Substituted phenylsulfonamides as MGAT2 inhibitors

Abstract

Compounds of Formulae I and II are disclosed: I II In compounds of formula I, R 1 is -OH or -NHC(=O)R10. The compounds of formula I are therefore benzenesulfonic acids or N-(phenylsulfonyl)carboxamides. The compounds of formula II are benzenesulfonamides. All of the compounds of formula I are MGAT2 inhibitors and are useful to treat obesity and metabolic dysfunction-associated steatotic liver disease (MASLD). All of the compounds of formula II are useful as intermediates in synthesizing N-(phenylsulfonyl)carboxamides of formula II, and a subset of compounds of formula II are also MGAT2 inhibitors and are useful to treat obesity and metabolic dysfunction-associated steatotic liver disease (MASLD).

Description

SUBSTITUTED PHENYLSULFONAMIDES AS MGAT2 INHIBITORS FIELD OF THE INVENTION 5

[0001] The present invention provides novel phenylsulfonamides, which are inhibitors of monacylglycerol acyltransferase 2 (MGAT2). The compounds are useful in preventing or treating metabolic dysfunction-associated steatotic liver disease (MASLD) and obesity. This invention also relates to pharmaceutical compositions containing these compounds and methods of using the same. 10 BACKGROUND OF THE INVENTION

[0002] The population of the world that is obese has been estimated to be ~ 30-50% (1). Health care costs due to obesity and associated risk factors are estimated to be 150 billion 15 dollars per year (2). Early results using FDA-approved glucagon-like peptide-1 (GLP-1) and dual GLP-1 / gastric inhibitory peptide (GIP) receptor agonists show substantial weight loss in individuals receiving high dose therapy. However, not all patients are able to achieve their weight loss goals using these drugs. Therefore, new therapies are needed that can be combined with GLP-1 and related drugs to achieve additional weight loss. In addition, side effects are associated with these 20 drugs that include GI distress, anorexia, and loss of muscle mass (3, 4). Therefore, long-term therapy may lead to a high rate of noncompliance. New non-incretin therapies are needed that can be used as adjuncts with lower dose incretins to reduce or eliminate side effects, or as monotherapies that can cause substantial weight loss on their own.

[0003] The prevalence of metabolic dysfunction-associated steatotic liver disease 25 (MASLD) continues to rise throughout the world and makes up ~20-45% of individuals in the United States (5). The annual health care cost for treating MASLD was estimated to be 222 billion dollars in 2017 (6). Presently, there are no diagnostic tests and only one FDA approved drug (Rezdiffra) (7) to help physicians recognize and treat the disease, resulting in a huge unmet medical need for diagnostics and additional drug therapies (8). 30

[0004] The links between increased accumulation of liver triglycerides with obesity and severe forms of MASLD that include metabolic dysfunction-associated steatohepatitis{H3007867.1}1 4927-5223-2016, v.1(MASH), fibrosis, and cirrhosis, are well established (9, 10). Triglycerides in the liver are mainly synthesized by the glycerol 3-phoshate pathway 11). Lesser amounts are synthesized by the monoacylglycerol pathway using the monacylglycerol acyltransferase 2 (MGAT2) and diacylglycerol acyltransferase 2 (DGAT2) enzymes (11). 5

[0005] Triglycerides can also come from the diet. They are hydrolyzed in the intestinal lumen to monoacylglycerides and fatty acids and transported into intestinal enterocytes where they are used for triglycerides resynthesis by MGAT2 and DGAT1 (12). Resynthesized triglycerides associate with chylomicrons that enter the lymph system and are transported to the liver (13). Dietary-derived obesity and insulin resistance brought on by caloric overload 10 are known risk factors for developing MASLD / MASH (14).

[0006] MGAT2 activity is highly expressed in the small intestines of mice and humans (15). MGAT2 knockout mice have been shown to be resistant to developing diet-induced obesity and MASLD (16, 17), as are mice with loss of MGAT2 only in the small intestines (18). MGAT2 KO mice expressing human MGAT2 in the intestines become obese and develop 15 MASLD like wild type mice when fed a high fat diet (18). Several MGAT2 inhibitors that have been shown to cause weight loss and lessen the severity of MASLD in mouse obesity models (19, 20). The MGAT2 inhibitor, BMS-963272, has been shown to reduce the severity of MASLD and MASH in mice fed multiple MASH-inducing diets, and to cause weight loss in a phase 1 clinical trial (21). These data strongly support the idea that inhibiting MGAT2 20 activity can be used in treating obesity and MASLD / MASH. SUMMARY OF THE INVENTION

[0007] It has been found that certain ortho-arylphenylsulfonylcarboxamides and ortho- arylphenylsulfonic acids in accordance with the present invention are effective at inhibiting 25 MGAT2 activity, and can be used in treating obesity and MASLD / MASH.

[0008] In one aspect, the invention relates to compounds of general formula I{H3007867.1}2 4927-5223-2016, v.1wherein R1is chosen from -OH , -NHC(=O)R10, and -NHCH2R11, 5 R2is chosen from hydrogen, (C1-C4)alkyl, (C1-C4)alkoxy, fluoro(C1-C4)alkyl, and halogen; Ar1is phenyl or a 6-membered heteroaryl; L1is a two-atom linker chosen from -CH2O-, -C(=O)NH-, -CH2C(=O)-, -C(=O)N(CH3)-, and -CH2N(CH3)-; B is a 4- to 7-membered carbomonocycle or heterocycle, each optionally substituted with 10 methyl; L2is a linker chosen from a direct bond, -C(=O)NHCH2- , -CH2C(=O)NHCH2-, -C(=O)NH-, - CH2-, -CH(OH)-, -C(=O)NHCH2CH2-, -CH2NHC=O-, -C(=O)OCH2-, -CH2-, -C(=O)-, - NHC(=O)NH-, W is chosen from (C2-C6)alkyl, (C1-C6)oxaalkyl, fluoro(C1-C6)alkyl, fluoro(C1-C6)oxaalkyl, 15 isR3is hydrogen or one to three substituents independently chosen from (C1-C4)alkyl, (C1- C4)alkoxy, (C1-C4)fluoroalkyl, (C1-C4)fluoroalkoxy, -NH(C1-C4)alkyl, -NH(C1-C4)fluoroalkyl, cyano, and halogen, with the proviso that, when L2is -CH2C(=O)NHCH2-, then R3includes 20 only a single fluorine; R10is chosen from methyl; trifluoromethyl; phenyl, optionally substituted with one or more methoxy or halo; 5-membered heterocyclyl, optionally substituted independently with one or{H3007867.1}3 4927-5223-2016, v.1more methyl or trifluoromethyl, or fused with phenyl; 6-membered heteroaryl; and C5or C6cycloalkyl, and R11is chosen from 5-membered heterocyclyl, optionally substituted independently with one or more methyl or trifluoromethyl, or fused with phenyl; 6-membered heteroaryl; and C5or C65 cycloalkyl.

[0009] In another aspect, the invention relates to pharmaceutical compositions comprising a pharmaceutically acceptable carrier and a compound of formula I and to methods for inhibiting MGAT2 activity. The compounds can be used in treating obesity and MASLD / MASH. 10

[0010] In another aspect, the invention relates to compounds of formula II 15 whereinR2is chosen from hydrogen, (C1-C4)alkyl, (C1-C4)alkoxy, fluoro(C1-C4)alkyl, and fluorine; Ar1is phenyl or a 6-membered heteroaryl; L1is a two-atom linker chosen from -CH2O-, -C(=O)NH-, -CH2C(=O)-, -C(=O)N(CH3)-, and -CH2N(CH3)-; 20 B’ is a 6-membered carbomonocycle or heterocycle, in which L1and L2are meta or para to each other; L2’is a linker chosen from a direct bond, -C(=O)NHCH2- , -CH2C(=O)NHCH2-, -C(=O)NH-, - CH2-, -C(=O)NHCH2CH2-, -CH2NHC=O-, -C(=O)OCH2-, -CH2-, -C(=O)-, -N-,{H3007867.1}4 4927-5223-2016, v.1W is chosen from (C2-C6)alkyl, (C1-C6)oxaalkyl, fluoro(C1-C6)alkyl, fluoro(C1-C6)oxaalkyl, (C3-C6)cycloalkyl, , wherein Ar2is phenyl, or heteroa ; 3R is hydrogen or one to three substituents independently chosen from (C1-C4)alkyl, (C1- 5 C4)alkoxy, (C1-C4)fluoroalkyl, (C1-C4)fluoroalkoxy, -NH(C1-C4)alkyl, -NH(C1-C4)fluoroalkyl, cyano, and halogen. The compounds of Formula II are useful as intermediates in the synthesis of compounds of formula I. 10

[0011] In another aspect, the invention relates to subgenus of the compounds of formula II in which Ar1is chosen from phenyl, pyridine and pyrazine; L1is a two-atom linker chosen from -CH2O- and -C(=O)NH-; B’ is chosen from pyridine, phenyl, and piperidine; 15 L2’is a linker chosen from: (a) when B’ is piperidine: a direct bond, -C(=O)NH-, -CH2-, -C(=O)NHCH2-, and -C(=O)-; and (b) when B’ is phenyl or pyridine: -C(=O)NHCH2- , -CH2C(=O)NHCH2-, -C(=O)NH-, - CH2-, and -NHC(=O)NH-; 20 kyl,, 1- C4)fluoroalkoxy, -NH(C1-C4)alkyl, -NH(C1-C4)fluoroalkyl, and halogen. This subgenus includes compounds that are useful as intermediates in the synthesis of 25 compounds of formula I and are also themselves inhibitors of MGAT2 activity.{H3007867.1}5 4927-5223-2016, v.1

[0012] The present invention also relates to a method for the treatment or prophylaxis of obesity and MASLD / MASH comprising administering to a patient in need of such treatment or prophylaxis a therapeutically effective amount of at least one of the compounds of the present 5 invention. BRIEF DESCRIPTION OF THE DRAWINGS

[0013] In the accompanying drawings like reference numerals indicate like elements and features in the various figures. For clarity, not every element may be labeled in every figure. In 10 addition, the drawings are not necessarily complete when viewed without reference to the text, emphasis instead being placed upon illustrating the principles of the invention.

[0014] FIG.1 presents a graph showing body weight in grams over an eight-day period for vehicle and two dose regimens of a compound of the invention. 15

[0015] FIG.2 presents a graph showing weight loss in percentage over an eight-day period for vehicle and two dose regimens of a compound of the invention.

[0016] FIG.3 presents a graph showing 24-hour food intake in grams for vehicle and two dose 20 regimens of a compound of the invention.

[0017] FIG.4 presents a graph showing the 7-day cumulative food intake (in grams) for vehicle and two dose regimens of a compound of the invention. 25

[0018] FIG.5 presents a scatter plot showing the levels (in mg / g of protein) of liver triacylglycerides (TAGs) in mice fed an L-amino acid diet minus choline diet (LMCD) in the absence of treatment (negative control), with a compound of the art (BMS-963272 i.e. positive control), and a compound of the invention. 30

[0019] FIG.6 presents a gray-scale rendering of liver tissue section slides that were stained with hematoxylin and eosin (H & E) staining.{H3007867.1}6 4927-5223-2016, v.1

[0020] FIG.7 presents a scatter plot showing the percent lipid area from quantitative histology per tissue area from the mice fed an LMCD diet in the absence of treatment (negative control), with a compound of the art (BMS-963272 i.e. positive control), and a compound of the invention. 5

[0021] FIG.8 presents a scatter plot showing percentage fibrosis area per tissue area for four groups of mice.

[0022] FIG.9 presents a bar graph showing the levels of inflammatory liver cytokines as measured by relative densitometry units for three groups of mice with control diet, LMCD diet with vehicle, LMCD 10 diet with positive control and LMCD diet with a compound of the invention.

[0023] FIG.10 presents a graph showing percent change in body weight as a function of time in days for four treatment regimens. 15

[0024] FIG.11 presents a graph showing percent change in body weight as a function of time in days for four treatment regimens.

[0025] FIG.12 presents a graph showing percent change in body weight as a function of time in days for four treatment regimens. 20

[0026] FIG.13 presents a bar graph showing cumulative food intake in grams over a 22-day period for eight treatment regimens. DETAILED DESCRIPTION 25

[0027] In one embodiment, the present invention provides compounds having the structure of formula I as described above:{H3007867.1}7 4927-5223-2016, v.1

[0028] In some embo these embodiments, R10may be chosen from optionally substituted phenyl, optionally substituted 5-membered 5 heterocyclyl, 6-membered heteroaryl, and bicyclic heteroaryl. In others, R10may be an optionally substituted 5-membered heterocyclyl, in particular, a 5-membered heteroaryl optionally substituted with methyl. In some embodiments, R10is thiophene, furan, thiazole, isothiazole, isoxazole, pyrazole, oxazole, thiadiazole, tetrahydrofuran, triazole, benzofuran, or imidazole. When R10a 6-membered heteroaryl, it may be pyridine. 10

[0029] In some embodiments of formula I, R1is -OH.

[0030] In any of the embodiments above for formula I, R2may be 5-methyl. In any of the embodiments above for formula I, Ar1may be phenyl, pyrazine or pyridine. In any of the 15 embodiments above for formula I, B may be pyridine, piperidine, piperazine, azetidine, or phenyl Often, when B is piperidine, piperazine, or azetidine, L2will be a direct bond.

[0031] In some embodiments of formula I, when B is a six-membered ring, such that positions may be defined as ortho, meta or para, L1and L2are para to one another. In the 20 subgenus in which B is pyridine, piperidine, piperazine, azetidine, or phenyl, L1and L2may be para to one another.

[0032] In any of the embodiments above for formula I, W ma Ar2may be chosen from phenyl, pyridine, and pyrimidine. In theseem o men s n w c{H3007867.1}8 4927-5223-2016, v.1Ar2is phenyl, R3may be hydrogen or one or two substituents independently chosen from -CF3, - OCF3, F, iPr, Cl, CH3, -OCH2CH3, CN, -CH2CF3, -OCH3, -NHCH2CF3, -OCH2CH2CF3, - OCHF2, -NHCH2CH2CF3, and -NHCH2CH3. In these embodiments in which Ar2is pyridine, R3may be hydrogen or one or two substituents independently chosen from -CF3, -OCF3, and (C1- 5 C4)alkyl. In these embodiments in which Ar2is pyrimidine, R3may be hydrogen or one or two substituents independently chosen from -CF3, -NH(C1-C4)fluoroalkyl, (C1-C4)alkyl, and -NH(C1-C4)alkyl.

[0033] In any of the embodiments above for formula I, W may be chosen from cyclopentyl, - 10 CH2CF3, -CH(CH3)2, -(CH2)4CH3, -(CH2)3CH3, -CF3, -(CH2)5CH3, and -CH2O(CH2)2CH3.

[0034] In any of the embodiments above for formula I, R2may be 4-methoxy, 4-fluoro, hydrogen, 4-isopropyl, 4-trifluoromethyl, or 5-methyl. 15

[0035] In another embodiment, the present invention provides compounds having the structure of formula II as described above: In some embodiments of, , dine and pyrazine; 20 L1is a two-atom linker chosen from -CH2O- and -C(=O)NH-; B’ is chosen from pyridine, phenyl, and piperidine; L2’is a linker chosen from: (a) when B’ is piperidine: a direct bond, -C(=O)NH-, -CH2-, -C(=O)NHCH2-, and -C(=O)-; and 25 (b) when B’ is phenyl or pyridine: -C(=O)NHCH2- , -CH2C(=O)NHCH2-, -C(=O)NH-, - CH2-, and -NHC(=O)NH-;{H3007867.1}9 4927-5223-2016, v.1W is chosen from (C2-C6)alkyl, (C1-C6)oxaalkyl, fluoro(C1-C6)alkyl, fluoro(C1-C6)oxaalkyl, , wherein Ar2is phenyl or pyridine; and or two substituents independently chosen from (C1-C4)fluoroalkyl, (C1-C4)fluoroalkoxy, -NH(C1-C4)alkyl, -NH(C1-C4)fluoroalkyl, and halogen. 5

[0036] In some embodiments of formula II, the compound is chosen from Examples 1, 2, 2A, 2C, 2D, 2E, 2F, 2G, 2h, 2I, 5, 5A, 5B, 5C, 6, 6A, 6B, 6C, 6D, 6E, 9, 10, 10B, 11, 12, 12B, 13, 13B, 13D, 13F, 13H, 13K, 13M, 14A, 14C, 14E, 15, 15B, 15C, 16, 16B, 16C, 17B, 17D, 17F, 18, 19, 19F, 19H, 20, 21, 21B, 21C, 21D, 21I, 22, 22B, 23B, 23C, 23D, 23L, 23M, 23N, 230, 10 23V, 23W, 23X, 23Y, 23Z, 23AI, 23AJ, 23AK, 23AO, 23AT, 23AU, 24, 24B, 24C, 24E, 24G, 24I, 24K, 24M, 24N, 24O, 25, 27, 27B, 27D, 27E, and 27DG.

[0037] The present invention may be embodied in other specific forms without departing from the spirit or essential attributes thereof. This invention encompasses all combinations of 15 preferred aspects of the invention noted herein. It is understood that any and all embodiments of the present invention may be taken in conjunction with any other embodiment or embodiments to describe additional embodiments. It is also to be understood that each individual element of the embodiments is its own independent embodiment. Furthermore, any element of an embodiment is meant to be combined with any and all other elements from any embodiment to describe an 20 additional embodiment. CHEMISTRY

[0038] Compounds of this invention may have one or more asymmetric centers. For example, compounds in which B is piperidine or azetidine or compounds in which L225 is -CH(OH)- will be chiral. Unless otherwise indicated, all chiral (enantiomeric and diastereomeric) and racemic forms of compounds of the present invention are included in the present invention. Many geometric isomers of olefins, C=N double bonds, and the like can also be present in the compounds, and all such stable isomers are contemplated in the present{H3007867.1}10 4927-5223-2016, v.1invention. Cis and trans geometric isomers of the compounds of the present invention are described and may be isolated as a mixture of isomers or as separated isomeric forms. The present compounds can be isolated in optically active or racemic forms. It is well known in the art how to prepare optically active forms, such as by resolution of racemic forms or by synthesis 5 from optically active starting materials. All chiral, (enantiomeric and diastereomeric) and racemic forms and all geometric isomeric forms of a structure are intended, unless the specific stereochemistry or isomer form is specifically indicated. When no specific mention is made of the configuration (cis, trans or R or S) of a compound (or of an asymmetric carbon), then any one of the isomers or a mixture of more than one isomer is intended. It is customary in the 10 pharmaceutical art to resolve diastereomers prior to in vitro or in vivo testing. The processes for preparation can use racemates, enantiomers, or diastereomers as starting materials. All processes used to prepare compounds of the present invention and intermediates made therein are considered to be part of the present invention. When enantiomeric or diastereomeric products are prepared, they can be separated by conventional methods, for example, by chromatography 15 or fractional crystallization. Compounds of the present invention, and salts thereof, may exist in multiple tautomeric forms, in which hydrogen atoms are transposed to other parts of the molecules and the chemical bonds between the atoms of the molecules are consequently rearranged. It should be understood that all tautomeric forms, insofar as they may exist, are included within the invention. 20

[0039] As used herein, the term "alkyl" or "alkylene", alone or as part of another group, is intended to include both branched and straight-chain saturated aliphatic hydrocarbon groups having from 1 to 10 carbons or the specified number of carbon atoms. For example, "C1-10 alkyl" (or alkylene), is intended to include C1, C2, C3, C4, C5, C6, C7, C8, C9, and C10 alkyl groups. For example, "C1-C6alkyl" denotes alkyl having 1 to 6 carbon atoms. Alkyl groups can be 25 unsubstituted or substituted with at least one hydrogen being replaced by another chemical group. Example alkyl groups include, but are not limited to, methyl (Me), ethyl (Et), propyl (e.g., n-propyl and isopropyl), butyl (e.g., n-butyl, isobutyl, t-butyl), and pentyl (e.g., n-pentyl, isopentyl, neopentyl), as well as chain isomers thereof.{H3007867.1}11 4927-5223-2016, v.1

[0040] "Alkenyl" or "alkenylene", alone or as part of another group, is intended to include hydrocarbon chains of either straight or branched configuration and having one or more carbon- carbon double bonds that may occur in any stable point along the chain. For example, "C2-6 alkenyl" (or alkenylene), is intended to include C2, C3, C4, C5, and C6alkenyl groups. Examples 5 of alkenyl include, but are not limited to, ethenyl, 1-propenyl, 2-propenyl, 2-butenyl, 3-butenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl, 2-methyl-2- propenyl, and 4-methyl-3-pentenyl.

[0041] "Alkynyl" or "alkynylene", alone or as part of another group, is intended to include10 hydrocarbon chains of either straight or branched configuration and having one or more carbon- carbon triple bonds that may occur in any stable point along the chain. For example, "C2-6alkynyl" (or alkynylene), is intended to include C2, C3, C4, C5, and C6 alkynyl groups; such as ethynyl, propynyl, butynyl, pentynyl, and hexynyl. 15

[0042] The term "alkoxy" or "alkyloxy", alone or as part of another group, refers to an -O-alkyl group, where alkyl is as defined above. "C1-6 alkoxy" (or alkyloxy), is intended to include C1, C2, C3, C4, C5, and C6alkoxy groups. Example alkoxy groups include, but are not limited to, methoxy, ethoxy, propoxy (e.g., n-propoxy and isopropoxy), and t-butoxy. Similarly, "alkylthio" or "thioalkoxy", alone orart of another group, represents an alkyl group or alkoxy 20 group as defined above with the indicated number of carbon atoms attached through a sulphur bridge; for example methyl-S- and ethyl-S-.

[0043] Oxaalkyl refers to alkyl residues in which one or more carbons (and their associated hydrogens) have been replaced by oxygen. Examples include methoxypropoxy, 3,6,9- 25 trioxadecyl and the like. The term oxaalkyl is intended as it is understood in the art [see Naming and Indexing of Chemical Substances for Chemical Abstracts, published by the American Chemical Society, 196, but without the restriction of 127(a)], i.e. it refers to compounds in which the oxygen is bonded via a single bond to its adjacent atoms (forming ether bonds); it does not refer to doubly bonded oxygen, as would be found in carbonyl groups. 30{H3007867.1}12 4927-5223-2016, v.1

[0044] "Halo" or "halogen", alone or as part of another group, includes fluoro, chloro, bromo, and iodo.

[0045] "Halo-C1-C6-alkyl" or "Haloalkyl" is intended to include both branched and straight- chain saturated aliphatic hydrocarbon groups having the specified number of carbon atoms, 5 substituted with 1 to 7 halogens, preferably 1 to 4 halogens, preferably F and / or Cl. Examples of haloalkyl include, but are not limited to, fluoromethyl, difluoromethyl, trifluoromethyl, trichloromethyl, pentafluoroethyl, pentachloroethyl, 1,1-difluoroethyl, 1-fluoroethyl, 2,2,2- trifluoroethyl, heptafluoropropyl, and heptachloropropyl. Examples of haloalkyl also include "fluoroalkyl" that is intended to include both branched and straight-chain saturated aliphatic 10 hydrocarbon groups having the specified number of carbon atoms, substituted with 1 to 7 fluorine atoms, preferably 1 to 4 fluorine atoms.

[0046] "Halo-C1-C4-alkoxy" or "haloalkyloxy" represents a haloalkyl group as defined above with the indicated number of carbon atoms attached through an oxygen bridge. For example, "C1-6haloalkoxy", is intended to include C1, C2, C3, C4, C5, and C6haloalkoxy groups. 15 Examples of haloalkoxy include, but are not limited to, trifluoromethoxy, 2,2,2-trifluoroethoxy, pentafluoroethoxy, and the like. Similarly, "haloalkylthio" or "thiohaloalkoxy" represents a haloalkyl group as defined above with the indicated number of carbon atoms attached through a sulphur bridge; for example trifluoromethyl-S-, and pentafluoroethyl-S-.

[0047] Unless otherwise indicated, the term "cycloalkyl" as employed herein alone or as 20 part of another group includes saturated or partially unsaturated (containing 1 or 2 double bonds) cyclic hydrocarbon groups containing 1 to 3 rings, including monocyclic alkyl, bicyclic alkyl (or bicycloalkyl), and tricyclic alkyl, containing a total of 3 to 10 carbons forming the ring (C3-C10 cycloalkyl), and which may be fused to 1 or 2 aromatic rings as described for aryl, which includes cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclodecyl, 25 cyclododecyl, cyclohexenyl, cyclobutenyl, norbornyl,{H3007867.1}13 4927-5223-2016, v.1,. Such groups when they include 2 free bonds may function as linking groups."Aryl" groups refer to monocyclic or polycyclic aromatic hydrocarbons, including, for example, phenyl, naphthyl, and phenanthranyl. Aryl moieties are well known and described, 5 for example, in Lewis, R.J., ed., Hawley's Condensed Chemical Dictionary, 13th Edition, John Wiley & Sons, Inc., New York (1997). "C6-10aryl" includes phenyl and naphthyl.

[0049] As used herein, the term "heterocycle," "heterocyclo", "heterocyclyl" or "heterocyclic" group is intended to mean a stable 4- to 14-membered monocyclic, bicyclic or tricyclic heterocyclic ring which is saturated or partially unsaturated or aromatic and which 10 consists of carbon atoms and 1, 2, 3, or 4 heteroatoms independently selected from nitrogen, oxygen and sulfur, including any bicyclic group in which any of the above-defined heterocyclic rings is fused to a benzene ring. The nitrogen and sulfur heteroatoms may optionally be oxidized (i.e., N→O and S(O)p, wherein p is 0, 1 or 2). The nitrogen atom may be substituted or unsubstituted (i.e., N or NR wherein R is H or another substituent, if defined). The heterocyclic 15 ring may be attached to its pendant group at any heteroatom or carbon atom that results in a stable structure. A nitrogen in the heterocycle may optionally be quaternized. It is preferred that the total number of S and O atoms in the heterocycle is not more than 1. Spiro and bridged rings are also included in the definition of heterocycle. A bridged ring occurs when one or more atoms (i.e., C, O, N, or S) link two non-adjacent carbon or nitrogen atoms. Examples of bridged rings 20 include, but are not limited to, one carbon atom, two carbon atoms, one nitrogen atom, two nitrogen atoms, and a carbon-nitrogen group. It is noted that a bridge always converts a monocyclic ring into a tricyclic ring. When a ring is bridged, the substituents recited for the ring may also be present on the bridge.

[0050] Exemplary monocyclic heterocyclic groups include azetidinyl, pyrrolidinyl, oxetanyl, 25 imidazolinyl, oxazolidinyl, isoxazolinyl, thiazolidinyl, isothiazolidinyl, tetrahydrofuranyl, piperidyl, piperazinyl, 2-oxopiperazinyl, 2-oxopiperidyl, 2-oxopyrrolodinyl, 2-oxoazepinyl,{H3007867.1}14 4927-5223-2016, v.1azepinyl, 4-piperidonyl, tetrahydropyranyl, morpholinyl, thiamorpholinyl, thiamorpholinyl sulfoxide, thiamorpholinyl sulfone, 1,3-dioxolane, and tetrahydro-1,1-dioxothienyl, and the like.

[0051] Exemplary bicyclic heterocyclo groups include quinuclidinyl.

[0052] As used herein, the term "aromatic heterocyclic group" or "heteroaryl" is a subset of 5 heterocycles and is intended to mean stable monocyclic and polycyclic aromatic hydrocarbons that include at least one heteroatom ring member such as sulfur, oxygen, or nitrogen. Heteroaryl groups include, without limitation, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazinyl, furyl, quinolyl, isoquinolyl, thienyl, imidazolyl, thiazolyl, indolyl, pyrroyl, oxazolyl, benzofuryl, benzothienyl, benzthiazolyl, isoxazolyl, pyrazolyl, triazolyl, tetrazolyl, indazolyl, 1,2,4- 10 thiadiazolyl, isothiazolyl, purinyl, carbazolyl, benzimidazolyl, indolinyl, benzodioxolanyl, and benzodioxane. The nitrogen and sulfur heteroatoms may optionally be oxidized (i.e., N→O and S(O)p, wherein p is 0, 1 or 2).

[0053] The designation " " or " " " "or attached to a ring or other group refers to a free bond or linking group.15

[0054] As referred to herein, the term "substituted" means that at least one hydrogen atom is replaced with a non-hydrogen group, provided that normal valencies are maintained and that the substitution results in a stable compound. When a substituent is keto (i.e., =O), then 2 hydrogens on the atom are replaced. Ring double bonds, as used herein, are double bonds that are formed between two adjacent ring atoms (e.g., C=C, C=N, or N=N). 20

[0055] When any variable occurs more than one time in any constituent or formula for a compound, its definition at each occurrence is independent of its definition at every other occurrence. Thus, for example, if a group is shown to be substituted with 0 to 3 R10, then said group may optionally be substituted with up to three R10groups, and at each occurrence R10is selected independently from the definition of R10. Also, combinations of substituents and / or 25 variables are permissible only if such combinations result in stable compounds.

[0056] As is commonly understood in the art, when a bond to a substituent on a ring is depicted crossing a bond connecting two atoms in a ring, then such substituent may be bonded to any atom on the ring. When a substituent is listed without indicating the atom by which such substituent is bonded to the rest of the compound of a given formula, then such substituent may{H3007867.1}15 4927-5223-2016, v.1be bonded via any atom in such substituent. Combinations of substituents and / or variables are permissible only if such combinations result in stable compounds.

[0057] The phrase "pharmaceutically acceptable" is employed herein to refer to those compounds, materials, compositions, and / or dosage forms that are, within the scope of sound 5 medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, and / or other problem or complication, commensurate with a reasonable benefit / risk ratio.

[0058] As used herein, and as would be understood by the person of skill in the art, the recitation of “a compound” - unless expressly further limited - is intended to include salts, 10 solvates and inclusion complexes of that compound. Thus, for example, the recitation “a compound of formula I” as depicted above, in which R1is -OH would include salts in which R1is -O- M+, wherein M is any counterion. Preferred salts include K+and Na+. In a particular emb diment, the term “compound of formula I” refers to the compound or a pharmaceutically acceptable salt thereof. Unless otherwise stated or depicted, structures depicted herein are also 15 meant to include all stereoisomeric (e.g., enantiomeric, diastereomeric, and cis-trans isomeric) forms of the structure; for example, the R and S configurations for each asymmetric center, (Z) and (E) double bond isomers, and (Z) and (E) conformational isomers. Therefore, single stereochemical isomers as well as enantiomeric, diastereomeric, and cis-trans isomeric (or conformational) mixtures of the present compounds are within the scope of the invention. 20 Unless otherwise stated, all tautomeric forms of the compounds of the invention are within the scope of the invention. Additionally, unless otherwise stated, structures depicted herein are also meant to include compounds that differ only in the presence of one or more isotopically enriched atoms. For example, compounds having the present structures except for the replacement of hydrogen by deuterium or tritium, or the replacement of a carbon by a13C- or 2514C-enriched carbon are within the scope of this invention. Such compounds are useful, for example, as analytical tools or probes in biological assays.

[0059] The term "solvate" refers to a compound of Formula I or II in the solid state, wherein molecules of a suitable solvent are incorporated in the crystal lattice. A suitable solvent for therapeutic administration is physiologically tolerable at the dosage administered. 30 Examples of suitable solvents for therapeutic administration are ethanol and water. When water{H3007867.1}16 4927-5223-2016, v.1is the solvent, the solvate is referred to as a hydrate. In general, solvates are formed by dissolving the compound in the appropriate solvent and isolating the solvate by cooling or using an antisolvent. The solvate is typically dried or azeotroped under ambient conditions. Inclusion complexes are described in Remington: The Science and Practice of Pharmacy 19th5 Ed. (1995) volume 1, page 176-177, which is incorporated herein by reference. The most commonly employed inclusion complexes are those with cyclodextrins, and all cyclodextrin complexes, natural and synthetic, are specifically encompassed within the claims.

[0060] As used herein, "pharmaceutically acceptable salts" refer to derivatives of the disclosed compounds wherein the parent compound is modified by making acid or base salts 10 thereof. Examples of pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic groups such as amines; and alkali or organic salts of acidic groups such as sulfonic and carboxylic acids. For example, such conventional non-toxic salts include sodium, potassium, calcium and ammonium salts. The pharmaceutically acceptable salts include the conventional non-toxic salts or the quaternary ammonium salts of the parent compound 15 formed, for example, from non-toxic inorganic or organic acids. For example, such conventional non-toxic salts include those derived from inorganic acids such as hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric, and nitric; and the salts prepared from organic acids such as acetic, propionic, succinic, glycolic, stearic, lactic, malic, tartaric, citric, ascorbic, pamoic, maleic, hydroxymaleic, phenylacetic, glutamic, benzoic, salicylic, sulfanilic, 2-acetoxybenzoic, 20 fumaric, toluenesulfonic, methanesulfonic, ethane disulfonic, oxalic, and isethionic, and the like.

[0061] The pharmaceutically acceptable salts of the present invention can be synthesized from the parent compound that contains a basic or acidic moiety by conventional chemical methods. Generally, such salts can be prepared by reacting the free acid or base forms of these compounds with a stoichiometric amount of the appropriate base or acid in water or in an organic 25 solvent, or in a mixture of the two; generally, nonaqueous media like ether, ethyl acetate, ethanol, isopropanol, or acetonitrile are preferred. Lists of suitable salts are found in Remington: The Science and Practice of Pharmacy, 22ndEdition, Allen, L. V. Jr., Ed.; Pharmaceutical Press, London, UK (2012), the disclosure of which is hereby incorporated by reference.{H3007867.1}17 4927-5223-2016, v.1

[0062] Isotopically labeled compounds of the present invention, i.e., wherein one or more of the atoms described are replaced by an isotope of that atom (e.g.,12C replaced by13C or by14C; and isotopes of hydrogen including tritium and deuterium), are also provided herein. Such compounds have a variety of potential uses, e.g., as standards and reagents in determining the 5 ability of a potential pharmaceutical compound to bind to target proteins or receptors, or for imaging compounds of this invention bound to biological receptors in vivo or in vitro.

[0063] Compounds of the present invention are, subsequent to their preparation, preferably isolated and purified to obtain a composition containing an amount by weight equal to or greater than 95%, preferably 98% or 99%. Compounds of the present invention are described as 10 "substantially pure" when greater than 95% pure.

[0064] Abbreviations as used herein, are defined as follows: AcOH = acetic acid; Ala = alanine; Atm = atmosphere; ACN = acetonitrile; Boc = t-butoxycarbonyl; BOP-Cl = bis(2-oxo-3- oxazolidinyl)phosphinic chloride; t-Bu = tert-butyl; Cbz = carboxybenzyl; d = day; DCM = 15 dichloromethane; DIEA = DIPEA = N,N-diisopropylethylamine; DMSO = dimethylsulfoxide; EDAC = 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride; FCC = flash column chromatography; Fmoc = fluorenylmethyloxycarbonyl; Glu = glutamic acid; h = hour; HOBt = 1-hydroxybenzotriazole; HPLC = high pressure liquid chromatography; LCMS = liquid chromatography – mass spectrometry; Leu = leucine; min = minute; MeOH = methanol; MPLC 20 = medium pressure liquid chromatography; NMR = nuclear magnetic resonance; Pd / C = palladium on carbon; PyBOP = benzotriazol-1-yloxy)tripyrrolidinophosphonium hexafluorophosphate; sat. = saturated; Ser = serine; SiO2 = silica gel; TEA = triethylamine; TFA = trifluoroacetic acid; Tyr = tyrosine; Z = Cbz = carboxybenzyl; ACN = acetonitrile; BBr3 = boron tribromide; B(Oi-Pr)3= triisopropyl borate; n-BuLi = n-butyl lithium; CsF = cesium 25 fluoride; DCM = dichloromethane; DME = dimethoxyethane; DMF = dimethylformamide; EA = EtOAc = ethyl acetate; EDC = 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide ; EtOH = ethanol; Et2O = diethyl ether; FA = formic acid; HATU = 1-[bis(dimethylamino)methylene]-1H- 1,2,3-triazolo[4,5-b]pyridinium 3-oxid hexafluorophosphate; h = hours; Karstedt’s catalyst = Pt(0)-1,3-divinyl-1,1,3,3-tetramethyldisiloxane complex; KOAc = potassium acetate; LAH =30 lithium aluminum hydride; min = minutes; MS-HPLC = mass-directed reverse phase semi-{H3007867.1}18 4927-5223-2016, v.1preparative chromatography; PDA = photo diode array; Pd(dppf)Cl2= [1,1′- bis(diphenylphosphino)ferrocene]dichloropalladium(II); Pd2(dba)3 = tris(dibenzylideneacetone) dipalladium(0); PPh3 = triphenyl phosphine; RT = room temperature; and THF = tetrahydrofuran. 5

[0065] The compounds of the present invention can be prepared in a number of ways known to one skilled in the art of organic synthesis. The compounds of the present invention can be synthesized using the methods described below, together with synthetic methods known in the art of synthetic organic chemistry, or by variations thereon as appreciated by those skilled in the 10 art. Preferred methods include, but are not limited to, those described below. The reactions are performed in a solvent or solvent mixture appropriate to the reagents and materials employed and suitable for the transformations being effected. It will be understood by those skilled in the art of organic synthesis that the functionality present on the molecule should be consistent with the transformations proposed. This will sometimes require a judgment to modify the order of the 15 synthetic steps or to select one particular process scheme over another in order to obtain a desired compound of the invention.

[0066] During the chemical syntheses, various protecting groups may be employed and subsequently removed in order to generate the compounds of the present invention. Exemplary protecting groups and conditions for their removal are described in Greene’s Protecting Groups 20 in Organic Synthesis P. G. M. Nuts, T. W. Greene, Fourth Edition, Wiley, New York, 2006. EXAMPLES

[0067] The following compounds of the invention have been prepared, isolated and characterized using the methods disclosed herein. They demonstrate a partial scope of the 25 invention and are not meant to be limiting of the scope of the invention. LC / MS Analysis Methods:

[0068] Method A - Compounds were analyzed on an Aquity Ultra Performance Liquid 30 Chromatograph employing an Acquity UPLC BEH C18, 1.7 um, 2.1 X 50 mm column.{H3007867.1}19 4927-5223-2016, v.1Detection was via an Aquity PDA detector and a Waters SQD single quadrupole mass spectrometer. The aqueous acetonitrile based solvent gradient was: 0-0.1 min - Isocratic – 10% of acetonitrile (.01%FA); 0.1-1.3 min - Linear gradient - 10%-90% acetonitrile (0.1% FA); 1.3- 1.8 min – Isocratic - 90% acetonitrile (0.1% FA); 1.8-1.9 min - Linear gradient - 90%-10% 5 acetonitrile (0.1% FA); 1.9-2.0 min – Isocratic - 10% acetonitrile (0.1% FA). Flow rate: 0.6 mL / min.

[0069] Method B - Compounds were analyzed on an Aquity Ultra Performance Liquid Chromatograph employing an Acquity UPLC BEH C18, 1.7 um, 2.1 X 50 mm column. 10 Detection was via an Aquity PDA detector and a Waters SQD single quadrupole mass spectrometer. The aqueous acetonitrile based solvent gradient was: 0-0.1 min - Isocratic – 20% of acetonitrile (0.1%FA); 0.1-1.3 min - Linear gradient - 20%-95% acetonitrile (0.1% FA); 1.3- 1.8 min – Isocratic - 95% acetonitrile (0.1% FA); 1.8-1.9 min - Linear gradient - 95%-20% acetonitrile (0.1% FA); 1.9-2.0 min – Isocratic - 20% acetonitrile (0.1% FA). Flow rate: 0.6 15 mL / min.

[0070] Method C – Compounds were analyzed on an Aquity Ultra Performance Liquid Chromatograph employing an Acquity UPLC BEH C18, 1.7 um, 2.1 X 50 mm column. Detection was via an Aquity PDA detector and a Waters SQD single quadrupole mass 20 spectrometer. The aqueous acetonitrile based solvent gradient was: 0-0.1 min - Isocratic – 2% of acetonitrile (0.1%FA); 0.1-1.3 min - Linear gradient - 2%-80% acetonitrile (0.1% FA); 1.3-1.8 min – Isocratic - 80% acetonitrile (0.1% FA); 1.8-1.9 min - Linear gradient - 80%-2% acetonitrile (0.1% FA); 1.9-2.0 min – Isocratic - 2% acetonitrile (0.1% FA). Flow rate: 0.6 mL / min. 25

[0071] All compounds use Method A unless otherwise noted. MS-HPLC purification Methods

[0072] Method A - Purification was carried out on a Waters 2489 photodiode array detector 30 coupled to a Waters 3100 mass detector for detection, and a Waters 2545 binary HPLC for{H3007867.1}20 4927-5223-2016, v.1separation employing a Waters XSelect CSH C18 prep column (30 x 100 mm; 5 μm particle). The aqueous acetonitrile based solvent gradient was 0-1 min - Isocratic – 5% of acetonitrile (0.25% FA); 1-7 min - Linear gradient – 5%-50% acetonitrile (0.25% FA); 7-9 min – Isocratic – 50% acetonitrile (0.25% FA); 9-12.5 min - Linear gradient – 50%-98% acetonitrile (0.25% FA); 5 12.5-17.5 min – Isocratic – 98% acetonitrile (0.25% FA); 17.5-18 min - Linear gradient – 98%- 5% acetonitrile (0.25% FA); 18-20 min – Isocratic - 5% acetonitrile (0.25% FA). Flow rate: 40 mL / min.

[0073] Method B - Purification was carried out on a Waters 2489 photodiode array detector 10 coupled to a Waters 3100 mass detector for detection, and a Waters 2545 binary HPLC for separation employing a Waters XSelect CSH C18 prep column (30 x 100 mm; 5 μm particle). The aqueous acetonitrile based solvent gradient was 0-1 min - Isocratic – 20% of acetonitrile (0.25% FA); 1-5 min - Linear gradient – 20%-50% acetonitrile (0.25% FA); 5-18 min - Linear gradient – 50%-100% acetonitrile (0.25% FA); 18-18.5 min – Isocratic – 100% acetonitrile 15 (0.25% FA); 18.5-19 min - Linear gradient – 100%-20% acetonitrile (0.25% FA); 19-20 min – Isocratic - 20% acetonitrile (0.25% FA). Flow rate: 40 mL / min.

[0074] NMR Spectroscopy -1H NMR Spectroscopy was conducted on a Bruker 400 MHz Avance II FTNMR Spectrometer, or Bruker 500 MHz Avance III Spectrometer 20 Intermediate 1N-(tert-butyl)-4-methyl benzenesulfonamide (Intermediate 1A)

[0075] To a stirred solution of 4-methylbenzene-1-sulfonyl chloride (10.0 g, 52.4 mmol) in DCM (100 mL) was added 2-methylpropan-2-amine (38.4 mL, 52.5mmol) dropwise at 0 °C. The mixture was allowed to warm up to RT and stirred overnight. The reaction was partitioned between DCM (100 mL) and H2O (50 mL). The organic layer was washed with water (2X), 1N 5 HCl (aq) (1X) and brine (1X). The organic layer was then dried (Na2SO4), filtered and concentrated in vacuo. To the residue was added hexanes and the precipitate was filtered, washed with more hexanes and dried in vacuo overnight to afford Intermediate 1A (11.4 g, 96%).1H NMR (CDCl3) d 7.77 (d, 2H), 7.27 (d, 2H), 4.47 (s, 1H), 2.42 (s, 3H), 1.22 (s, 9H). (2-(N-(tert-butyl)sulfamoyl)-5-methylphenyl)boronic acid (Intermediate 1) 10

[0076] A 500 mL round bottom flask which was pre-loaded with a stir bar and Intermediate 1A (8.73 g, 38.4 mmol) was put on high vacuum pump for overnight before the reaction was set up. THF (88 mL) was added to the flask and the reaction was cooled to -78oC for 10 min, then n-BuLi (2.5 M in Hexane, 30.8 mL, 77.0 mmol) was added dropwise over 5 min. The reaction was stirred at -78oC for 1 h and then allowed to warm up to 0oC. B(Oi-Pr)3 (10.7 mL, 46.2 15 mmol) was then added at 0oC. The reaction mixture was allowed to warm up to RT and stirred overnight. After the reaction was cooled down to 0oC, 2 N HCl (aq)(53 mL) was added and the mixture was stirred at 0oC for 30 min. EtOAc (100 mL) was then added to the reaction. The aqueous layer was extracted by EtOAc (3X). The combined organic layers were washed with brine (1X), dried (Na2SO4), filtered and concentrated in vacuo to give a residue which was 20 purified by silica gel chromatography (0 – 10% MeOH / DCM) to give an oily product. The oily product was mixed with water thoroughly and lyophilized to afford Intermediate 1 as a white solid (8.4 g, 81%). LCMS m / z 507.5 (2M - 2 H2O + H)+, dimerized borate ester.1H NMR (DMSO-d6) d 8.32 (s, 2H), 7.70 (t, 1H), 7.29 (t, 2H), 6.80 (s, 1H), 2.35 (s, 3H), 1.08 (s, 9H). 25

[0077] The following intermediates in Table 1 were prepared by following similar procedures as described for the preparation of Intermediate 1. Table 1{H3007867.1}22 4927-5223-2016, v.1Intermediate Structure NMR , , ), ){H3007867.1}23 4927-5223-2016, v.1Intermediate Structure NMR 1Example 1 5y y

[0078] To a stirred solution of 4-iodobenzoic acid (500 mg, 2.02 mmol) in DMF (20 mL) under nitrogen were added HATU (845 mg, 2.22 mmol) and DIEA (1.30 g, 10.1 mmol). The reaction was stirred for 30 min before the addition of methyl 2-(3-aminophenyl)acetate hydrochloride (488 mg, 2.42 mmol). The mixture was stirred for 1 h at RT. The reaction was{H3007867.1}24 4927-5223-2016, v.1partitioned between EtOAc and H2O, and the aqueous layer was extracted (25 mL, 2X) with EtOAc. The combined organic layers were washed with brine, dried (Na2SO4), filtered, and concentrated in vacuo. The residue was purified by silica gel chromatography (0 – 50% EtOAc / Hexanes) to afford compound 1-1 (586 mg, 61%). LCMS m / z 396.3 (M+H)+.1H NMR 5 (CDCl3) d 7.87 (s, 1H), 7.84-7.80 (d, 2H), 7.78-7.54 (m, 4H), 7.33-7.31 (t, 1H), 7.07-7.05 (d, 1H), 3.69 (s, 3H), 3.63(s, 2H). Methyl 2-(3-(2'-(N-(tert-butyl)sulfamoyl)-5'-methyl-[1,1'-biphenyl]-4- ylcarboxamido)phenyl)acetate (1-2) 10

[0079] Compound 1-1 (500 mg, 1.27 mmol) and Intermediate 1 were combined in DME (9 mL) and H2O (3 mL) and the reaction mixture was degassed by bubbling nitrogen gas through for 5 min. Then Pd2(dba)3, PPh3and CsF were added, and the reaction was stirred at RT for 3 h. The reaction mixture was filtered over Celite and partitioned between EtOAc and H2O, and the aqueous layer was extracted (25 mL, 2X) with EtOAc. The combined organic layers were 15 washed with brine, dried (Na2SO4), filtered, and concentrated in vacuo. The residue was purified by silica gel chromatography (0 – 50% EtOAc / hexanes) to afford compound 1-2 (303 mg, 48%). LCMS m / z 495.4 (M+H)+.1H NMR (CDCl3) d 8.51 (s, 1H), 8.09-7.97 (m, 3H), 7.73-7.59 (m, 3H), 7.37-7.32 (dd, 2H), 7.14-7.11 (dd, 2H), 4.19 (s, 1H), 3.72 (s, 3H), 2.45 (s, 3H), 1.04 (s, 9H). 20 2-(3-(2'-(N-(tert-butyl)sulfamoyl)-5'-methyl-[1,1'-biphenyl]-4-ylcarboxamido)phenyl)acetic acid (1-3)

[0080] A solution of lithium hydroxide (29.0 mg, 1.22 mmol) in water (1 mL) was added to a stirred solution of compound 1-2 (303 mg, 0.613 mmol) in THF (3 mL) and MeOH (3 mL). The reaction mixture was stirred overnight at RT. The reaction mixture was concentrated in vacuo. 25 The crude product was partition between EtOAc and H2O. The aqueous layer was cooled to 0°C and acidified to pH~5 with 1N HCl. The precipitate was filter and washed with water to afford a white solid as compound 1-3 (216 mg, 73% yield). LCMS m / z 481.4 (M+H)+.1H NMR (CD3OD) d 8.04-7.98 (dd, 3H), 7.62 (m, 4H), 7.35 (m, 2H), 7.14 (s, 1H), 7.10(d, 2H), 3.64 (s, 2H), 2.46 (s, 3H), 1.05 (s, 9H). 30{H3007867.1}25 4927-5223-2016, v.12'-(N-(tert-butyl)sulfamoyl)-N-(3-(2-(heptylamino)-2-oxoethyl)phenyl)-5'-methyl-[1,1'- biphenyl]-4-carboxamide (1-4)

[0081] To a stirred solution of compound 1-3 (50.0 mg, 0.104 mmol) in anhydrous DCM (0.70 mL) and DMF (0.20 mL) was added HATU (44.0 mg, 0.114 mmol) and DIEA (65mg, 5 0.520 mmol). The reaction was stirred for 10 min before the addition of heptylamine (19.0 mL, 0.125 mmol). The mixture was stirred for 1 h at RT. The reaction was concentrated in vacuo and the residue was purified by silica gel chromatography (0 – 100% EtOAc / Hexanes) to afford compound 1-4 (51 mg, 85%). LCMS m / z 578.6 (M+H)+.1H NMR (CDCl3) 8.14 (s, 1H), 8.07 (d, 1H), 7.66 (d, 4H), 7.36 (m, 2H), 7.12 (s,1H), 7.09 (d, 1H) 547(s, 1H), 3.78 (s, 1H), 3.59 (s,10 2H), 3.21 (q, 2H), 2.45 (s, 3H), 1.44 (m, 2H), 1.25 (m, 8H), 1.04 (s, 9H), 0.85 (m, 3H). N-(3-(2-(heptylamino)-2-oxoethyl)phenyl)-5'-methyl-2'-sulfamoyl-[1,1'-biphenyl]-4- carboxamide (Example 1)

[0082] To a solution of compound 1-4 (16 mg, 0.028 mmol) in DCM (1.0 mL) at 0 °C was 15 added 1M BBr3in DCM solution (111mL, 0.111 mmol). The reaction was stirred for 3 h while warming to RT. The reaction mixture was concentrated in vacuo and the residue was partitioned between saturated NaHCO3(aq) (5 mL) and EtOAc (25 mL). The aqueous layer was washed with EtOAc (25 mL) and the combined organic layers were concentrated in vacuo. The residue was purified by silica gel chromatography (0 - 5% MeOH / DCM) to afford Example 1 (12 mg, 20 38%). LCMS m / z 522.5 (M+H)+.1H NMR (CD3OD) d 8.01-7.94 (m, 3H), 7.66-7.54 (m, 4H), 7.39-7.30(m, 2H), 7.18 (s, 1H), 7.12 (d, 1H), 3.51 (s, 2H), 3.18 (t, 2H), 2.44 (s, 3H), 1.51-1.48 (m, 2H), 1.30-1.29 (m, 8H) 0.89-0.86 (m, 3H). Example 2 25{H30078674927-52'-(N-(tert-butyl)sulfamoyl)-N-(3-(2-(hexylamino)-2-oxoethyl)phenyl)-5'-methyl-[1,1'- biphenyl]-4-carboxamide (2-1)

[0083] Following a similar procedure as described for Example 1, compound 1-3 was coupled with hexylamine to afford compound 2-1 (48 mg, 81%). LCMS m / z 563.3 (M+H)+.1H 5 NMR (CDCl3) d 8.46 (s, 1H), 8.07 (d, 1H), 7.98 (d, 2H) 7.67-7.61 (m, 4H), 7.41-7.33 (m, 2H), 7.13 (s, 1H), 7.08(d, 1H), 5.48 (m, 1H), 3.83 (s, 1H), 3.60 (s, 2H), 3.24-3.19 (m, 2H), 2.45 (s, 3H), 1.45-1.42 (m, 2H), 1.28-1.21 (m, 8H), 1.04 (s,9H), 0.86-0.83 (m, 3H). N-(3-(2-(hexylamino)-2-oxoethyl)phenyl)-5'-methyl-2'-sulfamoyl-[1,1'-biphenyl]-4- 10 carboxamide (Example 2)

[0084] Compound 2-1 (20.0 mg, 0.035 mmol) was dissolved in DCM (0.1 mL), and TFA (0.9 mL). The mixture was stirred at RT overnight. The reaction was concentrated, azeotroped with toluene, then purified by silica gel chromatography (0 – 5% MeOH / DCM) to afford Example 2 as a white solid (25 mg, 63%). LCMS m / z 508.5 (M+H)+.1H NMR (CD3OD) δ 15 8.04-7.92 (m, 3H), 7.66-7.54 (m, 4H), 7.39-7.30 (m, 2H), 7.18 (s, 1H), 7.10 (d, 1H), 3.52 (s, 2H), 3.29-3.16 (m, 2H), 2.45 (s, 3H), 1.52-1.48 (m, 2H), 1.33-1.29 (m, 6H), 0.88 (t, 3H).

[0085] Following the methods described above for Example 1 and / or Example 2 and substituting the appropriate intermediates and reagents, the following compounds were prepared 20 as indicated in Table 2. Table 2 Example Structure LCMS1H NMR 4 , , ,{H300786.27 4927-5223-2016, v.1Example Structure LCMS1H NMR (M+H)+0 , , d, 28 ( , , , , , ), , N) - 6- 0 ), , , s,{H3007867.1}28 4927-5223-2016, v.1Example Structure LCMS1H NMR (M+H)+(t, d, ), , (t, , ,Example 3 C5 N-((5-methyl-4'-((4-((4-(trifluoromethyl)benzyl)carbamoyl)phenyl)carbamoyl)-[1,1'- biphenyl]-2-yl)sulfonyl)thiophene-2-carboxamide (Example 3)

[0086] Thiophene-2-carbonyl chloride (20 µL, 0.18 mmol) was added into a mixture of Example 2I (94.0 mg, 0.170 mmol) and TEA (46.0 µL, 0.330 mmol) in DCM (1.5 mL) / DMA 10 (1.3 mL). The reaction was stirred at RT for about 30 min and DCM (4 mL) was added. The resultant solution was washed with water. The organic layer was dried (Na2SO4), filtered and concentrated in vacuo. The residue was purified by a reverse phase flash chromatography (0 - 100% MeCN / H2O). The product was further purified by a silica gel chromatography (0 - 10%{H3007867.1}29 4927-5223-2016, v.1DCM / MeOH) to afford Example 3 (17 mg, 15%). LCMS m / z 678.2 (M+H)+.1H NMR (DMSO-d6) d 12.30 (s, 1H), 10.49 (s, 1H), 9.09 (t, 1H), 7.88~8.16 (m, 8H), 7.84 (s, 1H), 7.71 (d, 2H), 7.55 (d, 2H), 7.42~7.48 (m, 3H), 7.20 (s, 2H), 4.56 (d, 2H), 2.42 (s, 3H). 5 Example 4Capping Method B 10 N-((5-methyl-4'-((3-(2-oxo-2-((2-propoxyethyl)amino)ethyl)phenyl)carbamoyl)-[1,1'- biphenyl]-2-yl)sulfonyl)thiophene-2-carboxamide (Example 4)

[0087] To a stirred solution of Example 2A (20 mg, 0.039 mmol) in DCM (1 mL) was added 3,5-lutidine (0.045 mL, 0.39 mmol), followed by thiophene-2-carbonyl chloride (0.0083 mL, 0.078 mmol). The reaction was stirred at RT overnight, then more 3,5-lutidine (0.045 mL, 0.390 15 mmol) and 2-thiophenecarbonyl chloride (0.010 mL, 0.094 mmol) were added. The mixture was stirred at RT for another 3 h, and then quenched with MeOH (1 mL). The volatiles were removed in vacuo and the residue was purified by MS-HPLC (method A) to afford Example 4 (17 mg, 68%). LCMS m / z 620.3 (M+H)+.1H NMR (CDCl3) d 9.15 (br, 1H), 8.94 (s, 1H), 8.34 (d, 1H), 7.80, 7.79 (two singlet overlapping, 2H), 7.67 (d, 2H), 7.63 (d, 1H), 7.51 (d, 1H), 7.40 20 (dd, 1H), 7.32 (dd, 1H), 7.24 (d, 2H), 7.09 (d, 2H), 7.04 (m, 1H), 5.96 (t, 1H), 3.66 (s, 2H), 3.45 (m, 4H), 3.33 (t, 2H), 2.46 (s, 3H), 1.49 (m, 2H), 0.84 (t, 3H).

[0088] Following the capping methods described above for Example 3 or Example 4, the following compounds were prepared from their respective precursors as indicated in Table 3. 25 Table 3{H3007867.1}30 4927-5223-2016, v.1Structure Precursor Capping LCMS1H NMR Example Method (M+H)+63 , 5 ), , 63 , 5 ), , 41 5 62 ,31 4927-5223-2016, v.1Structure Precursor Capping LCMS1H NMR Example Method (M+H)+5 48 , 1 ), , , 44 , ), ,Example 5 4-Hy roxy- -(-(r uorome y) enzy) enzam e (-){H3007867.1}32 4927-5223-2016, v.1

[0089] To 4-hydroxybenzoic acid (1.00 g, 7.20 mmol) and 3-trifluoromethylbenzylamine (3.20 g, 18.1 mmol) in DCM (36 mL) was added EDC (3.50 g, 18.1 mmol), HOBt (2.40 g, 18.1 mmol) and DIEA (4.40 mL, 25.3 mmol). The solution was stirred at RT for 2 h, then solvent was evaporated and the residue was purified by silica gel chromatography (0 – 90% 5 EtOAc / hexanes) to afford compound 5-1 (1.60 g, 76%). LCMS m / z 296.3 (M+H)+.1H NMR (CDCl3) d 7.71-7.68 (m, 2H), 7.59 (b, 1H), 7.56-7.54 (m, 2H), 7.48-7.46 (m, 2H), 6.87-6.86 (m, 2H), 6.46 (m, 1H), 4.70-4.69 (m 2H). 4-((4-Iodobenzyl)oxy)-N-(3-(trifluoromethyl)benzyl)benzamide (5-2) 10

[0090] To a solution of compound 5-1 (300 mg, 1.00 mmol) in DMF (2.60 mL), was added potassium carbonate (705 mg, 5.10 mmol) and 4-Iodobenzyl bromide (454 mg, 1.50 mmol). The reaction was stirred at RT overnight. The reaction was partitioned between EtOAc and H2O. The organic layer was washed with H2O and brine, dried (Na2SO4), filtered and concentrated in vacuo to provide a yellow solid which was triturated with ACN to afford compound 5-2 (405 15 mg, 78%). LCMS m / z 512.2 (M+H)+.1H NMR (DMSO-d6) d 9.02-8.99 (t, 1H), 7.88-7.86 (m, 2H), 7.78-7.75 (m, 2H), 7.65 (b, 1H), 7.63-7.57 (m, 3H), 7.28-7.26 (m, 2H), 7.10-7.07 (m, 2H), 5.15 (s, 2H), 4.54-4.53 (d, 2H). 4-((2'-(N-(tert-butyl)sulfamoyl)-5'-methyl-[1,1'-biphenyl]-4-yl)methoxy)-N-(3- 20 (trifluoromethyl)benzyl)benzamide (5-3)

[0091] To a solution of compound 5-2 (401 mg, 0.780 mmol) in DME (4mL) and ethanol (1 mL) was added Intermediate 1 (213 mg, 0.780 mmol) and the reaction mixture was degassed by bubbling nitrogen gas through for three minutes. Cesium fluoride (237 mg, 1.60 mmol), PPh3(61.7 mg, 0.240 mmol), and Pd2(dba)3 (72 mg, 0.080 mmol) were added sequentially. The 25 reaction mixture was further degassed by bubbling nitrogen gas through for two minutes and then heated to 70oC for 1.5 h. The reaction mixture was cooled and filtered through Celite. Celite was washed with DCM, and the combined filtrate was concentrated and purified by silica gel chromatography (0 – 100% EtOAc) to afford compound 5-3 (384 mg, 80%). LCMS m / z 611.3 (M+H)+.1H NMR (CDCl3) d 8.06-8.04 (d, 1H), 7.82-7.78 (m, 2H), 7.61 (b, 1H), 7.59-{H3007867.1}33 4927-5223-2016, v.17.47 (m, 7H), 7.03-7.28 (m, 1H), 7.3-7.12 (s.1H), 7.06-7.02 (m, 2H), 6.45-6.42 (t, 1H), 5.19 (s, 2H), 4.7-4.71 (d, 2H), 3.49 (s, 1H), 2.44 (s, 3H), 0.99 (s, 9H). 4-((5'-Methyl-2'-sulfamoyl-[1,1'-biphenyl]-4-yl)methoxy)-N-(3- 5 (trifluoromethyl)benzyl)benzamide (Example 5)

[0092] A mixture of compound 5-3 (75.0 mg, 0.120 mmol), DCM (0.62 ml) and TFA (3.10 mL) were stirred overnight. The reaction was concentrated in vacuo and the residue was azeotroped with toluene, and then purified by MS-HPLC(method A) to afford Example 5 (47.8 mg, 70%). LCMS m / z 555.2 (M+H)+.1H NMR (CD3OD) d 8.0-7.98 (d, 1H), 7.89-7.86 (m, 2H),10 7.67.(b, 1H),7.64-7.51 (m, 5H) 7.46-7.44- (m, 2H), 7.37-7.34 (m.1H), 7.17-7.16 (m, 1H), 7.14- 7.11 (m, 2H), 5.23 (s, 2H), 4.6 (b, 2H), 2.44 (s, 3H).

[0093] Following the method described above for Example 5 and substituting the appropriate intermediates and reagents, the following Examples were prepared as indicated in Table 4. 15 Table 4 Example Structure Intermediate LCMS M+H+- m, m, . ), . , m, ), b, ), .4927-5223-2016, v.1Example 65 Methyl 2-(4-((4-iodobenzyl)oxy)phenyl)acetate (6-1)

[0094] To a solution of methyl-(4-hydroxyphenyl)acetate (500 mg, 3.01 mmol) in DMF (7.5 mL), was added potassium carbonate (2.10 g, 15.1 mmol) and 4-iodobenzyl bromide (1.34 g, 4.52 mmol). The reaction was stirred at RT for 72 h. The reaction was partitioned between EtOAc and H2O. The organics were washed with H2O and brine, dried over Na2SO4, and 10 filtered. The filtrate was concentrated in vacuo and the residue was purified by silica gel chromatography (0 – 100% EtOAc / hexanes) to afford compound 6-1 (1.0 g, 87%).1H NMR (CDCl3) d 7.74-7.71 (m, 2H), 7.22-7.17 (m, 4H), 6.93-6.90 (m, 2H), 5.01 (s, 2H), 3.70 (2, 3H), 3.58 (s, 2H). 15 Methyl 2-(4-((2'-(N-(tert-butyl)sulfamoyl)-5'-methyl-[1,1'-biphenyl]-4- yl)methoxy)phenyl)acetate (6-2)

[0095] Using a similar procedure as described for the preparation of compound 5-3 from compound 5-2, compound 6-1 (0.99 g, 2.59 mmol) was converted to compound 6-2 (1.02 g, 82%). LCMS m / z 426.2 (M+H)+.1H NMR (CDCl3) d 7.98-7.96 (d, 1H), 7.47-7.42 (m, 4H),{H3007867.1}35 4927-5223-2016, v.17.22 (m, 1H), 7.15-7.13 (m, 2H), 7.5 (s.1H), 6.88-6.87 (m, 2H), 5.05 (s, 2H), 3.62 (s, 3H), 3.51 (s, 2H), 3.41 (s, 1H), 2.36 (s, 3H), 0.91 (s, 9H). 2-(4-((2'-(N-(tert-butyl)sulfamoyl)-5'-methyl-[1,1'-biphenyl]-4-yl)methoxy)phenyl)acetic 5 acid (6-3)

[0096] To compound 6-2 (1.03 g, 2.14 mmol) in THF (14 mL) was added 1N LiOH (aq) (21 mL) followed by MeOH (11 mL). The solution was stirred at RT for 2 h, and then concentrated in vacuo. The crude residue was dried in vacuo. To the residue was added H2O which was washed with Et2O. The aqueous phase was acidified to pH~2 with 1N HCl, and extracted with 10 EtOAc. The EtOAc extracts were combined, washed with brine, dried over Na2SO4, filtered and concentrated in vacuo to provide compound 6-3 (0.97 g, 97%). LCMS m / z 468.3 (M+H)+.1H NMR (CDCl3) d 8.07-8.05 (d, 1H), 7.55-7.50 (m, 4H), 7.30 (m, 1H), 7.24-7.22 (m, 2H), 7.13 (m, 1H), 6.97-6.95 (m, 2H), 5.13 (s, 1H), 3.62 (s, H), 3.53 (s, 1H), 2.44 (s, 3H), 0.99 (s, 9H). 15 2-(4-((2'-(N-(tert-butyl)sulfamoyl)-5'-methyl-[1,1'-biphenyl]-4-yl)methoxy)phenyl)-N-(2,4- difluorobenzyl)acetamide (6-4)

[0097] To a solution of compound 6-3 (75 mg, 0.16 mmol) in DCM (2 mL) was added HATU (80 mg, 0.21 mmol) and DIEA (98 µL, 0.56 mmol). The reaction was stirred for 15 min, then 2,4-difluorobenzylamine (23 µL, 0.19 mmol) was added and the mixture was stirred for 70 20 min at RT. The solution was partitioned between EtOAc and H2O. The organic layer was washed with H2O, brine, dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by silica gel chromatography (0 – 75% EtOAc / hexanes) to provide compound 6-4 (78.5 mg, 83%). LCMS m / z 593.2 (M+H)+.1H NMR (CDCl3) d 8.07-8.05 (m, 1H), 7.56-7.50 (m 4H), 7.30-7.24 (m, 2H), 7.20-7.13 (m, 3H), 7.00-6.97 (m, 2H), 6.85-6.76 (m, 2H), 5.77 (m, 25 1H), 5.77 (s, 2H), 4.42-4.41 (m, 2H), 3.56 (s, 2H), 3.50 (s, 1H), 2.44 (s, 3H), 1.00 (s, 9H). N-(2,4-difluorobenzyl)-2-(4-((5'-methyl-2'-sulfamoyl-[1,1'-biphenyl]-4- yl)methoxy)phenyl)acetamide (Example 6)

[0098] To compound 6-4 (77 mg, 0.13 mmol) in DCM (0.65 mL) was added TFA (3.2 mL) 30 and the solution stirred overnight at RT. The reaction was concentrated in vacuo and purified{H3007867.1}36 4927-5223-2016, v.1directly by MS-HPLC (Method B) to provide Example 6 (11.4 mg, 16%). LCMS m / z 537.2 (M+H)+.1H NMR (CD3OD) d 8.07-8.05 (m, 1H), 7.98-7.96 (m 1H), 7.33-7.24 (m, 6H), 7.13 (s, 1H), 7.04-6.75 (m, 5H), 4.37-4.41 (s, 2H), 3.99 (s, 2H), 3.42 (s, 2H), 2.42 (s, 3H). 5

[0099] Following the method described above for Example 6 and substituting the appropriate reagents, the following Examples were prepared as indicated in Table 5. Table 5 MS1H NMR Example Structure (M+H)+3 , 3- 7 3 3- ), 9 2 ),{H3007867.1}37 4927-5223-2016, v.1MS1H NMR Example Structure (M+H)+7- 7 2 d - 2 d, ), 4xamp e 75 Capping Method A1 N-((5-methyl-4'-((4-((3-(trifluoromethyl)benzyl)carbamoyl)phenoxy)methyl)-[1,1'- biphenyl]-2-yl)sulfonyl)thiophene-2-carboxamide (Example 7)

[0100] To a solution of Example 5 (63 mg, 0.11 mmol) in DCM (3 mL) at 0oC was added 10 triethylamine (24 µL, 0.17 mmol) and 2-thiophenecarbonylchloride (13 µL, 0.12 mmol). At 2 h, the reaction was concentrated in vacuo and the residue was purified by MS-HPLC (method A) to afford Example 7 (35.9 mg, 48%). LCMS m / z 665.2 (M+H)+.1H NMR (CD3OD) d 9.01-8.99 (t, 1H), 8.15-8.13 (d, 1H), 7.90-7.88 (m, 2H), 7.74-7.53 (m, 5H), 7.53-7.9 (m, 6H), 7.14-7.12 (m. 3H), 7.0-6.98 (m, 1H), 5.2 (s, 2H), 4.66-4.64 (m, 2H), 2.46 (s, 3H). 15{H3007867.1}38 4927-5223-2016, v.1Example 7A4-((2'-(N-benzoylsulfamoyl)-5'-methyl-[1,1'-biphenyl]-4-yl)methoxy)-N-(3- 5 (trifluoromethyl)benzyl)benzamide (Example 7A)

[0101] To a solution of Example 5 (50 mg, 0.090 mmol) in DCM (1 mL) was added TEA (13.8 µL, 0.099 mmol) followed by benzoyl chloride (12 mL, 0.099 mmol). After stirring the reaction for 16 h an additional two equivalents of benzoyl chloride (11.5 mL, 0.099 mmol) was added and the reaction stirred for an additional 3 h. The reaction was quenched with MeOH (100 10 mL) and the solvent was removed in vacuo. The residue was purified by silica gel chromatography (0 – 100% EtOAc / Hexanes) to afford Example 7A (10.6 mg, 18%) as a white solid. LCMS m / z 659.3 (M+H)+.1H NMR (CDCl3) δ 8.30 (d, 1H), 7.83 (d, 2H), 7.64 – 7.47 (m, 5H), 7.42-7.32 (d, 9H), 7.22 (s, 1H), 7.03 (d, 2H), 6.42 (m, 1H), 5.09 (s, 2H), 4.73 (d, 2H), 2.45 (s, 3H). 15 Example 7By p y y y , p y y y - (trifluoromethyl)benzyl)benzamide (Example 7B){H3007867.1}39 4927-5223-2016, v.1

[0102] To a solution of Example 5 (48 mg, 0.086 mmol) in ACN (1 mL) was added TEA (24 mL, 0.17 mmol) followed by cyclopentanecarbonyl chloride (12 mL, 0.10 mmol). The reaction was stirred for 1 h before the addition of an additional two equivalents each of cyclopentanecarbonyl chloride (21 mL, 0.17 mmol) and TEA (24 mL, 0.17 mmol). The reaction 5 was then heated to 60° C before the addition of two more equivalents of cyclopentanecarbonyl chloride (21 mL, 0.17 mmol). After stirring 15 min the reaction mixture was cooled to RT and quenched with MeOH (100 mL) and then concentrated in vacuo. The residue was purified by silica gel chromatography (0 – 100% EtOAc / Hexanes) to afford Example 7B (25 mg, 45%) as a white solid. LCMS m / z 651.4 (M+H)+.1H NMR ( CDCl3) δ 8.20 (d, 1H), 7.80 (d, 2H), 7.61- 10 7.56 (m, 3H), 7.51-7.47(m, 3H), 7.41-7.36 (m, 3H), 7.12 (s, 1H), 7.04 (d, 2H), 6.43 (m, 1H), 5.19 (s, 2H), 4.72 (d, 2H), 2.45 (s, 3H) 2.21-2.17 (m, 1H), 1.65-1.60 (m, 6H), 1.48-1.46 (m, 2H) . Example 7C 15N-((5-methyl-4'-((4-((3-(trifluoromethyl)benzyl)carbamoyl)phenoxy)methyl)-[1,1'- biphenyl]-2-yl)sulfonyl)isoxazole-5-carboxamide (Example 7C)

[0103] To a solution of Example 5 (50 mg, 0.09 mmol) 3,5-lutidine (1 mL) was added 20 isoxazole-5-carbonyl chloride (13 mL, 0.14 mmol). After stirring at RT for 2 h the reaction was heated to 60° C and an additional two equivalents of isoxazole-5-carbonyl chloride (18 mL, 0.18 mmol) was added. The reaction was stirred for 15 min at 60° C and quenched with MeOH (100 µL). The solvent was removed in vacuo and the residue was purified by MS-HPLC (method A) to afford Example 7C (14.6 mg, 25%). LCMS m / z 650.3 (M+H)+.1H NMR (CD3OD) δ 8.46{H3007867.1}40 4927-5223-2016, v.1(d, 1H), 8.15 (d, 1H), 7.88 (d, 2H), 7.67-7.28 (m, 7H), 7.29 (d, 2H), 7.16-7.11 (m, 3H), 6.86 (d, 1H), 5.20 (s, 2H), 4.64 (s, 2H), 2.46 (s, 3H).

[0104] Following the procedures described previously and substituting the appropriate 5 precursors and reagents, the following Examples were prepared as indicated in Table 6 with the specified capping method. Table 6 Precursor Capping MS1H NMR Structure Example Method (M+H)+) ) , 7 ), 95 47{H3007867.1}41 4927-5223-2016, v.1Precursor Capping MS1H NMR Structure Example Method (M+H)+, , H) 4 d, 44 m,{H3007867.1}42 4927-5223-2016, v.1Precursor Capping MS1H NMR Structure Example Method (M+H)+, m,5 Methyl 2'-(N-(tert-butyl)sulfamoyl)-5'-methyl-[1,1'-biphenyl]-4-carboxylate (8-1){H3007867.1}43 4927-5223-2016, v.1

[0105] To a mixture of Intermediate 1 (1.55 g, 5.72 mmol), methyl 4-iodobenzoate (1.00 g, 3.82 mmol), Pd(dppf)Cl2CH2Cl2 (312 mg, 0.38 mmol), and Na2CO3 (810 mg, 7.64 mmol), was added dioxane (25 mL) and H2O (6 mL). The reaction mixture was degassed by bubbling nitrogen gas through for 5 min. and then was heated at 80oC for 4 h. The reaction mixture was 5 then cooled to room temperature, DCM (30 mL) was added and the mixture was filtered through a pad of Celite. The filtrate was washed with H2O (30 mL) and dried (Na2SO4), filtered and concentrated in vacuo. The residue was purified by silica gel chromatography (0 - 30% EtOAc / Hexanes) to afford compound 8-1 (1.42 g, 100%).1H NMR (CDCl3) d 8.12 (d, 2H), 8.06 (d, 1H), 7.60 (d, 2H), 7.32 (d, 1H), 7.11 (s, 1H), 3.97 (s, 3H), 3.48 (s, 1H), 2.45 (s, 3H), 1.02(s, 10 9H). 2'-(N-(tert-butyl)sulfamoyl)-5'-methyl-[1,1'-biphenyl]-4-carboxylic acid (8-2)

[0106] LiOH·H2O (330 mg, 7.86 mmol) was added into a mixture of compound 8-1 (1.42 g, 3.82 mmol) in THF (25 mL) and H2O (13 mL). The reaction mixture was stirred at RT for 4 h. 15 The reaction mixture was concentrated in vacuo and the residue was dissolved in H2O (30 mL). The pH value of the resulting solution was adjusted to about 2 by adding 1N HCl (aq) dropwise. The precipitate was filtered, washed with H2O (3X), and dried overnight in vacuo to afford compound 8-2 (1.27 g, 87%). LCMS (method A) m / z 348.2 (M+H)+.1H NMR (DMSO-d6) d 12.98 (s, 1H), 7.92~7.96 (m, 3H), 7.48 (d, 2H), 7.39 (d, 1H), 7.14 (s, 1H), 6.74 (s, 1H), 2.39 (s, 20 3H), 0.99 (s, 9H). tert-Butyl 4-(2'-(N-(tert-butyl)sulfamoyl)-5'-methyl-[1,1'-biphenyl]-4-ylcarboxamido) piperidine-1-carboxylate (8-3)

[0107] Using a similar procedure as described in Example 1, step 1, compound 8-2 (200 mg, 25 0.52 mmol), was coupled with tert-butyl 4-aminopiperidine-1-carboxylate (146 mg, 0.73 mmol), and purified by a reverse-phase chromatography (C-18, 0 - 100% ACN / H2O) to afford compound 8-3 (236 mg, 86%).1H NMR (CDCl3) d 8.04 (d, 1H), 7.86 (d, 2H), 7.57 (d, 2H), 7.31 (d, 1H), 7.10 (s, 1H), 6.37 (d, 1H), 4.16 (m, 3H), 3.77 (s, 1H), 2.98 (t, 2H), 2.44 (s, 3H), 2.07 (dd, 2H), 1.50 (s, 11H), 1.03 (s, 9H). 30{H3007867.1}44 4927-5223-2016, v.12'-(N-(tert-butyl)sulfamoyl)-5'-methyl-N-(piperidin-4-yl)-[1,1'-biphenyl]-4-carboxamide hydrochloride (8-4)

[0108] HCl (4M in dioxane, 850 µL, 3.40 mmol) was added into a mixture of compound 8-3 (360 mg, 0.68 mmol) in DCM (4 mL). The reaction was stirred at RT for 2 h. Solvent was 5 removed in vacuo to afford compound 8-4 (351 mg, 100%) which was used without purification. LCMS m / z 430.3 (M+H)+.1H NMR (CD3OD) d 8.00 (d, 1H), 7.90 (d, 2H), 7.55 (d, 2H), 7.38 (d, 1H), 7.16 (s, 1H), 4.20 (m, 1H), 3.51 (dd, 2H), 3.18 (td, 2H), 2.43 (s, 3H), 2.22 (dd, 2H), 1.89 (q, 2H), 1.06 (s, 9H). 10 2'-(N-(tert-butyl)sulfamoyl)-5'-methyl-N-(1-(2-(4-(trifluoromethyl)phenyl)acetyl)piperidin- 4-yl)-[1,1'-biphenyl]-4-carboxamide (8-5)

[0109] Compound 8-4 (202 mg, 0.430 mmol), was coupled with 2-(4- (trifluoromethyl)phenyl)acetic acid (124 mg, 0.610 mmol), using a similar procedure as described in Example 1, step1, and purified by a reverse-phase chromatography (0 - 100% 15 ACN / H2O) to afford compound 8-5 (242 mg, 91%). LCMS m / z 616.2 (M+H)+. 5'-Methyl-2'-sulfamoyl-N-(1-(2-(4-(trifluoromethyl)phenyl)acetyl)piperidin-4-yl)-[1,1'- biphenyl]-4-carboxamide (8-6)

[0110] Following a similar procedure as described in Example 2, step 2, compound 8-5 (242 20 mg, 0.390 mmol) was treated with TFA / DCM (9 / 1) to afford compound 8-6 (200 mg, 92%) after purification by silica gel chromatography (0 - 10% MeOH / DCM). LCMS m / z 560.2 (M+H)+. 1H NMR (DMSO-d6) d 8.35 (d, 1H), 7.91 (d, 1H), 7.83 (d, 2H), 7.68 (d, 2H), 7.41-7.49 (m, 4H),H), 7.13 (d, 1H), 4.36 (d, 1H), 4.01-4.08 (m, 2H), 3.87 (s, 2H), 3.17 (td, 1H), 2.77 (td, 1H), 2.39 (s, 3H), 1.84 (d, 2H), 1.38-1.44 (m, 2H). 25 N-((5-methyl-4'-((1-(2-(4-(trifluoromethyl)phenyl)acetyl)piperidin-4-yl)carbamoyl)-[1,1'- biphenyl]-2-yl)sulfonyl)thiophene-2-carboxamide (Example 8)

[0111] Compound 8-6 (115 mg, 0.210 mmol) was capped with thiophene-2-carbonyl chloride using capping method A. Product was first purified by a reverse phase chromatography 30 (0 - 100% ACN / H2O), followed by a silica gel chromatography (0 - 10% MeOH / DCM) to afford{H3007867.1}45 4927-5223-2016, v.1Example 8 (23 mg, 16%). LCMS m / z 670.3 (M+H)+.1H NMR (CD3OD) d 8.14 (d, 1H), 7.78 (m, 3H), 7.65 (d, 2H), 7.45~7.51 (m, 4H), 7.38 (d, 2H), 7.15 (s, 1H), 7.07 (t, 1H), 4.60 (d, 1H), 4.09~4.20 (m, 2H), 3.93 (d, 2H), 3.27 (t, 1H), 2.87 (td, 1H), 2.46 (s, 3H), 2.00 (m, 2H), 1.47~1.56 (m, 1H), 1.37~1.47 (m, 1H). 5 Example 9 and 9A4-(2'-(N-(tert-butyl)sulfamoyl)-5'-methyl-[1,1'-biphenyl]-4-ylcarboxamido)-N-(3- 10 (trifluoromethyl)phenyl)piperidine-1-carboxamide (9-1)

[0112] 1-Isocyanato-3-(trifluoromethyl)benzene (29 µL, 0.21 mmol) was added to a mixture of compound 8-4 (100 mg, 0.193 mmol) and DIEA (67.0 µL, 0.39 mmol) in DCM (2 mL). The reaction was stirred at RT for 1 hr. Solvent was removed in vacuo to give a residue which was purified by silica gel chromatography (0 - 10% MeOH / DCM) to afford compound 9-1 (94 mg, 15 79%). LCMS m / z 617.3 (M+H)+.1H NMR (CDCl3) d 8.02 (d, 1H), 7.86 (d, 2H), 7.72 (s, 1H), 7.55~7.61 (m, 3H), 7.27~7.32 (m, 2H), 7.10 (s, 1H), 6.67 (s, 1H), 6.53 (s, 1H), 4.23~4.28 (m, 1H), 4.16 (dd, 2H), 3.86 (s, 1H), 3.14 (t, 2H), 2.43 (s, 3H), 2.19 (t, 2H), 1.64 (q, 2H), 1.03 (s, 9H).{H3007867.1}46 4927-5223-2016, v.14-(5'-Methyl-2'-sulfamoyl-[1,1'-biphenyl]-4-ylcarboxamido)-N-(3-(trifluoromethyl)phenyl) piperidine-1-carboxamide (Example 9)

[0113] Following a similar procedure as described for Example 2, step 2, compound 9-1 (93 5 mg, 0.15 mmol) was treated with TFA / DCM (9 / 1) and converted to Example 9 (66.2 mg, 78%). LCMS m / z 561.3 (M+H)+.1H NMR (CD3OD) d 8.00 (d, 1H), 7.87 (td, 2H), 7.81 (s, 1H), 7.62 (d, 1H), 7.51 (td, 2H), 7.46 (t, 1H), 7.38 (d, 1H), 7.29 (d, 1H), 7.17 (d, 1H), 4.25 (d, 2H), 4.16- 4.22 (m, 1H), 3.10 (t, 2H), 2.45 (s, 3H), 2.05 (d, 2H), 1.65 (qd, 2H). 10 4-(5'-Methyl-2'-(N-(thiophene-2-carbonyl)sulfamoyl)-[1,1'-biphenyl]-4-ylcarboxamido)-N- (3-(trifluoromethyl)phenyl)piperidine-1-carboxamide (Example 9A)

[0114] Example 9 (64 mg, 0.114 mmol) was capped with thiophene-2-carbonyl chloride using capping method A, and purified first by a reverse phase chromatography (0 - 100% ACN / H2O), followed by a silica gel chromatography (0 - 10% MeOH / DCM) to afford Example 15 9A (20 mg, 26%). LCMS m / z 671.3 (M+H)+.1H NMR (CDCl3) d 9.13 (s, 1H), 8.20 (d, 1H), 7.75 (s, 1H), 7.64 (d, 2H), 7.55 (d, 2H), 7.43 (t, 1H), 7.28~7.32 (m, 3H), 7.19 (d, 3H), 7.03 (s, 2H), 6.86 (s, 1H), 4.13~4.22 (m, 3H), 3.21 (t, 2H), 2.37 (s, 3H), 2.17 (d, 2H), 1.75 (q, 2H). Example 10 and 10A 20{H3007867.1}47 4927-5223-2016, v.1tert-Butyl 4-(2'-(N-(tert-butyl)sulfamoyl)-N,5'-dimethyl-[1,1'-biphenyl]-4- ylcarboxamido)piperidine-1-carboxylate (10-1) 5

[0115] Using a similar procedure as described in Example 1, step 1, compound 8-2 (180 mg, 0.469 mmol), was coupled with tert-butyl 4-(methylamino)piperidine-1-carboxylate (141 mg, 0.657 mmol), and purified by silica gel chromatography (0 - 10% MeOH / DCM) to afford compound 10-1 (249 mg, 98%). LCMS m / z 544.3 (M+H)+.1H NMR (CDCl3) d 8.06 (d, 1H), 7.57 (d, 2H), 7.49 (d, 2H), 7.32 (d, 1H), 7.11 (s, 1H), 4.73 (s, 1H), 4.22 (s, 2H), 3.54 (s, 1H), 10 2.98 (t, 4H), 2.45 (s, 3H), 1.75 (d, 4H), 1.48 (s, 9H), 1.03 (s, 9H). 2'-(N-(tert-butyl)sulfamoyl)-N,5'-dimethyl-N-(piperidin-4-yl)-[1,1'-biphenyl]-4- carboxamide hydrochloride (10-2)

[0116] Following a similar procedure as described in Example 8, step 4, compound 10-1 15 (249 mg, 0.458 mmol) was converted to compound 10-2 (260 mg, quantitative, 85% purity). LCMS m / z 444.3 (M+H)+.1H NMR (DMSO-d6) d 8.72 (d, 2H), 7.93 (d, 1H), 7.34~7.47 (m,{H3007867.1}48 4927-5223-2016, v.15H), 7.15 (s, 1H), 6.70 (s, 1H), 3.62 (s, 2H), 3.36 (s, 2H), 3.07 (s, 1H), 2.85 (s, 3H), 2.40 (s, 3H), 2.05 (s, 2H), 1.84 (d, 2H), 0.98 (s, 9H). 4-(2'-(N-(tert-butyl)sulfamoyl)-N,5'-dimethyl-[1,1'-biphenyl]-4-ylcarboxamido)-N-(3- 5 (trifluoromethyl)phenyl)piperidine-1-carboxamide (10-3)

[0117] Following a similar procedure as described in Example 9, step1, compound 10-2 (110 mg, 0.230 mmol) reacted with 1-isocyanato-3-(trifluoromethyl)benzene and purified by silica gel chromatography (0 - 10% MeOH / DCM) to afford compound 10-3 (144 mg, 100%). LCMS m / z 631.3 (M+H)+.1H NMR (CDCl3) d 8.06 (d, 1H), 7.69 (s, 1H), 7.58 (d, 3H), 7.48 (d, 2H), 7.41 (t, 10 1H), 7.31 (t, 3H), 7.12 (s, 1H), 6.68 (s, 1H), 4.20 (s, 2H), 3.57 (s, 1H), 3.10 (s, 2H), 2.90 (s, 3H), 2.45 (s, 3H), 1.85 (d, 4H), 1.04 (s, 9H). 4-(N,5'-dimethyl-2'-sulfamoyl-[1,1'-biphenyl]-4-ylcarboxamido)-N-(3-(trifluoromethyl) phenyl)piperidine-1-carboxamide (Example 10) 15

[0118] Following a similar procedure as Example 2, step 2, compound 10-3 (144 mg, 0.229 mmol) was treated with TFA / DCM and purified by silica gel chromatography (0 – 10% MeOH / DCM) to afford Example 10 (103 mg, 78%). LCMS m / z 575.3 (M+H)+.1H NMR (CD3OD) d 8.00 (d, 1H), 7.80 (d, 1H), 7.61 (t, 1H), 7.52 (d, 2H), 7.46, 7.38 (d, 1H), 7.29 (d, 1H), 7.20 (d, 1H), 4.70 (s, 0.5H), 4.36 (d, 1H), 4.24 (d, 1H), 3.84 (s, 0.5H), 2.95-3.15 (m, 20 4H), 2.76 (t, 1H), 2.46 (s, 3H), 1.75-1.95 (m, 4H). 4-(N,5'-dimethyl-2'-(N-(thiophene-2-carbonyl)sulfamoyl)-[1,1'-biphenyl]-4-ylcarboxamido)- N-(3-(trifluoromethyl)phenyl)piperidine-1-carboxamide (Example 10A)

[0119] Example 10 (100 mg, 0.174 mmol) was capped with thiophene-2-carbonyl chloride 25 using capping method A, and purified first by a reverse phase chromatography (0 - 100% ACN / H2O), followed by silica gel chromatography (0 - 10% MeOH / DCM) to afford Example 10A (52 mg, 44%). LCMS m / z 685.3 (M+H)+.1H NMR (CD3OD) d 8.14 (d, 1H), 7.81 (s, 1H), 7.76 (d, 1H), 7.61 (t, 1H), 7.28-7.56 (m, 7H), 7.29 (d, 1H), 7.16 (d, 1H), 7.09 (t, 1H), 4.66 (s, 0.5H), 4.38 (d, 1H), 4.24 (d, 1H), 3.89 (s, 0.5H), 3.06 (s, 1H), 3.02 (s, 1H), 2.91 (s, 2H), 2.76 (t, 30 1H), 2.47 (s, 3H), 1.75-2.02 (m, 4H).{H3007867.1}49 4927-5223-2016, v.1

[0120] Following the method described above for Example 10 and substituting suitable reagents, Examples in Table 7 were prepared. 5 Table 7 Example Capping MS NMR Structure method (M+H)+8Example 11 and 11A{H3007867.1}50 4927-5223-2016, v.14-(2'-(N-(tert-butyl)sulfamoyl)-N,5'-dimethyl-[1,1'-biphenyl]-4-ylcarboxamido)-N-(4- (trifluoromethyl)benzyl)piperidine-1-carboxamide (11-1) 5

[0121] To compound 10-2 (150 mg, 0.31 mmol) in DCM (3 mL), was added 4- nitrochloroformic acid (94.6 mg, 0.47 mmol) and the reaction was stirred for 3 h at RT. The reaction was concentrated in vacuo to provide a crude para-nitro carbamate intermediate. LCMS: m / z 609.5 (M+H)+. The intermediate was re-dissolved in DMA (3 mL), DIEA (109 mL, 0.62 mmol) and 4-trifluoromethylbenzylamine (180 mL, 1.25 mmol) were added and the reaction10 was microwaved 100oC for 1h. Additional DIEA (109 uL, 0.62 mmol) and 4- trifluoromethylbenzylamine (180 mL, 1.25 mmol) were added in 2 h intervals. The reaction was concentrated in vacuo, and partitioned between EtOAc and H2O. The aqueous layer was extracted with EtOAc (2x). Combined organic layers was washed with brine, dried over Na2SO4, filtered, concentrated and purified by silica gel chromatography (0 – 100% 15 EtOAc / hexanes, then 0 – 20% MeOH / DCM), followed by reverse phase chromatography (5 – 10% ACN / H2O) to afford compound 11-1. LCMS m / z 645.5 (M+H)+.1H NMR (CDCl3) d 8.06-8.04 (d, 1H), 7.60-7.56 (m, 4H), 7.48-7.43 (m, 4H), 7.31-7.29 (m, 1H), 7.10 (s, 1H), 4.90 (s,{H3007867.1}51 4927-5223-2016, v.11H), 4.75 (b, 1H), 4.50-4.49 (d, 2H), 4.20 -4.00 (m, 2H), 2.54 (s, 1H), 3.10-2.83 (m, 4H), 2.44 (s, 3H),1.88-1.69 (m, 4H), 1.02 (s, 9H). 4-(N,5'-dimethyl-2'-sulfamoyl-[1,1'-biphenyl]-4-ylcarboxamido)-N-(4- (trifluoromethyl)benzyl)piperidine-1-carboxamide (Example 11) 5

[0122] Following a similar procedure as Example 2, step 2, compound 11-1 (72.0 mg, 0.11 mmol), was treated with TFA / DCM and purified by reverse phase chromatography (10 – 100% ACN / H2O) to provide Example 11 (65.2 mg, 99%). LCMS m / z 589.4 (M+H)+.1H NMR (CDCl3) d 8.05-8.03 (d, 1H), 7.60-7.4 (m, 8H), 7.33-7.31 (m, 1H), 7.14 (s, 1H), 4.91 (s, 1H), 4.75 (b, 1H), 4.49 (m, 2H), 4.28 (m, 2H), 4.13-4.02 (m, 2), 2.98-2.82 (m, 4H), 2.45 (s, 3H),1.82- 10 1.70 (m, 4H). 4-(N, 5'-dimethyl-2'-(N-(thiophene-2-carbonyl)sulfamoyl)-[1,1'-biphenyl]-4- ylcarboxamido)-N-(4-(trifluoromethyl)benzyl)piperidine-1-carboxamide (Example 11A)

[0123] Example 11 (62 mg, 0.11 mmol) was capped with thiophene-2-carbonyl chloride 15 using capping method B1. The reaction was quenched with MeOH, concentrated in vacuo, azeotroped with toluene and purified by reverse phase chromatography (0 – 100 % CAN / H2O with 0.25% formic acid) to afford Example 11A (51.5 mg, 70%). LCMS: m / z 699.4 (M+H)+. 1H NMR (CDCl3) d 8.26-8.22 (m, 1H), 7.60-7.58 (m, 3H), 7.44-7.26 (m, 8H), 7.11 (b, 1H), 7.06- 7.00 (m, 1H), 4.90 (s, 1H), 4.79-4.67 (b, 1H), 4.48 (m, 2H), 4.14-4.00 (m, 2), 2.99-2.63 (m, 5H), 20 2.45 (s, 3H),1.88-1.73 (m, 4H).

[0124] Following the method described above for Example 11 and substituting suitable reagents, Examples in Table 8 were prepared. 25 Table 8 Example MS NMR Structure{H3007867.1}52 4927-5223-2016, v.11H NMR (CD3OD) d 8.15-8.13 (d, 11B 1H), 7.78-7.77 (dd, 1H), 7.53-7.45 (m 2H) 737-733 (m 4H) 716 (b, ,5 tert-Butyl (4-((4-iodobenzyl)oxy)phenyl)carbamate (12-1)

[0125] DMF (21 mL) was added into a mixture of 1-(bromomethyl)-4-iodobenzene (3.70 g, 12.4 mmol), tert-butyl (4-hydroxyphenyl)carbamate (2.00 g, 9.60 mmol), and K2CO3(6.60 g, 47.8 mmol). The reaction was stirred at RT for 4 days. The reaction was diluted with DCM and washed with H2O (5 X). The organic layer was dried (Na2SO4), filtered and concentrated in 10 vacuo to give a residue which was dissolved in EtOAc. The title compound was crystallized, filtered and dried in vacuo to afford compound 12-1 (3.25 g, 80%).1H NMR (DMSO-d6) d 9.15 (s, 1H), 7.74 (d, 2H), 7.33 (d, 2H), 7.24 (d, 2H), 6.89 (d, 2H), 5.00 (s, 2H), 1.46 (s, 9H).{H3007867.1}53 4927-5223-2016, v.1tert-Butyl (4-((2'-(N-(tert-butyl)sulfamoyl)-5'-methyl-[1,1'-biphenyl]-4-yl)methoxy)phenyl) carbamate (12-2)

[0126] To a mixture of compound 12-1 (500 mg, 1.18 mmol), Intermediate 1 (478 mg, 1.76 5 mmol), Pd(dppf)Cl2CH2Cl2 (96mg, 0.12 mmol) and Na2CO3 (250 mg, 2.36 mmol), was added dioxane (8 mL) and H2O (2 mL). The reaction mixture was stirred and degassed by bubbling nitrogen gas through for 5 min. The reaction was then heated at 80oC for about 4 h. After cooling DCM (20 mL) was added to the reaction and the mixture was filtered through a Celite pad. The organic layer was washed with H2O (30 mL), dried (Na2SO4), filtered and concentrated 10 in vacuo. The residue was purified by silica gel chromatography (0 - 30% EtOAc / hexanes) to afford compound 12-2 (613 mg, 99%). LCMS m / z 525.2 (M+H)+.1H NMR (CDCl3) d 8.05 (d, 1H), 7.52 (q, 4H), 7.29 (d, 3H), 7.13 (s, 1H), 6.93 (d, 2H), 6.36 (s, 1H), 5.11 (s, 2H), 3.50 (s, 1H), 2.44 (s, 3H), 1.52(s, 9H), 0.99 (s, 9H). 15 4'-((4-Aminophenoxy)methyl)-N-(tert-butyl)-5-methyl-[1,1'-biphenyl]-2-sulfonamide (12-3)

[0127] Following a similar procedure as described in Example 8, step 4, compound 12-2 (607 mg, 1.15 mmole) was converted to compound 12-3 (609 mg, quantitative, 87% purity). LCMS m / z 425.3 (M+H)+.1H NMR (DMSO-d6) d 10.06 (s, 2H), 7.92 (d, 1H), 7.47 (d, 2H), 7.41 (d, 2H), 7.36 (d, 1H), 7.32 (d, 2H), 7.15 (d, 2H), 7.12 (s, 1H), 6.60 (s, 1H), 5.18 (s, 2H), 3.38 (s, 20 3H), 1.00 (s, 9H). N-(tert-butyl)-5-methyl-4'-((4-(3-(4-(trifluoromethyl)phenyl)ureido)phenoxy)methyl)-[1,1'- biphenyl]-2-sulfonamide (12-4)

[0128] Following a similar procedure as described in Example 9, step1, compound 12-3 (120 25 mg as 87% pure, 0.23 mmol) was reacted with 1-isocyanato-4-(trifluoromethyl)benzene and purified by silica gel chromatography (0 - 10% MeOH / DCM) to afford compound 12-4 (94 mg, 68%). LCMS m / z 612.3 (M+H)+. 5-Methyl-4'-((4-(3-(4-(trifluoromethyl)phenyl)ureido)phenoxy)methyl)-[1,1'-biphenyl]-2- 30 sulfonamide (Example 12){H3007867.1}54 4927-5223-2016, v.1

[0129] Following a similar procedure as Example 2, step 2, compound 12-4 (94 mg, 0.15 mmol) was treated with TFA / DCM and purified by silica gel chromatography (0 – 10% MeOH / DCM) to afford Example 12 (22 mg, 26%) LCMS m / z 556.3 (M+H)+.1H NMR (CD3OD) d 7.87 (d, 1H), 7.50 (d, 2H), 7.45 (d, 2H), 7.39 (d, 2H), 7.33 (d, 2H), 7.24 (d, 3H), 5 7.05 (s, 1H), 6.89 (d, 2H), 5.03 (s, 2H), 2.32 (s, 3H). N-((5-Methyl-4'-((4-(3-(4-(trifluoromethyl)phenyl)ureido)phenoxy)methyl)-[1,1'-biphenyl]- 2-yl)sulfonyl)thiophene-2-carboxamide (Example 12A)

[0130] Example 12 (22 mg, 0.040 mmol) was capped with thiophene-2-carbonyl chloride 10 using capping method B1, and purified first by a reverse phase chromatography (0 - 100% ACN / H2O), followed by another reverse phase chromatography (0 - 100% ACN / H2O) to afford Example 12A (16 mg, 59%). LCMS m / z 666.3 (M+H)+.1H NMR (CD3OD) d 8.14 (d, 1H), 7.73 (d, 1H), 7.63 (d, 2H), 7.57 (d, 2H), 7.35-7.45 (m, 6H), 7.30 (d, 2H), 7.14 (s, 1H), 7.01~7.03 (m, 3H), 5.11 (s, 2H), 2.45 (s, 3H). 15

[0131] Following the method described above for Example 12 and substituting suitable reagents, Examples in Table 8A were prepared. Table 8A Example Capping MS NMR Structure method (M+H)+, ,{H3007867.1}55 4927-5223-2016, v.1Example Capping MS NMR Structure method (M+H)+, ,p p 5tert-butyl 4-((4-iodobenzyl)oxy)piperidine-1-carboxylate (13-1)

[0132] To tert-butyl 4-hydroxypiperidine-1-carboxylate (1 g, 4.97 mmol) dissolved in DMF (7 mL) under N2at 0 °C was added sodium hydride (278 mg, 60% dispersion in mineral oil). After 15 minutes, the ice bath was removed, and the mixture was stirred at RT for 45 minutes. 4- 10 Iodobenzylbromide (1.62 g, 5.47 mmol) and tetrabutylammonium iodide (185 mg, 0.50 mmol) were added. The reaction was stirred at RT for 18 h, and quenched with water (10 mL). The{H3007867.1}56 4927-5223-2016, v.1mixture was extracted with DCM (100 mL), and the organic layer was washed with water (20 mL x 3), dried (Na2SO4), filtered and concentrated to give a mixture of pink liquid and some white solid. The pink liquid was purified by silica gel chromatography (0 – 60% EtOAc / hexanes) to afford compound 13-1 (1.36 g, 60%). LCMS m / z 318.1 (M+H-Boc)+.1H 5 NMR (CDCl3) d 7.67 (d, 2H), 7.09 (d, 2H), 4.49 (s, 2H), 3.78 (br., 2H), 3.55 (m, 1H), 3.10 (m, 2H), 1.84 (br., 2H), 1.58 (br., 2H), 1.455 (s, 9H). tert-butyl 4-((2'-(N-(tert-butyl)sulfamoyl)-5'-methyl-[1,1'-biphenyl]-4- yl)methoxy)piperidine-1-carboxylate (13-2) 10

[0133] Compound 13-1 (417 mg, 1.0 mmol) was dissolved in 4:1 dimethyl ether / EtOH (7.5 mL). Intermediate 1 (325.3 mg, 1.2 mmol) was added and the mixture was purged with N2 for 3 min. CsF (304 mg, 2.0 mmol), Pd2(dba)3(96mg, 0.12 mmol) and PPh3(79 mg, 0.3 mmol), were added and the reaction mixture was purged with N2 for 1 min. The reaction was then heated at 70oC for 1 h. The reaction and the mixture was filtered through a Celite pad which 15 was further washed with DCM. The combined filtrate was evaporated and purified by silica gel chromatography (0 - 100% EtOAc / hexanes) to afford compound 13-2 (442 mg, 86%). LCMS m / z 417.3 (M+H-Boc)+.1H NMR (CDCl3) d 8.06-8.04 (d, 1H), 7.52-7.50 (m, 2H), 7.44-7.42 (d, 2H), 7.29 (s, 1H), 7.11 (s, 1H), 4.63 (s, 2H), 3.81-3.78 (m, 2H), 3.64-3.57 (m, 1H), 3.52 (s, 1H), 3.17-3.11 (m, 2H), 2.44 (s, 3H), 1.94-1.84 (m, 2H), 1.69-1.59 (m, 2H), 1.46 (s, 9H). 20 N-(tert-butyl)-5-methyl-4'-((piperidin-4-yloxy)methyl)-[1,1'-biphenyl]-2-sulfonamide hydrochloride (13-3)

[0134] HCl (4M in dioxane, 288 µL, 1.15 mmol) was added into a mixture of compound 13- 2 (120 mg, 0.23 mmol) in DCM (3 mL). The reaction was stirred at RT for 2 h. Solvent was 25 removed in vacuo to afford compound 13-3 (351 mg, 100%) which was used without purification. LCMS m / z 416.2 (M+H)+.1H NMR (CDCl3) d 9.55 (s, 2H), 8.05-8.03 (d, 1H), 7.51-7.49 (m, 2H), 7.39-7.37 (d, 2H), 7.29 (s, 1H), 7.11 (s, 1H), 4.58 (s, 2H), 3.83-3.78 (m, 2H), 3.70 (s, 2H), 3.52 (s, 1H), 3.37-3.32 (m, 2H), 3.26-3.22 (m, 2H), 2.43 (s, 3H).{H3007867.1}57 4927-5223-2016, v.14-((2'-(N-(tert-butyl)sulfamoyl)-5'-methyl-[1,1'-biphenyl]-4-yl)methoxy)-N-(3- (trifluoromethyl)phenyl)piperidine-1-carboxamide (13-4) 1-Isocyanato-3-(trifluoromethyl)benzene (35 µL, 0.25 mmol) was added to a mixture of compound 13-3 (0.23 mmol) and Et3N (64.0 µL, 0.46 mmol) in DCM (2 mL). The reaction was 5 stirred at RT overnight. Solvent was removed in vacuo to give a residue which was purified by silica gel chromatography (0 - 10% MeOH / DCM) to afford compound 13-4 (109 mg, 79%). LCMS m / z 604.3 (M+H)+.1H NMR (CDCl3) d 8.04-8.02 (d, 1H), 7.67 (s, 1H), 7.59-7.57 (d, 2H), 7.51-7.35 (m, 5H), 7.28-7.25 (m, 2H), 7.10 (s, 1H), 6.76 (s, 1H), 4.62 (s, 2H), 3.81-3.67 (m, 3H), 3.54 (s, 1H), 3.37-3.31 (m, 2H), 2.42 (s, 3H), 1.97-1.88 (m, 2H), 1.79-1.69 (m, 2H). 10 4-((5'-methyl-2'-sulfamoyl-[1,1'-biphenyl]-4-yl)methoxy)-N-(3- (trifluoromethyl)phenyl)piperidine-1-carboxamide (Example 13) Compound 13-4 (109 mg, 0.18 mmol) was dissolved in DCM (2 mL), and TFA (2 mL) was added. The mixture was stirred for 2 days. Solvent was removed in vacuo and the residue 15 purified by silica gel chromatography (0 – 15% MeOH / DCM) to afford Example 13 as a white solid (80 mg, 81%). LCMS m / z 548.3 (M+H)+.1H NMR (CDCl3) d 8.04-8.03 (m, 1H), 7.66 (s, 1H), 7.58-7.56 (m, 1H), 7.49-7.38 (m, 5H), 7.32-7.29 (m, 2H), 7.14 (s, 1H), 6.54 (s, 1H), 4.44 (s, 2H), 4.15 (s, 2H), 3.82-3.73 (m, 3H), 3.40-3.34 (m, 2H), 2.44 (s, 3H), 2.02-1.95 (m, 2H), 1.79- 1.75 (m, 2H). 20 4-((5'-methyl-2'-(N-(thiophene-2-carbonyl)sulfamoyl)-[1,1'-biphenyl]-4-yl)methoxy)-N-(3- (trifluoromethyl)phenyl)piperidine-1-carboxamide (Example 13A) Example 13 (70 mg, 0.128 mmol) was capped with thiophene-2-carbonyl chloride using capping method A, and purified by silica gel chromatography (0 – 15% MeOH / DCM) to afford Example 25 13A as a white solid (47 mg, 56%). LCMS m / z 658.2 (M+H)+.1H NMR (CDCl3) d 8.26-8.24 (d, 1H), 7.96 (s, 1H), 7.68 (s, 1H), 7.61-7.55 (m, 2H), 7.42-7.35 (m, 2H), 7.31-7.19 (m, 2H), 7.09-7.01 (m, 2H), 6.55 (s, 1H), 4.59 (s, 2H), 3.81-3.72 (m, 3H), 3.41-3.34 (m, 2H), 2.44 (s, 3H), 2.01-1.91 (m, 2H), 1.81-1.73 (m, 2H).{H3007867.1}58 4927-5223-2016, v.1

[0135] Following the methods described above for Example 13 and 13A and substituting the appropriate intermediates and reagents, the following compounds were prepared as indicated in Table 9. 5 Table 9 Exam MS NMR DATA Structure le (M+H)+), 3-{H3007867.1}59 4927-5223-2016, v.113E1H NMR (CDCl3) d 8.25 (d, 1H), 7.59 (d, 1H), 7.39-7.34 , t, ), , , , ,{H3007867. }60 4927-5223-2016, v.113J1H NMR (CDCl3) d 8.20 (d, 1H), 7.68 (s, 1H), 7.57 (d, 1H), 7 , s, 3 ,{H3049213N1H NMR (CDCl3) d 8.26-8.24 (d, 1H), 7.70-7.66 (m, 2H), 5N-(tert-butyl)-5-methyl-4'-(((1-(2-methylpyrimidin-4-yl)piperidin-4-yl)oxy)methyl)-[1,1'- biphenyl]-2-sulfonamide (14-1)

[0136] To a solution of 13-3 (200 mg, 0.44 mmol) in DMA (6 mL) was added TEA (185 mL, 1.33 mmol), followed by 4-chloro-2-methylpyridine (68 mg, 0.53 mmol). After the cloudy 10 solution was stirred at RT overnight, the reaction was quenched with MeOH, and the mixture was concentrated. The residue was purified by reverse phase chromatography (0-100% ACN / H2O) to afford compound 14-1 (126 mg, 56%). LCMS m / z 509.4 (M+H)+.1H NMR (CDCl3) d 8.13-8.11 (d, 1H), 8.05-8.03 (d, 1H), 7.51-7.49 (dd, 4H), 7.29 (d, 1H), 7.10 (s, 1H), 6.36-6.34 (d, 1H), 4.65 (s, 1H), 4.04-3.99 (m, 2H), 3.75-3.71 (m, 1H), 3.51 (s, 1H), 3.44-3.38 (m, 15 2H), 2.50 (s, 3H), 2.43 (s, 3H), 1.99-1.94 (m, 2H), 1.77-1.59 (m, 2H).{H3007867.1}62 4927-5223-2016, v.15-methyl-4'-(((1-(2-methylpyrimidin-4-yl)piperidin-4-yl)oxy)methyl)-[1,1'-biphenyl]-2- sulfonamide (14-2)

[0137] Following a similar procedure as Example 2, step 2, compound 14-1 (145 mg, 0.28 5 mmol) was treated with TFA / DCM and purified by reverse phase chromatography (5-100% ACN / H2O) to afford 14-2 (70 mg, 72%). LCMS m / z 453.4 (M+H)+.1H NMR (CDCl3) d 8.12- 8.10 (d, 1H), 8.05-8.03 (d, 1H), 7.49-7.44 (m, 4H), 7.31-7.29 (m, 1H), 7.14 (m, 1H), 6.36-6.34 (d, 1H), 4.66 (s, 2H), 4.16 (s, 2H), 4.06-4.00 (m, 2H), 3.78-3.74 (m, 1H), 3.45-3.39 (m, 2H), 2.50 (s, 3H), 2.44 (s, 3H), 2.01-1.96 (m, 2H), 1.78-1,69 (m, 2H). 10 5-methyl-4'-(((1-(2-methylpyrimidin-4-yl)piperidin-4-yl)oxy)methyl)-[1,1'-biphenyl]-2- sulfonamide (Example 14) Capping method C 15

[0138] To a solution of 14-2 (93 mg, 0.21 mmol) in DMF (2.6 mL), 2-thiophenecarboxylic acid (32 mg, 0.25 mmol), DMAP (63.5 mg, 0.52mmol) and EDC (79.0 mg, 0.41 mmol) were added and the reaction stirred at RT overnight. The reaction was partitioned between EtOAc and sat. NaHCO3. The organic layer was washed with NaHCO3(3X), H2O (3X), brine (1X), 20 dried over Na2SO4, and concentrated in vacuo. Both the aqueous and the organic layers contained product. Each was separately purified by MS-HPLC to afford Example 14 (72 mg, 62%). LCMS m / z 563.3 (M+H)+.1H NMR (DMSO-D6) d 13.3-12.9 (b, 1H), 8.20-8.18 (d, 1H), 7.99-7.97 (d, 1H), 7.65-7.64 (d, 1H), 7.47 (s, 1H), 7.34-7.22 (m, 5H), 7.04-6.97 (m, 3H), 4.58 (s, 2H), 4.04 (b, 2H), 3.80-3.76 (m, 1H), 3.64-3.59 (dd, 2H), 2.50 (s, 3H), 2.45 (s, 3H), 1.99-1.94 25 (m, 2H), 1.67-1.59 (m, 2H).

[0139] Following the methods described above for Example 14 and 14-2 and substituting the appropriate intermediates and reagents, the following compounds were prepared as indicated in Table 10. 30{H3007867.1}63 4927-5223-2016, v.1Table 10 Exam MS NMR DATA Structure ple (M+H)+), , , , ), ,{H3007867.1}64 4927-5223-2016, v.114E1H NMR (CDCl3) d 8.48 (d, 1H), 8.03 (s, 1H), 7.47 (s, 4H), 3 8 , ), ,xampe 55 N-(tert-butyl)-5-methyl-4'-(((1-(4-(trifluoromethyl)benzyl)piperidin-4-yl)oxy)methyl)-[1,1'- biphenyl]-2-sulfonamide (15-1){H3007867.1}65 4927-5223-2016, v.1

[0140] To a solution of 13-3 (100 mg, 0.22 mmol) in 1,2-DCE (2.2 mL) was added TEA (31 mL, 0.22 mmol). The white slurry was stirred for 15 min., 4-trifluoromethylbenzaldehyde (30 mL, 0.22 mmol), Na(OAc)3BH (66 mg, 0.31 mmol) and HOAc (12.7 mL, 0.22 mmol) were added. After 15 minutes, the pink solution was quenched with H2O then partitioned between sat. 5 NaHCO3 and EtOAc. The EtOAc layer was washed with brine, dried (Na2SO4), filtered and concentrated to a dark oil. Purification by silica gel chromatography (0-100% EtOAc / hexanes) afforded 15-1 (54 mg, 43%). LCMS m / z 575.8 (M+H)+.1H NMR (CDCl3) d 8.05-8.03 (d, 1H), 7.58-7.56 (d, 2H), 7.50-7.41 (m, 6H), 7.28 (under CDCl3, 1H), 7.09 (m, 1H), 4.60 (s, 2H), 3.55 (s, 2H), 3.50-3.45 (m, 2H), 2.76-2.73 (m, 2H), 2.42 (s, 3H), 2.20-2.16 (m, 2H), 10 1.96-1.92 (m, 2H), 1.76-1.68 (m, 2H), 0.99 (s, 9H). 5-methyl-4'-(((1-(4-(trifluoromethyl)benzyl)piperidin-4-yl)oxy)methyl)-[1,1'-biphenyl]-2- sulfonamide (Example 15)

[0141] Following a similar procedure as Example 2, step 2, compound 15-1 (94 mg, 0.16 15 mmol) was treated with TFA / DCM and purified by silica gel chromatography (0-20% MeOH / DCM) to provide Example 15 (75 mg, 89%). LCMS m / z 519.3 (M+H)+.1H NMR (CDCl3) 8.05-8.03 (d, 1H), 7.58-7.56 (d, 2H), 7.48-7.43 (m, 6H), 7.31-7.29(d, 1H), 7.14-7.13 (m, 1H), 4.60 (s, 2H), 4.11 (s, 2H), 3.56 (s, 2H), 3.52-3.48 (m, 1H), 2.77-2.74 (m, 2H), 2.44 (s, 3H), 2.22-2.17 (m, 2H), 1.98-1.95 (m, 2H), 1.77-1.69 (m, 2H). 20 N-((5-methyl-4'-(((1-(4-(trifluoromethyl)benzyl)piperidin-4-yl)oxy)methyl)-[1,1'-biphenyl]- 2-yl)sulfonyl)thiophene-2-carboxamide (Example 15A)

[0142] Example 15 (70 mg, 0.14 mmol) was capped with thiophene-2-carboxylic acid using capping method C, and purified by MS-HPLC to afford Example 15A (43 mg, 51%). LCMS 25 m / z 629.3 (M+H)+.1H NMR (CD3OD / CDCl3) d 8.13-8.11 (d, 1H), 7.82-7.68 (m, 4H), 7.45-7.54 (d, 2H), 7.37-7.30 (m, 3H), 7.21-7.19 (d, 2H), 7.04 (m, 1H), 6.98-6.96 (t, 2H), 4.51 (s, 2H), 4.23 (s, 2H), 3.67-3.66 (m, 1H), 3.18 (b, 2H), 3.01 (b, 2H), 2.41 (s, 3H), 1.91 (b, 4H).{H3007867.1}66 4927-5223-2016, v.1

[0143] Following the methods described above for Example 15 and 15A and substituting the appropriate intermediates and reagents, the following compounds were prepared as indicated in Table 11. 5 Table 11 Exam MS NMR DATA Structure le (M+H)+1 0 9 t, 0 6{H3007867.1}67 4927-5223-2016, v.115E1H NMR (CD3OD) d 8.13-8.11 (d, 1H), 7.90-7.88 (d, 1H), t, ), 5N-(tert-butyl)-5-methyl-4'-(((1-(4-(trifluoromethyl)pyridin-2-yl)piperidin-4-yl)oxy)methyl)- [1,1'-biphenyl]-2-sulfonamide (16-1)

[0144] To a degassed solution of 13-3 (100 mg, 0.22mmol) in 1,4-Dioxane (0.5 mL), was added 2-chloro-4-trifluoromethylpyridine (40.1 mg, 0.22 mmol), Pd(OAc)2 (2.50 mg, 0.1mmol), 10 Binap (11.2 mg, 0.02 mmol) and sodium t-butoxide (63.7 mg, 0.66 mmol). The reaction was degassed with N2, and heated to 85oC for 2.5h. The reaction was cooled to RT, partitioned between EtOAc / H2O, washed with water (3X) and brine, dried, filtered, concentrated and purified by silica gel chromatography (0-20% EtOAc / hexanes) to provide 16-1 (84.2 mg, 68%){H3007867.1}68 4927-5223-2016, v.1as a white solid LCMS (VNP) m / z 562.3 (M+H)+.1H NMR (CD3OD / CDCl3) d 8.30-8.29 (d, 1H), 8.05-8.03 ((d, 1H), 7.51-7.49 (dd, 4H), 7.28 (d, 1H), 7.10 (s, 1H), 6.83 (s, 1H), 6.75-6.74 (d, 1H), 4.65 (s, 2H), 4.05-3.99 (m, 2H), 3.73-3.71 (m, 1H), 3.51 (s, 1H), 3.40-3.33 (m, 2H), 2.42 (s, 3H), 2.05-1.99 (m, 2H), 1.79-1.74 (m, 2H), 1.00 (s, 9H). 5 5-methyl-4'-(((1-(4-(trifluoromethyl)pyridin-2-yl)piperidin-4-yl)oxy)methyl)-[1,1'- biphenyl]-2-sulfonamide (Example 16)

[0145] A solution of 16-1 (97.0 mg, 0.17 mmol) in DCM (1.0 ml) and TFA (8.7 ml) was stirred at RT overnight. The reaction was concentrated in vacuo, azeotroped with toluene and 10 partitioned between DCM and sat. NaHCO3. The DCM layer was washed (3X) with sat. NaHCO3, dried Na2SO4, concentrated and purified by silica gel chromatography (0-80% EtOAc / hexanes) to provide Example 16 (79.1 mg, 90%). LCMS (VNP) m / z 506.3 (M+H)+.1H NMR (CDCl3) d 8.30-8.29 (d, 1H), 8.05-8.03 (d, 1H), 7.49-7.47 (m, 4H), 7.31-7.29 (m, 1H), 7.14 (s, 1H), 6.83 (s, 1H), 6.76-6.74 (d, 1H), 4.66 (s, 2H), 15 4.17 (m, 2H), 4.06-4.00 (m, 2H), 3.76-3.73 (m, 1H), 3.41-3.34 (m, 2H), 2.43 (s, 3H), 2.06-2.02 (m, 2H), 1.81-1.73 (m, 2H). N-((5-methyl-4'-(((1-(4-(trifluoromethyl)pyridin-2-yl)piperidin-4-yl)oxy)methyl)-[1,1'- biphenyl]-2-yl)sulfonyl)thiophene-2-carboxamide (Example 16A) 20

[0146] Example 16 (73.5 mg, 0.15 mmol) was capped with thiophene-2-carboxylic acid using capping method C. The reaction was concentrated in vacuo, purified by MS-HPLC (non-polar) and concentrated via GeneVac to afford Example 16A (72.4 mg, 76%) as a formic acid salt. LCMS (VNP) m / z 616.3 (M+H)+.1H NMR (DMSO-d6) d 12.1 (b, 1H), 8.33-8.32 (d, 1H), 8.04-8.02 (d, 1H), 7.93-7.92 (1H), 7.77-7.76 (d, 1H), 7.46-7.45 (d, 1H), 7.29-7.19 (dd, 4H),25 7.13-7.11 (m, 3H), 6.86-6.84 (d, 1H), 4.59 (s, 2H), 4.07-4.01 (m, 2H), 3.76-3.70 (m, 1H), 3.39- 3.32 (m, 2H), 2.40 (s, 3H), 1.99-1.95 (m, 2H), 1.60-1.52 (m, 2H).{H3007867.1}69 4927-5223-2016, v.1

[0147] Following the methods described above for Examples 16 and 16A and substituting the appropriate intermediates and reagents, the following compounds were prepared as indicated in Table 12. 5 Table 12 Example Structure MS (M+H)+NMR DATA 1H NMR CDCl d 804803 66 ), b,70 4927-5223-2016, v.11H NMR (CDCl3) d 12.1 (b, 1H), 8.41 (s, 1), 8.04-8.02 (d, - 0Example 17 5 N[1,1'biphenyl]-2-sulfonamide (17-1)

[0148] To a solution of 13-3 (500 mg, 1.10 mmol), in THF (8.5 mL), was added DIEA (0.38 mL), and 2,4-dichloropyrimidine (328 mg in 4 mL THF). After 3 h, the reaction was 10 concentrated to a yellow oil and purified by silica gel chromatography (0-100% EtOAc / hexanes) to provide 17-1 (402 mg, 69%) as a white solid. LCMS m / z 529.3 (M+H)+.1H NMR (CDCl3) d 8.05-8.02 (m, 2H), 7.51-7.42 (dd, 4H), 7.29 (m, 1H), 7.1 (m, 1H), 6.43-6.42 (d, 1H), 4.64 (s,{H3007867.1}71 4927-5223-2016, v.12H), 3.92 (b, 2H), 3.77-3.76 (m, 1H), 3.51 (b, 3H), 2.43 (s, 3H), 1.98-1.93 (m, 2H), 1.81-1.75 (m, 2H), 1.00 (s, 9H). N-(tert-butyl)-5-methyl-4'-(((1-(6-((2,2,2-trifluoroethyl)amino)pyridin-2-yl)piperidin-4- 5 yl)oxy)methyl)-[1,1'-biphenyl]-2-sulfonamide (17-2)

[0149] To a solution of 17-1 (70.0 mg, 0.13mmol) in EtOH (0.5 mL) was added 2, 2, 2- trifluoroethanamine hydrochloride (89.6 mg, 0.66 mmol) and DIEA (48.2 mL, 0.28 mmol). The reaction was heated to 80oC overnight in a sealed vial. The reaction was partitioned between EtOAc and sat. NaHCO3, washed with NaHCO3(2X) and brine, and purified by silica gel 10 chromatography (0-20% MeOH / DCM) to provide 17-2 (103 mg, 93%). LCMS m / z 592.3 (M+H)+.1H NMR (CDCl3) d 8.05-8.03 (d, 1H), 7.89-7.88 (d, 1H), 7.52-7.42 (dd, 4H), 7.29 (m, 1H), 7.10 (s, 1H), 6.01-6.00 (d, 1H), 5.30 (b, 1H), 4.64 (s, 2H), 4.12-4.08 (m, 2H), 3.95-3.93 (m, 2H), 3.73-3.72 (m, 1H), 3.52 (s, 2H), 3.40-3.36 (m, 2H), 2.42 (s, 3H), 1.97-1.93 (m, 2H), 1.73- 1.69 (m, 2H), 1.00 (s, 9H). 15 5-methyl-4'-(((1-(6-((2,2,2-trifluoroethyl)amino)pyridin-2-yl)piperidin-4-yl)oxy)methyl)- [1,1'-biphenyl]-2-sulfonamide (17-3)

[0150] A solution of 17-2 (101 mg, 0.17 mmol) in DCM (0.9 ml) and TFA (8.5 ml) was stirred at RT overnight. The reaction was concentrated in vacuo, azeotroped with toluene and 20 partitioned between DCM and sat. Na2CO3. The DCM layer was washed (3X) with Na2CO3, dried Na2SO4, filtered, concentrated and purified by silica gel chromatography (0-20% MeOH / DCM) to provide 17-3 (77 mg, 84%). LCMS m / z 536.3 (M+H)+.1H NMR (CDCl3) d 8.05-8.03 (d, 1H), 7.90-7.88 (d, 1H), 7.52-7.44 (m, 4H), 7.31-7.29 (m, 1H), 7.14 (s, 1H), 6.02-6.00 (d, 1H), 5.03 (b, 1H), 4.65 (s, 2H), 4.15-4.06 25 (m, 4H), 3.98-3.75 (m, 2H), 3.78-3.72 (m, 1H), 3.41-3.35 (m, 2H), 2.44 (s, 3H), 2.00-1.95 (m, 2H), 1.76-1.68 (m, 2H). 5-methyl-N-(thiophen-2-ylmethyl)-4’-(((1-(6-((2,2,2-trifluoroethyl)amino)72yridine-2- yl)piperidin-4-yl)oxy)methyl)-[1,1’-biphenyl]-2-sulfonamide (Example 17A or 17?){H3007867.1}72 4927-5223-2016, v.1

[0151] 17-3 (77.2 mg, 0.14 mmol) was capped with thiophene-2-carboxylic acid using capping method C. After 2 h 20 min, the reaction was partitioned between EtOAc and H2O. The EtOAc layer was washed with H2O, sat. ammonium chloride and brine, dried Na2SO4, filtered, concentrated and purified by C18 reverse phase chromatography (5-100% ACN / H2O) and 5 concentrated via GeneVac then lyophilized to afford Example 17A (27.4 mg, 30%). LCMS m / z 646.3 (M+H)+.1H NMR (CDCl3) d 8.02-8.00 (d, 1H), 7.86-7.84 (d, 1H), 7.69 (b, 1H), 7.56 (b, 1H), 7.35-7.24 (m, 5H), 7.05-7.03 (m, 2H), 6.37 (b, 1H), 4.58 (s, 2H), 4.16.12-4.01 (m, 2H), 4.00-3.98 (m, 2H), 3.77-3.74 (m, 1H), 3.46 (b, 2H), 2.38 (s, 3H), 1.98-1.92 (m, 2H), 1.60-1.56 (m, 2H). 10

[0152] Following the methods described above for Examples 17 and substituting the appropriate intermediates and reagents, the following compounds were prepared as indicated in Table 13. 15 Table 13 Example Structure MS (M+H)+NMR DATA ), 9- 3 , b,73 4927-5223-2016, v.13.53 (m, 4H), 2.61-2.53 (m, 2H), 2.35 (s, 3H), 1.96-1.93 0 d, s 4 , ), s, ), ),74 4927-5223-2016, v.1Example 18 5N-(tert-butyl)-4'-(((1-(3-fluoro-5-(trifluoromethyl)benzyl)piperidin-4-yl)oxy)methyl)-5- methyl-[1,1'-biphenyl]-2-sulfonamide (18-1)

[0153] To 13-3 (113 mg, 0.25 mmol) in 1,2-Dichloroethane (2.5 mL) was added TEA (35 mL, 0.25 mmol) and the reaction stirred ~20 min at RT, then 3-Fluoro-4- 10 trifluoromethylbenzaldehyde (35 mL, 0.25 mmol), NaBH(OAc)3 (74.0 mg, 0.35 mmol) and HOAc (14.3 mL, 0.25 mmol) were added successively. At 6.5 h, the reaction was quenched with H2O, extracted with EtOAc, washed with sat. NaHCO3 and brine, dried Na2SO4, filtered and concentrated. Purification by silica gel chromatography (0-100% EtOAc / hexanes) provided 18-1 (76.4 mg, 52%) as a white solid. LCMS m / z 593.3 (M+H)+.1H NMR (CDCl3) d 8.04-8.03 (d,15 1H), 7.55-7.48 (m, 3H), 7.43-7.41 (m, 2H), 7.28-7.19 (m, 3H), 7.10 (s, 1H), 4.60 (s, 2H), 3.53- 3.46 (m, 4H), 2.75-2.72 (m, 2H ), 2.42 (s, 3H), 2.22-2.18 (m, 2H), 1.96-1.93 (m, 2H), 1.77-1.68 (m, 2H).{H3007867.1}75 4927-5223-2016, v.14'-(((1-(3-fluoro-5-(trifluoromethyl)benzyl)piperidin-4-yl)oxy)methyl)-5-methyl-[1,1'- biphenyl]-2-sulfonamide (Example 18)

[0154] A solution of 18-1 (76.4 mg, 0.13 mmol) in DCM (0.7 mL) and TFA (7 mL) was stirred at RT overnight. The reaction was concentrated in vacuo, azeotroped with toluene, 5 partitioned between EtOAc and sat. NaHCO3, washed with brine, dried Na2SO4, filtered, concentrated and purified by C18 reverse phase chromatography (5-100% ACN / H2O) to provide Example 18 (58.5 mg, 85%). LCMS m / z 537.3 (M+H)+.1H NMR (CDCl3) d 8.05-8.03 (d, 1H), 7.55-7.52 (t, 3H), 7.48-7.43 (m, 4H), 7.31-7.29 (dd, 1H), 7.26-7.19 (m, 2H (partially under CDCl3peak), 7.14-7.13(m, 1H), 4.60 (s, 2H), 4.11 (s, 2H), 3.54-3.50 (m, 3H), 2.76-2.73 (m, 10 2H), 2.44 (s, 3H), 2.24-2.20 (m, 2H), 1.99-1.95 (m, 2H), 1.78-1.72 (m, 2H). N-((4'-(((1-(3-fluoro-5-(trifluoromethyl)benzyl)piperidin-4-yl)oxy)methyl)-5-methyl-[1,1'- biphenyl]-2-yl)sulfonyl)thiophene-2-carboxamide (Example 18A)

[0155] Example 18 (56.2 mg, 0.11 mmol) was capped with thiophene-2-carboxylic acid 15 using capping method C. The reaction was concentrated via GeneVac, purified by MS-HPLC (standard), concentrated via GeneVac and lyophilized to afford Example 18A (45.4 mg, 67%). LCMS m / z 647.3 (M+H)+.1H NMR (CDCl3) d 8.23-8.21 (d, 1H), 7.55-7.51 (m, 2H), 7.36-7.30 (m, 4H), 7.26 (m, 1H (und20(m, 3H), 4.51 (s, 2H), 3.69 (s, 2H), 3.18 (m, 1H), 2.81-2.77 (m, 2H ), 2.43 (m, 5H), 3.00-1.96 (m, 2H), 1.78-1.71 (m, 2H). 20 Example 19{H3007867.1}76 4927-5223-2016, v.1Methyl 5-((4-iodobenzyl)oxy)picolinate (19-1)

[0156] To a mixture of methyl 5-hydroxypicolinate (300 mg, 1.96 mmol), 4- 5 Iodobenzylalcohol (597 mg, 2.55 mmol), and PPh3 (926 mg, 3.53 mmol) in anhydrous THF (20 mL) at 0°C was added DEAD (40% in Toluene) (1.34 mL, 2.94 mmol) over 45 min. The reaction stirred 24 h as it warmed to RT, concentrated, purified by silica gel chromatography followed by purification by reverse phase C18 silica gel chromatography to provide 19-1 (163 mg, 23%). LCMS m / z 370.1 (M+H)+.1H NMR (CDCl3) d 8.47-8.46 (d, 1H), 8.13-8.11 (d, 2H), 10 7.77-7.74 (dd 2H), 7.32-7.30 (m, 1H), 7.20-7.18 (d, 2H), 5.13 (s, 2H), 4.00 (s, 3H). Methyl 5-((2'-(N-(tert-butyl)sulfamoyl)-5'-methyl-[1,1'-biphenyl]-4-yl)methoxy)picolinate (19-2)

[0157] A mixture of 19-1 (163 mg, 0.442 mmol), Intermediate 1 (144 mg, 0.53 mmol), 15 Pd(dppf)Cl2.DCM (36.1 mg, 0.04 mmol) and Na2CO3(70.3 mg, 0.66 mmol) in dioxane (4.8 mL) and H2O (1.2 mL) was bubbled with nitrogen for 2 min, sealed and heated at 80oC 1.5 h. The reaction cooled, was filtered though celite, washed with DCM and concentrated in vacuo. The residue was partitioned between EtOAc and H2O, washed with H2O and brine, dried over Na2SO4, filtered, concentrated in vacuo and purified by silica gel chromatography to afford 19-2 20 (181 mg, 87%). LCMS m / z 469.3 (M+H)+.1H NMR (CDCl3) d 8.51 (m, 1H), 8.16-8.13 (d, 1H),{H3007867.1}77 4927-5223-2016, v.18.07-8.05 (d, 1H), 7.58-7.51 (m, 4H), 7.38-7.35 (m, 1H),7.31-7.29 (m, 1H), 7.12(s, 1H), 5.25 (s, 2H), 4.01 (s, 3H), 3.50 (s, 1H), 2.44 (s, 3H), 1.01 (s, 9H). 5-((2'-(N-(tert-butyl)sulfamoyl)-5'-methyl-[1,1'-biphenyl]-4-yl)methoxy)picolinic acid (19-3) 5

[0158] To 19-2 (181 mg, 0.39 mmol) in THF (2.6 mL) was added 1N LiOH (3.9 mL).and MeOH (1.7 mL) and the solution stirred at room temperature 2.5 h. The reaction was cooled to room temperature and concentrated in vacuo. The solid was dissolved in H2O, acidified to pH=2 with 1N HCl and extracted with EtOAc (3X). The EtOAc extracts were combined, washed with brine, dried over Na2SO4, filtered and concentrated to provide 19-3 (154 mg, 88%). LCMS m / z 10 455.2 (M+H)+.1H NMR (CDCl3) d 8.37-8.36 (m, 1H), 8.21-8.20 (d, 1H), 8.07-8.05 (d, 1H), 7.59-7.45 (m, 5H), 7.32-7.30 (m, 1H), 7.13-7.12 (m, 1H), 5.27 (s, 2H), 3.53 (s, 1H), 2.45 (s, 3H), 1.02 (s, 9H). 5-((2'-(N-(tert-butyl)sulfamoyl)-5'-methyl-[1,1'-biphenyl]-4-yl)methoxy)-N-(3- 15 (trifluoromethyl)benzyl)picolinamide (19-4)

[0159] To a solution of 19-3 (152 mg, 0.34 mmol) in DCM (2. mL) was added HATU (166 mg, 0.44 mmol) and DIEA (200 µL, 1.17 mmol). The reaction stirred 15 min, then 3- trifluoromethylbenzylamine (136 µL, 0.40 mmol) was added and the reaction stirred overnight at room temperature. The solution was partitioned between DCM and H2O, washed with H2O and 20 brine, dried over Na2SO4, filtered, concentrated and purified by silica gel chromatography to provide 19-4 (166 mg, 81%). LCMS m / z 612.3 (M+H)+.1H NMR (CDCl3) d 8.30-8.29 (m, 2H), 8.22-8.20 (d,1H), 8.07-8.05 (d, 1H), 7.62-7.50 (m, 8H), 7.42--7.39 (dd, 1H), 7.31-7.27 (m, 1H), 7.12 (s, 1H), 5.24 (s, 2H), 4.74-4.72 (m, 2H), 3.49 (s, 1), 2.44 (s, 3H), 1.00 (s, 9H). 25 5-((5'-methyl-2'-sulfamoyl-[1,1'-biphenyl]-4-yl)methoxy)-N-(3- (trifluoromethyl)benzyl)picolinamide (Example 19)

[0160] Compound 19-4 (166 mg, 0.27 mmol), DCM (1.4 mL) and TFA (6.8 mL) were combined and stirred overnight. The solution was partitioned between DCM / Na2CO3, washed with H2O and brine, dried over Na2SO4, filtered and concentrated in vacuo. The solids were 30 filtered from MeOH and collected to provide Example 19 (119 mg, 79%). LCMS m / z 556.3{H3007867.1}78 4927-5223-2016, v.1(M+H)+.1H NMR (DMSO-d6) d 9.38-9.35 (t, 1H), 8.45-8.44 (d 1H), 8.05-8.02 (d, 1H), 7.92- 7.90 (d, 2H), 7.70-7.67 (m, 2H), 7.64-7.54 (m, 3H), 7.51-7.49 (m, 2H), 7.43-7.41 (m, 2H), 7.39- 7.37 (m, 1H), 7.19 (s, 2H), 7.13 (m, 1H), 5.32 (s, 2H), 4.56-4.54 (d, 2H), 2.38 (s, 3H). 5 5-((5'-methyl-2'-(N-(thiophene-2-carbonyl)sulfamoyl)-[1,1'-biphenyl]-4-yl)methoxy)-N-(3- (trifluoromethyl)benzyl)picolinamide hydrochloride (Example 19A)

[0161] Example 19 (106 mg, 0.19 mmol) was capped with thiophene-2-carbonyl chloride using capping method B, concentrated in vacuo and purified by MS-HPLC ( non-polar gradient) to afford Example 19A (99.7 mg, 75%) as an HCl salt. LCMS m / z 666.3 (M+H)+.1H NMR 10 (DMSO-d6) d 12.1 (b, 1H), 9.38-9.34 (t, 1H), 8.44 (d, 1H), 8.05-8.02 (m, 2H), 7.93-7.91 (d 2H), 7.77-7.76 (d, 1H), 7.69-7.54 (m, 5H), 7.47-7.42 (m, 3H), 7.28-7.25 (m, 2H), 7.14 (m, 1H), 7.09- 7.07 (t, 1H), 5.31 (s, 2H), 4.57-4.55 (d, 2H), 2.40 (s, 3H).

[0162] Following the methods described above for Examples 19 and 19A and substituting 15 the appropriate intermediates and reagents, the following compounds were prepared as indicated in Table 14. Table 14 Compound+NMR DATA Structure MS (M+H) s,{H3007867.1}79 4927-5223-2016, v.11H NMR (CDCl3) d 8.29-8.20 (m, 3H), 7.75 (s, 1H), 7.59- s, = 4 , d, ) b, d, ), ), ), 280 4927-5223-2016, v.11H NMR (CD3OD / DMSO-d6) d 8.52 (d, 1H), 8.41 (s, 1H), d, , t, d, , ).{ 3007867. }81 4927-5223-2016, v.11H NMR (CDCl3) d 8.30-8.20 (m, 4H), 8.04 (s, 1H), 7.60- 6 2 q, m,5 Example 20{H3007867.1}82 4927-5223-2016, v.1Methyl 6-((4-iodobenzyl)oxy)nicotinate (20-1)

[0163] To 4-Iodobenzyl alcohol (500 mg, 2.14 mmol) in anhydrous THF (4 mL) at 0oC was 5 added NaH (60% dispersion) (103 mg, 2.57 mmol) and the reaction stirred 25 min at RT. The reaction was cooled to -20oC, methyl 6-fluoronicotinate (498 mg, 3.21 mmol) was added, the bath was warmed to 0oC and additional THF (3 ml) was added. At 3 h, the reaction was quenched with H2O, concentrated in vacuo, and purified by silica gel chromatography to obtain 20-1 (669 mg, 85%). LCMS m / z 370.1 (M+H)+.1H NMR (CDCl3) d 8.84 (m, 1H), 8.20-8.17 10 (dd, 1H), 7.74-7.70 (m, 2H), 7.23-7.21 (m, 2H), 6.84-6.82 (m, 1H), 5.40 (s, 2H), 4.93 (s 3H). Methyl 6-((2'-(N-(tert-butyl)sulfamoyl)-5'-methyl-[1,1'-biphenyl]-4-yl)methoxy)nicotinate (20-2)

[0164] A mixture of 20-1 (416 mg, 0.1.13 mmol), Intermediate 1 (144 mg, 1.36 mmol), 15 Pd(dppf)Cl2.DCM (369 mg, 1.36 mmol) and Na2CO3(180 mg, 1.70 mmol) in dioxane (11 mL) and H2O (3 mL) was bubbled with nitrogen for 5 min, sealed and heated at 80oC 3 h. The reaction cooled, was partitioned between EtOAc and H2O, washed brine, dried over Na2SO4, filtered, concentrated in vacuo and purified by silica gel chromatography to afford 20-2 (338 mg, 64%). LCMS m / z 469.3 (M+H)+.1H NMR (CDCl3) d 8.86-8.85 (m, 1H), 8.22-8.19 (dd, 1H),{H3007867.1}83 4927-5223-2016, v.18.06-8.04 (d, 2H),7.53 (s, 4H), 7.30 (m, 1H), 7.13 (s, 1H), 6.88-6.85 (dd, 1H), 5.52 (s 2H), 3.94 (s, 3H), 2.44 (s, 3H), 1.00 (s, 9H). 6-((2'-(N-(tert-butyl)sulfamoyl)-5'-methyl-[1,1'-biphenyl]-4-yl)methoxy)nicotinic acid (20-3) 5

[0165] To 20-2 (428 mg, 0.91 mmol) in THF (6 mL) was added 1N LiOH (9.1 mL).and MeOH (4.5 mL) and the solution stirred at room temperature 3 h. The reaction was cooled to room temperature and concentrated in vacuo. The solid was dissolved in H2O, acidified to pH=2 with 1N HCl, stirred with EtOAc. until in solution, then extracted (2X) The EtOAc extracts were combined, washed with brine, dried over Na2SO4, filtered and concentrated to provide 20-310 (407 mg, 98%). LCMS m / z 455.3 (M+H)+.1H NMR (DMSO-d6) d 8.77-8.76 (m, 1H), 8.20- 8.71 (dd, 1H), 7.93-7.90 (d, 1H), 7.50-7.48 (m, 2H), 7.41-7.33 (m, 3H), 7.12 (m, 1H), 7.01-6.99 (d, 1H), 6.60 (s, 1H), 5.49 (s, 2H), 2.38 (s, 3H), 1.00 (s, 9H). 6-((2'-(N-(tert-butyl)sulfamoyl)-5'-methyl-[1,1'-biphenyl]-4-yl)methoxy)-N-(3- 15 (trifluoromethyl)benzyl)nicotinamide (20-4)

[0166] To a solution of 20-3 (100 mg, 0.22 mmol) in DCM (2. mL) was added HATU (110 mg, 0.29 mmol) and DIEA (134 µL, 0.77 mmol). The reaction stirred 15 min, then 3- trifluoromethylbenzylamine (37.8 µL, 0.26 mmol) was added and the reaction stirred 1h at room temperature. The solution was concentrated and purified by C18 reverse phase chromatography 20 to provide 20-4 (113 mg, 84%). LCMS m / z 612.4 (M+H)+.1H NMR (CDCl3) d 8.64 (m, 1H), 8.07-8.01 (m, 2H), 7.59-7.46 (m, 8H), 7.28-7.26 (m, 1H), 7.11 (s, 1H), 6.86-6.83 (m, 2H), 5.48 (s, 2H), 4.68 (m, 2H), 3.52 (s, 1H), 2.43 (s, 3H), 0.97 (s, 9H). 6-((5'-methyl-2'-sulfamoyl-[1,1'-biphenyl]-4-yl)methoxy)-N-(3- 25 (trifluoromethyl)benzyl)nicotinamide (Example 20)

[0167] Compound 20-4 (92.1 mg, 0.15 mmol), DCM (2 mL) and TFA (2 mL) were combined and stirred 5.5 h. To the reaction was added toluene and the reaction was azeotroped (3X), then purified by reverse phase C18 silica gel chromatography to provide Example 20 (18.1 mg, 27%). LCMS m / z 556.3 (M+H)+.1H NMR (CD3OD) d 8.72-8.71 (m, 1H), 8.18-8.15 (m,{H3007867.1}84 4927-5223-2016, v.11H), 8.00 -7.98 (d, 2H), 7.68-7.63 (m, 2H), 7.57-7.51 (m, 4H), 7.45-7.43 (m, 2H), 7.36-7.34 (m, 1H), 7.16 (s, 1H), 6.97-6.94 (m, 2H), 5.51 (s, 2H), 4.65 (m, 2H), 3.52 (s, 2H), 2.44 (s, 3H). 6-((5'-methyl-2'-(N-(thiophene-2-carbonyl)sulfamoyl)-[1,1'-biphenyl]-4-yl)methoxy)-N-(3- 5 (trifluoromethyl)benzyl)nicotinamide (Example 20A)

[0168] Example 20 (16.7 mg, 0.03 mmol) was capped with thiophene-2-carbonyl chloride using capping method B. The reaction was quenched with MeOH, concentrated in vacuo and purified by C18 reverse phase chromatography to afford Example 20A (15.2 mg, 76%). LCMS m / z 666.3 (M+H)+.1H NMR (CD3OD) d 9.14-9.10 (t, 1H), 8.72-8.71 (m, 1H), 8.18-8.15 (dd, 10 1H), 8.24 -8.10 (d, 2H), 7.71-7.62 (m, 3H), 7.58-7.51 (m, 2H), 7.43-7.34 (m, 4H), 7.27-7.25 (m, 2H), 7.11 (s, 1H), 7.00-6.93 (m, 2H), 5.46 (s, 2H), 4.65-4.64 (m, 2H), 2.43 (s, 3H). Example 21 15py y y

[0169] To (5-bromopyridin-2-yl)methanol (2.01 g, 10.69 mmol) in DCM (60 mL) at 0°C was added TEA (2.98 mL, 21.38 mmol) followed by MsCl (0.99mL, 12.83 mmol). The solution was stirred at 0°C for 1 hour. The residue was partitioned between water (30 mL) and DCM (60{H3007867.1}85 4927-5223-2016, v.1mL). The aqueous layer was washed once with DCM (60 mL). The combined organic layers were washed with NH4Cl, dried over Na2SO4, filtered and concentrated to afford a crude foam. The foam was purified by silica gel chromatography (0-5% MeOH / DCM) to afford a white solid 21-1 (2.67 g, 73% yield). LCMS: m / z 268.1 (M+H)+(1H NMR (CDCl3) 8.68 (d, 1H), 7.91 (d, 5 1H), 7.41 (d, 1H), 5.29 (s, 2H), 3.11 (s, 3H). tert-butyl 4-((5-bromopyridin-2-yl)methoxy)piperidine-1-carboxylate (21-2)

[0170] To tert-butyl 4-hydroxypiperidine-1-carboxylate in DMF (75 mL) at 0°C was added 60% NaH (498 mg, 12.45 mmol 60%) and the solution was stirred 15 min before the dropwise 10 addition of 21-1 (2.65 g, 9.96 mmol) dissolved in (25mL) DMF over 8 minutes. The reaction was stirred at 0°C for 3 hours. The reaction was partitioned between EtOAc and H2O, and the aqueous layer was extracted (2 x 25 mL) with EtOAc. The combined organic layers were washed with brine, dried (Na2SO4), filtered, and concentrated in vacuo to afford an amber oil purified by silica gel chromatography (0-100 EtOAc / Hexane) as a white solid 21-2 (1.28 g, 35%) 15 LCMS: m / z 373.2 (M+H)+(1H NMR (CDCl3) δ 8.61 (d, 1H), 7.83 (d, 1H), 7.40 (d, 1H), 4.63 (s, 2H), 3.80-3.77 (m, 2H), 3.64 –-3.60 (m, 1H), 3.16 - 3.09 (m, 2H), 1.91-1.87 (m, 2H), 1.63 -1.61 (m, 2H), 1.47 (s, 9H). Tert-butyl-4-((5-(2-(N-(tert-butyl)sulfamoyl)-5-methylphenyl)pyridin-2- 20 yl)methoxy)piperidine-1-carboxylate (21-3)

[0171] To 21-2 (1.24 g, 3.34 mmol) in 1,4 dioxane (35 mL) was added Intermediate 1 (1.13 g, 4.17 mmol), and Pd2(dba)3 (0.273 g, 0.334 mmol). The solution was purged with nitrogen for 15 min. To the reaction mixture was added Na2CO3 (0.708 g, 6.68 mmol) dissolved in water (3 mL) and the reaction was stirred at 100°C for 2 hours. The reaction mixture was 25 cooled to room temperature, filtered over Celite and partitioned between EtOAc and H2O. The aqueous layer was extracted (2 x 25 mL) with EtOAc and the combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by silica gel chromatography (0-100% EtOAc / Hexane) to afford a yellow solid 21-3 (1.61 g, 93%). LCMS: m / z 518.40 (M+H)+ 1H NMR (CDCl3) δ 8.56 (d, 1H), 8.07 (d, 1H), 7.91 30 (dd, 1H), 7.55 (d, 1H), 7.37 – 7.30 (m, 2H), 7.10 (s, 1H), 4.74 (s, 2H), 3.83 (br s, 1H), 3.74-3.63{H3007867.1}86 4927-5223-2016, v.1(m, 1H), 3.19 – 3.13 (m, 2H), 2.46 (s, 3H), 1.96 – 1.92 (m, 2H), 1.70-1.65 (m, 2H), 1.46 (s, 9H), 1.07 (s, 9H). N-(tert-butyl)-4-methyl-2-(6-((piperidin-4-yloxy)methyl)pyridin-3-yl)benzenesulfonamide 5 (21-4)

[0172] To a solution of 21-3 (1.61 g, 3.11 mmol) in DCM (25 mL) was added 4N HCl / dioxane solution. The reaction mixture was stirred 5 hours at room temperature. The reaction was concentrated in vacuo to afford a yellow solid 21-4 (1.62 g, quant. yield). LCMS: m / z 418.40 (M+H)+1H NMR (CD3OD) δ 8.86 (s, 1H), 8.63 (d, 1H), 8.14 (d, 1H), 8.07 (d, 1H), 10 7.55 (d, 1H), 7.34 (s, 1H), 5.12 (s, 2H), 4.09 (br s, 1H), 3.49-3.45 (m, 2H), 3.23 (m, 2H), 2.50 (s, 3H), 2.21 ( br s, 2H), 2.07 (br s, 2H), 1.13 (s, 9H). 4-((5-(2-(N-(tert-butyl)sulfamoyl)-5-methylphenyl)pyridin-2-yl)methoxy)-N-(3- (trifluoromethyl)phenyl)piperidine-1-carboxamide (21-5) 15

[0173] To 21-4 (125 mg, 0.276 mmol) in DCM (3 mL) was added TEA (83 µL, 0.598 mmol) and 1-isocyanato-3-(trifluoromethyl)benzene (45 µL, 0.329 mmol). The reaction mixture was stirred at room temperature for 30 min. The reaction was concentrated in vacuo, partitioned between EtOAc and H2O. The organic layer washed with saturated NH4Cl, dried over Mg2SO4, filtered, and concentrated in vacuo to afford yellow solid 21-5 used without 20 further purification (162 mg, 97%) LCMS: m / z 605.4 (M+H)+1H NMR (CD3OD) δ 8.41 (d, 1H), 7.92 (d, 1H), 7.81-7.78 (dd, 1H), 7.70 (s, 1H), 7.52-7.49 (d, 3H), 7.39-7.28 (m, 2H), 7.21- 7.15 (m, 1H), 7.07 (s, 1H) 4.64 (s, 2H), 3.80-3.68 (m, 3H), 3.28 (m, 2H), 2.34 (s, 3H), 1.95-1.90 ( m, 2H), 1.63-1.59 (m, 2H), 0.95 (s, 9H). 25 4-((5-(5-methyl-2-sulfamoylphenyl)pyridin-2-yl)methoxy)-N-(3- (trifluoromethyl)phenyl)piperidine-1-carboxamide (Example 21)

[0174] To a solution of 21-5 (160 mg, 0.265 mmol) in DCM (2 mL) was added TFA (2 mL). The reaction was stirred at room temperature for 16 hours. An additional (4 mL) of 1:1 TFA / DCM solution of was added and the reaction was stirred at room temperature over 3 days. 30 The reaction was concentrated, azeotroped from toluene, then purified by reverse phase{H3007867.1}87 4927-5223-2016, v.1chromatography (0-100% ACN / H2O) to afford a white solid Example 21 (105 mg, 72%) LCMS: m / z 549.6 (M+H)+1H NMR (CD3OD) δ 8.51 (d, 1H), 8.03 (d, 1H), 7.91-7.89 (dd, 1H), 7.79 (s, 1H), 7.63-7.61 (m, 2H), 7.46-7.40 (m, 2H), 7.29 (d, 1H), 7.20 (s, 1H) 4.76 (s, 2H), 3.92- 3.82 (m, 3H), 3.40-3.28 (m, 2H), 2.46(s, 3H), 2.06-2.01 ( m, 2H), 1.77-1.71 (m, 2H). 5 4-((5-(5-methyl-2-(N-(thiophene-2-carbonyl)sulfamoyl)phenyl)pyridin-2-yl)methoxy)-N-(3- (trifluoromethyl)phenyl)piperidine-1-carboxamide (Example 21A)

[0175] Example 21 (60mg, 0.109 mmol) was capped with thiophene-2-carbonyl chloride using capping method A. The reaction mixture was purified by reverse phase chromatography 10 HPLC / MS followed by treatment with 4N HCl / MeOH to afford a white solid Example 21A (17.6 mg, 24%) LCMS: m / z 659.7 (M+H)+ 1H NMR (CD3OD) δ 8.59 (d, 1H), 8.14 (d, 1H), 8.09 (d, 1H), 7.80-7.52 (m, 8H), 7.34 (s, 1H), 7.11-7.09 (m, 1H), 4.77 (s, 2H), 3.91-3.83 (m, 3H), 3.43-3.36 (m, 2H), 2.49 (s, 3H), 2.07-2.02 (m, 2H), 1.76-1.73 (m, 2H). 15

[0176] Following the methods described above for Examples 21 and 21A and substituting the appropriate intermediates and reagents, the following compounds were prepared as indicated in Table 15. Table 15 Example Capping MS NMR DATA Structure{H3007867.1}88 4927-5223-2016, v.1N / A 1H NMR (CDCl3) δ 8.58 (s, 1H), 8.08 (d, 1H), 7.87-7.84 (dd, 1H), 5 0 ), , ), ), -{H3007867.1}89 4927-5223-2016, v.12H), 2.52 (s, 3H), 2.08-2.03 (m, 2H), 1.79-1.72 (m, 2H). , - ), 0Example 225 Methyl 5-(5-bromopicolinamido)picolinate) (22-1)

[0177] To 5-bromopicolinic acid (1.0 g, 4.95 mmol) in DCM (50 mL) at room temperature under nitrogen was added HATU (4.14 g, 10.89 mmol) and DEA (2.59 mL, 14.85 mmol). The{H3007867.1}90 4927-5223-2016, v.1solution was stirred for 10 minutes before the addition of 5-aminopycolinate (0.828 g, 5.44 mmol). The reaction was stirred at 1 hour at room temperature. The reaction was partitioned between water (50 mL) and DCM (75 mL). The organic layers was washed with NH4Cl, dried over Na2SO4, filtered and concentrated. The crude precipitate was filtered over a fritted funnel 5 and washed with DCM (50 mL) to afford a tan solid as desired product. The filtrate was concentrated in vacuo and purified by silica gel chromatography (0-100% EtOAc / Hexane) products combined to afford a tan solid 22-1 (1.05 g, 63%). LCMS: m / z 323.5 (M+H)+ (1H NMR (CDCl3) 10.11 (s, 1H), 8.88 (d, 1H), 8.71 (d, 1H), 8.62-8.59 (dd, 1H), 8.22-8.19 (m, 2H), 8.10-8.08 (dd, 1H), 4.02 (s, 3H). 10 Methyl 5-(5-(2-(N-(tert-butyl)sulfamoyl)-5-methylphenyl)picolinamido)picolinate (22-2)

[0178] To 22-1 (1.04 g, 3.09 mmol), Intermediate 1 (1.05 g, 3.86 mmol), and Pd2(dba)3 (0.252 g, 0.309 mmol) were combined in 1,4 dioxane (30 mL) and purged with nitrogen for 15 min. To the reaction mixture was added Na2CO3(0.655 g, 6.18 mmol) dissolved in water (3 mL) 15 and the reaction was stirred at 100 °C for 2 hours. The reaction mixture was cooled to room temperature, filtered over Celite and partitioned between EtOAc and H2O. The aqueous layer was extracted (2 x 25 mL) with EtOAc and the combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by silica gel chromatography (0-100% EtOAc / Hexane) to afford (0.645 g, 43%) light red solid 22-2. LCMS 20 m / z 483.5 M+H(1H NMR (CDCl3) 10.3 (s, 1H), 8.82 (d, 1H), 8.72 (d, 1H), 8.67-8.64 (dd, 1H), 8.35 (d, 1H), 8.22 (d, 1H), 8.10-8.03 (m, 2H), 7.38 (d, 1H), 7.13 (s, 1H), 4.03 (s, 3H), 2.48 (s, 3H), 1.09 (s, 9H). 5-(5-(2-(N-(tert-butyl)sulfamoyl)-5-methylphenyl)picolinamido)picolinic acid (22-3) 25

[0179] A solution of lithium hydroxide (111 mg, 1.10 mmol) in water (8 mL) was added to a stirred solution of 22-2 (749 mg, 1.55 mmol) in THF (15 mL) and MeOH (2 mL). The reaction mixture was stirred overnight at room temperature. The reaction mixture was concentrated in vacuo. The crude aqueous layer cooled to 0°C then acidified to pH~4 with 1N HCl. The precipitate was filtered and washed with water to afford (630 mg, 87%) off-white solid 22-3.{H3007867.1}91 4927-5223-2016, v.1LCMS: m / z 469.4 (M+H)+ 1H NMR (MeOD) δ 9.05 (s, 1H), 8.64 (s, 1H), 8.45 (dd, 1H), 8.18 (d, 1H), 8.09 (d, 1H), 7.97-7.93 (m, 2H), 7.34 (d, 1H), 7.12 (s, 1H), 2.37 (s, 3H), 0.96 (s, 9H). 5-(2-(N-(tert-butyl)sulfamoyl)-5-methylphenyl)-N-((6-((3- 5 (trifluoromethyl)benzyl)carbamoyl)pyridine-3-yl)picolinamide (22-4)

[0180] To a stirred solution of 22-3 (200 mg, 0.427 mmol) in anhydrous DCM (4 mL) and DMF (4 mL) under nitrogen was added HATU (325 mg, 0.854 mmol) and DIEA (224 uL, 1.28 mmol). The reaction was stirred for 10 minutes followed by the addition of (3(trifluoromethyl)phenyl)methanamine (73µL, 0.512 mmol). The mixture was stirred 10 overnight at room temperature. The reaction was concentrated in vacuo. The residue was purified by silica gel chromatography (0-100% EtOAc / Hexane) to afford 22-4 (183 mg, 68%) white solid. LCMS: m / z 626.4 (M+H)+.1H NMR (CDCl3) δ 10.3 (s, 1H), 8.91 (s, 1H), 8.72 (s, 1H), 8..47-8.44 (dd, 1H), 8.37-8.28 (m, 3H), 8.09 (d, 1H), 8.05-8.02 (dd, 1H), 7.63-7.7.46 (m, 5H), 7.12 (s, 1H), 4.74 (d, 2H), 2.47 (s, 3H), 1.09 (s, 9H). 15 5-(5-methyl-2-sulfamoylphenyl)-N-(6-((3-(trifluoromethyl)benzyl)carbamoyl)pyridin-3- yl)picolinamide (Example 22)

[0181] To a solution of 22-4 (183 mg, 0.292 mmol) in DCM (0.3 mL) was added TFA (2.7 mL). The reaction was stirred at room temperature overnight. An additional (1 mL) of 9:1 20 TFA / DCM solution of was added and the reaction was stirred at room temperature overnight. The reaction was concentrated, azeotroped from toluene and purified by silica gel chromatography (0-5% MeOH / DCM) to afford Example 22 as a white solid (102 mg, 61%). LCMS: m / z 570.51H NMR (MeOD) δ 9.15 (d, 1H), 8.75 (d, 1H), 8.52-8.49 (dd, 1H), 8.28 (d, 1H), 8.16 (d, 1H), 8.07-8.04 (m, 2H), 7.70-7.46 (m, 5H), 7.25 (s, 1H), 4.70 (s, 2H), 2.49 (s, 3H). 25 Capping Method D 5-(5-methyl-2-(N-(thiophene-2-carbonyl)sulfamoyl)phenyl)-N-(6-((3- (trifluoromethyl)benzyl)carbamoyl)pyridin-3-yl)picolinamide (Example 22A){H3007867.1}92 4927-5223-2016, v.1

[0182] To a solution of Example 22 (50 mg, 0.0878 mmol) in pyridine (1 mL) at 60°C was added thiophene carbonyl chloride (47 µL). The reaction was stirred 90 minutes before quenching with 0.5 mL methanol. The reaction was cooled to room temperature, concentrated via azeotrope with toluene then purified by silica gel chromatography (0-100% EtOAc:Hexane) 5 to afford Example 22A as a light yellow solid ( 32 mg, 53%) LCMS (method S) m / z 680.31H NMR (MeOD) δ 9.14 (s, 1H), 8.66 (s, 1H), 8.51-8.48 (dd, 1H), 8.22-8.15 (m, 3H), 7.98-7.95 (dd, 2H), 7.75-7.65 (m, 3H), 7.57-7.52 (m, 4H), 7.24 (s, 1H),7.09-7.06 (t,1H) 4.70 (s, 2H), 2.50 (s, 3H). 10

[0183] Following the methods described above for Examples 22 and 22A and substituting the appropriate intermediates and reagents, the following compounds were prepared as indicated in Table 16. Table 16 Example MS NMR DATA Structure{H3007867.1}93 4927-5223-2016, v.11H NMR (DMSO) d 12.25 (bs, 1H), 10.96 (s, 1H), 9.46 (t, 1H), d, ), d, s, 5Example 23 5Methyl 4-((6-bromopyridin-3-yl)methoxy)benzoate (23-1)

[0184] To (6-bromopyridin-3-yl)methanol (2.0 g, 10.64 mmol), methyl 4-hydroxybenzoate (2.10 g, 13.83 mmol) and triphenyl phosphine (5.02 g, 19.52 mmol) in THF (75 mL) at 0°C under nitrogen was added DEAD (7.3 mL, 15.96 mmol) 40 wt% toluene drop wise over 15 10 minutes. The reaction was stirred overnight while warming room temperature. The reaction was{H3007867.1}94 4927-5223-2016, v.1concentrated in vacuo to afford a crude solid purified by silica gel chromatography (0-100% EtOAc / Hexane) to afford 23-1 (2.04 g, 60%) as a white solid. LCMS: m / z 337.4 (M+H)+ 1H NMR (CDCl3) 8.45(s, 1H), 8.03-8.00 (m, 2H), 7.65(m, 1H), 7.53 (d, 1H), 7.0-6.97 (m, 2H), 5.09 (s, 2H), 3.90 (s, 3H). 5 Methyl 4-((6-(2-(N-(tert-butyl)sulfamoyl)-5-chlorophenyl)pyridin-3-yl)methoxy)benzoate (23-2)

[0185] 23-1 (200mg, 0.621 mmol), Intermediate 4 (271 mg, 0.931 mmol), and Pd2(dba)3 (76 mg, 0.093 mmol) were combined in 1,4 dioxane (6 mL) and purged with nitrogen for 15 10 min. To the reaction mixture was added Na2CO3(132 mg, 1.24 mmol) dissolved in water (1 mL) and the reaction was stirred at 100°C for 18 hours. The reaction mixture was cooled to room temperature, filtered over Celite and partitioned between EtOAc and H2O. The aqueous layer was extracted (2 x 25 mL) with EtOAc and the combined organic layers were washed with brine, dried over Mg2SO4, filtered, and concentrated in vacuo. The residue was purified by silica gel 15 chromatography (0-100% EtOAc / Hexane) to afford 23-2 as a white solid (111 mg, 37%) LCMS: m / z 489.3 M+H (1H NMR (CDCl3) 8.68 (s, 1H), 8.13 (d, 1H), 8.05-8.03 (m, 2H), 7.97- 7.94 (m, 1H), 7.56-7.51 (m, 2H), 7.46 (d, 1H), 7.12 (s, 1H), 7.04-7.02 (m, 2H), 5.19 (s, 2H), 3.91 (s, 2H), 2.48 (s, 3H), 1.28 (s, 9H). 20 4-((6-(2-(N-(tert-butyl)sulfamoyl)-5-chlorophenyl)pyridin-3-yl)methoxy)benzoic acid (23-3)

[0186] A solution of lithium hydroxide (17 mg, 0.445 mmol) in water (8 mL) was added to a stirred solution of 23-2 (109 mg, 0.223 mmol) in THF (1 mL) and MeOH (0.5 mL). The reaction mixture was stirred overnight at room temperature. The reaction mixture was concentrated in vacuo. The crude aqueous layer cooled to 0°C then acidified to pH~4 with 1N HCl. The 25 precipitate was filtered and washed with water to afford 23-3, (90 mg, 86%) as a white solid. LCMS: m / z 475.4 (M+H)+ 1H NMR (CD3OD) δ 8.75 (s, 1H), 8.14-8.00 (m, 4H), 7.72-7.61 (m, 3H), 7.16-7.13 (m, 2H), 5.32 (s, 2H), 1.23 (s, 9H). 4-((6-(2-(N-(tert-butyl)sulfamoyl)-5-chlorophenyl)pyridine-3-yl)methoxy)-N-(3- 30 trifluoromethyl)benzyl)benzamide (23-4){H3007867.1}95 4927-5223-2016, v.1

[0187] To a stirred solution of 23-3 (88 mg, 0.185 mmol) in anhydrous DCM (4 mL) and DMF (0.1 mL) under nitrogen was added HATU (154 mg, 0.407 mmol) and DIEA (48 uL, 0.370 mmol). The reaction was stirred for 10 minutes followed by the addition of 3- (trifluoromethyl)phenyl)methanamine (32µL, 0.222 mmol). The mixture was stirred 90 minutes 5 at room temperature. The reaction was concentrated in vacuo. The residue was purified by silica gel chromatography (0-100% EtOAc / Hexane) to afford 23-4 (109 mg, 93%) as a white solid. LCMS: m / z 633.5 (M+H)+.1H NMR (CDCl3) δ 8.67 (s, 1H), 8.15-8.12 (d, 1H), 7.96-7.93 (m, 1H), 7.82-7.80 (d, 2H), 7.60-7.46 (m, 8H), 7.13(s, 1H), 7.06-7.03 (d, 2H), 6.43 (m, 1H), 5.19 (s, 2H), 4.72 (d, 2H), 1.32 (s, 9H). 10 4-((6-(5-chloro-2-sulfamoylphenyl)pyridine-3-yl)methoxy)-N-(3- (trifluoromethyl)benzyl)benzamide (23-5)

[0188] To a solution of 23-4 (107 mg, 0.169 mmol) in DCM (0.8 mL) was added TFA (2.8 mL). The reaction was stirred 16 hours at room temperature, concentrated via azeotrophe with15 toluene then purified by silica gel chromatography (0-5% MeOH / DCM) to afford white solid 23- 5 ( 75 mg, 77%) LCMS: m / z 576.5(M+H)+ 1H NMR (CDCl3) δ 8.70 (s, 1H), 8.16 (d, 1H), 7.80 (d, 2H), 7.60-7.46 (m, 7H), 7.04 (d, 2H), 6.44-6.39 (m, 3H), 5.20 (s, 2H), 4.71 (s, 2H). N-((4-chloro-2-(5-((4-((3-(trifluoromethyl)benzyl)carbamoyl)phenoxy)methyl)pyridine-2- 20 yl)phenyl)sulfonyl)thiophene-2-carboxamide (Example 23)

[0189] 23-5 (71 mg, 0.123 mmol) was capped with thiophene carbonyl chloride (99 µL, 0.925) using Capping Method D. The reaction was cooled to room temperature, concentrated via azeotrophe with toluene then purified by silica gel chromatography (0-100% EtOAc / Hexane) to afford Example 23 as a white solid (22 mg, 27%) LCMS: m / z 687.5 (M+H)+ 1H NMR 25 (CD3OD) δ 8.50 (s, 1H), 8.24 (d, 1H), 7.90-7.88 (m, 4H), 7.67-7.53 (m, 5H), 7.43-7.40 (m, 3H), 7.14 (d, 2H), 6.94 (t, 1H), 5.24 (s, 2H), 4.65 (s, 2H).

[0190] Following the methods described above for Examples 23 and 23-5 and substituting the appropriate intermediates and reagents, the following compounds were prepared as indicated 30 in Table 17.{H3007867.1}96 4927-5223-2016, v.1Table 17 Example MS NMR DATA Structure (M+H)+, d, 3 ), , , ,{H3007867.1}97 4927-5223-2016, v.11H NMR (CDCl3) δ 8.78 (s, 1H), 8.43 (d, 1H), 8.04 (d, 1H), 7.84- s, d , ,{H3007867.1}98 4927-5223-2016, v.11H NMR (CD3OD) δ 8.92-8.89 (m, 1H), 8.58 (s, 1H), 8.05-8.00 7 , -{H3007867.1}99 4927-5223-2016, v.11H NMR (CD3OD) d 8.74-7.73 (m, 1H), 8.34-8.32 (m 1H), 8.09- 2 - s, d, 8 9 , - 3 , -{H3007867.1}100 4927-5223-2016, v.11H NMR (DMSO-d6) d 9.07-9.04 (t, 1H), 8.68-8.67 (m, 1H), 8.28- 0 , , , ,{H3007867.1}101 4927-5223-2016, v.11H NMR (DMSO) d 8.84 (t, 1H), 8.80 (d, 1H), 8.45 (d, 1H), 8.08 , s, 7 d, ), d, ), s, s, 5 d, ), d, 5 ), s, 4 s, ), s, 5 m,{H3007867.1}102 4927-5223-2016, v.11H NMR (DMSO) d 12.29 (bs, 1H), 9.37 (t, 1H), 8.84 (s, 1H), 8.80 ), d, ), t, ), s, 0 ), d, ), ), d, s, d, ), 6 ), s, 0 ), d, ), d, ), s, ), d, ), ), ), d,{H3007867.1}103 4927-5223-2016, v.11H NMR (CDCl3) δ 8.71 (s, 1H), 8.32 (d, 2H), 8.22 (d, 1H), 8.09 (d, 57 1 s, ), ), m, s, ), m, 1 6- ), ), ), 4 8- ), m, 0 0 m, 9 7- ), m, s, d,{H3007867.1}104 4927-5223-2016, v.11H NMR (CDCl3) d 11.3-11.0 (b, 1H), 8.77-8.75 (m, 1H), 8.32-8.30 1- ), , m, s, H , 2 , , 3 - , 3 . ), 3 - s,{H3007867.1}105 4927-5223-2016, v.11H NMR (CD3OD) δ 8.58-8.57 (m, 1H), 8.04-8.02 (d, 1H), 7.93- δ J δ 7{ 3007867. }106 4927-5223-2016, v.1Example 24 5Methyl 4-(5-bromopicolinamido)benzoate (24-1)

[0191] To a solution of 5-bromopicolinic acid (0.50 g, 2.48 mmol) in (1:1) DMF (6 mL) / DCM (6 mL), was added HATU (0.94g, 2.48 mmol) and DIEA (1.30 mL, 7.40 mmol). The reaction stirred 15 min, methyl-4-aminobenzoate (0.39 g, 2.60 mmol) was added and the light 10 yellow solution stirred 72 h. The precipitated solids were filtered, washed with EtOAc and dried in vacuo to provide 24-1 (630 mg, 76%). LCMS m / z 337.1 (M+H)+.1H NMR (DMSO-d6) d 11.0 (s, 1H), 8.89-8.88 (m, 1H), 8.36-8.34 (m 1H), 8.12-8.07 (m, 3H), 7.98-7.95 (m, 2H), 3.84 (s 3H). 15 Methyl 4-(5-(2-(N-(tert-butyl)sulfamoyl)-5-methylphenyl)picolinamido)benzoate (24-2)

[0192] A mixture of 24-1 (349 mg, 1.04 mmol), Intermediate 1 (339 mg, 1.25 mmol), Pd(dppf)Cl2.DCM (84.9 mg, 0.10 mmol) and Na2CO3(166 mg, 1.56 mmol) in dioxane (11.1 mL) and H2O (2.8 mL) was bubbled with nitrogen for 2 min, sealed and heated at 80oC for 3 h.{H3007867.1}107 4927-5223-2016, v.1The reaction was partitioned between EtOAc and H2O, washed with H2O and brine, dried over Na2SO4, filtered and concentrated in vacuo. The residue was re-dissolved in DCM and precipitate was collected. The filtrate was purified by silica gel chromatography and the solids were combined with the precipitates above to afford 24-2 (319 mg, 64%). LCMS m / z 482.5 5 (M+H)+.1H NMR (DMSO-d6) d 11.1 (s, 1H), 8.70 (m, 1H), 8.23-8.21 (m 1H), 8.15-8.13 (m, 2H), 8.06-8.04 (m, 1H), 7.99-7.97 (m, 3H), 7.48-7.46 (m, 1H), 7.26 (s, 1H), 7.02 (s, 1H), 3.85 (s, 3H), 2.43 (s, 3H), 1.02 (s, 9H). 4-(5-(2-(N-(tert-butyl)sulfamoyl)-5-methylphenyl)picolinamido)benzoic acid (24-3) 10

[0193] To a slurry of 24-2 (330 mg, 0.69 mmol) in THF (4.6 mL) was added 1N LiOH (6.9 mL) and MeOH (3.4 mL). The mixture stirred at room temperature 3 h, then at 40oC for 30 min. The reaction was cooled to room temperature and concentrated in vacuo overnight. The light yellow solid was dissolved in H2O, acidified to pH=2 with 1N HCl; the white solids were filtered, collected, and dried in vacuo to provide 24-3 (295 mg, 92%). LCMS m / z 468.3 15 (M+H)+.1H NMR (DMSO-d6) d 11.0 (s, 1H), 8.70 (m, 1H), 8.23-8.21 (m 1H), 8.11-8.09 (m, 2H), 8.06-8.04 (dd, 1H), 7.99-7.94 (m, 3H), 749-7.47 (d, 1H), 7.26 (s, 1H), 7.0 (s, 1H), 2.43 (s, 3H), 1.02 (s, 9H). 5-(2-(N-(tert-butyl)sulfamoyl)-5-methylphenyl)-N-(4-((4- 20 (trifluoromethyl)benzyl)carbamoyl)phenyl)picolinamide (24-4)

[0194] To a solution of 24-3 (100.0 mg, 0.21 mmol) in DMF (2 mL) was added HATU (106 mg, 0.28 mmol) and DIEA (130 µL, 0.75 mmol). The reaction stirred 15 min, then 4- trifluoromethylbenzylamine (36.6 µL, 0.26 mmol) was added and the reaction stirred one week at room temperature. The solution was partitioned between EtOAc and H2O, washed with H2O 25 and brine, dried over Na2SO4, filtered, concentrated and purified by silica gel chromatography to provide 24-4 (101 mg, 75%). LCMS m / z 625.2 (M+H)+.1H NMR (CDCl3) d 10.2 (s, 1H), 8.71 (m, 1H), 8.36-8.34 (m 1H), 8.11-8.09 (dd, 1H), 8.04-8.01 (dd, 1H), 7.92-7.86 (m, 4H), 7.64-7.49 (dd, 4H), 7.40-7.38 (m, 1H), 7.13 (s, 1H), 6.60 (t, 1H), 4.74-4.73 (m, 2H), 3.68 (s, 3H), 2.49 (s, 3H), 1.1 (s, 9H). 30{H3007867.1}108 4927-5223-2016, v.15-(5-methyl-2-sulfamoylphenyl)-N-(4-((4- (trifluoromethyl)benzyl)carbamoyl)phenyl)picolinamide hydrochloride (Example 24)

[0195] 24-4 (101 mg, 0.16 mmol), DCM (0.8 mL) and TFA (4 mL) were combined and stirred 72 h. The reaction was concentrated in vacuo, azeotroped from toluene / DCM, 5 concentrated in vacuo, purified by MS- HPLC, and concentrated from 3M methanolic-HCl to afford Example 24 (47.0 mg, 51%) as an HCl salt. LCMS 569.2 (M+H)+.1H NMR (DMSO-d6) d 11.0 (s, 1H), 9.12-9.09 (t, 1H), 8.72 (m, 1H), 8.22-8.2 (m 1H), 8.09-8.03 (m, 3H), 7.98-7.92 (m, 3H), 7.72-7.70 (m, 2H), 7.56-7.54 (m, 2H), 7.50-7.48 (m, 1H), 7.39 (s, 2H), 7.27 (m, 1H), 4.58-4.56 (m, 2H), 3.92 (b, 2H), 2.43 (s, 3H). 10 5-(5-methyl-2-(N-(thiophene-2-carbonyl)sulfamoyl)phenyl)-N-(4-((4- (trifluoromethyl)benzyl)carbamoyl)phenyl)picolinamide hydrochloride (Example 24A)

[0196] To a solution of Example 24 (127 mg, 0.19 mmol) was capped with thiophene carbonyl chloride (99 µL, 0.925) using Capping Method B. The reaction was quenched with 15 MeOH cooled to RT, concentrated in vacuo and purified by MS-HPLC (non-polar gradient), then concentrated from methanolic HCl to afford Example 24A (46.3 mg, 34%) as an HCl salt. LCMS m / z 679.3 (M+H)+.1H NMR (DMSO-d6) d 12.4-12.2 (b, 1H), 8.62 (m, 1H), 8.18-8.16 (m, 1H), 8.11-8.07 (m 3H), 7.96-7.93 (m, 4H), 7.89-7.88 (m, 1H), 7.72-7.70 (m, 2H), 7.57-7.51 (m, 3H), 7.29 (s, 1H), 7.17-7.15 (m, 1H), 4.58-4.54 (m, 2H), 2.45 (s, 3H). 20

[0197] Following the methods described above for Examples 24 and 24A and substituting the appropriate intermediates and reagents, the following compounds were prepared as indicated in Table 18. 25 Table 18 Example MS NMR DATA109 4927-5223-2016, v.11H NMR (DMSO-d6) d 10.8 (s, 1H), 9.21-9.20 (m, 1H), 9.14-9.11 - , , - , 2 . ),{H3007867.1}110 4927-5223-2016, v.11H NMR (DMSO) d 11.03 (s, 1H), 9.65 (t, 1H), 9.22 (d, 1H), 9.07 (d, , d, , , , ), , d, , ), , , d, ,{H3007867.1}111 4927-5223-2016, v.11H NMR (DMSO) d 12.15 (bs, 1H), 10.96 (s, 1H), 9.29 (t, 1H), , , ), , , d, ), d, ), d, ), ), ), d, ), d, ), ), ),112 4927-5223-2016, v.11H NMR (DMSO) d 12.25 (bs, 1H), 10.96 (s, 1H), 9.37 (t, 1H), ), ), d, ), ), s, ), ), ), d, ), m, 5 3- ), m, 7 d,{H3007867.1}113 4927-5223-2016, v.11H NMR (CDCl3) d 11.1-10.6 (b, 1H), 8.70 (m, 1H), 8.25-8.15 8 , , -Example 25{H3007867.1}114 4927-5223-2016, v.1tert-butyl 4-((6-(2-(N-(tert-butyl)sulfamoyl)-5-methylphenyl)pyridin-3- yl)methoxy)piperidine-1-carboxylate (25-1) 5 Sodium hydride (6 g) was suspended in anhydrous DMF (40 mL) and cooled in an ice bath at 0°C. To it was added a solution of tert-butyl 4-hydroxypiperidine-1-carboxylate (25.16 g) in DMF (50 mL) at 0°C using a dropping funnel. After completion of addition the reaction mixture was stirred at 0oC for 1 h then warmed to 50°C for 1h during which time gas evolution stopped and the mixture became opaque and cloudy yellow. The reaction mixture was again cooled to 10 0°C and added a solution of 2-chloropyridine-benzyl chloride (20.25 g) in DMF (50 mL) using a{H3007867.1}115 4927-5223-2016, v.1dropping funnel during which time the solution became dark brown. After stirring o.n. at room temperature, the reaction mixture was poured onto ice-cold water. The reaction mixture was extracted with EtOAc (250 mL X 3). Combined organic layer was washed with water (100 mL), brine (100 mL), dried over anhydrous sodium sulfate, filtered and concentrated to give the crude 5 product as a dark brown oil. The crude residue was purified by ISCO silica gel column chromatography using an EtOAc / DCM (0-10%) gradient - product elutes 3-5% EtOAc / DCM to afford the product as a yellow oil. The yellow oil was dissolved in hexanes (300 mL) and allowed to stand at RT overnight. Filtration afforded 25-1 as a white crystalline solid (25 g, 61%).1H NMR (CDCl3) δ 8.35 (s, 1H), 7.67-7.65 (dd, 1H), 7.33-7.31 (d, 1H), 4.54 (s, 2H), 3.79- 10 3.76 (m, 2H), 3.59-3.55 (m, 1H), 3.15-3.08 (m, 2H), 1.86 ( br, 2H), 1.62-1.56 (m, 2H), 1.46 (s, 9H). tert-butyl 4-((6-(2-(N-(tert-butyl)sulfamoyl)-5-methylphenyl)pyridin-3- yl)methoxy)piperidine-1-carboxylate (25-2) 15 Intermediate 1 and 25-1 were dissolved with stirring in dioxane (100 mL). Sodium carbonate (4.49 g) was added followed by water (20 mL). The suspension was stirred for 20 min while a stream of N2was passed through. Tetrakis (1.49 g) was added and N2bubbling was continued for another 10 min. The reaction vessel was placed under an N2atmosphere and then heated to 100oC for 12 h. The yellow mixture was cooled to RT and then opened to air - and gradually 20 became dark colored. The solids were removed by filtration through Celite and the filtrate was concentrated on a rotovap and then evaporated 3 x 50ml from toluene to give the crude product as a dark yellow oil. Purification was carried out using chromotagraphy on a 120 G Silica column using a 0-50% EtOAc / hexanes gradient. The product elutes at 43% EtOAc / Hex. The appropriate fractions were evaporated to give a cream-colored solid that could be recrystallized 25 from hot EtOAc / hex to give a white crystalline solid 25-2 (3.8 g, 57%). LCMS m / z 518.5 (M+H) N-(tert-butyl)-4-methyl-2-(5-((piperidin-4-yloxy)methyl)pyridin-2-yl)benzenesulfonamide (25-3){H3007867.1}116 4927-5223-2016, v.1

[0198] Intermediate 25-2 (3.4 g) was dissolved in dry 1,4-dioxane (20mL) with stirring.7 ml of 4N HCl in dioxane was added and stirring was continued at RT for 15 h. LC / MS indicated about 15% of SM remaining so an additional 3 ml of 4 N HCl in dioxane was added and stirring was continued at RT for 5h. The hydrochloride salt accumulates as a gum on the bottom and 5 sides of the flask - the supernatent was decanted and the gum partitioned between 1 N NaOH and DCM. The DCM layer was washed with brine dried (Na2SO4) and concentrated to an off-white foam. The crude product was purified using a 120 g ISCO column eluting with 0-20% MeOH / DCM + 1% NH4OH. The product elutes at 10% MeOH / DCM / 1% NH4OH - isolated as a colorless syrup that forms a white solid upon standing (2.5g, 91%).1H NMR (CDCl3) δ 8.54 (s, 10 1H), 8.06-8.04 (d, 1H), 7.85-7.82 (dd, 1H), 7.50-7.48 (d, 1H), 7.33-7.31 (dd, 1H), 7.26-7.24 (m, 1H), 4.63 (s, 2H), 3.55-3.51 (m, 1H), 3.16-3.11 (m, 2H), 2.69-2.62 (m, 2H), 2.46 ( s, 3H), 2.02- 1.98 (m, 2H), 1.61-1.50 (m, 2H), 1.31 (s, 9H). N-(tert-butyl)-4-methyl-2-(5(((1-(4(trifluoromethyl)benzyl)piperidin-4- 15 yl)oxy)methyl)pyridine-2-yl)benzenesulfonamide (25-4)

[0199] To a solution of 25-3 (400 mg, 0.88 mmol) in DCE (9 mL) was added TEA (147µL, 1.06 mmol), 4-(trifluoromethyl)benzaldehyde (121µL, 0.88 mmol), sodium triacetoxyborohydride (261 mg, 1.23 mmol) and acetic acid ( 60µL, 1.06 mmol). The reaction was stirred of 2 days. The reaction was partitioned between EtOAc and H2O, organic layer 20 washed with saturated NaHCO3, saturated NaCl and dried over Na2SO4, filtered, and concentrated in vacuo then purified by silica gel chromatography (0-100%) to EtOAc / Hexane to afford 25-4 as a light yellow solid (279 mg, 55%) LCMS m / z 576.3 (M+H)1H NMR (CDCl3) δ 8.53 (s, 1H), 8.05 (d, 1H), 7.84-7.81 (dd, 1H), 7.57 (d, 2H), 7.49-7.44 (m, 3H), 7.33 (d, 1H), 7.24 (d, 2H), 4.60 (s, 2H), 3.55-3.49 (m, 3H), 2.76-2.73 (m, 2H), 2.45 (s, 3H), 2.22-2.18 ( m, 2H), 25 1.98-1.94 (m, 2H), 1.75-1.70 (m, 2H), 1.28 (s, 9H). 4-methyl-2-(5(((1-(4(trifluoromethyl)benzyl)piperidin-4-yl)oxy)methyl)pyridin-2- yl)benzenesulfonamide (Example 25)

[0200] A 9:1 solution of TFA / DCM (5 mL) was added to 25-4. The reaction was stirred at 30 room temperature 6 hours. The reaction was concentrated, azeotroped from toluene, then{H3007867.1}117 4927-5223-2016, v.1purified by reverse phase chromatography (0-100% ACN / H2O) to afford Example 25 (200 mg, 81%) LCMS: m / z 520.2 (M+H)+. 1H NMR (CDCl3) δ 8.56 (s, 1H), 8.07 (d, 1H), 7.87-7.84 (dd, 1H), 7.88-7.86 (dd, 1H), 7.57 (d, 1H), 7.50 (d, 1H), 7.45 (d, 1H), 7.37-7.35 (d, 1H), 7.29 (s, 1H), 6.41 (s, 2H), 4.62 (s, 2H), 3.56-3.51 (m, 3H), 2.76-2.74 (m, 2H), 2.47 (s, 3H), 2.24-2.17 ( m, 5 2H), 2.01-1.95 (m, 2H), 1.74-1.71 (m, 2H). N-((4-methyl-2-(5-(((1-(4-(trifluoromethyl)benzyl)piperidin-4-yl)oxy)methyl)pyridin-2- yl)phenyl)sulfonyl)thiophene-2-carboxamide (Example 25A)

[0201] Example 25 was capped with thiophene carboxylic acid using Capping Method C to 10 afford Example 25A LCMS m / z 630.2 (M+H)+.1H NMR (CDCl3) δ 8.62(s, 1H), 8.26 (d, 1H), 7.92 (d, 1H), 7.74 (s, 1H), 7.63-7.54 (m, 4H), 7.47-7.40 (m, 3H), 7.10-7.08 (t, 1H), 4.64 (s, 2H), 3.60 (s, 2H), 3.54-3.52 (m, 1H), 2.78-2.76 (m, 2H), 2.46 (s, 3H), 2.29-2.25 (m, 2H), 2.01-1.96 (m, 2H), 1.78-1.72 (m, 2H). 15 Example 265-(5-methyl-2-(N-(thiophene-2-ylmethyl)sulfamoyl)phenyl)-N-(6-((3- (trifluoromethyl)benzyl)carbamoyl)pyridine-3-yl)picolinamide (Example 26) 20

[0202] To a microwave vial was added Example 22 (25 mg, 0.0439 mmol), thiophene methanol ( 100 mg, 0.878 mmol), Cu(OAc)2 (2.4 mg, 0.0132 mmol) and K2CO3 (9.1 mg, 0.0658 mmol) and the reaction was heated to 150°C for 3 hours. The reaction was cooled to room temperature, diluted with Et2O and filtered. The crude precipitate was partitioned between{H3007867.1}118 4927-5223-2016, v.1EtOAc and water. The organic layer was washed with water, brine, dried over Na2SO4concentrated in vacuo and purified by MS-HPLC (20 min method) to afford light yellow solid, Example 26 (2.8 mg, 8%) LCMS: m / z 666.31H NMR (CD3OD) δ 9.04 (s, 1H), 8.53 (s, 1H), 8.39 (m, 1H), 8.14-8.06 (m, 2H), 7.88-7.78 (m, 2H), 7.59-7.32 (m, 6H), 7.15-7.10 (m, 2H), 6.76 5 (m, 1H), 6.67 (m,1H) 4.59 (s, 2H), 4.11 (s, 2H), 2.41 (s, 3H). Example 2710 N-(tert-butyl)-4-methyl-2-(5(((1-(5-(trifluoromethyl)pyridine-2-yl)piperidin-4- yl)oxy)methyl)pyridine-2-yl)benzenesulfonamide (27-1)

[0203] A solution of 21-4 (300 mg, 0.661 mmol) in 1,4 dioxane (7 mL) was purged with nitrogen for 15 minutes before the addition of 5-chloro-2-(trifluoromethyl)pyridine (150 mg, 0.826 mmol), Pd(OAc)2(7.4 mg, 0.033 mmol), BINAP (33 mg, 0.053 mmol), and NaOt-Bu 15 (127 mg, 1.32 mmol). The reaction was purged with nitrogen for 30 min. and stirred at 85°C for 18 hours. The reaction mixture was cooled to room temperature and partitioned between EtOAc and H2O. The aqueous layer was extracted (2 x 25 mL) with EtOAc and the combined{H3007867.1}119 4927-5223-2016, v.1organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by silica gel chromatography (0-100% EtOAc / Hexane) to afford 27-1 (95 mg, 26%) white solid. LCMS: m / z 563.3 M+H1H NMR (CDCl3) 8.56 (s, 1H), 8.39 (d, 1H), 8.05 (d, 1H), 7.86-7.83 (dd, 1H), 7.63-7.60 (dd, 1H), 7.49 (d, 1H), 7.36-7.32 (m, 2H), 7.25 (m, 5 1H), 6.68 (d, 1H), 4.66 (s, 2H), 4.11-4.02 (m, 2H), 3.78-3.74 (m, 1H), 3.45-3.39 (m , 2H), 2.45 (s, 3H), 2.05-1.98 (m, 2H), 1.78-1.70 (m, 2H), 1.30 (s, 9H). 4-methyl-2-(5(((1-(5-(trifluoromethyl)pyridin-2-yl)piperidin-4-yl)oxy)methyl)pyridine-2- yl)benzenesulfonamide (Example 27) 10

[0204] To a solution of 27-1 (142 mg, 0.252 mmol) in DCM (0.3 mL) was added TFA (2.7 mL). The reaction was stirred at room temperature for 18 hours. An additional (0.5 mL) of 9:1 TFA / DCM solution was added and the reaction was stirred at room temperature 1 hour. The reaction was concentrated, azeotroped from toluene, then purified by silica gel chromatography (0-100% EtOAc / Hexane) to afford Example 27 (91 mg, 72%) white solid LCMS: m / z 507.2 15 (M+H)+ 1H NMR (CD3OD) δ 8.64 (s, 1H), 8.33 (s, 1H), 8.04-7.98 (m, 2H), 7.73-7.70 (m, 1H), 7.63 (d, 1H), 7.46-7.44 (m, 1H), 7.40 (s, 1H), 6.92 (d, 1H), 4.75 (s, 2H), 4.13-4.07 (m, 2H), 3.86-3.83 (m, 1H), 3.49-3.42 (m, 2H), 2.49 (s, 3H), 2.08-2.02 ( m, 2H), 1.75-1.68 (m, 2H). N-((4-methyl-2-(5(((1-(5-(trifluoromethyl)pyridin-2-yl)piperidin-4-yl)oxy)methyl)pyridin-2- 20 yl)phenyl)sulfonyl)thiophene-2-carboxamide (Example 27A)

[0205] Example 27 (64 mg, 0.336 mmol) was capped with thiophene carboxylic acid (32 mg, 0.252 mmol) using Capping Method C to afford Example 27A. The reaction was partitioned between DCM and H2O. The organic layer was washed with saturated NH4Cl dried 25 over Na2SO4and concentrated in vacuo then purified by silica gel chromatography (0-10% MeOH / DCM) to afford Example 27A (77 mg, 76%) white solid LCMS (method S) m / z 617.2 (M+H)+ 1H NMR (CDCl3) δ 8.65 (s, 1H), 8.39 (s, 1H), 8.28 (d, 2H), 7.98-7.96 (m, 1H), 7.76 (d, 1H), 7.64-7.56 (m, 3H), 7.44-7.41 (d, 1H), 7.28 (s, 1H), 7.10 (t, 1H), 6.68 (d, 1H), 4.72 (s, 2H), 4.10-4.04 (m, 2H), 3.81-3.78 (m, 1H), 3.46-3.39 (m, 2H), 2.46 (s, 3H), 2.07-2.01 ( m, 2H), 30 1.80-1.74 (m, 2H).{H3007867.1}120 4927-5223-2016, v.1

[0206] Following the methods described above for Examples 27 and 27A and substituting the appropriate intermediates and reagents, the following compounds were prepared as indicated in Table 19. 5 Table 19 Example MS NMR DATA Structure M+H+, , 4 9{H3007867.1}121 4927-5223-2016, v.11H NMR (CDCl3) d 8.59-8.58 (d, 1H), 8.09-8.07 (d, 1H), 7.89-7.86 - d, 2 d, 9 , - 2 ),{H3007867.1}122 4927-5223-2016, v.11H NMR (CDCl3) d 8.62-8.59 (m, 1H), 8.23-8.19 (d,1H), 7.83-7.78 - 4 , - 5 0 ,{H3007867.1}123 4927-5223-2016, v.11H NMR (CDCl3) d 8.59-8.56 (m, 1H), 8.23-8.18 (d, 1H), 7.91-7.86 , 2 - 5 - , 0 7 , 8 ,{ . }124 4927-5223-2016, v.11H NMR (CDCl3) d 11.6-11.2 (b, 1H), 8.73-8.69 (m, 1H), 8.34-8.28 , - s, 1 , - 1 , - , 0 , , 7{H3007867.1}125 4927-5223-2016, v.11H NMR (CDCl3) d 8.63-8.60 (m, 1H), 8.23-8.19 (d,1H), 7.84-7.79 - 1 - s, 1 , - , 6 - , - , , 3 - 8{ . }126 4927-5223-2016, v.11H NMR (CDCl3) d 12.1-11.4 (b, 1H), 8.62-8.58 (m, 1H), 8.24-8.18 - 2 1 9 , - 8 , - , 7{H3007867.1}127 4927-5223-2016, v.11H NMR (DMSO-d6) d 11.5-11.4 (b, 1H), 8.62-8.59 (m, - , - , 8 , - 0 -{H3007867.1}128 4927-5223-2016, v.11H NMR (DMSO-d6) d 8.82-8.65 (m, 2H), 8.17-7.91 (m, 4H), 7.76- 6 - 5 - 4 8 5 - 7 -129 4927-5223-2016, v.11H NMR (DMSO-d6) d 8.71-8.68 (m, 1H), 8.41-8.39 (m 1H), 8.12- 8 - , , 1 - , 6{H3007867.1}130 4927-5223-2016, v.11H NMR (DMSO-d6) d 9.14 (s, 1H), 8.55-8.52 (m, 1H), 9 - , - 1 , 9 - 2 - 0{H3007867.1}131 4927-5223-2016, v.11H NMR (DMSO-d6) d 8.70-8.67 (m, 1H), 8.10-8.03 (m, 4H), 7.86- 27 9 - , , 27 4 27 2 - , , 6 27 s, 5{H3007867.1}132 4927-5223-2016, v.11H NMR (DMSO-d6) d 8.71-8.67 (m, 1H), 8.55-8.53 (m, 1H), 8.25- , 5 , - 8 -{H3007867.1}133 4927-5223-2016, v.11H NMR (CDCl3) d 8.26 (d, 1H), 8.00 (s, 1H), 7.60-7.56 (m, 1H), 8 4 4 1134 4927-5223-2016, v.18 2 ), 9 ),{H3007867.1}135 4927-5223-2016, v.11H NMR (CDCl3) d 8.17 (d, 1H), 7.87 (bs, 1H), 7.52-7.47 (m, 1H), 5 1 - 8 6 4 4 7 ),4927-5223-2016, v.11H NMR (CDCl3) d 8.16 (d, 1H), 7.21-7.16 (m, 2H), 7.18-7.12 (m, 6 ) 4 7 , 2 - 8 -137 4927-5223-2016, v.11H NMR (CDCl3) d 8.17 (d, 1H), 7.92 (bs, 1H), 7.51-7.47 (m, 1H), 8 - 5 s, 5 2 - 2 -{H3007867.1}138 4927-5223-2016, v.11H NMR (CDCl3) d 8.16 (d, 1H), 7.32-7.26 (m, 2H), 7.17-7.11 (m, 8 - 2 - 9 8 - 9139 4927-5223-2016, v.11H NMR (CDCl3) d 8.81 (bs, 1H), 8.21-8-08 (m, 1H), 7.94 (s 1H), 8 - 1 - 9 - 7 , - , 4 -140 4927-5223-2016, v.11H NMR (CDCl3) d 8.76 (bs, 1H), 8.17-8-04 (m, 1H), 7.98-7.89 (m, 8 - , 3 - , 7 - , 5 , 9 9{H3007867.1}141 4927-5223-2016, v.11H NMR (CDCl3) d 8.21-8-16 (m, 1H), 7.79-7.74 (m, 1H), 7.59-7.55 2 δ , 3 ), ). δ , , 0 8 δ , 3 ), ,{H3007867.1}142 4927-5223-2016, v.11H NMR (500 MHz, DMSO-d6) δ 8.45 (d, J = 2.1 Hz, 1H), 8.11 (d, J , , , 4 δ , , δ z, 8 7 δ J , 5 7 , ).{H3007867.1}143 4927-5223-2016, v.11H NMR (300 MHz, DMSO-d6) δ 8.42 (s, 1H), 8.06 – 6.75 (m, 13H), , δ , J – ), . δ s, δ J , 0 9{H3007867.1}144 4927-5223-2016, v.11H NMR (500 MHz, DMSO-d6) δ 8.62 (d, J = 2.1 Hz, 1H), 8.07 (d, J 600 8 , , δ 618 , , , δ , 3 617 , ), , m, 4 2- 616 ), m, m, 3 4{H3007867.1}145 4927-5223-2016, v.11H NMR (CDCl3) d 8.66-8.65(m, 1H), 8.30-8.26 (d, 1H), 7.98-7.94 2- ), d, s, 9 3 - 0 ), ,{H3007867.1}146 4927-5223-2016, v.11HNMR (CDCl3) d 8.41-8.38 (m, 1H), 8.31-8.28 (d, 1H), 7.97-7.92 2- - 2 - , 7 -4927-5223-2016, v.1672.31H NMR (CDCl3) 8.64-8.59 (m, 1H), 8.23-8.19 (m,1H), 7.94-7.88 - , 5 t, 0 - , - , 7 9 , - , - 24927-5223-2016, v.11H NMR (CDCl3) d 8.70-8.66 (m, 1H), 8.32-8.28 (d,1H), 8.02-7.96 - , 1 , 9 , - , - 4 0- , 1 , – ), , 8{H3007867.1}149 4927-5223-2016, v.11H NMR (500 MHz, DMSO-d6) z, , , 7 ), , 4 , J , , , s, 9 - s, 5 -{H3007867.1}150 4927-5223-2016, v.11H NMR (CDCl3) d 8.72-8.67 (m, 1H), 8.28-8.23 (m, 1H), 8.01-7.95 - 0 , 6 - 5 ), , 6 - , 5 - 4{H3007867.1}151 4927-5223-2016, v.11H NMR (CDCl3) d 8.69-8.63 (m, 1H), 8.28-8.21 (m, 1H), 8.07-7.99 - , 2 - , 4 - , 9 - 6 ),{H3007867.1}152 4927-5223-2016, v.11H NMR (CDCl3) d 8.81-8.71 (m, 1H), 8.29-8.16 (m, 2H), 7.81-7.72 -Example 29 5methyl 4-(5-bromopicolinamido)benzoate (29-1){H3007867.1}153 4927-5223-2016, v.1

[0207] To a stirred solution of 4-bromobenzoic acid (500 mg, 2.48 mmol) in anhydrous DMF (12 mL) under nitrogen was added HATU (2.17 g, 5.7 mmol) and DIEA (2.16 mL, 12.4 mmol). The reaction was stirred for 30 minutes followed by the addition of methyl 4- aminobenzoate (524 mg, 3.46 mmol). The mixture was stirred 2 h at room temperature. The 5 reaction mixture was taken up in DCM and washed with water, dried over sodium sulfate and evaporated. The residue was purified by reversed phase chromatography (10-100% ACN / H2O) to afford 29-1 (629 mg, 76%). LCMS (method A): m / z = 335.1, 337.1 (M+H)+.1H NMR (DMSO) d 10.99 (s, 1H), 8.88 (s, 1H), 8.35 (q, 1H), 8.09 (m, 3H), 7.96 (q, 2H), 3.84 (s, 3H). 10 methyl 4-(5-bromo-N-methylpicolinamido)benzoate (29-2)

[0208] NaH (60% suspension in paraffin oil) (84 mg, 2.11 mmol) was added in a mixture of 29-1 (529 mg, 1.58 mmol) in DMF (6 mL). The mixture was stirred at room temperature for about 10 min and, then, MeI (197 µL, 3.16 mmol) was added to the reaction. It was stirred at room temperature for about 2 h. After the reaction was completed MeOH (100 µL) was added to 15 quench the reaction. DCM (40 mL) was added. The resulted solution was washed with H2O (5 X) to remove DMF. The organic layer was dried over sodium sulfate, filtered and concentrated in vacuo to give a crude product which was purified by silica gel chromatography (0-40% Hexane / EtOAc) to afford 29-2 (613 mg, 99%). LCMS (method A): m / z = 349.1, 351.1 (M+H)+. 1H NMR (CDCl3) d 8.34 (s, 1H), 7.92 (d, 2H), 7.81 (d, 1H), 7.53 (d, 1H), 7.10 (d, 2H), 3.91 (s, 20 3H), 3.55 (s, 3H). methyl 4-(5-(2-(N-(tert-butyl)sulfamoyl)-5-methylphenyl)-N-methylpicolinamido)benzoate (29-3)

[0209] To compound 29-2 (467mg, 1.34 mmol) and Intermediate 1 (546 mg, 2.0 mmol) in 25 dioxane (8.5 mL) was added a solution of Na2CO3 (284 mg, 0.134mmol) in H2O (2.1 mL) and the mixture was degassed under N2for 35 min. Pd(dppf)Cl2.dcm (109 mg, 0.134 mmol) was added, and the reaction was again degassed (20 min). The reaction was heated to 80°C under N2for 4 hours, cooled to rt, filtered through celite and washed with DCM. The DCM layers were combined, washed with H2O (3x 300 ml) and brine, dried over Na2SO4, filtered and 30 concentrated. The residue was purified by column chromatography and eluting with 0-70%{H3007867.1}154 4927-5223-2016, v.1EtOAc / hexanes to give 29-3 (653 mg, 98%). LCMS: m / z = 496.4 (M+H)+;1H NMR (CDCl3) d 8.31 (s, 1H), 8.03 (d, 1H), 7.95 (d, 2H), 7.86 (dd, 1H), 7.68 (d, 1H), 7.31(dt, 1H), 7.19 (d, 2H), 6.99 (s, 1H), 3.91 (s, 3H), 3.59 (s, 3H), 3.31 (s, 1H), 2.43 (s, 3H), 0.98 (s, 9H). 5

[0210] 4-(5-(2-(N-(tert-butyl)sulfamoyl)-5-methylphenyl)-N- methylpicolinamido)benzoic acid hydrochloride (29-4)

[0211] To compound 29-3 (653 mg, 1.32 mmol) in THF (8.6 mL) and water (4.3mL) was added LiOH (110 mg, 2.64 mmol). The solution was stirred at RT for 4 h, and then concentrated in vacuo. The crude residue was dried in vacuo. To the residue was added H2O which was 10 washed with Et2O. The aqueous phase was acidified to pH~2 with 1N HCl, and extracted with EtOAc. The EtOAc extracts were combined, washed with brine, dried over Na2SO4, filtered and concentrated in vacuo to provide compound 29-4 (519 mg, 76%). LCMS: m / z = 482.4 (M+H)+; 1H NMR (CDCl3) d 12.91 (s, 1H), 8.29 (s, 1H), 7.92 (d, 1H), 7.84 (d, 3H), 7.65 (d, 1H), 7.41 (dd, 1H), 7.30(d, 2H), 7.08 (s, 1H), 6.84 (s, 1H), 3.46 (s, 3H), 3.34 (s, 3H), 0.95 (s, 9H). 15

[0212] 5-(2-(N-(tert-butyl)sulfamoyl)-5-methylphenyl)-N-methyl-N-(4-((3- (trifluoromethyl)benzyl) carbamoyl)phenyl)picolinamide (29-5)

[0213] To a stirred solution of 29-4 (100 mg, 0.193 mmol) in anhydrous DMF (1.2 mL) under nitrogen was added HATU (147 mg, 0.386 mmol) and DIEA (168 uL, 0.965 mmol). The20 reaction was stirred for 10 minutes followed by the addition of 3- (trifluoromethyl)phenyl)methanamine (39 µL, 0.27 mmol). The mixture was stirred 3 h at room temperature. The reaction was concentrated in vacuo. The residue was purified by reversed phase chromatography (10-100% ACN / H2O) to afford 29-5 (111 mg, 90%). LCMS: m / z = 639.5 (M+H)+;1H NMR (DMSO) d 9.10 (t, 1H), 8.29 (s, 1H), 7.92 (d, 1H), 7.82 (m, 3H), 7.56~7.66 25 (m, 5H), 7.41 (d, 1H), 7.31 (d, 2H), 7.07 (s, 1H), 6.83 (s, 1H), 4.53 (d, 2H), 3.45 (s, 3H), 3.37 (s, 3H), 0.92 (s, 9H). N-methyl-5-(5-methyl-2-sulfamoylphenyl)-N-(4-((3-(trifluoromethyl)benzyl)carbamoyl) phenyl)picolinamide (Example 29)

[0214] Compound 29-5 (111 mg, 0.174 mmol), DCM (0.29 mL) and TFA (2.6 mL) were 30 combined and stirred overnight. The solution was concentrated in vacuo, azeotroped from{H3007867.1}155 4927-5223-2016, v.1toluene, and purified by column chromatography in 0-10% MeOH / DCM, then concentrated to afford Example 29 (83 mg, 82%). LCMS: m / z = 583.4 (M+H)+;1H NMR (MeOD) d 8.34 (s, 1H), 7.97 (d, 1H), 7.80 (d, 1H), 7.76 (d, 2H), 7.62 (m, 2H), 7.54 (m, 3H), 7.39 (dd, 1H), 7.27 (d, 2H), 7.09 (s, 1H), 4.61 (s, 2H), 3.56 (s, 3H), 3.41 (s, 3H). 5 N-methyl-5-(5-methyl-2-(N-(thiophene-2-carbonyl)sulfamoyl)phenyl)-N-(4-((3- (trifluoromethyl)benzyl)carbamoyl)phenyl)picolinamide (Example 29A)

[0215] To a solution of Example 29 (73 mg, 0.125 mmol) was capped with thiophene carbonyl chloride (54 µL, 0.50) using Capping Method B. The reaction was quenched with 10 MeOH, concentrated in vacuo and purified by column chromatography in 0-10% MeOH / DCM, then concentrated to afford Example 29A (40.9 mg, 47%) LCMS: m / z = 693.4 (M+H)+;1H NMR (MeOD) d 8.20 (s, 1H), 8.01 (d, 1H), 7.70 (d, 2H), 7.64 (d, 2H), 7.53 (s, 1H), 7.38~7.52 (m, 5H), 7.35 (d, 1H), 7.21 (d, 2H), 7.00 (t, 1H), 6.95 (s, 1H), 4.50 (s, 2H), 3.44 (s, 3H), 2.31 (s, 3H). 15

[0216] Following the methods described above for Examples 29A and substituting the appropriate intermediates and reagents, the following compounds were prepared as indicated in Table 20. 20 Table 20 Example MS NMR DATA Structure{H3007867.1}156 4927-5223-2016, v.11H NMR (CDCl3) d 8.44-8.41 (dd, 1H), 8.29-8.27 (d, 1H), 8.14 (b, 6 - , 6 , 6 - s,{H3007867.1}157 4927-5223-2016, v.1

[0217] To 2-chloro-5-(chloromethyl)pyridine (5.00 g, 30.9 mmol) in DMF (100 ml) was added methyl 5-hydroxypicolinate (5.70 g, 37.0 mmol) and K2CO3(6.40 g, 46.3 mmol) and the 5 reaction was stirred at 70°C for 1.5 hours. The reaction was cooled to rt and concentrated in vacuo. The residue was partitioned between H2O / DCM (200ml / 200 ml), washed with H2O (3x 200 ml) and back extracted the combined H2O washes with DCM (1x 200 ml). The combined DCM washes were washed with brine, dried over Na2SO4, filtered and concentrated in vacuo. The residue was redissolved in DCM and hexanes were added until white solids began dropping 10 out of the solution. After overnight, the solids were filtered and collected to provide (4.20 g). The filtrates were purified by column chromatography in EtOAc / hex to provide an additional (3.23 g) of white solid, for a total yield of (7.43 g, 86%) compound 31-1. LCMS m / z 281.2{H3007867.1}158 4927-5223-2016, v.1(M+H)+.1H NMR (CDCl3) d 8.42-8.39 (m, 2H), 8.09-8.06 (d, 1H), 7.72-7.69 (dd, 1H), 7.35- 7.32 (d, 1H), 7.29-7.25 (dd, 1H), 5.10 (s, 2H), 3.93 (s, 3H). Methyl 5-((6-(2-(N-(tert-butyl)sulfamoyl)-5-methylphenyl)pyridin-3-yl)methoxy)picolinate 5 (31-2)

[0218] To compound 31-1 (3.68, 13.2 mmol) and Intermediate 1 (3.94 g, 14.5 mmol) in dioxane (88 ml) was added a solution of Na2CO3 in H2O (22 ml) and the mixture was degassed under N2for 35 min. Pd(dppf)Cl2.dcm was added, and the reaction was again degassed (20 min). The reaction was heated to 80°C under N2for 2 hours, cooled to rt, filtered through celite and 10 washed with DCM. The DCM layers were combined, washed with H2O (3x 300 ml) and brine, dried over Na2SO4, filtered and concentrated. Combined with a second reaction set up and worked up as above, for purification. Purified the two reactions as one via column chromatography and eluting with 0-100% EtOAc / hexanes provided a total of (9.09 g, 73%) compound 31-2 as a light yellow solid. LCMS m / z 470.3 (M+H)+.1H NMR (CDCl3) d 8.70-15 8.68 (m, 1H), 8.53-8.51 (d, 1H), 8.20-8.15 (d, 1H), 8.10-8.06 (d, 1H), 7.96-7.92 (dd, 1H), 7.59- 7.55 (d, 1H), 7.42-7.34 (m, 3H), 7.01 (s, 1H), 5.25 (s, 2H), 4.01 (s, 3H), 2.48 (s, 3H), 1.32 (s, 9H). 5-((6-(2-(N-(tert-butyl)sulfamoyl)-5-methylphenyl)pyridin-3-yl)methoxy)picolinic acid 20 (31-3)

[0219] To compound 31-2 (9.09g, 19.4 mmol) in THF (100 ml) was added LiOH (0.93 g, 38.7 mmol) in H2O (50 ml). The reaction was stirred at rt for 30 min. The reaction was concentrated in vacuo, redissolved in H2O (1 liter), and stirred overnight as it completely solubilized. The solution was acidified to pH=4 with 1M HCl. The white solids were filtered, 25 collected and dried in vacuo to obtain compound 31-3 as a light tan solid, (8.03 g, 83%). LCMS m / z 456.3 (M+H)+. 1H (DMSO-d6) d 12.99-12.79 (bs, 1H), 8.00-8.78 (m, 1H), 8.52-8.50 (d, 1H), 8.09-8.04 (m, 2H), 7.96-7.92 (d, 1H), 7.70-7.65 (m, 2H), 5.40 (s, 2H), 2.43 (s, 3H), 1.16 (s, 9H).{H3007867.1}159 4927-5223-2016, v.13-(trifluoromethyl)benzyl 5-((6-(2-(N-(tert-butyl)sulfamoyl)-5-methylphenyl)pyridin-3- yl)methoxy)picolinate (31-4)

[0220] Compound 31-3 (624 mg, 1.37 mmol), 3-(trifluoromethyl)benzyl alcohol (200 mg, 1.14 mmol), EDCI.HCl (262.6 mg, 1.37 mmol) and DMAP (13.9 mg, 0.114 mmol) were 5 combined in DCM (10 ml) and the amber solution stirred at rt overnight. The reaction was concentrated in vacuo and purified via column chromatography on 24 g gold Isco column, eluting 0-100% EtOAc / hexanes. Product fractions were collected to provide compound (31-4) as a white solid, (271 mg, 77%). LCMS m / z 614.5 (M+H)+.1H NMR (CDCl3) d 8.69-8.68 (m, 1H), 8.55-8.54 (d, 1H), 8.19-8.16 (d, 1H), 8.09-8.06 (d, 1H), 7.95-7.92 (dd, 1H), 7.77-7.75 (s, 10 1H), 7.71-7.68 (d, 1H), 7.64-7.50 (m, 3H), 7.41-7.35 (m, 2H), 7.01-7.00 (s, 1H), 5.50 (s, 2H), 5.26 (s, 2H), 2.48 (s, 3H), 1.32 (s, 9H). 3-(trifluoromethyl)benzyl 5-((6-(5-methyl-2-sulfamoylphenyl)pyridin-3- yl)methoxy)picolinate, 2,2,2-trifluoroacetate (31-5) 15

[0221] To compound 31-4 (267 mg, 0.44 mmol) in DCM (22 ml) was added TFA (2.20 ml, 0.2 M) and the reaction was stirred under a blanket of N2overnight. After 17 hours, approx. 15% sm remained. The reaction was warmed to 40°C for 4.5 hours. The reaction was concentrated in vacuo and azeotroped (3x) in DCM / toluene. Purification by silica gel chromatography, eluting with 0-20% MeOH / DCM provided compound 31-5 as a white solid, 20 (317 mg, Quant.) as a TFA salt. LCMS m / z 558.4 (M+H)+.1H NMR (CDCl3) d 8.97-8.94 (m, 1H), 8.72-8.69 (d, 1H), 8.32-8.25 (m, 2H), 8.09-8.05 (d, 1H), 7.80-7.50 (m, 7H), 7.26-7.24 (s, 1H), 6.25-6.02 (bs, 2H + H2O), 7.41-7.35 (m, 2H), 5.49 (s, 2H), 5.42 (s, 2H), 2.51 (s, 3H). 3-(trifluoromethyl)benzyl 5-((6-(5-methyl-2-(N-(thiophene-2- 25 carbonyl)sulfamoyl)phenyl)pyridin-3-yl)methoxy)picolinate (Example 31)

[0222] Thiophene-2-carboxylic acid (90.3 mg, 0.704 mmol), EDCI.HCl (180 mg, 0.928 mmol) and DMAP (143 mg, 1.17 mmol) was combined in DMA (2.5 ml), and was stirred 30 min. The above was added to 31-5 (314 mg, 0.469 mmol) in DMA (3.5 ml) and the reaction was stirred overnight under N2. Significant sm remained. A second addition of thiophene-2- 30 carboxylic acid (90.3 mg, 0.704 mmol), EDCI.HCl (180 mg, 0.928 mmol) and DMAP (143 mg,{H3007867.1}160 4927-5223-2016, v.11.17 mmol) was combined in DMA (2.5 ml) and stirred together for 30 minutes prior to adding to the reaction. After a second night, the reaction was warmed to 40°C and continued stirring for a third overnight. The reaction was progressing, but sm remained. A third addition of thiophene- 2-carboxylic acid (90.3 mg, 0.704 mmol), EDCI.HCl (180 mg, 0.928 mmol) and DMAP (143 5 mg, 1.17 mmol) combined in DMA (2.5 ml), was added to the reaction at 40°C and continued an additional 3 nights. The reaction was now complete and concentrated in vacuo to remove DMA. The residue was pre-adsorbed on celite in DCM and purified by silica gel chromatography followed by mass directed HPLC. Product fractions were combined and lyophilized to obtain Example 31 as a white solid, (105 mg, 34%). LCMS m / z 668.4 (M+H)+.1H NMR (DMSO-d6)10 d 8.61 (m, 1H), 8.48-8.47 (d, 1H), 8.10-8.08 (m, 1H), 8.01-7.95 (m,2H), 7.90-7.56 (m, 8), 7.45- 7.43 (m, 1H), 7.24-7.23 (m, 1H), 7.10-7.08 (dd, 1H), 5.39-5.33 (m, 2H), 2.36 (s, 3H). Example 3215{H3007867.1}161 4927-5223-2016, v.1N-(tert-butyl)-2-(5-(((6-(hydroxymethyl)pyridin-3-yl)oxy)methyl)pyridin-2-yl)-4- methylbenzenesulfonamide (32-1) 5

[0223] Into a pre-dried flask was combined compound 31-2 (5.00 g, 10.7 mmol) in anhydrous THF (100 ml) at 0°C. The reaction was stirred at 0°C as LiBH4 (2.0 M in THF) (10.7 ml, 21.3 mmol) was added dropwise. After 10 min, the bath was removed to help solubilize the compound. The bath was reinstated after approx.15 min and to the reaction slurry, EtOH (100 ml) was added and continued at for 5 min at 0°C. The bath was removed and the reaction 10 continued at rt. After 2 hrs, the reaction mixture indicated desired alcohol plus ethyl ester. The reaction was cooled to 0°C and additional LiBH4(10.7 ml) was added. The reaction continued at{H3007867.1}162 4927-5223-2016, v.10°C as it warmed to rt overnight. After 18 hours, the reaction was complete. The reaction was quenched with sat. NH4Cl at 0°C (25 ml) and concentrated in vacuo. Partitioned between NH4Cl / EtOAc (200 ml / 100 ml). The EtOAc layer was washed with brine, dried over Na2S04, filtered and concentrated. Purification by column chromatography eluting with 0-20% 5 MeOH / DCM provided compound 32-1 as an off-white solid, (3.95g, 84%). LCMS m / z 442.3 (M+H)+.1H NMR (CDCl3) d 8.69-8.67 (m, 1H), 8.38-8.36 (d, 1H), 8.09-8.06 (d, 1H), 7.95-7.92 (dd, 1H), 7.58-7.55 (d, 1H), 7.38-7.32 (m, 2H), 7.28-7.27 (1H obscured by CDCl3), 7.26-7.23 (m, 1H), 7.07 (s, 1H), 5.20 (s, 2H), 4.74 (s, 2H), 2.48 (s, 3H), 1.32 (s, 9H). 10 N-(tert-butyl)-2-(5-(((6-formylpyridin-3-yl)oxy)methyl)pyridin-2-yl)-4- methylbenzenesulfonamide (32-2)

[0224] To compound 32-1 (442 mg, 1.00 mmol) in CHCl3(5.0ml, 0.2M) was added MnO2(870 mg, 10.0 mmol) and the reaction was stirred at rt over a 72 hours. The reaction was filtered through celite and concentrated in vacuo. Purification by silica gel chromatography eluting with 15 0-100% EtOAc / hexanes provided compound 32-2 as a white solid, (357 mg, 83%). LCMS m / z 440.4 (M+H)+.1H NMR (CDCl3) d 10.0 (s 1H), 8.71-8.69 (d, 1H), 8.57-8.55 (d, 1H), 8.17-8.10 (d, 1H), 8.04-8.01 (d, 1H), 7.97-7.93 (dd, 1H), 7.60-7.57 (d, 1H), 7.46-7.42 (dd, 1H), 7.38-7.35 (m, 1H), 7.29-7.28 (1H obscured by CDCl3), 7.01-7.00 (s, 1H), 5.28 (s, 2H), 4.74 (s, 2H), 2.48 (s, 3H), 1.32 (s, 9H). 20 N-(tert-butyl)-2-(5-(((6-((4-fluorophenyl)(hydroxy)methyl)pyridin-3-yl)oxy)methyl)pyridin- 2-yl)-4-methylbenzenesulfonamide (32-3)

[0225] Into a predried vial under argon balloon was combined 32-2 (250 mg, 0.57 mmol) in anh. THF (2.3 ml, 0.25 M) and the reaction was cooled to 0°C. (4-fluorophenyl)magnesium 25 bromide (1.14 ml, 1M in THF) was added dropwise at 0°C. Once added, the reaction was stirred two min. and the bath was removed as the reaction continued at rt. At one hour, the reaction was quenched with sat. NH4Cl and extracted with EtOAc (3x). The EtOAc extracts were combined, washed with brine, dried over Na2SO4, filtered and concentrated. Purification was carried out by column chromatography eluting 0-100% EtOAc to provide compound 32-3 as a white solid. (256 30 mg, 83%). LCMS m / z 536.5 (M+H)+.1H NMR (CDCl3) d 8.67-8.66 (d, 1H), 8.38-8.35 (d, 1H),{H3007867.1}163 4927-5223-2016, v.18.09-8.06 (d, 1H), 7.94-7.90 (dd, 1H), 7.58-7.54 (d, 1H), 7.38-7.33 (m, 3H), 7.30-7.26 (2H obscured by CDCl3), 7.12-7.00 (m, 4H), 5.76-5.73 (d, 1H), 5.18 (s, 2H), 4.92-4.90 (d, 1H) 2.48 (s, 3H), 1.32 (s, 9H). 5 N-(tert-butyl)-2-(5-(((6-(4-fluorobenzoyl)pyridin-3-yl)oxy)methyl)pyridin-2-yl)-4- methylbenzenesulfonamide (32-4)

[0226] To 32-3 (253 mg, 0.473 mmol) in CHCl3(2.4 ml, (0.2M), was added MnO2(411 mg, 4.73 mmol) at rt. The reaction was stirred overnight, then filtered through celite, washed with DCM and concentrated in vacuo. Purification by silica gel chromatography eluting with 0-100% 10 EtOAc / hexanes provided compound 32-4 as a white solid, (242 mg, 96%). LCMS m / z 534.5 (M+H)+.1H NMR (CDCl3) d 8.72-8.70 (d, 1H), 8.49-8.48 (d, 1H), 8.22-8.26 (m, 3H), 8.10-8.07 (d, 1H), 7.98-7.94 (dd, 1H), 7.60-7.57 (d, 1H), 7.49-7.46 (dd, 1H), 7.38-7.36 (m, 1H), 7.29-7.27 (1H obscured by CDCl3), 7.21-7.14 (m, 2H), 7.02 (s, 1), 5.29 (s, 2H), 2.48 (s, 3H), 1.33 (s, 9H). 15 2-(5-(((6-(4-fluorobenzoyl)pyridin-3-yl)oxy)methyl)pyridin-2-yl)-4- methylbenzenesulfonamide (32-5)

[0227] To compound 32-4 (239 mg, 0.45 mmol) in DCM (2.2 ml, 0.2M) was added TFA (22 mL) and the reaction was stirred under a blanket of N2 overnight. The reaction was concentrated in vacuo and azeotroped (3x) in DCM / toluene. The residue was diluted with EtOAc, washed 20 with sat. Na2CO3 and brine, dried over Na2SO4 filtered and concentrated. Purification by silica gel chromatography, eluting with 0-100% EtOAc / hexanes provided compound 32-5 as a white solid, (179 mg, 84%). LCMS m / z 478.4 (M+H)+.1H NMR (DMSO-d6) d 8.81-8.80 (d, 1H), 8.55-8.54 (d, 1H), 8.14-8.07 (m, 4H), 7.94-7.92 (d, 1H), 7.81-7.77 (d, 1H), 7.72-7.68 (d, 1H), 7.48-7.33 (m, 6H), 5.44 (s, 2H), 2.43 (s, 3H). 25 N-((2-(5-(((6-(4-fluorobenzoyl)pyridin-3-yl)oxy)methyl)pyridin-2-yl)-4- methylphenyl)sulfonyl)thiophene-2-carboxamide (Example 32)

[0228] Thiophene-2-carboxylic acid (72.6 mg, 0.566 mmol), EDCI.HCl (145 mg, 0.754 mmol) and DMAP (115 mg, 0.942 mmol) was combined in DMA (4.0 ml), and was stirred 30 30 min. The above was added to compound 32-5 (180 mg, 0.377 mmol) in DMA (3.8 ml) and the{H3007867.1}164 4927-5223-2016, v.1reaction was stirred overnight under N2. A second addition of thiophene-2-carboxylic acid (72.6 mg, 0.566 mmol), EDCI.HCl (145 mg, 0.928 mmol) and DMAP (115 mg, 0.942 mmol) was combined in DMA (3.0 ml) and stirred together for 30 minutes prior to adding to the reaction and stirring at rt over a second night. The reaction was now complete and concentrated in vacuo to 5 remove DMA. The residue was purified by silica gel chromatography followed by purification by reverse phase chromatography. Product fractions were combined and lyophilized to obtain Example 32 as a white solid, (109 mg, 49%). LCMS m / z 588.5 (M+H)+.1H NMR (DMSO-d6) d 8.69 (d, 1H), 8..55 (d, 1H), 8.15-8.04 (m, 5H), 7.98-7.92 (m, 2H), 7.81-779 (m 1H), 7.65-7.63(m, 1H), 7.52-7.50 (m, 1H), 7.39-7.34 (m, 2H), 7.31 (m, 1H) 7.17-7.15 (dd, 1H), 5.43 (s, 2H), 10 2.42 (s, 3H).

[0229] Following the methods described above for Example 32 and substituting the appropriate intermediates and reagents, the following compounds were prepared as indicated in 15 Table 21. Table 21 Example MS NMR DATA Structure 3{H3007867.1}165 4927-5223-2016, v.132B1H NMR (DMSO-d6) d 8.63 (m, 588.4 1H), 8..51-8.50 (d, 1H), 8.11-7.97 6 -Example 33{H3007867.1}166 4927-5223-2016, v.12-(5-(((6-((3,5-bis(trifluoromethyl)phenyl)(hydroxy)methyl)pyridin-3- yl)oxy)methyl)pyridin-2-yl)-N-(tert-butyl)-4-methylbenzenesulfonamide (33-1) 5

[0230] Into a predried vial under argon balloon was combined compound 32-2 (500 mg, 1.14 mmol) in anh. THF (4.6 ml, (0.25 M) and the reaction was cooled to 0°C. 3,5-bis(trifluoromethyl)phenyl)magnesium bromide (5.0 ml, 2.51 mmol, 0.5M in THF) was added dropwise at 0°C. Once added, the reaction was stirred two min. and the bath was removed as the reaction continued at rt. At two hours, the reaction was quenched with sat. NH4Cl and 10 extracted with EtOAc (3x). The EtOAc extracts were combined, washed with brine, dried over Na2SO4, filtered and concentrated. Purification was carried out by column chromatography eluting 0-100% EtOAc to provide compound 33-1 as a light brown solid. (678 mg, 90%). LCMS m / z 654.5 (M+H)+.1H NMR (CDCl3) d 8.73-8.72 (d, 1H), 8.41-8.39 (d, 1H), 8.09-8.06 (d, 1H), 7.94-7.91 (dd, 1H), 7.88 (s, 2H), 7.81 (s, 1H), 7.58-7.55 (dd, 1H), 7.38-7.31(m, 2H), 7.27-7.26{H3007867.1}167 4927-5223-2016, v.1(1H obscured by CDCl3), 7.17-7.15 (d, 1H), 7.03 (s, 1H), 5.88-5.85 (d, 1H), 5.19 (s, 2H), 5.02- 5.00 (d, 1H) 2.47 (s, 3H), 1.32 (s, 9H). (l2-azaneyl)(2-(5-(((6-(3,5-bis(trifluoromethyl)benzoyl)pyridin-3-yl)oxy)methyl)pyridin-2- 5 yl)-4-methylphenyl)(tert-butoxy)-l5-sulfanone (33-2)

[0231] To compound 33-1 (675 mg, 1.03 mmol) in CHCl3 (5.20 ml, 0.2M), was added MnO2 (900 mg, 10.3 mmol) at rt. The reaction was stirred over two nights. The reaction was filtered through celite, washed with DCM and concentrated in vacuo. Purification by silica gel chromatography eluting with 0-100% EtOAc / hexanes provided compound 33-2 as a white solid, 10 (629 mg, 94%). LCMS m / z 652.5 (M+H)+.1H NMR (CDCl3) d 8.73-8.71 (d, 1H), 8.64 (s, 1H), (8.52-8.50 (d, 1H), 8.31-8.27 (d, 1H), 8.10-8.07 (m, 2H), 7.98-7.95 (dd, 1H), 7.61-7.58 (d, 1H), 7.54-7.50 (dd, 1H), 7.39-7.35 (m, 1H), 7.29-7.28 (1H obscured by CDCl3), 7.00 (s, 1H), 7.02 (s, 1), 5.31 (s, 2H), 2.48 (s, 3H), 1.33 (s, 9H). 15 2-(5-(((6-(3,5-bis(trifluoromethyl)benzoyl)pyridin-3-yl)oxy)methyl)pyridin-2-yl)-4- methylbenzenesulfonamide (33-3)

[0232] To compound 33-2 (627 mg, 0.96 mmol) in DCM (4.8 ml, 0.2M) was added TFA (48 ml) and the reaction was stirred under a blanket of N2 overnight. The reaction was warmed to 40°C after 17 hours at rt for two hours. The reaction was concentrated in vacuo and azeotroped 20 (3x) in DCM / toluene. The residue was diluted with EtOAc, washed with sat. Na2CO3 and brine, dried over Na2SO4 filtered and concentrated. Purification by silica gel chromatography, eluting with 0-100% EtOAc / hexanes provided compound 33-3 as a white solid, (539 mg, 94%). LCMS m / z 596.4 (M+H)+.1H NMR (DMSO-d6) d 8.81-8.79 (d, 1H), 8.60-8.58 (m, 3H), 8.41 (s, 1H), 8.28-8.25 (d, 1H), 8.10-8.06 (dd, 1H), 7.95-7.91 (d, 1H), 7.85-7.81 (dd, 1H), 7.71-7.68 (d, 1H), 25 7.48-7.40(m, 4H), 5.48 (s, 2H), 2.43 (s, 3H). N-((2-(5-(((6-(3,5-bis(trifluoromethyl)benzoyl)pyridin-3-yl)oxy)methyl)pyridin-2-yl)-4- methylphenyl)sulfonyl)furan-2-carboxamide (33-4)

[0233] 2-Furoic acid (80.2 mg, 0.72 mmol), EDCI.HCl (183 mg, 0.95 mmol) and DMAP 30 (146 mg, 1.2 mmol) was combined in DMA (6.0 ml), and was stirred 30 min. under N2. The{H3007867.1}168 4927-5223-2016, v.1above was added to compound 33-3 (284 mg, 0.48 mmol) in DMA (4.6 ml) and the reaction was stirred overnight under N2. A second addition of 2-Furoic acid (80.2 mg, 0.72 mmol), EDCI.HCl (183 mg, 0.95 mmol) and DMAP (148 mg, 1.2 mmol) was combined in DMA (6.0 ml) and stirred together for 30 minutes prior to adding to the reaction and stirring at rt over 3 5 days. The reaction was now complete and concentrated in vacuo to remove DMA. The residue was purified by silica gel chromatography followed by purification mass directed HPLC by a non-polar run. Product fractions were combined and lyophilized to obtain compound 33-4 as a white solid, (187 mg, 57%). LCMS m / z 690.5 (M+H)+.1H NMR (DMSO-d6) d 12.6-11.8 (bs,,1H), 8.71-7.70 (d, 1H), 8..61-8.58 (m, 3H), 8.42 (s, 1H), 8.29-8.26 (d, 1H), 10 8.08-8.03 (m, 2H), 7.96-7.94 (m, 1H), 7.86-7.82 (dd, 1H), 7.67-7.63 (d, 1H), 7.53-7.45 (m, 2H), 7.33-7.31 (d, 1H), 6.66-6.34 (dd, 1H), 5.46 (s, 2H), 2.42 (s, 3H). N-((2-(5-(((6-((3,5-bis(trifluoromethyl)phenyl)(hydroxy)methyl)pyridin-3- yl)oxy)methyl)pyridin-2-yl)-4-methylphenyl)sulfonyl)furan-2-carboxamide (Example 33) 15

[0234] To 33-4 (80.0 mg, 0.12mmol) in anh. THF (0.6 ml) was added NaBH4(8.78 mg, 0.23 mmol), and EtOH (0.6ml) at 0°C, The clear solution was stirred at rt for 2 hours. The reaction was cooled to 0°C and quenched with sat. NH4Cl. The reaction was concentrated in vacuo, then partitioned between EtOAc and sat. NH4Cl, then brine. The residue was combined with a second reaction prepared as above and purified by silica gel chromatography followed by mass directed 20 HPLC, non-polar gradient. Product fractions were collected and lyophilized to provide Example 33 as a white solid (37.0 mg, 46%) for the combined reactions. LCMS m / z 692.5 (M+H)+.1H NMR (DMSO-d6) d 12.5-11.8 (bs,,1H), 8.78-8.56 (m, 1H), 8..31-8.28 (m, 1H), 8.02-7.85 (m, 6H), 7.67-7.35 (m, 5H), 7.24-7.08 (m, 1H), 6.58-6.55 (m, 1H), 6.47-6.42 (bs, 1H), 5.90 (s, 1H), 5.30-5.19 (m, 1H), 2.36-2.33 (m, 3H). 25 Example 34{H3007867.1}169 4927-5223-2016, v.1N-(tert-butyl)-2-(5-(((6-((1,3-dioxoisoindolin-2-yl)methyl)pyridin-3-yl)oxy)methyl)pyridin- 2-yl)-4-methylbenzenesulfonamide (34-1) 5

[0235] To a mixture of compound 32-1 (1.00g, 2.30 mmol), isoindoline-1,3-dione (0.40 g, 2.80 mmol), and triphenylphosphine (1.20 g, 4.60 mmol), in anh. THF (100 ml) at 0°C, was added DIAD (0.90 ml, 4.60 mmol) dropwise. The reaction was stirred overnight. A second addition of triphenylphosphine (0.60g) and DIAD (0.45ml) was added and the reaction continued over a second night. The reaction was concentrated in vacuo and purified by silica gel 10 chromatography eluting 0-100% EtOAc to provide compound 34-1 (0.67g, 51%). LCMS: (M+H)+ 571.31H NMR (CDCl3) d 8.65-8.63 (d, 1H), 8.33-8.31 (d, 1H), 8.08-8.05 (d, 1H), 7.91-7.88 (m , 3H), 7.76-7.73 (m, 2H), 7.55-7.52 (d, 1H), 7.37-7.33 (m, 1H), 7.30-7.25 (m, 3H obscured by CDCl3), 7.06 (bs, 1H), 5.14 (s, 2H), 4.99 (s, 2H), 2.46 (s, 3H), 1.31 (s, 9H).{H3007867.1}170 4927-5223-2016, v.12-(5-(((6-(aminomethyl)pyridin-3-yl)oxy)methyl)pyridin-2-yl)-N-(tert-butyl)-4- methylbenzenesulfonamide (34-2)

[0236] To 34-1 (593 mg, 1.04 mmol) in MeOH (21 ml) was added hydrazine.H2O (0.25 ml) 5 dropwise. The reaction was stirred overnight, then concentrated in vacuo. The residue was redissolved in DCM with a small amount of MeOH. A white solid that did not enter solution was filtered. The remaining solution was purified by dry loading on celite in MeOH and eluting 0-100% EtOAc / hexanes followed by 0-20% MeOH / DCM. Product fractions were collected and concentrated to provide compound 34-2 (343.1 mg, 75%). LCMS: (M+H)+ 441.3.1H NMR 10 (CD3OD) 8.73-8.71 (d, 1H), 8.36-8.33 (d, 1H), 8.06-7.99 (m, 2H), 7.69-7.65 (d , 1H), 7.57-7.53 (dd, 1H), 7.47-7.38 (m, 3H), 5.31(s, 2H), 3.93 (s, 2H), 2.49 (s, 3H), 1.23(s, 9H). N-((5-((6-(2-(N-(tert-butyl)sulfamoyl)-5-methylphenyl)pyridin-3-yl)methoxy)pyridin-2- yl)methyl)-3-(trifluoromethyl)benzamide (34-3) 15

[0237] To 3-(trifluoromethyl)benzoic acid (43.2 mg, 0.227 mmol) in DMF (1.3 ml, 0.1M) was added HATU (112 mg, 0.295 mmol) and DIEA (103 mg, 0.795 mmol). The reaction was stirred 15 minutes, A slurry of 34-2, (100 mg, 0.227 mmol) was added in DMF (1.0 ml) and the reaction was stirred 3 hours 15 min. The reaction was partitioned between EtOAc / sat. NH4Cl, H2O and brine, dried over Na2SO4, filtered and concentrated. The residue was purified by silica 20 gel chromatography eluting 0-100% EtOAc / hexanes to provide compound 34-3 (114.5 mg, 82%) as a white solid. LCMS: (M+H)+ 613.41H NMR (CDCl3) d 8.69-8.67 (d, 1H), 8.38-8.36 (m, 1H), 8.15 (s, 1H), 8.09-8.04 (m , 2H), 7.95-7.91 (dd, 1H), 7.81-7.77 (d, 1H), 7.64-7.51 (m, 3H), 7.38-7.32 (m, 3H), 7.07-7.04 (s, 1H), 5.31(s, 2H), 4.77-4.73 (d, 2H), 2.82 (s, 1H), 2.47 (s, 3H), 1.32 (s, 9H). 25 N-((5-((6-(5-methyl-2-sulfamoylphenyl)pyridin-3-yl)methoxy)pyridin-2-yl)methyl)-3- (trifluoromethyl)benzamide (34-4)

[0238] To 34-3 (111.6 mg, 0.182 mmol) in DCM (0.9 ml) was added TFA (6.3 ml) and the reaction was stirred 72 hours. The reaction was concentrated in vacuo and azeotroped with 30 toluene in DCM (3x). Purification by silica gel chromatography, dry loaded in DCM / MeOH on{H3007867.1}171 4927-5223-2016, v.1celite and eluting 0-20% MeOH / DCM provided compound 34-4 (82.2 mg, 81%) as a white solid. LCMS: (M+H)+ 557.31H NMR (DMSO-d6) d 9.38-9.34 (t, 1H), 8.77-8.75 (d, 1H), 8.36-8.35 (d, 1H), 826 (s, 1H), 8.23-8.19 (d , 1H), 8.05-8.01 (dd, 1H), 7.94-7.7.90 (d, 2H), 7.76-7.71 (t, 1H), 7.68-7.65 (d, 1H), 7.54-7.50 (dd, 1H), 7.47-7.40 (m, 4H), 7.36-7.32 (d, 1H), 5.29 (s, 2H), 5 4.56-4.54 (d, 2H), 2.42 (s, 3H). N-((4-methyl-2-(5-(((6-((3-(trifluoromethyl)benzamido)methyl)pyridin-3- yl)oxy)methyl)pyridin-2-yl)phenyl)sulfonyl)thiophene-2-carboxamide (Example 34)

[0239] Under N2, combined thiophene-2-carboxylic acid (27.6 mg, 0.215 mmol), EDAC.HCl 10 (54.8 mg, 0.286 mmol), and DMAP (43.7 mg, 0.358 mmol) in DMF (2.5 ml) and the reaction was stirred for 15 min. and added to a solution of 34-4 (79.5 mg, 0.143 mmol) in of DMF (0.5 ml). The transfer vessel was washed with DMF (0.5 ml) and the reaction was stirred under N2overnight. Carried out a second addition of thiophene-2-carboxylic acid (27.6 mg, 0.215 mmol), EDAC.HCl, (54.8 mg, 0.286 mmol), DMAP (43.7 mg, 0.358 mmol) and added HOAT 15 (29.3 mg, 0.22 mmol), in DMF (0.5 ml) as above and continued over three additional nights. The reaction was partitioned between EtOAc and sat. NH4Cl and washed with sat. H2O (3x), Na2CO3, and brine, dried over Na2SO4, filtered and concentrated. The residue was dry loaded on celite in MeOH and purified by column chromatography eluting with 0-20% MeOH / DCM. The product fractions were combined to provide Example 34 (57.9 mg, 61 % yield) as a white solid. 20 LCMS: (M+H)+ 667.21H NMR (DMSO-d6) d 9.38-9.34 (t, 1H), 8.65-8.62 (d, 1H), 8.37-8.35 (d, 1H), 8.27-8.19 (m, 2H), 8.06-8.02 (d, 1H), 7.98-7.65 (m , 6H), 7.54-7.50 (dd, 1H), 7.48-7.43 (m, 1H), 7.37-7.33 (d, 1H), 7.28 (s, 1H), 7.14-7.10 (t, 1H), 5.27 (s, 2H), 4.55-4.52 (d, 2H), 2.40 (s, 3H). 25

[0240] Following the methods described above for Example 34 and substituting the appropriate intermediates and reagents, the following compounds were prepared as indicated in Table 22. 30 Table 22{H3007867.1}172 4927-5223-2016, v.1Example MS NMR DATA Structure (M+H)+, -{H3007867.1}173 4927-5223-2016, v.134E1H NMR (DMSO-d6) d 9.13-9.10 633.4 (t, 1H), 8.59-8.58 (m, 1H), 8.30- 8 8Example 35{H3007867.1}174 4927-5223-2016, v.1tert-butyl 4-((5-chloropyrazin-2-yl)methoxy)piperidine-1-carboxylate (35-1) 5 Generate alkoxide using NaH (1.85 g, 46.0 mmol), first at 0°C, then rt, then 50°C. Cooled the reaction in an ice bath and added 2-chloro-5-(iodomethyl)pyrazine (14.2 g, 56.0 mmol). The reaction was allowed to warm to rt overnight. The reaction was partitioned between EtOAc / H2O, brine washed, dried and purified by silica gel chromatography eluting 0-35% EtOAc / DCM to obtain compound 35-1 (9.0 g, 63%). LCMS m / z 228.2 (M-Boc)+. 10 tert-butyl 4-((5-(2-(N-(tert-butyl)sulfamoyl)-5-methylphenyl)pyrazin-2- yl)methoxy)piperidine-1-carboxylate (35-2){H3007867.1}175 4927-5223-2016, v.1Under standard Suzuki conditions, reacted Intermediate 1 (5.50 g, 20.3 mmol), 35-1 (5.53 g, 16.9 mmol). Pd(PPh3)4 (1.30 g, 0.15 mmol), and Na2CO3 (5.40 g, 51.0 mmol) in dioxane and H2O at 85°C. The reaction was purified by silica gel chromatography, 0-100% EtOAc / hexanes, to provide 35-2 (8.70 g, 99%) as an off-white foam.1H NMR (CDCl3) d 8.69 (s, 2H), 8.11-8.08 5 (d, 1H), 7.41-7.38 (dd, 1H), 7.29-7.27 (m, 1H), 6.49-6.48 (bs, 1H), 4.78 (s, 2), 3.87-3.66 (m, 3H), 3.21-3.13 (m, 2H), 2.49, (s, 3H), 1.99-1.90 (m, 2H), 1.72-1.62 (m, 2H), 1.47 (s, 9H), 1.30 (s, 9H). N-(tert-butyl)-4-methyl-2-(5-((piperidin-4-yloxy)methyl)pyrazin-2-yl)benzenesulfonamide 10 (35-3) Following the Rapaport procedure, combined 35-2 (7.70 g.14.0 mmol), and 1N HCl (75.0 ml, 74.0 mmol) in EtOAc. The reaction was purified by column chromatography eluting 0-20% MeOH / DCM / 1%NH4OH to give 35-3. LCMS m / z 419.5 (M+H)+. 15 N-(tert-butyl)-2-(5-(((1-(2-fluoro-4-(trifluoromethyl)phenyl)piperidin-4- yl)oxy)methyl)pyrazin-2-yl)-4-methylbenzenesulfonamide (35-4) Employing standard Buchwald conditions, combined 35-3 (1.15 g, 2.74 mmol), 2-fluoro-1-iodo- 4-(trifluoromethyl)benzene (870 mg, 3.00 mmol), BINAP (374 mg, 0.60 mmol), Pd2(dba)3 (275 mg, 0.30 mmol) and NaOtBu (870 mg, 9.0 mmol) in 1,4 dioxane and degassed. The reaction was 20 heated to 90°C for 15 hours. The reaction was cooled, then filtered through celite and concentrated in vacuo. Purification by silica gel chromatography in 0-40% EtOAC / DCM provided 35-4 (990 mg, 62%). 2-(5-(((1-(2-fluoro-4-(trifluoromethyl)phenyl)piperidin-4-yl)oxy)methyl)pyrazin-2-yl)-4- 25 methylbenzenesulfonamide (35-5) Combined 35-4 (970 mg, 1.67 mmol) in DCM (2.0 ml) and TFA (10.0 ml) and the reaction was stirred for three days. The reaction was azeotroped with toluene (2 x 50 ml) and the residue was purified by column chromatography 0-50% EtOAc / DCM to provide 35-5 (630 mg, 72%). LCMS m / z 525.5 (M+H)+. 30{H3007867.1}176 4927-5223-2016, v.1N-((2-(5-(((1-(2-fluoro-4-(trifluoromethyl)phenyl)piperidin-4-yl)oxy)methyl)pyrazin-2-yl)- 4-methylphenyl)sulfonyl)thiophene-2-carboxamide (Example 35) Combined 35-5 (315 mg, 0.60 mmol), thiophene-2-carboxylic acid (115 mg, 0.90 mmol), EDCI.HCl (230 mg, 1.20 mmol) and DMAP (183 mg, 1.50 mmol) in DMA and the reaction was 5 stirred at rt for 24 hours. A second addition of reagents, thiophene-2-carboxylic acid (115 mg, 0.90 mmol), EDCI.HCl (230 mg, 1.20 mmol) and DMAP (183 mg, 1.50 mmol), was added and the reaction was continued for 3 days at rt. The DMA was evaporated under high vacuum partitioned between DCM / H2O, washed with NaHCO3, brine washed and dried over Na2SO4. The concentrated residue was purified by silica gel chromatography eluted in 0-5% 10 MeOH / DCM, then triturated in Et2O hexanes (1:1). After concentrating in vacuo from CHCl3, the residue was triturated from CHCl3 / hexanes to provide Example 35 (340 mg, 89%) as a white solid. LCMS m / z 635.5 (M+H)+.1H NMR (CDCl3) d 10.1 (bs, 1H), 8.82-7.74 (m, 2H), 8.39- 8.35 (d, 1H), 7.72-7.70 (dd, 1H), 7.62-7.60 (dd, 1H), 7.51-7.48 (dd, 1H), 7.34-7.30 (m, 3H partially obscured by CDCl3), 7.14-7.11 (dd, 1H), 7.04-6.99 (t, 1H), 4.85 (s, 2H), 3.81-3.74 (m, 15 1H), 3.52-3.46 (m, 2H), 3.05-2.98 (m, 2H), 2.50 (s, 3H), 2.21-2.13 (m, 2H), 2.00-1.90 (m, 2H). Following the methods described above for Example 35 and substituting the appropriate intermediates and reagents, the following compounds were prepared as indicated in Table 23. 20 Table 23 1H NMR - 4177 4927-5223-2016, v.11Structur H NMR Example e LCMS - 6 - , , 0 6 -178 4927-5223-2016, v.11Structure LCMS H NMR Example 9 - 7 2Example 36{H3007867.1}179 4927-5223-2016, v.1tert-butyl 3-((4-bromobenzyl)oxy)azetidine-1-carboxylate (36-1) Sodium hydride (1.39 g, 34.6 mmol) was suspended in dry DMF (130ml) and cooled in an ice 5 bath. The above tert-butyl 3-hydroxyazetidine-1-carboxylate (5.00 g, 28.9 mmol) was dissolved in 10 ml of dry DMF and added dropwise. The mixture was stirred at 0oC for 15 min the warmed to RT for 15 min than warmed to 50oC for 30 min. The resulting off-white suspension was cooled in an ice bath and a solution of 3-bromobenzyl bromide (7.94 g, 31.8 mmol) in 10 ml of DMF was added dropwise. The ice-bath was removed and the mixture was warmed to RT and 10 then stirred at RT overnight during which time it became a slightly cloudy solution. DMF was{H3007867.1}180 4927-5223-2016, v.1removed in vacuo and the light-tan oil was partitioned between NH4Cl sol and EtOAc. After the organic layer was washed with brine and dried (Na2SO4) it was concentrated to provide a light tan oil. The crude product was purified on a 220 g ISCO column eluting with 10-30% EtOAc / hexane. The product was isolated as a colorless oil to provide 36-1 (9.6 g, 97%).1H NMR 5 (CDCl3) d 7.50-7.46 (m, 2H), 7.22-7.18 (m 2H), 4.39 (s, 2H), 4.32-4.26 (m, 1H), 4.08-4.03 (m, 2H), 3.87-3.83 (m, 2H), 1.43 (s, 9H), tert-butyl 3-((2'-(N-(tert-butyl)sulfamoyl)-5'-methyl-[1,1'-biphenyl]-4- yl)methoxy)azetidine-1-carboxylate (36-2) 10 36-1 (9.00 g, 26.3 mmol) and (2-(N-(tert-butyl)sulfamoyl)-5-methylphenyl)boronic acid (8.56 g, 31.6 mmol), Na2CO3 (8.36g, 78.9 mmol) and Pd(PPh3)4 (4.56 g, 3.95 g), were combined in a 500 mL glass pressure vessel and stirred in solvent comprised of 80% 1,4-dioxane and 20% water. The mixture was "degassed" by bubbling a stream of N2for 20 min. The vessel was sealed and then heated to 105oC for 48 h. After cooling to RT the mix was filtered through celite which was 15 then washed with more 1,4-dioxane. The filtrate was concentrated in vacuo and the residual orange oil was partitioned between DCM and Na2CO3. The organic layer was washed with brine, dried (Na2SO4) and concentrated to an orange oil. The crude product was purified by silica gel chromatography using a 220 g ISCO column and eluting with 0 to 3% MeOH in DCM. The impure product eluted as several peaks over the entire gradient. The material was then re- 20 chromatographed using 10 to 25% EtOAc in hexanes. Trituration with hexanes provided 36-2 (9.0 g, 70%) as a cream-colored solid. LCMS m / z 489.5 (M+H)+.1H NMR (CDCl3) d 8.06-8.02 (d, 1H), 7.52-7.38 (m, 4H), 7.29-7.26 (m 1H obscured by CDCl3), 7.10-7.08 (d, 1H), 4.50 (s, 2H), 4.39-4.31 (m, 1H), 4.12-4.06 (m, 2H), 3.92-3.88 (m, 2H), 3.51 (s, 1H)), 1.45 (s, 9H), 1.01 (s, 9H). 25 3-((2'-(N-(tert-butyl)sulfamoyl)-5'-methyl-[1,1'-biphenyl]-4-yl)methoxy)azetidin-1-ium (36-3) 36-2 (3.5 g, 7.16 mmol) was dissolved in 30 ml of dry 1,4-dioxane with stirring.4N HCl in dioxane (5.4 ml, 21.5 mmol) was added and stirring was continued at RT for 15 h. LC / MS 30 indicated about 15% of SM remaining so an additional 2 ml of 4N HCl in dioxane was added and{H3007867.1}181 4927-5223-2016, v.1stirring was continued at RT for 5h. The hydrochloride salt precipitates from the reaction mixture as a white solid that is collected by filtration to provide 36-3 (2.6 g, 85% yield). LCMS m / z 425.4 (M+H)+, 389.4 (M+H)+free base.5 N-(tert-butyl)-5-methyl-4'-(((1-(4-(trifluoromethyl)phenyl)azetidin-3-yl)oxy)methyl)-[1,1'- biphenyl]-2-sulfonamide (36-4) 36-3 (1.20 g, 3.09 mmol) was dissolved in toluene (57.7 ml) with sonication. The above iodobenzene (0.90 g, 3.30 mmol) was added followed by sodium-t-butoxide (0.95 g, 9.90 mmol), BINAP (0.41 g, 0.66 ml), and Pd2(dba)3 (0.30 g, 0.33 mmol), the solution was degassed for 20 10 min with a stream on N2and then the reaction mixture was placed under an Ar atmosphere. The dark purple mixture was heated to 90oC for 48 h. Heating was removed and the mixture was stirred for another 14 hours at RT. The dark suspension was filtered through a plug of celite which was washed with additional toluene. The organic solvent was concentrated in vacuo and the brown oily residue was purified using a 120 g silica ISCO column eluting with 0-35% 15 gradient of EtOAc / hexanes. The desired product was isolated, then triturated with 10%EtOAc - 90% hexanes. Filtration provided 36-4 as a cream colored solid (910 mg, 55% yield) 1H NMR (CDCl3) d 8.06-8.03 (d, 1H), 7.53-7.41 (m, 6H), 7.30-7.25 (m 1H obscured by CDCl3), 7.11-7.09 (m, 1H), 6.48-6.44 (d, 2H), 4.62-4.55 (m, 3H), 4.21-4.15 (m, 2H), 3.88-3.82 (m, 2H), 3.51 (s, 1H), 2.43 (s, 3H), 1.01 (S, 9H). 20 5-methyl-4'-(((1-(4-(trifluoromethyl)phenyl)azetidin-3-yl)oxy)methyl)-[1,1'-biphenyl]-2- sulfonamide (36-5) 36-4 was suspended in DCM (1.0 ml) and TFA (5 ml) was added. The solids immediately dissolved to give a light reddish-brown clear solution that was stirred at RT for 72 h. The 25 volatiles were concentrated in vacuo and the residual oil was azeotroped from 30 ml toluene (2x). After evaporation the residue was dissolved in 125 ml of EtOAc and washed with sat'd NaHCO3. The organic layer was dried (Na+SO4) and then evaporated. The crude material was purified using a 24 g GOLD ISCO column eluting with 0 to 25% EtOAc / DCM to provide 36-5. LCMS m / z 477.4 (M+H)+30{H3007867.1}182 4927-5223-2016, v.1N-((5-methyl-4'-(((1-(4-(trifluoromethyl)phenyl)azetidin-3-yl)oxy)methyl)-[1,1'-biphenyl]-2- yl)sulfonyl)thiophene-2-carboxamide (Example 36) 36-5 (500 mg, 1.05 mmol) was combined with thiophene-2-carboxylic acid (40.7 mg, 0.32 mmol) in DMA (5 ml) and treated with EDCI (65.7 mg, 0.42 mmol) and DMAP (64.6 mg, 0.53 5 mmol). After stirring at RT for 24 h a second portion of carboxylate and reagents were added. Stirring was then continued for an additional 48 h. The reaction mixture was concentrated in vacuo and then concentrated 2 x from 50 ml toluene. The clear oil that resulted was purified by silica gel chromatography to provide Example 36 (49.5 mg, 8.0% yield) as a white solid. LCMS m / z 587.3 (M+H)+ . 1H NMR (CDCl3) d 8.26-8.23 (d, 1H), 7.88 (s, 1H), 7.59-7.57 (dd 1H), 10 7.47-7.42 (d, 2H), 7.39-7.36 (dd, 1H), 7.25-7.19 (m, 5H), 7.08-7.05 (m, 1H), 7.03-6.99 (dd, 1H), 6.48-6.44 (d, 2H), 4.61-4.51 (m, 3H), 4.22-4.16 (m, 2H), 3.87-3.82 (m, 2H), 2.43 (s, 3H). Following the methods described above for Example 36 and substituting the appropriate intermediates and reagents, the following compounds were prepared as indicated in Table 24. 15 Table 24 1H NMR 0 , 8 ), , ,183 4927-5223-2016, v.11Example Structure LCMS H NMR , ), ,Example 37{H3007867.1}184 4927-5223-2016, v.1tert-butyl 3-((6-chloropyridin-3-yl)methoxy)-3-methylazetidine-1-carboxylate (37-1) To a solution of tert-butyl 3-hydroxy-3-methylazetidine-1-carboxylate (5.00 g, 26.7 mmol) in 5 DCM (50 ml) was added a catalytic amount of tetrabutylammonium bromide (1.03 g, 3.20 mmol), followed by a solution of 4N NaOH. The biphasic mixture was stirred at a high rate (1000 rpm) and the mixture was heated to 37oC for 72 h, then cooled to RT. The layers were partitioned in a separatory funnel, the DCM layer was washed with water and brine, then dried over Na2SO4. The solvent was removed in vacuo and the crude product was purified using a 120 10 g gold ISCO column eluting with 5-40% EtOAc in DCM. The column was held at 5% EtOAc / DCM for 30 min - until all of the bibenzyl ether bi-product had eluted. The gradient was then ramped to 40% EtOAc / DCM to obtain 37-1 (2.4 g, 29%) as a colorless oil. LCMS m / z 257.2 (M-56)+.1H NMR (CDCl3) d 8.36-8.34 (m, 1H), 7.68-7.65 (dd, 1H), 7.34-7.31 (d, 1H), 4.44 (s, 2H), 4.00-3.96 (d, 2H), 3.77-3.74 (d, 2H), 1.58 (s, 3H), 1.45, (s, 9H). 15 tert-butyl 3-((6-(2-(N-(tert-butyl)sulfamoyl)-5-methylphenyl)pyridin-3-yl)methoxy)-3- methylazetidine-1-carboxylate (37-2){H3007867.1}185 4927-5223-2016, v.1Intermediate 1 (1.73 g, 6.39 mmol) was dissolved with stirring in 1,4-dioxane (50 ml). Sodium carbonate (2.24 g, 21.1 mmol) was added followed by 10 ml of water. The suspension was stirred for 30 min while a stream of N2 was bubbled through. Pd(PPh3)4 (0.74 g, 0.64 mmol) was added and degassing with N2was continued for 20 min. The mixture was placed under a N25 atmosphere and heated to 100oC overnight. The reaction was cooled to RT and was stirred for an additional 72 h. The supernatent was decanted from the solids and concentrated in vacuo to give an orange oil. The oil was dissolved in 100 ml of EtOAc which resulted in precipitation of desired product as a white solid that was collected by filtration. The EtOAc solution was then concentrated directly onto celite and purified by silica gel chromatography. The column was 10 eluted with 15-75% EtOAc / hexanes. The product eluted at 45% EtOAc / hex. The product fractions were collected and combined with the filtered product above to provide 37-2 as a white solid, (1.9 g, 50% yield). LCMS m / z 504.5 (M+H)+.1H NMR (CDCl3) d 8.56-8.54 (m, 1H), 8.07-8.04 (d, 1H), 7.84-7.80 (dd, 1H), 7.51-7.48 (d, 1H), 7.35-7.31 (dd, 1H), 7.24 (s, 1H), 7.19 (s, 1H), 4.51 (s, 2H), 4.04-4.00 (d, 2H), 3.80-3.76 (d, 2H), 2.45 (s, 3H), 1.60, (s, 3H), 1.46 (s, 15 9H), 1.31 (s, 9H). N-(tert-butyl)-4-methyl-2-(5-(((3-methylazetidin-3-yl)oxy)methyl)pyridin-2- yl)benzenesulfonamide (37-3) The 37-2 (1.8 g, 3.57 mmol) was dissolved in anhydrous 1,4-dioxane (10 ml) with stirring.4N 20 HCl in dioxane (5 ml) was added and stirring was continued at RT for 15 h. LC / MS indicated about 15% of SM remaining so an additional 2 ml of 4N HCl in dioxane was added and stirring was continued at RT for an additional 5h. The hydrochloride salt accumulates as a gum on the bottom and sides of the flask - the supernatent was decanted and the gum partitioned between 1N NaOH and DCM. The DCM layer was washed with brine, dried over Na2SO4and concentrated25 to a yellowish oil. The crude product was purified by silica gel chromatography eluting with 0- 20% MeOH / DCM + 1% NH4OH. Two peaks were isolated; the first eluted at 10% and the second at 12%. The product eluted at 12% MeOH / DCM / 1% NH4OH and isolated as a white foam 37-3 (1g, 69 % yield). LCMS m / z 404.5 (M+H)+.1H NMR (CDCl3) d 8.57-8.55 (m, 1H), 8.07-8.04 (d, 1H), 7.85-7.82 (dd, 1H), 7.50-7.47 (d, 1H), . . , , . 5-7.23 (bs, 2H),{H3007867.1}186 4927-5223-2016, v.14.45 (s, 2H), 3.83-3.80 (d, 2H), 3.42-3.39 (dd, 2H), 2.45 (s, 3H), 1.71, (s, 1H), 1.63 (s, 3H), 1.31 (s, 9H). N-(tert-butyl)-4-methyl-2-(5-(((3-methyl-1-(5-(trifluoromethyl)pyridin-2-yl)azetidin-3- 5 yl)oxy)methyl)pyridin-2-yl)benzenesulfonamide (37-4) Combined 37-3 (450 mg, 1.12 mmol), 2-chloro-5-trifluoromethylpyridine (223 mg, 1.23 mmol), and K2CO3 (462 mg, 3.35 mmol) in DMF (5 ml) and heated the reaction at 100oC for 10 h. The reaction was cooled to RT and filtered to remove the solid K2CO3, then in vacuo to remove most of the DMF. The residual oil was purified by column chromatography to provide 37-4 (555 mg, 10 91 % yield) as a white foam. LCMS m / z 549.4 (M+H)+.1H NMR (CDCl3) d 8.57-8.55 (m, 1H), 8.41-8.38 (d, 1H), 8.07-8.03 (d, 1H), 7.85-7.81 (dd, 1H), 7.65-7.61 (dd, 1H), 7.50-7.47 (d, 1H), 7.35-7.31 (dd, 1H), 7.24 (s, 1H), 7.17, (s, 1H), 6.36-6.32 (d, 1H), 4.59 (s, 2H), 4.18-4.14 (d, 2H), 4.01-3.96 (d, 2H), 2.45 (s, 3H), 1.71, (s, 3H), 1.30 (s, 9H). 15 4-methyl-2-(5-(((3-methyl-1-(5-(trifluoromethyl)pyridin-2-yl)azetidin-3- yl)oxy)methyl)pyridin-2-yl)benzenesulfonamide (37-5) 37-4 (525 mg, 0.96 mmol) was suspended in DCM (2 ml) and TFA (8 ml) was added. The solids immediately dissolved to give a clear solution that was stirred at RT for 72 h. The volatiles were concentrated in vacuo and the residual oil was azeotroped from toluene (30 ml x 2). The residue 20 was dissolved in EtOAc (125 ml) and washed with sat'd NaHCO3. The organic layer was washed with brine, dried over Na2SO4 and concentrated. The crude material was evaporated onto celite and purified by silica gel chromatography eluting 0-50% EtOAc / DCM. The product was obtained as a white foam 37-5 (390 mg, 83%). LCMS m / z 493.3 (M+H)+.1H NMR (CDCl3) d 8.60-8.58 (m, 1H), 8.40-8.38 (m, 1H), 8.09-8.06 (d, 1H), 7.88-7.84 (dd, 1H), 7.65-7.61 (dd, 1H),25 7.53-7.49 (d, 1H), 7.38-7.34 (m, 1H), 7.29-7.28 (m, 1H), 6.38-6.32 (m, 3H), 4.60 (s, 2H), 4.17- 4.14 (d, 2H), 4.00-3.96 (d, 2H), 2.47 (s, 3H), 1.71, (s, 3H). N-((4-methyl-2-(5-(((3-methyl-1-(5-(trifluoromethyl)pyridin-2-yl)azetidin-3- yl)oxy)methyl)pyridin-2-yl)phenyl)sulfonyl)thiophene-2-carboxamide (Example 37){H3007867.1}187 4927-5223-2016, v.137-5 (200 mg, 0.41 mmol) was combined with 2-thiophene carboxylic acid (78.1 mg, 0.61 mmol) in DMA (6 ml) and treated with EDCI (126 mg, 0.81 mmol) and DMAP (124 mg, 1.02 mmol). After stirring at RT for 24 h a second portion of carboxylate and reagents were added. Stirring was then continued for an additional 48 h. The reaction mixture was concentrated in 5 vacuo. The off-white solid that resulted was dissolved in CHCl3 and purified using by silica gel chromatography. The product fractions eluted at 6.7 % MeOH in DCM and were collected and concentrated. The colorless oil was repurified via mass directed HPLC under standard conditions. ACN and water were concentrated via rotovap and the residual oil was concentrated from ACN (2 x 50 ml). The obtained white solid was then concentrated from CHCl3 (2 x 50 ml) 10 to provide a crystalline solid that was triturated with hexanes and filtered to give Example 37 (85 mg, 35% yield) as a white crystalline solid. LCMS m / z 603.4 (M+H)+.1H NMR (CDCl3) d 8.66-8.64 (m, 1H), 8.41-.8.39 (m, 1H), 8.30-8.26 (d, 1H), 7.96-7.92 (dd, 1H), 7.75-7.73 (dd, 1H), 7.65-7.62 (dd, 1H), 7.60-7.56 (m, 2H), 7.44-7.40 (m, 1H), 7.28-7.27 (m, 1H), 7.11-7.07 (m, 1H), 6.36-6.33 (d, 1H), 4.65 (s, 2H), 4.19-4.16 (d, 2H), 4.02-3.98 (d, 2H), 2.46 (s, 3H), 1.73, (s, 3H). 15 Following the methods described above for Example 37 and substituting the appropriate intermediates and reagents, the following compounds were prepared as indicated in Table 25. Table 25 20{H3007867.1}188 4927-5223-2016, v.11H NMR (CDCl3) d 12.5-11.7 (bs, 1H), 8.66-8.63 (m, 1H), 602.4 0 600.3 ), 2 602.3 8 616.3{H3007867.1}189 4927-5223-2016, v.11H NMR (CDCl3) d 12.2-10.7 (bs, 1H), 8.67-8.65 (m, 1H), , ,{H3007867.1}190 4927-5223-2016, v.11H NMR (DMSO-d6) d 12.5- 12.0 (bs, 1H), 8.11-7.98 (m, ).{H3007867.1}191 4927-5223-2016, v.11H NMR (DMSO-d6) d 12.2- 11.8 (bs, 1H), 8.66 (s, 1H), , ). ,{H3007867.1}192 4927-5223-2016, v.11H NMR (DMSO-d6) d 8.53 (bs, 1H), 8.04-7.99 (d, 1H), - ). - - - - - ).{H3007867.1}193 4927-5223-2016, v.1Example 385 2-(1-(4-(trifluoromethyl)phenyl)piperidin-4-yl)isoindoline-1,3-dione (38-1) 1-(4-(trifluoromethyl)phenyl)piperidin-4-ol (5.00 g, 20.4 mmol) was dissolved in THF (200 ml), phthalimide (3.90 g, 26.5 mmol), triphenylphosphine (6.95 g, 26.5 mmol), and diisopropyl azodicarboxylate (5.25 ml, 26.5 mmol)) were added, and the mixture was stirred at room{H3007867.1}194 4927-5223-2016, v.1temperature for 24 hours. The solvent was concentrated under reduced pressure, and an aqueous saturated sodium bicarbonate solution, and water were added to the resultant residue, followed by extraction with chloroform. The organic layer was washed with brine then dried with anhydrous sodium sulfate, the solvent concentrated in vacuo, and the resulting residue was 5 purified on a 120 g silver Isco column eluting with isocratic DCM. Three peaks were observed to rapidly elute - the third peak (just following the yellow fractions) eluted from 4 to 7.5 min. The fractions were concentrated in vacuo to give a yellowish solid that was triturated with hexanes and filtered to provide the desired product 38-1 (1.1 g, 14% yield) as a white granular solid. LCMS m / z 375.3 (M+H)+.1H NMR (CDCl3) d 7.87-7.81 (m, 2H), 7.75-7.70 (m, 2H), 7.51-7.46 10 (d, 2H), 6.98-6.94 (d, 2H), 4.39-4.28 (m, 1H), 3.98-3.91 (m, 2H), 2.98-2.89 (m, 2H), 2.70-2.58 (m, 2H), 1.85-1.78 (m, 2H). 1-(4-(trifluoromethyl)phenyl)piperidin-4-amine (38-2) The phthalimide derivative 38-1 (700 mg, 1.87 mmol) was dissolved in EtOH (18 ml) and hydrazine monohydrate (234 mg, 4.67 mmol) was added. The mixture was heated to reflux 15 temperature for 3 h. The white suspension was cooled to RT and filtered. The solids were washed with additional EtOH. The EtOH was then removed on a rotovap and the residue dissolved in CHCl3 / MeOH and concentrated directly onto celite. The crude material was dry- loaded and purified by silica gel chromatography eluting with DCM / MeOH (containing 1% NH4OH). The product eluted at 15 % MeOH / DCM (containing 1% NH4OH). Upon standing 20 under vacuum, 38-2 was obtained as white solid, (400 mg 96 % yield). LCMS m / z 246.3 (M+H)+. 5-bromo-N-(1-(4-(trifluoromethyl)phenyl)piperidin-4-yl)picolinamide (38-3) To 38-2 (440 mg, 1.80 mmol) and 5-bromopicolinic acid (400 mg, 1.98 mmol) in DCM (30 ml) 25 was added HATU (1.51 g, 3.96 mmol) and DIEA (0.94 ml, 5.40 mmol) and the reaction was stirred at RT for 2h. Partitioned between DCM and water, the organic layer was washed once more with water and then brine. The solution was dried over Na2SO4 and concentrated to an orange foam. The crude material was dissolved in DCM / EtOAc, concentrated directly onto celite and purified using an 80 g ISCO column eluting with 0-20 % EtOAc / DCM. The product{H3007867.1}195 4927-5223-2016, v.1fractions were concentrated to provide a white solid which was suspended in hexanes and filtered to provide 38-3 as a white crystalline solid, (620 mg, 80% yield). LCMS m / z 430.2 (M+H)+.1H NMR (CDCl3) d 8.60-8.57 (m, 1H), 8.11-8.06 (d, 1H), 8.00-7.96 (dd, 1H), 7.89-7.82 (d, 1H), 7.50-7.44 (d, 2H), 6.99-6.93 (d, 2H), 4.27-4.07 (m, 1H), 3.85-3.77 (m, 2H), 3.11-3.01 (m, 2H), 5 2.17-2.09 (m, 2H), 1.77-1.65 (m, 2H). 5-(2-(N-(tert-butyl)sulfamoyl)-5-methylphenyl)-N-(1-(4-(trifluoromethyl)phenyl)piperidin- 4-yl)picolinamide (38-4) Combined 38-3 (600 mg, 1.40 mmol), Intermediate 1 (456 mg, 1.68 mmol) Na2CO3(490 mg, 10 4.62 mmol), and Pd(PPh3)4 (162 mg, 0.14 mmol) in 1,4-dioxane (20 ml) and H2O (5 ml) and degassed by bubbling N2 for 20 min. The reaction was heated to 90oC for 6h then stirred at RT for 48 h. The reaction was filter through celite, rinsing the celite with additional 1,4-dioxane. The solution was concentrated in vacuo to give an orange oil. Purification by silica gel chromatography on a 40g GOLD column eluting with 0-25 % EtOAc / DCM provided an orange 15 oil that crystallized upon standing at RT to yield 38-4 (800 mg, 99 %). LCMS m / z 575.4 (M+H)+. 5-(5-methyl-2-sulfamoylphenyl)-N-(1-(4-(trifluoromethyl)phenyl)piperidin-4- yl)picolinamide (38-5) 38-4 (800 mg, 1.39 mmol) was suspended in DCM (2.0 ml) and TFA (8.0 ml) was added. The 20 solids immediately dissolved to give a light reddish-brown clear solution that was stirred at RT for 72 h. The volatiles were removed in vacuo and the residual oil was concentrated from 30 ml toluene (2x). After evaporation the residue was dissolved in 125 ml of EtOAc and washed with saturated NaHCO3. The organic layer was washed with brine, dried over Na2SO4 and evaporated to give the crude material as a brown oil that crystallized upon standing. The crude product was 25 dissolved in 1:1 CHCl3 / EtOAc and purified by silica gel chromatography. The product fractions were evaporated and triturated with a small amount of CHCl3 to give a solid. Hexanes were added and the suspension filtered to give provide 38-5 (480 mg, 66%) as an off-white solid. LCMS m / z 518.3 (M+H)+. 5-(5-methyl-2-(N-(5-methylfuran-2-carbonyl)sulfamoyl)phenyl)-N-(1-(4- 30 (trifluoromethyl)phenyl)piperidin-4-yl)picolinamide, (Example 38){H3007867.1}196 4927-5223-2016, v.1Combined 38-5 (240 mg, 0.46 mmol), 5-methylfuran-2-carboxylic acid (87.6 mg, 0.69 mmol), EDCI.HCl (178 mg, 0.93 mmol) and DMAP (141 mg, 1.16 mmol) in DMA (4.0 ml) and the reaction was stirred at RT for 24 hours. A second addition of reagents, as above was added and the reaction was continued for 3 days at RT. The DMA was evaporated under high vacuum, 5 partitioned between DCM / H2O, washed with NaHCO3, and brine and dried over Na2SO4. The concentrated residue was purified by silica gel chromatography The product fractions were concentrated in vacuo from CHCl3and the residue was triturated from CHCl3 / hexanes to provide Example 38 a white solid, (83.1 mg, 29%). LCMS m / z 627.4 (M+H)+.1H NMR (CDCl3) d 8.54-8.52 (m, 1H), 8.30-8.27 (d, 1H), 8.14-8.10 (d, 1H), 8.05-8.00 (d, 1H), 7.82 (bs, 1H), 7.73- 10 7.70 (dd, 1H), 7.52-7.44 (m, 3H), 7.11-7.08 (m, 2H), 7.00-6.95 (m, 2H), 6.17-6.15 (dd, 1H), 4.29-4.17 (m, 1H), 3.88-3.80 (m, 2H), 3.13-3.03 (m, 2H), 2.47 (s, 3H), 2.30 (s, 3H), 2.21-2.12 (m, 2H), 1.80-1.68 (m, 2H). Following the methods described above for Example 38 and substituting the appropriate 15 intermediates and reagents, the following compounds were prepared as indicated in Table 26. Table 26 , s, m,197 4927-5223-2016, v.12.47 (s, 3H), 2.21-2.14 (m, 2H), 1.80-1.68 (m, 2H).Example 395 tert-butyl 4-(2-(4-bromophenyl)acetyl)piperazine-1-carboxylate (39-1){H3007867.1}198 4927-5223-2016, v.1t-butyl 1-piperazinecarboxylate (5.00 g, 26.8 mmol) was combined with 4-bromophenyl acetic acid (6.93g, 32.2 mmol) in DMA (200 ml) and treated with EDCI (10.3 g.53.7 mmol) and DMAP (8.2 g.67.1 mmol). After stirring at RT for 24 h a second portion of carboxylate and reagents were added. The reaction mixture was concentrated in vacuo to remove DMA. The 5 yellow solid that resulted was dissolved in EtOAc and water and the layers were separated. The aqueous layer was saturated with NaCl and then extracted with additional EtOAc. The combined organic layers were washed with brine, dried over Na2SO4and concentrated to give a yellow solid. The solid was dissolved in 50 ml of 1:1 EtOAc / DCM and purified by column chromatography. The product fractions were concentrated in vacuo to provide a white solid that10 was suspended in hexanes and filtered to give 39-1, (9.5 g, 92% yield).1H NMR (CDCl3) d 7.47- 7.43 (m, 2H), 7.14-7.10 (m, 2H), 3.69 (s, 2H), 3.63-3.58 (m, 2H), 3.43-3.36 (m, 4H), 3.30-3.25 (m, 2H), 1.45 (s, 9H). tert-butyl 4-(2-(2'-(N-(tert-butyl)sulfamoyl)-5'-methyl-[1,1'-biphenyl]-4- yl)acetyl)piperazine-1-carboxylate (39-2) 15 Combined 39-1 (3.00 g, 7.83 mmol), Intermediate 1 (2.55 g, 9.39 mmol) Na2CO3(2.74 g, 25.8 mmol), and Pd(PPh3)4(0.90 g, 0.78 mmol) in 1,4-dioxane (20 ml) and H2O (5 ml) and degassed by bubbling N2 for 20 min. The reaction was heated to 90oC for 6h then stirred at RT for 48 h. The reaction was filtered through celite, rinsing the celite with additional 1,4-dioxane. The solution was concentrated in vacuo to give an orange oil. Purification by silica gel 20 chromatography provided an orange oil that crystallized upon standing at RT to yield 39-2, (4.05g, 98%). LCMS m / z 474.4 (M-tBu)+.1H NMR (CDCl3) d 8.05-8.02 (d, 2H), 7.50-7.47 (m, 2H), 7.34-7.30 (m, 2H), 7.29-7.25 (m, 1H, obscured by CDCl3), 7.12-7.10 (m, 1H), 3.80 (s, 2H), 3.63-3.58 (m, 2H), 3.52-3.39 (m, 5H), 3.36-3.31 (m, 2H), 2.42 (s, 3H), 1.47 (s, 9H), 0.99 (s, 9H). 25 N-(tert-butyl)-5-methyl-4'-(2-oxo-2-(piperazin-1-yl)ethyl)-[1,1'-biphenyl]-2-sulfonamide (39-3) 39-2 (4.94 g, 9.33 mmol) was suspended in 1,4-dioxane (20 ml) and 4N HCl / dioxane (5 ml) was added at RT. The white suspension was stirred at RT for 12 h as it gradually became a clear solution. LC / MS indicated that the reaction had progressed to 60% completion with 40% of the 30 N-Boc substrate 39-2 remaining. Additional 4N HCl in dioxane (2 ml) was added and the clear{H3007867.1}199 4927-5223-2016, v.1solution was stirred at RT overnight. The dioxane was concentrated in vacuo to provide the HCl salt as a white solid. The solid was dissolved in 100 ml of DCM, transferred to a separatory funnel and washed with 1N NaOH. The aqueous layer was re-extracted with an additional 75 ml of DCM and the combined organic layers were washed with brine and then dried over Na2SO4. 5 The solution was concentrated directly onto celite and purified directly by silica gel chromatography eluting with 0-20% MeOH / DCM (containing 1% NH4OH). The product fractions were concentrated, then the residue was rotovapped two times from CHCl3, (100 ml). The white solid obtained was then dissolved in 50 ml CHCl3 and mixed with 100 ml hexanes. Upon sonication a fluffy white solid was obtained and isolated by filtration to provide 39-3, (2.7 10 g, 67%) yield. LCMS m / z 430.6 (M+H)+ .1H NMR (CDCl3) d 8.05-8.02 (d, 2H), 7.50-7.46 (m, 2H), 7.35-7.31 (m, 2H), 7.29-7.25 (m, 1H, obscured by CDCl3), 7.12-7.10 (m, 1H), 3.78 (s, 2H), 3.64-3.59 (m, 2H), 3.53 (s, 1H), 3.47-3.42 (m, 2H), 2.85-2.72 (m, 4H), 2.42 (s, 3H), 0.99 (s, 9H). 15 N-(tert-butyl)-5-methyl-4'-(2-oxo-2-(4-(5-(trifluoromethyl)pyridin-2-yl)piperazin-1- yl)ethyl)-[1,1'-biphenyl]-2-sulfonamide (39-4) 39-3 (845 mg, 1.97 mmol) and 2-chloro-trifluoromethylpyridine (1.43 g.7.87 mmol) were dissolved in dry DMF 23.5 ml) and treated with K2CO3 (816 mg, 5.90 mmol). The suspension was stirred and heated to 60oC for 72 h. A small amount of SM was observed by LC / MS along 20 with the n-formyl-piperazine by-product (MW = 457.20). The mixture was cooled to RT and filtered through celite, and then washed with additional DMF. The filtrate was concentrated in vacuo. The yellow residue was dissolved in CHCl3and purified by silica gel chromatography. The product eluted as a broad peak and was concentrated to provide 39-4 as a white solid, (800 mg, 71% yield). LCMS m / z 575.4 (M+H)+ . 25 5-methyl-4'-(2-oxo-2-(4-(5-(trifluoromethyl)pyridin-2-yl)piperazin-1-yl)ethyl)-[1,1'- biphenyl]-2-sulfonamide (39-5) 39-4 (550 mg, 0.96 mmol), DCM (2 ml) and TFA (8 ml) were combined and the reaction was stirred at RT for 72 h The reaction was concentrated in vacuo and then concentrated twice from 30 CHCl3. The resulting oil was dissolved in DCM and washed with NaHCO3, then brine, dried{H3007867.1}200 4927-5223-2016, v.1over Na2SO4, filtered and concentrated to a yellow solid. The solid was purified by silica gel chromatography and the product fractions were combined, triturated with hexanes and filtered to provide 39-5 (420 mg, 85% yield) as a white solid. LCMS m / z 519.3 (M+H)+ . 5 5-methyl-N-((5-methyl-4'-(2-oxo-2-(4-(5-(trifluoromethyl)pyridin-2-yl)piperazin-1- yl)ethyl)-[1,1'-biphenyl]-2-yl)sulfonyl)furan-2-carboxamide (Example 39) Combined 39-5 (217 mg, 0.42 mmol), 5-methylfuran-2-carboxylic acid (76.6 mg, 0.61 mmol), EDCI.HCl (155 mg, 0.81 mmol) and DMAP (124 mg, 1.01 mmol) in DMA (7.0 ml) and the reaction was stirred at RT for 24 hours. A second addition of reagents, as above was added and 10 the reaction was continued for 3 days at RT. The DMA was evaporated under high vacuum, partitioned between DCM / H2O, washed with NaHCO3, and brine and dried over Na2SO4. The concentrated residue was purified by silica gel chromatography The product fractions were concentrated in vacuo from CHCl3 and the residue was triturated from CHCl3 / hexanes to provide Example 39 as white solid, (78.5 mg, 30% yield). LCMS m / z 627.3 (M+H)+.1H NMR (CDCl3) 15 d 8.41-8.38 (m, 1H), 8.25-8.20 (m, 2H), 7.69-7.64 (dd, 1H), 7.38-7.34 (dd, 1, 7.26-7.17 (m, 4H), 7.08-7.03 (m, 2H), 6.67-6.63 (d, 1H), 6.14-6.12 (dd, 1H), 3.83-3.78 (m, 4H), 3.66-3.61 (m, 6H), 2.41 (s, 3H), 2.34 (s, 3H). Following the methods described above for Example 39 and substituting the appropriate 20 intermediates and reagents, the following compounds were prepared as indicated in Table 27. Table 27 3 -4927-5223-2016, v.13.77 (m, 4H), 3.74-3.67 (m, 2H), 3.34-3.19 (m, 4H), 2.42 1 - - 2 1 94927-5223-2016, v.17.70-7.65 (dd, 2H), 7.48-7.46 39E 613.3 (m, 1H), 7.39-7.35 (dd, 1H), 7 2 - - - 3 - - 9203 4927-5223-2016, v.139I 627.3 (dd, 1H), 7.56-7.48 (dd, 3H), 7.41-7.38 (m, 1H), 7.31-7.29 , 1 , 3 - 0{H3007867.1}204 4927-5223-2016, v.11H NMR (DMSO-d6) d 7.99- 7.94 (d, 1H), 7.76-7.74 (d, - -Example 42{H3007867.1}205 4927-5223-2016, v.1tert-Butyl 4-((4-bromobenzyl)oxy)-4-methylpiperidine-1-carboxylate (42-1) To NaH (60 % in mineral oil) (205 mg, 5.11 mmol) in DMF 5 (mL) was slowly added tert-butyl 5 4-hydroxy-4-methylpiperidine-1-carboxylate (1.0 g, 4.65 mmol) as a solution in DMF (5 mL). Stir 20 min then slowly add 1-bromo-4-(bromomethyl)benzene as a solution in DMF (5 mL). Stir for 3 hr then quench with water, extract with ether (3x). Combined organics washed with 5.0 N NH4Cl, brine, dry, conc. over silica. Chromatography (SiO2, 0 to 10 % EtOAc:Hex) gives 42-1 (720 mg, 40 %). LCMS m / z 284.2 (M+H-Boc)+,1H NMR (CDCl3) d 7.50-7.44 (m, 2H), 7.26- 10 7.21 (m ,2H), 4.38, (s, 2H), 3.80-3.71 (m, 2H), 3.24-3.12 (m, 2H), 1.88-1.80 (m, 2H), 1.55-1.48 (m, 2H), 1.46 (s, 9H), 1.27 (s, 3H). tert-Butyl 4-((2'-(N-(tert-butyl)sulfamoyl)-5'-methyl-[1,1'-biphenyl]-4-yl)methoxy)-4- methylpiperidine-1-carboxylate (42-2) 15 To 42-1 (710 mg, 1.85 mmol) in dioxane (10 mL) and H2O (2 mL) was added Intermediate 1 (600 mg, 2.22 mmol) and Na2CO3 (590 mg, 5.56 mmol), and the mixture was degassed with N2 for 20 min. Pd(Ph3)4(110 mg, 0.093 mmol) was added and the mixture was heated under N2at 90oC for 18 hr. The mixture was cooled, diluted with EtOAc, washed with H2O, brine, dried,{H3007867.1}206 4927-5223-2016, v.1and concentrated. Chromatography (SiO2, 0 to 30 % EtOAc:Hex) gives 42-2 (870 mg, 89 %). LCMS m / z 531.4 (M+H)+,1H NMR (CDCl3) d 8.08-8.02 (m, 1H), 7.51-7.41 (m ,4H), 7.30-7.27 (m, 1H), 7.13-7.09 (m, 1H), 4.49, (s, 2H), 3.82-3.75 (m, 2H), 3.53 (bs, 1H), 3.27-3.15 (m, 2H), 2.43 (s, 3H), 1.92-1.84 (m, 2H), 1.56-1.50 (m, 2H), 1.48 (s, 9H), 1.31 (s, 3H), 1.01 (s, 9H). 5 N-(tert-Butyl)-5-methyl-4'-(((4-methylpiperidin-4-yl)oxy)methyl)-[1,1'-biphenyl]-2- sulfonamide hydrochloride salt (42-3) To 42-2 (870 mg, 1.65 mmol) in dioxane (10 mL) was added HCl (2.0 mL, 4.0 N in dioxane) and the mixture was stirred for 5 hr, then concentrated and triturated with Et2O to give crude 42-3 10 (640 mg, 83 %). N-(tert-Butyl)-5-methyl-4'-(((4-methyl-1-(4-(trifluoromethyl)phenyl)piperidin-4- yl)oxy)methyl)-[1,1'-biphenyl]-2-sulfonamide (42-4) To 42-3 (310 mg, 0.67 mmol) in dioxane (8 mL) was added 1-iodo-4-(trifluoromethyl)benzene 15 (290 mg, 1.06 mmol), S-Phos (27 mg, 0.067 mmol), and NaOtBu (190 mg, 2.00 mmol). The mixture was degassed with N2for 20 min, then Pd2(dba)3(30 mg, 0.033 mmol) was added and the mixture was heated under N2 at 100oC for 18 hr. The mixture was cooled, concentrated and chromatographed (SiO2, 0 to 30 % EtOAc:Hex) to give 42-4 (350 mg, 92 %). LCMS m / z 575.4 (M+H)+,1H NMR (CDCl3) d 8.07-8.02 (m, 1H), 7.51-7.41 (m, 6H), 7.30-7.25 (m, 1H), 7.12-7.09 20 (m, 1H), 7.00-6.92 (m, 2H), 4.53 (s, 2H), 3.59-3.49 (m, 3H), 3.34-3.23 (m, 2H), 2.43 (s, 3H), 2.08-1.98 (m, 2H), 1.79-1.68 (m, 2H), 1.36 (s, 3H), 0.99 (s, 9H). 5-Methyl-4'-(((4-methyl-1-(4-(trifluoromethyl)phenyl)piperidin-4-yl)oxy)methyl)-[1,1'- biphenyl]-2-sulfonamide (42-5) 25 To 42-4 (350 mg, 0.61 mmol) in DCM (1 mL) was added TFA (9 mL) and the mixture was stirred 18 hr. Mixture was concentrated, dissolved in DCM, washed with NaHCO3(2x), brine, dried and concentrated to give 42-5 (300 mg, 96 %). LCMS m / z 519.3 (M+H)+,1H NMR (CDCl3) d 8.09-8.02 (m, 1H), 7.57-7.44 (m, 6H), 7.33-7.28 (m, 2H), 7.18-7.12 (m, 1H), 7.02- 6.92 (m, 1H), 4.56 (s, 2H), 4.18-4.09 (m, 2H), 3.60-3.48 (m, 2H), 3.36-3.23 (m, 2H), 2.43 (s, 30 3H), 2.10-1.98 (m, 2H), 1.83-1.69 (m, 2H), 1.36 (s, 3H).{H3007867.1}207 4927-5223-2016, v.15-Methyl-N-((5-methyl-4'-(((4-methyl-1-(4-(trifluoromethyl)phenyl)piperidin-4- yl)oxy)methyl)-[1,1'-biphenyl]-2-yl)sulfonyl)furan-2-carboxamide (Example 42) To 5-methylfuran-2-carboxylic acid (22 mg, 0.173 mmol) in ACN (5 mL) was added EDCI (44 5 mg, 0.231 mmol) and DMAP (35 mg, 0.289 mmol). The mixture was stirred for 20 min then 42-5 (60 mg, 0.116 mmol) was added and the mixture was stirred 18 hr. The mixture was concentrated, diluted with DCM, washed with 5 N NH4Cl, NaHCO3, brine, dried and concentrated. Chromatography (SiO2, 0 to 4 % MeOH:DCM) gives Example 42 (60 mg, 83 %.), LCMS m / z 627.4 (M+H)+,1H NMR (CDCl3) d 8.29-8.20 (m, 1H), 7.86-7.75 (m, 1H), 7.54-7.44 (m, 2H), 7.40- 10 734 (m, 1H), 7.31-7.20 (m, 4H), 7.08-7.01 (m, 2H), 7.00-6.92 (m, 2H), 6.14-6.09 (m, 1H), 4.52 (s, 2H), 3.59-3.47 (m, 2H), 3.36-3.22 (m, 2H), 2.43 (s, 3H), 2.27 (s, 3H), 2.07-1.97 (m, 2H), 1.84- 1.68 (m, 2H), 1.36 (s, 3H). Following the methods described above for Example 42 and substituting the appropriate 15 intermediates and reagents, the following compounds were prepared as indicated in Table 28. Table 28{H3007867.1}208 4927-5223-2016, v.142B629.3 1H NMR (CDCl3) d 8.15 (d, 1H), 7.88 (bs, 1h), 7.43-7.37 - 42 - 42 42 - -{H3007867.1}209 4927-5223-2016, v.142F614.4 1H NMR (CDCl3) d 8.62-8.56 (m, 1H), 8.20 (d, 1H), 7.87- - - 7 - - 9- 7 - - , - 6 - -4927-5223-2016, v.12H), 1.78-1.65 (m, 2H) 1.29 (s, 3H). 7 - -Example 43{H3007867.1}211 4927-5223-2016, v.1teTo Mg (0.43 g 17.6 mmol) in an oven dried flask under N2 was added LiCl (18 mL, 8.83 mmol, 0.5M solution in THF), then DIBAL (1.0M in THF, 0.071 mL, 0.071 mmol) and the mixture was 5 cooled to 0oC.4-Bromobenzotrifluride (1.59 g, 7.06 mmol) was added in one portion and the mixture was stirred at 0oC for 30 min. In a separate oven dried flask, to N-Boc-3-Iodoazetidine (1.0 g, 3.53 mmol) in THF (20 mL) was added CoCl2 (11 mg, 0.088 mmol), and (1R,2R)- N1,N1,N2,N2-Tetramethylcyclohexane-1,2-diamine (18 mg, 0.106 mmol) and the mixture was cooled to 0oC under N2. The turbo Grignard prepared in the previous step was added to this 10 mixture via syringe, under N2, dropwise over 20 minutes. The mixture was stirred at 0oC for 2 hr. The mixture was quenched with 5 N NH4Cl, extracted with Et2O (2x), and the combined organics were washed with brine, dried, and concentrated. Chromatography (SiO2, 0 to 20 % EtOAc:Hex) gives 43-1 (740 mg, 35 %). LCMS m / z 202.1 (M+H-Boc)+,1H NMR (CDCl3) d 7.66-7.59 (m, 2H), 7.48-7.42 (m, 2H), 4.43-4.32 (m, 2H), 4.02-3.93 (m, 2H), 3.84-3.75 (m, 15 1H), 1.48 (s, 9H). 3-(4-(Trifluoromethyl)phenyl)azetidine hydrochloride salt (43-2) To 43-1 (0.70 g, 2.32 mmol) was added HCl (4.0 N in dioxane, 2.3 mL, 9.29 mmol) and the mixture was stirred for 18 hr then concentrated, and triturated with Et2O to give 43-2 (560 mg,{H3007867.1}212 4927-5223-2016, v.1100 %). LCMS m / z 202.1 (M+H)+,1H NMR (CDCl3) d 9.33-9.02 (bs, 1H), 8.99-8.68 (bs,1H), 7.79-7.73 (m, 2H), 7.67-7.62 (m, 2H), 4.34-4.16 (m, 3H), 4.14-4.03 (m, 2H). 2-(4-bromophenyl)-1-(3-(4-(trifluoromethyl)phenyl)azetidin-1-yl)ethan-1-one (43-3) 5 To 2-(4-bromophenyl)acetic acid (550 mg, 2.56 mmol) and 43-2 (550 mg, 2.32 mmol) in DCM (20 mL) and DMF (2.0 mL) was added HATU (1.3 g, 3.49 mmol) then DIEA (1.62 mL, 9.29 mmol) and the mixture was stirred 18hr. The mixture was diluted with EtOAc, washed with NH4Cl, NaHCO3, LiCl (5 %, 3x), brine, and concentrated. Chromatography (SiO2, 0 to 100 % EtOAc:Hex) gives 43-3 (680 mg, 74 %). LCMS m / z 398.2 (M+H)+,1H NMR (CDCl3) d 7.67-10 7.60 (m, 2H), 7.51-7.48 (m, 2H), 7.41-7.36 (m, 2H), 7.23-7.16 (m, 2H), 4.60-4.43 (m, 2H), 4.17- 4.07 (m, 2H), 3.92-3.81 (m, 1H), 3.49 (s, 2H). N-(tert-butyl)-5-methyl-4'-(2-oxo-2-(3-(4-(trifluoromethyl)phenyl)azetidin-1-yl)ethyl)-[1,1'- biphenyl]-2-sulfonamide (43-4) 15 To 43-3 (680 mg, 1.71 mmol) in dioxane (10 mL) and H2O (2 mL) was added Intermediate 1 (550 mg, 2.05 mmol) and Na2CO3(540 mg, 5.12 mmol), and the mixture was degassed with N2for 20 min. Pd(Ph3)4(99 mg, 0.085 mmol) was added and the mixture was heated under N2at 90 oC for 18 hr. The mixture was cooled, diluted with EtOAc, washed with H2O, brine, dried, and concentrated. Chromatography (SiO2, 0 to 30 % EtOAc:Hex) gives 43-4 (790 mg, 85 %). 20 LCMS m / z 545.5 (M+H)+,1H NMR (CDCl3) d 8.09-8.02 (m, 1H), 7.71-7.62 (m, 2H), 7.53-7.36 (m, 6H), 7.31-7.27 (m, 2H), 7.15-7.10 (m, 1H), 4.69-4.60 (m, 1H), 4.55-4.43 (m, 1H), 4.25-4.09 (m, 2H), 3.98-3.86 (m, 1H), 3.63-3.56 (m, 3H), 2.43 (s, 3H), 1.00 (s, 9H). 5-methyl-4'-(2-oxo-2-(3-(4-(trifluoromethyl)phenyl)azetidin-1-yl)ethyl)-[1,1'-biphenyl]-2- 25 sulfonamide (43-5) To 43-4 (790 mg, 1.44 mmol) was added TFA (10 mL) and the mixture was stirred 18 hr. Mixture was concentrated, dissolved in DCM, washed with NaHCO3(2x), brine, dried and concentrated to give 43-5 (580 mg, 84 %). LCMS m / z 489.4 (M+H)+,1H NMR (CDCl3) d 8.08- 8.03 (m, 1H), 7.67-7.62 (m, 2H), 7.50-7.38 (m, 6H), 7.33-7.28 (m, 1H), 7.17-7.14 (m, 1H), 4.70-{H3007867.1}213 4927-5223-2016, v.14.560 (m, 1H), 4.54-4.46 (m, 1H), 4.26-4.10 (m, 4H), 3.98-3.85 (m, 1H), 3.59 (s, 2H), 2.45 (s, 3H). N-((5-Methyl-4'-(2-oxo-2-(3-(4-(trifluoromethyl)phenyl)azetidin-1-yl)ethyl)-[1,1'-biphenyl]- 2-yl)sulfonyl)thiazole-5-carboxamide (Example 43). 5 To thiazole-5-carboxylic acid (24 mg, 0.184 mmol) in ACN (5 mL) was added EDCI (47 mg, 0.246 mmol) and DMAP (38 mg, 0.307 mmol). The mixture was stirred for 20 min then 43-5 (60 mg, 0.123 mmol) was added and the mixture was stirred 18 hr. The mixture was concentrated, diluted with DCM, washed with 5 N NH4Cl, NaHCO3, brine, dried and concentrated. Chromatography (SiO2, 0 to 4 % MeOH:DCM) gives Example 43 (52 mg, 71 %). LCMS m / z 10 600.5 (M+H)+,1H NMR (CDCl3) d 8.81 (s, 1H), 8.19-8.14 (m, 1H), 8.12 (s,1H), 7.61-7.55 (m, 2H), 7.5447.37 (m, 3H), 7.32-7.27 (m, 1H), 7.17-7.04 (m, 4H), 7.01-6.97 (m, 1H), 4.68-4.60 (m, 1H), 4.50-4.41 (m, 1H), 4.25-4.19 (m, 1H), 4.14-4.07 (m, 1H), 3.97-3.86 (m, 1H), 3.50-3.37 (m, 2H), 2.35 (s, 3H). 15 Following the methods described above for Example 43 and substituting the appropriate intermediates and reagents, the following compounds were prepared as indicated in Table 31. Table 31 5 64927-5223-2016, v.143B596.2 1H NMR (CDCl3) d 8.85 (s, 1H), 8.18-8.16 (d, 1H), 7.60- 7- - -Example 45 5- - y -- y-- - - - y p y pp -- yl)oxy)methyl)pyridin-2-yl)benzenesulfonamide (45-1){H3007867.1}215 4927-5223-2016, v.1Intermediate 25-3 (0.52 g, 1.25 mmol) was azeotroped from toluene (3 x 3 ml). The residue was combined with 4-iodobenzotrifluoride (0.22 ml, 1.5 mmol), Binap (0.078 g, 0.12 mmol) and tBuONa (0.36g, 3.74 mmol) in toluene (10.5 ml) and degassed with N2 approx.30 min. To the reaction was added Pd2(dba)3(0.057g, 0.062 mmol), the reaction was degassed under N2for 5 5 min. then heated at 90°C for 20.5 hours. The reaction was cooled to rt and concentrated in vacuo to remove toluene. The residue was redissolved in DCM and dry loaded onto celite for purification with a 40g Isco gold column eluting 0-50% EtOAc / hexanes. The product eluted at 38% and was collected and concentrated to provide 45-1, (485 mg, 69%). LCMS: (M+H)+562.5,1H NMR (CDCl3) 8.57-8.56 (m, 1H), 8.09-8.05 (d, 1H), 7.87-7.84 (dd, 10 1H), 7.52-7.47 (m, 3H), 7.36-7.32 (dd , 1H), 7.27-7.23 (m, 2H), 6.98-6.94 (m, 2H), 4.67 (s, 2H), 3.74-3.62 (m, 3H), 3.17-3.09 (m, 2H), 2.47 (s, 3H), 2.11-2.03 (m, 2H), 1.87-1.78 (m, 2H), 1.32 (s, 9H). 4-methyl-2-(5-(((1-(4-(trifluoromethyl)phenyl)piperidin-4-yl)oxy)methyl)pyridin-2- 15 yl)benzenesulfonamide (45-2) To 45-1 (485 mg, 0.86 mmol) in 4 ml of DCM, was added 40 ml of TFA and the reaction was stirred at rt for 72 h. The reaction was concentrated in vacuo and azeotroped with toluene (3x) in DCM. The residue was redissolved in EtOAc (250 ml) and washed with Na2CO3, (2x 100 ml), and brine, dried over Na2SO4 filtered and concentrated in vacuo. This was then stirred over ether 20 for 30 min., and filtered to collect white solids. Additionally, the filtrate was purified on 40g gold Isco column eluting with 0-100% EtOAc / Hex over 20 min. Collected product fractions from 68% EtOAc / hexanes and combined with white solids above to provide 45-2 (395.5 mg, 90.5%). LCMS: tr= 1.52 (M+H)+506.5,1H NMR (CDCl3) 8.60-8.59 (m, 1H), 8.12-8.08 (d, 1H), 7.92- 7.87 (dd, 1H), 7.55-7.47 (m, 3H7.32-7.28 (m, 1H), 6.99-6.93 (m, 2H), 25 4.68 (s, 2H), 3.76-3.61 (m, 3H), 3.19-3.10 (m, 2H), 2.49 (s, 3H), 2.12-2.03 (m, 2H), 1.89-1.78 (m, 2H). 2-(2-((1H-pyrrol-1-yl)sulfonyl)-5-methylphenyl)-5-(((1-(4-(trifluoromethyl) phenyl)piperidin-4-yl)oxy)methyl)pyridine (45-3){H3007867.1}216 4927-5223-2016, v.1To 45-2 (1 eq., 86.4 mg, 0.17 mmol) in toluene (2 mL) was added 2,5-dimethoxytetrahydrofuran (1.2 eq., 27.103 mg, 0.027 mL, 0.205 mmol) and a crystal of p-toluenesulfonic acid monohydrate. Reaction was heated to 100oC for 30 min. At 30 min, the reaction was cooled to rt but LCMS indicated the reaction only contained a trace amount of product. Repeated the 5 addition of 2,5 dimethoxytetrahydrofuran and pTsOH.H2O and continued at 100oC. After 30 minutes, the reaction was cooled to rt, quenched with sat. NaHCO3 and extracted 3x with EtOAc, The combined organic layers were washed with sat. NH4Cl and brine and dried over Na2SO4and concentrated in vacuo. The residue was purified by chromatography on a 15.5 mg gold column, eluting 0-100% EtOAc / hexanes over 20 min. Collected product fractions at 40% EtOAc / hexane 10 and concentrated to a white foamy solid to provide 45-3 (62.2 mg, 66%). LCMS m / z 556.5 (M+H)+.1H NMR (CDCl3) d 8.64-8.561 (m, 1H), 7.82-7.77 (m, 1H), 7.61-7.56 (d, 1H), 7.51- 7.46 (m, 3H), 7.34-7.29 (m, 1H), 7.27-7.24 (m, 1H), 6.99-6.91 (m, 4H), 6.25-6.21 (m, 2H), 4.70 (s, 2H), 3.76-3.62 (m, 3H), 3.19-3.10 (m, 2H), 2.43 (s, 3H), 2.12-2.03 (m, 2H), 1.89-1.79 (m, 2H). 15 4-methyl-2-(5-(((1-(4-(trifluoromethyl)phenyl)piperidin-4-yl)oxy)methyl)pyridin-2- yl)benzenesulfonic acid (Example 45) A solution of KOH (4 eq., 24.23 mg, 0.43 mmol) in EtOH (4.2 mL), was added to 45-3 (1 eq., 60 mg, 0.108 mmol) and heated to 50oC for 17h. LCMS, indicated desired, however still significant sm remained. Added an additional KOH (6 mg) in minimal EtOH and warmed the reaction to 20 70oC. At 6 hours, the reaction was progressing well, and the reaction was continued at 70oC overnight. After 17 hours trace starting material remained. The reaction was concentrated in vacuo and purified by mass directed HPLC. The product fractions were lyophilized to provide Example 45 as a white solid, (27.1 mg, 49%). LCMS m / z 507.5 (M+H)+.1H NMR (DMSO-d6) d 8.84-8.79 (m, 1H), 8.52-8.47 (m, 1H), 8.23-8.18 (m, 1H), 7.88-7.83 (m, 1H), 7.52-7.40 (m, 3H) 25 7.39-7.35 (m, 1H), 7.12-7.06 (m, 2H), 4.80 (s, 2H), 3.82-3.65 (m, 3H), 3.18-3.09 (m, 2H), 2.39 (s, 3H), 2.06-1.97 (m, 2H), 1.70-1.60 (m, 2H). Following the methods described above for Example 45 and substituting the appropriate intermediates and reagents, the following compounds were prepared as indicated in Table 30.{H3007867.1}217 4927-5223-2016, v.1Table 30 Example Structure LCMS ), , , , ), , - ), , ), , , - ). ), m, ), ).{ 3007867. }218 4927-5223-2016, v.145E480.4 1H NMR (DMSO) d 7.81 (d, 1H), 7.55-7.48 (m, 2H), 7.28- ), , , , ), , ), , , - ), , ), , , ), ),{H3007867.1}219 4927-5223-2016, v.12.28 (s, 3H), 1.89-1.81 (m, 2H), 1.68-1.55 (m, 2H), 1.25 (s, 3H). , m, ), m, 8 3 5- ), ), 0 8- H) ), m, m, s, 1 - ), ,{H3007867.1}220 4927-5223-2016, v.145N494.3 1H NMR (CD3OD) d 8.78-8.75 (m, 1H), 8.56-8.52 (m, 1H), , ), , - , , ), , 5 , , - ), , ,{H3007867.1}221 4927-5223-2016, v.145R457.3 1H NMR (DMSO-d6) d 8.92 (s, 1H), 8.20-8.18 (d, 1H), 7.83-7.72 , 7 - ), - ) ), , , - ), , , ), ,{H3007867.1}222 4927-5223-2016, v.12.07-1.97 (m, 2H), 1.82-1.71 (m, 2H). , , 9 - ) , 5 , 4 - ), , , 8 , 6 - , .{H3007867.1}223 4927-5223-2016, v.145AA524.2 1H NMR (DMSO-d6) d 8.82-8.79 (m, 1H), 8.48-8.44 (m,1H), 8.23- , , , , 3 , 7 , . ), , , ),BIOLOGY

[0241] It is desirable to find compounds with advantageous and improved characteristics 5 compared with known MGAT2 inhibitors, in one or more of the following categories that are given as examples, and are not intended to be limiting: (a) pharmacokinetic properties, including oral bioavailability, half life, and clearance; (b) pharmaceutical properties; (c) dosage requirements; (d) factors that increase the concentration of active drug at the receptor; (e) factors that decrease the liability for clinical drug-drug interactions; (f) factors that decrease the potential{H3007867.1}224 4927-5223-2016, v.1for adverse side-effects, including selectivity versus other biological targets; and (g) factors that improve manufacturing costs or feasibility.

[0242] As used herein, the term "patient" encompasses all mammalian species.

[0243] As used herein, the term "subject" refers to any human or nonhuman organism that 5 could potentially benefit from treatment with an MGAT2 inhibitor. Exemplary subjects include human beings of any age with risk factors for a disorder, disease, syndrome, or condition affected by the inhibition of MGAT2, or patients that have already experienced one episode of a disorder, disease, syndrome, or condition affected by the inhibition of MGAT2.

[0244] As used herein, "treating" or "treatment" cover the treatment of a disease-state in a 10 mammal, particularly in a human, and include: (a) inhibiting the disease-state, i.e., arresting its development; and / or (b) relieving the disease-state, i.e., causing regression of the disease state.

[0245] As used herein, "prophylaxis" or "prevention" covers the preventive treatment of a subclinical disease-state in a mammal, particularly in a human, aimed at reducing the probability of the occurrence of a clinical disease-state. Patients are selected for preventative therapy based 15 on factors that are known to increase risk of suffering a clinical disease state compared to the general population. "Prophylaxis" therapies can be divided into (a) primary prevention and (b) secondary prevention. Primary prevention is defined as treatment in a subject that has not yet presented with a clinical disease state, whereas secondary prevention is defined as preventing a second occurrence of the same or similar clinical disease state. 20

[0246] As used herein, "risk reduction" covers therapies that lower the incidence of development of a clinical disease state. As such, primary and secondary prevention therapies are examples of risk reduction.

[0247] "Therapeutically effective amount" is intended to include an amount of a compound of the present invention that is effective when administered alone or in combination to inhibit 25 MGAT2 and / or to prevent or treat the disorders listed herein. When applied to a combination, the term refers to combined amounts of the active ingredients that result in the preventive or therapeutic effect, whether administered in combination, serially, or simultaneously.

[0248] As MGAT2 inhibitors, it is believed that the compounds of Formula I, some of the compounds of Formula II, the examples and the compounds in Table 32 are useful in methods 30 for treating or preventing a disease, a syndrome, a condition or a disorder in a subject, including{H3007867.1}225 4927-5223-2016, v.1an animal, a mammal and a human in which the disease, the syndrome, the condition or the disorder is affected by the inhibition of MGAT2. Such methods comprise, consist of and / or consist essentially of administering to a subject, including an animal, a mammal, and a human, in need of such treatment or prevention, a therapeutically effective amount of a compound, salt or 5 solvate of Formula I.

[0249] In one embodiment, the present invention is directed to a compound of Formula I or II and stereoisomers, tautomers, salts, and solvates thereof, for the use in the treatment of diabetes and MASLD / MASH .

[0250] The term "pharmaceutical composition," as used herein, means any composition, 10 which contains at least one therapeutically or biologically active agent and is suitable for administration to the patient. Any of these formulations can be prepared by well-known and accepted methods of the art. See, for example, Gennaro, A.R., ed., Remington: The Science and Practice of Pharmacy, 20th Edition, Mack Publishing Co., Easton, Pa. (2000).

[0251] The compounds of this disclosure can be administered in such oral dosage forms as 15 tablets, capsules (each of which includes sustained release or timed release formulations), pills, powders, granules, elixirs, tinctures, suspensions, syrups, and emulsions. They may also be administered in intravenous (bolus or infusion), intraperitoneal, subcutaneous, or intramuscular form, all using dosage forms well known to those of ordinary skill in the pharmaceutical arts. They can be administered alone, but generally will be administered with a pharmaceutical carrier 20 selected on the basis of the chosen route of administration and standard pharmaceutical practice.

[0252] The preferred dose of the MGAT2 inhibitor is a biologically active dose. A biologically active dose is a dose that will modulate MGAT2 and have an appropriate effect. Desirably, the dose includes a dose range from about 0.01 mg to about 3000 mg, or any particular amount or range therein, in particular from about 0.05 mg to about 1000 mg, or any 25 particular amount or range therein, or, more particularly, from about 0.05 mg to about 250 mg, or any particular amount or range therein, of active ingredient in a regimen of about 1 to about 4 times per day for an average (70 kg) human; although, it is apparent to one skilled in the art that the therapeutically effective amount for a compound of Formula (I) will vary as will the diseases, syndromes, conditions, and disorders being treated.{H3007867.1}226 4927-5223-2016, v.1

[0253] Compounds of this invention can be administered in intranasal form via topical use of suitable intranasal vehicles, or via transdermal routes, using transdermal skin patches. When administered in the form of a transdermal delivery system, the dosage administration will, of course, be continuous rather than intermittent throughout the dosage regimen. 5

[0254] The compounds are typically administered in admixture with suitable pharmaceutical diluents, excipients, or carriers (collectively referred to herein as pharmaceutical carriers) suitably selected with respect to the intended form of administration, that is, oral tablets, capsules, elixirs, syrups and the like, and consistent with conventional pharmaceutical practices.

[0255] For instance, for oral administration in the form of a tablet or capsule, the active drug 10 component can be combined with an oral, non-toxic, pharmaceutically acceptable, inert carrier such as lactose, starch, sucrose, glucose, methyl cellulose, magnesium stearate, dicalcium phosphate, calcium sulfate, mannitol, sorbitol and the like; for oral administration in liquid form, the oral drug components can be combined with any oral, non-toxic, pharmaceutically acceptable inert carrier such as ethanol, glycerol, water, and the like. Moreover, when desired or necessary, 15 suitable binders, lubricants, disintegrating agents, and coloring agents can also be incorporated into the mixture. Suitable binders include starch, gelatin, natural sugars such as glucose or beta- lactose, corn sweeteners, natural and synthetic gums such as acacia, tragacanth, or sodium alginate, carboxymethylcellulose, polyethylene glycol, waxes, and the like. Lubricants used in these dosage forms include sodium oleate, sodium stearate, magnesium stearate, sodium 20 benzoate, sodium acetate, sodium chloride, and the like. Disintegrators include, without limitation, starch, methyl cellulose, agar, bentonite, xanthan gum, and the like.

[0256] The compounds of the present invention can also be administered in the form of liposome delivery systems, such as small unilamellar vesicles, large unilamellar vesicles, and multilamellar vesicles. Liposomes can be formed from a variety of phospholipids, such as 25 cholesterol, stearylamine, or phosphatidylcholines.

[0257] Compounds of the present invention may also be coupled with soluble polymers as targetable drug carriers. Such polymers can include polyvinylpyrrolidone, pyran copolymer, polyhydroxypropylmethacrylamide-phenol, polyhydroxyethylaspartamidephenol, or polyethyleneoxide-polylysine substituted with palmitoyl residues. Furthermore, the compounds 30 of the present invention may be coupled to a class of biodegradable polymers useful in achieving{H3007867.1}227 4927-5223-2016, v.1controlled release of a drug, for example, polylactic acid, polyglycolic acid, copolymers of polylactic and polyglycolic acid, polyepsilon caprolactone, polyhydroxy butyric acid, polyorthoesters, polyacetals, polydihydropyrans, polycyanoacylates, and crosslinked or amphipathic block copolymers of hydrogels. 5

[0258] Dosage forms (pharmaceutical compositions) suitable for administration may contain from about 1 milligram to about 100 milligrams of active ingredient per dosage unit. In these pharmaceutical compositions the active ingredient will ordinarily be present in an amount of about 0.5-95% by weight based on the total weight of the composition.

[0259] Gelatin capsules may contain the active ingredient and powdered carriers, such as 10 lactose, starch, cellulose derivatives, magnesium stearate, stearic acid, and the like. Similar diluents can be used to make compressed tablets. Both tablets and capsules can be manufactured as sustained release products to provide for continuous release of medication over a period of hours. Compressed tablets can be sugar coated or film coated to mask any unpleasant taste and protect the tablet from the atmosphere, or enteric coated for selective disintegration in the 15 gastrointestinal tract.

[0260] Liquid dosage forms for oral administration can contain coloring and flavoring to increase patient acceptance.

[0261] In general, water, a suitable oil, saline, aqueous dextrose (glucose), and related sugar solutions and glycols such as propylene glycol or polyethylene glycols are suitable carriers for 20 parenteral solutions. Solutions for parenteral administration may contain a water soluble salt of the active ingredient, suitable stabilizing agents, and if necessary, buffer substances. Antioxidizing agents such as sodium bisulfite, sodium sulfite, or ascorbic acid, either alone or combined, are suitable stabilizing agents. Also used are citric acid and its salts and sodium EDTA. In addition, parenteral solutions can contain preservatives, such as benzalkonium 25 chloride, methyl- or propyl-paraben, and chlorobutanol.

[0262] Suitable pharmaceutical carriers are described in Remington’s Pharmaceutical Sciences, Mack Publishing Company, a standard reference text in this field.

[0263] Representative useful pharmaceutical dosage-forms for administration of the compounds of this invention can be illustrated as follows: 30{H3007867.1}228 4927-5223-2016, v.1Capsules

[0264] A large number of unit capsules can be prepared by filling standard two-piece hard gelatin capsules each with 100 milligrams of powdered active ingredient, 150 milligrams of lactose, 50 milligrams of cellulose, and 6 milligrams magnesium stearate. 5 Soft Gelatin Capsules

[0265] A mixture of active ingredient in a digestible oil such as soybean oil, cottonseed oil or olive oil may be prepared and injected by means of a positive displacement pump into gelatin to form soft gelatin capsules containing 100 milligrams of the active ingredient. The capsules 10 should be washed and dried. Tablets

[0266] Tablets may be prepared by conventional procedures so that the dosage unit is 100 milligrams of active ingredient, 0.2 milligrams of colloidal silicon dioxide, 5 milligrams of 15 magnesium stearate, 275 milligrams of microcrystalline cellulose, 11 milligrams of starch and 98.8 milligrams of lactose. Appropriate coatings may be applied to increase palatability or delay absorption. Dispersion 20

[0267] A spray dried dispersion can be prepared for oral administration by methods know to one skilled in the art. Injectable

[0268] A parenteral composition suitable for administration by injection may be prepared by 25 stirring 1.5% by weight of active ingredient in 10% by volume propylene glycol and water. The solution should be made isotonic with sodium chloride and sterilized. Suspension

[0269] An aqueous suspension can be prepared for oral administration so that each 5 mL 30 contain 100 mg of finely divided active ingredient, 200 mg of sodium carboxymethyl cellulose, 5 mg of sodium benzoate, 1.0 g of sorbitol solution, U.S.P., and 0.025 mL of vanillin.{H3007867.1}229 4927-5223-2016, v.1

[0270] The disclosed compounds of Formula I and II may be useful in combination with one or more additional therapeutic agents. The additional therapeutic agent(s) may be administered in a single dosage form with at least one compound of the instant invention, or the additional therapeutic agent(s) may be administered in separate dosage form(s) from the dosage form 5 containing the compound of the instant invention.

[0271] When the compound disclosed herein is used contemporaneously with one or more other therapeutic agents, the compound may be administered either simultaneously with, or before or after, one or more other therapeutic agent(s).

[0272] The weight ratio of the weight of the compound of the instant invention to the weight 10 of the additional therapeutic agent(s) may be varied and will depend upon the therapeutically effective dose of each agent. Generally, a therapeutically effective dose of each will be used. Combinations including at least one compound of the instant invention, and other therapeutic agents will generally include a therapeutically effective dose of each active agent. In such combinations, the compound of the present invention disclosed herein and other therapeutic 15 agents may be administered separately or in conjunction. In addition, the administration of one element may be prior to, concurrent with, or subsequent to the administration of other agent(s).

[0273] The activity of the MGAT2 inhibitors of the present invention can be measured in a variety of in vitro assays. Exemplary assays are shown in the Examples below. 20 Example A Human and Murine MGAT2 assays MGAT2 Sf9 microsome preparation 25

[0274] Following codon-optimization for baculovirus expression in Sf9 insect cells, the human or mouse MOGAT2 coding sequence (NM_025098 or NM_177448) was synthesized by Genscript (Piscataway, New Jersey) and cloned into pFastBacHT B. Recombinant MOGAT2- containing baculovirus was generated using standard protocols described in the Bac-to-Bac® 30 Baculovirus Expression System manual (Invitrogen). Sf9 insect cells were infected with human{H3007867.1}230 4927-5223-2016, v.1MOGAT2-containing baculovirus at a multiplicity of infection between 2.5 and 5 and harvested by centrifugation 72-h post-infection.

[0275] The Sf9 microsomal fraction containing recombinant MGAT2 protein was isolated by 5 differential centrifugation following lysis by sonication using a procedure adapted from that described by Hall et al. (Hall et al.2012. J. Lipid Res.53: 990-999). Cell pellets were resuspended in microsome buffer (20 mM HEPES pH 7.4, 0.5 M sucrose) containing protease inhibitor cocktail with EDTA (Sigma S8820) and lysed by sonication. Initial lysates were subjected to centrifugation at 5,000 x g for 15 min at 4ºC to remove cellular debris. The 10 supernatant was further clarified by centrifugation at 15,000 x g for an additional 15 min at 4 ºC. The clarified supernatant was then transferred to ultra-clear centrifuge tubes (Beckman 344060) and filled to capacity with microsome buffer. The samples were spun at 100,000 x g in a swinging bucket rotor (Beckman SW40Ti) for 60 min at 4ºC in a Beckman Optima XL-90K ultracentrifuge to pellet the Sf9 microsomal membrane fraction. The supernatant was discarded 15 and the pellet containing microsomal membranes was gradually resuspended on ice in microsome buffer. Total protein concentration was determined using the Pierce BCA Protein Assay Kit (Thermo Fisher) relative to a BSA standard curve. The final MGAT2 Sf9 microsome preparation was aliquoted and stored at -80 ºC prior to use. The presence of full-length recombinant His-tagged MGAT2 protein was confirmed by western blot using anti-MGAT2 20 (Abcam ab63156) and anti-6X His tag (Abcam ab18184) antibodies. MGAT2 Thiol-Fluorescence Enzyme Assay

[0276] MGAT2 enzyme activity was measured using a thiol-fluorescence assay similar to25 that described by Cao et al. (Cao et al.2011. J. Biol Chem.286(48): 41838-41851). Briefly, 7- Diethylamino-3-(4-maleimidophenyl)-4-methylcoumarin (CPM) fluoresces upon adduct formation with the free sulfhydryl of Coenzyme-A (CoA) which is released through the MGAT2-catalyzed transfer of a fatty acid chain from acyl-CoA to a monoacylglycerol acceptor substrate to form diacylglycerol. As such, fluorescence is proportional to the amount of CoA 30 product released in the course of the MGAT2 reaction.{H3007867.1}231 4927-5223-2016, v.1MGAT2 activity assays were conducted in 384 well plates in a total volume of 15 µL at room temperature. Human MGAT2 Sf9 microsomes (7.5 µg / mL) were incubated in the presence of 100 µM oleoyl-CoA and 100 µM 2-oleoylglycerol in assay buffer (100 mM HEPES pH 7.4, 150 5 mM NaCl, 0.05% Tween-20, 0.05% BGG) with various concentrations of test compound in duplicate. Following a 45 min incubation, the assay was terminated by addition of 5 µL of 400 µM CPM in 50% ethanol containing 2 µM Compound A (Onorato et al.2015. J. Lipid Res.56: 747-753). Assay plates were protected from light and incubated for an additional 90 min prior to measuring fluorescence on an EnVision plate reader (Perkin Elmer) with ex / em 355 / 490 nm. 10 Mouse MGAT2 activity assays were conducted similarly except 10 µg / mL microsomes were incubated in the presence of 100 µM oleoyl-CoA and 50 µM 2-oleoylglycerol. Fluorescence was plotted as a function of log molar compound concentration and fit to a four parameter dose- response equation to determine compound IC50. 15

[0277] Compounds of the present invention were tested in the MGAT2 assays described above, and the results in the hMGAT2 assay are shown in Table 32 below. Table 32 Patent 6A C 8 C Patent otenc 6B C 13B C2324927-5223-2016, v.123P A 13I A 23W B 19G A 11 C 23X B233 4927-5223-2016, v.116B C 45K A 27BM A 16A A 34H A 27BN B234 4927-5223-2016, v.145E A 27CQ A 45AJ B 38A B 27CU A 27CF A235 4927-5223-2016, v.127CM A 43B A 27ED A 27CN A 27DW A 27EE A; IC50= 10; = 1 mM – 30 mM; D: IC50> 30 mM 5

[0278] Assay in vivo 7 day Weight loss study 16 week old male C57BL / 6J-60% DIO mice were purchased from Jackson Laboratories (Sacramento, CA). The care and use of animals was conducted in accordance with the 10 regulations of the Association for Assessment and Accreditation of Laboratory Animal Care (AAALAC). The protocols and any amendments or procedures were reviewed and approved by the Institutional Animal Care and Use Committee (IACUC) of Invivotek prior to study initiation.

[0279] Table 1.7 day weight loss study workflow Treatment Compound Dose Dosing regimen Diet Group size15

[0280] Mice were individually housed (n=8) and maintained on a 12 hour light and dark schedule. Mice were fed water and a 60% high fat diet (Research Diets #12492) ad libitum. Mice were acclimated for 7 days. Mice were subsequently orally gavaged with water for 7{H3007867.1}236 4927-5223-2016, v.1days prior to initiating the study to reduce oral administration (PO) trauma-induced weight loss.

[0281] Three treatment groups were used in a 7 day weight loss study (Table 1). Group 1 received vehicle (0.5% Methocel), Group 2 received 15mg / kg of cmpd 27Q formulated in 5 vehicle, and Group 3 received 50mg / kg cmpd 27Q formulated in vehicle. Mice were dosed once per day (QD) by oral gavage administration (PO) for a total of 7 days. Body weights and food intake measurements were taken daily. Animals were euthanized at the end of the study.

[0282] The average body weight loss for Groups 2 and 3 mice over 7 days was 1.3 g and 2.5 g compared to Group 1 mice, respectively (Figure 1). The percentage change in body weight 10 for Groups 2 and 3 mice over 7 days was ~3.6 % and ~6.8% compared to Group 1 mice, respectively. (Figure 2). The differences in weight loss (p>0.0001) and percentage change in body weight (p>0.001) between Group 1, and Groups 2 and 3 mice, were significant compared to mice receiving vehicle alone using two-way mixed ANOVA analysis.

[0283] Groups 2 and 3 mice consumed 10% and 17% less food over a 24 hr period 15 compared to Group 1 mice, respectively (Figure 3). The difference in food consumption between Group 1 and 2 mice was significant using two-way mixed ANOVA analysis (p>0.01). The difference in food consumption between Group 1 and 3 mice was significant using two- way mixed ANOVA analysis (p>0.001).

[0284] The 7 day cumulative food intake of Groups 2 and 3 mice was reduced by 9% and 20 20% compared to Group 1, respectively (Figure 4). The difference in cumulative food intake between Group 1 and 3 mice was significant using two-way mixed ANOVA analysis (p>0.001). MASLD / MASH study

[0285] Table 2. Treatment Compound Dose Dosing regimen Diet Group size237 4927-5223-2016, v.14 cmpd 23AX 30mg / kg In-diet LMCD 8acclimated to their environment for 4 weeks while being fed a chow diet and water ad libitum (Purina Rodent Diet #5053 (Bound Brook, NJ). After 4 weeks, mice were divided into 4 5 groups (n=8) (Table 2). Group 1 negative control mice were maintained on the chow diet until the end of the study. Groups 2, 3, and 4 were fed a L-amino acid diet with 45% kcal fat, 0.1% methionine, minus choline diet (LMCD) (Research Diets #A19010803i) for 8 weeks before the initiation of treatment.. After 8 weeks, Group 2 positive control mice were maintained on the LMCD for an additional 16 weeks. Group 3 mice were fed the LMCD containing 30mg / kg of 10 the MGAT inhibitor BMS-963272 (BMS) in the diet for 16 weeks. Group 4 mice were fed the LMCD diet containing 30 mg / kg of the MGAT2 inhibitor cmpd 23AX in the diet for 16 weeks. After 16 weeks of treatment, mice were euthanized.

[0287] The levels of liver triglycerides in Group 2 LMCD positive control mice were elevated 2.3-fold over levels determined in livers from Group 1 chow negative control mice 15 (Figure 5). Liver triglycerides levels in Group 3 mice treated with BMS-963272 remained as high as Group 2 LMCD positive control mice and were 2.5-fold higher than levels determined in livers from Group 1 chow negative control mice. Triglycerides levels in livers from Group 4 mice treated with compound 23AX were ~20% less than levels observed in livers from Group 2 LMCD positive control and Group 3 mice treated with BMS-963272. The fold elevation in 20 triglycerides levels in Group 2 LMCD positive control mice compared to Group 1 chow negative control mice was significant using two-way mixed ANOVA analysis (p<0.0001). The percentage reduction in liver triglycerides levels for Group 4 mice treated with cmpd 23AX compared to Group 2 LMCD positive control mice (p>0.01) or Group 3 mice treated with BMS-963272 (p>0.01) were significant using two-way mixed ANOVA analysis. 25

[0288] Liver tissue section slides were stained with hematoxylin and eosin (H & E) staining. Stained slides were viewed by histology by an independent certified veterinary pathologist for the presence of MASLD. Liver tissue from Group 1 chow negative control mice displayed normal hepatocyte morphology without the presence of any signs of MASLD (Figure 6). Liver tissue from Group 2 LMCD positive control mice displayed signs of{H3007867.1}238 4927-5223-2016, v.1MASLD when compared to livers from Group 1 chow negative control mice, displaying micro- and macrovesicular steatosis. Liver tissue from Group 3 mice treated with 30 mg / kg BMS-963272 showed reduced signs of MASLD when compared to livers of Group 2 LMCD positive control mice, with a reduction in macrovesicular steatosis. Liver tissue from Group 4 5 mice treated with 30 mg / kg cmpd 23AX showed reduced signs of MASLD when compared to livers fed the Group 2 LMCD positive control diet, with a reduction in micro- and macrovesicular steatosis.

[0289] The appearance of liver fibrosis indicates the development of MASH. Histological liver tissue staining using picrosirius red was used to determine the level of 10 fibrosis (Figure 6). Sirius Red stains collagen fibers and is seen as long thin strands. Liver tissue from Group 1 chow negative control mice displayed no visible signs of fibrosis. Liver tissue from Group 2 LMCD positive control mice had signs of fibrosis when compared to livers from Group 1 chow negative control mice. Liver tissue from Group 3 mice treated with 30 mg / kg BMS-963272 had signs of fibrosis like those observed in livers of Group 2 LMCD positive 15 control mice. Liver tissue from Group 4 mice treated with 30 mg / kg cmpd 23AX showed reduced signs of fibrosis when compared to livers of Group 2 LMCD positive control mice.

[0290] AI-aided quantitative histology was used to calculate the percentage lipid area per tissue area (Figure 7). Group 1 chow negative control mice had an average percentage lipid area of 1%, Group 2 LMCD positive control mice had an average percentage lipid area of 17% 20 (p,0.0001), Group 3 mice treated with 30 mg / kg BMS-963272 had an average percentage lipid area of ~15% (p,0.05), Group 4 mice treated with 30mg / kg cmpd 23AX had an average percentage lipid area of ~11.5% (p<0.001). The differences between Groups 1 and 2 were significant using two-way mixed ANOVA analysis. The differences between Group 2, and Groups 3 and 4 were significant using two-way mixed ANOVA analysis. 25

[0291] AI-aided quantitative histological analysis was used to calculate the percentage fibrosis area per tissue area (Figure 8). Group 1 chow negative control mice had an average percentage fibrosis area of 0.5%, Group 2 LMCD positive control had an average percentage fibrosis area of 7% (p,0.0001), Group 3 mice (LMCD containing 30mg / kg BMS-963272) had an average percentage fibrosis area of 7.3% (p,0.05), Group 4 mice treated with 30mg / kg cmpd 30 23AX had an average percentage fibrosis area of 5.7% (p<0.001) . The difference between{H3007867.1}239 4927-5223-2016, v.1Group 1 chow negative control and Group 2 LMCD positive control mice was significant using two-way mixed ANOVA analysis. The differences between Group 2 LMCD positive control mice and Group 4 mice treated with 30mg / kg cmpd 23AX were significant using two-way mixed ANOVA analysis. 5

[0292] A hallmark sign of MASH is the elevated expression of inflammatory cytokines (22). The protein levels of the inflammatory cytokines, IL-17, TNFa, and IL-1b were elevated 4.5-, 7.2-, and 11.3-fold in the livers of Group 2 positive control mice over those same levels determined in livers from Group 1 chow negative control mice (Figure 9). The levels of IL-17 and TNFa were reduced by 45- and 75% in the livers of Group 3 mice treated with 30 mg / kg 10 BMS-963272 over those levels determined in livers from Group 2 LMCD positive control mice. The levels of IL-17, TNFa, and IL-1b were reduced by 27-, 43-, and 58% respectively in the livers of Group 4 mice treated with 30 mg / kg cmpd 23AX over those levels determined in livers from Group 2 LMCD positive control mice. The differences between Group 1 chow negative control mice and Group 2 LMCD positive control mice in protein expression of IL- 15 17, TNFa, and IL-1b were significant using two-way mixed ANOVA analysis (p<0.001). The differences in percentage reduction in protein expression of the cytokines between Group 2 LMCD positive control mice, and Groups 3 mice treated with 30 mg / kg BMS-963272 and Group 4 mice treated with 30 mg / kg cmpd 23AX were significant using two-way mixed ANOVA analysis (p<0.002). 20

[0293] Weigh loss study in combination with GLP-1 drugs Table 3.22-day tirzepatide / semaglutide combination weight loss study Groups Compound Dose Dosing regiment Diet Group size{H3007867.1}240 4927-5223-2016, v.14 cmpd 27Q 50mg / kgS.C., QD (vehicle)60% HFD 8 PO, QD.

[0294] Sixteen-week old DIO mice were individually housed (n=8) and maintained on a 12 hour light and dark schedule. Mice were fed water and a 60% high fat diet (Research Diets 5 #12492) ad libitum. Upon arrival to Invivotek, mice were acclimated to the facility for 7 days. Mice were subsequently orally gavaged with water for 7 days prior to initiating the study to reduce oral administration (PO) trauma-induced weight loss.

[0295] Eight treatment groups of DIO mice were used in a 22-day study aimed at 10 determining the weight loss effects of combining cmpd 27Q with tirzepatide or semaglutide vs. tirzepatide or semaglutide alone (Table 3). Group 1 vehicle mice were administered 2 vehicle formulations (PBS, S.C.; 0.5% Methocel, PO) because tirzepatide and semaglutide were administered by subcutaneous injection and cmpd 27Q was given as an oral suspension in 0.5% Methocel. The corresponding vehicle was always co-administered depending on drug(s) 15 treatment.

[0296] Group 2 maximum tirzepatide dose mice received 3nmol / kg of tirzepatide by subcutaneous injection (S.C.) once per day (QD) (Table 3). Group 3 semaglutide maximum dose mice received 10nmol / kg of semaglutide by subcutaneous injection (S.C.) once per day{H3007867.1}241 4927-5223-2016, v.1(QD). Group 4 mice received 50mg / kg of cmpd 27Q orally (PO) once per day (QD). Group 5 minimum semaglutide dose mice received 1nmol / kg of semaglutide by subcutaneous injection (S.C.) once per day (QD). Group 6 maximum tirzepatide dose + cmpd 27Q mice received 3nmol / kg tirzepatide by subcutaneous injection (S.C.) once per day (QD) and 50mg / kg of 5 cmpd 27Q orally (PO) once per day. Group 7 maximum semaglutide dose + 27Q mice received 10nmol / kg tirzepatide by subcutaneous injection (S.C.) once per day (QD) and 50mg / kg of cmpd 27Q orally (PO) once per day. Group 8 minimum semaglutide dose + cmpd 27Q mice received 10nmol / kg semaglutide by subcutaneous injection (S.C.) once per day (QD) and 50mg / kg of cmpd 27Q orally (PO) once per day. The per cent body weight change 10 over time was measured on specific days.

[0297] The end of study per cent change in body weight between Group 1 vehicle mice and Group 2 maximum tirzepatide dose mice was -17.8% ( Figure 10). The end of study per cent change in body weight between Group 1 vehicle mice and Group 3 maximum semaglutide 15 dose mice was -14.3% ( Figure 11). The end of study per cent change in body weight between Group 1 vehicle mice and Group 4 cmpd 27Q-treated mice was -2.43% (Figure 10). The end of study per cent change in body weight between Group 1 vehicle mice and Group 5 minimum semaglutide dose mice was -0.28% (Figure 12 ). The end of study per cent change in body weight between Group 1 vehicle mice and Group 6 maximum tirzepatide dose + cmpd 27Q 20 after 17 days was -38% (Figure 10). The end of study per cent change in body weight between Group 1 vehicle mice and Group 7 maximum semaglutide dose + cmpd 27Q after 17 days was -32% (Figure 11). The end of study per cent change in body weight between Group 1 vehicle mice and Group 8 minimum semaglutide dose + cmpd 27Q mice was -16.8% (Figure 12). In all combination treatments with cmpd 27Q, the addition of cmpd 27Q was synergistic in 25 further reducing the per cent change in body weight when given with high dose tirzepatide, high dose semaglutide, and low dose semaglutide.

[0298] The percentage changes in body weights were significant between the Group 1 vehicle mice and Groups 2-8 mice were significant (p<0.0001 – p<0.001) The percentage 30 changes in body weights were significant between the Group 2 high dose tirzepatide mice and{H3007867.1}242 4927-5223-2016, v.1Group 6 high dose tirzepatide + cmpd 27Q mice (p<0.001). The per cent changes in body weights were significant between the Group 3 high dose semaglutide mice and Group 7 high semaglutide dose + cmpd 27Q mice (p<0.001). Statistical analysis was carried out using two- way ANOVA mixed model analysis. 5

[0299] End of study cumulative food intake was calculated by summing the food intake taken on specific days. The total food consumed by Group 2 high dose tirzepatide mice was less than that consumed by Group 1 vehicle mice by 35% (p<0.001) (Figure 13). The total food consumed by Group 3 high dose semaglutide mice was less than that consumed by Group 10 1 vehicle mice by ~24% (p<0.001). The total food consumed by Group 6 high dose tirzepatide + cmpd 27Q mice was less than that consumed by Group 1 vehicle mice by ~ 84% (p<0.0001). The total food consumed by Group 7 high dose semaglutide + cmpd 27Q mice was less than that consumed by Group 1 vehicle mice by ~77% (p<0.0001). 15

[0300] The total food consumed by Group 7 low dose semaglutide + cmpd 27Q mice was less than that consumed by Group 1 vehicle mice by ~27% (p<0.001). The total food consumed by Group 6 high dose tirzepatide + cmpd 27Q mice was less than that consumed by Group 2 high dose tirzepatide mice by ~75%, resulting in a further 4-fold reduction in food consumption over the food consumed by Group 2 high dose tirzepatide mice (p<0.0005). The 20 total food consumed by Group 7 high dose semaglutide + cmpd 27Q mice was less than that consumed by Group 3 high dose semaglutide mice by ~70%, resulting in a further 3.3-fold reduction in food consumption over the food consumed by Group 3 high dose semaglutide mice (p<0.0001). The total food consumed by Group 8 low dose semaglutide + cmpd 27Q mice was less than that consumed by Group 5 low dose semaglutide mice, resulting in a further 25 1.4-fold reduction in food consumed over that consumed by Group 5 low dose semaglutide mice (p<0.0001). In all combination treatments with cmpd 27Q, the addition of cmpd 27Q was synergistic in further reducing cumulative food consumption when given with high dose tirzepatide, high dose semaglutide, and low dose semaglutide. Statistical analysis was carried out using two-way ANOVA mixed model analysis. 30{H3007867.1}243 4927-5223-2016, v.1

[0301] While it is apparent that the embodiments of the application herein disclosed are well suited to fulfill the objectives stated above, it will be appreciated that numerous modifications and other embodiments may be implemented by those skilled in the art, and it is intended that the appended claims cover all such modifications and embodiments that fall within the true spirit and 5 scope of the present application.{H3007867.1}244 4927-5223-2016, v.1

Claims

1. WHAT IS CLAIMED IS:

1. A compound of formula: 5 wherein R1is chosen from -OH, -NHC(=O)R10, and -NHCH2R11, R2is chosen from hydrogen, (C1-C4)alkyl, (C1-C4)alkoxy, fluoro(C1-C4)alkyl, and halogen; Ar1is phenyl or a 6-membered heteroaryl; L1is a two-atom linker chosen from -CH2O-, -C(=O)NH-, -CH2C(=O)-, -C(=O)N(CH3)-, 10 and -CH2N(CH3)-; B is a 4- to 7-membered carbomonocycle or heterocycle, each optionally substituted with methyl; L2is a linker chosen from a direct bond, -C(=O)NHCH2- , -CH2C(=O)NHCH2-, -C(=O)NH-, - CH2-, -CH(OH)-, -C(=O)NHCH2CH2-, -CH2NHC=O-, -C(=O)OCH2-, -CH2-, -C(=O)-, - 15 NHC(=O)NH-, W is chosen from (C2-C6)alkyl, (C1-C6)oxaalkyl, fluoro(C1-C6)alkyl, fluoro(C1-C6)oxaalkyl, (C3-C6)cycloalkyl, , wherein Ar2is phenyl, or heteroa ; R3is hydrogen or one to three substituents independently chosen from (C1-C4)alkyl, (C1- 20 C4)alkoxy, (C1-C4)fluoroalkyl, (C1-C4)fluoroalkoxy, -NH(C1-C4)alkyl, -NH(C1-C4)fluoroalkyl, cyano, and halogen, with the proviso that, when L2is -CH2C(=O)NHCH2-, then R3includes only a single fluorine;{H3007867.1}245 4927-5223-2016, v.15 R10is chosen from methyl; trifluoromethyl; phenyl, optionally substituted independently with one or more methoxy or halo; 5-membered heterocyclyl, optionally substituted independently with one or more methyl or trifluoromethyl, or fused with phenyl; 6-membered heteroaryl; and C5 or C6 cycloalkyl, and R11is chosen from 5-membered heterocyclyl, optionally substituted independently with one or 10 more methyl or trifluoromethyl, or fused with phenyl; 6-membered heteroaryl; and C5or C6cycloalkyl.

2. A compound according to claim 1 wherein R1is -NHC(=O)R10. 15 3. A compound according to claim 2 wherein R10is chosen from optionally substituted phenyl, optionally substituted 5-membered heterocyclyl, 6-membered heteroaryl, and bicyclic heteroaryl.

4. A compound according to claim 3 wherein R10is optionally substituted 5-membered 20 heterocyclyl.

5. A compound according to claim 4 wherein R10is 5-membered heteroaryl optionally substituted with methyl. 25 6. A compound according to claim 3 wherein R10is chosen from thiophene, furan, thiazole, isothiazole, isoxazole, pyrazole, oxazole, thiadiazole, tetrahydrofuran, triazole, benzofuran, and imidazole.

7. A compound according to claim 3 wherein said 6-membered heteroaryl is pyridine. 30{H3007867.1}246 4927-5223-2016, v.

18. A compound according to claim 1 wherein R1is -OH.

9. A compound according to any of claims 1 to 8 wherein R2is 5-methyl. 5 10. A compound according to any of claims 1 to 8 wherein Ar1is phenyl, pyrazine or pyridine.

11. A compound according to any of claims 1 to 8 wherein B is chosen from pyridine, piperidine, piperazine, azetidine, and phenyl. 10 12. A compound according to claim 11 wherein B is piperidine, piperazine, or azetidine and L2is a direct bond.

13. A compound according to claim 11 wherein L1and L2are para to one another on said 15 pyridine, piperidine, piperazine, azetidine, or phenyl.

14. A compound according to any of claims 1 to 8 wherei 2 ischosen from phenyl, pyridine, and pyrimidine.20 15. A compound according to claim 14 wherein Ar2is phenyl and R3is hydrogen or one or two substituents independently chosen from -CF3, -OCF3, F, iPr, Cl, CH3, -OCH2CH3, CN, -CH2CF3, -OCH3, -NHCH2CF3, -OCH2CH2CF3, -OCHF2, -NHCH2CH2CF3, and -NHCH2CH3. 25 16. A compound according to claim 14 wherein Ar2is pyridine and R3is hydrogen or one or two substituents independently chosen from -CF3, -OCF3, and (C1-C4)alkyl.{H3007867.1}247 4927-5223-2016, v.

117. A compound according to claim 14 wherein Ar2is pyrimidine and R3is hydrogen or one or two substituents independently chosen from -CF3, -NH(C1-C4)fluoroalkyl, (C1-C4)alkyl, and -NH(C1-C4)alkyl. 5 18. A compound according to any of claims 1 to 8 wherein W is chosen from cyclopentyl, - CH2CF3, -CH(CH3)2, -(CH2)4CH3, -(CH2)3CH3, -CF3, -(CH2)5CH3, and -CH2O(CH2)2CH3.

19. A compound according to any of claims 1 to 8 wherein R2is chosen from 4-methoxy, 4- fluoro, hydrogen, 4-isopropyl, 4-trifluoromethyl, and 5-methyl. 10 20. A compound of formula: whereinR2is chosen from hydrogen, (C1-C4)alkyl, (C1-C4)alkoxy, fluoro(C1-C4)alkyl, and fluorine; 15 Ar1is phenyl or a 6-membered heteroaryl; L1is a two-atom linker chosen from -CH2O-, -C(=O)NH-, -CH2C(=O)-, -C(=O)N(CH3)-, and -CH2N(CH3)-; B’ is a 6-membered carbomonocycle or heterocycle, in which L1and L2are meta or para to each other; 20 L2’is a linker chosen from a direct bond, -C(=O)NHCH2- , -CH2C(=O)NHCH2-, -C(=O)NH-, - CH2-, -C(=O)NHCH2CH2-, -CH2NHC=O-, -C(=O)OCH2-, -CH2-, -C(=O)-, -NHC(=O)NH-, W is chosen from (C2-C6)alkyl, (C1-C6)oxaalkyl, fluoro(C1-C6)alkyl, fluoro(C1-C6)oxaalkyl, (C3-C6)cycloalkyl, , wherein Ar2is{H3007867.1}248 4927-5223-2016, v.1phenyl, or heteroaryl other than pyrazine; R3is hydrogen or one to three substituents independently chosen from (C1-C4)alkyl, (C1- C4)alkoxy, (C1-C4)fluoroalkyl, (C1-C4)fluoroalkoxy, -NH(C1-C4)alkyl, -NH(C1-C4)fluoroalkyl, cyano, and halogen. 5 21. A compound according to claim 20 of formula: whereinAr1is chosen from phenyl, pyridine and pyrazine; 10 L1is a two-atom linker chosen from -CH2O- and -C(=O)NH-; B’ is chosen from pyridine, phenyl, and piperidine; L2’is a linker chosen from: (c) when B’ is piperidine: a direct bond, -C(=O)NH-, -CH2-, -C(=O)NHCH2-, and -C(=O)-; and 15 (d) when B’ is phenyl or pyridine: -C(=O)NHCH2- , -CH2C(=O)NHCH2-, -C(=O)NH-, - CH2-, and -NHC(=O)NH-; W is chosen from (C2-C6)alkyl, (C1-C6)oxaalkyl, fluoro(C1-C6)alkyl, fluoro(C1-C6)oxaalkyl, , wherein Ar2is phenyl or pyridine; andor two substituents independently chosen from (C1-C4)fluoroalkyl, (C1- 20 C4)fluoroalkoxy, -NH(C1-C4)alkyl, -NH(C1-C4)fluoroalkyl, and halogen.

22. A compound according to claim 20 chosen from Table 32.{H3007867.1}249 4927-5223-2016, v.

123. A compound according to claim 21 chosen from Examples 1, 2, 2A, 2C, 2D, 2E, 2F, 2G, 2h, 2I, 5, 5A, 5B, 5C, 6, 6A, 6B, 6C, 6D, 6E, 9, 10, 10B, 11, 12, 12B, 13, 13B, 13D, 13F, 13H, 13K, 13M, 14A, 14C, 14E, 15, 15B, 15C, 16, 16B, 16C, 17B, 17D, 17F, 18, 19, 19F, 19H, 20, 21, 21B, 21C, 21D, 21I, 22, 22B, 23B, 23C, 23D, 23L, 23M, 23N, 230, 23V, 23W, 23X, 23Y, 5 23Z, 23AI, 23AJ, 23AK, 23AO, 23AT, 23AU, 24, 24B, 24C, 24E, 24G, 24I, 24K, 24M, 24N, 24O, 25, 27, 27B, 27D, 27E, and 27DG,.

24. A pharmaceutical composition comprising a compound of claim 1 or claim 21 and one or more pharmaceutically acceptable carrier. 10 25. A method for preventing or treating metabolic dysfunction-associated steatotic liver disease (MASLD) comprising administering a compound of claim 1 or claim 21 to a subject in need thereof. 15 26. A method for preventing or treating obesity comprising administering a compound of claim 1 or claim 21 to a subject in need thereof.{H3007867.1}250 4927-5223-2016, v.1

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