TGR5 antagonists and methods of use

Abstract

This disclosure provides compounds of Formula (I), and pharmaceutically acceptable salts thereof that are useful for treating a disease associated with TGR5.

Description

[0001] Attorney Docket No.43820-0007P01 (SBP Ref.22-015-02PCT) TGR5 ANTAGONISTS AND METHODS OF USE STATEMENT REGARDING FEDERALLY SPONSORED RESEARCH This invention was made with government support under DK117133 awarded by the National Institutes of Health. The government has certain rights in the invention. TECHNICAL FIELD This disclosure provides compounds of Formula (I), and pharmaceutically acceptable salts thereof that are useful for treating a disease associated with TGR5. BACKGROUND TGR5 is a highly conserved G-protein coupled receptor with wide tissue distribution that functions as a cell surface receptor for bile acids. TGR5 may also be referred to as G protein-coupled bile acid receptor 1 (GPBAR1), G-protein coupled receptor 19 (GPCR19), or membrane-type receptor for bile acids (M-BAR). The bile acid ligands of TGR5 induce internalization of protein from the cell membrane to the cytoplasm, and also incude production of cyclic adenosine monophosphate (cAMP). See Kawamata et al. (2003) J. Biol. Chem.278, pp. 9435-9440 and Maruyama, et al. (2002) Biochem. Biophys. Res. Commun. 298, pp. 714- 719. As such, TGR5 plays a role in regulating lipid and glucose metabolism, energy homeostasis, and inflammation. SUMMARY Some embodiments provide a compound of Formula (I): or a pharmaceutically X is selected from O (oxygen), S (sulfur) and NH; Attorney Docket No.43820-0007P01 (SBP Ref.22-015-02PCT) each R1is independently selected from halogen, cyano, nitro, C1-C6 alkyl, C1- C6 haloalkyl, C1-C6 alkoxy, -NH(C=O)C1-C6 alkyl, -NHSO2C1-C6 alkyl, phenyl, - NR1AR1B, and 5-10 membered heteroaryl; each R2is independently selected from halogen, nitro, C1-C6 alkyl, C1-C6 haloalkyl, phenyl, and 5-10 membered heteroaryl optionally substituted with 1-3 RA; R3is selected from halogen and C1-C6 alkyl; R4is selected from halogen and C1-C6 alkyl; each RAis independently selected from halogen, C1-C6 alkyl, and 3-10 membered heterocyclyl; each R1A, and R1Bis independently selected from hydrogen and C1-C6 alkyl; m is 0, 1, 2, or 3; and n is 0, 1, 2, or 3. Also provided herein is a pharmaceutical composition comprising a compound of Formula (I), or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients. Provided herein is a method of treating a disease associated with TGR5 in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as provided herein. As used herein, “a disease associated with TGR5” refers to polycycstic liver disease (PLD), cholangiocarcinoma, breast cancer, gastric adenocarcinoma, pancreatic cancer, lung cancer, liver cancer, colorectal cancer, or esophageal adenocarcinoma. Also provided herein is a method of treating a disease associated with TGR5 in a subject in need thereof, comprising (a) determining that the subject has a disease associated with TGR5; and (b) administering to the subject a therapeutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as provided herein. Provided herein is a method of treating a disease associated with TGR5, comprising administering to a subject identified or diagnosed as having a disease associated with TGR5 a therapeutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as provided herein. This disclosure also provides a method for inhibiting TGR5 activity in a mammalian cell, comprising contacting the mammalian cell with a compound of Formula (I), or a pharmaceutically acceptable salt thereof. Attorney Docket No.43820-0007P01 (SBP Ref.22-015-02PCT) Other embodiments include those described in the Detailed Description and / or in the claims. Additional Definitions To facilitate understanding of the disclosure set forth herein, a number of additional terms are defined below. Generally, the nomenclature used herein and the laboratory procedures in organic chemistry, medicinal chemistry, and pharmacology described herein are those well-known and commonly employed in the art. Unless defined otherwise, all technical and scientific terms used herein generally have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs. Each of the patents, applications, published applications, and other publications that are mentioned throughout the specification and the attached appendices are incorporated herein by reference in their entireties. The term “about” when referring to a number or a numerical range means that the number or numerical range referred to is an approximation, for example, within experimental variability and / or statistical experimental error, and thus the number or numerical range may vary up to ±10% of the stated number or numerical range. The term “acceptable” with respect to a formulation, composition or ingredient, as used herein, means having no persistent detrimental effect on the general health of the subject being treated. The phrase “therapeutically effective amount” means an amount of compound that, when administered to a subject in need of such treatment, is sufficient to (i) treat a disease associated with TGR5 (ii) attenuate, ameliorate, or eliminate one or more symptoms of a disease associated with TGR5 or (iii) delay the onset of one or more symptoms a disease associated with TGR5 as described herein. The term “pharmaceutically acceptable excipient” means a pharmaceutically- acceptable material, composition, or vehicle, such as a liquid or solid filler, diluent, carrier, solvent, or encapsulating material. In one embodiment, each component is “pharmaceutically acceptable” in the sense of being compatible with the other ingredients of a pharmaceutical formulation, and suitable for use in contact with the tissue or organ of humans and animals without excessive toxicity, irritation, allergic response, immunogenicity, or other problems or complications, commensurate with a reasonable benefit / risk ratio. See, e.g., Remington: The Science and Practice of Pharmacy, 21st ed.; Lippincott Williams & Wilkins: Philadelphia, PA, Attorney Docket No.43820-0007P01 (SBP Ref.22-015-02PCT) 2005; Handbook of Pharmaceutical Excipients, 6th ed.; Rowe et al., Eds.; The Pharmaceutical Press and the American Pharmaceutical Association: 2009; Handbook of Pharmaceutical Additives, 3rd ed.; Ash and Ash Eds.; Gower Publishing Company: 2007; Pharmaceutical Preformulation and Formulation, 2nd ed.; Gibson Ed.; CRC Press LLC: Boca Raton, FL, 2009. The term “pharmaceutically acceptable salt” refers to a formulation of a compound that does not cause significant irritation to an organism to which it is administered and does not abrogate the biological activity and properties of the compound. In certain instances, pharmaceutically acceptable salts are obtained by reacting a compound described herein, with acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid and the like. In some instances, pharmaceutically acceptable salts are obtained by reacting a compound having acidic group described herein with a base to form a salt such as an ammonium salt, an alkali metal salt, such as a sodium or a potassium salt, an alkaline earth metal salt, such as a calcium or a magnesium salt, a salt of organic bases such as dicyclohexylamine, N-methyl-D- glucamine, tris(hydroxymethyl)methylamine, and salts with amino acids such as arginine, lysine, and the like, or by other methods previously determined. The pharmacologically acceptable salt s not specifically limited as far as it can be used in medicaments. Examples of a salt that the compounds described hereinform with a base include the following: salts thereof with inorganic bases such as sodium, potassium, magnesium, calcium, and aluminum; salts thereof with organic bases such as methylamine, ethylamine and ethanolamine; salts thereof with basic amino acids such as lysine and ornithine; and ammonium salt. The salts may be acid addition salts, which are specifically exemplified by acid addition salts with the following: mineral acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, and phosphoric acid:organic acids such as formic acid, acetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, malic acid, tartaric acid, citric acid, methanesulfonic acid, and ethanesulfonic acid; acidic amino acids such as aspartic acid and glutamic acid. As used herein, the “subject” refers to any animal, including mammals such as primates (e.g., humans), mice, rats, other rodents, rabbits, dogs, cats, swine, cattle, sheep, horses, primates, and humans. In some embodiments, the subject is a human. In some embodiments, the subject has experienced and / or exhibited at least one symptom of the disease to be treated, e.g., polycystic liver disease (PLD) or a cancer described herein. Attorney Docket No.43820-0007P01 (SBP Ref.22-015-02PCT) As used herein, terms “treat” or “treatment” refer to therapeutic or palliative measures. Beneficial or desired clinical results include, but are not limited to, alleviation, in whole or in part, of symptoms associated with a disease associated with TGR5 diminishment of the frequency of symptoms related to a disease associated with TGR5, stabilized (i.e., not worsening) state of disease, delay or slowing of a disease associated with TGR5, progression, amelioration or palliation of the disease state (e.g., one or more symptoms of the disease associated with TGR5), and remission (whether partial or total), whether detectable or undetectable. “Treatment” can also mean prolonging survival as compared to expected survival if not receiving treatment. Whenever a group is described as being “optionally substituted” that group may be unsubstituted or substituted with one or more of the indicated substituents. Likewise, when a group is described as being “substituted” the substituent(s) may be selected from one or more the indicated substituents. The term “halogen” refers to fluoro (F), chloro (Cl), bromo (Br), or iodo (I). The term “oxo” refers to a divalent doubly bonded oxygen atom (i.e., “=O”). As used herein, oxo groups are attached to carbon atoms to form carbonyls. The term "cyano" refers to a -CN radical. The term “nitro” refers to a –NO2 radical. The term “alkyl” refers to a saturated acyclic hydrocarbon radical that may be a straight chain or branched chain, containing the indicated number of carbon atoms. For example, C1- C10 indicates that the group may have from 1 to 10 (inclusive) carbon atoms in it. Non-limiting examples include methyl, ethyl, iso-propyl, tert-butyl, n-hexyl. The term “saturated” as used in this context means only single bonds present between constituent carbon atoms and other available valences occupied by hydrogen and / or other substituents as defined herein. The term “haloalkyl” refers to an alkyl, in which one or more hydrogen atoms is / are replaced with an independently selected halogen. The term “alkoxy” refers to an -O-alkyl radical (e.g., -OCH3). The term “aryl” refers to a 6-20 carbon mono-, bi-, tri- or polycyclic group wherein at least one ring in the system is aromatic (e.g., 6-carbon monocyclic, 10-carbon bicyclic, or 14- carbon tricyclic aromatic ring system); and wherein 0, 1, 2, 3, or 4 atoms of each ring may be substituted by a substituent. Examples of aryl groups include phenyl, naphthyl, tetrahydronaphthyl, and the like. Attorney Docket No.43820-0007P01 (SBP Ref.22-015-02PCT) The term “cycloalkyl” as used herein refers to cyclic saturated or partially unsaturated hydrocarbon groups having, e.g., 3 to 20 ring carbons, preferably 3 to 16 ring carbons, and more preferably 3 to 12 ring carbons or 3-10 ring carbons or 3-6 ring carbons, wherein the cycloalkyl group may be optionally substituted. Examples of cycloalkyl groups include, without limitation, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl, and cyclooctyl. Cycloalkyl may include multiple fused and / or bridged rings. Non-limiting examples of fused / bridged cycloalkyl includes: bicyclo[1.1.0]butane, bicyclo[2.1.0]pentane, bicyclo[1.1.1]pentane, bicyclo[3.1.0]hexane, bicyclo[2.1.1]hexane, bicyclo[3.2.0]heptane, bicyclo[4.1.0]heptane, bicyclo[2.2.1]heptane, bicyclo[3.1.1]heptane, bicyclo[4.2.0]octane, bicyclo[3.2.1]octane, bicyclo[2.2.2]octane, and the like. Cycloalkyl also includes spirocyclic rings (e.g., spirocyclic bicycle wherein two rings are connected through just one atom). Non-limiting examples of spirocyclic cycloalkyls include spiro[2.2]pentane, spiro[2.5]octane, spiro[3.5]nonane, spiro[3.5]nonane, spiro[3.5]nonane, spiro[4.4]nonane, spiro[2.6]nonane, spiro[4.5]decane, spiro[3.6]decane, spiro[5.5]undecane, and the like. The term “saturated” as used in this context means only single bonds present between constituent carbon atoms. The term “heteroaryl”, as used herein, means a mono-, bi-, tri- or polycyclic group having 5 to 20 ring atoms, alternatively 5, 6, 9, 10, or 14 ring atoms; wherein at least one ring in the system contains one or more heteroatoms independently selected from the group consisting of N, O, and S and at least one ring in the system is aromatic (but does not have to be a ring which contains a heteroatom, e.g. tetrahydroisoquinolinyl, e.g., tetrahydroquinolinyl). Examples of heteroaryl include thienyl, pyridinyl, furyl, oxazolyl, oxadiazolyl, pyrrolyl, imidazolyl, triazolyl, thiodiazolyl, pyrazolyl, isoxazolyl, thiadiazolyl, pyranyl, pyrazinyl, pyrimidinyl, pyridazinyl, triazinyl, thiazolyl benzothienyl, benzoxadiazolyl, benzofuranyl, benzimidazolyl, benzotriazolyl, cinnolinyl, indazolyl, indolyl, isoquinolinyl, isothiazolyl, naphthyridinyl, purinyl, thienopyridinyl, pyrido[2,3-d]pyrimidinyl, pyrrolo[2,3-b]pyridinyl, quinazolinyl, quinolinyl, thieno[2,3-c]pyridinyl, pyrazolo[3,4-b]pyridinyl, pyrazolo[3,4- c]pyridinyl, pyrazolo[4,3-c]pyridine, pyrazolo[4,3-b]pyridinyl, tetrazolyl, chromane, 2,3- dihydrobenzo[b][1,4]dioxine, benzo[d][1,3]dioxole, 2,3-dihydrobenzofuran, tetrahydroquinoline, 2,3-dihydrobenzo[b][1,4]oxathiine, isoindoline, and others. In some embodiments, the heteroaryl is selected from thienyl, pyridinyl, furyl, pyrazolyl, imidazolyl, isoindolinyl, pyranyl, pyrazinyl, and pyrimidinyl. For purposes of clarification, heteroaryl also includes aromatic lactams, aromatic cyclic ureas, or vinylogous analogs thereof, in which each Attorney Docket No.43820-0007P01 (SBP Ref.22-015-02PCT) ring nitrogen adjacent to a carbonyl is tertiary (i.e., all three valences are occupied by non- hydrogen substituents), such as one or more of pyridone , , wherein each ring nitrogen adjacent to a carbonyl is tertiary (i.e., the oxo group herein is a constituent part of the heteroaryl ring). term “heterocyclyl” refers to a mono-, bi-, tri-, or polycyclic saturated or partially unsaturated ring system with 3-16 ring atoms (e.g., 5-8 membered monocyclic, 8-12 membered bicyclic, or 11-14 membered tricyclic ring system) having 1-3 heteroatoms if monocyclic, 1-6 heteroatoms if bicyclic, or 1-9 heteroatoms if tricyclic or polycyclic, said heteroatoms selected from O, N, or S (e.g., carbon atoms and 1-3, 1-6, or 1-9 heteroatoms of N, O, or S if monocyclic, bicyclic, or tricyclic, respectively), wherein one or more ring atoms may be substituted by 1-3 oxo (forming, e.g., a lactam) and one or more N or S atoms may be substituted by 1-2 oxido (forming, e.g., an N-oxide, an S-oxide, or an S,S-dioxide), valence permitting; and wherein 0, 1, 2 or 3 atoms of each ring may be substituted by 1-2 substituents. Examples of heterocyclyl groups include piperazinyl, pyrrolidinyl, dioxanyl, morpholinyl, tetrahydrofuranyl, tetrahydropyridyl, dihydropyrazinyl, dihydropyridyl, dihydropyrrolyl, dihydrofuranyl, dihydrothiophenyl, and the like. Heterocyclyl may include multiple fused and bridged rings. Non-limiting examples of fused / bridged heteorocyclyl includes: 2-azabicyclo[1.1.0]butane, 2- azabicyclo[2.1.0]pentane, 2-azabicyclo[1.1.1]pentane, 3-azabicyclo[3.1.0]hexane, 5- azabicyclo[2.1.1]hexane, 3-azabicyclo[3.2.0]heptane, octahydrocyclopenta[c]pyrrole, 3- azabicyclo[4.1.0]heptane, 7-azabicyclo[2.2.1]heptane, 6-azabicyclo[3.1.1]heptane, 7- azabicyclo[4.2.0]octane, 2-azabicyclo[2.2.2]octane, 3-azabicyclo[3.2.1]octane, 2- oxabicyclo[1.1.0]butane, 2-oxabicyclo[2.1.0]pentane, 2-oxabicyclo[1.1.1]pentane, 3- oxabicyclo[3.1.0]hexane, 5-oxabicyclo[2.1.1]hexane, 3-oxabicyclo[3.2.0]heptane, 3- Attorney Docket No.43820-0007P01 (SBP Ref.22-015-02PCT) oxabicyclo[4.1.0]heptane, 7-oxabicyclo[2.2.1]heptane, 6-oxabicyclo[3.1.1]heptane, 7- oxabicyclo[4.2.0]octane, 2-oxabicyclo[2.2.2]octane, 3-oxabicyclo[3.2.1]octane, and the like. Heterocyclyl also includes spirocyclic rings (e.g., spirocyclic bicycle wherein two rings are connected through just one atom). Non-limiting examples of spirocyclic heterocyclyls include 2-azaspiro[2.2]pentane, 4-azaspiro[2.5]octane, 1-azaspiro[3.5]nonane, 2-azaspiro[3.5]nonane, 7-azaspiro[3.5]nonane, 2-azaspiro[4.4]nonane, 6-azaspiro[2.6]nonane, 1,7- diazaspiro[4.5]decane, 7-azaspiro[4.5]decane 2,5-diazaspiro[3.6]decane, 3- azaspiro[5.5]undecane, 2-oxaspiro[2.2]pentane, 4-oxaspiro[2.5]octane, 1- oxaspiro[3.5]nonane, 2-oxaspiro[3.5]nonane, 7-oxaspiro[3.5]nonane, 2-oxaspiro[4.4]nonane, 6-oxaspiro[2.6]nonane, 1,7-dioxaspiro[4.5]decane, 2,5-dioxaspiro[3.6]decane, 1- oxaspiro[5.5]undecane, 3-oxaspiro[5.5]undecane, 3-oxa-9-azaspiro[5.5]undecane and the like. As used herein, examples of aromatic rings include: benzene, pyridine, pyrimidine, pyrazine, pyridazine, pyridone, pyrrole, pyrazole, oxazole, thioazole, isoxazole, isothiazole, and the like. As used herein, when a ring is described as being “partially unsaturated”, it means said ring has one or more additional degrees of unsaturation (in addition to the degree of unsaturation attributed to the ring itself; e.g., one or more double or triple bonds between constituent ring atoms), provided that the ring is not aromatic. Examples of such rings include: cyclopentene, cyclohexene, cycloheptene, dihydropyridine, tetrahydropyridine, dihydropyrrole, dihydrofuran, dihydrothiophene, and the like. For the avoidance of doubt, and unless otherwise specified, for rings and cyclic groups (e.g., aryl, heteroaryl, heterocyclyl, cycloalkyl, and the like described herein) containing a sufficient number of ring atoms to form bicyclic or higher order ring systems (e.g., tricyclic, polycyclic ring systems), it is understood that such rings and cyclic groups encompass those having fused rings, including those in which the points of fusion are located (i) on adjacent ring atoms (e.g., [x.x.0] ring systems, in which 0 represents a zero atom bridge )); (ii) a single ring atom (spiro-fused ring systems) Attorney Docket No.43820-0007P01 (SBP Ref.22-015-02PCT) ), or (iii) a contiguous array of ring atoms (bridged ring systems having all bridge lengths > 0) ). compounds of the present embodiments are intended to Isotopes, as used herein, include those atoms having the same atomic number but different mass numbers. By way of general example and without limitation, isotopes of hydrogen include tritium and deuterium, and isotopes of carbon include13C and14C. In addition, the compounds generically or specifically disclosed herein are intended to include all tautomeric forms. Thus, by way of example, a compound containing the moiety: encompasses the tautomeric form containing the moiety: . Similarly, a pyridinyl or pyrimidinyl moiety that is described to be optionally substituted with hydroxyl encompasses pyridone or pyrimidone tautomeric forms. The compounds provided herein may encompass various stereochemical forms. The compounds also encompass enantiomers (e.g., R and S isomers), diastereomers, as well as mixtures of enantiomers (e.g., R and S isomers) including racemic mixtures and mixtures of diastereomers, as well as individual enantiomers and diastereomers, which arise as a consequence of structural asymmetry in certain compounds. Unless otherwise indicated, when a disclosed compound is named or depicted by a structure without specifying the stereochemistry (e.g., a “flat” structure) and has one or more chiral centers, it is understood to represent all possible stereoisomers of the compound. Likewise, unless otherwise indicated, when a disclosed compound is named or depicted by a structure that specifies the stereochemistry (e.g., a structure with “wedge” and / or “dashed” bonds) and has one or more chiral centers, it is understood to represent the indicated stereoisomer of the compound. The details of one or more embodiments of this disclosure are set forth in the accompanying drawings and the description below. Other features and advantages of the present disclosure will be apparent from the description and drawings, and from the claims. Attorney Docket No.43820-0007P01 (SBP Ref.22-015-02PCT) BRIEF DESCRIPTION OF THE DRAWINGS FIGs. 1A-1E show overexpression of TGR5 in the PLD liver and PKD kidney. FIG. 1A shows expression of TGR5 in cholangiocytes of healthy humans, patients with ADPKD- associated PLD, wild type and PCK rats. FIG.1B shows expression of TGR5 in renal epithelial cells of healthy humans, patients with ADPKD, wild type and PCK rats. FIG. 1C shows expression of TGR5 in cultured cholangiocytes isolated from patients with ADPKD-associated PLD and PCK rats. FIG.1D shows TGR5 overexpression in PLD and PCK rat cholangiocytes as confirmed by western blotting. FIG. 1E shows presence of TGR5 in PLD cholangiocytes (PLDC) and PKD renal epithelial cells (PKD-REC), and in the microenvironment surrounding liver and kidney cysts by spatial transcriptomics analysis of human liver and kidney tissues. FIG. 2 shows concentration of bile acids in bile (A) and serum (B) of age- and sex- matched wild type (WT) and PCK rats as detected by Liquid Chromatography-Mass Spectrometry. FIGs. 3A and 3B show TGR5 antagonist SBI-364 decreased proliferation of human PLD cholangiocytes. FIG. 3A shows assessment of cell proliferation by direct cell Counting. FIG.3B shows assessment of cell proliferation by area of cell confluence. FIGs.4A-4C show TGR5 antagonist SBI-364 had no effects on proliferation of human PLD cholangiocytes with reduced expression of TGR5. FIG.4A shows expression of TGR5 in human PLD cholangiocytes transfected with specific TGR5 sh-RNA analyzed by Western Blot. FIG. 4B shows assessment of cell proliferation by direct cell counting. FIG. 4C shows assessment of cell proliferation by area of cell confluence. FIG.5 are representative microscopic images of PLD cholangiocytes that demonstrated that TGR5 antagonist SBI-364 decreased proliferation of human PLD cholangiocytes. FIGs. 6A and 6B show TGR5 antagonist SBI-364 decreased proliferation of rat PCK cholangiocytes. FIG. 6A shows assessment of cell proliferation by direct cell counting. FIG. 6B shows assessment of cell proliferation by area of cell confluence. FIGs. 7A-7C show TGR5 antagonist SBI-364 had no effects on proliferation of PCK rat cholangiocytes with reduced expression of TGR5. FIG. 7A shows expression of TGR5 in PCK rat cholangiocytes transfected with specific TGR5 sh-RNA as analyzed by Western blot. FIG. 7B shows assessment of cell proliferation by direct cell counting. FIG. 7C shows assessment of cell proliferation by area of cell confluence. FIG. 8 are representative images of PCK rat cholangiocytes that show that TGR5 antagonist SBI-364 decreased proliferation of PCK rat cholangiocytes. Attorney Docket No.43820-0007P01 (SBP Ref.22-015-02PCT) FIGs. 9A and 9B show TGR5 antagonist SBI-364 decreased proliferation of human WT9-12 PKD renal epithelial cells (PKD-REC). FIG. 9A shows assessment of cell proliferation by direct cell counting. FIG.9B shows assessment of cell proliferation by area of cell confluence. FIG.10 are representative images of WT9-12 PKD-REC that demonstrated that TGR5 antagonist SBI-364 decreased proliferation of human WT9-12 PKD renal epithelial cells (PKD-REC). FIG. 11 are confocal microscopy images that demonstrate that TGR5 antagonist SBI- 364 decreased levels of p-ERK (i.e., a cAMP downstream target) in human PLD cholangiocytes (top left), PCK rat cholangiocytes (top right) and PKC-REC (bottom). FIGs. 12A-12D show that TGR5 antagonist SBI-364 decreases growth of cystoids formed in 3-D culture by freshly isolated PCK rat cholangiocytes and renal epithelial cells (PCK-REC). FIG.12A is a schematic diagram depicts the cystoid development protocol. FIG. 12B are representative immunofluorescence confocal microscopy images that demonstrate that cystoids are positive for the epithelial cell marker, CK-7 (red). FIG.12C are light microscopy images of fully formed by PCK rat cholangiocyte cystoids that were treated with TGR5 agonist, TLCA, alone or in the presence of inactive compound, SBI-155, or TGR5 antagonist, SBI-364. FIG.12D are light microscopy images of fully formed by PCK-REC cystoids that were treated with TGR5 agonist, TLCA, alone or in the presence of inactive compound, SBI-155, or TGR5 antagonist, SBI-364. FIG.13 are confocal microscopy images (top) and violin plots (bottom) that show that TGR5 antagonist SBI-364 decreased immunoreactivity of PCNA (Proliferating Cell Nuclear Antigen, a marker of cell proliferation) in cystoids formed in 3-D cultures by freshly isolated PCK rat cholangiocytes and PCK rat renal epithelial cells (PCK-REC). FIGs.14A-14B show TGR5 antagonist SBI-364 decreased proliferation of human PLD cholangiocytes compared to a compound, SBI-319. FIG. 14A shows assessment of cell proliferation by direct cell counting. FIG. 14B shows assessment of cell proliferation by area of cell confluence. FIG.15 are representative images of human PLD cholangiocytes that demonstrated that TGR5 antagonist SBI-364 decreased their proliferation compared to SBI-319. FIGs. 16A-16B show TGR5 antagonist SBI-364 decreased proliferation of PCK rat cholangiocytes compared to SBI-319. FIG. 16A shows assessment of cell proliferation by direct cell counting. FIG.16B shows assessment of cell proliferation by area of cell confluence. Attorney Docket No.43820-0007P01 (SBP Ref.22-015-02PCT) FIG. 17 are representative images of PCK rat cholangiocytes that demonstrated that TGR5 antagonist SBI-364 decreased their proliferation compared to SBI-319. FIGs. 18A-18B show TGR5 antagonist SBI-364 decreased proliferation of human WT9-12 PKD renal epithelial cells (PKD-REC) compared to SBI-319. FIG. 18A shows assessment of cell proliferation by direct cell counting. FIG. 18B shows assessment of cell proliferation by area of cell confluence. FIG.19 are representative images of human WT9-12 PKD renal epithelial cells (PKD- REC) that demonstrated that TGR5 antagonist SBI-364 decreased their proliferation compared to SBI-319. FIG. 20 are confocal microscopy images that demonstrate that TGR5 antagonist SBI- 364 decreased levels of p-ERK (i.e., a cAMP downstream target) in human PLD cholangiocytes (top panels), PCK rat cholangiocytes (middle panels) and renal WT9-12 cells (bottom panels) compared to SBI-319. FIG. 21 show that TGR5 antagonist SBI-364 decreases growth of cystoids formed in 3-D culture by freshly isolated PCK rat cholangiocytes compared to SBI-319 (right). FIG.21 are light microscopy images of fully formed by PCK rat cholangiocyte cystoids that were treated with TGR5 agonist, TLCA, alone or in the presence of SBI-319 and SBI-364 (left). FIGs. 22A-22C show that TGR5 antagonist, compound SBI-319, decreased hepatic cystogenesis in PCK rats and reduced cell proliferation. FIG. 22A are representative light microscopy images of liver tissue stained with Masson-trichrom ( i.e., a marker of fibrosis). FIG. 22B are violin plots that show that hepatic cystic and fibrotic areas, number of hepatic cysts and hepatic cyst diameter were decreased after treatment with SBI-319. FIG. 22C are representative immunofluorescence confocal microscopy images of liver sections from un- treated and SBI-319-treated PCK rats stained with PCNA antibody. FIGs. 23A-23C show that TGR5 antagonist, compound SBI-319, decreased renal cystogenesis in PCK rats and reduced cell proliferation. FIG. 23A are representative light microscopy images of kidneys stained with Masson-trichrom ( i.e., a marker of fibrosis). FIG. 23B are violin plots that show that renal cystic and fibrotic areas, number of renal cysts and renal cyst diameter were decreased after treatment with SBI-319. FIG. 23C are representative immunofluorescence confocal microscopy images of kidney sections from un-treated and SBI- 319-treated PCK rats stained with PCNA antibody. FIGs.24A-24D show that in cholangiocytes of PCK rats, TGR5 is colocalized with Gas proteins but not Gai proteins and TGR5 antagonist SBI-319 decreased the coupling of TGR5 Attorney Docket No.43820-0007P01 (SBP Ref.22-015-02PCT) with Gas proteins. FIG. 24A are representative immunofluorescence confocal microscopy images that show that TGR5 (stained in red) is colocalized with Gas proteins (stained in green) in cholangiocytes of PCK rats but not wild type (WT) rats. FIG.24B are confocal images that show that no colocalization of TGR5 with Gai was observed in PCK rats. FIG. 24C is a schematic representation that outlines that TGR5 activation leads to TGR5+Gas coupling subsequently increasing cAMP levels. FIG. 24D shows that SBI-319 significantly decreased TGR5+Gas coupling as assessed by proximity ligation assay. FIGs. 25A-25C show that TGR5 antagonist, compound SBI-364, decreased hepatic cystogenesis in PCK rats and reduced cell proliferation in a dose-dependent manner. FIG.25A are representative light microscopy images of livers stained with Masson-trichrom ( i.e., a marker of fibrosis). FIG. 25B are violin plots that show that hepatic cystic and fibrotic areas, number of hepatic cysts and hepatic cyst diameter were decreased after treatment with SBI- 364 in a dose-depent manner. FIG. 25C are representative immunofluorescence confocal microscopy images of liver sections from un-treated and SBI-364-treated PCK rats stained with PCNA antibody. FIG. 26 are confocal images and violin plots that show that SBI-364 decreased TGR5+Gas coupling in cholangiocytes of PCK rats in a dose-dependent manner. TGR5+Gas coupling was assessed by proximity ligation assay. FIGs. 27A-27C show that TGR5 antagonist, compound SBI-364, decreased renal cystogenesis in PCK rats and reduced cell proliferation in a dose-dependent manner. FIG.27A are representative light microscopy images of kidneys stained with Masson-trichrom ( i.e., a marker of fibrosis). FIG. 27B are violin plots that show that renal cystic and fibrotic areas, number of renal cysts and renal cyst diameter were decreased after treatment with SBI-364 in a dose-depent manner. FIG.27C are representative immunofluorescence confocal microscopy images of kidney sections from un-treated and SBI-364-treated PCK rats stained with PCNA antibody. FIG. 28 are confocal images (top) and violin plots (bottom) that show that SBI-364 decreased TGR5+Gas coupling in renal epithelial cells of PCK rats in a dose-dependent manner. TGR5+Gas coupling was assessed by proximity ligation assay. FIGs.29A and 29B show that TGR5 is overexpressed in cholangiocarcinoma cell lines. FIG. 29A shows that TGR5 as assessed by immunofluorescence confocal microscopy is overexpressed in cholangiocarcinoma cell lines compared to healthy human cholangiocytes Attorney Docket No.43820-0007P01 (SBP Ref.22-015-02PCT) (NHC). FIG. 29B shows overexpression of TGR5 in HUCCT1 cell line as confirmed by Western blot. FIGs. 30A and 30B show that TGR5 antagonist SBI-364 decreased proliferation of HUCCT1 cells. FIG.30A shows assessment of cell proliferation by direct cell counting. FIG. 30B shows assessment of cell proliferation by area of cell confluence. FIGs. 31A and 31B show that TGR5 antagonist SBI-364 decreased proliferation of CCLP1 cells. FIG. 31A shows assessment of cell proliferation by direct cell counting. FIG. 31B shows assessment of cell proliferation by area of cell confluence. FIGs. 32A and 32B show that TGR5 antagonist SBI-364 decreased proliferation of EGI1. FIG.32A shows assessment of cell proliferation by direct cell counting. FIG.32B shows assessment of cell proliferation by area of cell confluence. FIGs. 33A and 33B show that TGR5 antagonist SBI-364 decreased proliferation of WITT cells. FIG.33A shows assessment of cell proliferation by direct cell counting. FIG.33B shows assessment of cell proliferation by area of cell confluence. FIG. 34 are representative images of HUCCT1 cells that demonstrate that TGR5 antagonist SBI-364 decreased proliferation of HUCCT1. FIG. 35 are representative immunofluorescence confocal microscopy images that demonstrate that TGR5 antagonist SBI-364 decreased levels of p-ERK (i.e., cAMP downstream target) in cholangiocarcinoma cell lines. FIG.36 is a graph showing that TGR5 antagonist SBI-364 decreased the tumor growth in mouse model of cholangiocarcinoma. DETAILED DESCRIPTION This disclosure provides compounds of Formula (I), and pharmaceutically acceptable salts thereof that are useful for treating a disease associated with TGR5. Formulae (I) Compounds Some embodiments provide a compound of Formula (I): or a pharmaceutically Attorney Docket No.43820-0007P01 (SBP Ref.22-015-02PCT) X is selected from O (oxygen), S (sulfur) and NH; ; or CR2; selected from halogen, cyano, nitro, C1-C6 alkyl, C1- C6 haloalkyl, C1-C6 alkoxy, -NH(C=O)C1-C6 alkyl, -NHSO2C1-C6 alkyl, phenyl, - NR1AR1B, and 5-10 membered heteroaryl; each R2is independently selected from halogen, nitro, C1-C6 alkyl, C1-C6 haloalkyl, phenyl, and 5-10 membered heteroaryl optionally substituted with 1-3 RA; R3is selected from halogen and C1-C6 alkyl; R4is selected from halogen and C1-C6 alkyl; each RAis independently selected from halogen, C1-C6 alkyl, and 3-10 membered heterocyclyl; each R1A, and R1Bis independently selected from hydrogen and C1-C6 alkyl; m is 0, 1, 2, or 3; and n is 0, 1, 2, or 3. In some embodiments, R3is halogen. In some embodiments, R3is fluoro. In some embodiments, R3is chloro. In some embodiments, R3is bromo. In some embodiments, R3is C1-C6 alkyl. In some embodiments, R3is C1-C3 alkyl. In some embodiments, R3is methyl. In some embodiments, R4is halogen. In some embodiments, R4is fluoro. In some embodiments, R4is chloro. In some embodiments, R4is C1-C6 alkyl. R4is C1-C3 alkyl. In some embodiments, R4is methyl. In some embodiments, R4is chloro or CH3.

[0002] Attorney Docket No.43820-0007P01 (SBP Ref.22-015-02PCT) , , embodiments, Y is . In some . In some embodiments, . In some embodiments, Y . In some embodiments, Y is . In some some In some Attorney Docket No.43820-0007P01 (SBP Ref.22-015-02PCT) In some embodiments, Z is N. In some embodiments, Z is CH or CR2. In some embodiments, X is O and Z is N. In some embodiments, X is O and Z is CH or CR2. In some embodiments, X is NH and Z is CH or CR2. In some embodiments, X is S and Z is CH or CR2. In some embodiments, m is 1. In some embodiments, m is 2. In some embodiments, m is 3. In some embodiments, at least one R1is halogen. In some embodiments, at least one R1is fluoro. In some embodiments, at least one R1is chloro. In some embodiments, each R1is independently selected from fluoro, chloro and bromo. In some embodiments, at least one R1is cyano. In some embodiments, at least one R1is nitro. In some embodiments, at least one R1is C1-C6 alkyl. In some embodiments, at least one R1is C1-C3 alkyl. In some embodiments, at least one R1is methyl. In some embodiments, at least one R1is C1-C6 haloalkyl. In some embodiments, at least one R1is C1-C3 haloalkyl. In some embodiments, at least one R1is trifluoromethyl. In some embodiments, at least one R1is difluoromethyl. In some embodiments, at least one R1is C1-C6 alkoxy. In some embodiments, at least one R1is C1-C4 alkoxy. In some embodiments, at least one R1is methoxy. In some embodiments, at least one R1is -NH(C=O)C1-C6 alkyl. In some embodiments, at least one R1is -NH(C=O)C1-C3 alkyl. In some embodiments, at least one R1is -NH(C=O)CH3. In some embodiments, at least one R1is -NHSO2C1-C6 alkyl. In some embodiments, at least one R1is -NHSO2C1-C3 alkyl. In some embodiments, at least one R1is -NHSO2CH3. In some embodiments, at least one R1is phenyl. In some embodiments, at least one R1is -NR1AR1B. Attorney Docket No.43820-0007P01 (SBP Ref.22-015-02PCT) In some embodiments, R1Ais hydrogen; and R1Bis C1-C6 alkyl. In some embodiments, R1Aand R1Bare each hydrogen. In some embodiments, R1Aand R1Bare independently selected C1-C6 alkyl. In some embodiments, R1Aand R1Bare independently selected C1-C3 alkyl. In some embodiments, R1Aand R1Bare each methyl. In some embodiments, at least one R1is 5-10 membered heteroaryl. In some embodiments, R1is 5-membered heteroaryl. In some embodiments, R1is 5-membered heteroaryl selected from the group consisting of pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, furanyl, thiophenyl, oxazolyl, isoxazolyl, isothiazolyl, thiazolyl, furzanyl, oxadiazolyl, thiadiazolyl, oxatriazolyl, and thiatriazolyl. In some embodiments, R1is tetrazolyl. In some embodiments, R1is 6-membered heteroaryl. In some embodiments, R1is 6- membered heteroaryl selected from the group consisting of pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, and triazinyl. In some embodiments, R1is pyridinyl, pyrimidinyl, pyridazinyl or pyrazinyl. In some embodiments, R1is pyridinyl, pyrimidinyl or pyridazinyl. In some embodiments, R1is pyridinyl or pyrimidinyl. In some embodiments, R1is pyridinyl. In some embodiments, m is 0. In some embodiments, n is 1. In some embodiments, n is 2. In some embodiments, n is 3. In some embodiments, Y is selected from the group , ,

[0003] Attorney Docket No.43820-0007P01 (SBP Ref.22-015-02PCT) , In some embodiments, Y is selected from the group , . is halogen. In some embodiments, at least one is fluoro. In some embodiments, at least one R2is chloro. In some embodiments, at least one R2is bromo. In some embodiments, at least one R2is nitro. In some embodiments, at least one R2is C1-C6 alkyl. In some embodiments, at least one R2is C1-C3 alkyl. In some embodiments, at least one R2is methyl. In some embodiments, at least one R2is phenyl. In some embodiments, at least one R2is 5-10 membered heteroaryl optionally substituted with 1-3 RA. In some embodiments, the R25-10 membered heteroaryl is a 5-6 membered heteroaryl. In some embodiments, the R25-10 membered heteroaryl is a 6 membered heteroaryl. In some embodiments, the R25-10 membered heteroaryl is a 6 membered heteroaryl selected from the group consisting of pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, and triazinyl. In some embodiments, the R25-10 membered heteroaryl is pyridinyl. In some embodiments, the R25-10 membered heteroaryl is 2-pyridinyl. In some embodiments, the R25-10 membered heteroaryl is 3-pyridinyl. In some embodiments, the R25-10 membered heteroaryl is 4-pyridinyl. In some embodiments, at least one RAis halogen. In some embodiments, at least one RAis chloro. In some embodiments, at least one RAis C1-C6 alkyl. In some embodiments, at least one RAis C1-C3 alkyl. In some embodiments, at least one RAis methyl. In some embodiments, at least one RAis 3-10 membered heterocyclyl. In some embodiments, RAis 5- Attorney Docket No.43820-0007P01 (SBP Ref.22-015-02PCT) 6 membered heterocyclyl. In some embodiments, RAis 6 membered heterocyclyl. In some embodiments, RAis 6 membered heterocyclyl selected from the group consisting of piperidinyl, tetrahydropyranyl, thianyl, morpholinyl, thiomorpholinyl, dioxanyl, piperazinyl, dithianyl, oxazinyl, tetrahydropyranonyl, piperidinonyl, dioxanonyl, oxazinanonyl, morpholinonyl, thiomorpholinonyl, piperazinonyl, tetrahydropyrimidinonyl, piperidinedionyl, oxazinanedionyl, dihydropyrimidindione, tetrahydropyridazinonyl, triazinanonyl, oxadiazinanonyl, dioxazinanonyl, morpholinedionyl, piperazinedionyl, piperazinetrionyl, and triazinanedionyl. In some embodiments, RAis morpholinyl. In some embodiments, RAis 4-morpholinyl. In some embodiments, n is 0. In some embodiments, at least two R2are independently selected halogen. In some embodiments, at least two R2are fluoro. In some embodiments, at least two R2are chloro. In some embodiments, at least two R2are bromo. In some embodiments, at least two R2are independently selected C1-C6 alkyl. In some embodiments, at least two R2are independently selected C1-C3 alkyl. In some embodiments, at least two R2are methyl. In some embodiments, at least two R2are independently selected C1-C6 haloalkyl. In some embodiments, at least two R2are independently selected C1-C3 haloalkyl. In some embodiments, at least two R2are trifluoromethyl. In some embodiments, at least two R2are independently selected C1-C6 alkoxy. In some embodiments, at least two R2are independently selected C1-C4 alkoxy. In some embodiments, at least two R2are methoxy. In some embodiments, X is O; Z is CH; m is 2 or 3; and n is 1. In some embodiments, X is O; Z is CH; m is 2; and n is 1. In some embodiments, X is O; Z is CH; m is 3; and n is 1. In some embodiments, X is O; Z is N; m is 2; and n is 1. In some embodiments, X is O; Z is N; m is 3; and n is 1. In some embodiments, X is S; Z is CH; m is 3; and n is 0 or 1. In some embodiments, X is S; Z is CH; m is 2 or 3; and n is 0 or 1. In some embodiments, X is S; Z is CH; m is 2; and n is 0 or 1. In some embodiments, X is S; Z is CH; m is 3; and n is 0 or 1. In some embodiments, X is O; Z is N; m is 3; Ring A is phenyl; and n is 1. In some embodiments, X is O; Z is N; m is 3; and n is 1. In some embodiments, X is O; Z is N; m is 2 or 3; and n is 1. In some . Attorney Docket No.43820-0007P01 (SBP Ref.22-015-02PCT) . . 5 . . . Attorney Docket No.43820-0007P01 (SBP Ref.22-015-02PCT) . In some . In some is selected from the group consisting of O , , In some is selected from the group consisting of . Attorney Docket No.43820-0007P01 (SBP Ref.22-015-02PCT) of , of Non-Limiting Exemplary Compounds In some embodiments, the compound is selected from the group consisting of the compounds in Examples 1-54 and Table A, or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is selected from the group consisting of the compounds in Examples 1-54, or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is selected from the group consisting of the compounds in Table A, or a pharmaceutically acceptable salt thereof. Pharmaceutical Compositions Some embodiments provide a pharmaceutical composition comprising a compound of Formula (I), or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients. Attorney Docket No.43820-0007P01 (SBP Ref.22-015-02PCT) Methods of Treatment Polycystic liver disease (PLD) is characterized by the development and growth of cholangiocyte-derived liver cysts. The pathogenesis of PLD involves defects in the primary cilium of the cholangiocyte that impair cilia function. Some patients are asymptomatic and require no therapeutic intervention, other patients suffer from a myriad of symptoms from the compressive effects of enlarged liver cysts, malnutrition, and liver decompensation. See, e.g., Masyuk, et al., (2017) 66, 4, pp.1197-1218. Provided herein are methods for treating a disease associated with TGR5 (e.g., PLD) by inhibiting the activity of TGR5. For example, provided herein are compounds that reduce or inhibit TGR5 function that are useful for treating a disease associated with TGR5. This reduction or inhibition of TGR5 function can be, for example, through allosteric binding that changes the conformation of the protein and reduces its affinity for one or more ligand(s), and / or through orthosteric binding that directly competes with one or more ligand(s) for binding to the receptor. The ability of test compounds to act as a TGR5 antagonist may be demonstrated by assays known in the art. The activity of the compounds and compositions provided herein as TGR5 antagonists can be assayed in vitro, in vivo, or in a cell line. In vitro assays include assays that determine activation of the protein and / or a change in its conformation. Potency of a TGR5 antagonist as provided herein can be determined by IC50value. A compound with a lower IC50value, as determined under substantially similar conditions, is a more potent TGR5 antagonist relative to a compound with a higher IC50value. Some embodiments provide a method of treating polycycstic liver disease (PLD) in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as provided herein. Some embodiments provide a method of treating PLD in a subject in need thereof, comprising (a) determining that the subject has PLD; and (b) administering to the subject a therapeutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as provided herein. In some embodiments, the methods described herein comprise determining that the subject has PLD. A subject can be determined to have PLD via varuous clinical methods, e.g., through the use of a regulatory agency-approved, e.g., FDA-approved test or assay for Attorney Docket No.43820-0007P01 (SBP Ref.22-015-02PCT) identifying PLD, in a subject or in a sample from the subject. In some embodiments, the test or assay is provided as a kit. Some embodiments provide a method of treating PLD, comprising administering to a subject identified or diagnosed as having PLD a therapeutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as provided herein. In some embodiments, the subject that has been identified or diagnosed as having PLD through the use of a regulatory agency-approved, e.g., FDA-approved test or assay for identifying PLD, in a subject or in a sample from the subject. In some embodiments, the test or assay is provided as a kit. In some embodiments of any of the methods or uses described herein, the subject has a clinical record indicating that the subject has PLD. Also provided are methods of treating a subject that include administering a therapeutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, to a subject having a clinical record that indicates that the subject has PLD. Some embodiments provide a method of treating cholangiocarcinoma, breast cancer, gastric adenocarcinoma, pancreatic cancer, lung cancer, liver cancer, colorectal cancer, or esophageal adenocarcinoma in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as provided herein. Some embodiments provide a method of treating cholangiocarcinoma, breast cancer, gastric adenocarcinoma, pancreatic cancer, lung cancer, liver cancer, colorectal cancer, or esophageal adenocarcinoma in a subject in need thereof, comprising (a) determining that the subject has cholangiocarcinoma, breast cancer, gastric adenocarcinoma, pancreatic cancer, lung cancer, liver cancer, colorectal cancer, or esophageal adenocarcinoma; and (b) administering to the subject a therapeutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as provided herein. In some embodiments, the methods described herein comprise determining that the subject has cholangiocarcinoma, breast cancer, gastric adenocarcinoma, pancreatic cancer, lung cancer, liver cancer, colorectal cancer, or esophageal adenocarcinoma. A subject can be determined to have cholangiocarcinoma, breast cancer, gastric adenocarcinoma, pancreatic cancer, lung cancer, liver cancer, colorectal cancer, or esophageal adenocarcinoma via varuous Attorney Docket No.43820-0007P01 (SBP Ref.22-015-02PCT) clinical methods, e.g., through the use of a regulatory agency-approved, e.g., FDA-approved test or assay for identifying cholangiocarcinoma, breast cancer, gastric adenocarcinoma, pancreatic cancer, lung cancer, liver cancer, colorectal cancer, or esophageal adenocarcinoma, in a subject or in a sample from the subject. In some embodiments, the test or assay is provided as a kit. Some embodiments provide a method of treating cholangiocarcinoma, breast cancer, gastric adenocarcinoma, pancreatic cancer, lung cancer, liver cancer, colorectal cancer, or esophageal adenocarcinoma, comprising administering to a subject identified or diagnosed as having cholangiocarcinoma, breast cancer, gastric adenocarcinoma, pancreatic cancer, lung cancer, liver cancer, colorectal cancer, or esophageal adenocarcinoma, a therapeutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as provided herein. In some embodiments, the subject that has been identified or diagnosed as having cholangiocarcinoma, breast cancer, gastric adenocarcinoma, pancreatic cancer, lung cancer, liver cancer, colorectal cancer, or esophageal adenocarcinoma through the use of a regulatory agency-approved, e.g., FDA-approved test or assay for identifying cholangiocarcinoma, breast cancer, gastric adenocarcinoma, pancreatic cancer, lung cancer, liver cancer, colorectal cancer, or esophageal adenocarcinoma, in a subject or in a sample from the subject. In some embodiments, the test or assay is provided as a kit. In some embodiments of any of the methods or uses described herein, the subject has a clinical record indicating that the subject has cholangiocarcinoma, breast cancer, gastric adenocarcinoma, pancreatic cancer, lung cancer, liver cancer, colorectal cancer, or esophageal adenocarcinoma. Also provided are methods of treating a subject that include administering a therapeutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, to a subject having a clinical record that indicates that the subject has cholangiocarcinoma, breast cancer, gastric adenocarcinoma, pancreatic cancer, lung cancer, liver cancer, colorectal cancer, or esophageal adenocarcinoma. Also provided herein is a method for inhibiting TGR5 activity in a mammalian cell, comprising contacting the mammalian cell with a compound of Formula (I), or a pharmaceutically acceptable salt thereof. In some embodiments, the contacting is in vitro. In some embodiments, the contacting is in vivo. In some embodiments, the contacting is in vivo, wherein the method comprises administering an effective amount of a compound of Formula (I), or a pharmaceutically Attorney Docket No.43820-0007P01 (SBP Ref.22-015-02PCT) acceptable salt thereof, to a subject having a cell comprising TGR5. As used herein, the term “contacting” refers to the bringing together of indicated moieties in an in vitro system or an in vivo system. For example, “contacting” a TGR5 protein with a compound provided herein includes the administration of a compound provided herein to an individual or subject, such as a human, having a TGR5 protein, as well as, for example, introducing a compound provided herein into a sample containing a cellular or purified preparation containing the TGR5 protein. EXAMPLES Compound Preparation The compounds disclosed herein can be prepared in a variety of ways using commercially available starting materials, compounds known in the literature, or from readily prepared intermediates, by employing standard synthetic methods and procedures either known to those skilled in the art, or in light of the teachings herein. The synthesis of the compounds disclosed herein can be achieved by generally following the schemes provided herein, with modification for specific desired substituents. Standard synthetic methods and procedures for the preparation of organic molecules and functional group transformations and manipulations can be obtained from the relevant scientific literature or from standard textbooks in the field. Although not limited to any one or several sources, classic texts such as R. Larock, Comprehensive Organic Transformations, VCH Publishers (1989); L. Fieser and M. Fieser, Fieser and Fieser's Reagents for Organic Synthesis, John Wiley and Sons (1994); Smith, M. B., March, J., March' s Advanced Organic Chemistry: Reactions, Mechanisms, and Structure, 5th edition, John Wiley & Sons: New York, 2001; and Greene, T.W., Wuts, P.G. M., Protective Groups in Organic Synthesis, 3rd edition, John Wiley & Sons: New York, 1999, are useful and recognized reference textbooks of organic synthesis known to those in the art. The following descriptions of synthetic methods are designed to illustrate, but not to limit, general procedures for the preparation of compounds of the present disclosure. The synthetic processes disclosed herein can tolerate a wide variety of functional groups; therefore, various substituted starting materials can be used. The processes generally provide the desired final compound at or near the end of the overall process, although it may be desirable in certain instances to further convert the compound to a pharmaceutically acceptable salt thereof. Attorney Docket No.43820-0007P01 (SBP Ref.22-015-02PCT) Preparation of Compounds All the compounds listed in Table A can be prepared using the procedures described in General Procedure A – General Procedure E sections described in Schemes 1-5. Scheme 1: General Procedure A. Reagents and conditions: (a) toluene, K2CO3, copper acetate, Ph3P, Tetrakis(triphenylphosphine)palladium (0), 110 °C (b) EtOAc, T3P, Et3N, 60 °C. Scheme 2: General Procedure B: Reagents and conditions: (a) POCl3, 100 °C (b) MeOH, Pd / C 10%, H2 (c) EtOAc, T3P, Et3N, 60 °C. Attorney Docket No.43820-0007P01 (SBP Ref.22-015-02PCT) R4R4H2N(a)H(b)N Et3N, tetrahydroxydiboron, MeOH, 60 °C (c) EtOAc, T3P, Et3N, 60 °C. °C (b) Zn, NH4Cl, water (c) POCl3, 100 °C (d) MeOH, H2, 10% Pd / C (e) EtOAc, T3P, Et3N, 60 °C Scheme 5: General Procedure E: Reagents and conditions: a. SOCl2, THF, 60 °C overnight then Pyridine, THF, 2-amino-5-bromopyridin-3-ol, 60 °C (23A), overnight; b. DDQ, PPh3, Dioxane, 110 °C, overnight ; c. Tetrahydroxydiboron, triethylamine, methanol, 60 °C, 1.5h ; Attorney Docket No.43820-0007P01 (SBP Ref.22-015-02PCT) d.3,4-difluoro-2-chlorobenzoic acid (4A), Pyridine, thionyl chloride, THF, DMF, 60 °C, overnight. Compounds 299-304 listed in Table B can be prepared using the procedures described in General Procedure G according to Scheme 6. F F R R dioxane: water (4:1), 100 °C / 130 °C, MW, 30 min; (b) FeSO4 ^7H2O, NH4Cl, Zn, EtOH: water (5:1), 50 °C, 22 h or B2(OH)4, 4,4’-bipyridine, DMF, RT, 1 h; (c) PyCIU, (i-Pr)2NEt, DMF, 80 °C, 16 h General Procedure A: Example 1. Preparation of 2-chloro-N-(3-(5-chlorobenzo[d]oxazol-2-yl)-2- methylphenyl)-4-nitrobenzamid (Compound 1) Step 1: Synthesis of 3-(5-chlorobenzo[d]oxazol-2-yl)-2-methylaniline: Attorney Docket No.43820-0007P01 (SBP Ref.22-015-02PCT) To a solution of 2-methyl-3-bromoaniline (15 mmol, 1.85 mL) in toluene (30 ml) was added 5-chloro-benzoxazole (20 mmol, 3.06 g), potassium carbonate (30 mmol, 4.1g ), copper acetate (3.8 mmol, 688 mg), triphenylphosphine (12 mmol, 3.14g), and lastly Tetrakis(triphenylphosphine)palladium(0) (3 mmol, 3.0 g). The mixture was heated at reflux for 1.5 h open to the atmosphere. The reaction mixture was cooled to RT. The mixture was filtered through a large paper filter and the filtrate was diluted with ethyl acetate and washed with saturated NaHCO3 and brine. The organic phase was dried over sodium sulfate, filtered, reduced in vacuo and the crude material was diluted with ethyl ether, a pinkish powdery material was filtered off. The ether phase was concentrated in vacuo to afford a dark material consisting of 3-(5-chlorobenzo[d]oxazol-2-yl)-2-methylaniline (8 g) and other impurities. This mixture was taken on into the next step as is. LC-MS (ESI): M / Z = 259 (M+1)+. Step 2: Synthesis of 2-chloro-N-(3-(5-chlorobenzo[d]oxazol-2-yl)-2-methylphenyl)-4- nitrobenzamid: (Compound 1) To a solution of crude 3-(5-chlorobenzo[d]oxazol-2-yl)-2-methylaniline (8.0 g) in ethyl acetate (100 mL) was added 2-chloro-4-nitrobenzoic acid (20 mmol, 4.0 g) trimethylamine (60 mmol, 8.4 mL) followed by tri-n-propylphosphonic anhydride (50% solution in ethyl acetate, (60 mmol, 19.4 mL). The mixture was heated at 60 °C for 24h. The reaction was cooled to RT, diluted with ethyl acetate (500 mL) and poured into water. The organic phase was washed with a 10% aqueous HCl solution, followed by a brine wash and a saturated NaHCO3wash. The organic phase was dried over anhydrous sodium sulfate, decanted, and reduced in vacuo. The title compound was obtained as 3.7 g grey powder (57%) The MS showed a clean mass at 442 (M + H). The product is further purified on an ISCO silica gel column using CHCl3- MeOH (0 - 3 % gradient) to afford the title compound (3.1 g) as a white powder. The LC-MS (ESI): M / Z = 443 (M+1)+, 47% overall yield for two steps. Example 2. Preparation of N-(3-(5-chlorobenzo[d]oxazol-2-yl)-2-methylphenyl)-2- fluoro-4-nitrobenzamide (Compound 290) Attorney Docket No.43820-0007P01 (SBP Ref.22-015-02PCT) To a solution of crude 3-(5-chlorobenzo[d]oxazol-2-yl)-2-methylaniline (0.3 mmol, 130 mg) in ethyl acetate (10 mL) was added 2-fluoro-4-nitrobenzoic acid (0.33 mmol, 61 mg) trimethylamine (1.2 mmol, 1.7 mL) followed by tri-n-propylphosphonic anhydride (50% solution in ethyl acetate, (1.2 mmol, 1.7 mL). The mixture was heated at 60 °C for 24h. The reaction was cooled to RT, diluted with ethyl acetate (50 mL) and poured into water. The organic phase was washed with a 10% aqueous HCl solution, followed by a brine wash and a saturated NaHCO3 wash. The organic phase was dried over anhydrous sodium sulfate, decanted, and reduced in vacuo. The desired product was obtained as a grey powder. The MS showed a clean mass at 427 (M+H). The product was further purified on an ISCO silica gel column using CHCl3-MeOH (0 - 3 % gradient) to afford the title compound (51 mg) as a white powder. The LC-MS (ESI): M / Z = 427 (M+1)+, 40% overall yield. Example 3. Preparation of N-(3-(5-chlorobenzo[d]oxazol-2-yl)-2-methylphenyl)-2- methyl-4-nitrobenzamide (Compound 6) To a solution of crude 3-(5-chlorobenzo[d]oxazol-2-yl)-2-methylaniline in ethyl acetate (10 mL) was added 2-methyl-4-nitrobenzoic acid (0.33 mmol, 59 mg) trimethylamine (1.2 mmol, 1.7 mL) followed by tri-n-propylphosphonic anhydride (50% solution in ethyl acetate, (1.2 mmol, 1.7 mL). The mixture was heated at 60 °C for 24h. The reaction was cooled to RT, diluted with ethyl acetate (50 mL) and poured into water. The organic phase was washed with a 10% aqueous HCl solution, followed by a brine wash and a saturated NaHCO3 wash. The organic phase is dried over anhydrous sodium sulfate, decanted, and reduced in vacuo. The desired product was obtained as a grey powder. The MS showed a clean mass at 423 (M+H). The product was purified on an ISCO silica gel column using CHCl3- MeOH (0 - 3 % gradient) to afford the desired product (64 mg) as a white powder. The LC-MS (ESI): M / Z = 423 (M+1)+, 51% overall yield. Example 4. Preparation of N-(3-(5-chlorobenzo[d]oxazol-2-yl)-2-methylphenyl)-4- nitrobenzamide (Compound 10) Attorney Docket No.43820-0007P01 (SBP Ref.22-015-02PCT) To a solution of crude 3-(5-chlorobenzo[d]oxazol-2-yl)-2-methylaniline in ethyl acetate (10 mL) was added 4-nitrobenzoic acid (0.33 mmol, 55 mg) trimethylamine (1.2 mmol, 1.7 mL) followed by tri-n-propylphosphonic anhydride (50% solution in ethyl acetate, (1.2 mmol, 1.7 mL). The mixture was heated at 60 °C for 24h. The reaction was cooled to RT, diluted with 50 ml of ethyl acetate and poured into water. The organic phase was washed with a 10% aqueous HCl solution, followed by a brine wash and a saturated NaHCO3wash. The organic phase was dried over anhydrous sodium sulfate, decanted, and reduced in vacuo. The desired product was obtained as a grey powder. The MS showed a clean mass at 408 (M+H). The product was purified on an ISCO silica gel column using CHCl3- MeOH (0 - 3 % gradient) to afford the title compound (38 mg) as a white powder. The LC-MS (ESI): M / Z = 408 (M+1)+, 33% overall yield. Example 5. Preparation of N-(3-(5-chlorobenzo[d]oxazol-2-yl)-2-methylphenyl)-4-nitro- 2-(trifluoromethyl)benzamide (Compound 11) To a solution of crude 3-(5-chlorobenzo[d]oxazol-2-yl)-2-methylaniline (0.3 mmol, 130 mg) in ethyl acetate (10 ml) was added 2-trifluoromethyl-4-nitrobenzoic acid (0.33 mmol, 78 mg) trimethylamine (1.2 mmol, 1.7 mL) followed by tri-n-propylphosphonic anhydride (50% solution in ethyl acetate, (1.2 mmol, 1.7 mL). The mixture was heated at 60 °C for 24h. The reaction was cooled to RT, diluted with ethyl acetate (50 mL) and poured into water. The organic phase was washed with a 10% aqueous HCl solution, followed by a brine wash and a saturated NaHCO3 wash. The organic phase was dried over anhydrous sodium sulfate, decanted, and reduced in vacuo. The desired product was obtained as a grey powder. The MS showed a clean mass at 477 (M+H). The product is further purified on an ISCO silica gel Attorney Docket No.43820-0007P01 (SBP Ref.22-015-02PCT) column using CHCl3- MeOH (0 - 3 % gradient) to afford 54 mg of the title compound as a white powder. The LC-MS (ESI): M / Z = 476 (M+1)+, 38% overall yield. Example 6. Preparation of 2-chloro-N-(3-(5-chlorobenzo[d]oxazol-2-yl)-2- methylphenyl)-3-nitrobenzamide (Compound 12) To a solution of crude 3-(5-chlorobenzo[d]oxazol-2-yl)-2-methylaniline (0.3 mmol, 130 mg) in ethyl acetate (10 mL) was added 2-chloro-3-nitrobenzoic acid (0.33 mmol, 78 mg) trimethylamine (1.2 mmol, 1.7 mL) followed by tri-n-propylphosphonic anhydride (50% solution in ethyl acetate, (1.2 mmol, 1.7 mL). The mixture was heated at 60 °C for 24h. The reaction was cooled to RT, diluted with ethyl acetate (50 mL) and poured into water. The organic phase was washed with a 10% aqueous HCl solution, followed by a brine wash and a saturated NaHCO3 wash. The organic phase is dried over anhydrous sodium sulfate, decanted, and reduced in vacuo. The desired product was obtained as a grey powder. The MS showed a clean mass at 443 (M+H). The product is further purified on an ISCO silica gel column using CHCl3- MeOH (0 - 3 % gradient) to afford the title compound (37 mg) as a white powder. The LC-MS (ESI): M / Z = 442 (M+1)+, 28% overall yield. Example 7. Preparation of 2-bromo-N-(3-(5-chlorobenzo[d]oxazol-2-yl)-2- methylphenyl)-4-nitrobenzamide (Compound 14) To a solution of crude 3-(5-chlorobenzo[d]oxazol-2-yl)-2-methylaniline (0.3 mmol, 130 mg) in ethyl acetate (10 mL) was added 2-bromo-4-nitrobenzoic acid (0.33 mmol, 161 mg) trimethylamine (1.2 mmol, 1.7 mL) followed by tri-n-propylphosphonic anhydride (50% Attorney Docket No.43820-0007P01 (SBP Ref.22-015-02PCT) solution in ethyl acetate, (1.2 mmol, 1.7 mL). The mixture was heated at 60 °C for 24h. The reaction was cooled to RT, diluted with ethyl acetate (50 mL) and poured into water. The organic phase was washed with a 10% aqueous HCl solution, followed by a brine wash and a saturated NaHCO3wash. The organic phase was dried over anhydrous sodium sulfate, decanted, and reduced in vacuo. The desired product was obtained as a grey powder. The MS showed a clean mass at 488 (M+H). The product is further purified on an ISCO silica gel column using CHCl3- MeOH (0 - 3 % gradient) to afford the title compound (59 mg) as a white powder. The LC-MS (ESI): M / Z = 488 (M+1)+, 40% overall yield. Example 8. Preparation of N-(3-(5-chlorobenzo[d]oxazol-2-yl)-2-methylphenyl)-2,4- difluorobenzamide (Compound 48) To a solution of crude 3-(5- - (0.3 mmol, 130 mg) in ethyl acetate (10 mL) was added 2,4-difluorobenzoic acid (0.33 mmol, 52 mg) trimethylamine (1.2 mmol, 1.7 mL) followed by tri-n-propylphosphonic anhydride (50% solution in ethyl acetate, (1.2 mmol, 1.7 mL). The mixture was heated at 60 °C for 24h. The reaction was cooled to RT, diluted with ethyl acetate (50 mL) and poured into water. The organic phase was washed with a 10% aqueous HCl solution, followed by a brine wash and a saturated NaHCO3 wash. The organic phase was dried over anhydrous sodium sulfate, decanted, and reduced in vacuo. The desired product was obtained as a grey powder. The MS showed a clean mass at 399 (M+H). The product was further purified on an ISCO silica gel column using CHCl3- MeOH (0 - 3 % gradient) to afford the title compound (59 mg) as a white powder. The LC-MS (ESI): M / Z = 399 (M+1)+, 52% overall yield. Example 9. Preparation of N-(3-(5-chlorobenzo[d]oxazol-2-yl)-2-methylphenyl)-4- cyano-2-fluorobenzamide (Compound 50) Attorney Docket No.43820-0007P01 (SBP Ref.22-015-02PCT) To a solution of crude 3-(5-chlorobenzo[d]oxazol-2-yl)-2-methylaniline (0.3 mmol, 130 mg) in ethyl acetate (10 mL) was added 4-cyano-2-fluorobenzoic acid (0.33 mmol, 54 mg) trimethylamine (1.2 mmol, 1.7 mL) followed by tri-n-propylphosphonic anhydride (50% solution in ethyl acetate, (1.2 mmol, 1.7 mL). The mixture was heated at 60 °C for 24h. The reaction was cooled to RT, diluted with ethyl acetate (50 mL) and poured into water. The organic phase was washed with a 10% aqueous HCl solution, followed by a brine wash and a saturated NaHCO3 wash. The organic phase was dried over anhydrous sodium sulfate, decanted, and reduced in vacuo. The desired product was obtained as a grey powder. The MS showed a clean mass at 406 (M+H). The product was purified on an ISCO silica gel column using CHCl3- MeOH (0 - 3 % gradient) to afford the title compound (51 mg) as a white powder. The LC-MS (ESI): M / Z = 406 (M+1)+, 42% overall yield. Example 10. Preparation of N-(3-(5-chlorobenzo[d]oxazol-2-yl)-2-methylphenyl)-2,3,4- trifluorobenzamide (Compound 54) To a solution of crude 3-(5-chlorobenzo[d]oxazol-2-yl)-2-methylaniline (0.3 mmol, 130 mg) in ethyl acetate (10 mL) was added 2,3,4-trifluorobenzoic acid (0.33 mmol, 53 mg) trimethylamine(1.2 mmol, 1.7 mL) followed by tri-n-propylphosphonic anhydride (50% solution in ethyl acetate, (1.2 mmol, 1.7 mL). The mixture was heated at 60 °C for 24h. The reaction was cooled to RT, diluted with ethyl acetate (50 mL) and poured into water. The organic phase is washed with a 10% aqueous HCl solution, followed by a brine wash and a saturated NaHCO3 wash. The organic phase is dried over anhydrous sodium sulfate, decanted, and reduced in vacuo. The desired product was obtained as a grey powder. The MS showed a clean mass at 417 (M+H). The product is further purified on an ISCO silica gel Attorney Docket No.43820-0007P01 (SBP Ref.22-015-02PCT) column using CHCl3- MeOH (0 - 3 % gradient) to afford the title compound (37 mg) as a white powder. The LC-MS (ESI): M / Z = 417(M+1)+, 38% overall yield. Example 11. Preparation of 4-chloro-N-(3-(5-chlorobenzo[d]oxazol-2-yl)-2- methylphenyl)-2-fluorobenzamide (Compound 52) To a solution of crude 3-(5-chlorobenzo[d]oxazol-2-yl)-2-methylaniline (0.3 mmol, 130 mg) in ethyl acetate (10 mL) was added 4-chloro-2-fluorobenzoic acid (0.33 mmol, 57 mg) trimethylamine (1.2 mmol, 1.7 mL) followed by tri-n-propylphosphonic anhydride (50% solution in ethyl acetate, (1.2 mmol, 1.7 mL). The mixture was heated at 60 °C for 24h. The reaction was cooled to RT, diluted with ethyl acetate (50 mL) and poured into water. The organic phase was washed with a 10% aqueous HCl solution, followed by a brine wash and a saturated NaHCO3 wash. The organic phase was dried over anhydrous sodium sulfate, decanted, and reduced in vacuo. The desired product was obtained as a grey powder. The MS showed a clean mass at 416 (M+H). The product was purified on an ISCO silica gel column using CHCl3- MeOH (0 - 3 % gradient) to afford the title compound (60 mg) as a white powder. The LC-MS (ESI): M / Z = 416 (M+1)+, 48% overall yield. Example 12. Preparation of 4-bromo-2-chloro-N-(3-(5-chlorobenzo[d]oxazol-2-yl)-2- methylphenyl)benzamide (Compound 55) To a solution of crude 3-(5-chlorobenzo[d]oxazol-2-yl)-2-methylaniline (0.3 mmol, 130 mg) in ethyl acetate (10 mL) was added 4-bromo-2-chlorobenzoic acid (4L) (0.33 mmol, 77 mg) trimethylamine (1.2 mmol, 1.7 mL) followed by tri-n-propylphosphonic anhydride (50% Attorney Docket No.43820-0007P01 (SBP Ref.22-015-02PCT) solution in ethyl acetate, (1.2 mmol, 1.7 mL). The mixture was heated at 60 °C for 24h. The reaction was cooled to RT, diluted with ethyl acetate (50 mL) and poured into water. The organic phase was washed with a 10% aqueous HCl solution, followed by a brine wash and a saturated NaHCO3wash. The organic phase is dried over anhydrous sodium sulfate, decanted, and reduced in vacuo. The desired product was obtained as a grey powder. The MS showed a clean mass at 477 M+H). The product was purified on an ISCO silica gel column using CHCl3- MeOH (0 - 3 % gradient) to afford the title compound (43 mg) as a white powder. The LC-MS (ESI): M / Z = 477 (M+1)+, 30% overall yield. Example 13. Preparation of 3-chloro-N-(3-(5-chlorobenzo[d]oxazol-2-yl)-2- methylphenyl)-[1,1'-biphenyl]-4-carboxamide (Compound 56) To a solution of crude 3- - (0.3 mmol, 130 mg) in ethyl acetate (10 mL) was added 3-chloro-[1,1'-biphenyl]-4-carboxylic acid (4M) (0.33 mmol, 77 mg) trimethylamine (1.2 mmol, 1.7 mL) followed by tri-n-propylphosphonic anhydride (50% solution in ethyl acetate, (1.2 mmol, 1.7 mL). The mixture is heated at 60 °C for 24h. The reaction is cooled to RT, diluted with ethyl acetate (50 mL) and poured into water. The organic phase is washed with a 10% aqueous HCl solution, followed by a brine wash and a saturated NaHCO3 wash. The organic phase is dried over anhydrous sodium sulfate, decanted, and reduced in vacuo. The desired product was obtained as a grey powder. The MS showed a clean mass at 474 (M+H). The product is further purified on an ISCO silica gel column using CHCl3- MeOH (0 - 3 % gradient) to afford the title compound (73 mg) as a white powder. The LC-MS (ESI): M / Z = 474 (M+1)+, 52% overall yield. Example 14. Preparation of N-(3-(benzo[d]thiazol-2-yl)-2-methylphenyl)-2-chloro-4- nitrobenzamide (Compound 2) Attorney Docket No.43820-0007P01 (SBP Ref.22-015-02PCT) Step 1. Preparation of 3-(benzo[d]thiazol-2-yl)-2-methylaniline: To a solution of 2-methyl-3-bromoaniline (10 mmol, 1.23 mL) in toluene (25 mL) was added benzothiazole (5 mmol, 900 mg), followed by potassium carbonate (10 mmol, 1.38 g), triphenylphosphine (5 mmol, 1.31 g), copper acetate (1.25 mmol, 226 mg), and Tetrakis(triphenylphosphine)palladium (0) (1.25 mmol, 1.4 g). The mixture was heated at reflux for 2h, open to the atmosphere. After cooling to RT, the mixture is filtered through a paper filter, and the filtrate is diluted with ethyl acetate and the organic phase is washed with saturated NaHCO3, brine and dried over anhydrous Na2SO4. The organic phase is then reduced in vacuo to afford 3-(benzo[d]thiazol-2-yl)-2-methylaniline (1.12 g, 39%) as a light grey powder. This mixture is taken on into the next step as is. The LC-MS (ESI): M / Z = 241 (M+1)+. Step 2. Preparation of N-(3-(benzo[d]thiazol-2-yl)-2-methylphenyl)-2-chloro-4- nitrobenzamide (Compound 2) To a solution of crude 3-(benzo[d]thiazol-2-yl)-2-methylaniline (1.12 g) in ethyl acetate (100 mL) was added 2- chloro-4-nitrobenzoic acid (20 mmol, 400 mg) trimethylamine (6 mmol, 0.84 mL) followed by tri-n-propylphosphonic anhydride (50% solution in ethyl acetate, (6 mmol, 1.9 mL). The mixture is heated at 60 °C for 24h. The reaction is cooled to RT, diluted with ethyl acetate (100 mL), and poured into water. The organic phase is washed with a 10% aqueous HCl solution, followed by a brine wash and a saturated HaHCO3 wash. The organic phase is dried over anhydrous sodium sulfate, decanted, and reduced in vacuo. The desired product was obtained as 380 mg grey powder (47% ) The product is further purified on an ISCO column using MeOH-CHCl3eluents (0 - 5 % gradient) to afford the title compound (310 mg) as a white powder. The LC-MS (ESI): M / Z = 426 (M+1)+, 37% overall yield for two steps. Example 15. Preparation of N-(3-(benzo[d]thiazol-2-yl)-2-methylphenyl)-2-fluoro-4- nitrobenzamide (Compound 5) Attorney Docket No.43820-0007P01 (SBP Ref.22-015-02PCT) To a solution of crude 3-(benzo[d]thiazol-2-yl)-2-methylaniline (0.3 mmol, 72 mg) in ethyl acetate (15 mL) was added 2-fluoro-4-nitrobenzoic acid (0.33 mmol, 61 mg) trimethylamine (1.2 mmol, 1.7 mL) followed by tri-n-propylphosphonic anhydride (50% solution in ethyl acetate, (1.2 mmol, 1.7 mL). The mixture is heated at 60 °C for 24h. The reaction is cooled to RT, diluted with ethyl acetate (50 mL) and poured into water. The organic phase is washed with a 10% aqueous HCl solution, followed by a brine wash and a saturated NaHCO3 wash. The organic phase is dried over anhydrous sodium sulfate, decanted, and reduced in vacuo. The desired product was obtained as a grey powder. The MS showed a clean mass at 408 (M+H). The product is further purified on an ISCO silica gel column using CHCl3-MeOH (0 - 3 % gradient) to afford the title compound (39 mg) as a white powder. The LC-MS (ESI): M / Z = 408 (M+1)+, 32% overall yield. Example 16. Preparation of N-(3-(benzo[d]thiazol-2-yl)-2-methylphenyl)-4-nitro-2- (trifluoromethyl)benzamide (Compound 291) To a solution of crude 3-(benzo[d]thiazol-2-yl)-2-methylaniline (0.3 mmol, 72 mg) in ethyl acetate (15 mL) was added 4-nitro-2-(trifluoromethyl)benzoic acid (0.33 mmol, 78 mg) trimethylamine (1.2 mmol, 1.7 mL) followed by tri-n-propylphosphonic anhydride (50% solution in ethyl acetate, (1.2 mmol, 1.7 mL). The mixture is heated at 60 °C for 24h. The reaction is cooled to RT, diluted with ethyl acetate (50 mL) and poured into water. The organic phase is washed with a 10% aqueous HCl solution, followed by a brine wash and a saturated NaHCO3wash. The organic phase is dried over anhydrous sodium sulfate, decanted, and reduced in vacuo. The desired product was obtained as a grey powder. The MS showed a clean mass at 458 (M+H). The product is further purified on an ISCO silica gel Attorney Docket No.43820-0007P01 (SBP Ref.22-015-02PCT) column using CHCl3- MeOH (0 - 3 % gradient) to afford the title compound (38 mg) as a white powder. The LC-MS (ESI): M / Z = 458 (M+1)+, 28% overall yield. Example 17. Preparation of N-(3-(benzo[d]thiazol-2-yl)-5-fluoro-2-methylphenyl)-4- cyano-2,3-difluorobenzamide (Compound 292) Step 1. Preparation of 3-(benzo[d]thiazol-2-yl)-5-fluoro-2-methylaniline: To a solution of 3-bromo-5-fluoro-2-methylaniline (10 mmol, 1.55 mL) in toluene (25 mL) was added benzothiazole (5 mmol, 900 mg), followed by potassium carbonate (10 mmol, 1.38 g), triphenylphosphine (5 mmol, 1.31 g), copper acetate (1.25 mmol, 226 mg), and Tetrakis(triphenylphosphine)palladium (0) (1.25 mmol, 1.4 g). The mixture was heated at reflux for 2h, open to the atmosphere. After cooling to RT, the mixture is filtered through a paper filter, and the filtrate is diluted with ethyl acetate and the organic phase is washed with saturated NaHCO3, brine and dried over anhydrous Na2SO4. The organic phase is then reduced in vacuo to afford crude 3-(benzo[d]thiazol-2-yl)-5-fluoro-2-methylaniline (1.43 g, 45%) as a light grey powder. This mixture is taken on into the next step as is. The LC-MS (ESI): M / Z = 259 (M+1)+. Step 2. Preparation of N-(3-(benzo[d]thiazol-2-yl)-5-fluoro-2-methylphenyl)-4-cyano-2,3- difluorobenzamide (Compound 292): To a solution of crude 3-(benzo[d]thiazol-2-yl)-5-fluoro-2-methylaniline (0.3 mmol, 72 mg) in ethyl acetate (15 mL) was added 4-cyano-2,3-difluorobenzoic acid (0.33 mmol, 60 mg) trimethylamine (1.2 mmol, 1.7 mL) followed by tri-n-propylphosphonic anhydride (50% solution in ethyl acetate, (1.2 mmol, 1.7 mL). The mixture is heated at 60 °C for 24h. The reaction is cooled to RT, diluted with ethyl acetate (50 mL) and poured into water. The organic phase is washed with a 10% aqueous HCl solution, followed by a brine wash and a saturated NaHCO3 wash. The organic phase is dried over anhydrous sodium sulfate, Attorney Docket No.43820-0007P01 (SBP Ref.22-015-02PCT) decanted, and reduced in vacuo. The desired product was obtained as a grey powder. The MS showed a clean mass at 424 (M + H). The product is further purified on an ISCO silica gel column using CHCl3- MeOH (0 - 3 % gradient) to afford the title compound (48 mg) as a white powder. The LC-MS (ESI): M / Z = 424 (M+1)+, 38% overall yield. Example 18. Preparation of N-(3-(benzo[d]thiazol-2-yl)-5-fluoro-2-methylphenyl)-2- chloro-3,4-difluorobenzamide (Compound 293) To a solution of crude 3- (0.3 mmol, 72 mg) in ethyl acetate (15 mL) was added 2-chloro-3,4-difluorobenzoic acid (0.33 mmol, 60 mg) trimethylamine (1.2 mmol, 1.7 mL) followed by tri-n-propylphosphonic anhydride (50% solution in ethyl acetate, (1.2 mmol, 1.7 mL). The mixture is heated at 60 °C for 24h. The reaction is cooled to RT, diluted with ethyl acetate (50 mL) and poured into water. The organic phase is washed with a 10% aqueous HCl solution, followed by a brine wash and a saturated NaHCO3wash. The organic phase is dried over anhydrous sodium sulfate, decanted, and reduced in vacuo. The desired product was obtained as a grey powder. The MS showed a clean mass at 433 (M+H). The product is further purified on an ISCO silica gel column using CHCl3- MeOH (0 - 3 % gradient) to afford the title compound (45 mg) as a white powder. The LC-MS (ESI): M / Z = 433 (M+1)+, 35% overall yield. Example 19. Preparation of N-(3-(benzo[d]thiazol-2-yl)-5-fluoro-2-methylphenyl)-4- cyano-2,5-difluorobenzamide (Compound 294)

[0004] Attorney Docket No.43820-0007P01 (SBP Ref.22-015-02PCT) To a solution of crude 3-(benzo[d]thiazol-2-yl)-5-fluoro-2-methylaniline (0.3 mmol, 72 mg) in ethyl acetate (15 mL) was added 4-cyano-2,5-difluorobenzoic acid (0.33 mmol, 60 mg) trimethylamine (1.2 mmol, 1.7 mL) followed by tri-n-propylphosphonic anhydride (50% solution in ethyl acetate, (1.2 mmol, 1.7 mL). The mixture is heated at 60 °C for 24h. The reaction is cooled to RT, diluted with 50 ml of ethyl acetate and poured into water. The organic phase is washed with a 10% aqueous HCl solution, followed by a brine wash and a saturated NaHCO3 wash. The organic phase is dried over anhydrous sodium sulfate, decanted, and reduced in vacuo. The desired product was obtained as a grey powder. The MS showed a clean mass at 424 (M+H). The product is further purified on an ISCO silica gel column using CHCl3- MeOH (0 - 3 % gradient) to afford the title compound (48 mg) as a white powder. The LC-MS (ESI): M / Z = 424 (M+1)+, 38% overall yield. General Procedure B: Example 20. Preparation of N-(3-(6-chlorobenzo[d]oxazol-2-yl)-2-methylphenyl)-2- fluoro-4-nitrobenzamide (Compound 3) Step 1: Preparation of 6-chloro-2-(2-methyl-3-nitrophenyl)benzo[d]oxazole: To 5 ml of POCl3was added 3-nitro-2-methylbenzoic acid (10 mmol, 1.57 g) and 2-amino-4- chlorophenol (10 mmol, 1.57 g) and this mixture was heated to 100 °C overnight. The reaction was cooled to room temperature and the POCl3was removed under vacuum. The residue was dissolved in ethyl acetate (100 mL) and sat. NaHCO3 (100 mL) and the layers were separated, the organic phase was dried over sodium sulfate, filtered, and evaporated under reduced pressure. The product further purified on an ISCO column silica using hexane- DCM eluents to afford of 6-chloro-2-(2-methyl-3-nitrophenyl)benzo[d]oxazole (2.5 g, 86% yield) as a white powder. The LC-MS (ESI): M / Z = 289 (M+1)+. Step 2: Preparation of 3-(6-chlorobenzo[d]oxazol-2-yl)-2-methylaniline: Attorney Docket No.43820-0007P01 (SBP Ref.22-015-02PCT) To 100 ml of MeOH was added 6-chloro-2-(2-methyl-3-nitrophenyl)benzo[d]oxazole (10 mmol, 2.88 g) and 500 mg of 5% Pd / C. The air was evacuated under vacuum and replaced by hydrogen gas (balloon). The reaction was stirred overnight, and the reaction was filtered through celite®, and the solvent removed under vacuum to yield 3-(6-chlorobenzo[d]oxazol- 2-yl)-2-methylaniline (2.5 g, 98% yield) as a white solid. The LC-MS (ESI): M / Z = 259 (M+1)+. Step 3: Preparation of N-(3-(6-chlorobenzo[d]oxazol-2-yl)-2-methylphenyl)-2-fluoro-4- nitrobenzamide (Compound 3) To a solution of 3-(6-chlorobenzo[d]oxazol-2-yl)-2-methylaniline (2.5 g) in ethyl acetate (100 mL) was added 2-fluoro-4-nitrobenzoic acid (20 mmol, 3.8 g) trimethylamine (60 mmol, 8.4 mL) followed by tri-n-propylphosphonic anhydride (50% solution in ethyl acetate, (60 mmol, 19.4 mL). The mixture is heated at 60 °C for 24h. The reaction is cooled to RT, diluted with ethyl acetate (500 mL), and poured into water. The organic phase is washed with a 10% aqueous HCl solution, followed by a brine wash and a saturated NaHCO3wash. The organic phase is dried over anhydrous sodium sulfate, decanted, and reduced in vacuo. The product was further purified on an ISCO column using CHCl3- MeOH (0 - 3 % gradient) to afford (2.9 g, 68% yield) of the title compound as a white powder. The LC-MS (ESI): M / Z = 426 (M+1)+. Example 21. Preparation of N-(3-(6-chlorobenzo[d]oxazol-2-yl)-2-methylphenyl)-4- nitro-2-(trifluoromethyl)benzamide (Compound 17) To a solution of 3-(6-chlorobenzo[d]oxazol-2-yl)-2-methylaniline (52 mg, 0.2 mmol) in ethyl acetate (10 mL) was added 2-trifluoromethyl-4-nitrobenzoic acid (0.22 mmol, 44 mg) trimethylamine (6 mmol, 0.8 mL) followed by tri-n-propylphosphonic anhydride (50% solution in ethyl acetate, (6 mmol, 1.9 mL). The mixture is heated at 60 °C for 24h. The reaction is cooled to RT, diluted with ethyl acetate (100 mL), and poured into water. The organic phase is washed with a 10% aqueous HCl solution, followed by a brine wash and a Attorney Docket No.43820-0007P01 (SBP Ref.22-015-02PCT) saturated NaHCO3 wash. The organic phase is dried over anhydrous sodium sulfate, decanted, and reduced in vacuo. The crude product was purified on an ISCO column using CHCl3-MeOH (0 - 3 % gradient) to afford the title compound (22 mg, 50% yield) as a white powder. The LC-MS (ESI): M / Z = 476 (M+1)+. Example 22. Preparation of 2-chloro-N-(3-(6-chlorobenzo[d]oxazol-2-yl)-2- methylphenyl)-4-nitrobenzamide (Compound 22) To a solution of 3-(6-chlorobenzo[d]oxazol-2-yl)-2-methylaniline (52 mg, 0.2 mmol) in ethyl acetate (10 mL) was added 4-nitro-2-(chloro)benzoic acid (0.22 mmol, 52 mg) trimethylamine (6 mmol, 0.8 mL) followed by tri-n-propylphosphonic anhydride (50% solution in ethyl acetate, (6 mmol, 1.9 mL). The mixture is heated at 60 °C for 24h. The reaction was cooled to RT, diluted with ethyl acetate (100 mL), and poured into water. The organic phase is washed with a 10% aqueous HCl solution, followed by a brine wash and a saturated NaHCO3 wash. The organic phase is dried over anhydrous sodium sulfate, decanted, and reduced in vacuo. The crude product was purified on an ISCO column using CHCl3-MeOH (0 - 3 % gradient) to afford the title compound (52 mg, 55% yield) as a white powder. The LC-MS (ESI): M / Z = 442 (M+1)+. Example 23. Preparation of N-(3-(6-chlorobenzo[d]oxazol-2-yl)-2-methylphenyl)-2,3,4- trifluorobenzamide (Compound 44) To a solution of 3-(6-chlorobenzo[d]oxazol-2-yl)-2-methylaniline (52 mg, 0.2 mmol) in ethyl acetate (10 mL) was added 2,3,4-trifluorobenzoic acid (0.22 mmol, 39 mg) trimethylamine (6 mmol, 0.8 mL) followed by tri-n-propylphosphonic anhydride (50% solution in ethyl acetate, Attorney Docket No.43820-0007P01 (SBP Ref.22-015-02PCT) (6 mmol, 1.9 mL). The mixture was heated at 60 °C for 24h. The reaction is cooled to RT, diluted with ethyl acetate (100 mL), and poured into water. The organic phase was washed with a 10% aqueous HCl solution, followed by a brine wash and a saturated NaHCO3 wash. The organic phase was dried over anhydrous sodium sulfate, decanted, and reduced in vacuo. The crude product was purified on an ISCO column using CHCl3-MeOH (0 - 3 % gradient) to afford the title compound (40 mg, 48% yield) as a white powder. The LC-MS (ESI): M / Z = 417 (M+1)+. Example 24. Preparation of N-(5-bromo-3-(6-chlorobenzo[d]oxazol-2-yl)-2- methylphenyl)-2-fluoro-4-nitrobenzamide (Compound 117) To a solution of 5- - (75 mg, 0.2 mmol) in ethyl acetate (10 mL) was added 2-fluoro-4-nitrobenzoic acid (0.22 mmol, 41 mg) trimethylamine (6 mmol, 0.8 mL) followed by tri-n-propylphosphonic anhydride (50% solution in ethyl acetate, (6 mmol, 1.9 mL). The mixture was heated at 60oC for 24h. The reaction was cooled to RT, diluted with ethyl acetate (100 mL), and poured into water. The organic phase was washed with a 10% aqueous HCl solution, followed by a brine wash and a saturated NaHCO3wash. The organic phase was dried over anhydrous sodium sulfate, decanted, and reduced in vacuo. The crude product was purified on an ISCO column using CHCl3-MeOH (0 - 3 % gradient) to afford the title compound (38 mg, 38% yield) as a white powder. The LC-MS (ESI): M / Z = 503 (M+1)+. Example 25. Preparation of N-(5-bromo-3-(6-chlorobenzo[d]oxazol-2-yl)-2- methylphenyl)-2-chloro-4-nitrobenzamide (Compound 118) Attorney Docket No.43820-0007P01 (SBP Ref.22-015-02PCT) To a solution of 5-bromo-3-(6-chlorobenzo[d]oxazol-2-yl)-2-methylaniline (75 mg, 0.2 mmol) in ethyl acetate (10 mL) was added 2-chloro-4-nitrobenzoic acid (0.22 mmol, 41 mg) trimethylamine (6 mmol, 0.8 mL) followed by tri-n-propylphosphonic anhydride (50% solution in ethyl acetate, (6 mmol, 1.9 mL). The mixture was heated at 60 °C for 24h. The reaction was cooled to RT, diluted with ethyl acetate (100 mL), and poured into water. The organic phase was washed with a 10% aqueous HCl solution, followed by a brine wash and a saturated NaHCO3 wash. The organic phase was dried over anhydrous sodium sulfate, decanted, and reduced in vacuo. The crude product was purified on an ISCO column using CHCl3-MeOH (0 - 3 % gradient) to afford the title compound (52 mg, 50% yield) as a white powder. The LC-MS (ESI): M / Z = 522 (M+1)+. Example 26. Preparation of N-(5-bromo-3-(6-chlorobenzo[d]oxazol-2-yl)-2- methylphenyl)-2,4-dichlorobenzamide (Compound 119) To a solution of 5-bromo-3-(6-chlorobenzo[d]oxazol-2-yl)-2-methylaniline (75 mg, 0.2 mmol) in ethyl acetate (10 mL) was added 2,4-dichlorobenzoic acid (0.22 mmol, 42 mg) trimethylamine (6 mmol, 0.8 mL) followed by tri-n-propylphosphonic anhydride (50% solution in ethyl acetate, (6 mmol, 1.9 mL). The mixture was heated at 60 °C for 24h. The reaction was cooled to RT, diluted with ethyl acetate (100 mL), and poured into water. The organic phase was washed with a 10% aqueous HCl solution, followed by a brine wash and a saturated NaHCO3 wash. The organic phase was dried over anhydrous sodium sulfate, decanted, and reduced in vacuo. The crude product was purified on an ISCO column using Attorney Docket No.43820-0007P01 (SBP Ref.22-015-02PCT) CHCl3-MeOH (0 - 3 % gradient) to afford the title compound (56 mg, 55% yield) as a white powder. The LC-MS (ESI): M / Z = 511 (M+1)+. Example 27. Preparation of N-(5-bromo-3-(6-chlorobenzo[d]oxazol-2-yl)-2- methylphenyl)-2,3,4-trifluorobenzamide (Compound 120) To a solution of 5-bromo- (75 mg, 0.2 mmol) in ethyl acetate (10 mL) was added 2,3,4-trifluorobenzoic acid (0.22 mmol, 39 mg) trimethylamine (6 mmol, 0.8 mL) followed by tri-n-propylphosphonic anhydride (50% solution in ethyl acetate, (6 mmol, 1.9 mL). The mixture was heated at 60 °C for 24h. The reaction was cooled to RT, diluted with ethyl acetate (100 mL), and poured into water. The organic phase was washed with a 10% aqueous HCl solution, followed by a brine wash and a saturated NaHCO3 wash. The organic phase was dried over anhydrous sodium sulfate, decanted, and reduced in vacuo. The crude product was purified on an ISCO column using CHCl3-MeOH (0 - 3 % gradient) to afford the title compound (47 mg, 48% yield) as a white powder. The LC-MS (ESI): M / Z = 496 (M+1)+. Example 28. Preparation of 3'-(6-chlorobenzo[d]oxazol-2-yl)-4'-methyl-5'-(2,3,4- trifluorobenzamido)-[1,1'-biphenyl]-4-carboxamide (Compound 127)

[0005] Attorney Docket No.43820-0007P01 (SBP Ref.22-015-02PCT) To a solution of 3'-amino-5'-(6-chlorobenzo[d]oxazol-2-yl)-4'-methyl-[1,1'-biphenyl]-4- carboxamide (75.4 mg, 0.2 mmol) in ethyl acetate (10 mL) was added 2,3,4-trifluorobenzoic acid (0.22 mmol, 39 mg) trimethylamine (6 mmol, 0.8 mL) followed by tri-n- propylphosphonic anhydride (50% solution in ethyl acetate, (6 mmol, 1.9 mL). The mixture was heated at 60 °C for 24h. The reaction was cooled to RT, diluted with ethyl acetate (100 mL), and poured into water. The organic phase was washed with a 10% aqueous HCl solution, followed by a brine wash and a saturated NaHCO3 wash. The organic phase was dried over anhydrous sodium sulfate, decanted, and reduced in vacuo. The crude product was purified on an ISCO column using CHCl3-MeOH (0 - 3 % gradient) to afford the title compound (42 mg, 39% yield) as a white powder. The LC-MS (ESI): M / Z = 536 (M+1)+. General Procedure C: Example 29: Preparation of N-(3-(5-chloro-1H-benzo[d]imidazol-2-yl)-5-fluoro-2- methylphenyl)-4-cyano-2,3-difluorobenzamide (Compound 4) Step 1: Preparation of 5-chloro-2-(5-fluoro-2-methyl-3-nitrophenyl)-1H-benzo[d]imidazole: To mixture of 4-chloro-orthophenylene diamine (216 mg, 2 mmol) was added 5-fluoro-3- nitro- 2-methyl-benzoic acid (2 mmol) and a stir bar. To this mixture was added POCl3(3 mL) and the mixture was then heated at 100 °C for 18h. The dark mixture was then cooled to RT and diluted with ethyl acetate (200 mL). To this mixture was added water / ice to destroy the POCl3. The organics were shaken with water and the organic layer was separated, dried over sodium sulfate, filtered, and reduced in vacuo. The organics were then scraped out and washed with ethyl ether. The tan material was taken on as crude solid. The LC-MS (ESI): M / Z =306 (M+1)+. Step 2: Preparation of 3-(5-chloro-1H-benzo[d]imidazol-2-yl)-5-fluoro-2-methylaniline: Attorney Docket No.43820-0007P01 (SBP Ref.22-015-02PCT) Crude 3-(5-chloro-1H-benzo[d]imidazol-2-yl)-5-fluoro-2-methylaniline was dissolved in MeOH (20 mL) and tetrahydroxydiboron (5 mmol, 445 mg) was added and trimethylamine (2 mL) was added. The mixture was heated at 60 °C for 2h. The mixture was cooled to room temperature and reduced in vacuo. The mixture was taken up in ethyl acetate (100 mL) and water (100 mL) and shaken. The layers were separated, and the organic layer was dried over anhydrous sodium sulphate, filtered, and was reduced in vacuo to afford 300 mg (61 %) of 3- (1H-benzo[d]imidazol-2-yl)-5-fluoro-2-methylaniline as a tan-brown solid. This material was taken on as crude solid. The LC-MS (ESI): M / Z = 277 (M+1)+. Step 3: Preparation of N-(3-(5-chloro-1H-benzo[d]imidazol-2-yl)-5-fluoro-2-methylphenyl)- 4-cyano-2,3-difluorobenzamide (compound 4) To a solution of crude 3-(1H-benzo[d]imidazol-2-yl)-5-fluoro-2-methylaniline in ethyl acetate (100 mL) was added 4-cyano-2,3-difluorobenzoic acid (2 mmol, 368 mg) trimethylamine (6 mmol, 0.84 mL) followed by tri-n-propylphosphonic anhydride (50% solution in ethyl acetate, (6 mmol, 1.9 mL). The mixture was heated at 60 °C for 24h. The reaction was cooled to RT, diluted with ethyl acetate (200 mL) and poured into water. The organic phase was washed with a 10% aqueous HCl solution, followed by a brine wash and a saturated NaHCO3 wash. The organic phase was dried over anhydrous sodium sulfate, filtered, and reduced in vacuo. The desired product was obtained as 3.7 g grey powder (57%) The product was purified on an ISCO column using CHCl3-MeOH (0 - 3 % gradient) to afford the title compound (310 mg, 40% yield) as a white powder. The LC-MS (ESI): M / Z = 442 (M+1)+. Example 30: Preparation of 2-chloro-N-(3-(5-chloro-1H-benzo[d]imidazol-2-yl)-5- fluoro-2-methylphenyl)-3,4-difluorobenzamide (Compound 295) To a solution of the crude material 100 mg above in ethyl acetate (30 mL) was added 4- cyano-2,3-difluorobenzoic acid (0.22 mmol, 37 mg) trimethylamine (3 mmol, 0.4 mL) Attorney Docket No.43820-0007P01 (SBP Ref.22-015-02PCT) followed by tri-n-propylphosphonic anhydride (50% solution in ethyl acetate, (3 mmol, 0.9 mL). The mixture is heated at 60 °C for 24h. The reaction was cooled to RT, diluted with ethyl acetate (100 mL) and poured into water. The organic phase was washed with a 10% aqueous HCl solution, followed by a brine wash and a saturated NaHCO3wash. The organic phase was dried over anhydrous sodium sulfate, filtered, and reduced in vacuo. The desired product was obtained as a grey powder. The product is further purified on an ISCO column using CHCl3- MeOH (0 - 3 % gradient) to afford the title compound (54 mg, 60% yield) as a white powder. The LC-MS (ESI): M / Z = 451 (M+1)+. Example 31: Preparation of 2-chloro-3,4-difluoro-N-(5-fluoro-3-(5-fluoro-1H- benzo[d]imidazol-2-yl)-2-methylphenyl)benzamide (Compound 296) To a solution of crude 3- - 2-methylaniline (100 mg) in ethyl acetate (30 mL) was added 2-chloro-3,4-difluorobenzoic acid (0.22 mmol, 37 mg) trimethylamine (3 mmol, 0.4 mL) followed by tri-n-propylphosphonic anhydride (50% solution in ethyl acetate, (3 mmol, 0.9 mL). The mixture was heated at 60 °C for 24h. The reaction was cooled to RT, diluted with ethyl acetate (100 mL) and poured into water. The organic phase was washed with a 10% aqueous HCl solution, followed by a brine wash and a saturated NaHCO3 wash. The organic phase was dried over anhydrous sodium sulfate, filtered, and reduced in vacuo. The desired product was obtained as grey powder, which was purified on an ISCO column using CHCl3-MeOH (0 - 3 % gradient) to afford the title compound (26 mg, 31% yield) as a white powder. The LC-MS (ESI): M / Z = 425 (M+1)+. Example 32: Preparation of 2-chloro-3,4-difluoro-N-(5-fluoro-3-(5-fluoro-1H- benzo[d]imidazol-2-yl)-2-methylphenyl)benzamide (Compound 297) Attorney Docket No.43820-0007P01 (SBP Ref.22-015-02PCT) To a solution of crude 3-(5- -5-fluoro-2-methylaniline (100 mg) in ethyl acetate (30 mL) was added 2-chloro-3,4-difluorobenzoic acid (0.22 mmol, 37 mg) trimethylamine (3 mmol, 0.4 mL) followed by tri-n-propylphosphonic anhydride (50% solution in ethyl acetate, (3 mmol, 0.9 mL). The mixture was heated at 60 °C for 24h. The reaction was cooled to RT, diluted with ethyl acetate (100 mL) and poured into water. The organic phase was washed with a 10% aqueous HCl solution, followed by a brine wash and a saturated NaHCO3 wash. The organic phase was dried over anhydrous sodium sulfate, filtered, and reduced in vacuo. The desired product was obtained as grey powder. The product was purified on an ISCO column using CHCl3-MeOH (0 - 3 % gradient) to afford the title compound (32 mg, 38% yield) as a white powder. The LC-MS (ESI): M / Z = 425 (M+1)+. General Procedure D: Example 33. Preparation of 4-chloro-N-(3-(5-chloro-1H-imidazo[4,5-b]pyridin-2-yl)-5- fluoro-2-methylphenyl)-2,3-difluorobenzamide (Compound 264) Step 1: Preparation of 6-chloro-2-nitropyridin-3-ol: Potassium nitrate (14 g, 138.4 mmol) was added in several portions to a mixture of 2- chloropyridine-5-ol (10 g, 77.2 mmol) in concentrated sulphuric acid (50 mL) at 0 °C and further stirred at room temperature for 16 hours. After completion of the reaction, the mixture Attorney Docket No.43820-0007P01 (SBP Ref.22-015-02PCT) was poured over crushed ice and the solid was filtered and dried to obtain 6-chloro-2- nitropyridin-3-ol (5 g, 78% yield). The LC-MS (ESI): M / Z = 175 (M+1)+. Step 2: Preparation of 2-amino-6-chloropyridin-3-ol: To a solution of 6-chloro-2-nitropyridin-3-ol (21 g, 126 mmol) in THF (250 mL) was added ammonium chloride (51.1 g, 965 mmol) in water (250 mL) and zinc dust (62.7 g, 965 mmol) and the mixture was stirred at room temperature for 1 hour. The zinc metal was filtered through celite®, the filtrate was extracted with ethyl acetate and the organic layer was removed under vacuum to obtain 2-amino-6-chloropyridin-3-ol (13.3 g, 75% yield). The LC- MS (ESI): M / Z = 145 (M+1)+. Step 3: Preparation of 5-chloro-2-(5-fluoro-2-methyl-3-nitrophenyl)-1H-imidazo[4,5- b]pyridine: To mixture of 2-amino-6-chloropyridin-3-ol (216 mg, 2 mmol) was added 5-fluoro-3-nitro-2- methy-5-fluoro-benzoic acid (2 mmol) and a stir bar. To this mixture was added POCl3(3 mL) and the mixture was then heated at 100 °C for 18h. The dark mixture was then cooled to RT and diluted with ethyl acetate (200 mL). To this mixture was added water / ice to destroy the POCl3. The organics were shaken with water and the organic layer was separated, dried over sodium sulfate, filtered, and reduced in vacuo. The organics were then scraped out and washed with ethyl ether. The Title compound was obtained as a tan material, which was taken on as is. The LC-MS (ESI): M / Z =306 (M+1)+. Step 4: Preparation of 3-(5-chloro-1H-imidazo[4,5-b]pyridin-2-yl)-5-fluoro-2-methylaniline: To MeOH (100 mL) was added 5-chloro-2-(5-fluoro-2-methyl-3-nitrophenyl)-1H- benzo[d]imidazole (5 mmol, 1.44 g) and 5% Pd / C (500 mg). The air was evacuated under vacuum and replaced by hydrogen gas (balloon). The reaction was stirred overnight, and the reaction was filtered through celite®, and the solvent removed under vacuum to yield 3-(6- chloro-1H-benzo[d]imidazol-2-yl)-5-fluoro-2-methylaniline (1.25 g, 98%) as a white solid. The product was used without further purification in the next step. The LC-MS (ESI): M / Z = 277 (M+1)+. Step 5: Preparation of 4-chloro-N-(3-(5-chloro-1H-imidazo[4,5-b]pyridin-2-yl)-5-fluoro-2- methylphenyl)-2,3-difluorobenzamide (Compound 264) Attorney Docket No.43820-0007P01 (SBP Ref.22-015-02PCT) To a solution of crude 3-(6-chloro-1H-benzo[d]imidazol-2-yl)-5-fluoro-2-methylaniline in ethyl acetate (100 mL) was added 4-chloro-2,3-difluorobenzoic acid (2 mmol, 184 mg) trimethylamine (6 mmol, 0.84 mL) followed by tri-n-propylphosphonic anhydride (50% solution in ethyl acetate, (6 mmol, 1.9 mL). The mixture was heated at 60 °C for 24h. The reaction was cooled to RT, diluted with ethyl acetate (200 mL) and poured into water. The organic phase was washed with a 10% aqueous HCl solution, followed by a brine wash and a saturated NaHCO3 wash. The organic phase was dried over anhydrous sodium sulfate, filtered, and reduced in vacuo. The desired product was obtained as a grey powder (1.8 g). The product was purified on an ISCO column using CHCl3-MeOH (0 - 3 % gradient) to afford the title compound (330 mg, 40% yield) as a white powder. The LC-MS (ESI): M / Z = 453 (M+1)+. Example 34. Preparation of N-(3-(5-chloro-1H-imidazo[4,5-b]pyridin-2-yl)-5-fluoro-2- methylphenyl)-2-fluoro-4-nitrobenzamide (Compound X) To a solution of crude 3-(6-chloro-1H-benzo[d]imidazol-2-yl)-5-fluoro-2-methylaniline (100 mg) in ethyl acetate (100 mL) was added 2-fluoro-4-nitrobenzoic acid (2 mmol, 370 mg) trimethylamine (6 mmol, 0.84 mL) followed by tri-n-propylphosphonic anhydride (50% solution in ethyl acetate, (6 mmol, 1.9 mL). The mixture is heated at 60 °C for 24h. The reaction was cooled to RT, diluted with ethyl acetate (200 mL) and poured into water. The organic phase was washed with a 10% aqueous HCl solution, followed by a brine wash and a saturated NaHCO3 wash. The organic phase was dried over anhydrous sodium sulfate, filtered, and reduced in vacuo. The desired product was obtained as 2.1 g dark grey powder. The product is further purified on an ISCO column using CHCl3-MeOH (0 - 3 % gradient) to afford the title compound (107 mg, 40% yield) as a white powder. The LC-MS (ESI): M / Z = 444 (M+1)+. Example 35. Preparation of 2,4-dichloro-N-(3-(5-chloro-1H-imidazo[4,5-b]pyridin-2-yl)- 5-fluoro-2-methylphenyl)benzamide (Compound 269) Attorney Docket No.43820-0007P01 (SBP Ref.22-015-02PCT) To a solution of crude 3-(6- 5-fluoro-2-methylaniline 100 mg in ethyl acetate (100 mL) was added 2,4-dichlorobenzoic acid (2 mmol, 382 mg) trimethylamine (6 mmol, 0.84 mL) followed by tri-n-propylphosphonic anhydride (50% solution in ethyl acetate, (6 mmol, 1.9 mL). The mixture was heated at 60 °C for 24h. The reaction was cooled to RT, diluted with ethyl acetate (200 mL) and poured into water. The organic phase was washed with a 10% aqueous HCl solution, followed by a brine wash and a saturated NaHCO3wash. The organic phase was dried over anhydrous sodium sulfate, filtered, and reduced in vacuo. The desired product was obtained as 1.9 g dark grey powder, which was further purified on an ISCO column using CHCl3- MeOH (0 - 3 % gradient) to afford the title compound (369 mg, 44% yield) as a white powder. The LC-MS (ESI): M / Z = 451 (M+1)+. Example 36. Preparation of 2-chloro-N-(3-(5-chloro-1H-imidazo[4,5-b]pyridin-2-yl)-5- fluoro-2-methylphenyl)-3,4-difluorobenzamide: (Compound 273) To a solution of crude 3-(6-chloro-1H-benzo[d]imidazol-2-yl)-5-fluoro-2-methylaniline 100 mg in ethyl acetate (100 mL) was added 2-chloro-3,4-difluorobenzoic acid (2 mmol, 384 mg) trimethylamine (6 mmol, 0.84 mL) followed by tri-n-propylphosphonic anhydride (50% solution in ethyl acetate, (6 mmol, 1.9 mL). The mixture was heated at 60 °C for 24h. The reaction was cooled to RT, diluted with ethyl acetate (200 mL) and poured into water. The organic phase was washed with a 10% aqueous HCl solution, followed by a brine wash and a saturated NaHCO3 wash. The organic phase was dried over anhydrous sodium sulfate, Attorney Docket No.43820-0007P01 (SBP Ref.22-015-02PCT) filtered, and reduced in vacuo. The desired product was obtained as a dark grey powder (1.6 g), which was further purified on an ISCO column using CHCl3-MeOH (0 - 3 % gradient) to afford the title compound (344 mg, 38% yield) as a white powder. The LC-MS (ESI): M / Z = 453 (M+1)+. General Procedure E: Example 37. Preparation of N-(3-(6-bromooxazolo[4,5-b]pyridin-2-yl)-5-fluoro-2- methylphenyl)-2-chloro-3,4-difluorobenzamide (Compound 289) Step 1: 2-yl)-5-fluoro-2-methyl-3- nitrobenzamide: To a solution of 2-methyl-3-nitro-5-fluorobenzoic acid (10 g, 0.050 mol) in THF (100 mL) was added 20 mL of thionyl chloride (0.274 mol), then stirred at 60 °C overnight. After it was cooled to room temperature, the mixture was evaporated in vacuum and poured into dry THF (200 mL, dry pyridine (20 mL, 0.251 mol) was dropped into the solution of THF, then of 2- amino-5-bromopyridin-3-ol (10.4 g 0.055 mol) was added and stirred at 60 °C overnight, the mixture solution was evaporated and extracted with EtOAc, washed with 0.5 N HCl solution and the organic layers were combined and dried over sodium sulfate and filtered. After evaporation under vacuum, the crude material was filtered to afford N-(5-bromo-3- hydroxypyridin-2-yl)-5-fluoro-2-methyl-3-nitrobenzamide (16.7 g, 90% yield). The LC-MS (ESI): M / Z = 371 (M+1)+. Step 2: Preparation of 6-bromo-2-(5-fluoro-2-methyl-3-nitrophenyl)oxazolo[4,5-b]pyridine: N-(5-bromo-3-hydroxypyridin-2-yl)-5-fluoro-2-methyl-3-nitrobenzamide (10 g, 0.027 mol) was dissolved in dry dioxane (200 mL). DDQ (18.5 g, 0.081 mol) and PPh3(21.3 g, 0.081 mol) were added. The mixture solution was heated at 110 °C overnight. When the reaction was determined to be complete by LCMS, the reaction mixture was cooled to room temperature Attorney Docket No.43820-0007P01 (SBP Ref.22-015-02PCT) and concentrated under reduced pressure. The resulting mixture was chromatographed on silica gel and eluted with dichloromethane (100%) to afford the product (5.7 g, 60% yield). The LC- MS (ESI): M / Z = 352 (M+1)+. Step 3: Preparation of 3-(6-bromooxazolo[4,5-b]pyridin-2-yl)-5-fluoro-2-methylaniline: To a solution of 6-bromo-2-(5-fluoro-2-methyl-3-nitrophenyl)-oxazolo[4,5-b]pyridine (3.0 g, 8.5 mmol) in HPLC grade methanol (70 mL) at 60 °C was added 3.8 g (42 mmol) of tetrahydroxydiboron followed by triethylamine (1 mL). The solution was kept at 60 °C for 90 min or more. When the reaction was determined to be complete by LCMS, the reaction mixture was cooled to room temperature and filtered to afford the product (1.2 g, 44 % yield). The LC- MS (ESI): M / Z = 322 (M+1)+. Step 4: Preparation of N-(3-(6-bromooxazolo[4,5-b]pyridin-2-yl)-5-fluoro-2-methylphenyl)-2- chloro-3,4-difluorobenzamide (Compound 289) To a solution of 2-chloro-3,4-diflulorobenzoic acid (8 g, 0.042 mol) in THF (100 mL) was added thionyl chloride (20 mL, 0.274 mol), then stirred at 60 °C overnight. After it was cooled to room temperature, the mixture was evaporated in vacuum and poured into dry THF (200 mL), then dry pyridine (10 mL, 0.125 mol) was dropped into the solution in THF, then of 3- (6-bromooxazolo[4,5-b]pyridin-2-yl)-5-fluoro-2-methylaniline (4.5g, 0.014 mol) was added, then dry DMF (150 mL) was added and stirred at 60 °C overnight. The mixture solution was evaporated and extracted with EtOAc, washed with 0.5 N NaOH solution, the organic layers were combined and dried over MgSO4. After evaporation under vacuum, the crude mixture was chromatographed on silica gel and eluted with dichloromethane and ethyl acetate (10%) to afford the title compound as a white solid (6 g, 86% yield). The LC-MS (ESI): M / Z = 496 (M+1)+. Example 38. Preparation of N-(3-(6-bromooxazolo[4,5-b]pyridin-2-yl)-5-fluoro-2- methylphenyl)-4-cyano-2,3-difluorobenzamide (Compound 236) Attorney Docket No.43820-0007P01 (SBP Ref.22-015-02PCT) To a solution of 4-cyano- mmol) in THF (10 mL) was added thionyl chloride (1 mL), then stirred at 60 °C overnight. After it was cooled to room temperature, the mixture was evaporated in vacuum and dry THF (10 mL), then dry pyridine (1 mL) was dropped into the solution in THF, then of 3-(6-bromooxazolo[4,5-b]pyridin-2- yl)-5-fluoro-2-methylaniline (141 mg, 0.44 mmol) was added, then dry DMF (5 mL) was added and stirred at 60 °C overnight. The mixture solution was evaporated and extracted with EtOAc, washed with 0.5 N NaOH solution, the organic layers were combined and dried over MgSO4. After evaporation under vacuum, the crude mixture was chromatographed on silica gel and eluted with dichloromethane and ethyl acetate (10%) to afford the title compound (64 mg, 33% yield) as a white solid. The LC-MS (ESI): M / Z = 488 (M+1)+. Example 39. Preparation of N-(3-(6-bromooxazolo[4,5-b]pyridin-2-yl)-5-fluoro-2- methylphenyl)-4-cyano-2,5-difluorobenzamide (Compound 237) To a solution of 4-cyano-2,5-difluorobenzoic acid (73 mg, 0.40 mmol) in THF (10 mL) was added thionyl chloride (1 mL), then stirred at 60 °C overnight. After it was cooled to room temperature, the mixture was evaporated in vacuum and dry THF (10 mL), then dry pyridine (1 mL) was dropped into the solution in THF, then of 3-(6-bromooxazolo[4,5-b]pyridin-2- yl)-5-fluoro-2-methylaniline (141 mg, 0.44 mmol) was added, then dry DMF (5 mL) was added and stirred at 60 °C overnight. The mixture solution was evaporated and extracted with EtOAc, washed with 0.5 N NaOH solution, the organic layers were combined and dried over MgSO4. After evaporation under vacuum, the crude mixture was chromatographed on Attorney Docket No.43820-0007P01 (SBP Ref.22-015-02PCT) silica gel and eluted with dichloromethane and ethyl acetate (10%) to afford the title compound (78 mg, 40% yield) as a white solid. The LC-MS (ESI): M / Z = 488 (M+1)+. Example 40. Preparation of N-(3-(6-bromooxazolo[4,5-b]pyridin-2-yl)-5-fluoro-2- methylphenyl)-2-fluoro-4-nitrobenzamide (Compound 234) To a solution of 2-fluoro-4-nitrobenzoic acid (75 mg, 0.40 mmol) in THF (10 mL) was added thionyl chloride (1 mL), then stirred at 60 °C overnight. After it was cooled to room temperature, the mixture was evaporated in vacuum and dry THF (10 mL), then dry pyridine (1 mL) was dropped into the solution in THF, then of 3-(6-bromooxazolo[4,5-b]pyridin-2- yl)-5-fluoro-2-methylaniline (141 mg, 0.44 mmol) was added, then dry DMF (5 mL) was added and stirred at 60 °C overnight. The mixture solution was evaporated and extracted with EtOAc, washed with 0.5 N NaOH solution, the organic layers were combined and dried over MgSO4. After evaporation under vacuum, the crude mixture was chromatographed on silica gel and eluted with dichloromethane and ethyl acetate (10%) to afford the title compound (75 mg, 38% yield) as a white solid. The LC-MS (ESI): M / Z = 489 (M+1)+. Example 41. Preparation of 4-bromo-N-(3-(6-bromooxazolo[4,5-b]pyridin-2-yl)-5-fluoro- 2-methylphenyl)-2-fluorobenzamide (Compound 245) To a solution of 2-fluoro-4-bromobenzoic acid (87 mg, 0.40 mmol) in THF (10 mL) was added thionyl chloride (1 mL), then stirred at 60 °C overnight. After it was cooled to room temperature, the mixture was evaporated in vacuum and dry THF (10 mL), then dry pyridine Attorney Docket No.43820-0007P01 (SBP Ref.22-015-02PCT) (1 mL) was dropped into the solution in THF, then of 3-(6-bromooxazolo[4,5-b]pyridin-2- yl)-5-fluoro-2-methylaniline (141 mg, 0.44 mmol) was added, then dry DMF (5 mL) was added and stirred at 60 °C overnight. The mixture solution was evaporated and extracted with EtOAc, washed with 0.5 N NaOH solution, the organic layers were combined and dried over MgSO4. After evaporation under vacuum, the crude mixture was chromatographed on silica gel and eluted with dichloromethane and ethyl acetate (10%) to afford the title compound (69 mg, 33% yield) as a white solid. The LC-MS (ESI): M / Z = 524 (M+1)+. Example 42. Preparation of N-(3-(6-bromooxazolo[4,5-b]pyridin-2-yl)-5-fluoro-2- methylphenyl)-4-chloro-2-fluorobenzamide (Compound 244) To a solution of 2-fluoro-4-chlorobenzoic acid (87 mg, 0.40 mmol) in THF (10 mL) was added thionyl chloride (1 mL), then stirred at 60 °C overnight. After it was cooled to room temperature, the mixture was evaporated in vacuum and dry THF (10 mL), then dry pyridine (1 mL) was dropped into the solution in THF, then of 3-(6-bromooxazolo[4,5-b]pyridin-2- yl)-5-fluoro-2-methylaniline (141 mg, 0.44 mmol) was added, then dry DMF (5 mL) was added and stirred at 60 °C overnight. The mixture solution was evaporated and extracted with EtOAc, washed with 0.5 N NaOH solution, the organic layers were combined and dried over MgSO4. After evaporation under vacuum, the crude mixture was chromatographed on silica gel and eluted with dichloromethane and ethyl acetate (10%) to afford the title compound (69 mg, 41% yield) as a white solid. The LC-MS (ESI): M / Z = 479 (M+1)+. Example 43. Preparation of N-(3-(6-bromooxazolo[4,5-b]pyridin-2-yl)-5-fluoro-2- methylphenyl)-3-chloro-2-fluorobenzamide (Compound 246) Attorney Docket No.43820-0007P01 (SBP Ref.22-015-02PCT) To a solution of 3-chloro-2-fluorobenzoic acid (87 mg, 0.40 mmol) in THF (10 mL) was added thionyl chloride (1 mL), then stirred at 60 °C overnight. After it was cooled to room temperature, the mixture was evaporated in vacuum and dry THF (10 mL), then dry pyridine (1 mL) was dropped into the solution in THF, then of 3-(6-bromooxazolo[4,5-b]pyridin-2- yl)-5-fluoro-2-methylaniline (141 mg, 0.44 mmol) was added, then dry DMF (5 mL) was added and stirred at 60 °C overnight. The mixture solution was evaporated and extracted with EtOAc, washed with 0.5 N NaOH solution, the organic layers were combined and dried over MgSO4. After evaporation under vacuum, the crude mixture was chromatographed on silica gel and eluted with dichloromethane and ethyl acetate (10%) afford the title compound (86 mg, 45% yield) as a white solid. The LC-MS (ESI): M / Z = 479 (M+1)+. Example 44. Preparation of N-(3-(6-bromooxazolo[4,5-b]pyridin-2-yl)-5-fluoro-2- methylphenyl)-2-chlorobenzamide (Compound 261) To a solution of 2-chlorobenzoic acid (62 mg, 0.40 mmol) in THF (10 mL) was added thionyl chloride (1 mL), then stirred at 60 °C overnight. After it was cooled to room temperature, the mixture was evaporated in vacuum and dry THF (10 mL), then dry pyridine (1 mL) was dropped into the solution in THF, then of 3-(6-bromooxazolo[4,5-b]pyridin-2-yl)-5-fluoro-2- methylaniline (141 mg, 0.44 mmol) was added, then dry DMF (5 mL) was added and stirred at 60 °C overnight. The mixture solution was evaporated and extracted with EtOAc, washed with 0.5 N NaOH solution, the organic layers were combined and dried over MgSO4. After evaporation under vacuum, the crude mixture was chromatographed on silica gel and eluted Attorney Docket No.43820-0007P01 (SBP Ref.22-015-02PCT) with dichloromethane and ethyl acetate (10%) to afford the title compound (92 mg, 50% yield) as a white solid. The LC-MS (ESI): M / Z = 461 (M+1)+. Example 45. Preparation of N-(3-(6-bromooxazolo[4,5-b]pyridin-2-yl)-5-fluoro-2- methylphenyl)-4-cyano-2-methylbenzamide (Compound 262) To a solution of 4-cyano- in THF (10 mL) was added thionyl chloride (1 mL), then stirred at 60 °C overnight. After it was cooled to room temperature, the mixture was evaporated in vacuum and dry THF (10 mL), then dry pyridine (1 mL) was dropped into the solution in THF, then of 3-(6-bromooxazolo[4,5-b]pyridin-2- yl)-5-fluoro-2-methylaniline (141 mg, 0.44 mmol) was added, then dry DMF (5 mL) was added and stirred at 60 °C overnight. The mixture solution was evaporated and extracted with EtOAc, washed with 0.5 N NaOH solution, the organic layers were combined and dried over MgSO4. After evaporation under vacuum, the crude mixture was chromatographed on silica gel and eluted with dichloromethane and ethyl acetate (10%) to afford the title compound (52 mg, 38% yield) as a white solid. The LC-MS (ESI): M / Z = 466 (M+1)+. Example 46. Preparation of N-(3-(6-bromooxazolo[4,5-b]pyridin-2-yl)-5-fluoro-2- methylphenyl)-2-chloro-4-cyanobenzamide (Compound 249) To a solution of 2-chloro-4-cyanobenzoic acid (64 mg, 0.40 mmol) in THF (10 mL) was added thionyl chloride (1 mL), then stirred at 60 °C overnight. After it was cooled to room temperature, the mixture was evaporated in vacuum and dry THF (10 mL), then dry pyridine Attorney Docket No.43820-0007P01 (SBP Ref.22-015-02PCT) (1 mL) was dropped into the solution in THF, then of 3-(6-bromooxazolo[4,5-b]pyridin-2- yl)-5-fluoro-2-methylaniline (141 mg, 0.44 mmol) was added, then DMF (5 mL) was added and stirred at 60 °C overnight. The mixture solution was evaporated and extracted with EtOAc, washed with 0.5 N NaOH solution, the organic layers were combined and dried over MgSO4. After evaporation under vacuum, the crude mixture was chromatographed on silica gel and eluted with dichloromethane and ethyl acetate (10%) to afford the title compound (76 mg, 39% yield) as a white solid. The LC-MS (ESI): M / Z = 486 (M+1)+. Example 47. Preparation of N-(3-(6-bromooxazolo[4,5-b]pyridin-2-yl)-5-fluoro-2- methylphenyl)-3-chloro-4-fluorobenzamide (Compound 258) To a solution of 3-chloro- in THF (10 mL) was added thionyl chloride (1 mL), then stirred at 60 °C overnight. After it was cooled to room temperature, the mixture was evaporated in vacuum and dry THF (10 mL), then dry pyridine (1 mL) was dropped into the solution in THF, then of 3-(6-bromooxazolo[4,5-b]pyridin-2- yl)-5-fluoro-2-methylaniline (141 mg, 0.44 mmol) was added, then dry DMF (5 mL) was added and stirred at 60 °C overnight. The mixture solution was evaporated and extracted with EtOAc, washed with 0.5 N NaOH solution, the organic layers were combined and dried over MgSO4. After evaporation under vacuum, the crude mixture was chromatographed on silica gel and eluted with dichloromethane and ethyl acetate (10%) to afford the title compound (84 mg, 44% yield) as a white solid. The LC-MS (ESI): M / Z = 479 (M+1)+. Example 48. Preparation of N-(3-(6-bromooxazolo[4,5-b]pyridin-2-yl)-5-fluoro-2- methylphenyl)-4-cyano-2-fluorobenzamide (Compound 253) Attorney Docket No.43820-0007P01 (SBP Ref.22-015-02PCT) To a solution of 4-cyano- in THF (10 mL) was added thionyl chloride (1 mL), then stirred at 60 °C overnight. After it was cooled to room temperature, the mixture was evaporated in vacuum and dry THF (10 mL), then dry pyridine (1 mL) was dropped into the solution in THF, then of 3-(6-bromooxazolo[4,5-b]pyridin-2- yl)-5-fluoro-2-methylaniline (141 mg, 0.44 mmol) was added, then dry DMF (5 mL) was added and stirred at 60 °C overnight. The mixture solution was evaporated and extracted with EtOAc, washed with 0.5 N NaOH solution, the organic layers were combined and dried over MgSO4. After evaporation under vacuum, the crude mixture was chromatographed on silica gel and eluted with dichloromethane and ethyl acetate (10%) to afford the title compound (62 mg, 33% yield) as a white product. The LC-MS (ESI): M / Z = 470 (M+1)+. Example 49. Preparation of N-(3-(6-bromooxazolo[4,5-b]pyridin-2-yl)-5-fluoro-2- methylphenyl)-2-chloro-4-fluorobenzamide (Compound 238) To a solution of 2-chloro-4-fluorobenzoic acid (70mg, 0.40 mmol) in THF (10 mL) was added thionyl chloride (1 mL), then stirred at 60 °C overnight. After it was cooled to room temperature, the mixture was evaporated in vacuum and dry THF (10 mL), then dry pyridine (1 mL) was dropped into the solution in THF, then of 3-(6-bromooxazolo[4,5-b]pyridin-2- yl)-5-fluoro-2-methylaniline (141 mg, 0.44 mmol) was added, then dry DMF (5 mL) was added and stirred at 60 °C overnight. The mixture solution was evaporated and extracted with EtOAc, washed with 0.5 N NaOH solution, the organic layers were combined and dried over MgSO4. After evaporation under vacuum, the crude mixture was chromatographed on Attorney Docket No.43820-0007P01 (SBP Ref.22-015-02PCT) silica gel and eluted with dichloromethane and ethyl acetate (10%) to afford the title compound (84 mg, 44% yield) as a white solid. The LC-MS (ESI): M / Z = 479 (M+1)+. Example 50. Preparation of N-(3-(6-bromooxazolo[4,5-b]pyridin-2-yl)-5-fluoro-2- methylphenyl)-2-chloro-3-fluorobenzamide) (Compound 250) To a solution of 2-chloro- in THF (10 mL) was added thionyl chloride (1 mL), then stirred at 60 °C overnight. After it was cooled to room temperature, the mixture was evaporated in vacuum and dry THF (10 mL), then dry pyridine (1 mL) was dropped into the solution in THF, then of 3-(6-bromooxazolo[4,5-b]pyridin-2- yl)-5-fluoro-2-methylaniline (141 mg, 0.44 mmol) was added, then dry DMF (5 mL) was added and stirred at 60 °C overnight. The mixture solution was evaporated and extracted with EtOAc, washed with 0.5 N NaOH solution, the organic layers were combined and dried over MgSO4. After evaporation under vacuum, the crude mixture was chromatographed on silica gel and eluted with dichloromethane and ethyl acetate (10%) to afford the title compound (80 mg, 42% yield) as a white solid. The LC-MS (ESI): M / Z = 479 (M+1)+. Example 51. Preparation of N-(3-(6-bromooxazolo[4,5-b]pyridin-2-yl)-5-fluoro-2- methylphenyl)-2,4-difluorobenzamide (Compound 251) To a solution of 2,4-difluorobenzoic acid (63 mg, 0.40 mmol) in THF (10 mL) was added thionyl chloride (1 mL), then stirred at 60 °C overnight. After it was cooled to room temperature, the mixture was evaporated in vacuum and dry THF (10 mL), then dry pyridine Attorney Docket No.43820-0007P01 (SBP Ref.22-015-02PCT) (1 mL) was dropped into the solution in THF, then of 3-(6-bromooxazolo[4,5-b]pyridin-2- yl)-5-fluoro-2-methylaniline (141 mg, 0.44 mmol) was added, then dry DMF (5 mL) was added and stirred at 60 °C overnight. The mixture solution was evaporated and extracted with EtOAc, washed with 0.5 N NaOH solution, the organic layers were combined and dried over MgSO4. After evaporation under vacuum, the crude mixture was chromatographed on silica gel and eluted with dichloromethane and ethyl acetate (10%) to afford the title compound (92 mg, 50% yield) as a white solid. The LC-MS (ESI): M / Z = 463 (M+1)+. Example 52. Preparation of N-(3-(6-bromooxazolo[4,5-b]pyridin-2-yl)-5-fluoro-2- methylphenyl)-2,4-dichlorobenzamide (Compound 241) To a solution of 2,4- THF (10 mL) was added thionyl chloride (1 mL), then stirred at 60 °C overnight. After it was cooled to room temperature, the mixture was evaporated in vacuum and dry THF (10 mL), then dry pyridine (1 mL) was dropped into the solution in THF, then of 3-(6-bromooxazolo[4,5-b]pyridin-2- yl)-5-fluoro-2-methylaniline (141 mg, 0.44 mmol) was added, then dry DMF (5 mL) was added and stirred at 60 °C overnight. The mixture solution was evaporated and extracted with EtOAc, washed with 0.5 N NaOH solution, the organic layers were combined and dried over MgSO4. After evaporation under vacuum, the crude mixture was chromatographed on silica gel and eluted with dichloromethane and ethyl acetate (10%) to afford the title compound (59 mg, 30% yield) as a white solid. The LC-MS (ESI): M / Z = 496 (M+1)+. Example 53. Preparation of N-(3-(6-bromooxazolo[4,5-b]pyridin-2-yl)-5-fluoro-2- methylphenyl)-2-chloro-4-methylbenzamide (Compound 248) Attorney Docket No.43820-0007P01 (SBP Ref.22-015-02PCT) To a solution of 2-chloro- in THF (10 mL) was added thionyl chloride (1 mL), then stirred at 60 °C overnight. After it was cooled to room temperature, the mixture was evaporated in vacuum and dry THF (10 mL), then dry pyridine (1 mL) was dropped into the solution in THF, then of 3-(6-bromooxazolo[4,5-b]pyridin-2- yl)-5-fluoro-2-methylaniline (141 mg, 0.44 mmol) was added, then dry DMF (5 mL) was added and stirred at 60 °C overnight. The mixture solution was evaporated and extracted with EtOAc, washed with 0.5 N NaOH solution, the organic layers were combined and dried over MgSO4. After evaporation under vacuum, the crude mixture was chromatographed on silica gel and eluted with dichloromethane and ethyl acetate (10%) to afford the title compound (91 mg, 43% yield) as a white solid. The LC-MS (ESI): M / Z = 475 (M+1)+. Example 54. Preparation of N-(3-(6-bromooxazolo[4,5-b]pyridin-2-yl)-5-fluoro-2- methylphenyl)-2,3-dichlorobenzamide (Compound 298) To a solution of 2,4-di-chloro- mg, in THF (10 mL) was added thionyl chloride (2 mL), then stirred at 60 °C overnight. After it was cooled to room temperature, the mixture was evaporated in vacuum and dry THF (10 mL), then dry pyridine (1 mL) was dropped into the solution in THF, then of 3-(6-bromooxazolo[4,5-b]pyridin-2- yl)-5-fluoro-2-methylaniline ( 282 mg, 0.88 mmol) was added, then dry DMF (10 mL) was added and stirred at 60 °C overnight. The mixture solution was evaporated and extracted with EtOAc, washed with 0.5 N NaOH solution, the organic layers were combined and dried over MgSO4. After evaporation under vacuum, the crude mixture was chromatographed on silica gel and eluted with dichloromethane and ethyl acetate (10%) to afford the title compound (182 mg, 43% yield) as a white solid. The LC-MS (ESI): M / Z = 493 (M+1)+. Attorney Docket No.43820-0007P01 (SBP Ref.22-015-02PCT) General Procedure F Example 55. Preparation of N-(3-(6-bromo-4-fluorobenzo[d]thiazol-2-yl)-5-fluoro- 2-methylphenyl)-2-chloro-3,4-difluorobenzamide (Compound 339) Step 1: Synthesis of 5-fluoro-2-methyl-3-nitrobenzaldehyde 5-Fluoro-2-methyl-3-nitrobenzoate (2 g, was dissolved in DCM (35 mL) and cooled under nitrogen to -90 °C. DIBAL (1M in Hexane) (1.33 g, 9.38 mL, 1 molar, 1 Eq, 9.38 mmol) was added very slowly down the side of the flask over 10 min. While at -90 °C the reaction was quenched by very slow addition of EtOH (~ 1 mL). Then a saturated solution of Rochelle’s salt was added, and the mixture was gradually warmed to rt. The mixture was further diluted with water and DCM, separated, and the orange-brown aqueous phase was extracted twice more with DCM. The combined organic phase (~200 mL) was washed with water, then brine, then dried over sodium sulfate, and the solvents were evaporated to give an orange oil with crystals trying to form (1.82 g). The crude material was stored overnight at - 20 °C, then purified using Isco NPFC (80g silica, dry loaded on Celite®, eluted with 5-10-60% EtOAc / Hex o / 12CV. Fractions 17-27 were combined and evaporated to afford the title compound (1.22g, 71% yield) as an off-white solid.1H NMR (400 MHz, CHLOROFORM- D) δ 10.38 (s, 1H), 7.80 (dd, J = 7.8, 2.9 Hz, 1H), 7.75 (dd, J = 7.3, 2.9 Hz, 1H), 2.77 (s, 3H). Step 2: Synthesis of 6-Bromo-4-fluoro-2-(5-fluoro-2-methyl-3-nitrophenyl) benzo[d]thiazole Attorney Docket No.43820-0007P01 (SBP Ref.22-015-02PCT) 2-Amino-5-bromo-3- mmol) was combined with 5- fluoro-2-methyl-3- and DMSO (4 mL). The mixture was stirred for 2 min to give a homogeneous yellow solution. Sodium metabisulfite (228 mg, 1.1 Eq, 1.2 mmol) was added to the solution and the walls of the vial were washed with additional DMSO (1 mL). The yellow heterogeneous mixture was heated under microwave conditions at 120 °C for 60-90 min. After 90 min, water was added which resulted in a yellow heterogeneous mixture and minor heat evolution. The mixture was tirred 5 min, then filtered to collect the solid ppt which was further washed with water. The crude product was dried overnight to give a pale-green solid (284 mg). The crude material was purified using Isco NPFC (24g silica, 2-60% EA / Hex). Fractions 11-15 were combined to afford the title compound (102 mg, 22% yield) as a white solid. The LC-MS (ESI): M / Z = 385 (M+1)+, 387 (M+2+1)+. Step 3: Synthesis of 3-(6-bromo-4-fluorobenzo[d]thiazol-2-yl)-5-fluoro-2-methylaniline 6-bromo-4-fluoro-2-(5-fluoro-2- thiazole (100 mg, 1 Eq, 260 μmol) was dissolved in HPLC grade methanol (2 mL) and heated to 60 °C. Hypodiboric acid (116 mg, 5 Eq, 1.30 mmol) was added, then triethylamine (21 mg, 29 μL, 0.8 Eq, 208 μmol) was added. The white heterogeneous mixture was stirred at 60 °C. Within about 15 min the mixture had turned to a milky yellow solution. The reaction mixture was stirred one day and then cooled to room temperature and filtered. Both the filtrate and the collected white solid contain the desired product (by1H NMR). Both phases were combined and purified using Isco NPFC (24g silica, 5-60% EA / H). Fractions 15-16 were combined and evaporated to afford the Attorney Docket No.43820-0007P01 (SBP Ref.22-015-02PCT) title compound (25.8 mg, 28% yield) as a white solid. The LC-MS (ESI): M / Z = 355 (M+1)+, 357 (M+2+1)+. Step 4: Synthesis of N-(3-(6-bromo-4-fluorobenzo[d]thiazol-2-yl)-5-fluoro- 2-methylphenyl)-2-chloro-3,4-difluorobenzamide To a nearly colorless homogeneous solution of 2-chloro-3,4-difluorobenzoic acid (13 mg, 0.95 Eq, 69 μmol) in THF (0.5 mL) in a 4 mL vial was added thionyl chloride (16 mg, 10 μL, 1.9 Eq, 65 μmol) (colorless & fuming), then the mixture was stirred at 65 °C. After a total of 6h the vial was cooled to rt, then the solvent was evaporated under vacuum. Dry THF (1 mL) was added. Dry pyridine (25 mg, 25 μL, 4.3 Eq, 0.31 mmol) was added, then 3-(6-bromo-4- fluorobenzo[d]thiazol-2-yl)-5-fluoro-2-methylaniline (26 mg, 1 Eq, 73 μmol) was added directly. The white heterogeneous mixture was again stirred at 65 °C. After 18h the mixture was allowed to cool to RT and treated with water. The mixture was partitioned between water and EtOAc, and the aqueous layer was extracted twice more with EtOAc. The combined organic phase was successively washed with water, then 10% HCl, then 2M NaOH, then brine. The organic phase was dried over sodium sulfate and evaporated to give an off-white solid. The material was purified using Isco NPFC (dry loaded on Celite®, 25g silica, 2-100% EtOAc / Hexane). Fractions 13-18 were combined and evaporated to afford the title compound (14 mg, 36% yield, 94% purity by LCMS) as a white solid. The LC-MS (ESI): M / Z = 527 (M- 1)-, 529 (M+2-1)-. Example 56. Preparation of 2-chloro-3,4-difluoro-N-(5-fluoro-3-(4- fluorobenzo[d]thiazol-2-yl)-2-methylphenyl)benzamide (Compound 340) Prepared according to the sequence of General Procedure F, using 5-fluoro-3-(4- fluorobenzo[d]thiazol-2-yl)-2-methylaniline (9.5 mg, 1.00 Eq, 34 μmol) instead of 3-(6- bromo-4-fluorobenzo[d]thiazol-2-yl)-5-fluoro-2-methylaniline. The title compound (2.3 mg, 15% yield) was obtained from fractions 27-29 as a white solid. The LC-MS (ESI): M / Z = 451 (M+1)+. Attorney Docket No.43820-0007P01 (SBP Ref.22-015-02PCT) Example 57. Preparation of N-(3-(6-bromobenzo[d]thiazol-2-yl)-5-fluoro-2- methylphenyl)-2-chloro-3,4-difluorobenzamide (Compound 341) Prepared according to sequence F, using 3-(6- bromobenzo[d]thiazol-2-yl)-5-fluoro-2-methylaniline (97 mg, 1.00 Eq, 0.29 mmol) instead of 3-(6-bromo-4-fluorobenzo[d]thiazol-2-yl)-5-fluoro-2-methylaniline. The title compound (14 mg, 9.5% yield) was obtained by filtration from MeOH / DCM as a white solid. The LC-MS (ESI): M / Z = 511 (M+1)+, 513 (M+2+1)+. Example 58. Preparation of 2-chloro-N-(3-(6-chlorobenzo[d]thiazol-2-yl)-5-fluoro-2- methylphenyl)-3,4-difluorobenzamide Prepared according to the sequence of General Procedure F, using 3-(6- chlorobenzo[d]thiazol-2-yl)-5-fluoro-2-methylaniline (88 mg, 1 Eq, 0.3 mmol) instead of 3-(6- bromo-4-fluorobenzo[d]thiazol-2-yl)-5-fluoro-2-methylaniline. The title compound (23 mg, 16% yield) was obtained from fractions 18-25 as a white solid. The LC-MS (ESI): M / Z = 467 (M+1)+. Example 59. 2-chloro-N-(3-(5-chlorobenzo[d]thiazol-2-yl)-5-fluoro-2-methylphenyl)-3,4- difluorobenzamide Attorney Docket No.43820-0007P01 (SBP Ref.22-015-02PCT) Compound 343 Prepared according to the sequence of General Procedure F, using 3-(5- chlorobenzo[d]thiazol-2-yl)-5-fluoro-2-methylaniline (75 mg, 1 Eq, 0.26 mmol) instead of 3- (6-bromo-4-fluorobenzo[d]thiazol-2-yl)-5-fluoro-2-methylaniline. The title compound (22 mg, 18%) was obtained from fractions 17-18 as a white solid. The LC-MS (ESI): M / Z = 467 (M+1)+. Example 60. 2-chloro-N-(3-(6-cyclopropyloxazolo[4,5-b]pyridin-2-yl)-5-fluoro-2- methylphenyl)-3,4-difluorobenzamide A mixture of N-(3-(6-bromooxazolo[4,5-b]pyridin-2-yl)-5-fluoro-2-methylphenyl)-2-chloro- 3,4-difluorobenzamide (100 mg, 1 Eq, 201 μmol), cyclopropylboronic acid (23 mg, 1.3 Eq, 262 μmol) and potassium carbonate (84 mg, 3 Eq, 604 μmol) in toluene (2 mL) and water (0.2 mL) was sparged with N2gas at rt for 1h to give a white heterogeneous mixture. After N2sparging, additional dry toluene (1 mL) was used to wash down the sides of the flask, then palladium acetate and tricyclohexylphosphine were added to the reaction mixture at rt. A reflux condenser with a septum was affixed to the flask, and then the reaction mixture was purged with N2gas for 15 minutes at rt. A balloon of argon was attached through the septum and the mixture was stirred at 90 °C. After 5.5 h, the mixture was allowed to cool and stirred at ambient temperature overnight. The white heterogeneous mixture was diluted with H2O and extracted three times with EtOAc. The combined organic layer was washed with brine, dried over Na2SO4, and filtered through paper. The solvents were evaporated to obtain a solid which was purified using both normal phase and reverse phase flash chromatography. A solid was obtained using deuterated chloroform. After washing and drying, the title compound (9.3 mg, 10% yield) was obtained. The LC-MS (ESI): M / Z = 458 (M+1)+. Example 61. tert-butyl (2-(3-(2-chloro-3,4-difluorobenzamido)-5-fluoro-2- methylphenyl)oxazolo[4,5-b]pyridin-6-yl)carbamate Attorney Docket No.43820-0007P01 (SBP Ref.22-015-02PCT) N-(3-(6-bromooxazolo[4,5-b] - -2-chloro-3,4- difluorobenzamide (0.12 g, 1.1 Eq, 0.24 mmol), tert-butyl carbamate (26 mg, 1.0 Eq, 0.22 mmol), tris(dibenzylideneacetone)dipalladium(0) (41 mg, 0.2 Eq, 0.044 mmol), 4,5- bis(diphenylphosphino)-9,9-dimethyl xanthene (77 mg, 0.6 Eq, 0.13 mmol), and cesium carbonate (0.4 g, 5.5 Eq, 1.2 mmol) were dissolved in dry 1,4-dioxane (2 mL) and sparged with N2for 3 min. The mixture was stirred at 100 °C (heterogeneous mixture turned red, then became yellow) for 90 min. The yellow heterogeneous mixture was cooled to room temperature and filtered through diatomaceous. The filtrate was purified by flash column chromatography (24 g silica, 2-100% EtOAc / Hex). Fractions 27-28 were combined and evaporated to give the title compound (37 mg, 31% yield) as a white solid. The LC-MS (ESI): M / Z = 533 (M+1)+. Example 62. N-(3-(6-aminooxazolo[4,5-b]pyridin-2-yl)-5-fluoro-2-methylphenyl)-2- chloro-3,4-difluorobenzamide Tert-butyl (2-(3-(2-chloro-3,4-difluorobenzamido)-5-fluoro-2-methylphenyl)oxazolo[4,5- b]pyridin-6-yl)carbamate (20 mg, 1 Eq, 38 μmol) was suspended in DCM (2 mL) and then treated with trifluoroacetic acid (0.19 g, 0.13 mL, 45 Eq, 1.7 mmol) and stirred 18h at rt. The mixture was diluted with DCM and water, and then 50% NaOH (1 mL) was added (to pH 14). The mixture was separated, and the aqueous layer was extracted twice more with DCM. The combined organic phase was washed with brine, dried over sodium sulfate, filtered through paper, and evaporated under vacuum to give the desired product as a white residue. The material was adsorbed to diatomaceous after dissolving in MeOH / DCM, and then purified using Isco NPFC (4g silica, 1-10% MeOH / DCM). Fractions 8-9 were combined and evaporated to give the title compound (3.7 mg, 23%) as a white solid. The LC-MS (ESI): M / Z = 433 (M+1)+. Attorney Docket No.43820-0007P01 (SBP Ref.22-015-02PCT) General Procedure G: Example 63. Preparation of 2-chloro-N-(3-(5-chloro-[1,2,4]triazolo[1,5-a]pyridin-2-yl)- 5-fluoro-2-methylphenyl)-3,4-difluorobenzamide (Compound 299) Step 1: Synthesis of 5- -[1,2,4]triazolo[1,5- a]pyridine: A 10 mL microwave vial was chloro-[1,2,4]triazolo[1,5-a]pyridine (0.43 mmol, 100 mg), 2-(5-fluoro-2-methyl-3-nitrophenyl)-4,4,5,5-tetramethyl-1,3,2- dioxaborolane (0.52 mmol, 145 mg), and Cs2CO3(1.3 mmol, 420 mg). After purging the vial with N2 for 10 min, Pd(dppf)Cl2-DCM (43 µmol, 35.1 mg, 10 mol%), and pre-purged dioxane: water (4:1, 5 mL) was added and purged the mixture for 10 more min. The vial was microwaved at 130 °C for 30 min. The reaction mixture was cooled to RT, filtered using syringe filter, and washed with EtOAc, and water. The organic layer was collected, dried over anhydrous sodium sulfate, decanted, and reduced in vacuo. The product was purified on an ISCO silica gel column using hexanes- EtOAc (0 - 60 % gradient) to afford the title compound (47 mg, 36% yield) as a white powder. The LC-MS (ESI): M / Z = 307 (M+1)+. Step 2: Synthesis of 3-(5-chloro-[1,2,4]triazolo[1,5-a]pyridin-2-yl)-5-fluoro-2-methylaniline:

[0006] Attorney Docket No.43820-0007P01 (SBP Ref.22-015-02PCT) A 4 dram vial was charged with 5-chloro-2-(5-fluoro-2-methyl-3-nitrophenyl)- [1,2,4]triazolo[1,5-a]pyridine (0.15 mmol, 47 mg), tetrahydroxydiboron (0.46 mmol, 42 mg), and 4,4'-bipyridine (4.1 mL, 2 mol %, 0.75 mmolar solution in DMF) and stirred at RT for 3 h. LC-MS after 1 h and 3 h looked the same (desired product and unreacted starting material in 60:40 ratio). Mixture was diluted with water and extracted the product in ether (3 times). The organic layer was collected, dried over anhydrous sodium sulfate, decanted, and reduced in vacuo. The product was purified by reverse hplc using water-acetonitrile (0 - 46 % gradient) to afford the title compound (18 mg, 42% yield). The LC-MS (ESI): M / Z = 318 (M+42)+. Step 3: Synthesis of 2-chloro-N-(3-(5-chloro-[1,2,4]triazolo[1,5-a]pyridin-2-yl)-5-fluoro-2- methylphenyl)-3,4-difluorobenzamide: (compound 299) To a solution of 2-chloro-3,4-difluorobenzoic acid (96 µmol, 19 mg) in dry dimethylformamide (0.5 mL) was added PyCIU (96 µmol, 32 mg), and (i-Pr)2NEt (256 µmol, 45 µL). The mixture was stirred at RT for 10 min. Subsequently, 3-(5-chloro-[1,2,4]triazolo[1,5-a]pyridin-2-yl)-5- fluoro-2-methylaniline (64 µmol, 18 mg) in dry dimethylformamide (0.5 mL) was added and stirred at 80 °C for 16 h under N2. The reaction mixture was cooled to RT and filtered using a syringe filter. The product was purified by reverse hplc using water-acetonitrile (0 - 70 % gradient) to afford the title compound (5 mg, 16% yield) as a white powder. The LC-MS (ESI): M / Z = 492 (M+42)+; 2% overall yield for three steps. Example 64. N-(3-(6-bromo-[1,2,4]triazolo[1,5-a]pyridin-2-yl)-5-fluoro-2-methylphenyl)- 2-chloro-3,4-difluorobenzamide (Compound 300) To a solution of 2-chloro-3,4-difluorobenzoic acid (0.16 mmol, 31 mg) in dry dimethylformamide (0.5 mL) was added PyCIU (0.16 mmol, 54 mg), and (i-Pr)2NEt (0.43 mmol, 76 µL). The mixture was stirred at RT for 10 min. Subsequently, 3-(6-bromo- [1,2,4]triazolo[1,5-a]pyridin-2-yl)-5-fluoro-2-methylaniline (0.11 mmol, 35 mg) in dry dimethylformamide (0.5 mL) was added and stirred at 80 °C for 16 h under N2. The reaction mixture was cooled to RT and filtered using a syringe filter. The product was purified by Attorney Docket No.43820-0007P01 (SBP Ref.22-015-02PCT) reverse HPLC using water-acetonitrile (0 - 70 % gradient) to afford the title compound (8 mg, 15% yield) as an off-white powder. The LC-MS (ESI): M / Z = 495 (M+1)+; 1.5% overall yield for three steps. Example 65. Preparation of 2-chloro-3,4-difluoro-N-(5-fluoro-3-(imidazo[1,2-a]pyridin- 2-yl)-2-methylphenyl)benzamide (Compound 301) To a solution of 2-chloro- mmol, 26 mg) in dry dimethylformamide (0.8 mL) was added PyCIU (0.14 mmol, 45 mg), and (i-Pr)2NEt (0.45 mmol, 78 µL). The mixture was stirred at RT for 10 min. Subsequently, 5-fluoro-3- (imidazo[1,2-a]pyridin-2-yl)-2-methylaniline (0.11 mmol, 27 mg) in dry dimethylformamide (1 mL) was added and stirred at 80 °C for 16 h under N2. The reaction mixture was cooled to RT and filtered using a syringe filter. The product was purified by reverse HPLC using water- acetonitrile (0 - 40 % gradient) to afford the title compound (9 mg, 20% yield) as a white powder. The LC-MS (ESI): M / Z = 457 (M+42)+; 9% overall yield for three steps. Example 66. Preparation of 2-chloro-3,4-difluoro-N-(5-fluoro-3-(6-fluoro- [1,2,4]triazolo[1,5-a]pyridin-2-yl)-2-methylphenyl)benzamide (Compound 302) Compound 302 was synthesized according to general procedure G. The product was purified by reverse HPLC using water-acetonitrile (0 - 72 % gradient) to afford the title compound (34 mg) as an off-white powder. The LC-MS (ESI): M / Z = 476 (M+42)+, 12% overall yield for three steps. (step 1, 49% yield; step 2, 81% yield; step 3, 29% yield). Attorney Docket No.43820-0007P01 (SBP Ref.22-015-02PCT) Example 67. Preparation of 2-chloro-N-(3-(7-chloroimidazo[1,2-a]pyridin-2-yl)-5-fluoro- 2-methylphenyl)-3,4-difluorobenzamide (Compound 303) F O Cl Compound 303 as synthesized product was purified by reverse HPLC using water-acetonitrile (0 - 65 % gradient) to afford the title compound (17 mg) as an off-white powder. The LC-MS (ESI): M / Z = 450 (M+1)+, 8% overall yield for three steps (step 1, 52% yield; step 2, 62% yield; step 3, 25% yield). Example 68. Preparation of N-(3-([1,2,4]triazolo[1,5-a]pyridin-2-yl)-5-fluoro-2- methylphenyl)-2-chloro-3,4-difluorobenzamide (Compound 304) Compound 304 was synthesized according to general procedure G. The product was purified by reverse HPLC using water-acetonitrile (0 - 60 % gradient) to afford the title compound (2 mg) as a white powder. The LC-MS (ESI): M / Z = 458 (M+42)+, 3% overall yield for three steps (step 1, 60% yield; step 2, 41% yield; step 3, 13% yield). The compounds in Table A, shown below, were synthesized analogously to the compounds shown in Examples 1-62. The compounds in Table B, shown below, were synthesized according to the sequence of General Procedure G or in an analogous manner. Example 69. Cellular TGR5 antagonist assay Attorney Docket No.43820-0007P01 (SBP Ref.22-015-02PCT) Chinese Hamster Ovary (CHO-K1) cells transfected with GPBAR1 TGR5 gene was purchased from DiscoverX, and cryopreserved stocks were prepared at 20M / mL density and 0.25 mL volume for thawing and immediate use in same-day compound testing. The assay starts with the dispense of EC85 (1.3 µM final) concentration Sodium Taurolithocholate (TLCA) and 500 µM final concentration 3-isobutyl-1-methylxanthine (IBMX) to the 1536-well assay plate, as well as compounds in the range of 100 µM to 3 nM final concentration. 500 cells / well were then dispensed and the mixture was incubated for 30 minutes at room temperature. The last step is the dispense of LANCE ULTRA cAMP detection reagent with another 30-minute incubation at room temperature, before reading the assay plate on the PHERAstar plate reader with HTRF module. The potency ranges in Tables A and B are as follows: IC50 = less than 50 nm nM = A; IC50 = 51 nm nM – 300 nM nM = B; IC50= 301 nm – 1000 nM = C; IC50= 1001 nm – 10 µM = D; and IC50= greater than 10 µM = E. Table A. TGR5 IC50 and m / z Values of Compounds of Formula (I). Compound Structure (M+H)+IC50 No. Attorney Docket No.43820-0007P01 (SBP Ref.22-015-02PCT) Compound Structure (M+H)+IC50 No. Attorney Docket No.43820-0007P01 (SBP Ref.22-015-02PCT) Compound Structure (M+H)+IC50 No. Attorney Docket No.43820-0007P01 (SBP Ref.22-015-02PCT) Compound Structure (M+H)+IC50 No. Attorney Docket No.43820-0007P01 (SBP Ref.22-015-02PCT) Compound Structure (M+H)+IC50 No. Attorney Docket No.43820-0007P01 (SBP Ref.22-015-02PCT) Compound Structure (M+H)+IC50 No. Attorney Docket No.43820-0007P01 (SBP Ref.22-015-02PCT) Compound Structure (M+H)+IC50 No. Attorney Docket No.43820-0007P01 (SBP Ref.22-015-02PCT) Compound Structure (M+H)+IC50 No. Attorney Docket No.43820-0007P01 (SBP Ref.22-015-02PCT) Compound Structure (M+H)+IC50 No. Attorney Docket No.43820-0007P01 (SBP Ref.22-015-02PCT) Compound Structure (M+H)+IC50 No. Attorney Docket No.43820-0007P01 (SBP Ref.22-015-02PCT) Compound Structure (M+H)+IC50 No. Attorney Docket No.43820-0007P01 (SBP Ref.22-015-02PCT) Compound Structure (M+H)+IC50 No. Attorney Docket No.43820-0007P01 (SBP Ref.22-015-02PCT) Compound Structure (M+H)+IC50 No. Attorney Docket No.43820-0007P01 (SBP Ref.22-015-02PCT) Compound Structure (M+H)+IC50 No. Attorney Docket No.43820-0007P01 (SBP Ref.22-015-02PCT) Compound Structure (M+H)+IC50 No. Attorney Docket No.43820-0007P01 (SBP Ref.22-015-02PCT) Compound Structure (M+H)+IC50 No. Attorney Docket No.43820-0007P01 (SBP Ref.22-015-02PCT) Compound Structure (M+H)+IC50 No. Attorney Docket No.43820-0007P01 (SBP Ref.22-015-02PCT) Compound Structure (M+H)+IC50 No. Attorney Docket No.43820-0007P01 (SBP Ref.22-015-02PCT) Compound Structure (M+H)+IC50 No. Attorney Docket No.43820-0007P01 (SBP Ref.22-015-02PCT) Compound Structure (M+H)+IC50 No. Attorney Docket No.43820-0007P01 (SBP Ref.22-015-02PCT) Compound Structure (M+H)+IC50 No. Attorney Docket No.43820-0007P01 (SBP Ref.22-015-02PCT) Compound Structure (M+H)+IC50 No. Attorney Docket No.43820-0007P01 (SBP Ref.22-015-02PCT) Compound Structure (M+H)+IC50 No. Attorney Docket No.43820-0007P01 (SBP Ref.22-015-02PCT) Compound Structure (M+H)+IC50 No. Attorney Docket No.43820-0007P01 (SBP Ref.22-015-02PCT) Compound Structure (M+H)+IC50 No. Attorney Docket No.43820-0007P01 (SBP Ref.22-015-02PCT) Compound Structure (M+H)+IC50 No. Attorney Docket No.43820-0007P01 (SBP Ref.22-015-02PCT) Compound Structure (M+H)+IC50 No. Attorney Docket No.43820-0007P01 (SBP Ref.22-015-02PCT) Compound Structure (M+H)+IC50 No. Attorney Docket No.43820-0007P01 (SBP Ref.22-015-02PCT) Compound Structure (M+H)+IC50 No. Attorney Docket No.43820-0007P01 (SBP Ref.22-015-02PCT) Compound Structure (M+H)+IC50 No. Attorney Docket No.43820-0007P01 (SBP Ref.22-015-02PCT) Compound Structure (M+H)+IC50 No. Attorney Docket No.43820-0007P01 (SBP Ref.22-015-02PCT) Compound Structure (M+H)+IC50 No. Attorney Docket No.43820-0007P01 (SBP Ref.22-015-02PCT) Compound Structure (M+H)+IC50 No. Attorney Docket No.43820-0007P01 (SBP Ref.22-015-02PCT) Compound Structure (M+H)+IC50 No. Attorney Docket No.43820-0007P01 (SBP Ref.22-015-02PCT) Compound Structure (M+H)+IC50 No. Attorney Docket No.43820-0007P01 (SBP Ref.22-015-02PCT) Compound Structure (M+H)+IC50 No. Attorney Docket No.43820-0007P01 (SBP Ref.22-015-02PCT) Compound Structure (M+H)+IC50 No. Attorney Docket No.43820-0007P01 (SBP Ref.22-015-02PCT) Compound Structure (M+H)+IC50 No. Attorney Docket No.43820-0007P01 (SBP Ref.22-015-02PCT) Compound Structure (M+H)+IC50 No. Attorney Docket No.43820-0007P01 (SBP Ref.22-015-02PCT) Compound Structure (M+H)+IC50 No. Attorney Docket No.43820-0007P01 (SBP Ref.22-015-02PCT) Compound Structure (M+H)+IC50 No. Attorney Docket No.43820-0007P01 (SBP Ref.22-015-02PCT) Compound Structure (M+H)+IC50 No. Attorney Docket No.43820-0007P01 (SBP Ref.22-015-02PCT) Compound Structure (M+H)+IC50 No. Attorney Docket No.43820-0007P01 (SBP Ref.22-015-02PCT) Compound Structure (M+H)+IC50 No. Attorney Docket No.43820-0007P01 (SBP Ref.22-015-02PCT) Compound Structure (M+H)+IC50 No. Attorney Docket No.43820-0007P01 (SBP Ref.22-015-02PCT) Compound Structure (M+H)+IC50 No. Attorney Docket No.43820-0007P01 (SBP Ref.22-015-02PCT) Compound Structure (M+H)+IC50 No. Attorney Docket No.43820-0007P01 (SBP Ref.22-015-02PCT) Compound Structure (M+H)+IC50 No. Attorney Docket No.43820-0007P01 (SBP Ref.22-015-02PCT) Compound Structure (M+H)+IC50 No. Attorney Docket No.43820-0007P01 (SBP Ref.22-015-02PCT) Compound Structure (M+H)+IC50 No. D Attorney Docket No.43820-0007P01 (SBP Ref.22-015-02PCT) Compound Structure (M+H)+IC50 No. Attorney Docket No.43820-0007P01 (SBP Ref.22-015-02PCT) Compound Structure (M+H)+IC50 No. Attorney Docket No.43820-0007P01 (SBP Ref.22-015-02PCT) Compound Structure (M+H)+IC50 No. F Attorney Docket No.43820-0007P01 (SBP Ref.22-015-02PCT) Compound Structure (M+H)+IC50 No. Attorney Docket No.43820-0007P01 (SBP Ref.22-015-02PCT) Compound Structure (M+H)+IC50 No. Table B. TGR5 IC50 and m / z Values of Compounds. Compound Structure (M+H)+IC50No. Attorney Docket No.43820-0007P01 (SBP Ref.22-015-02PCT) Compound Structure (M+H)+IC50 No. Example 70: Biological assays The expression of TGR5 in the PLD liver and PKD kidney was assessed using immunofluorescence confocal microscopy. As shown in FIGs. 1A-1C, TGR5 was detected in cholangiocytes of healthy humans, patients with ADPKD-associated PLD,wild type and PCK rats (FIG. 1A), renal epithelial cells of healthy humans, patients with ADPKD, wild type and PCK rats (FIG. 1B), and cultured cholangiocytes isolated from patientswith ADPKD- associated PLD and PCK rats (FIG. 1C). TGR5 overexpression in PLD and PCK rat cholangiocytes was confirmed by western blotting, as shown in FIG. 1D. The presence of TGR5 in PLD cholangiocytes (PLDC) and PKD renal epithelial cells (PKD-REC), and in the microenvironment surrounding liver and kidney cysts was further confirmed by spatial Attorney Docket No.43820-0007P01 (SBP Ref.22-015-02PCT) transcriptomics analysis of human liver and kidney tissues. (FIG. 1E). Data are presented as mean±SD. n=3-5 for each data set. Next, TGR5 ligands were to shown incease in bile and serum of PCK rats. Concentration of bile acids in bile and serum of age-and sex-matched wild type (WT) and PCK rats was detected by Liquid Chromatography-Mass Spectrometry (FIG.2). Data are presented as mean±SD, n=3 for each dataset. *-p<0.05,**-p<0.01,***-p<0.001. As shown in FIGs. 3A and 3B, TGR5 antagonist SBI-364 decreased proliferation of human PLD cholangiocytes. Cell proliferation was assessed by direct cell counting (FIG.3A) and area of cell confluence (FIG.3B). PLD cholangiocytes were stained with Cell Tracker Red CMPTX dye (Thermo Fisher Scientific) and added to respective wells of a 96-well plate at a cell concentration of 5,000 cells / well. The following day, a “time 0” reading was taken on a Celigo Imaging Cell Cytometer (Nexcelom) using the red fluorescence channel. Afterward, cells were treated for 24 and 48 h hours with vehicle (DMSO, marked as UN-TR [un-treated]), TLCA (TGR5 agonist) alone or in the presence of SBI-155 (inactive compound) and SBI-364. After 24 and 48 hours of treatment, the plate was analyzed again using the red fluorescence channel on the Celigo. Proliferation was quantitated based on red fluorescence intensity readings. Data are expressed as a fold change in the cell countor cell confluence at 24h and 48h compared to “time 0”. Cholangiocyte proliferation was decreased by 35%-40% after 24h and by 41%-54% after 48h of treatment. Data are presented as mean±SD, n=8-12 for each data set. *-p<0.05,****-p<0.0001. TGR5 antagonist SBI-364 had no effects on proliferation of human PLD cholangiocytes with reduced expression of TGR5. Western blot demonstrates that expression of TGR5 in human PLD cholangiocytes transfected with specific TGR5 sh-RNA was diminished compared to PLD cholangiocytes transfected with scrambled sh-RNA (FIG. 4A). Cell proliferation was assessed by direct cell counting (FIG. 4B) and area of cell confluence (FIG. 4C). PLD cholangiocytes were stained with Cell Tracker Red CMPTX dye (Thermo Fisher Scientific) and added to respective wells of a 96-well plate at a cell concentration of 5,000 cells / well. The following day, a “time 0” reading was taken on a Celigo Imaging Cell Cytometer (Nexcelom) using the red fluorescence channel. Afterward, cells were treated for 24 and 48h hours with vehicle (DMSO, marked as UN-TR [un-treated]), TLCA (TGR5agonist) alone or in the presence of SBI-155 (inactive compound) and SBI-364. After 24 and 48 hours of treatment, the plate was analyzed again using the red fluorescence channel on the Celigo. Proliferation was quantitated based on red fluorescence intensity readings. Data are expressed Attorney Docket No.43820-0007P01 (SBP Ref.22-015-02PCT) as a fold change in the cell countor cell confluence at 24h and 48h compared to “time 0”. Data are presented as mean±SD, n=8-12 for each data set. TGR5 antagonist SBI-364 decreased proliferation of human PLD cholangiocytes. FIG. 5 shows representative microscopic images of PLD cholangiocytes which demonstrates that TGR5 agonist, TLCA, increased cellproliferation in a time-dependent manner. Inactive compound,SBI-155, did not affect cel lproliferation. Incontrast, TGR5 antagonist SBI-364 reduced proliferation of PLD cholangiocytes in a time-dependent manner. SBI-155 and SBI- 364 were added in the presence of TLCA. TGR5 antagonist SBI-364 decreased proliferation of rat PCK cholangiocytes. Cell proliferation was assessed by direct cell counting (FIG.6A) and area of cell confluence (FIG. 6B). PCK rat cholangiocytes were stained with Cell Tracker Red CMPTX dye (Thermo Fisher Scientific) and added to respective wells of a 96-well plate at a cell concentration of 5,000 cells / well. The following day, a “time 0” reading was taken on a Celigo Imaging Cell Cytometer (Nexcelom) using the red fluorescence channel. Afterward, cells were treated for 24 and 48h hours with vehicle (DMSO, marked as UN-TR [un-treated]), TLCA (TGR5 agonist) alone or in the presence of SBI-155 (inactive compound) and SBI-364. After 24 and 48 hours of treatment, the plate was analyzed again using the red fluorescence channel on the Celigo. Proliferation was quantitated based on red fluorescence intensity readings. Data are expressed as a fold change in the cell countor cell confluence at 24h and 48h compared to “time 0”. Cholangiocyte proliferation was decreased by 45%-54% after 24h and by 47%-60% after 48h of treatment. Data arepresented as mean±SD, n=8-12 for each data set. *-p<0.05,****- p<0.0001. TGR5 antagonist SBI-364 had no effects on proliferation of PCK rat cholangiocytes with reduced expression of TGR5. Western blot demonstrates that expression of TGR5 in PCK rat cholangiocytes transfected with specific TGR5 sh-RNA was diminished compared to PCK rat cholangiocytes transfected with scrambled sh-RNA (FIG. 7A). Cell proliferation was assessed by direct cell counting (FIG. 7B) and area of cell confluence (FIG. 7C). PCK rat cholangiocytes were stained with Cell Tracker Red CMPTX dye (Thermo Fisher Scientific) and added to respective wells of a 96-well plate at a cell concentration of 5,000 cells / well. The following day, a “time 0” reading was taken on a Celigo Imaging Cell Cytometer (Nexcelom) using the red fluorescence channel. Afterward, cells were treated for 24 and 48 h hours with vehicle (DMSO, marked as UN-TR [un-treated]), TLCA (TGR5 agonist) alone or in the presence of SBI-155 (inactive compound) and SBI-364. After 24 and 48 hours of treatment, Attorney Docket No.43820-0007P01 (SBP Ref.22-015-02PCT) the plate was analyzed again using the red fluorescence channel on the Celigo. Proliferation was quantitated based on red fluorescence intensity readings. Data are expressed as a fold change in the cell count or cell confluence at 24 h and 48h compared to “time 0”. Data are presented as mean ± SD, n=8-12 for each data set. TGR5 antagonist SBI-364 decreased proliferation of PCK rat cholangiocytes. FIG. 8 are representative images of PCK rat cholangiocytes that show that TGR5 agonist, TLCA, increased cell proliferation in a time-dependent manner. Inactive compound, SBI-155, did not affect cell proliferation. TGR5 antagonist, SBI-364, reduced PCK rat cholangiocyte proliferation in a time-dependent manner. SBI-155 and SBI-364 were added in the presence of TLCA. TGR5 antagonist SBI-364 decreased proliferation of human WT9-12 PKD renal epithelial cells (PKD-REC). Cell proliferation was assessed by direct cell counting (FIG.9A) and area of cell confluence (FIG.9B). WT9-12 PKD-REC were stained with CellTracker Red CMPTX dye (Thermo Fisher Scientific) and added to respective wells of a 96-well plate at a cell concentration of 5,000 cells / well. The following day a “time 0” reading was taken on a Celigo Imaging Cell Cytometer (Nexcelom) using the red fluorescence channel. Afterward, cells were treated for 24 and 48 h hours with vehicle (DMSO, marked as UN-TR [un-treated]), TLCA (TGR5 agonist) alone or in the presence of SBI-155 (inactive compound) and SBI-364. After 24 and 48 hours of treatment, the plate was analyzed again using the red fluorescence channel on the Celigo. Proliferation was quantitated based on red fluorescence intensity readings. Data are expressed as a fold change in the cell count or cell confluence at 24 h and 48 h compared to “time 0”. WT9-12 PKD-REC proliferation was decreased by 30%-50% after 24 h and by 43%-55% after 48 h of treatment. Data are presented as mean ± SD, n=8-12 for each data set. * - p<0.05, ** - p<0.01, **** - p<0.0001. TGR5 antagonist SBI-364 decreased proliferation of human WT9-12 PKD renal epithelial cells (PKD-REC). FIG. 10 shows representative images of WT9-12 PKD-REC that demonstrated that TGR5 agonist, TLCA, increased proliferation in a time-dependent manner. Inactive compound, SBI-155, did not affect cell proliferation. TGR5 antagonist, SBI-364, reduced WT9-12 PKD-REC proliferation in a time-dependent manner. SBI-155 and SBI-364 were added in the presence of TLCA. TGR5 antagonist SBI-364 decreased levels of p-ERK (i.e., a cAMP downstream target) in human PLD cholangiocytes (top left), PCK rat cholangiocytes (top right) and PKC-REC (bottom) (FIG. 11). FIG. 11 shows representative immunofluorescence confocal microscopy Attorney Docket No.43820-0007P01 (SBP Ref.22-015-02PCT) images that demonstrate that levels of p-ERK (stained in red) were increased after treatment with TGR5 agonist, TLCA. No changes in p-ERK was observed in response to treatment with the inactive compound, SBI-155. In contrast, TGR5 antagonist, SBI-364, markedly decreased p-ERK levels. In PLDΔTGR5 and PCKΔTGR5 cholangiocytes (with diminished expression of TGR5) TLCA, SBI-155 and SBI-364 did not affect p-ERK levels. Cell were treated with all compounds for 30 min. SBI-155 and SBI-364 were added in the presence of TLCA. n = 5-6 for each treatment condition. TGR5 antagonist SBI-364 decreases growth of organoids formed in 3-D culture by freshly isolated PCK rat cholangiocytes and renal epithelial cells (REC). A schematic diagram as shown in FIG.12A depicts the cystoids development protocol. PCK rat cholangiocytes and REC were freshly isolated from liver and kidney, respectively, and placed in matrigel for 7-10 days in order to form organoids. FIG.12B shows representative immunofluorescence confocal microscopy images which demonstrate that cystoids are positive for the epithelial cell marker, CK-7 (red). Fully formed organoids were treated with TGR5 agonis, TLCA, alone or in the presence of inactive compand, SBI-155, or TGR5 antagonist, SBI-364. Light microscopy images were taken before treatment (i.e., “time 0”) and 48 h after treatment. (FIG.12C). The area of individual PCK rat cholangiocyte cystoids was detected by image J. For easy viewing the changes in cystoid circumference, the area of cystoids is depicted by the red dotted line. Un-treated (UN-TR) cystoids continue to grow over time. However, cystoids expanded more rapidly in the presence of TLCA alone or TCLA + SBI-155. In contrast, growth of cystoids was decreased in response to SBI-364. n= 6-10 cystoids analyzed for each data set. Data are expressed as % change in circumference area at 48 h compared to “time 0”. Light microscopy images were taken of fully formed by PCK-REC cystoids treated with TGR5 agonist, TLCA, alone or in the presence of inactive compound, SBI-155, or TGR5 antagonist, SBI-364 (FIG. 12D). TGR5 antagonist SBI-364 decreased immunoreactivity of PCNA (Proliferating Cell Nuclear Antigen, a marker of cell proliferation) in organoids formed in 3-D cultures by freshly isolated PCK rat cholangiocytes and PCK rat renal epithelial cells (PCK-REC). FIG.13 shows representative immunofluorescence confocal microscopy images that demonstrate that PCNA immunofluorescence (green) is increased in response to treatment with TLCA alone compared to un-treated (UN-TR) cystoids, did not change after treatment with the inactive compound, SBI-155 in the presence of TLCA, and decreased after treatment with SBI-364. Attorney Docket No.43820-0007P01 (SBP Ref.22-015-02PCT) TGR5 antagonist SBI-364 decreased proliferation of human PLD cholangiocytes compared to SBI-319. FIG.14A shows assessment of cell proliferation by direct cell counting. FIG.14B shows assessment of cell proliferation by area of cell confluence. Representative images were taken of human PLD cholangiocytes that demonstrated that TGR5 antagonist SBI-364 decreased their proliferation compared to SBI-319 (FIG.15). TGR5 antagonist SBI-364 decreased proliferation of PCK rat cholangiocytes compared to SBI-319. FIG.16A shows assessment of cell proliferation by direct cell counting. FIG.16B shows assessment of cell proliferation by area of cell confluence. Representative images of PCK rat cholangiocytes were taken that demonstrated that TGR5 antagonist SBI-364 decreased their proliferation compared to SBI-319 (FIG.17). TGR5 antagonist SBI-364 decreased proliferation of human WT9-12 PKD renal epithelial cells (PKD-REC) compared to SBI-319. FIG. 18A shows assessment of cell proliferation by direct cell counting. FIG. 18B shows assessment of cell proliferation by area of cell confluence. Representative images of human WT9-12 PKD renal epithelial cells (PKD-REC) were taken that demonstrated that TGR5 antagonist SBI-364 decreased their proliferation compared to SBI-319 (FIG.19). Confocal microscopy images were taken that demonstrate that TGR5 antagonist SBI- 364 decreased levels of p-ERK (i.e., a cAMP downstream target) in human PLD cholangiocytes (top panels), PCK rat cholangiocytes (middle panels) and renal WT9-12 cells (bottom panels) compared to SBI-319 (FIG.20). TGR5 antagonist SBI-364 decreased growth of cystoids formed in 3-D culture by freshly isolated PCK rat cholangiocytes compared to SBI-319 (right). FIG. 21 are light microscopy images of fully formed by PCK rat cholangiocyte cystoids that were treated with TGR5 agonist, TLCA, alone or in the presence of SBI-319 and SBI-364 (left). TGR5 antagonist, compound SBI-319, decreased hepatic cytogenesis in PCK rats and reduced cell proliferation. SBI-319-treated rats (n = 3 males, n=4 females) received daily intraperitoneal injections of SBI-319 in a dose of 3 mg / kg body weight. Control group (i.e., UN-TR, n=3 males and n=3 females) received injection of equal dose of DMCO. Rats were treated for 4 weeks. Representative light microscopy images of liver tissue (FIG.22A) stained with Masson-trichrom ( i.e., a marker of fibrosis). Representative images and scattered plots show that hepatic cystic and fibrotic areas (FIG.22B)were decreased after treatment with SBI- 319 in both, male and female PCK rats. Data are presented as mean ± SD, n=8-12 for each data Attorney Docket No.43820-0007P01 (SBP Ref.22-015-02PCT) set. * - p<0.05, ** - p<0.01, **** - p<0.0001. FIG.22C are representative immunofluorescence confocal microscopy images of liver sections from un-treated and SBI-319-treated PCK rats stained with PCNA antibody.. TGR5 antagonist, compound SBI-319, decreased renal cystogenesis in PCK rats and reduced cell proliferation. SBI-319-treated rats (n = 3 males, n=4 females) received daily intraperitoneal injections of SBI-319 in a dose of 3 mg / kg body weight. Control group (i.e., UN-TR, n=3 males and n=3 females) received injection of equal dose of DMCO. Rats were treated for 4 weeks. Representative light microscopy images of kidneys (FIG. 23A) stained with Masson-trichrom ( i.e., a marker of fibrosis). Representative images and scattered plots show that renal cystic and fibrotic areas, number of renal cysts, and renal cyst diameter (FIG. 23B) were decreased after treatment with SBI-319 in both, male and female PCK rats. Data are presented as mean ± SD, n=8-12 for each data set. * - p<0.05, ** - p<0.01, **** - p<0.0001. FIG. 23C are representative immunofluorescence confocal microscopy images of kidney sections from un-treated and SBI-319-treated PCK rats stained with PCNA antibody. In cholangiocytes of PCK rats, TGR5 is colocalized with Gas proteins but not Gai proteins and TGR5 antagonist SBI-319 decreased the coupling of TGR5 with Gas proteins. FIG. 24A are representative immunofluorescence confocal microscopy images that show that TGR5 (stained in red) is colocalized with Gas proteins (stained in green) in cholangiocytes of PCK rats but not wild type (WT) rats. In contrast, as shown in FIG. 24B, no colocalization of TGR5 with Gai was observed in PCK rats. FIG.24C is a schematic representation that outlines that TGR5 activation leads to TGR5+Gas coupling subsequently increasing cAMP levels. As shown in FIG. 24D, SBI-319 significantly decreased TGR5+Gas coupling (assessed by proximity ligation assay). n=8 randomly selected confocal microscopic fields. Area depicted by asterisks is shown with a higher magnification. TGR5 antagonist, compound SBI-364, decreased hepatic cystogenesis in PCK rats and reduced cell proliferation in a dose-dependent manner. FIG. 25A are representative light microscopy images of livers stained with Masson-trichrom ( i.e., a marker of fibrosis). FIG. 25B are violin plots that show that hepatic cystic and fibrotic areas, number of hepatic cysts and hepatic cyst diameter were decreased after treatment with SBI-364 in a dose-depent manner. FIG.25C are representative immunofluorescence confocal microscopy images of liver sections from un-treated and SBI-364-treated PCK rats stained with PCNA antibody. Attorney Docket No.43820-0007P01 (SBP Ref.22-015-02PCT) Confocal images were taken and violin plots that show that SBI-364 decreased TGR5+Gas coupling in cholangiocytes of PCK rats in a dose-dependent manner. TGR5+Gas coupling was assessed by proximity ligation assay (FIG.26). TGR5 antagonist, compound SBI-364, decreased renal cystogenesis in PCK rats and reduced cell proliferation in a dose-dependent manner. FIG. 27A are representative light microscopy images of kidneys stained with Masson-trichrom ( i.e., a marker of fibrosis). FIG. 27B are violin plots that show that renal cystic and fibrotic areas, number of renal cysts and renal cyst diameter were decreased after treatment with SBI-364 in a dose-depent manner. FIG. 27C are representative immunofluorescence confocal microscopy images of kidney sections from un-treated and SBI-364-treated PCK rats stained with PCNA antibody. Confocal images (top) were taken and violin plots (bottom) that show that SBI-364 decreased TGR5+Gas coupling in renal epithelial cells of PCK rats in a dose-dependent manner. TGR5+Gas coupling was assessed by proximity ligation assay (FIG.28). TGR5 is overexpressed in cholangiocarcinoma cell lines. As shown in FIG.29A, TGR5 (assessed by immunofluorescence confocal microscopy) is overexpressed in cholangiocarcinoma cell lines compared to healthy human cholangiocytes (NHC). As shown in FIG.29B, TGR5 overexpression in HUCCT1 cell line was confirmed by western blot. TGR5 antagonist SBI-364 decreased proliferation of HUCCT1 cells. Cell proliferation was assessed by direct cell counting (FIG. 30A) and area of cell confluence (FIG. 30B). HUCCT1 cells were stained with CellTracker Red CMPTX dye (Thermo Fisher Scientific) and added to respective wells of a 96-well plate at a cell concentration of 5,000 cells / well. The following day a “time 0” reading was taken on a Celigo Imaging Cell Cytometer (Nexcelom) using the red fluorescence channel. Afterward, cells were treated for 24 and 48 h hours with vehicle (DMSO, marked as UN-TR [un-treated]), TLCA (TGR5 agonist) alone or in the presence of SBI-155 (inactive compound) and SBI-364. After 24 and 48 hours of treatment, the plate was analyzed again using the red fluorescence channel on the Celigo. Proliferation was quantitated based on red fluorescence intensity readings. Data are expressed as a fold change in the cell count or cell confluence at 24 h and 48 h compared to “time 0”. HUCCT1 cell proliferation was decreased by 22%-32% after 24 h and by 31%-45% after 48 h of treatment. Data are presented as mean ± SD, n=8-12 for each data set. * - p<0.05, *** - p<0.001, **** - p<0.0001. TGR5 antagonist SBI-364 decreased proliferation of CCLP1 cells. Cell proliferation was assessed by direct cell counting (FIG.31A) and area of cell confluence (FIG.31B). CCLP1 Attorney Docket No.43820-0007P01 (SBP Ref.22-015-02PCT) cell were stained with CellTracker Red CMPTX dye (Thermo Fisher Scientific) and added to respective wells of a 96-well plate at a cell concentration of 5,000 cells / well. The following day a “time 0” reading was taken on a Celigo Imaging Cell Cytometer (Nexcelom) using the red fluorescence channel. Afterward, cells were treated for 24 and 48 h hours with vehicle (DMSO, marked as UN-TR [un-treated]), TLCA (TGR5 agonist) alone or in the presence of SBI-155 (inactive compound) and SBI-364. After 24 and 48 hours of treatment, the plate was analyzed again using the red fluorescence channel on the Celigo. Proliferation was quantitated based on red fluorescence intensity readings. Data are expressed as a fold change in the cell count or cell confluence at 24 h and 48 h compared to “time 0”. CCLP1 cell proliferation was decreased by 24%-45% after 24 h and by 32%-50% after 48 h of treatment. Data are presented as mean ± SD, n=8-12 for each data set. * - p<0.05, **** - p<0.0001. TGR5 antagonist SBI-364 decreased proliferation of EGI1. Cell proliferation was assessed by direct cell counting (FIG.32A) and area of cell confluence (FIG.32B). EGI1 cells were stained with CellTracker Red CMPTX dye (Thermo Fisher Scientific) and added to respective wells of a 96-well plate at a cell concentration of 5,000 cells / well. The following day a “time 0” reading was taken on a Celigo Imaging Cell Cytometer (Nexcelom) using the red fluorescence channel. Afterward, cells were treated for 24 and 48 h hours with vehicle (DMSO, marked as UN-TR [un-treated]), TLCA (TGR5 agonist) alone or in the presence of SBI-155 (inactive compound) and SBI-364. After 24 and 48 hours of treatment, the plate was analyzed again using the red fluorescence channel on the Celigo. Proliferation was quantitated based on red fluorescence intensity readings. Data are expressed as a fold change in the cell count or cell confluence at 24 h and 48 h compared to “time 0”. EGI1 cell proliferation was decreased by 17%-40% after 24 h and by 28%-55% after 48 h of treatment. Data are presented as mean ± SD, n=8-12 for each data set. * - p<0.05, ** -p<0.01, **** - p<0.001, **** - p<0.0001. TGR5 antagonist SBI-364 decreased proliferation of WITT cells. Cell proliferation was assessed by direct cell counting (FIG.33A) and area of cell confluence (FIG.33B). WITT cells were stained with CellTracker Red CMPTX dye (Thermo Fisher Scientific) and added to respective wells of a 96-well plate at a cell concentration of 5,000 cells / well. The following day a “time 0” reading was taken on a Celigo Imaging Cell Cytometer (Nexcelom) using the red fluorescence channel. Afterward, cells were treated for 24 and 48 h hours with vehicle (DMSO, marked as UN-TR [un-treated]), TLCA (TGR5 agonist) alone or in the presence of SBI-155 (inactive compound) and SBI-364. After 24 and 48 hours of treatment, the plate was Attorney Docket No.43820-0007P01 (SBP Ref.22-015-02PCT) analyzed again using the red fluorescence channel on the Celigo. Proliferation was quantitated based on red fluorescence intensity readings. Data are expressed as a fold change in the cell count or cell confluence at 24 h and 48 h compared to “time 0”. WITT cell proliferation was decreased by 18%-46% after 24 h and by 27%-57% after 48 h of treatment. Data are presented as mean ± SD, n=8-12 for each data set. ** - p<0.01, *** - p<0.001, **** - p<0.0001. TGR5 antagonist SBI-364 decreased proliferation of HUCCT1. FIG. 34 shows representative images of HUCCT1 cells that demonstrated that TGR5 agonist, TLCA, increased cell proliferation in a time-dependent manner. The inactive compound, SBI-155, did not affect cell proliferation. TGR5 antagonist, SBI-364, reduced HUCCT1 proliferation in a time-dependent manner. SBI-155 and SBI-364 were added in the presence of TLCA. TGR5 antagonist SBI-364 decreased levels of p-ERK (i.e., cAMP downstream target) in cholangiocarcinoma cell lines. FIG.35 shows representative immunofluorescence confocal microscopy images that demonstrate the increased levels of p-ERK (stained in red) in response to TGR5 agonist, TLCA. No changes in p-ERK was observed after treatment with inactive compound, SBI-155. In contrast, TGR5 antagonist, SBI-364, markedly decreased p-ERK levels. Cell were treated with all compounds for 30 min. SBI-155 and SBI-364 were added in the presence of TLCA. n = 5-6 for each treatment condition. TGR5 antagonist SBI-364 decreased the tumor growth in mouse model of cholangiocarcinoma. NOD SCID (Nonobese diabetic / severe combined immunodeficiency) male mice (n=5) were implanted with human tumors which express TGR5 (confirmed by western blot, data not shown). As shown in FIG.36, after 27 days of tumor implantation, mice were injected with SBI-319 (3 mg / kg) for 9 days. The graph shows that tumor size was reduced by 30% in response to treatment. Dotted blue line is a projection of a tumor growth in un- treated mice. It is to be understood that while the present application has been described in conjunction with the detailed description thereof, the foregoing description is intended to illustrate and not limit the scope of the present application, which is defined by the scope of the appended claims. Other aspects, advantages, and modifications are within the scope of the following claims.

Claims

Attorney Docket No.43820-0007P01 (SBP Ref.22-015-02PCT) WHAT IS CLAIMED IS:

1. A compound of Formula (I), or a pharmaceuticallyX is selected from , ; or CR2;each is independently selected from halogen, cyano, nitro, C1-C6 alkyl, C1- C6 haloalkyl, C1-C6 alkoxy, -NH(C=O)C1-C6 alkyl, -NHSO2C1-C6 alkyl, phenyl, - NR1AR1B, and 5-10 membered heteroaryl; each R2is independently selected from halogen, nitro, C1-C6 alkyl, C1-C6 haloalkyl, phenyl, and 5-10 membered heteroaryl optionally substituted with 1-3 RA; R3is selected from halogen and C1-C6 alkyl; R4is selected from halogen and C1-C6 alkyl; each RAis independently selected from halogen, C1-C6 alkyl, and 3-10 membered heterocyclyl; each R1A, and R1Bis independently selected from hydrogen and C1-C6 alkyl; m is 0, 1, 2, or 3; and n is 0, 1, 2, or 3.

2. The compound of claim 1, wherein R3is fluoro or chloro.

3. The compound of claim 1 or 2, wherein R3is fluoro.

4. The compound of any one of claims 1-3, wherein R4is chloro or CH3.

5. The compound of any one of claims 1-4, wherein R4is CH3.Attorney Docket No.43820-0007P01 (SBP Ref.22-015-02PCT) 6. The compound of any one of claims 1-5, ,, . ,9. The compound of any one of claims 1-7, wherein X is NH.

10. The compound of any one of claims 1-7, wherein X is S.

11. The compound of any one of claims 1-10, wherein Z is N.

12. The compound of any one of claims 1-10, wherein Z is CH or CR2.

13. The compound of any one of claims 1-7, wherein X is O and Z is N.

14. The compound of any one of claims 1-7, wherein X is O and Z is CH or CR2.

15. The compound of any one of claims 1-7, wherein X is NH and Z is CH or CR2.

16. The compound of any one of claims 1-7, wherein X is S and Z is CH or CR2.

17. The compound of any one of claims 8-16, wherein m is 1.

18. The compound of any one of claims 8-16, wherein m is 2.

19. The compound of any one of claims 8-16, wherein m is 3.

20. The compound of any one of claims 1-19, wherein at least one R1is halogen.

21. The compound of claim 20, wherein at least one R1is fluoro.

22. The compound of claim 20, wherein at least one R1is chloro.Attorney Docket No.43820-0007P01 (SBP Ref.22-015-02PCT) 23. The compound of any one of claims 1-20, wherein each R1is independently selected from fluoro, chloro and bromo.

24. The compound of any one of claims 1-19, wherein at least one R1is cyano.

25. The compound of any one of claims 1-19, wherein at least one R1is nitro.

26. The compound of any one of claims 1-19, wherein at least one R1is C1-C6 alkyl.

27. The compound of any one of claims 1-19 and 26, wherein at least one R1is methyl.

28. The compound of any one of claims 1-19, wherein at least one R1is C1-C6 haloalkyl.

29. The compound of any one of claims 1-19 and 28, wherein at least one R1is trifluoromethyl.

30. The compound of any one of claims 1-19, wherein at least one R1is C1-C6 alkoxy.

31. The compound of any one of claims 1-19 and 30, wherein at least one R1is methoxy.

32. The compound of any one of claims 1-19, wherein at least one R1is -NH(C=O)C1-C6 alkyl.

33. The compound of any one of claims 1-19 and 32, wherein at least one R1is -NH(C=O)CH3.

34. The compound of any one of claims 1-19, wherein at least one R1is -NHSO2C1-C6 alkyl.

35. The compound of any one of claims 1-19 and 34, wherein at least one R1is - NHSO2CH3.

36. The compound of any one of claims 1-19, wherein at least one R1is phenyl.

37. The compound of any one of claims 1-19, wherein at least one R1is -NR1AR1B.

38. The compound of claim 37, wherein R1Ais hydrogen; and R1Bis C1-C6 alkyl.

39. The compound of claim 37, wherein R1Aand R1Bare both hydrogen.

40. The compound of claim 37, wherein R1Aand R1Bare independently selected C1-C6 alkyl.

41. The compound of claim 37 or 40, wherein R1Aand R1Bare both methyl.

42. The compound of any one of claims 1-19, wherein at least one R1is 5-10 membered heteroaryl.

43. The compound of any one of claims 1-19 and 42, wherein R1is 5-membered heteroaryl.

44. The compound of claim 43, wherein R1is tetrazolyl.Attorney Docket No.43820-0007P01 (SBP Ref.22-015-02PCT) 45. The compound of any one of claims 1-19 and 42, wherein R1is 6-membered heteroaryl.

46. The compound of claim 45, wherein R1is pyridinyl, pyrimidinyl, pyridazinyl or pyrazinyl.

47. The compound of claim 46, wherein R1is pyridinyl, pyrimidinyl or pyridazinyl.

48. The compound of claim 46, wherein R1is pyridinyl or pyrimidinyl.

49. The compound of claim 46, wherein R1is pyridinyl.

50. The compound of any one of claims 1-16, wherein m is 0.

51. The compound of any one of claims 1-50, wherein n is 1.

52. The compound of any one of claims 1-50, wherein n is 2.

53. The compound of any one of claims 1-50, wherein n is 3.

54. The compound of any one of claims 1-53, wherein at least one R2is halogen.

55. The compound of any one of claims 1-54, wherein at least one R2is fluoro.

56. The compound of any one of claims 1-54, wherein at least one R2is chloro.

57. The compound of any one of claims 1-54, wherein at least one R2is bromo.

58. The compound of any one of claims 1-53, wherein at least one R2is nitro.

59. The compound of any one of claims 1-53, wherein at least one R2is C1-C6 alkyl.

60. The compound of any one of claims 1-53 and 59, wherein at least one R2is methyl.

61. The compound of any one of claims 1-53, wherein at least one R2is phenyl.

62. The compound of any one of claims 1-53, wherein at least one R2is 5-10 membered heteroaryl optionally substituted with 1-3 RA.

63. The compound of claim 62, wherein the R25-10 membered heteroaryl is a 5-6 membered heteroaryl.

64. The compound of any one of claims 1-53 and 62-63, wherein the R25-10 membered heteroaryl is a 6 membered heteroaryl.

65. The compound of any one of claims 1-53 and 62-64, wherein the R25-10 membered heteroaryl is pyridinyl.

66. The compound of any one of claims 1-53 and 62-65, wherein the R25-10 membered heteroaryl is 2-pyridinyl.

67. The compound of any one of claims 1-53 and 62-65, wherein the R25-10 membered heteroaryl is 3-pyridinyl.

68. The compound of any one of claims 1-53 and 62-65, wherein the R25-10 membered heteroaryl is 4-pyridinyl.Attorney Docket No.43820-0007P01 (SBP Ref.22-015-02PCT) 69. The compound of any one of claims 1-53 and 62-68, wherein at least one RAis halogen.

70. The compound of any one of claims 1-53 and 62-69, wherein at least one RAis chloro.

71. The compound of any one of claims 1-53 and 62-68, wherein at least one RAis C1-C6 alkyl.

72. The compound of any one of claims 1-53 and 62-68 and 71, wherein at least one RAis methyl.

73. The compound of any one of claims 1-53 and 62-68, wherein at least one RAis 3-10 membered heterocyclyl.

74. The compound of any one of claims 1-53, 62-68, and 73, wherein RAis 5-6 membered heterocyclyl.

75. The compound of any one of claims 1-53, 62-68, and 73-74, wherein RAis 6 membered heterocyclyl.

76. The compound of any one of claims 1-53, 62-68, and 73-75, wherein RAis morpholinyl.

77. The compound of claims 76, wherein RAis 4-morpholinyl.

78. The compound of any one of claims 1-50, wherein n is 0.

79. The compound of any one of claims 1-78, wherein at least two R2are independently selected halogen.

80. The compound of any one of claims 1-79, wherein at least two R2are fluoro.

81. The compound of any one of claims 1-79, wherein at least two R2are chloro.

82. The compound of any one of claims 1-79, wherein at least two R2are bromo.

83. The compound of any one of claims 1-78, wherein at least two R2are methyl.

84. The compound of any one of claims 1-78, wherein at least two R2are independently selected C1-C6 haloalkyl.

85. The compound of any one of claims 1-78 and 84, wherein at least two R2are trifluoromethyl.

86. The compound of any one of claims 1-78, wherein at least two R2are independently selected C1-C6 alkoxy.

87. The compound of any one of claims 1-78 and 86, wherein at least two R2are methoxy.

88. The compound of claim 1, wherein X is O; Z is CH; m is 2 or 3; and n is 1.Attorney Docket No.43820-0007P01 (SBP Ref.22-015-02PCT) 89. The compound of claim 1, wherein X is O; Z is CH; m is 2; and n is 1.

90. The compound of claim 1, wherein X is O; Z is CH; m is 3; and n is 1.

91. The compound of claim 1, wherein X is O; Z is N; m is 2; and n is 1.

92. The compound of claim 1, wherein X is O; Z is N; m is 3; and n is 1.

93. The compound of claim 1, wherein X is S; Z is CH; m is 3; and n is 0 or 1.

94. The compound of claim 1, wherein X is S; Z is CH; m is 2 or 3; and n is 0 or 1.

95. The compound of claim 1, wherein X is S; Z is CH; m is 2; and n is 0 or 1.

96. The compound of claim 1, wherein X is S; Z is CH; m is 3; and n is 0 or 1.

97. The compound of claim 1, wherein X is O; Z is N; m is 3; Ring A is phenyl; and n is 1.

98. The compound of claim 1, wherein X is O; Z is N; m is 3; and n is 1.

99. The compound of claim 1, wherein X is O; Z is N; m is 2 or 3; and n is 1.

100. A compound of Formula (I), or a pharmaceutically acceptable salt thereof, selected from the compounds described in Examples 1-54 and / or Table A, or a pharmaceutically acceptable salt of any of the foregoing.

101. A pharmaceutical composition comprising a compound of any one of claims 1- 100, or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable excipients.

102. A method of treating a disease associated with TGR5 in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of any one of claims 1-100, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of claim 101.

103. A method of treating a disease associated with TGR5 in a subject in need thereof, comprising (a) determining that the subject has a disease associated with TGR5; and (b) administering to the subject a therapeutically effective amount of a compound of any one of claims 1-100, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of claim 101.

104. A method of treating a disease associated with TGR5 comprising administering to a subject identified or diagnosed as having a disease associated with TGR5 a therapeutically effective amount of a compound of any one of claims 1-100, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of claim 101.

105. The method of any one of claims 102-104, wherein the disease associated with TGR5 is PLD.Attorney Docket No.43820-0007P01 (SBP Ref.22-015-02PCT) 106. The method of any one of claims 102-104, wherein the disease associated with TGR5 is cholangiocarcinoma, breast cancer, gastric adenocarcinoma, pancreatic cancer, lung cancer, liver cancer, colorectal cancer, or esophageal adenocarcinoma.

107. A method for inhibiting TGR5 function in a mammalian cell, the method comprising contacting the mammalian cell with a compound of any one of claims 1-100, or a pharmaceutically acceptable salt thereof.

108. A method of treating a disease or disorder by inhibiting Takeda G protein-coupled receptor 5 (TGR5) in a subject in need thereof, comprising administering to the subject a compound of Formula (II), or a pharmaceutically; 6 membered heteroaryl;X is selected from O (oxygen), S (sulfur) and NH; Z is N (nitrogen), CH or CR2; each R1is independently selected from halogen, cyano, nitro, C1-C6 alkyl, C1- C6 haloalkyl, C1-C6 alkoxy, -NH(C=O)C1-C6 alkyl, -NHSO2C1-C6 alkyl, phenyl, - NR1AR1B, or 5-10 membered heteroaryl; or two adjacent R1, together with the carbons they are attached to, join to form a 5-6-membered heterocyclyl or a 5-membered heteroaryl; each R2is independently selected from halogen, nitro, C1-C6 alkyl, phenyl, and 5-10 membered heteroaryl optionally substituted with 1-3 RA; R3is selected from hydrogen, halogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, phenyl optionally substituted with 1-3 RB, 5-10 membered heteroaryl, C3-C10 cycloalkyl, and -NR3A1R3B1; R4is selected from hydrogen, halogen, C1-C6 alkyl, C1-C6 alkoxy, -NR4AR4B, and C3-C10 cycloalkyl;Attorney Docket No.43820-0007P01 (SBP Ref.22-015-02PCT) each RAis independently selected from halogen, C1-C6 alkyl, and 3-10 membered heterocyclyl; each RBis independently selected from –C(=O)NR3A2R3B2, – OC(=O)NR3A2R3B2, –NHC(=O)NR3A2R3B2, -C(=O)OR3C2, and 3-10 membered heterocyclyl optionally substituted with C1-C6 alkyl; R5is halogen; each R1A, R1B, R3A1, R3B1, R3A2, R3B2, R4A, R4B, and R3C2is independently selected from hydrogen and C1-C6 alkyl; o is 0 or 1; m is 0, 1, 2, or 3; and n is 0, 1, 2, or 3.

109. The method of claim 108, wherein Ring A is phenyl.

110. The method of claim 108, wherein Ring A is 5-6 membered heteroaryl.

111. The method of claim 108 or 110 wherein Ring A is 5 membered heteroaryl.

112. The method of any one of claims 108 and 110-111, wherein Ring A is thienyl.

113. The method of any one of claims 108 and 110-112, wherein Ring A is 2-thienyl.

114. The method of any one of claims 108 and 110-112, wherein Ring A is 3-thienyl.

115. The method of any one of claims 108-114, wherein R3is hydrogen.

116. The method of any one of claims 108-114, wherein R3is halogen.

117. The method of any one of claims 108-114 and 116, wherein R3is fluoro.

118. The method of any one of claims 108-114, wherein R3is C1-C6 alkyl.

119. The method of any one of claims 108-114 and 118, wherein R3is methyl.

120. The method of any one of claims 108-114, wherein R3is C1-C6 haloalkyl.

121. The method of any one of claims 108-114 and 120, wherein R3is trifluoromethyl.

122. The method of any one of claims 108-114, wherein R3is C1-C6 alkoxy.

123. The method of any one of claims 108-114 and 122, wherein R3is methoxy.

124. The method of any one of claims 108-114, wherein R3is phenyl optionally substituted with 1-3 RB.

125. The method of any one of claims 108-114 and 124, wherein each RBis independently selected from –C(=O)NR3A2R3B2and 3-10 membered heterocyclyl optionally substituted with C1-C6 alkyl.Attorney Docket No.43820-0007P01 (SBP Ref.22-015-02PCT) 126. The method of any one of claims 108-114 and 125, wherein at least one RBis – C(=O)NR3A2R3B2.

127. The method of any one of claims 108-114 and 125-126, wherein at least one RBis – C(=O)NH2.

128. The method of claim 125 or 126, wherein one of R3A2is hydrogen and the other of R3B2is C1-C6 alkyl.

129. The method of claim 125 or 126, wherein R3A2and R3B2are both hydrogen.

130. The method of claim 125 or 126, wherein R3A2and R3B2are independently selected C1- C6 alkyl.

131. The method of claim 130, wherein the R3A2and / or R3B2C1-C6 alkyl is methyl.

132. The method of any one of claims 108-114 and 124, wherein at least one RBis – OC(=O)NR3A2R3B2.

133. The method of any one of claims 108-114 and 132, wherein at least one RBis – OC(=O)NH2.

134. The method of any one of claims 108-114 and 132, wherein one of R3A2is hydrogen and the other of R3B2is C1-C6 alkyl.

135. The method of any one of claims 108-114 and 132, wherein R3A2and R3B2are both hydrogen.

136. The method of any one of claims 108-114 and 132, wherein R3A2and R3B2are independently selected C1-C6 alkyl.

137. The method of any one of claims 108-114, 132 and 136, wherein the R3A2and / or R3B2C1-C6 alkyl is methyl.

138. The method of any one of claims 108-114 and 124, wherein at least one RBis – NHC(=O)NR3A2R3B2.

139. The method of any one of claims 108-114 and 138, wherein at least one RBis – NHC(=O)NH2.

140. The method of any one of claims 108-114 and 138, wherein one of R3A2is hydrogen and the other of R3B2is C1-C6 alkyl.

141. The method of any one of claims 108-114 and 138, wherein R3A2and R3B2are both hydrogen.

142. The method of any one of claims 108-114 and 138, wherein R3A2and R3B2are independently selected C1-C6 alkyl.Attorney Docket No.43820-0007P01 (SBP Ref.22-015-02PCT) 143. The method of any one of claims 108-114 and 138, wherein the R3A2and / or R3B2C1- C6 alkyl is methyl.

144. The method of any one of claims 108-114 and 124, wherein at least one RBis - C(=O)OR3C2.

145. The method of any one of claims 108-114 and 144, wherein R3C2is hydrogen.

146. The method of any one of claims 107-113 and 144, wherein R3C2is C1-C6 alkyl.

147. The method of any one of claims 107-113, 144, and 146, wherein R3C2is methyl.

148. The method of any one of claims 107-113, and 124, wherein at least one RBis 3-10 membered heterocyclyl optionally substituted with C1-C6 alkyl.

149. The method of any one of claims 108-114, 124, and 148, wherein the RB3-10 membered heterocyclyl is a 5-6 membered heterocyclyl.

150. The method of any one of claims 108-114, 124, and 148-149, wherein the RB3-10 membered heterocyclyl is piperazinyl.

151. The method of any one of claims 108-114, wherein R3is 5-10 membered heteroaryl.

152. The method of any one of claims 108-114 and 151, wherein the R35-10 membered heteroaryl is a 5-6 membered heteroaryl.

153. The method of any one of claims 108-114 and 151-152, wherein the R35-10 membered heteroaryl is a pyridyl, pyrimidinyl, or pyrazolyl.

154. The method of any one of claims 108-114 and 151-153, wherein the R35-10 membered heteroaryl is a 4-pyridyl, 5-pyrimidinyl, or 2-pyrazolyl.

155. The method of any one of claims 108-114, wherein R3is C3-C10 cycloalkyl.

156. The method of any one of claims 108-114 and 155, wherein the R3C3-C10 cycloalkyl is cyclopropyl.

157. The method of any one of claims 108-114, wherein R3is -NR3A1R3B1.

158. The method of any one of claims 108-114 and 157, wherein one of R3A1is hydrogen and the other of R3B1is C1-C6 alkyl.

159. The method of any one of claims 108-114 and 157, wherein R3A1and R3B1are both hydrogen.

160. The method of any one of claims 108-114 and 157, wherein R3A1and R3B1are independently selected C1-C6 alkyl.

161. The method of any one of claims 108-114 and 157, wherein the R3A1and / or R3B1C1- C6 alkyl is methyl.

162. The method of any one of claims 108-161, wherein R4is hydrogen.Attorney Docket No.43820-0007P01 (SBP Ref.22-015-02PCT) 163. The method of any one of claims 108-161, wherein R4is halogen.

164. The method of any one of claims 108-161 and 163, wherein R4is fluoro.

165. The method of any one of claims 108-161 and 163, wherein R4is chloro.

166. The method of any one of claims 108-161 and 163, wherein R4is bromo.

167. The method of any one of claims 108-161, wherein R4is C1-C6 alkyl.

168. The method of any one of claims 107-161, wherein R4is methyl.

169. The method of any one of claims 108-161, wherein R4is C1-C6 alkoxy.

170. The method of any one of claims 108-161, wherein R4is methoxy.

171. The method of any one of claims 108-161, wherein R4is -NR4AR4B.

172. The method of any one of claims 108-161 and 171, wherein R4Ais hydrogen and R4Bis C1-C6 alkyl.

173. The method of any one of claims 108-161 and 171, wherein R4Aand R4Bare both hydrogen.

174. The method of any one of claims 108-161 and 171, wherein R4Aand R4Bare independently selected C1-C6 alkyl.

175. The method of any one of claims 108-161 and 171, wherein the R4Aand / or R4BC1-C6 alkyl is methyl.

176. The method of any one of claims 108-161, wherein R4is C3-C10 cycloalkyl.

177. The method of any one of claims 108-161 and 176, wherein R4is cyclopropyl.

178. The method of any one of claims 108-177, wherein o is 1.

179. The method of any one of claims 108-178, wherein R5is halogen.

180. The method of any one of claims 108-179, wherein R5is fluoro.

181. The method of any one of claims 108-180, having the structure of Formula II-A. a pharmaceutically acceptable salt thereof,.

182. TheR3is fluoro or chloro.

183. The method of claim 181 or 182, wherein R3is fluoro.

184. The method of any one of claims 181-183 wherein R4is chloro or CH3.Attorney Docket No.43820-0007P01 (SBP Ref.22-015-02PCT) 185. The method of any one of claims 181-184, wherein R4is CH3.

186. The method of any one of claims 181-185, ,, .

187. The method of any one of claims 181-186,.

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