WO2017147047A1 - 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 MODULATORS AND METHODS OF THEIR USE

BACKGROUND

The farnesoid X receptor (FXR) is known to be expressed in the liver, kidney, and intestines. Lundquist, IV, J.T. et al. J. Med. Chem. 2010, 53, 1774-1787. FXR's native ligands are bile acids, for example, chenodeoxycholic acid. Id. In rodent models, activation of FXR by FXR agonists results in beneficial metabolic effects, for example, glucose lowering, insulin sensitization, triglyceride lowering, and cholesterol lowering. Abel, U. et al. Bioorg. & Med. Chem. Lett. 20 (2010) 491 1-4917; Richter, H.G.F. et al, Bioorg. & Med. Chem. Lett. 21 (2011) 1 134-1 140. 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.

There are multiple indications for modulators (i.e., agonists or partial agonists) of FXR including, for example, the treatment of dyslipidemia, liver disease, diabetes, diabetic nephropathy, vitamin-D-related diseases, drug-induced side effects, hepatitis, inflammatory bowel disease, hypertriglyceridemia, gallstones, nonalcoholic steatohepatitis, atherosclerosis, and Primary Billiary Cirrhosis. Lundquist, IV, J.T. et al. at 1774; Richter, H.G.F. et al. at 1 134; Abel, U. et al. at 491 1. As such, modulators of FXR are needed.

SUMMARY

The present disclosure is directed to com ounds of formula I

wherein R¹ is H, F, CI, Br, or I; R² is F, CI, Br, or I; R³ is Ci_-6alkyl or C₃-₆cycloalkyl; A is

X is O, -NH-, or -N(CH₃)-; and R⁴ is H, F, CI, or CN; and pharmaceutically acceptable salts thereof. Methods of making and using the compounds of formula I are also described.

DETAILED DESCRIPTION OF ILLUSTRATIVE EMBODIMENTS

The disclosure may be more fully appreciated by reference to the following description, including the following glossary of terms and the concluding examples. It is to be appreciated that certain features of the disclosed compositions and methods which are, for clarity, described herein in the context of separate aspects, may also be provided in combination in a single aspect. Conversely, various features of the disclosed compositions and methods that are, for brevity, described in the context of a single aspect, may also be provided separately or in any

subcombination.

The term "alkyl," when used alone or as part of a substituent group, refers to a straight- or branched-chain alkyl group having from 1 to 12 carbon atoms ("C_1-12"), preferably 1 to 6 carbons atoms ("Ci-6"), in the chain. Examples of alkyl groups include methyl (Me, Cialkyl) ethyl (Et, C2alkyl), n-propyl (C₃alkyl), isopropyl (C₃alkyl), butyl (C4alkyl), isobutyl (C4alkyl), sec-butyl (C4alkyl), tert-butyl (C4alkyl), pentyl (Csalkyl), isopentyl (Csalkyl), tert-pentyl (Csalkyl), hexyl (Cealkyl), isohexyl (Cealkyl), and groups that in light of the ordinary skill in the art and the teachings provided herein would be considered equivalent to any one of the foregoing examples.

The term "cycloalkyl," when used alone or as part of a substituent group, refers to an alkyl group having at least one ring. Preferably, the cycloalkyl groups of the disclosure have from 3 to 6 carbon atoms ("C3-6"). Examples of cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, methyl-cyclopropyl, methyl-cyclobutyl, methyl- cyclopentyl, and the like. When a range of carbon atoms is used herein, for example, C_1-6, all ranges, as well as individual numbers of carbon atoms are encompassed. For example, "C1-3" includes C_1-3, C_1-2, C_2-3, Ci, C₂, and C₃.

The term "halogen" represents chlorine, fluorine, bromine, or iodine. The term "halo" represents chloro, fluoro, bromo, or iodo.

As used herein, the term "compound(s) of formula I" includes those compounds of "formula I," as well as compounds of any of the formula I subgenera.

"FXR modulator" refers to a compound that is an agonist or partial agonist of FXR. "Pharmaceutically acceptable" means approved or approvable by a regulatory agency of the Federal or a state government or the corresponding agency in countries other than the United States, or that is listed in the U. S. Pharmacopoeia or other generally recognized pharmacopoeia for use in animals, and more particularly, in humans.

"Pharmaceutically acceptable salt" refers to a salt of a compound of the disclosure that is pharmaceutically acceptable and that possesses the desired pharmacological activity of the parent compound. In particular, such salts are non-toxic may be inorganic or organic acid addition salts and base addition salts. Specifically, such salts include: (1) acid addition salts, formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like; or formed with organic acids such as acetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid, gly colic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, 3-(4- hydroxybenzoyl)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-l -carboxylic acid, glucoheptonic acid, 3-phenylpropionic acid, trimethylacetic acid, tertiary butylacetic acid, lauryl sulfuric acid, gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylic acid, stearic acid, muconic acid, and the like; or (2) salts formed when an acidic proton present in the parent compound either is replaced by a metal ion, e.g., an alkali metal ion, an alkaline earth ion, or an aluminum ion; or coordinates with an organic base such as ethanolamine, diethanolamine, triethanolamine, N- methylglucamine and the like. Salts further include, by way of example only, sodium, potassium, calcium, magnesium, ammonium, tetraalkylammonium, and the like; and when the compound contains a basic functionality, salts of non-toxic organic or inorganic acids, such as

hydrochloride, hydrobromide, tartrate, mesylate, acetate, maleate, oxalate and the like. "Pharmaceutically acceptable vehicle" refers to a diluent, adjuvant, excipient or carrier with which a compound of the disclosure is administered. A "pharmaceutically acceptable excipient" refers to a substance that is non-toxic, biologically tolerable, and otherwise biologically suitable for administration to a subject, such as an inert substance, added to a pharmacological composition or otherwise used as a vehicle, carrier, or diluent to facilitate administration of an agent and that is compatible therewith. Examples of excipients include calcium carbonate, calcium phosphate, various sugars and types of starch, cellulose derivatives, gelatin, vegetable oils, and polyethylene glycols.

"Subject" includes humans. The terms "human," "patient," and "subject" are used interchangeably herein.

"Treating" or "treatment" of any disease or disorder refers, in one embodiment, to ameliorating the disease or disorder (i.e., arresting or reducing the development of the disease or at least one of the clinical symptoms thereof). In another embodiment "treating" or "treatment" refers to ameliorating at least one physical parameter, which may not be discernible by the subject. In yet another embodiment, "treating" or "treatment" refers to modulating the disease or disorder, either physically, (e.g., stabilization of a discernible symptom), physiologically, (e.g., stabilization of a physical parameter), or both. In yet another embodiment, "treating" or

"treatment" refers to delaying the onset of the disease or disorder.

"Compounds of the present disclosure," and equivalent expressions, are meant to embrace compounds of the Formula (I) as described herein, which expression includes the pharmaceutically acceptable salts, and the solvates, e.g., hydrates, where the context so permits. Similarly, reference to intermediates, whether or not they themselves are claimed, is meant to embrace their salts, and solvates, where the context so permits.

As used herein, the term "isotopic variant" refers to a compound that contains unnatural proportions of isotopes at one or more of the atoms that constitute such compound. For example, an "isotopic variant" of a compound can be radiolabeled, that is, contain one or more nonradioactive isotopes, such as for example, deuterium (²H or D), carbon-13 (¹ C), nitrogen-15 (¹⁵N), or the like. It will be understood that, in a compound where such isotopic substitution is made, the following atoms, where present, may vary, so that for example, any hydrogen may be ²H/D, any carbon may be ¹ C, or any nitrogen may be ¹⁵N, and that the presence and placement of such atoms may be determined within the skill of the art. Likewise, the disclosure may include the preparation of isotopic variants with radioisotopes, in the instance for example, where the resulting compounds may be used for drug and/or substrate tissue distribution studies.

Radiolabeled compounds of the disclosure can be used in diagnostic methods such as Single- photon emission computed tomography (SPECT). The radioactive isotopes tritium, i.e. H, and carbon-14, i.e. ¹⁴C, are particularly useful for their ease of incorporation and ready means of detection. Further, compounds may be prepared that are substituted with positron emitting isotopes, such as ⁿC, ¹⁸F, ¹⁵0 and ¹ N, and would be useful in Positron Emission Topography (PET) studies for examining substrate receptor occupancy.

All isotopic variants of the compounds of the disclosure, radioactive or not, are intended to be encompassed within the scope of the disclosure.

It is also to be understood that compounds that have the same molecular formula but differ in the nature or sequence of bonding of their atoms or the arrangement of their atoms in space are termed "isomers." Isomers that differ in the arrangement of their atoms in space are termed "stereoisomers," for example, diastereomers and enantiomers.

Stereoisomers that are not mirror images of one another are termed "diastereomers" and those that are non-superimposable mirror images of each other are termed "enantiomers." When a compound has an asymmetric center, for example, it is bonded to four different groups, a pair of enantiomers is possible. An enantiomer can be characterized by the absolute configuration of its asymmetric center and is described by the R-and S-sequencing rules of Cahn and Prelog, or by the manner in which the molecule rotates the plane of polarized light and designated as dextrorotatory or levorotatory (i.e. , as (+) or (-)-isomers respectively). A chiral compound can exist as either individual enantiomer or as a mixture thereof. A mixture containing equal proportions of the enantiomers is called a "racemic mixture."

"Tautomers" refer to compounds that are interchangeable forms of a particular compound structure, and that vary in the displacement of hydrogen atoms and electrons. Thus, two structures may be in equilibrium through the movement of π electrons and an atom (usually H). For example, enols and ketones are tautomers because they are rapidly interconverted by treatment with either acid or base. Another example of tautomerism is the aci-and nitro-forms of phenyl nitromethane, that are likewise formed by treatment with acid or base.

Tautomeric forms may be relevant to the attainment of the optimal chemical reactivity and biological activity of a compound of interest.

The compounds of this disclosure may possess one or more asymmetric centers; such compounds can therefore be produced as individual (R)-or (^-stereoisomers or as mixtures thereof.

Unless indicated otherwise, the description or naming of a particular compound in the specification and claims is intended to include both individual enantiomers and mixtures, racemic or otherwise, thereof. Within the present disclosure, any open valency appearing on a carbon, oxygen, or nitrogen atom in any structure described herein indicates the presence of a hydrogen atom. Where a chiral center exists in a structure, but no specific stereochemistry is shown for that center, both enantiomers, separately or as a mixture, are encompassed by that structure. The methods for the determination of stereochemistry and the separation of stereoisomers are well-known in the art.

The resent disclosure is directed to compounds of formula I:

According to the disclosure, R¹ is H, F, CI, Br, or I. In some aspects, R¹ is H. In other aspects, R¹ is F. In preferred aspects, R¹ is CI. In other aspects, R¹ is Br. In still other aspects, R¹ is I.

According to the disclosure, R² is F, CI, Br, or I. In some aspects, R² is F. In preferred aspects, R² is CI. In other aspects, R² is Br. In still other aspects, R² is I.

In a preferred aspect of the disclosure, R¹ and R² are positioned at the 2 and 6 positions of the henyl ring to which they are attached:

In preferred embodiments of the disclosure, R¹ and R² are both CI.

According to the disclosure, R³ is Ci-₆alkyl or C₃-₆cycloalkyl. In some aspects, R³ is Ci-₆alkyl, for example Cialkyl, C₂alkyl, C₃alkyl, C₄alkyl, Csalkyl, or Cealkyl. In preferred aspects, R³ is C₃-₆cycloalkyl, for example, C₃cycloalkyl, C₄cycloalkyl, Cscycloalkyl, or

Cecycloalkyl. In exemplary embodiments, R³ is cyclopropyl.

According to the disclosure, A is

In the embodiments wherein A is (b), X is O, -NH-, or -N(CH₃)-. In some aspects, X is O. In other aspects, X is -NH-. In still other aspects, X is -NH(CH₃)-.

In preferred aspects employing (b), the compound of formula I is a compound of formula

I-B:

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

In preferred aspects employing (c), the compound of formula I is a compound of formula

In preferred aspects employing (d), the compound of formula I is a compound of formula

I-E:

is:

In preferred aspects employing (e), the compound of formula I is a compound of formula

I-F:

In preferred aspects employing (f), the compound of formula I is a compound of formula

I-G:

H

In other aspects, A is:

In preferred aspects employing (g), the compound of formula I is a compound of formula

According to the disclosure, R⁴ is H, F, CI, or CN. In preferred aspects, R⁴ is H. In other aspects, R⁴ is F. In yet other aspects, R⁴ is CI. In other aspects, R⁴ is CN.

The disclosure also relates to methods of using the compounds described herein to treat subjects diagnosed with or suffering from a disease, disorder, or condition mediated by

Famesoid X Receptor (FXR). Compounds of the disclosure are FXR agonists or FXR partial agonists. The disclosed methods are accomplished by administering to the subject a compound of the disclosure in an amount sufficient to modulate FXR.

In some aspects, the compounds described herein are useful in the treatment of chronic cholestatic conditions, for example, 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 in the treatment of progressive familiar cholestasis (PFIC), alcohol-induced cirrhosis and associated cholestasis, and liver fibrosis. The compounds of the disclosure can be used to treat liver steatosis and associated syndromes, for example, non-alcoholic steatohepatitis (NASH). The compounds of the disclosure can be used to treat cholestatic and/or fibrotic effects associated with cirrhosis (alcohol-induced cirrhosis) or viral hepatitis.

In other aspects, the compounds described herein are useful in the treatment of gallstones, for example, to prevent cholesterol gallstone formation or to prevent re-formation of gallstones after surgical removal or lithotripsy. Doggrell, S. Curr. Opin. Investig. Drugs 2006, 7(4), 344- 348. In still other aspects, the compounds described herein are useful in 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, Am. J. Physiol. Endocrinol. Metab. 2006,

290(4), E716-22. That is, the compounds described herein can be used to lower total cholesterol level, lower LDL cholesterol levels, lower VLDL cholesterol levels, raise HDL cholesterol levels, and/or lower triglyceride levels. The compounds described herein can also be used to treat dyslipidemia.

The compounds of the disclosure can be used to treat lipid and lipoprotein disorders, for example, hypercholesterolemia, hypertriglyceridemia, and artherosclerosis. Hanniman et al. J. Lipid Res. 2005, 46(12), 2595-2604. In some aspects, the compounds of the disclosure can be used to treat cardiovascular disorders, for example, acute myocardial infarction, acute stroke, or thrombosis.

In other aspects, the compounds described herein are useful in improving insulin sensitivity and glucose tolerance. The compounds described herein are also useful in the treatment of metabolic disorders, for example, type II diabetes and complications of diabetes (e.g., diabetic nephropathy, diabetic retinopathy, diabetic neuropathy, peripheral arterial occlusive disease). Stayrook et al, Endocrinology 2005, 146(3), 984-91; Zhang et al, Proc. Natl. Acad. Sci. 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 can be useful in treating obesity.

Compounds of the disclosure are useful in treating cancer, for example, breast cancer, colon cancer, or prostate cancer. Niesor et al, Curr. Pharm. Des. 2001, 7(4), 231-59; 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 in treating

gastrointestinal conditions associated with a reduced uptake of dietary fat and fat-soluble dietary vitamins (e.g., vitamin D) that can be overcome by increasing intestinal levels of bile acids and phospholipids.

In other aspects, compound of the disclosure are useful in treating inflammatory bowel disorders such as, for example, Crohn's disease or colitis ulcerosa. Inagaki et al, Proc. Natl. Acad. Sci. USA. 2006, 103(10), 3920-3905. In other aspects, compounds of the disclosure are useful in treating hepatitis B virus (HBV). See , e.g., WO 2015/036442.

In treatment methods according to the disclosure, an effective amount of a

pharmaceutical agent according to the disclosure is administered to a subject suffering from or diagnosed as having such a disease, disorder, or condition. An "effective amount" means an amount or dose sufficient to generally bring about the desired therapeutic benefit in patients in need of such treatment for the designated disease, disorder, or condition. Effective amounts or doses of the compounds of the present disclosure may be ascertained by routine methods such as modeling, dose escalation studies or clinical trials, and by taking into consideration routine factors, e.g., the mode or route of administration or drug delivery, the pharmacokinetics of the compound, the severity and course of the disease, disorder, or condition, the subject's previous or ongoing therapy, the subject's health status and response to drugs, and the judgment of the treating physician. An example of a dose is in the range of from about 0.001 to about 200 mg of compound per kg of subject's body weight per day, preferably about 0.05 to 100 mg/kg/day, or about 1 to 35 mg/kg/day, in single or divided dosage units (e.g., BID, TID, QID). For a 70-kg human, an illustrative range for a suitable dosage amount is from about 0.05 to about 7 g/day, or about 0.2 to about 2.5 g/day.

In addition, the compounds of the disclosure may be used in combination with additional active ingredients in the treatment of the above conditions. The additional active ingredients may be coadministered separately with a compound of the disclosure or included with such an agent in a pharmaceutical composition according to the disclosure. In an exemplary embodiment, additional active ingredients are those that are known or discovered to be effective in the treatment of any of the diseases or disorders described herein. The combination may serve to increase efficacy (e.g., by including in the combination a compound potentiating the potency or effectiveness of an active agent according to the disclosure), decrease one or more side effects, or decrease the required dose of the active agent according to the disclosure.

The compounds of the disclosure are used, alone or in combination with one or more additional active ingredients, to formulate pharmaceutical compositions of the disclosure. A pharmaceutical composition of the disclosure comprises: (a) an effective amount of at least one compound in accordance with the disclosure; and (b) a pharmaceutically acceptable excipient.

Delivery forms of the pharmaceutical compositions containing one or more dosage units of the active agents may be prepared using suitable pharmaceutical excipients and compounding techniques known or that become available to those skilled in the art. The compositions may be administered in the inventive methods by a suitable route of delivery, e.g., oral, parenteral, rectal, topical, or ocular routes, or by inhalation.

The preparation may be in the form of tablets, capsules, sachets, dragees, powders, granules, lozenges, powders for reconstitution, liquid preparations, or suppositories. Preferably, the compositions are formulated for intravenous infusion, topical administration, or oral administration.

For oral administration, the compounds of the disclosure can be provided in the form of tablets or capsules, or as a solution, emulsion, or suspension. To prepare the oral compositions, the compounds may be formulated to yield a dosage of, e.g., from about 0.05 to about 100 mg/kg daily, or from about 0.05 to about 35 mg/kg daily, or from about 0.1 to about 10 mg/kg daily. For example, a total daily dosage of about 5 mg to 5 g daily may be accomplished by dosing once, twice, three, or four times per day.

Oral tablets may include a compound according to the disclosure mixed with

pharmaceutically acceptable excipients such as inert diluents, disintegrating agents, binding agents, lubricating agents, sweetening agents, flavoring agents, coloring agents and preservative agents. Suitable inert fillers include sodium and calcium carbonate, sodium and calcium phosphate, lactose, starch, sugar, glucose, methyl cellulose, magnesium stearate, mannitol, sorbitol, and the like. Exemplary liquid oral excipients include ethanol, glycerol, water, and the like. Starch, polyvinyl-pyrrolidone (PVP), sodium starch glycolate, microcrystalline cellulose, and alginic acid are suitable disintegrating agents. Binding agents may include starch and gelatin. The lubricating agent, if present, may be magnesium stearate, stearic acid or talc. If desired, the tablets may be coated with a material such as glyceryl monostearate or glyceryl distearate to delay absorption in the gastrointestinal tract, or may be coated with an enteric coating.

Capsules for oral administration include hard and soft gelatin capsules. To prepare hard gelatin capsules, compounds of the disclosure may be mixed with a solid, semi-solid, or liquid diluent. Soft gelatin capsules may be prepared by mixing the compound of the disclosure with water, an oil such as peanut oil or olive oil, liquid paraffin, a mixture of mono and di-glycerides of short chain fatty acids, polyethylene glycol 400, or propylene glycol.

Liquids for oral administration may be in the form of suspensions, solutions, emulsions or syrups or may be lyophilized or presented as a dry product for reconstitution with water or other suitable vehicle before use. Such liquid compositions may optionally contain:

pharmaceutically-acceptable excipients such as suspending agents (for example, sorbitol, methyl cellulose, sodium alginate, gelatin, hydroxyethylcellulose, carboxymethylcellulose, aluminum stearate gel and the like); non-aqueous vehicles, e.g., oil (for example, almond oil or fractionated coconut oil), propylene glycol, ethyl alcohol, or water; preservatives (for example, methyl or propyl p-hydroxybenzoate or sorbic acid); wetting agents such as lecithin; and, if desired, flavoring or coloring agents.

The active agents of this disclosure may also be administered by non-oral routes. For example, the compositions may be formulated for rectal administration as a suppository. For parenteral use, including intravenous, intramuscular, intraperitoneal, or subcutaneous routes, the compounds of the disclosure may be provided in sterile aqueous solutions or suspensions, buffered to an appropriate pH and isotonicity or in parenterally acceptable oil. Suitable aqueous vehicles include Ringer's solution and isotonic sodium chloride. Such forms will be presented in unit-dose form such as ampules or disposable injection devices, in multi-dose forms such as vials from which the appropriate dose may be withdrawn, or in a solid form or pre-concentrate that can be used to prepare an inj ectable formulation. Illustrative infusion doses may range from about 1 to 1000 .mu.g/kg/minute of compound, admixed with a pharmaceutical carrier over a period ranging from several minutes to several days.

For topical administration, the compounds may be mixed with a pharmaceutical carrier at a concentration of about 0.1 % to about 10% of drug to vehicle. Another mode of administering the compounds of the disclosure may utilize a patch formulation to affect transdermal delivery.

Compounds of the disclosure may alternatively be administered in methods of this disclosure by inhalation, via the nasal or oral routes, e.g., in a spray formulation also containing a suitable carrier.

Exemplary compounds useful in methods of the disclosure will now be described by reference to the illustrative synthetic schemes for their general preparation below and the specific examples that follow. Artisans will recognize that, to obtain the various compounds herein, starting materials may be suitably selected so that the ultimately desired substituents will be carried through the reaction scheme with or without protection as appropriate to yield the desired product. Alternatively, it may be necessary or desirable to employ, in the place of the ultimately desired substituent, a suitable group that may be carried through the reaction scheme and replaced as appropriate with the desired substituent. Unless otherwise specified, the variables are as defined above in reference to Formula (I). Reactions may be performed between the melting point and the reflux temperature of the solvent, and preferably between 0 °C and the reflux temperature of the solvent. Reactions may be heated employing conventional heating or microwave heating. Reactions may also be conducted in sealed pressure vessels above the normal reflux temperature of the solvent. Scheme 1.1

Scheme 1.2

Scheme 2

sites' fried iaie

Scheme 2.2

Scheme 3.1

Sc

Scheme 4.1

I Rtef mediate 12

Scheme 4.2

Scheme 4.2

Scheme 5.1

Scheme 5.2

Scheme 6.1

Intermediate 16

Scheme 6.2

Scheme 7.1

Intermediate 18

Scheme 7.2

EXAMPLES

Intermediate 1. ethyl 4-(azetidin-3-yl)benzoate.

Step 1. tert-butyl 3-(4-(ethoxycarbonyl)phenyl)azetidine-l-carboxylate. The title compound was prepared using the Negishi reaction as known in the art and described in U.S. Pat. Appl. Publ, 20140235614, 21 Aug 2014.

Step 2. ethyl 4-(azetidin-3-yl)benzoate. To a solution of tert-butyl 3-(4- (ethoxycarbonyl)phenyl)azetidine-l-carboxylate (1.53 g, 4.92 mmol) in THF (20.00 mL) was added HCl / dioxane (4.0 M, 30.00 mL) dropwsie. The resulting mixture was stirred at 25 °C for 30 min. TLC (PE / EA = 3 / 1) showed that the reaction was completed. The reaction mixture was concentrated to afford the title compound (802 mg, crude) as a red oil which was used for next step without further purification. +ESI-MS: m/z 205.9 [M + H]⁺ Intermediate 2. (2-((4-bromophenoxy)methoxy)ethyl)trimethylsilane.

The title compound was prepared as described in Tetrahedron Letters, 42(9), 1611-1613; 2001.

Intermediate 3. methyl 1.2.3.4-tetrahvdroisoquinoline-7-carboxylate.

Step 1. l -(7-bromo-3.4-dihvdroisoquinolin-2(lH)-yl)-2.2.2-trifluoroethan-l-one. The title compound was prepared in a manner as described in U.S. Pat. Appl. Publ., 20080081803, 03 Apr 2008 from 2-(4-bromopheny l)ethan- 1 -amine.

Step 2. 1.2.3.4-tetrahvdroisoquinoline-7-carbonitrile. The title compound was prepared in a manner as described in PCTInt. Appl., 9850364, 12 Nov 1998 from l -(7-bromo-3,4- dihydroisoquinolin-2(lH)-yl)-2,2,2-trifluoroethan-l -one.

Step 3. methyl 1.2.3.4-tetrahvdroisoquinoline-7-carboxylate. The title compound was prepared in a manner as described PCTInt. Appl, 2006117549, 09 Nov 2006 from 1 ,2,3,4- tetrahydroisoquinoline-7-carbonitrile.

Intermediate 4. 4-(bromomethyl)-5-cvclopropyl-3-(2.6-dichlorophenyl)isoxazole.

The title compound can be prepared as known in the art and by reference to PCTInt. Appl., 2009012125, 22 Jan 2009.

Intermediate 5. methyl isoindoline-5-carboxylate.

Step 1. tert-butyl 5-bromoisoindoline-2-carboxylate. The title compound can be prepared from isoindoline-l,3-dione and as described in PCT Int. Appl, 2014089324, 12 Jun 2014.

Step 2. methyl isoindoline-5-carboxylate. The title compound can be prepared from can be prepared from tert-butyl 5-bromoisoindoline-2-carboxylate as described in PCT Int. Appl, 2005095403, 13 Oct 2005.

Intermediate 6. ethyl 4-(l-(4-hvdroxyphenyl)azetidin-3-yl)benzoate.

Step 1. ethyl 4-(l-(4-((2-(trimethylsilyl)ethoxy)methoxy)phenyl)azetidin-3-yl)benzoate. To a solution of ethyl 4-(azetidin-3-yl)benzoate (Intermediate 1, 802 mg, 3.87 mmol, 1.0 eq) and (2- ((4-bromophenoxy)methoxy)ethyl)trimethylsilane (Intermediate 2, 1.54 g, 5.07 mmol, 1.30 eq) in toluene (30.00 mL) was added Cs₂C0₃ (2.54 g, 7.80 mmol, 2.00 eq), Pd(dba)₂ (448 mg, 0.78 mmol, 0.20 eq) and X-phos (558 mg, 1.17 mmol, 0.30 eq) under nitrogen. The mixture was degassed and refilled with nitrogen for three times. The reaction was stirred at 110 °C for 10 hours. TLC (PE / EA = 3 / 1) showed the reaction was completed. The reaction mixture was concentrated to dryness. The residue was purified by silica gel with using 2-10% EA in PE as eluent to give the title compound (1.1 g, 66 % yield) as yellow oil. +ESI-MS: m/z 428.2 [M +

H]⁺.

Step 2. ethyl 4-(l-(4-hydroxyphenyl)azetidin-3-yl)benzoate. To a solution of ethyl 4-(l-(4-((2- (trimethylsilyl)ethoxy)methoxy)phenyl)azetidin-3-yl)benzoate (1.1 g, 2.58 mmol, 1.0 eq) in

EtOH (40.00 mL) was added HC1 (1.0 M, 20.6 mL, 8.0 eq). The reaction mixture was stirred at 25 °C for 30 min. TLC (PE / EA = 3 / 1) showed that the starting material was consumed completely. The reaction mixture was quenched with aqueous NaHCCb (100 mL) and extracted with EA (100 mL X 3). The combined organic layer was dried over anhydrous Na₂S0₄ and concentrated to dryness. The residue was purified by silica gel with (PE:EA=15: 1 to 5: 1) to give the title compound (682 mg, 89% yield) as a yellow oil.

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

The title compound was prepared in a manner analogous to Intermediate 6, Steps 1 -2 using methyl isoindoline-5-carboxylate (Intermediate 5) in Step 1. Intermediate 8. ethyl 3-(azetidin-3-yl)benzoate.

The title compound was prepared in a manner analogous to Intermediate 1 , using ethyl 3- iodobenzoate in Step 1. Intermediate 9. ethyl 3-(l -(4-hydroxyphenyl)azetidin-3-yl)benzoate.

The title compound was prepared in a manner analogous to Intermediate 6, Steps 1-2 using ethyl 3-(azetidin-3-yl)benzoate (Intermediate 8) in Step 1. Intermediate 10. ethyl 3-(l -(2-chloro-4-hvdroxyphenyl)azetidin-3-yl)benzoate.

Step 1. (2-((4-bromo-3-chlorophenoxy)methoxy)ethyl)trimethylsilane. The title compound was prepared in a manner as described in Tetrahedron Letters, 42(9), 1611-1613; 2001.

Step 2. ethyl 3-(l-(2-chloro-4-hvdroxyphenyl)azetidin-3-yl)benzoate. The title compound was prepared in a manner analogous to Intermediate 6, Steps 1-2 using ethyl 3-(azetidin-3- yl)benzoate (Intermediate 8) and (2-((4-bromo-3-chlorophenoxy)methoxy)ethyl)trimethylsilane in Step 1.

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

The title compound was prepared in a manner analogous to Intermediate 6, Steps 1-2 using methyl isoindoline-5-carboxylate (Intermediate 5) and (2-((4-bromo-3- chlorophenoxy)methoxy)ethyl)trimethylsilane in Step 1.

Intermediate 12. methyl 3-(6-hvdroxy-l-methyl-1.2.3.4-tetrahvdroquinolin-2-yl)benzoate.

Step 1. methyl (Z)-3-(3-(5-methoxy-2-nitrophenyl)acryloyl)benzoate. To a solution of 5- methoxy-2-nitrobenzaldehyde (See, e.g., PCT Int. AppL, 2012109108, 16 Aug 2012; PCT Int. AppL, 2004094420, 04 Nov 2004) (3.26 g, 18.0 mmol) and methyl 3-acetylbenzoate (See, e.g., Asian Journal of Chemistry, 19(7), 5093-5097; 2007; PCT Int. AppL, 2006067445, 29 Jun 2006) (3.21 g, 18.0 mmol) in DCM (70 mL) was added ZrC (1.68 g, 7.2 mmol) in one portion at room temperature . Then the resulting mixture was stirred at 40°C for 17 hr. LC-MS showed reactant 5-methoxy-2-nitrobenzaldehyde was consumed completely. The reaction mixture was filtered and the filtrate was concentrated to dryness. The residue was purified by column

chromatography on silica gel using 5-50% EA in PE as eluent to give the title compound (5.10 g, 83%) as a yellow solid. +E SI-MS: m/z 342.1 [M +H]⁺

Step 2. methyl 3-(6-methoxy-1.2.3.4-tetrahvdroquinolin-2-yl)benzoate. To a solution of methyl (Z)-3-(3-(5-methoxy-2-nitrophenyl)acryloyl)benzoate (1.0 g, 2.9 mmol) in DCM (10 mL) was added Pd/C (10 mg) under nitrogen. The suspension was degassed under vacuum and purged with hydrogen three times. The mixture was stirred under hydrogen (15 psi) at 20 °C for 17 hours. LC-MS showed methyl (Z)-3-(3-(5-methoxy-2-nitrophenyl)acryloyl)benzoate was consumed completely and one main peak with the desired MS was observed. The reaction mixture was filtered and the filtrate was concentrated to dryness. The residue was purified by column chromatography on silica gel using 10% EA in PE to give the title compound (608 mg, 69.8%) as colorless oil. +E SI-MS: m/z 297.9 [M +H]⁺

Step 3. 3-(6-hvdroxy-1.2.3.4-tetrahvdroquinolin-2-yl)benzoic acid. A solution of methyl 3-(6- methoxy-l,2,3,4-tetrahydroquinolin-2-yl)benzoate (1.5 g, 5.04 mmol) in HBr/AcOH (50 mL, 40%w) was stirred at 100 °C for 12 hours. LCMS indicated the reactant methyl 3-(6-methoxy- l,2,3,4-tetrahydroquinolin-2-yl)benzoate was consumed completely. The reaction mixture was partitioned between EA (50 mL) and brine (50 mL). The organic phase was dried over NasS04, filtered and concentrated under reduced pressure. The title compound (1.3 g, 95.8%) was obtained as a white solid used in the next step without further purification.

+ESI-MS: m/z 269.9 [M +H]⁺

Step 4. methyl 3-(6-hvdroxy-1.2.3.4-tetrahvdroquinolin-2-yl)benzoate. To a solution of 3-(6- hydroxy-l,2,3,4-tetrahydroquinolin-2-yl)benzoic acid (1.3 g, 4.8 mmol) in MeOH (50 mL) was added SOCl₂ (3.4 g, 28.8 mmol). The mixture was stirred at 60°C for 1 hour. LC-MS showed 3- (6-hydroxy-l,2,3,4-tetrahydroquinolin-2-yl)benzoic acid was consumed completely and one main 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-((tert-butoxycarbonyl)oxy)-1.2.3.4-tetrahvdroquinolin-2-yl)benzoate. To a solution of methyl 3-(6-hydroxy-l,2,3,4-tetrahydroquinolin-2-yl)benzoate (1.35 g, 4.76 mmol) and Et₃N (1.45 g, 14.3 mmol) in DCM (5.0 mL) was added Boc₂0 (3.12 g, 14.3 mmol). The resulting mixture was stirred at 20°C for 1 hour. TLC (PE / EA = 1 / 1) showed the reactant methyl 3-(6-hydroxy-l,2,3,4-tetrahydroquinolin-2-yl)benzoate was consumed completely. The reaction mixture was filtered and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel using 5-15% EA in PE to give the title compound (1.7 g, 93.1%) as a white solid. ^XH-NMR (400MHz, CDC1₃), 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-((tert-butoxycarbonyl)oxy)-l-methyl-1.2.3.4-tetrahvdroquinolin-2- vDbenzoate. To a solution of methyl 3-(6-((tert-butoxycarbonyl)oxy)-l,2,3,4-tetrahydroquinolin- 2-yl)benzoate (0.5 g, 1.3 mmol) and HCHO (0.9 mL) in MeOH (10 mL) was added one drop of acetic acid. The reaction mixture was stirred for 5 min., and then NaBH(OAc)3 (246 mg, 3.9 mmol) was added 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), and extracted with EA (20 mL X 3). The combined organic phase was washed with brine (20 mL), dried over anhydrous Na₂S0₄ and concentrated to dryness. The crude title compound (470 mg, crude) was obtained as a colorless oil. +ESI-MS: m/z 398.0 [M +H]⁺ Step 7. methyl 3-(6-hvdroxy-l-methyl-1.2.3.4-tetrahvdroquinolin-2-yl)benzoate. To a solution of methyl 3-(6-((tert-butoxycarbonyl)oxy)-l -methyl- l,2,3,4-tetrahydroquinolin-2-yl)benzoate (470 mg, 1.18 mmol) in THF (30 mL) was added HCl/MeOH (4 M, 1.5 mL) .The mixture was stirred at 20 °C for 3 hours. LC-MS showed methyl 3-(6-((tert-butoxycarbonyl)oxy)-l-methyl-l, 2,3,4- tetrahydroquinolin-2-yl)benzoate was consumed completely and one main peak with the desired MS was detected. The reaction mixture was concentrated under reduce pressure to give a brown solid. The brown solid was washed with EA/PE=5/1 (30 mL) to give a white solid. The title compound (284 mg, 81.3%) was obtained as a white solid. +ESI-MS: m/z 297.9 [M +H]⁺ Intermediate 13. methyl 3-(8-chloro-6-hvdroxy-l-methyl-1.2.3.4-tetrahvdroquinolin-2- vDbenzoate.

Step 1. methyl 3-(6-((tert-butoxycarbonyl)oxy)-8-chloro-1.2.3.4-tetrahvdroquinolin-2- vDbenzoate. To a solution of methyl 3-(6-((tert-butoxycarbonyl)oxy)-l,2,3,4-tetrahydroquinolin- 2-yl)benzoate (Intermediate 12, product from Step 5, 466 mmol, 1.22 mmol) in anhydrous DMF (3 mL) was added NCS (162.28 mg, 1.22 mmol) in one portion. The reaction mixture was stirred at 20 °C for 1 hour. TLC (PE / EA = 4 / 1) showed the reaction was completed. The reaction mixture was partitioned between EA (30 mL) and water (30 mL). The organic phase was separated, and the aqueous was extracted with EA (10 mL X 2). The combined organic layers were washed with brine (10 mL X 2), dried over Na₂SC>4, filtered and concentrated under reduced pressure. The crude title compound (505 mg, crude) was obtained as a white solid. +ESI-MS: m/z 440.0 [M +Na]⁺

Step 2. methyl 3-(6-((tert-butoxycarbonyl)oxy)-8-chloro-l-methyl-1.2.3.4-tetrahvdroquinolin-2- vDbenzoate. To a solution of methyl 3-(6-((tert-butoxycarbonyl)oxy)-8-chloro-l, 2,3,4- tetrahydroquinolin-2-yl)benzoate (505 mg, 1.21 mmol) and Mel (0.3 mL, 4.84 mmol) in DMF (10 mL) was added sodium hydride (49 mg, 1.21 mmol) in one portion. The resulting mixture was stirred at 20°C for 16 hour. HPLC/LCMS showed that 19% of the desired compound was detected. The reaction mixture was diluted with water (50 mL) and extracted with EA (30 mL X 2). The combined organic layers were washed with brine (10 mL X 1), dried over anhydrous Na₂SC>4, filtered and concentrated at low pressure. The residue was purified by prep-HPLC (FA condition). The title compound (52 mg, 9.95%) was obtained as a colorless oil. ^-NMR (400 MHz, CDC1₃), 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-hvdroxy-l-methyl-1.2.3.4-tetrahvdroquinolin-2-yl)benzoate. The title compound was prepared in a manner analogous to Intermediate 1, Step 2.

Intermediate 14. ethyl 3-(6-hvdroxy-3.4-dihvdroisoquinolin-2(lH)-yl)benzoate.

Step 1. 6-methoxy-1.2.3.4-tetrahvdroisoquinoline. The title compound can be prepared as known in the art and as described in Journal of Medicinal Chemistry, 56(8), 3414-3418; 2013

Step 2. ethyl 3-(6-methoxy-3.4-dihvdroisoquinolin-2(lH)-yl)benzoate. A mixture of 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, 0.61 mmol), Cs₂C0₃ (7.98 g, 24.5 mmol) and X-phos (584 mg, 1.23 mmol) in DMF (15 mL) was degassed and purged with nitrogen for three times. The resulting mixture was stirred at 100°C for 2 hours under nitrogen. The reaction mixture was cooled to room temperature and diluted with H20 (30 mL), and extracted with EA (20 mL X 2). The combined organic layers were dried over anhydrous Na₂S0₄, filtered and concentrated to dryness. The residue was purified by chromatography on silica gel using 5-10% EA in PE as eluent to give the title compound (1.12 g, 58.7%) as a yellow liquid. +ESI-MS: m/z 311.7 [M +

H]⁺.

Step 3. ethyl 3-(6-hvdroxy-3.4-dihvdroisoquinolin-2(lH)-yl)benzoate. To a solution of ethyl 3- (6-methoxy-3,4-dihydroisoquinolin-2(lH)-yl)benzoate (1.0 g, 3.2 mmol) in DCM (5.00 mL) was added BBr3 (1.6 g, 6.4 mmol) at 0°C. The resulting mixture was stirred at 25°C for 4 hours. The reaction mixture was quenched by saturated NaHCC solution. The resulting mixture was extracted with DCM (10 mL X 2). The combined organic layers were washed with brine (10 mL), dried over anhydrous Na₂SC>4, filtered and concentrated to dryness. The residue was purified by chromatography on silica gel using 10-20% EA in PE as eluent to give the desired the title compound (0.49 g, 51.6%) as yellow liquid. +ESI-MS: m/z 297.8 [M + H]⁺.

Intermediate 15. (5-cvclopropyl-3-(2.6-dichlorophenyl)isoxazol-4-yl)methanol.

The title compound can be prepared as known in the art and as described in PCT Int. Appl, 2009012125, 22 Jan 2009. Intermediate 16: tert-butyl 6-bromo-2.3-dihvdro-lH-pyrido[2.3-bl [1.41oxazine-l-carboxylate.

Step 1. 2.6-dibromopyridin-3-amine. The title compound can be prepared from pyridin-3-amine as described in PCT Int. Appl, 2010111483, 30 Sep 2010.

Step 2. 6-bromo-lH-pyrido[2.3-bl [1.41oxazin-2(3H)-one. The title compound can be prepared from 2,6-dibromopyridin-3-amine as described in PCT Int. Appl, 2013003383, 03 Jan 2013.

Step 3. 6-bromo-2.3-dihvdro-lH-pyrido[2.3-bl [1.41oxazine. The title compound can be prepared from 6-bromo-lH-pyrido[2,3-b] [l ,4]oxazin-2(3H)-one as described in PCT Int. Appl,

2010107768, 23 Sep 2010.

Step 4. tert-butyl 6-bromo-2.3-dihvdro-lH-pyridor2.3-biri.41oxazine-l-carboxylate. To a solution of 6-bromo-2,3-dihydro-lH-pyrido[2,3-b] [l ,4]oxazine (3.5 g, 17.2 mmol), DMAP (1.05 g, 8.6 mmol) and TEA (7.16 mL) in DCM (30.00 mL) was added Boc₂0 (7.52 g, 34.5 mmol).

The resulting mixture was stirred at 40°C for 5 hours. TLC showed the reaction was completed.

The reaction was diluted with water (100 mL) and extracted with EA (200 mL). The organic layer was separated, dried over anhydrous Na2SC>4 and concentrated to dryness. The residue was purified by chromatography on silica gel using 10-25% EA in PE as eluent to give the desired the title compound (4.5 g, 87.8%) as white solid.

Intermediate 17. methyl 3-(bromomethyl)benzoate

The title compound can be prepared as known in the art and as described in PCT Int. Appl, 2012006475, 12 Jan 2012. Intermediate 18. methyl 3-((3-fluoro-5-hvdroxy-lH-pyrrolo[3.2-blpyridin-l-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/l-w096/4; 2005.

Step 2. ethyl 2.2-difluoro-2-(6-methoxy-3-nitropyridin-2-yl)acetate. To a solution of Cu (1.47 g, 23.2 mmol) in DMSO (15 mL) was added ethyl 2,2-difluoro-2-iodoacetate (3.86 g, 15.4 mmol) at 25°C in portions. The mixture was stirred at 25°C for 1 hour and a solution of 2- bromo-6-methoxy-3-nitropyridine (1.8 g, 7.7 mmol) in DMSO (5.00 mL) was added dropwisely. After addition, the reulting mixture was stirred for 15 hours at 25°C. LCMS showed the reaction was completed. The reaction mixture was diluted with H₂0 (30 mL) and extracted with EA (30 mL X 2). The combined organic layers were washed with brine (20 mL), dried over anhydrous Na2SC>4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel using 5-10% EA in PE as eluent to give the title compound (1.98 g, 93%) as yellow oil. +ESI-MS: m/z 277 [M +H]⁺

Step 3. 3.3 -difluoro-5 -methoxy- 1.3 -dihydro-2H-pyrrolo [3.2-bl pyridin-2-one. 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) was added Pd/C (200 mg, 10%) under nitrogen. The suspension was degassed under vacuum and purged with hydrogen for several times. The mixture was stirred under hydrogen (15 psi) for 12 hours at 25°C. The reaction mixture was filtered. NaOMe (774 mg, 14.3 mmol, 2.0 eq) was added to the filtrate and stirred at 25°C for 10 hours. The mixture was concentrated under reduced pressure. The residue was purified by column chromatography using 10-30% EA in PE as eluent to give the title compound (550 mg, 38%) as yellow solid.

XH-NMR (400MHz, CDC1₃), 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-lH-pyrrolo[3.2-blpyridine. To a solution of 3,3-difluoro-5-methoxy- l,3-dihydro-2H-pyrrolo[3,2-b]pyridin-2-one (550 mg, 2.75 mmol) in THF (10 mL) was added BH₃ · Me2S (1.1 mL, 11 mmol) at 25°C under nitrogen. The resulting mixture was stirred at 50°C for 1 hr. The reaction mixture was quenched by addition of MeOH (7 mL) dropwise at 0°C. The resulting mixture was concentrated under reduced pressure. The residue was purified by column chromatography using 15-25% EA in PE as eluent to afford the title compound (409 mg, 89.7%) as white solid. ^-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-lH-pyrrolor3.2-blpyridin-l-yl)methyl)benzoate. To a mixture of NaH (137 mg, 3.4 mmol) in DMF (5 mL) was added 3-fluoro-5-methoxy-lH- pyrrolo[3,2-b]pyridine (380 mg, 2.29 mmol) at 0 °C and stirred for 5 minutes. The reaction mixture was treated with methyl 3-(bromomethyl)benzoate (630 mg, 2.75 mmol) at 0°C and stirred at 25°C for 1 hour. The reaction was monitored by TLC (PE / EA = 3 / 1). The reaction mixture was quenched by H₂0 (10 mL), and extracted with EA (10 mL X 2). The combined organic layers were washed with brine (10 mL), dried over anhydrous Na2SC>4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography using 10-25% EA in PE as eluent to give the title compound (490 mg, 68% yield) as yellow solid. Step 6. methyl 3-((3-fluoro-5-hvdroxy-lH-pyrrolo[3.2-blpyridin-l-yl)methyl)benzoate.The title compound was prepared in a manner analogous to Intermediate 12, Step 3. Intermediate 19. methyl 3-(8-chloro-6-hvdroxychroman-2-yl)benzoate.

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

Step 2. ethyl 3-acetylbenzoate. The title compound can be prepared as known in the art and by reference to Asian Journal of Chemistry, 19(7), 5093-5097; 2007; PCTInt. Appl, 2006067445, 29 Jun 2006.

Step 3. (E)-3-(3-(3-chloro-2-hvdroxy-5-methoxyphenyl)acryloyl)benzoic acid. To a solution of 3-chloro-2-hydroxy-5-methoxybenzaldehyde (2.0, 10.7 mol) and ethyl 3-acetylbenzoate (2.68 g, 13.9 mmol) in EtOH (60 mL) was add a solution of NaOH (640 mg, 16 mmol) in H₂0 (60 mL) drop wise at 25 °C. The resulting mixture was stirred at 25 °C for 1 hour. LC-MS showed the reaction was completed. The mixture was concentrated and the residue was acidified with IN HC1 solution to pH=3 and extracted with EA (50 mL X 3). The combined organic layers were dried over anhydrous Na2SC>4, filtered and concentrated to give the crude title compound (2.5 g, crude) as a yellow solid. +E SI-MS: m/z 333.1 [M + H]⁺.

Step 4. methyl (E)-3-(3-(3-chloro-2-hvdroxy-5-methoxyphenyl)acryloyl)benzoate. To a solution of (E)-3-(3-(3-chloro-2-hydroxy-5-methoxyphenyl)acryloyl)benzoic acid (2.5 g, 7.5 mmol) in anhydrous DMF (20 mL) was added K₂C0₃ (3.15 g, 22.5 mmol) and Mel (4.20 g, 30 mmol) at 25°C. The resulting mixture was stirred at 25°C for 30 min. LC-MS showed the reaction was completed. The mixture was diluted with H₂0 (100 mL) and extracted with EA (100 mL X 2). The combined organic layers were dried over anhydrous Na2SC>4, filtered and concentrated to dryness. The residue was purified by silica gel using 5-10% EA in PE as eluent to give the title compound (2.5 g, 92%) as a yellow solid. ^-NMR (400 MHz, CDC1₃), 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-hvdroxy-5-methoxyphenyl)propanoyl)benzoate. To a solution of methyl (E)-3-(3-(3-chloro-2-hydroxy-5-methoxyphenyl)acryloyl)benzoate (2.5 g, 9.7 mmol) in MeOH (60 mL) was added RhCl(PPh₃)₃ (2.69 g, 2.91 mmol) under nitrogen. The suspension was degassed under vacuum and purged with hydrogen for several times. The reaction mixture was stirred under hydrogen (45 psi) for 3 hours at 40°C. TLC (PE/EA = 5/1) showed that the methyl (E)-3-(3-(3-chloro-2-hydroxy-5-methoxyphenyl)acryloyl)benzoate was consumed. The mixture was concentrated to dryness. The residue was purified by silica gel using 10% EA in PE as eluent to give the title compound (2.1 g, 85%) as light yellow oil.

Step 6. methyl 3-(3-(3-chloro-2.5-dihvdroxyphenyl)propanoyl)benzoate. To a solution of methyl 3-(3-(3-chloro-2-hydroxy-5-methoxyphenyl)propanoyl)benzoate (1.8 g, 4.96 mmol) in DCM (5 mL) was added BBr₃ (1.6 mL) dropwise. The resulting mixture was stirred at 25°C for 10 min. TLC (PE/EA = 5/1) showed that methyl 3-(3-(3-chloro-2-hydroxy-5- methoxyphenyl)propanoyl)benzoate was consumed. The mixture was quenched with aqueous NaHC0₃ (50 mL) and extracted with EA (50 mL X 3). The combined organic layers were dried over anhydrous Na2SC>4, filtered and concentrated to dryness. The residue was purified by silica gel using 20-30% EA in PE as eluent to give the title compound (608 mg, 36%) as a white solid. Step 7. methyl 3-(3-(3-chloro-2.5-dihvdroxyphenyl)-l-hvdroxypropyl)benzoate. To a solution of methyl 3-(3-(3-chloro-2,5-dihydroxyphenyl)propanoyl)benzoate (601 mg, 1.8 mmol) in MeOH (5 mL) was added NaBH₄ (206 mg, 5.4 mmol) in one portion. The resulting mixture was stirred at 25°C for 10 min. The reaction was monitored by TLC (PE/EA = 1/1). The mixture was quenched with H₂0 (50 mL) and extracted with EA (50 mL X 3). The organic layers were dried over anhydrous Na2SC>4, filtered and concentrated to dryness. The residue was purified by silica gel using 20-50% EA in PE to give the title compound (520 mg, 83.1%) as red solid.

Step 8. methyl 3-(8-chloro-6-hvdroxychroman-2-yl)benzoate. To a solution of methyl 3-(3-(3- chloro-2,5-dihydroxyphenyl)-l-hydroxypropyl)benzoate (508 mg, 1.49 mmol) and PPh₃ (467 mg, 1.78 mmol) in DCM (3 mL) was added DIAD (600 mg, 2.98 mmol) at 25°C. The resulting mixture was stirred at 25°C for 1 hour. LC-MS showed that the reaction was completed. The reaction mixture was concentrated to dryness. The residue was purified by flash column using 20-30% EA in PE to give the title compound (353 mg, 75%) as red oil. +ESI-MS: m/z 319.1 [M + H]⁺.

Compound 1. 4-(l-(4-((5-cvclopropyl-3-(2.6-dichlorophenyl)isoxazol-4- yl)methoxy)phenyl)azetidin-3-yl)benzoic acid.

Step 1. ethyl 4-(l-(4-((5-cvclopropyl-3-(2.6-dichlorophenyl)isoxazol-4- yl)methoxy)phenyl)azetidin-3-yl)benzoate. To a solution of sodium hydride (120 mg, 3.0 mmol, 2.0 eq) in anhydrous DMF (15 mL) was added ethyl 4-(l-(4-hydroxyphenyl)azetidin-3- yl)benzoate (Intermediate 6, 450 mg, 1.5 mmol, 1.0 eq) at 25 °C. After stirring at 25 °C for 10 min, 4-(bromomethyl)-5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazole (Intermediate 4, 524 mg, 1.5 mmol, 1.0 eq) was added and the mixture was stirred for 20 min. at 25°C. TLC (PE / EA = 3 / 1) showed that the reaction was completed. The mixture was quenched with H₂0 (50 mL) and extracted with EA (50 mL X 2). The combined organic layer was dried over anhydrous Na₂SC>4 and concentrated to dryness. The residue was purified by silica gel using 10-20% EA in PE to give the title compound (619 mg, 69.3% yield) as yellow oil.

+ESI-MS: m/z 563.2 [M + H]⁺.

Step 2. 4-(l-(4-((5-cvclopropyl-3-(2.6-dichlorophenyl)isoxazol-4-yl)methoxy)phenyl)azetidin-3- vDbenzoic acid. To a solution of ethyl 4-(l-(4-((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4- yl)methoxy)phenyl)azetidin-3-yl)benzoate (203 mg, 0.355 mmol) in EtOH (5.00 mL) was added NaOH (71 mg, 1.77 mmol, 5.0 eq) in H₂0 (5.00 mL). The mixture was stirred at 60 °C for 1 hour. LCMS showed that the reaction was completed. The mixture was concentrated and the residue was acidified with 1.0 M HCl solution until pH=2~3. The reaction mixture was extracted with EA (30 mL X 3) and the organic layer was dried over anhydrous Na2SC>4 and concentrated at low pressure. The residue was purified by pre-HPLC (HC1 conditions) to give the title compound (69 mg, 36.8% yield) as a white solid. ^-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-cvclopropyl-3-(2.6-dichlorophenyl)isoxazol-4-yl)methoxy)phenyl)-

1.2.3.4-tetrahvdroisoquinoline-7-carboxylic acid.

Step 1. methyl 2-(4-((2-(trimethylsilyl)ethoxy)methoxy)phenyl)-1.2.3.4-tetrahvdroisoquinoline- 7-carboxylate. A mixture of Pd(dba)₂ (241 mg, 0.42 mmol, 0.1 eq), methyl 1,2,3,4- tetrahydroisoquinoline-7-carboxylate (Intermediate 3, 800 mg, 4.18 mmol, 1.0 eq)(HC\ salt), (2- ((4-bromophenoxy)methoxy)ethyl)trimethylsilane (Intermediate 2, 2.54 g, 8.36 mmol, 2.0 eq) and CS2CO₃ (6.81 g, 20.9 mmol, 5.0eq) was degassed and refilled with nitrogen for three times. Anhydrous DMF (20 mL) was added and the mixture was stirred at 100 °C for 12 hr under nitrogen. TLC (PE / EA =6 / 1) showed the reaction was completed. The mixture was filtered and the volatile was removed under reduced pressure. The residue was purified by chromatography on silica gel using 0-3% EA in PE to give the title compound (676 mg, 39.1% yield) as yellow oil. +E SI-MS: m/z 413.9 [M+H]⁺.

Step 2. methyl 2-(4-hvdroxyphenyl)-1.2.3.4-tetrahvdroisoquinoline-7-carboxylate. To a solution of methyl 2-(4-((2-(trimethylsilyl)ethoxy)methoxy)phenyl)- 1 ,2,3,4-tetrahy droisoquinoline-7- carboxylate (476 mg, 1.15 mmol, l .Oeq) in THF (2 mL) and MeOH (2 mL) was added HC1 (2 mL, 12 M, 20.8 eq). The reaction was stirred for 2 hr at 25 °C. TLC (DCM / MeOH = 10 / 1) showed the reaction was completed. The reaction was neutralized with saturated NaHCCb solution to pH = 6-7. The resulting mixture was extracted by EA (10 mL X 2). The combined organic layers were washed with brine, dried over anhydrous Na2SC>4, and concentrated to dryness. The residue was purified by chromatography on silica gel using 5-25% EA in PE to give the title compound (230 mg, 70.6% yield) as yellow oil. +ESI-MS: m/z 283.8 [M +H]⁺ Step 3. 2-(4-((5-cvclopropyl-3-(2.6-dichlorophenyl)isoxazol-4-yl)methoxy)phenyl)-l .2.3.4- tetrahvdroisoquinoline-7-carboxylic acid. To a solution of methyl 2-(4-hydroxyphenyl)-l, 2,3,4- tetrahydroisoquinoline-7-carboxylate (230.00 mg, 0.81 mmol, 1.0 eq) in anhydrous DMF (4 mL) was added sodium hydride (39 mg, 0.97 mmol, 1.2 eq) in one portion. After stirring for a while, 4-(bromomethyl)-5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazole (Intermediate 4, 310 mg, 0.89 mmol, 1.1 eq) was added and the solution was stirred at 25 °C for 2 hr. TLC (DCM / MeOH = 10 / 1) showed that the reaction was completed. The reaction was quenched with H₂0 (30 mL) and acidified to pH=2~3 by HC1 solution (1.0 M). The reaction mixture was extracted with EA (20 mL X 3). The combined organic layers were washed with brine, dried over anhydrous Na₂SC>4, and concentrated to dryness. The residue was purified with pre-HPLC (HC1 condition) to give the title compound (38 mg, 7.96% yield) as white solid. 1H NMR (400MHz, CD₃OD) 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-cvclopropyl-3-(2.6-dichlorophenyl)isoxazol-4- yl)methoxy)phenyl)isoindoline-5-carboxylic acid.

The title compound was prepared in a manner analogous to Compound 1, Steps 1-2, using methyl 2-(4-hydroxyphenyl)isoindoline-5-carboxylate (Intermediate 7). The title compound (48 mg) was obtained as a yellow solid. ^-NMR (DMSO, 400 MHz) δ= 7.98 - 7.86 (m, 2H), 7.66 - 7.62 (m, 2H), 7.59 - 7.53 (m, 1H), 7.49 (d, J=8.0 Hz, 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). +E SI-MS: m/z 520.9 [M +H]⁺

Compound 4. 3-(l-(4-((5-cvclopropyl-3-(2.6-dichlorophenyl)isoxazol-4- yl)methoxy)phenyl)azetidin-3-yl)benzoic acid.

The title compound was prepared in a manner analogous to Compound 1, Steps 1-2, using ethyl 3-(l-(4-hydroxyphenyl)azetidin-3-yl)benzoate (Intermediate 9). The title compound was obtained (130 mg) as white solid. i-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), 1.17-1.09 (m, 4H). +ESI-MS: m/z 535.1 [M + H]⁺.

Compound 5. 3-(l-(2-chloro-4-((5-cvclopropyl-3-(2.6-dichlorophenyl)isoxazol-4- yl)methoxy)phenyl)azetidin-3-yl)benzoic acid.

The title compound was prepared in a manner analogous to Compound 1, Steps 1-2, using ethyl 3-(l-(2-chloro-4-hydroxyphenyl)azetidin-3-yl)benzoate (Intermediate 10). The title compound (113 mg) was obtained as white solid. 'H NMR (400MHZ, CD30D) 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-cvclopropyl-3-(2.6-dichlorophenyl)isoxazol-4- yl)methoxy)phenyl)isoindoline-5-carboxylic acid.

The title compound was prepared in a manner analogous to Compound 1, Steps 1-2, using methyl 2-(2-chloro-4-hydroxyphenyl)isoindoline-5-carboxylate (Intermediate 11) in Step 1. The title compound (11 mg) was obtained as yellow solid. ^XH NMR (400MHz, DMSO) δ = 7.89 (s, IH), 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, IH), 7.43 (d, J=7.9 Hz, IH), 7.14 (d, J=9.3 Hz, IH), 6.87 (d, J=3.1 Hz, IH), 6.72 (dd, J=2.6, 8.8 Hz, IH), 4.84 (s, 2H), 4.59 (d, J=4.4 Hz, 4H), 2.42 (br. s., IH), 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-cvclopropyl-3-(2.6-dichlorophenyl)isoxazol-4-yl)methoxy)-l-methyl-

1.2.3.4-tetrahvdroquinolin-2-yl)benzo:

The title compound was prepared in a manner analogous to Compound 1, Steps 1-2, using methyl 3-(6-hydroxy-l-methyl-l,2,3,4-tetrahydroquinolin-2-yl)benzoate (Intermediate 12). The title compound (321 mg) was obtained as a pink solid. ^-NMR (400MHz, CDC1₃), 5 = 8.11 (br. s., IH), 8.07 (d, J=7.9 Hz, IH), 8.00 (d, J=6.2 Hz, IH), 7.58 - 7.49 (m, 2H), 7.45 - 7.39 (m, 2H), 7.38 - 7.31 (m, IH), 6.77 (d, J=8.4 Hz, IH), 6.62 (br. s., IH), 4.92 - 4.69 (m, 3H), 2.92 (br. s., 5H), 2.53 (br. s., IH), 2.42 (br. s., IH), 2.27 - 2.10 (m, IH), 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-cvclopropyl-3-(2.6-dichlorophenyl)isoxazol-4-yl)methoxy)-l- methyl-1.2.3.4-tetrahvdroquinolin-2-yl)benzoic acid).

Racemic Compound 7 (200 mg) was submitted for SFC separation, and two isomers were separated by using the following method: "Column: Chiralcel OJ-3 150x4.6 mm I.D., 3 μηι Mobile phase: A: C02 B: methanol (0.05% DEA) Gradient: from 5% to 40% of B in 5 min and hold 40% for 2.5 min, then 5% of B for 2.5 min Flow rate: 2.5mL/min Column temp.: 35 °C Wavelength: 220nm" Compound 8 (60 mg) and Compound 9 (63 mg) were obtained as yellow solid. ((R)-3-(6-((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)methoxy)-l-methyl-l, 2,3,4- tetrahydroquinolin-2-yl)benzoic acid) - ^XH-NMR (400MHz, CD₃OD), 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-cvclopropyl-3-(2.6-dichlorophenyl)isoxazol-4-yl)methoxy)-l- methyl-1.2.3.4-tetrahvdroquinolin-2-yl)benzoic acid

((S)-3-(6-((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)methoxy)-l-methyl-l, 2,3,4- tetrahydroquinolin-2-yl)benzoic acid) - ^XH-NMR (400MHz, CD₃OD), 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-cvclopropyl-3-(2.6-dichlorophenyl)isoxazol-4-yl)methoxy)-l- methyl-1.2.3.4-tetrahvdroquinolin-2-yl)benzoic acid.

The title compound was prepared in a manner analogous to Compound 1, Steps 1-2, using methyl 3-(8-chloro-6-hydroxy-l-methyl-l,2,3,4-tetrahydroquinolin-2-yl)benzoate (Intermediate 13). The title compound (39 mg) was obtained as a white solid. ^XH-NMR (400MHz, CD₃OD), 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-cvclopropyl-3-(2.6-dichlorophenyl)isoxazol-4- yl)methoxy)-l-methyl-1.2.3.4-tetrahvdroquinolin-2-yl)benzoic acid).

Racemic 3-(8-chloro-6-((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)methoxy)-l-methyl- l,2,3,4-tetrahydroquinolin-2-yl)benzoic acid (compound 10) (35 mg) was submitted for SFC separation, and two isomers were separated by using the following method: "Column: Chiralcel OJ-3 150x4.6mm I.D., 3μηι; Mobile phase: A: C02 B:methanol (0.05% DEA); Gradient: from 5% to 40% of B in 5.0min and hold 40% for 2.5 min, then 5% of B for 2.5 min; Flow rate:

2.5mL/min; Column temperature: 35C Wavelength: 220nm"

((R)-3-(8-chloro-6-((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)methoxy)-l-methyl- l,2,3,4-tetrahydroquinolin-2-yl)benzoic acid) (13.2 mg) and ((S)-3-(8-chloro-6-((5-cyclopropyl- 3-(2,6-dichlorophenyl)isoxazol-4-yl)methoxy)-l-methyl-l,2,3,4-tetrahydroquinolin-2-yl)benzoic acid) (13.6 mg) were obtained as yellow solid. ((R)-3-(8-chloro-6-((5-cyclopropyl-3-(2,6- dichlorophenyl)isoxazol-4-yl)methoxy)-l-methyl-l,2,3,4-tetrahydroquinolin-2-yl)benzoic acid) is i-NMR (400 MHz, CD₃OD), δ = 8.06 (s, 1H), 7.86 (d, J=7.5 Hz, 1H), 7.59 (d, J=8.0 Hz, 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, IH), 2.86 (s, 3H), 2.80 - 2.67 (m, IH), 2.52 - 2.38 (m, IH), 2.36 - 2.23 (m, 2H), 2.04 - 1.93 (m, IH), 1.25 - 1.12 (m, 4H). +E SI-MS: m/z 582.9 [M +H]⁺

Compound 12. ((S)-3-(8-chloro-6-((5-cvclopropyl-3-(2.6-dichlorophenyl)isoxazol-4- yl)methoxy)-l-methyl-1.2.3.4-tetrahvdroquinolin-2-yl)benzoic acid).

((S)-3-(8-chloro-6-((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)methoxy)-l -methyl- l,2,3,4-tetrahydroquinolin-2-yl)benzoic acid)- ^-NMR (400MHz, CD₃OD), δ = 8.06 (s, IH), 7.86 (d, J=7.5 Hz, IH), 7.59 (d, J=7.5 Hz, IH), 7.53 - 7.40 (m, 3H), 7.37 (t, J=7.5 Hz, IH), 6.65 (d, J=2.5 Hz, IH), 6.35 (d, J=2.5 Hz, IH), 4.83 (s, 3H), 4.25 (dd, J=4.0, 7.5 Hz, IH), 2.86 (s, 3H), 2.78 - 2.66 (m, IH), 2.51 - 2.37 (m, IH), 2.37 - 2.23 (m, 2H), 2.02 - 1.86 (m, IH), 1.25 - 1.12 (m, 4H). +ESI-MS: m/z 583.1 [M +H]⁺

Compound 13. 3-(6-((5-cvclopropyl-3-(2.6-dichlorophenyl)isoxazol-4-yl)methoxy)-3.4- dihydroisoquinolin-2(lH)-yl)benzoic acid.

The title compound was prepared in a manner analogous to Compound 1, Steps 1-2, using ethyl 3-(6-hydroxy-3,4-dihydroisoquinolin-2(lH)-yl)benzoate in Step 1. The title compound (79 mg) was obtained as white solid. ^-NMR (400MHz, CDC1₃), δ= 8.05 (s, IH), 7.91 (m, IH), 7.83 (m, IH), 7.51 (m., IH), 7.44 - 7.39 (m, 2H), 7.35 (d, J=7.1 Hz, IH), 7.03 (d, J=7.9 Hz, IH), 6.73 (d, J=7.5 Hz, IH), 6.63 (s, IH), 4.81 (s, 2H), 4.57 (s, 2H), 3.75 (s, 2H), 3.15 (s, 2H), 2.18 (s, IH), 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-cvclopropyl-3-(2.6-dichlorophenyl)isoxazol-4-yl)methoxy)-2.3- dihvdro-lH-pyrido[2.3-bl[1.41oxazin-l-yl)methyl)benzoic acid.

Step 1. tert-butyl 6-((5-cvclopropyl-3-(2.6-dichlorophenyl)isoxazol-4-yl)methoxy)-2.3-dihvdro- lH-pyridor2.3-bi ri.41oxazine-l-carboxylate. To a solution of tert-butyl 6-bromo-2,3-dihydro- lH-pyrido[2,3-b] [l,4]oxazine-l-carboxylate (Intermediate 16, 2.0 g, 6.35 mmol) and (5- cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)methanol (Intermediate 15, 3.61 g, 12.7 mmol) in toluene (20 mL) was added Cs₂C0₃ (4.14 g, 12.7 mmol), Pd(dba)₂ (182 mg, 0.32 mmol) and BINAP (198 mg, 0.32 mmol) under nitrogen. The resulting mixture was stirred at 110°C for 12 hours. The mixture was cooled to room temperature and concentrated to dryness. The residue was purified by column chromatography on silica gel using 5-20% EA in PE as eluent to give the desired compound (1.1 g, 33.4%) as light yellow oil. +E SI-MS: m/z 518.1 [M +H]⁺

Step 2. 6-((5-cvclopropyl-3-(2.6-dichlorophenyl)isoxazol-4-yl)methoxy)-2.3-dihvdro-lH- pyrido[2.3-bl[1.41oxazine. A mixture of tert-butyl 6-((5-cyclopropyl-3-(2,6- dichlorophenyl)isoxazol-4-yl)methoxy)-2,3-dihydro-lH-pyrido[2,3-b] [l,4]oxazine-l-carboxylate (1.0 g, 1.93 mmol) in HCl/MeOH (4 M, 10 mL) was stirred at 25°C for 30 min. The reaction was quenched with saturated NaHCCb solution and extracted with EA (50 mL X 2). The combined organic layers were washed with brine, dried over anhydrous Na₂S0₄ and concentrated to dryness. The residue was purified by column chromatography on silica gel using 20-100% EA in PE as eluent to give the title compound (0.78 g, 97%) as green oil.

Step 3. methyl 3-((6-((5-cvclopropyl-3-(2.6-dichlorophenyl)isoxazol-4-yl)methoxy)-2.3-dihvdro- 1 H-pyrido[2.3-bl [ 1.41 oxazin- 1 -yl)methyl)benzoate. A mixture of 6-((5-cyclopropyl-3-(2,6- dichlorophenyl)isoxazol-4-yl)methoxy)-2,3-dihydro-lH-pyrido[2,3-b] [l,4]oxazine (400 mg, 0.96 mmol), methyl 3-(bromomethyl)benzoate (438 mg, 1.92 mmol) and K2CO₃ (265 mg, 1.92 mmol) in DMF (25 mL) was stirred at 70°C for 2 hours. The mixture was diluted with EA (50 mL) and water (50 mL). The aqueous layer was neutralized to pH=6-7 by addition of HC1 (2M) solution. The organic phase was washed with brine (20 mL), dried over anhydrous Na2SC>₄, and concentrated to dryness. The residue was purified by column chromatography on silica gel using 10-25% EA in PE as eluent to give the title compound (410 mg, 76%) as yellow oil.

Step 4. 3-((6-((5-cvclopropyl-3-(2.6-dichlorophenyl)isoxazol-4-yl)methoxy)-2.3-dihvdro-lH- pyrido[2.3 -bl [ 1.41 oxazin- 1 -yl)methyl)benzoic acid. To a solution of methyl 3-((6-((5- cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)methoxy)-2,3-dihydro-lH-pyrido[2,3- b] [l,4]oxazin-l-yl)methyl)benzoate (200 mg, 0.35 mmol) in THF (2 mL) was added NaOH (28 mg, 0.7 mmol) in H₂0 (2 mL). The mixture was stirred at 25 °C for 2 hours. The mixture was acidified with IN HCl to pH=l-2 and extracted with EA (50 mL). The organic layer was washed with brine (10 mL), dried over anhydrous Na2SC>4 and concentracted to dryness. The residue was purified by prep-HPLC (HCl condition) to give the title compound (19 mg, 9.8%) as a white solid. Ti-NMR (400MHz, CD₃OD), 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-cvclopropyl-3-(2.6-dichlorophenyl)isoxazol-4-yl)methoxy)-3-fluoro- lH-pyrrolo[3.2-blpyridin-l-yl)methyl)benzoic acid.

The title compound was prepared in a manner analogous to Compound 1, Steps 1-2, using methyl 3-((3-fluoro-5-hydroxy-lH-pyrrolo[3,2-b]pyridin-l-yl)methyl)benzoate (Intermediate 18). The title compound (2.03 mg) was obtained as white solid. ^-NMR (400MHz, CD₃OD), 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, 4 H). +ESI-MS: m/z 552.0 [M +H]⁺

Compound 16. 3-(8-chloro-6-((5-cvclopropyl-3-(2.6-dichlorophenyl)isoxazol-4- yl)methoxy)chroman-2-yl)benzoic acid.

The title compound was prepared in a manner analogous to Compound 1, Steps 1-2, using methyl 3-(8-chloro-6-hydroxychroman-2-yl)benzoate (Intermediate 19). The title compound (185 mg) was obtained as white solid. Ti-NMR (400 MHz, DMSO), δ= 13.0 (br. s., 0.1H), 8.01 (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, 1Η),5.24-5.22 (m, 1H), 4.82 (s, 2H), 2.95-2.87 (m, 1Η),.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

Farnesoid X Receptor (FXR) assay is a cell based reporter assay sold as a kit by Indigo Biosciences (cat# IB00601-32). In brief, compounds were diluted at 2x final concentration in Cell Recovery Medium (CRM). Indigo's FXR reporter cells were thawed and 100 added per well to 96-well plates. Compounds were tested at a top concentration of 100 μΜ with an 8 point dilution curve, 3-fold dilution between points. Chenodeoxycholic acid (CDCA) was used a positive control, top concentration of 1200 μΜ. 100 of diluted compounds added to each cell seeded well. Treated cells were then incubated for 22 - 25 hours at 37°C, 5% CO2. The next day, media was removed from cells and Luciferase Detection Reagent added to wells (100 μΙ7 well). Assay plate was allowed to rest for 25 minutes at room temperature without shaking.

Luminescence was read on a Victor X3 multi-label plate reader (Perkin Elmer, Waltham, MA), set to read at 0.5 second per well. Results for certain exemplary compounds of the disclosure are shown in Table 1.

TR-FRET FXR Assay

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 EC50s. In summary, 20 μΐ. reactions were carried out in 384-well plates containing various concentrations of agonist, 5nM FXR/LBD, 500nM Fluorescein and 5nM AntiGST Antibody. Plates were incubated at 37°C for 90 min. Changes in fluorescence were monitored using the Victor X3 multilabel plate reader (PerkinElmer). All binding curves were generated by plotting emission ratios vs. ligand concentrations, and % activation is reported as a function of % CDCA activation. Results for certain exemplary compounds of the disclosure are shown in Table 1.

Table 1

Claims

What is Claimed:

A compound of formula I

wherein

R¹ is selected from the group consisting of H, F, CI, Br, and I;

R² is selected from the group consisting of F, CI, Br, and I;

R³ is selected from the group consisting of Ci-₆alkyl and C3-₆cycloalkyl;

A is selected from the group consisting of

X is selected from the group consisting of O, -NH-, and -N(CH₃)-; and

R⁴ is selected from the group consisting of H, F, CI, and CN;

or a pharmaceutically acceptable salt thereof. 2. The compound of claim 1 , wherein R¹ and R² are each CI.

3. The compound of any one of the preceding claims, wherein R² is C3-₆cycloalkyl.

4. The compound of any one of the preceding claims, wherein

R¹ is CI:

R² is CI; R is C₃cycloalkyl;

X is selected from the group consisting of O and -N(CH₃)-; R⁴ is selected from the group consisting of H and CI.

The compound of claim 1 of the formula I-A:

6. The compound of claim 1 of the formula I-B:

The compound of claim 1 of formula I-C:

The compound of claim 1 of the formula I-D:

I-D.

9. The compound of claim 1 of the formula I-E:

10. The compound of any one of the preceding claims, wherein R⁴ is H.

1 1. The compound of any one of claims 1 to 9, wherein R⁴ is CI.

12. The compound of claim 1 of the formula I-F:

H

The compound of claim 1 of the formula I-G:

H

14. The compound of claim 1 of the formula I-H:

15. The compound of any one of the preceding claims, wherein

R¹ is CI;

R² is CI; and

R³ is C₃cycloalkyl.

16. The compound of claim 1 , wherein the compound is selected from the group consisting of

4-(l -(4-((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4- yl)methoxy)phenyl)azetidin-3-yl)benzoic acid,

3-(6-((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)methoxy)-l -methyl- l,2,3,4-tetrahydroquinolin-2-yl)benzoic acid,

2-(4-((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)methoxy)phenyl)- l,2,3,4-tetrahydroisoquinoline-7-carboxylic acid,

2- (4-((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4- yl)methoxy)phenyl)isoindoline-5-carboxylic acid,

3- (l -(4-((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4- yl)methoxy)phenyl)azetidin-3-yl)benzoic acid,

3-(6-((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)methoxy)-3,4- dihydroisoquinolin-2(lH)-yl)benzoic acid,

((R)-3-(6-((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)methoxy)-l - methyl-l,2,3,4-tetrahydroquinolin-2-yl)benzoic acid)

((S)-3-(6-((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)methoxy)-l- methyl-l,2,3,4-tetrahydroquinolin-2-yl)benzoic acid),

3-(l -(2-chloro-4-((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4- yl)methoxy)phenyl)azetidin-3-yl)benzoic acid, 2- (2-chloro-4-((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4- yl)methoxy)phenyl)isoindoline-5-carboxylic acid,

3- (8-chloro-6-((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)methoxy)-l - methyl-l,2,3,4-tetrahydroquinolin-2-yl)benzoic acid,

((R)-3-(8-chloro-6-((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4- yl)methoxy)-l -methyl- l,2,3,4-tetrahydroquinolin-2-yl)benzoic acid),

((S)-3-(8-chloro-6-((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4- yl)methoxy)-l -methyl- l,2,3,4-tetrahydroquinolin-2-yl)benzoic acid),

3-((6-((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)methoxy)-2,3- dihydro-lH-pyrido[2,3-b] [l,4]oxazin-l -yl)methyl)benzoic acid,

3-((5-((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)methoxy)-3-fluoro- lH-pyrrolo[3,2-b]pyridin-l -yl)methyl)benzoic acid, and

3-(8-chloro-6-((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4- yl)methoxy)chroman-2-yl)benzoic acid.

17. A compound as depicted in Table 1.

18. A pharmaceutical composition comprising a compound of any one of the preceding

claims, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient. 19. A method of modulating a famesoid X receptor comprising contacting the receptor with a compound of any one of claims 1 -17.

20. A method of treating a patient diagnosed with a disease or disorder modulated by

famesoid X receptor comprising administering to the patient an effective amount of a compound of any one of claims 1 -17. 21. The method of claim 20, wherein the disease or disorder is nonalcoholic steatohepatitis.

22. A method of making a compound of formula I.