 (t, 1H), 4.30 (dd, 1H), 3.89-3.76 (m, 3H), 3.19-3.01 (m, 4H), 2.82 (dd, 1H), 2.62 (dd, 1H), 2.47 (t, 4H), 2.28 (m, 2H), 2.19 (m, 2H), 2.09-1.98 (m, 2H), 1.20 (s, 3H).
Example 96
Preparation of (S)-2-(6-((3-fluoro-9-(3-(methylsulfonyl)propoxy)-6,7-dihydro-5H-dibenzo[a,c][7]annulen-2-yl)methoxy)-2,3-dihydrobenzofuran-3-yl)acetic acid
<96-1> Preparation of methyl 3-fluoro-9-(3-(methylsulfonyl)propoxy)-6,7-dihydro-5H-dibenzo[a,c][7]annulene-2-carboxylate




According to the procedures as described in <1-8>, the compound obtained in <85-7> was used to prepare the title compound (white solid, 471 mg, >100% yield).
1H NMR (600 MHz, CDCl3) δ 7.87 (d, 1H), 7.28 (d, 1H), 7.01 (d, 1H), 6.84 (dd, 1H), 6.77 (d, 1H), 4.15 (t, 2H), 3.93 (s, 3H), 3.28 (t, 2H), 2.96 (s, 3H), 2.49 (t, 2H), 2.44 (t, 2H), 2.38-2.35 (m, 2H), 2.18 (m, 2H).
<96-2> Preparation of (3-fluoro-9-(3-(methylsulfonyl)propoxy)-6,7-dihydro-5H-dibenzo[a,c][7]annulen-2-yl)methanol




According to the procedures as described in <1-9>, the compound obtained in <96-1> was used to prepare the title compound (white solid, 314 mg, 81% yield).
1H NMR (300 MHz, CDCl3) δ 7.34 (d, 1H), 7.26 (d, 1H), 6.93 (d, 1H), 6.83 (dd, 1H), 6.77 (d, 1H), 4.78 (d, 2H), 4.15 (t, 2H), 3.28 (t, 2H), 2.96 (s, 3H), 2.45 (t, 2H), 2.44 (t, 2H), 2.38-2.34 (m, 2H), 2.16 (m, 2H), 1.76 (t, 1H).
<96-3> Preparation of (S)-methyl 2-(6-((3-fluoro-9-(3-(methylsulfonyl)propoxy)-6,7-dihydro-5H-dibenzo[a,c][7]annulen-2-yl)methoxy)-2,3-dihydrobenzofuran-3-ylacetate




According to the procedures as described in <1-10>, the compound obtained in <96-2> (white solid, 96 mg, 61% yield).
1H NMR (300 MHz, CDCl3) δ 7.42 (d, 1H), 7.25 (d, 1H), 7.04 (d, 1H), 6.97 (d, 1H), 6.83 (dd, 1H), 6.79 (d, 1H), 6.53-6.50 (m, 2H), 5.10 (s, 2H), 4.76 (t, 1H), 4.27 (dd, 1H), 4.17 (t, 2H), 3.86-3.76 (m, 1H), 3.72 (s, 3H), 3.29 (t, 2H), 2.97 (s, 3H), 2.76 (dd, 1H), 2.56 (dd, 1H), 2.47 (m, 4H), 2.37 (m, 2H), 2.17 (m, 2H).
<96-4> Preparation of (S)-2-(6-((3-fluoro-9-(3-(methylsulfonyl)propoxy)-6,7-dihydro-5H-dibenzo[a,c][7]annulen-2-yl)methoxy)-2,3-dihydrobenzofuran-3-yl)acetic acid




According to the procedures as described in <1-11>, the compound obtained in <96-3> (white solid, 76 mg, 81% yield).
MS m/z 553 [M−H]−.
1H NMR (300 MHz, CDCl3) δ 7.42 (d, 1H), 7.25 (d, 1H), 7.07 (d, 1H), 6.97 (d, 1H), 6.83 (dd, 1H), 6.78 (d, 1H), 6.52 (dd, 1H), 6.50 (d, 1H), 5.10 (s, 2H), 4.77 (t, 1H), 4.29 (dd, 1H), 4.16 (t, 2H), 3.83-3.80 (m, 1H), 3.29 (t, 2H), 2.97 (s, 3H), 2.81 (dd, 1H), 2.62 (dd, 1H), 2.47 (m, 4H), 2.39-2.35 (m, 2H), 2.17 (m, 2H).
Example 97
Preparation of (S)-2-(6-((9-(3-(ethylsulfonyl)propoxy)-3-fluoro-6,7-dihydro-5H-dibenzo[a,c][7]annulen-2-yl)methoxy)-2,3-dihydrobenzofuran-3-yl)acetic acid
<97-1> Preparation of methyl 9-(3-(ethylsulfonyl)propoxy)-3-fluoro-6,7-dihydro-5H-dibenzo[a,c][7]annulene-2-carboxylate




According to the procedures as described in <38-1>, the compound obtained in <85-7> was used to prepare the title compound (white solid, 281.5 mg, 96% yield).
1H NMR (300 MHz, CDCl3) δ 7.88 (d, 1H), 7.30 (d, 1H), 7.03 (d, 1H), 6.86 (dd, 1H), 6.79 (d, 1H), 4.17 (t, 2H), 3.94 (s, 3H), 3.30-3.20 (m, 2H), 3.05 (q, 2H), 2.57-2.29 (m, 6H), 2.20 (m, 2H), 1.45 (t, 3H).
<97-2> Preparation of (9-(3-(ethylsulfonyl)propoxy)-3-fluoro-6,7-dihydro-5H-dibenzo[a,c][7]annulen-2-yl)methanol




According to the procedures as described in <1-9>, the compound obtained in <97-1> was used to prepare the title compound (white solid, 194.2 mg, 74% yield).
1H NMR (300 MHz, CDCl3) δ 7.36 (d, 1H), 7.28 (d, 1H), 6.95 (d, 1H), 6.84 (dd, 1H), 6.78 (d, 1H), 4.79 (d, 2H), 4.16 (t, 2H), 3.27-3.15 (m, 2H), 3.05 (q, 2H), 2.52-2.29 (m, 6H), 2.17 (m, 1H), 1.79 (t, 1H), 1.45 (t, 3H).
<97-3> Preparation of (S)-methyl 2-(6-((9-(3-(ethylsulfonyl)propoxy)-3-fluoro-6,7-dihydro-5H-dibenzo[a,c][7]annulen-2-yl) methoxy)-2,3-dihydrobenzofuran-3-ylacetate




According to the procedures as described in <1-10>, the compound obtained in <97-2> was used to prepare the title compound (white solid, 150.4 mg, 99% yield).
1H NMR (300 MHz, CDCl3) δ 7.42 (d, 1H), 7.26 (d, 1H), 7.04 (d, 1H), 6.97 (d, 1H), 6.84 (dd, 1H), 6.79 (d, 1H), 6.55-6.47 (m, 2H), 5.10 (s, 2H), 4.77 (t, 1H), 4.28 (dd, 1H), 4.16 (t, 2H), 3.84-3.74 (m, 1H), 3.72 (s, 3H), 3.28-3.15 (m, 2H), 3.06 (q, 2H), 2.76 (dd, 1H), 2.57 (dd, 1H), 2.51-2.41 (m, 4H), 2.41-2.29 (m, 2H), 2.24-2.09 (m, 2H), 1.45 (t, 3H).
<97-4> Preparation of (S)-2-(6-((9-(3-(ethylsulfonyl)propoxy)-3-fluoro-6,7-dihydro-5H-dibenzo[a,c][7]annulen-2-yl)methoxy)-2,3-dihydrobenzofuran-3-yl)acetic acid




According to the procedures as described in <1-11>, the compound obtained in <97-3> was used to prepare the title compound (white foam, 120.8 mg, 82% yield).
MS m/z 567 [M−H]−.
1H NMR (300 MHz, CDCl3) δ 7.42 (d, 1H), 7.26 (d, 1H), 7.08 (d, 1H), 6.97 (d, 1H), 6.84 (dd, 1H), 6.78 (d, 1H), 6.56-6.46 (m, 2H), 5.10 (s, 2H), 4.77 (t, 1H), 4.30 (dd, 1H), 4.16 (t, 2H), 3.82 (m, 1H), 3.28-3.16 (m, 2H), 3.06 (q, 2H), 2.82 (dd, 1H), 2.63 (dd, 1H), 2.47 (m, 4H), 2.42-2.29 (m, 2H), 2.18 (m, 2H), 1.45 (t, 3H).
Example 98
Preparation of (S)-2-(6-((9-((1,1-dioxidotetrahydro-2H-thiopyran-4-yl)oxy)-3-fluoro-6,7-dihydro-5H-dibenzo[a,c][7]annulen-2-yl)methoxy)-2,3-dihydrobenzofuran-3-yl)acetic acid
<98-1> Preparation of methyl 9-((1,1-dioxidotetrahydro-2H-thiopyran-4-yl)oxy)-3-fluoro-6,7-dihydro-5H-dibenzo[a,c][7]annulene-2-carboxylate




The compound obtained in <85-7> (200 mg, 0.699 mmol) was dissolved in DMF (4 mL), which was then added with 1,1-dioxidotetrahydro-2H-thiopyran-4-yl 4-methylbenzenesulfonate (425 mg, 1.4 mmol) and K2CO3 (193 mg, 1.4 mmol) and stirred at 90° C. for 15 hours. The reaction mixture was cooled to room temperature, diluted with EtOAc, and washed with a saturated NH4Cl aqueous solution and brine. The organic layer was dried over sodium sulfate, concentrated under reduced pressure, and the residue thus obtained was purified by silica gel chromatography to obtain the title compound (white foam, 234 mg, 80% yield).
1H NMR (600 MHz, CDCl3) δ 7.89 (d, 1H), 7.33 (d, 1H), 7.03 (d, 1H), 6.89 (dd, 1H), 6.83 (d, 1H), 4.73-4.70 (m, 1H), 3.94 (s, 3H), 3.45 (td, 2H), 2.96 (dd, 2H), 2.53 (t, 2H), 2.45 (t, 2H), 2.41 (t, 2H), 2.22-2.15 (m, 2H).
<98-2> Preparation of 4-((9-fluoro-10-(hydroxymethyl)-6,7-dihydro-5H-dibenzo[a,c][7]annulen-3-yl)oxy)tetrahydro-2H-thiopyran 1,1-dioxide




According to the procedures as described in <1-9>, the compound obtained in <98-1> was used to prepare the title compound (white foam, 170 mg, 79% yield).
1H NMR (600 MHz, CDCl3) δ 7.36 (d, 1H), 7.30 (d, 1H), 6.95 (d, 1H), 6.88 (dd, 1H), 6.82 (d, 1H), 4.79 (d, 1H), 4.72-4.69 (m, 1H), 3.45 (td, 2H), 2.97 (dd, 2H), 2.54-2.45 (m, 5H), 2.42-2.37 (m, 2H), 2.19-2.16 (m, 2H), 1.85 (t, 1H).
<98-3> Preparation of (S)-methyl 2-(6-((9-((1,1-dioxidotetrahydro-2H-thiopyran-4-yl)oxy)-3-fluoro-6,7-dihydro-5H-dibenzo[a,c][7]annulen-2-yl)methoxy)-2,3-dihydrobenzofuran-3-ylacetate




According to the procedures as described in <1-10>, the compound obtained in <98-2> was used to prepare the title compound (white foam, 97 mg, 77% yield).
1H NMR (600 MHz, CDCl3) δ 7.42 (d, 1H), 7.27 (d, 1H), 7.04 (d, 1H), 6.98 (d, 1H), 6.88 (dd, 1H), 6.82 (d, 1H), 6.52 (dd, 1H), 6.49 (d, 1H), 5.10 (s, 2H), 4.76 (t, 1H), 4.72-4.69 (m, 1H), 4.27 (dd, 1H), 3.84-3.79 (m, 1H), 3.72 (s, 3H), 3.45 (td, 2H), 2.98-2.93 (m, 2H), 2.75 (dd, 1H), 2.57 (dd, 1H), 2.53-2.45 (m, 6H), 2.39 (t, 2H), 2.20-2.15 (m, 2H).
<98-4> Preparation of (S)-2-(6-((9-((1,1-dioxidotetrahydro-2H-thiopyran-4-yl)oxy)-3-fluoro-6,7-dihydro-5H-dibenzo[a,c][7]annulen-2-yl)methoxy)-2,3-dihydrobenzofuran-3-yl)acetic acid




According to the procedures as described in <1-11>, the compound obtained in <98-3> was used to prepare the title compound (white foam, 82 mg, 88% yield).
MS m/z 566 [M−H]−.
1H NMR (600 MHz, CDCl3) δ 7.41 (d, 1H), 7.27 (d, 1H), 7.07 (d, 1H), 6.98 (d, 1H), 6.88 (dd, 1H), 6.82 (d, 1H), 6.52 (dd, 1H), 6.49 (d, 1H), 5.10 (s, 2H), 4.77 (t, 1H), 4.71-4.69 (m, 1H), 4.29 (dd, 1H), 3.84-3.79 (m, 1H), 3.45 (td, 2H), 2.98-2.94 (m, 2H), 2.81 (dd, 1H), 2.62 (dd, 1H), 2.53-2.45 (m, 6H), 2.42-2.36 (m, 2H), 2.20-2.15 (m, 2H).
Example 99
Preparation of (S)-2-(6-((3-fluoro-9-((4-hydroxy-1,1-dioxidotetrahydro-2H-thiopyran-4-yl)methoxy)-6,7-dihydro-5H-dibenzo[a,c][7]annulen-2-yl)methoxy)-2,3-dihydrobenzofuran-3-yl)acetic acid
<99-1> Preparation of methyl 3-fluoro-9-((4-hydroxytetrahydro-2H-thiopyran-4-yl)methoxy)-6,7-dihydro-5H-dibenzo[a,c][7]annulene-2-carboxylate




According to the procedures as described in <56-1>, the compound obtained in <85-7> was used to prepare the title compound (white foam, 219 mg, 59% yield).
1H NMR (300 MHz, CDCl3) δ 7.89 (d, 1H), 7.31 (d, 1H), 7.03 (d, 1H), 6.88 (dd, 1H), 6.82 (d, 1H), 3.94 (s, 3H), 3.83 (s, 2H), 3.17-3.04 (m, 2H), 2.56-2.41 (m, 6H), 2.25-2.07 (m, 5H), 1.85 (m, 2H).
<99-2> Preparation of methyl 3-fluoro-9-((4-hydroxy-1,1-dioxidotetrahydro-2H-thiopyran-4-yl)methoxy)-6,7-dihydro-5H-dibenzo[a,c][7]annulene-2-carboxylate




According to the procedures as described in <56-2>, the compound obtained in <99-1> was used to prepare the title compound (colorless oil, 382 mg, 107% yield).
1H NMR (300 MHz, CDCl3) δ 7.88 (d, 1H), 7.31 (d, 1H), 7.03 (d, 1H), 6.88 (dd, 1H), 6.82 (d, 1H), 3.94 (s, 3H), 3.92 (s, 2H), 3.51 (m, 2H), 3.02-2.88 (m, 2H), 2.71 (s, 1H), 2.48 (m, 4H), 2.33-2.25 (m, 4H), 2.21 (m, 2H).
<99-3> Preparation of 4-(((9-fluoro-10-(hydroxymethyl)-6,7-dihydro-5H-dibenzo[a,c][7]annulen-3-yl)oxy)methyl)-4-hydroxytetrahydro-2H-thiopyran 1,1-dioxide




According to the procedures as described in <1-9>, the compound obtained in <99-2> was used to prepare the title compound (white foam, 294 mg, 82% yield).
1H NMR (300 MHz, CDCl3) δ 7.36 (d, 1H), 7.29 (dd, 1H), 6.94 (d, 1H), 6.85 (dd, 1H), 6.81 (d, 1H), 4.78 (d, 2H), 3.90 (s, 2H), 3.49 (m, 2H), 3.01-2.87 (m, 2H), 2.75 (s, 1H), 2.45 (t, 4H), 2.27 (m, 4H), 2.17 (m, 3H).
<99-4> Preparation of (S)-methyl 2-(6-((3-fluoro-9-((4-hydroxy-1,1-dioxidotetrahydro-2H-thiopyran-4-yl)methoxy)-6,7-dihydro-5H-dibenzo[a,c][7]annulen-2-yl)methoxy)-2,3-dihydrobenzofuran-3-ylacetate




According to the procedures as described in <1-10>, the compound obtained in <99-3> was used to prepare the title compound (colorless oil, 138 mg, 72% yield).
1H NMR (300 MHz, CDCl3) δ 7.41 (d, 1H), 7.27 (d, 1H), 7.04 (d, 1H), 6.97 (d, 1H), 6.85 (dd, 1H), 6.81 (d, 1H), 6.56-6.43 (m, 2H), 5.09 (s, 2H), 4.75 (t, 1H), 4.26 (dd, 1H), 3.90 (s, 2H), 3.84-3.73 (m, 1H), 3.71 (s, 3H), 3.50 (m, 2H), 2.94 (m, 2H), 2.75 (dd, 1H), 2.56 (dd, 1H), 2.46 (t, 4H), 2.32-2.22 (m, 4H), 2.18 (m, 2H).
<99-5> Preparation of (S)-2-(6-((3-fluoro-9-((4-hydroxy-1,1-dioxidotetrahydro-2H-thiopyran-4-yl)methoxy)-6,7-dihydro-5H-dibenzo[a,c][7]annulen-2-yl)methoxy)-2,3-dihydrobenzofuran-3-yl)acetic acid




According to the procedures as described in <1-11>, the compound obtained in <99-4> was used to prepare the title compound (white foam, 103 mg, 76% yield).
MS m/z 595 [M−H]−.
1H NMR (300 MHz, CDCl3) δ 7.42 (d, 1H), 7.28 (d, 1H), 7.07 (d, 1H), 6.98 (d, 1H), 6.86 (dd, 1H), 6.81 (d, 1H), 6.56-6.43 (m, 2H), 5.10 (s, 2H), 4.77 (t, 1H), 4.30 (dd, 1H), 3.91 (s, 2H), 3.83 (m, 1H), 3.59-3.41 (m, 2H), 3.03-2.89 (m, 2H), 2.80 (dd, 1H), 2.62 (dd, 1H), 2.47 (t, 4H), 2.29 (m, 4H), 2.17 (m, 2H).
Example 100
Preparation of (1S,2S)-2-(4-((9-((1,1-dioxidotetrahydro-2H-thiopyran-4-yl)oxy)-3-fluoro-6,7-dihydro-5H-dibenzo[a,c][7]annulen-2-yl)methoxy)phenyl)cyclopropanecarboxylic acid
<100-1> Preparation of (1S,2S)-ethyl 2-(4-((9-((1,1-dioxidotetrahydro-2H-thiopyran-4-yl)oxy)-3-fluoro-6,7-dihydro-5H-dibenzo[a,c][7]annulen-2-yl)methoxy)phenyl)cyclopropanecarboxylate




According to the procedures as described in <2-16>, the compound obtained in <98-2> was used to prepare the title compound (white foam, 82 mg, 65% yield).
1H NMR (600 MHz, CDCl3) δ 7.42 (d, 1H), 7.27 (d, 1H), 7.04 (d, 2H), 6.98 (d, 1H), 6.92 (d, 2H), 6.87 (dd, 1H), 6.82 (d, 1H), 5.12 (s, 2H), 4.72-4.69 (m, 1H), 4.16 (q, 2H), 3.45 (td, 2H), 2.98-2.93 (m, 2H), 2.50-2.45 (m, 7H), 2.39 (t, 2H), 2.20-2.15 (m, 2H), 1.83-1.81 (m, 1H), 1.56-1.54 (m, 1H), 1.29-1.24 (m, 4H).
<100-2> Preparation of (1S,2S)-2-(4-((9-((1,1-dioxidotetrahydro-2H-thiopyran-4-yl)oxy)-3-fluoro-6,7-dihydro-5H-dibenzo[a,c][p]annulen-2-yl)methoxy)phenyl)cyclopropanecarboxylic acid




According to the procedures as described in <2-17>, the compound obtained in <100-1> was used to prepare the title compound (white foam, 77 mg, 98% yield).
MS m/z 550 [M−H]−.
1H NMR (600 MHz, CDCl3) δ 7.41 (d, 1H), 7.26 (d, 1H), 7.05 (d, 2H), 6.98 (d, 1H), 6.93 (d, 2H), 6.88 (dd, 1H), 6.82 (d, 1H), 5.13 (s, 2H), 4.72-4.69 (m, 1H), 3.45 (td, 2H), 2.98-2.94 (m, 2H), 2.56-2.54 (m, 1H), 2.53-2.43 (m, 6H), 2.42-2.36 (m, 2H), 2.20-2.15 (m, 2H), 1.85-1.82 (m, 1H), 1.65-1.60 (m, 1H), 1.36-1.34 (m, 1H).
Example 101
Preparation of (1S,2S)-2-(4-((3-fluoro-9-((4-hydroxy-1,1-dioxidotetrahydro-2H-thiopyran-4-yl)methoxy)-6,7-dihydro-5H-dibenzo[a,c][7]annulen-2-yl)methoxy)phenyl)cyclopropanecarboxylic acid
<101-1> Preparation of (1S,2S)-ethyl 2-(4-((3-fluoro-9-((4-hydroxy-1,1-dioxidotetrahydro-2H-thiopyran-4-yl)methoxy)-6,7-dihydro-5H-dibenzo[a,c][7]annulen-2-yl)methoxy)phenyl)cyclopropanecarboxylate




According to the procedures as described in <2-16>, the compound obtained in <99-3> was used to prepare the title compound (white foam, 148 mg, 71% yield).
1H NMR (300 MHz, CDCl3) δ 7.42 (d, 1H), 7.27 (d, 1H), 7.07-7.00 (m, 2H), 6.98 (d, 1H), 6.95-6.89 (m, 2H), 6.86 (dd, 1H), 6.81 (d, 1H), 5.12 (s, 2H), 4.16 (q, 2H), 3.90 (s, 2H), 3.50 (m, 2H), 3.01-2.85 (m, 2H), 2.53-2.38 (m, 5H), 2.27 (m, 4H), 2.18 (m, 2H), 1.82 (m, 1H), 1.54 (m, 1H), 1.31-1.20 (m, 3H).
<101-2> Preparation of (1S,2S)-2-(4-((3-fluoro-9-((4-hydroxy-1,1-dioxidotetrahydro-2H-thiopyran-4-yl)methoxy)-6,7-dihydro-5H-dibenzo[a,c][7]annulen-2-yl)methoxy)phenyl)cyclopropanecarboxylic acid




According to the procedures as described in <1-11>, the compound obtained in <101-1> was used to prepare the title compound (white foam, 128 mg, 91% yield).
MS m/z 579 [M−H]−.
1H NMR (300 MHz, CDCl3) δ 7.42 (d, 1H), 7.27 (d, 1H), 7.10-7.02 (m, 2H), 6.98 (d, 1H), 6.96-6.90 (m, 2H), 6.86 (dd, 1H), 6.81 (d, 1H), 5.13 (s, 2H), 3.91 (s, 2H), 3.59-3.40 (m, 2H), 2.96 (m, 2H), 2.64-2.53 (m, 1H), 2.47 (t, 4H), 2.35-2.23 (m, 4H), 2.23-2.11 (m, 2H), 1.89-1.77 (m, 1H), 1.62 (m, 1H), 1.36 (m, 1H).
Example 102
Preparation of (1S,2S)-2-(4-((3-fluoro-9-(3-(methylsulfonyl)propoxy)-6,7-dihydro-5H-dibenzo[a,c][7]annulen-2-yl)methoxy)phenyl)cyclopropanecarboxylic acid
<102-1> Preparation of (1S,2S)-ethyl 2-(4-((3-fluoro-9-(3-(methylsulfonyl)propoxy)-6,7-dihydro-5H-dibenzo[a,c][7]annulen-2-yl)methoxy)phenyl)cyclopropanecarboxylate




According to the procedures as described in <2-16>, the compound obtained in <96-2> was used to prepare the title compound (white foam, 90 mg, 58% yield).
1H NMR (300 MHz, CDCl3) δ 7.42 (d, 1H), 7.24 (d, 1H), 7.04 (d, 2H), 6.97 (d, 1H), 6.92 (d, 2H), 6.83 (dd, 1H), 6.78 (d, 1H), 5.11 (s, 2H), 4.16 (q, 2H), 4.15 (t, 2H), 3.28 (m, 2H), 2.97 (s, 3H), 2.51-2.41 (m, 5H), 2.41-2.32 (m, 2H), 2.17 (m, 2H), 1.81 (m, 1H), 1.55 (m, 1H), 1.27 (t, 3H), 1.25 (m, 1H)
<102-2> Preparation of (1S,2S)-2-(4-((3-fluoro-9-(3-(methylsulfonyl)propoxy)-6,7-dihydro-5H-dibenzo[a,c][7]annulen-2-yl)methoxy)phenyl)cyclopropanecarboxylic acid




According to the procedures as described in <1-11>, the compound obtained in <102-1> was used to prepare the title compound (white foam, 81 mg, 94% yield).
MS m/z 537 [M−H]−
1H NMR (600 MHz, CDCl3) δ 7.41 (d, 1H), 7.23 (d, 1H), 7.05 (d, 2H), 6.96 (d, 1H), 6.92 (d, 2H), 6.83 (dd, 1H), 6.77 (d, 1H), 5.11 (s, 2H), 4.14 (t, 2H), 3.27 (m, 2H), 2.96 (s, 3H), 2.57-2.54 (m, 1H), 2.45 (m, 4H), 2.37-2.35 (m, 2H), 2.16 (m, 2H), 1.82 (m, 1H), 1.61 (m, 1H), 1.35 (m, 1H)
Example 103
Preparation of (1S,2S)-2-(4-((9-((1,1-dioxidotetrahydro-2H-thiopyran-4-yl)methoxy)-3-fluoro-6,7-dihydro-5H-dibenzo[a,c][7]annulen-2-yl)methoxy)phenyl)cyclopropanecarboxylic acid
<103-1> Preparation of (1S,2S)-ethyl 2-(4-((9-((1,1-dioxidotetrahydro-2H-thiopyran-4-yl)methoxy)-3-fluoro-6,7-dihydro-5H-dibenzo[a,c][7]annulen-2-yl)methoxy)phenyl)cyclopropanecarboxylate




According to the procedures as described in <2-16>, the compound obtained in <85-9> was used to prepare the title compound (white foam, 124.3 mg, 61% yield).
1H NMR (300 MHz, CDCl3) δ 7.42 (d, 1H), 7.25 (d, 1H), 7.04 (d, 2H), 6.97 (d, 1H), 6.92 (d, 2H), 6.83 (dd, 1H), 6.77 (d, 1H), 5.12 (s, 2H), 4.16 (q, 2H), 3.90 (d, 2H), 3.21-2.89 (m, 4H), 2.53-2.41 (m, 5H), 2.30 (m, 2H), 2.25-2.12 (m, 2H), 2.12-1.99 (m, 3H), 1.88-1.77 (m, 1H), 1.60-1.50 (m, 1H), 1.32-1.25 (m, 4H).
<103-2> Preparation of (1S,2S)-2-(4-((9-((1,1-dioxidotetrahydro-2H-thiopyran-4-yl)methoxy)-3-fluoro-6,7-dihydro-5H-dibenzo[a,c][7]annulen-2-yl)methoxy)phenyl)cyclopropanecarboxylic acid




According to the procedures as described in <1-11>, the compound obtained in <103-1> was used to prepare the title compound (white foam, 94.2 mg, 79% yield).
MS m/z 587 [M+Na]+.
1H NMR (300 MHz, CDCl3) δ 7.42 (d, 1H), 7.25 (d, 1H), 7.06 (d, 2H), 6.98 (d, 1H), 6.93 (d, 2H), 6.83 (dd, 1H), 6.78 (d, 1H), 5.12 (s, 2H), 3.91 (d, 2H), 3.21-2.97 (m, 4H), 2.56 (m, 1H), 2.47 (m, 4H), 2.30 (m, 2H), 2.23-2.13 (m, 2H), 2.13-2.00 (m, 3H), 1.89-1.77 (m, 1H), 1.62 (m, 1H), 1.36 (m, 1H).
Example 104
Preparation of (1S,2S)-2-(4-(((3-fluoro-9-(3-(methylsulfonyl)propoxy)-6,7-dihydro-5H-dibenzo[a,c][7]annulen-2-yl)methyl)amino)phenyl)cyclopropanecarboxylic acid
<104-1> Preparation of 3-fluoro-9-(3-(methylsulfonyl)propoxy)-6,7-dihydro-5H-dibenzo[a,c][7]annulene-2-carbaldehyde




According to the procedures as described in <3-3>, the compound obtained in <96-2> was used to prepare the title compound (white solid, 77 mg, 74% yield), which was used in the next step.
<104-2> Preparation of (1S,2S)-ethyl 2-(4-(((3-fluoro-9-(3-(methylsulfonyl)propoxy)-6,7-dihydro-5H-dibenzo[a,c][7]annulen-2-yl)methyl)amino)phenyl)cyclopropanecarboxylate




According to the procedures as described in <3-4>, the compound obtained in <104-1> was used to prepare the title compound (white foam, 92 mg, 80% yield).
1H NMR (300 MHz, CDCl3) δ 7.27 (d, 1H), 7.17 (d, 1H), 6.94 (d, 1H), 6.93 (d, 2H), 6.81 (dd, 1H), 6.76 (d, 1H), 6.59 (d, 2H), 4.38 (s, 2H), 4.15 (q, 2H), 4.14 (t, 2H), 3.27 (t, 2H), 2.96 (s, 3H), 2.46-2.33 (m, 6H), 2.15 (m, 2H), 1.77 (m, 1H), 1.50 (m, 1H), 1.26 (t, 3H), 1.21 (m, 1H).
<104-3> Preparation of (1S,2S)-2-(4-(((3-fluoro-9-(3-(methylsulfonyl)propoxy)-6,7-dihydro-5H-dibenzo[a,c][7]annulen-2-yl)methyl)amino)phenyl)cyclopropanecarboxylic acid




According to the procedures as described in <3-5>, the compound obtained in <104-2> was used to prepare the title compound (white foam, 82 mg, 93% yield).
MS m/z 536 [M−H]−.
1H NMR (600 MHz, CDCl3) δ 7.27 (d, 1H), 7.16 (d, 1H), 6.93 (d, 1H), 6.92 (d, 2H), 6.80 (dd, 1H), 6.76 (d, 1H), 6.59 (d, 2H), 4.38 (s, 2H), 4.14 (t, 2H), 3.27 (t, 2H), 2.96 (s, 3H), 2.51-2.47 (m, 1H), 2.43 (m, 4H), 2.37-2.33 (m, 2H), 2.14 (m, 2H), 1.77 (m, 1H), 1.56 (m, 1H), 1.32 (m, 1H).
Example 105
Preparation of (1S,2S)-2-(4-(((9-(3-(ethylsulfonyl)propoxy)-3-fluoro-6,7-dihydro-5H-dibenzo[a,c][7]annulen-2-yl)methyl)amino)phenyl)cyclopropanecarboxylic acid
<105-1> Preparation of 9-(3-(ethylsulfonyl)propoxy)-3-fluoro-6,7-dihydro-5H-dibenzo[a,c][7]annulene-2-carbaldehyde




According to the procedures as described in <3-3>, the compound obtained in <97-2> was used to prepare the title compound (white solid, 73.2 mg, 81% yield).
1H NMR (300 MHz, CDCl3) δ 10.38 (s, 1H), 7.81 (d, 1H), 7.30 (d, 1H), 7.07 (d, 1H), 6.87 (dd, 1H), 6.80 (d, 1H), 4.17 (t, 2H), 3.29-3.16 (m, 2H), 3.06 (q, 2H), 2.55 (t, 2H), 2.45 (t, 2H), 2.42-2.32 (m, 2H), 2.22 (m, 2H), 1.45 (t, 3H).
<105-2> Preparation of (1S,2S)-ethyl 2-(4-(((9-(3-(ethylsulfonyl)propoxy)-3-fluoro-6,7-dihydro-5H-dibenzo[a,c][7]annulen-2-yl)methyl)amino)phenyl)cyclopropanecarboxylate




According to the procedures as described in <3-4>, the compound obtained in <105-1> was used to prepare the title compound (white foam, 116.7 mg, 106% yield).
1H NMR (300 MHz, CDCl3) δ 7.31 (d, 1H), 7.19 (d, 1H), 6.99-6.88 (m, 3H), 6.82 (dd, 1H), 6.78 (d, 1H), 6.62 (d, 2H), 4.39 (s, 2H), 4.21-4.09 (m, 4H), 3.28-3.16 (m, 2H), 3.06 (q, 2H), 2.51-2.31 (m, 7H), 2.15 (m, 2H), 1.84-1.73 (m, 1H), 1.56-1.48 (m, 1H), 1.45 (t, 3H), 1.32-1.18 (m, 4H).
<105-3> Preparation of (1S,2S)-2-(4-(((9-(3-(ethylsulfonyl)propoxy)-3-fluoro-6,7-dihydro-5H-dibenzo[a,c][7]annulen-2-yl)methyl)amino)phenyl)cyclopropanecarboxylic acid




According to the procedures as described in <1-11>, the compound obtained in <105-2> was used to prepare the title compound (white foam, 92.4 mg, 84% yield).
MS m/z 550 [M−H]−.
1H NMR (300 MHz, CDCl3) δ=7.29 (d, 1H), 7.17 (d, 1H), 6.99-6.87 (m, 3H), 6.82 (dd, 1H), 6.77 (d, 1H), 6.60 (d, 2H), 4.39 (s, 2H), 4.13 (t, 2H), 3.30-3.12 (m, 2H), 3.05 (q, 2H), 2.56-2.27 (m, 7H), 2.13 (m, 2H), 1.83-1.72 (m, 1H), 1.58 (m, 1H), 1.44 (t, 3H), 1.32 (m, 1H).
Example 106
Preparation of 2-((S)-6-((3-fluoro-9-(((R)-tetrahydrofuran-3-yl)oxy)-6,7-dihydro-5H-dibenzo[a,c][7]annulen-2-yl)methoxy)-2,3-dihydrobenzofuran-3-yl)acetic acid
<106-1> Preparation of (R)-methyl 3-fluoro-9-((tetrahydrofuran-3-yl)oxy)-6,7-dihydro-5H-dibenzo[a,c][7]annulene-2-carboxylate




The compound obtained in <85-7> (100 mg, 0.349 mmol) was dissolved in DMF (1 mL), which was then added with (S)-tetrahydrofuran-3-yl methanesulfonate (prepared in accordance with the reference [Journal of the American Chemical Society, 1993, vol. 115, p. 801-803]; 87 mg, 0.524 mmol) and Cs2CO3 (171 mg, 0.524 mmol), and stirred at 90° C. for 15 hours. The reaction mixture was cooled to room temperature, extracted with EtOAc, a saturated NH4Cl aqueous solution and brine. The organic layer was dried over sodium sulfate, concentrated under reduced pressure, and the residue thus obtained was purified by silica gel chromatography to obtain the title compound (white foam, 108 mg, 87% yield).
1H NMR (600 MHz, CDCl3) δ 7.87 (d, 1H), 7.28 (d, 1H), 7.01 (d, 1H), 6.81 (dd, 1H), 6.75 (d, 1H), 4.99-4.95 (m, 1H), 4.04-3.98 (m, 3H), 3.94-3.91 (m, 4H), 2.50 (t, 2H), 2.44 (t, 2H), 2.22-2.16 (m, 4H).
<106-2> Preparation of (R)-(3-fluoro-9-((tetrahydrofuran-3-yl)oxy)-6,7-dihydro-5H-dibenzo[a,c][7]annulen-2-yl) methanol




According to the procedures as described in <1-9>, the compound obtained in <106-1> was used to prepare the title compound (white foam, 170 mg, 79% yield).
1H NMR (600 MHz, CDCl3) δ 7.36 (d, 1H), 7.27 (d, 1H), 6.94 (d, 1H), 6.81 (dd, 1H), 6.76 (d, 1H), 4.99-4.97 (m, 1H), 4.79 (d, 2H), 4.05-4.00 (m, 3H), 3.95-3.91 (m, 1H), 2.48-2.44 (m, 4H), 2.25-2.15 (m, 4H), 1.84 (t, 1H).
<106-3> Preparation of methyl 2-((S)-6-((3-fluoro-9-(((R)-tetrahydrofuran-3-yl)oxy)-6,7-dihydro-5H-dibenzo[a,c][7]annulen-2-yl)methoxy)-2,3-dihydrobenzofuran-3-ylacetate




According to the procedures as described in <1-10>, the compound obtained in <106-2> was used to prepare the title compound (white foam, 139 mg, 92% yield).
1H NMR (600 MHz, CDCl3) δ 7.42 (d, 1H), 7.25 (d, 1H), 7.04 (d, 1H), 6.97 (d, 1H), 6.81 (dd, 1H), 6.76 (d, 1H), 6.53 (dd, 1H), 6.50 (d, 1H), 5.10 (s, 2H), 4.98-4.96 (m, 1H), 4.76 (t, 1H), 4.27 (dd, 1H), 4.05-3.99 (m, 3H), 3.94-3.91 (m, 1H), 3.83-3.80 (m, 1H), 3.72 (s, 3H), 2.76 (dd, 1H), 2.57 (dd, 1H), 2.49-2.45 (m, 4H), 2.24-2.15 (m, 4H).
<106-4> Preparation of 2-((S)-6-((3-fluoro-9-(((R)-tetrahydrofuran-3-yl)oxy)-6,7-dihydro-5H-dibenzo[a,c][7]annulen-2-yl)methoxy)-2,3-dihydrobenzofuran-3-yl)acetic acid




According to the procedures as described in <1-11>, the compound obtained in <106-3> was used to prepare the title compound (white foam, 118 mg, 99% yield).
MS m/z 504 [M−H]−.
1H NMR (600 MHz, CDCl3) δ 7.42 (d, 1H), 7.25 (d, 1H), 7.07 (d, 1H), 6.97 (d, 1H), 6.81 (dd, 1H), 6.76 (d, 1H), 6.53 (dd, 1H), 6.50 (d, 1H), 5.10 (s, 2H), 4.98-4.96 (m, 1H), 4.77 (t, 1H), 4.30 (dd, 1H), 4.05-3.99 (m, 3H), 3.95-3.91 (m, 1H), 3.83-3.80 (m, 1H), 2.81 (dd, 1H), 2.62 (dd, 1H), 2.48-2.45 (m, 4H), 2.25-2.15 (m, 4H).
Example 107
Preparation of (S)-2-(6-((3-fluoro-9-(2-morpholinoethoxy)-6,7-dihydro-5H-dibenzo[a,c][7]annulen-2-yl)methoxy)-2,3-dihydrobenzofuran-3-yl)acetic acid
<107-1> Preparation of (3-fluoro-9-(2-morpholinoethoxy)-6,7-dihydro-5H-dibenzo[a,c][7]annulen-2-yl)methanol




A solution of the compound obtained in <85-7> (100 mg, 0.349 mmol) in DMF (3.5 mL) was added with 4-(2-chloroethyl)morpholine.HCl (98 mg, 0.524 mmol) and Cs2CO3 (284 mg, 0.873 mmol) and stirred at 90° C. for 15 hours. The reaction mixture was cooled, added with a saturated NH4Cl aqueous solution, and extracted with EtOAc two times. The organic layer was collected, dried over MgSO4, concentrated, and purified by silica gel chromatography to obtain methyl 2-(3-fluoro-9-(2-morpholinoethoxy)-6,7-dihydro-5H-dibenzo[a,c][7]annulen-2-ylacetate (white solid, 138 mg, 98.9% yield). According to the procedures as described in <1-9>, methyl 2-(3-fluoro-9-(2-morpholinoethoxy)-6,7-dihydro-5H-dibenzo[a,c][7]annulen-2-ylacetate (138 mg, 0.345 mmol) was used to obtain the title compound (pale yellow oil, 122 mg, 95.2% yield).
1H NMR (300 MHz, CDCl3) δ 7.36 (d, 1H), 7.28-7.25 (m, 1H), 6.94 (d, 1H), 6.87 (dd, 1H), 6.81 (d, 1H), 4.79 (s, 2H), 4.16 (t, 2H), 3.88-3.62 (m, 4H), 2.83 (t, 2H), 2.73-2.54 (m, 4H), 2.46 (m, 4H), 2.17 (m, 2H).
<107-2> Preparation of (S)-methyl 2-(6-((3-fluoro-9-(2-morpholinoethoxy)-6,7-dihydro-5H-dibenzo[a,c][7]annulen-2-yl)methoxy)-2,3-dihydrobenzofuran-3-ylacetate




According to the procedures as described in <1-10>, the compound obtained in <107-1> was used to prepare the title compound (white solid, 221 mg, 99% yield).
1H NMR (300 MHz, CDCl3) δ 7.42 (d, 1H), 7.25 (d, 1H), 7.03 (d, 1H), 6.96 (d, 1H), 6.86 (dd, 1H), 6.80 (d, 1H), 6.57-6.38 (m, 2H), 5.09 (s, 2H), 4.76 (t, 1H), 4.27 (dd, 1H), 4.15 (t, 2H), 3.79-3.73 (m, 5H), 3.71 (s, 3H), 2.83 (t, 2H), 2.76 (dd, 1H), 2.63-2.41 (m, 9H), 2.22-2.09 (m, 2H).
<107-3> Preparation of (S)-2-(6-((3-fluoro-9-(2-morpholinoethoxy)-6,7-dihydro-5H-dibenzo[a,c][7]annulen-2-yl) methoxy)-2,3-dihydrobenzofuran-3-yl)acetic acid




According to the procedures as described in <1-11>, the compound obtained in <107-2> was used to prepare the title compound (white solid, 132 mg, 62.1% yield).
MS m/z 594 [M−H]−.
1H NMR (300 MHz, CDCl3) δ 7.39 (d, 1H), 7.23 (s, 1H), 7.05 (d, 1H), 6.95 (d, 1H), 6.85 (dd, 1H), 6.79 (d, 1H), 6.48 (d, 2H), 5.06 (s, 2H), 4.74 (t, 1H), 4.35-4.15 (m, 3H), 3.87-3.71 (m, 5H), 2.92 (t, 2H), 2.80-2.69 (m, 5H), 2.63-2.40 (m, 13H), 2.23-2.10 (m, 2H).
Example 108
Preparation of (S)-3-(4-((9-(3-(methylsulfonyl)propoxy)-6,7-dihydro-5H-dibenzo[a,c][7]annulen-2-yl) methoxy)phenyl)hex-4-ynoic acid
<108-1> Preparation of 1-allyl-3-methoxybenzene




A solution of (3-methoxyphenyl)magnesium bromide (1M toluene/THF solution, 100 mL, 100.0 mmol) in THF (150 mL) at 0° C. was slowly added with allyl bromide (13.0 mL, 150.0 mmol), which was then heated to room temperature and stirred for 18 hours. The mixture was added with a saturated NH4Cl aqueous solution and extracted with Et2O. The organic layer was dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue thus obtained was purified by silica gel chromatography to obtain the title compound (colorless oil, 12.0 g, 81% yield).
1H NMR (300 MHz, CDCl3) δ 7.21 (dd, 1H), 6.78 (d, 2H), 6.74 (s, 1H), 5.97 (m, 1H), 5.12-5.05 (m, 2H), 3.80 (s, 3H), 3.38 (d, 2H)
<108-2> Preparation of methyl 3-bromo-4-(3-(3-methoxyphenyl)propyl)benzoate




The compound obtained in <108-1> (6.22 g, 42.0 mmol) was dissolved in THF (42 mL), added with 9-BBN (0.5 mol THF solution, 100 mL, 50.0 mmol), stirred for 3 hours. The mixture was added with DMF (100 mL), K2CO3 (17.5 g, 126.0 mmol), methyl 3-bromo-4-iodobenzoate (15.7 g, 46.0 mmol) and PdCl2(dppf) (1.72 g, 2.1 mmol), substituted with nitrogen, and stirred at 110° C. for 18 hours. The reaction mixture was cooled to room temperature, added with a saturated NH4Cl aqueous solution, and extracted with EtOAc. The organic layer was washed with brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue thus obtained was purified by silica gel chromatography to obtain the title compound (colorless oil, 10.6 g, 69% yield).
1H NMR (300 MHz, CDCl3) δ 8.20 (s, 1H), 7.88 (d, 1H), 7.26 (d, 1H), 7.21 (m, 1H), 6.78 (d, 1H), 6.75-6.73 (m, 2H), 3.90 (s, 3H), 3.79 (s, 3H), 2.81 (t, 2H), 2.68 (t, 2H), 1.99-1.93 (m, 2H)
<108-3> Preparation of methyl 4-(3-(3-methoxyphenyl)propyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2-yl)benzoate




The compound obtained in <108-2> (10.6 g, 29.2 mmol) was dissolved in DMF (30 mL), added with bis(pinacolato)diboron (8.9 g, 35.0 mmol), KOAc (8.6 g, 87.6 mmol) and PdCl2(dppf) (1.22 g, 1.5 mmol), and then substituted with nitrogen. After stirring at 110° C. for 16 hours, the reaction mixture was cooled to room temperature, added with a saturated NH4Cl aqueous solution, and extracted with EtOAc. The organic layer was dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue thus obtained was purified by silica gel chromatography to obtain the title compound (pale green oil, 13.0 g, 100% yield).
1H NMR (300 MHz, CDCl3) δ 8.42 (d, 1H), 7.98 (dd, 1H), 7.23 (d, 1H), 7.22-7.16 (m, 1H), 6.78 (d, 1H), 6.74-6.72 (m, 2H), 3.90 (s, 3H), 3.79 (s, 3H), 2.98 (t, 2H), 2.65 (t, 2H), 1.93-1.83 (m, 2H), 1.34 (s, 12H).
<108-4> Preparation of methyl 4-(3-(2-bromo-5-methoxyphenyl)propyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2-yl)benzoate




The compound obtained in <108-3> (13.0 g, 29.2 mmol) was dissolved in acetonitrile (150 mL), added with N-bromosuccinimide (5.2 g, 29.2 mmol) at 0° C., heated to room temperature, and stirred for 2 hours. The reaction mixture thus obtained was concentrated under reduced pressure, added with hexane, and filtered. The filtrate was concentrated under reduced pressure, and the residue thus obtained was purified by silica gel chromatography to obtain the title compound (pale green oil, 13.6 g, 95% yield).
1H NMR (300 MHz, CDCl3) δ 8.43 (d, 1H), 8.00 (dd, 1H), 7.39 (d, 1H), 7.27 (d, 1H), 6.74 (d, 1H), 6.61 (dd, 1H), 3.90 (s, 3H), 3.76 (s, 3H), 3.03 (t, 2H), 2.74 (t, 2H), 1.93-1.83 (m, 2H), 1.34 (s, 12H).
<108-5> Preparation of methyl 9-methoxy-6,7-dihydro-5H-dibenzo[a,c][7]annulene-2-carboxylate




The compound obtained in <108-4> (13.6 g, 27.7 mmol) was dissolved in 1,4-dioxane (140 mL), added with K2CO3 (11.5 g, 83.2 mmol) and PdCl2(dppf) (1.1 g, 1.4 mmol), substituted with nitrogen, and stirred at 110° C. for 16 hours. The reaction mixture was cooled to room temperature, concentrated under reduced pressure, diluted with dichloromethane, filtered through Celite, and concentrated under reduced pressure. The residue thus obtained was purified by silica gel chromatography to obtain the title compound (colorless oil, 4.6 g, 58% yield).
1H NMR (300 MHz, CDCl3) δ 8.02 (d, 1H), 7.92 (dd, 1H), 7.35 (d, 1H), 7.29 (d, 1H), 6.89 (dd, 1H), 6.81 (d, 1H), 3.93 (s, 3H), 3.86 (s, 3H), 2.55 (t, 2H), 2.46 (t, 2H), 2.25-2.16 (m, 2H).
<108-6> Preparation of methyl 9-hydroxy-6,7-dihydro-5H-dibenzo[a,c][7]annulene-2-carboxylate




The compound obtained in <108-5> (685 mg, 2.43 mmol) was dissolved in dichloromethane (25 mL), slowly added with BBr3 (1M dichloromethane solution, 4.85 mL, 4.85 mmol) at 0° C., heated to room temperature, and stirred for 1 hour. The reaction mixture was consecutively added with methanol and water at 0° C., and then extracted with dichloromethane. The organic layer was dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue thus obtained was purified by silica gel chromatography to obtain the title compound (colorless foam, 643 mg, 99% yield).
1H NMR (300 MHz, CDCl3) δ 8.01 (d, 1H), 7.92 (dd, 1H), 7.29 (d, 2H), 6.83 (dd, 1H), 6.75 (d, 1H), 5.08 (s, 1H), 3.93 (s, 3H), 2.54 (t, 2H), 2.43 (t, 2H), 2.24-2.14 (m, 2H).
<108-7> Preparation of methyl 9-(3-(methylsulfonyl)propoxy)-6,7-dihydro-5H-dibenzo[a,c][7]annulene-2-carboxylate




The compound obtained in <108-6> (100 mg, 0.37 mmol) was dissolved in DMF (4 mL), added with 3-(methylsulfonyl)propyl 4-methylbenzenesulfonate (131 mg, 0.45 mmol) and Cs2CO3 (182 mg, 0.56 mmol), and stirred at 50° C. for 15 hours. The reaction mixture was cooled to room temperature, diluted with EtOAc, and washed with a saturated NH4Cl aqueous solution and brine. The organic layer was dried over magnesium sulfate, concentrated under reduced pressure, and the residue thus obtained was purified by silica gel chromatography to obtain the title compound (white foam, 165 mg, 99% yield).
1H NMR (300 MHz, CDCl3) δ 8.01 (d, 1H), 7.93 (dd, 1H), 7.35 (d, 1H), 7.30 (d, 1H), 6.87 (dd, 1H), 6.80 (d, 1H), 4.17 (t, 2H), 3.93 (s, 3H), 3.29 (t, 2H), 2.98 (s, 3H), 2.54 (t, 2H), 2.46 (t, 2H), 2.43-2.34 (m, 2H), 2.25-2.16 (m, 2H).
<108-8> Preparation of (9-(3-(methylsulfonyl)propoxy)-6,7-dihydro-5H-dibenzo[a,c][7]annulen-2-yl)methanol




The compound obtained in <108-7> (165 mg, 0.43 mmol) was dissolved in THF (4 mL) and slowly added with LiAlH4 (1M THF solution, 849 μL, 0.85 mmol) at 0° C. After stirring for 2 hours, the mixture was added with a saturated NH4Cl aqueous solution and filtered. The filtrate was washed with brine, and the organic layer was dried over magnesium sulfate and concentrated under reduced pressure. The residue thus obtained was purified by silica gel chromatography to obtain the title compound (white foam, 124 mg, 81% yield).
1H NMR (300 MHz, CDCl3) δ 7.34 (d, 1H), 7.32 (d, 1H), 7.29-7.21 (m, 2H), 6.85 (dd, 1H), 6.79 (d, 1H), 4.74 (d, 2H), 4.17 (t, 2H), 3.29 (t, 2H), 2.97 (s, 3H), 2.49 (t, 2H), 2.46 (t, 2H), 2.42-2.33 (m, 2H), 2.22-2.13 (m, 2H), 1.65 (t, 1H).
<108-9> Preparation of (S)-methyl 3-(4-((9-(3-(methylsulfonyl)propoxy)-6,7-dihydro-5H-dibenzo[a,c][7]annulen-2-yl)methoxy)phenyl)hex-4-ynoate




The compound obtained in <108-8> (124 mg, 0.34 mmol), (S)-methyl 3-(4-hydroxyphenyl)hex-4-ynoate (prepared in accordance with the reference [Bioorganic & Medicinal Chemistry Letters, 2012, 22, p. 1267-1270]; 75 mg, 0.34 mmol) and tributylphosphine (129 μL, 0.52 mmol) were dissolved in THF (3.5 mL), which was then added with 1,1′-(azodicarbonyl)dipiperidine) (130 mg, 0.52 mmol) and stirred at room temperature for 2 hours. The mixture was concentrated and purified by silica gel chromatography to obtain the title compound (white foam, 145 mg, 75% yield).
1H NMR (300 MHz, CDCl3) δ 7.39 (d, 1H), 7.32 (d, 1H), 7.31 (d, 1H), 7.28 (d, 2H), 7.24 (d, 2H), 6.94 (d, 2H), 6.85 (dd, 1H), 6.79 (d, 1H), 5.07 (s, 2H), 4.17 (t, 2H), 4.06 (m, 1H), 3.66 (s, 3H), 3.29 (t, 2H), 2.98 (s, 3H), 2.71 (m, 2H), 2.49 (m, 4H), 2.38 (m, 2H), 2.18 (m, 2H), 1.82 (d, 3H).
<108-10> Preparation of (S)-3-(4-((9-(3-(methylsulfonyl)propoxy)-6,7-dihydro-5H-dibenzo[a,c][7]annulen-2-yl)methoxy)phenyl)hex-4-ynoic acid




The compound obtained in <108-9> (142 mg, 0.25 mmol) was dissolved in methanol (2 mL) and THF (1 mL), added with 2N NaOH (380 μL, 0.76 mmol), and stirred at 75° C. for 2 hours. The mixture was cooled to room temperature, added with water, and then added with 0.5M citric acid aqueous solution so that the pH was adjusted to  ̃4. The mixture was extracted with dichloromethane, dried over magnesium sulfate, and the residue thus obtained was purified by silica gel chromatography to obtain the title compound (white foam, 88 mg, 64% yield).
MS m/z 545 [M−H]−.
1H NMR (300 MHz, CDCl3) δ 7.38 (d, 1H), 7.32 (d, 2H), 7.31 (d, 1H), 7.30 (d, 1H), 7.24 (d, 1H), 6.95 (d, 2H), 6.85 (dd, 1H), 6.79 (d, 1H), 5.07 (s, 2H), 4.17 (t, 2H), 4.06 (m, 1H), 3.29 (s, 3H), 2.97 (s, 3H), 2.76 (m, 2H), 2.49 (m, 4H), 2.38 (m, 2H), 2.19 (m, 2H), 1.84 (d, 3H).
Example 109
Preparation of (S)-3-(4-((9-((1,1-dioxidotetrahydro-2H-thiopyran-4-yl)methoxy)-6,7-dihydro-5H-dibenzo[a,c][7]annulen-2-yl)methoxy)phenyl)hex-4-ynoic acid
<109-1> Preparation of methyl 9-((1,1-dioxidotetrahydro-2H-thiopyran-4-yl)methoxy)-6,7-dihydro-5H-dibenzo[a,c][7]annulene-2-carboxylate




The compound obtained in <108-6> (100 mg, 0.37 mmol) was dissolved in DMF (4 mL), added with (1,1-dioxidotetrahydro-2H-thiopyran-4-yl)methyl 4-methylbenzenesulfonate (142 mg, 0.45 mmol) and Cs2CO3 (182 mg, 0.56 mmol), and then stirred at 50° C. for 2.5 hours. The reaction mixture was cooled to room temperature, diluted with EtOAc, and then washed with a saturated NH4Cl aqueous solution. The organic layer was dried over magnesium sulfate, concentrated under reduced pressure, and the residue thus obtained was purified by silica gel chromatography to obtain the title compound (white foam, 148 mg, 96% yield).
1H NMR (300 MHz, CDCl3) δ 8.00 (d, 1H), 7.92 (dd, 1H), 7.35 (d, 1H), 7.29 (d, 1H), 6.86 (dd, 1H), 6.78 (d, 1H), 3.92 (s, 3H), 3.91 (d, 2H), 3.10 (m, 4H), 2.54 (t, 2H), 2.44 (t, 2H), 2.32 (m, 2H), 2.20 (m, 2H), 2.07 (m, 2H).
<109-2> Preparation of 4-(((10-(hydroxymethyl)-6,7-dihydro-5H-dibenzo[a,c][7]annulen-3-yl)oxy)methyl)tetrahydro-2H-thiopyran 1,1-dioxide




The compound obtained in <109-1> (147 mg, 0.36 mmol) was dissolved in THF (3.5 mL) and slowly added with LiAlH4 (1M THF solution, 709 μL, 0.71 mmol) at 0° C. After stirring for 1.5 hours, the mixture was added with a saturated NH4Cl aqueous solution and filtered. The filtrate thus obtained was washed with brine, and the organic layer was dried over magnesium sulfate, concentrated under reduced pressure. The residue was purified by silica gel chromatography to obtain the title compound (white foam, 112 mg, 82% yield).
1H NMR (300 MHz, CDCl3) δ 7.34 (d, 1H), 7.32 (d, 1H), 7.27 (d, 1H), 7.23 (d, 1H), 6.84 (dd, 1H), 6.79 (d, 1H), 4.74 (d, 2H), 3.92 (d, 2H), 3.12 (m, 4H), 2.48 (m, 4H), 2.33 (m, 2H), 2.19 (m, 2H), 2.07 (m, 3H), 1.64 (t, 1H).
<109-3> Preparation of 4-(((10-(bromomethyl)-6,7-dihydro-5H-dibenzo[a,c][7]annulen-3-yl)oxy)methyl)tetrahydro-2H-thiopyran 1,1-dioxide




The compound obtained in <109-2> (680 mg, 1.76 mmol) was dissolved in dichloromethane (14 mL), which was then slowly added with DMF (68 μL, 0.88 mmol) and thionyl bromide (0.15 mL, 1.94 mmol), and stirred at room temperature for 1 hour. The reaction mixture was concentrated and purified by silica gel chromatography to obtain the title compound (white solid, 618 mg, 78% yield).
1H NMR (600 MHz, CDCl3) δ 7.35 (d, 1H), 7.31 (d, 1H), 7.29 (d, 1H), 7.20 (d, 1H), 6.85 (dd, 1H), 6.78 (d, 1H), 4.56 (s, 2H), 3.91 (d, 2H), 3.71-3.13 (m, 2H), 3.08-3.03 (m, 2H), 2.50-2.45 (m, 4H), 2.34-2.31 (m, 2H), 2.19-2.16 (m, 2H), 2.09-2.05 (m, 3H).
<109-4> Preparation of (S)-methyl 3-(4-((9-((1,1-dioxidotetrahydro-2H-thiopyran-4-yl)methoxy)-6,7-dihydro-5H-dibenzo[a,c][7]annulen-2-yl)methoxy)phenyl)hex-4-ynoate




Method 1: The compound obtained in <109-2> (110 mg, 0.29 mmol), (S)-methyl 3-(4-hydroxyphenyl)hex-4-ynoate (prepared in accordance with the reference [Bioorganic & Medicinal Chemistry Letters, 2012, 22, p. 1267-1270]; 62 mg, 0.29 mmol) and tributylphosphine (106 μL, 0.43 mmol) were dissolved in THF (3.5 mL), which was then added with 1,1′-(azodicarbonyl)dipiperidine) (108 mg, 0.43 mmol) and stirred at room temperature for 2 hours. The mixture was concentrated and purified by silica gel chromatography to obtain the title compound (white foam, 103 mg, 62% yield).
Method 2: the compound obtained in <109-3> (100 mg, 0.22 mmol) and (S)-methyl 3-(4-hydroxyphenyl)hex-4-ynoate (prepared in accordance with the reference [Bioorganic & Medicinal Chemistry Letters, 2012, 22, p. 1267-1270]; 58 mg, 0.27 mmol) were dissolved in acetone (3 mL), which was then added with Cs2CO3 (87 mg, 0.27 mmol) and stirred at room temperature for 16 hours. The reaction mixture was filtered, and the filtrate thus obtained was concentrated and purified by silica gel chromatography to obtain the title compound (white foam, 120 mg, 92% yield).
1H NMR (300 MHz, CDCl3) δ 7.39 (d, 1H), 7.32 (d, 1H), 7.31 (d, 1H), 7.30 (d, 2H), 7.24 (d, 1H), 6.94 (d, 2H), 6.84 (dd, 1H), 6.79 (d, 1H), 5.07 (s, 2H), 4.06 (m, 1H), 3.91 (d, 2H), 3.67 (s, 3H), 3.10 (m, 4H), 2.72 (m, 2H), 2.49 (m, 4H), 2.34 (m, 2H), 2.18 (m, 2H), 2.08 (m, 3H), 1.83 (d, 3H).
<109-5> Preparation of (S)-3-(4-((9-((1,1-dioxidotetrahydro-2H-thiopyran-4-yl)methoxy)-6,7-dihydro-5H-dibenzo[a,c][7]annulen-2-yl)methoxy)phenyl)hex-4-ynoic acid




The compound obtained in <109-4> (103 mg, 0.18 mmol) was dissolved in methanol (1.5 mL) and THF (0.8 mL), which was then added with 2N NaOH (263 μL, 0.53 mmol) and stirred at 75° C. for 2 hours. The mixture was cooled to room temperature, added with water, and then further added with 0.5M citric acid aqueous solution so that the pH was adjusted to  ̃4. The mixture was extracted with dichloromethane, dried over magnesium sulfate, and concentrated under reduced pressure. The residue thus obtained was purified by silica gel chromatography to obtain the title compound (white foam, 73 mg, 72% yield).
MS m/z 571 [M−H]−.
1H NMR (300 MHz, CDCl3) δ 7.39 (d, 1H), 7.32 (d, 2H), 7.31 (m, 2H), 7.24 (d, 1H), 6.96 (d, 2H), 6.84 (dd, 1H), 6.79 (d, 1H), 5.07 (s, 2H), 4.06 (m, 1H), 3.92 (d, 2H), 3.19-3.12 (m, 4H), 2.76 (m, 2H), 2.49 (m, 4H), 2.33 (m, 2H), 2.18 (m, 2H), 2.07 (m, 3H), 1.83 (d, 3H).
Example 110
Preparation of (S)-3-(4-((9-((1,1-dioxidotetrahydro-2H-thiopyran-4-yl)oxy)-6,7-dihydro-5H-dibenzo[a,c][7]annulen-2-yl)methoxy)phenyl)hex-4-ynoic acid
<110-1> Preparation of 4-((10-(bromomethyl)-6,7-dihydro-5H-dibenzo[a,c][7]annulen-3-yl)oxy)tetrahydro-2H-thiopyran 1,1-dioxide




The compound obtained in <64-2> (83 mg, 0.22 mmol) was dissolved in dichloromethane (2.2 mL), which was then slowly added with DMF (8.5 μL, 0.11 mmol) and thionyl bromide (18.6 μL, 0.24 mmol), and the mixture thus formed was stirred at room temperature for 2 hours. The reaction mixture was concentrated and purified by silica gel chromatography to obtain the title compound (white foam, 93 mg, 97% yield).
1H NMR (300 MHz, CDCl3) δ 7.36-7.29 (m, 3H), 7.20 (d, 1H), 6.89 (dd, 1H), 6.83 (d, 1H), 4.74-4.68 (m, 1H), 4.56 (s, 2H), 3.51-3.41 (m, 2H), 3.00-2.92 (m, 2H), 2.55-2.35 (m, 8H), 2.22-2.15 (m, 2H).
<110-2> Preparation of (S)-methyl 3-(4-((9-((1,1-dioxidotetrahydro-2H-thiopyran-4-yl)oxy)-6,7-dihydro-5H-dibenzo[a,c][7]annulen-2-yl)methoxy)phenyl)hex-4-ynoate




The compound obtained in <110-1> (93 mg, 0.21 mmol) and (S)-methyl 3-(4-hydroxyphenyl)hex-4-ynoate (prepared in accordance with the reference [Bioorganic & Medicinal Chemistry Letters, 2012, 22, p. 1267-1270]; 55 mg, 0.25 mmol) was dissolved in acetone (1 mL), added with Cs2CO3 (81 mg, 0.25 mmol), and the mixture thus formed was stirred at room temperature for 16 hours. The reaction mixture was filtered, and the filtrate thus obtained was purified by silica gel chromatography to obtain the title compound (white foam, 114 mg, 95% yield).
1H NMR (300 MHz, CDCl3) δ 7.40-7.22 (m, 6H), 6.97-6.83 (m, 4H), 5.07 (s, 2H), 4.73-4.68 (m, 1H), 4.11-4.03 (m, 1H), 3.66 (s, 3H), 3.52-3.41 (m, 2H), 2.99-2.92 (m, 2H), 2.80-2.62 (m, 2H), 2.55-2.35 (m, 7H), 2.23-2.14 (m, 2H), 1.84-1.82 (m, 3H).
<110-3> Preparation of (S)-3-(4-((9-((1,1-dioxidotetrahydro-2H-thiopyran-4-yl)oxy)-6,7-dihydro-5H-dibenzo[a,c][7]annulen-2-yl)methoxy)phenyl)hex-4-ynoic acid




According to the procedures as described in <1-11>, the compound obtained in <110-2> was used to prepare the title compound (white foam, 83 mg, 74% yield).
MS m/z 557 [M−H]−.
1H NMR (300 MHz, CDCl3) δ 7.39-7.23 (m, 6H), 6.97-6.83 (m, 4H), 5.07 (s, 2H), 4.73-4.68 (m, 1H), 4.11-4.03 (m, 1H), 3.52-3.40 (s, 2H), 3.00-2.92 (m, 2H), 2.85-2.67 (m, 2H), 2.58-2.32 (m, 7H), 2.23-2.14 (m, 2H), 1.84-1.82 (m, 3H).
Example 111
Preparation of (S)-3-(4-((9-(3-(ethylsulfonyl)propoxy)-6,7-dihydro-5H-dibenzo[a,c][7]annulen-2-yl)methoxy)phenyl)hex-4-ynoic acid
<111-1> Preparation of (S)-methyl 3-(4-((9-(3-(ethylsulfonyl)propoxy)-6,7-dihydro-5H-dibenzo[a,c][7]annulen-2-yl)methoxy)phenyl)hex-4-ynoate




According to the procedures as described in <108-3>, the compound obtained in <66-2> was used to prepare the title compound (yellow oil, 57 mg, 66% yield).
1H NMR (300 MHz, CDCl3) δ 7.39 (d, 1H), 7.34-7.23 (m, 5H), 6.97-6.93 (m, 2H), 6.85 (dd, 1H), 6.79 (d, 1H), 5.07 (s, 2H), 4.17 (t, 2H), 4.10-4.04 (m, 1H), 3.67 (s, 3H), 3.25-3.20 (m, 2H), 3.10-3.02 (m, 2H), 2.81-2.62 (m, 2H), 2.52-2.46 (m, 4H), 2.42-2.33 (m, 2H), 2.22-2.16 (m, 2H), 1.83 (d, 3H), 1.45 (t, 3H).
<111-2> Preparation of (S)-3-(4-((9-(3-(ethylsulfonyl)propoxy)-6,7-dihydro-5H-dibenzo[a,c][7]annulen-2-yl)methoxy)phenyl)hex-4-ynoic acid




According to the procedures as described in <1-11>, the compound obtained in <111-1> was used to prepare the title compound (white foam, 33 mg, 58% yield).
MS m/z 559 [M−H]−.
1H NMR (300 MHz, CDCl3) δ 7.39 (d, 1H), 7.34-7.23 (m, 5H), 6.98-6.93 (m, 2H), 6.85 (dd, 1H), 6.79 (d, 1H), 5.07 (s, 2H), 4.17 (t, 2H), 4.10-4.04 (m, 1H), 3.25-3.20 (m, 2H), 3.09-3.02 (m, 2H), 2.85-2.67 (m, 2H), 2.52-2.46 (m, 4H), 2.42-2.33 (m, 2H), 2.22-2.16 (m, 2H), 1.83 (d, 3H), 1.45 (t, 3H).
Example 112
Preparation of (S)-3-(4-((9-((1,1-dioxidotetrahydro-2H-thiopyran-4-yl)methoxy)-3-fluoro-6,7-dihydro-5H-dibenzo[a,c][7]annulen-2-yl)methoxy)phenyl)hex-4-ynoic acid
<112-1> Preparation of (S)-methyl 3-(4-((9-((1,1-dioxidotetrahydro-2H-thiopyran-4-yl)methoxy)-3-fluoro-6,7-dihydro-5H-dibenzo[a,c][7]annulen-2-yl)methoxy)phenyl)hex-4-ynoate




According to the procedures as described in <108-3>, the compound obtained in <85-9> was used to prepare the title compound (yellow oil, 112.8 mg, 64% yield).
1H NMR (300 MHz, CDCl3) δ 7.44-7.24 (m, 4H), 6.99-6.77 (m, 5H), 5.13 (s, 2H), 4.10-4.04 (m, 1H), 3.91 (m, 2H), 3.67 (m, 3H), 3.18-3.00 (m, 4H), 2.80-2.62 (m, 2H), 2.50-2.43 (m, 4H), 2.36-2.28 (m, 2H), 2.20-2.14 (m, 2H), 2.10-2.05 (m, 3H), 1.82 (m, 3H).
<112-2> Preparation of (S)-3-(4-((9-((1,1-dioxidotetrahydro-2H-thiopyran-4-yl)methoxy)-3-fluoro-6,7-dihydro-5H-dibenzo[a,c][7]annulen-2-yl)methoxy)phenyl)hex-4-ynoic acid




According to the procedures as described in <1-11>, the compound obtained in <112-1> was used to prepare the title compound (white foam, 55 mg, 49% yield).
MS m/z 589 [M−H]−.
1H NMR (300 MHz, CDCl3) δ 7.44-7.24 (m, 4H), 6.99-6.94 (m, 3H), 6.85-6.77 (m, 2H), 5.13 (s, 2H), 4.10-4.04 (m, 1H), 3.90 (m, 2H), 3.18-3.00 (m, 4H), 2.85-2.65 (m, 2H), 2.50-2.43 (m, 4H), 2.33-2.27 (m, 2H), 2.20-2.13 (m, 2H), 2.10-2.04 (m, 3H), 1.83 (m, 3H).
Example 113
Preparation of (S)-3-(4-((9-((1,1-dioxidotetrahydro-2H-thiopyran-4-yl)methoxy)-6,7-dihydrodibenzo[b,d]oxepin-2-yl)methoxy)phenyl)hex-4-ynoic acid
<113-1> Preparation of methyl 9-((1,1-dioxidotetrahydro-2H-thiopyran-4-yl)methoxy)-6,7-dihydrodibenzo[b,d]oxepin-2-carboxylate




According to the procedures as described in <47-1>, the compound obtained in <2-11> was used to prepare the title compound (white foam, 155 mg, 100% yield).
1H NMR (600 MHz, CDCl3) δ 8.08 (d, 1H), 7.97 (dd, 1H), 7.43 (d, 1H), 7.15 (d, 1H), 6.91 (dd, 1H), 6.81 (d, 1H), 4.61 (t, 2H), 3.94-3.90 (m, 5H), 3.17-3.14 (m, 2H), 3.08-3.03 (m, 2H), 2.80 (t, 2H), 2.34-2.30 (m, 2H), 2.10-2.05 (m, 3H).
<113-2> Preparation of 4-(((2-(hydroxymethyl)-6,7-dihydrodibenzo[b,d]oxepin-9-yl)oxy)methyl)tetrahydro-2H-thiopyran 1,1-dioxide




According to the procedures as described in <1-9>, the compound obtained in <113-1> was used to prepare the title compound (white solid, 122 mg, 85% yield).
1H NMR (600 MHz, CDCl3) δ 7.40-7.38 (m, 2H), 7.29 (dd, 1H), 7.10 (d, 1H), 6.90 (dd, 1H), 6.84 (d, 1H), 4.68 (s, 2H), 4.55 (t, 2H), 3.93 (d, 2H), 3.19-3.14 (m, 2H), 3.12-3.07 (m, 2H), 2.77 (t, 2H), 2.35-2.31 (m, 2H), 2.11-2.03 (m, 3H).
<113-3> Preparation of (S)-methyl 3-(4-((9-((1,1-dioxidotetrahydro-2H-thiopyran-4-yl)methoxy)-6,7-dihydrodibenzo[b,d]oxepin-2-yl)methoxy)phenyl)hex-4-ynoate




According to the procedures as described in <108-3>, the compound obtained in <113-2> was used to prepare the title compound (white foam, 125 mg, 70% yield).
1H NMR (600 MHz, CDCl3) δ 7.42 (d, 1H), 7.35 (d, 1H), 7.34 (dd, 1H), 7.29-7.27 (m, 2H), 7.12 (d, 1H), 6.94-6.92 (m, 2H), 6.88 (dd, 1H), 6.82 (d, 1H), 5.04 (s, 2H), 4.55 (t, 2H), 4.06-4.04 (m, 1H), 3.91 (d, 2H), 3.65 (s, 3H), 3.16-3.12 (m, 2H), 3.06-3.02 (m, 2H), 2.79-2.73 (m, 3H), 2.67-2.63 (m, 1H), 2.31-2.29 (m, 2H), 2.08-2.03 (m, 3H), 1.81 (d, 3H).
<113-4> Preparation of (S)-3-(4-((9-((1,1-dioxidotetrahydro-2H-thiopyran-4-yl)methoxy)-6,7-dihydrodibenzo[b,d]oxepin-2-yl)methoxy)phenyl)hex-4-ynoic acid




According to the procedures as described in <1-11>, the compound obtained in <113-3> was used to prepare the title compound (white foam, 104 mg, 88% yield).
MS m/z 573 [M−H]−.
1H NMR (600 MHz, CDCl3) δ 7.41 (d, 1H), 7.36 (d, 1H), 7.33 (dd, 1H), 7.31-7.29 (m, 2H), 7.12 (d, 1H), 6.95-6.92 (m, 2H), 6.88 (dd, 1H), 6.82 (d, 1H), 5.04 (s, 2H), 4.55 (t, 2H), 4.06-4.03 (m, 1H), 3.91 (d, 2H), 3.65 (s, 3H), 3.16-3.12 (m, 2H), 3.06-3.01 (m, 2H), 2.81-2.76 (m, 3H), 2.72-2.68 (m, 1H), 2.32-2.28 (m, 2H), 2.09-2.01 (m, 3H), 1.81 (d, 3H).
Example 114
Preparation of (S)-3-(4-((3-((1,1-dioxidotetrahydro-2H-thiopyran-4-yl)methoxy)-6,7-dihydro-5H-benzo[3,4]cyclohepta[1,2-b]pyridin-10-yl)methoxy)phenyl)hex-4-ynoic acid
<114-1> Preparation of 2-allyl-6-methoxypyridine




A mixture of 2-bromo-6-methoxypyridine (2 mL, 16.488 mmol), 2-allyl-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (3.4 mL, 18.136 mmol), CsF (7.51 g, 49.463 mmol) and THF (60 mL) was substituted with nitrogen for a few minutes while stirring. The mixture was added with Pd(PPh3)4 (1.91 g, 1.649 mmol) and refluxed for 20 hours. After cooled to room temperature, the reaction mixture was added with distilled water and extracted with EtOAc. The organic layer was collected, dried over MgSO4, concentrated, and purified by silica gel chromatography to obtain the title compound (colorless oil, 1.838 g, 75% yield).
1H NMR (300 MHz, CDCl3) δ 7.48 (t, 1H), 6.73 (d, 1H), 6.56 (d, 1H), 6.08 (m, 1H), 5.21-5.03 (m, 2H), 3.92 (s, 3H), 3.47 (d, 2H).
<114-2> Preparation of methyl 3-bromo-4-(3-(6-methoxypyridin-2-yl)propyl)benzoate




<108-2>, the compound obtained in <114-1> was used to prepare the title compound (colorless oil, 2.368 g, 53% yield).
1H NMR (300 MHz, CDCl3) δ 8.20 (d, 1H), 7.88 (dd, 1H), 7.47 (dd, 1H), 7.31 (d, 1H), 6.72 (dd, 1H), 6.56 (d, 1H), 3.92 (s, 3H), 3.91 (s, 3H), 2.90-2.81 (m, 2H), 2.77 (t, 2H), 2.15-2.02 (m, 2H).
<114-3> Preparation of methyl 4-(3-(6-methoxypyridin-2-yl)propyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaboran-2-yl)benzoate




According to the procedures as described in <108-3>, the compound obtained in <114-2> was used to prepare the title compound (white solid, 1.671 g, 63% yield).
1H NMR (300 MHz, CDCl3) δ 8.42 (d, 1H), 7.99 (dd, 1H), 7.44 (t, 1H), 7.40 (m, 1H), 7.27 (d, 1H), 6.69 (d, 1H), 6.53 (d, 1H), 3.91 (s, 1H), 3.90 (s, 3H), 3.06-2.96 (m, 2H), 2.80-2.66 (m, 2H), 1.99 (m, 2H), 1.34 (s, 12H).
<114-4> Preparation of methyl 4-(3-(3-bromo-6-methoxypyridin-2-yl)propyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaboran-2-yl)benzoate




A solution of the compound obtained in <114-3> (1.44 g, 3.501 mmol) in THF (35 mL) 0° C. was added with 1,3-dibromo-5,5-dimethylhydantoin (1.00 g, 3.501 mmol), heated to room temperature, and stirred for 63 hours. The reaction mixture was added with a saturated Na2S2O3 aqueous solution and distilled water, and then extracted with EtOAc. The organic layer was collected, dried over Na2SO4, concentrated, and purified by silica gel chromatography to obtain the title compound (colorless oil, 1.838 g, 75% yield).
1H NMR (300 MHz, CDCl3) δ 8.43 (d, 1H), 8.00 (dd, 1H), 7.60 (d, 1H), 7.29 (d, 1H), 6.45 (d, 1H), 3.90 (s, 3H), 3.88 (s, 3H), 3.10-2.99 (m, 2H), 2.96-2.83 (m, 2H), 2.00 (m, 2H), 1.34 (s, 12H).
<114-5> Preparation of methyl 3-methoxy-6,7-dihydro-5H-benzo[3,4]cyclohepta[1,2-b]pyridine-10-carboxylate




According to the procedures as described in <108-5>, the compound obtained in <114-4> was used to prepare the title compound (white solid, 416 mg, 64% yield).
1H NMR (300 MHz, CDCl3) δ 7.98 (d, 1H), 7.94 (dd, 1H), 7.63 (d, 1H), 7.33 (d, 1H), 6.74 (d, 1H), 3.99 (s, 3H), 3.93 (s, 3H), 2.61 (m, 4H), 2.43-2.27 (m, 2H).
<114-6> Preparation of methyl 3-hydroxy-6,7-dihydro-5H-benzo[3,4]cyclohepta[1,2-b]pyridine-10-carboxylate




According to the procedures as described in <108-6>, the compound obtained in <114-5> was used to prepare the title compound (off-white solid, 278 mg, 59% yield).
1H NMR (300 MHz, CDCl3) δ 7.95 (d, 1H), 7.92 (dd, 1H), 7.63 (d, 1H), 7.33 (d, 1H), 6.60 (d, 1H), 3.93 (s, 3H), 2.64 (t, 2H), 2.61 (t, 2H), 2.41 (m, 2H).
<114-7> methyl 3-((1,1-dioxidotetrahydro-2H-thiopyran-4-yl)methoxy)-6,7-dihydro-5H-benzo[3,4]cyclohepta[1,2-b]pyridine-10-carboxylate




According to the procedures as described in <47-1>, the compound obtained in <114-6> was used to prepare the title compound (colorless oil, 119 mg, 74% yield).
1H NMR (300 MHz, CDCl3) δ 7.98-7.91 (m, 2H), 7.64 (d, 1H), 7.34 (d, 1H), 6.72 (d, 1H), 4.29 (d, 2H), 3.93 (s, 3H), 3.20-2.97 (m, 4H), 2.60 (m, 4H), 2.33 (m, 2H), 2.06 (m, 3H).
<114-8> Preparation of 4-(((10-(hydroxymethyl)-6,7-dihydro-5H-benzo[3,4]cyclohepta[1,2-b]pyridin-3-yl)oxy)methyl)tetrahydro-2H-thiopyran 1,1-dioxide




According to the procedures as described in <1-9>, the compound obtained in <114-7> was used to prepare the title compound (white foam, 87 mg, 83% yield).
1H NMR (300 MHz, CDCl3) δ 7.61 (d, 1H), 7.33-7.22 (m, 3H), 6.70 (d, 1H), 4.75 (d, 2H), 4.28 (d, 2H), 3.19-2.97 (m, 4H), 2.62 (t, 2H), 2.53 (t, 2H), 2.37-2.23 (m, 4H), 2.14-1.98 (m, 3H), 1.66 (t, 1H).
<114-9> Preparation of (S)-methyl 3-(4-((3-((1,1-dioxidotetrahydro-2H-thiopyran-4-yl)methoxy)-6,7-dihydro-5H-benzo[3,4]cyclohepta[1,2-b]pyridin-10-yl)methoxy)phenyl)hex-4-ynoate




According to the procedures as described in <108-9>, the compound obtained in <114-8> was used to prepare the title compound (white foam, 72 mg, 55% yield).
1H NMR (300 MHz, CDCl3) δ 7.60 (d, 1H), 7.39-7.23 (m, 7H), 6.98-6.88 (m, 2H), 6.70 (d, 1H), 5.07 (s, 2H), 4.28 (d, 2H), 4.09 (m, 1H), 3.66 (s, 3H), 3.20-2.95 (m, 4H), 2.73 (m, 2H), 2.63 (t, 2H), 2.54 (t, 2H), 2.30 (m, 4H), 2.06 (m, 3H), 1.83 (d, 3H).
<114-10> Preparation of (S)-3-(4-((3-((1,1-dioxidotetrahydro-2H-thiopyran-4-yl)methoxy)-6,7-dihydro-5H-benzo[3,4]cyclohepta[1,2-b]pyridin-10-yl)methoxy)phenyl)hex-4-ynoic acid




According to the procedures as described in <1-11>, the compound obtained in <114-9> was used to prepare the title compound (white foam, 78 mg, 85% yield).
MS m/z 572 [M−H]−.
1H NMR (300 MHz, CDCl3) δ 7.60 (d, 1H), 7.37-7.20 (m, 7H), 6.98-6.88 (m, 2H), 6.70 (d, 1H), 5.07 (s, 2H), 4.28 (d, 2H), 4.06 (m, 1H), 3.20-1.95 (m, 4H), 2.76 (m, 2H), 2.63 (t, 2H), 2.54 (t, 2H), 2.30 (m, 4H), 2.07 (m, 3H), 1.83 (d, 3H).
Example 115
Preparation of (R)-3-cyclopropyl-3-(3-((9-((1,1-dioxidotetrahydro-2H-thiopyran-4-yl)methoxy)-6,7-dihydro-5H-dibenzo[a,c][7]annulen-2-yl)methoxy)phenyl)propanoic acid
<115-1> Preparation of (R)-methyl 3-cyclopropyl-3-(3-((9-((1,1-dioxidotetrahydro-2H-thiopyran-4-yl)methoxy)-6,7-dihydro-5H-dibenzo[a,c][7]annulen-2-yl)methoxy)phenyl)propanoate




According to the procedures as described in <110-2>, the compound obtained in <109-3> and (R)-methyl 3-cyclopropyl-3-(3-hydroxyphenyl)propanoate (prepared in accordance with the reference [ACS Medicinal Chemistry Letters, 2012, vol. 3, p. 726-730]) were used to prepare the title compound (white foam, 98.5 mg, 93% yield).
1H NMR (300 MHz, CDCl3) δ 7.41 (s, 1H), 7.41 (s, 1H), 7.36-7.29 (m, 2H), 7.27-7.19 (m, 2H), 6.90-6.75 (m, 5H), 5.07 (s, 2H), 3.92 (d, 2H), 3.60 (s, 3H), 3.21-2.96 (m, 4H), 2.73 (dd, 2H), 2.49 (m, 4H), 2.41-2.25 (m, 3H), 2.25-2.13 (m, 2H), 2.12-1.96 (m, 3H), 1.01 (m, 1H), 0.56 (m, 1H), 0.40 (m, 1H), 0.25 (m, 1H), 0.14 (m, 1H).
<115-2> Preparation of (R)-3-cyclopropyl-3-(3-((9-((1,1-dioxidotetrahydro-2H-thiopyran-4-yl)methoxy)-6,7-dihydro-5H-dibenzo[a,c][7]annulen-2-yl)methoxy)phenyl)propanoic acid




According to the procedures as described in <1-11>, the compound obtained in <115-1> was used to prepare the title compound (white foam, 74.7 mg, 76% yield).
MS m/z 573 [M−H]−.
1H NMR (300 MHz, CDCl3) δ 7.41 (s, 1H), 7.37-7.28 (m, 2H), 7.28-7.20 (m, 2H), 6.92-6.81 (m, 4H), 6.79 (s, 1H), 5.07 (s, 2H), 3.91 (s, 2H), 3.23-2.92 (m, 4H), 2.78 (d, 2H), 2.49 (m, 4H), 2.41-2.24 (m, 3H), 2.24-2.12 (m, 2H), 2.12-1.97 (m, 3H), 1.00 (m, 1H), 0.58 (m, 1H), 0.41 (m, 1H), 0.28 (m, 1H), 0.16 (m, 1H).
Example 116
Preparation of 3-cyclopropyl-3-(4-((9-((1,1-dioxidotetrahydro-2H-thiopyran-4-yl)methoxy)-6,7-dihydro-5H-dibenzo[a,c][7]annulen-2-yl)methoxy)phenyl)propanoic acid
<116-1> Preparation of methyl 3-cyclopropyl-3-(4-((9-((1,1-dioxidotetrahydro-2H-thiopyran-4-yl)methoxy)-6,7-dihydro-5H-dibenzo[a,c][7]annulen-2-yl)methoxy)phenyl)propanoate




According to the procedures as described in <110-2>, the compound obtained in <109-3> and methyl 3-cyclopropyl-3-(4-hydroxyphenyl)propanoate (prepared in accordance with the reference [WO 2008/130514 A1]) were used to prepare the title compound (white foam, 98.5 mg, 93% yield).
1H NMR (300 MHz, CDCl3) δ 7.39 (d, 1H), 7.35-7.29 (m, 2H), 7.25 (d, 1H), 7.16 (d, 2H), 6.94 (d, 2H), 6.85 (dd, 1H), 6.79 (d, 1H), 5.06 (s, 2H), 3.92 (d, 2H), 3.59 (s, 3H), 3.23-2.95 (m, 4H), 2.82-2.62 (m, 2H), 2.56-2.40 (m, 4H), 2.38-2.26 (m, 3H), 2.25-2.12 (m, 2H), 2.13-1.98 (m, 3H), 0.99 (m, 1H), 0.57 (m, 1H), 0.42 (m, 1H), 0.31-0.19 (m, 1H), 0.19-0.06 (m, 1H).
<116-2> Preparation of 3-cyclopropyl-3-(4-((9-((1,1-dioxidotetrahydro-2H-thiopyran-4-yl)methoxy)-6,7-dihydro-5H-dibenzo[a,c][7]annulen-2-yl)methoxy)phenyl)propanoic acid




According to the procedures as described in <1-11>, the compound obtained in <116-1> was used to prepare the title compound (white foam, 74.7 mg, 76% yield).
MS m/z 573 [M−H]−.
1H NMR (300 MHz, CDCl3) δ 7.39 (s, 1H), 7.35-7.28 (m, 2H), 7.24 (d, 1H), 7.16 (d, 2H), 6.94 (d, 2H), 6.84 (dd, 1H), 6.79 (d, 1H), 5.06 (s, 2H), 3.91 (d, 2H), 3.22-2.94 (m, 4H), 2.76 (m, 2H), 2.49 (m, 4H), 2.41-2.25 (m, 3H), 2.19 (m, 2H), 2.12-1.97 (m, 3H), 1.03 (m, 1H), 0.88 (m, 1H), 0.58 (m, 1H), 0.42 (m, 1H), 0.26 (m, 1H), 0.16 (m, 1H).
Example 117
Preparation of (S)-3-(4-((9-((1,1-dioxidotetrahydro-2H-thiopyran-4-yl)methoxy)-6,7-dihydro-5H-dibenzo[a,c][7]annulen-2-yl)methoxy)phenyl)hexanoic acid
<117-1> Preparation of (S)-methyl 3-(4-((9-((1,1-dioxidotetrahydro-2H-thiopyran-4-yl)methoxy)-6,7-dihydro-5H-dibenzo[a,c][7]annulen-2-yl)methoxy)phenyl)hexanoate




According to the procedures as described in <110-2>, the compound obtained in <109-3> and (S)-methyl 3-(4-hydroxyphenyl)hexanoate (prepared in accordance with the reference [WO2008/130514 A1]) were used to prepare the title compound (colorless oil, 41 mg, 48% yield).
1H NMR (300 MHz, CDCl3) δ 7.39 (d, 1H), 7.36-7.20 (m, 3H), 7.10 (m, 2H), 6.97-6.89 (m, 2H), 6.84 (dd, 1H), 6.79 (d, 1H), 5.05 (s, 2H), 3.91 (d, 2H), 3.58 (s, 3H), 3.22-2.97 (m, 5H), 2.63-2.42 (m, 6H), 2.31 (m, 2H), 2.18 (m, 2H), 2.13-2.00 (m, 3H), 1.62-1.47 (m, 2H), 1.22-1.12 (m, 2H), 0.85 (t, 3H).
<117-2> Preparation of (S)-3-(4-((9-((1,1-dioxidotetrahydro-2H-thiopyran-4-yl)methoxy)-6,7-dihydro-5H-dibenzo[a,c][7]annulen-2-yl)methoxy)phenyl)hexanoic acid




According to the procedures as described in <1-11>, the compound obtained in <117-1> was used to prepare the title compound (white foam, 27 mg, 71% yield).
MS m/z 575 [M−H]−.
1H NMR (300 MHz, CDCl3) δ 7.38 (s, 1H), 7.35-7.28 (m, 2H), 7.24 (d, 2H), 7.11 (d, 2H), 6.93 (d, 2H), 6.83 (dd, 1H), 6.79 (d, 1H), 5.05 (s, 2H), 3.91 (d, 2H), 3.21-2.96 (m, 5H), 2.60 (t, 2H), 2.49 (m, 4H), 2.30 (m, 2H), 2.18 (m, 2H), 2.12-1.96 (m, 3H), 1.59 (m, 2H), 1.18 (m, 2H), 0.85 (t, 3H).
Example 118
Preparation of (R,Z)-3-(4-((9-((1,1-dioxidotetrahydro-2H-thiopyran-4-yl)methoxy)-6,7-dihydro-5H-dibenzo[a,c][7]annulen-2-yl)methoxy)phenyl)hex-4-enoic acid
<118-1> Preparation of (R,Z)-methyl 3-(4-((9-((1,1-dioxidotetrahydro-2H-thiopyran-4-yl)methoxy)-6,7-dihydro-5H-dibenzo[a,c][7]annulen-2-yl)methoxy)phenyl)hex-4-enoate




A solution of the compound <109-4> (173 mg, 0.295 mmol) in EtOAc (3 mL) was added with Pd/C (10 wt % loading dry basis, 21 mg), which was then stirred under a hydrogen atmosphere for 6 hours. The reaction mixture was filtered through Celite, washed EtOAc, concentrated, and then purified by silica gel chromatography to obtain the title compound (white foam, 57 mg, 29% yield).
1H NMR (300 MHz, CDCl3) δ 7.38 (d, 1H), 7.35-7.27 (m, 2H), 7.24 (d, 1H), 7.19-7.09 (m, 2H), 6.98-6.87 (m, 2H), 6.84 (dd, 1H), 6.79 (d, 1H), 5.58-5.45 (m, 2H), 5.05 (s, 2H), 4.21-4.05 (m, 1H), 3.92 (d, 2H), 3.62 (s, 3H), 3.12 (m, 4H), 2.77-2.55 (m, 2H), 2.49 (m, 4H), 2.32 (m, 2H), 2.18 (m, 2H), 2.06 (m, 3H), 1.69 (d, 3H).
<118-2> Preparation of (R,Z)-3-(4-((9-((1,1-dioxidotetrahydro-2H-thiopyran-4-yl)methoxy)-6,7-dihydro-5H-dibenzo[a,c][7]annulen-2-yl)methoxy)phenyl)hex-4-enoic acid




According to the procedures as described in <1-11>, the compound obtained in <118-1> was used to prepare the title compound (white foam, 45 mg, 84% yield).
MS m/z 573 [M−H]−.
1H NMR (300 MHz, CDCl3) δ 7.38 (d, 1H), 7.35-7.27 (m, 2H), 7.24 (d, 1H), 7.20-7.10 (m, 2H), 6.97-6.88 (m, 2H), 6.84 (dd, 1H), 6.79 (d, 1H), 5.61-5.44 (m, 2H), 5.05 (s, 2H), 4.20-4.07 (m, 1H), 3.91 (d, 2H), 3.12 (m, 4H), 2.80-2.58 (m, 2H), 2.49 (m, 4H), 2.30 (m, 2H), 2.18 (m, 2H), 2.06 (m, 3H), 1.69 (d, 3H).
Example 119
Preparation of (S)-3-(4-((9-((1,1-dioxidotetrahydro-2H-thiopyran-4-yl)methoxy)-6,7-dihydro-5H-dibenzo[a,c][7]annulen-2-yl)methoxy)phenyl)-3-(5-methylisoxazol-3-yl)propanoic acid
<119-1> Preparation of (S)-methyl 3-(4-(benzyloxy)phenyl)hex-4-ynoate




A mixture of (S)-methyl 3-(4-hydroxyphenyl)hex-4-ynoate (prepared in accordance with the reference [Bioorganic & Medicinal Chemistry Letters, 2012, 22, p. 1267-1270]; 1.06 g, 4.857 mmol) and Cs2CO3 (1.90 g, 5.828 mmol) in acetone (25 mL) was added with benzyl bromide (0.64 mL, 5.342 mmol), and stirred at room temperature for 17.5 hours. The reaction mixture was filtered and washed with acetone. The filtrate thus obtained was concentrated under reduced pressure, added with EtOAc (50 mL) and piperazine (1.26 g, 14.570 mmol), and then stirred at room temperature for 2 hours. The solid thus obtained was filtered, consecutively washed with EtOAc, 1M HCl aqueous solution, a saturated NaHCO3 aqueous solution and brine, dried over MgSO4, and then concentrated. The residue was purified by silica gel chromatography to obtain the title compound (yellow solid, 1.38 g, 92% yield).
1H NMR (300 MHz, CDCl3) δ 7.46-7.26 (m, 7H), 6.96-6.87 (m, 2H), 5.04 (s, 2H), 4.06 (m, 1H), 3.66 (s, 3H), 2.85-2.59 (m, 2H), 1.82 (d, 3H).
<119-2> Preparation of (R,Z)-methyl 3-(4-(benzyloxy)phenyl)hex-4-enoate




According to the procedures as described in <118-1>, the compound obtained in <119-1> was used to prepare the title compound (white solid, 1.40 g, 94% yield).
1H NMR (300 MHz, CDCl3) δ 7.46-7.28 (m, 5H), 7.18-7.12 (m, 2H), 6.95-6.85 (m, 2H), 5.57-5.44 (m, 2H), 5.03 (s, 2H), 4.19-4.08 (m, 1H), 3.62 (s, 3H), 3.58 (s, 3H), 2.77-2.55 (m, 2H), 1.69 (d, 3H).
<119-3> Preparation of (S)-methyl 3-(4-(benzyloxy)phenyl)-4-oxobutanoate




A mixture of the compound obtained in <119-2> (1.398 g, 4.504 mmol) in 1,4-dioxane (40 mL)/distilled water (10 mL) was added with 2,6-lutidine (1.05 mL, 9.008 mmol), and then slowly added with OsO4 (4 wt % aqueous solution, 0.55 mL, 0.0901 mmol). After 2 minutes, the mixture was added with a solution of NaIO4 (3.85 g, 18.016 mmol) in distilled water (20 mL), and stirred at room temperature for 4 hours. The reaction mixture was added with EtOAc, 0.5M HCl aqueous solution, and the layers thus formed were separated. The organic layer was consecutively washed with 0.5M HCl aqueous solution, a saturated NaHCO3 aqueous solution and brine, dried over Na2SO4, and concentrated. The residue thus obtained was purified by silica gel chromatography to obtain the title compound (yellow solid, 746 mg, 60% yield).
1H NMR (300 MHz, CDCl3) δ 9.66 (s, 1H), 7.39 (m, 5H), 7.15-7.05 (m, 2H), 7.03-6.93 (m, 2H), 5.06 (s, 2H), 4.10 (dd, 1H), 3.66 (s, 3H), 3.13 (dd, 1H), 2.58 (dd, 1H).
<119-4> Preparation of (S)-methyl 3-(4-(benzyloxy)phenyl)-4-(hydroxyimino)butanoate




A solution of the compound obtained in <119-3> (203 mg, 0.680 mmol) in EtOH (14 mL) was consecutively added with NH2OH.HCl (71 mg, 1.021 mmol) and distilled water (0.4 mL), and then stirred at room temperature for 1 hour. The reaction mixture thus obtained was concentrated under reduced pressure, added with EtOAc and distilled water, and the layers thus formed were separated. The aqueous layer was extracted with EtOAc one more time, and the organic layer was collected, dried over MgSO4, and concentrated. The residue thus obtained was purified by silica gel chromatography to obtain the title compound (yellow solid, 184 mg, 86% yield).
1H NMR (300 MHz, CDCl3) δ 7.52 (d, 1H), 7.48-7.29 (m, 5H), 7.17-7.11 (m, 2H), 7.05 (s, 1H), 6.97-6.91 (m, 2H), 5.05 (s, 2H), 4.06 (m, 1H), 3.64 (s, 3H), 2.98 (dd, 1H), 2.67 (dd, 1H).
<119-5> Preparation of (S)-methyl 3-(4-(benzyloxy)phenyl)-3-(5-methylisoxazol-3-yl)propanoate




A solution of the compound obtained in <119-4> (107 mg, 0.341 mmol) in DMF (1.5 mL) was added with NCS (46 mg, 0.341 mmol) and stirred at room temperature for 3 hours. The mixture was added with EtOAc and distilled water, and the layers thus formed were separated. The organic layer was washed with brine, dried over Na2SO4, and the filtrate was concentrated and dried. The residue was added with CH2Cl2 (4.3 mL) and dissolved to form a solution, which was then added with propyne (3 wt % heptane solution), stirred and slowly added with triethylamine (0.095 mL, 0.683 mmol). The reaction mixture thus obtained was stirred at room temperature for 17 hours. The reaction mixture was diluted by adding EtOAc, and then consecutively washed with a saturated NH4Cl aqueous solution and brine. The resultant was dried over Na2SO4, concentrated and purified by silica gel chromatography to obtain the title compound (white solid, 37 mg, 31% yield).
1H NMR (300 MHz, CDCl3) δ 7.46-7.28 (m, 5H), 7.21-7.11 (m, 2H), 6.95-6.84 (m, 2H), 5.70 (s, 1H), 5.03 (s, 2H), 4.49 (t, 1H), 3.63 (s, 3H), 3.26 (dd, 1H), 2.89 (dd, 1H), 2.33 (d, 3H).
<119-6> Preparation of (S)-methyl 3-(4-hydroxyphenyl)-3-(5-methylisoxazol-3-yl)propanoate




A solution of the compound obtained in <119-5> (25.6 mg, 0.0729 mmol) in CH2Cl2 (1.5 mL) at 0° C. was added with BCl3 (1.0M CH2Cl2 solution, 0.115 mL, 0.146 mmol), heated to room temperature and stirred for 2 hours. The mixture was slowly added with MeOH at 0° C., further added with distilled water and extracted with CH2Cl2. The organic layer was collected, dried over Na2SO4, concentrated and purified by silica gel chromatography to obtain the title compound (colorless oil, 18.7 mg, 98% yield).
1H NMR (300 MHz, CDCl3) δ 7.16-7.04 (m, 2H), 6.80-6.68 (m, 2H), 5.71 (s, 1H), 5.51 (s, 1H), 4.47 (t, 1H), 3.62 (s, 3H), 3.24 (dd, 1H), 2.90 (dd, 1H), 2.33 (d, 3H).
<119-7> Preparation of methyl 3-(4-((9-((1,1-dioxidotetrahydro-2H-thiopyran-4-yl)methoxy)-6,7-dihydro-5H-dibenzo[a,c][7]annulen-2-yl)methoxy)phenyl)-3-(5-methylisoxazol-3-yl)propanoate




According to the procedures as described in <110-2>, the compounds obtained in <109-3> and <119-6> were used to prepare the title compound (colorless oil, 108 mg, 126% yield).
1H NMR (300 MHz, CDCl3) δ 7.38 (d, 1H), 7.34-7.22 (m, 3H), 7.21-7.13 (m, 2H), 6.97-6.88 (m, 2H), 6.84 (dd, 1H), 6.79 (d, 1H), 5.71 (s, 1H), 5.05 (s, 2H), 4.49 (t, 1H), 3.92 (d, 2H), 3.63 (s, 3H), 3.26 (dd, 1H), 3.20-2.97 (m, 4H), 2.90 (dd, 1H), 2.48 (m, 4H), 2.38-2.25 (m, 5H), 2.18 (m, 2H), 2.06 (m, 3H).
<119-8> Preparation of (S)-3-(4-((9-((1,1-dioxidotetrahydro-2H-thiopyran-4-yl)methoxy)-6,7-dihydro-5H-dibenzo[a,c][7]annulen-2-yl)methoxy)phenyl)-3-(5-methylisoxazol-3-yl)propanoic acid




According to the procedures as described in <1-11>, the compound obtained in <119-7> was used to prepare the title compound (white foam, 58 mg, 55% yield).
MS m/z 614 [M−H]−.
1H NMR (300 MHz, CDCl3) δ 7.38 (d, 1H), 7.33-7.21 (m, 3H), 7.21-7.13 (m, 2H), 6.97-6.88 (m, 2H), 6.84 (dd, 1H), 6.79 (d, 1H), 5.70 (s, 1H), 5.05 (s, 2H), 4.46 (t, 1H), 3.92 (d, 2H), 3.30 (dd, 1H), 3.21-2.98 (m, 4H), 2.93 (dd, 1H), 2.48 (m, 4H), 2.38-2.24 (m, 5H), 2.17 (m, 2H), 2.06 (m, 3H).
Example 120
Preparation of (S)-3-(4-((9-((1,1-dioxidotetrahydro-2H-thiopyran-4-yl)methoxy)-6,7-dihydro-5H-dibenzo[a,c][7]annulen-2-yl)methoxy)phenyl)-3-(isoxazol-3-yl)propanoic acid
<120-1> Preparation of (S)-ethyl 3-(4-((9-((1,1-dioxidotetrahydro-2H-thiopyran-4-yl)methoxy)-6,7-dihydro-5H-dibenzo[a,c][7]annulen-2-yl)methoxy)phenyl)-3-(isoxazol-3-yl)propanoate




According to the procedures as described in <110-2>, the compound obtained in <109-3> and (S)-ethyl 3-(4-hydroxyphenyl)-3-(isoxazol-3-yl)propanoate (prepared in accordance with the reference [WO 2008/30520 A1]; 42 mg, 0.16 mmol) were used to prepare the title compound (white foam, 80 mg, 95% yield).
1H NMR (600 MHz, CDCl3) δ 8.27 (d, 1H), 7.37 (d, 1H), 7.32-7.29 (m, 2H), 7.23 (d, 1H), 7.20-7.17 (m, 2H), 6.96-6.93 (m, 2H), 6.84 (dd, 1H), 6.79 (d, 1H), 6.08 (d, 1H), 5.05 (s, 2H), 4.58 (t, 1H), 4.10-4.06 (m, 2H), 3.91 (d, 2H), 3.29-3.25 (m, 1H), 3.17-3.13 (m, 2H), 3.07-3.03 (m, 2H), 2.95-2.91 (m, 1H), 2.51-2.46 (m, 4H), 2.34-2.31 (m, 2H), 2.19-2.17 (m, 2H), 2.09-2.05 (m, 3H), 1.17 (t, 3H).
<120-2> Preparation of (S)-3-(4-((9-((1,1-dioxidotetrahydro-2H-thiopyran-4-yl)methoxy)-6,7-dihydro-5H-dibenzo[a,c][7]annulen-2-yl)methoxy)phenyl)-3-(isoxazol-3-yl)propanoic acid




According to the procedures as described in <1-11>, the compound obtained in <120-1> was used to prepare the title compound (white foam, 71 mg, 93% yield).
MS m/z 600 [M−H]−.
1H NMR (600 MHz, CDCl3) δ 8.29 (d, 1H), 7.37 (d, 1H), 7.32-7.29 (m, 2H), 7.23 (d, 1H), 7.19-7.17 (m, 2H), 6.96-6.93 (m, 2H), 6.84 (dd, 1H), 6.79 (d, 1H), 6.07 (d, 1H), 5.05 (s, 2H), 4.55 (t, 1H), 3.91 (d, 2H), 3.37-3.33 (m, 1H), 3.17-3.13 (m, 2H), 3.07-3.03 (m, 2H), 3.00-2.96 (m, 1H), 2.51-2.46 (m, 4H), 2.33-2.30 (m, 2H), 2.20-2.15 (m, 2H), 2.09-2.04 (m, 3H).
Example 121
Preparation of 3-(4-((9-((1,1-dioxidotetrahydro-2H-thiopyran-4-yl)methoxy)-6,7-dihydro-5H-dibenzo[a,c][7]annulen-2-yl)methoxy)phenyl)-3-(3-methylisoxazol-5-yl)propanoic acid
<121-1> Preparation of methyl 3-(4-((9-((1,1-dioxidotetrahydro-2H-thiopyran-4-yl)methoxy)-6,7-dihydro-5H-dibenzo[a,c][7]annulen-2-yl)methoxy)phenyl)-3-(3-methylisoxazol-5-yl)propanoate




According to the procedures as described in <110-2>, the compound obtained in <109-3> was used to prepare the title compound (white foam, 64.6 mg, >100% yield).
1H NMR (300 MHz, CDCl3) δ 7.37 (d, 1H), 7.30 (m, 2H), 7.23 (d, 1H), 7.18 (d, 2H), 6.93 (d, 2H), 6.83 (dd, 1H), 6.78 (d, 1H), 5.79 (s, 1H), 5.05 (s, 2H), 4.58 (t, 1H), 3.90 (d, 2H), 3.62 (s, 3H), 3.18-3.01 (m, 5H), 2.91 (dd, 1H), 2.48 (m, 4H), 2.32 (m, 2H), 2.23 (s, 3H), 2.17 (m, 2H), 2.06 (m, 3H).
<121-2> Preparation of 3-(4-((9-((1,1-dioxidotetrahydro-2H-thiopyran-4-yl)methoxy)-6,7-dihydro-5H-dibenzo[a,c][7]annulen-2-yl)methoxy)phenyl)-3-(3-methylisoxazol-5-yl)propanoic acid




According to the procedures as described in <1-11>, the compound obtained in <121-1> was used to prepare the title compound (white foam, 40.9 mg, 66% yield).
MS m/z 637 [M+Na]+.
1H NMR (300 MHz, CDCl3) δ 7.37 (d, 1H), 7.30 (m, 2H), 7.23 (d, 1H), 7.18 (d, 2H), 6.94 (d, 2H), 6.83 (dd, 1H), 6.78 (d, 1H), 5.80 (s, 1H), 5.05 (s, 2H), 4.58 (t, 1H), 3.90 (d, 2H), 3.22-3.05 (m, 5H), 2.94 (dd, 1H), 2.48 (m, 4H), 2.32 (m, 2H), 2.23 (s, 3H), 2.17 (m, 2H), 2.06 (m, 3H).
Example 122
Preparation of (S)-3-(4-((3-(3-(methylsulfonyl)propoxy)-6,7-dihydro-5H-benzo[3,4]cyclohepta[1,2-b]pyridin-10-yl)methoxy)phenyl)hex-4-ynoic acid
<122-1> Preparation of methyl 3-(3-(methylsulfonyl)propoxy)-6,7-dihydro-5H-benzo[3,4]cyclohepta[1,2-b]pyridine-10-carboxylate




According to the procedures as described in <1-8>, the compound obtained in <116-6> was used to prepare the title compound (white solid, 94 mg, 72% yield).
1H NMR (300 MHz, CDCl3) δ 8.01-7.90 (m, 2H), 7.64 (d, 1H), 7.33 (d, 1H), 6.72 (d, 1H), 4.51 (t, 2H), 3.93 (s, 3H), 3.32-3.19 (m, 2H), 2.96 (s, 3H), 2.59 (m, 4H), 2.44-2.24 (m, 4H).
<122-2> Preparation of (3-(3-(methylsulfonyl)propoxy)-6,7-dihydro-5H-benzo[3,4]cyclohepta[1,2-b]pyridin-10-yl)methanol




According to the procedures as described in <1-9>, the compound obtained in <122-1> was used to prepare the title compound (white solid, 65 mg, 72% yield).
1H NMR (300 MHz, CDCl3) δ 7.61 (d, 1H), 7.35-7.21 (m, 3H), 6.70 (d, 1H), 4.74 (d, 2H), 4.50 (t, 2H), 3.33-3.20 (m, 2H), 2.96 (s, 3H), 2.61 (t, 2H), 2.53 (t, 2H), 2.44-2.20 (m, 4H), 1.81 (t, 1H).
<122-3> Preparation of 10-(bromomethyl)-3-(3-(methylsulfonyl)propoxy)-6,7-dihydro-5H-benzo[3,4]cyclohepta[1,2-b]pyridine




According to the procedures as described in <110-1>, the compound obtained in <122-2> was used to prepare the title compound (white solid, 74.8 mg, 95% yield).
1H NMR (300 MHz, CDCl3) δ 7.60 (d, 1H), 7.35-7.19 (m, 3H), 6.71 (d, 1H), 4.56 (s, 2H), 4.51 (t, 2H), 3.35-3.21 (m, 2H), 2.96 (s, 3H), 2.62 (t, 2H), 2.52 (t, 2H), 2.44-2.33 (m, 2H), 2.33-2.21 (m, 2H).
<122-4> Preparation of (S)-methyl 3-(4-((3-(3-(methylsulfonyl)propoxy)-6,7-dihydro-5H-benzo[3,4]cyclohepta[1,2-b]pyridin-10-yl)methoxy)phenyl)hex-4-ynoate




According to the procedures as described in <110-2>, the compound obtained in <122-3> was used to prepare the title compound (white solid, 86 mg, 87% yield).
1H NMR (300 MHz, CDCl3) δ 7.60 (d, 1H), 7.39-7.22 (m, 5H), 6.99-6.89 (m, 2H), 6.70 (d, 1H), 5.07 (s, 2H), 4.50 (t, 2H), 4.08 (m, 1H), 3.66 (s, 3H), 3.33-3.16 (m, 2H), 2.96 (s, 3H), 2.82-2.65 (m, 2H), 2.62 (t, 2H), 2.53 (t, 2H), 2.44-2.23 (m, 4H), 1.83 (d, 3H).
<122-5> Preparation of (S)-3-(4-((3-(3-(methylsulfonyl)propoxy)-6,7-dihydro-5H-benzo[3,4]cyclohepta[1,2-b]pyridin-10-yl)methoxy)phenyl)hex-4-ynoic acid




According to the procedures as described in <1-11>, the compound obtained in <122-4> was used to prepare the title compound (white foam, 71 mg, 85% yield).
MS m/z 570 [M+Na]+.
1H NMR (300 MHz, CDCl3) δ 7.60 (d, 1H), 7.38-7.27 (m, 5H), 7.00-6.87 (m, 2H), 6.70 (d, 1H), 5.07 (s, 2H), 4.50 (t, 2H), 4.06 (m, 1H), 3.31-3.21 (m, 2H), 2.96 (s, 3H), 2.76 (m, 2H), 2.62 (t, 2H), 2.53 (t, 2H), 2.42-2.21 (m, 4H), 1.83 (d, 3H).
Example 123
Preparation of (S)-3-(4-((3-(3-(ethylsulfonyl)propoxy)-6,7-dihydro-5H-benzo[3,4]cyclohepta[1,2-b]pyridin-10-yl)methoxy)phenyl)hex-4-ynoic acid
<123-1> Preparation of methyl 3-(3-(ethylsulfonyl)propoxy)-6,7-dihydro-5H-benzo[3,4]cyclohepta[1,2-b]pyridine-10-carboxylate




According to the procedures as described in <38-1>, the compound obtained in <116-6> was used to prepare the title compound (white solid, 102 mg, 75% yield).
1H NMR (300 MHz, CDCl3) δ 8.01-7.89 (m, 2H), 7.64 (d, 1H), 7.33 (d, 1H), 6.72 (d, 1H), 4.51 (t, 2H), 3.93 (s, 3H), 3.25-3.15 (m, 2H), 3.05 (q, 2H), 2.59 (m, 4H), 2.43-2.23 (m, 4H), 1.43 (t, 3H).
<123-2> Preparation of (3-(3-(ethylsulfonyl)propoxy)-6,7-dihydro-5H-benzo[3,4]cyclohepta[1,2-b]pyridin-10-yl) methanol




According to the procedures as described in <1-9>, the compound obtained in <123-1> was used to prepare the title compound (colorless oil, 74 mg, 80% yield).
1H NMR (300 MHz, CDCl3) δ 7.60 (d, 1H), 7.35-7.22 (m, 3H), 6.69 (d, 1H), 4.74 (d, 2H), 4.49 (t, 2H), 3.26-3.16 (m, 2H), 3.04 (q, 2H), 2.61 (t, 2H), 2.53 (t, 2H), 2.44-2.21 (m, 4H), 1.74 (t, 1H), 1.43 (t, 3H).
<123-3> Preparation of 10-(bromomethyl)-3-(3-(ethylsulfonyl)propoxy)-6,7-dihydro-5H-benzo[3,4]cyclohepta[1,2-b]pyridine




According to the procedures as described in <109-3>, the compound obtained in <123-2> was used to prepare the title compound (white foam, 80.7 mg, 99% yield).
1H NMR (300 MHz, CDCl3) δ 7.60 (d, 1H), 7.35-7.18 (m, 3H), 6.71 (d, 1H), 4.55 (s, 2H), 4.50 (t, 2H), 3.25-3.15 (m, 2H), 3.05 (q, 2H), 2.61 (t, 2H), 2.52 (t, 2H), 2.41-2.20 (m, 4H), 1.44 (t, 3H).
<123-4> Preparation of (S)-methyl 3-(4-((3-(3-(ethylsulfonyl)propoxy)-6,7-dihydro-5H-benzo[3,4]cyclohepta[1,2-b]pyridin-10-yl)methoxy)phenyl)hex-4-ynoate




According to the procedures as described in <110-2>, the compound obtained in <123-3> was used to prepare the title compound (white foam, 94 mg, 89% yield).
1H NMR (300 MHz, CDCl3) δ 7.60 (d, 1H), 7.38-7.21 (m, 5H), 6.99-6.87 (m, 2H), 6.70 (d, 1H), 5.07 (s, 2H), 4.50 (t, 2H), 4.07 (m, 1H), 3.66 (s, 3H), 3.29-3.15 (m, 2H), 3.04 (q, 2H), 2.84-2.66 (m, 2H), 2.63 (t, 2H), 2.53 (t, 2H), 2.43-2.20 (m, 4H), 1.83 (d, 3H), 1.43 (t, 3H).
<123-5> Preparation of (S)-3-(4-((3-(3-(ethylsulfonyl)propoxy)-6,7-dihydro-5H-benzo[3,4]cyclohepta[1,2-b]pyridin-10-yl)methoxy)phenyl)hex-4-ynoic acid




According to the procedures as described in <1-11>, the compound obtained in <123-4> was used to prepare the title compound (white foam, 85 mg, 93% yield).
MS m/z 584 [M+Na]+.
1H NMR (300 MHz, CDCl3) δ 7.60 (d, 1H), 7.38-7.25 (m, 5H), 7.00-6.89 (m, 2H), 6.70 (d, 1H), 5.07 (s, 2H), 4.49 (t, 2H), 4.11-3.99 (m, 1H), 3.29-3.14 (m, 2H), 3.05 (q, 2H), 2.76 (m, 2H), 2.62 (t, 2H), 2.53 (t, 2H), 2.33 (m, 4H), 1.83 (dd, 3H), 1.43 (t, 3H).
Example 124
Preparation of (S)-3-(4-((3-((1,1-dioxidotetrahydro-2H-thiopyran-4-yl)oxy)-6,7-dihydro-5H-benzo[3,4]cyclohepta[1,2-b]pyridin-10-yl)methoxy)phenyl)hex-4-ynoic acid
<124-1> Preparation of methyl 3-((1,1-dioxidotetrahydro-2H-thiopyran-4-yl)oxy)-6,7-dihydro-5H-benzo[3,4]cyclohepta[1,2-b]pyridine-10-carboxylate




According to the procedures as described in <55-1>, the compound obtained in <116-6> was used to prepare the title compound (yellow solid, 116 mg, 81% yield).
1H NMR (300 MHz, CDCl3) δ 7.99-7.91 (m, 2H), 7.66 (d, 1H), 7.37-7.30 (d, 1H), 6.75 (d, 1H), 5.53 (m, 1H), 3.93 (s, 3H), 3.50-3.33 (m, 2H), 3.05-2.90 (m, 2H), 2.65-2.51 (m, 6H), 2.44 (m, 2H), 2.40-2.25 (m, 2H).
<124-2> Preparation of 4-((10-(hydroxymethyl)-6,7-dihydro-5H-benzo[3,4]cyclohepta[1,2-b]pyridin-3-yl)oxy)tetrahydro-2H-thiopyran 1,1-dioxide




According to the procedures as described in <1-9>, the compound obtained in <124-1> was used to prepare the title compound (white foam, 100 mg, 90% yield).
1H NMR (300 MHz, CDCl3) δ 7.63 (d, 1H), 7.35-7.21 (m, 3H), 6.72 (d, 1H), 5.59-5.46 (m, 1H), 4.74 (d, 2H), 3.42 (m, 2H), 3.08-2.91 (m, 2H), 2.65-2.34 (m, 8H), 2.29 (m, 2H), 1.74 (t, 1H).
<124-3> Preparation of 4-((10-(bromomethyl)-6,7-dihydro-5H-benzo[3,4]cyclohepta[1,2-b]pyridin-3-yl)oxy)tetrahydro-2H-thiopyran 1,1-dioxide




According to the procedures as described in <110-1>, the compound obtained in <124-2> was used to prepare the title compound (white foam, 110.6 mg, 87% yield).
1H NMR (300 MHz, CDCl3) δ 7.63 (d, 1H), 7.35-7.28 (m, 2H), 7.24 (d, 1H), 6.73 (d, 1H), 5.52 (m, 1H), 4.55 (s, 2H), 3.50-3.34 (m, 2H), 3.04-2.91 (m, 2H), 2.65-2.49 (m, 6H), 2.48-2.35 (m, 2H), 2.29 (m, 2H).
<124-4> Preparation of (S)-methyl 3-(4-((3-((1,1-dioxidotetrahydro-2H-thiopyran-4-yl)oxy)-6,7-dihydro-5H-benzo[3,4]cyclohepta[1,2-b]pyridin-10-yl)methoxy)phenyl)hex-4-ynoate




According to the procedures as described in <110-2>, the compound obtained in <124-3> was used to prepare the title compound (white foam, 124 mg, 87% yield).
1H NMR (300 MHz, CDCl3) δ 7.62 (d, 1H), 7.41-7.26 (m, 5H), 7.00-6.90 (m, 2H), 6.73 (d, 1H), 5.52 (m, 1H), 5.07 (s, 2H), 4.06 (m, 1H), 3.66 (s, 3H), 3.52-3.31 (m, 2H), 2.99 (m, 2H), 2.83-2.48 (m, 8H), 2.49-2.35 (m, 2H), 2.29 (m, 2H), 1.83 (d, 3H).
<124-5> Preparation of (S)-3-(4-((3-((1,1-dioxidotetrahydro-2H-thiopyran-4-yl)oxy)-6,7-dihydro-5H-benzo[3,4]cyclohepta[1,2-b]pyridin-10-yl)methoxy)phenyl)hex-4-ynoic acid




According to the procedures as described in <1-11>, the compound obtained in <124-4> was used to prepare the title compound (white foam, 115 mg, 95% yield).
MS m/z 560 [M+H]+.
1H NMR (300 MHz, CDCl3) δ 7.62 (d, 1H), 7.40-7.25 (m, 5H), 7.02-6.86 (m, 2H), 6.73 (d, 1H), 5.52 (m, 1H), 5.07 (s, 2H), 4.06 (m, 1H), 3.53-3.32 (m, 2H), 2.99 (m, 2H), 2.66-2.49 (m, 6H), 2.48-2.35 (m, 2H), 2.30 (m, 2H), 1.83 (d, 3H).
Example 125
Preparation of (S)-3-(4-((5-methyl-7-(3-(methylsulfonyl)propoxy)-9,10-dihydrophenanthren-3-yl)methoxy)phenyl)hex-4-ynoic acid
<125-1> Preparation of 6-(bromomethyl)-4-methyl-2-(3-(methylsulfonyl)propoxy)-9,10-dihydrophenanthrene




According to the procedures as described in <110-1>, the compound obtained in <11-7> was used to prepare the title compound (white solid, 104 mg, 89% yield).
1H NMR (300 MHz, CDCl3) δ 7.61 (s, 1H), 7.25-7.14 (m, 2H), 6.71 (d, 1H), 6.66 (d, 1H), 4.55 (s, 2H), 4.15 (t, 2H), 3.27 (m, 2H), 2.97 (s, 3H), 2.72 (s, 4H), 2.61 (s, 3H), 2.44-2.28 (m, 2H).
<125-2> Preparation of (S)-methyl 3-(4-((5-methyl-7-(3-(methylsulfonyl)propoxy)-9,10-dihydrophenanthren-3-yl)methoxy)phenyl)hex-4-ynoate




According to the procedures as described in <110-2>, the compound obtained in <125-1> was used to prepare the title compound (white foam, 55 mg, 84% yield).
1H NMR (300 MHz, CDCl3) δ 7.63 (s, 1H), 7.34-7.19 (m, 4H), 6.93 (m, 2H), 6.68 (d, 1H), 6.66 (d, 1H), 5.07 (s, 2H), 4.14 (t, 2H), 4.06 (m, 1H), 3.66 (s, 3H), 3.34-3.21 (m, 2H), 2.96 (s, 3H), 2.81-2.60 (m, 6H), 2.54 (s, 3H), 2.42-2.27 (m, 2H), 1.82 (d, 3H).
<125-3> Preparation of (S)-3-(4-((5-methyl-7-(3-(methylsulfonyl)propoxy)-9,10-dihydrophenanthren-3-yl)methoxy)phenyl)hex-4-ynoic acid




According to the procedures as described in <1-11>, the compound obtained in <125-2> was used to prepare the title compound (white foam, 37.2 mg, 73% yield).
MS m/z 569 [M+Na]+.
1H NMR (600 MHz, CDCl3) δ 7.62 (d, 1H), 7.31-7.27 (m, 2H), 7.25 (d, 1H), 7.21 (dd, 1H), 6.96-6.90 (m, 2H), 6.68 (d, 1H), 6.65 (d, 1H), 5.06 (s, 2H), 4.12 (t, 2H), 4.07-4.00 (m, 1H), 3.29-3.22 (m, 2H), 2.95 (s, 3H), 2.79 (dd, 1H), 2.74-2.66 (m, 5H), 2.52 (s, 3H), 2.38-2.30 (m, 2H), 1.82 (d, 3H).
Example 126
Preparation of (S)-3-(4-((7-(2-ethoxyethoxy)-5-methyl-9,10-dihydrophenanthren-3-yl)methoxy)phenyl)hex-4-ynoic acid
<126-1> Preparation of 6-(bromomethyl)-2-(2-ethoxyethoxy)-4-methyl-9,10-dihydrophenanthrene




According to the procedures as described in <110-1>, the compound obtained in <12-2> was used to prepare the title compound (white foam, 228 mg, 85% yield).
1H NMR (600 MHz, CDCl3) δ 7.61 (d, 1H), 7.22-7.15 (m, 2H), 6.75 (d, 1H), 6.69 (d, 1H), 4.54 (s, 2H), 4.17-4.11 (m, 2H), 3.84-3.75 (m, 2H), 3.61 (q, 2H), 2.71 (s, 4H), 2.59 (s, 3H), 1.24 (t, 3H).
<126-2> Preparation of (S)-methyl 3-(4-((7-(2-ethoxyethoxy)-5-methyl-9,10-dihydrophenanthren-3-yl)methoxy)phenyl)hex-4-ynoate




According to the procedures as described in <110-2>, the compound obtained in <126-1> was used to prepare the title compound (colorless oil, 110 mg, 122% yield).
1H NMR (300 MHz, CDCl3) δ 7.63 (s, 1H), 7.33-7.17 (m, 4H), 6.98-6.90 (m, 2H), 6.74 (d, 1H), 6.71 (d, 1H), 5.07 (s, 2H), 4.15 (m, 2H), 4.06 (m, 1H), 3.81 (m, 2H), 3.66 (s, 3H), 3.61 (q, 2H), 2.82-2.59 (m, 6H), 2.53 (s, 3H), 1.83 (d, 3H), 1.26 (t, 3H).
<126-3> Preparation of (S)-3-(4-((7-(2-ethoxyethoxy)-5-methyl-9,10-dihydrophenanthren-3-yl)methoxy)phenyl)hex-4-ynoic acid




According to the procedures as described in <1-11>, the compound obtained in <126-2> was used to prepare the title compound (white foam, 72 mg, 67% yield).
MS m/z 521 [M+Na]+.
1H NMR (600 MHz, CDCl3) δ 7.62 (d, 1H), 7.31-7.27 (m, 2H), 7.26-7.23 (m, 1H), 7.20 (dd, 1H), 6.96-6.91 (m, 2H), 6.73 (d, 1H), 6.69 (d, 1H), 5.06 (s, 2H), 4.19-4.09 (m, 2H), 4.04 (m, 1H), 3.82-3.75 (m, 2H), 3.61 (q, 2H), 2.79 (dd, 1H), 2.74-2.66 (m, 5H), 2.52 (s, 3H), 1.82 (d, 3H), 1.24 (t, 3H).
Example 127
Preparation of (S)-3-(4-((5-methyl-7-(3-(methylsulfonyl)propoxy)-9,10-dihydrophenanthren-1-yl)methoxy)phenyl)hex-4-ynoic acid
<127-1> Preparation of 1-(bromomethyl)-5-methyl-7-(3-(methylsulfonyl)propoxy)-9,10-dihydrophenanthrene




According to the procedures as described in <110-1>, the compound obtained in <10-8> was used to prepare the title compound (white foam, 126 mg, 95% yield).
1H NMR (600 MHz, CDCl3) δ 7.54 (dd, 1H), 7.28-7.18 (m, 2H), 6.69 (d, 1H), 6.67 (d, 1H), 4.59 (s, 2H), 4.13 (t, 2H), 3.30-3.22 (m, 2H), 2.96 (s, 3H), 2.83-2.76 (m, 2H), 2.76-2.71 (m, 2H), 2.55 (s, 3H), 2.39-2.32 (m, 2H).
<127-2> Preparation of (S)-methyl 3-(4-((5-methyl-7-(3-(methylsulfonyl)propoxy)-9,10-dihydrophenanthren-1-yl)methoxy)phenyl)hex-4-ynoate




According to the procedures as described in <110-2>, the compound obtained in <127-1> was used to prepare the title compound (white foam, 50 mg, 76% yield).
1H NMR (300 MHz, CDCl3) δ 7.60 (dd, 1H), 7.34-7.26 (m, 5H), 6.95 (m, 2H), 6.71 (d, 1H), 6.66 (d, 1H), 5.09 (s, 2H), 4.17-4.02 (m, 3H), 3.67 (s, 3H), 3.32-3.21 (m, 2H), 2.97 (s, 3H), 2.84-2.61 (m, 6H), 2.57 (s, 3H), 2.36 (m, 2H), 1.83 (d, 3H).
<127-3> Preparation of (S)-3-(4-((5-methyl-7-(3-(methylsulfonyl)propoxy)-9,10-dihydrophenanthren-1-yl)methoxy)phenyl)hex-4-ynoic acid




According to the procedures as described in <1-11>, the compound obtained in <127-2> was used to prepare the title compound (white foam, 39.1 mg, 85% yield).
MS m/z 569 [M+Na]+.
1H NMR (600 MHz, CDCl3) δ 7.59 (dd, 1H), 7.34-7.30 (m, 2H), 7.30-7.25 (m, 2H), 6.95 (m, 2H), 6.70 (d, 1H), 6.65 (d, 1H), 5.08 (s, 2H), 4.13 (t, 2H), 4.06 (m, 1H), 3.26 (m, 2H), 2.96 (s, 3H), 2.81 (dd, 1H), 2.77-2.67 (m, 5H), 2.56 (s, 3H), 2.34 (m, 2H), 1.83 (d, 3H).
Example 128
Preparation of (S)-3-(4-((11-methyl-9-(3-(methylsulfonyl)propoxy)-6,7-dihydro-5H-dibenzo[a,c][7]annulen-2-yl)methoxy)phenyl)hex-4-ynoic acid
<128-1> Preparation of 10-(bromomethyl)-1-methyl-3-(3-(methylsulfonyl)propoxy)-6,7-dihydro-5H-dibenzo[a,c][7]annulene




According to the procedures as described in <110-1>, the compound obtained in <5-9> was used to prepare the title compound (white foam, 98 mg, 81% yield).
1H NMR (600 MHz, CDCl3) δ 7.30-7.22 (m, 2H), 7.19 (d, 1H), 6.72 (d, 1H), 6.61 (d, 1H), 4.57-4.49 (m, 2H), 4.14 (t, 2H), 3.30-3.24 (m, 2H), 2.96 (s, 3H), 2.49 (ddd, 1H), 2.41 (ddd, 1H), 2.39-2.20 (m, 7H), 2.07-1.95 (m, 2H).
<128-2> Preparation of (S)-methyl 3-(4-((11-methyl-9-(3-(methylsulfonyl)propoxy)-6,7-dihydro-5H-dibenzo[a,c][7]annulen-2-yl)methoxy)phenyl)hex-4-ynoate




According to the procedures as described in <110-2>, the compound obtained in <128-1> was used to prepare the title compound (white foam, 63 mg, 100% yield).
1H NMR (300 MHz, CDCl3) δ 7.34-7.18 (m, 5H), 6.92 (m, 2H), 6.71 (d, 1H), 6.62 (d, 1H), 5.07 (s, 2H), 4.18-4.00 (m, 3H), 3.66 (s, 3H), 3.28 (m, 2H), 2.97 (s, 3H), 2.82-2.59 (m, 2H), 2.56-2.19 (m, 9H), 2.08-1.95 (m, 2H), 1.82 (d, 3H).
<128-3> Preparation of (S)-3-(4-((11-methyl-9-(3-(methylsulfonyl)propoxy)-6,7-dihydro-5H-dibenzo[a,c][7]annulen-2-yl)methoxy)phenyl)hex-4-ynoic acid




According to the procedures as described in <1-11>, the compound obtained in <128-2> was used to prepare the title compound (white foam, 50.0 mg, 85% yield).
MS m/z 583 [M+Na]+.
1H NMR (600 MHz, CDCl3) δ 7.32-7.26 (m, 4H), 7.23 (d, 1H), 6.92 (m, 2H), 6.71 (d, 1H), 6.62 (d, 1H), 5.06 (s, 2H), 4.13 (t, 2H), 4.03 (m, 1H), 3.27 (m, 2H), 2.96 (s, 3H), 2.78 (dd, 1H), 2.69 (dd, 1H), 2.50 (m, 1H), 2.41 (m, 1H), 2.38-2.19 (m, 7H), 2.05-1.97 (m, 2H), 1.82 (d, 3H).
Example 129
Preparation of (S)-3-(4-((9-(3-(methylsulfonyl)propoxy)dibenzo[d,f][1,3]dioxepin-2-yl)methoxy)phenyl)hex-4-ynoic acid
<129-1> Preparation of 2-(bromomethyl)-9-(3-(methylsulfonyl)propoxy)dibenzo[d,f][1,3]dioxepin




According to the procedures as described in <110-1>, the compound obtained in <80-6> was used to prepare the title compound (white solid, 57 mg, 47% yield).
1H NMR (600 MHz, CDCl3) δ 7.66 (d, 1H), 7.62 (d, 1H), 7.25 (dd, 1H), 7.06 (d, 1H), 6.75 (dd, 1H), 6.64 (d, 1H), 5.54 (s, 2H), 4.53 (s, 2H), 4.13 (t, 2H), 3.29-3.23 (m, 2H), 2.96 (s, 3H), 2.41-2.32 (m, 2H).
<129-2> Preparation of (S)-methyl 3-(4-((9-(3-(methylsulfonyl)propoxy)dibenzo[d,f][1,3]dioxepin-2-yl)methoxy)phenyl)hex-4-ynoate




According to the procedures as described in <110-2>, the compound obtained in <129-1> was used to prepare the title compound (white solid, 66 mg, 89% yield).
1H NMR (600 MHz, CDCl3) δ 7.69 (d, 1H), 7.61 (d, 1H), 7.31-7.27 (m, 3H), 7.11 (d, 1H), 6.95-6.91 (m, 2H), 6.74 (dd, 1H), 6.64 (d, 1H), 5.56 (s, 2H), 5.04 (s, 2H), 4.13 (t, 2H), 4.06 (m, 1H), 3.65 (s, 3H), 3.29-3.22 (m, 2H), 2.95 (s, 3H), 2.75 (dd, 1H), 2.65 (dd, 1H), 2.40-2.32 (m, 2H), 1.82 (d, 3H).
<129-3> Preparation of (S)-3-(4-((9-(3-(methylsulfonyl)propoxy)dibenzo[d,f][1,3]dioxepin-2-yl)methoxy)phenyl)hex-4-ynoic acid




According to the procedures as described in <1-11>, the compound obtained in <129-2> was used to prepare the title compound (white foam, 47 mg, 73% yield).
MS m/z 573 [M+Na]+.
1H NMR (600 MHz, CDCl3) δ 7.68 (d, 1H), 7.61 (d, 1H), 7.32-7.29 (m, 2H), 7.28 (dd, 1H), 7.11 (d, 1H), 6.95-6.92 (m, 2H), 6.74 (dd, 1H), 6.64 (d, 1H), 5.56 (s, 2H), 5.04 (s, 2H), 4.13 (t, 2H), 4.05 (m, 1H), 3.25 (m, 2H), 2.95 (s, 3H), 2.81 (dd, 1H), 2.70 (dd, 1H), 2.36 (m, 2H), 1.82 (d, 3H).
Example 130
Preparation of (S)-3-(4-((6,6-dimethyl-9-(3-(methylsulfonyl)propoxy)-6,7-dihydrodibenzo[b,d]oxepin-2-yl)methoxy)phenyl)hex-4-ynoic acid
<130-1> Preparation of 2-(bromomethyl)-6,6-dimethyl-9-(3-(methylsulfonyl)propoxy)-6,7-dihydrodibenzo[b,d]oxepin




According to the procedures as described in <110-1>, the compound obtained in <43-7> was used to prepare the title compound (white foam, 112 mg, 91% yield).
1H NMR (300 MHz, CDCl3) δ 7.4 (d, 1H), 7.39 (d, 1H), 7.31 (dd, 1H), 7.00 (d, 1H), 6.90 (dd, 1H), 6.78 (d, 1H), 4.56 (s, 2H), 4.17 (t, 2H), 3.29 (m, 2H), 2.97 (s, 3H), 2.57 (s, 2H), 2.46-2.30 (m, 2H), 1.40 (s, 6H).
<130-2> Preparation of (S)-methyl 3-(4-((6,6-dimethyl-9-(3-(methylsulfonyl)propoxy)-6,7-dihydrodibenzo[b,d]oxepin-2-yl)methoxy)phenyl)hex-4-ynoate




According to the procedures as described in <110-2>, the compound obtained in <130-1> was used to prepare the title compound (white foam, 125 mg, 88% yield).
1H NMR (600 MHz, CDCl3) δ 7.44 (d, 1H), 7.38 (d, 1H), 7.33 (dd, 1H), 7.31-7.27 (m, 2H), 7.04 (d, 1H), 6.96-6.92 (m, 2H), 6.89 (dd, 1H), 6.77 (d, 1H), 5.04 (s, 2H), 4.16 (t, 2H), 4.09-4.03 (m, 1H), 3.65 (s, 3H), 3.33-3.23 (m, 2H), 2.96 (s, 3H), 2.75 (dd, 1H), 2.65 (dd, 1H), 2.56 (s, 2H), 2.42-2.33 (m, 2H), 1.82 (d, 3H), 1.40 (s, 6H).
<130-3> Preparation of (S)-3-(4-((6,6-dimethyl-9-(3-(methylsulfonyl)propoxy)-6,7-dihydrodibenzo[b,d]oxepin-2-yl)methoxy)phenyl)hex-4-ynoic acid




According to the procedures as described in <1-11>, the compound obtained in <130-2> was used to prepare the title compound (white foam, 109 mg, 89% yield).
MS m/z 599 [M+Na]+.
1H NMR (600 MHz, CDCl3) δ 7.44 (d, 1H), 7.37 (d, 1H), 7.33 (dd, 1H), 7.31-7.28 (m, 2H), 7.04 (d, 1H), 6.96-6.93 (m, 2H), 6.88 (dd, 1H), 6.77 (d, 1H), 5.04 (s, 2H), 4.15 (t, 2H), 4.05 (m, 1H), 3.32-3.23 (m, 2H), 2.96 (s, 3H), 2.80 (dd, 1H), 2.70 (dd, 1H), 2.56 (s, 2H), 2.43-2.28 (m, 2H), 1.82 (d, 3H), 1.40 (s, 6H).
Example 131
Preparation of (S)-3-(4-((1-methyl-3-(3-(methylsulfonyl)propoxy)-6,7-dihydro-5H-benzo[3,4]cyclohepta[1,2-d]pyrimidin-10-yl)methoxy)phenyl)hex-4-ynoic acid
<131-1> Preparation of 10-(bromomethyl)-1-methyl-3-(3-(methylsulfonyl)propoxy)-6,7-dihydro-5H-benzo[3,4]cyclohepta[1,2-d]pyrimidine




According to the procedures as described in <110-1>, the compound obtained in <90-10> was used to prepare the title compound (white foam, 47 mg, 84% yield).
1H NMR (300 MHz, CDCl3) δ 7.36-7.20 (m, 3H), 4.65-4.45 (m, 4H), 3.37-3.26 (m, 2H), 2.96 (s, 5H), 2.64 (m, 2H), 2.48 (s, 3H), 2.44-2.31 (m, 8H), 2.31-2.08 (m, 2H).
<131-2> Preparation of (S)-methyl 3-(4-((1-methyl-3-(3-(methylsulfonyl)propoxy)-6,7-dihydro-5H-benzo[3,4]cyclohepta[1,2-d]pyrimidin-10-yl)methoxy)phenyl)hex-4-ynoate




According to the procedures as described in <110-2>, the compound obtained in <131-1> was used to prepare the title compound (colorless oil, 38 mg, 62% yield).
1H NMR (600 MHz, CDCl3) δ 7.34 (dd, 1H), 7.30-7.26 (m, 4H), 6.93-6.89 (m, 2H), 5.07 (s, 2H), 4.53 (h, 2H), 4.05 (m, 1H), 3.65 (s, 3H), 3.35-3.27 (m, 2H), 2.94 (s, 3H), 2.74 (dd, 1H), 2.67-2.57 (m, 3H), 2.45 (m, 1H), 2.42-2.34 (m, 6H), 2.22 (m, 1H), 2.18-2.09 (m, 1H), 1.81 (d, 3H).
<131-3> Preparation of (S)-3-(4-((1-methyl-3-(3-(methylsulfonyl)propoxy)-6,7-dihydro-5H-benzo[3,4]cyclohepta[1,2-d]pyrimidin-10-yl)methoxy)phenyl)hex-4-ynoic acid




According to the procedures as described in <1-11>, the compound obtained in <131-2> was used to prepare the title compound (white foam, 28 mg, 76% yield).
MS m/z 585 [M+Na]+.
1H NMR (600 MHz, CDCl3) δ 7.36-7.32 (d, 1H), 7.31-7.26 (m, 4H), 6.91 (d, 2H), 5.08 (s, 2H), 4.54 (h, 2H), 4.04 (m, 1H), 3.34-3.25 (m, 2H), 2.94 (s, 3H), 2.79 (dd, 1H), 2.69 (dd, 1H), 2.62 (m, 2H), 2.45 (m, 1H), 2.41-2.32 (m, 6H), 2.22 (m, 1H), 2.13 (m, 1H), 1.82 (d, 3H).
Example 132
Preparation of (S)-3-(4-((9-((1,1-dioxidotetrahydro-2H-thiopyran-4-yl)methoxy)-6,7-dihydro-5H-dibenzo[a,c][7]annulen-2-yl)methoxy)phenyl)butanoic acid
<132-1> Preparation of (S)-methyl 3-(4-((9-((1,1-dioxidotetrahydro-2H-thiopyran-4-yl)methoxy)-6,7-dihydro-5H-dibenzo[a,c][7]annulen-2-yl)methoxy)phenyl)butanoate




According to the procedures as described in <110-2>, the compound obtained in <109-3> and (S)-methyl 3-(4-hydroxyphenyl)butanoate (prepared in accordance with the reference [WO2008/130514 A1, 2008]; 31 mg, 0.16 mmol) were used to prepare the title compound (white foam, 69 mg, 92% yield).
1H NMR (600 MHz, CDCl3) δ 7.39 (d, 1H), 7.33-7.30 (m, 2H), 7.24 (d, 1H), 7.16-7.13 (m, 2H), 6.95-6.92 (m, 2H), 6.84 (dd, 1H), 6.79 (d, 1H), 5.06 (s, 2H), 3.91 (d, 2H), 3.62 (s, 3H), 3.26-3.22 (m, 1H), 3.17-3.13 (m, 2H), 3.07-3.02 (m, 2H), 2.61-2.57 (m, 1H), 2.54-2.46 (m, 5H), 2.34-2.30 (m, 2H), 2.20-2.15 (m, 2H), 2.09-2.05 (m, 3H), 1.27 (d, 3H).
<132-2> Preparation of (S)-3-(4-((9-((1,1-dioxidotetrahydro-2H-thiopyran-4-yl)methoxy)-6,7-dihydro-5H-dibenzo[a,c][7]annulen-2-yl)methoxy)phenyl)butanoic acid




According to the procedures as described in <1-11>, the compound obtained in <132-1> was used to prepare the title compound (white foam, 55 mg, 79% yield).
MS m/z 547 [M−H]−.
1H NMR (600 MHz, CDCl3) δ 7.39 (d, 1H), 7.33-7.30 (m, 2H), 7.24 (d, 1H), 7.17-7.14 (m, 2H), 6.95-6.93 (m, 2H), 6.84 (dd, 1H), 6.79 (d, 1H), 5.06 (s, 2H), 3.91 (d, 2H), 3.26-3.22 (m, 1H), 3.17-3.13 (m, 2H), 3.07-3.02 (m, 2H), 2.66-2.62 (m, 1H), 2.58-2.54 (m, 1H), 2.51-2.46 (m, 4H), 2.34-2.30 (m, 2H), 2.20-2.17 (m, 2H), 2.09-2.04 (m, 3H), 1.30 (d, 3H).
Example 133
Preparation of (R)-3-(4-((9-((1,1-dioxidotetrahydro-2H-thiopyran-4-yl)methoxy)-6,7-dihydro-5H-dibenzo[a,c][7]annulen-2-yl)methoxy)phenyl)butanoic acid
<133-1> Preparation of (R)-methyl 3-(4-((9-((1,1-dioxidotetrahydro-2H-thiopyran-4-yl)methoxy)-6,7-dihydro-5H-dibenzo[a,c][7]annulen-2-yl)methoxy)phenyl)butanoate




According to the procedures as described in <110-2>, the compound obtained in <109-3> and (R)-methyl 3-(4-hydroxyphenyl)butanoate (prepared in accordance with the reference [WO2008/130514 A1, 2008]; 31 mg, 0.16 mmol) were used to prepare the title compound (white foam, 68 mg, 90% yield).
1H NMR (600 MHz, CDCl3) δ 7.39 (d, 1H), 7.33-7.30 (m, 2H), 7.24 (d, 1H), 7.16-7.13 (m, 2H), 6.95-6.92 (m, 2H), 6.84 (dd, 1H), 6.79 (d, 1H), 5.06 (s, 2H), 3.91 (d, 2H), 3.62 (s, 3H), 3.26-3.22 (m, 1H), 3.17-3.13 (m, 2H), 3.07-3.02 (m, 2H), 2.61-2.57 (m, 1H), 2.54-2.46 (m, 5H), 2.34-2.30 (m, 2H), 2.20-2.15 (m, 2H), 2.10-2.05 (m, 3H), 1.27 (d, 3H).
<133-2> Preparation of (R)-3-(4-((9-((1,1-dioxidotetrahydro-2H-thiopyran-4-yl)methoxy)-6,7-dihydro-5H-dibenzo[a,c][7]annulen-2-yl)methoxy)phenyl)butanoic acid




According to the procedures as described in <1-11>, the compound obtained in <133-1> was used to prepare the title compound (white foam, 55 mg, 79% yield).
MS m/z 547 [M−H]−.
1H NMR (600 MHz, CDCl3) δ 7.39 (d, 1H), 7.33-7.30 (m, 2H), 7.24 (d, 1H), 7.17-7.14 (m, 2H), 6.95-6.93 (m, 2H), 6.84 (dd, 1H), 6.79 (d, 1H), 5.06 (s, 2H), 3.91 (d, 2H), 3.26-3.22 (m, 1H), 3.17-3.13 (m, 2H), 3.07-3.02 (m, 2H), 2.65-2.62 (m, 1H), 2.58-2.54 (m, 1H), 2.52-2.46 (m, 4H), 2.34-2.30 (m, 2H), 2.20-2.15 (m, 2H), 2.09-2.02 (m, 3H), 1.30 (d, 3H).
Example 134
Preparation of (S)-3-(4-((9-((1,1-dioxidotetrahydro-2H-thiopyran-4-yl)methoxy)-6,7-dihydro-5H-dibenzo[a,c][7]annulen-2-yl)methoxy)phenyl)-4-ethoxybutanoic acid
<134-1> Preparation of (S)-methyl 3-(4-(benzyloxy)phenyl)hex-4-ynoate




A solution of (S)-methyl 3-(4-hydroxyphenyl)hex-4-ynoate (prepared in accordance with the reference [Bioorganic & Medicinal Chemistry Letters, 2012, 22, p. 1267-12′70]; 500 mg, 2.29 mmol) in acetone (11 mL) was added with benzyl bromide (0.3 mL, 2.52 mmol) and Cs2CO3 (896 mg, 2.75 mmol), and the mixture thus obtained was stirred at room temperature for 15 hours. The reaction mixture was filtered and washed with acetone. The filtrate thus obtained was concentrated and purified by silica gel chromatography to obtain the title compound (white solid, 671 mg, 95% yield).
1H NMR (600 MHz, CDCl3) δ 7.43-7.42 (m, 2H), 7.40-7.37 (m, 2H), 7.34-7.32 (m, 1H), 7.31-7.28 (m, 2H), 6.93-6.91 (m, 2H), 5.04 (s, 2H), 4.07-4.04 (m, 1H), 3.66 (s, 3H), 2.77-2.73 (m, 1H), 2.67-2.64 (m, 1H), 1.82 (d, 3H).
<134-2> Preparation of (R,Z)-methyl 3-(4-(benzyloxy)phenyl)hex-4-enoate




A solution of the compound obtained in <134-1> (671 mg, 2.18 mmol) in ethyl acetate (30 mL) was added with a Lindlar catalyst (100 mg) and stirred under a hydrogen atmosphere for 6 hours. The reaction mixture thus obtained was filtered, and the filtrate was concentrated and purified by silica gel chromatography to obtain the title compound (colorless oil, 620 mg, 92% yield).
1H NMR (600 MHz, CDCl3) δ 7.43-7.41 (m, 2H), 7.39-7.37 (m, 2H), 7.33-7.32 (m, 1H), 7.17-7.13 (m, 2H), 6.92-6.90 (m, 2H), 5.53-5.50 (m, 2H), 5.03 (s, 2H), 4.15-4.13 (m, 1H), 3.62 (s, 3H), 2.72-2.68 (m, 1H), 2.62-2.58 (m, 1H), 1.69-1.68 (m, 3H).
<134-3> Preparation of (S)-methyl 3-(4-(benzyloxy)phenyl)-4-oxobutanoate




A solution of the compound obtained in <134-2> (620 mg, 2.00 mmol) in acetone (20 mL) and distilled water (5 mL) was slowly added with 2,6-lutidine (0.46 mL, 3.99 mmol) and OsO4 (4 wt % aqueous solution, 0.24 mL, 0.04 mmol), and then stirred at room temperature for 5 minutes. The reaction mixture thus obtained was slowly added with NaIO4 (1M aqueous solution, 8 mL, 8.00 mmol) and stirred for 4 hours. The mixture was diluted with a saturated Na2S2O3 aqueous solution and extracted with EtOAc. The organic layer was washed with 0.5M HCl aqueous solution, dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue thus obtained was purified by silica gel chromatography to obtain the title compound (colorless oil, 417 mg, 70% yield).
1H NMR (600 MHz, CDCl3) δ 9.67 (s, 1H), 7.43-7.41 (m, 2H), 7.40-7.38 (m, 2H), 7.35-7.31 (m, 1H), 7.13-7.09 (m, 2H), 7.00-6.97 (m, 2H), 5.06 (s, 2H), 4.11-4.09 (m, 1H), 3.66 (s, 3H), 3.15-3.11 (m, 1H), 2.60-2.56 (m, 1H).
<134-4> Preparation of (S)-methyl 3-(4-(benzyloxy)phenyl)-4-hydroxybutanoate




A solution of the compound obtained in <134-3> (417 mg, 1.40 mmol) in EtOAc (6.3 mL) and acetic acid (0.7 mL) was slowly added with sodium cyanoborohydride (88 mg, 1.40 mmol) and then stirred at room temperature for 20 minutes. The mixture thus obtained was added with a saturated NH4Cl aqueous solution and extracted with EtOAc. The organic layer was washed with brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue thus obtained was purified by silica gel chromatography to obtain the title compound (white solid, 399 mg, 95% yield).
1H NMR (600 MHz, CDCl3) δ 7.43-7.41 (m, 2H), 7.40-7.37 (m, 2H), 7.34-7.31 (m, 1H), 7.17-7.14 (m, 2H), 6.96-6.93 (m, 2H), 5.04 (s, 2H), 3.77-3.72 (m, 1H), 3.63 (s, 3H), 3.33-3.30 (m, 1H), 2.81-2.77 (m, 1H), 2.65-2.61 (m, 1H).
<134-5> Preparation of (S)-methyl 3-(4-(benzyloxy)phenyl)-4-ethoxybutanoate




A solution of the compound obtained in <134-4> (220 mg, 0.73 mmol) in chloroform (3 mL) was cooled to 0° C., and then slowly added with DIPEA (0.38 mL, 2.20 mmol) and triethyloxonium tetrafluoroborate (1M chloroform solution, 1.83 mL, 1.83 mmol). The mixture was stirred at room temperature for 15 hours, washed with brine, dried over sodium sulfate, filtered, and then concentrated under reduced pressure. The residue thus obtained was purified by silica gel chromatography to obtain the title compound (colorless oil, 220 mg, 92% yield).
1H NMR (600 MHz, CDCl3) δ 7.43-7.41 (m, 2H), 7.40-7.37 (m, 2H), 7.34-7.31 (m, 1H), 7.17-7.14 (m, 2H), 6.92-6.90 (m, 2H), 5.03 (s, 2H), 3.59 (s, 3H), 3.57-3.54 (m, 1H), 3.50-3.38 (m, 4H), 2.86-3.83 (m, 1H), 2.59-2.55 (m, 1H), 1.17 (t, 3H).
<134-6> Preparation of (S)-methyl 4-ethoxy-3-(4-hydroxyphenyl)butanoate




A solution of the compound obtained in <134-5> (217 mg, 0.66 mmol) in methanol (6 mL) was added with 10% Pd/C (21 mg, 0.02 mmol) and stirred under a hydrogen atmosphere for 4 hours. The reaction mixture was filtered through Celite, washed EtOAc, and then the filtrate was concentrated under reduced pressure. The residue thus obtained was purified by silica gel chromatography to obtain the title compound (white solid, 156 mg, 99% yield).
1H NMR (600 MHz, CDCl3) δ 7.07-7.04 (m, 2H), 6.69-6.67 (m, 2H), 3.61 (s, 3H), 3.57-3.55 (m, 1H), 3.52-3.44 (m, 3H), 3.40-3.36 (m, 1H), 2.86-3.83 (m, 1H), 2.59-2.55 (m, 1H), 1.17 (t, 3H).
<134-7> Preparation of (S)-methyl 3-(4-((9-((1,1-dioxidotetrahydro-2H-thiopyran-4-yl)methoxy)-6,7-dihydro-5H-dibenzo[a,c][7]annulen-2-yl)methoxy)phenyl)-4-ethoxybutanoate




According to the procedures as described in <110-2>, the compounds obtained in <109-3> and <134-6> were used to prepare the title compound (white foam, 90 mg, 95% yield).
1H NMR (600 MHz, CDCl3) δ 7.39 (d, 1H), 7.33-7.30 (m, 2H), 7.24 (d, 1H), 7.16-7.14 (m, 2H), 6.95-6.92 (m, 2H), 6.84 (dd, 1H), 6.79 (d, 1H), 5.05 (s, 2H), 3.91 (d, 2H), 3.60 (s, 3H), 3.57-3.55 (m, 1H), 3.51-3.43 (m, 3H), 3.41-3.38 (m, 1H), 3.18-3.14 (m, 2H), 3.07-3.03 (m, 2H), 2.87-2.83 (m, 1H), 2.59-2.55 (m, 1H), 2.51-2.47 (m, 4H), 2.34-2.30 (m, 2H), 2.20-2.16 (m, 2H), 2.10-2.05 (m, 3H), 1.17 (t, 3H).
<134-8> Preparation of (S)-3-(4-((9-((1,1-dioxidotetrahydro-2H-thiopyran-4-yl)methoxy)-6,7-dihydro-5H-dibenzo[a,c][7]annulen-2-yl)methoxy)phenyl)-4-ethoxybutanoic acid




According to the procedures as described in <1-11>, the compound obtained in <134-7> was used to prepare the title compound (white foam, 82 mg, 93% yield).
MS m/z 591 [M−H]−.
1H NMR (600 MHz, CDCl3) δ 7.38 (d, 1H), 7.32-7.30 (m, 2H), 7.24 (d, 1H), 7.16-7.14 (m, 2H), 6.95-6.92 (m, 2H), 6.84 (dd, 1H), 6.79 (d, 1H), 5.05 (s, 2H), 3.91 (d, 2H), 3.59-3.57 (m, 1H), 3.51-3.46 (m, 3H), 3.38-3.36 (m, 1H), 3.16-3.13 (m, 2H), 3.07-3.03 (m, 2H), 2.92-2.89 (m, 1H), 2.65-2.61 (m, 1H), 2.52-2.46 (m, 4H), 2.34-2.30 (m, 2H), 2.20-2.16 (m, 2H), 2.09-2.05 (m, 3H), 1.17 (t, 3H).
Example 135
Preparation of (S)-3-(4-(((9-(3-(methylsulfonyl)propoxy)-6,7-dihydro-5H-dibenzo[a,c][7]annulen-2-yl)methyl)amino)phenyl)hex-4-ynoic acid
<135-1> Preparation of (S)-methyl 3-(4-(((trifluoromethyl)sulfonyl)oxy)phenyl)hex-4-ynoate




A solution of (S)-methyl 3-(4-hydroxyphenyl)hex-4-ynoate (prepared in accordance with the reference [Bioorganic & Medicinal Chemistry Letters, 2012, 22, p. 1267-1270]; 395 mg, 1.81 mmol) in pyridine (10 mL) at 0° C. was added with triflic acid anhydride (0.37 mL, 2.17 mmol), heated to room temperature, and then stirred for 15 hours. The reaction mixture thus obtained was diluted with EtOAc and 1M HCl aqueous solution. The aqueous layer was extracted with EtOAc one more time, and the organic layer was washed with brine, dried over MgSO4, concentrated, and then purified by silica gel chromatography to obtain the title compound (colorless oil, 415 mg, 65% yield).
1H NMR (600 MHz, CDCl3) δ 7.49-7.44 (m, 2H), 7.23-7.19 (m, 2H), 4.14 (m, 1H), 3.66 (s, 2H), 2.78 (dd, 1H), 2.66 (dd, 1H), 1.83 (d, 2H).
<135-2> Preparation of (S)-methyl 3-(4-aminophenyl)hex-4-ynoate




A solution of the compound obtained in <135-1> (415 mg, 1.185 mmol), benzophenone-imine (0.28 mL, 1.659 mmol) and Cs2CO3 (1.16 g, 3.554 mmol) in THF (5 mL) was substituted with nitrogen, added with Xantphos (41 mg, 0.0711 mmol) and Pd2(dba)3 (33 mg, 0.0355 mmol), and refluxed for 12 hours. The reaction mixture thus obtained was cooled room temperature, filtered through Celite, and then washed with CH2Cl2. The concentrated filtrate was dissolved in THF (4 mL), and the solution thus formed was added with 3M HCl aqueous solution (1.2 mL, 3.554 mmol) and stirred for 30 minutes. The reaction mixture was diluted with EtOAc, added with a saturated NaHCO3 aqueous solution, and the layers were separated. The aqueous layer was extracted with CH2Cl2, and the organic layer was dried over Na2SO4, concentrated and purified by silica gel chromatography to obtain the title compound (yellow oil, 134 mg, 52% yield).
1H NMR (600 MHz, CDCl3) δ 7.17-7.11 (m, 2H), 6.66-6.59 (m, 2H), 3.99 (m, 1H), 3.65 (s, 3H), 3.60 (br s, 2H), 2.72 (dd, 1H), 2.62 (dd, 1H), 1.81 (d, 3H).
<135-3> Preparation of (S)-methyl 3-(4-(((9-(3-(methylsulfonyl)propoxy)-6,7-dihydro-5H-dibenzo[a,c][7]annulen-2-yl)methyl)amino)phenyl)hex-4-ynoate




According to the procedures as described in <3-4>, the compounds obtained in <6-1> and <135-2> were used to prepare the title compound (yellow foam, 138 mg, 97% yield).
1H NMR (600 MHz, CDCl3) δ 7.32 (d, 1H), 7.27 (d, 1H), 7.26-7.22 (m, 1H), 7.18 (d, 1H), 7.17-7.14 (m, 2H), 6.83 (dd, 1H), 6.78 (d, 1H), 6.63-6.58 (m, 2H), 4.32 (s, 2H), 4.15 (t, 2H), 4.06-3.96 (m, 2H), 3.65 (s, 3H), 3.31-3.24 (m, 2H), 2.96 (s, 3H), 2.72 (dd, 1H), 2.63 (dd, 1H), 2.51-2.42 (m, 4H), 2.39-2.31 (m, 2H), 2.17 (m, 2H), 1.81 (d, 3H).
<135-4> Preparation of (S)-3-(4-(((9-(3-(methylsulfonyl)propoxy)-6,7-dihydro-5H-dibenzo[a,c][7]annulen-2-yl)methyl)amino)phenyl)hex-4-ynoic acid




According to the procedures as described in <1-11>, the compound obtained in <135-3> was used to prepare the title compound (yellow foam, 96 mg, 71% yield).
MS m/z 544 [M−H]−.
1H NMR (600 MHz, CDCl3) δ 7.31 (d, 1H), 7.27 (d, 1H), 7.25-7.22 (m, 1H), 7.18 (m, 3H), 6.83 (dd, 1H), 6.78 (d, 1H), 6.64-6.58 (m, 2H), 4.32 (s, 2H), 4.14 (t, 2H), 3.99 (m, 1H), 3.31-3.23 (m, 2H), 2.96 (s, 3H), 2.76 (dd, 1H), 2.68 (dd, 1H), 2.53-2.40 (m, 4H), 2.40-2.30 (m, 2H), 2.16 (m, 2H), 1.81 (d, 3H).
Example 136
Preparation of (S)-3-(4-(((9-((1,1-dioxidotetrahydro-2H-thiopyran-4-yl)methoxy)-6,7-dihydro-5H-dibenzo[a,c][7]annulen-2-yl)methyl)amino)phenyl)hex-4-ynoic acid
<136-1> Preparation of (S)-methyl 3-(4-(((9-((1,1-dioxidotetrahydro-2H-thiopyran-4-yl)methoxy)-6,7-dihydro-5H-dibenzo[a,c][7]annulen-2-yl)methyl)amino)phenyl)hex-4-ynoate




According to the procedures as described in <3-4>, the compounds obtained in <78-3> and <135-2> were used to prepare the title compound (yellow oil, 136 mg, 100% yield).
1H NMR (600 MHz, CDCl3) δ 7.31 (d, 1H), 7.27 (d, 1H), 7.24 (dd, 1H), 7.18 (d, 1H), 7.17-7.14 (m, 2H), 6.82 (dd, 1H), 6.77 (d, 1H), 6.63-6.57 (m, 2H), 4.32 (s, 2H), 4.03 (br s, 1H), 3.99 (m, 1H), 3.90 (d, 2H), 3.65 (s, 3H), 3.18-3.10 (m, 2H), 3.03 (m, 2H), 2.72 (dd, 1H), 2.63 (dd, 1H), 2.52-2.41 (m, 4H), 2.31 (m, 2H), 2.17 (m, 2H), 2.10-1.99 (m, 3H), 1.80 (d, 3H).
<136-2> Preparation of (S)-3-(4-(((9-((1,1-dioxidotetrahydro-2H-thiopyran-4-yl)methoxy)-6,7-dihydro-5H-dibenzo[a,c][7]annulen-2-yl)methyl)amino)phenyl)hex-4-ynoic acid




According to the procedures as described in <1-11>, the compound obtained in <136-1> was used to prepare the title compound (yellow foam, 75 mg, 56% yield).
MS m/z 570 [M−H]−.
1H NMR (600 MHz, CDCl3) δ 7.31 (d, 1H), 7.27 (d, 1H), 7.24 (dd, 1H), 7.20-7.15 (m, 3H), 6.82 (dd, 1H), 6.77 (d, 1H), 6.63-6.58 (m, 2H), 4.32 (s, 2H), 3.99 (m, 1H), 3.90 (d, 2H), 3.19-3.09 (m, 2H), 3.08-2.96 (m, 2H), 2.77 (dd, 1H), 2.68 (dd, 1H), 2.52-2.39 (m, 4H), 2.35-2.24 (m, 2H), 2.16 (m, 2H), 2.11-1.98 (m, 3H), 1.81 (d, 3H).
Example 137
Preparation of 3-(4-((9-((1,1-dioxidotetrahydro-2H-thiopyran-4-yl)methoxy)-6,7-dihydro-5H-dibenzo[a,c][7]annulen-2-yl)methoxy)phenyl)-3-(4-fluorophenyl)propanoic acid
<137-1> Preparation of methyl 3-(4-((9-((1,1-dioxidotetrahydro-2H-thiopyran-4-yl)methoxy)-6,7-dihydro-5H-dibenzo[a,c][7]annulen-2-yl)methoxy)phenyl)-3-(4-fluorophenyl)propanoate




According to the procedures as described in <110-2>, the compound obtained in <109-3> and methyl 3-(4-fluorophenyl)-3-(4-hydroxyphenyl)propanoate (prepared in accordance with the reference [Bioorganic & Medicinal Chemistry Letters, 2012, 22, p. 1267-1270]) were used to prepare the title compound (colorless oil, 85 mg, 99% yield).
1H NMR (600 MHz, CDCl3) δ 7.36 (d, 1H), 7.31-7.27 (m, 2H), 7.22 (d, 1H), 7.19-7.14 (m, 2H), 7.13-7.09 (m, 2H), 6.98-6.93 (m, 2H), 6.93-6.89 (m, 2H), 6.82 (dd, 1H), 6.77 (d, 1H), 5.03 (s, 2H), 4.48 (t, 1H), 3.90 (d, 2H), 3.57 (s, 3H), 3.21-3.11 (m, 2H), 3.04 (m, 2H), 2.99 (dd, 2H), 2.47 (m, 4H), 2.31 (m, 2H), 2.16 (m, 2H), 2.11-2.00 (m, 3H).
<137-2> Preparation of 3-(4-((9-((1,1-dioxidotetrahydro-2H-thiopyran-4-yl)methoxy)-6,7-dihydro-5H-dibenzo[a,c][7]annulen-2-yl)methoxy)phenyl)-3-(4-fluorophenyl)propanoic acid




According to the procedures as described in <1-11>, the compound obtained in <137-1> was used to prepare the title compound (white foam, 63 mg, 79% yield).
MS m/z 627 [M−H]−.
1H NMR (600 MHz, CDCl3) δ 7.36 (d, 1H), 7.29 (m, 2H), 7.22 (d, 1H), 7.19-7.14 (m, 2H), 7.11 (m, 2H), 6.98-6.93 (m, 2H), 6.93-6.88 (m, 2H), 6.82 (dd, 1H), 6.77 (d, 1H), 5.03 (s, 2H), 4.46 (t, 1H), 3.90 (d, 2H), 3.19-3.09 (m, 2H), 3.03 (m, 4H), 2.47 (m, 4H), 2.38-2.23 (m, 2H), 2.17 (m, 2H), 2.12-1.97 (m, 3H).
Example 138
Preparation of (S)-3-(4-((11-methyl-9-(((R)-tetrahydrofuran-3-yl)oxy)-6,7-dihydro-5H-dibenzo[a,c][7]annulen-2-yl)methoxy)phenyl)hex-4-ynoic acid
<138-1> Preparation of methyl 11-methyl-9-(((R)-tetrahydrofuran-3-yl)oxy)-6,7-dihydro-5H-dibenzo[a,c][7]annulene-2-carboxylate




According to the procedures as described in <106-1>, the compound obtained in <7-6> was used to prepare the title compound (white foam, 71 mg, 93% yield).
1H NMR (600 MHz, CDCl3) δ 7.94 (d, 1H), 7.91 (dd, 1H), 7.30 (d, 1H), 6.72-6.70 (m, 1H), 6.60 (d, 1H), 4.99-4.96 (m, 1H), 4.05-3.99 (m, 3H), 3.95-3.92 (m, 1H), 3.91 (s, 3H), 2.58-2.55 (m, 1H), 2.45-2.37 (m, 2H), 2.30 (s, 3H), 2.25-2.17 (m, 3H), 2.09-2.01 (m, 2H).
<138-2> Preparation of (11-methyl-9-(((R)-tetrahydrofuran-3-yl)oxy)-6,7-dihydro-5H-dibenzo[a,c][7]annulen-2-yl)methanol




According to the procedures as described in <1-9>, the compound obtained in <138-1> was used to prepare the title compound (white foam, 60 mg, 92% yield).
1H NMR (600 MHz, CDCl3) δ 7.26-7.22 (m, 3H), 6.70 (d, 1H), 7.60 (d, 1H), 6.98-6.96 (m, 1H), 4.05-3.99 (m, 3H), 3.94-3.91 (m, 1H), 2.52-2.49 (m, 1H), 2.44-2.40 (m, 1H), 2.38-2.33 (m, 1H), 2.30 (s, 3H), 2.26-2.19 (m, 3H), 2.05-1.99 (m, 2H), 1.61 (t, 1H).
<138-3> Preparation of (R)-3-((10-(bromomethyl)-1-methyl-6,7-dihydro-5H-dibenzo[a,c][7]annulen-3-yl)oxy)tetrahydrofuran




According to the procedures as described in <110-1>, the compound obtained in <138-2> was used to prepare the title compound (white foam, 58 mg, 82% yield).
1H NMR (600 MHz, CDCl3) δ 7.29 (d, 1H), 7.25 (dd, 1H), 7.20 (d, 1H), 6.70 (d, 1H), 6.60 (d, 1H), 4.98-4.96 (m, 1H), 4.56-4.52 (m, 2H), 4.04-3.99 (m, 3H), 3.94-3.91 (m, 1H), 2.52-2.48 (m, 1H), 2.44-2.41 (m, 1H), 2.37-2.32 (m, 1H), 2.30 (s, 3H), 2.28-2.19 (m, 3H), 2.05-1.99 (m, 2H).
<138-4> Preparation of (S)-methyl 3-(4-((11-methyl-9-(((R)-tetrahydrofuran-3-yl)oxy)-6,7-dihydro-5H-dibenzo[a,c][7]annulen-2-yl)methoxy)phenyl)hex-4-ynoate




According to the procedures as described in <110-2>, the compound obtained in <138-3> was used to prepare the title compound (white foam, 75 mg, 95% yield).
1H NMR (600 MHz, CDCl3) δ 7.30-7.27 (m, 4H), 7.24-7.23 (m, 1H), 6.94-6.91 (m, 2H), 6.68 (d, 1H), 6.60 (d, 1H), 5.07 (s, 2H), 4.98-4.96 (m, 1H), 4.05-4.00 (m, 4H), 3.94-3.92 (m, 1H), 3.66 (s, 3H), 2.52-2.48 (m, 1H), 2.77-2.73 (m, 1H), 2.67-2.63 (m, 1H), 2.52-2.49 (m, 1H), 2.44-2.41 (m, 1H), 2.38-2.33 (m, 1H), 2.28-2.19 (m, 6H), 2.05-2.00 (m, 2H), 1.83-1.82 (m, 3H).
<138-5> Preparation of (S)-3-(4-((11-methyl-9-(((R)-tetrahydrofuran-3-yl)oxy)-6,7-dihydro-5H-dibenzo[a,c][7]annulen-2-yl)methoxy)phenyl)hex-4-ynoic acid




According to the procedures as described in <1-11>, the compound obtained in <138-4> was used to prepare the title compound (white foam, 54 mg, 74% yield).
MS m/z 509 [M−H]−.
1H NMR (600 MHz, CDCl3) δ 7.30-7.28 (m, 4H), 7.24-7.23 (m, 1H), 6.94-6.92 (m, 2H), 6.68 (d, 1H), 6.60 (d, 1H), 5.07 (s, 2H), 4.98-4.95 (m, 1H), 4.06-3.99 (m, 4H), 3.94-3.92 (m, 1H), 2.52-2.48 (m, 1H), 2.82-2.78 (m, 1H), 2.72-2.69 (m, 1H), 2.52-2.49 (m, 1H), 2.43-2.40 (m, 1H), 2.38-2.32 (m, 1H), 2.28-2.19 (m, 6H), 2.05-1.99 (m, 2H), 1.83-1.82 (m, 3H).
Example 139
Preparation of (R)-3-(4-((9-((1,1-dioxidotetrahydro-2H-thiopyran-4-yl)methoxy)-6,7-dihydro-5H-dibenzo[a,c][7]annulen-2-yl)methoxy)phenyl)pent-4-ynoic acid
<139-1> Preparation of (R)-methyl 3-(4-((9-((1,1-dioxidotetrahydro-2H-thiopyran-4-yl)methoxy)-6,7-dihydro-5H-dibenzo[a,c][7]annulen-2-yl)methoxy)phenyl)pent-4-ynoate




According to the procedures as described in <110-2>, the compound obtained in <109-3> was used to prepare the title compound (white foam, 75.2 mg, 75% yield).
1H NMR (300 MHz, CDCl3) δ 7.39 (d, 1H), 7.33-7.30 (m, 4H), 7.24 (d, 1H), 6.96 (d, 2H), 6.85 (dd, 1H), 6.79 (d, 1H), 5.08 (s, 2H), 4.14 (t, 1H), 3.92 (d, 2H), 3.68 (s, 3H), 3.18-3.02 (m, 4H), 2.83 (dd, 1H), 2.71 (dd, 1H), 2.48 (m, 4H), 2.33 (m, 2H), 2.29 (d, 1H), 2.18 (m, 2H), 2.07 (m, 3H).
<139-2> Preparation of (R)-3-(4-((9-((1,1-dioxidotetrahydro-2H-thiopyran-4-yl)methoxy)-6,7-dihydro-5H-dibenzo[a,c][7]annulen-2-yl)methoxy)phenyl)pent-4-ynoic acid




According to the procedures as described in <1-11>, the compound obtained in <139-1> was used to prepare the title compound (white foam, 65.4 mg, 90% yield).
MS m/z 580 [M+Na]+.
1H NMR (300 MHz, CDCl3) δ 7.39 (d, 1H), 7.34-7.30 (m, 4H), 7.24 (d, 1H), 6.96 (d, 2H), 6.84 (dd, 1H), 6.79 (d, 1H), 5.08 (s, 2H), 4.12 (t, 1H), 3.92 (d, 2H), 3.18-3.01 (m, 4H), 2.88 (dd, 1H), 2.76 (dd, 1H), 2.49 (m, 4H), 2.33 (m, 2H), 2.30 (d, 1H), 2.18 (m, 2H), 2.07 (m, 3H).
Example 140
Preparation of (S)-3-(4-((5-ethyl-9-(((R)-tetrahydrofuran-3-yl)oxy)-6,7-dihydro-5H-dibenzo[b,d]azepin-2-yl)methoxy)phenyl)hex-4-ynoic acid
<140-1> Preparation of (R)-ethyl 5-ethyl-9-((tetrahydrofuran-3-yl)oxy)-6,7-dihydro-5H-dibenzo[b,d]azepin-2-carboxylate




According to the procedures as described in <106-1>, the compound obtained in <44-6> was used to prepare the title compound (white foam, 110 mg, 85% yield).
1H NMR (600 MHz, CDCl3) δ 7.96-7.93 (m, 2H), 7.33 (d, 1H), 7.02 (d, 1H), 6.84 (dd, 1H), 6.75 (d, 1H), 4.99-4.97 (m, 1H), 4.36 (q, 2H), 4.05-3.99 (m, 3H), 3.95-3.90 (m, 1H), 3.53 (t, 2H), 3.17 (q, 2H), 2.71 (t, 2H), 2.27-2.19 (m, 2H), 1.38 (t, 3H), 1.09 (t, 3H).
<140-2> Preparation of (R)-(5-ethyl-9-((tetrahydrofuran-3-yl)oxy)-6,7-dihydro-5H-dibenzo[b,d]azepin-2-yl)methanol




According to the procedures as described in <1-9>, the compound obtained in <140-1> was used to prepare the title compound (white foam, 91 mg, 90% yield).
1H NMR (600 MHz, CDCl3) δ 7.31-7.29 (m, 3H), 7.03-7.02 (m, 1H), 6.82 (dd, 1H), 6.76 (d, 1H), 4.99-4.96 (m, 1H), 4.68 (d, 2H), 4.05-3.99 (m, 3H), 3.94-3.91 (m, 1H), 3.42 (t, 2H), 3.10 (q, 2H), 2.65 (t, 2H), 2.24-2.20 (m, 2H), 1.60 (t, 1H), 1.04 (t, 3H).
<140-3> Preparation of (S)-methyl 3-(4-((5-ethyl-9-(((R)-tetrahydrofuran-3-yl)oxy)-6,7-dihydro-5H-dibenzo[b,d]azepin-2-yl) methoxy)phenyl)hex-4-ynoate




According to the procedures as described in <108-3>, <140-2> was used to prepare the title compound (white foam, 55 mg, 38% yield).
1H NMR (600 MHz, CDCl3) δ 7.35-7.33 (m, 2H), 7.31-7.28 (m, 3H), 7.05-7.03 (m, 1H), 6.96-6.94 (m, 2H), 6.82 (dd, 1H), 6.76 (d, 1H), 5.02 (s, 2H), 4.99-4.96 (m, 1H), 4.08-3.99 (m, 4H), 3.94-3.91 (m, 1H), 3.66 (s, 3H), 3.43 (t, 2H), 3.10 (q, 2H), 2.78-2.74 (m, 1H), 2.68-2.64 (m, 3H), 2.24-2.20 (m, 2H), 1.83 (d, 3H), 1.05 (t, 3H).
<140-4> Preparation of (S)-3-(4-((5-ethyl-9-(((R)-tetrahydrofuran-3-yl)oxy)-6,7-dihydro-5H-dibenzo[b,d]azepin-2-yl)methoxy)phenyl)hex-4-ynoic acid




According to the procedures as described in <1-11>, the compound obtained in <140-3> was used to prepare the title compound (white foam, 45 mg, 90% yield).
MS m/z 524 [M−H]−.
1H NMR (600 MHz, CDCl3) δ 7.35-7.33 (m, 2H), 7.32-7.28 (m, 3H), 7.05-7.03 (m, 1H), 6.97-6.95 (m, 2H), 6.82 (dd, 1H), 6.77 (d, 1H), 5.02 (s, 2H), 4.98-4.96 (m, 1H), 4.06-3.99 (m, 4H), 3.94-3.91 (m, 1H), 3.43 (t, 2H), 3.10 (q, 2H), 2.82-2.78 (m, 1H), 2.73-2.69 (m, 1H), 2.66 (t, 2H), 2.24-2.20 (m, 2H), 1.84 (d, 3H), 1.05 (t, 3H).
Example 141
Preparation of sodium (1S,2S)-2-(4-(((9-(3-(methylsulfonyl)propoxy)-6,7-dihydro-5H-dibenzo[a,c][7]annulen-2-yl)methyl)amino)phenyl)cyclopropanecarboxylate




The compound obtained in <6-3> (90.5 mg, 0.174 mmol) was suspended in water (1.9 mL), which was then added with 1N NaOH (183 μL, 0.183 mmol) and stirred. The mixture was diluted with acetonitrile, stirred until the solid was completely dissolved, and then concentrated under reduced pressure to obtain the title compound (white solid, 89.5 mg, 95% yield).
1H NMR (300 MHz, DMSO-d6) δ 7.27 (s, 1H), 7.23-7.7.14 (m, 3H), 6.91-6.86 (m, 2H), 6.70 (d, 2H), 6.47 (d, 2H), 4.19 (s, 2H), 4.10 (t, 2H), 2.47 (m, 5H), 2.35 (m, 4H), 2.14-2.04 (m, 4H), 1.85 (m, 1H), 1.25 (m, 1H), 1.01 (m, 1H), 0.63 (m, 1H).
Example 142
Preparation of sodium 2-((3S)-6-((11-methyl-9-(3-(methylsulfonyl)propoxy)-6,7-dihydro-5H-dibenzo[a,c][7]annulen-2-yl)methoxy)-2,3-dihydrobenzofuran-3-ylacetate




The compound obtained in <7-10> (56.8 mg, 0.103 mmol) was suspended in water (1.2 mL), added with 1N NaOH (108 μL, 0.108 mmol), and then stirred until the solid was completely dissolved. The mixture was diluted with acetonitrile and concentrated under reduced pressure to obtain the title compound (white solid, 56.6 mg, 96% yield).
1H NMR (300 MHz, DMSO-d6) δ 7.26 (m, 3H), 7.04 (d, 1H), 6.76 (d, 1H), 6.69 (d, 1H), 6.41-6.36 (m, 2H), 5.04 (s, 2H), 4.63 (t, 2H), 4.12-4.07 (m, 3H), 3.55 (m, 1H), 3.26 (m, 3H), 3.01 (s, 3H), 2.29 (dd, 2H), 2.15 (m, 6H), 2.05-1.93 (m, 4H).
Example 143
Preparation of sodium (1S,2S)-2-(4-((11-methyl-9-(3-(methylsulfonyl)propoxy)-6,7-dihydrodibenzo[b,d]oxepin-2-yl)methoxy)phenyl)cyclopropanecarboxylate




According to the procedures as described in <142>, the compound obtained in <39-2> was used to prepare the title compound (white solid, 55.1 mg, 94% yield).
1H NMR (300 MHz, DMSO-d6) δ 7.34 (m, 2H), 7.08 (d, 1H), 6.90 (d, 2H), 6.84 (d, 2H), 6.79 (m, 2H), 5.05 (s, 2H), 4.29 (m, 2H), 4.10 (t, 2H), 3.26 (m, 2H), 3.01 (s, 3H), 2.58 (m, 2H), 2.22 (s, 3H), 2.13 (m, 2H), 1.95 (m, 1H), 1.33 (m, 1H), 1.07 (m, 1H), 0.07 (m, 1H).
Example 144
Preparation of sodium (1S,2S)-2-(4-((9-(3-(ethylsulfonyl)propoxy)-11-methyl-6,7-dihydro-5H-dibenzo[a,c][7]annulen-2-yl)methoxy)phenyl)cyclopropanecarboxylate




According to the procedures as described in <142>, the compound obtained in <58-2> was used to prepare the title compound (white solid, 72.6 mg, 95% yield).
1H NMR (300 MHz, DMSO-d6) δ 7.31-7.24 (m, 3H), 6.92 (d, 2H), 6.85 (d, 2H), 6.78 (d, 1H), 6.71 (d, 1H), 5.08 (s, 2H), 4.11 (t, 2H), 3.25 (m, 2H), 3.15 (q, 2H), 2.45 (m, 2H), 2.17 (s, 3H), 2.15 (m, 3H), 1.97 (m, 4H), 1.34 (m, 1H), 1.24 (t, 3H), 1.09 (m, 1H), 1.72 (m, 1H).
Example 145
Sodium (S)-2-(6-(((9-(3-(methylsulfonyl)propoxy)-6,7-dihydro-5H-dibenzo[a,c][7]annulen-2-yl)methyl)amino)-2,3-dihydrobenzofuran-3-ylacetate




According to the procedures as described in <142>, the compound obtained in <82-2> was used to prepare the title compound (white solid, 65.3 mg, 96% yield).
1H NMR (300 MHz, DMSO-d6) δ 7.27 (s, 1H), 7.24-7.15 (m, 3H), 6.92-6.86 (m, 2H), 6.82 (d, 1H), 6.06-6.00 (m, 2H), 5.96 (s, 1H), 4.53 (t, 1H), 4.19 (d, 2H), 4.10 (t, 2H), 4.00 (t, 1H), 3.45 (m, 1H), 3.27 (m, 2H), 3.01 (s, 3H), 2.35 (m, 4H), 2.25 (dd, 1H), 2.18-2.02 (m, 4H), 1.91 (dd, 1H).
Example 146
Preparation of sodium (S)-3-(4-((9-(3-(methylsulfonyl)propoxy)-6,7-dihydro-5H-dibenzo[a,c][7]annulen-2-yl) methoxy)phenyl)hex-4-ynoate




According to the procedures as described in <142>, the compound obtained in <108-10> was used to prepare the title compound (white solid, 45.8 mg, 92% yield).
1H NMR (300 MHz, DMSO-d6) δ 7.35-7.20 (m, 6H), 6.92-6.87 (m, 4H), 5.06 (s, 2H), 4.10 (t, 2H), 3.95 (m, 1H), 3.27 (t, 2H), 3.01 (s, 3H), 2.37 (m, 4H), 2.25 (dd, 1H), 2.16-2.06 (m, 5H), 1.71 (d, 3H).
Example 147
Preparation of sodium (S)-3-(4-((9-((1,1-dioxidotetrahydro-2H-thiopyran-4-yl)methoxy)-6,7-dihydro-5H-dibenzo[a,c][7]annulen-2-yl)methoxy)phenyl)hex-4-ynoate




According to the procedures as described in <142>, the compound obtained in <109-4> was used to prepare the title compound (white solid, 18.6 mg, 99% yield).
1H NMR (300 MHz, DMSO-d6) δ 7.34-7.20 (m, 6H), 6.91-6.87 (m, 4H), 5.06 (s, 2H), 3.95 (m, 1H), 3.90 (d, 2H), 3.18 (m, 2H), 3.05 (m, 2H), 2.36 (m, 4H), 2.25 (dd, 1H), 2.16-2.04 (m, 6H), 1.79 (m, 2H), 1.74 (d, 3H).
The chemical structures of the compounds prepared in the above Examples 1 to 147 are shown in Table 1 below.









TABLE 1





No.
Chemical name
Structure







 1
2-((3S)-6-((11-methyl-9- (3-(methylsulfonyl) propoxy)-6,7-dihydro-5H- dibenzo[a,c][7]annulen-4- yl)methoxy)-2,3- dihydrobenzofuran- 3-yl)acetic acid






 


 2
(1S,2S)-2-(4-((9-(3- (methylsulfonyl) propoxy)-6,7- dihydrodibenzo[b,d] oxepin-2-yl)methoxy)phenyl) cyclopropanecarboxylic acid






 


 3
(1S,2S)-2-(4-(((9-(2- ethoxyethoxy)- 6,7-dihydrodibenzo[b,d] oxepin-2-yl)methyl) amino)phenyl) cyclopropanecarboxylic acid






 


 4
(1S,2S)-2-(4-(((9-(3- (methylsulfonyl) propoxy)-6,7- dihydrodibenzo[b,d] oxepin-2-yl)methyl)amino) phenyl) cyclopropanecarboxylic acid






 


 5
(S)-2-(6-((9-(3-(methylsulfonyl) propoxy)-6,7-dihydro-5H- dibenzo[a,c][7]annulen-2- yl)methoxy)- 2,3-dihydrobenzofuran-3-yl) acetic acid






 


 6
(1S,2S)-2-(4-(((9-(3- (methylsulfonyl) propoxy)-6,7-dihydro-5H- dibenzo[a,c][7]annulen-2-yl) methyl)amino)phenyl) cyclopropanecarboxylic acid






 


 7
2-((3S)-6-((11-methyl-9-(3- (methylsulfonyl)propoxy)-6,7- dihydro-5H-dibenzo[a,c][7] annulen-2-yl)methoxy)-2,3- dihydrobenzofuran-3-yl) acetic acid






 


 8
(1R,2R)-2-(4-(((10-methyl-8-(3- (methylsulfonyl)propoxy)-6H- benzo[c]chromen-4-yl)methyl) amino)phenyl) cyclopropanecarboxylic acid






 


 9
(1S,2S)-2-(4-(((10-methyl-8-(3- (methylsulfonyl)propoxy)-6H- benzo[c]chromen-2-yl)methyl) amino)phenyl) cyclopropanecarboxylic acid






 


10
(S)-2-(6-((5-methyl-7-(3- (methylsulfonyl)propoxy)-9,10- dihydrophenanthren-1-yl)methoxy)- 2,3-dihydrobenzofuran-3-yl) acetic acid






 


11
(S)-2-(6-((5-methyl-7-(3-(methyl- sulfonyl)propoxy)-9,10-dihydro- phenanthren-3-yl)methoxy)-2,3- dihydrobenzofuran-3-yl) acetic acid






 


12
(S)-2-(6-((7-(2-ethoxyethoxy)-5- methyl-9,10-dihydrophenanthren- 3-yl)methoxy)-2,3- dihydrobenzofuran-3-yl) acetic acid






 


13
2-((3S)-6-((11-methyl-9-(3- (methylsulfonyl)propoxy)-6,7- dihydrodibenzo[b,d]oxepin-4- yl)methoxy)-2,3- dihydrobenzofuran-3-yl) acetic acid






 


14
2-((3S)-6-((11-methyl-9-(3- (methylsulfonyl)propoxy)-6,7- dihydrodibenzo[b,d]oxepin-2-yl) methoxy)-2,3-dihydrobenzofuran- 3-yl)acetic acid






 


15
(1S,2S)-2-(4-(((11-methyl-9-(3- (methylsulfonyl)propoxy)-6,7- dihydrodibenzo[b,d]oxepin-2-yl) methyl) amino)phenyl) cyclopropanecarboxylic acid






 


16
(1S,2S)-2-(4-(((8- (2-ethoxyethoxy)- 10-methyl-6H-benzo[c] chromen-2-yl)methyl)amino) phenyl) cyclopropanecarboxylic acid






 


17
(S)-2-(6-((8-(2-ethoxyethoxy)- 10-methyl-6H-benzo[c]chromen- 2-yl)methoxy)-2,3-dihydro- benzofuran-3-yl)acetic acid






 


18
(1S,2S)-2-(4-(((9-(3- (methylsulfonyl) propoxy)-5,7-dihydrodibenzo [c,e]oxepin-2-yl)methyl) amino)phenyl) cyclopropanecarboxylic acid






 


19
(1S,2S)-2-(4-(((11-methyl-9-(3- (methylsulfonyl)propoxy)-5,7- dihydrodibenzo[c,e]oxepin-4-yl) methyl)amino)phenyl) cyclopropanecarboxylic acid






 


20
(S)-2-(6-((9-(3-(methylsulfonyl) propoxy)-5,7-dihydrodibenzo [c,e]oxepin-2-yl)methoxy)-2,3- dihydrobenzofuran-3-yl) acetic acid






 


21
(1S,2S)-2-(4-(((3-(3- (methylsulfonyl)propoxy)-6,7- dihydrodibenzo[b,d] oxepin-10-yl)methyl)amino) phenyl) cyclopropanecarboxylic acid






 


22
(1S,2S)-2-(4-(((9-(2- ethoxyethoxy)- 5,7-dihydrodibenzo[c,e]oxepin- 2-yl)methyl)amino)phenyl) cyclopropanecarboxylic acid






 


23
(S)-2-(6-((9-(2-ethoxyethoxy)- 5,7-dihydrodibenzo[c,e]oxepin- 2-yl)methoxy)-2,3- dihydrobenzofuran-3- yl)acetic acid






 


24
(1S,2S)-2-(4-((9-(3- (methylsulfonyl) propoxy)-5,7-dihydrodibenzo [c,e]oxepin-2-yl)methoxy) phenyl)cyclopropanecarboxylic acid






 


25
(1S,2S)-2-(4-((9-(3- (methylsulfonyl) propoxy)-6,7-dihydro-5H- dibenzo[a,c][7]annulen-2-yl) methoxy)phenyl) cyclopropanecarboxylic acid






 


26
(S)-2-(6-((10-methyl-8-(3- (methylsulfonyl)propoxy)-6H- benzo[c]chromen-2-yl)methoxy)- 2,3-dihydrobenzofuran-3-yl) acetic acid






 


27
(S)-2-(6-((9-(2-ethoxyethoxy)- 6,7-dihydro-5H-dibenzo[a,c][7] annulen-2-yl)methoxy)-2,3- dihydrobenzofuran-3-yl) acetic acid






 


28
(1S,2S)-2-(4-(((9-(2- ethoxyethoxy)- 6,7-dihydro-5H-dibenzo[a,c] [7]annulen-2-yl)methyl)amino) phenyl)cyclopropanecarboxylic acid






 


29
(1S,2S)-2-(4-(((11-methyl-9-(3- (methylsulfonyl)propoxy)-6,7- dihydro-5H-dibenzo[a,c][7] annulen-2-yl)methyl)amino) phenyl) cyclopropanecarboxylic acid






 


30
(1S,2S)-2-(4-((10-methyl-8-(3- (methylsulfonyl)propoxy)-6H- benzo[c]chromen-2-yl)methoxy) phenyl) cyclopropanecarboxylic acid






 


31
(1S,2S)-2-(4-((5-methyl-7-(3- (methylsulfonyl)propoxy)-9,10- dihydrophenanthren-3-yl) methoxy)phenyl) cyclopropanecarboxylic acid






 


32
(S)-2-(6-((9-(3-(methylsulfonyl) propoxy)-6,7-dihydrodibenzo [b,d]oxepin-2-yl)methoxy)-2,3- dihydrobenzofuran-3-yl) acetic acid






 


33
2-((3S)-6-((11-methyl-9-(3- (methylsulfonyl)propoxy)-5,7- dihydrodibenzo[c,e]oxepin-2-yl) methoxy)-2,3-dihydrobenzofuran- 3-yl)acetic acid






 


34
(1S,2S)-2-(4-(((11-methyl-9-(3- (methylsulfonyl)propoxy)-5,7- dihydrodibenzo[c,e]oxepin-2-yl) methyl)amino)phenyl) cyclopropanecarboxylic acid






 


35
2-((3S)-6-((9-(2-ethoxyethoxy)- 11-methyl-6,7-dihydro-5H- dibenzo[a,c][7]annulen-2-yl) methoxy)-2,3- dihydrobenzofuran-3-yl) acetic acid






 


36
2-((3S)-6-((9-((1,1- dioxidotetrahydro-2H- thiopyran-4-yl)oxy)-11- methyl-6,7-dihydrodibenzo [b,d]oxepin-2-yl)methoxy)- 2,3-dihydrobenzofuran-3-yl) acetic acid






 


37
2-((3S)-6-((9-(2-(1,1- dioxidothiomorpholino)ethoxy)- 11-methyl-6,7- dihydrodibenzo[b,d] oxepin-2-yl)methoxy)-2,3- dihydrobenzofuran-3-yl) acetic acid






 


38
2-((3S)-6-((9-(3-(ethylsulfonyl) propoxy)-11-methyl-6,7- dihydrodibenzo[b,d]oxepin-2-yl) methoxy)-2,3- dihydrobenzofuran-3- yl)acetic acid






 


39
(1S,2S)-2-(4-((11-methyl-9-(3- (methylsulfonyl)propoxy)-6,7- dihydrodibenzo[b,d]oxepin-2-yl) methoxy)phenyl) cyclopropanecarboxylic acid






 


40
(1S,2S)-2-(2-fluoro-4-((11- methyl-9-(3-(methylsulfonyl) propoxy)-6,7-dihydrodibenzo[b,d] oxepin-2-yl)methoxy)phenyl) cyclopropanecarboxylic acid






 


41
(1S,2S)-2-(4-((9-(3- (ethylsulfonyl)propoxy)- 11-methyl-6,7- dihydrodibenzo[b,d] oxepin-2-yl)methoxy)-2- fluorophenyl) cyclopropanecarboxylic acid






 


42
(S)-2-(6-((3-(3-(methylsulfonyl) propoxy)-6,7-dihydrodibenzo [b,d]oxepin-10-yl)methoxy)-2,3- dihydrobenzofuran-3- yl)acetic acid






 


43
(S)-2-(6-((6,6-dimethyl-9-(3- (methylsulfonyl)propoxy)-6,7- dihydrodibenzo[b,d]oxepin-2-yl) methoxy)-2,3- dihydrobenzofuran-3- yl)acetic acid






 


44
(S)-2-(6-((5-ethyl-9-(3- (methylsulfonyl)propoxy)-6,7- dihydro-5H-dibenzo[b,d] azepin-2-yl)methoxy)-2,3- dihydrobenzofuran-3- yl)acetic acid






 


45
(1S,2S)-2-(4-((5-ethyl-9-(3- (methylsulfonyl)propoxy)-6,7- dihydro-5H-dibenzo[b,d] azepin-2-yl)methoxy)phenyl) cyclopropanecarboxylic acid






 


46
2-((3S)-6-((9-((4-hydroxy-1,1- dioxidotetrahydro-2H-thiopyran- 4-yl)methoxy)-11-methyl-6,7- dihydrodibenzo[b,d]oxepin-2-yl) methoxy)-2,3-dihydrobenzofuran- 3-yl)acetic acid






 


47
2-((3S)-6-((9-((1,1- dioxidotetrahydro-2H- thiopyran-4-yl)methoxy)-11- methyl-6,7-dihydrodibenzo[b,d] oxepin-2-yl)methoxy)-2,3- dihydrobenzofuran-3-yl) acetic acid






 


48
(1S,2S)-2-(4-((9-((1,1- dioxidotetrahydro-2H- thiopyran-4-yl)oxy)-11-methyl- 6,7-dihydrodibenzo[b,d]oxepin- 2-yl)methoxy)phenyl) cyclopropanecarboxylic acid






 


49
(1S,2S)-2-(4-((9-(3-(ethylsulfonyl) propoxy)-11-methyl-6,7- dihydrodibenzo[b,d]oxepin-2- yl)methoxy)phenyl) cyclopropanecarboxylic acid






 


50
(1S,2S)-2-(4-((9-((1,1- dioxidotetrahydro-2H-thiopyran- 4-yl)oxy)-11-methyl-6,7- dihydrodibenzo[b,d]oxepin-2- yl)methoxy)-2-fluorophenyl) cyclopropanecarboxylic acid






 


51
(1S,2S)-2-{2-fluoro-4-[9-(4- hydroxy-1,1-dioxido-hexahydro- thiopyran-4-ylmethoxy)-11- methyl-6,7-dihydro-5- oxa-dibenzo[a,c] cyclohepten-2-ylmethoxy]- phenyl}- cyclopropanecarboxylic acid






 


52
(1S,2S)-2-(4-(((9-((1,1- dioxidotetrahydro-2H-thiopyran- 4-yl)oxy)-11-methyl-6,7- dihydrodibenzo[b,d] oxepin-2-yl)methyl)amino)-2- fluorophenyl) cyclopropanecarboxylic acid






 


53
(1S,2S)-2-(4-(((9-(3- (ethylsulfonyl) propoxy)-11-methyl-6,7- dihydrodibenzo[b,d]oxepin- 2-yl)methyl)amino)-2- fluorophenyl) cyclopropanecarboxylic acid






 


54
2-((3S)-6-((6,6,11-trimethyl-9- (3-(methylsulfonyl)propoxy)- 6,7-dihydrodibenzo[b,d]oxepin- 2-yl)methoxy)-2,3- dihydrobenzofuran-3-yl) acetic acid






 


55
2-((3S)-6-((9-((1,1- dioxidotetrahydro-2H-thiopyran- 4-yl)oxy)-11-methyl-6,7-dihydro- 5H-dibenzo[a,c][7] annulen-2-yl)methoxy)-2,3- dihydrobenzofuran-3- yl)acetic acid






 


56
2-((3S)-6-((9-((4-hydroxy-1,1- dioxidotetrahydro-2H-thiopyran- 4-yl)methoxy)-11-methyl-6,7- dihydro-5H- dibenzo[a,c][7]annulen- 2-yl)methoxy)-2,3-dihydro- benzofuran-3-yl)acetic acid






 


57
2-((3S)-6-((9-(3-(ethylsulfonyl) propoxy)-11-methyl-6,7- dihydro-5H-dibenzo[a,c][7] annulen-2-yl)methoxy)-2,3- dihydrobenzofuran-3-yl) acetic acid






 


58
(1S,2S)-2-(4-((11-methyl-9-(3- (methylsulfonyl)propoxy)-6,7- dihydro-5H-dibenzo[a,c][7] annulen-2-yl)methoxy)phenyl) cyclopropanecarboxylic acid






 


59
(1S,2S)-2-(4-((9-((1,1- dioxidotetrahydro-2H- thiopyran-4-yl)oxy)-11- methyl-6,7-dihydro-5H- dibenzo[a,c][7]annulen- 2-yl)methoxy)phenyl) cyclopropanecarboxylic acid






 


60
(1S,2S)-2-(4-((9-((4-hydroxy- 1,1-dioxidotetrahydro-2H- thiopyran-4-yl)methoxy)-11- methyl-6,7-dihydro-5H- dibenzo[a,c][7] annulen-2-yl)methoxy)phenyl) cyclopropanecarboxylic acid






 


61
(1S,2S)-2-(4-((9-(3- (ethylsulfonyl) propoxy)-11-methyl-6,7- dihydro-5H-dibenzo[a,c][7] annulen-2-yl)methoxy)phenyl) cyclopropanecarboxylic acid






 


62
(1S,2S)-2-(2-fluoro-4-((9-((4- hydroxy-1,1-dioxidotetrahydro- 2H-thiopyran-4-yl)methoxy)-11- methyl-6,7-dihydro-5H-dibenzo [a,c][7]annulen-2-yl) methoxy)phenyl) cyclopropanecarboxylic acid






 


63
(1S,2S)-2-(2-fluoro-4-(((9-((4- hydroxy-1,1-dioxidotetrahydro- 2H-thiopyran-4-yl)methoxy)-11- methyl-6,7-dihydro-5H-dibenzo [a,c][7]annulen-2-yl) methyl)amino)phenyl) cyclopropanecarboxylic acid






 


64
(S)-2-(6-((9-((1,1- dioxidotetrahydro-2H- thiopyran-4-yl)oxy)-6,7- dihydro-5H-dibenzo[a,c][7] annulen-2-yl)methoxy)-2,3- dihydrobenzofuran-3-yl) acetic acid






 


65
(S)-2-(6-((9-((4-hydroxy-1,1- dioxidotetrahydro-2H-thiopyran- 4-yl)methoxy)-6,7-dihydro-5H- dibenzo[a,c][7]annulen-2-yl) methoxy)-2,3- dihydrobenzofuran- 3-yl)acetic acid






 


66
(S)-2-(6-((9-(3-(ethylsulfonyl) propoxy)-6,7-dihydro-5H- dibenzo[a,c][7]annulen-2-yl) methoxy)-2,3- dihydrobenzofuran- 3-yl)acetic acid






 


67
(1S,2S)-2-(4-((9-((1,1- dioxidotetrahydro-2H- thiopyran-4-yl)oxy)-6,7- dihydro-5H-dibenzo[a,c] [7]annulen-2-yl)methoxy) phenyl) cyclopropanecarboxylic acid






 


68
(1S,2S)-2-(4-((9-((4-hydroxy-1,1- dioxidotetrahydro-2H- thiopyran-4- yl)methoxy)-6,7-dihydro-5H- dibenzo[a,c][7]annulen-2- yl)methoxy)phenyl) cyclopropanecarboxylic acid






 


69
(1S,2S)-2-(4-((9-(3- (ethylsulfonyl) propoxy)-6,7-dihydro-5H- dibenzo[a,c][7]annulen- 2-yl)methoxy)phenyl) cyclopropanecarboxylic acid






 


70
(1S,2S)-2-(4-(((9-((1,1- dioxidotetrahydro-2H- thiopyran-4-yl)oxy)-6,7- dihydro-5H-dibenzo[a,c] [7]annulen-2-yl)methyl) amino)phenyl) cyclopropanecarboxylic acid






 


71
(1S,2S)-2-(4-(((9-((4-hydroxy- 1,1-dioxidotetrahydro-2H- thiopyran-4-yl)methoxy)- 6,7-dihydro-5H- dibenzo[a,c][7]annulen- 2-yl)methyl)amino)phenyl) cyclopropanecarboxylic acid






 


72
(1S,2S)-2-(4-(((9-(3- (ethylsulfonyl) propoxy)-6,7-dihydro-5H- dibenzo[a,c][7]annulen- 2-yl)methyl)amino)phenyl) cyclopropanecarboxylic acid






 


73
(1S,2S)-2-(4-(((9-((1,1- dioxidotetrahydro-2H- thiopyran-4-yl)oxy)-11- methyl-6,7- dihydrodibenzo[b,d] oxepin-2-yl)methyl)amino) phenyl) cyclopropanecarboxylic acid






 


74
(1S,2S)-2-(4-(((9-(3- (ethylsulfonyl)propoxy)-11- methyl-6,7-dihydro-5H- dibenzo[a,c][7]annulen- 2-yl)methyl)amino)phenyl) cyclopropanecarboxylic acid






 


75
(1S,2S)-2-(4-(((9-((1,1- dioxidotetrahydro-2H- thiopyran-4-yl)methoxy)-11- methyl-6,7-dihydro-5H- dibenzo[a,c][7]annulen- 2-yl)methyl)amino)phenyl) cyclopropanecarboxylic acid






 


76
(1S,2S)-2-(4-(((9-((1,1- dioxidotetrahydro-2H-thiopyran- 4-yl)oxy)-11-methyl-6,7-dihydro- 5H-dibenzo[a,c][7]annulen- 2-yl)methyl)amino)phenyl) cyclopropanecarboxylic acid






 


77
(1S,2S)-2-(4-(((9-((4-hydroxy- 1,1-dioxidotetrahydro-2H- thiopyran-4-yl)methoxy)-11- methyl-6,7-dihydro- 5H-dibenzo[a,c][7]annulen- 2-yl)methyl)amino)phenyl) cyclopropanecarboxylic acid






 


78
(1S,2S)-2-(4-(((9-((1,1- dioxidotetrahydro-2H-thiopyran- 4-yl)methoxy)-6,7-dihydro-5H- dibenzo[a,c][7]annulen- 2-yl)methyl)amino)phenyl) cyclopropanecarboxylic acid






 


79
2-((S)-6-(((R)-6-methyl-9-(3- (methylsulfonyl)propoxy)-6,7- dihydrodibenzo[b,d]oxepin- 2-yl)methoxy)-2,3- dihydrobenzofuran- 3-yl)acetic acid






 


80
(S)-2-(6-((9-(3-(methylsulfonyl) propoxy)dibenzo[d,f][1,3] dioxepin-2-yl)methoxy)-2,3- dihydrobenzofuran-3-yl) acetic acid






 


81
2-((3S)-6-((1-methyl-3- morpholino-6,7-dihydro-5H- benzo[3,4]cyclohepta [1,2-d]pyrimidin-10-yl) methoxy)-2,3- dihydrobenzofuran- 3-yl)acetic acid






 


82
(S)-2-(6-(((9-(3-(methylsulfonyl) propoxy)-6,7-dihydro-5H- dibenzo[a,c][7]annulen-2-yl) methyl)amino)-2,3- dihydrobenzofuran-3-yl) acetic acid






 


83
(S)-2-(6-(((9-((1,1- dioxidotetrahydro-2H- thiopyran-4-yl)methoxy)-6,7- dihydro-5H-dibenzo[a,c] [7]annulen-2-yl)methyl)amino)- 2,3-dihydrobenzofuran-3-yl) acetic acid






 


84
(S)-2-(6-((9-((1,1- dioxidotetrahydro-2H- thiopyran-4-yl)methoxy)- 6,7-dihydro-5H-dibenzo [a,c][7]annulen-2-yl) methoxy)-2,3- dihydrobenzofuran-3-yl) acetic acid






 


85
(S)-2-(6-((9-((1,1- dioxidotetrahydro-2H- thiopyran-4-yl)methoxy)-3- fluoro-6,7-dihydro-5H-dibenzo [a,c][7]annulen-2-yl) methoxy)-2,3-dihydro- benzofuran-3-yl)acetic acid






 


86
(1S,2S)-2-(4-(((9-((1,1- dioxidotetrahydro-2H-thiopyran- 4-yl)methoxy)-3-fluoro-6,7- dihydro-5H-dibenzo[a,c] [7]annulen-2-yl)methyl) amino)phenyl) cyclopropanecarboxylic acid






 


87
(1S,2S)-2-(4-(((9-(3- (ethylsulfonyl)propoxy)- 11-methyl-6,7- dihydrodibenzo[b,d] oxepin-2-yl)methyl)amino) phenyl) cyclopropanecarboxylic acid






 


88
2-((3S)-6-((9-(2-ethoxyethoxy)- 11-methyl-6,7-dihydrodibenzo [b,d]oxepin-2-yl)methoxy)- 2,3-dihydrobenzofuran-3-yl) acetic acid






 


89
(1S,2S)-2-(4-((1-methyl-3- morpholino-6,7-dihydro-5H- benzo[3,4]cyclohepta[1,2-d] pyrimidin-10-yl) methoxy)phenyl) cyclopropanecarboxylic acid






 


90
2-((3S)-6-((1-methyl-3-(3- (methylsulfonyl)propoxy)-6,7- dihydro-5H-benzo[3,4] cyclohepta[1,2-d]pyrimidin- 10-yl)methoxy)-2,3- dihydrobenzofuran- 3-yl)acetic acid






 


91
(S)-2-(6-(((9-(2-ethoxyethoxy)- 6,7-dihydro-5H-dibenzo[a,c][7] annulen-2-yl)methyl)amino)- 2,3-dihydrobenzofuran-3-yl) acetic acid






 


92
(S)-2-(6-(((9-(3-(ethylsulfonyl) propoxy)-6,7-dihydro-5H- dibenzo[a,c][7] annulen-2-yl)methyl) amino)-2,3- dihydrobenzofuran- 3-yl)acetic acid






 


93
(S)-2-(6-((9-((4-methyl-1,1- dioxidotetrahydro-2H-thiopyran- 4-yl)methoxy)-6,7-dihydro-5H- dibenzo[a,c][7]annulen-2- yl)methoxy)-2,3- dihydrobenzofuran- 3-yl)acetic acid






 


94
(1S,2S)-2-(4-(((9-((4-methyl-1,1- dioxidotetrahydro-2H-thiopyran- 4-yl)methoxy)-6,7-dihydro- 5H-dibenzo[a,c][7]annulen-2-yl) methyl)amino)phenyl) cyclopropanecarboxylic acid






 


95
(S)-2-(6-((3-fluoro-9- ((4-methyl-1,1- dioxidotetrahydro-2H- thiopyran-4-yl)methoxy)- 6,7-dihydro-5H- dibenzo[a,c][7]annulen-2- yl)methoxy)-2,3- dihydrobenzofuran- 3-yl)acetic acid






 


96
(S)-2-(6-((3-fluoro-9-(3-(methyl- sulfonyl)propoxy)-6,7-dihydro- 5H-dibenzo[a,c][7]annulen- 2-yl)methoxy)-2,3- dihydrobenzofuran- 3-yl)acetic acid






 


97
(S)-2-(6-((9-(3-(ethylsulfonyl) propoxy)-3-fluoro-6,7-dihydro- 5H-dibenzo[a,c][7]annulen-2- yl)methoxy)-2,3- dihydrobenzofuran- 3-yl)acetic acid






 


98
(S)-2-(6-((9-((1,1- dioxidotetrahydro- 2H-thiopyran-4-yl)oxy)-3- fluoro-6,7-dihydro-5H- dibenzo[a,c][7] annulen-2-yl)methoxy)-2,3- dihydrobenzofuran-3-yl) acetic acid






 


99
(S)-2-(6-((3-fluoro-9-((4- hydroxy-1,1-dioxidotetrahydro- 2H-thiopyran- 4-yl)methoxy)-6,7-dihydro-5H- dibenzo[a,c][7]annulen-2- yl)methoxy)-2,3-dihydrobenzo- furan-3-yl)acetic acid






 


100 
(1S,2S)-2-(4-((9-((1,1- dioxidotetrahydro-2H-thiopyran- 4-yl)oxy)-3-fluoro-6,7-dihydro- 5H-dibenzo[a,c][7]annulen-2-yl) methoxy)phenyl) cyclopropanecarboxylic acid






 


101 
(1S,2S)-2-(4-((3-fluoro-9-((4- hydroxy-1,1-dioxidotetrahydro- 2H-thiopyran-4-yl)methoxy)- 6,7-dihydro- 5H-dibenzo[a,c][7]annulen- 2-yl)methoxy)phenyl) cyclopropanecarboxylic acid






 


102 
(1S,2S)-2-(4-((3-fluoro-9-(3- (methylsulfonyl)propoxy)- 6,7-dihydro- 5H-dibenzo[a,c][7]annulen- 2-yl)methoxy)phenyl) cyclopropanecarboxylic acid






 


103 
(1S,2S)-2-(4-((9-((1,1- dioxidotetrahydro-2H- thiopyran-4-yl)methoxy)-3- fluoro-6,7-dihydro-5H-dibenzo [a,c][7]annulen-2-yl) methoxy)phenyl) cyclopropanecarboxylic acid






 


104 
(1S,2S)-2-(4-(((3-fluoro-9-(3- (methylsulfonyl)propoxy)-6,7- dihydro-5H-dibenzo[a,c][7] annulen-2-yl)methyl)amino) phenyl)cyclopropanecarboxylic acid






 


105 
(1S,2S)-2-(4-(((9-(3- (ethylsulfonyl) propoxy)-3-fluoro- 6,7-dihydro-5H- dibenzo[a,c][7]annulen- 2-yl)methyl)amino)phenyl) cyclopropanecarboxylic acid






 


106 
2-((S)-6-((3-fluoro-9-(((R)- tetrahydrofuran-3- yl)oxy)-6,7-dihydro- 5H-dibenzo[a,c][7] annulen-2-yl)methoxy)-2,3- dihydrobenzofuran-3-yl) acetic acid






 


107 
(S)-2-(6-((3-fluoro-9-(2- morpholinoethoxy)-6,7-dihydro- 5H-dibenzo[a,c][7]annulen-2-yl) methoxy)-2,3- dihydrobenzofuran- 3-yl)acetic acid






 


108 
(S)-3-(4-((9-(3-(methylsulfonyl) propoxy)-6,7-dihydro-5H- dibenzo[a,c][7]annulen-2-yl) methoxy)phenyl) hex-4-ynoic acid






 


109 
(S)-3-(4-((9-((1,1- dioxidotetrahydro-2H-thiopyran- 4-yl)methoxy)-6,7-dihydro-5H- dibenzo[a,c][7]annulen- 2-yl)methoxy)phenyl)hex- 4-ynoic acid






 


110 
(S)-3-(4-((9-((1,1- dioxidotetrahydro-2H- thiopyran-4- yl)oxy)-6,7-dihydro- 5H-dibenzo [a,c][7]annulen-2-yl) methoxy)phenyl) hex-4-ynoic acid






 


111 
(S)-3-(4-((9-(3-(ethylsulfonyl) propoxy)-6,7-dihydro-5H- dibenzo[a,c][7]annulen-2-yl) methoxy)phenyl) hex-4-ynoic acid






 


112 
(S)-3-(4-((9-((1,1- dioxidotetrahydro-2H-thiopyran- 4-yl)methoxy)-3-fluoro-6,7- dihydro-5H-dibenzo[a,c][7] annulen-2-yl)methoxy)phenyl) hex-4-ynoic acid






 


113 
(S)-3-(4-((9-((1,1- dioxidotetrahydro-2H- thiopyran-4-yl)methoxy)- 6,7-dihydrodibenzo [b,d]oxepin-2-yl)methoxy) phenyl)hex-4-ynoic acid






 


114 
(S)-3-(4-((3-((1,1- dioxidotetrahydro-2H-thiopyran- 4-yl)methoxy)-6,7-dihydro-5H- benzo[3,4]cyclohepta[1,2-b] pyridin-10-yl)methoxy)phenyl) hex-4-ynoic acid






 


115 
(R)-3-cyclopropyl-3-(3-((9- ((1,1-dioxidotetrahydro- 2H-thiopyran-4- yl)methoxy)-6,7-dihydro-5H- dibenzo[a,c][7]annulen-2-yl) methoxy)phenyl)propanoic acid






 


116 
3-cyclopropyl-3-(4-((9-((1,1- dioxidotetrahydro-2H- thiopyran-4-yl)methoxy)- 6,7-dihydro-5H- dibenzo[a,c][7]annulen-2- yl)methoxy)phenyl) propanoic acid






 


117 
(S)-3-(4-((9-((1,1- dioxidotetrahydro-2H- thiopyran-4-yl) methoxy)-6,7-dihydro-5H- dibenzo[a,c][7]annulen- 2-yl)methoxy)phenyl) hexanoic acid






 


118 
(R,Z)-3-(4-((9-((1,1- dioxidotetrahydro-2H- thiopyran-4-yl) methoxy)-6,7-dihydro-5H- dibenzo[a,c][7]annulen- 2-yl)methoxy)phenyl)hex-4- enoic acid






 


119 
(S)-3-(4-((9-((1,1- dioxidotetrahydro-2H-thiopyran- 4-yl)methoxy)-6,7-dihydro-5H- dibenzo[a,c][7]annulen- 2-yl)methoxy)phenyl)-3-(5- methylisoxazol-3-yl) propanoic acid






 


120 
(S)-3-(4-((9-((1,1- dioxidotetrahydro-2H-thiopyran- 4-yl)methoxy)-6,7-dihydro-5H- dibenzo[a,c][7]annulen- 2-yl)methoxy)phenyrol)-3- (isoxazol-3-yl)propanoic acid






 


121 
3-(4-((9-((1,1- dioxidotetrahydro-2H-thiopyran- 4-yl)methoxy)-6,7-dihydro- 5H-dibenzo[a,c][7] annulen-2-yl)methoxy)phenyl)- 3-(3-methylisoxazol-5-yl) propanoic acid






 


122 
(S)-3-(4-((3-(3-(methylsulfonyl) propoxy)-6,7-dihydro-5H-benzo [3,4]cyclohepta[1,2-b]pyridin- 10-yl)methoxy)phenyl)hex-4- ynoic acid






 


123 
(S)-3-(4-((3-(3-(ethylsulfonyl) propoxy)-6,7-dihydro-5H-benzo [3,4]cyclohepta[1,2-b]pyridin- 10-yl)methoxy)phenyl)hex-4- ynoic acid






 


124 
(S)-3-(4-((3-((1,1- dioxidotetrahydro-2H-thiopyran- 4-yl)oxy)-6,7-dihydro-5H-benzo [3,4]cyclohepta[1,2-b] pyridin-10-yl)methoxy)phenyl) hex-4-ynoic acid






 


125 
(S)-3-(4-((5-methyl-7-(3- (methylsulfonyl)propoxy)- 9,10-dihydrophenanthren-3- yl)methoxy) phenyl)hex-4-ynoic acid






 


126 
(S)-3-(4-((7-(2-ethoxyethoxy)- 5-methyl-9,10- dihydrophenanthren- 3-yl)methoxy)phenyl)hex-4- ynoic acid






 


127 
(S)-3-(4-((5-methyl-7-(3- (methylsulfonyl)propoxy)-9,10- dihydrophenanthren-1-yl) methoxy)phenyl)hex-4- ynoic acid






 


128 
(S)-3-(4-((11-methyl-9-(3- (methylsulfonyl)propoxy)-6,7- dihydro-5H-dibenzo[a,c][7] annulen-2-yl)methoxy)phenyl) hex-4-ynoic acid






 


129 
(S)-3-(4-((9-(3-(methylsulfonyl) propoxy)dibenzo[d,f][1,3] dioxepin-2-yl)methoxy)phenyl) hex-4-ynoic acid






 


130 
(S)-3-(4-((6,6-dimethyl-9-(3- (methylsulfonyl)propoxy)-6,7- dihydrodibenzo[b,d]oxepin-2- yl)methoxy)phenyl)hex-4- ynoic acid






 


131 
(S)-3-(4-((1-methyl-3-(3- (methylsulfonyl)propoxy)-6,7- dihydro-5H-benzo[3,4] cyclohepta[1,2-d]pyrimidin-10- yl)methoxy)phenyl)hex-4- ynoic acid






 


132 
(S)-3-(4-((9-((1,1- dioxidotetrahydro-2H-thiopyran- 4-yl)methoxy)-6,7-dihydro-5H- dibenzo[a,c][7] annulen-2-yl)methoxy) phenyl)butanoic acid






 


133 
(R)-3-(4-((9-((1,1- dioxidotetrahydro-2H-thiopyran- 4-yl)methoxy)-6,7-dihydro-5H- dibenzo[a,c][7]annulen- 2-yl)methoxy)phenyl) butanoic acid






 


134 
(S)-3-(4-((9-((1,1- dioxidotetrahydro-2H- thiopyran-4-yl)methoxy)- 6,7-dihydro-5H-dibenzo[a,c] [7]annulen-2-yl)methoxy) phenyl)-4-ethoxybutanoic acid






 


135 
(S)-3-(4-(((9-(3- (methylsulfonyl)propoxy)-6,7- dihydro-5H-dibenzo[a,c] [7]annulen-2-yl)methyl) amino)phenyl)hex-4-ynoic acid






 


136 
(S)-3-(4-(((9-((1,1- dioxidotetrahydro-2H-thiopyran- 4-yl)methoxy)-6,7-dihydro- 5H-dibenzo[a,c][7] annulen-2-yl)methyl)amino) phenyl)hex-4-ynoic acid






 


137 
3-(4-((9-((1,1- dioxidotetrahydro-2H- thiopyran-4-yl)methoxy)-6,7- dihydro-5H-dibenzo[a,c][7] annulen-2-yl)methoxy)phenyl)- 3-(4-fluorophenyl) propanoic acid






 


138 
(S)-3-(4-((11-methyl-9-(((R)- tetrahydrofuran-3-yl)oxy)-6,7- dihydro-5H-dibenzo[a,c][7] annulen-2-yl)methoxy)phenyl) hex-4-ynoic acid






 


139 
(R)-3-(4-((9-((1,1- dioxidotetrahydro-2H- thiopyran-4-yl)methoxy)- 6,7-dihydro-5H-dibenzo[a,c] [7]annulen-2-yl)methoxy) phenyl)pent-4-ynoic acid






 


140 
(S)-3-(4-((5-ethyl-9-(((R)- tetrahydrofuran-3-yl)oxy)-6,7- dihydro-5H-dibenzo[b,d] azepin-2-yl)methoxy)phenyl) hex-4-ynoic acid






 


141 
Sodium (1S,2S)-2-(4-(((9- (3-(methylsulfonyl)propoxy)- 6,7-dihydro-5H-dibenzo [a,c][7]annulen-2-yl) methyl)amino)phenyl) cyclopropanecarboxylate






 


142 
Sodium 2-((3S)-6-((11- methyl-9-(3-(methylsulfonyl) propoxy)-6,7-dihydro-5H- dibenzo[a,c][7]annulen- 2-yl)methoxy)-2,3- dihydrobenzofuran-3-ylacetate






 


143 
Sodium (1S,2S)-2-(4-((11- methyl-9-(3-(methylsulfonyl) propoxy)- 6,7-dihydrodibenzo[b,d] oxepin-2-yl)methoxy)phenyl) cyclopropanecarboxylate






 


144 
Sodium (1S,2S)-2-(4-((9-(3- (ethylsulfonyl)propoxy)-11- methyl-6,7-dihydro-5H- dibenzo[a,c][7]annulen-2-yl) methoxy)phenyl) cyclopropanecarboxylate






 


145 
Sodium (S)-2-(6-(((9-(3- (methylsulfonyl)propoxy)-6,7- dihydro-5H-dibenzo[a,c] [7]annulen-2-yl)methyl) amino)-2,3-dihydrobenzofuran- 3-ylacetate






 


146 
Sodium (S)-3-(4-((9-(3- (methylsulfonyl)propoxy)-6,7- dihydro-5H-dibenzo[a,c][7] annulen-2-yl)methoxy)phenyl) hex-4-ynoate






 


147 
Sodium (S)-3-(4-((9- ((1,1-dioxidotetrahydro-2H- thiopyran-4-yl)methoxy)-6,7- dihydro-5H-dibenzo[a,c] [7]annulen-2-yl)methoxy) phenyl)hex-4-ynoate













Test Example 1
Measurement of 50% Inhibitory Concentration (ID50) for GPR40 Agonist Binding
To examine the efficacy of the compounds according to one exemplary embodiment of the present invention in modulating GPR40, the half maximal inhibitory concentrations (IC50) of the compounds according to one exemplary embodiment of the present invention were measured by Microbeta2TM (PerkinElmer Inc.) using a change in radiation dose emitted from 3H-labeled propanoic acid (i.e., 3-(4-((2,6′-dimethyl-6-((4-(3H))-phenylmethoxy)biphenyl-3-yl)methoxy)phenyl)propanoic acid), which is a radioactive isotope which binds to a human GPR40 protein, as an indicator.
Specifically, a test compound was prepared by serial dilution with DMSO, and 100 μL of a binding buffer (including 25 mM HEPES (pH 7.5), 5 mM MgCl2, 100 mM NaCl, and 0.1% free fatty acid BSA; Sigma-Aldrich Corp.) was put into each well of a 96-well transparent plate. Thereafter, each of the diluted compound, propanoic acid which was prepared by dissolving propanoic acid in DMSO to a concentration of 500 mM and not labeled with a radioactive isotope, and DMSO was dispensed at 5 μL per well. 3H-labeled propanoic acid was dissolved in a binding buffer at a concentration of 1 nM and dispensed at 50 μL into the corresponding wells, and a membrane protein including a human GPR40 protein was dissolved in a binding buffer at a concentration of 20 μg/well and dispensed at 100 μL, into the corresponding wells.
After the dispensation was completed, the plate was incubated at a temperature of 25° C. and a rotary speed of 230 rpm for 2 hours while shaking. A human GPR40 complex was transferred to Filtermat A (PerkinElmer Inc.) using a cell harvester (PerkinElmer Inc.), washed 10 times with 50 mM tris-HCl, dried, and then scintillated using Meltilex (PerkinElmer Inc.). Thereafter, an emitted radiation dose was measured using Microbeta2TM. The radiation doses emitted from the complex in the well containing 10 mM unlabeled propanoic acid and the complex in the well containing DMSO alone were set as 0% and 100%, respectively. Thus, a change curve for each of the radiation doses was plotted to calculate the half maximal inhibitory concentration of the test compound. The test results are listed in Table 2.










TABLE 2








Half maximal




inhibitory



Compound
concentration (nM)



















Example 1
157.8



Example 6
116.2



Example 14
17.7



Example 18
752.1



Example 25
102.8



Example 31
45.7



Example 38
39.1



Example 41
125.0



Example 44
75.7



Example 47
53.1



Example 59
71.0



Example 61
26.6



Example 65
159.8



Example 76
14.7



Example 79
84.4



Example 81
180.7



Example 93
50.5



Example 105
16.2



Example 108
9.6



Example 109
5.6










As listed in Table 2, it was revealed that the compounds according to one exemplary embodiment of the present invention inhibited the binding of propanoic acid to GRP40 at a low concentration.
Test Example 2
Measurement of Hypoglycemic Rate in Rats
An effect of the compound according to one exemplary embodiment of the present invention on blood glucose inhibition after glucose loading was examined in male ZFDM rats (Japan SLC, Inc.).
Specifically, male ZFDM rats (7 week-old) pre-fed for a week were fasted overnight, and used as an animal to be tested. A test compound was prepared into a 0.5% methylcellulose suspension, which was orally administered to rats at a dose of 0.1 to 30 mg/kg before an hour of glucose loading (1.5 g/kg). As the control, 0.5% methylcellulose was administered. After the glucose administration, blood was drawn from the rats' tails after 0, 15, 30, 60 and 120 minutes to measure a blood glucose level. The area under the curve (AUC) for compound treatment was calculated using a blood glucose change profile from t=0 to 120 minutes, and a hypoglycemic rate (%) for the control was calculated. The results are listed in the following Table 3.










TABLE 3







Compound
Hypoglycemic rate (%)









Example 6
18.0



Example 26
31.0



Example 57
21.7



Example 78
27.4



Example 108
37.5










As listed in Table 3, it can be seen that the compounds according to one exemplary embodiment of the present invention had a hypoglycemic effect.

## Claims

1. A compound selected from the group consisting of a tricyclic compound of Formula I, and a pharmaceutically acceptable salt, isomer, and solvate thereof:



wherein
V and W are each independently ═C(R14)—, or ═N—;
X is —CH2—, —O—, —O—CH2—O—, —S—, —C(═O)—, —S(═O)—, —S(═O)2—, or —NR15—;
Y is a C1-6 alkylene;
Z is —O—, —S—, —C(═O)—, —S(═O)—, —S(═O)2—, or —NR15—;
Ar is one of the following substituents (a) to (c),




wherein A is —CH2—, —CF2—, —O—, —NR15—, —S—, —S(═O)—, —S(═O)2—, —C(═O)—, or —CH(OR15)—;
B is a C1-3 alkylene;
R1 is hydrogen, a halogen, hydroxy, amino, nitro, cyano, a C1-6 alkyl, a C1-10 alkoxy, a C1-6 alkylthio, acyl, a C1-6 alkylsulfonyloxy, a C3-12 carbocyclyl, a C3-12 carbocyclyloxy, a C3-12 carbocyclylsulfonyloxy, a 5- to 14-membered heterocyclyl, a 5- to 14-membered heterocyclyloxy, or a 5- to 14-membered heterocyclylsulfonyloxy;
R2, R3, R4, R5, R6, and R7 are each independently hydrogen, a halogen, amino, cyano, a C1-6 alkyl, a C1-6 alkoxy, a C1-6 alkylthio, acyl, a C3-12 carbocyclyl, or a 5- to 14-membered heterocyclyl;
R8 is hydrogen, a halogen, hydroxy, amino, nitro, cyano, a C1-6 alkyl, a C1-6 alkoxy, or a C1-6 alkylthio;
R9 and R10 are each independently hydrogen, a halogen, hydroxy, a C1-6 alkyl, or a C1-6 alkoxy;
R11 is hydroxy, amino, or a C1-6 alkoxy;
R12 is hydrogen, a C1-6 alkyl, a C2-6 akenyl, a C2-6 alkynyl, a C1-6 alkoxy, a C1-6 alkoxy-C1-6 alkyl, a C3-12 carbocyclyl, or a 5- to 14-membered heterocyclyl;
R13 is hydrogen, or a C1-6 alkyl;
R14 is hydrogen, a halogen, amino, —CF3, nitro, cyano, a C1-6 alkyl, a C1-6 alkoxy, a C1-6 alkylthio, acyl, a C3-12 carbocyclyl, or a 5- to 14-membered heterocyclyl;
R15 is hydrogen, or a C1-6 alkyl; and
n, o, and p are each independently 0, 1, 2, or 3;
provided that the alkylene, the alkyl, the akenyl, the alkynyl, the alkoxy, the alkylthio, the amino, the acyl, the alkylsulfonyloxy, the carbocyclyl, the carbocyclyloxy, the carbocyclylsulfonyloxy, the heterocyclyl, the heterocyclyloxy, and the heterocyclylsulfonyloxy may each independently be substituted with at least one substituent selected from the group consisting of a 4- to 7-membered heterocyclyl (unsubstituted or substituted with 1 to 3 substituents selected from the group consisting of hydroxy, a halogenated C1-6 alkyl, and a C1-6 alkoxy-carbonyl), a C3-8 cycloalkyl, hydroxy, a C1-6 alkoxy, a halogenated C1-6 alkoxy, amino, a mono- or di-C1-6 alkyl-amino, an N—C1-6 alkyl-N—C1-6 alkyl-carbonyl-amino, a C7-16 aralkyloxy, a C1-6 alkylthio, a C1-6 alkylsulfinyl, a C1-6 alkylsulfonyl, and a mono- or di-C1-6 alkyl-phosphono; and
the heterocyclyl contains 1 to 4 heteroelements selected from the group consisting of N, O, S, S(═O), and S(═O)2.

2. The compound of claim 1,
wherein
V and W are each independently ═C(R14)—, or ═N—;
X is —CH2—, —O—, —O—CH2—O—, —S—, or —NR15—;
Y is a C1-3 alkylene;
Z is —O—, —S—, or —NR15—, provided that Z is substituted at the 2nd or 3rd carbon atom of Ar;
Ar is one of the substituents (a) to (c);
A is —CH2—, —CF2—, —O—, or —NR15—;
B is a C1-2 alkylene;
R1 is hydrogen, a halogen, hydroxy, amino, nitro, cyano, a C1-6 alkyl, a C1-10 alkoxy, a C1-6 alkylthio, acyl, a C1-6 alkylsulfonyloxy, a C3-12 carbocyclyl, a C3-12 carbocyclyloxy, a C3-12 carbocyclylsulfonyloxy, a 5- to 14-membered heterocyclyl, a 5- to 14-membered heterocyclyloxy, or a 5- to 14-membered heterocyclylsulfonyloxy;
R2 is hydrogen, a halogen, amino, cyano, a C1-6 alkyl, a C1-6 alkoxy, a C1-6 alkylthio, a C3-12 carbocyclyl, or a 5- to 14-membered heterocyclyl;
R3, R4, R5, and R6 are each independently hydrogen, a halogen, amino, a C1-6 alkyl, or a C1-6 alkoxy;
R7 is hydrogen, a halogen, amino, cyano, a C1-6 alkyl, a C1-6 alkoxy, a C1-6 alkylthio, a C3-12 carbocyclyl, or a 5- to 14-membered heterocyclyl;
R8 is hydrogen, a halogen, amino, a C1-6 alkyl, or a C1-6 alkoxy;
R9 and R10 are each independently hydrogen, a halogen, hydroxy, a C1-6 alkyl, or a C1-6 alkoxy;
R11 is hydroxy, or a C1-6 alkoxy;
R12 is hydrogen, a C1-6 alkyl, a C2-6 akenyl, a C2-6 alkynyl, a C1-6 alkoxy, a C1-6 alkoxy-C1-6 alkyl, a C3-12 carbocyclyl, or a 5- to 14-membered heterocyclyl;
R13 is hydrogen, or a C1-6 alkyl;
R14 is hydrogen, a halogen, amino, —CF3, a C1-6 alkyl, a C1-6 alkoxy, acyl, a C3-12 carbocyclyl, or a 5- to 14-membered heterocyclyl;
R15 is hydrogen, or a C1-6 alkyl; and
n, o, and p are each independently 0, 1, or 2;
provided that the alkylene, the alkyl, the alkynyl, the alkoxy, the alkylthio, the amino, the acyl, the alkylsulfonyloxy, the carbocyclyl, the carbocyclyloxy, the carbocyclylsulfonyloxy, the heterocyclyl, and the heterocyclyloxy may each independently substituted with at least one substituent selected from the group consisting of a 4- to 7-membered heterocyclyl (unsubstituted or substituted with 1 to 3 substituents selected from the group consisting of hydroxy, a halogenated C1-6 alkyl, and a C1-6 alkoxy-carbonyl), a C3-8 cycloalkyl, hydroxy, a C1-6 alkoxy, a halogenated C1-6 alkoxy, amino, a mono- or di-C1-6 alkyl-amino, an N—C1-6 alkyl-N—C1-6 alkyl-carbonyl-amino, a C7-16 aralkyloxy, a C1-6 alkylthio, a C1-6 alkylsulfinyl, a C1-6 alkylsulfonyl, and a mono- or di-C1-6 alkyl-phosphono; and
the heterocyclyl contains 1 to 4 heteroelements selected from the group consisting of N, O, S, S(═O), and S(═O)2.

3. The compound of claim 1,
wherein
V and W are each independently ═C(R14)—, or ═N—;
X is —CH2—, —O—CH2—O—, —O—, —S—, or —NR15—;
Y is a C1-3 alkylene;
Z is —O—, —S—, or —NR15—, provided that Z is substituted at the 2nd or 3rd carbon atom of Ar;
Ar is one of the substituents (a) to (c);
A is —CH2—, —CF2—, —O—, or —NR15—;
B is a C1-2 alkylene;
R1 is hydrogen, a halogen, hydroxy, amino, a C1-6 alkyl, a C1-10 alkoxy, acyl, a C1-6 alkylsulfonyloxy, a C3-12 carbocyclyloxy, a 5- to 14-membered heterocyclyl, or a 5- to 14-membered heterocyclyloxy;
R2, R3, R4, R5, R6, R7, and R8 are each independently hydrogen, a halogen, amino, a C1-6 alkyl, or a C1-6 alkoxy;
R9 and R10 are each independently hydrogen, or a halogen;
R11 is hydroxy, or a C1-6 alkoxy;
R12 is hydrogen, a C1-6 alkyl, a C2-6 akenyl, a C2-6 alkynyl, a C1-6 alkoxy, a C1-6 alkoxy-C1-6 alkyl, a C3-12 carbocyclyl, or a 5- to 14-membered heterocyclyl;
R13 is hydrogen;
R14 is hydrogen, a halogen, amino, a C1-6 alkyl, a C1-6 alkoxy, or acyl;
R15 is hydrogen, methyl, ethyl, or isopropyl; and
n, o, and p are each independently 0, 1, or 2;
provided that the alkylene, the alkyl, the alkynyl, the alkoxy, the amino, the acyl, the alkylsulfonyloxy, the carbocyclyloxy, the heterocyclyl, and the heterocyclyloxy may each independently be substituted with at least one substituent selected from the group consisting of a 4- to 7-membered heterocyclyl (unsubstituted or substituted with 1 to 3 substituents selected from the group consisting of hydroxy, a halogenated C1-6 alkyl, and a C1-6 alkoxy-carbonyl), a C3-8 cycloalkyl, hydroxy, a C1-6 alkoxy, a halogenated C1-6 alkoxy, amino, a mono- or di-C1-6 alkyl-amino, an N—C1-6 alkyl-N—C1-6 alkyl-carbonyl-amino, a C7-16 aralkyloxy, a C1-6 alkylthio, a C1-6 alkylsulfinyl, a C1-6 alkylsulfonyl, and a mono- or di-C1-6 alkyl-phosphono; and
the heterocyclyl contains 1 to 4 heteroelements selected from the group consisting of N, O, S, S(═O), and S(═O)2.

4. The compound of claim 1,
wherein
V and W are each independently ═CH—, or ═N—;
X is —CH2—, —O—, —O—CH2—O—, or —N(CH2CH3)—;
Y is methylene;
Z is —O— or —NH—, provided that Z is substituted at the 2nd or 3rd carbon atom of Ar;
Ar is one of the substituents (a) to (c);
A is —O—;
B is methylene;
R1 is methylsulfonylpropoxy, ethylsulfonylpropoxy, ethoxyethoxy, morpholino, morpholinoethoxy, tetrahydrofuranyloxy,




R2 is hydrogen, or methyl;
R3, R4, R5, and R6 are each independently hydrogen, or methyl;
R7 and R8 are each independently hydrogen, or fluoro;
R9 and R10 are hydrogen;
R11 is hydroxy;
R12 is hydrogen, methyl, propyl, cyclopropyl, ethoxymethyl, ethynyl, —CH═CH—CH3, —C≡C—CH3, fluorophenyl, or methyloxazolyl;
R13 is hydrogen;
n and o are each independently 0, 1, or 2; and
p may be 0 or 1.

5. The compound of claim 1, which is selected from the group consisting of:
(1) 2-((3S)-6-((11-methyl-9-(3-(methylsulfonyl)propoxy)-6,7-dihydro-5H-dibenzo[a,c][7]annulen-4-yl)methoxy)-2,3-dihydrobenzofuran-3-yl)acetic acid;
(2) (1S,2S)-2-(4-((9-(3-(methylsulfonyl)propoxy)-6,7-dihydrodibenzo[b,d]oxepin-2-yl)methoxy)phenyl)cyclopropanecarboxylic acid;
(3) (1S,2S)-2-(4-(((9-(2-ethoxyethoxy)-6,7-dihydrodibenzo[b,d]oxepin-2-yl)methyl)amino)phenyl)cyclopropanecarboxylic acid;
(4) (1S,2S)-2-(4-(((9-(3-(methylsulfonyl)propoxy)-6,7-dihydrodibenzo[b,d]oxepin-2-yl)methyl)amino)phenyl)cyclopropanecarboxylic acid;
(5) (S)-2-(6-((9-(3-(methylsulfonyl)propoxy)-6,7-dihydro-5H-dibenzo[a,c][7]annulen-2-yl)methoxy)-2,3-dihydrobenzofuran-3-yl)acetic acid;
(6) (1S,2S)-2-(4-(((9-(3-(methylsulfonyl)propoxy)-6,7-dihydro-5H-dibenzo[a,c][7]annulen-2-yl)methyl)amino)phenyl)cyclopropanecarboxylic acid;
(7) 2-((3S)-6-((11-methyl-9-(3-(methylsulfonyl)propoxy)-6,7-dihydro-5H-dibenzo[a,c][7]annulen-2-yl)methoxy)-2,3-dihydrobenzofuran-3-yl)acetic acid;
(8) (1R,2R)-2-(4-(((10-methyl-8-(3-(methylsulfonyl)propoxy)-6H-benzo[c]chromen-4-yl)methyl)amino)phenyl)cyclopropanecarboxylic acid;
(9) (1S,2S)-2-(4-(((10-methyl-8-(3-(methylsulfonyl)propoxy)-6H-benzo[c]chromen-2-yl)methyl)amino)phenyl)cyclopropanecarboxylic acid;
(10) (S)-2-(6-((5-methyl-7-(3-(methylsulfonyl)propoxy)-9,10-dihydrophenanthren-1-yl)methoxy)-2,3-dihydrobenzofuran-3-yl)acetic acid;
(11) (S)-2-(6-((5-methyl-7-(3-(methylsulfonyl)propoxy)-9, 10-dihydrophenanthren-3-yl)methoxy)-2,3-dihydrobenzofuran-3-yl)acetic acid;
(12) (S)-2-(6-((7-(2-ethoxyethoxy)-5-methyl-9,10-dihydrophenanthren-3-yl)methoxy)-2,3-dihydrobenzofuran-3-yl)acetic acid;
(13) 2-((3S)-6-((11-methyl-9-(3-(methylsulfonyl)propoxy)-6,7-dihydrodibenzo[b,d]oxepin-4-yl)methoxy)-2,3-dihydrobenzofuran-3-yl)acetic acid;
(14) 2-((3S)-6-((11-methyl-9-(3-(methylsulfonyl)propoxy)-6,7-dihydrodibenzo[b,d]oxepin-2-yl)methoxy)-2,3-dihydrobenzofuran-3-yl)acetic acid;
(15) (1S,2S)-2-(4-(((11-methyl-9-(3-(methylsulfonyl)propoxy)-6,7-dihydrodibenzo[b,d]oxepin-2-yl)methyl)amino)phenyl)cyclopropanecarboxylic acid;
(16) (1S,2S)-2-(4-(((8-(2-ethoxyethoxy)-10-methyl-6H-benzo[c]chromen-2-yl)methyl)amino)phenyl)cyclopropanecarboxylic acid;
(17) (S)-2-(6-((8-(2-ethoxyethoxy)-10-methyl-6H-benzo[c]chromen-2-yl)methoxy)-2,3-dihydrobenzofuran-3-yl)acetic acid;
(18) (1S,2S)-2-(4-(((9-(3-(methylsulfonyl)propoxy)-5,7-dihydrodibenzo[c,e]oxepin-2-yl)methyl)amino)phenyl)cyclopropanecarboxylic acid;
(19) (1S,2S)-2-(4-(((11-methyl-9-(3-(methylsulfonyl)propoxy)-5,7-dihydrodibenzo[c,e]oxepin-4-yl)methyl)amino)phenyl)cyclopropanecarboxylic acid;
(20) (S)-2-(6-((9-(3-(methylsulfonyl)propoxy)-5,7-dihydrodibenzo[c,e]oxepin-2-yl)methoxy)-2,3-dihydrobenzofuran-3-yl)acetic acid;
(21) (1S,2S)-2-(4-(((3-(3-(methylsulfonyl)propoxy)-6,7-dihydrodibenzo[b,d]oxepin-10-yl)methyl)amino)phenyl)cyclopropanecarboxylic acid;
(22) (1S,2S)-2-(4-(((9-(2-ethoxyethoxy)-5,7-dihydrodibenzo[c,e]oxepin-2-yl)methyl)amino)phenyl)cyclopropanecarboxylic acid;
(23) (S)-2-(6-((9-(2-ethoxyethoxy)-5,7-dihydrodibenzo[c,e]oxepin-2-yl)methoxy)-2,3-dihydrobenzofuran-3-yl)acetic acid;
(24) (1S,2S)-2-(4-((9-(3-(methylsulfonyl)propoxy)-5,7-dihydrodibenzo[c,e]oxepin-2-yl)methoxy)phenyl)cyclopropanecarboxylic acid;
(25) (1S,2S)-2-(4-((9-(3-(methylsulfonyl)propoxy)-6,7-dihydro-5H-dibenzo[a,c][7]annulen-2-yl)methoxy)phenyl)cyclopropanecarboxylic acid;
(26) (S)-2-(6-((10-methyl-8-(3-(methylsulfonyl)propoxy)-6H-benzo[c]chromen-2-yl)methoxy)-2,3-dihydrobenzofuran-3-yl)acetic acid;
(27) (S)-2-(6-((9-(2-ethoxyethoxy)-6,7-dihydro-5H-dibenzo[a,c][7]annulen-2-yl)methoxy)-2,3-dihydrobenzofuran-3-yl)acetic acid;
(28) (1S,2S)-2-(4-(((9-(2-ethoxyethoxy)-6,7-dihydro-5H-dibenzo[a,c][7]annulen-2-yl)methyl)amino)phenyl)cyclopropanecarboxylic acid;
(29) (1S,2S)-2-(4-(((11-methyl-9-(3-(methylsulfonyl)propoxy)-6,7-dihydro-5H-dibenzo[a,c][7]annulen-2-yl)methyl)amino)phenyl)cyclopropanecarboxylic acid;
(30) (1S,2S)-2-(4-((10-methyl-8-(3-(methylsulfonyl)propoxy)-6H-benzo[c]chromen-2-yl)methoxy)phenyl)cyclopropanecarboxylic acid;
(31) (1S,2S)-2-(4-((5-methyl-7-(3-(methylsulfonyl)propoxy)-9,10-dihydrophenanthren-3-yl)methoxy)phenyl)cyclopropanecarboxylic acid;
(32) (S)-2-(6-((9-(3-(methylsulfonyl)propoxy)-6,7-dihydrodibenzo[b,d]oxepin-2-yl)methoxy)-2,3-dihydrobenzofuran-3-yl)acetic acid;
(33) 2-((3S)-6-((11-methyl-9-(3-(methylsulfonyl)propoxy)-5,7-dihydrodibenzo[c,e]oxepin-2-yl)methoxy)-2,3-dihydrobenzofuran-3-yl)acetic acid;
(34) (1S,2S)-2-(4-(((11-methyl-9-(3-(methylsulfonyl)propoxy)-5,7-dihydrodibenzo[c,e]oxepin-2-yl)methyl)amino)phenyl)cyclopropanecarboxylic acid;
(35) 2-((3S)-6-((9-(2-ethoxyethoxy)-11-methyl-6,7-dihydro-5H-dibenzo[a,c][7]annulen-2-yl)methoxy)-2,3-dihydrobenzofuran-3-yl)acetic acid;
(36) 2-((3S)-6-((9-((1,1-dioxidotetrahydro-2H-thiopyran-4-yl)oxy)-11-methyl-6,7-dihydrodibenzo[b,d]oxepin-2-yl)methoxy)-2,3-dihydrobenzofuran-3-yl)acetic acid;
(37) 2-((3S)-6-((9-(2-(1,1-dioxidothiomorpholino)ethoxy)-11-methyl-6,7-dihydrodibenzo[b,d]oxepin-2-yl)methoxy)-2,3-dihydrobenzofuran-3-yl)acetic acid;
(38) 2-((3S)-6-((9-(3-(ethylsulfonyl)propoxy)-11-methyl-6,7-dihydrodibenzo[b,d]oxepin-2-yl)methoxy)-2,3-dihydrobenzofuran-3-yl)acetic acid;
(39) (1S,2S)-2-(4-((11-methyl-9-(3-(methylsulfonyl)propoxy)-6,7-dihydrodibenzo[b,d]oxepin-2-yl)methoxy)phenyl)cyclopropanecarboxylic acid;
(40) (1S,2S)-2-(2-fluoro-4-((11-methyl-9-(3-(methylsulfonyl)propoxy)-6,7-dihydrodibenzo[b,d]oxepin-2-yl)methoxy)phenyl)cyclopropanecarboxylic acid;
(41) (1S,2S)-2-(4-((9-(3-(ethylsulfonyl)propoxy)-11-methyl-6,7-dihydrodibenzo[b,d]oxepin-2-yl)methoxy)-2-fluorophenyl)cyclopropanecarboxylic acid;
(42) (S)-2-(6-((3-(3-(methylsulfonyl)propoxy)-6,7-dihydrodibenzo[b,d]oxepin-10-yl)methoxy)-2,3-dihydrobenzofuran-3-yl)acetic acid;
(43) (S)-2-(6-((6,6-dimethyl-9-(3-(methylsulfonyl)propoxy)-6,7-dihydrodibenzo[b,d]oxepin-2-yl)methoxy)-2,3-dihydrobenzofuran-3-yl)acetic acid;
(44) (S)-2-(6-((5-ethyl-9-(3-(methylsulfonyl)propoxy)-6,7-dihydro-5H-dibenzo[b,d]azepin-2-yl)methoxy)-2,3-dihydrobenzofuran-3-yl)acetic acid;
(45) (1S,2S)-2-(4-((5-ethyl-9-(3-(methylsulfonyl)propoxy)-6,7-dihydro-5H-dibenzo[b,d]azepin-2-yl)methoxy)phenyl)cyclopropanecarboxylic acid;
(46) 2-((3S)-6-((9-((4-hydroxy-1,1-dioxidotetrahydro-2H-thiopyran-4-yl)methoxy)-11-methyl-6,7-dihydrodibenzo[b,d]oxepin-2-yl)methoxy)-2,3-dihydrobenzofuran-3-yl)acetic acid;
(47) 2-((3S)-6-((9-((1,1-dioxidotetrahydro-2H-thiopyran-4-yl)methoxy)-11-methyl-6,7-dihydrodibenzo[b,d]oxepin-2-yl)methoxy)-2,3-dihydrobenzofuran-3-yl)acetic acid;
(48) (1S,2S)-2-(4-((9-((1,1-dioxidotetrahydro-2H-thiopyran-4-yl)oxy)-11-methyl-6,7-dihydrodibenzo[b,d]oxepin-2-yl)methoxy)phenyl)cyclopropanecarboxylic acid;
(49) (1S,2S)-2-(4-((9-(3-(ethylsulfonyl)propoxy)-11-methyl-6,7-dihydrodibenzo[b,d]oxepin-2-yl)methoxy)phenyl)cyclopropanecarboxylic acid;
(50) (1S,2S)-2-(4-((9-((1,1-dioxidotetrahydro-2H-thiopyran-4-yl)oxy)-11-methyl-6,7-dihydrodibenzo[b,d]oxepin-2-yl)methoxy)-2-fluorophenyl)cyclopropanecarboxylic acid;
(51) (1S,2S)-2-{2-fluoro-4-[9-(4-hydroxy-1,1-dioxido-hexahydro-thiopyran-4-ylmethoxy)-11-methyl-6,7-dihydro-5-oxa-dibenzo[a,c]cyclohepten-2-ylmethoxy]-phenyl}-cyclopropanecarboxylic acid;
(52) (1S,2S)-2-(4-(((9-((1,1-dioxidotetrahydro-2H-thiopyran-4-yl)oxy)-11-methyl-6,7-dihydrodibenzo[b,d]oxepin-2-yl)methyl)amino)-2-fluorophenyl)cyclopropanecarboxylic acid;
(53) (i1S,2S)-2-(4-(((9-(3-(ethylsulfonyl)propoxy)-11-methyl-6,7-dihydrodibenzo[b,d]oxepin-2-yl)methyl)amino)-2-fluorophenyl)cyclopropanecarboxylic acid;
(54) 2-((3S)-6-((6,6,11-trimethyl-9-(3-(methylsulfonyl)propoxy)-6,7-dihydrodibenzo[b,d]oxepin-2-yl)methoxy)-2,3-dihydrobenzofuran-3-yl)acetic acid;
(55) 2-((3S)-6-((9-((1,1-dioxidotetrahydro-2H-thiopyran-4-yl)oxy)-11-methyl-6,7-dihydro-5H-dibenzo[a,c][7]annulen-2-yl)methoxy)-2,3-dihydrobenzofuran-3-yl)acetic acid;
(56) 2-((3S)-6-((9-((4-hydroxy-1,1-dioxidotetrahydro-2H-thiopyran-4-yl)methoxy)-11-methyl-6,7-dihydro-5H-dibenzo[a,c][7]annulen-2-yl)methoxy)-2,3-dihydrobenzofuran-3-yl)acetic acid;
(57) 2-((3S)-6-((9-(3-(ethylsulfonyl)propoxy)-11-methyl-6,7-dihydro-5H-dibenzo[a,c][7]annulen-2-yl)methoxy)-2,3-dihydrobenzofuran-3-yl)acetic acid;
(58) (1S,2S)-2-(4-((11-methyl-9-(3-(methylsulfonyl)propoxy)-6,7-dihydro-5H-dibenzo[a,c][7]annulen-2-yl)methoxy)phenyl)cyclopropanecarboxylic acid;
(59) (1S,2S)-2-(4-((9-((1,1-dioxidotetrahydro-2H-thiopyran-4-yl)oxy)-11-methyl-6,7-dihydro-5H-dibenzo[a,c][7]annulen-2-yl)methoxy)phenyl)cyclopropanecarboxylic acid;
(60) (1S,2S)-2-(4-((9-((4-hydroxy-1,1-dioxidotetrahydro-2H-thiopyran-4-yl)methoxy)-11-methyl-6,7-dihydro-5H-dibenzo[a,c][7]annulen-2-yl)methoxy)phenyl)cyclopropanecarboxylic acid;
(61) (1S,2S)-2-(4-((9-(3-(ethylsulfonyl)propoxy)-11-methyl-6,7-dihydro-5H-dibenzo[a,c][7]annulen-2-yl)methoxy)phenyl)cyclopropanecarboxylic acid;
(62) (1S,2S)-2-(2-fluoro-4-((9-((4-hydroxy-1,1-dioxidotetrahydro-2H-thiopyran-4-yl)methoxy)-11-methyl-6,7-dihydro-5H-dibenzo[a,c][7]annulen-2-yl)methoxy)phenyl)cyclopropanecarboxylic acid;
(63) (1S,2S)-2-(2-fluoro-4-(((9-((4-hydroxy-1,1-dioxidotetrahydro-2H-thiopyran-4-yl)methoxy)-11-methyl-6,7-dihydro-5H-dibenzo[a,c][7]annulen-2-yl)methyl)amino)phenyl)cyclopropanecarboxylic acid;
(64) (S)-2-(6-((9-((1,1-dioxidotetrahydro-2H-thiopyran-4-yl)oxy)-6,7-dihydro-5H-dibenzo[a,c][7]annulen-2-yl)methoxy)-2,3-dihydrobenzofuran-3-yl)acetic acid;
(65) (S)-2-(6-((9-((4-hydroxy-1,1-dioxidotetrahydro-2H-thiopyran-4-yl)methoxy)-6,7-dihydro-5H-dibenzo[a,c][7]annulen-2-yl)methoxy)-2,3-dihydrobenzofuran-3-yl)acetic acid;
(66) (S)-2-(6-((9-(3-(ethylsulfonyl)propoxy)-6,7-dihydro-5H-dibenzo[a,c][7]annulen-2-yl)methoxy)-2,3-dihydrobenzofuran-3-yl)acetic acid;
(67) (1S,2S)-2-(4-((9-((1,1-dioxidotetrahydro-2H-thiopyran-4-yl)oxy)-6,7-dihydro-5H-dibenzo[a,c][7]annulen-2-yl)methoxy)phenyl)cyclopropanecarboxylic acid;
(68) (1S,2S)-2-(4-((9-((4-hydroxy-1,1-dioxidotetrahydro-2H-thiopyran-4-yl)methoxy)-6,7-dihydro-5H-dibenzo[a,c][7]annulen-2-yl)methoxy)phenyl)cyclopropanecarboxylic acid;
(69) (1S,2S)-2-(4-((9-(3-(ethylsulfonyl)propoxy)-6,7-dihydro-5H-dibenzo[a,c][7]annulen-2-yl)methoxy)phenyl)cyclopropanecarboxylic acid;
(70) (1S,2S)-2-(4-(((9-((1,1-dioxidotetrahydro-2H-thiopyran-4-yl)oxy)-6,7-dihydro-5H-dibenzo[a,c][7]annulen-2-yl)methyl)amino)phenyl)cyclopropanecarboxylic acid;
(71) (1S,2S)-2-(4-(((9-((4-hydroxy-1,1-dioxidotetrahydro-2H-thiopyran-4-yl)methoxy)-6,7-dihydro-5H-dibenzo[a,c][7]annulen-2-yl)methyl)amino)phenyl)cyclopropanecarboxylic acid;
(72) (1S,2S)-2-(4-(((9-(3-(ethylsulfonyl)propoxy)-6,7-dihydro-5H-dibenzo[a,c][7]annulen-2-yl)methyl)amino)phenyl)cyclopropanecarboxylic acid;
(73) (1S,2S)-2-(4-(((9-((1,1-dioxidotetrahydro-2H-thiopyran-4-yl)oxy)-11-methyl-6,7-dihydrodibenzo[b,d]oxepin-2-yl)methyl)amino)phenyl)cyclopropanecarboxylic acid;
(74) (i1S,2S)-2-(4-(((9-(3-(ethylsulfonyl)propoxy)-11-methyl-6,7-dihydro-5H-dibenzo[a,c][7]annulen-2-yl)methyl)amino)phenyl)cyclopropanecarboxylic acid;
(75) (1S,2S)-2-(4-(((9-((1,1-dioxidotetrahydro-2H-thiopyran-4-yl)methoxy)-11-methyl-6,7-dihydro-5H-dibenzo[a,c][7]annulen-2-yl)methyl)amino)phenyl)cyclopropanecarboxylic acid;
(76) (1S,2S)-2-(4-(((9-((1,1-dioxidotetrahydro-2H-thiopyran-4-yl)oxy)-11-methyl-6,7-dihydro-5H-dibenzo[a,c][7]annulen-2-yl)methyl)amino)phenyl)cyclopropanecarboxylic acid;
(77) (1S,2S)-2-(4-(((9-((4-hydroxy-1,1-dioxidotetrahydro-2H-thiopyran-4-yl)methoxy)-11-methyl-6,7-dihydro-5H-dibenzo[a,c][7]annulen-2-yl)methyl)amino)phenyl)cyclopropanecarboxylic acid;
(78) (1S,2S)-2-(4-(((9-((1,1-dioxidotetrahydro-2H-thiopyran-4-yl)methoxy)-6,7-dihydro-5H-dibenzo[a,c][7]annulen-2-yl)methyl)amino)phenyl)cyclopropanecarboxylic acid;
(79) 2-((S)-6-(((R)-6-methyl-9-(3-(methylsulfonyl)propoxy)-6,7-dihydrodibenzo[b,d]oxepin-2-yl)methoxy)-2,3-dihydrobenzofuran-3-yl)acetic acid;
(80) (S)-2-(6-((9-(3-(methylsulfonyl)propoxy)dibenzo[d,f][1,3]dioxepin-2-yl)methoxy)-2,3-dihydrobenzofuran-3-yl)acetic acid;
(81) 2-((3S)-6-((1-methyl-3-morpholino-6,7-dihydro-5H-benzo[3,4]cyclohepta[1,2-d]pyrimidin-10-yl)methoxy)-2,3-dihydrobenzofuran-3-yl)acetic acid;
(82) (S)-2-(6-(((9-(3-(methylsulfonyl)propoxy)-6,7-dihydro-5H-dibenzo[a,c][7]annulen-2-yl)methyl)amino)-2,3-dihydrobenzofuran-3-yl)acetic acid;
(83) (S)-2-(6-(((9-((1,1-dioxidotetrahydro-2H-thiopyran-4-yl)methoxy)-6,7-dihydro-5H-dibenzo[a,c][7]annulen-2-yl)methyl)amino)-2,3-dihydrobenzofuran-3-yl)acetic acid;
(84) (S)-2-(6-((9-((1,1-dioxidotetrahydro-2H-thiopyran-4-yl)methoxy)-6,7-dihydro-5H-dibenzo[a,c][7]annulen-2-yl)methoxy)-2,3-dihydrobenzofuran-3-yl)acetic acid;
(85) (S)-2-(6-((9-((1,1-dioxidotetrahydro-2H-thiopyran-4-yl)methoxy)-3-fluoro-6,7-dihydro-5H-dibenzo[a,c][7]annulen-2-yl)methoxy)-2,3-dihydrobenzofuran-3-yl)acetic acid;
(86) (1S,2S)-2-(4-(((9-((1,1-dioxidotetrahydro-2H-thiopyran-4-yl)methoxy)-3-fluoro-6,7-dihydro-5H-dibenzo[a,c][7]annulen-2-yl)methyl)amino)phenyl)cyclopropanecarboxylic acid;
(87) (1S,2S)-2-(4-(((9-(3-(ethylsulfonyl)propoxy)-11-methyl-6,7-dihydrodibenzo[b,d]oxepin-2-yl)methyl)amino)phenyl)cyclopropanecarboxylic acid;
(88) 2-((3S)-6-((9-(2-ethoxyethoxy)-11-methyl-6,7-dihydrodibenzo[b,d]oxepin-2-yl)methoxy)-2,3-dihydrobenzofuran-3-yl)acetic acid;
(89) (1S,2S)-2-(4-((1-methyl-3-morpholino-6,7-dihydro-5H-benzo[3,4]cyclohepta[1,2-d]pyrimidin-10-yl)methoxy)phenyl)cyclopropanecarboxylic acid;
(90) 2-((3S)-6-((1-methyl-3-(3-(methylsulfonyl)propoxy)-6,7-dihydro-5H-benzo[3,4]cyclohepta[1,2-d]pyrimidin-10-yl)methoxy)-2,3-dihydrobenzofuran-3-yl)acetic acid;
(91) (S)-2-(6-(((9-(2-ethoxyethoxy)-6,7-dihydro-5H-dibenzo[a,c][7]annulen-2-yl)methyl)amino)-2,3-dihydrobenzofuran-3-yl)acetic acid;
(92) (S)-2-(6-(((9-(3-(ethylsulfonyl)propoxy)-6,7-dihydro-5H-dibenzo[a,c][7]annulen-2-yl)methyl)amino)-2,3-dihydrobenzofuran-3-yl)acetic acid;
(93) (S)-2-(6-((9-((4-methyl-1,1-dioxidotetrahydro-2H-thiopyran-4-yl)methoxy)-6,7-dihydro-5H-dibenzo[a,c][7]annulen-2-yl)methoxy)-2,3-dihydrobenzofuran-3-yl)acetic acid;
(94) (1S,2S)-2-(4-(((9-((4-methyl-1,1-dioxidotetrahydro-2H-thiopyran-4-yl)methoxy)-6,7-dihydro-5H-dibenzo[a,c][7]annulen-2-yl)methyl)amino)phenyl)cyclopropanecarboxylic acid;
(95) (S)-2-(6-((3-fluoro-9-((4-methyl-1,1-dioxidotetrahydro-2H-thiopyran-4-yl)methoxy)-6,7-dihydro-5H-dibenzo[a,c][7]annulen-2-yl)methoxy)-2,3-dihydrobenzofuran-3-yl)acetic acid;
(96) (S)-2-(6-((3-fluoro-9-(3-(methylsulfonyl)propoxy)-6,7-dihydro-5H-dibenzo[a,c][7]annulen-2-yl)methoxy)-2,3-dihydrobenzofuran-3-yl)acetic acid;
(97) (S)-2-(6-((9-(3-(ethylsulfonyl)propoxy)-3-fluoro-6,7-dihydro-5H-dibenzo[a,c][7]annulen-2-yl)methoxy)-2,3-dihydrobenzofuran-3-yl)acetic acid;
(98) (S)-2-(6-((9-((1,1-dioxidotetrahydro-2H-thiopyran-4-yl)oxy)-3-fluoro-6,7-dihydro-5H-dibenzo[a,c][7]annulen-2-yl)methoxy)-2,3-dihydrobenzofuran-3-yl)acetic acid;
(99) (S)-2-(6-((3-fluoro-9-((4-hydroxy-1,1-dioxidotetrahydro-2H-thiopyran-4-yl)methoxy)-6,7-dihydro-5H-dibenzo[a,c][7]annulen-2-yl)methoxy)-2,3-dihydrobenzofuran-3-yl)acetic acid;
(100) (1S,2S)-2-(4-((9-((1,1-dioxidotetrahydro-2H-thiopyran-4-yl)oxy)-3-fluoro-6,7-dihydro-5H-dibenzo[a,c][7]annulen-2-yl)methoxy)phenyl)cyclopropanecarboxylic acid;
(101) (1S,2S)-2-(4-((3-fluoro-9-((4-hydroxy-1,1-dioxidotetrahydro-2H-thiopyran-4-yl)methoxy)-6,7-dihydro-5H-dibenzo[a,c][7]annulen-2-yl)methoxy)phenyl)cyclopropanecarboxylic acid;
(102) (1S,2S)-2-(4-((3-fluoro-9-(3-(methylsulfonyl)propoxy)-6,7-dihydro-5H-dibenzo[a,c][7]annulen-2-yl)methoxy)phenyl)cyclopropanecarboxylic acid;
(103) (1S,2S)-2-(4-((9-((1,1-dioxidotetrahydro-2H-thiopyran-4-yl)methoxy)-3-fluoro-6,7-dihydro-5H-dibenzo[a,c][7]annulen-2-yl)methoxy)phenyl)cyclopropanecarboxylic acid;
(104) (1S,2S)-2-(4-(((3-fluoro-9-(3-(methylsulfonyl)propoxy)-6,7-dihydro-5H-dibenzo[a,c][7]annulen-2-yl)methyl)amino)phenyl)cyclopropanecarboxylic acid;
(105) (1S,2S)-2-(4-(((9-(3-(ethylsulfonyl)propoxy)-3-fluoro-6,7-dihydro-5H-dibenzo[a,c][7]annulen-2-yl)methyl)amino)phenyl)cyclopropanecarboxylic acid;
(106) 2-((S)-6-((3-fluoro-9-(((R)-tetrahydrofuran-3-yl)oxy)-6,7-dihydro-5H-dibenzo[a,c][7]annulen-2-yl)methoxy)-2,3-dihydrobenzofuran-3-yl)acetic acid;
(107) (S)-2-(6-((3-fluoro-9-(2-morpholinoethoxy)-6,7-dihydro-5H-dibenzo[a,c][7]annulen-2-yl)methoxy)-2,3-dihydrobenzofuran-3-yl)acetic acid;
(108) (S)-3-(4-((9-(3-(methylsulfonyl)propoxy)-6,7-dihydro-5H-dibenzo[a,c][7]annulen-2-yl)methoxy)phenyl)hex-4-ynoic acid;
(109) (S)-3-(4-((9-((1,1-dioxidotetrahydro-2H-thiopyran-4-yl)methoxy)-6,7-dihydro-5H-dibenzo[a,c][7]annulen-2-yl)methoxy)phenyl)hex-4-ynoic acid;
(110) (S)-3-(4-((9-((1,1-dioxidotetrahydro-2H-thiopyran-4-yl)oxy)-6,7-dihydro-5H-dibenzo[a,c][7]annulen-2-yl)methoxy)phenyl)hex-4-ynoic acid;
(111) (S)-3-(4-((9-(3-(ethylsulfonyl)propoxy)-6,7-dihydro-5H-dibenzo[a,c][7]annulen-2-yl)methoxy)phenyl)hex-4-ynoic acid;
(112) (S)-3-(4-((9-((1,1-dioxidotetrahydro-2H-thiopyran-4-yl)methoxy)-3-fluoro-6,7-dihydro-5H-dibenzo[a,c][7]annulen-2-yl)methoxy)phenyl)hex-4-ynoic acid;
(113) (S)-3-(4-((9-((1,1-dioxidotetrahydro-2H-thiopyran-4-yl)methoxy)-6,7-dihydrodibenzo[b,d]oxepin-2-yl)methoxy)phenyl)hex-4-ynoic acid;
(114) (S)-3-(4-((3-((1,1-dioxidotetrahydro-2H-thiopyran-4-yl)methoxy)-6,7-dihydro-5H-benzo[3,4]cyclohepta[1,2-b]pyridin-10-yl)methoxy)phenyl)hex-4-ynoic acid;
(115) (R)-3-cyclopropyl-3-(3-((9-((1,1-dioxidotetrahydro-2H-thiopyran-4-yl)methoxy)-6,7-dihydro-5H-dibenzo[a,c][7]annulen-2-yl)methoxy)phenyl)propanoic acid;
(116) 3-cyclopropyl-3-(4-((9-((1,1-dioxidotetrahydro-2H-thiopyran-4-yl)methoxy)-6,7-dihydro-5H-dibenzo[a,c][7]annulen-2-yl)methoxy)phenyl)propanoic acid;
(117) (S)-3-(4-((9-((1,1-dioxidotetrahydro-2H-thiopyran-4-yl)methoxy)-6,7-dihydro-5H-dibenzo[a,c][7]annulen-2-yl)methoxy)phenyl)hexanoic acid;
(118) (R,Z)-3-(4-((9-((1,1-dioxidotetrahydro-2H-thiopyran-4-yl)methoxy)-6,7-dihydro-5H-dibenzo[a,c][7]annulen-2-yl)methoxy)phenyl)hex-4-enoic acid;
(119) (S)-3-(4-((9-((1,1-dioxidotetrahydro-2H-thiopyran-4-yl)methoxy)-6,7-dihydro-5H-dibenzo[a,c][7]annulen-2-yl)methoxy)phenyl)-3-(5-methylisoxazol-3-yl)propanoic acid;
(120) (S)-3-(4-((9-((1,1-dioxidotetrahydro-2H-thiopyran-4-yl)methoxy)-6,7-dihydro-5H-dibenzo[a,c][7]annulen-2-yl)methoxy)phenyl)-3-(isoxazol-3-yl)propanoic acid;
(121) 3-(4-((9-((1,1-dioxidotetrahydro-2H-thiopyran-4-yl)methoxy)-6,7-dihydro-5H-dibenzo[a,c][7]annulen-2-yl)methoxy)phenyl)-3-(3-methylisoxazol-5-yl)propanoic acid;
(122) (S)-3-(4-((3-(3-(methylsulfonyl)propoxy)-6,7-dihydro-5H-benzo[3,4]cyclohepta[1,2-b]pyridin-10-yl)methoxy)phenyl)hex-4-ynoic acid;
(123) (S)-3-(4-((3-(3-(ethylsulfonyl)propoxy)-6,7-dihydro-5H-benzo[3,4]cyclohepta[1,2-b]pyridin-10-yl)methoxy)phenyl)hex-4-ynoic acid;
(124) (S)-3-(4-((3-((1,1-dioxidotetrahydro-2H-thiopyran-4-yl)oxy)-6,7-dihydro-5H-benzo[3,4]cyclohepta[1,2-b]pyridin-10-yl)methoxy)phenyl)hex-4-ynoic acid;
(125) (S)-3-(4-((5-methyl-7-(3-(methylsulfonyl)propoxy)-9,10-dihydrophenanthren-3-yl)methoxy)phenyl)hex-4-ynoic acid;
(126) (S)-3-(4-((7-(2-ethoxyethoxy)-5-methyl-9,10-dihydrophenanthren-3-yl)methoxy)phenyl)hex-4-ynoic acid;
(127) (S)-3-(4-((5-methyl-7-(3-(methylsulfonyl)propoxy)-9,10-dihydrophenanthren-1-yl)methoxy)phenyl)hex-4-ynoic acid;
(128) (S)-3-(4-((11-methyl-9-(3-(methylsulfonyl)propoxy)-6,7-dihydro-5H-dibenzo[a,c][7]annulen-2-yl)methoxy)phenyl)hex-4-ynoic acid;
(129) (S)-3-(4-((9-(3-(methylsulfonyl)propoxy)dibenzo[d,f][1,3]dioxepin-2-yl)methoxy)phenyl)hex-4-ynoic acid;
(130) (S)-3-(4-((6,6-dimethyl-9-(3-(methylsulfonyl)propoxy)-6,7-dihydrodibenzo[b,d]oxepin-2-yl)methoxy)phenyl)hex-4-ynoic acid;
(131) (S)-3-(4-((1-methyl-3-(3-(methylsulfonyl)propoxy)-6,7-dihydro-5H-benzo[3,4]cyclohepta[1,2-d]pyrimidin-10-yl)methoxy)phenyl)hex-4-ynoic acid;
(132) (S)-3-(4-((9-((1,1-dioxidotetrahydro-2H-thiopyran-4-yl)methoxy)-6,7-dihydro-5H-dibenzo[a,c][7]annulen-2-yl)methoxy)phenyl)butanoic acid;
(133) (R)-3-(4-((9-((1,1-dioxidotetrahydro-2H-thiopyran-4-yl)methoxy)-6,7-dihydro-5H-dibenzo[a,c][7]annulen-2-yl)methoxy)phenyl)butanoic acid;
(134) (S)-3-(4-((9-((1,1-dioxidotetrahydro-2H-thiopyran-4-yl)methoxy)-6,7-dihydro-5H-dibenzo[a,c][7]annulen-2-yl)methoxy)phenyl)-4-ethoxybutanoic acid;
(135) (S)-3-(4-(((9-(3-(methylsulfonyl)propoxy)-6,7-dihydro-5H-dibenzo[a,c][7]annulen-2-yl)methyl)amino)phenyl)hex-4-ynoic acid;
(136) (S)-3-(4-(((9-((1,1-dioxidotetrahydro-2H-thiopyran-4-yl)methoxy)-6,7-dihydro-5H-dibenzo[a,c][7]annulen-2-yl)methyl)amino)phenyl)hex-4-ynoic acid;
(137) 3-(4-((9-((1,1-dioxidotetrahydro-2H-thiopyran-4-yl)methoxy)-6,7-dihydro-5H-dibenzo[a,c][7]annulen-2-yl)methoxy)phenyl)-3-(4-fluorophenyl)propanoic acid;
(138) (S)-3-(4-((11-methyl-9-(((R)-tetrahydrofuran-3-yl)oxy)-6,7-dihydro-5H-dibenzo[a,c][7]annulen-2-yl)methoxy)phenyl)hex-4-ynoic acid;
(139) (R)-3-(4-((9-((1,1-dioxidotetrahydro-2H-thiopyran-4-yl)methoxy)-6,7-dihydro-5H-dibenzo[a,c][7]annulen-2-yl)methoxy)phenyl)pent-4-ynoic acid;
(140) (S)-3-(4-((5-ethyl-9-(((R)-tetrahydrofuran-3-yl)oxy)-6,7-dihydro-5H-dibenzo[b,d]azepin-2-yl)methoxy)phenyl)hex-4-ynoic acid;
(141) sodium (1S,2S)-2-(4-(((9-(3-(methylsulfonyl)propoxy)-6,7-dihydro-5H-dibenzo[a,c][7]annulen-2-yl)methyl)amino)phenyl)cyclopropanecarboxylate;
(142) sodium 2-((3S)-6-((11-methyl-9-(3-(methylsulfonyl)propoxy)-6,7-dihydro-5H-dibenzo[a,c][7]annulen-2-yl)methoxy)-2,3-dihydrobenzofuran-3-ylacetate;
(143) sodium (1S,2S)-2-(4-((11-methyl-9-(3-(methylsulfonyl)propoxy)-6,7-dihydrodibenzo[b,d]oxepin-2-yl)methoxy)phenyl)cyclopropanecarboxylate;
(144) sodium (1S,2S)-2-(4-((9-(3-(ethylsulfonyl)propoxy)-11-methyl-6,7-dihydro-5H-dibenzo[a,c][7]annulen-2-yl)methoxy)phenyl)cyclopropanecarboxylate;
(145) sodium (S)-2-(6-(((9-(3-(methylsulfonyl)propoxy)-6,7-dihydro-5H-dibenzo[a,c][7]annulen-2-yl)methyl)amino)-2,3-dihydrobenzofuran-3-ylacetate;
(146) sodium (S)-3-(4-((9-(3-(methylsulfonyl)propoxy)-6,7-dihydro-5H-dibenzo[a,c][7]annulen-2-yl)methoxy)phenyl)hex-4-ynoate; and
(147) sodium (S)-3-(4-((9-((1,1-dioxidotetrahydro-2H-thiopyran-4-yl)methoxy)-6,7-dihydro-5H-dibenzo[a,c][7]annulen-2-yl)methoxy)phenyl)hex-4-ynoate.

6. A pharmaceutical composition comprising the compound of claim 1 and a pharmaceutically acceptable carrier.

7. A method of treating type II diabetes mellitus in a mammal in need thereof said method comprising administering the compound of claim 1 to the mammal.

8. A method of inhibiting GPR40 in a mammal having a disease selected from the group consisting of diabetes, impaired glucose tolerance, ketosis, acidosis, diabetic neuropathy, diabetic nephropathy, diabetic retinopathy, macular edema, hyperlipidemia, genital disorders, skin diseases, arthropathia, osteopenia, arteriosclerosis, thrombotic diseases, dyspepsia, memory and learning difficulties, depression, manic depression, schizophrenia, attention-deficit hyperactivity disorder, visual impairments, appetite dysregulation, obesity, hypoglycemia, hypertension, edemas, insulin resistance, labile diabetes, lipoatrophia, insulin allergies, insulinoma, lipotoxicity, pancreatic fatigue, hyperinsulinemia, cancers, metabolic syndromes, immune diseases, inflammatory diseases, multiple sclerosis and acute renal failure, said method comprising administering the compound of claim 1 to the mammal.