NZ789188A - FXR (NR1H4) modulating compounds - Google Patents

Abstract

The present disclosure relates generally to compounds which bind to the NR1H4 receptor (FXR) and act as agonists of FXR. The disclosure further relates to the use of the compounds for the preparation of a medicament for the treatment of diseases and/or conditions through binding of said nuclear receptor by said compounds and to a process for the synthesis of said compounds. ptor by said compounds and to a process for the synthesis of said compounds.

Description

FXR (NR1H4) MODULATING COMPOUNDS CROSS REFERENCE TO RELATED ATIONS This application is a divisional application of New Zealand patent ation number 763011, which is a divisional application of New Zealand patent ation number 748625, which claims the benefit of US Provisional App. No. 62/349,490, filed June 13, 2016, the entirety of which is hereby incorporated by nce.

SEQUENCE LISTING The Sequence Listing associated with this application is provided in text format in lieu of a paper copy, and is hereby incorporated by reference into the specification. The name of the text file containing the Sequence Listing is 1165_PF_ST25.txt. The text file created on May 16, 2017, is about 550 bytes and submitted electronically via EFS-Web.

FIELD The t disclosure relates to compounds which bind to the NR1H4 receptor (FXR) and act as agonists or modulators of FXR. The disclosure further relates to the use of the nds for the treatment and/or prophylaxis of diseases and/or conditions through binding of said nuclear receptor by said compounds.

BACKGROUND Multicellular organisms are dependent on advanced mechanisms of information transfer between cells and body compartments. The information that is transmitted can be highly complex and can result in the alteration of genetic programs involved in cellular differentiation, proliferation, or reproduction. The signals, or hormones, are often low molecular weight molecules, such as es, fatty acid, or cholesterol derivatives.

Many of these signals produce their s by tely changing the transcription of ic genes. One well-studied group of proteins that mediate a cell’s se to a variety of signals is the family of transcription factors known as nuclear receptors, hereinafter referred to often as “NR.” Members of this group include receptors for steroid hormones, vitamin D, ecdysone, cis and trans retinoic acid, thyroid hormone, bile acids, cholesterol-derivatives, fatty acids (and other somal proliferators), as well as so-called orphan receptors, proteins that 1004042117 [Annotation] Mel.Chan None set by Mel.Chan [Annotation] Mel.Chan MigrationNone set by Mel.Chan [Annotation] Mel.Chan Unmarked set by Mel.Chan ation] Mel.Chan None set by Mel.Chan [Annotation] Mel.Chan MigrationNone set by Mel.Chan [Annotation] Mel.Chan Unmarked set by Mel.Chan are structurally similar to other members of this group, but for which no ligands are known.

Orphan ors may be indicative of unknown signalling pathways in the cell or may be nuclear receptors that on without ligand tion. The activation of transcription by some of these orphan receptors may occur in the absence of an exogenous ligand and/or through signal transduction ys originating from the cell surface.

In general, three functional domains have been defined in NRs. An amino terminal domain is believed to have some regulatory function. It is followed by a DNA—binding domain (hereinafter referred to as “DBD”), which y comprises two zinc finger elements and recognizes a specific Hormone Responsive Element (hereinafter referred to as “HRE”) within the promoters of responsive genes. Specific amino acid residues in the “DBD” have been shown to confer DNA sequence binding icity. A —binding—domain nafter referred to as “LBD”) is at the carboxy—terminal region of known NRs.

In the absence of hormone, the LED appears to interfere with the interaction of the DBD with its HRE. Hormone binding seems to result in a conformational change in the NR and thus opens this interference. A NR without the LED constitutively activates transcription but at a low level.

Coactivators or transcriptional activators are proposed to bridge between sequence specific transcription factors, and the basal transcription machinery and in addition to ce the chromatin structure of a target cell. Several proteins like SRC—l, ACTR, and Gripl interact with NRs in a ligand enhanced manner.

Nuclear receptor modulators like steroid hormones affect the growth and function of specific cells by g to intracellular ors and forming r receptor—ligand complexes. Nuclear receptor—hormone complexes then interact with a HRE in the control region of specific genes and alter specific gene expression.

The id X or alpha (hereinafter also often referred to as NRlH4 when referring to the human receptor) is a prototypical type 2 nuclear receptor which activates genes upon binding to a promoter region of target genes in a heterodimeric fashion with Retinoid X Receptor. The relevant physiological ligands of NRlH4 are bile acids. The most potent one is [Annotation] Mel.Chan None set by Mel.Chan [Annotation] Mel.Chan MigrationNone set by Mel.Chan [Annotation] Mel.Chan Unmarked set by Mel.Chan [Annotation] Mel.Chan None set by an [Annotation] Mel.Chan MigrationNone set by Mel.Chan [Annotation] Mel.Chan Unmarked set by Mel.Chan chenodeoxycholic acid (CDCA), which regulates the expression of several genes that participate in bile acid tasis. Farnesol and derivatives, together called farnesoids, are originally described to activate the rat orthologue at high concentration but they do not activate the human or mouse receptor. FXR is expressed in the liver, throughout the entire gastrointestinal tract including the esophagus, stomach, duodenum, small intestine, colon, ovary, adrenal gland and kidney. Beyond controlling ellular gene expression, FXR seems to be also involved in paracrine and endocrine signalling by upregulating the expression of the cytokine Fibroblast Growth Factor 15 (rodents) or 19 (monkeys, humans A).

Although numerous FXR agonists are known, there is a need for improved FXR agonists.

SUMMARY The t disclosure provides nds bind to the NRlH4 receptor (FXR) and act as agonists or modulators of FXR. The disclosure further relates to the use of the compounds for the treatment and/or prophylaxis of diseases and/or ions through binding of said r receptor by said compounds.

The present sure provides compounds according to Formula (I): wherein: Q is phenylene or pyridylene, each of which is optionally tuted with one or two substituents independently selected from n, methyl, C1_4—alkoxy, halo—C1_4—alkoxy, —CH2F, —CHF2, and —CF3; Yis N or CH; [Annotation] Mel.Chan None set by Mel.Chan [Annotation] Mel.Chan MigrationNone set by Mel.Chan [Annotation] an Unmarked set by Mel.Chan [Annotation] Mel.Chan None set by Mel.Chan ation] Mel.Chan ionNone set by Mel.Chan [Annotation] Mel.Chan Unmarked set by an A is pyridylene or phenylene, each of which is optionally substituted with one or two groups independently selected from halogen, C1_4—alkoxy, halo—C1_4—alkoxy, lkyl, and halo— lkyl; Z is isoxazole substituted with R1 or pyrazole substituted with R1; R1 is CM—alkyl or C3_6—cycloalkyl, n said C1_4—alkyl is optionally substituted with l to 3 substituents independently selected from fluoro, hydroxyl, C1_3—alkoxy, and fluoro—C1_3—alkoxy, and said C3_6—cycloalkyl is optionally substituted with l to 3 substituents independently ed from fluoro, hydroxyl, C1_3—alkyl, fluoro—C1_3—alkyl, €1-3— alkoxy, and fluoro—C1_3—alkoxy; R2 and R3 are independently selected from hydrogen, halogen, methoxy, —CF3, —CHF2, — CHZF, —OCH2F, —OCHF2, —OCF3, and methyl; R4 is —C02R5 or R5R6; R5 is en, C1_6—alkyl, or halo—C1_6—alkyl; and R6 is hydrogen or C1_6—alkyl, wherein said C1_6—alkyl is optionally substituted with l to 6 substituents independently selected from halogen, -SO3H, and —COZH; or a pharmaceutically acceptable salt, a stereoisomer, a mixture of stereoisomers, or a tautomer thereof.

Some embodiments provide for pharmaceutical compositions comprising a compound of formula (I) and a pharmaceutically acceptable excipient.

Also provided herein are s of treating a patient haVing an FXR mediated condition comprising administering a compound of formula (I) to a patient in need thereof.

[Annotation] Mel.Chan None set by Mel.Chan [Annotation] an MigrationNone set by Mel.Chan [Annotation] an Unmarked set by Mel.Chan ation] Mel.Chan None set by Mel.Chan [Annotation] Mel.Chan MigrationNone set by Mel.Chan [Annotation] an Unmarked set by Mel.Chan DESCRIPTION OF THE FIGURES Plasma exposure of Example 3 and Comparative Example 2 versus plasma FGFl9 levels in cynomolgus monkey.

FGFl9 levels generated in cynomolgus monkey with increasing oral doses of Example 3 and Comparative Example 2.

DETAILED DESCRIPTION Definitions The following description sets forth exemplary embodiments of the present technology.

It should be recognized, however, that such description is not ed as a limitation on the scope of the t disclosure but is d ed as a description of exemplary embodiments.

As used in the present specification, the ing words“, phrases and symbols are generally intended to have the meanings as set forth below, except tn the extent that the context in which they are used indicates otherwise.

The disclosures illustratively described herein may suitably be practiced in the absence of any element or ts, limitation or limitations, not specifically disclosed herein. Thus, for example, the terms ising39 6" , ing,:9 6‘containing”, etc. shall be read expansively and without limitation. Additionally, the terms and expressions employed herein have been used as terms of description and not of tion, and there is no intention in the use of such terms and expressions of excluding any equivalents of the features shown and described or portions thereof, but it is recognized that various modifications are possible within the scope of the disclosure claimed.

A dash (“—”) that is not between two letters or symbols is used to indicate a point of attachment for a substituent. For example, —C(O)NH2 is attached through the carbon atom. A dash at the front or end of a chemical group is a matter of convenience; chemical groups may be depicted with or without one or more dashes without losing their ordinary meaning. A wavy line drawn tBJgh a line in a structure indicates a point of attachment of a group. Unless chemically [Annotation] Mel.Chan None set by Mel.Chan [Annotation] Mel.Chan MigrationNone set by Mel.Chan [Annotation] Mel.Chan Unmarked set by Mel.Chan [Annotation] Mel.Chan None set by Mel.Chan [Annotation] Mel.Chan MigrationNone set by Mel.Chan [Annotation] Mel.Chan Unmarked set by Mel.Chan or structurally required, no directionality is indicated or implied by the order in which a chemical group is written or named.

The prefix “CH” indicates that the ing group has from u to V carbon atoms. For example, “CH, alkyl” indicates that the alkyl group has from 1 to 6 carbon atoms.

Reference to ” a value or parameter herein es (and describes) embodiments that are directed to that value or parameter per se. In certain embodiments, the term “about” includes the indicated amount i 10%. In other embodiments, the term “about” includes the indicated amount i 5%. In certain other embodiments, the term “about” includes the indicated amount i 1%. Also, to the term “about X” includes description of “X”. Also, the singular forms “a” and “the” include plural references unless the context clearly dictates otherwise. Thus, e.g., reference to “the compound” includes a plurality of such compounds and reference to “the assay” es reference to one or more assays and equivalents thereof known to those skilled in the art.

In the context of the present disclosure “alkyl” means a saturated hydrocarbon chain, which may be ht chained or branched. In the context of the present disclosure, “C1_6—alkyl” means a saturated alkyl chain having 1 to 6 carbon atoms which may be straight chained or branched. es thereof include methyl, ethyl, propyl, isopropyl, l, isobutyl, tert- butyl, yl, isopentyl, neopentyl and n—hexyl.

The term “haloalkyl” means that one or more hydrogen atoms in the alkyl chain are replaced by a n. A non—limiting example thereof is CF3.

A “cycloalkyl” group means a saturated or lly rated mono—, bi— or spirocyclic arbon ring system.

An “alkoxy” group refers to —O—alkyl, wherein alkyl is as defined herein. Examples of alkoxy groups include methoxy, , n—propoxy, iso—propoxy, n—butoxy, tert—butoxy, sec— butoxy, n—pentoxy, n—hexoxy, and l,2—dimethylbutoxy.

“Halogen” or “halo” refers to a F, Cl, Br, or I atom. alydroxyl” or “hydroxy” refers to —OH.

[Annotation] Mel.Chan None set by Mel.Chan [Annotation] Mel.Chan MigrationNone set by Mel.Chan [Annotation] Mel.Chan Unmarked set by Mel.Chan [Annotation] Mel.Chan None set by Mel.Chan [Annotation] Mel.Chan MigrationNone set by Mel.Chan [Annotation] Mel.Chan Unmarked set by Mel.Chan “Haloalkoxy” refers to an alkoxy group as defined herein wherein one or more en atoms in the alkyl chain are replaced by a halogen.

“Fluoroalkyl” refers to an alkyl group as defined herein wherein one or more hydrogen atoms in the alkyl chain are ed by fluoro.

“Fluoroalkoxy” refers to an alkoxy group as d herein wherein one or more hydrogen atoms in the alkyl chain are replaced by fluoro.

The terms “optional” or “optionally” means that the uently described event or circumstance may or may not occur, and that the description includes instances where said event or circumstance occurs and instances in which it does not. Also, the term “optionally substituted” refers to any one or more hydrogen atoms on the designated atom or group may or may not be replaced by a moiety other than hydrogen.

Furthermore, the compounds of the present sure may be subject to erism.

Where tautomerism, e.g. keto—enol tautomerism, of compounds of the present disclosure or their prodrugs may occur, the individual forms, like e.g. the keto and enol form, are each within the scope of the sure as well as their es in any ratio. The same applies for stereoisomers, like e.g. enantiomers, cis/trans isomers, conformers and the like.

The term “protecting group” refers to a moiety of a compound that masks or alters the properties of a functional group or the properties of the compound as a whole. Chemical protecting groups and strategies for protection/deprotection are well known in the art. See e.g., Protective Groups in Organic Chemistry, Theodora W. Greene, John Wiley & Sons, Inc., New York, 1991. Protecting groups are often utilized to mask the reactivity of certain functional , to assist in the efficiency of desired chemical reactions, e.g., making and breaking chemical bonds in an ordered and planned fashion. The term “deprotecting” refers to removing the protecting group.

A “leaving group” includes a lar fragment that can depart with a pair of electrons from a covalent bond to the reacting carbon atom during a chemical reaction.

[Annotation] Mel.Chan None set by Mel.Chan ation] an MigrationNone set by Mel.Chan [Annotation] Mel.Chan Unmarked set by Mel.Chan [Annotation] Mel.Chan None set by Mel.Chan [Annotation] Mel.Chan MigrationNone set by Mel.Chan [Annotation] Mel.Chan Unmarked set by Mel.Chan It will be appreciated by the skilled person that when lists of alternative substituents include members which, because of their y requirements or other reasons, cannot be used to substitute a particular group, the list is intended to be read with the knowledge of the skilled person to include only those members of the list which are suitable for substituting the particular group.

In some embodiments, the compounds of the present disclosure can be in the form of a “prodrug.” The term “prodrug” is defined in the pharmaceutical field as a biologically inactive derivative of a drug that upon administration to the human body is converted to the biologically active parent drug according to some chemical or enzymatic pathway. Examples of prodrugs include fied carboxylic acids.

In the human liver, UDP—glucuronosyltransferases act on n compounds having amino, carbamyl, thio (sulfhydryl) or hydroxyl groups to conjugate uridine diphosphate—d—D— glucuronic acid through glycoside bonds, or to esterify compounds with carboxy or hydroxyl groups in the process of phase II metabolism. Compounds of the present disclosure may be glucuronidated, that is to say, conjugated to glucuronic acid, to form glucuronides, particularly (B—D)glucuronides.

One step in the ion of bile is the conjugation of the individual bile acids with an amino acid, particularly glycine or taurine. nds of the t disclosure may be conjugated with e or taurine at a substitutable position.

The compounds of the present disclosure can be in the form of a pharmaceutically acceptable salt. The term “pharmaceutically acceptable salts” refers to salts ed from pharmaceutically acceptable non—toxic bases or acids, including inorganic bases or acids and organic bases or acids. In case the compounds of the present disclosure contain one or more acidic or basic groups, the sure also comprises their corresponding pharmaceutically or toxicologically acceptable salts, in particular their pharmaceutically utilizable salts. Thus, the compounds of the t disclosure which contain acidic groups can be present on these groups and can be used ing to the sure, for example, as alkali metal salts, alkaline earth metal salts or ammonium salts. More precise examples of such salts include sodium salts, potassium salts, calcium salts, magnesium salts or salts with ammonia or organic amines such as, [Annotation] an None set by Mel.Chan [Annotation] Mel.Chan ionNone set by Mel.Chan [Annotation] Mel.Chan Unmarked set by Mel.Chan [Annotation] Mel.Chan None set by Mel.Chan [Annotation] Mel.Chan MigrationNone set by Mel.Chan [Annotation] Mel.Chan Unmarked set by Mel.Chan for example, ethylamine, ethanolamine, triethanolamine or amino acids. The compounds of the present disclosure which contain one or more basic groups, i.e. groups which can be protonated, can be t and can be used according to the disclosure in the form of their addition salts with inorganic or organic acids. Examples of suitable acids e hydrogen chloride, hydrogen bromide, phosphoric acid, sulfuric acid, nitric acid, methanesulfonic acid, p—toluenesulfonic acid, naphthalenedisulfonic acids, oxalic acid, acetic acid, tartaric acid, lactic acid, salicylic acid, benzoic acid, formic acid, propionic acid, c acid, diethylacetic acid, malonic acid, ic acid, c acid, fumaric acid, maleic acid, malic acid, sulfaminic acid, phenylpropionic acid, gluconic acid, ascorbic acid, isonicotinic acid, citric acid, adipic acid, and other acids known to the person d in the art. If the nds of the present disclosure simultaneously contain acidic and basic groups in the molecule, the disclosure also includes, in addition to the salt forms mentioned, inner salts or betaines (zwitterions). The respective salts can be obtained by customary methods which are known to the person skilled in the art like, for example, by contacting these with an organic or inorganic acid or base in a t or dispersant, or by anion exchange or cation ge with other salts. The present disclosure also includes all salts of the compounds of the present disclosure which, owing to low physiological compatibility, are not directly suitable for use in pharmaceuticals but which can be used, for example, as intermediates for chemical reactions or for the preparation of ceutically able salts.

Further the compounds of the present disclosure may be present in the form of solvates, such as those which include as solvate water, or pharmaceutically acceptable solvates, such as alcohols, in particular ethanol. A “solvate” is formed by the interaction of a solvent and a compound.

In certain embodiments, provided are optical isomers, racemates, or other mixtures thereof of the compounds described herein or a pharmaceutically acceptable salt or a mixture thereof. If desired, isomers can be separated by methods well known in the art, e.g. by liquid chromatography. In those ions, the single enantiomer or diastereomer, i.e., optically active form, can be obtained by asymmetric synthesis or by resolution. Resolution can be accomplished, for example, by conventional methods such as crystallization in the presence of a ing agent, or chromatography, using for example, a chiral high pressure liquid chromatography (HPLC) column.

[Annotation] Mel.Chan None set by Mel.Chan [Annotation] Mel.Chan MigrationNone set by an [Annotation] Mel.Chan Unmarked set by Mel.Chan [Annotation] Mel.Chan None set by Mel.Chan [Annotation] Mel.Chan MigrationNone set by Mel.Chan [Annotation] Mel.Chan Unmarked set by Mel.Chan A “stereoisomer” refers to a compound made up of the same atoms bonded by the same bonds but having different three—dimensional ures, which are not interchangeable. The t invention contemplates various stereoisomers and mixtures thereof and includes “enantiomers,” which refers to two stereoisomers whose molecules are nonsuperimposeable mirror images of one another. “Diastereomers” are stereoisomers that have at least two asymmetric atoms, but which are not mirror—images of each other.

The compounds disclosed herein and their pharmaceutically acceptable salts may include an asymmetric center and may thus give rise to enantiomers, diastereomers, and other stereoisomeric forms that may be defined, in terms of absolute stereochemistry, as (R)— or (S)— or, as (D)— or (L)— for amino acids. The present invention is meant to include all such le isomers, as well as their racemic and optically pure forms. Optically active (+) and (—), (R)— and (S)—, or (D)— and (L)— isomers may be prepared using chiral synthons or chiral reagents, or resolved using conventional ques, for example, chromatography and fractional crystallization. tional techniques for the preparation/isolation of individual enantiomers include chiral synthesis from a suitable optically pure precursor or resolution of the racemate (or the racemate of a salt or derivative) using, for example, chiral high re liquid tography (HPLC). When the compounds described herein contain olefinic double bonds or other s of geometric asymmetry, and unless ied otherwise, it is intended that the compounds e both E and Z geometric isomers.

Compositions provided herein that include a compound described herein or pharmaceutically acceptable salts, isomer, or a mixture thereof may include racemic mixtures, or es containing an enantiomeric excess of one enantiomer or single diastereomers or diastereomeric mixtures. All such isomeric forms of these compounds are sly included herein the same as if each and every isomeric form were specifically and individually listed.

Any formula or structure given herein, is also intended to represent unlabeled forms as well as isotopically labeled forms of the compounds. Isotopically labeled nds have structures depicted by the formulas given herein except that one or more atoms are replaced by an atom having a selected atomic mass or mass number. es of isotopes that can be incorporated into compounds of the disclosure include isotopes of hydrogen, carbon, nitrogen, [Annotation] Mel.Chan None set by Mel.Chan [Annotation] Mel.Chan MigrationNone set by Mel.Chan [Annotation] Mel.Chan Unmarked set by Mel.Chan [Annotation] Mel.Chan None set by Mel.Chan [Annotation] Mel.Chan MigrationNone set by an [Annotation] Mel.Chan Unmarked set by Mel.Chan oxygen, phosphorous, fluorine and chlorine, such as, but not limited to 2H (deuterium, D), H (tritium), “C, 13C, 14C, 15N, 18F, 31P, 32P, 353, 36C1 and 1251. Various isotopically labeled compounds of the present disclosure, for e those into which radioactive es such as 3H, 13C and 14C are orated. Such isotopically labelled compounds may be useful in metabolic studies, on kinetic studies, detection or imaging techniques, such as positron emission tomography (PET) or single—photon emission computed tomography (SPECT) including drug or substrate tissue distribution assays or in radioactive treatment of patients.

Isotopically labeled nds of this disclosure and prodrugs thereof can generally be prepared by carrying out the procedures disclosed in the schemes or in the examples and preparations described below by substituting a readily available isotopically labeled reagent for a non— isotopically labeled reagent.

The disclosure also includes “deuterated analogs” of compounds of Formula (I) in which from 1 to n hydrogens attached to a carbon atom is/are replaced by deuterium, in which n is the number of ens in the le. Such compounds may exhibit increased resistance to metabolism and thus be useful for increasing the half—life of any compound of Formula I when administered to a mammal, e.g. a human. See, for example, Foster, “Deuterium Isotope Effects in Studies of Drug Metabolism,” Trends Pharmacol. Sci. 524—527 (1984). Such compounds are synthesized by means well known in the art, for example by employing starting materials in which one or more hydrogens have been replaced by deuterium.

Deuterium labelled or substituted therapeutic compounds of the disclosure may have ed DMPK (drug metabolism and pharmacokinetics) properties, relating to bution, metabolism and excretion (ADME). Substitution with heavier isotopes such as deuterium may afford certain therapeutic advantages ing from r metabolic stability, for example increased in viva half—life, reduced dosage ements and/or an improvement in therapeutic index. An 18F labeled compound may be useful for PET or SPECT s.

The concentration of such a heavier isotope, specifically deuterium, may be defined by an ic ment factor. In the compounds of this disclosure any atom not specifically designated as a particular isotope is meant to represent any stable isotope of that atom. Unless otherwise stated, when a position is designated specifically as “H” or “hydrogen”, [Annotation] Mel.Chan None set by Mel.Chan ation] Mel.Chan MigrationNone set by Mel.Chan [Annotation] Mel.Chan Unmarked set by Mel.Chan [Annotation] Mel.Chan None set by an [Annotation] Mel.Chan MigrationNone set by Mel.Chan [Annotation] Mel.Chan Unmarked set by Mel.Chan the position is understood to have hydrogen at its natural abundance isotopic composition. Accordingly, in the compounds of this disclosure any atom specifically designated as a deuterium (D) is meant to represent deuterium. rmore, the present sure provides pharmaceutical compositions comprising at least one compound of the present disclosure, or a prodrug compound thereof, or a pharmaceutically acceptable salt or solvate thereof as active ingredient together with a pharmaceutically acceptable carrier. aceutical composition” means one or more active ingredients, and one or more inert ingredients that make up the carrier, as well as any product which results, directly or indirectly, from combination, complexation or aggregation of any two or more of the ingredients, or from iation of one or more of the ingredients, or from other types of reactions or interactions of one or more of the ingredients. Accordingly, the pharmaceutical compositions of the present disclosure encompass any composition made by admixing at least one compound of the present disclosure and a pharmaceutically acceptable carrier.

List of Abbreviations and ms Abbreviation Meaning (i)—BINAP 2'—Bis(diphenylphosphino)— l ,l '—binaphthalene 2—MeTHF yl tetrahydrofuran ACN or MeCN Acetonitrile aq. aqueous Bn Benzyl BOC or Boc t—Butyloxycarbonyl BSA Bovine serum albumin BSS Balanced Salt on calcd calculated DAST (diethylamino)sulfur trifluoride DCM Dichloromethane [Annotation] Mel.Chan None set by Mel.Chan [Annotation] Mel.Chan MigrationNone set by Mel.Chan [Annotation] an Unmarked set by Mel.Chan ation] Mel.Chan None set by Mel.Chan [Annotation] Mel.Chan MigrationNone set by Mel.Chan [Annotation] Mel.Chan Unmarked set by Mel.Chan DIBAL—H Diisobutylaluminum hydride DMF Dimethylformamide DMSO Dimethylsulfoxide EA Ethyl acetate EDTA Ethylenediaminetetraacetic acid ESI Electronspray Ionization Et Ethyl EtzO Diethyl ether EtOAc Ethyl acetate FBS Fetal bovine serum h or hr(s) Hour(s) HATU l— [Bis(dimethylamino)methylene] — lH— l ,2,3— triazolo[4,5—b]pyridinium 3—oxid hexafluorophosphate HPLC High performance liquid chromatography IPA pyl alcohol IPTG pyl B—D— l—thiogalactopyranoside LCMS or Liquid Chromatography Mass Spectrometry LC/MS Me Methyl MEM Minimum Essential Medium MeOH Methanol min Minute(s) MS Mass Spectrometry m/z o—charge ratio NADPH Dihydronicotinamide—adenine dinucleotide phosphate NMP N—methylpyrrolidone NMR Nuclear Magnetic Resonance spectroscopy n—BuLi n—butyllithium [Annotation] Mel.Chan None set by Mel.Chan [Annotation] Mel.Chan MigrationNone set by Mel.Chan [Annotation] Mel.Chan Unmarked set by Mel.Chan [Annotation] Mel.Chan None set by an [Annotation] Mel.Chan MigrationNone set by Mel.Chan [Annotation] Mel.Chan Unmarked set by Mel.Chan rpm Revolutions per minute PE Petroleum ether RT or rt Room temperature sat. saturated TBAF Tetrabutylammonium fluoride TBDMS t—butyldimethylsilyl TBS t—butyldimethylsilyl TEMPO 2,2,6,6—Tetramethylpiperidine l—oxyl TFA Trifluoroacetic acid THF tetrahydrofuran TMS trimethylsilyl UPLC Ultra mance Liquid Chromatography Compounds ed herein are compounds according to Formula (I): wherein: Q is phenylene or pyridylene, each of which is ally substituted with one or two substituents independently selected from halogen, , C1_4—alkoxy, halo—C1_4—alkoxy, —CH2F, —CHF2, and —CF3; Yis N or CH; [Annotation] Mel.Chan None set by Mel.Chan [Annotation] Mel.Chan MigrationNone set by Mel.Chan [Annotation] Mel.Chan Unmarked set by Mel.Chan [Annotation] Mel.Chan None set by Mel.Chan [Annotation] Mel.Chan MigrationNone set by Mel.Chan [Annotation] Mel.Chan Unmarked set by Mel.Chan A is pyridylene or phenylene, each of which is ally substituted with one or two groups independently selected from halogen, C1_4—alkoxy, 1_4—alkoxy, C1_4—alkyl, and halo— C1_4—alkyl; Z is isoxazole substituted with R1 or pyrazole substituted with R1; R1 is CM—alkyl or C3_6—cycloalkyl, n said C1_4—alkyl is optionally substituted with l to 3 substituents independently selected from fluoro, hydroxyl, C1_3—alkoxy, and fluoro—C1_3—alkoxy, and said C3_6—cycloalkyl is optionally substituted with l to 3 substituents independently selected from fluoro, yl, C1_3—alkyl, fluoro—C1_3—alkyl, €1-3— alkoxy, and fluoro—C1_3—alkoxy; R2 and R3 are independently ed from hydrogen, halogen, methoxy, —CF3, —CHF2, — CHZF, —OCH2F, —OCHF2, —OCF3, and methyl; R4 is —C02R5 or —C(O)NR5R6; R5 is hydrogen, lkyl, or halo—C1_6—alkyl; and R6 is hydrogen or C1_6—alkyl, wherein said C1_6—alkyl is optionally substituted with l to 6 substituents ndently selected from halogen, -SO3H, and —COZH; or a pharmaceutically acceptable salt, a stereoisomer, a mixture of stereoisomers, or a er thereof.

One embodiment provides for compounds of Formula (Ia): [Annotation] Mel.Chan None set by Mel.Chan [Annotation] Mel.Chan MigrationNone set by Mel.Chan [Annotation] Mel.Chan Unmarked set by Mel.Chan [Annotation] Mel.Chan None set by Mel.Chan [Annotation] Mel.Chan MigrationNone set by Mel.Chan [Annotation] Mel.Chan Unmarked set by Mel.Chan Q is phenylene or pyridylene, each of which is optionally tuted with one or two substituents independently selected from halogen, methyl, C1_4—alkoxy, halo—C1_4—alkoxy, —CH2F, —CHF2, and —CF3; Yis N or CH; A is pyridylene or phenylene, each of which is optionally substituted with one or two groups independently ed from halogen, C1_4—alkoxy, halo—C1_4—alkoxy, C1_4—alkyl, and halo— C1_4—alkyl; R1 is CM—alkyl or C3_6—cycloalkyl, n said C1_4—alkyl is optionally substituted with l to 3 substituents independently selected from fluoro, yl, C1_3—alkoxy, and fluoro—C1_3—alkoxy, and said C3_6—cycloalkyl is ally substituted with l to 3 substituents independently selected from fluoro, hydroxyl, C1_3—alkyl, fluoro—C1_3—alkyl, lkoxy, and fluoro—C1_3— alkoxy; R2 and R3 are independently selected from hydrogen, halogen, methoxy, —CF3, —CHF2, — CHZF, —OCH2F, , —OCF3, and methyl; R4 is (302115 or —C(O)NR5R6; R5 is hydrogen, lkyl, or halo—C1_6—alkyl; R6 is hydrogen or C1_6—alkyl, wherein said C1_6—alkyl is optionally substituted with l to 6 substituents independently selected from n, -SO3H, and —COZH; or a pharmaceutically acceptable salt, a stereoisomer, a mixture of stereoisomers, or a tautomer thereof.

One embodiment provides for compounds of formula (Ia): [Annotation] Mel.Chan None set by Mel.Chan [Annotation] Mel.Chan MigrationNone set by an [Annotation] an Unmarked set by an [Annotation] Mel.Chan None set by Mel.Chan [Annotation] an MigrationNone set by Mel.Chan [Annotation] Mel.Chan Unmarked set by Mel.Chan wherein: Q is phenylene optionally substituted with one or two halogen; Y is N or CH; A is lene optionally substituted with one or two groups independently selected from halogen and C1_4—alkoxy; R1 is CM-alkyl or C3_6—cycloalkyl; R2 and R3 are independently selected from hydrogen and halogen; R4 is —C02R5 or —C(O)NR5R6; R5 is hydrogen; and R6 is C1_2—alkyl optionally substituted with —COZH or -SO3H; or pharmaceutically acceptable salt, a stereoisomer, a mixture of stereoisomers, or a tautomer thereof.

In one embodiment, Q is phenylene or pyridylene, each of which is optionally tuted with one or two substituents independently selected from halogen, methyl, —CHF2, and —CF3. In some embodiments, Q is ene optionally substituted with one or two substituents independently selected from halogen, methyl, and —CF3. In some embodiments, Q is pyridylene optionally substituted with one or two substituents independently ed from halogen, methyl, and —CF3.

[Annotation] Mel.Chan None set by Mel.Chan [Annotation] Mel.Chan MigrationNone set by Mel.Chan [Annotation] Mel.Chan Unmarked set by Mel.Chan [Annotation] Mel.Chan None set by an [Annotation] Mel.Chan ionNone set by Mel.Chan [Annotation] an Unmarked set by Mel.Chan In one embodiment, Q is phenylene optionally substituted with one or two halogen. In some embodiments, Q is pyridylene optionally substituted with one or two halogen. In some embodiments, Q is phenylene optionally substituted with one or two chloro. In some embodiments, Q is pyridylene optionally substituted with one or two chloro.

In one embodiment, Q is phenylene substituted with one chloro. In some embodiments, Q is pyridylene substituted with one chloro.

In one embodiment, R1 is C1_4—alkyl. In some embodiments, R1 is C3_6—cycloalkyl. In some embodiments, R1 is cyclopropyl or methyl. In some ments, R1 is ropyl.

In one embodiment, R2 and R3 are not both hydrogen. In some ments, R2 and R3 are independently selected from hydrogen, halogen, methoxy, —OCHF2, —OCF3, and methyl.

In some embodiments, R2 and R3 are independently selected from halogen, methoxy, , — OCF3, and methyl.

In one ment, R2 and R3 are halogen. In some embodiments, R2 and R3 are chloro.

In one embodiment, one of R2 and R3 is a halogen and the other is hydrogen. In one embodiment, one of R2 and R3 is a chloro and the other is hydrogen. In some embodiments, one of R2 and R3 is a fluoro and the other is hydrogen.

In one embodiment, Y is N. In some embodiments, Y is CH.

In one embodiment, A is pyridylene optionally substituted with one or two halogen. In some embodiments, A is pyridylene optionally tuted with one or two C1_4—alkoxy.

In one embodiment, A is pyridylene substituted with one fluoro. In some ments, A is pyridylene substituted with one methoxy. In one embodiment, A is unsubstituted pyridylene.

In one embodiment, A is phenylene optionally tuted with one or two halogen. In one embodiment, A is phenylene optionally substituted with one or two C1_4—alkoxy.

[Annotation] Mel.Chan None set by an [Annotation] Mel.Chan MigrationNone set by Mel.Chan [Annotation] Mel.Chan Unmarked set by Mel.Chan [Annotation] Mel.Chan None set by Mel.Chan [Annotation] Mel.Chan MigrationNone set by Mel.Chan ation] Mel.Chan Unmarked set by Mel.Chan In one embodiment, A is phenylene substituted with one fluoro. In one embodiment, A is phenylene substituted with one methoxy. In one embodiment, A is unsubstituted phenylene.

In one embodiment, R4 is —COZR5, and R5 is hydrogen. In one embodiment, R4 is — COZRS and R5 is C1_6—alkyl or halo—C1_6—alkyl.

In one embodiment, R4 is —C(O)NR5R6, R5 is lkyl or halo—C1_6—alkyl, and R6 is C1- z—alkyl, wherein said C1_2—alkyl is tuted with -SO3H or —COZH.

In one embodiment, R4 is —C(O)NR5R6, R5 is hydrogen, and R6 is C1_2—alkyl, wherein said C1_2—alkyl is substituted with -SOgH or —COZH.

In one embodiment, R4—A is: R4Q§wherein the pyridylene is optionally substituted with one or two groups independently selected from halogen, lkoxy, halo—C1_4—alkoxy, C1_4—alkyl, and halo—€1-4— alkyl.

In one embodiment, R4—A is: I \ o / N | O / N O I HN HO \ O HN / N HO \ / N OH SO3H C02H 01' N O I , , , .

In one embodiment, R4—A is: F I \ o / N | O / N | HN HO \ O / N I I HNW / N CH SO3H OI‘ COZH ’ ’ [Annotation] Mel.Chan None set by Mel.Chan [Annotation] Mel.Chan MigrationNone set by Mel.Chan [Annotation] Mel.Chan Unmarked set by an [Annotation] Mel.Chan None set by Mel.Chan [Annotation] Mel.Chan MigrationNone set by Mel.Chan [Annotation] Mel.Chan Unmarked set by Mel.Chan In one ment, R4—A is: I \ o /N | O / N | HN o /N W\ HNW OH SO3H OI' C02H In one embodiment, R4—A is HO \ N/ 0/ " m Ow N /N [Annotation] Mel.Chan None set by Mel.Chan [Annotation] Mel.Chan MigrationNone set by Mel.Chan [Annotation] Mel.Chan Unmarked set by Mel.Chan [Annotation] an None set by Mel.Chan [Annotation] Mel.Chan MigrationNone set by Mel.Chan [Annotation] Mel.Chan Unmarked set by Mel.Chan CI OH F HO \ CI /N F F OH O / ,\N / \ CI CI H020 /N ;and F or a pharmaceutically acceptable salt, a stereoisomer, a mixture of stereoisomers, or a tautomer thereof.

In one embodiment, provided herein is a compound having the following formula: o%N OH o / HO _N 0' CI CI or a pharmaceutically acceptable salt thereof.

In one ment, provided herein is a nd having the ing formula: [Annotation] Mel.Chan None set by Mel.Chan [Annotation] Mel.Chan MigrationNone set by Mel.Chan [Annotation] Mel.Chan Unmarked set by Mel.Chan [Annotation] Mel.Chan None set by an [Annotation] Mel.Chan MigrationNone set by Mel.Chan [Annotation] an Unmarked set by Mel.Chan 0>—</:\$*N:>—QOOH / \ HO _N CI CI CI The chemical name of each of these compounds is provided in Table 1 below.

Table 1 Example ure IUPAC Name 2—chloro—4—((5—cyclopropyl— 3—(2,4—difluorophenyl)isoxazol—4— OH 0 Ho/‘b/N yl)methoxy)phenyl)—3— yazetidin—l—yl)isonicotinic CI acid m$NW:F/BN0 2—(3—(2—chloro—4—((5—cyclopropyl— 3—(2,6—dichloro—4— fluorophenyl)isoxazol—4— yl)methoxy)phenyl)—3— hydroxyazetidin—l—yl)isonicotinic 6—(3—(2—chloro—4—((5—cyclopropyl— ngygoc 3—(2,6—dichloro—4— //"N fluorophenyl)isoxazol—4— yl)methoxy)phenyl)—3— hydroxyazetidin— l—yl)—5 — fluoronicotinic acid H:>—</:I§TN>1—QOC 6—(3—(2—chloro—4—((3—(2,6— / /O‘NC dichloro—4—fluorophenyl)—5 — methylisoxazol—4— yl)methoxy)phenyl)—3— hydroxyazetidin— l—yl)—5 — fluoronicotinic acid [Annotation] Mel.Chan None set by an [Annotation] Mel.Chan MigrationNone set by Mel.Chan [Annotation] an Unmarked set by Mel.Chan [Annotation] Mel.Chan None set by Mel.Chan [Annotation] Mel.Chan MigrationNone set by Mel.Chan [Annotation] Mel.Chan Unmarked set by Mel.Chan 6—(3—(2—chloro—4—((4—cyclopropyl— 1—(2,6—dichloro—4—fluorophenyl)— PW”N 1H—pyrazol—5— N yl)methoxy)phenyl)—3— [\N CI CI hydroxyazetidin— 1—yl)—5 — fluoronicotinic acid —(( 1 S ,3S)—3—(2—chloro—4—((5— cyclopropyl—3—(2,6—dichloro—4— W0 U” fluorophenyl)isoxazol—4— yl)methoxy)phenyl)—3— / \W' CI CI hydroxycyclobutyl)—6— methoxynicotinic acid 2—(6—(3 —(2—chloro—4—((5— cyclopropyl—3—(2,6—dichloro—4— henyl)isoxazol—4— yl)methoxy)phenyl)—3— hydroxyazetidin— 1—yl)—5 — fluoronicotinamido)ethane— 1— sulfonic acid (6—(3—(2—chloro—4—((5— cyclopropyl—3—(2,6—dichloro—4— fluorophenyl)isoxazol—4— yl)methoxy)phenyl)—3— hydroxyazetidin— 1—yl)—5 — fluoronicotinoyl)glycine Pharmaceutical Compositions and Modes of Administration The present disclosure r provides pharmaceutical itions comprising at least one compound of the present disclosure, or a prodrug, a ceutically acceptable salt, or solvate thereof as active ingredient together with a pharmaceutically acceptable carrier.

[Annotation] Mel.Chan None set by Mel.Chan [Annotation] Mel.Chan MigrationNone set by an [Annotation] Mel.Chan Unmarked set by Mel.Chan [Annotation] an None set by Mel.Chan [Annotation] Mel.Chan MigrationNone set by Mel.Chan [Annotation] Mel.Chan ed set by Mel.Chan The pharmaceutical composition of the present disclosure may additionally comprise one or more other compounds as active ingredients like a g or other nuclear receptor modulators.

The itions are suitable for oral, rectal, topical, parenteral (including subcutaneous, uscular, and intravenous), ocular (ophthalmic), pulmonary (nasal or buccal inhalation) or nasal administration, although the most suitable route in any given case will depend on the nature and severity of the conditions being treated and on the nature of the active ingredient. They may be conveniently presented in unit dosage form and prepared by any of the methods well—known in the art of pharmacy.

In practical use, the compounds of the present disclosure can be combined as the active ingredient in intimate admixture with a pharmaceutical carrier according to conventional pharmaceutical compounding techniques. The carrier may take a wide variety of forms depending on the form of preparation d for administration, e.g., oral or parenteral (including intravenous). In preparing the compositions for oral dosage form, any of the usual pharmaceutical media may be employed, such as, for example, water, glycols, oils, alcohols, flavoring agents, preservatives, coloring agents and the like in the case of oral liquid preparations, such as, for example, suspensions, elixirs and solutions; or carriers such as starches, sugars, microcrystalline cellulose, diluents, granulating agents, lubricants, binders, egrating agents and the like in the case of oral solid preparations such as, for example, powders, hard and soft capsules and tablets, with the solid oral preparations being preferred over the liquid preparations.

Because of their ease of administration, tablets and capsules represent the most advantageous oral dosage unit form in which case solid pharmaceutical carriers are employed. If d, tablets may be coated by standard s or ueous techniques. Such compositions and preparations should contain at least 0.1 percent of active compound. The percentage of active nd in these compositions may, of , be varied and may iently be between about 2 percent to about 60 percent of the weight of the unit. The amount of active compound in such therapeutically useful compositions is such that an effective [Annotation] Mel.Chan None set by Mel.Chan [Annotation] Mel.Chan MigrationNone set by Mel.Chan [Annotation] Mel.Chan Unmarked set by Mel.Chan [Annotation] Mel.Chan None set by Mel.Chan [Annotation] Mel.Chan MigrationNone set by Mel.Chan [Annotation] Mel.Chan Unmarked set by Mel.Chan dosage will be obtained. The active compounds can also be stered intranasally as, for example, liquid drops or spray.

The tablets, pills, es, and the like may also contain a binder such as gum tragacanth, acacia, corn starch or gelatin; excipients such as dicalcium phosphate; a disintegrating agent such as corn starch, potato starch, alginic acid; a lubricant such as magnesium stearate; and a sweetening agent such as sucrose, lactose or saccharin. When a dosage unit form is a capsule, it may contain, in addition to materials of the above type, a liquid carrier such as a fatty oil.

Various other materials may be present as coatings or to modify the physical form of the dosage unit. For instance, tablets may be coated with shellac, sugar or both. A syrup or elixir may contain, in addition to the active ient, sucrose as a sweetening agent, methyl and propylparabens as preservatives, a dye and a flavoring such as cherry or orange flavor.

Since the compounds of the t disclosure mostly represent carboxylic acids or similar anionic isosters thereof, and since salt forms of ionic compounds can substantially affect bioavailability, the compounds of the present disclosure may also be used as salts with various countercations to yield an orally available formulation. Such pharmaceutically acceptable cations may be t others mono— or bivalent ions such as ammonium, the alkaline metals sodium or potassium or the ne earth metals magnesium or calcium, certain pharmaceutically acceptable amines such as tris(hydroxymethyl)aminomethane, ethylendiamine, diethylamine, piperazine or others, or certain cationic amino acids such as lysine or arginine.

The compounds of the present disclosure may also be administered parenterally.

Solutions or suspensions of these active nds can be ed in water suitably mixed with a surfactant such as hydroxy—propylcellulose. Dispersions can also be prepared in glycerol, liquid polyethylene glycols and mixtures thereof in oils. Under ordinary conditions of storage and use, these preparations contain a vative to prevent the growth of microorganisms.

The pharmaceutical forms suitable for injectable use include sterile s ons or dispersions and sterile powders for the extemporaneous preparation of e able solutions or sions. In all cases, the form must be sterile and must be fluid to the extent that easy [Annotation] Mel.Chan None set by Mel.Chan [Annotation] Mel.Chan MigrationNone set by Mel.Chan ation] Mel.Chan Unmarked set by Mel.Chan [Annotation] Mel.Chan None set by Mel.Chan [Annotation] Mel.Chan MigrationNone set by an [Annotation] Mel.Chan Unmarked set by an syringability exists. It must be stable under the conditions of manufacture and storage and must be preserved against the contaminating action of microorganisms such as bacteria and fungi. The carrier can be a solvent or dispersion medium ning, for example, water, ethanol, polyol (e. g., glycerol, ene glycol and liquid polyethylene ), suitable mixtures thereof, and ble oils.

Any suitable route of administration may be employed for providing a mammal, especially a human, with an effective dose of a compound of the present disclosure. For example, oral, rectal, topical, parenteral, ocular, pulmonary, nasal, and the like may be employed. Dosage forms e tablets, troches, dispersions, suspensions, solutions, capsules, creams, ointments, aerosols, and the like. In some embodiments, compounds of the present sure are administered orally. ed herein are also kits that include a compound of the disclosure, or a pharmaceutically acceptable salt, tautomer, stereoisomer, e of stereoisomers, prodrug, or ated analog thereof, and suitable packaging. In one embodiment, a kit further includes instructions for use. In one aspect, a kit includes a compound of the disclosure, or a ceutically acceptable salt, tautomer, stereoisomer, mixture of stereoisomers, prodrug, or deuterated analog thereof, and a label and/or ctions for use of the compounds in the treatment of the indications, including the diseases or conditions, described herein.

Provided herein are also es of cture that include a compound described herein or a pharmaceutically acceptable salt, tautomer, stereoisomer, mixture of stereoisomers, prodrug, or deuterated analog thereof in a suitable container. The container may be a vial, jar, ampoule, preloaded syringe, and enous bag.

Treatment Methods and Uses “Treatment” or “treating” is an approach for obtaining beneficial or desired results including clinical results. Beneficial or desired clinical results may include one or more of the following: a) inhibiting the disease or condition (e.g., decreasing one or more symptoms resulting from the disease or condition, and/or diminishing the extent of the disease or [Annotation] Mel.Chan None set by Mel.Chan [Annotation] Mel.Chan MigrationNone set by Mel.Chan [Annotation] Mel.Chan Unmarked set by Mel.Chan [Annotation] Mel.Chan None set by Mel.Chan [Annotation] Mel.Chan MigrationNone set by Mel.Chan [Annotation] Mel.Chan Unmarked set by Mel.Chan condition); b) g or arresting the development of one or more clinical symptoms ated with the disease or condition (e.g., stabilizing the disease or ion, preventing or delaying the worsening or progression of the disease or condition, and/or preventing or delaying the spread (e.g., metastasis) of the disease or condition); and/or c) relieving the disease, that is, causing the regression of clinical symptoms (e.g., ameliorating the disease state, providing partial or total remission of the disease or condition, ing effect of r medication, delaying the progression of the disease, sing the quality of life, and/or prolonging al.

“Prevention” or “preventing” means any treatment of a disease or condition that causes the clinical symptoms of the disease or condition not to develop. nds may, in some embodiments, be administered to a subject (including a human) who is at risk or has a family history of the disease or condition.

“Subject” refers to an animal, such as a mammal (including a human), that has been or will be the object of treatment, observation or experiment. The methods described herein may be useful in human therapy and/or nary ations. In some embodiments, the subject is a mammal. In one embodiment, the subject is a human.

The term “therapeutically effective ” or “effective amount” of a compound bed herein or a pharmaceutically acceptable salt, er, stereoisomer, mixture of stereoisomers, prodrug, or deuterated analog thereof means an amount sufficient to effect treatment when administered to a subject, to provide a therapeutic benefit such as amelioration of symptoms or slowing of disease progression. For example, a eutically effective amount may be an amount sufficient to decrease a symptom of a disease or condition responsive to inhibition of Cot activity. The therapeutically effective amount may vary depending on the subject, and disease or condition being treated, the weight and age of the subject, the severity of the disease or condition, and the manner of administering, which can readily be determined by one or ordinary skill in the art.

The sure further s to the use of said compounds for the treatment and/or prophylaxis of diseases and/or conditions through binding of said nuclear receptor by said compounds. Further the present disclosure relates to the use of said compounds for the [Annotation] Mel.Chan None set by Mel.Chan [Annotation] Mel.Chan ionNone set by Mel.Chan [Annotation] Mel.Chan Unmarked set by Mel.Chan [Annotation] Mel.Chan None set by Mel.Chan [Annotation] Mel.Chan MigrationNone set by Mel.Chan [Annotation] Mel.Chan Unmarked set by Mel.Chan preparation of a ment for the treatment and/or prophylaxis of diseases and/or conditions through g of said nuclear receptor by said compounds.

Also provided herein are methods of treating a patient having a FXR ed ion comprising administering a compound of formula (I), or pharmaceutically acceptable salt thereof, or a pharmaceutical composition sing a compound of formula (I), or pharmaceutically acceptable salt thereof.

In some embodiments, a compound of formula (I), or ceutically acceptable salt thereof, or a pharmaceutical composition comprising a compound of formula (I), or ceutically acceptable salt thereof is provided for use in the treatment of a FXR mediated condition.

In some embodiments, a compound of formula (I), or pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a compound of formula (I), or pharmaceutically able salt thereof, is provided for the manufacture of a medicament for the treatment of a FXR mediated condition.

In some embodiments, the FXR mediated condition is: a c intrahepatic or some form of extrahepatic cholestatic condition; liver fibrosis; an obstructive inflammatory er of the liver; chronic inflammatory disorder of the liver; liver cirrhosis; liver steatosis or an associated syndrome; cholestatic or fibrotic effects that are associated with alcohol—induced cirrhosis or with viral—bome forms of hepatitis; liver e or liver ischemia after major liver resection; chemotherapy associated steatohepatitis (CASH); acute liver failure; or atory Bowel Disease.

In some embodiments, the FXR mediated condition is: ation] an None set by Mel.Chan [Annotation] Mel.Chan MigrationNone set by Mel.Chan [Annotation] Mel.Chan Unmarked set by Mel.Chan [Annotation] Mel.Chan None set by Mel.Chan [Annotation] an MigrationNone set by Mel.Chan [Annotation] Mel.Chan Unmarked set by Mel.Chan a lipid and lipoprotein disorder; Type I Diabetes; Type 11 es; clinical cations of Type I and Type 11 Diabetes selected from the group consisting of ic nephropathy, diabetic neuropathy, diabetic retinopathy and other observed effects of clinically st long term Diabetes; Non—Alcoholic Fatty Liver Disease (NAFLD); Non—Alcoholic Steatohepatitis (NASH); a metabolic syndrome selected from the group consisting of ed conditions of dyslipidemia, diabetes and abnormally high body—mass index; acute myocardial infarction; acute stroke; or thrombosis which occurs as an endpoint of chronic obstructive atherosclerosis.

In some embodiments, the FXR mediated condition is: a non—malignant hyperproliferative disorder; and a malignant hyperproliferative disorder selected from the group consisting of hepatocellular carcinoma, colon adenoma, and polyposis; colon adenocarcinoma; breast cancer; pancreas adenocarcinoma; Barrett's esophagus; or other forms of neoplastic diseases of the gastrointestinal tract and the liver.

In some embodiments, the FXR mediated condition is Non—Alcoholic Steatohepatitis (NASH).

In some ments, the present disclosure relates to the use of compounds according to Formula (I) in the preparation of a medicament for the prophylaxis and/or ent of chronic intrahepatic or some forms of extrahepatic cholestatic conditions, of liver fibrosis, of acute intraheptic cholestatic conditions, of obstructive or chronic atory disorders that arise out [Annotation] Mel.Chan None set by Mel.Chan [Annotation] Mel.Chan MigrationNone set by Mel.Chan ation] Mel.Chan Unmarked set by Mel.Chan [Annotation] Mel.Chan None set by Mel.Chan [Annotation] Mel.Chan MigrationNone set by Mel.Chan ation] Mel.Chan Unmarked set by Mel.Chan of improper bile composition, of gastrointestinal conditions with a reduced uptake of dietary fat and fat—soluble y ns, of atory bowel diseases, of lipid and lipoprotein disorders, of Type II Diabetes and clinical complications of Type I and Type II Diabetes, of conditions and diseases which result from chronic fatty and fibrotic degeneration of organs due to enforced lipid and specifically triglyceride accumulation and subsequent activation of profibrotic ys, of obesity and metabolic syndrome (combined conditions of dyslipidemia, diabetes and abnormally high ass index), of acute myocardial infarction, of acute stroke, of thrombosis which occurs as an endpoint of chronic obstructive atherosclerosis, of persistant infections by intracellular bacteria or parasitic protozoae, of non—malignant hyperproliferative disorders, of malignant hyperproliferative disorders, of colon adenocarcinoma and cellular carcinoma in particular, of liver steatosis and ated syndromes, of liver failure or liver malfunction as an outcome of chronic liver diseases or of surgical liver resection, of Hepatitis B infection, of Hepatitis C infection and/or of cholestatic and fibrotic s that are associated with alcohol—induced cirrhosis or with viral—borne forms of tis.

Medicaments as referred to herein may be prepared by conventional ses, including the combination of a compound according to the t disclosure and a pharmaceutically acceptable carrier.

FXR is proposed to be a r bile acid sensor. As a result, it modulates both, the synthetic output of bile acids in the liver and their recycling in the intestine (by regulating bile acid binding proteins). But beyond bile acid physiology, FXR seems to be involved in the regulation of many diverse physiological processes which are relevant in the etiology and for the treatment of diseases as diverse as cholesterol gallstones, metabolic disorders such as Type II Diabetes, dyslipidemias or obesity, chronic matory diseases such as atory Bowel Diseases or chronic intrahepatic forms of cholestasis and many other diseases.

FXR tes a complex pattern of response genes in the liver and in the gastrointestinal tract. The gene products have impact on diverse physiological processes. In the course of functional analysis of FXR, the first tory network that was analyzed was the regulation of bile acid synthesis. While the LXRs induce the key enzyme of the conversion of cholesterol into bile acids, Cyp7Al, via the induction of the regulatory nuclear receptor LRH—l, [Annotation] Mel.Chan None set by an [Annotation] Mel.Chan MigrationNone set by Mel.Chan [Annotation] Mel.Chan Unmarked set by Mel.Chan [Annotation] an None set by Mel.Chan [Annotation] Mel.Chan MigrationNone set by Mel.Chan [Annotation] an Unmarked set by Mel.Chan FXR represses the induction of Cyp7Al via the lation of mRNA encoding SHP, a further nuclear receptor that is dominant repressive over LRH—l. Since FXR binds the end products of this y, primary bile acids such as cholic acid (CA) or CDCA, this can be regarded as an example of feedback inhibition on the gene expression level. Parallel to the repression of bile acid synthesis via SHP, FXR induces a range of so—called ABC (for ATP—binding cassette) transporters that are sible for the export of toxic bile acids from the hepatocyte cytosol into the canaliculi, the small bile duct ramifications where the bile originates. This hepatoprotective function of FXR became first apparent with the analysis of FXR knockout mice. where under— or overexpression of several ABC—transporters in the liver was shown.

Further detailed analysis revealed that the major bile salt excretory pump BSEP or ABCB ll (as well as the key enzyme which mediates lipid transfer from lipoproteins to olipids, PLTP, and the two key canalicular membrane orters for phospholipids, MRP—2 (ABCC4) and MDR—3 (ABCB4),are direct targets for ligand—directed transcriptional activation by FXR.

The fact that FXR seems to be the major metabolite sensor and regulator for the synthesis, export and re—circulation of bile acids suggested the use of FXR s to induce bile flow and change bile acid composition s more hydrophilic composition. With the development of the first synthetic FXR ligand GW4064 as a tool compound and of the semi— synthetic artificial bile acid ligand 6—alpha—ethyl—CDCA, the effects of superstimulation of FXR by potent agonists could be analyzed. It was shown that both ligands induce bile flow in bile duct ligated animals. Moreover, in addition to choleretic effects, also hepatoprotective effects could be demonstrated. This hepatoprotective effect was further narrowed down to an anti—fibrotic effect that results from the repression of Tissue Inhibitors of Matrix—Metalloproteinases, TIMP—1 and 2, the induction of collagen—deposit resolving Matrix—Metalloproteinase 2 in hepatic stellate cells and the subsequent reduction of alpha—collagen mRNA and Transforming growth factor beta eta) mRNA which are both pro—fibrotic factors by FXR agonists. Furthermore, anti— tatic activity was demonstrated in bile—duct ligated animal models as well as in animal models of estrogen—induced cholestasis.

Genetic studies demonstrate that in hereditary forms of cholestasis (Progressive Familiar Intrahepatic Cholestasis = PFIC, Type I — IV) either nuclear localization of FXR itself is reduced as a consequence of a on in the FICl gene (in PFIC Type I, also called Byler’s [Annotation] Mel.Chan None set by an [Annotation] Mel.Chan MigrationNone set by Mel.Chan [Annotation] Mel.Chan Unmarked set by Mel.Chan ation] Mel.Chan None set by Mel.Chan [Annotation] Mel.Chan MigrationNone set by an [Annotation] Mel.Chan Unmarked set by an Disease) (F. Chen et al., Gastroenterology 2004, 126, 756; L. Alvarez et al., Hum. M01. Genet. 2004, 13, 2451) or levels of the FXR target gene encoding MDR—3 phospholipid export pump are reduced (in PFIC Type III). Taken together there is a growing body of evidence that FXR binding compounds will demonstrate substantial clinical utility in the therapeutic regimen of chronic cholestatic ions such as Primary Biliary Cirrhosis (PBC) or Primary Sclerosing Cholangitis (PSC).

The deep impact that FXR activation has on bile acid metabolism and excretion is not only relevant for cholestatic syndromes but even more directly for a therapy against gallstone formation. Cholesterol gallstones form due to low solubility of cholesterol that is actively pumped out of the liver cell into the lumen of the canaliculi. It is the relative percentage of content of the three major ents, bile acids, phospholipids and free cholesterol that determines the formation of mixed micelles and hence apparent solubility of free cholesterol in the bile. FXR polymorphisms map as quantitative trait loci as one factor contributing to gallstone disease. Using the synthetic FXR tool compound GW4064 it could be demonstrated that activation of FXR leads to an ement of the Cholesterol Saturation Index (CSI) and ly to an hment of gallstone formation in C57L gallstone susceptible mice s drug treatment in FXR knockout mice shows no effect on one formation.

These results qualify FXR as a good target for the development of small molecule agonists that can be used to prevent cholesterol gallstone formation or to prevent mation of gallstones after surgical removal or shockwave lithotripsy.

Thus, in one embodiment of the disclosure, the compound according to Formula (I) and pharmaceutical compositions comprising said nd is used for the prophylaxis and/or treatment of obstructive or chronic inflammatory disorders that arise out of improper bile composition such as cholelithiasis also known as cholesterol gallstones.

Beyond its strong hepatoprotective and choleretic as well as anti—fibrotic effects that FXR shows upon small molecule stimulated activation in the liver, FXR seems to have a role in protecting the intestine from stic transformation and from the development of polyps and their transition into adenocarcinoma in the gut. Similar to the situation in the intestine absence of FXR leads to a high increase in the formation of Hepatocellular Cacrcinoma (HCC), the most [Annotation] an None set by Mel.Chan [Annotation] Mel.Chan MigrationNone set by Mel.Chan [Annotation] Mel.Chan Unmarked set by Mel.Chan [Annotation] Mel.Chan None set by Mel.Chan ation] Mel.Chan MigrationNone set by Mel.Chan [Annotation] Mel.Chan ed set by Mel.Chan prominent form of liver cancer. Whereas a functional FXR prevents the formation of colon adenocarcinoma and hepatocellular carcinoma, FXR tion induces liver regeneration after hepatectomy.

The combined hepatoprotective, anti—neoplastic and liver regenerative effects associated with FXR activation can be therapeutically exploited for the use of FXR agonists in the treatment of severe liver diseases. In one embodiment, the compounds according to the disclosure and pharmaceutical compositions sing said compounds are used in the treatment of liver diseases such as HCC, stimulation of liver regrowth and amelioration of side effects associated with major liver resection, liver cirrhosis independent of the etiology and prevention or treatment of liver ischemia in the course of liver transplantation or major liver surgery.

Since the discovery of the first synthetic FXR t and its administration to rodents it became evident that FXR is a key regulator of serum triglycerides. Over the past six years accumulating evidence has been published that activation of FXR by synthetic agonists leads to icant reduction of serum triglycerides, mainly in the form of reduced VLDL, but also to d total serum cholesterol .

But the lowering of serum triglycerides is not a stand alone effect. Treatment of db/db or ob/ob mice with synthetic FXR t GW4064 ed in marked and combined reduction of serum triglycerides, total cholesterol, free fatty acids, ketone bodies such as 3—OH Butyrate.

Moreover, FXR activation engages with the intracellular insulin signaling pathway in hepatocytes, resulting in reduced output of glucose from liver gluconeogenesis but concomitant increase in liver en. Insulin sensitivity as well as glucose tolerance were positively impacted by FXR treatment. An effect on reduction of body weight was also recently ed in mice overfed with a high lipid diet. This weight loss effect might results from FXR’s induction of FGF—l9, a fibroblast growth factor that is known to lead to weight loss and athletic phenotype.

The effect of FXR agonist on reduction of body weight has been demonstrated.

Taken together, these pharmacological effects of FXR agonists can be exploited in ent therapeutic ways: FXR binding compounds are thought to be good candidates for the treatment of Type II Diabetes because of their insulin sensitization, glycogenogenic, and lipid ng effects. ation] Mel.Chan None set by Mel.Chan [Annotation] Mel.Chan MigrationNone set by Mel.Chan [Annotation] Mel.Chan Unmarked set by Mel.Chan [Annotation] Mel.Chan None set by Mel.Chan [Annotation] Mel.Chan MigrationNone set by Mel.Chan [Annotation] Mel.Chan Unmarked set by Mel.Chan In one embodiment, the nds according to the disclosure and pharmaceutical compositions comprising said nds are used in the prophylaxis and/or ent of Type II Diabetes which can be overcome by diated upregulation of systemic insulin sensitivity and intracellular insulin signalling in liver, increased peripheral glucose uptake and metabolisation, increased glycogen storage in liver, decreased output of glucose into serum from liver—bome gluconeogenesis.

In a r embodiment, said compounds and pharmaceutical compositions are used for the prophylaxis and/or treatment of chronic intrahepatic, such as PBC, PSC, progressive familiar cholestasis (PFIC), alcohol—induced cirrhosis and associated cholestasis, and some forms of extrahepatic cholestatic conditions, or liver fibrosis.

The disclosure also relates to a nd of Formula (I) or a pharmaceutical composition comprising said compound for the laxis and/or treatment of gastrointestinal conditions with a reduced uptake of dietary fat and fat—soluble y vitamins which can be overcome by increased intestinal levels of bile acids and phospholipids.

In a further embodiment, said compound or ceutical composition is used for preventing and/or treating a disease selected from the group consisting of lipid and lipoprotein ers such as hypercholesterolemia, hypertriglyceridemia, and atherosclerosis as a clinically manifest condition which can be rated by FXR’s beneficial effect on lowering total plasma cholesterol, lowering serum triglycerides, increasing conversion of liver cholesterol into bile acids and increased clearance and metabolic conversion of VLDL and other oteins in the liver.

In one further embodiment, said compound and pharmaceutical composition are used for the laxis and/or treatment of diseases where the combined lipid lowering, anti— cholestatic and anti—fibrotic effects of FXR—targeted medicaments can be exploited for the treatment of liver steatosis and associated syndromes such as Non—Alcoholic Steatohepatitis (NASH), or for the treatment of cholestatic and fibrotic effects that are associated with alcohol— d cirrhosis, or with viral—borne forms of hepatitis.

[Annotation] Mel.Chan None set by an [Annotation] Mel.Chan MigrationNone set by an [Annotation] Mel.Chan Unmarked set by Mel.Chan [Annotation] Mel.Chan None set by Mel.Chan [Annotation] Mel.Chan MigrationNone set by Mel.Chan [Annotation] Mel.Chan Unmarked set by an In conjunction with the hypolipidemic effects it was also shown that loss of functional FXR leads to increased atherosclerosis in ApoE ut mice. Therefore, FXR agonists might have clinical utility as anti—atherosclerotic and cardioprotective drugs. The downregulation of Endothelin—l in Vascular Smooth Muscle Cells might also contribute to such beneficial therapeutic effects.

The disclosure also relates to a compound according to Formula (I) or a pharmaceutical ition comprising said compound for preventive and posttraumatic ent of a cardiovascular disorder, such as acute myocardial infarction, acute stroke, or thrombosis which occur as an endpoint of chronic ctive atherosclerosis.

Beyond controlling intestinal and colonic polyp formation, FXR seems to be sed in breast cancer tissue and cell lines but not in healthy breast tissue and seems to interact with the Estrogen Receptor in ER positive breast cancer cells.

This would allow to regard FXR also as a potential target for the treatment of proliferative es, especially metastasizing cancer forms that express a small molecule responsive form of FXR.

In a further embodiment, said nds and pharmaceutical compositions are used for the prophylaxis and/or treatment of malignant hyperproliferative disorders such as different forms of cancer, specifically certain forms of , liver or colon cancer where interference with an FXR ligand will have a beneficial impact.

Finally, FXR seems also to be involved in the control of antibacterial defense in the intestine although an exact mechanism is not provided. From these published data, however, one can conclude that treatment with FXR agonists might have a beneficial impact in the therapy of Inflammatory Bowel Disorders (IBD), in particular those forms where the upper (ileal) part of the ine is affected (e.g. ileal Crohn’s e) because this seems to be the site of action of FXR’s control on bacterial growth. In IBD, the desensitization of the adaptive immune response is somehow impaired in the intestinal immune system. Bacterial overgrowth might then be the causative trigger towards establishment of a chronic inflammatory response. Hence, dampening [Annotation] Mel.Chan None set by Mel.Chan [Annotation] Mel.Chan ionNone set by Mel.Chan [Annotation] Mel.Chan Unmarked set by Mel.Chan [Annotation] Mel.Chan None set by Mel.Chan [Annotation] Mel.Chan MigrationNone set by Mel.Chan [Annotation] Mel.Chan Unmarked set by Mel.Chan of bacterial growth by FXR—bome mechanisms might be a key mechanism to prevent acute inflammatory episodes.

Thus, the disclosure also relates to a compound according to a (I) or a pharmaceutical composition comprising said compound for preventing and/or treating a disease related to an Inflammatory Bowel Disease, such as Crohn’s disease or Colitis ulcerosa. FXR— ed restoration of intestinal barrier function and reduction in non—commensal ial load is believed to be helpful in reducing the exposure of ial antigens to the intestinal immune system and can therefore reduce inflammatory responses.

The disclosure further relates to a compound or ceutical composition for the prophylaxis and/or treatment of obesity and associated disorders such as lic syndrome (combined conditions of dyslipidemias, diabetes and abnormally high ass index) which can be overcome by FXR—mediated lowering of serum triglycerides, blood glucose and increased insulin sensitivity and FXR—mediated weight loss.

In a further embodiment, the compounds or pharmaceutical composition of the present disclosure are useful in preventing and/or treating al complications of Type I and Type II Diabetes. Examples of such complications include Diabetic Nephropathy, Diabetic Retinopathy, Diabetic athies, or Peripheral Arterial Occlusive Disease . Other clinical cations of Diabetes are also encompassed by the present disclosure.

Furthermore, ions and diseases which result from chronic fatty and ic degeneration of organs due to enforced lipid and specifically triglyceride accumulation and subsequent activation of profibrotic pathways may also be prevented and/or d by administering the compounds or pharmaceutical composition of the present disclosure. Such conditions and diseases encompass NASH and chronic cholestatic conditions in the liver, Glomerulosclerosis and Diabetic Nephropathy in the kidney, Macula Degeneration and Diabetic Retinopathy in the eye and neurodegenerative diseases, such as mer’s Disease in the brain, or Diabetic Neuropathies in the peripheral nervous system.

[Annotation] Mel.Chan None set by Mel.Chan ation] Mel.Chan MigrationNone set by Mel.Chan [Annotation] Mel.Chan Unmarked set by Mel.Chan ation] Mel.Chan None set by Mel.Chan [Annotation] Mel.Chan MigrationNone set by Mel.Chan [Annotation] Mel.Chan Unmarked set by Mel.Chan Dosage The effective dosage of active ingredient ed may vary depending on the particular compound ed, the mode of administration, the condition being treated and the severity of the condition being d. Such dosage may be ascertained y by a person skilled in the art.

When treating or preventing FXR mediated conditions for which nds of the present disclosure are indicated, generally satisfactory results are obtained when the compounds of the present disclosure are administered at a daily dosage of from about 0.1 milligram to about 100 milligram per kilogram of animal body weight. In some embodiments, the nds of the t disclosure are given as a single daily dose or in divided doses two to six times a day, or in sustained release form. For most large mammals, the total daily dosage is from about 1 milligram to about 1000 milligrams, or from about 1 milligram to about 50 milligrams. In the case of a 70 kg adult human, the total daily dose will generally be from about 7 milligrams to about 350 milligrams. This dosage regimen may be adjusted to provide the optimal therapeutic response. In some embodiments, the total daily dosage is from about 1 ram to about 900 rams, about 10 milligrams to about 800 milligrams, about 20 milligrams to about 700 milligrams, about 30 milligrams to about 600 milligrams, about 40 milligrams to about 550 milligrams, or about 50 milligrams to about 400 milligrams.

The compounds of the present application or the compositions f may be administered once, twice, three, or four times daily, using any suitable mode described above.

Also, administration or treatment with the compounds may be continued for a number of days; for example, commonly treatment would continue for at least 7 days, 14 days, or 28 days, for one cycle of treatment. Treatment cycles are well known in cancer chemotherapy, and are frequently alternated with resting periods of about 1 to 28 days, commonly about 7 days or about 14 days, between . The treatment cycles, in other embodiments, may also be continuous.

In a particular embodiment, the methods provided herein comprise administering to the subject an initial daily dose of about 1 to 800 mg of a compound described herein and increasing the dose by increments until clinical efficacy is achieved. Increments of about 5, 10, 25, 50, or [Annotation] Mel.Chan None set by Mel.Chan [Annotation] an MigrationNone set by Mel.Chan ation] Mel.Chan ed set by Mel.Chan [Annotation] Mel.Chan None set by Mel.Chan [Annotation] Mel.Chan MigrationNone set by Mel.Chan ation] Mel.Chan Unmarked set by Mel.Chan 100 mg can be used to increase the dose. The dosage can be sed daily, every other day, twice per week, or once per week.

Combination Therapies In some embodiments, a compound disclosed herein is administered in combination with one or more additional therapeutic agents to treat or prevent a disease or condition disclosed herein. In some embodiments, the one or more additional therapeutic agents are a(n) ACE inhibitor, Acetyl CoA carboxylase inhibitor, Adenosine A3 receptor agonist, Adiponectin receptor agonist, AKT protein kinase inhibitor, AMP—activated protein s (AMPK), Amylin receptor agonist, Angiotensin II AT—l receptor antagonist, Autotaxin inhibitors, Bioactive lipid, Calcitonin agonist, Caspase inhibitor, Caspase—3 stimulator, Cathepsin inhibitor, Caveolin 1 inhibitor, CCR2 chemokine antagonist, CCR3 chemokine antagonist, CCRS chemokine antagonist, Chloride channel stimulator, CNRl inhibitor, Cyclin D1 inhibitor, Cytochrome P450 7A1 inhibitor, DGATl/2 inhibitor, idyl ase IV inhibitor, Endosialin modulator, Eotaxin ligand inhibitor, Extracellular matrix protein tor, Farnesoid X receptor agonist, Fatty acid se tors, FGFl receptor agonist, Fibroblast growth factor (FGF—lS, FGF— l9, FGF—Zl) ligands, Galectin—3 inhibitor, Glucagon receptor agonist, Glucagon—like peptide 1 agonist, G—protein coupled bile acid receptor 1 agonist, og (Hh) modulator, Hepatitis C virus NS3 protease inhibitor, Hepatocyte nuclear factor 4 alpha modulator (HNF4A), Hepatocyte growth factor modulator, HMG CoA ase inhibitor, IL—lO agonist, IL—l7 antagonist, Ileal sodium bile acid cotransporter inhibitor, Insulin sensitizer, integrin modulator, intereukin—l receptor—associated kinase 4 (IRAK4) inhibitor, Jak2 tyrosine kinase inhibitor, Klotho beta stimulator, 5—Lipoxygenase inhibitor, Lipoprotein lipase inhibitor, Liver X receptor, LPL gene stimulator, Lysophosphatidate—l receptor antagonist, Lysyl oxidase homolog 2 inhibitor, Matrix metalloproteinases (MMPs) inhibitor, MEKK—S protein kinase tor, ne copper amine oxidase (VAP— 1) inhibitor, Methionine aminopeptidase—2 inhibitor, Methyl CpG binding protein 2 modulator, MicroRNA—21(miR—21) inhibitor, Mitochondrial uncoupler, Myelin basic protein ator, NACHT LRR PYD domain protein 3 (NLRP3) tor , NAD—dependent deacetylase sirtuin stimulator, NADPH oxidase inhibitor (NOX), Nicotinic acid receptor 1 agonist, P2Yl3 purinoceptor stimulator, PDE 3 inhibitor, PDE 4 tor, PDE 5 inhibitor, PDGF receptor beta modulator, Phospholipase C inhibitor, PPAR alpha agonist, PPAR delta [Annotation] Mel.Chan None set by Mel.Chan [Annotation] Mel.Chan MigrationNone set by Mel.Chan [Annotation] an Unmarked set by an ation] an None set by an [Annotation] Mel.Chan MigrationNone set by Mel.Chan [Annotation] Mel.Chan Unmarked set by Mel.Chan agonist, PPAR gamma agonist, PPAR gamma modulator, Protease—activated or—2 antagonist, Protein kinase modulator, Rho ated protein kinase inhibitor, Sodium glucose transporter—2 inhibitor, SREBP transcription factor inhibitor, STAT—l inhibitor, Stearoyl CoA desaturase—l inhibitor, Suppressor of cytokine signalling—l stimulator, Suppressor of cytokine signalling—3 stimulator, Transforming growth factor B (TGF—B), orming growth factor B activated Kinase 1 (TAKl), Thyroid hormone receptor beta agonist, TLR—4 antagonist, Transglutaminase tor, Tyrosine kinase receptor modulator, GPCR modulator, nuclear hormone receptor modulator, WNT modulators, or YAP/TAZ modulator.

Non—limiting examples of the one or more additional eutic agents include: ACE tors, such as enalapril; Acetyl CoA carboxylase (ACC) inhibitors, such as DRM—Ol, gemcabene, PF—05175157, and QLT—09l382; Adenosine receptor agonists, such as CF—lOZ, CF—lOl, CF—SOZ, and CGS21680; Adiponectin receptor agonists, such as ADP—355; Amylin/calcitonin receptor agonists, such as KBP—042; AMP activated protein kinase stimulators, such as 0—304; Angiotensin II AT—l receptor antagonists, such as irbesartan; AutotaXin inhibitors, such as PAT—505, PAT—048, GLPG—l690, X—l65, PF—8380, and AM—063; Bioactive lipids, such as DS—lOZ; Cannabinoid receptor type 1 (CNRl) tors, such as namacizumab and GWP—42004; Caspase inhibitors, such as emricasan; Pan cathepsin B inhibitors, such as VBY—376; Pan cathepsin inhibitors, such as VBY—825; CRS chemokine antagonists, such as cenicriViroc; CCR2 chemokine antagonists, such as ermanium; CCR3 chemokine antagonists, such as bertilimumab; Chloride channel stimulators, such as ostone; Diglyceride acyltransferase 2 (DGATZ) inhibitors, such as IONIS—DGATZRx; Dipeptidyl peptidase IV inhibitors, such as linagliptin; [Annotation] Mel.Chan None set by Mel.Chan [Annotation] Mel.Chan MigrationNone set by Mel.Chan [Annotation] Mel.Chan Unmarked set by Mel.Chan [Annotation] Mel.Chan None set by an [Annotation] Mel.Chan MigrationNone set by Mel.Chan [Annotation] Mel.Chan Unmarked set by Mel.Chan n ligand inhibitors, such as bertilimumab; Extracellular matrix protein modulators, such as CNX—024; Farnesoid X or (FXR) agonists, such as 2266, AKN—083, EDP—305, GNF— 5120, LJN—452, LMB-763, obeticholic acid, , Px-103, M790, M780, M450, M480, PX20606, EYP-001, and INT-2228; Farnesoid X receptor (FXR)/ G—protein coupled bile acid receptor l(TGR5) agonists, such as 7; Fatty acid synthase inhibitors, such as TVB —2640; Fibroblast growth factor 19 (thGFl9)/cytochrome P450 (CYP)7Al inhibitors, such as NGM-282; Fibroblast growth factor 21(FGF—21) ligand, such as EMS—986171, EMS—986036; Fibroblast growth factor 21(FGF—21)/glucagon like peptide 1 (GLP—l) agonists, such as Galectin—3 inhibitors, such as GR—MD—02; Glucagon—like peptide l(GLPlR) agonists, such as AC—3l74, liraglutide, semaglutide; G—protein coupled bile acid receptor l(TGR5) agonists, such as RDX—009, INT—777; Heat shock n 47 (HSP47) inhibitors, such as ND—L02—s0201; HMG CoA reductase inhibitors, such as statin, tatin, pitavastatin, pravastatin, rosuvastatin, and simvastatin; IL—lO agonists, such as peg—ilodecakin; Ileal sodium bile acid cotransporter inhibitors, such as A—4250, volixibat potassium ethanolate e (SHP—262), and GSK2330672; Insulin sensitizers, such as, KBP—042, MSDC—0602K, PX—102, RG—125 (AZD4076), and VVP-100X; beta Klotho (KLB)— FGFlc agonist, such as NGM—3l3; —Lipoxygenase inhibitors, such as tipelukast (MN—001); Lipoprotein lipase inhibitors, such as CAT—2003; LPL gene stimulators, such as alipogene tiparvovec; Liver X or (LXR) modulators, such as 3, PX—L493, EMS—852927, T— 0901317, GW—3965, and SR—9238; [Annotation] an None set by Mel.Chan [Annotation] Mel.Chan MigrationNone set by Mel.Chan [Annotation] Mel.Chan ed set by Mel.Chan [Annotation] Mel.Chan None set by Mel.Chan [Annotation] Mel.Chan MigrationNone set by an [Annotation] Mel.Chan Unmarked set by an Lysophosphatidate—l or nists, such as EMT—053011, UD—009. AR—479, ITMN-10534, EMS-986020, and KI—l6l98; Lysyl oxidase homolog 2 inhibitors, such as umab; Semicarbazide—Sensitive Amine Oxidase/Vascular Adhesion Protein—l (SSAO/VAP—l) Inhibitors, such as PXS—4728A; Methionine aminopeptidase—2 inhibitors, such as ZGN—839; Methyl CpG binding n 2 modulators, such as mercaptamine; ondrial uncouplers, such as 2,4—dinitrophenol; Myelin basic protein stimulators, such as ime; NADPH oxidase l/4 inhibitors, such as GKT—83l; Nicotinic acid receptor 1 agonists, such as ARI—3037MO; NACHT LRR PYD domain protein 3 (NLRP3) inhibitors, such as KDDF—201406—03, and NBC—6; Nuclear receptor modulators, such as DUR—928; P2Yl3 purinoceptor stimulators, such as CER—209; PDE 3/4 inhibitors, such as tipelukast (MN—001); PDE 5 tors, such as sildenafil; PDGF receptor beta modulators, such as BOT—191, BOT—509; PPAR agonists, such as elafibranor (GFT—SOS), MEX—8025, deuterated pioglitazone R— enantiomer, pioglitazone, DRX—065, saroglitazar, and IVA—337; Protease—activated receptor—2 antagonists, such as PZ—235; Protein kinase modulators, such as CNX—Ol4; Rho associated protein kinase (ROCK) inhibitors, such as KD—OZS; Sodium glucose transporter—2(SGLT2) inhibitors, such as ipragliflozin, remogliflozin etabonate, ertugliflozin, dapagliflozin, and sotagliflozin; SREBP transcription factor inhibitors, such as CAT—2003 and MDV—4463; Stearoyl CoA desaturase—l inhibitors, such as aramchol; Thyroid hormone receptor beta agonists, such as MGL—3 196, MGL—3745, 9; TLR—4 antagonists, such as JKB—lZl; Tyrosine kinase receptor modulators, such as CNX—OZS; GPCR modulators, such as CNX—023; and ation] an None set by Mel.Chan [Annotation] Mel.Chan MigrationNone set by Mel.Chan [Annotation] Mel.Chan Unmarked set by Mel.Chan [Annotation] Mel.Chan None set by Mel.Chan [Annotation] Mel.Chan MigrationNone set by Mel.Chan [Annotation] Mel.Chan Unmarked set by Mel.Chan Nuclear hormone receptor modulators, such as PX—102.

In certain specific embodiments, the one or more additional therapeutic agents are ed from A—4250, AC—3174, acetylsalicylic acid, AK—20, alipogene tiparvovec, aramchol, ARI—3037MO, ASP—8232, bertilimumab, e anhydrous, BI—1467335, EMS—986036, BMS— 986171, EMT-053011, BOT-191, BTT-1023, CAT-2003, cenicriViroc, GER-209, CF- 102, CGS21680, CNX—014, CNX—023, CNX—024, CNX—025, cobiprostone, colesevelam, dapagliflozin, deuterated pioglitazone R—enantiomer, 2,4—dinitrophenol, DRX—065, DS—102, DUR—928, EDP—305, elafibranor OS), emricasan, enalapril, ertugliflozin, evogliptin, F— 351, GKT-831, GNF—S 120, GR—MD—02, hydrochlorothiazide, icosapent ethyl ester, IMM—124—E, INT—767, IONIS—DGATZRX, ipragliflozin, Irbesarta, propagermanium, IVA—337, JKB—121, KB— GE-001, KBP-042, KD-025, M790, M780, M450, metformin, sildenafil, LC-280126, linagliptin, liraglutide, LJN—452, LMB—763, 25, MDV—4463, mercaptamine, MGL—3196, MGL— 3745, MSDC-0602K, zumab, NC-101, ND-L02—s0201, NGM-282, NGM—3l3, NGM— 386, NGM—395, norursodeoxycholic acid, 0—304, obeticholic acid, , olesoxime, PAT— 505, PAT—048, peg—ilodecakin, pioglitazone, pirfenidone, 4, PX20606, PX—102, 3, PX—L493, 28A, PZ—235, RDX—009, remogliflozin etabonate, RG—125 (AZD4076), saroglitazar, semaglutide, simtuzumab, solithromycin, sotagliflozin, statins (atorvastatin, fluvastatin, statin, pravastatin, rosuvastatin, simvastatin), TCM—606F, TEV—45478, tipelukast (MN—001), TLY—012, TRX—3 18, TVB—2640, UD—009, ursodeoxycholic acid, VBY— 376, VBY—825, VK—2809, Vismodegib, volixibat potassium late e (SHP—626), VVP— 100X, 1, WNT—974, and ZGN—839.

EXAMPLES The following examples are ed to demonstrate specific ments of the disclosure. It should be appreciated by those of skill in the art that the techniques disclosed in the examples which follow ent techniques to function well in the practice of the disclosure, and thus can be considered to constitute specific modes for its practice. However, those of skill in the art should, in light of the present disclosure, appreciate that many changes can be made in the specific embodiments which are disclosed and still obtain a like or similar result without departing from the spirit and scope of the disclosure.

[Annotation] Mel.Chan None set by Mel.Chan [Annotation] Mel.Chan MigrationNone set by Mel.Chan [Annotation] Mel.Chan Unmarked set by Mel.Chan [Annotation] Mel.Chan None set by Mel.Chan [Annotation] Mel.Chan MigrationNone set by Mel.Chan [Annotation] Mel.Chan Unmarked set by Mel.Chan The compounds of the present sure can be prepared according to the procedures of the following Schemes and Examples, using appropriate materials and are further exemplified by the following specific examples. Moreover, by utilizing the procedures described herein, in conjunction with ordinary skills in the art, additional compounds of the t disclosure d herein can be readily prepared. The compounds illustrated in the examples are not, however, to be ued as forming the only genus that is considered as the disclosure. The examples further illustrate details for the preparation of the compounds of the present disclosure.

Those skilled in the art will readily understand that known variations of the conditions and processes of the ing preparative procedures can be used to prepare these nds. For sizing compounds which are embodiments described in the present disclosure, inspection of the structure of the nd to be sized will provide the identity of each substituent group. The identity of the final product will generally render apparent the identity of the necessary starting materials by a simple process of inspection, given the examples herein. The instant compounds are generally isolated in the form of their pharmaceutically acceptable salts, such as those described above. In general, compounds described herein are typically stable and isolatable at room temperature and pressure The free bases corresponding to the isolated salts can be generated by neutralization with a suitable base, such as aqueous sodium hydrogen carbonate, sodium carbonate, sodium hydroxide and potassium hydroxide, and extraction of the liberated amine— free base into an c solvent, followed by evaporation. The amine—free base, isolated in this , can be further converted into another ceutically acceptable salt by dissolution in an c solvent, followed by addition of the appropriate acid and subsequent evaporation, itation or crystallization. The carboxylic free acids corresponding to the isolated salts can be generated by neutralization with a suitable acid, such as aqueous hydrochloric acid, sodium hydrogen sulfate, sodium dihydrogen phosphate, and extraction of the liberated ylic—free acid into an organic t, followed by evaporation. The carboxylic acid, isolated in this manner, can be further converted into another pharmaceutically acceptable salt by ution in an organic solvent, followed by addition of the appropriate base and subsequent evaporation, precipitation or crystallization.

[Annotation] an None set by an [Annotation] Mel.Chan MigrationNone set by Mel.Chan [Annotation] Mel.Chan ed set by Mel.Chan [Annotation] Mel.Chan None set by Mel.Chan [Annotation] Mel.Chan MigrationNone set by Mel.Chan [Annotation] Mel.Chan ed set by Mel.Chan An illustration of the preparation of compounds of the present disclosure is shown below. Unless otherwise indicated in the schemes, the variables have the same meaning as described above. The examples presented below are intended to illustrate ular embodiments of the disclosure. Suitable starting materials, building blocks and reagents employed in the synthesis as described below are commercially available from Sigma—Aldrich or Acros Organics, for example, or can be routinely prepared by procedures described in the literature, for example in "March's ed Organic Chemistry: Reactions, Mechanisms, and Structure", 5th Edition; John Wiley & Sons or T. Eicher, S. Hauptmann "The Chemistry of Heterocycles; Structures, Reactions, Synthesis and Application", 2nd edition, Wiley—VCH 2003; Fieser et al. “Fiesers’ Reagents for organic Synthesis” John Wiley & Sons 2000.

General Synthetic Scheme Compounds of Formula (I) wherein Y is N can be synthesized according to the following general synthetic .

X\/z R2 OH OH 2 0,0 R + PG—N —> \/Z HA (B) (c) F HN R2 OH _, Q’O\/z —’ A-N R2 I ’0 ection A—X R4 \/Z R3 / R4 3 F R (D) (E) F In the general synthetic scheme above, X is a leaving group, PG is a protecting group, and the remaining les are as ed herein. A compound of formula (C) can be prepared by reacting a compound of formula (A) with a compound of formula (B) in the ce of a base to form a compound of formula (C). A compound of formula (D) is formed from a compound of formula (C) under appropriate deprotection conditions. A nd of formula (D) can be combined with a compound of formula (E) in the presence of a base to give a compound of Formula (I).

[Annotation] Mel.Chan None set by Mel.Chan [Annotation] Mel.Chan MigrationNone set by Mel.Chan [Annotation] Mel.Chan ed set by Mel.Chan [Annotation] Mel.Chan None set by Mel.Chan [Annotation] Mel.Chan MigrationNone set by Mel.Chan [Annotation] Mel.Chan Unmarked set by Mel.Chan Appropriate compounds of structure (A) and (B) can be prepared according to the specific methods described in the following Examples or by methods known in the art. In some embodiments, X is halo. In some embodiments, PG is BOC.

General Synthesis 1 NC Br OH \\ #:7/ + HN/j \ /N I Step 1 / N Step 2 *0 OTBS NC N \\ NC W l + BKJE;:]/ N ——————————>- \\ 0 /N I CI Step3 /N 1b 1c 1d Step4 NC NW \ Cl Step1: ydr0xyazetidinyl)isonic0tin0nitrile (1a) Potassium carbonate (4.6 g, 33 mmol) was added to 2—chloro—4—pyridinecarbonitrile (2.0 g, 14.4 mmol) and oxyazetidine hydrochloride (1.7 g, 16 mmol) in NMP (12 mL) at room ature, and the mixture was heated to 80 °C for 2 hrs in a sealed tube. The mixture was cooled to room temperature, treated with H20 and ted with EtOAc. The organic layers, were washed with brine, dried with NaZSO4 and concentrated. Purification by chromatography (ISCO 24 g silica column) using a gradient 1:1 hexanes/ EtOAc — 100% EtOAc gave 2—(3— hydroxyazetidin— 1—yl)isonicotinonitrile (la).

[Annotation] Mel.Chan None set by Mel.Chan [Annotation] Mel.Chan MigrationNone set by Mel.Chan [Annotation] Mel.Chan Unmarked set by Mel.Chan [Annotation] Mel.Chan None set by an [Annotation] Mel.Chan MigrationNone set by Mel.Chan [Annotation] Mel.Chan Unmarked set by Mel.Chan Step 2: 2-(3-0xoazetidinyl)is0nic0tin0nitrile (1b) N—methylmorpholine (1.9 g, 16 mmol) then tetrapropylammonium perruthenate (190 mg, 0.5 mmol) were added to 2—(3—hydroxyazetidin—1—yl)isonicotinonitrile (1.9 g, 10.7 mmol) in CH2Cl2 (200 mL) with molecular sieves (1 g, ted powdered, 4 A) at room temperature.

After 20 minutes with vigorous stirring, the mixture was filtered through a pad of Celite and concentrated. Purification by chromatography (ISCO 24 g silica column) using a gradient 100% s — 1:3 s/EtOAc gave 2—(3 —oxoazetidin—1—yl)isonicotinonitrile (1b).

Synthesis of 1c: (4-br0m0chlorophenoxy)(tert-butyl)dimethylsilane (1c) To the on of 4—bromo—3—chlorophenol (250 g, 1.21 mol) and TBSCl (272 g, 1.81 mol) in DMF (2.0 L) was added imidazole (164 g, 2.41 mol). Then the reaction was stirred at 30 °C for 12 h. The reaction mixture was poured into H20 (3 L) and extracted with EtOAc (2 L) twice. The combined organic layers were washed with H20 (1 L) and brine (1 L), dried over , filtered and concentrated in vacuo. Purification by silica gel chromatography eluted with petroleum ether gave (4—bromo—3—chlorophenoxy)(tert—butyl)dimethylsilane (1c).

Step 3: 2-(3-(4-((tert-Butyldimethylsilyl)0xy)chlor0phenyl)hydr0xyazetidin yl)is0nic0tin0nitrile (1d) Isopropylmagnesium chloride lithium chloride complex (1.3 ml, 1.7 mmol, 1.5 M in THF) was added dropwise to (4—bromo—3—chlorophenoxy)(tert—butyl)dimethylsilane (1c, 370 mg, 1.15 mmol) in THF (0.9 ml) at room temperature. After 3 h, the reaction was cooled to 0 °C and treated with 2—(3 —oxoazetidin—1—yl)isonicotinonitrile (199 mg, 1.15 mmol) in one portion as a solid. After 1 h, the reaction was quenched with H20 and Et0Ac. The organic layer was washed with brine, dried with Na2S04 and concentrated. Purification by chromatography (ISCO 4 g silica ) using a nt 100% hexanes —1:3 hexanes/EtOAc gave 2—(3—(4—((tert— butyldimethylsilyl)oxy)—2—chlorophenyl)—3—hydroxyazetidin—1—yl)isonicotinonitrile (1d).

Step 4: 2-Chlor0hydr0xyphenyl)hydr0xyazetidinyl)isonic0tin0nitrile (1e) To a solution of 2—(3—(4—((tert—butyldimethylsilyl)oxy)—2—chlorophenyl)—3— hydroxyazetidin—1—yl)isonicotinonitrile (1d) (180 mg, 0.43 mmol) in 2—MeTHF (4 mL) was [Annotation] Mel.Chan None set by Mel.Chan [Annotation] Mel.Chan MigrationNone set by Mel.Chan [Annotation] Mel.Chan ed set by Mel.Chan [Annotation] Mel.Chan None set by Mel.Chan [Annotation] Mel.Chan MigrationNone set by Mel.Chan ation] Mel.Chan Unmarked set by Mel.Chan added 1 M TBAF solution in THF (0.6 mL, 0.59 mmol) at room temperature. After 30 minutes, the mixture was quenched with water, extracted with EtOAc. The organic phase was washed with brine (10 mL), dried with NaZSO4, and concentrate to give 2—(3—(2—chloro—4— hydroxyphenyl)—3—hydroxyazetidin— sonicotinonitrile (1e), which was used without further purification.

General Synthesis 2 OH (PH [11\ 0 0 o H H N \ CI \,o / q CI CI CI CI CI CI W0“ ' ’ ’ 8| CI Step 1 Step 2 Step 3 F F F 2a 2b 26 F 2d HO / —> CI CI Step 4 Step 1: 2,6-dichlor0fluorobenzaldehyde 0Xime (2b) A suspension of 2,6—dichloro—4—fluorobenzaldehyde (6.0 g, 31.2 mmol), NHZOH-HCl (4.3g, 62.4 mmol), N32C03 (8.3g, 78.7 mmol) in ethanol—water (50 ml, 5:1) was stirred at room ature for 3 h. The reaction was condensed under vacuum and the residue was treated with water followed by extraction with ethyl acetate. The ethyl e layer was washed with brine, dried over NaZSO4, and concentrated to afford 2,6—dichloro—4—fluorobenzaldehyde oxime (2b).

Step 2: chlor0flu0r0-N-hydroxybenzimidoyl chloride (2c) To a solution of 2,6—dichloro—4—fluorobenzaldehyde oxime (2b, 5.5g, 26.7mmol) in DMF (10 mL) was added N—chlorosuccinimide (4.3 g, 32.0 mmol). The reaction was stirred at RT for l h. The mixture quenched with H20 and extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous NaZSO4, ed and concentrated to give [Annotation] Mel.Chan None set by Mel.Chan [Annotation] Mel.Chan MigrationNone set by Mel.Chan [Annotation] Mel.Chan Unmarked set by Mel.Chan [Annotation] an None set by an [Annotation] Mel.Chan MigrationNone set by Mel.Chan [Annotation] Mel.Chan Unmarked set by Mel.Chan the 2,6—dichloro—4—fluoro—N—hydroxybenzimidoyl chloride (2c) that was used without further purification in the next step.

Step 3: ethyl 5-cyclopr0pyl(2,6-dichlor0flu0r0phenyl)is0xazolecarb0xylate (2d) To a solution of 3—cyclopropyl—3—oxo—propionic acid ethyl ester (5.0g, 32.0mmol) in 30 mL THF was added Et3N (10.8g, mol), the reaction was stirred at RT for 30 min, then the reaction mixture from the us step (2,6—dichloro—4—fluoro—N—hydroxybenzimidoyl de (2c)) was added dropwise. The resulting mixture was d for 2 h at RT. The solvent was removed and the e was partitioned with 100 mL water and 50 mL EtOAc. The organic layer was washed with brine, dried, filtered, concentrated and purified by silica gel column (PE/EAle/l) to give ethyl 5—cyclopropyl—3—(2,6—dichloro—4—fluorophenyl)isoxazole—4— carboxylate (2d).

Step 4: (5-cyclopropyl(2,6-dichlor0fluorophenyl)is0xazolyl)methanol (2e) To the solution of ethyl 5—cyclopropyl—3—(2,6—dichloro—4—fluorophenyl)isoxazole—4— carboxylate (2d, 3.4g, 9.3mmol) in THF (30ml) was added LiAlH4 (l l.lml, ll.lmmol, l M in hexane) dropwise at 0 OC. The on was stirred for 30 min. 1.0 ml water was added, then 2.0 g 10% NaOH, 3.0 mL water were added. The mixture was filtered and concentrated. The crude was purified by silica gel column (PE/EA=2/l) to give (5—cyclopropyl—3—(2,6—dichloro—4— fluorophenyl)isoxazol—4—yl)methanol (2e). LCMS (ESI): m/z 302.0 (M+l)+. 1H NMR (500 MHZ, CDC13)I 8 7.22-7.20(d, J=8.5Hz, 2H), 4.42-4.4l(d, J=6.0Hz, 2H), 2.l9-2.l6(m, 1H), 1.41- l.39(m, lH), l.29-l.26(m, 2H), l.l6-l.l3(m, 2H).

[Annotation] an None set by Mel.Chan [Annotation] Mel.Chan MigrationNone set by Mel.Chan [Annotation] Mel.Chan Unmarked set by Mel.Chan [Annotation] Mel.Chan None set by an [Annotation] Mel.Chan MigrationNone set by Mel.Chan ation] an Unmarked set by Mel.Chan General Synthesis 3 O \ N N/ Br Step1 N Ill Step2 O Step3 3a 3b F F o _ OH 0 __ / N \ ' / N —O N m \ Step4 —O N ()0 CI OTBS Cl OH 3c 3d Step 1: methyl 5-flu0r0(3-hydr0xyazetidinyl)nic0tinate (3a) A mixture of azetidin—3—ol hydrochloride (2.8 g, 26 mmol), methyl 6—bromo—5— fluoronicotinate (5.0 g, 21 mmol), and potassium carbonate (7.4 g, 53 mmol) in DMF (100 mL) was heated at 65 °C for 19 hours. The mixture was purified by flash chromatography (silica gel) to provide the desired product. LCMS—ESI+ (m/z): [M+H]+ calcd for C10H12FN203: 227.1; found: 227.0.

Step 2: methyl 5-flu0r0(3-0xoazetidinyl)nic0tinate (3b) A on of methyl 5—fluoro—6—(3—hydroxyazetidin—1—yl)nicotinate (4.7 g, 21 mmol) in dichloromethane (270 mL) was treated with Dess—Martin periodinane (9.7 g, 23 mmol). After 6 hours of stirring at room temperature, an additional portion of Dess—Martin periodinane (1.5 g) was added, and the e was allowed to stir overnight at room temperature. After stirring overnight, the mixture was treated with aqueous sodium thiosulfate on and saturated aqueous sodium hydrogen carbonate solution. The aqueous phase was extracted three times with dichloromethane. The combined extracts were dried over anhydrous magnesium sulfate, filtered, concentrated to s under reduced pressure. The residue was purified twice by flash chromatography (silica gel) to provide the desired material. LCMS—ESI+ (m/z): [M+H2O+H]+ calcd for C10H12FN204: 243.1; found: 243.0.

[Annotation] Mel.Chan None set by an [Annotation] Mel.Chan MigrationNone set by Mel.Chan [Annotation] an Unmarked set by Mel.Chan ation] Mel.Chan None set by Mel.Chan [Annotation] Mel.Chan MigrationNone set by Mel.Chan [Annotation] Mel.Chan Unmarked set by Mel.Chan Step 3: methyl 6-(3—(4-((tert-butyldimethylsilyl)0xy)chlor0phenyl)hydr0xyazetidin yl)flu0r0nic0tinate (3c) A solution of (4—bromo—3—chlorophenoxy)(tert—butyl)dimethylsilane (4.5 g, 14 mmol) in 2—methyltetrahydrofuran (14 mL) was treated with isopropylmagnesium chloride/lithium chloride solution (Aldrich, 1.3M, 11 mL, 15 mmol) dropwise via syringe. The ing mixture was stirred for approximately one hour and then was cooled in an ice—water bath. Methyl 5— fluoro—6—(3 —oxoazetidin—1—yl)nicotinate (2.0 g, 8.9 mmol) was added portions over 2 hours. The mixture was allowed to stand overnight at room temperature. The mixture was ed with 10 % aqueous citric acid solution. The aqueous phase was extracted three times with ethyl acetate. The combined cs were washed once with saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure to provide the crude desired t which was d forward without further purification. LCMS—ESI+ (m/z): [M+H]+ calcd for C22H29ClFN204Si: 467.2; found: 467.1.

Step 4: methyl 6-(3-(2-chlor0hydr0xyphenyl)hydr0xyazetidinyl)flu0r0nic0tinate Crude methyl 6—(3—(4—((tert—butyldimethylsilyl)oxy)—2—chlorophenyl)—3— hydroxyazetidin—1—yl)—5—fluoronicotinate (approximately 10 mmol) was taken up in tetrahydrofuran (70 mL) and treated with tetra—n—butylammonium fluoride solution (Aldrich, 1.0 M in THF, 18 mL, 18 mmol). The mixture was allowed to stand at room temperature until deemed complete by LC/MS and then purified by flash chromatography (silica gel) to provide Intermediate 3d. LCMS—ESI+ (m/z): [M+H]+ calcd for C16H15C1FN204: 353.1; found: 353.0.

[Annotation] Mel.Chan None set by Mel.Chan ation] Mel.Chan MigrationNone set by Mel.Chan [Annotation] Mel.Chan Unmarked set by Mel.Chan [Annotation] Mel.Chan None set by Mel.Chan [Annotation] Mel.Chan MigrationNone set by an [Annotation] Mel.Chan Unmarked set by Mel.Chan Example 1: 5-((4-Br0m0chlor0phen0xy)methyl)cyclopr0pyl(2,6-dichlor0phenyl)- 1H-pyrazole Step 1: 2,4-diflu0r0benzaldehyde 0Xime This compound was synthesized according to the procedure as described in General Synthesis 2, Step 1 starting with 2,4—difluorobenzaldehyde (10 g, 70 mmol).

Step 2: 2,4-diflu0r0-N-hydroxybenzimidoyl chloride HQ CI This compound was sized according to the procedure as described in General Synthesis 2, Step 2 starting with 2,4—difluorobenzaldehyde 0Xime (9 g, 57 mmol).

Step 3: ethyl opropyl(2,4-diflu0r0phenyl)isoxazolecarb0xylate This compound was sized according to the procedure as described in General Synthesis 2, Step 3 starting with 2,4—difluoro—N—hydroxybenzin1idoyl chloride (11 g, 57 mmol).

Step 4: ficyclopropylfi-(2,4-difluorophenyl)isoxazolyl)methanol [Annotation] Mel.Chan None set by Mel.Chan [Annotation] Mel.Chan MigrationNone set by Mel.Chan [Annotation] Mel.Chan Unmarked set by Mel.Chan [Annotation] Mel.Chan None set by Mel.Chan [Annotation] Mel.Chan MigrationNone set by Mel.Chan ation] Mel.Chan Unmarked set by Mel.Chan This compound was sized according to the procedure as bed in General Synthesis 2, Step 4 starting with ethyl 5—cyclopropyl—3—(2,4—difluorophenyl)isoxazole—4— carboxylate (2.2 g, 8 mmol).

Step 5: 4-(Ch10r0methyl)cyclopr0pyl-3—(2,4-difluorophenyl)isoxazole To a solution of (5—cyclopropyl—3—(2,4—difluorophenyl)isoxazol—4—yl)methanol (l 13 mg, 0.45 mmol) in CHzClz (2.3 mL) was added thionyl chloride (164 uL, 2.3 mmol) at 0 OC. The mixture was heated to reflux for 15 min and cooled to room temperature. The mixture was concentrated in vacuo. Additional CHzClz (5 mL) was added and the mixture was concentrated again. This process was ed a third time to remove excess thionyl chloride. The crude e was used in the next step without further purification.

Step 6: 2-(3-(2-Ch10r0((5-cyclopr0pyl(2,4-difluorophenyl)isoxazol yl)meth0xy)phenyl)hydr0xyazetidinyl)isonic0tin0nitrile [Annotation] Mel.Chan None set by Mel.Chan [Annotation] Mel.Chan MigrationNone set by Mel.Chan [Annotation] Mel.Chan Unmarked set by Mel.Chan [Annotation] Mel.Chan None set by Mel.Chan [Annotation] an MigrationNone set by Mel.Chan [Annotation] Mel.Chan Unmarked set by Mel.Chan 4—(chloromethyl)—5—cyclopropyl—3—(2,4—difluorophenyl)isoxazole (113 mg, 0.45 mmol), 2—(3—(2—chloro—4—hydroxyphenyl)—3—hydroxyazetidin—1—yl)isonicotinonitrile (Intermediate 1e) (149 mg, 0.5 mmol) and K2CO3 (124 mg, 0.9 mmol) were combined in anhydrous DMF (2.3 mL) at room ature. The mixture was heated to 65 0C under nitrogen. After 2 h, the solution was cooled to room ature, quenched with H20 and extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous NaZSO4, filtered and concentrated. Purification by chromatography: ISCO (12g silica column) using a gradient of 100% CHzClz — 3:1 CHzClz / ed 60:35:5 CHzClzzEtzOzMeOH gave the title compound.

Step 7: 2-(3-(2-chlor0((5-cyclopropyl(2,4-difluorophenyl)isoxazol—4- yl)meth0xy)phenyl)hydr0xyazetidinyl)isonic0tinic acid (Example 1) 10 M aqueous sodium ide (0.67 ml) was added to 2—(3—(2—chloro—4—((5— cyclopropyl—3—(2,4—difluorophenyl)isoxazol—4—yl)methoxy)phenyl)—3—hydroxyazetidin— 1 — yl)isonicotinonitrile (210 mg, 0.39 mmol) in ethanol (2 mL) and H20 (2 mL) at room temperature and the mixture was heated at 60 °C for 90 minutes in a sealed tube. The mixture was cooled to room temperature and adjusted pH to about 5 with 1 M HCl which caused a itate to fall out of solution. The solution was filtered and the solid was rinsed with EtzO and dried in vacuo to give 2—(3—(2—chloro—4—((5—cyclopropyl—3—(2,4—difluorophenyl)isoxazol—4— yl)methoxy)phenyl)—3—hydroxyazetidin—1—yl)isonicotinic acid (Example 1). 1H NMR (300 MHz, 6)1H NMR (300 MHz, DMSO-d6) 8 13.41 (s, 1H), 8.19 (dd, J: 5.2, 0.8 Hz, 1H), 7.59 (td, J: 8.5, 6.5 Hz, 1H), 7.49 — 7.34 (m, 2H), 7.28 — 7.15 (m, 1H), 7.05 — 6.96 (m, 2H), 6.88 — 6.74 (m, 2H), 6.20 (s, 1H), 5.00 (s, 2H), 4.47 (d, J: 9.3 Hz, 2H), 4.18 (d, J: 9.2 Hz, 2H), 2.40 (tt, J: 8.3, 5.3 Hz, 1H), 1.20 — 1.00 (m, 4H). MS (ESI+) (m/z) 554.0 (M + H).

[Annotation] Mel.Chan None set by Mel.Chan [Annotation] Mel.Chan MigrationNone set by Mel.Chan [Annotation] Mel.Chan Unmarked set by an [Annotation] Mel.Chan None set by Mel.Chan ation] Mel.Chan MigrationNone set by Mel.Chan [Annotation] Mel.Chan Unmarked set by Mel.Chan Example 2: 2-(3-(2-ch10r0((5-cyclopropyl(2,6-dichlor0fluorophenyl)is0xazol yl)meth0xy)phenyl)hydr0xyazetidinyl)is0nic0tinic acid BocN:>—©~OTBDMS Intermediate A l Step 1 BocN:>—QOH OH 0 0 0 /,l\l //N CI CI BocN O HO //N Step 2 Step 3 Step 4 0' Cl 0' CI Cl CI CI —' F F /o o OH / . HCI O l OH HN o / \ / / \ N o / ‘ N Br / N / N Step 6 0' CI CI 0' Step 5 CI CI F F 0' CI CI Example 2 F Synthesis of ediate A: To a solution of mo—3—chlorophenoxy)(tert—butyl)dimethylsilane (1c, 60 g, 187 mmol) in THF (500 mL) was added dropwise n—BuLi (2.5 M, 75 mL) at —78 °C under N2. The reaction was d at —78 °C for l h. Next a solution of tert—butyl 3—oxoazetidine—l—carboxylate (27 g, 155 mmol) in THF (500 mL) was added dropwise to the mixture at —78 OC. Then the reaction was stirred at 20 °C for 3 h. The reaction mixture was poured into H20 (1 L) and extracted with EtOAc (2 L) three times. The combined organic layers were washed with water (1 L), dried over NaZSO4, filtered and concentrated in vacuo. The crude product was purified by [Annotation] Mel.Chan None set by an [Annotation] Mel.Chan ionNone set by Mel.Chan [Annotation] Mel.Chan ed set by Mel.Chan [Annotation] Mel.Chan None set by Mel.Chan [Annotation] Mel.Chan MigrationNone set by Mel.Chan [Annotation] Mel.Chan Unmarked set by Mel.Chan silica gel chromatography eluted with 10:1 petroleum etherzEtOAc to give 3—(4—((tert butyldimethylsilyl)oxy)—2—chlorophenyl)azetidin—3—ol (Intermediate A).

Step 1: tert-butyl 3-(2-ch10r0hydr0xyphenyl)hydr0xyazetidine-l-carboxylate To a on of tert—butyl 3—(4—((tert—butyldimethylsilyl)oxy)—2—chlorophenyl)—3— hydroxyazetidine—1—carboxylate (Intermediate A, 1.27 g, 3.07 mmol) in THF (50.0 mL) at — °C was added 1M TBAF in THF (3.68 mL, 3.68 mmol) dropwise. The on was stirred for 2 hours and was concentrated to afford tert—butyl 3—(2—chloro—4—hydroxyphenyl)—3— hydroxyazetidine—1—carboxylate, which was used without further purification.

Step 2: 4-(ch10r0methyl)cyclopropyl(2,6-dichloroflu0r0phenyl)isoxazole A solution of (5—cyclopropyl—3—(2,6—dichloro—4—f1uorophenyl)isoxazol—4—yl)methanol (2e); 845 mg, 2.80 mmol) in DCM (28.0 mL) was cooled to 0°C. Thionyl chloride (1.02 mL, 14.0 mmol) was added and the solution was heated at 45 °C for 1 hour. The reaction was concentrated to dryness and used without cation in the next step.

Step 3: tert-butyl 3-(2-ch10r0((5-cyclopr0pyl(2,6-dichlor0flu0r0phenyl)is0xazol yl)meth0xy)phenyl)hydr0xyazetidine-l-carboxylate A on of tert—butyl 3—(2—chloro—4—hydroxyphenyl)—3—hydroxyazetidine—1— carboxylate (922 mg, 3.07 mmol) in DMF (28.0 mL) was added to crude 4—(chloromethyl)—5— cyclopropyl—3—(2,6—dichloro—4—fluorophenyl)isoxazole, followed by the addition of potassium carbonate (773 mg, 5.60 mmol). The mixture was heated at 60 °C for 8 hours. The reaction was concentrated, diluted with water and extracted with EtOAc (3x). The combined organic layers were washed with water, brine, dried over MgSO4, filtered and concentrated. The crude product was purified by silica gel chromatography (DCM/EtzO/MeOH) to afford tert—butyl 3—(2—chloro— cyclopropyl—3—(2,6—dichloro—4—fluorophenyl)isoxazol—4—yl)methoxy)phenyl)—3— yazetidine—1—carboxylate. LCMS—ESI+ (m/z): [(M+H)—BOC]+ calcd 483.04; found 483.04.

[Annotation] Mel.Chan None set by Mel.Chan [Annotation] Mel.Chan MigrationNone set by Mel.Chan [Annotation] Mel.Chan Unmarked set by Mel.Chan [Annotation] Mel.Chan None set by Mel.Chan [Annotation] Mel.Chan MigrationNone set by Mel.Chan [Annotation] Mel.Chan Unmarked set by Mel.Chan Step 4: hlor0((S-cyclopropyl(2,6-dichlor0fluorophenyl)isoxazol yl)meth0xy)phenyl)azetidin01 To a solution of tert—butyl 3—(2—chloro—4—((5—cyclopropyl—3—(2,6—dichloro—4— fluorophenyl)isoxazol—4—yl)methoxy)phenyl)—3—hydroxyazetidine—1—carboxylate (1.52 g, 2.60 mmol) in DCM (130 mL) was added 4 N HCl in 1,4—dioxane (26.0 mL, 104 mmol). The solution was stirred at room temperature for 2.5 hours and was concentrated to s to afford 3—(2—chloro—4—((5—cyclopropyl—3—(2,6—dichloro—4—fluorophenyl)isoxazol—4— yl)methoxy)phenyl)azetidin—3—ol as the hydrochloride salt, which was used without further purification. LCMS—ESI+ (m/z): [M+H]+ calcd 483.04; found 483.03.

Step 5: methyl 2-(3-(2-chlor0((5-cyclopr0pyl(2,6-dichlor0flu0r0phenyl)isoxazol yl)meth0xy)phenyl)hydr0xyazetidinyl)is0nic0tinate A mixture of methyl 2—bromopyridine—4—carboxylate (0.466 g, 2.16 mmol), 3—(2—chloro— 4—((5—cyclopropyl—3—(2,6—dichloro—4—fluorophenyl)isoxazol—4—yl)methoxy)phenyl)azetidin—3—ol as the hydrochloride salt (1.02 g, 1.96 mmol), cesium ate (2.56 g, 7.85 mmol), (i)—BINAP (0.244 g, 0.392 mmol), palladium acetate trimer (88.0 mg, 0.131 mmol) and 1,4—dioxane (40.0 mL) was heated at 85 °C for 18 hours. The reaction was cooled to room temperature, filtered over celite and purified by silica gel chromatography (acetone / hexanes) to afford methyl 2—(3— (2—chloro—4—((5—cyclopropyl—3—(2,6—dichloro—4—fluorophenyl)isoxazol—4—yl)methoxy)phenyl)—3— hydroxyazetidin—1—yl)isonicotinate. LCMS—ESI+ (m/z): [M+H]+ calcd 618.08; found 618.20.

Step 6: 2-(3-(2-ch10r0((5-cyclopropyl(2,6-dichloroflu0r0phenyl)isoxazol h0xy)phenyl)hydr0xyazetidinyl)isonic0tinic acid (Example 2).

To a solution of 2—(3—(2—chloro—4—((5—cyclopropyl—3—(2,6—dichloro—4— fluorophenyl)isoxazol—4—yl)methoxy)phenyl)—3—hydroxyazetidin—1—yl)isonicotinate (617 mg, 0.997 mmol) in THF / water (1:1, 10 mL) was added m ide monohydrate (83.6 mg, 1.99 mmol). The on was stirred for 90 s, concentrated to remove THF and diluted with water. Acetic acid (0.23 mL, 3.99 mmol) was added while stirring which resulted in the precipitation of solids. The solids were filtered, washed with water, IPA and ether, and dried under vacuum to afford 2—(3—(2—chloro—4—((5—cyclopropyl—3—(2,6—dichloro—4— [Annotation] an None set by Mel.Chan [Annotation] Mel.Chan MigrationNone set by Mel.Chan [Annotation] Mel.Chan Unmarked set by Mel.Chan [Annotation] Mel.Chan None set by Mel.Chan [Annotation] Mel.Chan ionNone set by an [Annotation] Mel.Chan Unmarked set by Mel.Chan fluorophenyl)is0xazol—4—yl)meth0xy)pheny1)—3—hydr0xyazetidin—1—y1)is0nicotinic acid (Example 2). LCMS-ESI+ (m/z): [M+H]+ calcd 604.06; found 604.15. 1H NMR (300 MHz, DMSO—d6) 5 13.47 (br s, 1H), 8.18 (dd, J: 5.3, 0.8 Hz, 1H), 7.69 (d, J: 8.5 Hz, 2H), 7.37 (d, J: 8.7 Hz, 1H), 7.02 (dd, J = 5.3, 1.4 Hz, 1H), 6.93 (d, J: 2.6 Hz, 1H), 6.86 (br s, 1H), 6.75 (dd, J: 8.6, 2.6 Hz, 1H), 6.20 (s, 1H), 4.91 (s, 2H), 4.49 (d, J = 9.3 Hz, 2H), 4.19 (d, J = 9.3 Hz, 2H), 2.46 — 2.37 (m, 1H), 1.23 — 1.04 (m, 4H).

Example 3: 6-(3-(2-ch10r0((5-cyclopropyl(2,6-dichlor0fluorophenyl)isoxazol yl)meth0xy)phenyl)hydr0xyazetidinyl)flu0r0nic0tinic acid Boch—QOTBDMS Intermediate A lStep 1 O BocN:>—©\ O / ONCI / A10 BocN / A10 Step 2 Step 3 Step 4 \ /_F\ Q Step 5 M00169: MN/ N Example 3 F Steps 1—4 were as described for the synthesis of Example 2.

[Annotation] Mel.Chan None set by Mel.Chan [Annotation] an MigrationNone set by Mel.Chan [Annotation] Mel.Chan Unmarked set by an [Annotation] Mel.Chan None set by an [Annotation] Mel.Chan MigrationNone set by Mel.Chan [Annotation] Mel.Chan Unmarked set by Mel.Chan Step 5: methyl 6-(3-(2-chloro((5-cyclopropyl(2,6-dichlor0fluorophenyl)is0xazol yl)meth0xy)phenyl)hydr0xyazetidinyl)flu0r0nic0tinate A mixture of methyl 6—chloro—5—fluoropyridine (235 mg, 1.24 mmol), 3—(2—chloro—4—((5— cyclopropyl—3—(2,6—dichloro—4—fluorophenyl)isoxazol—4—yl)methoxy)phenyl)azetidin—3—ol as the hydrochloride salt (495 mg, 0.952 mmol) and potassium carbonate (1.05 g, 7.61 mmol) in DMF (30.0 mL) was heated at 60 °C for 1 hour. The reaction was concentrated, diluted with water and extracted with EtOAc (3x). The combined organic layers were washed with brine, dried over MgSO4, filtered and concentrated. The crude mixture was purified by silica gel chromatography (DCM / EtzO / MeOH) to afford methyl 6—(3—(2—chloro—4—((5—cyclopropyl—3—(2,6—dichloro—4— fluorophenyl)isoxazol—4—yl)methoxy)phenyl)—3—hydroxyazetidin—1—yl)—5—fluoronicotinate.

LCMS—ESI+ (m/z): [M+H]+ calcd 636.07; found .

Step 6: 6-(3-(2-chlor0((5-cyclopr0pyl(2,6-dichlor0fluorophenyl)isoxazol yl)meth0xy)phenyl)hydr0xyazetidinyl)flu0r0nic0tinic acid (Example 3) To a on of methyl 2—chloro—4—((5—cyclopropyl—3—(2,6—dichloro—4— fluorophenyl)isoxazol—4—yl)methoxy)phenyl)—3—hydroxyazetidin—1—yl)—5—fluoronicotinate (364 mg, 0.571 mmol) in THF / water (1:1, 20.0 mL) was added lithium hydroxide monohydrate (41.3 mg, 0.984 mmol). The solution was stirred for 18 hours, concentrated to remove THF and diluted with water (10.0 mL). The pH was adjusted to 3 using 1N HCl. The solids were filtered, washed with water, dissolved in ACN / water and lyophilized to afford 6—(3—(2—chloro—4—((5— cyclopropyl—3—(2,6—dichloro—4—fluorophenyl)isoxazol—4—yl)methoxy)phenyl)—3—hydroxyazetidin— —fluoronicotinic acid (Example 3). LCMS—ESI+ (m/z): [M+H]+ calcd 622.05; found 622.12. 1H NMR (400 MHz, DMSO-d6) 8 12.84 (bs, 1H), 8.44 (t, J = 1.7 Hz, 1H), 7.79 — 7.63 (m, 3H), 7.39 (d, J = 8.7 Hz, 1H), 6.95 (d, J = 2.5 Hz, 1H), 6.77 (dd, J = 8.6, 2.6 Hz, 1H), 6.28 (s, 1H), 4.93 (s, 2H), 4.70 (d, J = 9.8 Hz, 2H), 4.34 (d, J = 9.5 Hz, 2H), 2.50-2.43 (m, 1H), 1.22 — 1.08 (m, 4H).

[Annotation] Mel.Chan None set by Mel.Chan ation] an MigrationNone set by Mel.Chan [Annotation] Mel.Chan Unmarked set by Mel.Chan [Annotation] Mel.Chan None set by an [Annotation] Mel.Chan MigrationNone set by Mel.Chan [Annotation] Mel.Chan Unmarked set by Mel.Chan Intermediate 4: (3-(2,6-dichlor0flu0r0pheny1)methylis0xazolyl)methanol HO //N CI Cl Following General Synthesis 2, beginning with 2,6—dichloro—4—fluorobenzaldehyde in Step 1 and using ethyl acetoacetate in Step 3, (3—(2,6—dichloro—4—fluorophenyl)—5— methylisoxazol—4—yl)methanol (Intermediate 4) was synthesized. LCMS—ESI+ (m/z): [M+H]+ calcd 276.00; found .

Example 4: Preparation of 6-(3-(2-ch10r0((3-(2,6-dich10r0flu0r0pheny1) methylis0xazolyl)meth0xy)phenyl)hydr0xyazetidinyl)flu0r0nic0tinic acid 0%N OH o x,/ HO _N a m 0 Following the general procedure described for Example 3, using intermediate 4, 6—(3— (2—chloro—4—((3—(2,6—dichloro—4—fluorophenyl)—5—methylisoxazol—4—yl)methoxy)phenyl)—3— hydroxyazetidin—l—yl)—5—fluoronicotinic acid was synthesized. SI+ (m/z): [M+H]+ calcd 596.04; found 596.12. 1H NMR (400 MHz, DMSO-d6) 8 12.82 (bs, 1H), 8.44 (t, J: 1.6 Hz, 1H), 7.74 — 7.66 (m, 3H), 7.39 (d, J: 8.7 Hz, 1H), 6.90 (d, J: 2.6 Hz, 1H), 6.75 (dd, J: 8.7, 2.6 Hz, 1H), 6.26 (s, 1H), 4.87 (s, 2H), 4.69 (d, J = 9.8 Hz, 2H), 4.34 (d, J: 9.8 Hz, 2H), 2.57 (s, [Annotation] Mel.Chan None set by Mel.Chan [Annotation] Mel.Chan MigrationNone set by Mel.Chan [Annotation] Mel.Chan Unmarked set by Mel.Chan [Annotation] Mel.Chan None set by Mel.Chan [Annotation] Mel.Chan MigrationNone set by Mel.Chan [Annotation] Mel.Chan ed set by Mel.Chan Example 5: 2-chlor0((4-cyclopr0pyl(2,6-dichlor0fluorophenyl)-1H-pyrazol yl)meth0xy)phenyl)hydr0xyazetidinyl)flu0r0nic0tinic acid Step1 0' 0' Step2 3020 /N’N F |:C| HOfiI/N\ 0' Step3 Step4 lN,N\ CI CI CI CI F F / \ CI CI Me020 /N F W0 ”N Step6 N / \ CI CI H020 /N Example5 Step 1: (2,6-dichlor0fluorophenyl)hydrazine hydrochloride To a — 5 °C solution (internal temperature, wet ice/acetone bath) of 2,6—dichloro—4— fluoroaniline (3.0 g, 17 mmol) in 37 % hydrochloric acid (30 mL) and trifluoroacetic acid (20 mL) was added dropwise an aqueous solution of sodium nitrite (1.4 g, 20 mmol, 6 mL water).

The reaction was stirred for 90 minutes, then a solution of stannous chloride dihydrate (5.6 g, 25 mmol) in 37 % hloric acid (16 mL) was added over 15 minutes, keeping the internal temperature 3 2 OC. The mixture was d ght at room temperature. The mixture was [Annotation] Mel.Chan None set by Mel.Chan ation] Mel.Chan MigrationNone set by Mel.Chan [Annotation] Mel.Chan Unmarked set by Mel.Chan [Annotation] Mel.Chan None set by Mel.Chan [Annotation] Mel.Chan MigrationNone set by Mel.Chan [Annotation] Mel.Chan Unmarked set by Mel.Chan filtered and the collected solid was washed with isopropyl alcohol and dried under house vacuum to provide the title compound. LCMS—ESI+ (m/z): [M+H]+ calcd for C6H6C12FN2: 195.0; found: 194.9.

Step 2: ethyl 4-cyc10pr0pyl(2,6-dichlor0flu0r0phenyl)-1H-pyrazole-S-carboxylate N,N—Dimethylformamide dimethyl acetal (2.7 mL, 20 mmol) was added to ethyl 3— cyclopropyl—2—oxopropanoate (Synnovator, 1.6 g, 10 mmol) and stirred overnight at room temperature. The mixture was then concentrated to dryness under d pressure. To the residue was added successively ethanol (40 mL), (2,6—dichloro—4—fluorophenyl)hydrazine hydrochloride (2.6 g, 11 mmol), and 37 % hydrochloric acid (150 uL). The reaction was d at room temperature for four hours, followed by 2 days of heating at reflux. The cooled mixture was purified by flash chromatography a gel) to provide the title compound. LCMS—ESI+ (m/z): [M+H]+ calcd for C15H14C12FN202: 343.0; found: 343.1.

Step 3: (4-cyc10pr0pyl(2,6-dichlor0flu0r0phenyl)-1H-pyraz01yl)methanol A solution of ethyl 4—cyclopropyl—1—(2,6—dichloro—4—fluorophenyl)—1H—pyrazole—5— carboxylate (1.5 g, 4.4 mmol) in tetrahydrofuran (50 mL) was cooled to between —12 and —10 0C. A solution of lithium aluminum hydride ch, 2 M in tetrahydrofuran, 2.6 mL, 5.2 mmol) was added dropwise. The mixture was allowed to stir for 35 minutes. The mixture was ed r ure) and purified by flash chromatography (silica gel) to e the title compound. SI+ (m/z): [M+H]+ calcd for C13H12C12FN20: 301.0; found: 301.1.

Step 4: 5-(chloromethyl)cyc10pr0pyl(2,6-dichlor0flu0r0phenyl)-1H-pyrazole Thionyl chloride (110 uL, 1.5 mmol) was added to a solution of (4—cyclopropyl—1—(2,6— dichloro—4—fluorophenyl)—1H—pyrazol—5—yl)methanol (0.15 g, 0.51 mmol) in dichloromethane (2.5 mL). The mixture was heated at 60 °C for 40 minutes and then concentrated under reduced pressure to provide the crude desired t, which was carried forward without further purification. LCMS—ESI+ (m/z): [M+H]+ calcd for C13H11C13FN2: 319.0; found: 319.1.

[Annotation] Mel.Chan None set by an [Annotation] Mel.Chan MigrationNone set by Mel.Chan [Annotation] Mel.Chan Unmarked set by Mel.Chan [Annotation] Mel.Chan None set by Mel.Chan [Annotation] Mel.Chan ionNone set by Mel.Chan [Annotation] Mel.Chan Unmarked set by an Step 5: methyl 6-(3-(2-chloro((4-cyclopr0pyl(2,6-dichlor0flu0r0phenyl)-1H- pyrazol-S-yl)meth0xy)phenyl)hydr0xyazetidinyl)flu0r0nic0tinate A solution of 4—(chloromethyl)—5—cyclopropyl—3—(2,6—dichloro—4—fluorophenyl)isoxazole (0.16 g, 0.51 mmol) in DMF (3 mL) was treated with methyl 6—(3—(2—chloro—4—hydroxyphenyl)— 3—hydroxyazetidin—1—yl)—5—fluoronicotinate (0.20 g, 0.56 mmol), sodium iodide (0.13 g, 0.86 mmol), and potassium carbonate (0.14 g, 1.0 mmol). The mixture was heated 65 °C overnight and then purified by flash chromatography a gel) to provide the desired material. LCMS— ESI+ (m/z): [M+H]+ calcd for C29H24C13F2N4O4: 635.1; found: 635.2.

Step 6: 6-(3-(2-chlor0((4-cyclopr0pyl(2,6-dichlor0flu0r0phenyl)-1H-pyrazol yl)meth0xy)phenyl)hydr0xyazetidinyl)flu0r0nic0tinic acid le 5) A mixture of methyl 2—chloro—4—((4—cyclopropyl—1—(2,6—dichloro—4—fluorophenyl)— 1H—pyrazol—5—yl)methoxy)phenyl)—3—hydroxyazetidin—1—yl)—5—fluoronicotinate (0.35 g, 0.39 mmol) and lithium hydroxide monohydrate (49 mg, 1.2 mmol) were taken up in 1:1 aqueous tetrahydrofuran (6 mL), and the mixture was d at room temperature. Upon completion, the mixture was acidified with glacial acetic acid and concentrated. The residue was purified by flash chromatography (silica gel) to provide 6—(3—(2—chloro—4—((4—cyclopropyl—1—(2,6—dichloro—4— fluorophenyl)—1H—pyrazol—5—yl)methoxy)phenyl)—3—hydroxyazetidin—1—yl)—5—fluoronicotinic acid (Example 5). LCMS—ESI+ (m/z): [M+H]+ calcd for C23H22C13F2N4O4: 621.1; found: 621.2. 1H NMR (400 MHz, DMSO-d6) 8 12.85 (s, 1H), 8.44 (t, J = 1.6 Hz, 1H), 7.76 (d, J = 8.3 Hz, 2H), 7.70 (dd, J = 12.7, 1.7 Hz, 1H), 7.49 (s, 1H), 7.40 (d, J = 8.7 Hz, 1H), 7.00 (d, J = 2.6 Hz, 1H), 6.80 (dd, J = 8.7, 2.6 Hz, 1H), 6.28 (s, 1H), 5.01 (s, 2H), 4.69 (d, J = 9.8 Hz, 2H), 4.34 (d, J = 9.6 Hz, 2H), 1.89 (tt, J = 8.4, 5.1 Hz, 1H), 0.93 (m, 2H), 0.65 (m, 2H).

[Annotation] Mel.Chan None set by Mel.Chan [Annotation] Mel.Chan MigrationNone set by Mel.Chan [Annotation] Mel.Chan Unmarked set by Mel.Chan [Annotation] Mel.Chan None set by Mel.Chan [Annotation] Mel.Chan ionNone set by Mel.Chan [Annotation] Mel.Chan Unmarked set by Mel.Chan Example 6: 5-((1S,3S)(2-ch10r0((5-cyclopr0pyl(2,6-dichlor0 fluorophenyl)isoxazolyl)meth0xy)phenyl)hydr0xycyc10butyl)meth0xynic0tinic acid MeOZCWN o ediate 5 Steps1-9 o o l 0 on /,N Step10 Br/Qo /,N Step11 /,N MeOZC W0 CI CI CI CI m CI CI CI CI F F F o / Q Step12 /N H020 W —> U CI CI Synthesis of ediate 5 Step 1: m0methoxypyridin-3—yl)methanol Br Br CH20H \ COzMe \ I I \o N/ \O N To a solution of methyl 5—bromo—6—methoxynicotinate (52.8 g, 215.0 mmol) in THF (500 mL) was added DIBAL—H (1.0 M, in toluene) (344 ml, 344 mmol) at —20°C. Then the mixture was stirred at RT for 2 h. The mixture was quenched with sat. NH4Cl and diluted with ethyl e. The organic portion was washed with brine, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure and purified by flash chromatography on silica gel (PE/EtOAc = 4/1) to give the title compound.

[Annotation] Mel.Chan None set by Mel.Chan [Annotation] an MigrationNone set by an [Annotation] Mel.Chan Unmarked set by Mel.Chan [Annotation] Mel.Chan None set by Mel.Chan [Annotation] an MigrationNone set by Mel.Chan [Annotation] Mel.Chan Unmarked set by an Step 2: 3-br0m0(((tert-butyldimethylsilyl)0xy)methyl)meth0xypyridine Br CHZOH B r I\ TBDSCI TBDMSO |\ \ON/ NO// To a solution of (5—bromo—6—methoxypyridin—3—yl)methanol (42.2 g, 194 mmol) and tert—butyldimethylsilyl de (35.0 g, 232mmol) in CHzClz (500 ml) was added imidazole (19.8 g, 291 mmol). The mixture was stirred at RT for 8 h. The mixture was quenched with water and diluted with ethyl acetate. The organic portion was washed with brine, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure and purified by flash chromatography on silica gel (PE/EtOAc = 10/1) to give the title compound.

Step 3: 3-(benzy10xy)(5-(((tert-butyldimethylsilyl)0xy)methyl)meth0xypyridin yl)cyclobutanol Br goB TBDMSO \ ” | + :0 _,TBDMSO N o 3—bromo—5—(((tert—butyldimethylsilyl)oxy)methyl)—2—methoxypyridine (61.2 g, 184 mmol) was ved in absolute THF (500 mL) under argon,) a 1.6 M on of n—butyllithium (138 mL, 221 mmol) in THF was added dropwise at —78°C. The mixture was stirred for 30 min at the same temperature. A solution of 3—(benzyloxy)cyclobutan—l—one (35.7 g, 202mmol) in THF (100 mL) was then added at —780 C, and the mixture was subsequently stirred at this ature for 30 min. Saturated aqueous ammonium chloride was subsequently added and the mixture was extracted with ethyl acetate. The organic phase was washed with water and saturated sodium chloride solution, dried over magnesium sulfate and filtered. After removal of the solvent on a rotary evaporator, the residue was purified by flash chromatography on silica gel OAc = 2/ 1) to give the title compound.

[Annotation] Mel.Chan None set by Mel.Chan [Annotation] Mel.Chan ionNone set by Mel.Chan [Annotation] Mel.Chan Unmarked set by Mel.Chan [Annotation] Mel.Chan None set by Mel.Chan [Annotation] Mel.Chan MigrationNone set by Mel.Chan [Annotation] Mel.Chan Unmarked set by Mel.Chan Step 4: 3-(benzyloxy)(5-(hydr0xymethyl)methoxypyridinyl)cyclobutan01 TBDMSO \ I —>HO \ / | N/ O NO// To a solution of 3—(benzyloxy)—l—(5—(((tert—butyldimethylsilyl)oxy)methyl)—2— methoxypyridin—3—yl)cyclobutan—l—ol (31.6 g, 73.6mmol) in THF (300mL) was added TBAF (88 mL, 1 mol/L). The mixture was d at rt for 6 hours, then poured into water and extracted with ethyl e. The organic phase was washed with water and saturated sodium chloride solution, dried over magnesium sulfate and filtered. The c phase was concentrated to give the title compound.

Step 5: 5-(3-(benzy10xy)hydr0xycyc10butyl)meth0xynic0tinic acid O OBn HO HO HO \ —> HO \ | | N 0/ N/ 0/ To a solution of 3—(benzyloxy)—l—(5—(hydroxymethyl)—2—methoxypyridin—3— yl)cyclobutan—l—ol (23.2 g, 73.6 mmol) in MeCN (300 mL) and H20 (100 mL) was added iodobenzene diacetate (64.4 g, 200mmol) and TEMPO (7.86g, 50 mmol), and the solution was stirred at room temperature for 2 hrs. The mixture was quenched with sat. sodium bicarbonate solution and diluted with ethyl acetate. The organic portion was washed with brine, dried over anhydrous sodium e, filtered; the c phase was concentrated to give the title compound.

Step 6: methyl 5-(3-(benzy10xy)hydr0xycyclobutyl) methoxynicotinate O OBn O OBn HO HO HO \ MeO \ I —» I / / N o/ N o/ To a solution of 5—(3—(benzyloxy)—l—hydroxycyclobutyl)—6—methoxynicotinic acid (17.5g, crude) in THF/MeOH (200/50 mL) was added TMSNZCHg (50 mL, 20 mol/L) at 0 0C.

[Annotation] Mel.Chan None set by Mel.Chan [Annotation] Mel.Chan MigrationNone set by Mel.Chan [Annotation] Mel.Chan Unmarked set by Mel.Chan [Annotation] Mel.Chan None set by Mel.Chan [Annotation] Mel.Chan MigrationNone set by Mel.Chan [Annotation] Mel.Chan Unmarked set by Mel.Chan The mixture was stirred at room temperature for 3 hours, then poured into water and extracted with ethyl e. The c phase was washed with water and saturated sodium chloride solution, dried over magnesium sulfate and filtered. The filtrate was trated under reduced pressure and purified by flash chromatography on silica gel (PE/EA=10. 1) to give the title Step 7: methyl 5-(3-(benzyloxy)flu0r0cyc10butyl)meth0xynic0tinate o OBn o OBn MeO \ —> I MeO To a cooled solution of methyl benzyloxy)—l—hydroxycyclobutyl)—6— methoxynicotinate (15 .2g, 44.3 mmol) in DCM (200mL) was added DAST (8.0 mL) at —78°C dropwise by syringe. After stirring 5 minutes at —78° C, the reaction was allowed to warm to —20° C. and stirred for 75 minutes, then it was quenched with H20 (100 mL) diluted with EtOAc and the phases were separated. The organic phase was washed with sat. aq. NaHC03 and brine, then dried over MgSO4, filtered, and concentrated. The crude product was purified by chromatography (PE: EtOAc=4: 1) to give the title compound.

Step 8: methyl 5-(3-hydr0xycyc10butyl)meth0xynic0tinate O OBn O OH I —> MeO \ / / N o/ To a solution of methyl benzyloxy)—1—fluorocyclobutyl)—6—methoxynicotinate (12.7 g, 3.68 mmol) in MeOH (200 mL) and formic acid (10 mL) was added Pd black (3.0 g).

The reaction was stirred vigorously under N2. After about 1.5 hrs, additional Pd black was added (1.5 g) and the reaction stirred overnight. The reaction mixture was filtered and concentrated.

The residue was dissolved in EtOAc and washed with sat. N32CO3. The organic phase was dried over MgSO4, filtered and trated to an oily residue. The residue was purified by chromatography (MeOH: CHzClz = 1:20) to give the title compound.

[Annotation] Mel.Chan None set by Mel.Chan [Annotation] Mel.Chan ionNone set by Mel.Chan [Annotation] Mel.Chan Unmarked set by Mel.Chan [Annotation] Mel.Chan None set by Mel.Chan [Annotation] Mel.Chan MigrationNone set by Mel.Chan [Annotation] Mel.Chan Unmarked set by Mel.Chan Step 9: methyl 6-meth0xy(3-0x0cyclobutyl)nic0tinate (Intermediate 5) 0 0H 0 o MeO \ —> MeO \ / I N O/ N/ o/ To a solution of methyl 5—(3—hydroxycyclobuty1)—6—methoxynicotinate (4.0 g, 16.9 mmol) in MeCN (100 mL) and H20 (30 mL) was added iodobenzene ate (16.1 g, 50 mmol) and TEMPO (2.92 g, 18.6 mmol), and the solution was stirred at room temperature for 2 hrs. The mixture was ed with sat. N32CO3 and then diluted with ethyl acetate. The organic n was washed with brine, dried over anhydrous sodium sulfate, filtered, and the organic phase was concentrated and purified by chromatography (PE: EA: 5:1) to give Intermediate 5.

Step 10: 4-((4-br0m0chlor0phen0xy)methyl)cyclopr0pyl(2,6-dichlor0 fluorophenyl)isoxazole A on of crude 4—(chloromethy1)—5—cyclopropy1—3—(2,6—dichloro—4— fluoropheny1)isoxazole (prepared as bed in Example 2, step 2; 0.42 g, 1.3 mmol) in N,N— dimethylformamide (DMF, 6 mL) was treated with 4—bromo—3—chlorophenol (0.27 g, 1.3 mmol), sodium iodide (0.34 g, 2.2 mmol), and potassium carbonate (0.37 g, 2.6 mmol). The mixture was heated at 60 °C for 35 minutes before it was cooled and purified by flash tography (silica gel) to provide the desired material. LCMS—ESI+ (m/z): [M+H]+ calcd for C19H13BrC13FN02: 491.9; found: 492.0.

Step 11: Methyl 5-(3-(2-chlor0((5-cyclopropyl(2,6-dichlor0fluorophenyl)isoxazol- eth0xy)phenyl)hydr0xycyclobutyl)meth0xynic0tinate Under an atmosphere of Argon, a solution of 4—((4—bromo—3—chlorophenoxy)methyl)—5— cyclopropy1—3—(2,6—dichloro—4—f1uoropheny1)isoxazole (0.83 g, 1.7 mmmol) in 2— methyltetrahydrofuran (2 mL) was treated with isopropylmagnesium chloride/lithium chloride solution (Aldrich, 1.3 M in tetrahydrofuran, 1.3 mL, 1.7 mmol) dropwise via syringe. After the passage of four hours, an additional volume of isopropylmagnesium chloride/lithium chloride solution (1.3 mL) was added. In a separate vessel, under an atmosphere of Argon, a solution of methyl 6—methoxy—5—(3—oxocyclobuty1)nicotinate (Intermediate 5), 0.21 g, 0.90 mmol) in [Annotation] an None set by an [Annotation] Mel.Chan MigrationNone set by Mel.Chan [Annotation] Mel.Chan Unmarked set by Mel.Chan [Annotation] Mel.Chan None set by Mel.Chan [Annotation] Mel.Chan MigrationNone set by Mel.Chan [Annotation] Mel.Chan Unmarked set by an tetrahydrofuran (5 mL) was treated with lanthanum (III) chloride/2 lithium chloride solution (Aldrich, 0.6 M in tetrahydrofuran, 1.5 mL, 0.9 mmol). This mixture was stirred for one hour at room temperature before it was cooled in a —8 °C wet ice/acetone bath. The Grignard solution from above was added dropwise to the ketone solution via syringe. The reaction mixture was stirred overnight under an Argon atmosphere. The mixture was quenched with ted aqueous ammonium chloride solution. The aqueous phase was ted three times with ethyl acetate. The ed organics were washed once with saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The crude e was purified by flash chromatography a gel) to provide the title compound. LCMS—ESI+ (m/z): [M+H]+ calcd for C31H27C13FN206: 647.1; found: 647.1.

Step 12: 5-((1S,3S)(2-ch10r0((5-cyclopropyl(2,6-dichlor0fluorophenyl)isoxazol- 4-yl)meth0xy)phenyl)hydr0xycyclobutyl)meth0xynic0tinic acid (Example 6) A mixture of methyl 5—(3—(2—chloro—4—((5—cyclopropyl—3—(2,6—dichloro—4— fluorophenyl)isoxazol—4—yl)methoxy)phenyl)—3—hydroxycyclobutyl)—6—methoxynicotinate (0.26 g, 0.40 mmol) and lithium hydroxide monohydrate (33 mg, 0.79 mmol) were taken up in 1:1 aqueous tetrahydrofuran (10 mL) and stirred overnight at room temperature. The volatiles were mostly removed by under reduced pressure. The aqueous mixture was diluted with water and treated dropwise with 10 % aqueous hydrochloric acid. The resulting mixture was extracted with ethyl acetate three times. The combined organics were washed with saturated aqueous sodium chloride solution (with a small amount of hydrochloric acid added). The combined organics were dried over anhydrous magnesium e, filtered, and concentrated under reduced pressure.

The residue was purified first by flash chromatography a gel) and then by preparative HPLC (acetonitrile/water, TFA). The combined fractions collected by HPLC were neutralized with saturated aqueous sodium hydrogen carbonate solution, saturated with sodium chloride, and ted three times with ethyl acetate. The combined organics were dried over anhydrous magnesium sulfate, filtered, and concentrated. The residue was taken up in ethyl acetate, treated with anhydrous magnesium sulfate, ed, and concentrated. Again the residue was taken up in ethyl e and filtered through a pad of Celite diatomaceous earth. The filtrate was concentrated to provide ,3S)—3—(2—chloro—4—((5—cyclopropyl—3—(2,6—dichloro—4— fluorophenyl)isoxazol—4—yl)methoxy)phenyl)—3—hydroxycyclobutyl)—6—methoxynicotinic acid [Annotation] an None set by Mel.Chan [Annotation] Mel.Chan MigrationNone set by Mel.Chan [Annotation] Mel.Chan Unmarked set by Mel.Chan [Annotation] Mel.Chan None set by Mel.Chan [Annotation] Mel.Chan MigrationNone set by Mel.Chan [Annotation] Mel.Chan Unmarked set by Mel.Chan le 6). LCMS—ESI+ (m/z): [M+H]+ calcd for C13FN206: 633.1; found: 633.1. 1H NMR (400 MHZ, DMSO—d6) 5 13.00 (bS, 1H), 8.58 (d, J = 2.2 HZ, 1H), 8.13 (dd, J = 2.3, 0.8 HZ, 1H), 7.72 (d, J = 8.5 HZ, 2H), 7.51 (d, J = 8.7 HZ, 1H), 6.94 (d, J = 2.6 HZ, 1H), 6.79 (dd, J = 8.7, 2.6 HZ, 1H), 4.94 (S, 2H), 3.90 (S, 3H), 3.15 — 3.03 (m, 2H), 2.91 (p, J = 8.8 HZ, 1H), 2.49 — 2.41 (m, 1H), 2.41— 2.30 (m, 2H), 1.21 — 1.09 (m, 4H).

Example 7: 2-(6-(3-(2-chlor0((5-cyclopr0pyl(2,6-dichlor0fluorophenyl)is0xazol yl)meth0xy)phenyl)hydr0xyazetidinyl)fluoronicotinamid0)ethane-l-sulfonic acid 0 /O‘ \ N CI CI 0 //N CI ,9 F o OH A solution of 6—(3—(2—chloro—4—((5—cyclopropy1—3—(2,6—dichloro—4— fluoropheny1)isoxazol—4—y1)methoxy)pheny1)—3—hydroxyazetidin—1—y1)—5—fluoronicotinic acid (Example 3, 0.11 g, 0.18 mmol) in DMF (4 mL) was treated with HATU (1— [bis(dimethylamino)methylene]—1H—1,2,3—triazolo[4,5—b]pyridinium 3—oxid orophosphate, 0.10 g, 0.27 mmol) followed by taurine (34 mg, 0.27 mmol) and N,N—diisopropylethylamine (90 uL, 0.54 mmol). The mixture was stirred ght at room temperature and was then ed by preparative HPLC (water/acetonitrile/TFA). The combined fractions were treated with ammonium hydroxide solution and concentrated to give 2—(6—(3—(2—chloro—4—((5—cyclopropy1—3— (2,6—dichloro—4—fluoropheny1)isoxazol—4—y1)methoxy)pheny1)—3—hydroxyazetidin— 1 —y1)—5 — fluoronicotinamido)ethane—1—su1fonic acid (Example 7) as the ammonium salt. LCMS—ESI+ (m/z): [M+H]+ calcd for C30H26C13F2N4O7S: 729.1; found: 729.2. 1H NMR (400 MHz, DMSO— d6) 8 8.34 (m, 2H), 7.73 — 7.61 (m, 3H), 7.37 (d, J = 8.6 Hz, 1H), 7.29 — 6.95 (m, 4H), 6.92 (d, J = 2.5 Hz, 1H), 6.75 (dd, J = 8.6, 2.5 Hz, 1H), 6.22 (s, 1H), 4.90 (s, 2H), 4.63 (d, J = 9.6 Hz, 2H), 4.29 (d, J = 9.6 Hz, 2H), 3.46 (q, J = 6.5 Hz, 2H), 2.63 (t, J = 7.3 Hz, 2H), 2.45 — 2.38 (m, 1H), 1.16 (dt, J = 8.5, 3.1 Hz, 2H), 1.10 (dt, J = 5.4, 2.9 Hz, 2H).

[Annotation] Mel.Chan None set by Mel.Chan [Annotation] Mel.Chan MigrationNone set by Mel.Chan [Annotation] Mel.Chan ed set by Mel.Chan [Annotation] Mel.Chan None set by Mel.Chan [Annotation] Mel.Chan MigrationNone set by Mel.Chan [Annotation] Mel.Chan Unmarked set by Mel.Chan Example 8: (6-(3-(2-chlor0((5-cyclopr0pyl(2,6-dichlor0fluorophenyl)isoxazol yl)meth0xy)phenyl)hydr0xyazetidinyl)flu0r0nic0tin0yl)glycine F W0 U” OWN CI CI i F Step 1: methyl (6-(3-(2-ch10r0((5-cyclopr0pyl(2,6-dichlor0fluorophenyl)isoxazol yl)meth0xy)phenyl)hydr0xyazetidinyl)fluoronicotinoyl)glycinate A on of 6—(3—(2—chloro—4—((5—cyclopropyl—3—(2,6—dichloro—4— fluorophenyl)isoxazol—4—yl)methoxy)phenyl)—3—hydroxyazetidin— l —yl)—5—fluoronicotinic acid (Example 3, 0.12 g, 0.19 mmol) in DMF (4 mL) was treated with HATU (l— [bis(dimethylamino)methylene]—lH—l,2,3—triazolo[4,5—b]pyridinium 3—oxid hexafluorophosphate, 0.11 g, 0.29 mmol) followed by glycine methyl ester hydrochloride (36 mg, 0.29 mmol) and N,N—diisopropylethylamine (100 ML, 0.58 mmol). The mixture was d overnight at room temperature and was then ed with ted aqueous sodium hydrogen carbonate solution.

The aqueous phase was extracted twice with ethyl e. The combined extracts were washed once with 1:1 saturated aqueous sodium chloride solution/saturated aqueous sodium hydrogen carbonate solution, dried over anhydrous ium sulfate, filtered, and concentrated under reduced pressure to give the desired product, which was carried forward without further purification. LCMS—ESI+ (m/z): [M+H]+ calcd for C31H26C13F2N4O6: 693.1; found: 693.2.

Step 2: (6-(3-(2-chlor0((5-cyclopr0pyl(2,6-dichlor0flu0r0phenyl)isoxazol yl)meth0xy)phenyl)hydr0xyazetidinyl)flu0r0nic0tin0yl)glycine (Example 8) A mixture of crude methyl (6—(3—(2—chloro—4—((5—cyclopropyl—3—(2,6—dichloro—4— fluorophenyl)isoxazol—4—yl)methoxy)phenyl)—3—hydroxyazetidin— l —yl)—5 — fluoronicotinoyl)glycinate (approximately 0. 19 mmol) and lithium hydroxide monohydrate (38 mg, 0.91 mmol) in aqueous tetrahydrofuran (2:1, 3 mL) was stirred at room temperature for 3.5 hours. The volatile solvent was d under d pressure. The residue was diluted with [Annotation] Mel.Chan None set by Mel.Chan ation] Mel.Chan MigrationNone set by Mel.Chan [Annotation] Mel.Chan Unmarked set by Mel.Chan [Annotation] Mel.Chan None set by an [Annotation] Mel.Chan MigrationNone set by Mel.Chan [Annotation] Mel.Chan Unmarked set by Mel.Chan water and acidified to pH 1 with 10 % aqueous hydrochloric acid. The acidic s mixture was extracted three times with ethyl acetate. The combined organic extracts were washed once with saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, filtered, and concentrated to dryness under reduced pressure. The residue was ed by flash chromatography (silica gel) to provide (6—(3—(2—chloro—4—((5—cyclopropyl—3—(2,6—dichloro—4— fluorophenyl)isoxazol—4—yl)methoxy)phenyl)—3—hydroxyazetidin— 1 —yl)—5—fluoronicotinoyl)glycine (Example 8). LCMS—ESI+ (m/z): [M+H]+ calcd for C30H24C13F2N4O6: 679.1; found: 679.3. 1H NMR (400 MHz, DMSO-d6) 8 12.68 (s, 1H), 8.68 (t, J = 5.8 Hz, 1H), 8.44 (t, J = 1.7 Hz, 1H), 7.80 (dd, J = 13.2, 1.8 Hz, 1H), 7.71 (d, J = 8.5 Hz, 2H), 7.39 (d, J = 8.7 Hz, 1H), 6.95 (d, J = 2.5 Hz, 1H), 6.77 (dd, J = 8.6, 2.6 Hz, 1H), 6.26 (s, 1H), 4.93 (s, 2H), 4.66 (d, J = 9.5 Hz, 2H), 4.32 (d, J = 9.3 Hz, 2H), 3.87 (d, J = 5.8 Hz, 2H), 2.48 — 2.42 (partially obscured by DMSO, m, 1H), 1.16 (m, 4H). e 9: FRET activity assay ination of a ligand mediated cofactor peptide interaction to quantify ligand binding to the nuclear receptor FXR was performed as follows.

Preparation of human FXR alpha ligand binding domain: The human FXRalpha LBD was expressed in E. coli strain BL21(DE3) as an N—terminally GST tagged fusion protein. The DNA encoding the FXR ligand binding domain was cloned into vector pDEST15 (Invitrogen).

Expression was under control of an IPTG inducible T7 promoter. The amino acid boundaries of the ligand binding domain were amino acids 2 of Database entry NM_005123 (RefSeq).

Expression and purification of the FXR—LBD: An overnight preculture of a transformed E. coli strain was diluted 1:20 in LB—Ampicillin medium and grown at 30°C to an optical density of 0.4—0.6. Gene expression was then induced by addition of 0.5 mM IPTG. Cells were ted an onal 6 h at 30°C, 180 rpm. Cells were collected by centrifugation (7000 x g, 7 min, rt). Per liter of original cell culture, cells were resuspended in 10 mL lysis buffer (50 mM Glucose, 50 mM Tris pH 7.9, 1 mM EDTA and 4 mg/mL lysozyme) and left on ice for 30 min.

Cells were then subjected to sonication and cell debris removed via centrifugation (22000 x g, 30 min, 4 °C). Per 10 mL of supernatant 0.5 mL prewashed Glutathione 4B sepharose slurry n) was added and the suspension kept slowly rotating for 1 h at 4 OC. Glutathione 4B [Annotation] an None set by Mel.Chan [Annotation] Mel.Chan ionNone set by Mel.Chan [Annotation] Mel.Chan Unmarked set by Mel.Chan [Annotation] Mel.Chan None set by Mel.Chan [Annotation] Mel.Chan ionNone set by an [Annotation] Mel.Chan Unmarked set by an sepharose beads were pelleted by centrifugation (2000 x g, 15 sec, 4 °C) and washed twice in wash buffer (25 mM Tris, 50 mM KCl, 4 mM MgClz and 1M NaCl). The pellet was resuspended in 3 mL elution buffer per liter of original culture (elution buffer: 20 mM Tris, 60 mM KCl, 5 mM MgClz and 80 mM glutathione added immediately prior to use as powder). The suspension was left rotating for 15 min at 4 0C, the beads ed and eluted again with half the volume of elution buffer than the first time. The eluates were pooled and dialysed ght in 20 mM Hepes buffer (pH 7.5) containing 60 mM KCl, 5 mM MgClz as well as 1 mM dithiothreitol and % (v/v) glycerol. The protein was analysed by SDS—Page.

The method measures the ability of putative ligands to modulate the interaction between the purified bacterial expressed FXR ligand binding domain (LBD) and a synthetic biotinylated peptide based on residues 676—700 of SRC—l (LCD2, 676—700). The sequence of the peptide used was B-CPSSHSSLTERHKILHRLLQEGSPS-COOH (SEQ ID NO: 1) where the N- terminus was biotinylated (B). The ligand binding domain (LBD) of FXR was expressed as fusion protein with GST in BL—21 cells using the vector pDEST15. Cells were lysed by sonication, and the fusion proteins purified over hione sepharose (Pharmacia) according to the manufacturers instructions. For screening of compounds for their influence on the FXR— peptide interaction, the Perkin Elmer LANCE technology was applied. This method relies on the binding dependent energy transfer from a donor to an acceptor fluorophor attached to the g partner of interest. For ease of handling and reduction of background from compound fluorescence LANCE technology makes use of generic fluorophore labels and time resolved detection Assays were done in a final volume of 25 uL in a 384 well plate, in a Tris—based buffer (20 mM Tris—HCl pH 7.5; 60 mM KCl, 5 mM MgC12; 35 ng/uL BSA), containing 20—60 ng/well recombinantly expressed FXR—LBD fused to GST, 200—600 nM N—terminally biotinylated e, representing SRCl aminoacids 676—700, 200 ng/well Streptavidin—xlAPC ate(Prozyme) and 6—10 ng/well Eu W1024 — antiGST (Perkin Elmer). DMSO content of the samples was kept at 1%. After generation of the assay mix and diluting the potentially FXR modulating s, the assay was brated for 1 h in the dark at rt in FIA—plates black 384 well (Greiner). The LANCE signal was detected by a Perkin Elmer VICTOR2VTM Multilabel Counter. The results were visualized by plotting the ratio between the emitted light at 665 and 615 nm. A basal level of FXR—peptide ion is observed in the absence of added ligand.

Ligands that promote the x formation induce a concentration—dependent increase in time— [Annotation] Mel.Chan None set by Mel.Chan [Annotation] an MigrationNone set by Mel.Chan [Annotation] Mel.Chan Unmarked set by Mel.Chan [Annotation] Mel.Chan None set by Mel.Chan [Annotation] Mel.Chan MigrationNone set by an [Annotation] Mel.Chan Unmarked set by Mel.Chan resolved fluorescent signal. Compounds which bind equally well to both ric FXR and to the FXR—peptide complex would be expected to give no change in signal, whereas ligands which bind preferentially to the monomeric receptor would be expected to induce a concentration— dependent decrease in the observed signal.

To assess the agonistic potential of the compounds, EC50 values were determined for example compounds and are listed below in Table 2 (FRET ECso).

Example 10: Mammalian one hybrid (MlH) assay ination of a ligand mediated Gal4 promoter driven ctivation to quantify ligand binding mediated activation of FXR was performed as follows.

The cDNA part encoding the FXR ligand g domain was cloned into vector pCMV—BD (Stratagene) as a fusion to the yeast GAL4 DNA binding domain under the control of the CMV er. The amino acid boundaries of the ligand binding domain were amino acids 187—472 of Database entry NM_005123 (RefSeq). The plasmid pFR—Luc (Stratagene) was used as the reporter plasmid, containing a synthetic promoter with five tandem repeats of the yeast GAL4 binding sites, driving the sion of the Photinus pyralis (American firefly) luciferase gene as the reporter gene. In order to improve experimental accuracy the plasmid pRL—CMV (Promega) was sfected. pRL—CMV contains the constitutive CMV promoter, lling the expression of the Renilla reniformis rase. All Gal4 reporter gene assays were done in HEK293 cells (obtained from DSMZ, Braunschweig, Germany) grown in MEM with L— Glutamine and Earle's BSS supplemented with 10% fetal bovine serum, 0.1 mM nonessential amino acids, 1 mM sodium te, and 100 units Penicilin/Streptavidin per mL at 37 °C in 5% C02. Medium and supplements were obtained from Invitrogen. For the assay, 5 x 105 cells were plated per well in 96 well plates in 100 uL per well MEM without Phenol Red and L—Glutamine and with Earle's BSS supplemented with 10% charcoal/dextran treated FBS (HyClone, South Logan, Utah), 0.1 mM nonessential amino acids, 2 mM glutamine, 1 mM sodium pyruvate, and 100 units lin/ Streptavidin per mL, ted at 37 °C in 5% C02. The following day the cells were >90% confluence. Medium was removed and cells were transiently transfected using uL per well of an OptiMEM — polyethylene—imine—based transfection—reagent (OptiMEM, Invitrogen; Polyethyleneimine, Aldrich Cat No. 40,827—7) including the three plasmids described ation] Mel.Chan None set by Mel.Chan ation] Mel.Chan MigrationNone set by Mel.Chan ation] Mel.Chan Unmarked set by Mel.Chan [Annotation] Mel.Chan None set by Mel.Chan [Annotation] Mel.Chan ionNone set by Mel.Chan [Annotation] Mel.Chan Unmarked set by Mel.Chan above. MEM with the same composition as used for plating cells was added 2—4 h after addition of transfection mixture. Then compound stocks, prediluted in MEM were added (final vehicle concentration not ing 0.1%). Cells were incubated for additional 16 h before firefly and renilla luciferase activities were measured sequentially in the same cell extract using a Dual— Light—Luciferase—Assay system (Dyer et al., Anal. Biochem. 2000, 282, 158—161). All experiments were done in triplicates.

To assess the FXR agonistic potency of the example compounds, potency was determined in the MlH assay and is listed below in Table 2 (MlH EC50).

Table 2 FRET EC50 (nM) M1H ECso (nM) 1 263 3000 2 831 7.4 3.8 Example 11: Metabolite ID assay in human liver microsomes The metabolic stability of Example 3 and Comparative Example 1 in human liver microsmoes was conducted according to the following procedure. Human liver microsomes (35 uL protein concentration 20 mg/mL), 350 uL of 100 mM potassium phosphate buffer (pH 7.4), 245 uL of deionized water and 0.7 uL of compound stock on (5mM) were combined in a 1.5 mL entrifuge tube. The tube was sealed and gently vortexed for 10 seconds, then placed in an orf ThermoMixer C and pre—warmed at 37 °C with shaking at 1100 rpm for minutes.

[Annotation] Mel.Chan None set by Mel.Chan [Annotation] Mel.Chan MigrationNone set by Mel.Chan [Annotation] an Unmarked set by Mel.Chan [Annotation] Mel.Chan None set by Mel.Chan [Annotation] Mel.Chan MigrationNone set by Mel.Chan [Annotation] Mel.Chan Unmarked set by Mel.Chan NADPH solution (70 uL; 10 mM in water) was added while shaking, the mixture was aspirated several times with pipet, and 200 uLwas removed to a fresh 1.5 mL microcentrifuge tube on ice containing 200 uL of cold acetonitrile. This aliquot was vortexed at high speed for 10 seconds then placed on ice. After 30 and 60 minutes additional 200 pl aliquots were removed and transferred to fresh 1.5 mL microcentrifuge tube on ice containing 200 uL of cold acetonitrile. These were vortexed at high speed for 10 s then placed on ice.

The d ts were centrifuged at 14,300 rpm in a microcentrifuge for 10 minutes at 10 0C, then the supernatant was transferred to a deepwell (1 mL) 96 well plate and sealed with a silicon mat. The sample was transferred to the Cool Stack of the autoinjector (temperature set to 10 OC) and 20 uL was injected into the Thermo Elite Orbitrap mass spectrometer. 20 [LL samples were analyzed by UPLC—MS in order to identify and quantify the metabolites (Agilent 1290 G4220 binary pump UPLC with Agilent G13 16 TCC column oven; Waters Acquity UPLC BEH C18 (130 A pore size, 1.7 um particle size, 2.1 x 50 mm) column held at 40 OC; Agilent 1290 G4212 DAD diode array with wavelength range 190 to 400 nm; Thermo Electron ap Elite mass spectrometer in FTMS positive mode).

Final omal protein tration: 1 mg/mL Final NADPH concentration: 1 mM Final substrate concentration: 5 uM Time points: 0, 30, 60 minutes tion volume per time point: 200 uL Comparative Example 1, a direct comparator to Example 3 that lacks a 4— fluorophenyl tuent present in the compounds disclosed herein, was found to be metabolized to a diol compound (M1) under the conditions described above (Scheme 1). Incorporation of the 4—f1uoro substituent inhibited formation of lite M1 under the same conditions.

[Annotation] Mel.Chan None set by Mel.Chan ation] Mel.Chan MigrationNone set by an [Annotation] Mel.Chan Unmarked set by Mel.Chan [Annotation] Mel.Chan None set by Mel.Chan [Annotation] Mel.Chan MigrationNone set by Mel.Chan [Annotation] Mel.Chan Unmarked set by Mel.Chan Scheme 1 Comparative e 1 M1 m/z 604.0610 m/z 638.0664 Abundance by UV 23% Example 3 M1 m/z 622.0512 M/Z 638.0664 Abundance by UV <1% Example 12: Assessment of In Vivo codynamics in Cynomolgus Monkey In vivo pharmacodynamics of a representative compound of Formula (I) and a comparative e compound were determined as follows.

Test Article and Formulation Oral suspension doses of a representative compound of Formula (1) (Example 3) and Comparative Example 2 (Example 13/9 of US. Patent No. 9,139,539) were formulated at trations of 2, 6, 20, and 60 mg/mL in aqueous suspensions of 0.5% sodium carboxymethylcellulose (Na CMC), 1% ethanol, and 98.5% SOmM Tris buffer, at pH 8.

Animals Each dosing group consisted of three male Cynomolgus monkeys. At dosing, the animals weighed between 2.5 and 4.4 kg.

[Annotation] Mel.Chan None set by Mel.Chan ation] Mel.Chan MigrationNone set by Mel.Chan [Annotation] an Unmarked set by Mel.Chan [Annotation] Mel.Chan None set by Mel.Chan [Annotation] Mel.Chan MigrationNone set by Mel.Chan [Annotation] Mel.Chan Unmarked set by Mel.Chan Dosing The test articles were administered to the monkeys via oral gavage at 5 mL/kg. Prior to withdrawal, the gavage tube was flushed with approximately 10 mL of water.

Sample Collection Venous blood samples were taken at specified time points after dosing from each animal. The blood samples were ted and transferred into tubes containing potassium (K2) EDTA anticoagulant.

Determination of FGFl9 Concentrations in Plasma The FGFl9 ELISA assay kit from BioVendor (product number RDl9l lO7200R) was used to determine FGFl9 concentrations in the collected blood samples.

Determination of Drug Concentratsion in Plasma An aliquot of 50 uL of each plasma sample from the 10 and 30 mg/kg dosing groups and the t = 0 samples from the 100 and 300 mg/kg groups were treated with 200 uL of acetonitrile (ACN) containing internal standard. An aliquot of 25 uL of the remaining samples from the 100 mg/kg group was combined with 25 uL of blank plasma to effect a 1:2 on and treated with 200 uL of acetonitrile (ACN) containing internal standard. An aliquot of 10 uL of the remaining samples from the 300 mg/kg group was combined with 40 uL of blank plasma to effect a 1:5 dilution and treated with 200 uL of acetonitrile (ACN) containing internal rd.

The above solutions were centrifuged at 5000 RPM for 10 minutes and 50 uL of supernatant was transferred to a clean 96—well plate, followed by the addition of 200 uL of water. An aliquot of uL was injected to the API 5000 LC/MS/MS system. s exceeding the ation range of the instrument were diluted and re—analyzed.

HPLC Conditions A Zorbax Extend C18 HPLC column (50 x 2.1 mm, 3.5 u) from t Technologies (Part # —902) was used. Mobile phase A contained an aqueous solution of 1% acetonitrile in 10 mM ammonium formate adjusted to pH 3.0 with formic acid. Mobile phase B contained [Annotation] Mel.Chan None set by Mel.Chan [Annotation] Mel.Chan MigrationNone set by Mel.Chan [Annotation] Mel.Chan Unmarked set by Mel.Chan [Annotation] Mel.Chan None set by Mel.Chan [Annotation] Mel.Chan MigrationNone set by an [Annotation] Mel.Chan Unmarked set by Mel.Chan and 10% 10 mM ammonium formate in acetonitrile adjusted to pH 5.2 with formic acid. A Thermo Aria lexer with two identical Agilent 1200 series binary pumps (P/N G1312A Bin Pump) was used for elution and separation. The n program used is set forth in the following Table 3.

Table 3. (mL/min) (‘70) (‘70) Sample Loading 0.50 85 15 180 Ramp 0.50 50 50 90 Ramp 0.50 99 1 60 Elution 0.50 99 1 120 Re—equilibrium 0.50 85 15 An API 5000 triple quadrupole mass spectrometer from AB Sciex, Foster City, CA was used in multiple reaction monitoring mode to fy the compounds. The mass spectrometry parameters used are set forth in the ing Table 4.

Table 4.

Ion yer Spray voltage Collision gas Gas 1 (Arb) Gas 2 (Arb) temperature (V) (Arb) SOUTCC (0C) Turbo Ion 5500 70 50 6 550 Spray ation] Mel.Chan None set by Mel.Chan ation] Mel.Chan MigrationNone set by Mel.Chan [Annotation] Mel.Chan ed set by Mel.Chan [Annotation] Mel.Chan None set by Mel.Chan [Annotation] Mel.Chan ionNone set by Mel.Chan [Annotation] Mel.Chan Unmarked set by Mel.Chan Results FGF19 levels were compared following oral administration of increasing doses of Example 3 or Comparative Example 2 (3 to 300 mg/kg). Dose—dependent increases in plasma exposure were observed for both nds and the maximal AUC achieved with each compound at 300mg/kg were comparable (Figure 1). e 3 ependently increased plasma FGF19, reaching a Cmax of 16000 pg/ml at the highest dose (Figure 2). Administration of Comparative Example 2 also caused increases in plasma FGF19, but the maximal level of FGF19 was significantly lower (Cmax 3000 ng/ml) than for Example 3. Furthermore, maximal FGF19 induction by Comparative Example 2 was achieved at 5 mg/kg; higher doses provided no further increase despite greater plasma drug exposures (Figure 2). This Example demonstrates that IV or oral stration of Example 3 can induce greater FGF19 levels than Comparative Example 2.

Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure Thus, it should be understood that although the present disclosure has been specifically disclosed by preferred embodiments and optional features, modification, ement and ion of the disclosures embodied therein herein disclosed may be resorted to by those skilled in the art, and that such modifications, improvements and variations are considered to be within the scope of this disclosure. The materials, methods, and examples provided here are representative of preferred embodiments, are exemplary, and are not intended as limitations on the scope of the disclosure.

The disclosure has been described broadly and generically herein. Each of the narrower species and subgeneric groupings falling within the generic disclosure also form part of the disclosure. This includes the generic description of the sure with a proviso or negative limitation removing any subject matter from the genus, regardless of whether or not the excised material is specifically recited herein.

[Annotation] Mel.Chan None set by Mel.Chan [Annotation] Mel.Chan MigrationNone set by Mel.Chan [Annotation] Mel.Chan Unmarked set by Mel.Chan [Annotation] an None set by an [Annotation] Mel.Chan MigrationNone set by Mel.Chan ation] Mel.Chan ed set by Mel.Chan In addition, Where features or aspects of the disclosure are described in terms of Markush groups, those skilled in the art Will recognize that the disclosure is also thereby described in terms of any individual member or subgroup of members of the Markush group.

It is to be understood that While the disclosure has been described in conjunction with the above embodiments, that the foregoing description and examples are intended to illustrate and not limit the scope of the disclosure. Other aspects, advantages and cations Within the scope of the disclosure Will be apparent to those skilled in the art to which the disclosure pertains.

[Annotation] Mel.Chan None set by Mel.Chan ation] Mel.Chan MigrationNone set by an [Annotation] Mel.Chan Unmarked set by Mel.Chan [Annotation] Mel.Chan None set by Mel.Chan [Annotation] Mel.Chan MigrationNone set by an [Annotation] Mel.Chan Unmarked set by Mel.Chan

Claims (17)

1. A compound according to Formula (I): R/4A—Y Q’Ovz R2 wherein: Q is phenylene or pyridylene, each of which is optionally substituted with one or two substituents independently selected from halogen, methyl, C1_4—alkoxy, halo—C1_4—alkoxy, —CH2F, —CHF2, and —CF3; Y is N or CH; A is pyridylene or phenylene, each of which is optionally substituted with one or two groups independently selected from halogen, C1_4—alkoxy, halo—C1_4—alkoxy, C1_4—alkyl, and halo— C1_4—alkyl; Z is isoxazole substituted with R1 or pyrazole substituted with R1; R1 is CM—alkyl or C3_6—cycloalkyl, wherein said C1_4—alkyl is optionally substituted with l to 3 substituents independently selected from fluoro, hydroxyl, C1_3—alkoxy, and fluoro—C1_3—alkoxy, and said ycloalkyl is optionally substituted with l to 3 substituents ndently selected from fluoro, hydroxyl, C1_3—alkyl, fluoro—C1_3—alkyl, C1_3—alkoxy, and fluoro—C1_3—alkoxy; R2 and R3 are independently selected from hydrogen, halogen, methoxy, —CF3, —CHF2, — CHZF, —OCH2F, —OCHF2, —OCF3, and methyl; R4 is (302115 or —C(O)NR5R6; R5 is hydrogen, C1_6—alkyl, or halo—C1_6—alkyl; and R6 is hydrogen or C1_6—alkyl, n said lkyl is ally substituted with l to 6 substituents independently selected from halogen, -SO3H, and —COZH; or a pharmaceutically acceptable salt, a isomer, a e of stereoisomers, or a tautomer thereof. None set by Mel.Chan MigrationNone set by Mel.Chan ed set by an None set by Mel.Chan MigrationNone set by Mel.Chan Unmarked set by Mel.Chan

2. A compound according to Formula (Ia): wherein: Q is phenylene or pyridylene, each of which is optionally substituted with one or two substituents independently selected from halogen, methyl, C1_4—alkoxy, halo—C1_4—alkoxy, —CH2F, —CHF2, and —CF3; Yis N or CH; A is pyridylene or phenylene, each of which is optionally substituted with one or two groups independently selected from halogen, C1_4—alkoxy, halo—C1_4—alkoxy, C1_4—alkyl, and halo— C1_4—alkyl; R1 is CM—alkyl or C3_6—cycloalkyl, wherein said C1_4—alkyl is optionally substituted with l to 3 substituents independently selected from fluoro, hydroxyl, lkoxy, and fluoro—C1_3—alkoxy, and said C3_6—cycloalkyl is optionally substituted with l to 3 substituents independently selected from fluoro, hydroxyl, C1_3—alkyl, fluoro—C1_3—alkyl, C1_3—alkoxy, and fluoro—C1_3—alkoxy; R2 and R3 are independently selected from hydrogen, halogen, y, —CF3, —CHF2, — CHZF, —OCH2F, —OCHF2, —OCF3, and methyl; R4 is (302115 or —C(O)NR5R6; R5 is hydrogen, lkyl, or halo—C1_6—alkyl; R6 is hydrogen or C1_6—alkyl, n said C1_6—alkyl is optionally substituted with l to 6 substituents independently selected from halogen, -SO3H, and —COZH; None set by Mel.Chan MigrationNone set by Mel.Chan Unmarked set by Mel.Chan None set by Mel.Chan MigrationNone set by an Unmarked set by an or ceutically acceptable salt, a stereoisomer, a mixture of stereoisomers, or a tautomer thereof.

3. A compound of claim 2 having the structure of Formula (Ia): wherein: Q is phenylene optionally substituted with one or two halogen; Yis N or CH; A is pyridylene optionally substituted with one or two groups independently selected from n and C1_4—alkoxy; R1 is CM—alkyl or C3_6—cycloalkyl; R2 and R3 are independently selected from hydrogen and halogen; R4 is (302115 or —C(O)NR5R6; R5 is hydrogen; and R6 is C1_2—alkyl optionally substituted with —COZH or -SO3H; or pharmaceutically acceptable salt, a stereoisomer, a e of stereoisomers, or a tautomer thereof.

4. The compound of any one of claims 1—3, wherein Q is phenylene substituted with one chloro; or a pharmaceutically acceptable salt, a stereoisomer, a mixture of stereoisomers, or a tautomer thereof. None set by Mel.Chan MigrationNone set by Mel.Chan Unmarked set by Mel.Chan None set by Mel.Chan MigrationNone set by an Unmarked set by Mel.Chan

5. The compound of any one of claims 1—4, wherein R1 is cyclopropyl or methyl; or a ceutically acceptable salt, a stereoisomer, a mixture of stereoisomers, or a tautomer thereof.

6. The compound of any one of the preceding claims, wherein R2 and R3 are chloro; or a pharmaceutically acceptable salt, a stereoisomer, a mixture of stereoisomers, or a tautomer thereof.

7. The compound of any one of claims 1—5, wherein one of R2 and R3 is fluoro and the other is hydrogen; or a pharmaceutically acceptable salt, a stereoisomer, a mixture of isomers, or a tautomer thereof.

8. The compound of any one of the preceding claims, wherein Y is N; or a pharmaceutically acceptable salt, a stereoisomer, a mixture of stereoisomers, or a tautomer thereof.

9. The compound of claim 8, wherein A is pyridylene substituted with one fluoro; or a pharmaceutically acceptable salt, a stereoisomer, a e of stereoisomers, or a tautomer thereof.

10. The compound of claim 8, wherein A is unsubstituted pyridylene; or a pharmaceutically acceptable salt, a stereoisomer, a mixture of stereoisomers, or a tautomer f.

11. ll. The compound of claim 8 or 9, wherein R4 is —COZR5, and R5 is hydrogen; or a pharmaceutically acceptable salt, a stereoisomer, a mixture of stereoisomers, or a er thereof.

12. The compound of claim 8 or 9, wherein: R4 is —C(O)NR5R6; R5 is hydrogen; and R6 is C1_2—alkyl, wherein said C1_2—alkyl is substituted with -SOgH or —COZH; None set by Mel.Chan MigrationNone set by Mel.Chan Unmarked set by Mel.Chan None set by Mel.Chan MigrationNone set by Mel.Chan Unmarked set by Mel.Chan or a pharmaceutically able salt, a stereoisomer, a mixture of stereoisomers, or a tautomer

13. The nd of any one of claims l—7, wherein Y is CH; or a pharmaceutically acceptable salt, a stereoisomer, a mixture of stereoisomers, or a tautomer thereof.

14. The compound of claim 13 wherein A is pyridylene substituted with one methoxy; or a pharmaceutically acceptable salt, a stereoisomer, a mixture of stereoisomers, or a tautomer thereof.

15. The compound of claim 13 wherein R4 is —COZR5 and R5 is hydrogen; or a pharmaceutically acceptable salt, a stereoisomer, a e of stereoisomers, or a tautomer thereof.

16. The compound ing to any one of claims l—8, wherein R4—A is: R4Q§ wherein the pyridylene is optionally substituted with one or two , groups independently selected from halogen, C1_4—alkoxy, halo—C1_4—alkoxy, C1_4—alkyl, and halo—€1-4— alkyl; or a pharmaceutically acceptable salt, a stereoisomer, a e of stereoisomers, or a tautomer thereof.

17. The compound ing to any one of claims l—7, wherein R4—A is: YCR‘lsosH,