TW201741307A - FXR modulators and methods of their use - Google Patents

Abstract

The present disclosure is directed to modulators of farnesoid X receptor. Methods of making and using these modulators is also described.

Description

FXR regulator and its use method

The present disclosure relates to modulators of farnesoid X receptors. Methods of making and using such conditioning agents are also described.

The farnesoid X receptor (FXR) system is known to be expressed in the liver, kidney, and intestine. Lundquist, IV, JT et al . , J. Med. Chem. 2010, 53, 1774-1787. FXR's natural system is cholic acid, such as chodeoxycholic acid. Id. In rodent models, activation of FXR by FXR agonists results in beneficial metabolic effects such as glucose drop, insulin sensitization, triglyceride decline, and cholesterol drop. Abel, U., et al., Bioorg. & Med. Chem. Lett. 20 (2010) 4911-4917; Richter, HGF et al., Bioorg. & Med. Chem. Lett. 21 (2011) 1134-1140. FXR agonists have also been shown to have hepatoprotective effects by preventing lipid accumulation, reducing fibrosis, and reducing inflammation in the liver. Abel, U., et al. at 4911.

FXR modulators (ie, agonists or partial agonists) have a variety of indications, including, for example, abnormal dyslipidemia, liver disease, diabetes, diabetic nephropathy, vitamin D-related diseases, drug-induced side effects, hepatitis, inflammatory bowel Treatment of disease, hypertriglyceridemia, gallstones, nonalcoholic steatohepatitis, atherosclerosis, and primary biliary cirrhosis. Lundquist, IV, J.T., et al., 1774; Richter, H.G.F., et al., 1134; Abel, U., et al., 4911. Therefore, a modulator of FXR is required.

The present disclosure relates to a compound of formula I, Wherein R ¹ is H, F, Cl, Br, or I; R ² is F, Cl, Br, or I; R ³ is C _1-6 alkyl or C _3-6 cycloalkyl; X is O, -NH-, or -N(CH ₃ )-; and R ⁴ is H, F, Cl, or CN; and a pharmaceutically acceptable salt thereof. Methods of making and using the compounds of formula I are also described.

The disclosure can be more fully understood by reference to the following description, including the <RTIgt; It will be understood that certain features of the disclosed compositions and methods described herein in the context of the various aspects may be provided in combination in a single aspect. Conversely, various features of the compositions and methods described in the context of a single aspect may be provided separately or in any sub-combination.

The term "alkyl", when used alone or as part of a substituent, means having from 1 to 12 carbon atoms ("C _1-12 "), preferably from 1 to 6 carbon atoms in the chain. A linear or branched alkyl group ("C _1-6 "). Examples of the alkyl group include methyl (Me, C ₁ alkyl), ethyl (Et, C ₂ alkyl), n-propyl (C ₃ alkyl), isopropyl (C ₃ alkyl), butyl ( C ₄ alkyl), isobutyl (C ₄ alkyl), secondary butyl (C ₄ alkyl), tertiary butyl (C ₄ alkyl), pentyl (C ₅ alkyl), isopentyl (C ₅ alkyl), tertiary pentyl (C ₅ alkyl), hexyl (C ₆ alkyl), isohexyl (C ₆ alkyl), and according to those of ordinary skill in the art and as provided herein A group of equivalents of any of the above examples that can be considered by the technology.

The term "cycloalkyl", when used alone or as part of a substituent, refers to an alkyl group having at least one ring. Preferably, the cycloalkyl groups disclosed herein have from 3 to 6 carbon atoms (" _C3-6 "). Examples of the cycloalkyl group include a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, a methyl-cyclopropyl group, a methyl-cyclobutyl group, a methyl-cyclopentyl group, and the like.

When a range of carbon atoms is used herein, for example, C _1-6 , all ranges and individual numbers of carbon atoms are encompassed. For example, "C _1-3 " includes C _1-3 , C _1-2 , C _2-3 , C ₁ , C ₂ , and C ₃ .

The term "halogen" means chlorine, fluorine, bromine, or iodine. The term "halo" means a chloro group, a fluoro group, a bromo group, or an iodine group.

As used herein, the term "compound(s) of formula I" includes the compounds of the formula "I" and any compound of the subclass I.

"FXR modulator" means a compound which is an agonist or partial agonist of FXR.

The term "pharmaceutically acceptable" means approved or approved by the competent authority of the United States federal or state government or a country other than the United States, or listed in the US Pharmacopoeia or other generally recognized pharmacopoeia. Used in animals (especially humans).

&quot;Pharmaceutically acceptable salt&quot; refers to a salt of a compound of the present disclosure which is pharmaceutically acceptable and which possesses the desired pharmacological activity of the parent compound. In particular, the salts are non-toxic and may be inorganic or organic acid addition salts and base addition salts. Specifically, such salts include: (1) acid addition salts formed by inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like; or organic acids. Formed, for example, acetic acid, propionic acid, caproic acid, cyclopentylpropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, 3-(4-hydroxybenzhydryl)benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, 1,2-ethane-disulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid , 4-chlorobenzenesulfonic acid, 2-naphthalenesulfonic acid, 4-toluenesulfonic acid, camphorsulfonic acid, 4-methylbicyclo[2.2.2]-oct-2-ene-1-carboxylic acid, grape heptanoic acid, 3-phenylpropionic acid, trimethylacetic acid, tertiary butyl acetic acid, lauryl sulfate, gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylic acid, stearic acid, muconic acid, and the like; or (2) a salt formed when an acid proton in a parent compound is replaced by a metal ion, such as an alkali metal ion, an alkaline earth ion or an aluminum ion; or a salt formed by coordinating the acidic proton with an organic base, such as ethanol Amines, diethanolamines, triethanolamines, N-methylglucamines, and the like. For illustration purposes only, the salt can be further packaged Containing sodium, potassium, calcium, magnesium, ammonium, tetraalkylammonium and the like; and when the compound contains basic functionality, non-toxic salts of organic or inorganic acids, such as hydrochloride, hydrobromide, tartaric acid Salts, mesylate, acetate, maleate, oxalate, and the like.

&quot;Pharmaceutically acceptable vehicle&quot; means a diluent, adjuvant, excipient, or carrier with which the compound of the present disclosure is administered. "Pharmaceutically acceptable excipient" means a substance that is non-toxic, biologically tolerant or biologically suitable for administration to a body, for example, as a pharmaceutical composition or as a pharmaceutical composition. A vehicle, carrier or diluent is an inert substance that facilitates administration of the agent and is compatible therewith. Examples of the excipient include calcium carbonate, calcium phosphate, various sugars, and various types of starch, cellulose derivatives, gelatin, vegetable oil, and polyethylene glycol.

"Subject" contains people. The terms "human", "patient" and "subject" are used interchangeably herein.

In one embodiment, "treating or treating" any disease or condition refers to amelioration of the disease or condition (ie, preventing or reducing the progression of the disease or at least one of its clinical symptoms). In another embodiment, "treating or treating" refers to amelioration of at least one physical parameter, possibly a parameter that is not identifiable by an individual. In yet another embodiment, "treating or treating" refers to modulating a disease or condition, whether the disease or condition is physically (eg, identifiable by symptoms), physiologically (eg, stabilization of body parameters), Or a disease or condition of both. In yet another embodiment, "treating or treating" refers to delaying the onset of a disease or condition.

"Compound of the present disclosure" and equivalent expression are intended to encompass a compound of formula (I) as described herein, and when the context permits, the expression includes pharmaceutically acceptable salts and solvates, for example Hydrate. Likewise, when the context permits, reference to an intermediate is intended to cover its salts and solvates, whether or not they are claimed.

As used herein, the term "isotopic variant" refers to a compound comprising an unnatural proportion of isotopes at one or more of the atoms that make up the compound. For example, the compound "isotopic variant" may be a radioactive label, i.e. containing one or more non-radioactive isotopes, for example, such as deuterium ⁽² H or D), carbon--13 ⁽¹³ C), nitrogen-15 ⁽¹⁵ N), or the like. It will be appreciated that in compounds where such isotopic substitutions occur, the following atoms may be altered if present, so that, for example, any hydrogen may be ² H/D, any carbon may be ¹³ C, or any nitrogen. It may be ¹⁵ N and the presence and location of such atoms can be determined within the skill of the art. As such, the disclosure may include the preparation of isotopic variations having a radioisotope, such as where the resulting compound is useful in drug and/or matrix distribution studies. The radiolabeled compounds of the present disclosure can be used in diagnostic methods, such as single photon emission computed tomography (SPECT). The radioisotope strontium (ie, ³ H) and carbon-14 (ie, ¹⁴ C) are particularly suitable because they are easy to incorporate and have off-the-shelf detection methods. In addition, compounds substituted with positron-emitting isotopes (eg, ¹¹ C, ¹⁸ F, ¹⁵ O, and ¹³ N) can be prepared and can be used in positron tomography (PET) studies to examine the possession of the receptor.

All isotopic variations of the compounds disclosed herein, whether or not they are radioactive, are encompassed within the scope of the present disclosure.

It should also be understood that compounds having the same molecular formula but differing in the nature or order of their atomic bonds or in the arrangement of their atoms in space are referred to as "isomers". The isomers in which their atoms are arranged in space are called "stereoisomers", such as non-image isomers and mirror image isomers.

Stereoisomers that are not mirror images of each other are called "diastereomers", and stereoisomers that are non-superimposable mirror images of each other are called "enantiomers". When a compound has an asymmetric center, for example, the centerline is bonded to four different groups, it may have a pair of mirror image isomers. Mirror isomers can be characterized by the absolute configuration of their asymmetric centers, which are described by the R and S sequence rules of Cahn and Prelog, or by the way the molecule rotates the plane of polarization to specify right-handed or left-handed rotation. (ie, (+) or (-) isomers, respectively). Palm compounds may be present as individual mirror image isomers or as a mixture thereof. Mixtures containing the same proportion of mirror image isomers are referred to as "racemic mixtures".

"Tautomer" means a compound having a structural form of a specific compound that can be converted to each other, the difference being the transposition of a hydrogen atom and electrons. Therefore, the two structures are in equilibrium by the movement of π electrons and atoms (usually H). For example, enol and ketone tautomers can be rapidly converted to each other by treatment with an acid or a base. Another example of tautomerism is the acid and nitro form of phenylnitromethane, which is also formed by treatment with an acid or a base.

Tautomeric forms may be associated with achieving optimal chemical reactivity and biological activity of the desired compound.

The compounds of the present disclosure may have one or more asymmetric centers; such compounds may thus be produced as individual (R) or (S) stereoisomers or as a mixture thereof.

The description or naming of a particular compound in the specification and claims is intended to include two individual mirror image isomers, and such racemic mixtures or other mixtures, unless otherwise indicated. Within the present disclosure, any open valence of a carbon, oxygen, or nitrogen atom present in any of the structures described herein indicates the presence of a hydrogen atom. When there is a palm center in the structure, but the center does not show a specific stereochemistry, the structure covers two mirrors. Isomers, either separately or in the form of a mixture. Methods for determining stereochemistry and isolating stereoisomers are well known in the art.

The present disclosure relates to a compound of formula I,

According to the disclosure, R ¹ is H, F, Cl, Br, or I. In some aspects, R ¹ is H. In other aspects, R ¹ is F. In a preferred aspect, R ¹ is Cl. In other aspects, R ¹ is Br. In still other aspects, R ¹ is I.

According to the disclosure, R ² is F, Cl, Br, or I. In some aspects, R ² is F. In a preferred aspect, R ² is Cl. In other aspects, R ² is Br. In still other aspects, R ² is based I.

In a preferred aspect of the present disclosure, the R ¹ and R ² lines are at the 2 and 6 positions of the phenyl ring to which they are attached:

In a preferred embodiment of the present disclosure, both R ¹ and R ² are Cl.

According to the disclosure, R ³ is C _1-6 alkyl or C _3-6 cycloalkyl. In some aspects, R ³ is C _1-6 alkyl, such as C ₁ alkyl, C ₂ alkyl, C ₃ alkyl, C ₄ alkyl, C ₅ alkyl, or C ₆ alkyl. In a preferred embodiment, R ³ is C _3-6 cycloalkyl, such as C ₃ cycloalkyl, C ₄ cycloalkyl, C ₅ cycloalkyl, or C ₆ cycloalkyl. In an exemplary embodiment, R ₃ is a cyclopropyl group.

According to the disclosure, the A system

In some aspects, the A series:

In a preferred aspect of (a), the compound of formula I is a compound of formula IA:

In other aspects, the A series:

In the embodiment of the A system (b), X is O, -NH-, or -N(CH ₃ )-. In some aspects, X is O. In other aspects, X is -NH-. In still other aspects, X is based -NH (CH ₃₎ -.

In a preferred embodiment of (b), the compound of formula I is a compound of formula IB:

In other preferred aspects of (b), the compound of formula I is a compound of formula IC:

In some aspects, the A series:

In a preferred embodiment of (c), the compound of formula I is a compound of formula ID:

In still other aspects, the A system:

In a preferred aspect of (d), the compound of formula I is a compound of formula IE:

In other aspects, the A series:

In a preferred aspect of (e), the compound of formula I is a compound of formula IF:

In some aspects, the A series:

In a preferred embodiment of (f), the compound of formula I is a compound of formula IG:

In other aspects, the A series:

In a preferred aspect of (g), the compound of formula I is a compound of formula IH:

According to the disclosure, R ⁴ is H, F, Cl, or CN. In a preferred aspect, R ⁴ is H. In other aspects, R ⁴ is F. In still other aspects, R ⁴ is Cl. In other aspects, R ⁴ is CN.

The disclosure also relates to methods of using the compounds described herein to treat an individual diagnosed with or having a disease, disorder, or condition mediated by the farnesoid X receptor (FXR). The compounds disclosed herein are FXR agonists or FXR partial agonists. The disclosed methods are achieved by administering to a subject a compound sufficient to modulate the amount of FXR.

In some aspects, the compounds described herein are useful for treating chronic biliary stagnation conditions, such as primary biliary cirrhosis (PBC) or primary sclerosing cholangitis (PSC). Rizzo et al., Curr. Drug Targets Immune Endocr. Metabol. Disord. 2005, 5(3), 289-303; Zollner, Mol. Pharm. 2006, 3(3), 231-51; Cai et al., Expert Opin. Ther. Targets 2006, 10(3) 409-421. The compounds described herein are also useful for the treatment of progressive familial cholestasis (PFIC), alcohol-induced cirrhosis and associated biliary stasis, and liver fibrosis. The compounds disclosed herein are useful in the treatment of hepatic steatosis and related syndromes such as nonalcoholic steatohepatitis (NASH). The compounds disclosed herein are useful for the treatment of bile stasis and/or fibrosis associated with cirrhosis (alcoholic cirrhosis) or viral hepatitis.

In other aspects, the compounds described herein are useful in the treatment of gallstones, such as preventing the formation of cholesterol gallstones or preventing the re-formation of gallstones after surgical resection or lithotripsy. Doggrell, S. Curr. Opin. Investig. Drugs 2006, 7(4), 344-348.

In still other aspects, the compounds described herein are useful for reducing serum triglycerides and/or reducing total serum cholesterol. Kast et al., Mol. Endocrinol. 2001, 15(10), 1720-1728; Urizar et al., Science 2002, 296 (5573), 1703-1706; Lambert et al., J. Biol. Chem. 2003, 278, 2563 -2570; Watanabe et al., J. Clin. Invest. 2004, 113(10), 1408-1418; Figge et al., J. Biol. Chem. 2004, 279(4), 2790-2799; Bilz et al. .J. Physiol. Endocrinol. Metab. 2006, 290(4), E716-22. That is, the compounds described herein can be used to reduce total cholesterol, reduce LDL cholesterol, reduce VLDL cholesterol, increase HDL cholesterol, and/or reduce triglyceride levels. The compounds described herein can also be used to treat abnormal dyslipidemia.

The compounds disclosed herein are useful in the treatment of lipid and lipoprotein disorders such as hypercholesterolemia, hypertriglyceridemia, and artherosclerosis. Hanniman et al., J. Lipid Res. 2005, 46(12), 2595-2604. In some aspects, the compounds disclosed herein are useful for treating cardiovascular conditions, such as acute myocardial infarction, acute stroke, or thrombosis.

In other aspects, the compounds described herein are useful for improving insulin sensitivity and glucose tolerance. The compounds described herein are also useful for the treatment of metabolic disorders such as Type II diabetes and diabetic complications (eg, diabetic nephropathy, diabetic retinopathy, diabetic neuropathy, peripheral arterial occlusive disease). Stayrook et al., Endocrinology 2005, 146(3), 984-91; Zhang et al., Proc. Natl. USA 2006, 103(4), 1006-1011; Cariou et al., J. Biol. Chem. 2006, 281, 11039-11049; Ma et al., J. Clin. Invest. 2006. 116(4). 1102-1109; Duran-Sandoval et al., Biochimie 2005, 87(1), 93-98, Holt et al., Genes Dev. 2003, 17(13), 1581-1591. The compounds described herein are useful for treating obesity.

The compounds disclosed herein are useful for treating cancer, such as breast cancer, colorectal cancer, or prostate cancer. Niesor et al., Curr. Pharm. Des. 2001, 7(4), 231-259; Silva, J. Lipid Res. 2006, 47(4), 724-733; De Gottardi et al., Dig. Dis. Sci. 2004, 49(6), 982-989.

In still other aspects, the compounds described herein are useful for treating gastrointestinal conditions associated with reduced intake of dietary fats and fat-soluble dietary vitamins (eg, vitamin D), which can be overcome by increasing the quality of the intestinal bile acids and phospholipids. .

In other aspects, the compounds disclosed herein are useful for treating inflammatory bowel disease, such as, for example, Crohn&apos;s disease or ulcerative colitis. Inagaki et al., Proc. Natl. Acad. Sci. USA. 2006, 103(10), 3920-3905.

In other aspects, the compounds disclosed herein are useful for the treatment of hepatitis B virus (HBV). See for example WO 2015/036442.

In a method of treatment according to the present disclosure, an effective amount of an agent according to the present disclosure is administered to an individual having or diagnosed with the disease, disorder, or condition. By "effective amount" is meant an amount or dose sufficient to generally achieve the desired therapeutic benefit in a patient in need of treatment for the specified disease, disorder, or condition. An effective amount or dose of a compound of the present disclosure can be by conventional methods (eg, model experiments, dose escalation studies, or clinical trials), as well as by consideration of conventional factors (eg, administration or drug delivery) Confirmation of the mode or route, the pharmacokinetics of the compound, the severity and duration of the disease, the condition, or the condition, the pre- or ongoing therapy of the individual, the health of the individual and the response to the drug, and the judgment of the attending physician. Dosage examples are in the range of from about 0.001 to about 200 mg of compound per kilogram of body weight per day, preferably from about 0.05 to 100 mg/kg/day, or from about 1 to 35 mg/kg/day; in single dose units or Fractional dosage units (eg BID, TID, QID). For a 70 kg person, an exemplary range of suitable dosages is from about 0.05 to about 7 g/day, or from about 0.2 to about 2.5 g/day.

In addition, the compounds of the present disclosure can be used in combination with additional active ingredients to treat the above conditions. Other active ingredients may be co-administered separately from the compounds of the present disclosure, or may be included in the pharmaceutical compositions according to the present disclosure. In an exemplary embodiment, the additional active ingredients are those that are known or found to be effective in treating any of the diseases or conditions described herein. The combination can be used to increase the therapeutic effect (e.g., by including in the combination a compound that enhances the potency or effectiveness of the active agent according to the present disclosure), to reduce one or more side effects, or to reduce the desired dosage of the active agent according to the present disclosure.

The compounds of the present disclosure are used alone or in combination with one or more other active ingredients to formulate the pharmaceutical compositions of the present disclosure. The pharmaceutical compositions of the present disclosure comprise: (a) an effective amount of at least one compound according to the present disclosure; and (b) a pharmaceutically acceptable excipient.

The delivery form of the pharmaceutical composition containing the active agent in one or more dosage units can be prepared using suitable pharmaceutical excipients and compounding techniques which are known or available to those of ordinary skill in the art. In the methods of the invention, the composition can be administered by a suitable route of administration, for example, orally, parenterally, rectally, topically, or via the eye, or by inhalation.

The preparation may be in the form of a tablet, a capsule, a sachet, a dragee, a powder, a granule, a lozenge, a powder for reconstitution, a liquid preparation, or a suppository. Preferably, the composition is formulated for intravenous infusion, topical administration, or oral administration.

For oral administration, the compounds of the present disclosure may be provided in the form of a tablet or capsule, or in the form of a solution, emulsion, or suspension. To prepare an oral composition, the compound can be formulated to yield a dosage of, for example, from about 0.05 to about 100 mg/kg per day, or from about 0.05 to about 35 mg/kg per day, or from about 0.1 to about 10 mg/kg per day. For example, a total daily dose of about 5 mg to 5 g per day can be accomplished by administering once, twice, three times, or four times a day.

Oral lozenges can include a mixture of pharmaceutically acceptable excipients (eg, inert diluents, disintegrating agents, binders, lubricants, sweeteners, flavoring agents, coloring agents, and preservatives) according to the present disclosure. Compound. Suitable inert fillers include sodium carbonate, calcium carbonate, sodium phosphate, calcium phosphate, lactose, starch, sugar, glucose, methylcellulose, magnesium stearate, mannitol, sorbitol, and the like. Exemplary liquid oral vehicles include ethanol, glycerin, water, and the like. Starch, polyvinylpyrrolidone (PVP), sodium starch glycolate, microcrystalline cellulose, and alginic acid are suitable disintegrants. The binder may include starch and gelatin. The lubricant, if present, can be magnesium stearate, stearic acid, or talc. If desired, the tablet may be coated with a material such as glyceryl monostearate or glyceryl distearate to delay absorption in the gastrointestinal tract or may be coated by enteric coating.

Capsules for oral administration include hard gelatin capsules and soft gelatin capsules. For the preparation of hard gelatin capsules, the compounds of the present disclosure may be combined with a solid, semi-solid, or liquid diluent. Soft gelatin capsules can be obtained by combining the disclosed compounds with water, oil (such as peanut oil or Olive oil), liquid paraffin, a mixture of monoglycerides of short chain fatty acids and diglycerides, polyethylene glycol 400, or propylene glycol are prepared.

The liquid for oral administration can be in the form of a suspension, solution, emulsion, or syrup, or can be lyophilized or presented as a dried product for reconstitution with water or other suitable vehicle before use. The liquid compositions may optionally contain: pharmaceutically acceptable excipients such as suspending agents (for example, sorbitol, methylcellulose, sodium alginate, gelatin, hydroxyethylcellulose, carboxymethylcellulose) , aluminum stearate gel, and the like; non-aqueous vehicles such as oils (eg almond oil, or fractionated coconut oil), propylene glycol, ethanol, or water; preservatives (eg, methylparaben, a propyl paraben, or sorbic acid; a wetting agent such as lecithin; and, if desired, a flavoring agent, or a coloring agent.

The active agents of the present disclosure may also be administered by a non-oral route. For example, the composition can be formulated as a suppository for rectal administration. For parenteral use (including intravenous, intramuscular, intraperitoneal, or subcutaneous routes), the compounds of the present disclosure may be provided in sterile aqueous solutions or suspensions buffered to the appropriate pH and isotonicity, or Provided in a parenterally acceptable oil. Suitable aqueous vehicles include Ringer's solution and isotonic sodium chloride. Such forms will be presented in unit dosage form (e.g., ampoules or disposable injection devices), in multi-dose forms (e.g., vials from which appropriate dosages may be taken), or in solid or pre-concentrated form for injectable formulations. Exemplary infusion doses of the compound can range from about 1 to 1000. mu.g/kg/minute and are mixed with the pharmaceutical carrier over a period of minutes to days.

For topical administration, the compound can be combined with the pharmaceutical carrier to a concentration of from about 0.1% to about 10% drug to vehicle. Another mode of administration of the compounds of the present disclosure may utilize patch formulations to achieve transdermal delivery.

Alternatively, in the methods of the present disclosure, the compounds of the present disclosure may be administered by inhalation via the nasal or oral route, for example, in a spray formulation that also contains a suitable carrier.

Exemplary compounds that can be used in the methods of the present disclosure will now be described with reference to the following generally prepared illustrative synthetic schemes and the following specific examples. Those skilled in the art will be able to appreciate that in order to obtain the various compounds herein, the starting materials can be suitably selected such that the permeation reaction scheme will carry the final desired substituent (with or without appropriate protection) to produce The desired product. Alternatively, a suitable group may be required or desired at the position of the final desired substituent, which may be carried throughout the reaction scheme and, where appropriate, substituted with the desired substituent. Unless otherwise indicated, this variable refers to the definition of formula (I) above. The reaction can be carried out between the melting point and the reflux temperature of the solvent, preferably between 0 ° C and the reflux temperature of the solvent. The reaction may be heated by conventional heating or microwave heating. The reaction can also be carried out in a sealed pressure vessel at a normal reflux temperature above the solvent.

Instance

Intermediate 1: ethyl 4-(azin-3-yl)benzoate.

Step 1: 3-(4-(ethoxycarbonyl)phenyl)azinium-1-carboxylic acid tert-butyl ester. The title compound is prepared using Negishi (the Negishi) the reaction, the reaction system technology as known in the art and as described in US Patent Application Publication No. 20140235614 (August 21, 2014) in the.

Step 2: Ethyl 4-(azin-3-yl)benzoate. Add HCl/II dropwise to a solution of 3-(4-(ethoxycarbonyl)phenyl)azinium-1-carboxylic acid tert-butyl ester (1.53 g, 4.92 mmol) in THF (20.00 mL) Dioxane (4.0 M, 30.00 mL). The resulting mixture was stirred at 25 ° C for 30 minutes. TLC (PE/EA = 3/1) showed that the reaction was completed. The reaction mixture was concentrated with EtOAc EtOAc m. +ESI-MS: m/z 205.9[M+H] ⁺

Intermediate 2: (2-((4-Bromophenoxy)methoxy)ethyl)trimethylnonane.

The title compound was prepared as described in Tetrahedron Letters, 42 (9), 1611-1613;

Intermediate 3: Methyl 1,1,3,4-tetrahydroisoquinoline-7-carboxylate.

Step 1: 1-(7-Bromo-3,4-dihydroisoquinolin-2(1H)-yl)-2,2,2-trifluoroethyl-1-one. The title compound is prepared in the case of U.S. Patent Application Publication No. 20080081803 (April 3, 2008) in the manner and prepared from 2- (4-bromophenyl) ethan-l-amine.

Step 2: 1,2,3,4-tetrahydroisoquinoline-7-carbonitrile. The title compound was prepared as described in PCT International Patent Application No. 9850364 ( November 12 , 1998 ) and prepared from 1-(7-bromo-3,4-dihydroisoquinoline-2 ( 1H)-yl)-2,2,2-trifluoroethyl-1-one.

Step 3: Methyl 1,2,3,4-tetrahydroisoquinoline-7-carboxylate. The title compound is prepared in the preparation of and as in PCT International Patent Application No. 2006117549 (09 November 2006) from 1,2,3,4-tetrahydro embodiment isoquinoline-7-carbonitrile.

Intermediate 4: 4-(bromomethyl)-5-cyclopropyl-3-(2,6-dichlorophenyl)iso 4-(bromomethyl)-5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazole).

The title compound can be prepared with reference to PCT International Patent Application No. 2009012125 (Jan. 22, 2009) as are known in the art.

Intermediate 5: Methyl isoindoline-5-carboxylate.

Step 1: 5-Butyl bromoisoindoline-2-carboxylic acid butyl ester. The title compound can be prepared from isoporphyrin-1,3-dione and prepared as described in PCT International Patent Application No. 2014089324 (June 12, 2014).

Step 2: Methyl isoindoline-5-carboxylate. The title compound can be prepared from 5-bromoisoindoline-2-carboxylic acid tert-butyl ester as described in PCT International Patent Application No. 2005095403 (October 13, 2005).

Intermediate 6: ethyl 4-(1-(4-hydroxyphenyl)azin-3-yl)benzoate.

Step 1: 4-(1-(4-(2-(Trimethylmethyl)ethoxy)methoxy)phenyl)azin-3-yl)benzoic acid ethyl ester. Ethyl 4-(azin-3-yl)benzoate (intermediate 1,802 mg, 3.87 mmol, 1.0 eq ) and (2-((4-bromophenoxy)methoxy)ethyl) Cs ₂ CO ₃ (2.54 g, 7.80 mmol, 2.00 eq ), Pd(dba) ₂ was added to a solution of trimethyl decane (intermediate 2, 1.54 g, 5.07 mmol, 1.30 eq ) in toluene (30.00 mL) (448 mg, 0.78 mmol, 0.20 eq ) and X-phos (558 mg, 1.17 mmol, 0.30 eq ). The mixture was degassed and then refilled three times with nitrogen. The reaction was stirred at 110 ° C for 10 hours. TLC (PE/EA = 3/1) showed that the reaction was completed. The reaction mixture was concentrated to dryness. The residue was purified by EtOAc (EtOAc EtOAc (EtOAc) +ESI-MS: m/z 428.2 [M+H] ⁺ .

Step 2: 4-(1-(4-Hydroxyphenyl)azin-3-yl)benzoic acid ethyl ester. Ethyl 4-(1-(4-((2-(trimethylmethyl)ethoxy)methoxy)phenyl)indol-3-yl)benzoate (1.1 g, 2.58 mmol, 1.0 EQ) in EtOH (40.00mL) was added in of HCl (1.0M, 20.6mL, 8.0 eq ). The resulting mixture was stirred at 25 ° C for 30 minutes. TLC (PE/EA = 3/1) shows that the starting material has been completely consumed. The reaction mixture was extracted with EA (100mL X 3) with aqueous NaHCO ₃ (100 mL) quenched. The combined organic layers were dried over anhydrous Na ₂ SO ₄ and then concentrated to dryness. The residue was purified with EtOAc (EtOAc: EtOAc (EtOAc)

Intermediate 7: methyl 2-(4-hydroxyphenyl)isoindoline-5-carboxylate.

The title compound was prepared in a similar manner to the intermediate 6, step 1 to 2, using the isoindoline-5-carboxylic acid methyl ester (intermediate 5) in step 1.

Intermediate 8: ethyl 3-(azin-3-yl)benzoate.

The title compound was prepared in a similar manner to Intermediate 1 using ethyl 3-iodobenzoate in Step 1.

Intermediate 9: ethyl 3-(1-(4-hydroxyphenyl)azin-3-yl)benzoate.

The title compound was prepared in a similar manner to Intermediate 6, Steps 1 to 2, using ethyl 3-(azin-3-yl)benzoate ( Intermediate 8) in Step 1.

Intermediate 10: ethyl 3-(1-(2-chloro-4-hydroxyphenyl)azin-3-yl)benzoate.

Step 1: (2-((4-Bromo-3-chlorophenoxy)methoxy)ethyl)trimethyldecane. The title compound was prepared as described in Tetrahedron Letters, 42 (9), 1611-1613;

Step 2: Ethyl 3-(1-(2-chloro-4-hydroxyphenyl)azin-3-yl)benzoate. The title compound is used in a similar manner to the intermediate 6, step 1 to 2, using ethyl 3-(azin-3-yl)benzoate (intermediate 8) and (2-((4-bromo)) Prepared by 3-chlorophenoxy)methoxy)ethyl)trimethyldecane.

Intermediate 11: methyl 2-(2-chloro-4-hydroxyphenyl)isoindoline-5-carboxylate.

The title compound is used in a similar manner to the intermediate 6, step 1 to 2, using the isoindoline-5-carboxylic acid methyl ester (intermediate 5) and (2-((4-bromo-3-). Prepared by chlorophenoxy)methoxy)ethyl)trimethyldecane.

Intermediate 12: methyl 3-(6-hydroxy-1-methyl-1,2,3,4-tetrahydroquinolin-2-yl)benzoate.

Step 1: (Z)-3-(3-(5-Methoxy-2-nitrophenyl)propenyl)benzoic acid methyl ester. In 5-methoxy-2-n-benzaldehyde (see, for example, PCT International Patent Application No. 2012109108, August 16, 2012; PCT International Patent Application No. 2004094420, November 04, 2004) (3.26) g, 18.0 mmol) and methyl 3-ethyl benzoate (see, for example, Asian Journal of Chemistry, 19(7), 5093-5097; 2007; PCT International Patent Application No. 2006067445, June 29, 2006) (3.21g, 18.0mmol) in DCM (70mL) in the solution in one portion at room temperature was added ZrCl ₄ (1.68g, 7.2mmol). The resulting mixture was then stirred at 40 ° C for 17 hours. LC-MS showed the reactant 5-methoxy-2-n-benzaldehyde was completely consumed. The reaction mixture was filtered and the filtrate was concentrated to dry. The residue was purified by column chromatography eluting with EtOAc (EtOAc: EtOAc +ESI-MS :m/z 342.1[M+H] ⁺

Step 2: Methyl 3-(6-methoxy-1,2,3,4-tetrahydroquinolin-2-yl)benzoate. Methyl (Z)-3-(3-(5-methoxy-2-nitrophenyl)propenyl)benzoic acid methyl ester (1.0 g, 2.9 mmol) in DCM (10 mL) Pd/C (10 mg) was added. The suspension was degassed in vacuo and then purged three times with hydrogen. The mixture was stirred at 20 ° C for 17 hours under hydrogen (15 psi). LC-MS showed that methyl (Z)-3-(3-(5-methoxy-2-nitrophenyl)propenyl)benzoate was completely consumed and one peak with the desired MS was observed. The reaction mixture was filtered and the filtrate was concentrated to dry. The residue was purified by column chromatography eluting EtOAc (EtOAc:EtOAc +ESI-MS :m/z 297.9[M+H] ⁺

Step 3: 3-(6-Hydroxy-1,2,3,4-tetrahydroquinolin-2-yl)benzoic acid. Methyl 3-(6-methoxy-1,2,3,4-tetrahydroquinolin-2-yl)benzoate (1.5 g, 5.04 mmol) in HBr /EtOAc (50 mL, 40% w) The solution was stirred at 100 ° C for 12 hours. LCMS indicated that the reaction methyl 3-(6-methoxy-1,2,3,4-tetrahydroquinolin-2-yl)benzoate was completely consumed. The reaction mixture was partitioned between EtOAc (50 mL) The organic phase was dried over Na ₂ SO _4, filtered and then concentrated under reduced pressure. The title compound (1.3 g, 95.8%) eluted

+ESI-MS :m/z 269.9[M+H] ⁺

Step 4: Methyl 3-(6-hydroxy-1,2,3,4-tetrahydroquinolin-2-yl)benzoate. Add SOCl ₂ (3.4 g, a solution of 3-(6-hydroxy-1,2,3,4-tetrahydroquinolin-2-yl)benzoic acid (1.3 g, 4.8 mmol) in MeOH (50 mL) 28.8 mmol). The mixture was stirred at 60 ° C for 1 hour. LC-MS showed that 3-(6-hydroxy-1,2,3,4-tetrahydroquinolin-2-yl)benzoic acid was completely consumed and a major peak with the desired MS was observed. The reaction mixture was concentrated under reduced pressure to give a residue. The crude title compound (1.37 g, crude) was used in the next step without further purification.

+ESI-MS: m/z 283.9[M+H] ⁺

Step 5: Methyl 3-(6-((tertiarybutoxycarbonyl)oxy)-1,2,3,4-tetrahydroquinolin-2-yl)benzoate. 3- (6-hydroxy-1,2,3,4-tetrahydro-quinolin-2-yl) benzoate (1.35g, 4.76mmol) and Et ₃ N (1.45g, 14.3mmol) in DCM ( Boc ₂ O (3.12 g, 14.3 mmol) was added to the solution in 5.0 mL). The resulting mixture was stirred at 20 ° C for 1 hour. TLC (PE/EA = 1/1) showed that the reaction product methyl 3-(6-hydroxy-1,2,3,4-tetrahydroquinolin-2-yl)benzoate was completely consumed. The reaction mixture was filtered and concentrated under reduced pressure. The residue was purified by EtOAc EtOAc EtOAc (EtOAc) ¹ H-NMR (400 MHz, CDCl ₃ ), δ = 8.06 (s, 1H), 7.97 (d, J = 7.5 Hz, 1H), 7.59 (d, J = 7.9 Hz, 1H), 7.43 (t, J = 7.7 Hz, 1H), 6.85-6.79 (m, 2H), 6.56-6.48 (m, 1H), 4.49 (dd, J = 3.1, 9.3 Hz, 1H), 4.06 (br.s., 1H), 3.93 ( s, 3H), 2.93 (ddd, J = 5.3, 10.7, 16.2 Hz, 1H), 2.72 (td, J = 4.7, 16.5 Hz, 1H), 2.14 - 2.08 (m, 1H), 2.04-1.93 (m, 1H), 1.56 (s, 9H).

Step 6: Methyl 3-(6-((tertiary butoxycarbonyl)oxy)-1-methyl-1,2,3,4-tetrahydroquinolin-2-yl)benzoate. Methyl 3-(6-((tertiary butoxycarbonyl)oxy)-1,2,3,4-tetrahydroquinolin-2-yl)benzoate (0.5 g, 1.3 mmol) and HCHO ( A drop of acetic acid was added to a solution of 0.9 mL) in MeOH (10 mL). The reaction mixture was stirred for 5 min then NaBH(OAc) ₃ (246 mg, 3.9 mmol) was then taken in one portion. The resulting mixture was stirred at 25 ° C for 24 hours. LC-MS showed the reaction was completed. The reaction mixture was quenched with water (20 mL) then EtOAc (EtOAc) The combined organic phases were washed with brine (20mL), dried over anhydrous Na ₂ SO ₄ and then concentrated to dryness. The crude title compound (470 mg, crude) was obtained. +ESI-MS :m/z 398.0[M+H] ⁺

Step 7: Methyl 3-(6-hydroxy-1-methyl-1,2,3,4-tetrahydroquinolin-2-yl)benzoate. Methyl 3-(6-((tertiarybutoxycarbonyl)oxy)-1-methyl-1,2,3,4-tetrahydroquinolin-2-yl)benzoate (470 mg, 1.18 mmol) HCl/MeOH (4M, 1.5 mL) was added in EtOAc (30 mL). The mixture was stirred at 20 ° C for 3 hours. LC-MS showed that methyl 3-(6-((tertiarybutoxycarbonyl)oxy)-1-methyl-1,2,3,4-tetrahydroquinolin-2-yl)benzoate was completely Consume and detect a main peak with the desired MS. The reaction mixture was concentrated under reduced pressure to give a brown solid. The brown solid was washed with EA /EtOAc = 5 / 1 (30 mL) to give a white solid. The title compound (284 mg, 81.3%) was obtained. +ESI-MS :m/z 297.9[M+H] ⁺

Intermediate 13: methyl 3-(8-chloro-6-hydroxy-1-methyl-1,2,3,4-tetrahydroquinolin-2-yl)benzoate.

Step 1: Methyl 3-(6-((tertiarybutoxycarbonyl)oxy)-8-chloro-1,2,3,4-tetrahydroquinolin-2-yl)benzoate. Methyl 3-(6-((tertiarybutoxycarbonyl)oxy)-1,2,3,4-tetrahydroquinolin-2-yl)benzoate (Intermediate 12, product from Step 5 NCS (162.28 mg, 1.22 mmol) was added in one portion in a solution of EtOAc EtOAc. The reaction mixture was stirred at 20 ° C for 1 hour. TLC (PE/EA = 4/1) showed that the reaction was completed. The reaction mixture was partitioned between EtOAc (30 mL) The organic phase was separated and the aqueous phase was extracted with EA (10 mL×2). The combined organic layers were washed, dried over Na ₂ SO _4, filtered and then concentrated under reduced pressure with brine (10mL × 2). The title compound (505 mg, crude) +ESI-MS :m/z 440.0[M+Na] ⁺

Step 2: 3-(6-((Tris-butoxycarbonyl)oxy)-8-chloro-1-methyl-1,2,3,4-tetrahydroquinolin-2-yl)benzoic acid ester. Methyl 3-(6-((tertiarybutoxycarbonyl)oxy)-8-chloro-1,2,3,4-tetrahydroquinolin-2-yl)benzoate (505 mg, 1.21 mmol) Sodium hydride (49 mg, 1.21 mmol) was added in one portion to a solution of EtOAc. The resulting mixture was stirred at 20 ° C for 16 hours. HPLC/LCMS showed 19% of the desired compound was detected. The reaction mixture was diluted with water (50 mL) and then extracted with EA (30mL×2). The combined organic layers were washed with brine (10mL × 1), dried over anhydrous dried over Na ₂ SO _4, filtered and then concentrated under reduced pressure. The residue was purified by preparative HPLC (FA conditions). The title compound (52 mg, 9.95%) was obtained.

¹ H-NMR (400 MHz, CDCl ₃ ), δ = 8.01 (s, 1H), 7.89-1.87 (d, J = 7.6 Hz, 1H), 7.57-7.55 (d, J = 7.6 Hz 1H), 7.06-7.05 (d, J = 2.4 Hz 1H), 6.71-6.70 (d, J = 2.4 Hz 1H), 4.24 - 4.20 (m, 1H), 3.88 (s, 3H), 2.89 (s, 3H), 2.80 - 2.77 ( m, 1 H), 2.55-2.51 (m, 1 H), 2.29-2.26 (m, 1 H), 1.91-1.88 (m, 1 H), 1.52 (s, 9H).

Step 3: Methyl 3-(8-chloro-6-hydroxy-1-methyl-1,2,3,4-tetrahydroquinolin-2-yl)benzoate. The title compound was prepared in a similar manner to Intermediate 1, Step 2.

Intermediate 14: ethyl 3-(6-hydroxy-3,4-dihydroisoquinolin-2(1H)-yl)benzoate.

Step 1: 6-Methoxy-1,2,3,4-tetrahydroisoquinoline. The title compound can be prepared as known in the art and as described in Journal of Medicinal Chemistry, 56(8), 3414-3418;

Step 2: Ethyl 3-(6-methoxy-3,4-dihydroisoquinolin-2(1H)-yl)benzoate. 6-Methoxy-1,2,3,4-tetrahydroisoquinoline (1.0 g, 6.13 mmol), ethyl 3-iodobenzoate (2.03 g, 7.35 mmol), Pd(dba) ₂ (352 mg A mixture of Cs ₂ CO ₃ (7.98 g, 24.5 mmol) and X-phos (584 mg, 1.23 mmol) in DMF (15 mL). The resulting mixture was stirred at 100 ° C for 2 hours under nitrogen. The reaction mixture was cooled to room temperature and diluted with H ₂ O (30mL), then extracted with EA (20mL × 2). The combined organic layer was dried over anhydrous Na ₂ SO _4, filtered and then concentrated to dryness. The residue was purified by chromatography on EtOAc (EtOAc: EtOAc (EtOAc) +ESI-MS: m/z 311.7 [M+H] ⁺ .

Step 3: Ethyl 3-(6-hydroxy-3,4-dihydroisoquinolin-2(1H)-yl)benzoate. Ethyl 3-(6-methoxy-3,4-dihydroisoquinolin-2(1H)-yl)benzoate (1.0 g, 3.2 mmol) in DCM (5.00 mL) BBr ₃ (1.6 g, 6.4 mmol) was added to the solution. The resulting mixture was stirred at 25 ° C for 4 hours. The reaction mixture was quenched with saturated NaHCO ₃ solution. The resulting mixture was extracted with DCM (10 mL×2). The combined organic layers were washed (10 mL) with brine, dried over anhydrous Na ₂ SO _4, filtered and then concentrated to dryness. The residue was purified by chromatography on EtOAc (EtOAc: EtOAc: EtOAc) +ESI-MS : m/z 297.8 [M+H] ⁺ .

Intermediate 15: (5-cyclopropyl-3-(2,6-dichlorophenyl) iso 5-cyclopropyl-3-(2,6-dichlorophenylisoxazol-4-yl)methanol).

The title compound can be prepared as known in the art and are as described in PCT International Patent Application No. 2009012125 in the art (January 22, 2009).

Intermediate 16: 6-bromo-2,3-dihydro-1H-pyrido[2,3-b][1,4] Tert-butyl 6-bromo-2, 3-dihydro-1H-pyrido[2,3-b][1,4]oxazine-1-carboxylate).

Step 1: 2,6-Dibromopyridin-3-amine. The title compound can be prepared from pyridin-3-amine and prepared as described in PCT International Patent Application No. 2010111483 (September 30, 2010).

Step 2: 6-Bromo-1H-pyrido[2,3-b][1,4] -2(3H)-ketone. The title compound can be prepared from 2,6-dibromopyridin-3-amine and prepared as described in PCT International Patent Application No. 2013003383 (January 03, 2013).

Step 3: 6-Bromo-2,3-dihydro-1H-pyrido[2,3-b][1,4] . The title compound can be prepared from 6-bromo-1H-pyrido[2,3-b][1,4] -2(3H)-one is prepared as described in PCT International Patent Application No. 2010107768 (September 23, 2010).

Step 4: 6-Bromo-2,3-dihydro-1H-pyrido[2,3-b][1,4] 3-carboxylic acid tertiary butyl ester. In 6-bromo-2,3-dihydro-1H-pyrido[2,3-b][1,4] (3.5g, 17.2mmol), DMAP ( 1.05g, 8.6mmol) and TEA (7.16mL) in DCM was added in the Boc (30.00 mL) solution of ₂ O (7.52g, _34.5mmol). The resulting mixture was stirred at 40 ° C for 5 hours. TLC showed the reaction was complete. The reaction was diluted with water (100 mL) then EtOAc (EtOAc) The organic layer was separated, dried over anhydrous Na ₂ SO ₄ and then concentrated to dryness. The residue was purified by chromatography on EtOAc (EtOAc: EtOAc (EtOAc)

Intermediate 17: Methyl 3-(bromomethyl)benzoate

The title compound can be prepared as known in the art and are as described in PCT International Patent Application No. 2012006475 in the art (January 12, 2012).

Intermediate 18: methyl 3-((3-fluoro-5-hydroxy-1H-pyrrolo[3,2-b]pyridin-1-yl)methyl)benzoate (methyl 3-((3-fluoro-) 5-hydroxy-1H-pyrrolo[3,2-b]pyridin-1-yl)methyl)benzoate).

Step 1: 2-Bromo-6-methoxy-3-nitropyridine. The title compound can be prepared as known in the art and as described in Huaxue Tongbao, 68(8), w096/1-w096/4;

Step 2: Ethyl 2,2-difluoro-2-(6-methoxy-3-nitropyridin-2-yl)acetate. Ethyl 2,2-difluoro-2-iodoacetate (3.86 g, 15.4 mmol) was added portionwise in a solution of EtOAc (l.l. The mixture was stirred at 25 ° C for 1 hour and then a solution of 2-bromo-6-methoxy-3-nitropyridine (1.8 g, 7.7 mmol) in DMSO (5.00 mL) was added dropwise. The mixture was stirred at 25 ° C for 15 hours. LCMS showed the reaction was completed. The reaction mixture was diluted with H ₂ O (30mL), then extracted with EA (30mL × 2). The combined organic layers were washed (20mL) with brine, dried over anhydrous Na ₂ SO _4, filtered and then concentrated under reduced pressure. The residue was purified by column chromatography eluting with EtOAc (EtOAc:EtOAc: +ESI-MS :m/z 277[M+H] ⁺

Step 3: 3,3-Difluoro-5-methoxy-1,3-dihydro-2H-pyrrolo[3,2-b]pyridin-2-one. Pd was added to a solution of ethyl 2,2-difluoro-2-(6-methoxy-3-nitropyridin-2-yl)acetate (1.98 g, 7.17 mmol) in MeOH (30 mL) /C (200 mg, 10%). The suspension was degassed in vacuo and then purged several times with hydrogen. The mixture was stirred under hydrogen (15 psi) at 25 °C for 12 hours. The reaction mixture was filtered. NaOMe (774 mg, 14.3 mmol, 2.0 eq ) was added to the filtrate and then stirred at 25 ° C for 10 hours. The mixture was concentrated under reduced pressure. The residue was purified by column chromatography eluting with EtOAc (EtOAc: EtOAc)

¹ H-NMR (400 MHz, CDCl ₃ ), δ = 7.80 (br.s., 1H), 7.19-7.17 (d, J = 8.8 Hz 1H), 6.80-6.78 (d, J = 8.8 Hz, 1H), 3.9(s,3H),

Step 4: 3-Fluoro-5-methoxy-1H-pyrrolo[3,2-b]pyridine. 3,3-Difluoro-5-methoxy-1,3-dihydro-2H-pyrrolo[3,2-b]pyridin-2-one (550 mg, 2.75 mmol) at 25 ° C under nitrogen BH was added to (10 mL) in solution in THF of _{3 .Me 2 S (1.1mL, 11mmol} ). The resulting mixture was stirred at 50 ° C for 1 hour. The reaction mixture was quenched by dropwise addition of MeOH (7 mL) at 0 °C. The resulting mixture was concentrated under reduced pressure. The residue was purified by column chromatography (15~25% EtOAc) eluting ¹ H-NMR (400 MHz, DMSO), δ = 10.91 (br.s., 1H), 7.68-7.65 (dd, J = 2.2, 8.8 Hz, 1H), 7.46-7.44 (t, J = 2.2 Hz, 1H) ), 6.6-6.58 (d, J = 8.8 Hz, 1H), 3.84 (s, 3H).

Step 5: Methyl 3-((3-fluoro-5-methoxy-1H-pyrrolo[3,2-b]pyridin-1-yl)methyl)benzoate. 3-Fluoro-5-methoxy-1H-pyrrolo[3,2-b]pyridine (380 mg, 2.29 mmol) was added to a mixture of NaH (137 mg, 3.4 mmol) in DMF (5 mL). Then stir for 5 minutes. The reaction mixture was treated with methyl 3-(bromomethyl)benzoate (630 mg, 2.75 mmol) and then stirred at 25 ° C for one hour. The reaction was monitored by TLC (PE/EA = 3/1). The reaction mixture was washed with H ₂ O (10mL) was quenched and then extracted with EA (10mL × 2). The combined organic layers were washed (10 mL) with brine, dried over anhydrous Na ₂ SO _4, filtered and then concentrated under reduced pressure. The residue was purified by column chromatography eluting with EtOAc (EtOAc)

Step 6: Methyl 3-((3-fluoro-5-hydroxy-1H-pyrrolo[3,2-b]pyridin-1-yl)methyl)benzoate. The title compound was prepared in a similar manner to Intermediate 12, Step 3.

Intermediate 19: 3-(8-chloro-6-hydroxy Methyl 3-(8-chloro-6-hydroxychroman-2-yl)benzoate.

Step 1: 3-Chloro-2-hydroxy-5-methoxybenzaldehyde. The title compound can be prepared as known in the art and as described in Organic Letters, 16(13), 3544-3547 ; 2014 .

Step 2: 3-ethyl benzoic acid ethyl ester. The title compound can be prepared as described in the art and as described in Asian Journal of Chemistry, 19(7), 5093-5097; 2007; PCT International Patent Application No. 2006067445 ( June 29 , 2006 ) .

Step 3: (E)-3-(3-(3-Chloro-2-hydroxy-5-methoxyphenyl)propenyl)benzoic acid. 3-Chloro-2-hydroxy-5-methoxybenzaldehyde (2.0, 10.7 mol) and ethyl 3-ethyl benzoate (2.68 g, 13.9 mmol) in EtOH (60 mL) was added dropwise NaOH (640mg, 16mmol) of a solution (60 mL) in H ₂ O. The resulting mixture was stirred at 25 ° C for 1 hour. LC-MS showed the reaction was completed. The mixture was concentrated and acidified to pH = 3 with 1N HCl solution and then extracted with EA (50mL×3). The combined organic layers were dried over anhydrous Na ₂ SO _4, filtered and concentrated to give the crude product as a yellow solid of title compound (2.5g, crude). +ESI-MS: m/z 333.1 [M+H] ⁺ .

Step 4: (E)-3-(3-(3-Chloro-2-hydroxy-5-methoxyphenyl)propenyl)benzoic acid methyl ester. (E)-3-(3-(3-Chloro-2-hydroxy-5-methoxyphenyl)propenyl)benzoic acid (2.5 g, 7.5 mmol) in anhydrous DMF (20 mL) K ₂ CO ₃ (3.15 g, 22.5 mmol) and MeI (4.20 g, 30 mmol) were added to the solution. The resulting mixture was stirred at 25 ° C for 30 minutes. LC-MS showed the reaction was completed. The mixture was diluted with H ₂ O (100 mL) and then extracted with EA (100 mL×2). The combined organic layers were dried over anhydrous Na ₂ SO _4, filtered and then concentrated to dryness. The residue was purified by EtOAc (EtOAc (EtOAc) ¹ H-NMR (400 MHz, CDCl ₃ ), δ = 8.64 (s, 1H), 8.27-8.25 (d, J = 7.6 Hz, 1H), 8.22-8.20 (d, J = 7.6 Hz, 1H), 8.02 7.98 (d, J = 15.6 Hz, 1H), 7.63 - 7.58 (m, 2H), 7.10 - 7.09 (d, J = 3.2 Hz, 1H), 7.02-7.01 (d, J = 3.2 Hz, 1H), 3.97 (s, 3H), 3.84 (S, 6H). +ESI-MS : m/z 361.1 [M+H] ⁺ .

Step 5: Methyl 3-(3-(3-chloro-2-hydroxy-5-methoxyphenyl)propenyl)benzoate. Methyl (E)-3-(3-(3-chloro-2-hydroxy-5-methoxyphenyl)propenyl)benzoate (2.5 g, 9.7 mmol) in MeOH (60 mL) To the solution was added RhCl(PPh ₃ ) ₃ (2.69 g, 2.91 mmol). The suspension was degassed in vacuo and then purged several times with hydrogen. The reaction mixture was stirred at 40 ° C for 3 h under hydrogen (45 psi). TLC (PE/EA = 5/1) showed that (E)-3-(3-(3-chloro-2-hydroxy-5-methoxyphenyl)propenyl)benzoic acid methyl ester was consumed. The mixture was concentrated to dryness. The residue was purified by EtOAc (EtOAc (EtOAc)

Step 6: Methyl 3-(3-(3-chloro-2,5-dihydroxyphenyl)propanyl)benzoate. Add BBr dropwise to a solution of methyl 3-(3-(3-chloro-2-hydroxy-5-methoxyphenyl)propanyl)benzoate (1.8 g, 4.96 mmol) in DCM (5 mL) ₃ (1.6 mL). The resulting mixture was stirred at 25 ° C for 10 minutes. TLC (PE/EA = 5/1) showed that methyl 3-(3-(3-chloro-2-hydroxy-5-methoxyphenyl)propenyl)benzoate was consumed. The mixture was washed with NaHCO ₃ (50mL) solution was quenched and then extracted with EA (50mL × 3). The combined organic layers were dried over anhydrous Na ₂ SO _4, filtered and then concentrated to dryness. The residue was purified by EtOAc (EtOAc: EtOAc (EtOAc)

Step 7: Methyl 3-(3-(3-chloro-2,5-dihydroxyphenyl)hydroxypropyl)benzoate. Add NaBH ₄ (206 mg) to a solution of methyl 3-(3-(3-chloro-2,5-dihydroxyphenyl)propanyl)benzoate (601 mg, 1.8 mmol) in MeOH (5 mL) , 5.4 mmol). The resulting mixture was stirred at 25 ° C for 10 minutes. The reaction was monitored by TLC (PE/EA = 1/1). The mixture (50mL) was quenched with H ₂ O, and then extracted with EA (50mL × 3). The organic layer was dried over anhydrous Na ₂ SO _4, filtered and then concentrated to dryness. The residue was purified by EtOAc (EtOAc (EtOAc:EtOAc)

Step 8: 3-(8-chloro-6-hydroxyl Methyl-2-benzoate. Methyl 3-(3-(3-chloro-2,5-dihydroxyphenyl)-1-hydroxypropyl)benzoate (508 mg, 1.49 mmol) and PPh ₃ (467 mg, 1.78 mmol) at 25 °C DIAD (600 mg, 2.98 mmol) was added to a solution in DCM (3 mL). The resulting mixture was stirred at 25 ° C for 1 hour. LC-MS showed the reaction was completed. The reaction mixture was concentrated to dryness. The residue was purified by flash column (20~30% EtOAc) +ESI-MS : m/z 319.1 [M+H] ⁺ .

Compound 1.4-(1-(4-((5-cyclopropyl-3-(2,6-dichlorophenyl))) Zin-4-yl)methoxy)phenyl)azin-3-yl)benzoic acid.

Step 1: 4-(1-(4-((5-cyclopropyl-3-(2,6-dichlorophenyl))) Ethylzol-4-yl)methoxy)phenyl)azin-3-yl)benzoic acid ethyl ester. Add ethyl 4-(1-(4-hydroxyphenyl)azin-3-yl)benzoate to a solution of sodium hydride (120 mg, 3.0 mmol, 2.0 eq ) in anhydrous DMF (15 mL) (Intermediate 6,450 mg, 1.5 mmol, 1.0 eq ). After stirring at 25 ° C for 10 minutes, 4-(bromomethyl)-5-cyclopropyl-3-(2,6-dichlorophenyl) A solution of the azole (intermediate 4, 524 mg, 1.5 mmol, 1.0 eq ) was added and then the mixture was stirred at 25 ° C for 20 min. TLC (PE/EA = 3/1) showed that the reaction was completed. The mixture (50mL) was quenched with H ₂ O, and then extracted with EA (50mL × 2). The combined organic layers were dried over anhydrous Na ₂ SO ₄ and then concentrated to dryness. The residue was purified by EtOAc (EtOAc EtOAc) +ESI-MS: m/z 563.2 [M+H] ⁺ .

Step 2: 4-(1-(4-((5-cyclopropyl-3-(2,6-dichlorophenyl))) Zin-4-yl)methoxy)phenyl)azin-3-yl)benzoic acid. 4-(1-(4-((5-cyclopropyl-3-(2,6-dichlorophenyl))) 4-yl) methoxy) phenyl) -3- Da nitrogen-yl) benzoate (203mg, 0.355mmol) in EtOH (5.00mL) was added in the in H ₂ O (5.00mL) NaOH (71 mg, 1.77 mmol, 5.0 eq ). The mixture was stirred at 60 ° C for 1 hour. LCMS showed the reaction was completed. The mixture was concentrated and the residue was acidified with aq. The reaction mixture (30mL × 3) and extracted with EA, and the organic layer was dried over anhydrous sulfate and then concentrated under low pressure Na ₂ SO _4. The residue was purified by EtOAc EtOAcqqqq ¹ H-NMR (DMSO, 400 MHz), δ = 7.91 (d, J = 8.0 Hz, 1H), 7.63-7.61 (m, 2H), 7.56-7.52 (m, 1H), 7.48 (d, J = 8.4 Hz) , 1H), 6.66 (d, J = 8.4 Hz, 1H), 6.37 (d, J = 8.4 Hz, 1H), 4.74 (s, 2H), 4.17 - 4.13 (m, 2H), 3.99 - 3.94 (m, 1H), 3.71-3.68 (m, 2H), 2.41-2.36 (m, 1H), 1.18-1.08 (m, 4H). ESI-MS: m/z 535.0 [M+H] ⁺ .

Compound 2.2-(4-((5-cyclopropyl-3-(2,6-dichlorophenyl))) Zin-4-yl)methoxy)phenyl)-1,2,3,4-tetrahydroisoquinoline-7-carboxylic acid.

Step 1: 2-(4-((2-(Trimethyldecyl)ethoxy)methoxy)phenyl)-1,2,3,4-tetrahydroisoquinolin-7-carboxylic acid ester. Pd(dba) ₂ (241 mg, 0.42 mmol, 0.1 eq ), methyl 1,2,3,4-tetrahydroisoquinolin-7-carboxylate (intermediate 3,800 mg, 4.18 mmol, 1.0 eq ) HCl salt), (2-((4-bromophenoxy)methoxy)ethyl)trimethyldecane (Intermediate 2, 2.54 g, 8.36 mmol, 2.0 eq ) and Cs ₂ CO ₃ (6.81 g, A mixture of 20.9 mmol, 5.0 eq ) was degassed and then refilled with nitrogen three times. Anhydrous DMF (20 mL) was added and the mixture was stirred at <RTI ID=0.0></RTI><RTIID=0.0> TLC (PE/EA = 6/1) showed the reaction was completed. The mixture was filtered and the volatiles were removed under reduced pressure. The residue was purified by chromatography on EtOAc (EtOAc: EtOAc) +ESI-MS : m/z 413.9 [M+H] ⁺ .

Step 2: Methyl 2-(4-hydroxyphenyl)-1,2,3,4-tetrahydroisoquinoline-7-carboxylate. Methyl 2-(4-((2-(trimethylmethyl))ethoxy)methoxy)phenyl)-1,2,3,4-tetrahydroisoquinolin-7-carboxylate ( 476 mg, 1.15 mmol, 1.0 eq ) HCl (2 mL, 12M, 20.8 eq ). The reaction was stirred at 25 °C for 2 hours. TLC (DCM / MeOH = 10/1) showed that the reaction was completed. The reaction was neutralized with saturated NaHCO ₃ solution to pH = 6 ~ 7. The resulting mixture was extracted with EA (10 mL×2). The combined organic layers were washed with brine, dried over anhydrous Na ₂ SO ₄ and then concentrated to dryness. The residue was purified by chromatography on EtOAc (EtOAc: EtOAc) +ESI-MS :m/z 283.8[M+H] ⁺

Step 3: 2-(4-((5-cyclopropyl-3-(2,6-dichlorophenyl)) Zin-4-yl)methoxy)phenyl)-1,2,3,4-tetrahydroisoquinoline-7-carboxylic acid. Methyl 2-(4-hydroxyphenyl)-1,2,3,4-tetrahydroisoquinoline-7-carboxylate (230.00 mg, 0.81 mmol, 1.0 eq ) in anhydrous DMF (4 mL) Sodium hydride (39 mg, 0.97 mmol, 1.2 eq ) was added in one portion to the solution. After stirring for a while, 4-(bromomethyl)-5-cyclopropyl-3-(2,6-dichlorophenyl) The azole (intermediate 4, 310 mg, 0.89 mmol, 1.1 eq ) was added and the solution was stirred at 25 ° C for 2 h. TLC (DCM / MeOH = 10/1) showed that the reaction was completed. The reaction was quenched with H ₂ O (30mL), then treated with HCl solution (1.0M) was acidified to pH = 2 ~ 3. The reaction mixture was extracted with EA (20 mL×3). The combined organic layers were washed with brine, dried over anhydrous Na ₂ SO ₄ and then concentrated to dryness. The residue was purified using EtOAcqqqqqqq ¹ H NMR (400 MHz, CD ₃ OD) δ = 8.00 (d, J = 8.0 Hz, 1H), 7.94 (s, 1H), 7.58-7.51 (m, 4H), 7.51-7.44 (m, 2H), 7.04 (d, J = 9.0 Hz, 2H), 5.00 (s, 2H), 4.85 (br.s., 2H), 4.00 (t, J = 6.0 Hz, 2H), 3.41 (br.s., 2H), 2.37 (quin, J = 6.7 Hz, 1H), 1.26-1.20 (m, 4H). +ESI-MS: m/z 535.1[M+H] ⁺

Compound 3.2-(4-((5-cyclopropyl-3-(2,6-dichlorophenyl))) Zyridin-4-yl)methoxy)phenyl)isoindoline-5-carboxylic acid.

The title compound was prepared in a similar manner to Compound 1, Steps 1 to 2, using methyl 2-(4-hydroxyphenyl)isoindoline-5-carboxylate ( Intermediate 7). The title compound (48 mg) was obtained as a yellow solid. ^{1 H-NMR (DMSO, 400MHz} ) δ = 7.98-7.86 (m, 2H), 7.66-7.62 (m, 2H), 7.59-7.53 (m, 1H), 7.49 (d, J = 8.0Hz, 1H), 6.74 (d, J = 9.0 Hz, 2H), 6.55 (d, J = 8.5 Hz, 2H), 4.76 (s, 2H), 4.56 (s, 5H), 2.40 (br.s., 1H), 1.18- 1.08 (m, 4H). +ESI-MS: m/z 520.9[M+H] ⁺

Compound 4.3-(1-(4-((5-cyclopropyl-3-(2,6-dichlorophenyl))) Zin-4-yl)methoxy)phenyl)azin-3-yl)benzoic acid.

The title compound was prepared in a similar manner to Compound 1, Steps 1 to 2, using ethyl 3-(1-(4-hydroxyphenyl)azin-3-yl)benzoate ( Intermediate 9). The title compound (130 mg) was obtained as a white solid. ¹ H-NMR (DMSO, 400 MHz), δ = 7.95 (br, 1H), 7.81 (d, J = 8.0 Hz, 1H), 7.63-7.52 (m, 4H), 7.48-7.44 (m, 1H), 6.66 (d, J = 8.4 Hz, 1H), 6.37 (d, J = 8.4 Hz, 1H), 4.74 (s, 2H), 4.16-4.13 (m, 2H), 3.99-3.92 (m, 1H), 3.70- 3.67 (m, 2H), 2.41-2.36 (m, 1H), 1.7-1.09 (m, 4H). +ESI-MS : m/z 535.1 [M+H] ⁺ .

Compound 5.3-(1-(2-chloro-4-((5-cyclopropyl-3-(2,6-dichlorophenyl))) Zin-4-yl)methoxy)phenyl)azin-3-yl)benzoic acid.

The title compound was used in a similar manner to Compound 1, Steps 1 to 2, using ethyl 3-(1-(2-chloro-4-hydroxyphenyl)azin-3-yl)benzoate (Intermediate 10) preparation. The title compound (113 mg) was obtained as white crystal. ¹ H NMR (400 MHz, CD3 OD) δ = 8.05 (s, 1H), 7.90 (d, J = 7.5 Hz, 1H), 7.68-7.61 (m, 1H), 7.53-7.45 (m, 4H), 6.73-6.65 (m, 2H), 6.62-6.57 (m, 1H), 4.43-4.33 (m, 2H), 3.94-3.86 (m, 3H), 2.36-2.22 (m, 1H), 1.21-1.16 (m, 4H) . +ESI-MS : m/z 570.8 [M+H] ⁺ .

Compound 6.2-(2-chloro-4-((5-cyclopropyl-3-(2,6-dichlorophenyl)) Zyridin-4-yl)methoxy)phenyl)isoindoline-5-carboxylic acid.

The title compound is used in a similar manner to Compound 1, Steps 1 to 2, using 2-(2-chloro-4-hydroxyphenyl)isoindoline-5-carboxylic acid methyl ester (Intermediate 11) in Step 1. To prepare. The title compound (11 mg) was obtained as a yellow solid. ¹ H NMR (400 MHz, DMSO) δ = 7.89 (s, 1 H), 7.86-7.84 (d, J = 8 Hz, 1 H), 7.61 (d, J = 7.1 Hz, 2H), 7.53 (dd, J = 6.8 , 9.0 Hz, 1H), 7.43 (d, J = 7.9 Hz, 1H), 7.14 (d, J = 9.3 Hz, 1H), 6.87 (d, J = 3.1 Hz, 1H), 6.72 (dd, J = 2.6 , 8.8 Hz, 1H), 4.84 (s, 2H), 4.59 (d, J = 4.4 Hz, 4H), 2.42 (br.s., 1H), 1.18-1.14 (m, 2H), 1.10 (d, J =3.1 Hz, 2H). +ESI-MS : m/z 556.9 [M+H] ⁺ .

Compound 7.3-(6-((5-cyclopropyl-3-(2,6-dichlorophenyl)) Zol-4-yl)methoxy)-1-methyl-1,2,3,4-tetrahydroquinolin-2-yl)benzoic acid.

The title compound was used in a similar manner to Compound 1, Steps 1 to 2, using methyl 3-(6-hydroxy-1-methyl-1,2,3,4-tetrahydroquinolin-2-yl)benzoate (Intermediate 12) to prepare. The title compound (321 mg) was obtained as a white solid. ¹ H-NMR (400 MHz, CDCl ₃ ), δ=8.11 (br.s., 1H), 8.07 (d, J = 7.9 Hz, 1H), 8.00 (d, J = 6.2 Hz, 1H), 7.58-7.49 (m, 2H), 7.45-7.39 (m, 2H), 7.38-7.31 (m, 1H), 6.77 (d, J = 8.4 Hz, 1H), 6.62 (br.s., 1H), 4.92-4.69 ( m, 3H), 2.92 (br.s., 5H), 2.53 (br.s., 1H), 2.42 (br.s., 1H), 2.27-2.10 (m, 1H), 1.34-1.27 (m, 2H), 1.21-1.12 (m, 2H). +ESI-MS :m/z 548.9[M+H] ⁺

Compound 8. ((R)-3-(6-((5-cyclopropyl-3-(2,6-dichlorophenyl))) Zol-4-yl)methoxy)-1-methyl-1,2,3,4-tetrahydroquinolin-2-yl)benzoic acid).

Racemic Compound 7 (200 mg) was sent for SFC separation, and the two isomers were separated by using the following method: "column: Chiralcel OJ-3 150 x 4.6 mm ID, 3 μm mobile phase: A: CO2 B: methanol (0.05% DEA) gradient: from 5% to 40% of B in 5 minutes and then 40% for 2.5 minutes, followed by 5% of B for 2.5 minutes Flow rate: 2.5 mL/min column temperature: 35 ° C wavelength: 220 nm" gave Compound 8 (60 mg) and Compound 9 (63 mg) as a yellow solid. ((R)-3-(6-((5-cyclopropyl-3-(2,6-dichlorophenyl))) Zin-4-yl)methoxy)-1-methyl-1,2,3,4-tetrahydroquinolin-2-yl)benzoic acid) ^-1 H-NMR (400 MHz, CD ₃ OD), δ =7.88 (d, J = 6.6 Hz, 1H), 7.84 (s, 1H), 7.53-7.49 (m, 2H), 7.57-7.48 (m, 2H), 7.48-7.42 (m, 1H), 7.42-7.34 (m, 2H), 6.60-6.49 (m, 2H), 6.40 (d, J = 2.6 Hz, 1H), 4.76 (s, 3H), 4.45 (t, J = 5.1 Hz, 1H), 2.77 (s, 3H), 2.59-2.48 (m, 1H), 2.49-2.36 (m, 1H), 2.26 (q, J = 6.7 Hz, 1H), 2.19-2.07 (m, 1H), 2.03-1.88 (m, 1H) , 1.21-1.11 (m, 4H). +ESI-MS :m/z 548.9[M+H] ⁺

Compound 9. ((S)-3-(6-((5-cyclopropyl-3-(2,6-dichlorophenyl))) Zol-4-yl)methoxy)-1-methyl-1,2,3,4-tetrahydroquinolin-2-yl)benzoic acid).

((S)-3-(6-((5-cyclopropyl-3-(2,6-dichlorophenyl))) Zin-4-yl)methoxy)-1-methyl-1,2,3,4-tetrahydroquinolin-2-yl)benzoic acid) ^-1 H-NMR (400 MHz, CD ₃ OD), δ =7.88 (d, J = 6.6 Hz, 1H), 7.84 (s, 1H), 7.53-7.49 (m, 2H), 7.57-7.48 (m, 2H), 7.48-7.42 (m, 1H), 7.42-7.34 (m, 2H), 6.60-6.49 (m, 2H), 6.40 (d, J = 2.6 Hz, 1H), 4.76 (s, 3H), 4.45 (t, J = 5.1 Hz, 1H), 2.77 (s, 3H), 2.59-2.48 (m, 1H), 2.49-2.36 (m, 1H), 2.26 (quin, J = 6.7 Hz, 1H), 2.19-2.07 (m, 1H), 2.03-1.88 (m, 1H) , 1.21-1.11 (m, 4H). +ESI-MS: m/z 548.9[M+H] ⁺

Compound 10.3-(8-chloro-6-((5-cyclopropyl-3-(2,6-dichlorophenyl)) Zol-4-yl)methoxy)-1-methyl-1,2,3,4-tetrahydroquinolin-2-yl)benzoic acid.

The title compound was used in a similar manner to Compound 1, Steps 1 to 2, using 3-(8-chloro-6-hydroxy-1-methyl-1,2,3,4-tetrahydroquinolin-2-yl) Methyl benzoate (intermediate 13) was prepared. The title compound (39 mg) was obtained as white crystal. ¹ H-NMR (400 MHz, CD ₃ OD), δ = 8.04 (s, 1H), 7.90 (d, J = 7.9 Hz, 1H), 7.59 (d, J = 7.9 Hz, 1H), 7.49-7.38 (m) , 4H), 6.71 (d, J = 2.6 Hz, 1H), 6.43 (d, J = 2.6 Hz, 1H), 4.85 (br.s., 2H), 4.53-4.35 (m, 1H), 2.94 (s , 3H), 2.83-2.68 (m, 1H), 2.56-2.44 (m, 1H), 2.44-2.33 (m, 1H), 2.32-2.19 (m, 1H), 2.18-2.03 (m, 1H), 1.17 (d, J = 2.6 Hz, 2H), 1.16 (s, 2H). +ESI-MS: m/z 583.0[M+H] ⁺

Compound 11. ((R)-3-(8-chloro-6-((5-cyclopropyl-3-(2,6-dichlorophenyl))) Zol-4-yl)methoxy)-1-methyl-1,2,3,4-tetrahydroquinolin-2-yl)benzoic acid).

Racemic 3-(8-chloro-6-((5-cyclopropyl-3-(2,6-dichlorophenyl)) Zyridin-4-yl)methoxy)-1-methyl-1,2,3,4-tetrahydroquinolin-2-yl)benzoic acid (Compound 10) (35 mg) was sent for SFC separation and borrowed The two isomers were separated by the following method: "column: Chiralcel OJ-3 150 x 4.6 mm ID 3 μm; mobile phase: A: CO2 B: methanol (0.05% DEA); gradient: from 5 in 5.0 minutes % to 40% of B then maintains 40% for 2.5 minutes, followed by 5% of B for 2.5 minutes; flow rate: 2.5 mL/min; column temperature: 35C wavelength: 220 nm"

Obtained ((R)-3-(8-chloro-6-((5-cyclopropyl-3-(2,6-dichlorophenyl))) as a yellow solid Zin-4-yl)methoxy)-1-methyl-1,2,3,4-tetrahydroquinolin-2-yl)benzoic acid) (13.2 mg) and ((S)-3-(8 -Chloro-6-((5-cyclopropyl-3-(2,6-dichlorophenyl)) Zol-4-yl)methoxy)-1-methyl-1,2,3,4-tetrahydroquinolin-2-yl)benzoic acid) (13.6 mg). ((R)-3-(8-chloro-6-((5-cyclopropyl-3-(2,6-dichlorophenyl))) Zoxa-4-yl)methoxy)-1-methyl-1,2,3,4-tetrahydroquinolin-2-yl)benzoic acid) ¹ H-NMR (400 MHz, CD ₃ OD), δ =8.06(s,1H),7.86(d,J=7.5Hz,1H), 7.59(d,J=8.0Hz,1H),7.52-7.43(m,3H),7.42-7.28(m,1H), 6.65 (d, J = 2.5 Hz, 1H), 6.35 (d, J = 2.5 Hz, 1H), 4.83 (s, 3H), 4.25 (dd, J = 4.0, 7.5 Hz, 1H), 2.86 (s, 3H) ), 2.80-2.67 (m, 1H), 2.52-2.38 (m, 1H), 2.36-2.23 (m, 2H), 2.04-1.93 (m, 1H), 1.25-1.12 (m, 4H). +ESI-MS :m/z 582.9[M+H] ⁺

Compound 12. ((S)-3-(8-chloro-6-((5-cyclopropyl-3-(2,6-dichlorophenyl))) Zol-4-yl)methoxy)-1-methyl-1,2,3,4-tetrahydroquinolin-2-yl)benzoic acid).

((S)-3-(8-chloro-6-((5-cyclopropyl-3-(2,6-dichlorophenyl))) Zin-4-yl)methoxy)-1-methyl-1,2,3,4-tetrahydroquinolin-2-yl)benzoic acid) ^-1 H-NMR (400 MHz, CD ₃ OD), δ =8.06(s,1H),7.86(d, J =7.5Hz,1H), 7.59(d, J =7.5Hz,1H),7.53-7.40(m,3H),7.37(t, J =7.5Hz, 1H), 6.65 (d, J = 2.5 Hz, 1H), 6.35 (d, J = 2.5 Hz, 1H), 4.83 (s, 3H), 4.25 (dd, J = 4.0, 7.5 Hz, 1H), 2.86 ( s, 3H), 2.78-2.66 (m, 1H), 2.51-2.37 (m, 1H), 2.37-2.23 (m, 2H), 2.02-1.86 (m, 1H), 1.25-1.12 (m, 4H). +ESI-MS :m/z 583.1[M+H] ⁺

Compound 13.3-(6-((5-cyclopropyl-3-(2,6-dichlorophenyl)) Zol-4-yl)methoxy)-3,4-dihydroisoquinolin-2(1H)-yl)benzoic acid.

The title compound is used in a similar manner to Compound 1, Steps 1 to 2, using 3-(6-hydroxy-3,4-dihydroisoquinolin-2(1H)-yl)benzoic acid ethyl ester in Step 1. preparation. The title compound (79 mg) was obtained as white crystal. ¹ H-NMR (400MHz, CDCl ₃ ), δ = 8.05 (s, 1H), 7.91 (m, 1H), 7.83 (m., 1H), 7.51 (m., 1H), 7.44-7.39 (m, 2H) ), 7.35 (d, J = 7.1 Hz, 1H), 7.03 (d, J = 7.9 Hz, 1H), 6.73 (d, J = 7.5 Hz, 1H), 6.63 (s, 1H), 4.81 (s, 2H) ), 4.57 (s, 2H), 3.75 (s, 2H), 3.15 (s, 2H), 2.18 (s, 1H), 1.31-1.28 (m, 2H), 1.16 (d, J = 7.5 Hz, 2H) . +ESI-MS : m/z 534.8 [M+H] ⁺ .

Compound 14.3-((6-((5-cyclopropyl-3-(2,6-dichlorophenyl))) Zin-4-yl)methoxy)-2,3-dihydro-1H-pyrido[2,3-b][1,4] -1-yl)methyl)benzoic acid.

Step 1: 6-((5-Cyclopropyl-3-(2,6-dichlorophenyl)) Zin-4-yl)methoxy)-2,3-dihydro-1H-pyrido[2,3-b][1,4] 3-carboxylic acid tertiary butyl ester. In 6-bromo-2,3-dihydro-1H-pyrido[2,3-b][1,4] in nitrogen 1-carboxylic acid tert-butyl butyl ester (intermediate 16, 2.0 g, 6.35 mmol) and (5-cyclopropyl-3-(2,6-dichlorophenyl) iso Cs ₂ CO ₃ (4.14 g, 12.7 mmol), Pd(dba) ₂ (182 mg, 0.32 mmol) was added to a solution of oxazol-4-yl)methanol ( Intermediate 15 , 3.61 g, 12.7 mmol) in toluene (20 mL). ) and BINAP (198 mg, 0.32 mmol). The resulting mixture was stirred at 110 ° C for 12 hours. The mixture was cooled to room temperature and then concentrated to dryness. The residue was purified by column chromatography on silica gel (5-20% EA in PE) to give the desired compound as a pale yellow oil (1.1 g, 33.4%) . +ESI-MS :m/z 518.1[M+H] ⁺

Step 2: 6-((5-Cyclopropyl-3-(2,6-dichlorophenyl)) Zin-4-yl)methoxy)-2,3-dihydro-1H-pyrido[2,3-b][1,4] . 6-((5-cyclopropyl-3-(2,6-dichlorophenyl)) Zin-4-yl)methoxy)-2,3-dihydro-1H-pyrido[2,3-b][1,4] A mixture of 1-carboxylic acid tert-butyl ketone (1.0 g, 1.93 mmol) in EtOAc / MeOH (4M,EtOAc) The reaction was quenched with saturated NaHCO ₃ solution then extracted with EA (50mL × 2). The combined organic layers were washed with brine, dried over anhydrous Na ₂ SO ₄ and then concentrated to dryness. The residue was purified by column chromatography eluting with EtOAc (EtOAc:EtOAc)

Step 3: 3-((6-((5-cyclopropyl-3-(2,6-dichlorophenyl))) Zin-4-yl)methoxy)-2,3-dihydro-1H-pyrido[2,3-b][1,4] Methyl-1-methyl)methyl)benzoate. 6-((5-cyclopropyl-3-(2,6-dichlorophenyl)) Zin-4-yl)methoxy)-2,3-dihydro-1H-pyrido[2,3-b][1,4] (400 mg, 0.96 mmol), a mixture of methyl 3-(bromomethyl)benzoate (438 mg, 1.92 mmol) and K ₂ CO ₃ (265 mg, 1.92 mmol) in DMF (25 mL) . The mixture was diluted with EA (50 mL) and water (50 mL). The aqueous layer was neutralized to pH = 6-7 by the addition of a solution of HCl (2M). The organic phase was washed with brine (20mL), dried over anhydrous Na ₂ SO _4, then concentrated to dryness. The residue was purified by column chromatography eluting with EtOAc (EtOAc:EtOAc:

Step 4: 3-((6-((5-cyclopropyl-3-(2,6-dichlorophenyl))) Zin-4-yl)methoxy)-2,3-dihydro-1H-pyrido[2,3-b][1,4] -1-yl)methyl)benzoic acid. In 3-((6-((5-cyclopropyl-3-(2,6-dichlorophenyl))) Zin-4-yl)methoxy)-2,3-dihydro-1H-pyrido[2,3-b][1,4] 1-yl) methyl) benzoate (200mg, 0.35mmol) in THF NaOH in H ₂ O (2mL) of (28mg, 0.7mmol) was added (2mL) in the solution. The mixture was stirred at 25 ° C for 2 hours. The mixture was acidified with 1N HCl to pH = 1-2 then extracted with EA (50 mL). The organic layer was washed (10 mL) with brine, dried over anhydrous Na ₂ SO ₄ and then concentrated to dryness. The residue was purified by EtOAcqqqqqqq ¹ H-NMR (400 MHz, CD ₃ OD), δ = 8.68 (s, 1H), 8.72-8.66 (m, 1H), 8.64 (d, J = 7.5 Hz, 1H), 8.40-8.23 (m, 5H) , 7.83 (d, J = 8.4 Hz, 1H), 7.87-7.80 (m, 1H), 6.85 (d, J = 8.4 Hz, 1H), 5.74 (s, 2H), 5.20 (s, 2H), 5.09 ( d, J = 4.0 Hz, 2H), 4.01 (br.s., 2H), 3.27 (d, J = 3.1 Hz, 1H), 2.06-1.85 (m, 6H) + ESI-MS : m/z 552.0 [ M+H] ⁺

Compound 15.3-((5-((5-cyclopropyl-3-(2,6-dichlorophenyl))) Zol-4-yl)methoxy)-3-fluoro-1H-pyrrolo[3,2-b]pyridin-1-yl)methyl)benzoic acid.

The title compound was used in a similar manner to Compound 1, Steps 1 to 2, using 3-((3-fluoro-5-hydroxy-1H-pyrrolo[3,2-b]pyridin-1-yl)methyl)benzene Methyl formate (intermediate 18) was prepared. The title compound (2.03 mg) was obtained as white crystal. ¹ H-NMR (400 MHz, CD ₃ OD), δ = 7.80 (d, J = 7.5 Hz, 1H), 7.67 (s, 1H), 7.48 (d, J = 8.8 Hz, 1H), 7.32-7.18 (m) , 6H), 6.29 (d, J = 9.3 Hz, 1H), 5.24 (t, J = 4.6 Hz, 2H), 5.21 (s, 2H), 5.16 (s, 2H), 2.57-2.44 (m, 1H) , 1.2-1.05 (m, 4H). +ESI-MS :m/z 552.0[M+H] ⁺

Compound 16.3-(8-chloro-6-((5-cyclopropyl-3-(2,6-dichlorophenyl)) Zin-4-yl)methoxy) -2-yl)benzoic acid.

The title compound is used in a similar manner to compound 1, steps 1 to 2, using 3-(8-chloro-6-hydroxyl Methyl-2-benzoate (intermediate 19) was prepared. The title compound (185 mg) was obtained as a white solid. ¹ H-NMR (400 MHz, DMSO), δ = 13.0 (br.s., 0.1H), 8.1 (s, 1H), 7.90 (d, J = 7.6 Hz, 1H), 7.68-7.62 (m, 3H) , 7.57-7.51 (m, 2H), 6.75 (d, J = 3.2 Hz, 1H), 6.56 (d, J = 3.2 Hz, 1H), 5.24 - 5.22 (m, 1H), 4.82 (s, 2H), 2.95-2.87(m,1H),.2.66-2.62(m,1H),2.24-2.23(m,1H), 2.22-2.19(m,1H),1.96-1.89(m,1H),1.22-1.11( m, 4H). +ESI-MS : m/z 572.1 [M+H] ⁺ .

Farnesoid X receptor assay

The farnesoid X receptor (FXR) assay was performed by Indigo Biosciences (cat# IB00601-32) as a set of cell-based reporter assays sold. Briefly, compounds were diluted in cell recovery medium (CRM) at a 2 fold final concentration. Indigo's FXR reporter cells were thawed and added to 96-well plates at 100 μL per well. Compounds were tested at a maximum concentration of 100 [mu]M with an 8-point dilution curve (3-fold dilution between points). Choleoxycholic acid ( CDCA ) was used as a positive control group with a maximum concentration of 1200 μM. 100 μL of the diluted compound was added to each well-inoculated well. The treated cells were then incubated at 37 ° C, 5% CO ₂ for 22 to 25 hours. The next day, the medium was removed from the cells and luciferase detection reagent was added to the wells (100 μl/well). The assay plate was allowed to stand at room temperature for 25 minutes without shaking. Illumination was read on a Victor X3 multi-labeled disc reader (Perkin Elmer, Waltham, MA) set to read at 0.5 seconds per well. The results of some of the illustrative compounds disclosed herein are shown in Table 1.

TR-FRET FXR Verification

FXR agonists were tested in a cell-free FXR co-activation assay. The FXR activation assay was performed using the LanthaScreen® TR-FRET FXR Coactivator Kit (ThermoFisher Scientific) to determine the EC50. In total, 20 [mu]L of reaction was performed in 384 well plates containing different concentrations of agonist, 5 nM FXR/LBD, 500 nM fluorescent agent and 5 nM AntiGST antibody. The plate was incubated at 37 ° C for 90 minutes. Fluorescence changes were monitored using a Victor X3 multi-label reader (PerkinElmer). All binding curves were generated by plotting the emission ratio versus ligand concentration, and % activation was reported as a function of CDCA% activation. The results of some of the illustrative compounds disclosed herein are shown in Table 1.

Claims (22)

a compound of formula I, Wherein R ¹ is selected from the group consisting of H, F, Cl, Br, and I; R ² is selected from the group consisting of F, Cl, Br, and I; and R ³ is selected from C _1-6 a group consisting of an alkyl group and a C _3-6 cycloalkyl group; the A group is selected from the group consisting of: X is selected from the group consisting of O, -NH-, and -N(CH ₃ )-; and R ⁴ is selected from the group consisting of H, F, Cl, and CN; or it is pharmaceutically acceptable Salt. The compound of claim 1, wherein each of R ¹ and R ² is Cl. The compound of any one of the preceding claims, wherein R ² is a C _3-6 cycloalkyl group. The compound of any one of the preceding claims, wherein R ¹ is Cl; R ² is Cl; R ³ is C ₃ cycloalkyl; and X is selected from the group consisting of O and -N(CH ₃ )- Group; and R ⁴ is selected from the group consisting of H and Cl. The compound of claim 1, which has the formula IA: The compound of claim 1, which has the formula IB: The compound of claim 1, which has the formula IC: The compound of claim 1, which has the formula ID: The compound of claim 1, which has the formula IE: The compound of any one of the preceding claims, wherein R ⁴ is H. The compound of any one of claims 1 to 9, wherein R ⁴ is Cl. The compound of claim 1, which has the formula IF: The compound of claim 1, which has the formula IG: The compound of claim 1 which has the formula IH: The compound of any one of the preceding claims, wherein R ¹ is Cl; R ² is Cl; and R ³ is C ₃ cycloalkyl. The compound of claim 1, wherein the compound is selected from the group consisting of 4-(1-(4-((5-cyclopropyl-3-(2,6-dichlorophenyl))) different Zin-4-yl)methoxy)phenyl)azin-3-yl)benzoic acid, 3-(6-((5-cyclopropyl-3-(2,6-dichlorophenyl)) Zin-4-yl)methoxy)-1-methyl-1,2,3,4-tetrahydroquinolin-2-yl)benzoic acid, 2-(4-((5-cyclopropyl-3) -(2,6-dichlorophenyl)iso Zin-4-yl)methoxy)phenyl)-1,2,3,4-tetrahydroisoquinoline-7-carboxylic acid, 2-(4-((5-cyclopropyl-3-(2) ,6-dichlorophenyl) Zin-4-yl)methoxy)phenyl)isoindoline-5-carboxylic acid, 3-(1-(4-((5-cyclopropyl-3-(2,6-dichlorophenyl)) )different Zin-4-yl)methoxy)phenyl)azin-3-yl)benzoic acid, 3-(6-((5-cyclopropyl-3-(2,6-dichlorophenyl)) Zin-4-yl)methoxy)-3,4-dihydroisoquinolin-2(1H)-yl)benzoic acid, ((R)-3-(6-((5-cyclopropyl-3) -(2,6-dichlorophenyl)iso (Z)-4-yl)methoxy)-1-methyl-1,2,3,4-tetrahydroquinolin-2-yl)benzoic acid), ((S)-3-(6-((5) -cyclopropyl-3-(2,6-dichlorophenyl)iso Zin-4-yl)methoxy)-1-methyl-1,2,3,4-tetrahydroquinolin-2-yl)benzoic acid), 3-(1-(2-chloro-4-() (5-cyclopropyl-3-(2,6-dichlorophenyl)iso Zin-4-yl)methoxy)phenyl)azin-3-yl)benzoic acid, 2-(2-chloro-4-((5-cyclopropyl-3-(2,6-dichlorobenzene) Base) Zin-4-yl)methoxy)phenyl)isoindoline-5-carboxylic acid, 3-(8-chloro-6-((5-cyclopropyl-3-(2,6-dichlorobenzene) Base) Zin-4-yl)methoxy)-1-methyl-1,2,3,4-tetrahydroquinolin-2-yl)benzoic acid, ((R)-3-(8-chloro-6-) ((5-cyclopropyl-3-(2,6-dichlorophenyl)) (Z)-4-yl)methoxy)-1-methyl-1,2,3,4-tetrahydroquinolin-2-yl)benzoic acid), ((S)-3-(8-chloro-6) -((5-cyclopropyl-3-(2,6-dichlorophenyl)) Zin-4-yl)methoxy)-1-methyl-1,2,3,4-tetrahydroquinolin-2-yl)benzoic acid), 3-((6-((5-cyclopropyl)) -3-(2,6-dichlorophenyl)iso Zin-4-yl)methoxy)-2,3-dihydro-1H-pyrido[2,3-b][1,4] -1-yl)methyl)benzoic acid, 3-((5-((5-cyclopropyl-3-(2,6-dichlorophenyl))) Zin-4-yl)methoxy)-3-fluoro-1H-pyrrolo[3,2-b]pyridin-1-yl)methyl)benzoic acid, and 3-(8-chloro-6-(( 5-cyclopropyl-3-(2,6-dichlorophenyl)iso Zin-4-yl)methoxy) -2-yl)benzoic acid. A compound as shown in Table 1. A pharmaceutical composition comprising a compound according to any one of the preceding claims, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient. A method of modulating a farnesoid X receptor comprising contacting the receptor with a compound of any one of claims 1 to 17. A method of treating a patient diagnosed with a disease or condition modulated by a farnesoid X receptor, comprising administering to the patient an effective amount of a compound of any one of claims 1 to 17. The method of claim 20, wherein the disease or condition is nonalcoholic steatohepatitis. A method of making a compound of formula I.