Compounds of Formula (I) and Formula (II), pharmaceutically acceptable salt thereof, stereoisomers of any of the foregoing, or mixtures thereof are agonists of the APJ Receptor and have use in treating cardiovascular and other conditions. Compounds of Formula (I) and Formula (II) have the following structures: (I); (II). Intermediates (V) are also claimed. [structure]

Description

73 parts

›CROSS REFERENCES TO RELATED APPLICATIONS

This application claims the benefit of U.S. Provisional Application No. 62/422,688, filed on Nov. 16, 2016, which is hereby incorporated by reference in its entirety and for all purposes as if fully set forth herein.

›FIELD OF THE INVENTION

The present invention relates to compounds capable of acting as agonists of the APJ Receptor, and compositions that include compounds that are agonists of the APJ Receptor. The compounds and compositions may be used to activate the APJ Receptor and to treat various disease conditions. An example of one area where such compounds may be used is in the treatment of cardiovascular conditions. In particular, the compounds may be used to improve contractility and ejection fraction in subjects with chronic heart failure and may be used to treat patients with heart failure with reduced ejection fraction and patients with heart failure with preserved ejection fraction.

›BACKGROUND OF THE INVENTION

Apelin is the endogenous ligand for APJ (APLNR, angiotensin receptor like-1). The APJ receptor is a member of the rhodopsin-like G protein-coupled receptor (GPCR) family. The apelin/APJ system has been observed in many tissues such as heart, kidney, pancreas, lung and the central nervous system. This suggests diverse roles of the system in the physiology and pathology of mammals.

Apelin peptides are processed from a 77 residue pre-pro form into smaller bioactive fragments, mainly a 36 residue form (Apelin 42-77—also referred to as Apelin-36) and a smaller 13 residue polypeptide (Apelin 65-77—also referred to as Apelin-13) Hosoya et al., J. Biol. Chem. 275:21061-21067, 2000. Apelin peptides were previously determined to be endogenous ligands for the orphan APJ receptor, a member of the seven transmembrane G-protein-coupled receptor superfamily. Tatemoto et al., Biochem. Biophysi. Res. Commun. 251:471-476, 1998. One of the shorter more active isoforms identified, pyroglutamated apelin-13 ([PE65]Apelin-13 (65-77), has been reported to be the most potent and abundant form of apelin in cardiac tissue. Maguire et al., Hypertension 54:598-604, 2009. In vitro and preclinical models have suggested that the apelin/APJ system has a role in cardiovascular homeostasis as well as metabolism. Barnes et al., Heart 96:1011-1016, 2010. Circulating apelin levels are transient and Apelin-13 has a brief plasma half-life of <5 min leading to short-lived cardiovascular effects.

In vitro, exogenous apelin increases contractility at subnanomolar concentrations in atrial strips and whole rat hearts, and increases sarcomere shortening by up to 140% in isolated cardiomyocyctes. Barnes et al., Heart 96:1011-1016, 2010. Apelin also has a potent inotropic effect in an ex vivo isolated heart assay. In vivo, acute apelin infusion restores ejection fraction, increases cardiac output and reduces left ventricular end-diastolic pressure in rats with chronic heart failure. Berry et al., Circulation 110:187-193, 2004. Exogenous apelin potently enhances myocardial contractility without inducing left ventricular hypertrophy concomitant with reduction in ventricular preload and afterload. Barnes et al., Heart 96:1011-1016, 2010.

Studies from Kawamata et al and Hosoya et al have shown that that shorter peptide apelin-13 had approximately a 3.5-fold higher in vitro affinity to the APJ receptor than apelin-36. Kawamata et al., BBA 1538: 162-171, 2001, Hosoya et al., JBC 275: 21061-21067. Apelin-13 analogues were reported having a single substitution with either canonical or non-canonical amino acids. The authors also reported double and triple substitutions in apelin 66-77 and apelin 63-77, but not in apelin-13. The emphasis was on peptides reported to have higher in vitro affinity and potency than apelin-13. Nishizawa et al., in: T. Shioiri (ed.), Peptide Science 2000: Proceedings of the 37 th Japanese Peptide Symposium, pp. 151-154. Several if not all of these modified peptides are reported in later studies. U.S. Pat. No. 7,635,751.

In a 2003 study (Medhurst et al., J. Neurochemistry 84:1162-1172, 2003) in vitro activity of apelin-36, apelin-17 and apelin-13 was compared. It was concluded that all three peptides were approximately equipotent. C-terminal amidation resulted in about a 14-fold decrease in affinity. A more recent study (Hamada et al., J. Mol. Med. 22:547-552, 2008) reported cyclic analogues of apelin-13. When tested for in vitro activity all three analogues maintained function activity, although with reduced potency relative to apelin-13.

A shortened 12 amino acid-apelin peptide having ligand activity on APJ was reported in a 2009 patent (U.S. Pat. No. 7,635,751). The peptide could have a substitution of one non-canonical amino acid. In another application, WO 2013/111110 A2 and U.S. Pat. No. 8,673,848, cyclic mimetics of apelin have also been reported.

Another study reported synthesizing analogs of apelin-13 with amino acid substitutions with non-canonical amino acids at the C-terminal end of the molecule but no pegylation at the N- or C-terminus or another site specific location. The use of internal PEG spacers (short PEG (n=4 or 6), however, was also reported in lower activity peptide analogs with deletions in the middle of the sequence that contained fewer amino acid residues than apelin-13. Murza et al. Chem Med Chem 7:318-325, 2012. Additionally, PCT/US2013/075773 describes a group of modifications, including substitution of non-canonical amino acids and changes at the N- and C-terminal of the apelin molecule that can affect, inter alfa, the potency of the molecule. The increased potency can be a result of increased half-life or decreased degradation relative to wild-type apelin.

Despite the advancements that have been made with respect to peptides, a need exists for small molecule agonists of the APJ receptor. However, some progress has been made in this area. For example, WO 2014/044738 discloses various benzimidazole-carboxylic acid amide derivatives as modulators of the APJ Receptor. Other small molecule agonists of the APJ receptor are disclosed in U.S. Pat. Appl. Pub. No. US 2016/0340336, WO 2016/187308, WO 2015/184011, and WO 2015/188073.

A need continues to exist for agonists of the APJ receptor that may be used to treat various cardiovascular and other conditions. The present application discloses such agonists of the APJ receptor s that may be suitable for use as therapeutic agents in treating a variety of conditions. These compounds may find particular benefit in treating cardiovascular conditions. For example, such compounds may be beneficial in treating conditions such as chronic systolic heart failure and chronic diastolic heart failure.

›SUMMARY OF THE INVENTION · 1 of 3

In one aspect, the invention provides a compound of Formula I or Formula II:

or a pharmaceutically acceptable salt thereof, a tautomer thereof, a pharmaceutically acceptable salt of the tautomer, a stereoisomer of any of the foregoing, or a mixture thereof,

wherein:

R 1 is an unsubstituted furanyl, or is a furanyl substituted with 1, 2, or 3 R 1a substituents;

R 1a in each instance is independently selected from —F, —Cl, —Br, —I, —C 1 -C 6 alkyl, —C 1 -C 6 haloalkyl, —C 1 -C 6 perhaloalkyl, —(C 1 -C 6 alkyl)-O—(C 1 -C 6 alkyl), —CN, —OH, —O—(C 1 -C 6 alkyl), —O—(C 1 -C 6 haloalkyl), —O—(C 1 -C 6 perhaloalkyl), —C 2 -C 6 alkenyl, —O—(C 1 -C 6 alkyl)-OH, —O—(C 1 -C 6 alkyl)-O—(C 1 -C 6 alkyl), —O—(C 1 -C 6 haloalkyl)-OH, —O—(C 1 -C 6 haloalkyl)-O—(C 1 -C 6 alkyl), —O—(C 1 -C 6 perhaloalkyl)-OH, —O—(C 1 -C 6 perhaloalkyl)-O—(C 1 -C 6 alkyl), —NH 2 , —NH(C 1 -C 6 alkyl), —N(C 1 -C 6 alkyl) 2 , —C(═O)—(C 1 -C 6 alkyl), —C(═O)OH, —C(═O)—O—(C 1 -C 6 alkyl), —C(═O)NH 2 , —C(═O)NH(C 1 -C 6 alkyl), or —C(═O)N(C 1 -C 6 alkyl) 2 ;

R 2 is selected from —H, or C 1 -C 4 alkyl or is absent in the compounds of Formula II;

R 3 is selected from an unsubstituted C 1 -C 10 alkyl, a C 1 -C 10 alkyl substituted with 1, 2, or 3 R 3a substituents, a group of formula —(CR 3b R 3c )-Q, a group of formula —(CR 3b R 3c )—C(═O)-Q, a group of formula —(C 3d R 3e )—(CR 3f R 3g )-Q, a group of formula —(CR 3d R 3e )—(CR 3f R 3g )—C(═O)-Q, a group of formula —(CR 3d R 3e )—(CR 3f R 3g )—CH(OH)-Q, a group of formula —(CR 3d R 3e )—(CR 3f R 3g )—(CR 3f R 3g )-Q, a group of formula —(CR 3b ═CR 3c )-Q, a group of formula —(C 3 -C 8 cycloalkyl)-Q, a group of formula -(heterocyclyl)-Q, or -Q, wherein the heterocyclyl of the -(heterocyclyl)-Q group has 5 to 7 ring members of which 1, 2, or 3 are heteroatoms independently selected from N, O, or S and is unsubstituted or is substituted with 1, 2, or 3 R 3h substituents, and further wherein the C 3 -C 8 cycloalkyl of the —(C 3 -C 8 cycloalkyl)-Q group is unsubstituted or is substituted with 1 or 2 R 3h substituents;

R 3a in each instance is independently selected from —F, —Cl, —CN, —OH, —O—(C 1 -C 6 alkyl), —O—(C 1 -C 6 haloalkyl), —O—(C 1 -C 6 perhaloalkyl), —O—(C 1 -C 6 alkyl)-OH, —O—(C 1 -C 6 alkyl)-O—(C 1 -C 6 alkyl), —C 2 -C 6 alkenyl, —C 2 -C 6 alkynyl, —NH 2 , —NH(C 1 -C 6 alkyl), or —N(C 1 -C 6 alkyl) 2 ;

R 3b and R 3c are independently selected from —H, —F, —Cl, —CN, —C 1 -C 6 alkyl, —C 1 -C 6 haloalkyl, —C 1 -C 6 perhaloalkyl, —OH, —O—(C 1 -C 6 alkyl), —O—(C 1 -C 6 haloalkyl), —O—(C 1 -C 6 perhaloalkyl), —O—(C 1 -C 6 alkyl)-OH, —O—(C 1 -C 6 alkyl)-O—(C 1 -C 6 alkyl), —NH 2 , —NH(C 1 -C 6 alkyl), or —N(C 1 -C 6 alkyl) 2 ;

R 3d and R 3e are independently selected from —H, —F, —Cl, —CN, —C 1 -C 6 alkyl, —C 1 -C 6 haloalkyl, —C 1 -C 6 perhaloalkyl, —OH, —(C 1 -C 6 alkyl)-OH, —(C 1 -C 6 alkyl)-O—(C 1 -C 6 alkyl), —O—(C 1 -C 6 alkyl), —O—(C 1 -C 6 haloalkyl), —O—(C 1 -C 6 perhaloalkyl), —O—(C 1 -C 6 alkyl)-OH, —O—(C 1 -C 6 alkyl)-O—(C 1 -C 6 alkyl), —NH 2 , —NH(C 1 -C 6 alkyl), or —N(C 1 -C 6 alkyl) 2 ;

R 3f and R 3g are independently selected from —H, —F, —Cl, —CN, —C 1 -C 6 alkyl, —C 1 -C 6 haloalkyl, —C 1 -C 6 perhaloalkyl, —OH, —(C 1 -C 6 alkyl)-OH, —(C 1 -C 6 alkyl)-O—(C 1 -C 6 alkyl), —O—(C 1 -C 6 alkyl), —O—(C 1 -C 6 haloalkyl), —O—(C 1 -C 6 perhaloalkyl), —O—(C 1 -C 6 alkyl)-OH, —O—(C 1 -C 6 alkyl)-O—(C 1 -C 6 alkyl), —NH 2 , —NH(C 1 -C 6 alkyl), or —N(C 1 -C 6 alkyl) 2 ;

R 3h in each instance is independently selected from —F, —Cl, —CN, —C 1 -C 6 alkyl, —C 1 -C 6 haloalkyl, —C 1 -C 6 perhaloalkyl, —OH, —O—(C 1 -C 6 alkyl), —O—(C 1 -C 6 haloalkyl), —O—(C 1 -C 6 perhaloalkyl), —O—(C 1 -C 6 alkyl)-OH, —O—(C 1 -C 6 alkyl)-O—(C 1 -C 6 alkyl), —NH 2 , —NH(C 1 -C 6 alkyl), —N(C 1 -C 6 alkyl) 2 , —C(═O)—(C 1 -C 6 alkyl), —C(═O)—(C 3 -C 6 cycloalkyl), —C(═O)—O—(C 1 -C 6 alkyl), oxo, or —C(═O)-(heterocyclyl), wherein the heterocyclyl group of the R h —C(═O)-(heterocyclyl) has 5 or 6 ring members of which 1 or 2 are heteroatoms independently selected from N, or S or has 3 or 4 ring members of which 1 is a heteroatom selected from N, O, or S;

Q is a monocyclic or bicyclic C 6 -C 10 aryl group, a monocyclic or bicyclic heteroaryl group with 5 to 10 ring members containing 1, 2, or 3 heteroatoms independently selected from N, O, or S, a C 3 -C 8 cycloalkyl group, a 3 to 10 membered heterocyclyl group containing 1, 2, or 3 heteroatoms independently selected from N, O, or S, —C(═O)NH(—C 1 -C 6 alkyl), —C(═O)N(—C 1 -C 6 alkyl) 2 , or S(═O) 2 —C 1 -C 6 alkyl, wherein the C 6 -C 10 aryl, the heteroaryl, the cycloalkyl, and the heterocyclyl Q groups are unsubstituted or are substituted with 1, 2, 3, or 4 R Q substituent;

R Q in each instance is independently selected from —F, —Cl, —Br, —I, —CN, —C 1 -C 6 alkyl, —C 1 -C 6 haloalkyl, —C 1 -C 6 perhaloalkyl, —C 2 -C 6 alkenyl, —C 2 -C 6 alkynyl, —OH, —O—(C 1 -C 6 alkyl), —O—(C 1 -C 6 haloalkyl), —O—(C 1 -C 6 perhaloalkyl), —NH 2 , —NH(C 1 -C 6 alkyl), —N(C 1 -C 6 alkyl) 2 , —NHC(═O)(C 1 -C 6 alkyl), —C(═O)—(C 1 -C 6 alkyl), —C(═O)OH, —C(═O)—O—(C 1 -C 6 alkyl), —C(═O)NH 2 , —C(═O)NH(C 1 -C 6 alkyl), —C(═O)N(C 1 -C 6 alkyl) 2 , —S(═O) 2 —(C 1 -C 6 alkyl), —(C 1 -C 6 alkyl)-OH, —(C 1 -C 6 alkyl)-O—(C 1 -C 6 alkyl), phenyl, a heterocyclyl group, a —(C 1 -C 6 alkyl)heterocyclyl group, or a heteroaryl group with 5 or 6 ring members and 1, 2, or 3, heteroatoms independently selected from N, O, or S, wherein the heterocyclyl groups of the R Q heterocyclyl and —(C 1 -C 6 alkyl)heterocyclyl groups have 3 to 6 ring members of which 1 or 2 are heteroatoms independently selected from N, O, or S, wherein the Q heterocyclyl group may additionally be substituted with 1 or 2 oxo substituents, and the Q heteroaryl group may include an N-oxide if the heteroaryl includes a N heteroatom, and further wherein the heterocyclyl and the heterocyclyl of the (C 1 -C 6 alkyl)heterocyclyl R Q groups may be further substituted with one or two oxo substituents and a substituent selected from —F, —Cl, —Br, —I, —CN, —OH, —C 1 -C 6 alkyl, or —C(═O)—(C 1 -C 6 alkyl);

›SUMMARY OF THE INVENTION · 2 of 3

R 4 is selected from a monocyclic or bicyclic C 6 -C 10 aryl group, a monocyclic or bicyclic heteroaryl group with 5 to 10 ring members containing 1, 2, or 3 heteroatoms independently selected from N, O, or S, a monocyclic or bicyclic heterocyclyl group with 5 to 10 ring members containing 1, 2, 3, or 4 heteroatoms independently selected from N, O, or S, a monocyclic 3-6 membered cycloalkyl group, or a straight or branched chain C 1 -C 6 alkyl group, wherein the C 6 -C 10 aryl, the heteroaryl, the heterocyclyl, and the cycloalkyl R 4 group are unsubstituted or are substituted with 1, 2, 3, or 4 R 4a substituents, and further wherein the straight or branched chain C 1 -C 6 alkyl R 4 group is unsubstituted or is substituted with 1, 2, or 3 R 4b substituents;

R 4a in each instance is independently selected from —F, —Cl, —Br, —I, —CN, —C 1 -C 6 alkyl, —C 1 -C 6 haloalkyl, —C 1 -C 6 perhaloalkyl, —(C 1 -C 6 alkyl)-OH, —(C 1 -C 6 alkyl)-O—(C 1 -C 6 alkyl), —OH, —O—(C 1 -C 6 alkyl), —O—(C 1 -C 6 haloalkyl), —O—(C 1 -C 6 perhaloalkyl), —NH 2 , —NH(C 1 -C 6 alkyl), —N(C 1 -C 6 alkyl) 2 , NH(C 1 -C 6 alkyl-OH), —N(C 1 -C 6 alkyl-OH) 2 , —C(═O)—(C 1 -C 6 alkyl), —C(═O)OH, —C(═O)—O—(C 1 -C 6 alkyl), —C(═O)NH 2 , —C(═O)NH(C 1 -C 6 alkyl), —C(═O)N(C 1 -C 6 alkyl) 2 , phenyl, —S(═O) 2 —(C 1 -C 6 alkyl), —(C 1 -C 6 alkyl)-heterocyclyl, or heterocyclyl wherein the heterocyclyl of the —(C 1 -C 6 alkyl)-heterocyclyl and heterocyclyl R 4a groups is a 3-6 membered ring comprising 1 or 2 heteroatoms independently selected from N, O, or S, and is unsaturated or partially unsaturated and is optionally substituted with 1 or 2 oxo substituents and may include an S═O or SO 2 moiety, and further wherein the heterocyclyl of the R 4 group may be further substituted with 1 oxo substituent; and

R 4b in each instance is selected from —F, —Cl, —Br, —I, —CN, —OH, —O—(C 1 -C 6 alkyl), —O—(C 1 -C 6 haloalkyl), —O—(C 1 -C 6 perhaloalkyl), —NH 2 , —NH(C 1 -C 6 alkyl), —N(C 1 -C 6 alkyl) 2 , NH(C 1 -C 6 alkyl-OH), —N(C 1 -C 6 alkyl-OH) 2 , —C(═O)—(C 1 -C 6 alkyl), —C(═O)OH, —C(═O)—O—(C 1 -C 6 alkyl), —C(═O)NH 2 , —C(═O)NH(C 1 -C 6 alkyl), —C(═O)N(C 1 -C 6 alkyl) 2 , or —S(═O) 2 —(C 1 -C 6 alkyl).

Numerous other embodiments of the compound of Formula I and Formula II are set forth herein.

Also provided are pharmaceutical compositions that include at least one pharmaceutically acceptable excipient, carrier or diluent and the compound or the pharmaceutically acceptable salt thereof, the tautomer thereof, the pharmaceutically acceptable salt of the tautomer, the stereoisomer of any of the foregoing, or the mixture thereof according to any one of the embodiments.

In other embodiments, the invention provides a method of treating a cardiovascular condition. Such methods typically include administering to a subject an effective amount of the compound or the pharmaceutically acceptable salt thereof, the tautomer thereof, the pharmaceutically acceptable salt of the tautomer, the stereoisomer of any of the foregoing, or the mixture thereof according to any one of the embodiments or a pharmaceutical composition of any of the embodiments. In some such embodiments, the cardiovascular condition is heart failure. In some such embodiments, the cardiovascular condition is heart failure with reduced ejection fraction whereas in other embodiments it is heart failure with preserved ejection fraction. Thus, in some embodiments, the cardiovascular condition is chronic systolic heart failure or chronic diastolic heart failure. In other embodiments, the cardiovascular condition is acute heart failure whereas in other embodiments, the cardiovascular condition is hypertension.

In still other embodiments, the invention provides a method of improving cardiac contractility in a subject. Such methods typically include administering to the subject an effective amount of the compound or the pharmaceutically acceptable salt thereof, the tautomer thereof, the pharmaceutically acceptable salt of the tautomer, the stereoisomer of any of the foregoing, or the mixture thereof according to any one of the embodiments or a pharmaceutical composition of any of the embodiments.

In still other embodiments, the invention provides a method of increasing ejection fraction in a subject suffering from a cardiovascular condition. Such methods typically include administering to the subject an effective amount of the compound or the pharmaceutically acceptable salt thereof, the tautomer thereof, the pharmaceutically acceptable salt of the tautomer, the stereoisomer of any of the foregoing, or the mixture thereof according to any one of the embodiments or a pharmaceutical composition of any of the embodiments. In such embodiments, the ejection fraction is increased in the subject after administration.

In still other embodiments, the invention provides a method of treating a condition in a subject where it is desired to activate the APJ Receptor. Such methods typically include administering to the subject an effective amount of the compound or the pharmaceutically acceptable salt thereof, the tautomer thereof, the pharmaceutically acceptable salt of the tautomer, the stereoisomer of any of the foregoing, or the mixture thereof according to any one of the embodiments or a pharmaceutical composition of any of the embodiments. In some such embodiments, the condition is obesity or diabetes whereas in other such embodiments, the condition is diabetic nephropathy.

In other embodiments, the invention provides the compound or the pharmaceutically acceptable salt thereof, the tautomer thereof, the pharmaceutically acceptable salt of the tautomer, the stereoisomer of any of the foregoing, or the mixture thereof according to any one of the embodiments or a pharmaceutical composition of any of the embodiments for use in treating a cardiovascular condition. In some such embodiments, the cardiovascular condition is heart failure. In some such embodiments, the cardiovascular condition is heart failure with reduced ejection fraction whereas in other embodiments it is heart failure with preserved ejection fraction. Thus, in some embodiments, the cardiovascular condition is chronic systolic heart failure or chronic diastolic heart failure. In other embodiments, the cardiovascular condition is acute heart failure whereas in other embodiments, the cardiovascular condition is hypertension.

›SUMMARY OF THE INVENTION · 3 of 3

In still other embodiments, the invention provides the compound or the pharmaceutically acceptable salt thereof, the tautomer thereof, the pharmaceutically acceptable salt of the tautomer, the stereoisomer of any of the foregoing, or the mixture thereof according to any one of the embodiments or a pharmaceutical composition of any of the embodiments for improving the cardiac contractility in a subject suffering from a cardiovascular condition.

In still other embodiments, the invention provides the compound or the pharmaceutically acceptable salt thereof, the tautomer thereof, the pharmaceutically acceptable salt of the tautomer, the stereoisomer of any of the foregoing, or the mixture thereof according to any one of the embodiments or a pharmaceutical composition of any of the embodiments for improving the ejection fraction in a subject suffering from a cardiovascular condition.

In still other embodiments, the invention provides the compound or the pharmaceutically acceptable salt thereof, the tautomer thereof, the pharmaceutically acceptable salt of the tautomer, the stereoisomer of any of the foregoing, or the mixture thereof according to any one of the embodiments or a pharmaceutical composition of any of the embodiments for treating a condition in a subject where it is desired to activate the APJ Receptor. In some such embodiments, the condition is obesity or diabetes whereas in other such embodiments, the condition is diabetic nephropathy.

Other objects, features and advantages of the invention will become apparent to those skilled in the art from the following description and claims.

›BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1A is a graph of left ventricular dP/dt max as a function of concentration of Example 210.0 compared with vehicle in ex vivo naive Sprague Dawley rat hearts obtained using the Langendorff apparatus. This shows Example 210.0 increases load independent cardiac contractility in isolated perfused rat hearts.

FIG. 1B is a graph of left ventricular dP/dt min as a function of concentration of Example 210.0 compared with vehicle in ex vivo naive Sprague Dawley rat hearts obtained using the Langendorff apparatus. This shows Example 210.0 increases load independent cardiac relaxation in isolated perfused rat hearts.

FIG. 2A is a graph of left ventricular dP/dt max as a function of concentration of Example 51.0 compared with vehicle in ex vivo naive Sprague Dawley rat hearts obtained using the Langendorff apparatus. This shows Example 51.0 increases load independent cardiac contractility in isolated perfused rat hearts.

FIG. 2B is a graph of left ventricular dP/dt min as a function of concentration of Example 51.0 compared with vehicle in ex vivo naive Sprague Dawley rat hearts obtained using the Langendorff apparatus. This shows Example 51.0 increases load independent cardiac relaxation in isolated perfused rat hearts.

FIG. 3 is a graph plotting different concentrations of angiotensin (AngII) with fixed concentration of pyrapelin-13 added to the human APJ-AT1R (angiotensin Type 1) double stable CHO cell line. The function of the inositol phosphate accumulation (IP1) was measured by Time-resolved fluorescence resonance energy (TR-FRET) at 620 nm and 665 nm respectively. Addition of pyrapelin-13 induces the positive cooperativity on the AT1R upon activation by APJ receptor.

FIG. 4 is a graph plotting different concentrations of angiotensin (AngII) with fixed concentration of pyrapelin-13 added to the human APJ receptor expressed in the CHO cell line. The function of the inositol phosphate accumulation (IP1) was measured by Time-resolved fluorescence resonance energy (TR-FRET) at 620 nm and 665 nm respectively. There was no positive cooperativity observed upon treatment with pyrapelin-13 when the human APJ receptor is expressed alone.

FIG. 5 is a graph plotting different concentrations of angiotensin (AngII) with fixed concentration of pyrapelin-13 added to the human AT1R receptor expressed in the CHO cell line. The function of the inositol phosphate accumulation (IP1) was measured by Time-resolved fluorescence resonance energy (TR-FRET) at 620 nm and 665 nm respectively. There was no positive cooperativity observed when the human AT1R receptor is expressed alone by pyrapelin-13 in the absence of APJ expression.

FIG. 6A is a graph of left ventricular (LV) developed pressure (DevP) as a function of administration of losartan or control (DMSO) in ex vivo naive Sprague Dawley rat hearts obtained using the Langendorff apparatus showing there is no impact on developed pressure with losartan as compared to the control (DMSO).

FIG. 6B is a graph of left ventricular (LV) dP/dt max as a function of administration of losartan or control (DMSO) in ex vivo naive Sprague Dawley rat hearts obtained using the Langendorff apparatus showing there is no impact on cardiac contraction with losartan as compared to the control (DMSO).

FIG. 6C is a graph of left ventricular (LV) systolic pressure (Sys) as a function of administration of losartan or control (DMSO) in ex vivo naive Sprague Dawley rat hearts obtained using the Langendorff apparatus showing there is no impact on systolic pressure with losartan as compared to the control (DMSO).

FIG. 6D is a graph of left ventricular (LV) dP/dt min as a function of administration of losartan or control (DMSO) in ex vivo naive Sprague Dawley rat hearts obtained using the Langendorff apparatus showing there is no impact on cardiac relaxation with losartan as compared to the control (DMSO).

FIG. 7 is a graph showing the effect of different concentrations of APJ agonist Example 56.0 alone or in combination with losartan on the left ventricular (LV) dP/dt max in ex vivo naive Sprague Dawley rat hearts obtained using the Langendorff apparatus.

FIG. 8A is a graph showing the in vivo efficacy in a MI induced heart failure model of different concentrations of APJ agonist Example 56.0 alone or in combination with losartan or with captopril on the left ventricular (LV) dP/dt max .

FIG. 8B is a graph showing the in vivo efficacy in a MI induced heart failure model of different concentrations of APJ agonist Example 56.0 alone or in combination with losartan or with captopril on the ejection fraction.

FIG. 8C is a graph showing the in vivo efficacy in a MI induced heart failure model of different concentrations of APJ agonist Example 56.0 alone or in combination with losartan or with captopril on the stroke volume.

FIG. 8D is a graph showing the in vivo efficacy in a MI induced heart failure model of different concentrations of APJ agonist Example 56.0 alone or in combination with losartan or with captopril on the heart rate.

›DETAILED DESCRIPTION OF THE INVENTION · 1 of 20

Unless otherwise indicated, all numbers expressing quantities of ingredients, reaction conditions, and so forth used in the specification and claims are to be understood as being modified in all instances by the term “about.” Accordingly, unless indicated to the contrary, the numerical parameters set forth in the following specification and attached claims are approximations that may vary depending upon the standard deviation found in their respective testing measurements.

As used herein, if any variable occurs more than one time in a chemical formula, its definition on each occurrence is independent of its definition at every other occurrence. If the chemical structure and chemical name conflict, the chemical structure is determinative of the identity of the compound. The compounds of the present disclosure may contain one or more chiral centers and/or double bonds and therefore, may exist as stereoisomers, such as double-bond isomers (i.e., geometric isomers), enantiomers or diastereomers. Accordingly, any chemical structures within the scope of the specification depicted, in whole or in part, with a relative configuration encompass all possible enantiomers and stereoisomers of the illustrated compounds including the stereoisomerically pure form (e.g., geometrically pure, enantiomerically pure or diastereomerically pure) and enantiomeric and stereoisomeric mixtures. Enantiomeric and stereoisomeric mixtures can be resolved into the component enantiomers or stereoisomers using separation techniques or chiral synthesis techniques well known to the skilled artisan.

The term “comprising” is meant to be open ended, i.e., all encompassing and non-limiting. It may be used herein synonymously with “having” or “including”. Comprising is intended to include each and every indicated or recited component or element(s) while not excluding any other components or elements. For example, if a composition is said to comprise A and B. This means that the composition has A and B in it, but may also include C or even C, D, E, and other additional components.

Certain compounds of the invention may possess asymmetric carbon atoms (optical centers) or double bonds; the racemates, enantiomers, diastereomers, geometric isomers and individual isomers are all intended to be encompassed within the scope of the invention. Furthermore, atropisomers and mixtures thereof such as those resulting from restricted rotation about two aromatic or heteroaromatic rings bonded to one another are intended to be encompassed within the scope of the invention. For example, when R 4 is a phenyl group and is substituted with two groups bonded to the C atoms adjacent to the point of attachment to the N atom of the triazole, then rotation of the phenyl may be restricted. In some instances, the barrier of rotation is high enough that the different atropisomers may be separated and isolated.

As used herein and unless otherwise indicated, the term “stereoisomer” or “stereomerically pure” means one stereoisomer of a compound that is substantially free of other stereoisomers of that compound. For example, a stereomerically pure compound having one chiral center will be substantially free of the mirror image enantiomer of the compound. A stereomerically pure compound having two chiral centers will be substantially free of other diastereomers of the compound. A typical stereomerically pure compound comprises greater than about 80% by weight of one stereoisomer of the compound and less than about 20% by weight of other stereoisomers of the compound, more preferably greater than about 90% by weight of one stereoisomer of the compound and less than about 10% by weight of the other stereoisomers of the compound, even more preferably greater than about 95% by weight of one stereoisomer of the compound and less than about 5% by weight of the other stereoisomers of the compound, and most preferably greater than about 97% by weight of one stereoisomer of the compound and less than about 3% by weight of the other stereoisomers of the compound. If the stereochemistry of a structure or a portion of a structure is not indicated with, for example, bold or dashed lines, the structure or portion of the structure is to be interpreted as encompassing all stereoisomers of it. A bond drawn with a wavy line indicates that both stereoisomers are encompassed. This is not to be confused with a wavy line drawn perpendicular to a bond which indicates the point of attachment of a group to the rest of the molecule.

As described above, this invention encompasses the use of stereomerically pure forms of such compounds, as well as the use of mixtures of those forms. For example, mixtures comprising equal or unequal amounts of the enantiomers of a particular compound of the invention may be used in methods and compositions of the invention. These isomers may be asymmetrically synthesized or resolved using standard techniques such as chiral columns or chiral resolving agents. See, e.g., Jacques, J., et al., Enantiomers, Racemates and Resolutions (Wiley-Interscience, New York, 1981); Wilen, S. H., et al. (1997) Tetrahedron 33:2725; Eliel, E. L., Stereochemistry of Carbon Compounds (McGraw-Hill, NY, 1962); and Wilen, S. H., Tables of Resolving Agents and Optical Resolutions p. 268 (E. L. Eliel, Ed., Univ. of Notre Dame Press, Notre Dame, Ind., 1972).

As known by those skilled in the art, certain compounds of the invention may exist in one or more tautomeric forms. Because one chemical structure may only be used to represent one tautomeric form, it will be understood that for convenience, referral to a compound of a given structural formula includes tautomers of the structure represented by the structural formula.

As noted above, compounds of the invention may exist in multiple tautomeric forms. This is particularly true in compounds of Formula I where R 2 is H. These forms are illustrated below as Tautomer A and Tautomer B:

Compounds of the invention are depicted structurally and named as compounds in the “Tautomer A” form. However, it is specifically contemplated and known that the compounds exist in “Tautomer B” form and thus compounds in “Tautomer B” form are expressly considered to be part of the invention. For this reason, the claims refer to compounds of Formula I and Formula II. Depending on the compound, some compounds may exist primarily in one form more than another. Also, depending on the compound and the energy required to convert one tautomer to the other, some compounds may exist as mixtures at room temperature whereas others may be isolated in one tautomeric form or the other. Examples of other tautomers associated with compounds of the invention are those with a pyridone group (a pyridinyl) for which hydroxypyridine is a tautomer and compounds with a ketone group with the enol tautomer. Examples of these are shown below.

›DETAILED DESCRIPTION OF THE INVENTION · 2 of 20

Compounds of the present disclosure include, but are not limited to, compounds of Formula I and Formula II and all pharmaceutically acceptable forms thereof. Pharmaceutically acceptable forms of the compounds recited herein include pharmaceutically acceptable salts, solvates, crystal forms (including polymorphs and clathrates), chelates, non-covalent complexes, prodrugs, and mixtures thereof. In certain embodiments, the compounds described herein are in the form of pharmaceutically acceptable salts. As used herein, the term “compound” encompasses not only the compound itself, but also a pharmaceutically acceptable salt thereof, a solvate thereof, a chelate thereof, a non-covalent complex thereof, a prodrug thereof, and mixtures of any of the foregoing. In some embodiments, the term “compound” encompasses the compound itself, pharmaceutically acceptable salts thereof, tautomers of the compound, pharmaceutically acceptable salts of the tautomers, and ester prodrugs such as (C 1 -C 4 )alkyl esters. In other embodiments, the term “compound” encompasses the compound itself, pharmaceutically acceptable salts thereof, tautomers of the compound, pharmaceutically acceptable salts of the tautomers.

The term “solvate” refers to the compound formed by the interaction of a solvent and a compound. Suitable solvates are pharmaceutically acceptable solvates, such as hydrates, including monohydrates and hemi-hydrates.

The compounds of the invention may also contain naturally occurring or unnatural proportions of atomic isotopes at one or more of the atoms that constitute such compounds. For example, the compounds may be radiolabeled with radioactive isotopes, such as for example tritium ( 3 H), iodine-125 ( 125 I) or carbon-14 ( 14 C). Radiolabeled compounds are useful as therapeutic or prophylactic agents, research reagents, e.g., assay reagents, and diagnostic agents, e.g., in vivo imaging agents. All isotopic variations of the compounds of the invention, whether radioactive or not, are intended to be encompassed within the scope of the invention. For example, if a variable is said or shown to be H, this means that variable may also be deuterium (D) or tritium (T).

“Alkyl” refers to a saturated branched or straight-chain monovalent hydrocarbon group derived by the removal of one hydrogen atom from a single carbon atom of a parent alkane. Typical alkyl groups include, but are not limited to, methyl, ethyl, propyls such as propan-1-yl and propan-2-yl, butyls such as butan-1-yl, butan-2-yl, 2-methyl-propan-1-yl, 2-methyl-propan-2-yl, tert-butyl, and the like. In certain embodiments, an alkyl group comprises 1 to 20 carbon atoms. In some embodiments, alkyl groups include 1 to 10 carbon atoms or 1 to 6 carbon atoms whereas in other embodiments, alkyl groups include 1 to 4 carbon atoms. In still other embodiments, an alkyl group includes 1 or 2 carbon atoms. Branched chain alkyl groups include at least 3 carbon atoms and typically include 3 to 7, or in some embodiments, 3 to 6 carbon atoms. An alkyl group having 1 to 6 carbon atoms may be referred to as a (C 1 -C 6 )alkyl group and an alkyl group having 1 to 4 carbon atoms may be referred to as a (C 1 -C 4 )alkyl. This nomenclature may also be used for alkyl groups with differing numbers of carbon atoms. The term “alkyl may also be used when an alkyl group is a substituent that is further substituted in which case a bond between a second hydrogen atom and a C atom of the alkyl substituent is replaced with a bond to another atom such as, but not limited to, a halogen, or an O, N, or S atom. For example, a group —O—(C 1 -C 6 alkyl)-OH will be recognized as a group where an —O atom is bonded to a C 1 -C 6 alkyl group and one of the H atoms bonded to a C atom of the C 1 -C 6 alkyl group is replaced with a bond to the O atom of an —OH group. As another example, a group —O—(C 1 -C 6 alkyl)-O—(C 1 -C 6 alkyl) will be recognized as a group where an —O atom is bonded to a first C 1 -C 6 alkyl group and one of the H atoms bonded to a C atom of the first C 1 -C 6 alkyl group is replaced with a bond to a second O atom that is bonded to a second C 1 -C 6 alkyl group.

“Alkenyl” refers to an unsaturated branched or straight-chain hydrocarbon group having at least one carbon-carbon double bond derived by the removal of one hydrogen atom from a single carbon atom of a parent alkene. The group may be in either the Z- or E-form (cis or trans) about the double bond(s). Typical alkenyl groups include, but are not limited to, ethenyl; propenyls such as prop-1-en-1-yl, prop-1-en-2-yl, prop-2-en-1-yl (allyl), and prop-2-en-2-yl; butenyls such as but-1-en-1-yl, but-1-en-2-yl, 2-methyl-prop-1-en-1-yl, but-2-en-1-yl, but-2-en-1-yl, but-2-en-2-yl, buta-1,3-dien-1-yl, and buta-1,3-dien-2-yl; and the like. In certain embodiments, an alkenyl group has 2 to 20 carbon atoms and in other embodiments, has 2 to 6 carbon atoms. An alkenyl group having 2 to 6 carbon atoms may be referred to as a (C 2 -C 6 )alkenyl group.

“Alkynyl” refers to an unsaturated branched or straight-chain hydrocarbon having at least one carbon-carbon triple bond derived by the removal of one hydrogen atom from a single carbon atom of a parent alkyne. Typical alkynyl groups include, but are not limited to, ethynyl; propynyl; butynyl, 2-pentynyl, 3-pentynyl, 2-hexynyl, 3-hexynyl and the like. In certain embodiments, an alkynyl group has 2 to 20 carbon atoms and in other embodiments, has 2 to 6 carbon atoms. An alkynyl group having 2 to 6 carbon atoms may be referred to as a —(C 2 -C 6 )alkynyl group.

“Alkoxy” refers to a radical —OR where R represents an alkyl group as defined herein. Representative examples include, but are not limited to, methoxy, ethoxy, propoxy, butoxy, and the like. Typical alkoxy groups include 1 to 10 carbon atoms, 1 to 6 carbon atoms or 1 to 4 carbon atoms in the R group. Alkoxy groups that include 1 to 6 carbon atoms may be designated as —O—(C 1 -C 6 ) alkyl or as —O—(C 1 -C 6 alkyl) groups. In some embodiments, an alkoxy group may include 1 to 4 carbon atoms and may be designated as —O—(C 1 -C 4 ) alkyl or as —O—(C 1 -C 4 alkyl) groups group.

›DETAILED DESCRIPTION OF THE INVENTION · 3 of 20

“Aryl” refers to a monovalent aromatic hydrocarbon group derived by the removal of one hydrogen atom from a single carbon atom of a parent aromatic ring system. Aryl encompasses monocyclic carbocyclic aromatic rings, for example, benzene. Aryl also encompasses bicyclic carbocyclic aromatic ring systems where each of the rings is aromatic, for example, naphthalene. Aryl groups may thus include fused ring systems where each ring is a carbocyclic aromatic ring. In certain embodiments, an aryl group includes 6 to 10 carbon atoms. Such groups may be referred to as C 6 -C 10 aryl groups. Aryl, however, does not encompass or overlap in any way with heteroaryl as separately defined below. Hence, if one or more carbocyclic aromatic rings is fused with an aromatic ring that includes at least one heteroatom, the resulting ring system is a heteroaryl group, not an aryl group, as defined herein.

“Carbonyl” refers to the radical —C(O) which may also be referred to as —C(═O) group.

“Carboxy” refers to the radical —C(O)OH which may also be referred to as —C(═O)OH.

“Cyano” refers to the radical —CN.

“Cycloalkyl” refers to a saturated cyclic alkyl group derived by the removal of one hydrogen atom from a single carbon atom of a parent cycloalkane. Typical cycloalkyl groups include, but are not limited to, groups derived from cyclopropane, cyclobutane, cyclopentane, cyclohexane, cycloheptane, cyclooctane, and the like. Cycloalkyl groups may be described by the number of carbon atoms in the ring. For example, a cycloalkyl group having 3 to 8 ring members may be referred to as a (C 3 -C 8 )cycloalkyl, a cycloalkyl group having 3 to 7 ring members may be referred to as a (C 3 -C 7 )cycloalkyl and a cycloalkyl group having 4 to 7 ring members may be referred to as a (C 4 -C 7 )cycloalkyl. In certain embodiments, the cycloalkyl group can be a (C 3 -C 10 )cycloalkyl, a (C 3 -C 8 )cycloalkyl, a (C 3 -C 7 )cycloalkyl, a (C 3 -C 6 )cycloalkyl, or a (C 4 -C 7 )cycloalkyl group and these may be referred to as C 3 -C 10 cycloalkyl, C 3 -C 8 cycloalkyl, C 3 -C 7 cycloalkyl, C 3 -C 6 cycloalkyl, or C 4 -C 7 cycloalkyl groups using alternative language.

“Heterocyclyl” refers to a cyclic group that includes at least one saturated, partially unsaturated, but non-aromatic, cyclic ring. Heterocyclyl groups include at least one heteroatom as a ring member. Typical heteroatoms include, O, S and N and are independently chosen. Heterocyclyl groups include monocyclic ring systems and bicyclic ring systems. Bicyclic heterocyclyl groups include at least one non-aromatic ring with at least one heteroatom ring member that may be fused to a cycloalkyl ring or may be fused to an aromatic ring where the aromatic ring may be carbocyclic or may include one or more heteroatoms. The point of attachment of a bicyclic heterocyclyl group may be at the non-aromatic cyclic ring that includes at least one heteroatom or at another ring of the heterocyclyl group. For example, a heterocyclyl group derived by removal of a hydrogen atom from one of the 9 membered heterocyclic compounds shown below may be attached to the rest of the molecule at the 5-membered ring or at the 6-membered ring.

In some embodiments, a heterocyclyl group includes 5 to 10 ring members of which 1, 2, 3 or 4 or 1, 2, or 3 are heteroatoms independently selected from O, S, or N. In other embodiments, a heterocyclyl group includes 3 to 7 ring members of which 1, 2, or 3 heteroatom are independently selected from O, S, or N. In such 3-7 membered heterocyclyl groups, only 1 of the ring atoms is a heteroatom when the ring includes only 3 members and includes 1 or 2 heteroatoms when the ring includes 4 members. In some embodiments, a heterocyclyl group includes 3 or 4 ring members of which 1 is a heteroatom selected from O, S, or N. In other embodiments, a heterocyclyl group includes 5 to 7 ring members of which 1, 2, or 3 are heteroatoms independently selected from O, S, or N. Typical heterocyclyl groups include, but are not limited to, groups derived from epoxides, aziridine, azetidine, imidazolidine, morpholine, piperazine, piperidine, hexahydropyrimidine, 1,4,5,6-tetrahydropyrimidine, pyrazolidine, pyrrolidine, quinuclidine, tetrahydrofuran, tetrahydropyran, benzimidazolone, pyridinone, and the like. Heterocyclyl groups may be fully saturated, but may also include one or more double bonds. Examples of such heterocyclyl groups include, but are not limited to, 1,2,3,6-tetrahydropyridinyl, 3,6-dihydro-2H-pyranyl, 3,4-dihydro-2H-pyranyl, 2,5-dihydro-1H-pyrolyl, 2,3-dihydro-1H-pyrolyl, 1H-azirinyl, 1,2-dihydroazetenyl, and the like. Substituted heterocyclyl also includes ring systems substituted with one or more oxo (═O) or oxide (—O − ) substituents, such as piperidinyl N-oxide, morpholinyl-N-oxide, 1-oxo-1-thiomorpholinyl, pyridinonyl, benzimidazolonyl, benzo[d]oxazol-2(3H)-only, 3,4-dihydroisoquinolin-1(2H)-only, indolin-only, 1H-imidazo[4,5-c]pyridin-2(3H)-only, 7H-purin-8(9H)-only, imidazolidin-2-only, 1H-imidazol-2(3H)-only, 1,1-dioxo-1-thiomorpholinyl, and the like.

“Disease” refers to any disease, disorder, condition, symptom, or indication.

“Halo” or “halogen” refers to a fluoro, chloro, bromo, or iodo group.

“Haloalkyl” refers to an alkyl group in which at least one hydrogen is replaced with a halogen. Thus, the term “haloalkyl” includes monohaloalkyl (alkyl substituted with one halogen atom) and polyhaloalkyl (alkyl substituted with two or more halogen atoms). Representative “haloalkyl” groups include difluoromethyl, 2,2,2-trifluoroethyl, 2,2,2-trichloroethyl, and the like. The term “perhaloalkyl” means, unless otherwise stated, an alkyl group in which each of the hydrogen atoms is replaced with a halogen atom. For example, the term “perhaloalkyl”, includes, but is not limited to, trifluoromethyl, pentachloroethyl, 1,1,1-trifluoro-2-bromo-2-chloroethyl, and the like.

“Heteroaryl” refers to a monovalent heteroaromatic group derived by the removal of one hydrogen atom from a single atom of a parent heteroaromatic ring system. Heteroaryl groups typically include 5- to 14-membered, but more typically include 5- to 10-membered aromatic, monocyclic, bicyclic, and tricyclic rings containing one or more, for example, 1, 2, 3, or 4, or in certain embodiments, 1, 2, or 3, heteroatoms chosen from O, S, or N, with the remaining ring atoms being carbon. In monocyclic heteroaryl groups, the single ring is aromatic and includes at least one heteroatom. In some embodiments, a monocyclic heteroaryl group may include 5 or 6 ring members and may include 1, 2, 3, or 4 heteroatoms, 1, 2, or 3 heteroatoms, 1 or 2 heteroatoms, or 1 heteroatom where the heteroatom(s) are independently selected from O, S, or N. In bicyclic aromatic rings, both rings are aromatic. In bicyclic heteroaryl groups, at least one of the rings must include a heteroatom, but it is not necessary that both rings include a heteroatom although it is permitted for them to do so. For example, the term “heteroaryl” includes a 5- to 7-membered heteroaromatic ring fused to a carbocyclic aromatic ring or fused to another heteroaromatic ring. In tricyclic aromatic rings, all three of the rings are aromatic and at least one of the rings includes at least one heteroatom. For fused, bicyclic and tricyclic heteroaryl ring systems where only one of the rings contains one or more heteroatoms, the point of attachment may be at the ring including at least one heteroatom or at a carbocyclic ring. When the total number of S and O atoms in the heteroaryl group exceeds 1, those heteroatoms are not adjacent to one another. In certain embodiments, the total number of S and O atoms in the heteroaryl group is not more than 2. In certain embodiments, the total number of S and O atoms in the aromatic heterocycle is not more than 1. Heteroaryl does not encompass or overlap with aryl as defined above. Examples of heteroaryl groups include, but are not limited to, groups derived from acridine, carbazole, cinnoline, furan, imidazole, indazole, indole, indolizine, isobenzofuran, isochromene, isoindole, isoquinoline, isothiazole, 2H-benzo[d][1,2,3]triazole, isoxazole, naphthyridine, oxadiazole, oxazole, perimidine, phenanthridine, phenanthroline, phenazine, phthalazine, pteridine, purine, pyrazine, pyrazole, pyridazine, pyridine, pyrimidine, pyrrole, pyrrolizine, quinazoline, quinoline, quinolizine, quinoxaline, tetrazole, thiadiazole, thiazole, thiophene, triazole, and the like. In certain embodiments, the heteroaryl group can be between 5 to 20 membered heteroaryl, such as, for example, a 5 to 14 membered or 5 to 10 membered heteroaryl. In certain embodiments, heteroaryl groups can be those derived from thiophene, pyrrole, benzothiophene, 2H-benzo[d][1,2,3]triazole benzofuran, indole, pyridine, quinoline, imidazole, benzimidazole, oxazole, tetrazole, and pyrazine.

›DETAILED DESCRIPTION OF THE INVENTION · 4 of 20

“Pharmaceutically acceptable” refers to generally recognized for use in animals, and more particularly in humans.

“Pharmaceutically acceptable salt” refers to a salt of a compound that is pharmaceutically acceptable and that possesses the desired pharmacological activity of the parent compound. Such salts include: (1) acid addition salts, formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like; or formed with organic acids such as acetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, 3-(4-hydroxybenzoyl) benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, and the like; or (2) salts formed when an acidic proton present in the parent compound either is replaced by a metal ion, e.g., an alkali metal ion, an alkaline earth ion, or an aluminum ion; or coordinates with an organic base such as ethanolamine, diethanolamine, triethanolamine, N-methylglucamine, dicyclohexylamine, and the like.

“Pharmaceutically acceptable excipient” refers to a broad range of ingredients that may be combined with a compound or salt of the present invention to prepare a pharmaceutical composition or formulation. Typically, excipients include, but are not limited to, diluents, colorants, vehicles, anti-adherants, glidants, disintegrants, flavoring agents, coatings, binders, sweeteners, lubricants, sorbents, preservatives, and the like.

“Stereoisomer” refers to an isomer that differs in the arrangement of the constituent atoms in space. Stereoisomers that are mirror images of each other and optically active are termed “enantiomers,” and stereoisomers that are not mirror images of one another and are optically active are termed “diastereomers.”

“Subject” includes mammals and humans. The terms “human” and “subject” are used interchangeably herein.

“Therapeutically effective amount” refers to the amount of a compound that, when administered to a subject for treating a disease, or at least one of the clinical symptoms of a disease or disorder, is sufficient to affect such treatment for the disease, disorder, or symptom. As those skilled in the art will recognize this amount is typically not limited to a single dose, but may comprise multiple dosages over a significant period of time as required to bring about a therapeutic or prophylactic response in the subject. Thus, a “therapeutically effective amount” is not limited to the amount in a single capsule or tablet, but may include more than one capsule or tablet, which is the dose prescribed by a qualified physician or medical care provider. The “therapeutically effective amount” can vary depending on the compound, the disease, disorder, and/or symptoms of the disease or disorder, severity of the disease, disorder, and/or symptoms of the disease or disorder, the age of the subject to be treated, and/or the weight of the subject to be treated. An appropriate amount in any given instance can be readily apparent to those skilled in the art or capable of determination by routine experimentation.

“Treating” or “treatment” of any disease or disorder refers to arresting or ameliorating a disease, disorder, or at least one of the clinical symptoms of a disease or disorder, reducing the risk of acquiring a disease, disorder, or at least one of the clinical symptoms of a disease or disorder, reducing the development of a disease, disorder or at least one of the clinical symptoms of the disease or disorder, or reducing the risk of developing a disease or disorder or at least one of the clinical symptoms of a disease or disorder. “Treating” or “treatment” also refers to inhibiting the disease or disorder, either physically, (e.g., stabilization of a discernible symptom), physiologically, (e.g., stabilization of a physical parameter), or both, or inhibiting at least one physical parameter which may not be discernible to the subject. Further, “treating” or “treatment” refers to delaying the onset of the disease or disorder or at least symptoms thereof in a subject which may be exposed to or predisposed to a disease or disorder even though that subject does not yet experience or display symptoms of the disease or disorder.

Reference will now be made in detail to embodiments of the present disclosure. While certain embodiments of the present disclosure will be described, it will be understood that it is not intended to limit the embodiments of the present disclosure to those described embodiments. To the contrary, reference to embodiments of the present disclosure is intended to cover alternatives, modifications, and equivalents as may be included within the spirit and scope of the embodiments of the present disclosure as defined by the appended claims.

Embodiments

The embodiments listed below are presented in numbered form for convenience and in ease and clarity of reference in referring back to multiple embodiments.

1. In a first embodiment, the invention provides a compound of Formula I or Formula II:

or a pharmaceutically acceptable salt thereof, a tautomer thereof, a pharmaceutically acceptable salt of the tautomer, a stereoisomer of any of the foregoing, or a mixture thereof,

wherein:

R 1 is an unsubstituted furanyl, or is a furanyl substituted with 1, 2, or 3 R 1a substituents;

›DETAILED DESCRIPTION OF THE INVENTION · 5 of 20

R 2 is selected from —H, or C 1 -C 4 alkyl or is absent in the compounds of Formula II;

R 3 is selected from an unsubstituted C 1 -C 10 alkyl, a C 1 -C 10 alkyl substituted with 1, 2, or 3 R 3a substituents, a group of formula —(CR 3b R 3c )-Q, a group of formula —(CR 3b R 3c )—C(═O)-Q, a group of formula —(CR 3d R 3e )—(CR 3f R 3g )-Q, a group of formula —(CR 3d R 3e )—(CR 3f R 3g )—C(═O)-Q, a group of formula —(CR 3d R 3e )—(CR 3f R 3g )—CH(OH)-Q, a group of formula —(CR 3d R 3e )—(CR 3f R 3g )—(CR 3f R 3g )-Q, a group of formula —(CR 3b ═CR 3c )-Q, a group of formula —(C 3 -C 8 cycloalkyl)-Q, a group of formula -(heterocyclyl)-Q, or Q, wherein the heterocyclyl of the -(heterocyclyl)-Q group has 5 to 7 ring members of which 1, 2, or 3 are heteroatoms independently selected from N, O, or S and is unsubstituted or is substituted with 1, 2, or 3 R 3h substituents, and further wherein the C 3 -C 8 cycloalkyl of the —(C 3 -C 8 cycloalkyl)-Q group is unsubstituted or is substituted with 1 or 2 R 3h substituents;

R 3d and R 3c are independently selected from —H, —F, —Cl, —CN, —C 1 -C 6 alkyl, —C 1 -C 6 haloalkyl, —C 1 -C 6 perhaloalkyl, —OH, —(C 1 -C 6 alkyl)-OH, —(C 1 -C 6 alkyl)-O—(C 1 -C 6 alkyl), —O—(C 1 -C 6 alkyl), —O—(C 1 -C 6 haloalkyl), —O—(C 1 -C 6 perhaloalkyl), —O—(C 1 -C 6 alkyl)-OH, —O—(C 1 -C 6 alkyl)-O—(C 1 -C 6 alkyl), —NH 2 , —NH(C 1 -C 6 alkyl), or —N(C 1 -C 6 alkyl) 2 ;

Q is a monocyclic or bicyclic C 6 -C 10 aryl group, a monocyclic or bicyclic heteroaryl group with 5 to 10 ring members containing 1, 2, or 3 heteroatoms independently selected from N, O, or S, a C 3 -C 8 cycloalkyl group, a 3 to 10 membered heterocyclyl group containing 1, 2, or 3 heteroatoms independently selected from N, O, or S, —C(═O)NH(—C 1 -C 6 alkyl), —C(═O)N(—C 1 -C 6 alkyl) 2 , or —S(═O) 2 —C 1 -C 6 alkyl, wherein the C 6 -C 10 aryl, the heteroaryl, the cycloalkyl, and the heterocyclyl Q groups are unsubstituted or are substituted with 1, 2, 3, or 4 R Q substituent;

R Q in each instance is independently selected from —F, —Cl, —Br, —I, —CN, —C 1 -C 6 alkyl, —C 1 -C 6 haloalkyl, —C 1 -C 6 perhaloalkyl, —C 2 -C 6 alkenyl, —C 2 -C 6 alkynyl, —OH, —O—(C 1 -C 6 alkyl), —O—(C 1 -C 6 haloalkyl), —O—(C 1 -C 6 perhaloalkyl), —NH 2 , —NH(C 1 -C 6 alkyl), —N(C 1 -C 6 alkyl) 2 , —NHC(═O)(C 1 -C 6 alkyl), —C(═O)—(C 1 -C 6 alkyl), —C(═O)OH, —C(═O)—O—(C 1 -C 6 alkyl), —C(═O)NH 2 , —C(═O)NH(C 1 -C 6 alkyl), —C(═O)N(C 1 -C 6 alkyl) 2 , —S(═O) 2 —(C 1 -C 6 alkyl), —(C 1 -C 6 alkyl)-OH, —(C 1 -C 6 alkyl)-O—(C 1 -C 6 alkyl), phenyl, a heterocyclyl group, a —(C 1 -C 6 alkyl)heterocyclyl group, or a heteroaryl group with 5 or 6 ring members and 1, 2, or 3, heteroatoms independently selected from N, O, or S, wherein the heterocyclyl groups of the R Q heterocyclyl and —(C 1 -C 6 alkyl)heterocyclyl groups have 3 to 6 ring members of which 1 or 2 are heteroatoms independently selected from N, O, or S, wherein the Q heterocyclyl group may additionally be substituted with 1 or 2 oxo substituents, and the Q heteroaryl group may include an N-oxide if the heteroaryl includes a N heteroatom, and further wherein the heterocyclyl and the heterocyclyl of the —(C 1 -C 6 alkyl)heterocyclyl R Q groups may be further substituted with one or two oxo substituents and a substituent selected from —F, —Cl, —Br, —I, —CN, —OH, —C 1 -C 6 alkyl, or —C(═O)—(C 1 -C 6 alkyl);

›DETAILED DESCRIPTION OF THE INVENTION · 6 of 20

In some embodiments of the compound of embodiment 1 or the pharmaceutically acceptable salt thereof, the tautomer thereof, the pharmaceutically acceptable salt of the tautomer, the stereoisomer of any of the foregoing, or the mixture thereof,

R 1 is a furan-2yl that is unsubstituted or is substituted with 1 or 2 R 1a substituents;

R 1a is independently selected from —F, —Cl, —Br, —I, —C 1 -C 6 alkyl, —C 1 -C 6 haloalkyl, —C 1 -C 6 perhaloalkyl, or —(C 1 -C 6 alkyl)-O—(C 1 -C 6 alkyl);

R 2 is —H;

R 3 is a group of formula —(CR 3d R 3e )—(CR 3f R 3g )-Q;

R 3d and R 3e are independently selected from —H, —C 1 -C 6 alkyl, —(C 1 -C 6 alkyl)-OH, or —(C 1 -C 6 alkyl)-O—(C 1 -C 6 alkyl);

R 3f and R 3g are independently selected from —H, —F, —C 1 -C 6 alkyl, —OH, —O—(C 1 -C 6 alkyl), —O—(C 1 -C 6 alkyl)-OH, —O—(C 1 -C 6 alkyl)-O—(C 1 -C 6 alkyl), or —NH 2 ;

Q is a monocyclic heteroaryl group with 5 or 6 ring members containing 1 or 2 heteroatoms selected from N, O, or S, and Q is unsubstituted or is substituted with 1 or 2 R Q substituents;

R 4 is a phenyl substituted with 1, 2, or 3 R 4a substituent; and

R 4a is independently selected from —F, —Br, —CN, —C 1 -C 6 alkyl, —C 1 -C 6 haloalkyl, —C 1 -C 6 perhaloalkyl, —(C 1 -C 6 alkyl)-OH, —O—(C 1 -C 6 alkyl), —O—(C 1 -C 6 haloalkyl), —O—(C 1 -C 6 perhaloalkyl), or —(C 1 -C 6 alkyl)-heterocyclyl, wherein the heterocyclyl of the —(C 1 -C 6 alkyl)-heterocyclyl R 4a group is a 3-6 membered ring comprising 1 or 2 heteroatoms independently selected from N, O, or S.

In some such embodiments, R 4 is a phenyl substituted with 2-O—(C 1 -C 6 alkyl) R 4a substituents such as with 2-O—(C 1 -C 2 alkyl) substituents or in some embodiments with 2 —OCH 3 groups. In some such embodiments, Q is a pyrimidinyl, pyridinyl, or pyrazinyl group substituted with 1 on 2 R Q substituent.

2. The compound of embodiment 1 or the pharmaceutically acceptable salt thereof, the tautomer thereof, the pharmaceutically acceptable salt of the tautomer, the stereoisomer of any of the foregoing, or the mixture thereof, wherein R 1 is an unsubstituted furan-2-yl or is a furan-2-yl substituted with 1, 2, or 3 R 1a substituents.

3. The compound of embodiment 1 or embodiment 2 or the pharmaceutically acceptable salt thereof, the tautomer thereof, the pharmaceutically acceptable salt of the tautomer, the stereoisomer of any of the foregoing, or the mixture thereof, wherein R 1 is a an unsubstituted furan-2-yl or a furan-2-yl substituted with 1 or 2 R 1a substituents independently selected from —F, —Cl, —Br, —I, —C 1 -C 6 alkyl, —C 1 -C 6 haloalkyl, —C 1 -C 6 perhaloalkyl, or —(C 1 -C 6 alkyl)-O—(C 1 -C 6 alkyl).

4. The compound of embodiment 3 or the pharmaceutically acceptable salt thereof, the tautomer thereof, the pharmaceutically acceptable salt of the tautomer, the stereoisomer of any of the foregoing, or the mixture thereof, wherein R 1 is an unsubstituted or substituted furan-2-yl having the formula

wherein the symbol , when drawn across a bond, indicates the point of attachment to the rest of the molecule.

5. The compound of embodiment 4 or the pharmaceutically acceptable salt thereof, the tautomer thereof, the pharmaceutically acceptable salt of the tautomer, the stereoisomer of any of the foregoing, or the mixture thereof, wherein R 1 is a furan-2-yl having the formula

wherein the symbol , when drawn across a bond, indicates the point of attachment to the rest of the molecule.

6. The compound of embodiment 4 or the pharmaceutically acceptable salt thereof, the tautomer thereof, the pharmaceutically acceptable salt of the tautomer, the stereoisomer of any of the foregoing, or the mixture thereof, wherein R 1 is a furan-2-yl having the formula

wherein the symbol , when drawn across a bond, indicates the point of attachment to the rest of the molecule.

7. The compound of any one of embodiments 1-3 or the pharmaceutically acceptable salt thereof, the tautomer thereof, the pharmaceutically acceptable salt of the tautomer, the stereoisomer of any of the foregoing, or the mixture thereof, wherein R 1 is an unsubstituted furan-2-yl or a substituted furan-2-yl and R 1a is independently selected from —CH 3 , —CH 2 CH 3 , —C(CH 3 ) 3 , —CF 3 , —CH 2 OCH 3 , or —Br.

8. The compound of any one of embodiments 1-7 or the pharmaceutically acceptable salt thereof, the tautomer thereof, the pharmaceutically acceptable salt of the tautomer, the stereoisomer of any of the foregoing, or the mixture thereof, wherein R 2 is —H or is absent in the compounds of Formula II.

9. The compound of any one of embodiments 1-8 or the pharmaceutically acceptable salt thereof, the tautomer thereof, the pharmaceutically acceptable salt of the tautomer, the stereoisomer of any of the foregoing, or the mixture thereof, wherein R 2 is —H.

10. The compound of any one of embodiments 1-9 or the pharmaceutically acceptable salt thereof, the tautomer thereof, the pharmaceutically acceptable salt of the tautomer, the stereoisomer of any of the foregoing, or the mixture thereof, wherein R 4 is a phenyl, pyridinyl, pyrimidinyl, naphthyl, tetrahydropyranyl, cyclohexyl, cyclopentyl, or cyclopropyl, any of which may be unsubstituted or substituted with 1, 2, 3, or 4 R 4a substituents.

11. The compound of any one of embodiments 1-10 or the pharmaceutically acceptable salt thereof, the tautomer thereof, the pharmaceutically acceptable salt of the tautomer, the stereoisomer of any of the foregoing, or the mixture thereof, wherein R 4a is in each instance independently selected from —F, —Br, —CN, —C 1 -C 6 alkyl, —C 1 -C 6 haloalkyl, —C 1 -C 6 perhaloalkyl, —(C 1 -C 6 alkyl)-OH, —O—(C 1 -C 6 alkyl), —O—(C 1 -C 6 haloalkyl), —O—(C 1 -C 6 perhaloalkyl), or —(C 1 -C 6 alkyl)-heterocyclyl, wherein the heterocyclyl of the —(C 1 -C 6 alkyl)-heterocyclyl R 4a group is a 3-6 membered ring comprising 1 or 2 heteroatoms independently selected from N, O, or S.

›DETAILED DESCRIPTION OF THE INVENTION · 7 of 20

12. The compound of embodiment 11 or the pharmaceutically acceptable salt thereof, the tautomer thereof, the pharmaceutically acceptable salt of the tautomer, the stereoisomer of any of the foregoing, or the mixture thereof, wherein R 4a is in each instance independently selected from —CH 3 , —F, —Br, —CN, —CF 3 , —OCH 3 , —CH 2 OH, or —CH 2 -pyrrolidine.

13. The compound of any one of embodiments 1-9 or the pharmaceutically acceptable salt thereof, the tautomer thereof, the pharmaceutically acceptable salt of the tautomer, the stereoisomer of any of the foregoing, or the mixture thereof, wherein R 4 is selected from

wherein the symbol , when drawn across a bond, indicates the point of attachment to the rest of the molecule.

14. The compound of any one of embodiments 1-9 or the pharmaceutically acceptable salt thereof, the tautomer thereof, the pharmaceutically acceptable salt of the tautomer, the stereoisomer of any of the foregoing, or the mixture thereof, wherein R 4 is a phenyl substituted with 1 or 2 R 4a substituents.

15. The compound of embodiment 14 or the pharmaceutically acceptable salt thereof, the tautomer thereof, the pharmaceutically acceptable salt of the tautomer, the stereoisomer of any of the foregoing, or the mixture thereof, wherein the R 4a substituents are —O—(C 1 -C 2 alkyl) groups.

16. The compound of embodiment 15 or the pharmaceutically acceptable salt thereof, the tautomer thereof, the pharmaceutically acceptable salt of the tautomer, the stereoisomer of any of the foregoing, or the mixture thereof, wherein R 4 is

wherein the symbol , when drawn across a bond, indicates the point of attachment to the rest of the molecule.

17. The compound of any one of embodiments 1-16 or the pharmaceutically acceptable salt thereof, the tautomer thereof, the pharmaceutically acceptable salt of the tautomer, the stereoisomer of any of the foregoing, or the mixture thereof, wherein Q is selected from pyrimidinyl, pyrazinyl, pyradizinyl, pyridinyl, phenyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, piperidin-2-onyl, tetrahydropyrimidin-2(1H)-onyl, 1,3-oxazinan-2-onyl, pyrrolidin-2-onyl, pyrrolidinyl, cyclohexyl, benzimidazolyl, isoindolinonyl, 1H-imidazo[4,5-c]pyridinyl, pyrazolo[1,5-a]pyridinyl, imidazo[1,2-a]pyridinyl, imidazo[1,5-a]pyridinyl, 6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazinyl, or 3,4-dihydro-2H-pyrano[3,2-b]pyridinyl, any of which may be unsubstituted or substituted with 1 or 2 R Q substituents.

18. The compound of embodiment 17 or the pharmaceutically acceptable salt thereof, the tautomer thereof, the pharmaceutically acceptable salt of the tautomer, the stereoisomer of any of the foregoing, or the mixture thereof, wherein Q is an unsubstituted phenyl or is a phenyl substituted with 1 or 2 R Q substituents.

19. The compound of any one of embodiments 1-16 or the pharmaceutically acceptable salt thereof, the tautomer thereof, the pharmaceutically acceptable salt of the tautomer, the stereoisomer of any of the foregoing, or the mixture thereof, wherein Q is a monocyclic heteroaryl group with 5 or 6 ring members containing 1 or 2 heteroatoms selected from N, O, or S and Q is unsubstituted or is substituted with 1 or 2 R Q substituents.

20. The compound of embodiment 19 or the pharmaceutically acceptable salt thereof, the tautomer thereof, the pharmaceutically acceptable salt of the tautomer, the stereoisomer of any of the foregoing, or the mixture thereof, wherein Q is a pyrimidinyl, pyridinyl, or pyrazinyl group and Q is unsubstituted or is substituted with 1 or 2 R Q substituents.

21. The compound of any one of embodiments 1-16 or the pharmaceutically acceptable salt thereof, the tautomer thereof, the pharmaceutically acceptable salt of the tautomer, the stereoisomer of any of the foregoing, or the mixture thereof, wherein Q is selected from

wherein the symbol , when drawn across a bond, indicates the point of attachment to the rest of the molecule.

22. The compound of embodiment 21 or the pharmaceutically acceptable salt thereof, the tautomer thereof, the pharmaceutically acceptable salt of the tautomer, the stereoisomer of any of the foregoing, or the mixture thereof, wherein Q is selected from

wherein the symbol , when drawn across a bond, indicates the point of attachment to the rest of the molecule.

23. The compound of embodiment 21 or the pharmaceutically acceptable salt thereof, the tautomer thereof, the pharmaceutically acceptable salt of the tautomer, the stereoisomer of any of the foregoing, or the mixture thereof, wherein Q is

wherein the symbol , when drawn across a bond, indicates the point of attachment to the rest of the molecule.

24. The compound of embodiment 21 or the pharmaceutically acceptable salt thereof, the tautomer thereof, the pharmaceutically acceptable salt of the tautomer, the stereoisomer of any of the foregoing, or the mixture thereof, wherein Q is

wherein the symbol , when drawn across a bond, indicates the point of attachment to the rest of the molecule.

25. The compound of embodiment 21 or the pharmaceutically acceptable salt thereof, the tautomer thereof, the pharmaceutically acceptable salt of the tautomer, the stereoisomer of any of the foregoing, or the mixture thereof, wherein Q is

wherein the symbol , when drawn across a bond, indicates the point of attachment to the rest of the molecule.

26. The compound of embodiment 21 or the pharmaceutically acceptable salt thereof, the tautomer thereof, the pharmaceutically acceptable salt of the tautomer, the stereoisomer of any of the foregoing, or the mixture thereof, wherein Q is

wherein the symbol , when drawn across a bond, indicates the point of attachment to the rest of the molecule.

27. The compound of embodiment 21 or the pharmaceutically acceptable salt thereof, the tautomer thereof, the pharmaceutically acceptable salt of the tautomer, the stereoisomer of any of the foregoing, or the mixture thereof, wherein Q is

wherein the symbol , when drawn across a bond, indicates the point of attachment to the rest of the molecule.

›DETAILED DESCRIPTION OF THE INVENTION · 8 of 20

28. The compound of embodiment 21 or the pharmaceutically acceptable salt thereof, the tautomer thereof, the pharmaceutically acceptable salt of the tautomer, the stereoisomer of any of the foregoing, or the mixture thereof, wherein Q is

wherein the symbol , when drawn across a bond, indicates the point of attachment to the rest of the molecule.

29. The compound of embodiment 21 or the pharmaceutically acceptable salt thereof, the tautomer thereof, the pharmaceutically acceptable salt of the tautomer, the stereoisomer of any of the foregoing, or the mixture thereof, wherein Q is

wherein the symbol , when drawn across a bond, indicates the point of attachment to the rest of the molecule.

30. The compound of embodiment 21 or the pharmaceutically acceptable salt thereof, the tautomer thereof, the pharmaceutically acceptable salt of the tautomer, the stereoisomer of any of the foregoing, or the mixture thereof, wherein Q is

wherein the symbol , when drawn across a bond, indicates the point of attachment to the rest of the molecule.

31. The compound of embodiment 21 or the pharmaceutically acceptable salt thereof, the tautomer thereof, the pharmaceutically acceptable salt of the tautomer, the stereoisomer of any of the foregoing, or the mixture thereof, wherein Q is

wherein the symbol , when drawn across a bond, indicates the point of attachment to the rest of the molecule.

32. The compound of embodiment 21 or the pharmaceutically acceptable salt thereof, the tautomer thereof, the pharmaceutically acceptable salt of the tautomer, the stereoisomer of any of the foregoing, or the mixture thereof, wherein Q is

wherein the symbol , when drawn across a bond, indicates the point of attachment to the rest of the molecule.

33. The compound of embodiment 21 or the pharmaceutically acceptable salt thereof, the tautomer thereof, the pharmaceutically acceptable salt of the tautomer, the stereoisomer of any of the foregoing, or the mixture thereof, wherein Q is

wherein the symbol , when drawn across a bond, indicates the point of attachment to the rest of the molecule.

34. The compound of embodiment 21 or the pharmaceutically acceptable salt thereof, the tautomer thereof, the pharmaceutically acceptable salt of the tautomer, the stereoisomer of any of the foregoing, or the mixture thereof, wherein Q is

wherein the symbol , when drawn across a bond, indicates the point of attachment to the rest of the molecule.

35. The compound of embodiment 21 or the pharmaceutically acceptable salt thereof, the tautomer thereof, the pharmaceutically acceptable salt of the tautomer, the stereoisomer of any of the foregoing, or the mixture thereof, wherein Q is

wherein the symbol , when drawn across a bond, indicates the point of attachment to the rest of the molecule.

36. The compound of embodiment 21 or the pharmaceutically acceptable salt thereof, the tautomer thereof, the pharmaceutically acceptable salt of the tautomer, the stereoisomer of any of the foregoing, or the mixture thereof, wherein Q is

wherein the symbol , when drawn across a bond, indicates the point of attachment to the rest of the molecule.

37. The compound of any one of embodiments 1-36 or the pharmaceutically acceptable salt thereof, the tautomer thereof, the pharmaceutically acceptable salt of the tautomer, the stereoisomer of any of the foregoing, or the mixture thereof, wherein R 3 is selected from a group of formula —(CR 3b R 3c )-Q, a group of formula —(CR 3d R 3e )—(CR 3f R 3g )-Q, a group of formula —(CR 3d R 3e )—(CR 3f R 3g )—C(═O)-Q, a group of formula —(CR 3d R 3e )—(CR 3f R 3g )—CH(OH)-Q, a group of formula —(CR 3d R 3e )—(CR 3f R 3g )—(CR 3f R 3g )-Q, a group of formula —(C 3 -C 8 cycloalkyl)-Q, a group of formula -(heterocyclyl)-Q, or Q.

38. The compound of embodiment 37 or the pharmaceutically acceptable salt thereof, the tautomer thereof, the pharmaceutically acceptable salt of the tautomer, the stereoisomer of any of the foregoing, or the mixture thereof, wherein R 3 is selected from a group of formula —(CR 3d R 3e )—(CR 3f R 3g )-Q, a group of formula —(C 3 -C 8 cycloalkyl)-Q, or a group of formula -(heterocyclyl)-Q.

39. The compound of embodiment 37 or the pharmaceutically acceptable salt thereof, the tautomer thereof, the pharmaceutically acceptable salt of the tautomer, the stereoisomer of any of the foregoing, or the mixture thereof, wherein R 3 is a group of formula —(CR 3d R 3e )—(CR 3f R 3g )-Q.

40. The compound of embodiment 39 or the pharmaceutically acceptable salt thereof, the tautomer thereof, the pharmaceutically acceptable salt of the tautomer, the stereoisomer of any of the foregoing, or the mixture thereof, wherein R 3 is a group of formula —(CR 3d R 3e )—(CR 3f R 3g )-Q and further wherein,

R 3d and R 3e are independently selected from —H, —C 1 -C 6 alkyl, —(C 1 -C 6 alkyl)-OH, or —(C 1 -C 6 alkyl)-O—(C 1 -C 6 alkyl); and

R 3f and R 3g are independently selected from —H, —F, —C 1 -C 6 alkyl, —OH, —O—(C 1 -C 6 alkyl), —O—(C 1 -C 6 alkyl)-OH, —O—(C 1 -C 6 alkyl)-O—(C 1 -C 6 alkyl), or —NH 2 .

41. The compound of embodiment 37 or the pharmaceutically acceptable salt thereof, the tautomer thereof, the pharmaceutically acceptable salt of the tautomer, the stereoisomer of any of the foregoing, or the mixture thereof, wherein R 3 is a group of formula —(C 3 -C 8 cycloalkyl)-Q.

42. The compound of embodiment 41 or the pharmaceutically acceptable salt thereof, the tautomer thereof, the pharmaceutically acceptable salt of the tautomer, the stereoisomer of any of the foregoing, or the mixture thereof, wherein the C 3 -C 8 cycloalkyl of the —(C 3 -C 8 cycloalkyl)-Q R 3 group is a cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl that is unsubstituted or is substituted with 1 R 3h substituent.

43. The compound of embodiment 37 or the pharmaceutically acceptable salt thereof, the tautomer thereof, the pharmaceutically acceptable salt of the tautomer, the stereoisomer of any of the foregoing, or the mixture thereof, wherein R 3 is a group of formula -(heterocyclyl)-Q.

›DETAILED DESCRIPTION OF THE INVENTION · 9 of 20

44. The compound of embodiment 43 or the pharmaceutically acceptable salt thereof, the tautomer thereof, the pharmaceutically acceptable salt of the tautomer, the stereoisomer of any of the foregoing, or the mixture thereof, wherein the heterocyclyl of the -(heterocyclyl)-Q R 3 group is a tetrahydrofuranyl, isoxazolidinyl, tetrahydropyranyl, or piperidinyl that is unsubstituted or is substituted with 1 or 2 R 3h substituent.

45. The compound of embodiment 37 or the pharmaceutically acceptable salt thereof, the tautomer thereof, the pharmaceutically acceptable salt of the tautomer, the stereoisomer of any of the foregoing, or the mixture thereof, wherein R 3 is a group of formula —(CR 3b R 3c )-Q.

46. The compound of embodiment 45 or the pharmaceutically acceptable salt thereof, the tautomer thereof, the pharmaceutically acceptable salt of the tautomer, the stereoisomer of any of the foregoing, or the mixture thereof, wherein.

R 3b and R 3c are independently selected from H or —C 1 -C 6 alkyl.

47. The compound of embodiment 37 or the pharmaceutically acceptable salt thereof, the tautomer thereof, the pharmaceutically acceptable salt of the tautomer, the stereoisomer of any of the foregoing, or the mixture thereof, wherein R 3 is a group of formula —(CR 3d R 3e )—(CR 3f R 3g )—C(═O)-Q.

48. The compound of embodiment 37 or the pharmaceutically acceptable salt thereof, the tautomer thereof, the pharmaceutically acceptable salt of the tautomer, the stereoisomer of any of the foregoing, or the mixture thereof, wherein R 3 is a group of formula —(CR 3d R 3e )—(CR 3f R 3g )—CH(OH)-Q.

49. The compound of embodiment 37 or the pharmaceutically acceptable salt thereof, the tautomer thereof, the pharmaceutically acceptable salt of the tautomer, the stereoisomer of any of the foregoing, or the mixture thereof, wherein R 3 is a group of formula —(CR 3d R 3e )—(CR 3f R 3g )—(CR 3f R 3g )-Q.

50. The compound of embodiment 37 or the pharmaceutically acceptable salt thereof, the tautomer thereof, the pharmaceutically acceptable salt of the tautomer, the stereoisomer of any of the foregoing, or the mixture thereof, wherein R 3 is a group of formula -Q.

51. The compound of any one of embodiments 1-36 or the pharmaceutically acceptable salt thereof, the tautomer thereof, the pharmaceutically acceptable salt of the tautomer, the stereoisomer of any of the foregoing, or the mixture thereof, wherein R 3 is selected from

wherein the symbol , when drawn across a bond, indicates the point of attachment to the rest of the molecule.

52. The compound of any one of embodiments 1-36 or the pharmaceutically acceptable salt thereof, the tautomer thereof, the pharmaceutically acceptable salt of the tautomer, the stereoisomer of any of the foregoing, or the mixture thereof, wherein R 3 is selected from

wherein the symbol , when drawn across a bond, indicates the point of attachment to the rest of the molecule.

53. The compound of embodiment 52 or the pharmaceutically acceptable salt thereof, the tautomer thereof, the pharmaceutically acceptable salt of the tautomer, the stereoisomer of any of the foregoing, or the mixture thereof, wherein R 3 is selected from

wherein the symbol , when drawn across a bond, indicates the point of attachment to the rest of the molecule.

54. The compound of embodiment 52 or the pharmaceutically acceptable salt thereof, the tautomer thereof, the pharmaceutically acceptable salt of the tautomer, the stereoisomer of any of the foregoing, or the mixture thereof, wherein R 3 is selected from

wherein the symbol , when drawn across a bond, indicates the point of attachment to the rest of the molecule.

55. The compound of embodiment 52 or the pharmaceutically acceptable salt thereof, the tautomer thereof, the pharmaceutically acceptable salt of the tautomer, the stereoisomer of any of the foregoing, or the mixture thereof, wherein R 3 is selected from

wherein the symbol , when drawn across a bond, indicates the point of attachment to the rest of the molecule.

56. The compound of embodiment 1, wherein the compound is selected from

N-(4-(2,6-dimethoxyphenyl)-5-(2-furanyl)-4H-1,2,4-triazol-3-yl)-2-(2-methyl-1H-benzimidazol-1-yl)ethanesulfonamide; N-(4-(2,6-dimethoxyphenyl)-5-(2-furanyl)-4H-1,2,4-triazol-3-yl)-2-(1-oxo-1,3-dihydro-2H-isoindol-2-yl)ethanesulfonamide; (1R,2S)—N-(4-(4,6-dimethoxy-5-pyrimidinyl)-5-(5-methyl-2-furanyl)-4H-1,2,4-triazol-3-yl)-1-methoxy-1-(5-methyl-2-pyrimidinyl)-2-propanesulfonamide; (2R)—N-(4-(2,6-dimethoxyphenyl)-5-(2-furanyl)-4H-1,2,4-triazol-3-yl)-1-(7-fluoro-1-(methoxymethyl)-1H-imidazo[4,5-c]pyridin-4-yl)-2-propanesulfonamide; (2S)—N-(4-(2,6-dimethoxyphenyl)-5-(2-furanyl)-4H-1,2,4-triazol-3-yl)-1-(7-fluoro-1-(methoxymethyl)-1H-imidazo[4,5-c]pyridin-4-yl)-2-propanesulfonamide; (2S)—N-(4-(2,6-dimethoxyphenyl)-5-(2-furanyl)-4H-1,2,4-triazol-3-yl)-1-(7-fluoro-1H-imidazo[4,5-c]pyridin-4-yl)-2-propanesulfonamide; (2R)—N-(4-(2,6-dimethoxyphenyl)-5-(2-furanyl)-4H-1,2,4-triazol-3-yl)-1-(7-fluoro-1-methyl-1H-imidazo[4,5-c]pyridin-4-yl)-2-propanesulfonamide; (2R)—N-(4-(4,6-dimethoxy-5-pyrimidinyl)-5-(5-methyl-2-furanyl)-4H-1,2,4-triazol-3-yl)-1-(5-fluoro-2-pyrimidinyl)-2-propanesulfonamide; (2S)—N-(4-(4,6-dimethoxy-5-pyrimidinyl)-5-(5-methyl-2-furanyl)-4H-1,2,4-triazol-3-yl)-1-(5-fluoro-2-pyrimidinyl)-2-propanesulfonamide; (2R)—N-(4-(2,6-dimethoxyphenyl)-5-(2-furanyl)-4H-1,2,4-triazol-3-yl)-1-(7-fluoro-1H-imidazo[4,5-c]pyridin-4-yl)-2-propanesulfonamide; N-(5-chloro-2-((2R)-2-((4-(2,6-dimethoxyphenyl)-5-(2-furanyl)-4H-1,2,4-triazol-3-yl)sulfamoyl)propyl)-3-pyridinyl)acetamide; (1S,2S)-1-(5-cyano-2-pyridinyl)-N-(4-(2,6-dimethoxyphenyl)-5-(5-methyl-2-furanyl)-4H-1,2,4-triazol-3-yl)-1-hydroxy-2-propanesulfonamide; (2R)-1-(5-chloro-2-pyridinyl)-N-(4-(2,6-dimethoxyphenyl)-5-(2-furanyl)-4H-1,2,4-triazol-3-yl)-2-propanesulfonamide; (2R)-1-(5-cyano-2-pyridinyl)-N-(4-(2,6-dimethoxyphenyl)-5-(5-methyl-2-furanyl)-4H-1,2,4-triazol-3-yl)-2-propanesulfonamide; N-(5-chloro-2-((2S)-2-((4-(2,6-dimethoxyphenyl)-5-(2-furanyl)-4H-1,2,4-triazol-3-yl)sulfamoyl)propyl)-3-pyridinyl)acetamide; (2S)-1-(5-chloro-2-pyridinyl)-N-(4-(2,6-dimethoxyphenyl)-5-(2-furanyl)-4H-1,2,4-triazol-3-yl)-2-propanesulfonamide; N-(2-((2R)-2-((4-(2,6-dimethoxyphenyl)-5-(2-furanyl)-4H-1,2,4-triazol-3-yl)sulfamoyl)propyl)-5-fluoro-3-pyridinyl)acetamide; (2R)—N-(4-(2,6-dimethoxyphenyl)-5-(5-methyl-2-furanyl)-4H-1,2,4-triazol-3-yl)-1-(5-methyl-2-pyrimidinyl)-2-propanesulfonamide; 5-chloro-2-((2R)-2-((4-(2,6-dimethoxyphenyl)-5-(2-furanyl)-4H-1,2,4-triazol-3-yl)sulfamoyl)propyl)-3-pyridinecarboxamide; (2R)-1-(5-chloro-3-cyano-2-pyridinyl)-N-(4-(2,6-dimethoxyphenyl)-5-(2-furanyl)-4H-1,2,4-triazol-3-yl)-2-propanesulfonamide; (2S)-1-(5-chloro-3-cyano-2-pyridinyl)-N-(4-(2,6-dimethoxyphenyl)-5-(2-furanyl)-4H-1,2,4-triazol-3-yl)-2-propanesulfonamide; 2-(5-cyano-2-pyridinyl)-N-(4-(2,6-dimethoxyphenyl)-5-(5-methyl-2-furanyl)-4H-1,2,4-triazol-3-yl)ethanesulfonamide; 5-chloro-2-((2S)-2-((4-(2,6-dimethoxyphenyl)-5-(2-furanyl)-4H-1,2,4-triazol-3-yl)sulfamoyl)propyl)-N,N-diethyl-3-pyridinecarboxamide; (2R)-1-(5-bromo-2-pyrimidinyl)-N-(4-(2,6-dimethoxyphenyl)-5-(2-furanyl)-4H-1,2,4-triazol-3-yl)-2-propanesulfonamide; (2R)-1-(5-bromo-2-pyridinyl)-N-(4-(2,6-dimethoxyphenyl)-5-(2-furanyl)-4H-1,2,4-triazol-3-yl)-2-propanesulfonamide; (2R)—N-(4-(2,6-dimethoxyphenyl)-5-(5-methyl-2-furanyl)-4H-1,2,4-triazol-3-yl)-1-(5-methyl-2-pyrazinyl)-2-propanesulfonamide; (2R)—N-(4-(2,6-dimethoxyphenyl)-5-(2-furanyl)-4H-1,2,4-triazol-3-yl)-1-(5-fluoro-2-pyridinyl)-2-propanesulfonamide; N-(4-(2,6-dimethoxyphenyl)-5-(5-methyl-2-furanyl)-4H-1,2,4-triazol-3-yl)-2-(5-methyl-2-pyrimidinyl)ethanesulfonamide; 2-(5-chloro-3-(2-oxo-1-azetidinyl)-2-pyridinyl)-N-(4-(2,6-dimethoxyphenyl)-5-(2-furanyl)-4H-1,2,4-triazol-3-yl)ethanesulfonamide; N-(2-((2S)-2-((4-(2,6-dimethoxyphenyl)-5-(2-furanyl)-4H-1,2,4-triazol-3-yl)sulfamoyl)propyl)-5-fluoro-3-pyridinyl)acetamide; (2R)-1-(3-cyano-5-fluoro-2-pyridinyl)-N-(4-(2,6-dimethoxyphenyl)-5-(2-furanyl)-4H-1,2,4-triazol-3-yl)-2-propanesulfonamide; (2R)-1-(5-cyano-2-pyridinyl)-N-(4-(2,6-dimethoxyphenyl)-5-(2-furanyl)-4H-1,2,4-triazol-3-yl)-2-propanesulfonamide; (2R)—N-(4-(2,6-dimethoxyphenyl)-5-(5-methyl-2-furanyl)-4H-1,2,4-triazol-3-yl)-1-(6-methyl-3-pyridazinyl)-2-propanesulfonamide; (2R)—N-(4-(2,6-dimethoxyphenyl)-5-(2-furanyl)-4H-1,2,4-triazol-3-yl)-1-(5-methyl-2-pyrazinyl)-2-propanesulfonamide; (2S)-1-(5-cyano-2-pyridinyl)-N-(4-(2,6-dimethoxyphenyl)-5-(5-methyl-2-furanyl)-4H-1,2,4-triazol-3-yl)-2-propanesulfonamide; N-(4-(2,6-dimethoxyphenyl)-5-(2-furanyl)-4H-1,2,4-triazol-3-yl)-2-(5-fluoro-2-pyrimidinyl)ethanesulfonamide; 2-(5-cyano-2-pyridinyl)-N-(4-(2,6-dimethoxyphenyl)-5-(2-furanyl)-4H-1,2,4-triazol-3-yl)ethanesulfonamide; (2S)-1-(5-bromo-2-pyrimidinyl)-N-(4-(2,6-dimethoxyphenyl)-5-(2-furanyl)-4H-1,2,4-triazol-3-yl)-2-propanesulfonamide; (2S)-1-(5-chloro-2-pyrimidinyl)-N-(4-(2,6-dimethoxyphenyl)-5-(2-furanyl)-4H-1,2,4-triazol-3-yl)-2-propanesulfonamide; (2S)—N-(4-(2,6-dimethoxyphenyl)-5-(5-methyl-2-furanyl)-4H-1,2,4-triazol-3-yl)-1-(5-methyl-2-pyrazinyl)-2-propanesulfonamide; N-(4-(2,6-dimethoxyphenyl)-5-(2-furanyl)-4H-1,2,4-triazol-3-yl)-2-(5-methyl-2-pyrimidinyl)ethanesulfonamide; (1R,2S)-1-(5-cyano-2-pyridinyl)-N-(4-(2,6-dimethoxyphenyl)-5-(5-methyl-2-furanyl)-4H-1,2,4-triazol-3-yl)-1-hydroxy-2-propanesulfonamide; N-(4-(2,6-dimethoxyphenyl)-5-(2-furanyl)-4H-1,2,4-triazol-3-yl)-2-(5-fluoro-2-pyridinyl)ethanesulfonamide; (2R)—N-(4-(2,6-dimethoxyphenyl)-5-(2-furanyl)-4H-1,2,4-triazol-3-yl)-1-(6-methyl-3-pyridazinyl)-2-propanesulfonamide; (2S)—N-(4-(2,6-dimethoxyphenyl)-5-(5-methyl-2-furanyl)-4H-1,2,4-triazol-3-yl)-1-(6-methyl-3-pyridazinyl)-2-propanesulfonamide; (2R)—N-(4-(2,6-dimethoxyphenyl)-5-(2-furanyl)-4H-1,2,4-triazol-3-yl)-1-(4-pyrimidinyl)-2-propanesulfonamide; (2R)—N-(4-(2,6-dimethoxyphenyl)-5-(2-furanyl)-4H-1,2,4-triazol-3-yl)-1-(5-pyrimidinyl)-2-propanesulfonamide; (2S)—N-(4-(2,6-dimethoxyphenyl)-5-(2-furanyl)-4H-1,2,4-triazol-3-yl)-1-(4-pyrimidinyl)-2-propanesulfonamide; N-(4-(2,6-dimethoxyphenyl)-5-(2-furanyl)-4H-1,2,4-triazol-3-yl)-2-(6-methoxy-3-pyridinyl)ethanesulfonamide; 2-(5-chloro-2-pyridinyl)-N-(4-(2,6-dimethoxyphenyl)-5-(2-furanyl)-4H-1,2,4-triazol-3-yl)ethanesulfonamide; 2-(5-chloro-2-pyrimidinyl)-N-(4-(2,6-dimethoxyphenyl)-5-(2-furanyl)-4H-1,2,4-triazol-3-yl)ethanesulfonamide; 2-(5-chloro-3-cyano-2-pyridinyl)-N-(4-(2,6-dimethoxyphenyl)-5-(2-furanyl)-4H-1,2,4-triazol-3-yl)ethanesulfonamide; (2S)—N-(4-(2,6-dimethoxyphenyl)-5-(2-furanyl)-4H-1,2,4-triazol-3-yl)-1-(5-fluoro-2-pyrimidinyl)-2-propanesulfonamide; (2R)—N-(4-(2,6-dimethoxyphenyl)-5-(2-furanyl)-4H-1,2,4-triazol-3-yl)-1-(5-fluoro-2-pyrimidinyl)-2-propanesulfonamide; (2R,3S)—N-(4-(2,6-dimethoxyphenyl)-5-(5-methyl-2-furanyl)-4H-1,2,4-triazol-3-yl)-3-(5-ethyl-2-pyrimidinyl)-2-butanesulfonamide; (2S,3R)—N-(4-(2,6-dimethoxyphenyl)-5-(5-methyl-2-furanyl)-4H-1,2,4-triazol-3-yl)-3-(5-fluoro-2-pyrimidinyl)-2-butanesulfonamide; (1S,2S)—N-(4-(2,6-dimethoxyphenyl)-5-(5-methyl-2-furanyl)-4H-1,2,4-triazol-3-yl)-1-(5-fluoro-2-pyridinyl)-1-hydroxy-2-propanesulfonamide; (2R)-2-(5-cyano-2-pyridinyl)-N-(4-(2,6-dimethoxyphenyl)-5-(5-methyl-2-furanyl)-4H-1,2,4-triazol-3-yl)-2-hydroxyethanesulfonamide; (1R,2R)—N-(4-(2,6-dimethoxyphenyl)-5-(5-methyl-2-furanyl)-4H-1,2,4-triazol-3-yl)-1-(5-fluoro-2-pyridinyl)-1-hydroxy-2-propanesulfonamide; (2R)—N-(4-(2,6-dimethoxyphenyl)-5-(5-methyl-2-furanyl)-4H-1,2,4-triazol-3-yl)-2-(5-fluoro-2-pyridinyl)-2-hydroxyethanesulfonamide; (2S)—N-(4-(2,6-dimethoxyphenyl)-5-(5-methyl-2-furanyl)-4H-1,2,4-triazol-3-yl)-2-(5-fluoro-2-pyridinyl)-2-hydroxyethanesulfonamide; (1R,2R)-1-(4-cyano-2-fluorophenyl)-N-(4-(2,6-dimethoxyphenyl)-5-(5-methyl-2-furanyl)-4H-1,2,4-triazol-3-yl)-1-hydroxy-2-propanesulfonamide; (3S,4S)—N-(4-(2,6-dimethoxyphenyl)-5-(5-methyl-2-furanyl)-4H-1,2,4-triazol-3-yl)-1-hydroxy-4-(5-methyl-2-pyrimidinyl)-3-pentanesulfonamide; (1R,2R)—N-(4-(2,6-dimethoxyphenyl)-5-(5-methyl-2-furanyl)-4H-1,2,4-triazol-3-yl)-1-hydroxy-1-(5-methyl-2-pyridinyl)-2-propanesulfonamide; (1S,2S)—N-(4-(2,6-dimethoxyphenyl)-5-(5-methyl-2-furanyl)-4H-1,2,4-triazol-3-yl)-1-hydroxy-1-(5-methyl-2-pyridinyl)-2-propanesulfonamide; (2S)-2-(5-cyano-2-pyridinyl)-N-(4-(2,6-dimethoxyphenyl)-5-(5-methyl-2-furanyl)-4H-1,2,4-triazol-3-yl)-2-hydroxy ethanesulfonamide; (3S,4R)—N-(4-(2,6-dimethoxyphenyl)-5-(5-methyl-2-furanyl)-4H-1,2,4-triazol-3-yl)-4-(5-fluoro-2-pyrimidinyl)-1-methoxy-3-pentanesulfonamide; (1S,2R)-1-(5-cyano-3-fluoro-2-pyridinyl)-N-(4-(2,6-dimethoxy phenyl)-5-(5-methyl-2-furanyl)-4H-1,2,4-triazol-3-yl)-1-hydroxy-2-propanesulfonamide; (2S)—N-(4-(2,6-dimethoxyphenyl)-5-(5-methyl-2-furanyl)-4H-1,2,4-triazol-3-yl)-4-hydroxy-1-(5-methyl-2-pyrimidinyl)-2-butanesulfonamide; (2R)—N-(4-(2,6-dimethoxyphenyl)-5-(5-methyl-2-furanyl)-4H-1,2,4-triazol-3-yl)-4-hydroxy-1-(5-methyl-2-pyrimidinyl)-2-butanesulfonamide; (2R)—N-(4-(2,6-dimethoxyphenyl)-5-(5-methyl-2-furanyl)-4H-1,2,4-triazol-3-yl)-4-methoxy-1-(5-methyl-2-pyrimidinyl)-2-butanesulfonamide; (2R)—N-(4-(2,6-dimethoxyphenyl)-5-(5-methyl-2-furanyl)-4H-1,2,4-triazol-3-yl)-1-(5-fluoro-2-pyrimidinyl)-3-methoxy-2-propanesulfonamide; (1R,2R)—N-(4-(2,6-dimethoxyphenyl)-5-(5-methyl-2-furanyl)-4H-1,2,4-triazol-3-yl)-1-(4-fluoro-2-(hydroxymethyl)phenyl)-1-hydroxy-2-propanesulfonamide; (1S,2S)—N-(4-(2,6-dimethoxyphenyl)-5-(5-methyl-2-furanyl)-4H-1,2,4-triazol-3-yl)-1-(4-fluoro-2-(hydroxymethyl)phenyl)-1-hydroxy-2-propanesulfonamide; (3R,4R)—N-(4-(2,6-dimethoxyphenyl)-5-(5-methyl-2-furanyl)-4H-1,2,4-triazol-3-yl)-4-(5-fluoro-2-pyrimidinyl)-1-methoxy-3-pentanesulfonamide; (3R,4S)—N-(4-(2,6-dimethoxyphenyl)-5-(5-methyl-2-furanyl)-4H-1,2,4-triazol-3-yl)-4-(5-fluoro-2-pyrimidinyl)-1-methoxy-3-pentanesulfonamide; (3S,4S)—N-(4-(2,6-dimethoxyphenyl)-5-(5-methyl-2-furanyl)-4H-1,2,4-triazol-3-yl)-4-(5-fluoro-2-pyrimidinyl)-1-methoxy-3-pentanesulfonamide; (1R,2S)-1-(4-cyano-2-fluorophenyl)-N-(4-(2,6-dimethoxy phenyl)-5-(5-methyl-2-furanyl)-4H-1,2,4-triazol-3-yl)-1-hydroxy-2-propanesulfonamide; (1S,2R)-1-(4-cyano-2-fluorophenyl)-N-(4-(2,6-dimethoxy phenyl)-5-(5-methyl-2-furanyl)-4H-1,2,4-triazol-3-yl)-1-hydroxy-2-propanesulfonamide; (1S,2S)-1-(4-cyano-2-fluorophenyl)-N-(4-(2,6-dimethoxyphenyl)-5-(5-methyl-2-furanyl)-4H-1,2,4-triazol-3-yl)-1-hydroxy-2-propanesulfonamide; (2S)—N-(4-(2,6-dimethoxyphenyl)-5-(5-methyl-2-furanyl)-4H-1,2,4-triazol-3-yl)-4-methoxy-1-(5-methyl-2-pyrimidinyl)-2-butanesulfonamide; (3R,4R)—N-(4-(2,6-dimethoxyphenyl)-5-(5-methyl-2-furanyl)-4H-1,2,4-triazol-3-yl)-1-hydroxy-4-(5-methyl-2-pyrimidinyl)-3-pentanesulfonamide; (3R,4S)—N-(4-(2,6-dimethoxyphenyl)-5-(5-methyl-2-furanyl)-4H-1,2,4-triazol-3-yl)-1-hydroxy-4-(5-methyl-2-pyrimidinyl)-3-pentanesulfonamide; (3S,4R)—N-(4-(2,6-dimethoxyphenyl)-5-(5-methyl-2-furanyl)-4H-1,2,4-triazol-3-yl)-1-hydroxy-4-(5-methyl-2-pyrimidinyl)-3-pentanesulfonamide; (2S)—N-(4-(2,6-dimethoxyphenyl)-5-(5-methyl-2-furanyl)-4H-1,2,4-triazol-3-yl)-1-(5-fluoro-2-pyrimidinyl)-3-methoxy-2-propanesulfonamide; (1R,2S)—N-(4-(2,6-dimethoxyphenyl)-5-(5-methyl-2-furanyl)-4H-1,2,4-triazol-3-yl)-1-(5-fluoro-2-pyridinyl)-1-hydroxy-2-propanesulfonamide; (1S,2R)—N-(4-(2,6-dimethoxyphenyl)-5-(5-methyl-2-furanyl)-4H-1,2,4-triazol-3-yl)-1-(5-fluoro-2-pyridinyl)-1-hydroxy-2-propanesulfonamide; (1R,2R)-1-(3-cyano-4-fluorophenyl)-N-(4-(2,6-dimethoxyphenyl)-5-(5-methyl-2-furanyl)-4H-1,2,4-triazol-3-yl)-1-hydroxy-2-propanesulfonamide; (1S,2S)-1-(3-cyano-4-fluorophenyl)-N-(4-(2,6-dimethoxyphenyl)-5-(5-methyl-2-furanyl)-4H-1,2,4-triazol-3-yl)-1-hydroxy-2-propanesulfonamide; (1R,2R)—N-(4-(2,6-dimethoxyphenyl)-5-(5-methyl-2-furanyl)-4H-1,2,4-triazol-3-yl)-1-(2,4-dimethyl-1,3-oxazol-5-yl)-1-hydroxy-2-propanesulfonamide; (1R,2S)—N-(4-(2,6-dimethoxyphenyl)-5-(5-methyl-2-furanyl)-4H-1,2,4-triazol-3-yl)-1-(2,4-dimethyl-1,3-oxazol-5-yl)-1-hydroxy-2-propanesulfonamide; (1S,2R)—N-(4-(2,6-dimethoxyphenyl)-5-(5-methyl-2-furanyl)-4H-1,2,4-triazol-3-yl)-1-(2,4-dimethyl-1,3-oxazol-5-yl)-1-hydroxy-2-propanesulfonamide; (1S,2S)—N-(4-(2,6-dimethoxyphenyl)-5-(5-methyl-2-furanyl)-4H-1,2,4-triazol-3-yl)-1-(2,4-dimethyl-1,3-oxazol-5-yl)-1-hydroxy-2-propanesulfonamide; 2-(4-chlorophenyl)-N-(5-(2-furanyl)-4-(1R,2R)-2-methoxy cyclopentyl)-4H-1,2,4-triazol-3-yl)ethanesulfonamide; 2-(4-chlorophenyl)-N-(5-(2-furanyl)-4-(1S,2S)-2-methoxy cyclopentyl)-4H-1,2,4-triazol-3-yl)ethanesulfonamide; 2-(4-chlorophenyl)-N-(5-(2-furanyl)-4-(2-pyridinyl)-4H-1,2,4-triazol-3-yl)ethane sulfonamide; (1R,2S)-1-(6-chloro-2-pyridinyl)-N-(4-(2,6-dimethoxyphenyl)-5-(5-methyl-2-furanyl)-4H-1,2,4-triazol-3-yl)-1-hydroxy-2-propanesulfonamide; (1R,2S)-1-(5-cyano-6-methyl-2-pyridinyl)-N-(4-(2,6-dimethoxyphenyl)-5-(5-methyl-2-furanyl)-4H-1,2,4-triazol-3-yl)-1-hydroxy-2-propanesulfonamide; (1R,2S)—N-(4-(2,6-dimethoxyphenyl)-5-(5-methyl-2-furanyl)-4H-1,2,4-triazol-3-yl)-1-hydroxy-1-(6-methyl-2-pyridinyl)-2-propanesulfonamide; (1R,2R)-1-(5-cyano-6-methyl-2-pyridinyl)-N-(4-(2,6-dimethoxyphenyl)-5-(5-methyl-2-furanyl)-4H-1,2,4-triazol-3-yl)-1-hydroxy-2-propanesulfonamide; (1S,2R)-1-(5-cyano-6-methyl-2-pyridinyl)-N-(4-(2,6-dimethoxyphenyl)-5-(5-methyl-2-furanyl)-4H-1,2,4-triazol-3-yl)-1-hydroxy-2-propanesulfonamide; (1S,2S)-1-(5-cyano-6-methyl-2-pyridinyl)-N-(4-(2,6-dimethoxyphenyl)-5-(5-methyl-2-furanyl)-4H-1,2,4-triazol-3-yl)-1-hydroxy-2-propanesulfonamide; (2S)—N-(4-(2,6-dimethoxyphenyl)-5-(4,5-dimethyl-2-furanyl)-4H-1,2,4-triazol-3-yl)-1-(5-fluoro-2-pyrimidinyl)-2-propanesulfonamide; (1R,2R)—N-(4-(2,6-dimethoxyphenyl)-5-(5-methyl-2-furanyl)-4H-1,2,4-triazol-3-yl)-1-hydroxy-1-(2-pyridinyl)-2-propanesulfonamide; (1S,2S)—N-(4-(2,6-dimethoxyphenyl)-5-(5-methyl-2-furanyl)-4H-1,2,4-triazol-3-yl)-1-hydroxy-1-(2-pyridinyl)-2-propanesulfonamide; (2R)—N-(4-(2,6-dimethoxyphenyl)-5-(4,5-dimethyl-2-furanyl)-4H-1,2,4-triazol-3-yl)-1-(5-fluoro-2-pyrimidinyl)-2-propanesulfonamide; (2R)—N-(4-(2,6-dimethoxyphenyl)-5-(5-ethyl-2-furanyl)-4H-1,2,4-triazol-3-yl)-1-(5-fluoro-2-pyrimidinyl)-2-propanesulfonamide; (2S)—N-(4-(2,6-dimethoxyphenyl)-5-(5-ethyl-2-furanyl)-4H-1,2,4-triazol-3-yl)-1-(5-fluoro-2-pyrimidinyl)-2-propanesulfonamide; (1S,2R)—N-(4-(2,6-dimethoxyphenyl)-5-(5-methyl-2-furanyl)-4H-1,2,4-triazol-3-yl)-1-(5-fluoro-2-pyrimidinyl)-1-hydroxy-2-propanesulfonamide; (2R)—N-(4-(2,6-dimethoxyphenyl)-5-(5-methyl-2-furanyl)-4H-1,2,4-triazol-3-yl)-1-(5-fluoro-2-pyrimidinyl)-2-propanesulfonamide; (2S)—N-(4-(2,6-dimethoxyphenyl)-5-(5-methyl-2-furanyl)-4H-1,2,4-triazol-3-yl)-1-(5-fluoro-2-pyrimidinyl)-2-propanesulfonamide; (1S,2S)—N-(4-(2,6-dimethoxyphenyl)-5-(5-methyl-2-furanyl)-4H-1,2,4-triazol-3-yl)-1-(5-fluoro-2-pyrimidinyl)-1-hydroxy-2-propanesulfonamide; (1R,2S)—N-(4-(2,6-dimethoxyphenyl)-5-(5-methyl-2-furanyl)-4H-1,2,4-triazol-3-yl)-1-(5-fluoro-2-pyrimidinyl)-1-hydroxy-2-propanesulfonamide; N-(4-(2,6-dimethoxyphenyl)-5-(5-ethyl-2-furanyl)-4H-1,2,4-triazol-3-yl)-2-(5-fluoro-2-pyrimidinyl)ethanesulfonamide; (1R,2S)—N-(4-(2,6-dimethoxyphenyl)-5-(5-methyl-2-furanyl)-4H-1,2,4-triazol-3-yl)-2-(5-fluoro-2-pyrimidinyl)cyclopentanesulfonamide; (1S,2R)—N-(4-(2,6-dimethoxyphenyl)-5-(5-methyl-2-furanyl)-4H-1,2,4-triazol-3-yl)-2-(5-fluoro-2-pyrimidinyl)cyclopentanesulfonamide; (1S,2S)—N-(4-(2,6-dimethoxyphenyl)-5-(2-furanyl)-4H-1,2,4-triazol-3-yl)-2-(5-fluoro-2-pyrimidinyl)cyclohexanesulfonamide; (1R,2S)—N-(4-(2,6-dimethoxyphenyl)-5-(2-furanyl)-4H-1,2,4-triazol-3-yl)-2-(5-fluoro-2-pyrimidinyl)cyclopentanesulfonamide; (1R,2S)—N-(4-(2,6-dimethoxyphenyl)-5-(2-furanyl)-4H-1,2,4-triazol-3-yl)-2-(5-fluoro-2-pyrimidinyl)cyclohexanesulfonamide; 2-(4-chlorophenyl)-N-(4-(2,6-dimethoxyphenyl)-5-(3-methyl-2-furanyl)-4H-1,2,4-triazol-3-yl)ethanesulfonamide; N-(4-(2,6-dimethoxyphenyl)-5-(5-(trifluoromethyl)-2-furanyl)-4H-1,2,4-triazol-3-yl)-2-(5-fluoro-2-pyrimidinyl)ethanesulfonamide; (2R,3S)—N-(4-(2,6-dimethoxyphenyl)-5-(5-methyl-2-furanyl)-4H-1,2,4-triazol-3-yl)-3-(5-fluoro-2-pyrimidinyl)-2-butanesulfonamide; (2S,3S)—N-(4-(2,6-dimethoxyphenyl)-5-(5-methyl-2-furanyl)-4H-1,2,4-triazol-3-yl)-3-(5-fluoro-2-pyrimidinyl)-2-butanesulfonamide; 2-(4-chlorophenyl)-N-(4-(2,6-dimethoxyphenyl)-5-(2-furanyl)-4H-1,2,4-triazol-3-yl)ethanesulfonamide; 2-(4-chlorophenyl)-N-(5-(2-furanyl)-4-(2-methoxy-6-methylphenyl)-4H-1,2,4-triazol-3-yl)ethanesulfonamide; 3-(4-chlorophenyl)-N-(4-(2,6-dimethoxyphenyl)-5-(2-furanyl)-4H-1,2,4-triazol-3-yl)-1-propanesulfonamide; (1R,2S)—N-(4-(2,6-dimethoxyphenyl)-5-(5-methyl-2-furanyl)-4H-1,2,4-triazol-3-yl)-1-hydroxy-1-(5-methyl-2-pyrimidinyl)-2-propanesulfonamide; (1R,2S)—N-(4-(2,6-dimethoxyphenyl)-5-(5-methyl-2-furanyl)-4H-1,2,4-triazol-3-yl)-1-(5-fluoro-2-pyrimidinyl)-1-methoxy-2-propanesulfonamide; (1S,2S)—N-(4-(2,6-dimethoxyphenyl)-5-(5-methyl-2-furanyl)-4H-1,2,4-triazol-3-yl)-1-ethoxy-1-(5-methyl-2-pyrimidinyl)-2-propanesulfonamide; (1R,2S)—N-(4-(2,6-dimethoxyphenyl)-5-(5-methyl-2-furanyl)-4H-1,2,4-triazol-3-yl)-1-ethoxy-1-(5-methyl-2-pyrimidinyl)-2-propanesulfonamide; 2-(2-cyano-4-fluorophenyl)-N-(4-(2,6-dimethoxyphenyl)-5-(5-methyl-2-furanyl)-4H-1,2,4-triazol-3-yl)ethanesulfonamide; (1R,2S)—N-(4-(2,6-dimethoxyphenyl)-5-(5-methyl-2-furanyl)-4H-1,2,4-triazol-3-yl)-1-(2-methoxy ethoxy)-1-(5-methyl-2-pyrimidinyl)-2-propanesulfonamide; (1S,2S)—N-(4-(2,6-dimethoxyphenyl)-5-(5-methyl-2-furanyl)-4H-1,2,4-triazol-3-yl)-1-(2-hydroxy ethoxy)-1-(5-methyl-2-pyrimidinyl)-2-propanesulfonamide; (1R,2R)—N-(4-(2,6-dimethoxyphenyl)-5-(5-methyl-2-furanyl)-4H-1,2,4-triazol-3-yl)-1-(5-fluoro-2-pyrimidinyl)-1-methoxy-2-propanesulfonamide; (2R)—N-(4-(2,6-dimethoxyphenyl)-5-(5-methyl-2-furanyl)-4H-1,2,4-triazol-3-yl)-2-(5-fluoro-2-pyrimidinyl)-1-propanesulfonamide; (1S,2S)—N-(4-(2,6-dimethoxyphenyl)-5-(5-methyl-2-furanyl)-4H-1,2,4-triazol-3-yl)-1-(5-fluoro-2-pyrimidinyl)-1-methoxy-2-propanesulfonamide; N-(4-(2,6-dimethoxyphenyl)-5-(5-methyl-2-furanyl)-4H-1,2,4-triazol-3-yl)-2-(5-fluoro-2-pyrimidinyl)ethanesulfonamide; (2S)—N-(4-(2,6-dimethoxyphenyl)-5-(5-methyl-2-furanyl)-4H-1,2,4-triazol-3-yl)-2-(5-fluoro-2-pyrimidinyl)-1-propanesulfonamide; (2R)—N-(4-(2,6-dimethoxyphenyl)-5-(5-methyl-2-furanyl)-4H-1,2,4-triazol-3-yl)-1-(5-fluoro-2-pyrimidinyl)-2-butanesulfonamide; (2S)—N-(4-(2,6-dimethoxyphenyl)-5-(5-methyl-2-furanyl)-4H-1,2,4-triazol-3-yl)-1-(5-fluoro-2-pyrimidinyl)-2-butanesulfonamide; (2R)—N-(4-(2,6-dimethoxyphenyl)-5-(2-furanyl)-4H-1,2,4-triazol-3-yl)-2-(5-fluoro-2-pyrimidinyl)-1-propanesulfonamide; (2S)—N-(4-(2,6-dimethoxyphenyl)-5-(2-furanyl)-4H-1,2,4-triazol-3-yl)-2-(5-fluoro-2-pyrimidinyl)-1-propanesulfonamide; (1R,2R)—N-(4-(2,6-dimethoxyphenyl)-5-(5-methyl-2-furanyl)-4H-1,2,4-triazol-3-yl)-1-ethoxy-1-(5-methyl-2-pyrimidinyl)-2-propanesulfonamide; 2-(2-cyano-4-fluorophenyl)-N-(4-(2,6-dimethoxyphenyl)-5-(5-(trifluoromethyl)-2-furanyl)-4H-1,2,4-triazol-3-yl)ethanesulfonamide; (2R)—N-(4-(2,6-dimethoxyphenyl)-5-(2-furanyl)-4H-1,2,4-triazol-3-yl)-1-(5-fluoro-2-pyrimidinyl)-2-butanesulfonamide; (2S)—N-(4-(2,6-dimethoxyphenyl)-5-(2-furanyl)-4H-1,2,4-triazol-3-yl)-1-(5-fluoro-2-pyrimidinyl)-2-butanesulfonamide; (2R,3R)—N-(4-(2,6-dimethoxyphenyl)-5-(5-methyl-2-furanyl)-4H-1,2,4-triazol-3-yl)-3-(5-fluoro-2-pyrimidinyl)-2-butanesulfonamide; 2-(4-chlorophenyl)-N-(4-(2,6-dimethoxyphenyl)-5-(5-methyl-2-furanyl)-4H-1,2,4-triazol-3-yl)ethanesulfonamide; 2-(4-chlorophenyl)-N-(4-(2,6-dimethoxyphenyl)-5-(5-(methoxymethyl)-2-furanyl)-4H-1,2,4-triazol-3-yl)ethanesulfonamide; 2-(4-chlorophenyl)-N-(4-(2,6-dimethoxyphenyl)-5-(5-(trifluoromethyl)-2-furanyl)-4H-1,2,4-triazol-3-yl)ethanesulfonamide; N-(5-(5-bromo-2-furanyl)-4-(2,6-dimethoxyphenyl)-4H-1,2,4-triazol-3-yl)-2-(4-chlorophenyl)ethanesulfonamide; N-(5-(5-tert-butyl-2-furanyl)-4-(2,6-dimethoxyphenyl)-4H-1,2,4-triazol-3-yl)-2-(4-chlorophenyl)ethanesulfonamide; N-(5-(5-tert-butyl-2-furanyl)-4-(2,6-dimethoxyphenyl)-4H-1,2,4-triazol-3-yl)-2-(2-cyano-4-fluorophenyl)ethanesulfonamide; (2R)-2-(4-chloro-2-(methylsulfonyl)phenyl)-N-(4-(2,6-dimethoxyphenyl)-5-(5-methyl-2-furanyl)-4H-1,2,4-triazol-3-yl)-2-hydroxyethanesulfonamide; (2S)-2-(4-chloro-2-(methylsulfonyl)phenyl)-N-(4-(2,6-dimethoxyphenyl)-5-(5-methyl-2-furanyl)-4H-1,2,4-triazol-3-yl)-2-hydroxyethanesulfonamide; (2R,3S)—N-(4-(2,6-dimethoxyphenyl)-5-(5-methyl-2-furanyl)-4H-1,2,4-triazol-3-yl)-3-(5-methyl-1-oxido-2-pyrazinyl)-2-butanesulfonamide; (2S,3R)—N-(4-(2,6-dimethoxyphenyl)-5-(5-methyl-2-furanyl)-4H-1,2,4-triazol-3-yl)-3-(5-methyl-1-oxido-2-pyrazinyl)-2-butanesulfonamide; (2S,3R)—N-(4-(2,6-dimethoxyphenyl)-5-(5-methyl-2-furanyl)-4H-1,2,4-triazol-3-yl)-3-(5-methyl-2-pyrazinyl)-2-butanesulfonamide; (1R,2S)-1-(2,4-dicyanophenyl)-N-(4-(2,6-dimethoxyphenyl)-5-(5-methyl-2-furanyl)-4H-1,2,4-triazol-3-yl)-1-methoxy-2-propanesulfonamide; (1S,2R)-1-(2,4-dicyanophenyl)-N-(4-(2,6-dimethoxyphenyl)-5-(5-methyl-2-furanyl)-4H-1,2,4-triazol-3-yl)-1-methoxy-2-propanesulfonamide; (2R)—N-(4-(2,6-dimethoxyphenyl)-5-(5-methyl-2-furanyl)-4H-1,2,4-triazol-3-yl)-1-((2R)-2-(methoxymethyl)-6-oxo-1-piperidinyl)-2-propanesulfonamide; (2R)—N-(4-(2,6-dimethoxyphenyl)-5-(5-methyl-2-furanyl)-4H-1,2,4-triazol-3-yl)-1-((2S)-2-(methoxymethyl)-6-oxo-1-piperidinyl)-2-propanesulfonamide; (1R,2S)—N-(4-(2,6-dimethoxyphenyl)-5-(5-methyl-2-furanyl)-4H-1,2,4-triazol-3-yl)-1-hydroxy-1-(5-methoxy-2-pyrazinyl)-2-propanesulfonamide; (1R,2R)-1-(4-chloro-2-(methylsulfonyl)phenyl)-N-(4-(2,6-dimethoxyphenyl)-5-(5-methyl-2-furanyl)-4H-1,2,4-triazol-3-yl)-1-hydroxy-2-propanesulfonamide; (3R,5R)-5-(1-azetidinylcarbonyl)-N-(4-(2,6-dimethoxyphenyl)-5-(5-methyl-2-furanyl)-4H-1,2,4-triazol-3-yl)-1-(5-fluoro-2-pyrimidinyl)-3-piperidinesulfonamide; (3S,5S)-5-(1-azetidinylcarbonyl)-N-(4-(2,6-dimethoxyphenyl)-5-(5-methyl-2-furanyl)-4H-1,2,4-triazol-3-yl)-1-(5-fluoro-2-pyrimidinyl)-3-piperidinesulfonamide; (3R,5S)-5-(1-azetidinylcarbonyl)-N-(4-(2,6-dimethoxyphenyl)-5-(5-methyl-2-furanyl)-4H-1,2,4-triazol-3-yl)-1-(5-fluoro-2-pyrimidinyl)-3-piperidinesulfonamide; (3S,5R)-5-(1-azetidinylcarbonyl)-N-(4-(2,6-dimethoxyphenyl)-5-(5-methyl-2-furanyl)-4H-1,2,4-triazol-3-yl)-1-(5-fluoro-2-pyrimidinyl)-3-piperidinesulfonamide; ethyl (3S,5R)-5-((4-(2,6-dimethoxyphenyl)-5-(2-furanyl)-4H-1,2,4-triazol-3-yl)sulfamoyl)-1-(5-fluoro-2-pyrimidinyl)-3-piperidinecarboxylate; (1S,2R)-1-(4-chloro-2-(methylsulfonyl)phenyl)-N-(4-(2,6-dimethoxyphenyl)-5-(5-methyl-2-furanyl)-4H-1,2,4-triazol-3-yl)-1-hydroxy-2-propanesulfonamide; ethyl (3R,5R)-5-(4-(2,6-dimethoxyphenyl)-5-(2-furanyl)-4H-1,2,4-triazol-3-yl)sulfamoyl)-1-(5-fluoro-2-pyrimidinyl)-3-piperidinecarboxylate; (3R,5S)-5-(1-azetidinylcarbonyl)-N-(4-(2,6-dimethoxyphenyl)-5-(2-furanyl)-4H-1,2,4-triazol-3-yl)-1-(5-fluoro-2-pyrimidinyl)-3-piperidinesulfonamide; N-(4-(2,6-dimethoxyphenyl)-5-(2-furanyl)-4H-1,2,4-triazol-3-yl)-2-((6R)-3,6-dimethyl-2-oxotetrahydro-1(2H)-pyrimidinyl)ethanesulfonamide; N-(4-(2,6-dimethoxyphenyl)-5-(5-methyl-2-furanyl)-4H-1,2,4-triazol-3-yl)-2-((6R)-3,6-dimethyl-2-oxotetrahydro-1(2H)-pyrimidinyl)ethanesulfonamide; (3S,5R)-1-acetyl-N-(4-(2,6-dimethoxyphenyl)-5-(5-methyl-2-furanyl)-4H-1,2,4-triazol-3-yl)-5-(4-fluorophenyl)-3-piperidinesulfonamide; (2S,3R)—N-(4-(4-methoxy-2-oxo-1,2-dihydro-3-pyridinyl)-5-(5-methyl-2-furanyl)-4H-1,2,4-triazol-3-yl)-3-(5-methyl-2-pyrimidinyl)-2-butanesulfonamide; (3R,5S)—N-(4-(2,6-dimethoxyphenyl)-5-(2-furanyl)-4H-1,2,4-triazol-3-yl)-1-(5-fluoro-2-pyrimidinyl)-5-hydroxy-3-piperidinesulfonamide; 2-(2R,4R)-2-cyano-2,4-dimethyl-5-oxo-1-pyrrolidinyl)-N-(4-(2,6-dimethoxyphenyl)-5-(2-furanyl)-4H-1,2,4-triazol-3-yl)ethanesulfonamide; N-(4-(2,6-dimethoxyphenyl)-5-(2-furanyl)-4H-1,2,4-triazol-3-yl)-2-(2S)-2-methyl-6-oxo-1-piperidinyl)ethanesulfonamide; (3S,5S)-1-acetyl-N-(4-(2,6-dimethoxyphenyl)-5-(5-methyl-2-furanyl)-4H-1,2,4-triazol-3-yl)-5-(4-fluorophenyl)-3-piperidinesulfonamide; (3R,5S)-1-acetyl-N-(4-(2,6-dimethoxyphenyl)-5-(5-methyl-2-furanyl)-4H-1,2,4-triazol-3-yl)-5-(4-fluorophenyl)-3-piperidinesulfonamide; (2S,3R)-3-(5-fluoro-2-pyrimidinyl)-N-(4-(2-methoxyphenyl)-5-(5-methyl-2-furanyl)-4H-1,2,4-triazol-3-yl)-2-butanesulfonamide; (3S,9aR)—N-(4-(2,6-dimethoxyphenyl)-5-(5-methyl-2-furanyl)-4H-1,2,4-triazol-3-yl)-6-oxooctahydro-2H-quinolizine-3-sulfonamide; (3R,5S)-5-cyano-N-(4-(2,6-dimethoxyphenyl)-5-(5-methyl-2-furanyl)-4H-1,2,4-triazol-3-yl)-1-(5-fluoro-2-pyrimidinyl)-3-piperidinesulfonamide; N-(4-(2,6-dimethoxyphenyl)-5-(2-furanyl)-4H-1,2,4-triazol-3-yl)-2-((3R,5S)-3,5-dimethyl-2-oxo-1-pyrrolidinyl)ethanesulfonamide; N-(4-(2,6-dimethoxyphenyl)-5-(2-furanyl)-4H-1,2,4-triazol-3-yl)-2-((2R)-2-(methoxymethyl)-6-oxo-1-piperidinyl)ethanesulfonamide; (1S,2R)—N-(4-(2,6-dimethoxyphenyl)-5-(5-methyl-2-furanyl)-4H-1,2,4-triazol-3-yl)-1-hydroxy-1-(5-methoxy-2-pyrazinyl)-2-propanesulfonamide; (3S,5R)—N-(4-(2,6-dimethoxyphenyl)-5-(2-furanyl)-4H-1,2,4-triazol-3-yl)-1-(5-fluoro-2-pyrimidinyl)-5-methoxy-3-piperidinesulfonamide; (3R)—N-(4-(2,6-dimethoxyphenyl)-5-(5-methyl-2-furanyl)-4H-1,2,4-triazol-3-yl)-1-(5-fluoro-2-pyrimidinyl)-3-piperidinesulfonamide; (3R,4S)—N-(4-(2,6-dimethoxyphenyl)-5-(2-furanyl)-4H-1,2,4-triazol-3-yl)-4-(5-fluoro-2-pyrimidinyl)tetrahydro-3-furansulfonamide; (3S,4R)—N-(4-(2,6-dimethoxyphenyl)-5-(2-furanyl)-4H-1,2,4-triazol-3-yl)-4-(5-fluoro-2-pyrimidinyl)tetrahydro-3-furansulfonamide; (3R)-7-chloro-N-(4-(2,6-dimethoxyphenyl)-5-(2-furanyl)-4H-1,2,4-triazol-3-yl)-3,4-dihydro-2H-pyrano[3,2-b]pyridine-3-sulfonamide; (3S)-7-chloro-N-(4-(2,6-dimethoxyphenyl)-5-(2-furanyl)-4H-1,2,4-triazol-3-yl)-3,4-dihydro-2H-pyrano[3,2-b]pyridine-3-sulfonamide; (2S,3R)-3-(5-fluoro-2-pyrimidiny))-N-(5-(5-methyl-2-furanyl)-4-(tetrahydro-2H-pyran-4-yl)-4H-1,2,4-triazol-3-yl)-2-butanesulfonamide; (3R,4R)—N-(4-(2,6-dimethoxyphenyl)-5-(2-furanyl)-4H-1,2,4-triazol-3-yl)-4-(5-fluoro-2-pyrimidinyl)tetrahydro-2H-pyran-3-sulfonamide; (3S,4S)—N-(4-(2,6-dimethoxyphenyl)-5-(2-furanyl)-4H-1,2,4-triazol-3-yl)-4-(5-fluoro-2-pyrimidinyl)tetrahydro-2H-pyran-3-sulfonamide; (2S)—N-(4-(2,6-dimethoxyphenyl)-5-(5-methyl-2-furanyl)-4H-1,2,4-triazol-3-yl)-1-(2S)-2-(methoxymethyl)-6-oxo-1-piperidinyl)-2-propanesulfonamide; (2S,3R)-3-(5-fluoro-2-pyrimidiny))-N-(4-(4-methoxy-2-oxo-1,2-dihydro-3-pyridinyl)-5-(5-methyl-2-furanyl)-4H-1,2,4-triazol-3-yl)-2-butanesulfonamide; (3R,5S)—N-(4-(2,6-dimethoxyphenyl)-5-(2-furanyl)-4H-1,2,4-triazol-3-yl)-5-(4-fluorophenyl)-3-piperidinesulfonamide; (2S,3R)—N-(4-(3,5-dibromo-2,6-dimethoxyphenyl)-5-(5-methyl-2-furanyl)-4H-1,2,4-triazol-3-yl)-3-(5-fluoro-2-pyrimidiny))-2-butanesulfonamide; (1R,2S)-2-(4-chlorophenyl)-N-(4-(2,6-dimethoxyphenyl)-5-(2-furanyl)-4H-1,2,4-triazol-3-yl)cyclopropanesulfonamide; (1S,2R)-2-(4-chlorophenyl)-N-(4-(2,6-dimethoxyphenyl)-5-(2-furanyl)-4H-1,2,4-triazol-3-yl)cyclopropanesulfonamide; 2-(4-chlorophenyl)-N-(4-(2-cyano-6-methoxyphenyl)-5-(2-furanyl)-4H-1,2,4-triazol-3-yl)ethanesulfonamide; 2-(2-bromo-4-fluorophenyl)-N-(4-(2,6-dimethoxy phenyl)-5-(2-furanyl)-4H-1,2,4-triazol-3-yl)ethanesulfonamide; N-(4-(2,6-dimethoxyphenyl)-5-(2-furanyl)-4H-1,2,4-triazol-3-yl)-2-(4-fluoro-2-(methylsulfonyl)phenyl)ethanesulfonamide; N-(2-(2-(4-(2,6-dimethoxyphenyl)-5-(2-furanyl)-4H-1,2,4-triazol-3-yl)sulfamoyl)ethyl)-5-fluorophenyl)acetamide; (2R)—N-(4-(2,6-dimethoxyphenyl)-5-(2-furanyl)-4H-1,2,4-triazol-3-yl)-2-(4-fluorophenyl)-1-propanesulfonamide; N-(4-(2,6-dimethoxyphenyl)-5-(2-furanyl)-4H-1,2,4-triazol-3-yl)-3-oxo-3-(1-pyrrolidinyl)-1-propanesulfonamide; (3S)-3-cyclopentyl-N-(4-(2,6-dimethoxyphenyl)-5-(2-furanyl)-4H-1,2,4-triazol-3-yl)-3-hydroxy-1-propanesulfonamide; (3R)-3-cyclopentyl-N-(4-(2,6-dimethoxyphenyl)-5-(2-furanyl)-4H-1,2,4-triazol-3-yl)-3-hydroxy-1-propanesulfonamide; N-(4-(2,6-dimethoxyphenyl)-5-(2-furanyl)-4H-1,2,4-triazol-3-yl)-2-((4S)-4-methyl-2-oxo-1,3-oxazinan-3-yl)ethanesulfonamide; N-(4-(2,6-dimethoxyphenyl)-5-(2-furanyl)-4H-1,2,4-triazol-3-yl)-2-(2-methoxy-3-pyridinyl)ethanesulfonamide; (2R)—N-(4-(2,6-dimethoxyphenyl)-5-(2-furanyl)-4H-1,2,4-triazol-3-yl)-1-(3-methoxy-2-pyrazinyl)-2-propanesulfonamide; (2S)—N-(4-(2,6-dimethoxyphenyl)-5-(2-furanyl)-4H-1,2,4-triazol-3-yl)-1-(3-methoxy-2-pyrazinyl)-2-propanesulfonamide; N-(4-(2,6-dimethoxyphenyl)-5-(5-methyl-2-furanyl)-4H-1,2,4-triazol-3-yl)-2-((6S)-3,6-dimethyl-2-oxotetrahydro-1(2H)-pyrimidinyl)ethanesulfonamide; (2S)-1-(4-chlorophenyl)-N-(4-(2,6-dimethoxyphenyl)-5-(2-furanyl)-4H-1,2,4-triazol-3-yl)-2-propanesulfonamide; (3S)—N-(4-(2,6-dimethoxyphenyl)-5-(2-furanyl)-4H-1,2,4-triazol-3-yl)-1-(5-fluoro-2-pyrimidinyl)-3-piperidinesulfonamide; N-(4-(2,6-dimethoxyphenyl)-5-(2-furanyl)-4H-1,2,4-triazol-3-yl)-2-(4-fluorophenyl)ethanesulfonamide; (2R)-1-(4-chlorophenyl)-N-(4-(2,6-dimethoxyphenyl)-5-(2-furanyl)-4H-1,2,4-triazol-3-yl)-2-propanesulfonamide; 2-(4-chlorophenyl)-N-(5-(2-furanyl)-4-(2-methoxyphenyl)-4H-1,2,4-triazol-3-yl)ethanesulfonamide; 2-(2-cyano-4-fluorophenyl)-N-(4-(2,6-dimethoxyphenyl)-5-(2-furanyl)-4H-1,2,4-triazol-3-yl)ethanesulfonamide; (1S,2R)—N-(4-(2,6-dimethoxyphenyl)-5-(5-methyl-2-furanyl)-4H-1,2,4-triazol-3-yl)-1-hydroxy-1-(5-methyl-2-pyrimidinyl)-2-propanesulfonamide; (1R,2S)-1-(5-chloro-2-pyrimidinyl)-N-(4-(2,6-dimethoxyphenyl)-5-(5-methyl-2-furanyl)-4H-1,2,4-triazol-3-yl)-1-hydroxy-2-propanesulfonamide; (1S,2R)—N-(4-(2,6-dimethoxyphenyl)-5-(5-methyl-2-furanyl)-4H-1,2,4-triazol-3-yl)-1-hydroxy-1-(5-methyl-2-pyrazinyl)-2-propanesulfonamide; 2-(5-chloro-1′-methyl-1′,2′,3′,6′-tetrahydro-3,4′-bipyridin-2-yl)-N-(4-(2,6-dimethoxyphenyl)-5-(2-furanyl)-4H-1,2,4-triazol-3-yl)ethanesulfonamide; 2-(5-chloro-3-(3,6-dihydro-2H-pyran-4-yl)-2-pyridinyl)-N-(4-(2,6-dimethoxyphenyl)-5-(2-furanyl)-4H-1,2,4-triazol-3-yl)ethanesulfonamide; (1S,2R)-1-(5-chloro-2-pyrimidinyl)-N-(4-(2,6-dimethoxyphenyl)-5-(5-methyl-2-furanyl)-4H-1,2,4-triazol-3-yl)-1-hydroxy-2-propanesulfonamide; (2S,3S)—N-(4-(2,6-dimethoxyphenyl)-5-(5-methyl-2-furanyl)-4H-1,2,4-triazol-3-yl)-3-hydroxy-3-(5-methyl-2-pyrimidinyl)-2-butanesulfonamide; (2R,3R)—N-(4-(2,6-dimethoxyphenyl)-5-(2-furanyl)-4H-1,2,4-triazol-3-yl)-3-(5-fluoro-2-pyrimidinyl)-2-butanesulfonamide; (2S,3S)—N-(4-(2,6-dimethoxyphenyl)-5-(2-furanyl)-4H-1,2,4-triazol-3-yl)-3-(5-fluoro-2-pyrimidinyl)-2-butanesulfonamide; 2-(5-chloro-3-(4-morpholinylmethyl)-2-pyridinyl)-N-(4-(2,6-dimethoxyphenyl)-5-(2-furanyl)-4H-1,2,4-triazol-3-yl)ethanesulfonamide; 2-(5-chloro-1′,2′,3′,6′-tetrahydro-3,4′-bipyridin-2-yl)-N-(4-(2,6-dimethoxyphenyl)-5-(2-furanyl)-4H-1,2,4-triazol-3-yl)ethanesulfonamide; 2-(5-chloro-3,3′-bipyridin-2-yl)-N-(4-(2,6-dimethoxyphenyl)-5-(2-furanyl)-4H-1,2,4-triazol-3-yl)ethanesulfonamide; 2-(5-chloro-3,4′-bipyridin-2-yl)-N-(4-(2,6-dimethoxyphenyl)-5-(2-furanyl)-4H-1,2,4-triazol-3-yl)ethanesulfonamide; 2-(5-chloro-3-(1H-pyrazol-3-yl)-2-pyridinyl)-N-(4-(2,6-dimethoxyphenyl)-5-(2-furanyl)-4H-1,2,4-triazol-3-yl)ethanesulfonamide; 2-(1′-acetyl-5-chloro-1′,2′,3′,6′-tetrahydro-3,4′-bipyridin-2-yl)-N-(4-(2,6-dimethoxyphenyl)-5-(2-furanyl)-4H-1,2,4-triazol-3-yl)ethanesulfonamide; (2R,3S)—N-(4-(2,6-dimethoxyphenyl)-5-(5-methyl-2-furanyl)-4H-1,2,4-triazol-3-yl)-3-(5-fluoro-2-pyrimidinyl)-3-hydroxy-2-butanesulfonamide; (1R,2R)—N-(4-(2,6-dimethoxyphenyl)-5-(5-methyl-2-furanyl)-4H-1,2,4-triazol-3-yl)-1-methoxy-1-(5-methyl-2-pyrimidinyl)-2-propanesulfonamide; (2S,3S)-3-(5-cyano-2-pyridinyl)-N-(4-(2,6-dimethoxyphenyl)-5-(5-methyl-2-furanyl)-4H-1,2,4-triazol-3-yl)-3-hydroxy-2-butanesulfonamide; (2S,3R)—N-(4-(2,6-dimethoxyphenyl)-5-(5-methyl-2-furanyl)-4H-1,2,4-triazol-3-yl)-3-(5-fluoro-2-pyrimidinyl)-3-hydroxy-2-butanesulfonamide; (2R,3R)-3-(5-cyano-2-pyrimidinyl)-N-(4-(2,6-dimethoxyphenyl)-5-(5-methyl-2-furanyl)-4H-1,2,4-triazol-3-yl)-3-fluoro-2-butanesulfonamide; (2S,3S)-3-(5-cyano-2-pyrimidinyl)-N-(4-(2,6-dimethoxyphenyl)-5-(5-methyl-2-furanyl)-4H-1,2,4-triazol-3-yl)-3-fluoro-2-butanesulfonamide; (2S)-2-(5-cyano-2-pyrimidinyl)-N-(4-(2,6-dimethoxyphenyl)-5-(5-methyl-2-furanyl)-4H-1,2,4-triazol-3-yl)-2-fluoro-1-propanesulfonamide; 2-(5-chloro-3-(2-(1-pyrrolidinyl)ethyl)-2-pyridinyl)-N-(4-(2,6-dimethoxy phenyl)-5-(2-furanyl)-4H-1,2,4-triazol-3-yl)ethanesulfonamide; (2R)-2-(5-cyano-2-pyrimidinyl)-N-(4-(2,6-dimethoxyphenyl)-5-(5-methyl-2-furanyl)-4H-1,2,4-triazol-3-yl)-2-hydroxy-1-propanesulfonamide; (2R)—N-(4-(2,6-dimethoxyphenyl)-5-(2-furanyl)-4H-1,2,4-triazol-3-yl)-1-(5-fluoro-4-methyl-2-pyrimidinyl)-2-propanesulfonamide; (2S)—N-(4-(2,6-dimethoxyphenyl)-5-(2-furanyl)-4H-1,2,4-triazol-3-yl)-1-(5-fluoro-4-methyl-2-pyrimidinyl)-2-propanesulfonamide; 2-(3-(2-(1-azetidinyl)ethyl)-5-chloro-2-pyridinyl)-N-(4-(2,6-dimethoxyphenyl)-5-(2-furanyl)-4H-1,2,4-triazol-3-yl)ethanesulfonamide; (2R,3R)—N-(4-(2,6-dimethoxyphenyl)-5-(5-methyl-2-furanyl)-4H-1,2,4-triazol-3-yl)-3-(5-fluoro-2-pyrimidinyl)-3-hydroxy-2-butanesulfonamide; (2S,3S)—N-(4-(2,6-dimethoxyphenyl)-5-(5-methyl-2-furanyl)-4H-1,2,4-triazol-3-yl)-3-(5-fluoro-2-pyrimidinyl)-3-hydroxy-2-butanesulfonamide; (2R)—N-(4-(2,6-dimethoxyphenyl)-5-(5-methyl-2-furanyl)-4H-1,2,4-triazol-3-yl)-2-fluoro-2-(5-fluoro-2-pyrimidinyl)-1-propanesulfonamide; 2-(5-chloro-3-(2-((3S)-3-hydroxy-1-pyrrolidinyl)ethyl)-2-pyridinyl)-N-(4-(2,6-dimethoxyphenyl)-5-(2-furanyl)-4H-1,2,4-triazol-3-yl)ethanesulfonamide; 2-(5-chloro-3-(2-(4-morpholinyl)ethyl)-2-pyridinyl)-N-(4-(2,6-dimethoxyphenyl)-5-(2-furanyl)-4H-1,2,4-triazol-3-yl)ethanesulfonamide; (2R)—N-(4-(2,6-dimethoxyphenyl)-5-(2-furanyl)-4H-1,2,4-triazol-3-yl)-1-(5-fluoro-3-((4R)-4-hydroxy-2-oxo-1-pyrrolidinyl)-2-pyridinyl)-2-propanesulfonamide; (2S)—N-(4-(2,6-dimethoxyphenyl)-5-(2-furanyl)-4H-1,2,4-triazol-3-yl)-1-(5-fluoro-3-((4R)-4-hydroxy-2-oxo-1-pyrrolidinyl)-2-pyridinyl)-2-propanesulfonamide; (2S)-2-(5-cyano-2-pyrimidinyl)-N-(4-(2,6-dimethoxyphenyl)-5-(5-methyl-2-furanyl)-4H-1,2,4-triazol-3-yl)-2-hydroxy-1-propanesulfonamide; (2S,3R)-3-amino-N-(4-(2,6-dimethoxyphenyl)-5-(5-methyl-2-furanyl)-4H-1,2,4-triazol-3-yl)-3-(5-fluoro-2-pyrimidinyl)-2-butanesulfonamide; (1R,2R)—N-(4-(2,6-dimethoxyphenyl)-5-(5-methyl-2-furanyl)-4H-1,2,4-triazol-3-yl)-1-hydroxy-1-(5-methyl-2-pyrimidinyl)-2-propanesulfonamide; (2R)-2-(5-cyano-2-pyrimidinyl)-N-(4-(2,6-dimethoxyphenyl)-5-(5-methyl-2-furanyl)-4H-1,2,4-triazol-3-yl)-2-fluoro-1-propanesulfonamide; (2R,3R)-3-amino-N-(4-(2,6-dimethoxyphenyl)-5-(5-methyl-2-furanyl)-4H-1,2,4-triazol-3-yl)-3-(5-fluoro-2-pyrimidinyl)-2-butanesulfonamide; (1R,2S)—N-(4-(2,6-dimethoxyphenyl)-5-(5-methyl-2-furanyl)-4H-1,2,4-triazol-3-yl)-1-hydroxy-1-(5-methyl-2-pyrazinyl)-2-propanesulfonamide; (2S)—N-(4-(2,6-dimethoxyphenyl)-5-(5-methyl-2-furanyl)-4H-1,2,4-triazol-3-yl)-2-(5-fluoro-2-pyrimidinyl)-2-hydroxy-1-propanesulfonamide; (1S,2S)—N-(4-(2,6-dimethoxyphenyl)-5-(5-methyl-2-furanyl)-4H-1,2,4-triazol-3-yl)-1-methoxy-1-(5-methyl-2-pyrimidinyl)-2-propanesulfonamide; (2S)—N-(4-(2,6-dimethoxyphenyl)-5-(2-furanyl)-4H-1,2,4-triazol-3-yl)-2-(5-methyl-2-pyrimidinyl)-1-propanesulfonamide; 2-(2-cyano-4-fluorophenyl)-N-(4-(4,6-dimethoxy-5-pyrimidinyl)-5-(2-furanyl)-4H-1,2,4-triazol-3-yl)ethanesulfonamide; 2-(4-chlorophenyl)-N-(4-(4,6-dimethoxy-5-pyrimidinyl)-5-(2-furanyl)-4H-1,2,4-triazol-3-yl)ethanesulfonamide; 2-(4-chlorophenyl)-N-(5-(2-furanyl)-4-(2-(hydroxymethyl)-6-methoxy phenyl)-4H-1,2,4-triazol-3-yl)ethanesulfonamide; 2-(4-chlorophenyl)-N-(5-(2-furanyl)-4-(2-methoxy-6-(methoxy methyl)phenyl)-4H-1,2,4-triazol-3-yl)ethanesulfonamide; 2-(4-chlorophenyl)-N-(5-(2-furanyl)-4-(2-methoxy-6-(1-pyrrolidinylmethyl)phenyl)-4H-1,2,4-triazol-3-yl)ethanesulfonamide; N-(4-(2,6-dimethoxyphenyl)-5-(2-furanyl)-4H-1,2,4-triazol-3-yl)-2-(2,4-dimethyl-1,3-thiazol-5-yl)ethanesulfonamide; N-(4-(2,6-dimethoxyphenyl)-5-(2-furanyl)-4H-1,2,4-triazol-3-yl)-2-(1-methyl-1H-imidazol-5-yl)ethanesulfonamide; N-(4-(2,6-dimethoxyphenyl)-5-(2-furanyl)-4H-1,2,4-triazol-3-yl)-2-(2-ethyl-4-methyl-1H-imidazol-5-yl)ethanesulfonamide; 2-(4-chloro-1-methyl-1H-pyrazol-3-yl)-N-(4-(2,6-dimethoxyphenyl)-5-(2-furanyl)-4H-1,2,4-triazol-3-yl)ethanesulfonamide; (1R,2S)—N-(4-(2,6-dimethoxyphenyl)-5-(5-methyl-2-furanyl)-4H-1,2,4-triazol-3-yl)-1-methoxy-1-(5-methyl-2-pyrimidinyl)-2-propanesulfonamide; (2S,3R)—N-(4-(2,6-dimethoxyphenyl)-5-(5-methyl-2-furanyl)-4H-1,2,4-triazol-3-yl)-3-(5-methyl-2-pyrimidinyl)-2-butanesulfonamide; (1R,2S)—N-(4-(2,6-dimethoxyphenyl)-5-(5-methyl-2-furanyl)-4H-1,2,4-triazol-3-yl)-1-imidazo[1,2-a]pyridin-2-yl-1-methoxy-2-propanesulfonamide; (1S,2R)—N-(4-(2,6-dimethoxyphenyl)-5-(5-methyl-2-furanyl)-4H-1,2,4-triazol-3-yl)-1-hydroxy-1-imidazo[1,2-a]pyridin-2-yl-2-propanesulfonamide; (1S,2R)—N-(4-(2,6-dimethoxyphenyl)-5-(5-methyl-2-furanyl)-4H-1,2,4-triazol-3-yl)-1-hydroxy-1-pyrazolo[1,5-a]pyridin-2-yl-2-propanesulfonamide; (1S,2R)—N-(4-(2,6-dimethoxyphenyl)-5-(5-methyl-2-furanyl)-4H-1,2,4-triazol-3-yl)-1-hydroxy-1-pyrazolo[1,5-a]pyridin-7-yl-2-propanesulfonamide; (1R,2R)—N-(4-(2,6-dimethoxyphenyl)-5-(5-methyl-2-furanyl)-4H-1,2,4-triazol-3-yl)-1-imidazo[1,2-a]pyridin-2-yl-1-methoxy-2-propanesulfonamide; (1R,2S)—N-(4-(2,6-dimethoxyphenyl)-5-(5-methyl-2-furanyl)-4H-1,2,4-triazol-3-yl)-1-hydroxy-1-imidazo[1,5-a]pyridin-1-yl-2-propanesulfonamide; (1S,2S)—N-(4-(2,6-dimethoxyphenyl)-5-(5-methyl-2-furanyl)-4H-1,2,4-triazol-3-yl)-1-hydroxy-1-pyrazolo[1,5-a]pyridin-2-yl-2-propanesulfonamide; (1R,2R)—N-(4-(2,6-dimethoxyphenyl)-5-(5-methyl-2-furanyl)-4H-1,2,4-triazol-3-yl)-1-hydroxy-1-pyrazolo[1,5-a]pyridin-7-yl-2-propanesulfonamide; (1S,2S)—N-(4-(2,6-dimethoxyphenyl)-5-(5-methyl-2-furanyl)-4H-1,2,4-triazol-3-yl)-1-hydroxy-1-pyrazolo[1,5-a]pyridin-7-yl-2-propanesulfonamide; (1R,2R)—N-(4-(2,6-dimethoxyphenyl)-5-(5-methyl-2-furanyl)-4H-1,2,4-triazol-3-yl)-1-hydroxy-1-imidazo[1,2-a]pyridin-3-yl-2-propanesulfonamide; (1S,2S)—N-(4-(2,6-dimethoxyphenyl)-5-(5-methyl-2-furanyl)-4H-1,2,4-triazol-3-yl)-1-imidazo[1,2-a]pyridin-2-yl-1-methoxy-2-propanesulfonamide; (1R,2S)—N-(4-(2,6-dimethoxyphenyl)-5-(5-methyl-2-furanyl)-4H-1,2,4-triazol-3-yl)-1-hydroxy-1-(1,3-thiazol-4-yl)-2-propanesulfonamide; (1R,2R)—N-(4-(2,6-dimethoxyphenyl)-5-(5-methyl-2-furanyl)-4H-1,2,4-triazol-3-yl)-1-hydroxy-1-imidazo[1,5-a]pyridin-1-yl-2-propanesulfonamide; (1R,2S)—N-(4-(2,6-dimethoxyphenyl)-5-(5-methyl-2-furanyl)-4H-1,2,4-triazol-3-yl)-1-hydroxy-1-(1-methyl-1H-imidazol-4-yl)-2-propanesulfonamide; (1S,2R)—N-(4-(2,6-dimethoxyphenyl)-5-(5-methyl-2-furanyl)-4H-1,2,4-triazol-3-yl)-1-hydroxy-1-(1-methyl-1H-imidazol-4-yl)-2-propanesulfonamide; (1R,2S)—N-(4-(2,6-dimethoxyphenyl)-5-(5-methyl-2-furanyl)-4H-1,2,4-triazol-3-yl)-1-hydroxy-1-(2-methyl-1,3-oxazol-4-yl)-2-propanesulfonamide; (1R,2R)—N-(4-(2,6-dimethoxyphenyl)-5-(5-methyl-2-furanyl)-4H-1,2,4-triazol-3-yl)-1-hydroxy-1-imidazo[1,2-a]pyridin-2-yl-2-propanesulfonamide; (1R,2S)—N-(4-(2,6-dimethoxyphenyl)-5-(5-methyl-2-furanyl)-4H-1,2,4-triazol-3-yl)-1-hydroxy-1-pyrazolo[1,5-a]pyridin-2-yl-2-propanesulfonamide; (1S,2R)—N-(4-(2,6-dimethoxyphenyl)-5-(5-methyl-2-furanyl)-4H-1,2,4-triazol-3-yl)-1-imidazo[1,2-a]pyridin-2-yl-1-methoxy-2-propanesulfonamide; (1S,2R)—N-(4-(2,6-dimethoxyphenyl)-5-(5-methyl-2-furanyl)-4H-1,2,4-triazol-3-yl)-1-hydroxy-1-imidazo[1,5-a]pyridin-1-yl-2-propanesulfonamide; (1R,2S)—N-(4-(2,6-dimethoxyphenyl)-5-(5-methyl-2-furanyl)-4H-1,2,4-triazol-3-yl)-1-hydroxy-1-imidazo[1,2-a]pyridin-2-yl-2-propanesulfonamide; (1R,2R)-1-(6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazin-2-yl)-N-(4-(2,6-dimethoxyphenyl)-5-(5-methyl-2-furanyl)-4H-1,2,4-triazol-3-yl)-1-hydroxy-2-propane sulfonamide; (1R,2S)-1-(6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazin-2-yl)-N-(4-(2,6-dimethoxyphenyl)-5-(5-methyl-2-furanyl)-4H-1,2,4-triazol-3-yl)-1-hydroxy-2-propane sulfonamide; (1S,2R)-1-(6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazin-2-yl)-N-(4-(2,6-dimethoxyphenyl)-5-(5-methyl-2-furanyl)-4H-1,2,4-triazol-3-yl)-1-hydroxy-2-propane sulfonamide; (1S,2S)-1-(6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazin-2-yl)-N-(4-(2,6-dimethoxyphenyl)-5-(5-methyl-2-furanyl)-4H-1,2,4-triazol-3-yl)-1-hydroxy-2-propane sulfonamide; (1R,2R)-1-(3,4-dihydro-2H-pyrano[3,2-b]pyridin-8-yl)-N-(4-(2,6-dimethoxyphenyl)-5-(5-methyl-2-furanyl)-4H-1,2,4-triazol-3-yl)-1-hydroxy-2-propanesulfonamide; (1S,2S)-1-(3,4-dihydro-2H-pyrano[3,2-b]pyridin-8-yl)-N-(4-(2,6-dimethoxyphenyl)-5-(5-methyl-2-furanyl)-4H-1,2,4-triazol-3-yl)-1-hydroxy-2-propanesulfonamide; (1S,2R)-1-(3,4-dihydro-2H-pyrano[3,2-b]pyridin-8-yl)-N-(4-(2,6-dimethoxyphenyl)-5-(5-methyl-2-furanyl)-4H-1,2,4-triazol-3-yl)-1-hydroxy-2-propanesulfonamide; (1R,2S)—N-(4-(2,6-dimethoxyphenyl)-5-(5-methyl-2-furanyl)-4H-1,2,4-triazol-3-yl)-1-hydroxy-1-imidazo[1,2-a]pyridin-3-yl-2-propanesulfonamide; (2R)-1-(5-fluoro-2-pyrimidinyl)-N-(4-(2-methoxyphenyl)-5-(5-methyl-2-furanyl)-4H-1,2,4-triazol-3-yl)-2-propanesulfonamide; (2S)-1-(5-fluoro-2-pyrimidinyl)-N-(4-(2-methoxyphenyl)-5-(5-methyl-2-furanyl)-4H-1,2,4-triazol-3-yl)-2-propanesulfonamide; (1R,2S)—N-(4-(2,6-dimethoxyphenyl)-5-(5-methyl-2-furanyl)-4H-1,2,4-triazol-3-yl)-1-hydroxy-1-pyrazolo[1,5-a]pyridin-7-yl-2-propanesulfonamide; (1S,2R)—N-(4-(2,6-dimethoxyphenyl)-5-(5-methyl-2-furanyl)-4H-1,2,4-triazol-3-yl)-1-hydroxy-1-(1-methyl-1H-imidazol-2-yl)-2-propanesulfonamide; (1R,2R)—N-(4-(2,6-dimethoxyphenyl)-5-(5-methyl-2-furanyl)-4H-1,2,4-triazol-3-yl-1-hydroxy-1-(1,3-thiazol-4-yl)-2-propanesulfonamide; (1S,2R)—N-(4-(2,6-dimethoxyphenyl)-5-(5-methyl-2-furanyl)-4H-1,2,4-triazol-3-yl-1-hydroxy-1-imidazo[1,2-a]pyridin-5-yl-2-propanesulfonamide; (1R,2R)—N-(4-(2,6-dimethoxyphenyl)-5-(5-methyl-2-furanyl)-4H-1,2,4-triazol-3-yl-1-hydroxy-1-(2-methyl-1,3-oxazol-4-yl)-2-propanesulfonamide; (1S,2S)—N-(4-(2,6-dimethoxyphenyl)-5-(5-methyl-2-furanyl)-4H-1,2,4-triazol-3-yl)-1-hydroxy-1-(2-methyl-1,3-oxazol-4-yl)-2-propanesulfonamide; (1R,2R)—N-(4-(2,6-dimethoxyphenyl)-5-(5-methyl-2-furanyl)-4H-1,2,4-triazol-3-yl)-1-hydroxy-1-(1-methyl-1H-imidazol-4-yl)-2-propanesulfonamide; (1S,2S)—N-(4-(2,6-dimethoxyphenyl)-5-(5-methyl-2-furanyl)-4H-1,2,4-triazol-3-yl)-1-hydroxy-1-(1-methyl-1H-imidazol-4-yl)-2-propanesulfonamide; (1R,2S)-1-(3,4-dihydro-2H-pyrano[3,2-b]pyridin-8-yl)-N-(4-(2,6-dimethoxyphenyl)-5-(5-methyl-2-furanyl)-4H-1,2,4-triazol-3-yl)-1-hydroxy-2-propanesulfonamide; (1S,2R)—N-(4-(2,6-dimethoxyphenyl)-5-(5-methyl-2-furanyl)-4H-1,2,4-triazol-3-yl)-1-hydroxy-1-(2-methyl-1,3-oxazol-4-yl)-2-propanesulfonamide; (1R,2R)—N-(4-(2,6-dimethoxyphenyl)-5-(5-methyl-2-furanyl)-4H-1,2,4-triazol-3-yl)-1-hydroxy-1-pyrazolo[1,5-a]pyridin-2-yl-2-propanesulfonamide; (1S,2S)—N-(4-(2,6-dimethoxyphenyl)-5-(5-methyl-2-furanyl)-4H-1,2,4-triazol-3-yl)-1-hydroxy-thiazol-4-yl)-2-propanesulfonamide; (1R,2R)—N-(4-(2,6-dimethoxyphenyl)-5-(5-methyl-2-furanyl)-4H-1,2,4-triazol-3-yl)-1-hydroxy-1-imidazo[1,2-a]pyridin-5-yl-2-propanesulfonamide; (1S,2S)—N-(4-(2,6-dimethoxyphenyl)-5-(5-methyl-2-furanyl)-4H-1,2,4-triazol-3-yl)-1-hydroxy-1-imidazo[1,2-a]pyridin-5-yl-2-propanesulfonamide; (1S,2R)—N-(4-(2,6-dimethoxyphenyl)-5-(5-methyl-2-furanyl)-4H-1,2,4-triazol-3-yl)-1-hydroxy-thiazol-4-yl)-2-propanesulfonamide; (1S,2S)—N-(4-(2,6-dimethoxyphenyl)-5-(5-methyl-2-furanyl)-4H-1,2,4-triazol-3-yl)-1-hydroxy-1-imidazo[1,2-a]pyridin-2-yl-2-propanesulfonamide; (2R)-1-(5-fluoro-2-pyrimidinyl)-N-(5-(2-furanyl)-4-(2-methoxyphenyl)-4H-1,2,4-triazol-3-yl)-2-propanesulfonamide; (2S)-1-(5-fluoro-2-pyrimidinyl)-N-(5-(2-furanyl)-4-(2-methoxyphenyl)-4H-1,2,4-triazol-3-yl)-2-propanesulfonamide; (1S)—N-(4-(2,6-dimethoxyphenyl)-5-(5-methyl-2-furanyl)-4H-1,2,4-triazol-3-yl)-1-(3-hydroxy-3-oxetanyl)ethanesulfonamide; (2R)—N-(4-(2-fluorophenyl)-5-(2-furanyl)-4H-1,2,4-triazol-3-yl)-1-(5-fluoro-2-pyrimidinyl)-2-propanesulfonamide; (2S)—N-(4-(2-fluorophenyl)-5-(2-furanyl)-4H-1,2,4-triazol-3-yl)-1-(5-fluoro-2-pyrimidinyl)-2-propanesulfonamide; (2R)—N-(4-cyclohexyl-5-(2-furanyl)-4H-1,2,4-triazol-3-yl)-1-(5-fluoro-2-pyrimidinyl)-2-propanesulfonamide; (2S)—N-(4-cyclohexyl-5-(2-furanyl)-4H-1,2,4-triazol-3-yl)-1-(5-fluoro-2-pyrimidinyl)-2-propanesulfonamide; (2R)-1-(5-fluoro-2-pyrimidinyl)-N-(5-(2-furanyl)-4-(1-naphthalenyl)-4H-1,2,4-triazol-3-yl)-2-propanesulfonamide; (2S)-1-(5-fluoro-2-pyrimidinyl)-N-(5-(2-furanyl)-4-(1-naphthalenyl)-4H-1,2,4-triazol-3-yl)-2-propanesulfonamide; (2R)—N-(4-(2,4-dimethoxyphenyl)-5-(2-furanyl)-4H-1,2,4-triazol-3-yl)-1-(5-fluoro-2-pyrimidinyl)-2-propanesulfonamide; (2S)—N-(4-(2,4-dimethoxyphenyl)-5-(2-furanyl)-4H-1,2,4-triazol-3-yl)-1-(5-fluoro-2-pyrimidinyl)-2-propanesulfonamide; (2R)—N-(4-cyclopentyl-5-(5-methyl-2-furanyl)-4H-1,2,4-triazol-3-yl)-1-(5-fluoro-2-pyrimidinyl)-2-propanesulfonamide; (2S)—N-(4-cyclopentyl-5-(5-methyl-2-furanyl)-4H-1,2,4-triazol-3-yl)-1-(5-fluoro-2-pyrimidinyl)-2-propanesulfonamide; (2R)-1-(5-fluoro-2-pyrimidinyl)-N-(5-(5-methyl-2-furanyl)-4-(tetrahydro-2H-pyran-4-yl)-4H-1,2,4-triazol-3-yl)-2-propanesulfonamide; (2S)-1-(5-fluoro-2-pyrimidinyl)-N-(5-(5-methyl-2-furanyl)-4-(tetrahydro-2H-pyran-4-yl)-4H-1,2,4-triazol-3-yl)-2-propanesulfonamide; (2R)-1-(5-fluoro-2-pyrimidinyl)-N-(5-(2-furanyl)-4-(2-(trifluoromethyl)phenyl)-4H-1,2,4-triazol-3-yl)-2-propanesulfonamide; (2S)-1-(5-fluoro-2-pyrimidinyl)-N-(5-(2-furanyl)-4-(2-(trifluoromethyl)phenyl)-4H-1,2,4-triazol-3-yl)-2-propanesulfonamide; (2R)—N-(4-cyclopropyl-5-(5-methyl-2-furanyl)-4H-1,2,4-triazol-3-yl)-1-(5-fluoro-2-pyrimidinyl)-2-propanesulfonamide; (2S)—N-(4-cyclopropyl-5-(5-methyl-2-furanyl)-4H-1,2,4-triazol-3-yl)-1-(5-fluoro-2-pyrimidinyl)-2-propanesulfonamide; (3R,5S)-1-(6-cyano-2-pyrazinyl)-N-(4-(2,6-dimethoxyphenyl)-5-(5-methyl-2-furanyl)-4H-1,2,4-triazol-3-yl)-5-hydroxy-3-piperidinesulfonamide; (3R,5S)-1-(6-chloro-5-cyano-3-pyridinyl)-N-(4-(2,6-dimethoxyphenyl)-5-(5-methyl-2-furanyl)-4H-1,2,4-triazol-3-yl)-5-hydroxy-3-piperidinesulfonamide; (3S,5R)-1-(6-chloro-5-cyano-3-pyridinyl)-N-(4-(2,6-dimethoxyphenyl)-5-(5-methyl-2-furanyl)-4H-1,2,4-triazol-3-yl)-5-hydroxy-3-piperidinesulfonamide; (3R,5S)—N-(4-(2,6-dimethoxyphenyl)-5-(5-methyl-2-furanyl)-4H-1,2,4-triazol-3-yl)-1-(5-fluoro-2-pyrimidinyl)-5-hydroxy-3-piperidinesulfonamide; (3R,5S)—N-(4-(2,6-dimethoxyphenyl)-5-(5-methyl-2-furanyl)-4H-1,2,4-triazol-3-yl)-5-hydroxy-1-(4-methoxy-2-pyrimidinyl)-3-piperidinesulfonamide; (3S,5R)—N-(4-(2,6-dimethoxyphenyl)-5-(5-methyl-2-furanyl)-4H-1,2,4-triazol-3-yl)-5-hydroxy-1-(4-methoxy-2-pyrimidinyl)-3-piperidinesulfonamide; (3S,5R)—N-(4-(2,6-dimethoxyphenyl)-5-(5-methyl-2-furanyl)-4H-1,2,4-triazol-3-yl)-1-(4,6-dimethyl-2-pyrimidinyl)-5-hydroxy-3-piperidinesulfonamide; (3R,5S)-1-(5-chloro-2-pyrimidinyl)-N-(4-(2,6-dimethoxyphenyl)-5-(5-methyl-2-furanyl)-4H-1,2,4-triazol-3-yl)-5-hydroxy-3-piperidinesulfonamide; (3S,5R)-1-(5-chloro-2-pyrimidinyl)-N-(4-(2,6-dimethoxyphenyl)-5-(5-methyl-2-furanyl)-4H-1,2,4-triazol-3-yl)-5-hydroxy-3-piperidinesulfonamide; (3R,5S)-1-(3-cyano-4-fluorophenyl)-N-(4-(2,6-dimethoxy phenyl)-5-(5-methyl-2-furanyl)-4H-1,2,4-triazol-3-yl)-5-hydroxy-3-piperidinesulfonamide; (3S,5R)-1-(3-cyano-4-fluorophenyl)-N-(4-(2,6-dimethoxy phenyl)-5-(5-methyl-2-furanyl)-4H-1,2,4-triazol-3-yl)-5-hydroxy-3-piperidinesulfonamide; (3R,5S)-1-(3-cyano-5-fluoro-2-pyridinyl)-N-(4-(2,6-dimethoxy phenyl)-5-(5-methyl-2-furanyl)-4H-1,2,4-triazol-3-yl)-5-hydroxy-3-piperidinesulfonamide; (3S,5R)-1-(3-cyano-5-fluoro-2-pyridinyl)-N-(4-(2,6-dimethoxy phenyl)-5-(5-methyl-2-furanyl)-4H-1,2,4-triazol-3-yl)-5-hydroxy-3-piperidinesulfonamide; (3R,5R)—N-(4-(2,6-dimethoxyphenyl)-5-(5-methyl-2-furanyl)-4H-1,2,4-triazol-3-yl)-1-(5-fluoro-2-pyrimidinyl)-5-hydroxy-3-piperidinesulfonamide; (3S,5R)—N-(4-(2,6-dimethoxyphenyl)-5-(5-methyl-2-furanyl)-4H-1,2,4-triazol-3-yl)-1-(5-fluoro-2-pyrimidinyl)-5-hydroxy-3-piperidinesulfonamide; (3S,5S)—N-(4-(2,6-dimethoxyphenyl)-5-(5-methyl-2-furanyl)-4H-1,2,4-triazol-3-yl)-1-(5-fluoro-2-pyrimidinyl)-5-hydroxy-3-piperidinesulfonamide; (3R,5S)-1-(4-cyano-2-pyridinyl)-N-(4-(2,6-dimethoxyphenyl)-5-(5-methyl-2-furanyl)-4H-1,2,4-triazol-3-yl)-5-hydroxy-3-piperidinesulfonamide; (3S,5R)-1-(4-cyano-2-pyridinyl)-N-(4-(2,6-dimethoxyphenyl)-5-(5-methyl-2-furanyl)-4H-1,2,4-triazol-3-yl)-5-hydroxy-3-piperidinesulfonamide; (3R,5S)-1-(5-cyano-3-pyridinyl)-N-(4-(2,6-dimethoxyphenyl)-5-(5-methyl-2-furanyl)-4H-1,2,4-triazol-3-yl)-5-hydroxy-3-piperidinesulfonamide; (3S,5R)-1-(5-cyano-3-pyridinyl)-N-(4-(2,6-dimethoxyphenyl)-5-(5-methyl-2-furanyl)-4H-1,2,4-triazol-3-yl)-5-hydroxy-3-piperidinesulfonamide; (3R,5S)—N-(4-(2,6-dimethoxyphenyl)-5-(5-methyl-2-furanyl)-4H-1,2,4-triazol-3-yl)-5-hydroxy-1-(5-methoxy-2-pyrimidinyl)-3-piperidinesulfonamide; (3S,5R)—N-(4-(2,6-dimethoxyphenyl)-5-(5-methyl-2-furanyl)-4H-1,2,4-triazol-3-yl)-5-hydroxy-1-(5-methoxy-2-pyrimidinyl)-3-piperidinesulfonamide; (3R,5S)—N-(4-(2,6-dimethoxyphenyl)-5-(5-methyl-2-furanyl)-4H-1,2,4-triazol-3-yl)-1-(4,6-dimethyl-2-pyrimidinyl)-5-hydroxy-3-piperidinesulfonamide; (3S,5R)-3-((4-(2,6-dimethoxy phenyl)-5-(5-methyl-2-furanyl)-4H-1,2,4-triazol-3-yl)sulfamoyl)-5-hydroxy-N,N-dimethyl-1-piperidinecarboxamide; (3R)-3-((4-(2,6-dimethoxyphenyl)-5-(2-furanyl)-4H-1,2,4-triazol-3-yl)sulfamoyl)-N,N-dimethyl-1-piperidinecarboxamide; (3S)—N-(4-(2,6-dimethoxyphenyl)-5-(2-furanyl)-4H-1,2,4-triazol-3-yl)-1-((1-methylethyl)sulfonyl)-3-piperidinesulfonamide; (3S)-3-((4-(2,6-dimethoxyphenyl)-5-(2-furanyl)-4H-1,2,4-triazol-3-yl)sulfamoyl)-N,N-dimethyl-1-piperidinecarboxamide; (2S)-1-((2R)-2-cyano-2-methyl-6-oxo-1-piperidinyl)-N-(4-(2,6-dimethoxyphenyl)-5-(2-furanyl)-4H-1,2,4-triazol-3-yl)-2-propanesulfonamide; (2S)-1-((2S)-2-cyano-2-methyl-6-oxo-1-piperidinyl)-N-(4-(2,6-dimethoxyphenyl)-5-(2-furanyl)-4H-1,2,4-triazol-3-yl)-2-propanesulfonamide; (3S,4S)—N-(4-(2,6-dimethoxyphenyl)-5-(2-furanyl)-4H-1,2,4-triazol-3-yl)-3-(5-fluoro-2-pyrimidinyl)-2-methyl-4-isoxazolidinesulfonamide; N-(4-(2,6-dimethoxyphenyl)-5-(2-furanyl)-4H-1,2,4-triazol-3-yl)-2-(4-methyl-1,3-thiazol-2-yl)ethanesulfonamide; N-(4-(2,6-dimethoxyphenyl)-5-(2-furanyl)-4H-1,2,4-triazol-3-yl)-2-(4,5-dimethyl-1,3-thiazol-2-yl)ethanesulfonamide; N-(4-(2,6-dimethoxyphenyl)-5-(2-furanyl)-4H-1,2,4-triazol-3-yl)-2-(2-methyl-1,3-oxazol-4-yl)ethanesulfonamide; N-(4-(2,6-dimethoxyphenyl)-5-(2-furanyl)-4H-1,2,4-triazol-3-yl)-2-(2,5-dimethyl-1,3-oxazol-4-yl)ethanesulfonamide; (3S)-3-cyclohexyl-N-(4-(2,6-dimethoxyphenyl)-5-(2-furanyl)-4H-1,2,4-triazol-3-yl)-3-hydroxy-1-propanesulfonamide; (3R)-3-cyclopentyl-N-(4-(2,6-dimethoxyphenyl)-5-(2-furanyl)-4H-1,2,4-triazol-3-yl)-3-hydroxy-1-butanesulfonamide; (3S)-3-cyclopentyl-N-(4-(2,6-dimethoxyphenyl)-5-(2-furanyl)-4H-1,2,4-triazol-3-yl)-3-hydroxy-1-butanesulfonamide; 1-(4-chlorophenyl)-N-(5-(2-furanyl)-4-(2-methoxyphenyl)-4H-1,2,4-triazol-3-yl)methane sulfonamide; (2S,3R)-3-(5-chloro-2-pyrimidinyl)-N-(4-(4,6-dimethoxy-5-pyrimidinyl)-5-(5-methyl-2-furanyl)-4H-1,2,4-triazol-3-yl)-2-butanesulfonamide; (1R,2S)-1-(5-chloro-2-pyrimidinyl)-N-(4-(4,6-dimethoxy-5-pyrimidinyl)-5-(5-methyl-2-furanyl)-4H-1,2,4-triazol-3-yl)-1-methoxy-2-propanesulfonamide; (1R,2S)-1-(5-chloro-2-pyrimidinyl)-1-methoxy-N-(4-(1-(methoxymethyl)cyclopropyl)-5-(5-methyl-2-furanyl)-4H-1,2,4-triazol-3-yl)-2-propanesulfonamide; (1R,2S)-1-(5-chloro-2-pyrimidinyl)-1-methoxy-N-(4-(2-methoxy ethyl)-5-(5-methyl-2-furanyl)-4H-1,2,4-triazol-3-yl)-2-propanesulfonamide; (1R,2S)-1-(5-chloro-2-pyrimidinyl)-N-(4-(1,3-dimethoxy-2-propanyl)-5-(5-methyl-2-furanyl)-4H-1,2,4-triazol-3-yl)-1-methoxy-2-propanesulfonamide; (1R,2S)-1-(5-chloro-2-pyrimidinyl)-1-methoxy-N-(5-(5-methyl-2-furanyl)-4-(2-propanyl)-4H-1,2,4-triazol-3-yl)-2-propanesulfonamide; (1R,2S)-1-(5-chloro-2-pyrimidinyl)-1-methoxy-N-(5-(5-methyl-2-furanyl)-4-((3S)-tetrahydro-2H-pyran-3-yl)-4H-1,2,4-triazol-3-yl)-2-propanesulfonamide; or (1R,2S)-1-(5-chloro-2-pyrimidinyl)-1-methoxy-N-(5-(5-methyl-2-furanyl)-4-((3R)-tetrahydro-2H-pyran-3-yl)-4H-1,2,4-triazol-3-yl)-2-propanesulfonamide; or

›DETAILED DESCRIPTION OF THE INVENTION · 10 of 20

the pharmaceutically acceptable salt thereof, the tautomer thereof, the pharmaceutically acceptable salt of the tautomer, the stereoisomer of any of the foregoing, or the mixture thereof. In some such embodiments, the embodiment provides any of the compounds shown above or a pharmaceutically acceptable salt thereof. In still other such embodiments, the embodiment provides any of the compounds shown above or a pharmaceutically acceptable salt thereof, or a mixture thereof.

57. The compound of embodiment 1, wherein the compound is selected from

or the pharmaceutically acceptable salt thereof, the tautomer thereof, the pharmaceutically acceptable salt of the tautomer, the stereoisomer of any of the foregoing, or the mixture thereof. In some such embodiments, the embodiment provides any of the compounds shown above or a pharmaceutically acceptable salt thereof. In still other such embodiments, the embodiment provides any of the compounds shown above or a pharmaceutically acceptable salt thereof, or a mixture thereof.

58. The compound of embodiment 1, wherein the compound is selected from

(1S,2S)-1-(5-chloro-2-pyrimidinyl)-N-(4-(1,3-dimethoxy-2-propanyl)-5-(5-methyl-2-furanyl)-4H-1,2,4-triazol-3-yl)-1-(2-propanyloxy)-2-propanesulfonamide; (2S,3R)—N-(4-(4,6-dimethoxy-5-pyrimidinyl)-5-(5-methyl-2-furanyl)-4H-1,2,4-triazol-3-yl)-3-(5-fluoro-2-pyrimidinyl)-2-butanesulfonamide; (2S,3R)—N-(5-(5-bromo-2-furanyl)-4-(4,6-dimethoxy-5-pyrimidinyl)-4H-1,2,4-triazol-3-yl)-3-(5-fluoro-2-pyrimidinyl)-2-butanesulfonamide; (2S,3R)—N-(4-(4,6-dimethoxy-5-pyrimidinyl)-5-(5-trideuteromethyl-2-furanyl)-4H-1,2,4-triazol-3-yl)-3-(5-fluoro-2-pyrimidinyl)-2-butanesulfonamide; (1S,2S)-1-(5-chloro-2-pyrimidinyl)-N-(4-cyclopropyl-5-(5-methyl-2-furanyl)-4H-1,2,4-triazol-3-yl)-1-(2-propanyloxy)-2-propanesulfonamide; (2S,3R)-3-(5-chloro-2-pyrimidinyl)-N-(4-((2S)-1-methoxy-2-propanyl)-5-(5-methyl-2-furanyl)-4H-1,2,4-triazol-3-yl)-2-butanesulfonamide; (2S,3R)-3-(5-chloro-2-pyridinyl)-N-(4-(4,6-dimethoxy-5-pyrimidinyl)-5-(5-methyl-2-furanyl)-4H-1,2,4-triazol-3-yl)-2-butanesulfonamide; (1S,2S)—N-(4-(4,6-dimethoxypyrimidin-5-yl)-5-(5-methylfuran-2-yl)-4H-1,2,4-triazol-3-yl)-1-isopropoxy-1-(5-methylpyrimidin-2-yl)propane-2-sulfonamide; (3R,4S)—N-(4-(2,6-dimethoxyphenyl)-5-(5-methyl-2-furanyl)-4H-1,2,4-triazol-3-yl)-4-hydroxytetrahydro-2H-pyran-3-sulfonamide; (3S,4R)—N-(4-(2,6-dimethoxyphenyl)-5-(5-methyl-2-furanyl)-4H-1,2,4-triazol-3-yl)-4-hydroxytetrahydro-2H-pyran-3-sulfonamide; (3R,4R)—N-(4-(2,6-dimethoxyphenyl)-5-(5-methyl-2-furanyl)-4H-1,2,4-triazol-3-yl)-4-hydroxytetrahydro-2H-pyran-3-sulfonamide; (3S,4S)—N-(4-(2,6-dimethoxyphenyl)-5-(5-methyl-2-furanyl)-4H-1,2,4-triazol-3-yl)-4-hydroxytetrahydro-2H-pyran-3-sulfonamide; (1R,3R,4R)—N-(4-(2,6-dimethoxyphenyl)-5-(5-methylfuran-2-yl)-4H-1,2,4-triazol-3-yl)-3,4-dihydroxycyclohexane-1-sulfonamide; (1S,3R,4R)—N-(4-(2,6-dimethoxyphenyl)-5-(5-methylfuran-2-yl)-4H-1,2,4-triazol-3-yl)-3,4-dihydroxycyclohexane-1-sulfonamide; N-(4-(2,6-dimethoxyphenyl)-5-(5-methyl-2-furanyl)-4H-1,2,4-triazol-3-yl)-3-(hydroxymethyl)benzenesulfonamide; (R)—N-(4-(2,6-dimethoxyphenyl)-5-(5-methylfuran-2-yl)-4H-1,2,4-triazol-3-yl)-3-(1-hydroxyethyl)benzenesulfonamide; or (S)—N-(4-(2,6-dimethoxyphenyl)-5-(5-methylfuran-2-yl)-4H-1,2,4-triazol-3-yl)-3-(1-hydroxyethyl)benzenesulfonamide; or

59. The compound of embodiment 1, wherein the compound has the formula IA

or is the pharmaceutically acceptable salt thereof, the tautomer thereof, the pharmaceutically acceptable salt of the tautomer, the stereoisomer of any of the foregoing, or the mixture thereof,

wherein:

R 1a′ is selected from —H or —C 1 -C 4 alkyl;

R 3d and R 3e are independently selected from —H, or —C 1 -C 3 alkyl;

R 3f and R 3g are independently selected from —H, —C 1 -C 3 alkyl, —OH, or —O—(C 1 -C 3 alkyl);

Q is a phenyl group, a monocyclic heteroaryl group with 6 ring members containing 1 or 2 N heteroatoms, or a bicyclic heteroaryl group with 9 or 10 ring members containing 1 or 2 N heteroatoms, wherein the phenyl, the monocyclic heteroaryl, and the bicyclic heteroaryl aryl Q groups are unsubstituted or are substituted with 1 or 2 R Q substituent; and

R Q is independently selected from —F, —Cl, —CN, —C 1 -C 6 alkyl, —O—(C 1 -C 6 alkyl), —NHC(═O)(C 1 -C 6 alkyl), or —S(═O) 2 —(C 1 -C 6 alkyl).

60. The compound of embodiment 59 or is the pharmaceutically acceptable salt thereof, the tautomer thereof, the pharmaceutically acceptable salt of the tautomer, the stereoisomer of any of the foregoing, or the mixture thereof,

wherein:

R 1a′ is selected from —H, —CH 3 , or —CH 2 CH 3 ;

R 3d and R 3e are independently selected from —H, or —CH 3 ;

R 3f and R 3g are independently selected from —H, —CH 3 , —OH, —OCH 3 , or —OCH 2 CH 3 ;

Q is a phenyl, a pyrimidinyl, a pyridinyl, a pyrazinyl, or an imidazo[1,2a]pyridinyl group any of which are unsubstituted or are substituted with 1 or 2 R Q substituent; and

R Q is independently selected from —F, —Cl, —CN, —CH 3 , —OCH 3 , —NHC(═O)—CH 3 , or —S(═O) 2 —CH 3 .

61. A pharmaceutical composition, comprising the compound of any one of embodiments 1-60 or the pharmaceutically acceptable salt thereof, the tautomer thereof, the pharmaceutically acceptable salt of the tautomer, the stereoisomer of any of the foregoing, or the mixture thereof, and at least one pharmaceutically acceptable excipient.

62. A pharmaceutical composition, comprising the compound of any one of embodiments 1-60 or the pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable excipient.

›DETAILED DESCRIPTION OF THE INVENTION · 11 of 20

63. A pharmaceutical composition, comprising the compound of any one of embodiments 1-60 and at least one pharmaceutically acceptable excipient.

64. A pharmaceutical composition, comprising the pharmaceutically acceptable salt of the compound of any one of embodiments 1-60 and at least one pharmaceutically acceptable excipient.

65. The pharmaceutical composition of embodiment 64, further comprising a therapeutic agent selected from an α-blocker, a β-blocker, an angiotensin converting enzyme (ACE) inhibitor, an angiotensin-receptor blocker (ARB), a calcium channel blocker, a diuretic, an inhibitor of the funny current, a myosin activator, or a neutral endopeptidase (NEP) inhibitor.

66. The pharmaceutical composition of embodiment 64, further comprising a therapeutic agent selected from an angiotensin converting enzyme (ACE) inhibitor or an angiotensin-receptor blocker (ARB).

67. A method of treating a cardiovascular condition, the method comprising: administering to a subject an effective amount of the compound of any one of embodiments 1-60 or the pharmaceutically acceptable salt thereof, the stereoisomer of any of the foregoing, or the mixture thereof, or the pharmaceutical composition of any one of embodiments 61-66.

68. The method of embodiment 67, wherein the cardiovascular condition is heart failure.

69. The method of embodiment 67, wherein the cardiovascular condition is heart failure with reduced ejection fraction.

70. The method of embodiment 67, wherein the cardiovascular condition is heart failure with preserved ejection fraction.

71. The method of embodiment 67, wherein the cardiovascular condition is chronic systolic heart failure or chronic diastolic heart failure.

72. The method of embodiment 67, wherein the cardiovascular condition is acute heart failure.

73. The method of embodiment 67, wherein the cardiovascular condition is hypertension.

74. A method of improving cardiac contractility in a subject suffering from a cardiovascular condition, the method comprising: administering to the subject an effective amount of the compound of any one of embodiments 1-60 or the pharmaceutically acceptable salt thereof, the stereoisomer of any of the foregoing, or the mixture thereof, or the pharmaceutical composition of any one of embodiments 61-66, wherein cardiac contractility is improved in the subject after administration.

75. A method of increasing ejection fraction in a subject suffering from a cardiovascular condition, the method comprising: administering to the subject an effective amount of the compound of any one of embodiments 1-60 or the pharmaceutically acceptable salt thereof, the stereoisomer of any of the foregoing, or the mixture thereof, or the pharmaceutical composition of any one of embodiments 61-66, wherein the ejection fraction is increased in the subject after administration.

76. A method of treating a condition in a subject where it is desired to activate the APJ Receptor, the method comprising: administering to the subject an effective amount of the compound of any one of embodiments 1-60 or the pharmaceutically acceptable salt thereof, the stereoisomer of any of the foregoing, or the mixture thereof or the pharmaceutical composition of any one of embodiments 61-66.

77. The method of embodiment 76, wherein the condition is obesity or diabetes.

78. The method of embodiment 76, wherein the condition is diabetic nephropathy or chronic kidney disease.

79. The method of any one of embodiments 67-78, wherein the method includes administering at least one additional therapeutic agent to the subject, wherein the additional therapeutic agent is selected from an α-blocker, a β-blocker, an angiotensin converting enzyme (ACE) inhibitor, an angiotensin-receptor blocker (ARB), a calcium channel blocker, a diuretic, an inhibitor of the funny current, a myosin activator, or a neutral endopeptidase (NEP) inhibitor.

80. The method of any one of embodiments 67-78, wherein the method includes administering at least one additional therapeutic agent to the subject, wherein the additional therapeutic agent is selected from an angiotensin converting enzyme (ACE) inhibitor or an angiotensin-receptor blocker (ARB).

81. A compound of any one of embodiments 1-60 or the pharmaceutically acceptable salt thereof, the stereoisomer of any of the foregoing, or the mixture thereof, or the pharmaceutical composition of any one of embodiments 61-66 for use in treating a cardiovascular condition.

82. The compound of embodiments 81, wherein the cardiovascular condition is heart failure.

83. The compound of embodiment 801 wherein the cardiovascular condition is heart failure with reduced ejection fraction.

84. The compound of embodiment 81, wherein the cardiovascular condition is heart failure with preserved ejection fraction.

85. The compound of embodiment 81, wherein the cardiovascular condition is chronic systolic heart failure or chronic diastolic heart failure.

86. The compound of embodiment 81, wherein the cardiovascular condition is hypertension.

87. The compound of embodiment 81, wherein the cardiovascular condition is hypertension.

88. A compound of any one of embodiments 1-60 or the pharmaceutically acceptable salt thereof, the stereoisomer of any of the foregoing, or the mixture thereof, or the pharmaceutical composition of any one of embodiments 61-66 for use in activating the APJ Receptor or for treating a condition where it is desirable to activate the APJ Receptor.

89. The compound of embodiment 88, wherein the condition is obesity or diabetes.

90. The compound of embodiment 88, wherein the condition is diabetic nephropathy or chronic kidney disease.

91. A use of the compound of any one of embodiments 1-60 or the pharmaceutically acceptable salt thereof, the stereoisomer of any of the foregoing, or the mixture thereof in the preparation of a medicament for treating a cardiovascular condition.

92. The use of embodiment 91, further comprising a therapeutic agent selected from an α-blocker, a β-blocker, an angiotensin converting enzyme (ACE) inhibitor, an angiotensin-receptor blocker (ARB), a calcium channel blocker, a diuretic, an inhibitor of the funny current, a myosin activator, or a neutral endopeptidase (NEP) inhibitor.

›DETAILED DESCRIPTION OF THE INVENTION · 12 of 20

93. The use of embodiment 91, further comprising a therapeutic agent selected from an angiotensin converting enzyme (ACE) inhibitor or an angiotensin-receptor blocker (ARB).

94. The use of the compound of embodiment 91, wherein the cardiovascular condition is heart failure.

95. The use of the compound of embodiment 91, wherein the cardiovascular condition is heart failure with reduced ejection fraction.

96. The use of the compound of embodiment 91, wherein the cardiovascular condition is heart failure with preserved ejection fraction.

97. The use of the compound of embodiment 91, wherein the cardiovascular condition is chronic systolic heart failure or chronic diastolic heart failure.

98. The use of the compound of embodiment 91, wherein the cardiovascular condition is acute heart fail.

99. The use of the compound of embodiment 91, wherein the cardiovascular condition is acute heart failure.

100. A use of the compound of any one of embodiments 1-60 or the pharmaceutically acceptable salt thereof, the stereoisomer of any of the foregoing, or the mixture thereof in the preparation of a medicament for activating the APJ Receptor or treating a condition where it is desirable to activate the APJ Receptor.

101. The use of embodiment 100, wherein the condition is obesity or diabetes.

102. The use of embodiment 100, wherein the condition is diabetic nephropathy or chronic kidney disease.

103. A treatment regimen for a cardiovascular disease, the regimen comprising: the compound of any one of embodiments 1-60 or the pharmaceutically acceptable salt thereof, the stereoisomer of any of the foregoing, or the mixture thereof.

104. The treatment regimen of embodiment 103, wherein the regimen further comprises a therapeutic agent selected from an α-blocker, a β-blocker, an angiotensin converting enzyme (ACE) inhibitor, an angiotensin-receptor blocker (ARB), a calcium channel blocker, a diuretic, an inhibitor of the funny current, a myosin activator, or a neutral endopeptidase (NEP) inhibitor.

105. The treatment regimen of embodiment 103, wherein the regimen further comprises a therapeutic agent selected from an angiotensin converting enzyme (ACE) inhibitor or an angiotensin-receptor blocker (ARB).

106. A kit, the kit comprising: the compound of any one of embodiments 1-60 or the pharmaceutically acceptable salt thereof, the stereoisomer of any of the foregoing, or the mixture thereof.

107. The kit of embodiment 106, wherein the kit further comprises a therapeutic agent selected from an α-blocker, a β-blocker, an angiotensin converting enzyme (ACE) inhibitor, an angiotensin-receptor blocker (ARB), a calcium channel blocker, a diuretic, an inhibitor of the funny current, a myosin activator, or a neutral endopeptidase (NEP) inhibitor.

108. The kit of embodiment 106, wherein the kit further comprises a therapeutic agent selected from an angiotensin converting enzyme (ACE) inhibitor or an angiotensin-receptor blocker (ARB).

109. In one embodiment, the invention provides a compound of Formula V, a salt thereof, a tautomer thereof, or a salt of the tautomer:

wherein:

R 1 is an unsubstituted furanyl, or is a furanyl substituted with 1, 2, or 3 R 1a substituents;

R 3 is selected from an unsubstituted C 1 -C 10 alkyl, a C 1 -C 10 alkyl substituted with 1, 2, or 3 R 3a substituents, a group of formula —(CR 3b R 3c )-Q, a group of formula —(CR 3b R 3c )—C(═O)-Q, a group of formula —(CR 3d R 3e )—(CR 3f R 3g )-Q, a group of formula —(CR 3d R 3e )—(CR 3f R 3g )—C(═O)-Q, a group of formula —(CR 3d R 3e )—(CR 3f R 3g )—CH(OH)-Q, a group of formula —(CR 3d R 3e )—(CR 3f R 3g )—(CR 3f R 3g )-Q, a group of formula —(CR 3b ═CR 3c )-Q, a group of formula —(C 3 -C 8 cycloalkyl)-Q, a group of formula -(heterocyclyl)-Q, or -Q, wherein the heterocyclyl of the -(heterocyclyl)-Q group has 5 to 7 ring members of which 1, 2, or 3 are heteroatoms independently selected from N, O, or S and is unsubstituted or is substituted with 1, 2, or 3 R 3h substituents, and further wherein the C 3 -C 8 cycloalkyl of the —(C 3 -C 8 cycloalkyl)-Q group is unsubstituted or is substituted with 1 or 2 R 3h substituents;

›DETAILED DESCRIPTION OF THE INVENTION · 13 of 20

Q is a monocyclic or bicyclic C 6 -C 10 aryl group, a monocyclic or bicyclic heteroaryl group with 5 to 10 ring members containing 1, 2, or 3 heteroatoms independently selected from N, O, or S, a C 3 -C 8 cycloalkyl group, a 3 to 10 membered heterocyclyl group containing 1, 2, or 3 heteroatoms independently selected from N, O, or S, —C(═O)NH(—C 1 -C 6 alkyl), —C(═O)N(—C 1 -C 6 alkyl) 2 , or —S(═O) 2 —C 1 -C 6 alkyl, wherein the C 6 -C 10 aryl, the heteroaryl, the cycloalkyl, and the heterocyclyl Q groups are unsubstituted or are substituted with 1, 2, 3, or 4 R Q substituent;

R Q in each instance is independently selected from —F, —Cl, —Br, —I, —CN, —C 1 -C 6 alkyl, —C 1 -C 6 haloalkyl, —C 1 -C 6 perhaloalkyl, —C 2 -C 6 alkenyl, —C 2 -C 6 alkynyl, —OH, —O—(C 1 -C 6 alkyl), —O—(C 1 -C 6 haloalkyl), —O—(C 1 -C 6 perhaloalkyl), —NH 2 , —NH(C 1 -C 6 alkyl), —N(C 1 -C 6 alkyl) 2 , —NHC(═O)(C 1 -C 6 alkyl), —C(═O)—(C 1 -C 6 alkyl), —C(═O)OH, —C(═O)—O—(C 1 -C 6 alkyl), —C(═O)NH 2 , —C(═O)NH(C 1 -C 6 alkyl), —C(═O)N(C 1 -C 6 alkyl) 2 , —S(═O) 2 —(C 1 -C 6 alkyl), —(C 1 -C 6 alkyl)-OH, —(C 1 -C 6 alkyl)-O—(C 1 -C 6 alkyl), phenyl, a heterocyclyl group, a —(C 1 -C 6 alkyl)heterocyclyl group, or a heteroaryl group with 5 or 6 ring members and 1, 2, or 3, heteroatoms independently selected from N, O, or S, wherein the heterocyclyl groups of the R Q heterocyclyl and —(C 1 -C 6 alkyl)heterocyclyl groups have 3 to 6 ring members of which 1 or 2 are heteroatoms independently selected from N, O, or S, wherein the Q heterocyclyl group may additionally be substituted with 1 or 2 oxo substituents, and the Q heteroaryl group may include an N-oxide if the heteroaryl includes a N heteroatom, and further wherein the heterocyclyl and the heterocyclyl of the —(C 1 -C 6 alkyl)heterocyclyl R Q groups may be further substituted with one or two oxo substituents and a substituent selected from —F, —Cl, —Br, —I, —CN, —OH, —C 1 -C 6 alkyl, or —C(═O)—(C 1 -C 6 alkyl);

110. The compound of embodiment 109, the salt thereof, the tautomer thereof, or the salt of the tautomer, wherein the compound has any of the R 1 , R 1a , R 3 , R 3d , R 3e , R 3f , R 3g , R 3h , R 4 , R 4a , R 4b , Q or R Q , values or combinations of values of any one of embodiments 2-55.

111. In another embodiment, the invention provides a method for preparing a compound of Formula VI, a salt thereof, a tautomer thereof, or a salt of the tautomer:

the method comprising:

a) cyclizing a compound of Formula V, a salt thereof, a tautomer thereof, or a salt of the tautomer in the presence of an acid or a base to form the compound of Formula VI, the salt thereof, the tautomer thereof, or the salt of the tautomer,

wherein:

R 1 is an unsubstituted furanyl, or is a furanyl substituted with 1, 2, or 3 R 1a substituents;

›DETAILED DESCRIPTION OF THE INVENTION · 14 of 20

R 3 is selected from an unsubstituted C 1 -C 10 alkyl, a C 1 -C 10 alkyl substituted with 1, 2, or 3 R 3a substituents, a group of formula —(CR 3b R 3c )-Q, a group of formula —(CR 3b R 3c )—C(═O)-Q, a group of formula —(CR 3d R 3e )—(CR 3f R 3g )-Q, a group of formula —(CR 3d R 3e )—(CR 3f R 3g )—C(═O)-Q, a group of formula —(CR 3d R 3e )—(CR 3f R 3g )—CH(OH)-Q, a group of formula —(CR 3d R 3e )—(CR 3f R 3g )—(CR 3f R 3g )-Q, a group of formula —(CR 3b ═CR 3c )-Q, a group of formula —(C 3 -C 8 cycloalkyl)-Q, a group of formula -(heterocyclyl)-Q, or -Q, wherein the heterocyclyl of the -(heterocyclyl)-Q group has 5 to 7 ring members of which 1, 2, or 3 are heteroatoms independently selected from N, O, or S and is unsubstituted or is substituted with 1, 2, or 3 R 3h substituents, and further wherein the C 3 -C 8 cycloalkyl of the —(C 3 -C 8 cycloalkyl)-Q group is unsubstituted or is substituted with 1 or 2 R 3h substituents;

Q is a monocyclic or bicyclic C 6 -C 10 aryl group, a monocyclic or bicyclic heteroaryl group with 5 to 10 ring members containing 1, 2, or 3 heteroatoms independently selected from N, O, or S, a C 3 -C 8 cycloalkyl group, a 3 to 10 membered heterocyclyl group containing 1, 2, or 3 heteroatoms independently selected from N, O, or S, —C(═O)NH(—C 1 -C 6 alkyl), —C(═O)N(—C 1 -C 6 alkyl) 2 , or —S(═O) 2 —C 1 -C 6 alkyl, wherein the C 6 -C 10 aryl, the heteroaryl, the cycloalkyl, and the heterocyclyl Q groups are unsubstituted or are substituted with 1, 2, 3, or 4 R Q substituent;

R Q in each instance is independently selected from —F, —Cl, —Br, —I, —CN, —C 1 -C 6 alkyl, —C 1 -C 6 haloalkyl, —C 1 -C 6 perhaloalkyl, —C 2 -C 6 alkenyl, —C 2 -C 6 alkynyl, —OH, —O—(C 1 -C 6 alkyl), —O—(C 1 -C 6 haloalkyl), —O—(C 1 -C 6 perhaloalkyl), —NH 2 , —NH(C 1 -C 6 alkyl), —N(C 1 -C 6 alkyl) 2 , —NHC(═O)(C 1 -C 6 alkyl), —C(═O)—(C 1 -C 6 alkyl), —C(═O)OH, —C(═O)—O—(C 1 -C 6 alkyl), —C(═O)NH 2 , —C(═O)NH(C 1 -C 6 alkyl), —C(═O)N(C 1 -C 6 alkyl) 2 , —S(═O) 2 —(C 1 -C 6 alkyl), —(C 1 -C 6 alkyl)-OH, —(C 1 -C 6 alkyl)-O—(C 1 -C 6 alkyl), phenyl, a heterocyclyl group, a —(C 1 -C 6 alkyl)heterocyclyl group, or a heteroaryl group with 5 or 6 ring members and 1, 2, or 3, heteroatoms independently selected from N, O, or S, wherein the heterocyclyl groups of the R Q heterocyclyl and —(C 1 -C 6 alkyl)heterocyclyl groups have 3 to 6 ring members of which 1 or 2 are heteroatoms independently selected from N, O, or S, wherein the Q heterocyclyl group may additionally be substituted with 1 or 2 oxo substituents, and the Q heteroaryl group may include an N-oxide if the heteroaryl includes a N heteroatom, and further wherein the heterocyclyl and the heterocyclyl of the —(C 1 -C 6 alkyl)heterocyclyl R Q groups may be further substituted with one or two oxo substituents and a substituent selected from —F, —Cl, —Br, —I, —CN, —OH, —C 1 -C 6 alkyl, or —C(═O)—(C 1 -C 6 alkyl);

›DETAILED DESCRIPTION OF THE INVENTION · 15 of 20

112. The method of embodiment 111, wherein R 1 , R 1a , R 3 , R 3d , R 3e , R 3f , R 3g , R 3h , R 4 , R 4a , R 4b , Q or R Q , have any of the values or combination of values of any one of embodiments 2-55.

113. The method of embodiment 111 or embodiment 112, wherein cyclizing further comprises heating the compound of Formula V, the salt thereof, the tautomer thereof, or the salt of the tautomer in the presence of the acid or the base.

114. The method of embodiment 113, wherein heating the compound of Formula V, the salt thereof, the tautomer thereof, or the salt of the tautomer comprises heating the compound to a temperature of from 50° C. to 100° C.

115. The method of embodiment 113, wherein heating the compound of Formula V, the salt thereof, the tautomer thereof, or the salt of the tautomer comprises heating the compound to a temperature of from 60° C. to 85° C.

116. The method of any one of embodiments 111-115, wherein the cyclizing of the compound of Formula V, the salt thereof, the tautomer thereof, or the salt of the tautomer is performed in the presence of the base.

117. The method of any one of embodiments 111-116, wherein the base is a metal hydroxide.

118. The method of embodiment 117, wherein the metal hydroxide is selected from NaOH or LiOH.

119. The method of any one of embodiments 116-118, wherein the cyclizing is carried out in an alcohol solvent.

120. The method of embodiment 119, wherein the alcohol is isopropanol.

121. The method of any one of embodiments 111-115, wherein cyclizing further comprises heating the compound of Formula V, the salt thereof, the tautomer thereof, or the salt of the tautomer in the presence of the acid.

122. The method of embodiment 121, wherein the acid is selected from a sulfonic acid, a carboxylic acid, polyphosphoric acid, phosphoric acid, sulfuric acid, or hydrochloric acid.

123. The method of embodiment 122, wherein the sulfonic acid is methanesulfonic acid.

124. The method of embodiment 122, wherein the acid is trifluoroacetic acid, acetic acid, or trichloroacetic acid.

125. The method of any one of embodiments 121-124, wherein the cyclizing is carried out in a cyclic ether, an acyclic ether, N,N-dimethylformamide, or acetonitrile.

126. The method of embodiment 125, wherein the cyclizing is carried out in a cyclic ether.

127. The method of embodiment 126, wherein the cyclic ether is selected from tetrahydrofuran, tetrahydropyran, or 1,4-dioxane.

128. The method of embodiment 126, wherein the cyclic ether is 1,4-dioxane.

In some embodiments, the compound is a salt. Such salts may be anhydrous or associated with water as a hydrate. In some embodiments, the compound may be in a neutral form as a base or an acid.

Also provided are pharmaceutical compositions that include the compound or the pharmaceutically acceptable salt thereof, the tautomer thereof, the pharmaceutically acceptable salt of the tautomer, the stereoisomer of any of the foregoing, or the mixture thereof according to any one of the embodiments and at least one pharmaceutically acceptable excipient, carrier or diluent. In some such embodiments, the compound or the pharmaceutically acceptable salt thereof, the tautomer thereof, the pharmaceutically acceptable salt of the tautomer, the stereoisomer of any of the foregoing, or the mixture thereof according to any one of the embodiments is present in an amount effective for the treatment of a cardiovascular condition or other condition such as obesity or diabetes, for activating the APJ Receptor. In some embodiments, the pharmaceutical composition is formulated for oral delivery whereas in other embodiments, the pharmaceutical composition is formulated for intravenous delivery. In some embodiments, the pharmaceutical composition is formulated for oral administration once a day or QD, and in some such formulations is a tablet.

In some embodiments, the subject is a mammal. In some such embodiments, the mammal is a rodent. In other such embodiments, the mammal is a canine. In still other embodiments, the subject is a primate and, in some such embodiments, is a human.

The pharmaceutical compositions or formulations for the administration of the compounds of this invention may conveniently be presented in unit dosage form and may be prepared by any of the methods well known in the art. All methods include the step of bringing the active ingredient into association with the carrier which constitutes one or more accessory ingredients. In general, the pharmaceutical compositions are prepared by uniformly and intimately bringing the active ingredient into association with a liquid carrier or a finely divided solid carrier or both, and then, if necessary, shaping the product into the desired formulation. In the pharmaceutical composition, the active object compound is included in an amount sufficient to produce the desired effect upon the process or condition of diseases.

The pharmaceutical compositions containing the active ingredient may be in a form suitable for oral use, for example, as tablets, troches, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules, or syrups or elixirs. Compositions intended for oral use may be prepared according to any method known to the art for the manufacture of pharmaceutical compositions. Such compositions may contain one or more agents selected from sweetening agents, flavoring agents, coloring agents and preserving agents in order to provide pharmaceutically elegant and palatable preparations. Tablets contain the active ingredient in admixture with other non-toxic pharmaceutically acceptable excipients which are suitable for the manufacture of tablets. These excipients may be, for example, inert diluents, such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; granulating and disintegrating agents, for example, corn starch, or alginic acid; binding agents, for example starch, gelatin or acacia, and lubricating agents, for example magnesium stearate, stearic acid, or talc. The tablets may be uncoated or they may be coated by known techniques to delay disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action over a longer period. For example, a time delay material such as glyceryl monostearate or glyceryl distearate may be employed. They may also be coated by the techniques described in U.S. Pat. Nos. 4,256,108, 4,160,452, and 4,265,874 to form osmotic therapeutic tablets for control release.

›DETAILED DESCRIPTION OF THE INVENTION · 16 of 20

Formulations for oral use may also be presented as hard gelatin capsules wherein the active ingredient is mixed with an inert solid diluent, for example, calcium carbonate, calcium phosphate, or kaolin, or as soft gelatin capsules wherein the active ingredient is mixed with water or an oil medium, for example peanut oil, liquid paraffin, or olive oil.

Aqueous suspensions contain the active materials in admixture with excipients suitable for the manufacture of aqueous suspensions. Such excipients are suspending agents, for example sodium carboxymethylcellulose, methylcellulose, hydroxy-propylmethylcellulose, sodium alginate, polyvinyl-pyrrolidone, gum tragacanth and gum acacia; dispersing or wetting agents may be a naturally-occurring phosphatide, for example lecithin, or condensation products of an alkylene oxide with fatty acids, for example polyoxy-ethylene stearate, or condensation products of ethylene oxide with long chain aliphatic alcohols, for example heptadecaethyleneoxycetanol, or condensation products of ethylene oxide with partial esters derived from fatty acids and a hexitol such as polyoxyethylene sorbitol monooleate, or condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol anhydrides, for example polyethylene sorbitan monooleate. The aqueous suspensions may also contain one or more preservatives, for example ethyl, or n-propyl, p-hydroxybenzoate, one or more coloring agents, one or more flavoring agents, and one or more sweetening agents, such as sucrose or saccharin.

Oily suspensions may be formulated by suspending the active ingredient in a vegetable oil, for example arachis oil, olive oil, sesame oil, or coconut oil, or in a mineral oil such as liquid paraffin. The oily suspensions may contain a thickening agent, for example beeswax, hard paraffin, or cetyl alcohol. Sweetening agents such as those set forth above, and flavoring agents may be added to provide a palatable oral preparation. These compositions may be preserved by the addition of an anti-oxidant such as ascorbic acid.

Dispersible powders and granules suitable for preparation of an aqueous suspension by the addition of water provide the active ingredient in admixture with a dispersing or wetting agent, suspending agent and one or more preservatives. Suitable dispersing or wetting agents and suspending agents are exemplified by those already mentioned above. Additional excipients, for example sweetening, flavoring and coloring agents, may also be present.

The pharmaceutical compositions of the invention may also be in the form of oil-in-water emulsions. The oily phase may be a vegetable oil, for example olive oil or arachis oil, or a mineral oil, for example liquid paraffin or mixtures of these. Suitable emulsifying agents may be naturally-occurring gums, for example gum acacia or gum tragacanth, naturally-occurring phosphatides, for example soy bean, lecithin, and esters or partial esters derived from fatty acids and hexitol anhydrides, for example sorbitan monooleate, and condensation products of the said partial esters with ethylene oxide, for example polyoxyethylene sorbitan monooleate. The emulsions may also contain sweetening and flavoring agents.

Syrups and elixirs may be formulated with sweetening agents, for example glycerol, propylene glycol, sorbitol or sucrose. Such formulations may also contain a demulcent, a preservative, and flavoring and coloring agents.

The pharmaceutical compositions may be in the form of a sterile injectable aqueous or oleagenous suspension. This suspension may be formulated according to the known art using those suitable dispersing or wetting agents and suspending agents which have been mentioned above. The sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally acceptable diluent or solvent, for example as a solution in 1,3-butane diol. Among the acceptable vehicles and solvents that may be employed are water, Ringer's solution, and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose, any bland fixed oil may be employed including synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid find use in the preparation of injectables.

The pharmaceutical compositions may also be administered in the form of suppositories for rectal administration of the drug. These compositions can be prepared by mixing the drug with a suitable non-irritating excipient which is solid at ordinary temperatures but liquid at the rectal temperature and will therefore melt in the rectum to release the drug. Such materials include, for example, cocoa butter and polyethylene glycols.

For topical use, creams, ointments, jellies, solutions, or suspensions, etc., containing the compounds of the invention are employed. As used herein, topical application is also meant to include the use of mouthwashes and gargles.

The compounds of the invention can be administered to provide systemic distribution of the compound within the patient. Therefore, in some embodiments, the compounds of the invention are administered to produce a systemic effect in the body.

As indicated above, the compounds of the invention may be administered via oral, mucosal (including sublingual, buccal, rectal, nasal, or vaginal), parenteral (including subcutaneous, intramuscular, bolus injection, intra-arterial, or intravenous), transdermal, or topical administration. In some embodiments, the compounds of the invention are administered via mucosal (including sublingual, buccal, rectal, nasal, or vaginal), parenteral (including subcutaneous, intramuscular, bolus injection, intra-arterial, or intravenous), transdermal, or topical administration. In other embodiments, the compounds of the invention are administered via oral administration. In still other embodiments, the compounds of the invention are not administered via oral administration.

›DETAILED DESCRIPTION OF THE INVENTION · 17 of 20

Different therapeutically effective amounts may be applicable for different conditions, as will be readily known by those of ordinary skill in the art. Similarly, amounts sufficient to treat or prevent such conditions, but insufficient to cause, or sufficient to reduce, adverse effects associated with conventional therapies are also encompassed by the above described dosage amounts and dose frequency schedules.

The compound of the invention, the pharmaceutically acceptable salt thereof, the tautomer thereof, the pharmaceutically acceptable salt of the tautomer, the stereoisomer of any of the foregoing, or the mixture thereof may find use in treating a number of conditions. For example, in some embodiments, the invention comprises methods or uses that include the use or administration of the compound, the pharmaceutically acceptable salt thereof, the tautomer thereof, the pharmaceutically acceptable salt of the tautomer, the stereoisomer of any of the foregoing, or the mixture thereof of the invention, in treating a subject suffering from a cardiovascular condition. In some embodiments, the cardiovascular condition includes, but is not limited to, coronary heart disease, stroke, heart failure, systolic heart failure, diastolic heart failure, diabetic heart failure, heart failure with preserved ejection fraction, heart failure with reduced ejection fraction, cardiomyopathy, myocardial infarction, myocardial remodeling after cardiac surgery, valvular heart disease, hypertension including, essential hypertension, pulmonary hypertension, portal hypertension, systolic hypertension, aortic aneurysm such as abdominal aortic aneurysm, or atrial fibrillation including improving arrhythmia. In some embodiments, the cardiovascular condition is heart failure. In some such embodiments, the heart failure is heart failure with reduced ejection fraction whereas in other embodiments it is heart failure with preserved ejection fraction. In other such embodiments the subject may have systolic heart failure or chronic diastolic heart failure and is thus useful in treating heart failure patients with systolic dysfunction and in treating heart failure patients with diastolic dysfunction. In some embodiments, the cardiovascular condition may be acute heart failure whereas in other embodiments, the cardiovascular condition is hypertension.

As noted, the compounds of the invention may be used to treat a number of diseases and disorders. Thus, in some embodiments, the invention provides a method of treating a disease or disorder selected from acute decompensated heart failure, chronic heart failure, pulmonary hypertension, atrial fibrillation, Brugada syndrome, ventricular tachycardia, atherosclerosis, hypertension, restenosis, ischemic cardiovascular diseases, cardiomyopathy, cardiac fibrosis, arrhythmia, water retention, diabetes, gestational diabetes, obesity, peripheral arterial disease, cerebrovascular accidents, transient ischemic attacks, traumatic brain injuries, amyotrophic lateral sclerosis, burn injuries, sunburn, edema, and preeclampsia in a subject. Such methods include administering a compound of the invention, a pharmaceutically acceptable salt thereof, a tautomer thereof, a pharmaceutically acceptable salt of the tautomer, a stereoisomer of any of the foregoing, a mixture thereof, or a pharmaceutical composition that includes any of these to a subject in need thereof.

In some embodiments, the invention provides a method of improving cardiac contractility in a subject suffering from a cardiovascular condition which includes administration of the compound, the pharmaceutically acceptable salt thereof, the tautomer thereof, the pharmaceutically acceptable salt of the tautomer, the stereoisomer of any of the foregoing, or the mixture thereof of the invention to the subject. The improvement in cardiac contraction may lead to significant improvements in methods for treating heart failure patients.

In some embodiments, the invention provides a method of improving cardiac relaxation in a subject suffering from a cardiovascular condition which includes administration of the compound, the pharmaceutically acceptable salt thereof, the tautomer thereof, the pharmaceutically acceptable salt of the tautomer, the stereoisomer of any of the foregoing, or the mixture thereof of the invention to the subject. The improvement in cardiac relaxation may lead to significant improvements in methods for treating heart failure patients.

In some embodiments, the invention provides a method of improving ventricular arterial coupling in a subject suffering from a cardiovascular condition which includes administration of the compound, the pharmaceutically acceptable salt thereof, the tautomer thereof, the pharmaceutically acceptable salt of the tautomer, the stereoisomer of any of the foregoing, or the mixture thereof of the invention to the subject. The improvement in ventricular arterial coupling may lead to significant improvements in methods for treating heart failure patients.

In some embodiments, the invention provides a method of increasing ejection fraction in a subject suffering from a cardiovascular condition which includes administration of the compound, the pharmaceutically acceptable salt thereof, the tautomer thereof, the pharmaceutically acceptable salt of the tautomer, the stereoisomer of any of the foregoing, or the mixture thereof of the invention to the subject.

The compounds of the invention may also find potential benefit in improving cardiac relaxation and thus find utility in treating certain heart failure patients. The compounds of the invention may thus find utility in improving inotropic function in some embodiments and may also find utility in improving lusitropic function.

In some embodiments, the invention provides a method of treating condition in a subject where it is desired to activate the APJ Receptor. Such methods include administration of the compound, the pharmaceutically acceptable salt thereof, the tautomer thereof, the pharmaceutically acceptable salt of the tautomer, the stereoisomer of any of the foregoing, or the mixture thereof of the invention to the subject. In some such embodiments, the condition is obesity or diabetes whereas in other embodiments, the condition is diabetic nephropathy or chronic kidney disease. In some such embodiments, the condition is type II diabetes. In other embodiments, the condition is cardiac wasting.

›DETAILED DESCRIPTION OF THE INVENTION · 18 of 20

The compounds of the invention may find utility in treating a number of other conditions. For example, the compounds of the invention may find utility in treating patients with conditions related to renal perfusion, hyperglycemia, aquaresis, and diuresis. In some embodiments, the invention provides a method of treating one of these subjects that includes administration of the compound, the pharmaceutically acceptable salt thereof, the tautomer thereof, the pharmaceutically acceptable salt of the tautomer, the stereoisomer of any of the foregoing, or the mixture thereof of the invention to the subject. The compounds of the invention may further find utility in arginine vasopressin (AVP) regulation and in angiotensin receptor (AT1R) regulation.

The compounds of the invention may find utility in treating a number of other conditions or producing desired outcomes or results. For example, the compounds of the invention may find utility in activating stem cells, more specifically cardiac stem cells, and even more specifically endogenous cardiac stem cells. Thus, the compounds of the invention may find utility in activating heart stem cells in a subject such as in a human patient. The compounds of the invention may yet further find utility in regrowing tissue and in assisting functional recovery after transplanting cells such as cells with bone marrow-derived mesenchymal stem cells. The compounds of the invention may also find utility in increasing cardiac stem cell proliferation and may be used to do such in patients that have suffered a myocardial infarction. As another example, the compounds of the invention may find utility in reducing infarct size, in promoting cardiac repair, and in activating stem cells and progenitors in post-myocardial infarction subjects. As still yet another example, the compounds of the invention may be used during surgery such as heart bypass surgery or heart transplant procedures as a therapeutic to reduce reperfusion injury. In some embodiments, the invention provides a method of treating one of these subjects or improving the condition in a subject that includes administration of the compound, the pharmaceutically acceptable salt thereof, the tautomer thereof, the pharmaceutically acceptable salt of the tautomer, the stereoisomer of any of the foregoing, or the mixture thereof of the invention to the subject.

Some methods of the invention comprise the administration of a compound of the invention and an additional therapeutic agent (i.e., a therapeutic agent other than a compound of the invention). Thus, the compounds of the invention can be used in combination with at least one other therapeutic agent. Examples of additional therapeutic agents include, but are not limited to, antibiotics, anti-emetic agents, antidepressants, antifungal agents, anti-inflammatory agents, antineoplastic agents, antiviral agents, cytotoxic agents, and other anticancer agents, immunomodulatory agents, alpha-interferons, β-interferons, alkylating agents, hormones, and cytokines. In one embodiment, the invention encompasses administration of an additional therapeutic agent that is used to treat subjects with chronic heart failure or hypertension.

As described above some methods of the invention comprise the administration of a compound of the invention and an additional therapeutic agent (i.e., a therapeutic agent other than a compound of the invention). In some embodiments, the invention encompasses administration of an additional therapeutic agent that is used to treat subjects with chronic heart failure or hypertension. In some embodiments, the invention comprises methods or uses that include the use of a compound, the pharmaceutically acceptable salt thereof, the tautomer thereof, the pharmaceutically acceptable salt of the tautomer, the stereoisomer of any of the foregoing, or the mixture thereof of the invention and a therapeutic agent such as, but not limited to, an α-blocker, a β-blocker, an angiotensin converting enzyme (ACE) inhibitor, an angiotensin-receptor blocker (ARB), a calcium channel blocker, a diuretic, an inhibitor of the funny current, a myosin activator, a neutral endopeptidase (NEP) inhibitor, a vasodilator, an aldosterone antagonist, a natriuretic, a saluretic, a centrally acting hypertensive, an aldosterone synthase inhibitor, or an endothelin receptor antagonist. In some embodiments, the invention comprises methods or uses that include the use of a compound, the pharmaceutically acceptable salt thereof, the tautomer thereof, the pharmaceutically acceptable salt of the tautomer, the stereoisomer of any of the foregoing, or the mixture thereof of the invention and a therapeutic agent selected from an α-blocker, a β-blocker, an angiotensin converting enzyme (ACE) inhibitor, an angiotensin-receptor blocker (ARB), a calcium channel blocker, a diuretic, an inhibitor of the funny current, a myosin activator, or a neutral endopeptidase (NEP) inhibitor. In some such embodiments, the invention includes a method that includes administering a compound of the invention, the pharmaceutically acceptable salt thereof, the tautomer thereof, the pharmaceutically acceptable salt of the tautomer, the stereoisomer of any of the foregoing, or the mixture thereof and an additional therapeutic agent such as an angiotensin converting enzyme (ACE) inhibitor or an angiotensin-receptor blocker (ARB). In some such embodiments, the additional therapeutic agent is thus an angiotensin converting enzyme (ACE) inhibitor whereas in others it is an angiotensin-receptor blocker (ARB). In other such embodiments, the invention includes a method that includes administering a compound of the invention, the pharmaceutically acceptable salt thereof, the tautomer thereof, the pharmaceutically acceptable salt of the tautomer, the stereoisomer of any of the foregoing, or the mixture thereof and an additional therapeutic agent such as a neutral endopeptidase (NEP) inhibitor. In other such embodiments, the invention includes a method that includes administering a compound of the invention, the pharmaceutically acceptable salt thereof, the tautomer thereof, the pharmaceutically acceptable salt of the tautomer, the stereoisomer of any of the foregoing, or the mixture thereof and an additional therapeutic agent such as an inhibitor of the funny current. In some embodiments, the method of use may include two or more additional therapeutic agents. For example, in some embodiments, the invention may include a compound of the invention, the pharmaceutically acceptable salt thereof, the tautomer thereof, the pharmaceutically acceptable salt of the tautomer, the stereoisomer of any of the foregoing, or the mixture thereof and additional therapeutic agents such as an ACE inhibitor and a NEP inhibitor.

›DETAILED DESCRIPTION OF THE INVENTION · 19 of 20

Therapeutic agents such as α-blockers may be used in conjunction with the compounds of the invention. Examples of α-blockers include, but are not limited to, doxazosin, prazosin, tamsulosin, and terazosin and their pharmaceutically acceptable salts.

Therapeutic agents such as β-blockers may be used in conjunction with the compounds of the invention. Examples of β-blockers include, but are not limited to, acebutolol, acetutolol, atenolol, bisoprol, bupranolol, carteolol, carvedilol, celiprolol, esmolol, mepindolol, metoprolol, nadolol, oxprenolol, penbutolol, pindolol, propranolol, taliprolol, and their pharmaceutically acceptable salts.

Calcium channel blockers may also be used as therapeutic agents in conjunctions with the compounds of the present invention. Examples of calcium channel blockers, include, but are not limited to, dihydropyridines (DHPs) and non-DHPs. Examples of DHPs include, but are not limited to, amlodipine, felodipine, isradipine, lacidipine, nicardipine, nifedipine, nigulpidine, nilutipine, nimodiphine, nisoldipine, nitrendipine, nivaldipine, ryosidine, and their pharmaceutically acceptable salts. Examples of Non-DHPs include, but are not limited to, anipamil, diltiazem, fendiline, flunarizine, gallpamil, mibefradil, prenylamine, tiapamil, verapamil, and their pharmaceutically acceptable salts.

Diuretics may also be used in conjunction with the compounds of the present invention. Examples include, but are not limited to, thiazide derivatives such as, but not limited to, amiloride, chlorothalidon, chlorothiazide, hydrochlorthiazide, and methylchlorothiazide and pharmaceutically acceptable salts thereof.

Centrally acting hypertensive agents may also be used in conjunction with the compounds of the present invention. Examples, include, but are not limited to, clonidine, guanabenz, guanfacine, methyldopa, and pharmaceutically acceptable salts thereof.

ACE inhibitors may be used in conjunction with the compounds of the present invention. Examples of ACE inhibitors that may be used include, but are not limited to, alaceptril, benazepril, benazaprilat, captopril, ceronapril, cilazapril, delapril, enalapril, analaprilat, fosinopril, Lisinopril, moexipiril, moveltopril, perindopril, quinapril, quinaprilat, ramipril, ramiprilat, spriapril, temocapril, trendolapril, and zofenopril and their pharmaceutically acceptable salts. Examples of some dual ACE/NEP inhibitors include, but are not limited to omapatrilat, fasidotril, and fasidotrilat and their pharmaceutically acceptable salts.

ARBs may also be used as therapeutic agents in conjunction with the compounds of the present invention. Examples of ARBs include, but are not limited to, candesartan, eprosartan, irbesartan, losartan, olmesartan, tasosartan, telmisartan, and valsartan and their pharmaceutically acceptable salts. Examples of some dual ARB/NEP inhibitors include, but are not limited to combinations of valsartan and sacubitril and their pharmaceutically acceptable salts.

NEP inhibitors may also be used as therapeutic agents in conjunction with the compounds of the present invention. An example of a NEP inhibitor includes, but it not limited to, sacubitril and its pharmaceutically acceptable salts.

Aldosterone synthase inhibitors may also be used as therapeutic agents in combination with the compounds of the present invention. Examples of aldosterone synthase inhibitors include, but are not limited to, anastrozole, fadrozole, and exemestane and their pharmaceutically acceptable salts.

Endothelin antagonists are other therapeutic agents that may be used in conjunction with the compounds of the present invention. Examples include, but are not limited to, bosentan, enrasentan, atrasentan, darusentan, macitentan, sitaxentan, and tezosentan, and their pharmaceutically acceptable salts.

Inhibitors of the funny current (I f ) may also be used in conjunction with the compounds of the invention. An example of an inhibitor of the funny current is ivabradine and its pharmaceutically acceptable salts.

Myosin activators may also be used in conjunction with the compounds of the invention. Examples of myosin activators include cardiac myosin activators.

It will be recognized that for purposes of this application, a therapeutic agent other than one of the present invention includes compounds such as known prodrugs that are converted into the therapeutic agent after administration. For example, a compound without antineoplastic activity, but that is converted into an antineoplastic agent in the body after administration, may be administered along with a compound of the invention. As another example, sacubitril is considered a NEP inhibitor for the purposes of this application even though it is a prodrug that is converted into sacubitrilat by de-ethylation via esterases.

When administered as a combination, the therapeutic agents can be formulated as separate compositions that are administered at the same time or sequentially at different times, or the therapeutic agents can be given as a single composition. The phrase “co-therapy” (or “combination-therapy”), in defining use of a compound of the present invention and another pharmaceutical agent, is intended to embrace administration of each agent in a sequential manner in a regimen that will provide beneficial effects of the drug combination, and is intended as well to embrace co-administration of these agents in a substantially simultaneous manner, such as in a single capsule having a fixed ratio of these active agents or in multiple, separate capsules for each agent. Specifically, the administration of compounds of the present invention may be in conjunction with additional therapies known to those skilled in the art in the prevention or treatment of cardiovascular conditions.

If formulated as a fixed dose, such combination products employ the compounds of this invention within the accepted dosage ranges. Compounds of any of the embodiments described herein may also be administered sequentially with known agents for use in treating cardiovascular conditions such as heart failure and hypertension when a combination formulation is inappropriate. The invention is not limited in the sequence of administration as compounds of the invention may be administered either prior to, simultaneous with, or after administration of a known therapeutic agent.

›DETAILED DESCRIPTION OF THE INVENTION · 20 of 20

The invention is further described by reference to the following examples, which are intended to exemplify the claimed invention but not to limit it in any way.

›EXAMPLES · 1 of 46

Unless otherwise noted, all materials were obtained from commercial suppliers and were used without further purification. Anhydrous solvents were obtained from Sigma-Aldrich (Milwaukee, Wis.) and used directly. All reactions involving air- or moisture-sensitive reagents were performed under a nitrogen or argon atmosphere. Purity was measured using Agilent 1100 Series high performance liquid chromatography (HPLC) systems with UV detection at 254 nm and 215 nm (System A: Agilent Zorbax Eclipse XDB-C8 4.6×150 mm, 5 micron, 5 to 100% ACN in H 2 O with 0.1% TFA for 15 min at 1.5 mL/min; System B: Zorbax SB-C8, 4.6×75 mm, 10 to 90% ACN in H 2 O with 0.1% formic acid for 12 min at 1.0 mL/min). Silica gel chromatography was generally performed with prepacked silica gel cartridges (Biotage or Teledyne-Isco). 1 H NMR spectra were recorded on a Bruker AV-400 (400 MHz) spectrometer or a Varian 400 MHz spectrometer at ambient temperature, or the NMR spectra were collected with a Bruker Avance III spectrometer operating at a proton frequency of 500.13 MHz using a 10 μL Protasis CapNMR flow probe. NMR samples were delivered to the flow probe using a Protasis One-Minute NMR™ Automation system comprised of a Discovery Tower™ Sample Manager and a Waters Liquid Handler made by CTC, Switzerland (Model 2777). All observed protons are reported as parts per million (ppm) downfield from tetramethylsilane (TMS) or another internal reference in the appropriate solvent indicated. Data are reported as follows: chemical shift, multiplicity (s=singlet, d=doublet, t=triplet, q=quartet, br=broad, m=multiplet), coupling constants, and number of protons. Low-resolution mass spectral (MS) data were determined on an Agilent 1100 Series LC-MS with UV detection at 254 nm and 215 nm and a low resonance electrospray mode (ESI).

A wide variety of sulfonamide tails and R 4 groups can be used to synthesize compounds of the invention such as those set forth in WO 2016/187308 and U.S. Pat. Appl. Pub. No. US 2016/0340336 which are hereby incorporated by reference in their entireties and for all purposes as if specifically set forth herein. Thus, compounds of the present invention may be prepared using any of the R 3 , R 4 , and Q groups taught in WO 2016/187308 and U.S. Pat. Appl. Pub. No. US 2016/0340336.

The following Abbreviations are used to refer to various reagents and solvents:

ACN Acetonitrile AcOH Acetic Acid d day or days DAST Diethylaminosulfur trifluoride DCM Dichloromethane DEA Diethylamine DIEA N,N-Diisopropylethylamine DIPA N,N-Diisopropylamine DMF N,N-Dimethylformamide DMAc Dimethylacetamide DMAP 4-Dimethylaminopyridine DMSO Dimethylsulfoxide EtOAc Ethyl Acetate EtOH Ethanol EtOTf Ethyl trifluoromethanesulfonate h hour or hours HATU 1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxidhexafluorophosphate HMDS Hexamethyldisilazane HBTU N,N,N′,N′-Tetramethyl-O-(1H-benzotriazol-1-yl)uronium hexafluorophosphate IPA Isopropanol KHMDS Potassium bis(trimethylsilyl)amide LiHMDS Lithium bis(trimethylsilyl)amide MeOH Methanol min minute or minutes MeOTf Methyl trifluoromethanesulfonate MSA Methanesulfonic acid RBF RBF RT Room temperature SFC Supercritical fluid chromatography TASF Tris(dimethylamino)sulfonium difluorotrimethylsilicate TBAF tetrabutylammonium fluoride TBS t-Butyldimethylsilane TBDMS t-Butyldimethylsilane TBSOTf t-Butyldimethylsilyl trifluoromethanesulfonate TEA Triethylamine TFA Trifluoroacetic acid THF Tetrahydrofuran TLC Thin Layer Chromatography

Example 1.0. Preparation of N-(4-(2,6-dimethoxyphenyl)-5-(2-furanyl)-4H-1,2,4-triazol-3-yl)-2-(2-methyl-1H-benzimidazol-1-yl)ethanesulfonamide

N-(4-(2,6-Dimethoxyphenyl)-5-(2-furanyl)-4H-1,2,4-triazol-3-yl)-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)ethanesulfonamide, Example 1.1. Example 1.1 was prepared from Example 362.03 and 2-phthalimidoethanesulfonyl chloride (commercially available from Oakwood Products, Inc., SC, USA) using the procedure described in Example 111.0 to give the title compound Example 1.1. 1 H NMR (400 MHz, CDCl 3 ) δ 10.93 (br. s., 1H) 7.79-7.94 (m, 2H) 7.66-7.79 (m, 2H) 7.39-7.58 (m, 2H) 6.70 (d, J=8.61 Hz, 2H) 6.25-6.46 (m, 1H) 6.03 (d, J=3.33 Hz, 1H) 4.11 (t, J=7.04 Hz, 2H) 3.80 (s, 3H) 3.80 (s, 3H) 3.41 (t, J=7.04 Hz, 2H). LCMS-ESI (pos.), m/z: 524.2 (M+H) + .

2-Amino-N-(4-(2,6-dimethoxyphenyl)-5-(2-furanyl)-4H-1,2,4-triazol-3-yl)ethanesulfonamide, Example 1.2. To a stirred solution of 1.1 (4.86 g, 9.28 mmol) in MeOH (37 mL) was added anhydrous hydrazine (1.5 mL, 46.4 mmol). The reaction mixture was stirred at RT for 18 h. LCMS analysis indicated the reaction was complete. The white precipitate was isolated by filtration to afford by-product 2,3-dihydrophthalazine-1,4-dione as a white solid. The mother liquor was concentrated and more by-product 2,3-dihydrophthalazine-1,4-dione was removed by filtration. The secondary mother liquor was concentrated in vacuo and re-crystallized to afford the title compound 1.2 (2.65 g, 6.74 mmol, 72.6% yield) as a white crystalline solid. 1 H NMR (500 MHz, DMSO-d6) δ 7.62 (dd, J=1.71, 0.73 Hz, 1H) 7.43 (t, J=8.44 Hz, 1H) 6.81 (d, J=8.56 Hz, 2H) 6.38 (dd, J=3.42, 1.71 Hz, 1H) 5.71 (d, J=3.42 Hz, 1H) 3.67 (s, 3H)) 3.67 (s, 3H) 3.30 (t, J=6.48 Hz, 2H) 3.09 (t, J=6.48 Hz, 2H). LCMS-ESI (pos.), m/z: 394.0 (M+H) + .

N-(4-(2,6-Dimethoxyphenyl)-5-(2-furanyl)-4H-1,2,4-triazol-3-yl)-2-((2-nitrophenyl)amino)ethanesulfonamide, Example 1.3. Under an atmosphere of nitrogen, 1.2 (0.550 g, 1.40 mmol) was suspended in DMAc (2.55 mL) and TEA (0.59 mL, 4.19 mmol) was added. The reaction was treated with 1-fluoro-2-nitrobenzene (0.074 mL, 0.70 mmol). After 24 h, the reaction was treated with additional fluoronitrobenzene (0.110 mL) and the reaction was stirred at RT for 72 h. The reaction was diluted with Et 2 O and filtered. The organics were dried over Na 2 SO 4 , filtered and concentrated in vacuo. The initial product was purified on silica gel eluting with 60% to 85% THF in hexanes to afford 1.3 (0.43 g, 0.84 mmol, 60% yield). 1 H NMR (400 MHz, DMSO-d 6 ) δ 13.52 (s, 1H) 8.29 (t, J=5.58 Hz, 1H) 8.08 (d, J=8.41 Hz, 1H) 7.85 (s, 1H) 7.57 (t, J=8.51 Hz, 1H) 7.49 (t, J=7.43 Hz, 1H) 6.84-6.95 (m, 3H) 6.72 (t, J=7.83 Hz, 1H) 6.50-6.61 (m, 1H) 6.04 (d, J=3.52 Hz, 1H) 3.72 (s, 5H) 3.64 (q, J=6.19 Hz, 2H) 3.27 (t, J=6.55 Hz, 2H). LCMS-ESI (pos.), m/z: 515.0 (M+H) + .

›EXAMPLES · 2 of 46

2-((2-Aminophenyl)amino)-N-(4-(2,6-dimethoxyphenyl)-5-(2-furanyl)-4H-1,2,4-triazol-3-yl)ethanesulfonamide, Example 1.4. Example 1.3 (0.110 g, 0.21 mmol) was suspended in EtOH (2.00 mL). The reaction was treated with 10% palladium on carbon (0.023 g, 0.214 mmol) and placed under an atmosphere of H 2 . The reaction was stirred ar RT for 2 h. LCMS analysis showed the reaction was incomplete. The reaction was further purged with H 2 and placed under an atmosphere of H 2 for an additional 4 h. Only a trace of starting material was visible by LCMS. The reaction was purged with N 2 , and the catalyst was removed by filtration through Celite® brand filter aid. The filtrate was purified on silica gel eluting with 2-5% MeOH in DCM to afford 1.4 (0.075 g, 0.16 mmol, 72% yield). 1 H NMR (400 MHz, DMSO-d 6 ) δ 7.84 (dd, J=1.76, 0.78 Hz, 1H) 7.57 (t, J=8.51 Hz, 1H) 6.90 (d, J=8.61 Hz, 2H) 6.51-6.58 (m, 2H) 6.43-6.51 (m, 2H) 6.29-6.36 (m, 1H) 6.03 (d, J=3.13 Hz, 1H) 3.69-3.74 (m, 6H) 3.27-3.39 (m, 2H) 3.10-3.26 (m, 2H). LCMS-ESI (pos.), m/z: 485.1 (M+H) + . 1.0 was isolated as a side-product (0.016 g, 0.031 mmol, 14.72% yield).

N-(4-(2,6-Dimethoxyphenyl)-5-(2-furanyl)-4H-1,2,4-triazol-3-yl)-2-(2-methyl-1H-benzimidazol-1-yl)ethanesulfonamide, Example 1.0. The title compound was prepared using the procedure described in Example 1.4. Example 1.0 was isolated as a side-product of the reaction. 1 H NMR (400 MHz, DMSO-d 6 ) δ 13.60 (br. s., 1H) 7.86 (s, 1H) 7.62 (t, J=8.51 Hz, 1H) 7.48-7.55 (m, 1H) 7.20-7.28 (m, 1H) 7.10-7.20 (m, 2H) 6.95 (d, J=8.61 Hz, 2H) 6.56 (dd, J=3.52, 1.76 Hz, 1H) 6.07 (d, J=3.52 Hz, 1H) 4.43 (t, J=7.04 Hz, 2H) 3.75 (s, 3H) 3.75 (s, 3H) 3.41 (t, J=7.04 Hz, 2H) 2.47 (s, 3H). LCMS-ESI (pos.), m/z: 509.1 (M+H) + .

Example 2.0. Preparation of N-(4-(2,6-dimethoxyphenyl)-5-(2-furanyl)-4H-1,2,4-triazol-3-yl)-2-(2-methyl-1H-benzimidazol-1-yl)ethanesulfonamide

N-(4-(2,6-Dimethoxyphenyl)-5-(2-furanyl)-4H-1,2,4-triazol-3-yl)-2-(1-oxo-1,3-dihydro-2H-isoindol-2-yl)ethanesulfonamide, Example 2.0. Under an atmosphere of N 2 , 1.2 (0.17 g, 0.42 mmol) was combined with methyl 2-(bromomethyl)benzoate (0.048 g, 0.210 mmol) and Hunig's base (0.366 mL, 2.095 mmol) in ACN (7.62 mL). The reaction was stirred overnight at RT. The reaction was then diluted with DCM and saturated aqueous NH 4 Cl. The layers were separated and the organic layer was dried over Na 2 SO 4 , filtered, and concentrated in vacuo. The initial material was purified on silica gel eluting with 5%-15% ACN with 0.1% MeOH in DCM. A second column chromatography on silica gel was performed eluting with 2.5% to 3.0% MeOH in DCM to afford Example 2.0 (0.019 g, 0.037 mmol, 17.80% yield). 1 H NMR (400 MHz, DMSO-d 6 ) δ 13.44 (br. s., 1H) 7.80-7.89 (m, 1H) 7.67 (d, J=7.63 Hz, 1H) 7.52-7.64 (m, 3H) 7.44-7.52 (m, 1H) 6.90 (d, J=8.61 Hz, 2H) 6.54 (dd, J=3.52, 1.76 Hz, 1H) 6.04 (d, J=3.33 Hz, 1H) 4.51 (s, 2H) 3.79-3.84 (m, 2H) 3.73-3.79 (m, 6H) 3.29 (d, J=7.24 Hz, 2H). LCMS-ESI (pos.), m/z: 510.0 (M+H) + .

Example 3.0. Preparation of (1R,2S)—N-(4-(4,6-dimethoxypyrimidin-5-yl)-5-(5-methylfuran-2-yl)-4H-1,2,4-triazol-3-yl)-1-methoxy-1-(5-methylpyrimidin-2-yl)propane-2-sulfonamide

(1R,2S)—N-(4-(4,6-Dimethoxypyrimidin-5-yl)-5-(5-methylfuran-2-yl)-4H-1,2,4-triazol-3-yl)-1-methoxy-1-(5-methylpyrimidin-2-yl)propane-2-sulfonamide, Example 3.0. The title compound was prepared employing (1R,2S)-1-methoxy-1-(5-methylpyrimidin-2-yl)propane-2-sulfonamide (Example 373.0), 2-5-isothiocyanato-4,6-dimethoxypyrimidine (Example 372.1) and 5-methylfuran-2-carbohydrazide following the general procedure described in Example 314.0 employing MSA instead of TFA. 1 H NMR (300 MHz, CDCl 3 ) δ 1.40 (d, J=7.02 Hz, 3H) 2.32 (d, J=15.78 Hz, 6H) 3.36 (s, 3H) 3.67-3.85 (m, 1H) 3.98 (d, J=5.85 Hz, 6H) 4.95 (d, J=4.68 Hz, 1H) 5.99-6.07 (m, 1H) 6.27 (d, J=3.51 Hz, 1H) 8.55 (s, 1H) 8.62 (s, 2H) 11.19 (br. s., 1H). LCMS-ESI (pos.) m/z: 531.0 (M+H) + .

Example 4.0. Preparation of (2S)—N-(4-(2,6-dimethoxyphenyl)-5-(2-furanyl)-4H-1,2,4-triazol-3-yl)-1-(7-fluoro-1-(methoxymethyl)-1H-imidazo[4,5-c]pyridin-4-yl)-2-propanesulfonamide and (2R)—N-(4-(2,6-dimethoxyphenyl)-5-(2-furanyl)-4H-1,2,4-triazol-3-yl)-1-(7-fluoro-1-(methoxymethyl)-1H-imidazo[4,5-c]pyridin-4-yl)-2-propanesulfonamide

4-Chloro-7-fluoro-1H-imidazo[4,5-c]pyridine, Example 4.1. Sulfamic acid (187 μL, 4.15 mmol) was added to a solution of 2-chloro-5-fluoropyridine-3,4-diamine (commercially available from Bellen, Beijing, China) (670 mg, 4.15 mmol) and ethyl orthoformate (2.76 mL, 16.6 mmol) in MeOH (10 mL) and the mixture was heated at reflux for 16 h. Thereafter, the mixture was cooled to RT, diluted with saturated aqueous NaHCO 3 , and extracted with DCM. The DCM extracts were combined, washed with brine, dried over Na 2 SO 4 , filtered and concentrated in vacuo. The residue was purified on a silica gel column, employing a gradient of 0-20% MeOH in DCM, to afford 4.1 (560 mg, 3.26 mmol, 79%).

4-Chloro-7-fluoro-3-(methoxymethyl)-3H-imidazo[4,5-c]pyridine and 4-chloro-7-fluoro-1-(methoxymethyl)-1H-imidazo[4,5-c]pyridine, Example 4.2. Chloromethyl methyl ether (89 μL, 1.17 mmol) was added to a solution of 4.1 (50 mg, 0.29 mmol) and morpholine (152 μL, 1.75 mmol) in DCM (1 mL), and the mixture was stirred for 3 d at RT. Thereafter, the mixture was diluted with saturated aqueous NaHCO 3 and extracted with EtOAc. The combined organic layers were washed with brine, dried over Na 2 SO 4 , filtered, and concentrated in vacuo. The residue was purified on a silica gel preparative layer plate employing 40% EtOAc in hexanes as eluent to afford 4.2 (30 mg, 0.14 mmol, 48%).

(E)-7-Fluoro-1-(methoxymethyl)-4-(prop-1-en-1-yl)-1H-imidazo[4,5-c]pyridine and (Z)-7-fluoro-1-(methoxymethyl)-4-(prop-1-en-1-yl)-1H-imidazo[4,5-c]pyridine, Example 4.3. A mixture of potassium (E)-trifluoro(prop-1-en-1-yl)borate (commercially available from Frontier Scientific Services Inc.) (782 mg, 5.29 mmol), 4.2 (570 mg, 2.64 mmol), triphenylphosphine (208 mg, 0.79 mmol), and cesium carbonate (861 mg, 2.64 mmol) in dioxane (5 mL) was sparged with argon for 1 min. Palladium (II) chloride (47 mg, 0.26 mmol) was added, the mixture was sparged for 1 min, and then it was stirred at 80° C. for 16 h. Thereafter, the mixture was cooled to RT, diluted with saturated aqueous NaHCO 3 , and extracted with EtOAc. The combined organic layers were then washed with brine, dried over Na 2 SO 4 , filtered, and concentrated in vacuo. The residue was purified on a silica gel column employing a gradient of 0-100% EtOAc in hexanes to afford Example 4.3 (370 mg, 1.67 mmol, 63%). LCMS-ESI (pos.) m/z: 222.2 (M+H) + .

›EXAMPLES · 3 of 46

7-Fluoro-1-(methoxymethyl)-1H-imidazo[4,5-c]pyridine-4-carbaldehyde, Example 4.4. Osmium tetroxide (8.5 mg, 0.033 mmol) was added to a stirred solution of 4.3 (370 mg, 1.67 mmol) in ACN:water (4:1, 5 mL) at RT. After 10 min, sodium periodate (1073 mg, 5.02 mmol) was added and the mixture was stirred for 16 h at RT. Thereafter, the mixture was diluted with saturated aqueous NaHCO 3 and extracted with EtOAc. The combined organic layers were then washed with brine, dried over Na 2 SO 4 , filtered, and concentrated in vacuo. The residue was purified on a silica gel column employing a gradient of 0-100% EtOAc in hexanes to afford Example 4.4 (220 mg, 1.05 mmol, 63%). 1 H NMR (400 MHz, CDCl 3 ) δ 10.25-10.40 (m, 1H) 8.37-8.51 (m, 1H) 8.21-8.33 (m, 1H) 5.62-5.73 (m, 2H) 3.24-3.37 (m, 3H).

(E)-N-(4-(2,6-Dimethoxyphenyl)-5-(furan-2-yl)-4H-1,2,4-triazol-3-yl)-1-(7-fluoro-1-(methoxymethyl)-1H-imidazo[4,5-c]pyridin-4-yl)-N-(2-(trimethylsilyl)ethyl)prop-1-ene-2-sulfonamide and (Z)—N-(4-(2,6-dimethoxyphenyl)-5-(furan-2-yl)-4H-1,2,4-triazol-3-yl)-1-(7-fluoro-1-(methoxymethyl)-1H-imidazo[4,5-c]pyridin-4-yl)-N-(2-(trimethylsilyl)ethyl)prop-1-ene-2-sulfonamide, Example 4.5. Lithium bis(trimethylsilyl)amide (1.0 M solution in THF, 717 μL, 0.72 mmol) was added to a stirred solution of Example 366.0 (162 mg, 0.26 mmol) in THF at 0° C. After 10 min, a solution of 4.4 (50 mg, 0.24 mmol) in THF was added. The mixture was removed from the cooling bath and stirred for 16 h at RT after which LCMS analysis indicated that the reaction was complete. Thereafter, the mixture was diluted with 1N aqueous HCl and extracted with EtOAc. The combined organic layers were washed with brine, dried over Na 2 SO 4 , filtered, and concentrated in vacuo. The residue was purified on a silica gel column employing a gradient of 0-100% EtOAc in hexanes to afford Example 4.5 (75 mg, 0.11 mmol, 47%). LCMS-ESI (pos.) m/z: 670.2 (M+H) + .

(2R)—N-(4-(2,6-Dimethoxyphenyl)-5-(furan-2-yl)-4H-1,2,4-triazol-3-yl)-1-(7-fluoro-1-(methoxymethyl)-1H-imidazo[4,5-c]pyridin-4-yl)-N-(2-(trimethylsilyl)ethyl)propane-2-sulfonamide and (2S)—N-(4-(2,6-dimethoxyphenyl)-5-(furan-2-yl)-4H-1,2,4-triazol-3-yl)-1-(7-fluoro-1-(methoxymethyl)-1H-imidazo[4,5-c]pyridin-4-yl)-N-(2-(trimethylsilyl)ethyl)propane-2-sulfonamide, Example 4.6. Example 4.5 (75 mg, 0.11 mmol) was dissolved in MeOH and the resulting solution was sparged with N 2 for 2 min before Pd/C (12 mg, 5% Pd dry basis, 50% water, wet paste) (commercially available from Alfa Aesar, Ward Hill, Mass., USA) was carefully added. Hydrogen was introduced at 1 atm (balloon) and the mixture was vigorously stirred until TLC analysis indicated that the reaction was complete (3 h). Thereafter, the mixture was flushed with N 2 , filtered over Celite® brand filter aid taking care to keep the pad wet with solvent and concentrated in vacuo. The residue was purified on a silica gel column employing a gradient of 0-100% EtOAc in hexanes to afford Example 4.6 (62 mg, 0.092 mmol, 82%).

(2S)—N-(4-(2,6-dimethoxyphenyl)-5-(2-furanyl)-4H-1,2,4-triazol-3-yl)-1-(7-fluoro-1-(methoxymethyl)-1H-imidazo[4,5-c]pyridin-4-yl)-2-propanesulfonamide and (2R)—N-(4-(2,6-dimethoxyphenyl)-5-(2-furanyl)-4H-1,2,4-triazol-3-yl)-1-(7-fluoro-1-(methoxymethyl)-1H-imidazo[4,5-c]pyridin-4-yl)-2-propanesulfonamide, Example 4.0. Example 4.6 (62 mg, 0.092 mmol) was dissolved in DMF (0.5 mL). Tris(dimethylamino)sulfonium difluorotrimethylsilicate (commercially available from Sigma-Aldrich Corp., St. Louis, Mo., USA, 25 mg, 0.092 mmol) was added and the resulting mixture was stirred at 80° C. for 3 h. Thereafter, the mixture was cooled to RT and concentrated in vacuo. The residue was purified on a reverse-phase column employing a gradient of 10-80% ACN in water (0.1% TFA in both eluents) to afford Example 4.0 (53 mg, 0.077 mmol, 84%). 1 H NMR (400 MHz, CDCl 3 ) δ 8.44 (d, J=2.74 Hz, 1H) 8.26 (s, 1H) 7.54 (m, 1H) 7.28 (m, 1H) 7.14 (m, 1H) 6.72 (dd, J=8.61, 1.96 Hz, 1H) 6.36 (m, 1H) 6.05 (d, J=3.52 Hz, 1H) 5.19 (d, J=11.35 Hz, 2H) 3.84-4.03 (m, 2H) 3.79 (s, 3H) 3.78 (s, 3H) 3.57 (dd, J=15.26, 3.91 Hz, 1H) 3.30 (s, 3H) 1.55 (d, J=6.65 Hz, 3H). LCMS-ESI (pos.) m/z: 572.0 (M+H) + .

Example 5.0. Preparation of (2S)—N-(4-(2,6-dimethoxyphenyl)-5-(2-furanyl)-4H-1,2,4-triazol-3-yl)-1-(7-fluoro-1H-imidazo[4,5-c]pyridin-4-yl)-2-propanesulfonamide or (2R)—N-(4-(2,6-dimethoxyphenyl)-5-(2-furanyl)-4H-1,2,4-triazol-3-yl)-1-(7-fluoro-1H-imidazo[4,5-c]pyridin-4-yl)-2-propanesulfonamide

(2S)—N-(4-(2,6-Dimethoxyphenyl)-5-(2-furanyl)-4H-1,2,4-triazol-3-yl)-1-(7-fluoro-1H-imidazo[4,5-c]pyridin-4-yl)-2-propanesulfonamide and (2R)—N-(4-(2,6-dimethoxyphenyl)-5-(2-furanyl)-4H-1,2,4-triazol-3-yl)-1-(7-fluoro-1H-imidazo[4,5-c]pyridin-4-yl)-2-propanesulfonamide, Example 5.1. Example 4.0 (53 mg, 0.077 mmol) was dissolved in hydrochloric acid/dioxane (4M/dioxane, 2.3 mL, 0.077 mmol) and the mixture was stirred for 30 min at RT. Thereafter, the mixture was concentrated in vacuo to afford Example 5.1. LCMS-ESI (pos.) m/z: 528.2 (M+H) + .

(2S)—N-(4-(2,6-Dimethoxyphenyl)-5-(2-furanyl)-4H-1,2,4-triazol-3-yl)-1-(7-fluoro-1H-imidazo[4,5-c]pyridin-4-yl)-2-propanesulfonamide or (2R)—N-(4-(2,6-dimethoxyphenyl)-5-(2-furanyl)-4H-1,2,4-triazol-3-yl)-1-(7-fluoro-1H-imidazo[4,5-c]pyridin-4-yl)-2-propanesulfonamide, Example 5.0. Purification of Example 5.1 by SFC [30×250 mm AD-H column with 39 g/min MeOH (20 mM NH 3 ) in 31 g/min CO 2 at 100 bar] afforded two enantiomers. The title compound Example 5.0 was the first isomer to elute under these conditions. 1 H NMR (400 MHz, CD 3 OD) δ 8.37 (s, 1H) 8.17 (d, J=2.15 Hz, 1H) 7.50-7.63 (m, 2H) 6.82 (dd, J=8.51, 2.64 Hz, 2H) 6.43 (dd, J=3.52, 1.76 Hz, 1H) 6.12 (d, J=3.52 Hz, 1H) 3.81 (dd, J=10.56, 6.46 Hz, 1H) 3.73 (d, J=1.96 Hz, 6H) 3.33 (m, 2H) 1.22 (m, 3H). LCMS-ESI (pos.) m/z: 528.1 (M+H) + .

Example 6.0. Preparation of (2S)—N-(4-(2,6-dimethoxyphenyl)-5-(2-furanyl)-4H-1,2,4-triazol-3-yl)-1-(7-fluoro-1-methyl-1H-imidazo[4,5-c]pyridin-4-yl)-2-propanesulfonamide or (2R)—N-(4-(2,6-dimethoxyphenyl)-5-(2-furanyl)-4H-1,2,4-triazol-3-yl)-1-(7-fluoro-1-methyl-1H-imidazo[4,5-c]pyridin-4-yl)-2-propanesulfonamide

›EXAMPLES · 4 of 46

N-(4-(2,6-Dimethoxyphenyl)-5-(furan-2-yl)-4H-1,2,4-triazol-3-yl)-1-(7-fluoro-1H-imidazo[4,5-c]pyridin-4-yl)-N-(2-(trimethylsilyl)ethyl)propane-2-sulfonamide, Example 6.1. Boron trifluoride diethyl etherate (44 μL, 0.36 mmol) was added to a solution of 4.6 (80 mg, 0.12 mmol) in DCM and the mixture was stirred for 40 min at RT. Thereafter, the mixture was diluted with water and extracted with DCM. The organic extracts were then combined, dried over Na 2 SO 4 , filtered, and concentrated in vacuo to afford Example 6.1. LCMS-ESI (pos.) m/z: 628.2 (M+H) + .

(2S)—N-(4-(2,6-Dimethoxyphenyl)-5-(furan-2-yl)-4H-1,2,4-triazol-3-yl)-1-(7-fluoro-1-methyl-1H-imidazo[4,5-c]pyridin-4-yl)-N-(2-(trimethylsilyl)ethyl)propane-2-sulfonamide and (2R)—N-(4-(2,6-dimethoxyphenyl)-5-(furan-2-yl)-4H-1,2,4-triazol-3-yl)-1-(7-fluoro-1-methyl-1H-imidazo[4,5-c]pyridin-4-yl)-N-(2-(trimethylsilyl)ethyl)propane-2-sulfonamide, Example 6.2. Potassium tert-butoxide (1.0 M in THF, 526 μL, 0.53 mmol) was added to a stirred solution of 6.1 (110 mg, 0.18 mmol) in THF. Iodomethane (11 μL, 0.18 mmol) was then added and the mixture was stirred for 16 h at RT. Thereafter, the mixture was diluted with 1 N aqueous HCl and extracted with EtOAc. The organic extracts were then combined, washed with brine, dried over Na 2 SO 4 , filtered, and concentrated in vacuo to afford 6.2 (101 mg, 0.16 mmol, 90%). LCMS-ESI (pos.) m/z: 642.3 (M+H) + .

(2S)—N-(4-(2,6-Dimethoxyphenyl)-5-(2-furanyl)-4H-1,2,4-triazol-3-yl)-1-(7-fluoro-1-methyl-1H-imidazo[4,5-c]pyridin-4-yl)-2-propanesulfonamide and (2R)—N-(4-(2,6-dimethoxyphenyl)-5-(2-furanyl)-4H-1,2,4-triazol-3-yl)-1-(7-fluoro-1-methyl-1H-imidazo[4,5-c]pyridin-4-yl)-2-propanesulfonamide, Example 6.3. Example 6.2 (70 mg, 0.11 mmol) was dissolved in DMF (0.5 mL). Tris(dimethylamino)sulfonium difluorotrimethylsilicate (commercially available from Sigma-Aldrich Corp., St. Louis, Mo., USA) (30 mg, 0.11 mmol) was added and the resulting mixture was stirred at 65° C. for 72 h. Thereafter, the mixture was cooled to RT and concentrated in vacuo. The residue was purified on a reverse-phase column employing a gradient of 10-70% ACN in water (0.1% TFA in both eluents) to afford Example 6.3 (43 mg, 0.067 mmol, 61%). 1 H NMR (400 MHz, CD 3 OD) δ 8.52 (s, 1H) 8.46 (d, J=4.11 Hz, 1H) 7.51-7.62 (m, 2H) 6.83 (d, J=8.61 Hz, 2H) 6.42 (dd, J=3.52, 1.76 Hz, 1H) 6.11 (d, J=3.52 Hz, 1H) 4.16 (s, 3H) 3.91 (d, J=7.04 Hz, 1H) 3.77 (m, 1H) 3.76 (app s, 6H) 3.54 (dd, J=14.48, 7.43 Hz, 1H) 1.32 (d, J=6.65 Hz, 3H). LCMS-ESI (pos.) m/z: 542.1 (M+H) + .

(2S)—N-(4-(2,6-Dimethoxyphenyl)-5-(2-furanyl)-4H-1,2,4-triazol-3-yl)-1-(7-fluoro-1-methyl-1H-imidazo[4,5-c]pyridin-4-yl)-2-propanesulfonamide or (2R)—N-(4-(2,6-dimethoxyphenyl)-5-(2-furanyl)-4H-1,2,4-triazol-3-yl)-1-(7-fluoro-1-methyl-1H-imidazo[4,5-c]pyridin-4-yl)-2-propanesulfonamide, Example 6.0. Purification of 6.3 by SFC [30×400 mm AD column with 35 g/min MeOH (20 mM NH 3 ) in 65 g/min CO 2 at 100 bar] afforded two enantiomers. The title compound Example 6.0 was the first isomer to elute under these conditions. 1 H NMR (400 MHz, CDCl 3 ) δ 8.20 (d, J=2.35 Hz, 1H) 7.87 (s, 1H) 7.40-7.49 (m, 2H) 6.66 (d, J=8.61 Hz, 2H) 6.32 (dd, J=3.62, 1.86 Hz, 1H) 5.96-6.00 (m, 1H) 4.04 (s, 3H) 3.87-3.95 (m, 1H) 3.79-3.87 (m, 1H) 3.77 (s, 3H) 3.72 (s, 3H) 3.28-3.40 (m, 1H) 1.31 (d, J=6.85 Hz, 3H). LCMS-ESI (pos.) m/z: 542.2 (M+H) + .

Example 7.0. Preparation of (2S)—N-(4-(4,6-dimethoxy-5-pyrimidinyl)-5-(5-methyl-2-furanyl)-4H-1,2,4-triazol-3-yl)-1-(5-fluoro-2-pyrimidinyl)-2-propanesulfonamide and (2R)—N-(4-(4,6-dimethoxy-5-pyrimidinyl)-5-(5-methyl-2-furanyl)-4H-1,2,4-triazol-3-yl)-1-(5-fluoro-2-pyrimidinyl)-2-propanesulfonamide

(2S)—N-(4-(4,6-Dimethoxy-5-pyrimidinyl)-5-(5-methyl-2-furanyl)-4H-1,2,4-triazol-3-yl)-1-(5-fluoro-2-pyrimidinyl)-2-propanesulfonamide and (2R)—N-(4-(4,6-dimethoxy-5-pyrimidinyl)-5-(5-methyl-2-furanyl)-4H-1,2,4-triazol-3-yl)-1-(5-fluoro-2-pyrimidinyl)-2-propanesulfonamide, Example 7.0. The title compound was prepared employing 5-methyl-2-furohydrazide (commercially available from Chembridge Corporation, San Diego, Calif., USA), Example 372.1, and Example 353.0 and the procedure described in the synthesis of Example 314.0 employing AcOH instead of TFA. 1 H NMR (400 MHz, CDCl 3 ) δ 8.52 (d, J=0.98 Hz, 2H) 6.26 (d, J=3.52 Hz, 1H) 6.03 (d, J=3.52 Hz, 1H) 3.98 (s, 3H) 3.96 (s, 3H) 3.81 (ddd, J=9.44, 6.80, 4.69 Hz, 1H) 3.69 (dd, J=14.67, 4.69 Hz, 1H) 3.09 (dd, J=14.87, 9.59 Hz, 1H) 1.33 (d, J=7.62 Hz, 3H). LCMS-ESI (pos.) m/z: 505.0 (M+H) + .

Example 8.0. Preparation of (2S)—N-(4-(2,6-dimethoxyphenyl)-5-(2-furanyl)-4H-1,2,4-triazol-3-yl)-1-(7-fluoro-1H-imidazo[4,5-c]pyridin-4-yl)-2-propanesulfonamide or (2R)—N-(4-(2,6-dimethoxyphenyl)-5-(2-furanyl)-4H-1,2,4-triazol-3-yl)-1-(7-fluoro-1H-imidazo[4,5-c]pyridin-4-yl)-2-propanesulfonamide

(2S)—N-(4-(2,6-Dimethoxyphenyl)-5-(2-furanyl)-4H-1,2,4-triazol-3-yl)-1-(7-fluoro-1H-imidazo[4,5-c]pyridin-4-yl)-2-propanesulfonamide or (2R)—N-(4-(2,6-dimethoxyphenyl)-5-(2-furanyl)-4H-1,2,4-triazol-3-yl)-1-(7-fluoro-1H-imidazo[4,5-c]pyridin-4-yl)-2-propanesulfonamide, Example 8.0. Further purification of 5.1 by SFC [30×250 mm AD-H column with 39 g/min MeOH (20 mM NH 3 ) in 31 g/min CO 2 at 100 bar] afforded the second enantiomer. The title compound, Example 8.0, was the second isomer to elute under these conditions. 1 H NMR (400 MHz, CD 3 OD) δ 1.22 (m, 3H) 3.33 (m, 2H) 3.73 (d, J=1.96 Hz, 6H) 3.81 (dd, J=10.56, 6.46 Hz, 1H) 6.12 (d, J=3.52 Hz, 1H) 6.43 (dd, J=3.52, 1.76 Hz, 1H) 6.82 (dd, J=8.51, 2.64 Hz, 2H) 7.50-7.63 (m, 2H) 8.17 (d, J=2.15 Hz, 1H) 8.37 (s, 1H). LCMS ESI (pos.) m/z: 528.1 (M+H) + .

Example 9.0. Preparation of N-(5-chloro-2-((2R)-2-((4-(2,6-dimethoxyphenyl)-5-(2-furanyl)-4H-1,2,4-triazol-3-yl)sulfamoyl)propyl)-3-pyridinyl)acetamide or N-(5-chloro-2-((2S)-2-((4-(2,6-dimethoxyphenyl)-5-(2-furanyl)-4H-1,2,4-triazol-3-yl)sulfamoyl)propyl)-3-pyridinyl)acetamide

(S)-1-(3-Bromo-5-chloropyridin-2-yl)-N-(4-(2,6-dimethoxyphenyl)-5-(furan-2-yl)-4H-1,2,4-triazol-3-yl)-N-(2-(trimethylsilyl)ethyl)propane-2-sulfonamide and (R)-1-(3-bromo-5-chloropyridin-2-yl)-N-(4-(2,6-dimethoxyphenyl)-5-(furan-2-yl)-4H-1,2,4-triazol-3-yl)-N-(2-(trimethylsilyl)ethyl)propane-2-sulfonamide, Example 9.1. To a solution of Example 366.0 (1.15 g, 1.871 mmol) in THF (5 mL) was added lithium bis(trimethylsilyl)amide, (1.0 M solution in THF, 2.2 mL, 2.20 mmol). After 15 min, 3-bromo-5-chloropicolinaldehyde (470 mg, 2.132 mmol) was added as a solution in THF (1 mL). The resulting reaction was stirred at RT overnight. The reaction was then quenched with water (0.5 mL), concentrated to dryness and dried under vacuum. The initial material was absorbed onto a plug of silica gel and purified by chromatography through a Redi-Sep pre-packed silica gel column eluting with a gradient of 0% to 100% EtOAc in hexanes. The two isolated isomers were combined and concentrated in vacuo to yield (E/Z)-1-(3-bromo-5-chloropyridin-2-yl)-N-(4-(2,6-dimethoxyphenyl)-5-(furan-2-yl)-4H-1,2,4-triazol-3-yl)-N-(2-(trimethylsilyl)ethyl)prop-1-ene-2-sulfonamide (726 mg). To a solution of the olefin intermediate in EtOH (5 mL) was added Raney 2800 nickel slurry in water (0.2 mL, 1.87 mmol). Hydrogen was then bubbled through the mixture for 1 min and then the mixture was stirred at RT under a hydrogen atmosphere for 8 h. The hydrogen balloon was then removed and the reaction was purged with nitrogen and left to stand overnight. The reaction was redissolved in DCM (2 mL) and the reaction was reinitiated by addition of more Raney 2800 nickel slurry in water (0.2 mL, 1.871 mmol). Hydrogen was then bubbled through the solution for 1 min and then the mixture was stirred at RT under a hydrogen atmosphere for 8 h. More Raney 2800 nickel slurry in water (0.2 mL, 1.871 mmol) was added, and the reaction was placed under an atmosphere of hydrogen and stirred for a further 3 h. The initial reaction mixture was then filtered through a plug of Celite® brand filter aid, the filter was rinsed with MeOH and DCM, and the filtrate was then concentrated to dryness. The initial material was absorbed onto a plug of silica gel and purified by chromatography through a Redi-Sep pre-packed silica gel column eluting with a gradient of 0% to 100% EtOAc in hexanes to provide the title compound (584 mg, 0.86 mmol, 46% yield) as a yellow foam. LCMS-ESI (pos.) m/z: 682.0 (M+H) + .

›EXAMPLES · 5 of 46

N-(5-Chloro-2-((2R)-2-((4-(2,6-dimethoxyphenyl)-5-(2-furanyl)-4H-1,2,4-triazol-3-yl)sulfamoyl)propyl)-3-pyridinyl)acetamide and N-(5-chloro-2-((2S)-2-((4-(2,6-dimethoxyphenyl)-5-(2-furanyl)-4H-1,2,4-triazol-3-yl)sulfamoyl)propyl)-3-pyridinyl)acetamide, Example 9.2. 1-(3-Bromo-5-chloropyridin-2-yl)-N-(4-(2,6-dimethoxyphenyl)-5-(furan-2-yl)-4H-1,2,4-triazol-3-yl)propane-2-sulfonamide (91 mg, 0.16 mmol) was combined with XantPhos (26 mg, 0.044 mmol), acetamide (33 mg, 0.56 mmol), cesium carbonate (103 mg, 0.32 mmol), and Pd 2 (dba) 3 (23 mg, 0.025 mmol) in a 10 mL microwave vial. Dioxane (0.5 mL) was then added. The mixture was heated in a microwave for 30 min at 120° C. under argon. The reaction was then filtered through a syringe filter, rinsed with DCM and MeOH, and then concentrated in vacuo. The material was purified by reverse-phase preparative HPLC using an Agilent SB C18 column, 0.1% TFA in ACN/H 2 O, gradient 10% to 60% over 25 min. The desired fractions were combined to give the title compound (52 mg, 0.092 mmol, 60% yield). 1 H NMR (500 MHz, CDCl 3 ) δ 1.48 (d, J=6.60 Hz, 3H), 2.14 (s, 3H), 3.18 (dd, J=14.92, 3.67 Hz, 1H), 3.32-3.41 (m, 1H) 3.44 (dt, J=6.85, 3.42 Hz, 1H), 3.72 (d, J=4.16 Hz, 6H), 5.95 (d, J=3.67 Hz, 1H), 6.33 (dd, J=3.55, 1.83 Hz, 1H), 6.67 (t, J=8.07 Hz, 2H), 7.40-7.48 (m, 1H), 7.52 (t, J=8.56 Hz, 1H), 8.34 (d, J=2.20 Hz, 1H), 8.60 (d, J=1.96 Hz, 1H), 9.13 (s, 1H). LCMS ESI (pos.) m/z: 561.1 (M+H) + .

N-(5-Chloro-2-((2R)-2-((4-(2,6-dimethoxyphenyl)-5-(2-furanyl)-4H-1,2,4-triazol-3-yl)sulfamoyl)propyl)-3-pyridinyl)acetamide or N-(5-chloro-2-((2S)-2-((4-(2,6-dimethoxyphenyl)-5-(2-furanyl)-4H-1,2,4-triazol-3-yl)sulfamoyl)propyl)-3-pyridinyl)acetamide, Example 9.0. The enantiomers in Example 9.2 were separated on an AD-H column (2×15 cm) eluting with 35% MeOH/CO 2 (with 20 mM NH 3 ), 100 bar, 65 mL/min. The first peak to elute on the AD column was Example 9.0 (13 mg, 0.023 mmol, 15% yield). 1 H NMR (500 MHz, CDCl 3 ) δ 1.45 (d, J=6.85 Hz, 3H) 2.10 (s, 3H) 2.99 (dd, J=14.67, 4.40 Hz, 1H) 3.24-3.35 (m, 1H) 3.36-3.45 (m, 1H) 3.71 (d, J=7.34 Hz, 6H) 5.93 (d, J=3.42 Hz, 1H) 6.33 (d, J=1.96 Hz, 1H) 6.66 (dd, J=11.86, 8.44 Hz, 2H) 7.46 (d, J=1.22 Hz, 1H) 7.51 (t, J=8.44 Hz, 1H) 8.16 (d, J=2.20 Hz, 1H) 8.24 (d, J=1.71 Hz, 1H) 8.64 (br. s., 1H). LCMS ESI (pos.) m/z: 561.1 (M+H) + .

Example 10.0. Preparation of (1S,2S)-1-(5-cyano-2-pyridinyl)-N-(4-(2,6-dimethoxyphenyl)-5-(5-methyl-2-furanyl)-4H-1,2,4-triazol-3-yl)-1-hydroxy-2-propanesulfonamide or (1R,2R)-1-(5-cyano-2-pyridinyl)-N-(4-(2,6-dimethoxyphenyl)-5-(5-methyl-2-furanyl)-4H-1,2,4-triazol-3-yl)-1-hydroxy-2-propanesulfonamide

(1R,2S)-1-(5-Bromopyridin-2-yl)-N-(4-(2,6-dimethoxyphenyl)-5-(5-methylfuran-2-yl)-4H-1,2,4-triazol-3-yl)-1-hydroxy-N-(2-(trimethylsilyl)ethyl)propane-2-sulfonamide and (1S,2R)-1-(5-bromopyridin-2-yl)-N-(4-(2,6-dimethoxyphenyl)-5-(5-methylfuran-2-yl)-4H-1,2,4-triazol-3-yl)-1-hydroxy-N-(2-(trimethylsilyl)ethyl)propane-2-sulfonamide or (1R,2R)-1-(5-bromopyridin-2-yl)-N-(4-(2,6-dimethoxyphenyl)-5-(5-methylfuran-2-yl)-4H-1,2,4-triazol-3-yl)-1-hydroxy-N-(2-(trimethylsilyl)ethyl)propane-2-sulfonamide and (1S,2S)-1-(5-bromopyridin-2-yl)-N-(4-(2,6-dimethoxyphenyl)-5-(5-methylfuran-2-yl)-4H-1,2,4-triazol-3-yl)-1-hydroxy-N-(2-(trimethylsilyl)ethyl)propane-2-sulfonamide, Example 10.1. To a stirred solution of N-(4-(2,6-dimethoxyphenyl)-5-(5-methylfuran-2-yl)-4H-1,2,4-triazol-3-yl)-N-(2-(trimethylsilyl)ethyl)ethanesulfonamide (Example 369.0, 403 mg, 0.82 mmol) in THF (3 mL) at −78° C. was added n-butyllithium (1.6 M solution in hexanes, 500 μL, 0.80 mmol) dropwise over 10 min. A solution of 5-bromopicolinaldehyde (183 mg, 0.984 mmol, Aldrich) in THF (1 mL) was then added dropwise over 5 min. The cooling bath was removed, and the reaction was warmed to RT overnight. The reaction was then quenched with a saturated aqueous NH 4 Cl solution and extracted twice with EtOAc. The organic layer was washed with brine and then concentrated in vacuo. The initial material was purified by reverse-phase preparative HPLC using an Agilent SB C8 column, 0.1% TFA in ACN/H 2 O, gradient 40% to 95% over 25 min. The desired fractions were lyophilized to give two fractions (syn and anti stereochemistry), the initial fraction from the column (81 mg, 0.12 mmol) and the second eluting fraction, the title compound Example 10.1 (130 mg, 0.192 mmol, 23%).

(1R,2R)-1-(5-Cyanopyridin-2-yl)-N-(4-(2,6-dimethoxyphenyl)-5-(5-methylfuran-2-yl)-4H-1,2,4-triazol-3-yl)-1-hydroxy-N-(2-(trimethylsilyl)ethyl)propane-2-sulfonamide and (1S,2S)-1-(5-cyanopyridin-2-yl)-N-(4-(2,6-dimethoxyphenyl)-5-(5-methylfuran-2-yl)-4H-1,2,4-triazol-3-yl)-1-hydroxy-N-(2-(trimethylsilyl)ethyl)propane-2-sulfonamide, Example 10.2. To a solution of 10.1 (130 mg, 0.16 mmol) in DMF (2 mL) was added tetrakis(triphenylphosphine)palladium(0) (46.3 mg, 0.040 mmol) and zinc cyanide (31.3 mg, 0.27 mmol). The resulting mixture was heated in a microwave for 60 min at 120° C. under argon. The material was then filtered through a syringe filter and then purified by reverse-phase preparative HPLC using an Agilent SB C8 column, 0.1% TFA in ACN/H 2 O, gradient 30% to 95% over 25 min. The desired fraction was lyophilized overnight to give the title compound Example 10.2 (44.3 mg, 0.071 mmol, 43% yield).

(1S,2S)-1-(5-Cyano-2-pyridinyl)-N-(4-(2,6-dimethoxyphenyl)-5-(5-methyl-2-furanyl)-4H-1,2,4-triazol-3-yl)-1-hydroxy-2-propanesulfonamide and (1R,2R)-1-(5-cyano-2-pyridinyl)-N-(4-(2,6-dimethoxyphenyl)-5-(5-methyl-2-furanyl)-4H-1,2,4-triazol-3-yl)-1-hydroxy-2-propanesulfonamide, Example 10.3. To a solution of 10.2 (44.3 mg, 0.060 mmol) in DMF (1 mL) was added tris(dimethylamino)sulfonium difluorotrimethylsilicate (80 mg, 0.290 mmol). The resulting solution was heated at 60° C. for 2 h under argon. The initial material was purified by reverse-phase preparative HPLC using an Agilent SB C8 column, 0.1% TFA in ACN/H 2 O, gradient 20% to 60% over 25 min. The desired fraction was lyophilized overnight to give Example 10.3 (9.2 mg, 0.014 mmol, 24.03% yield.

›EXAMPLES · 6 of 46

(1S,2S)-1-(5-Cyano-2-pyridinyl)-N-(4-(2,6-dimethoxyphenyl)-5-(5-methyl-2-furanyl)-4H-1,2,4-triazol-3-yl)-1-hydroxy-2-propanesulfonamide and (1R,2R)-1-(5-cyano-2-pyridinyl)-N-(4-(2,6-dimethoxyphenyl)-5-(5-methyl-2-furanyl)-4H-1,2,4-triazol-3-yl)-1-hydroxy-2-propanesulfonamide, Example 10.0. Chiral separation of Example 10.3 was performed using an IA column eluting with 25% MeOH/CO 2 , 100 bar, 80 mL/min. The first peak to elute on the IA column was the title compound, Example 10.0 (3.76 mg, 7.17 μmol, 12%) 1 H NMR (400 MHz, CD 3 OD) δ 1.08 (d, J=7.04 Hz, 3H) 2.26 (s, 3H) 3.63-3.72 (m, 1H) 3.76 (d, J=6.26 Hz, 6H) 5.41 (s, 1H) 5.96 (d, J=3.33 Hz, 1H) 6.02 (d, J=2.35 Hz, 1H) 6.85 (dd, J=8.51, 2.84 Hz, 2H) 7.56 (t, J=8.51 Hz, 1H) 7.73 (d, J=8.22 Hz, 1H) 8.16 (dd, J=8.22, 2.15 Hz, 1H) 8.85 (d, J=1.37 Hz, 1H). LCMS ESI (pos.) m/z: 525.1 (M+H) + .

Example 11.0. Preparation of (2R)-1-(5-chloro-2-pyridinyl)-N-(4-(2,6-dimethoxyphenyl)-5-(2-furanyl)-4H-1,2,4-triazol-3-yl)-2-propanesulfonamide or (2S)-1-(5-chloro-2-pyridinyl)-N-(4-(2,6-dimethoxyphenyl)-5-(2-furanyl)-4H-1,2,4-triazol-3-yl)-2-propanesulfonamide

Example 12.0. Preparation of (2R)-1-(5-cyano-2-pyridinyl)-N-(4-(2,6-dimethoxyphenyl)-5-(5-methyl-2-furanyl)-4H-1,2,4-triazol-3-yl)-2-propanesulfonamide or (2S)-1-(5-cyano-2-pyridinyl)-N-(4-(2,6-dimethoxyphenyl)-5-(5-methyl-2-furanyl)-4H-1,2,4-triazol-3-yl)-2-propanesulfonamide

(2R)-1-(5-Cyano-2-pyridinyl)-N-(4-(2,6-dimethoxyphenyl)-5-(5-methyl-2-furanyl)-4H-1,2,4-triazol-3-yl)-2-propanesulfonamide and (2S)-1-(5-cyano-2-pyridinyl)-N-(4-(2,6-dimethoxyphenyl)-5-(5-methyl-2-furanyl)-4H-1,2,4-triazol-3-yl)-2-propanesulfonamide, Example 12.1. To a solution of 1-(5-bromopyridin-2-yl)-N-(4-(2,6-dimethoxyphenyl)-5-(5-methylfuran-2-yl)-4H-1,2,4-triazol-3-yl)propane-2-sulfonamide (prepared using Example 367.0 and an analagous sulfonyl chloride prepared in a similar manner to that described in the preparation of 353.2 employing potassium (E)-propenyl-1-trifluoroborate (3.22 g, 21.8 mmol) and 2,5-dibromopyridine (4.75 g, 20.1 mmol) to prepare the requisite alkene) (104 mg, 0.184 mmol) in DMF (1.5 mL), was added tetrakis(triphenylphosphine)palladium(0) (62 mg, 0.054 mmol) and zinc cyanide (36 mg, 0.31 mmol). Argon was then bubbled through the mixture for one min and then the microwave vial was sealed. The resulting mixture was heated in a microwave for 1 h at 120° C. under argon. The reaction was then filtered and rinsed with MeOH and then concentrated in vacuo. The material thus obtained was purified by reverse-phase preparative HPLC using an Agilent SB C8 column, 0.1% TFA in ACN/H 2 O, gradient 10% to 70% over 25 min. The desired fraction was lyophilized to give Example 12.1 (35.6 mg, 0.070 mmol, 38.0% yield).

Example 13.0. Preparation of N-(5-chloro-2-((2S)-2-((4-(2,6-dimethoxyphenyl)-5-(2-furanyl)-4H-1,2,4-triazol-3-yl)sulfamoyl)propyl)-3-pyridinyl)acetamide and N-(5-chloro-2-((2R)-2-((4-(2,6-dimethoxyphenyl)-5-(2-furanyl)-4H-1,2,4-triazol-3-yl)sulfamoyl)propyl)-3-pyridinyl)acetamide

N-(5-Chloro-2-((2S)-2-((4-(2,6-dimethoxyphenyl)-5-(2-furanyl)-4H-1,2,4-triazol-3-yl)sulfamoyl)propyl)-3-pyridinyl)acetamide and N-(5-chloro-2-((2R)-2-((4-(2,6-dimethoxyphenyl)-5-(2-furanyl)-4H-1,2,4-triazol-3-yl)sulfamoyl)propyl)-3-pyridinyl)acetamide, Example 13.0. The title compound is described in Example 9.2 in the preparation of 9.0. 1 H NMR (500 MHz, CDCl 3 ) δ 9.13 (s, 1H) 8.60 (d, J=1.96 Hz, 1H) 8.34 (d, J=2.20 Hz, 1H) 7.52 (t, J=8.56 Hz, 1H) 7.40-7.48 (m, 1H) 6.67 (t, J=8.07 Hz, 2H) 6.33 (dd, J=3.55, 1.83 Hz, 1H) 5.95 (d, J=3.67 Hz, 1H) 3.72 (d, J=4.16 Hz, 6H) 3.44 (dt, J=6.85, 3.42 Hz, 1H) 3.32-3.41 (m, 1H) 3.18 (dd, J=14.92, 3.67 Hz, 1H) 2.14 (s, 3H) 1.48 (d, J=6.60 Hz, 3H). LCMS-ESI (pos.) m/z: 561.0 (M+H) + .

Example 14.0. Preparation of (2R)-1-(5-chloro-2-pyridinyl)-N-(4-(2,6-dimethoxyphenyl)-5-(2-furanyl)-4H-1,2,4-triazol-3-yl)-2-propanesulfonamide and (2S)-1-(5-chloro-2-pyridinyl)-N-(4-(2,6-dimethoxyphenyl)-5-(2-furanyl)-4H-1,2,4-triazol-3-yl)-2-propanesulfonamide

(2R)-1-(5-Chloro-2-pyridinyl)-N-(4-(2,6-dimethoxyphenyl)-5-(2-furanyl)-4H-1,2,4-triazol-3-yl)-2-propanesulfonamide and (2S)-1-(5-chloro-2-pyridinyl)-N-(4-(2,6-dimethoxyphenyl)-5-(2-furanyl)-4H-1,2,4-triazol-3-yl)-2-propanesulfonamide. To a solution of 1-(5-chloropyridin-2-yl)-N-(4-(2,6-dimethoxyphenyl)-5-(furan-2-yl)-4H-1,2,4-triazol-3-yl)-N-(2-(trimethylsilyl)ethyl)propane-2-sulfonamide (prepared in an analogous fashion using reactions described in Examples 4.5 and 4.6 employing Example 365.0 and 5-chloropicolinaldehyde (85 mg, 0.60 mmol) (92 mg, 0.152 mmol)) in DMF (0.5 mL) was added tris(dimethylamino)sulfonium difluorotrimethylsilicate (95 mg, 0.345 mmol). The resulting solution was heated at 60° C. for over 4 h. The reaction mixture was then cooled to RT. The material was purified by reverse-phase preparative HPLC using an Agilent SB C8 column, 0.1% TFA in ACN/H 2 O, gradient 10% to 70% over 25 min (collected the peaks that were visible at 220 nm). The desired fraction were lyophilized overnight to give the title compound Example 14.0. 1 H NMR (400 MHz, CDCl 3 ) δ 1.35 (d, J=6.85 Hz, 3H) 3.12 (dd, J=14.28, 6.85 Hz, 1H) 3.41-3.61 (m, 2H) 3.75 (d, J=5.67 Hz, 6H) 6.01 (dd, J=3.52, 0.59 Hz, 1H) 6.34 (dd, J=3.52, 1.76 Hz, 1H) 6.68 (dd, J=8.51, 2.64 Hz, 2H) 7.37-7.54 (m, 3H) 7.79 (dd, J=8.41, 2.35 Hz, 1H) 8.62 (d, J=2.35 Hz, 1H). LCMS ESI (pos.) m/z: 504.1 (M+H) + .

›EXAMPLES · 7 of 46

Example 15.0. Preparation of N-(2-((2R)-2-((4-(2,6-dimethoxyphenyl)-5-(2-furanyl)-4H-1,2,4-triazol-3-yl)sulfamoyl)propyl)-5-fluoro-3-pyridinyl)acetamide or N-(2-((2S)-2-((4-(2,6-dimethoxyphenyl)-5-(2-furanyl)-4H-1,2,4-triazol-3-yl)sulfamoyl)propyl)-5-fluoro-3-pyridinyl)acetamide

N-(2-((2R)-2-((4-(2,6-Dimethoxyphenyl)-5-(2-furanyl)-4H-1,2,4-triazol-3-yl)sulfamoyl)propyl)-5-fluoro-3-pyridinyl)acetamide or N-(2-((2S)-2-((4-(2,6-dimethoxyphenyl)-5-(2-furanyl)-4H-1,2,4-triazol-3-yl)sulfamoyl)propyl)-5-fluoro-3-pyridinyl)acetamide, Example 15.0. The enantiomers of Example 15.1 were separated on an AD-H column (2×15 cm) eluting with 30% MeOH/CO 2 (with 20 mM NH 3 ), 100 bar, 65 mL/min. The first peak to elute on the AD column was the title compound, Example 15.0 (31 mg, 0.056 mmol, 35% yield). 1 H NMR (500 MHz, CDCl 3 ) δ 1.46 (d, J=6.60 Hz, 3H) 2.12 (s, 3H) 3.00 (dd, J=14.55, 4.52 Hz, 1H) 3.27-3.45 (m, 2H) 3.72 (app s, 6H) 5.93 (d, J=3.42 Hz, 1H) 6.32 (dd, J=3.42, 1.71 Hz, 1H) 6.66 (dd, J=10.64, 8.68 Hz, 2H) 7.39-7.55 (m, 2H) 8.01-8.16 (m, 2H) 8.74 (br. s., 1H) 10.94 (br. s., 1H). LCMS ESI (pos.) m/z: 545.1 (M+H) + .

Example 16.0. Preparation of (2S)—N-(4-(2,6-dimethoxyphenyl)-5-(5-methyl-2-furanyl)-4H-1,2,4-triazol-3-yl)-1-(5-methyl-2-pyrimidinyl)-2-propanesulfonamide or (2R)—N-(4-(2,6-dimethoxyphenyl)-5-(5-methyl-2-furanyl)-4H-1,2,4-triazol-3-yl)-1-(5-methyl-2-pyrimidinyl)-2-propanesulfonamide

(2S)—N-(4-(2,6-Dimethoxyphenyl)-5-(5-methyl-2-furanyl)-4H-1,2,4-triazol-3-yl-1-(5-methyl-2-pyrimidinyl)-2-propanesulfonamide and (2R)—N-(4-(2,6-dimethoxyphenyl)-5-(5-methyl-2-furanyl)-4H-1,2,4-triazol-3-yl)-1-(5-methyl-2-pyrimidinyl)-2-propanesulfonamide, Example 16.1. The title compound was prepared in an analagous to that described in Example 7.0 employing 2-chloro-5-methylpyrimidine.

(2S)—N-(4-(2,6-Dimethoxyphenyl)-5-(5-methyl-2-furanyl)-4H-1,2,4-triazol-3-yl)-1-(5-methyl-2-pyrimidinyl)-2-propanesulfonamide or (2R)—N-(4-(2,6-dimethoxyphenyl)-5-(5-methyl-2-furanyl)-4H-1,2,4-triazol-3-yl)-1-(5-methyl-2-pyrimidinyl)-2-propanesulfonamide, Example 16.0. Purification of 16.1 by SFC [30×150 mm IA column with 35 g/min MeOH (neat) in 65 g/min CO 2 at 100 bar] afforded two enantiomers. The title compound, Example 16.0, was the first isomer to elute under these conditions. 1 H NMR (500 MHz, CDCl 3 ) δ 11.23 (br. s., 1H) 8.51 (s, 2H) 7.39-7.51 (m, 1H) 6.67 (dd, J=8.44, 3.30 Hz, 2H) 5.91 (d, J=2.69 Hz, 1H) 5.79 (d, J=3.42 Hz, 1H) 3.79-3.88 (m, 1H) 3.75 (d, J=11.00 Hz, 6H) 3.65 (dd, J=14.79, 4.77 Hz, 1H) 3.05 (dd, J=14.67, 9.54 Hz, 1H) 2.29 (s, 3H) 2.32 (s, 3H) 1.31 (d, J=6.85 Hz, 3H). LCMS-ESI (pos.) m/z: 499.0 (M+H) + .

Example 17.0. Preparation of 5-chloro-2-((2S)-2-((4-(2,6-dimethoxyphenyl)-5-(2-furanyl)-4H-1,2,4-triazol-3-yl)sulfamoyl)propyl)-3-pyridinecarboxamide or 5-chloro-2-((2R)-2-((4-(2,6-dimethoxyphenyl)-5-(2-furanyl)-4H-1,2,4-triazol-3-yl)sulfamoyl)propyl)-3-pyridinecarboxamide

(S)-1-(5-Chloro-3-cyanopyridin-2-yl)-N-(4-(2,6-dimethoxyphenyl)-5-(furan-2-yl)-4H-1,2,4-triazol-3-yl)-N-(2-(trimethylsilyl)ethyl)propane-2-sulfonamide and (R)-1-(5-chloro-3-cyanopyridin-2-yl)-N-(4-(2,6-dimethoxyphenyl)-5-(furan-2-yl)-4H-1,2,4-triazol-3-yl)-N-(2-(trimethylsilyl)ethyl)propane-2-sulfonamide, Example 17.1. The title compound was prepared employing Example 9.1 following the method described in Example 359.1. LCMS-ESI (pos.) m/z: 629.0 (M+H) + .

(S)-5-Chloro-2-(2-(N-(4-(2,6-dimethoxyphenyl)-5-(furan-2-yl)-4H-1,2,4-triazol-3-yl)-N-(2-(trimethylsilyl)ethyl)sulfamoyl)propyl)nicotinamide and (R)-5-chloro-2-(2-(N-(4-(2,6-dimethoxyphenyl)-5-(furan-2-yl)-4H-1,2,4-triazol-3-yl)-N-(2-(trimethylsilyl)ethyl)sulfamoyl)propyl)nicotinamide, Example 17.3. Hydrogen peroxide (30%/water, 0.1 mL, 0.98 mmol) was added to a solution of 17.1 (170 mg, 0.23 mmol) and potassium carbonate (46 mg, 0.33 mmol) in DMSO (1 mL) at 0° C. The reaction vessel was then removed from the cooling bath and stirred until LCMS analysis indicated that the transformation was complete (2 h). Thereafter, the mixture was acidified to pH 3 with 1 N aqueous HCl and diluted with MeOH until all solids dissolved. The initial material obtained was purified on a reverse-phase column employing a gradient of 30-60% ACN in water (0.1% TFA in both eluents) to afford Example 17.2. LCMS-ESI (pos.) m/z: 647.0 (M+H) + .

5-Chloro-2-((2S)-2-((4-(2,6-dimethoxyphenyl)-5-(2-furanyl)-4H-1,2,4-triazol-3-yl)sulfamoyl)propyl)-3-pyridinecarboxamide and 5-chloro-2-((2R)-2-((4-(2,6-dimethoxyphenyl)-5-(2-furanyl)-4H-1,2,4-triazol-3-yl)sulfamoyl)propyl)-3-pyridinecarboxamide, Example 17.3. Example 17.2 (128 mg, 0.17 mmol) was azeotroped with benzene (2×) and then dissolved in DMF (1 mL). Tris(dimethylamino)sulfonium difluorotrimethylsilicate (commercially available from Sigma-Aldrich Corp., St. Louis, Mo., USA) (170 mg, 0.62 mmol) was added and the resulting mixture was stirred at 60° C. for 4.5 h. Thereafter, the mixture was cooled to RT and concentrated in vacuo. The residue was purified on a reverse-phase column employing a gradient of 10-70% ACN in water (0.1% TFA in both eluents, to afford Example 17.3 (81 mg, 0.12 mmol, 73%). LCMS-ESI (pos.) m/z: 547.0 (M+H) + .

5-Chloro-2-((2S)-2-((4-(2,6-dimethoxyphenyl)-5-(2-furanyl)-4H-1,2,4-triazol-3-yl)sulfamoyl)propyl)-3-pyridinecarboxamide or 5-chloro-2-((2R)-2-((4-(2,6-dimethoxyphenyl)-5-(2-furanyl)-4H-1,2,4-triazol-3-yl)sulfamoyl)propyl)-3-pyridinecarboxamide, Example 17.0. Purification of Example 17.3 by SFC [20×250 mm AD-H column with 35% EtOH (neat) in CO 2 at 100 bar] afforded two enantiomers. The title compound was the first isomer to elute under these conditions. 1 H NMR (500 MHz, CD 3 OD) δ 8.58 (d, J=2.44 Hz, 1H) 7.85 (d, J=2.45 Hz, 1H) 7.60 (d, J=1.22 Hz, 1H) 7.56 (t, J=8.56 Hz, 1H) 6.85 (dd, J=8.56, 3.91 Hz, 2H) 6.43 (dd, J=3.67, 1.71 Hz, 1H) 6.13 (d, J=3.42 Hz, 1H) 3.78 (d, J=3.18 Hz, 6H) 3.74 (m, J=4.40 Hz, 1H) 3.59 (dd, J=14.55, 4.28 Hz, 1H) 3.06 (dd, J=14.55, 9.90 Hz, 1H) 1.22 (d, J=6.85 Hz, 3H). LCMS-ESI (pos.) m/z: 547.0 (M+H) + .

›EXAMPLES · 8 of 46

Example 18.0. Preparation of (2S)-1-(5-chloro-3-cyano-2-pyridinyl)-N-(4-(2,6-dimethoxyphenyl)-5-(2-furanyl)-4H-1,2,4-triazol-3-yl)-2-propanesulfonamide and (2R)-1-(5-chloro-3-cyano-2-pyridinyl)-N-(4-(2,6-dimethoxyphenyl)-5-(2-furanyl)-4H-1,2,4-triazol-3-yl)-2-propanesulfonamide

(R)-1-(3-Bromo-5-chloropyridin-2-yl)-N-(4-(2,6-dimethoxyphenyl)-5-(furan-2-yl)-4H-1,2,4-triazol-3-yl)propane-2-sulfonamide and (S)-1-(3-bromo-5-chloropyridin-2-yl)-N-(4-(2,6-dimethoxyphenyl)-5-(furan-2-yl)-4H-1,2,4-triazol-3-yl)propane-2-sulfonamide, Example 18.1. The title compound was prepared employing Example 9.1 and the procedure described in the synthesis of Example 4.0. LCMS-ESI (pos.) m/z: 582.0 (M+H) + .

(2S)-1-(5-Chloro-3-cyano-2-pyridinyl)-N-(4-(2,6-dimethoxyphenyl)-5-(2-furanyl)-4H-1,2,4-triazol-3-yl)-2-propanesulfonamide and (2R)-1-(5-chloro-3-cyano-2-pyridinyl)-N-(4-(2,6-dimethoxyphenyl)-5-(2-furanyl)-4H-1,2,4-triazol-3-yl)-2-propanesulfonamide, Example 18.0. The title compound was prepared employing Example 18.1 and the procedure described in the synthesis of Example 50.0. 1 H NMR (500 MHz, CDCl 3 ) δ 8.68 (d, J=2.20 Hz, 1H) 7.87 (d, J=2.20 Hz, 1H) 7.39-7.52 (m, 2H) 6.69 (t, J=8.44 Hz, 2H) 6.29-6.37 (m, 1H) 6.00 (d, J=3.67 Hz, 1H) 3.78-3.85 (m, 1H) 3.76 (d, J=4.40 Hz, 6H) 3.69 (dd, J=14.92, 4.89 Hz, 1H) 3.14 (dd, J=15.04, 8.93 Hz, 1H) 1.32 (d, J=6.85 Hz, 3H). LCMS-ESI (pos.) m/z: 529.0 (M+H) + .

Example 19.0. Preparation of 2-(5-cyano-2-pyridinyl)-N-(4-(2,6-dimethoxyphenyl)-5-(5-methyl-2-furanyl)-4H-1,2,4-triazol-3-yl)ethanesulfonamide

2-(5-Bromopyridin-2-yl)ethanesulfonyl fluoride, Example 19.1. Example 19.1 was prepared employing 2-(5-bromopyridin-2-yl)ethanesulfonic acid (prepared following conditions described in Example 352.2 employing 2,5-dibromopyridine) and following the conditions described in Example 24.0.

2-(5-Cyano-2-pyridinyl)-N-(4-(2,6-dimethoxyphenyl)-5-(5-methyl-2-furanyl)-4H-1,2,4-triazol-3-yl)ethanesulfonamide, Example 19.0. To a solution of 2-(5-bromopyridin-2-yl)-N-(4-(2,6-dimethoxyphenyl)-5-(5-methylfuran-2-yl)-4H-1,2,4-triazol-3-yl)ethanesulfonamide 2,2,2-trifluoroacetate (112 mg, 0.169 mmol, prepared in an analogous fashion to that described in Example 24.0) in DMF (2 mL) was added tetrakis(triphenylphosphine)palladium(0) (37.5 mg, 0.032 mmol) and dicyanozinc (32.6 mg, 0.278 mmol). Argon was bubbled through the mixture for one min and then the microwave vial was sealed. The resulting mixture was heated in a microwave for 30 min at 120° C. under argon. Tetrakis(triphenylphosphine)palladium(0) (37.5 mg, 0.032 mmol) and dicyanozinc (32.6 mg, 0.278 mmol) were then added to the reaction mixture and argon was bubbled through the mixture for 1 min. The mixture was then heated at 120° C. for another 30 min. The reaction mixture was then filtered through a syringe filter and purified by reverse-phase preparative HPLC using a Phenomenex Gemini 10u C18, 250×30 mm column, 0.1% TFA in ACN/H 2 O, gradient 10% to 70% over 21 min. The desired fraction were lyophilized over the weekend. The material was absorbed onto a plug of silica gel and purified by chromatography through a Redi-Sep pre-packed silica gel column (4 g) eluting with a gradient of 0% to 100% EtOAc in DCM to give Example 19.0 (27.3 mg, 0.055 mmol, 33% yield). 1 H NMR (400 MHz, CDCl 3 ) δ 2.32 (s, 3H) 3.26-3.40 (m, 2H) 3.43-3.54 (m, 2H) 3.74 (app s, 6H) 5.81 (d, J=3.52 Hz, 1H) 5.92 (dd, J=3.42, 0.88 Hz, 1H) 6.68 (d, J=8.61 Hz, 2H) 7.32 (d, J=8.22 Hz, 1H) 7.47 (t, J=8.51 Hz, 1H) 7.85 (dd, J=8.02, 2.15 Hz, 1H) 8.78 (d, J=1.37 Hz, 1H) 10.86 (s, 1H). LCMS ESI (pos.) m/z: 495.1 (M+H) + .

Example 20.0. Preparation of (2R)-1-(5-chloro-3-cyano-2-pyridinyl)-N-(4-(2,6-dimethoxyphenyl)-5-(2-furanyl)-4H-1,2,4-triazol-3-yl)-2-propanesulfonamide or (2S)-1-(5-chloro-3-cyano-2-pyridinyl)-N-(4-(2,6-dimethoxyphenyl)-5-(2-furanyl)-4H-1,2,4-triazol-3-yl)-2-propanesulfonamide

(2R)-1-(5-Chloro-3-cyano-2-pyridinyl)-N-(4-(2,6-dimethoxyphenyl)-5-(2-furanyl)-4H-1,2,4-triazol-3-yl)-2-propanesulfonamide or (2S)-1-(5-chloro-3-cyano-2-pyridinyl)-N-(4-(2,6-dimethoxyphenyl)-5-(2-furanyl)-4H-1,2,4-triazol-3-yl)-2-propanesulfonamide, Example 20.0. Example 18.0 was purified on an AD-H column eluting with 30% MeOH/100 bar CO 2 45 mins to isolate the first peak as the title compound (19 mg, 0.036 mmol, 26% yield). 1 H NMR (500 MHz, CDCl 3 ) δ 1.32 (d, J=6.85 Hz, 3H) 3.14 (dd, J=15.04, 8.93 Hz, 1H) 3.70 (dd, J=14.92, 4.89 Hz, 1H) 3.76 (d, J=4.40 Hz, 6H) 3.78-3.85 (m, 1H) 6.00 (d, J=3.42 Hz, 1H) 6.33 (dd, J=3.42, 1.71 Hz, 1H) 6.69 (t, J=8.19 Hz, 2H) 7.43-7.51 (m, 2H) 7.87 (d, J=2.45 Hz, 1H) 8.68 (d, J=2.44 Hz, 1H). LCMS ESI (pos.) m/z: 529.1 (M+H) + .

Example 21.0. Preparation of 5-chloro-2-((2R)-2-((4-(2,6-dimethoxyphenyl)-5-(2-furanyl)-4H-1,2,4-triazol-3-yl)sulfamoyl)propyl)-N,N-diethyl-3-pyridinecarboxamide or 5-chloro-2-((2S)-2-((4-(2,6-dimethoxyphenyl)-5-(2-furanyl)-4H-1,2,4-triazol-3-yl)sulfamoyl)propyl)-N,N-diethyl-3-pyridinecarboxamide

(R)-5-Chloro-2-(2-(N-(4-(2,6-dimethoxyphenyl)-5-(furan-2-yl)-4H-1,2,4-triazol-3-yl)-N-(2-(trimethylsilyl)ethyl)sulfamoyl)propyl)nicotinic acid and (S)-5-chloro-2-(2-(N-(4-(2,6-dimethoxyphenyl)-5-(furan-2-yl)-4H-1,2,4-triazol-3-yl)-N-(2-(trimethylsilyl)ethyl)sulfamoyl)propyl)nicotinic acid, Example 21.1. To a solution of Example 9.1 (101 mg, 0.148 mmol) in THF (1 mL) was added isopropylmagnesium chloride, (2.0 M in THF, 0.2 mL, 0.400 mmol). The reaction mixture was allowed to stir at RT for 1.45 h. The reaction was cooled to 0° C. and then carbon dioxide gas was bubbled into the vial for 35 min. The reaction was concentrated in vacuo. The initial material obtained was purified by reverse-phase preparative HPLC using an Agilent SB C8 column, 0.1% TFA in ACN/H 2 O, gradient 40% to 70% over 25 min. The desired fraction was lyophilized overnight to give the title compound (47.3 mg, 0.073 mmol, 49% yield). 1 H NMR 500 MHz, CDCl 3 ) δ 0.03-0.16 (m, 9H) 1.38-1.48 (m, 2H) 2.16-2.23 (m, 3H) 3.70 (apps, 6H) 4.38-4.45 (m, 2H) 5.94 (d, J=3.42 Hz, 1H) 6.32 (dd, J=3.42, 1.71 Hz, 1H) 6.57 (d, J=8.56 Hz, 2H) 7.33 (t, J=8.44 Hz, 1H) 7.48 (d, J=1.22 Hz, 1H) 7.78 (s, 1H) 8.21 (d, J=2.45 Hz, 1H) 8.67 (d, J=2.44 Hz, 1H).

›EXAMPLES · 9 of 46

(R)-5-Chloro-2-(2-(N-(4-(2,6-dimethoxyphenyl)-5-(furan-2-yl)-4H-1,2,4-triazol-3-yl)-N-(2-(trimethylsilyl)ethyl)sulfamoyl)propyl)-N,N-diethylnicotinamide compound with (S)-5-chloro-2-(2-(N-(4-(2,6-dimethoxyphenyl)-5-(furan-2-yl)-4H-1,2,4-triazol-3-yl)-N-(2-(trimethylsilyl)ethyl)sulfamoyl)propyl)-N,N-diethylnicotinamide, Example 21.2. To a solution of Example 21.2 (47.3 mg, 0.073 mmol) in DCM (1.0 mL) was added Hunig's base (40 μL, 0.229 mmol) and HTBU (52.8 mg, 0.139 mmol). After 40 min, DEA (40 μL, 0.387 mmol) was added, and the reaction was stirred at RT for 30 mins. The reaction was then concentrated in vacuo. The initial material was purified by reverse-phase preparative HPLC using an Agilent SB C8 column, 0.1% TFA in ACN/H 2 O, gradient 40% to 70% over 25 min. The desired fractions were lyophilized to give the title compound, Example 21.2 (38 mg, 0.055 mmol, 75% yield).

5-Chloro-2-((2R)-2-((4-(2,6-dimethoxyphenyl)-5-(2-furanyl)-4H-1,2,4-triazol-3-yl)sulfamoyl)propyl)-N,N-diethyl-3-pyridinecarboxamide or 5-chloro-2-((2S)-2-((4-(2,6-dimethoxyphenyl)-5-(2-furanyl)-4H-1,2,4-triazol-3-yl)sulfamoyl)propyl)-N,N-diethyl-3-pyridinecarboxamide, Example 21.0. To a solution of Example 21.2 (38.4 mg, 0.055 mmol) in DMF (0.5 mL) was added tris(dimethylamino)sulfonium difluorotrimethylsilicate (65 mg, 0.236 mmol). The resulting solution was heated at 60° C. for 4 h. The reaction was then cooled to RT. The initial material was purified by reverse-phase preparative HPLC using an Agilent SB C8 column, 0.1% TFA in ACN/H 2 O, gradient 10% to 80% over 25 min. The desired fractions were lyophilized to give the racemic product (28 mg, 0.046 mmol, 84% yield). Chiral separation was performed using an IC column eluting with 40% MeOH/CO 2 , 100 bar, 60 mL/min. The second peak to elute on the IC column was Example 21.0 (8.0 mg, 0.013 mmol, 24% yield) was isolated. 1 H NMR (500 MHz, CDCl 3 ) δ 1.08 (br. s., 3H) 1.21 (br. s., 2H) 1.30 (d, J=6.85 Hz, 3H) 1.67 (br. s., 1H) 2.86 (br. s., 1H) 3.14 (br. s., 2H) 3.23-3.53 (m, 2H) 3.62 (br. s., 1H) 3.74 (br. s., 6H) 3.97 (br. s., 1H) 5.97 (d, J=3.42 Hz, 1H) 6.24-6.36 (m, 1H) 6.66 (d, J=8.56 Hz, 2H) 7.38-7.60 (m, 3H) 8.52 (d, J=1.22 Hz, 1H) 11.06 (br. s., 1H). LCMS ESI (pos.) m/z: 603.1 (M+H) + .

Example 22.0. Preparation of (2S)-1-(5-bromo-2-pyrimidinyl)-N-(4-(2,6-dimethoxyphenyl)-5-(2-furanyl)-4H-1,2,4-triazol-3-yl)-2-propanesulfonamide or (2R)-1-(5-bromo-2-pyrimidinyl)-N-(4-(2,6-dimethoxyphenyl)-5-(2-furanyl)-4H-1,2,4-triazol-3-yl)-2-propanesulfonamide

1-(5-Bromopyrimidin-2-yl)propane-2-sulfonyl chloride, Example 22.1. The title compound was prepared employing 5-bromo-2-iodopyrimidine (commercially available from Oakwood Chemical, West Columbia, S.C., USA) following the general procedure described in Example 72.0. LCMS-ESI (pos.) m/z: 298.9 (M+H) + .

(2S)-1-(5-Bromo-2-pyrimidinyl)-N-(4-(2,6-dimethoxyphenyl)-5-(2-furanyl)-4H-1,2,4-triazol-3-yl)-2-propanesulfonamide and (2R)-1-(5-bromo-2-pyrimidinyl)-N-(4-(2,6-dimethoxyphenyl)-5-(2-furanyl)-4H-1,2,4-triazol-3-yl)-2-propanesulfonamide, Example 22.2. The title compound was prepared employing Example 22.1 and Example 362.03 and the procedure described in Example 111.0. LCMS-ESI (pos.) m/z: 548.9 (M+H) + .

(2S)-1-(5-Bromo-2-pyrimidinyl)-N-(4-(2,6-dimethoxyphenyl)-5-(2-furanyl)-4H-1,2,4-triazol-3-yl)-2-propanesulfonamide or (2R)-1-(5-bromo-2-pyrimidinyl)-N-(4-(2,6-dimethoxyphenyl)-5-(2-furanyl)-4H-1,2,4-triazol-3-yl)-2-propanesulfonamide, Example 22.0. Purification of Example 22.2 by SFC [30×150 mm IA column with 28 g/min MeOH (neat) in 52 g/min CO 2 at 100 bar] afforded two enantiomers. The title compound was the first isomer to elute under these conditions. 1 H NMR (500 MHz, CDCl 3 ) δ 11.07 (br. s., 1H) 8.72 (s, 2H) 7.33-7.63 (m, 2H) 6.68 (d, J=6.36 Hz, 2H) 6.33 (br. s., 1H) 6.00 (d, J=3.18 Hz, 1H) 3.80 (m, J=3.18 Hz, 1H) 3.75 (d, J=9.29 Hz, 6H) 3.65 (dd, J=14.92, 4.16 Hz, 1H) 3.03 (dd, J=14.92, 9.78 Hz, 1H) 1.31 (d, J=6.60 Hz, 3H). LCMS-ESI (pos.) m/z: 548.9 (M+H) + .

Example 23.0. Preparation of (2R)-1-(5-bromo-2-pyridinyl)-N-(4-(2,6-dimethoxyphenyl)-5-(2-furanyl)-4H-1,2,4-triazol-3-yl)-2-propanesulfonamide or (2S)-1-(5-bromo-2-pyridinyl)-N-(4-(2,6-dimethoxyphenyl)-5-(2-furanyl)-4H-1,2,4-triazol-3-yl)-2-propanesulfonamide

(2R)-1-(5-Bromo-2-pyridinyl)-N-(4-(2,6-dimethoxyphenyl)-5-(2-furanyl)-4H-1,2,4-triazol-3-yl)-2-propanesulfonamide or (2S)-1-(5-bromo-2-pyridinyl)-N-(4-(2,6-dimethoxyphenyl)-5-(2-furanyl)-4H-1,2,4-triazol-3-yl)-2-propanesulfonamide, Example 23.0. Chiral separation was performed with an IA column eluting with 24% MeOH/CO 2 , 100 bar, 60 mL/min. The second peak to elute on the IA column was the title compound (10.0 mg, 0.018 mmol, 4% yield). 1 H NMR (500 MHz, CDCl 3 ) δ 1.27 (d, J=6.85 Hz, 3H) 2.85 (dd, J=13.94, 9.78 Hz, 1H) 3.45-3.54 (m, 1H) 3.55-3.64 (m, 1H) 3.74 (d, J=5.38 Hz, 6H) 5.99 (d, J=3.67 Hz, 1H) 6.33 (dd, J=3.55, 1.83 Hz, 1H) 6.67 (d, J=8.31 Hz, 2H) 7.10 (d, J=8.31 Hz, 1H) 7.33-7.54 (m, 2H) 7.74 (dd, J=8.31, 2.20 Hz, 1H) 8.59 (s, 1H) 11.03 (br. s., 1H). LCMS ESI (pos.) m/z: 547.1 (M+H) + .

Example 24.0. Preparation of (2R)—N-(4-(2,6-dimethoxyphenyl)-5-(5-methyl-2-furanyl)-4H-1,2,4-triazol-3-yl)-1-(5-methyl-2-pyrazinyl)-2-propanesulfonamide or (2S)—N-(4-(2,6-dimethoxyphenyl)-5-(5-methyl-2-furanyl)-4H-1,2,4-triazol-3-yl)-1-(5-methyl-2-pyrazinyl)-2-propanesulfonamide

(2R)—N-(4-(2,6-Dimethoxyphenyl)-5-(5-methyl-2-furanyl)-4H-1,2,4-triazol-3-yl)-1-(5-methyl-2-pyrazinyl)-2-propanesulfonamide or (2S)—N-(4-(2,6-dimethoxyphenyl)-5-(5-methyl-2-furanyl)-4H-1,2,4-triazol-3-yl)-1-(5-methyl-2-pyrazinyl)-2-propanesulfonamide, Example 24.0. To a suspension of 1-(5-methylpyrazin-2-yl)propane-2-sulfonic acid (284 mg, 1.313 mmol) in DCM (5 mL) was added DAST (0.2 mL, 1.514 mmol, 1.15 eq). The reaction was stirred at RT for 4 h. The reaction was then concentrated to dryness, azeotroped twice with benzene, and then dried under high vacuum. To a suspension of 4-(2,6-dimethoxyphenyl)-5-(5-methylfuran-2-yl)-4H-1,2,4-triazol-3-amine, Example 367.0 (200 mg, 0.666 mmol), in THF (5 mL) was added potassium bis(trimethylsilyl)amide solution in THF (1.0 M, 2 mL, 2.0 mmol). The brown solution was stirred at RT for 2 h. The sulfonyl fluoride in 4 mL THF (4 mL) was then added dropwise to the solution of Example 367.0 over 2 min. The resulting brown solution was stirred at RT overnight. The reaction was quenched with water (0.2 mL) and concentrated to dryness. The initial material was purified by reverse-phase preparative HPLC using a Phenomenex Gemini 10u C18, 250×50 mm column. The mobile phase was 0.1% TFA in ACN/H 2 O and the gradient was 20-60% for 26 min. The desired fraction were lyophilized overnight to give (2S)—N-(4-(2,6-dimethoxyphenyl)-5-(5-methyl-2-furanyl)-4H-1,2,4-triazol-3-yl)-1-(5-methyl-2-pyrazinyl)-2-propanesulfonamide and (2R)—N-(4-(2,6-dimethoxyphenyl)-5-(5-methyl-2-furanyl)-4H-1,2,4-triazol-3-yl)-1-(5-methyl-2-pyrazinyl)-2-propanesulfonamide (35 mg, 0.071 mmol, 11% yield). Chiral separation was performed with an AD-H column eluting with 35% MeOH/CO 2 , 100 bar, 60 mL/min. The second peak to elute on the AD-H column was (2S)—N-(4-(2,6-dimethoxyphenyl)-5-(5-methyl-2-furanyl)-4H-1,2,4-triazol-3-yl)-1-(5-methyl-2-pyrazinyl)-2-propanesulfonamide or (2R)—N-(4-(2,6-dimethoxyphenyl)-5-(5-methyl-2-furanyl)-4H-1,2,4-triazol-3-yl)-1-(5-methyl-2-pyrazinyl)-2-propanesulfonamide (12 mg, 0.024 mmol, 4% yield). 1 H NMR (500 MHz, CDCl 3 ) δ 1.26 (d, J=6.60 Hz, 3H) 2.32 (s, 3H) 2.55 (s, 3H) 2.85 (dd, J=13.82, 9.90 Hz, 1H) 3.46-3.55 (m, 1H) 3.57 (ddd, J=10.21, 6.66, 4.16 Hz, 1H) 3.75 (d, J=3.91 Hz, 6H) 5.80 (d, J=3.42 Hz, 1H) 5.86-5.97 (m, 1H) 6.68 (dd, J=8.56, 1.47 Hz, 2H) 7.47 (t, J=8.56 Hz, 1H) 8.32 (s, 1H) 8.40 (s, 1H) 10.93 (br. s., 1H). LCMS ESI (pos.) m/z: 499.2 (M+H) + .

›EXAMPLES · 10 of 46

Example 25.0. Preparation of (2R)—N-(4-(2,6-dimethoxyphenyl)-5-(2-furanyl)-4H-1,2,4-triazol-3-yl)-1-(5-fluoro-2-pyridinyl)-2-propanesulfonamide or (2S)—N-(4-(2,6-dimethoxyphenyl)-5-(2-furanyl)-4H-1,2,4-triazol-3-yl)-1-(5-fluoro-2-pyridinyl)-2-propanesulfonamide

(2R)—N-(4-(2,6-Dimethoxyphenyl)-5-(2-furanyl)-4H-1,2,4-triazol-3-yl)-1-(5-fluoro-2-pyridinyl)-2-propanesulfonamide or (2S)—N-(4-(2,6-dimethoxyphenyl)-5-(2-furanyl)-4H-1,2,4-triazol-3-yl)-1-(5-fluoro-2-pyridinyl)-2-propanesulfonamide, Example 25.0. Following the procedure described in Example 34.0 employing Example 365.0 and 5-fluoropicolinaldehyde delivered the racemic title compound. The first peak to elute on an AD-H column eluted with 35% IPA/65% hexanes isocratic for 45 mins was Example 25.0 (15.2 mg, 0.031 mmol, 27.6% yield). 1 H NMR (500 MHz, CDCl 3 ) δ 1.27 (d, J=6.85 Hz, 3H) 2.87 (dd, J=13.82, 9.66 Hz, 1H) 3.47-3.63 (m, 2H) 3.74 (d, J=5.38 Hz, 6H) 5.99 (d, J=3.67 Hz, 1H) 6.33 (dd, J=3.55, 1.83 Hz, 1H) 6.67 (dd, J=8.44, 1.34 Hz, 2H) 7.17 (dd, J=8.56, 4.16 Hz, 1H) 7.32 (td, J=8.31, 2.93 Hz, 1H) 7.42-7.51 (m, 2H) 8.39 (d, J=2.69 Hz, 1H) 11.03 (br. s., 1H). LCMS ESI (pos.) m/z: 488.1 (M+H) + .

Example 26.0. Preparation of N-(4-(2,6-dimethoxyphenyl)-5-(5-methyl-2-furanyl)-4H-1,2,4-triazol-3-yl)-2-(5-methyl-2-pyrimidinyl)ethanesulfonamide

N-(4-(2,6-Dimethoxyphenyl)-5-(5-methyl-2-furanyl)-4H-1,2,4-triazol-3-yl)-2-(5-methyl-2-pyrimidinyl)ethanesulfonamide, Example 26.0. To a 0° C. suspension of 2-(5-methylpyrimidin-2-yl)ethanesulfonic acid (394 mg, 1.95 mmol, prepared in an analagous manner to that described in Example 352.2 employing 2-chloro-5-methylpyrimidine) in DCM (10 mL) was added oxalyl chloride (215 μL, 2.46 mmol, 1.26 eq), followed by DMF (1 drop). The reaction was stirred over 2 h and then the reaction was concentrated to dryness, azeotroped twice with benzene, and then dried under high vacuum. To a 0° C. suspension of 4-(2,6-dimethoxyphenyl)-5-(5-methylfuran-2-yl)-4H-1,2,4-triazol-3-amine (Example 367.0, 157 mg, 0.52 mmol) in THF (5 mL) was added potassium bis(trimethylsilyl)amide (1 M solution in THF, 1.6 mL, 1.60 mmol). The reaction was stirred at 0° C. for 2 h. The amino triazole solution (still at 0° C.) was added to a 0° C. suspension of the sulfonyl chloride intermediate in THF (5 mL) dropwise over 2 min. Once the addition was complete, the cooling bath was removed and the brown mixture was warmed to RT. The reaction was quenched with water (0.5 mL) and then concentrated down to an oil. The oil was then redissolved using water and MeOH. The material thus obtained was purified by reverse-phase preparative HPLC using an Agilent SB C8 column, 0.1% TFA in ACN/H 2 O, gradient 10% to 50% over 25 min. The desired fractions were lyophilized over the weekend to give N-(4-(2,6-dimethoxyphenyl)-5-(5-methyl-2-furanyl)-4H-1,2,4-triazol-3-yl)-2-(5-methyl-2-pyrimidinyl)ethanesulfonamide, Example 26.0 (55 mg, 22% yield). 1 H NMR (500 MHz, CDCl 3 ) δ 2.32 (s, 3H) 2.35 (s, 3H) 3.37-3.51 (m, 2H) 3.56-3.66 (m, 2H) 3.75 (app s, 6H) 5.82 (d, J=3.42 Hz, 1H) 5.92 (dd, J=3.42, 0.98 Hz, 1H) 6.67 (d, J=8.56 Hz, 2H) 7.46 (t, J=8.56 Hz, 1H) 8.62 (s, 2H). LCMS ESI (pos.) m/z: 485.1 (M+H) + .

Example 27.0. Preparation of 2-(5-chloro-3-(2-oxo-1-azetidinyl)-2-pyridinyl)-N-(4-(2,6-dimethoxyphenyl)-5-(2-furanyl)-4H-1,2,4-triazol-3-yl)ethanesulfonamide

(E)-2-(3-Bromo-5-chloropyridin-2-yl)-N-(4-(2,6-dimethoxyphenyl)-5-(furan-2-yl)-4H-1,2,4-triazol-3-yl)-N-(2-(trimethylsilyl)ethyl)ethenesulfonamide and (Z)-2-(3-bromo-5-chloropyridin-2-yl)-N-(4-(2,6-dimethoxyphenyl)-5-(furan-2-yl)-4H-1,2,4-triazol-3-yl)-N-(2-(trimethylsilyl)ethyl)ethenesulfonamide, Example 27.1. Lithium bis(trimethylsilyl)amide (1.0 M solution in THF, 0.84 mL, 0.84 mmol) was added to a stirred solution of Example 365.0 (449 mg, 0.75 mmol) in THF (4 mL) at RT and the mixture was stirred for 15 min. Subsequently, a solution of 3-bromo-5-chloropicolinaldehyde (commercially available from Bellen, Beijing, China) (195 mg, 0.89 mmol) in THF (1.0 mL) was added and the resulting mixture was stirred at RT until LCMS indicated that the reaction was complete (1.3 h). Thereafter, the reaction was quenched with water (0.5 mL) and concentrated in vacuo. The residue was purified on a silica gel column employing a gradient of 0-100% EtOAc in hexanes to afford Example 27.1. LCMS-ESI (pos.) m/z: 666.0 (M+H) + .

2-(3-Bromo-5-chloropyridin-2-yl)-N-(4-(2,6-dimethoxyphenyl)-5-(furan-2-yl)-4H-1,2,4-triazol-3-yl)-N-(2-(trimethylsilyl)ethyl)ethanesulfonamide, Example 27.2. Example 27.1 (383 mg, 0.57 mmol) was dissolved in DCM (1 mL). The solution was briefly sparged with N 2 before Crabtree's catalyst ((1,5-cyclooctadiene)(pyridine)(tricyclohexyl-phosphine)-iridium(I) hexafluorophosphate, 465 mg, 0.58 mmol, commercially available from Sigma-Aldrich Corp., St. Louis, Mo., USA) was carefully added. Hydrogen was introduced at 1 atm (balloon) and the mixture was vigorously stirred for 17 h at RT after which LCMS analysis showed that the reaction was complete. Thereafter, the mixture was flushed with N 2 and concentrated in vacuo. The residue was purified on a silica gel column employing a gradient of 0-100% EtOAc in hexanes to afford 27.2 (61 mg, 0.09 mmol, 22%). LCMS-ESI (pos.) m/z: 668.0 (M+H) + .

2-(3-Bromo-5-chloro-2-pyridinyl)-N-(4-(2,6-dimethoxyphenyl)-5-(2-furanyl)-4H-1,2,4-triazol-3-yl)ethanesulfonamide Example 27.3. Example 27.2 (24 mg, 0.035 mmol) was dissolved in DMF (1 mL). Tris(dimethylamino)sulfonium difluorotrimethylsilicate (TAS-F, commercially available from Sigma-Aldrich Corp., St. Louis, Mo., USA) (30 mg, 0.11 mmol) was added, and the resulting mixture was heated at 60° C. for 16 h whereupon LCMS analysis indicated that the reaction was complete. Thereafter, the mixture was cooled to RT and directly purified by reverse-phase HPLC, employing a gradient of 30-60% ACN in water (0.1% TFA in both eluents), to afford Example 27.3 (9 mg, 0.015 mmol, 44%). 1 H NMR (500 MHz, CD 2 Cl 2 ) δ 8.34 (s, 1H) 7.80 (s, 1H) 7.47 (d, J=8.56 Hz, 1H) 7.41 (s, 1H) 6.66 (d, J=8.56 Hz, 2H) 6.27 (s, 1H) 5.97 (dd, J=3.67, 0.73 Hz, 1H) 3.66 (app s, 6H) 3.32-3.39 (m, 2H) 3.18-3.30 (m, 2H). LCMS-ESI (pos.) m/z: 568.0 (M+H) + .

›EXAMPLES · 11 of 46

2-(5-Chloro-3-(2-oxo-1-azetidinyl)-2-pyridinyl)-N-(4-(2,6-dimethoxyphenyl)-5-(2-furanyl)-4H-1,2,4-triazol-3-yl)ethanesulfonamide, Example 27.0. A mixture of Example 27.3 (49.5 mg, 0.087 mmol), 2-azetidinone (11.0 mg, 0.155 mmol), copper(I) iodide (4 mg, 0.021 mmol), trans-N,N′-dimethylcyclohexane-1,2-diamine (0.024 mL, 0.155 mmol), and potassium carbonate (34 mg, 0.246 mmol) in dioxane (0.5 mL) was heated at 110° C. under argon overnight in a sealed 1 dram vial. The reaction was then cooled to RT. The material thus obtained was purified by reverse-phase preparative HPLC using an Agilent SB C8 column, 0.1% TFA in ACN/H 2 O, gradient 20% to 55% over 25 min. The desired fractions were lyophilized overnight to give 2-(5-chloro-3-(2-oxo-1-azetidinyl)-2-pyridinyl)-N-(4-(2,6-dimethoxyphenyl)-5-(2-furanyl)-4H-1,2,4-triazol-3-yl)ethanesulfonamide, Example 27.0 (3.44 mg, 6.15 μmol, 7.07% yield). 1 H NMR (500 MHz, CDCl 3 ) δ 3.13 (t, J=4.52 Hz, 2H) 3.32-3.41 (m, 2H) 3.46-3.53 (m, 2H) 3.74 (app s, 6H) 3.87 (t, J=4.65 Hz, 2H) 6.02 (d, J=3.42 Hz, 1H) 6.34 (dd, J=3.67, 1.71 Hz, 1H) 6.68 (d, J=8.56 Hz, 2H) 7.43-7.53 (m, 2H) 7.99 (d, J=2.20 Hz, 1H) 8.34 (d, J=1.96 Hz, 1H). LCMS ESI (pos.) m/z: 559.1 (M+H) + .

Example 28.0. Preparation of N-(2-((2R)-2-((4-(2,6-dimethoxyphenyl)-5-(2-furanyl)-4H-1,2,4-triazol-3-yl)sulfamoyl)propyl)-5-fluoro-3-pyridinyl)acetamide and N-(2-((2S)-2-((4-(2,6-dimethoxyphenyl)-5-(2-furanyl)-4H-1,2,4-triazol-3-yl)sulfamoyl)propyl)-5-fluoro-3-pyridinyl)acetamide

N-(2-((2R)-2-((4-(2,6-Dimethoxyphenyl)-5-(2-furanyl)-4H-1,2,4-triazol-3-yl)sulfamoyl)propyl)-5-fluoro-3-pyridinyl)acetamide and N-(2-((2S)-2-((4-(2,6-dimethoxyphenyl)-5-(2-furanyl)-4H-1,2,4-triazol-3-yl)sulfamoyl)propyl)-5-fluoro-3-pyridinyl)acetamide, Example 28.0. To a solution of N-(2-(2-(N-(4-(2,6-dimethoxyphenyl)-5-(furan-2-yl)-4H-1,2,4-triazol-3-yl)-N-(2-(trimethylsilyl)ethyl)sulfamoyl)propyl)-5-fluoropyridin-3-yl)acetamide (103.9 mg, 0.161 mmol) in DMF (0.5 mL) was added tris(dimethylamino)sulfonium difluorotrimethylsilicate (89 mg, 0.323 mmol). The resulting solution was heated at 70° C. over 4 h. The reaction mixture was cooled to RT. The material obtained was then purified by reverse-phase preparative HPLC using an Agilent SB C18 column, 0.1% TFA in ACN/H 2 O, gradient 10% to 60% over 25 min. The desired fractions were lyophilized overnight to give N-(2-((2R)-2-((4-(2,6-dimethoxyphenyl)-5-(2-furanyl)-4H-1,2,4-triazol-3-yl)sulfamoyl)propyl)-5-fluoro-3-pyridinyl)acetamide and N-(2-((2S)-2-((4-(2,6-dimethoxyphenyl)-5-(2-furanyl)-4H-1,2,4-triazol-3-yl)sulfamoyl)propyl)-5-fluoro-3-pyridinyl)acetamide, Example 28.0 (65.0 mg, 0.12 mmol, 74% yield). 1 H NMR (500 MHz, CDCl 3 ) δ 1.49 (d, J=6.85 Hz, 3H) 2.17 (s, 3H) 3.19 (dd, J=15.04, 3.79 Hz, 1H) 3.32-3.40 (m, 1H) 3.42 (dt, J=6.79, 3.33 Hz, 1H) 3.72 (d, J=6.60 Hz, 6H) 5.92 (d, J=3.67 Hz, 1H) 6.33 (dd, J=3.67, 1.71 Hz, 1H) 6.66 (t, J=8.07 Hz, 2H) 7.46 (d, J=1.22 Hz, 1H) 7.51 (t, J=8.56 Hz, 1H) 8.25 (d, J=2.69 Hz, 1H) 8.44 (dd, J=10.27, 2.69 Hz, 1H) 9.22 (s, 1H). LCMS ESI (pos.) m/z: 545.1 (M+H) + .

Example 29.0. Preparation of (2R)-1-(3-cyano-5-fluoro-2-pyridinyl)-N-(4-(2,6-dimethoxyphenyl)-5-(2-furanyl)-4H-1,2,4-triazol-3-yl)-2-propanesulfonamide or (2S)-1-(3-cyano-5-fluoro-2-pyridinyl)-N-(4-(2,6-dimethoxyphenyl)-5-(2-furanyl)-4H-1,2,4-triazol-3-yl)-2-propanesulfonamide

(2R)-1-(3-Cyano-5-fluoro-2-pyridinyl)-N-(4-(2,6-dimethoxyphenyl)-5-(2-furanyl)-4H-1,2,4-triazol-3-yl)-2-propanesulfonamide and (2S)-1-(3-cyano-5-fluoro-2-pyridinyl)-N-(4-(2,6-dimethoxyphenyl)-5-(2-furanyl)-4H-1,2,4-triazol-3-yl)-2-propanesulfonamide, Example 29.0. The enantiomers were separated by DAS; purification method was 30% MeOH/CO 2 (with 20 mM NH 3 ), 100 bar, 65 mL/min on AD-H column (2×15 cm). The first peak to elute on the AD column was (2R)-1-(3-cyano-5-fluoro-2-pyridinyl)-N-(4-(2,6-dimethoxyphenyl)-5-(2-furanyl)-4H-1,2,4-triazol-3-yl)-2-propanesulfonamide (31 mg, 0.056 mmol, 35% yield) was isolated. 1 H NMR 500 MHz, CDCl 3 ) δ 1.46 (d, J=6.60 Hz, 3H) 2.12 (s, 3H) 3.00 (dd, J=14.55, 4.52 Hz, 1H) 3.27-3.45 (m, 2H) 3.72 (app s, 6H) 5.93 (d, J=3.42 Hz, 1H) 6.32 (dd, J=3.42, 1.71 Hz, 1H) 6.66 (dd, J=10.64, 8.68 Hz, 2H) 7.39-7.55 (m, 2H) 8.01-8.16 (m, 2H) 8.74 (br. s., 1H) 10.94 (br. s., 1H). LCMS ESI (pos.) m/z: 545.1 (M+H) + .

Example 30.0. Preparation of (2R)-1-(5-cyano-2-pyridinyl)-N-(4-(2,6-dimethoxyphenyl)-5-(2-furanyl)-4H-1,2,4-triazol-3-yl)-2-propanesulfonamide or (2S)-1-(5-cyano-2-pyridinyl)-N-(4-(2,6-dimethoxyphenyl)-5-(2-furanyl)-4H-1,2,4-triazol-3-yl)-2-propanesulfonamide

(2R)-1-(5-Cyano-2-pyridinyl)-N-(4-(2,6-dimethoxyphenyl)-5-(2-furanyl)-4H-1,2,4-triazol-3-yl)-2-propanesulfonamide or (2S)-1-(5-cyano-2-pyridinyl)-N-(4-(2,6-dimethoxyphenyl)-5-(2-furanyl)-4H-1,2,4-triazol-3-yl)-2-propanesulfonamide, Example 30.0. To a solution of 1-(5-bromopyridin-2-yl)-N-(4-(2,6-dimethoxyphenyl)-5-(furan-2-yl)-4H-1,2,4-triazol-3-yl)propane-2-sulfonamide 2,2,2-trifluoroacetate (70.4 mg, 0.106 mmol) in DMF (2 mL) was added tetrakis(triphenylphosphine)palladium(0) (11.1 mg, 9.61 μmol) and zinc cyanide (20 mg, 0.170 mmol). The resulting mixture was heated in a microwave for 120 min at 120° C. under argon. The reaction was then filtered through a syringe filter, rinsed with MeOH, and then concentrated in vacuo. The material thus obtained was purified by reverse-phase preparative HPLC using an Agilent Eclipse Plus C18 column, 0.1% TFA in ACN/H 2 O, gradient 10% to 70% over 25 min. The desired fraction was lyophilized to give the racemate (39 mg, 0.079 mmol, 74% yield). Chiral separation was performed with an IA column eluting with 20% MeOH/CO 2 , 100 bar, 60 mL/min. The first peak to elute on the IA column was the title compound (10.0 mg, 19% yield). 1 H NMR (500 MHz, CDCl 3 ) δ 1.29 (d, J=6.60 Hz, 3H) 2.97 (dd, J=13.94, 9.29 Hz, 1H) 3.50-3.70 (m, 2H) 3.74 (d, J=3.42 Hz, 6H) 6.00 (d, J=3.42 Hz, 1H) 6.34 (dd, J=3.67, 1.71 Hz, 1H) 6.68 (d, J=8.56 Hz, 2H) 7.31 (d, J=8.07 Hz, 1H) 7.41-7.59 (m, 2H) 7.85 (dd, J=8.07, 1.96 Hz, 1H) 8.79 (s, 1H) 10.99 (br. s., 1H). LCMS ESI (pos.) m/z: 495.1 (M+H) + .

›EXAMPLES · 12 of 46

Example 31.0. Preparation of (2R)—N-(4-(2,6-dimethoxyphenyl)-5-(5-methyl-2-furanyl)-4H-1,2,4-triazol-3-yl)-1-(6-methyl-3-pyridazinyl)-2-propanesulfonamide or (2S)—N-(4-(2,6-dimethoxyphenyl)-5-(5-methyl-2-furanyl)-4H-1,2,4-triazol-3-yl)-1-(6-methyl-3-pyridazinyl)-2-propanesulfonamide

(2R)—N-(4-(2,6-Dimethoxyphenyl)-5-(5-methyl-2-furanyl)-4H-1,2,4-triazol-3-yl)-1-(6-methyl-3-pyridazinyl)-2-propanesulfonamide or (2S)—N-(4-(2,6-dimethoxyphenyl)-5-(5-methyl-2-furanyl)-4H-1,2,4-triazol-3-yl)-1-(6-methyl-3-pyridazinyl)-2-propanesulfonamide, Example 31.0. To a 0° C. suspension of 1-(6-methylpyridazin-3-yl)propane-2-sulfonic acid (310 mg, 1.433 mmol) in DCM (10 mL) was added oxalyl chloride (240 μL, 2.74 mmol) followed by DMF (4.89 mg, 0.067 mmol). The reaction was then stirred for 3 h. The reaction was concentrated to dryness, azeotroped twice with benzene, and then dried under high vacuum. To a slurry of 4-(2,6-dimethoxyphenyl)-5-(5-methylfuran-2-yl)-4H-1,2,4-triazol-3-amine, Example 367.0 (201 mg, 0.67 mmol) in THF (5 mL) was added potassium tert-butoxide (1.0 M solution in THF, 0.8 mL, 0.800 mmol) dropwise over 1 min. After stirring for 10 min, this slurry was added to a slurry of the sulfonyl chloride intermediate in THF (10 mL). The reaction was stirred at RT for 6 h. The reaction was then quenched with water (0.2 mL) and then concentrated to dryness. The initial material obtained was purified by reverse-phase preparative HPLC using an Agilent SB C8 column, 0.1% TFA in ACN/H 2 O, gradient 10% to 50% over 25 min. The desired fraction was lyophilized overnight to give the racemate (37 mg, 0.074 mmol, 11.09% yield). Chiral separation was performed with an AD-H column eluting with 32% MeOH/CO 2 , 100 bar, 60 mL/min. The first peak to elute on the AD-H column was the title compound, Example 31.0 (11 mg, 0.022 mmol, 3% yield). 1 H NMR (500 MHz, CDCl 3 ) δ 1.30 (d, J=6.85 Hz, 3H) 2.32 (s, 3H) 2.69 (s, 3H) 3.05 (dd, J=13.94, 10.03 Hz, 1H) 3.59 (ddd, J=10.21, 6.66, 3.91 Hz, 1H) 3.62-3.67 (m, 1H) 3.77 (app s, 6H) 5.81 (d, J=3.42 Hz, 1H) 5.91 (dd, J=3.55, 0.86 Hz, 1H) 6.66 (d, J=2.93 Hz, 1H) 6.68 (d, J=3.18 Hz, 1H) 7.15-7.31 (m, 2H) 7.45 (t, J=8.44 Hz, 1H) 10.95 (br. s., 1H). LCMS ESI (pos.) m/z: 499.2 (M+H) + .

Example 32.0. Preparation of (2R)—N-(4-(2,6-dimethoxyphenyl)-5-(2-furanyl)-4H-1,2,4-triazol-3-yl)-1-(5-methyl-2-pyrazinyl)-2-propanesulfonamide or (2S)—N-(4-(2,6-dimethoxyphenyl)-5-(2-furanyl)-4H-1,2,4-triazol-3-yl)-1-(5-methyl-2-pyrazinyl)-2-propanesulfonamide

(2R)—N-(4-(2,6-Dimethoxyphenyl)-5-(2-furanyl)-4H-1,2,4-triazol-3-yl)-1-(5-methyl-2-pyrazinyl)-2-propanesulfonamide and (2S)—N-(4-(2,6-dimethoxyphenyl)-5-(2-furanyl)-4H-1,2,4-triazol-3-yl)-1-(5-methyl-2-pyrazinyl)-2-propanesulfonamide. Chiral separation was performed with an AD-H column eluting with 35% MeOH/CO 2 , 100 bar, 60 mL/min. The first peak to elute on the AD-H column was the title compound (36 mg, 0.075 mmol, 9% yield). 1 H NMR (500 MHz, CDCl 3 ) δ 1.27 (d, J=6.60 Hz, 3H) 2.55 (s, 3H) 2.85 (dd, J=13.94, 10.03 Hz, 1H) 3.52 (m, J=3.91 Hz, 1H) 3.58 (m, J=6.79, 3.58, 3.58 Hz, 1H) 3.75 (d, J=3.67 Hz, 6H) 6.00 (d, J=3.42 Hz, 1H) 6.33 (dd, J=3.67, 1.71 Hz, 1H) 6.68 (d, J=8.56 Hz, 2H) 7.44-7.49 (m, 2H) 8.31 (s, 1H) 8.39 (s, 1H) 11.02 (br. s., 1H). LCMS ESI (pos.) m/z: 485.1 (M+H) + .

Example 33.0. Preparation of (2R)-1-(5-cyano-2-pyridinyl)-N-(4-(2,6-dimethoxyphenyl)-5-(5-methyl-2-furanyl)-4H-1,2,4-triazol-3-yl)-2-propanesulfonamide or (2S)-1-(5-cyano-2-pyridinyl)-N-(4-(2,6-dimethoxyphenyl)-5-(5-methyl-2-furanyl)-4H-1,2,4-triazol-3-yl)-2-propanesulfonamide

(2R)-1-(5-Cyano-2-pyridinyl)-N-(4-(2,6-dimethoxyphenyl)-5-(5-methyl-2-furanyl)-4H-1,2,4-triazol-3-yl)-2-propanesulfonamide or (2S)-1-(5-cyano-2-pyridinyl)-N-(4-(2,6-dimethoxyphenyl)-5-(5-methyl-2-furanyl)-4H-1,2,4-triazol-3-yl)-2-propanesulfonamide, Example 33.0. To a solution of 1-(5-bromopyridin-2-yl)-N-(4-(2,6-dimethoxyphenyl)-5-(5-methylfuran-2-yl)-4H-1,2,4-triazol-3-yl)propane-2-sulfonamide (103.6 mg, 0.184 mmol) in DMF (1.5 mL) was added tetrakis(triphenylphosphine)palladium(0) (62 mg, 0.054 mmol) and zinc cyanide (36 mg, 0.307 mmol). Argon was bubbled through the mixture for 1 min and then the microwave vial was sealed. The resulting mixture was heated in a microwave for 1 h at 120° C. under argon. The reaction was then filtered through a syringe filter, rinsed with MeOH, and then concentrated in vacuo. The material was purified by reverse-phase preparative HPLC using an Agilent SB C8 column, 0.1% TFA in ACN/H 2 O, gradient 10% to 70% over 25 min. The desired fraction was lyophilized to give a racemate (35.6 mg, 0.070 mmol, 38.0% yield). Chiral separation was performed with an IA column eluting with 25% MeOH/CO 2 , 100 bar, 60 mL/min. The second peak to elute on the IA column was the title compound (8.2 mg, 0.016 mmol, 8.75% yield). 1 H NMR (500 MHz, CDCl 3 ) δ 1.28 (d, J=6.60 Hz, 3H) 2.26-2.35 (m, 3H) 2.96 (dd, J=14.06, 9.17 Hz, 1H) 3.54-3.61 (m, 1H) 3.61-3.69 (m, 1H) 3.74 (d, J=3.91 Hz, 6H) 5.80 (d, J=3.42 Hz, 1H) 5.91 (dd, J=3.42, 0.98 Hz, 1H) 6.67 (d, J=8.56 Hz, 2H) 7.30 (d, J=8.07 Hz, 1H) 7.47 (t, J=8.44 Hz, 1H) 7.84 (dd, J=8.07, 2.20 Hz, 1H) 8.79 (d, J=1.47 Hz, 1H) 10.92 (br. s., 1H). LCMS ESI (pos.) m/z: 509.1 (M+H) + .

Example 34.0. Preparation of N-(4-(2,6-dimethoxyphenyl)-5-(2-furanyl)-4H-1,2,4-triazol-3-yl)-2-(5-fluoro-2-pyrimidinyl)ethanesulfonamide

N-(4-(2,6-Dimethoxyphenyl)-5-(2-furanyl)-4H-1,2,4-triazol-3-yl)-2-(5-fluoro-2-pyrimidinyl)ethanesulfonamide, Example 34.0. To a solution of diethyl ((N-(4-(2,6-dimethoxyphenyl)-5-(furan-2-yl)-4H-1,2,4-triazol-3-yl)-N-(2-(trimethylsilyl)ethyl)sulfamoyl)methyl)phosphonate (Example 365.0, 546 mg, 0.909 mmol) in THF (3 mL) was added lithium bis(trimethylsilyl)amide (1 M solution in THF (1.1 mL, 1.100 mmol). After 15 min, 5-fluoropyrimidine-2-carbaldehyde (136.4 mg, 1.082 mmol) was added as a solution in THF (1 mL). The reaction was stirred for 1 h. The initial material was absorbed onto a plug of silica gel and purified by chromatography through a Redi-Sep pre-packed silica gel column (12 g), eluting with a gradient of 0% to 100% EtOAc in hexanes. The two isolated isomers were combined and concentrated in vacuo. To a solution of the olefin (355 mg, 0.62 mmol) in EtOH (20 mL) was added Raney 2800 nickel slurry in water (0.5 mL). The reaction was stirred at RT under a H 2 atmosphere over 1.5 h. The reaction mixture was then filtered through a pad of Celite® brand filter aid, the pad was rinsed with MeOH and DCM, and then the filtrate was concentrated to dryness. The filtrate (349 mg, 0.61 mmol) was dissolved in DMF (2 mL) and then tris(dimethylamino)sulfonium difluorotrimethylsilicate (333 mg, 1.209 mmol, 1.98 equiv) was added. The resulting solution was heated at 60° C. overnight. The reaction mixture was cooled to RT. The reaction was then diluted with water (200 mL) and EtOAc. The aqueous layer was extracted with EtOAc (3×). The combined organic layers were washed with brine, dried over Na 2 SO 4 , concentrated in vacuo, and then dried under high vacuum. The initial material was absorbed onto a plug of silica gel and purified by chromatography through a Redi-Sep pre-packed silica gel column (12 g), eluting with a gradient of 0% to 5% MeOH in DCM to give the title compound (146.4 mg, 0.31 mmol, 34% yield). 1 H NMR (500 MHz, CDCl 3 ) δ 3.37-3.50 (m, 2H) 3.53-3.64 (m, 2H) 3.75 (app s, 6H) 6.01 (d, J=3.67 Hz, 1H) 6.34 (dd, J=3.42, 1.71 Hz, 1H) 6.68 (d, J=8.56 Hz, 2H) 7.40-7.52 (m, 2H) 8.52 (s, 2H) 11.03 (br. s., 1H). LCMS ESI (pos.) m/z: 515.1 (M+H) + .

›EXAMPLES · 13 of 46

Example 35.0. Preparation of 2-(5-cyano-2-pyridinyl)-N-(4-(2,6-dimethoxyphenyl)-5-(2-furanyl)-4H-1,2,4-triazol-3-yl)ethanesulfonamide

2-(5-Cyano-2-pyridinyl)-N-(4-(2,6-dimethoxyphenyl)-5-(2-furanyl)-4H-1,2,4-triazol-3-yl)ethanesulfonamide, Example 35.0. To a solution of 2-(5-bromopyridin-2-yl)-N-(4-(2,6-dimethoxyphenyl)-5-(furan-2-yl)-4H-1,2,4-triazol-3-yl)ethanesulfonamide (101.8 mg, 0.191 mmol) in DMF (1.5 mL) was added tetrakis(triphenylphosphine)palladium(0) (29.3 mg, 0.025 mmol) and zinc cyanide (33 mg, 0.281 mmol). The resulting mixture was heated in a microwave for 30 min at 120° C. under argon. The reaction was then filtered through a syringe filter, rinsed with MeOH, and then concentrated in vacuo. The material was purified by reverse-phase preparative HPLC using an Agilent Eclipse Plus C18 column, 0.1% TFA in ACN/H 2 O, gradient 30% to 60% over 25 min. Desired fractions were lyophilized overnight to give the title compound (40.9 mg, 0.085 mmol, 44.7% yield). 1 H NMR (500 MHz, CDCl 3 ) δ 3.32-3.38 (m, 2H) 3.47-3.54 (m, 2H) 3.74 (app s, 6H) 6.01 (d, J=3.42 Hz, 1H) 6.34 (dd, J=3.42, 1.71 Hz, 1H) 6.68 (d, J=8.31 Hz, 2H) 7.33 (d, J=8.07 Hz, 1H) 7.48 (m, J=17.12 Hz, 2H) 7.86 (dd, J=8.19, 2.08 Hz, 1H) 8.78 (d, J=1.71 Hz, 1H). LCMS ESI (pos.) m/z: 481.1 (M+H) + .

Example 36.0. Preparation of (2R)-1-(5-bromo-2-pyrimidinyl)-N-(4-(2,6-dimethoxyphenyl)-5-(2-furanyl)-4H-1,2,4-triazol-3-yl)-2-propanesulfonamide or (2S)-1-(5-bromo-2-pyrimidinyl)-N-(4-(2,6-dimethoxyphenyl)-5-(2-furanyl)-4H-1,2,4-triazol-3-yl)-2-propanesulfonamide

(2R)-1-(5-Bromo-2-pyrimidinyl)-N-(4-(2,6-dimethoxyphenyl)-5-(2-furanyl)-4H-1,2,4-triazol-3-yl)-2-propanesulfonamide or (2S)-1-(5-bromo-2-pyrimidinyl)-N-(4-(2,6-dimethoxyphenyl)-5-(2-furanyl)-4H-1,2,4-triazol-3-yl)-2-propanesulfonamide. To a 0° C. suspension of 1-(5-bromopyrimidin-2-yl)propane-2-sulfonic acid (295 mg, 1.049 mmol) in DCM (5 mL) was added oxalyl chloride (0.12 mL, 1.371 mmol, 1.3 eq) followed by DMF (1 drop). The reaction was stirred for 2 h. The reaction was then concentrated to dryness, azeotroped twice with benzene, and then dried under high vacuum. To a 0° C. suspension of 4-(2,6-dimethoxyphenyl)-5-(furan-2-yl)-4H-1,2,4-triazol-3-amine, Example 362.03, (150 mg, 0.524 mmol) in THF (3 mL) was added potassium bis(trimethylsilyl)amide (1 M solution in THF, 1.6 mL, 1.600 mmol). The amino triazole solution (still at 0° C.) was added to a 0° C. suspension of the sulfonyl chloride in THF (3 mL) dropwise over 5 min. Once the addition was complete, the cooling bath was removed and the brown mixture was warmed to RT overnight. The reaction was then quenched with water (0.5 mL) and then concentrated to dryness. The initial material was purified by reverse-phase preparative HPLC using an Agilent SB C8 column, 0.1% TFA in ACN/H 2 O, gradient 10% to 70% over 25 min. The desired fractions were lyophilized overnight to give the racemate (53.2 mg, 0.097 mmol, 18.48% yield). Chiral separation was performed with an IA column eluting with 35% MeOH/CO 2 , 100 bar, 60 mL/min. The second peak to elute on the IA column was the title compound (13.5 mg, 0.025 mmol, 4.69% yield). 1 H NMR (500 MHz, CDCl 3 ) δ 1.31 (d, J=6.60 Hz, 3H) 3.04 (dd, J=14.67, 9.78 Hz, 1H) 3.65 (dd, J=14.92, 4.16 Hz, 1H) 3.76 (d, J=9.29 Hz, 6H) 3.79-3.87 (m, 1H) 6.00 (d, J=3.18 Hz, 1H) 6.34 (br. s., 1H) 6.68 (d, J=6.60 Hz, 2H) 7.37-7.67 (m, 2H) 8.72 (s, 2H) 11.08 (br. s., 1H). LCMS ESI (pos.) m/z: 549.1 (M+H) + .

Example 37.0. Preparation of (2R)-1-(5-chloro-2-pyrimidinyl)-N-(4-(2,6-dimethoxyphenyl)-5-(2-furanyl)-4H-1,2,4-triazol-3-yl)-2-propanesulfonamide or (2S)-1-(5-chloro-2-pyrimidinyl)-N-(4-(2,6-dimethoxyphenyl)-5-(2-furanyl)-4H-1,2,4-triazol-3-yl)-2-propanesulfonamide

(2R)-1-(5-Chloro-2-pyrimidinyl)-N-(4-(2,6-dimethoxyphenyl)-5-(2-furanyl)-4H-1,2,4-triazol-3-yl)-2-propanesulfonamide or (2S)-1-(5-chloro-2-pyrimidinyl)-N-(4-(2,6-dimethoxyphenyl)-5-(2-furanyl)-4H-1,2,4-triazol-3-yl)-2-propanesulfonamide, Example 37.0. To a solution of 1-(5-chloropyrimidin-2-yl)-N-(4-(2,6-dimethoxyphenyl)-5-(furan-2-yl)-4H-1,2,4-triazol-3-yl)-N-(2-(trimethylsilyl)ethyl)propane-2-sulfonamide (20.7 mg, 0.034 mmol) in DMF (0.5 mL) was added tris(dimethylamino)sulfonium difluorotrimethylsilicate (85 mg, 0.309 mmol). The resulting solution was heated at 60° C. over 4 h. The reaction mixture was then cooled to RT. The material obtained was purified by reverse-phase preparative HPLC using an Agilent SB C8 column, 0.1% TFA in ACN/H 2 O, gradient 10% to 70% over 25 min. The desired fraction was lyophilized overnight. The second peak to separate on the AD-H column eluted with 20% MeOH/100 bar CO 2 45 mins was isolated to give the title compound (4.1 mg, 8.12 μl, 24% yield). 1 H NMR (500 MHz, CDCl 3 ) δ 1.31 (d, J=6.85 Hz, 3H) 3.06 (dd, J=14.92, 9.78 Hz, 1H) 3.67 (dd, J=14.92, 4.40 Hz, 1H) 3.76 (d, J=9.54 Hz, 6H) 3.78-3.84 (m, 1H) 6.00 (d, J=3.67 Hz, 1H) 6.33 (dd, J=3.42, 1.47 Hz, 1H) 6.68 (dd, J=8.56, 2.93 Hz, 2H) 7.43-7.51 (m, 2H) 8.62 (s, 2H) 11.07 (br. s., 1H). LCMS ESI (pos.) m/z: 505.1 (M+H) + .

Example 38.0. Preparation of (2S)—N-(4-(2,6-dimethoxyphenyl)-5-(5-methyl-2-furanyl)-4H-1,2,4-triazol-3-yl)-1-(5-methyl-2-pyrazinyl)-2-propanesulfonamide or (2R)—N-(4-(2,6-dimethoxyphenyl)-5-(5-methyl-2-furanyl)-4H-1,2,4-triazol-3-yl)-1-(5-methyl-2-pyrazinyl)-2-propanesulfonamide

(2S)—N-(4-(2,6-Dimethoxyphenyl)-5-(5-methyl-2-furanyl)-4H-1,2,4-triazol-3-yl)-1-(5-methyl-2-pyrazinyl)-2-propanesulfonamide and (2R)—N-(4-(2,6-dimethoxyphenyl)-5-(5-methyl-2-furanyl)-4H-1,2,4-triazol-3-yl)-1-(5-methyl-2-pyrazinyl)-2-propanesulfonamide, Example 38.0. The title compound was prepared employing Example 367.0 and following the general procedure described in Example 70.0. LCMS-ESI (pos.) m/z: 499.0 (M+H) + .

(2S)—N-(4-(2,6-Dimethoxyphenyl)-5-(5-methyl-2-furanyl)-4H-1,2,4-triazol-3-yl)-1-(5-methyl-2-pyrazinyl)-2-propanesulfonamide or (2R)—N-(4-(2,6-dimethoxyphenyl)-5-(5-methyl-2-furanyl)-4H-1,2,4-triazol-3-yl)-1-(5-methyl-2-pyrazinyl)-2-propanesulfonamide, Example 38.0. Purification of Example 38.1 by SFC [30×250 mm AD-H column with 28 g/min EtOH (neat) in 52 g/min CO 2 at 100 bar] afforded two enantiomers. The title compound was the second isomer to elute on subjecting Example 38.1 to the SFC conditions described above. 1 H NMR (500 MHz, CDCl 3 ) δ 10.93 (br. s., 1H) 8.40 (s, 1H) 8.32 (s, 1H) 7.47 (t, J=8.56 Hz, 1H) 6.68 (dd, J=8.56, 1.47 Hz, 2H) 5.86-5.97 (m, 1H) 5.80 (d, J=3.42 Hz, 1H) 3.75 (d, J=3.91 Hz, 6H) 3.57 (ddd, J=10.21, 6.66, 4.16 Hz, 1H) 3.46-3.55 (m, 1H) 2.85 (dd, J=13.82, 9.90 Hz, 1H) 2.55 (s, 3H) 2.32 (s, 3H) 1.26 (d, J=6.60 Hz, 3H). LCMS-ESI (pos.) m/z: 499.0 (M+H) + .

›EXAMPLES · 14 of 46

Example 39.0. Preparation of N-(4-(2,6-dimethoxyphenyl)-5-(2-furanyl)-4H-1,2,4-triazol-3-yl)-2-(5-methyl-2-pyrimidinyl)ethanesulfonamide

N-(4-(2,6-Dimethoxyphenyl)-5-(2-furanyl)-4H-1,2,4-triazol-3-yl)-2-(5-methyl-2-pyrimidinyl)ethanesulfonamide, Example 39.0. To a 0° C. suspension of 2-(5-methylpyrimidin-2-yl)ethanesulfonic acid (324 mg, 1.60 mmol, prepared in an analagous manner to that described in Example 352.2 employing 2-chloro-5-methylpyrimidine) in DCM (4 mL)) was added oxalyl chloride (175 μL, 2.0 mmol, 1.25 eq.) followed by DMF (1 drop). The reaction was stirred for 2 h. The reaction was then concentrated to dryness, azeotroped twice with benzene, and then dried under high vacuum. To a 0° C. suspension of 4-(2,6-dimethoxyphenyl)-5-(furan-2-yl)-4H-1,2,4-triazol-3-amine (Example 362.03, 152 mg, 0.53 mmol) in THF (4 mL) was added potassium bis(trimethylsilyl)amide (1 M solution in THF, 1.2 mL, 1.2 mmol). The amino triazole solution (still at 0° C.) was then added to a 0° C. suspension of the sulfonyl chloride in THF (4 mL), dropwise over 3 min. Once the addition was complete, the cooling bath was removed and the mixture was warmed to RT for 4 h. The reaction was quenched with water (0.5 mL). The initial material obtained was concentrated down to an oil and then redissolved using water and MeOH. The material was purified by reverse-phase preparative HPLC using an Agilent SB C8 column, 0.1% TFA in ACN/H 2 O, gradient 10% to 50% over 25 min. The desired fraction was lyophilized to give N-(4-(2,6-dimethoxyphenyl)-5-(2-furanyl)-4H-1,2,4-triazol-3-yl)-2-(5-methyl-2-pyrimidinyl)ethanesulfonamide, Example 39.0 (39.7 mg, 0.084 mmol, 16% yield). 1 H NMR (500 MHz, CDCl 3 ) δ 2.35 (s, 3H) 3.37-3.51 (m, 2H) 3.52-3.66 (m, 2H) 3.75 (app s, 6H) 6.01 (dd, J=3.67, 0.49 Hz, 1H) 6.34 (dd, J=3.42, 1.71 Hz, 1H) 6.68 (d, J=8.56 Hz, 2H) 7.36-7.52 (m, 2H) 8.62 (s, 2H). LCMS ESI (pos.) m/z: 471.1 (M+H) + .

Example 40.0. Preparation of (1R,2S)-1-(5-cyano-2-pyridinyl)-N-(4-(2,6-dimethoxyphenyl)-5-(5-methyl-2-furanyl)-4H-1,2,4-triazol-3-yl)-1-hydroxy-2-propanesulfonamide or (1S,2R)-1-(5-cyano-2-pyridinyl)-N-(4-(2,6-dimethoxyphenyl)-5-(5-methyl-2-furanyl)-4H-1,2,4-triazol-3-yl)-1-hydroxy-2-propanesulfonamide

(1R,2S)-1-(5-Cyano-2-pyridinyl)-N-(4-(2,6-dimethoxyphenyl)-5-(5-methyl-2-furanyl)-4H-1,2,4-triazol-3-yl)-1-hydroxy-2-propanesulfonamide or (1S,2R)-1-(5-cyano-2-pyridinyl)-N-(4-(2,6-dimethoxyphenyl)-5-(5-methyl-2-furanyl)-4H-1,2,4-triazol-3-yl)-1-hydroxy-2-propanesulfonamide, Example 40.0. To a solution of (1R,2S)-1-(5-bromopyridin-2-yl)-N-(4-(2,6-dimethoxyphenyl)-5-(5-methylfuran-2-yl)-4H-1,2,4-triazol-3-yl)-1-hydroxypropane-2-sulfonamide 2,2,2-trifluoroacetate (prepared in Example 10.1, 113 mg, 0.16 mmol) in DMF (2 mL) was added tetrakis(triphenylphosphine)palladium(0) (40 mg, 0.035 mmol) and zinc cyanide (30.5 mg, 0.26 mmol). The resulting mixture was heated in a microwave for 60 min at 120° C. under argon. The material was filtered through a syringe filter and then purified by reverse-phase preparative HPLC using an Agilent SB C8 column, 0.1% TFA in ACN/H 2 O, gradient 30% to 80% over 25 min. The desired fraction was lyophilized overnight to give a racemic mixture of the title compound (30.4 mg, 0.058 mmol, 36% yield) as a TFA salt. Chiral separation was performed with an OJ-H column eluting with 50% MeOH/CO 2 , 100 bar, 80 mL/min. The first peak to elute on the OJ-H column was the title compound (10.16 mg, 0.019 mmol, 12% yield). 1 H NMR (500 MHz, MeOH) δ 1.19 (d, J=6.60 Hz, 3H) 2.26 (s, 3H) 3.46-3.66 (m, 1H) 3.79 (d, J=9.29 Hz, 6H) 4.99 (d, J=5.62 Hz, 1H) 5.95 (d, J=2.93 Hz, 1H) 6.02 (d, J=2.44 Hz, 1H) 6.86 (dd, J=8.19, 5.99 Hz, 2H) 7.57 (t, J=8.56 Hz, 1H) 7.62 (d, J=8.07 Hz, 1H) 8.01-8.14 (m, 1H) 8.81 (s, 1H). LCMS ESI (pos.) m/z: 525.1 (M+H) + .

Example 41.0. Preparation of N-(4-(2,6-dimethoxyphenyl)-5-(2-furanyl)-4H-1,2,4-triazol-3-yl)-2-(5-fluoro-2-pyridinyl)ethanesulfonamide

N-(4-(2,6-Dimethoxyphenyl)-5-(2-furanyl)-4H-1,2,4-triazol-3-yl)-2-(5-fluoro-2-pyridinyl)ethanesulfonamide, Example 41.0. Diethyl ((N-(4-(2,6-dimethoxyphenyl)-5-(furan-2-yl)-4H-1,2,4-triazol-3-yl)-N-(2-(trimethylsilyl)ethyl)sulfamoyl)methyl)phosphonate (Example 365.0, 41 mg, 0.068 mmol) was dissolved in THF (0.5 mL). To this was added lithium bis(trimethylsilyl)amide, (1.0 M solution in THF, 0.085 mL, 0.085 mmol). After 15 min, 5-fluoro-2-formylpyridine (14.1 mg, 0.113 mmol) was added. After 2.75 h, the reaction was quenched with MeOH (0.5 mL), concentrated to dryness, and dried under high vacuum. The olefin was dissolved in EtOH (1.0 mL) and palladium, 10 wt. % on activated carbon (43.0 mg, 0.040 mmol) was added. The resulting mixture was stirred under a hydrogen atmosphere at RT overnight. The reaction was passed through a syringe filter, the filter was rinsed with EtOAc and DCM, and then concentrated to dryness. The filtrate was dissolved in TBAF, (1.0 M solution in THF, 1.0 mL, 1.00 mmol). The resulting solution was heated at 60° C. in a sealed vial for 4 h. The reaction mixture was concentrated to remove the THF. The initial material was purified by reverse-phase preparative HPLC using an Agilent Eclipse Plus C18 column, 0.1% TFA in ACN/H 2 O, gradient 10% to 50% over 25 min. The desired fractions were then lyophilized overnight. The material thus obtained was absorbed onto a plug of silica gel and purified by chromatography through a Redi-Sep pre-packed silica gel column (4 g), eluting with a gradient of 0% to 6% MeOH in DCM to give the title compound (5.2 mg, 11.0 μmol, 16% yield). 1 H NMR (400 MHz, CDCl 3 ) δ 3.22-3.31 (m, 2H) 3.44-3.51 (m, 2H) 3.74 (app s, 6H) 6.00 (dd, J=3.52, 0.59 Hz, 1H) 6.34 (dd, J=3.62, 1.86 Hz, 1H) 6.67 (d, J=8.61 Hz, 2H) 7.18 (dd, J=8.61, 4.30 Hz, 1H) 7.32 (td, J=8.41, 2.93 Hz, 1H) 7.41-7.50 (m, 2H) 8.37 (d, J=2.93 Hz, 1H) 11.03 (br. s., 1H). LCMS ESI (pos.) m/z: 214.1 (M+H) + .

Example 42.0. Preparation of (2R)—N-(4-(2,6-dimethoxyphenyl)-5-(2-furanyl)-4H-1,2,4-triazol-3-yl)-1-(6-methyl-3-pyridazinyl)-2-propanesulfonamide or (2S)—N-(4-(2,6-dimethoxyphenyl)-5-(2-furanyl)-4H-1,2,4-triazol-3-yl)-1-(6-methyl-3-pyridazinyl)-2-propanesulfonamide

›EXAMPLES · 15 of 46

(2R)—N-(4-(2,6-dimethoxyphenyl)-5-(2-furanyl)-4H-1,2,4-triazol-3-yl)-1-(6-methyl-3-pyridazinyl)-2-propanesulfonamide or (2S)—N-(4-(2,6-dimethoxyphenyl)-5-(2-furanyl)-4H-1,2,4-triazol-3-yl)-1-(6-methyl-3-pyridazinyl)-2-propanesulfonamide, Example 42.0. To a 0° C. suspension of 1-(6-methylpyridazin-3-yl)propane-2-sulfonic acid (prepared in an analogous fashion to that described in Example 351.0, 225 mg, 1.04 mmol) in DCM (5 mL) was added oxalyl chloride (120 μL, 1.37 mmol, 1.3 eq) followed by DMF (0.383 mg, 5.24 μmop. The reaction was stirred at RT for 2 h. The reaction was concentrated to dryness, azeotroped twice with benzene and then dried under high vacuum. A very dark blue-green solid was isolated. To an orange slurry of 4-(2,6-dimethoxyphenyl)-5-(furan-2-yl)-4H-1,2,4-triazol-3-amine (Example 362.03, 150 mg, 0.524 mmol) in THF (4 mL) was added potassium tert-butoxide (1.0 M solution in THF, 1.0 mL, 1.00 mmol) dropwise over 1 min. After stirring for 10 min, the solution was added to a slurry of the sulfonyl chloride in THF (4 mL). The reaction was stirred at RT for 3 h. The reaction was quenched with water (0.3 mL) and then concentrated to dryness. The initial material was purified by reverse-phase preparative HPLC using an Agilent SB C8 column, 0.1% TFA in ACN/H 2 O, gradient 10% to 50% over 25 min. The desired fraction was lyophilized overnight to give the title compound as a racemic mixture (18.2 mg, 0.038 mmol, 7% yield). Chiral separation was performed with an IA column eluting with 27% MeOH/CO 2 , 100 bar, 60 mL/min. The first peak to elute on the IA column was the title compound (3.0 mg, 6.19 μmol, 1% yield). 1 H NMR (500 MHz, CDCl 3 ) δ 1.28-1.37 (m, 3H) 2.70 (s, 3H) 3.07 (dd, J=13.69, 9.78 Hz, 1H) 3.52-3.62 (m, 1H) 3.62-3.69 (m, 1H) 3.78 (s, 3H) 3.78 (s, 3H) 6.01 (dd, J=3.67, 0.49 Hz, 1H) 6.33 (dd, J=3.67, 1.71 Hz, 1H) 6.68 (dd, J=8.56, 3.42 Hz, 2H) 7.16-7.32 (m, 2H) 7.38-7.54 (m, 2H) 10.99 (br. s., 1H). LCMS ESI (pos.) m/z: 485.1 (M+H) + .

Example 43.0. Preparation of (2R)—N-(4-(2,6-dimethoxyphenyl)-5-(5-methyl-2-furanyl)-4H-1,2,4-triazol-3-yl)-1-(6-methyl-3-pyridazinyl)-2-propanesulfonamide or (2S)—N-(4-(2,6-dimethoxyphenyl)-5-(5-methyl-2-furanyl)-4H-1,2,4-triazol-3-yl)-1-(6-methyl-3-pyridazinyl)-2-propanesulfonamide

(2R)—N-(4-(2,6-dimethoxyphenyl)-5-(5-methyl-2-furanyl)-4H-1,2,4-triazol-3-yl)-1-(6-methyl-3-pyridazinyl)-2-propanesulfonamide or (2S)—N-(4-(2,6-dimethoxyphenyl)-5-(5-methyl-2-furanyl)-4H-1,2,4-triazol-3-yl)-1-(6-methyl-3-pyridazinyl)-2-propanesulfonamide, Example 43.0. To a 0° C. suspension of 1-(6-methylpyridazin-3-yl)propane-2-sulfonic acid (prepared in an analogous fashion to that described in Example 351.0, 310 mg, 1.433 mmol) in DCM (10 mL) was added oxalyl chloride (240 μL, 2.74 mmol) followed by DMF (4.89 mg, 0.067 mmol). The reaction was stirred for 3 h. The reaction was then concentrated to dryness, azeotroped twice with benzene, and dried under high vacuum. To a slurry of 4-(2,6-dimethoxyphenyl)-5-(5-methylfuran-2-yl)-4H-1,2,4-triazol-3-amine (Example 367.0, 201 mg, 0.669 mmol) in THF (5 mL) was added potassium tert-butoxide, 1.0 M solution in THF (0.8 mL, 0.800 mmol) dropwise over one min. After stirring for 10 min, this slurry was added to a slurry of the sulfonyl chloride in THF (10 mL). The reaction was stirred at RT for 6 h. The reaction was quenched with water (0.2 mL) and then concentrated to dryness. The initial material was purified by reverse-phase preparative HPLC using an Agilent SB C8 column, 0.1% TFA in ACN/H 2 O, gradient 10% to 50% over 25 min. The desired fraction was lyophilized overnight to give a racemic mixture of the title compound (37 mg, 0.074 mmol, 11% yield). Chiral separation was performed with an AD-H column eluting with 32% MeOH/CO 2 , 100 bar, 60 mL/min. The second peak to elute on the AD-H column was the title compound (12 mg, 0.024 mmol, 4% yield). 1 H NMR (500 MHz, CDCl 3 ) δ 1.30 (d, J=6.85 Hz, 3H) 2.32 (s, 3H) 2.69 (s, 3H) 3.05 (dd, J=13.94, 10.03 Hz, 1H) 3.59 (ddd, J=10.21, 6.66, 3.91 Hz, 1H) 3.62-3.67 (m, 1H) 3.77 (s, 3H) 3.77 (s, 3H) 5.81 (d, J=3.42 Hz, 1H) 5.91 (dd, J=3.42, 0.73 Hz, 1H) 6.66 (d, J=3.18 Hz, 1H) 6.68 (d, J=3.18 Hz, 1H) 7.22-7.28 (m, 2H) 7.45 (t, J=8.44 Hz, 1H) 10.96 (br. s., 1H). LCMS ESI (pos.) m/z: 499.2 (M+H) + .

Example 44.0. Preparation of (2R)—N-(4-(2,6-dimethoxyphenyl)-5-(2-furanyl)-4H-1,2,4-triazol-3-yl)-1-(4-pyrimidinyl)-2-propanesulfonamide or (2S)—N-(4-(2,6-dimethoxyphenyl)-5-(2-furanyl)-4H-1,2,4-triazol-3-yl)-1-(4-pyrimidinyl)-2-propanesulfonamide

(2R)—N-(4-(2,6-Dimethoxyphenyl)-5-(2-furanyl)-4H-1,2,4-triazol-3-yl)-1-(4-pyrimidinyl)-2-propanesulfonamide and (2S)—N-(4-(2,6-dimethoxyphenyl)-5-(2-furanyl)-4H-1,2,4-triazol-3-yl)-1-(4-pyrimidinyl)-2-propanesulfonamide, Example 44.0. To a solution of N-(4-(2,6-dimethoxyphenyl)-5-(furan-2-yl)-4H-1,2,4-triazol-3-yl)-1-(pyrimidin-5-yl)-N-(2-(trimethylsilyl)ethyl)propane-2-sulfonamide (made in analogous fashion to that described in Example 4.0 using pyrimidine-4-carbaldehyde from Aldrich) in DMF (1 mL) was added tris(dimethylamino)sulfonium difluorotrimethylsilicate. The resulting solution was heated at 60° C. After 4 h of heating, the reaction was cooled to RT and allowed to stand overnight. The material was purified by reverse-phase preparative HPLC using an Agilent SB C18 column, 0.1% TFA in ACN/H 2 O, gradient 10% to 60% over 25 min. The desired fractions were combined and then lyophilized overnight to give a racemic mixture of the title compound. Chiral separation was then performed with an AD column eluting with 20% MeOH/CO 2 , 100 bar, 60 mL/min. The first peak to elute on the AD column was the title compound (7.9 mg, 0.017 mmol, 42% yield). 1 H NMR (500 MHz, CDCl 3 ) δ 1.27-1.38 (m, 3H) 2.84 (dd, J=14.31, 9.90 Hz, 1H) 3.44-3.58 (m, 1H) 3.61-3.71 (m, 1H) 3.75 (d, J=2.45 Hz, 6H) 6.00 (d, J=3.67 Hz, 1H) 6.34 (dd, J=3.42, 1.71 Hz, 1H) 6.68 (dd, J=8.44, 2.81 Hz, 2H) 7.20 (d, J=4.89 Hz, 1H) 7.37-7.52 (m, 2H) 8.61 (d, J=5.13 Hz, 1H) 9.13 (s, 1H) 11.01 (br. s., 1H). LCMS ESI (pos.) m/z: 471.1 (M+H) + .

›EXAMPLES · 16 of 46

Example 45.0. Preparation of (2R)—N-(4-(2,6-dimethoxyphenyl)-5-(2-furanyl)-4H-1,2,4-triazol-3-yl)-1-(5-pyrimidinyl)-2-propanesulfonamide or (2S)—N-(4-(2,6-dimethoxyphenyl)-5-(2-furanyl)-4H-1,2,4-triazol-3-yl)-1-(5-pyrimidinyl)-2-propanesulfonamide

(2R)—N-(4-(2,6-Dimethoxyphenyl)-5-(2-furanyl)-4H-1,2,4-triazol-3-yl)-1-(5-pyrimidinyl)-2-propanesulfonamide or (2S)—N-(4-(2,6-dimethoxyphenyl)-5-(2-furanyl)-4H-1,2,4-triazol-3-yl)-1-(5-pyrimidinyl)-2-propanesulfonamide, Example 45.0. To a solution of N-(4-(2,6-dimethoxyphenyl)-5-(furan-2-yl)-4H-1,2,4-triazol-3-yl)-1-(pyrimidin-5-yl)-N-(2-(trimethylsilyl)ethyl)propane-2-sulfonamide (made in analogous fashion to that described in Example 4.0 using pyrimidine-5-carbaldehyde from Aldrich) in 1 mL of DMF was added tris(dimethylamino)sulfonium difluorotrimethylsilicate. The resulting solution was heated at 60° C. After 4 h of heating, the reaction was cooled to RT and allowed to stand overnight. The material was purified by reverse-phase preparative HPLC using an Agilent SB C18 column, 0.1% TFA in ACN/H 2 O, gradient 10% to 60% over 25 min. The desired fractions were combined and then lyophilized overnight to give a racemic mixture of the title compound (19 mg, 0.040 mmol, 80% yield). The first peak to elute to elute from the AD column was the title compound (8.5 mg, 0.018 mmol, 45% yield). 1 H NMR (500 MHz, CDCl 3 ) δ 1.25 (d, J=6.85 Hz, 3H) 2.69 (dd, J=14.18, 10.27 Hz, 1H) 3.21 (ddd, J=10.33, 6.79, 3.91 Hz, 1H) 3.41 (dd, J=14.06, 3.79 Hz, 1H) 3.75 (d, J=7.82 Hz, 6H) 5.99 (d, J=3.42 Hz, 1H) 6.34 (dd, J=3.67, 1.71 Hz, 1H) 6.70 (dd, J=8.56, 1.22 Hz, 2H) 7.38-7.60 (m, 2H) 8.56 (s, 2H) 9.10 (s, 1H) 11.07 (br. s., 1H). LCMS ESI (pos.) m/z: 471.1 (M+H) + .

Example 46.0. Preparation of (2R)—N-(4-(2,6-dimethoxyphenyl)-5-(2-furanyl)-4H-1,2,4-triazol-3-yl)-1-(4-pyrimidinyl)-2-propanesulfonamide or (2S)—N-(4-(2,6-dimethoxyphenyl)-5-(2-furanyl)-4H-1,2,4-triazol-3-yl)-1-(4-pyrimidinyl)-2-propanesulfonamide

(2R)—N-(4-(2,6-Dimethoxyphenyl)-5-(2-furanyl)-4H-1,2,4-triazol-3-yl)-1-(4-pyrimidinyl)-2-propanesulfonamide or (2S)—N-(4-(2,6-dimethoxyphenyl)-5-(2-furanyl)-4H-1,2,4-triazol-3-yl)-1-(4-pyrimidinyl)-2-propanesulfonamide, Example 46.0. To a solution of N-(4-(2,6-dimethoxyphenyl)-5-(furan-2-yl)-4H-1,2,4-triazol-3-yl)-1-(pyrimidin-5-yl)-N-(2-(trimethylsilyl)ethyl)propane-2-sulfonamide (made in analogous fashion to that described in Example 4.0 using pyrimidine-6-carbaldehyde from Aldrich) in 1 mL of DMF was added tris(dimethylamino)sulfonium difluorotrimethylsilicate. The resulting solution was heated at 60° C. After 4 h of heating, the reaction was cooled to RT and allowed to stand overnight. The material was purified by reverse-phase preparative HPLC using an Agilent SB C18 column, 0.1% TFA in ACN/H 2 O, gradient 10% to 60% over 25 min. The desired fractions were combined and then lyophilized overnight to give a racemic mixture of the title compound, Chiral separation was performed with an AD column eluting with 20% MeOH/CO 2 , 100 bar, 60 mL/min. The second peak to elute on the AD column was the title compound (7.0 mg, 0.015 mmol, 36.8% yield). 1 H NMR (500 MHz, CDCl 3 ) δ 1.30 (d, J=6.85 Hz, 3H) 2.84 (dd, J=14.18, 10.03 Hz, 1H) 3.41-3.57 (m, 1H) 3.61-3.70 (m, 1H) 3.75 (d, J=2.20 Hz, 6H) 6.00 (d, J=3.42 Hz, 1H) 6.34 (d, J=1.71 Hz, 1H) 6.68 (dd, J=8.31, 2.20 Hz, 2H) 7.23 (br. s., 1H) 7.38-7.57 (m, 2H) 8.68 (br. s., 1H) 9.16 (br. s., 1H) 11.02 (br. s., 1H). LCMS ESI (pos.) m/z: 471.1 (M+H) + .

Example 47.0. Preparation of N-(4-(2,6-dimethoxyphenyl)-5-(2-furanyl)-4H-1,2,4-triazol-3-yl)-2-(6-methoxy-3-pyridinyl)ethanesulfonamide

N-(4-(2,6-Dimethoxyphenyl)-5-(furan-2-yl)-4H-1,2,4-triazol-3-yl)-2-(6-methoxypyridin-3-yl)-N-(2-(trimethylsilyl)ethyl)ethanesulfonamide, Example 47.1. Example 365.0 (41.0 mg, 0.068 mmol) was dissolved in THF (0.5 mL). To this was added lithium bis(trimethylsilyl)amide, (1.0 M solution in THF, 0.085 mL, 0.085 mmol). After 20 min, 6-methoxynicotinaldehyde (15.0 mg, 0.109 mmol) was added. After 30 min, the reaction was quenched with MeOH (0.5 mL) and then concentrated to dryness and dried under high vacuum. The residue was dissolved in EtOAc (0.5 mL), and palladium (10 wt. % on activated carbon, 7.1 mg, 6.67 μmol, 0.5 eq) was added. The resulting mixture was stirred under a hydrogen atmosphere at RT overnight. Next, the mixture was filtered through a syringe filter, the filter was rinsed with EtOAc and DCM, and the filtrated was concentrated in vacuo.

N-(4-(2,6-Dimethoxyphenyl)-5-(2-furanyl)-4H-1,2,4-triazol-3-yl)-2-(6-methoxy-3-pyridinyl)ethanesulfonamide, Example 47.0. Example 47.1 was dissolved in THF (0.5 mL) and TBAF (1.0 M solution in THF, 0.5 mL, 0.50 mmol) was added. The resulting solution was heated at 60° C. in a sealed vial for 16 h. The reaction mixture was then concentrated in vacuo. The material was purified by reverse-phase preparative HPLC using an Agilent Eclipse Plus C18 column, 0.1% TFA in ACN/H 2 O, gradient 10% to 50% over 25 min (collected the peaks that were visible at 220 nm). The isolated fractions were lyophilized overnight to give the title compound (6.1 mg, 0.013 mmol, 18% yield). 1 H NMR (500 MHz, CDCl 3 ) δ 3.02-3.09 (m, 2H) 3.22-3.29 (m, 2H) 3.75 (app s, 6H) 3.96 (s, 3H) 6.00 (dd, J=3.55, 0.61 Hz, 1H) 6.34 (dd, J=3.55, 1.83 Hz, 1H) 6.70 (d, J=8.56 Hz, 2H) 6.76 (d, J=8.56 Hz, 1H) 7.46-7.51 (m, 2H) 7.54 (dd, J=8.56, 2.20 Hz, 1H) 8.04 (br. s., 1H). LCMS ESI (pos.) m/z: 486.1 (M+H) + .

Example 48.0. Preparation of 2-(5-chloro-2-pyridinyl)-N-(4-(2,6-dimethoxyphenyl)-5-(2-furanyl)-4H-1,2,4-triazol-3-yl)ethanesulfonamide

2-(5-Chloropyridin-2-yl)-N-(4-(2,6-dimethoxyphenyl)-5-(furan-2-yl)-4H-1,2,4-triazol-3-yl)-N-(2-(trimethylsilyl)ethyl)ethanesulfonamide, Example 48.1. To a solution of Example 365.0 (104 mg, 0.173 mmol) in THF (1 mL) was added lithium bis(trimethylsilyl)amide, (1.0 M solution in THF, 200 μL, 0.20 mmol). After 15 min, 5-chloropicolinaldehyde (38 mg, 0.27 mmol) was added. After 2 h, the reaction was quenched with MeOH (0.5 mL) and then concentrated to dryness and dried under high vacuum. The initial material was absorbed onto a plug of silica gel and purified by chromatography through a Redi-Sep pre-packed silica gel column (4 g) eluting with a gradient of 0% to 70% EtOAc in hexanes. The olefin (100 mg, 0.17 mmol) was dissolved in DCM (2 mL) and then hydrogen was bubbled through the solution for 1 min. Then, Crabtree catalyst (467 mg, 0.10 mmol, 0.6 eq) was added. The reaction was stirred overnight. The reaction mixture was absorbed onto a plug of silica gel and purified by chromatography through a Redi-Sep pre-packed silica gel column (4 g) eluting with a gradient of 0% to 100% EtOAc in hexanes. The product eluted at 100% EtOAc to give 2-(5-chloropyridin-2-yl)-N-(4-(2,6-dimethoxyphenyl)-5-(furan-2-yl)-4H-1,2,4-triazol-3-yl)-N-(2-(trimethylsilyl)ethyl)ethanesulfonamide (Example 48.1, 55 mg, 0.093 mmol, 53.8% yield).

›EXAMPLES · 17 of 46

2-(5-Chloro-2-pyridinyl)-N-(4-(2,6-dimethoxyphenyl)-5-(2-furanyl)-4H-1,2,4-triazol-3-yl)ethanesulfonamide, Example 48.0. To a solution of Example 48.1 (55 mg, 0.093 mmol) in DMF (1 mL) was added tris(dimethylamino)sulfonium difluorotrimethylsilicate (78.5 mg, 0.29 mmol). The resulting amber solution was heated at 60° C. overnight. The reaction was then cooled to RT. The material was purified by reverse-phase preparative HPLC using an Agilent SB C8 column, 0.1% TFA in ACN/H 2 O, gradient 10% to 80% over 25 min. The desired fraction was lyophilized overnight to give the title compound (4.22 mg, 9% yield). 1 H NMR (500 MHz, CD 2 Cl 2 ) δ 3.20-3.30 (m, 2H) 3.36-3.45 (m, 2H) 3.75 (app s, 6H) 6.06 (d, J=3.67 Hz, 1H) 6.36 (dd, J=3.67, 1.71 Hz, 1H) 6.74 (d, J=8.56 Hz, 2H) 7.25 (d, J=8.56 Hz, 1H) 7.49 (d, J=1.71 Hz, 1H) 7.53 (t, J=8.56 Hz, 1H) 7.71 (dd, J=8.31, 2.45 Hz, 1H) 8.54 (d, J=1.71 Hz, 1H). LCMS ESI (pos.) m/z: 490.1 (M+H) + .

Example 49.0. Preparation of 2-(5-chloro-2-pyrimidinyl)-N-(4-(2,6-dimethoxyphenyl)-5-(2-furanyl)-4H-1,2,4-triazol-3-yl)ethanesulfonamide

(E)-2-(5-Chloropyrimidin-2-yl)-N-(4-(2,6-dimethoxyphenyl)-5-(furan-2-yl)-4H-1,2,4-triazol-3-yl)-N-(2-(trimethylsilyl)ethyl)ethenesulfonamide and (Z)-2-(5-chloropyrimidin-2-yl)-N-(4-(2,6-dimethoxyphenyl)-5-(furan-2-yl)-4H-1,2,4-triazol-3-yl)-N-(2-(trimethylsilyl)ethyl) ethenesulfonamide, Example 49.1. The title compound was prepared employing 5-chloropyrimidine-2-carbaldehyde (commercially available from Ark Pharm, Inc., Libertyville, Ill., USA) and Example 365.1 following the procedure described in Example 34.0. LCMS-ESI (pos.) m/z: 589.2 (M+H) + .

2-(5-Chloropyrimidin-2-yl)-N-(4-(2,6-dimethoxyphenyl)-5-(furan-2-yl)-4H-1,2,4-triazol-3-yl)-N-(2-(trimethylsilyl)ethyl)ethanesulfonamide, Example 49.2. Example 49.1 (322 mg, 0.55 mmol) was dissolved in THF/t-BuOH (1:1 v/v, 10 mL). The solution was briefly sparged with H 2 before Wilkinson's catalyst (chlorotris(triphenylphosphine)rhodium (I), (172 mg, 0.19 mmol, commercially available from Strem Chemicals, Inc., Newburyport, Mass., USA)) was added. Hydrogen was introduced at 1 atm (balloon), and the mixture was vigorously stirred for 17 h at RT after which LCMS analysis showed that the reaction was 20% complete. Thus, a second aliquot of Wilkinson's catalyst (203 mg, 0.22 mmol) and THF/t-BuOH (1:1 v/v, 6 mL) was added, and the mixture was stirred for a further 17 h at RT under H 2 atmosphere. Thereafter, the mixture was flushed with N 2 and concentrated in vacuo. The residue was purified on a silica gel column employing a gradient of 0-100% EtOAc in hexanes to afford 49.2 (147 mg, 0.25 mmol, 45%). LCMS-ESI (pos.) m/z: 591.1 (M+H) + .

2-(5-Chloro-2-pyrimidinyl)-N-(4-(2,6-dimethoxyphenyl)-5-(2-furanyl)-4H-1,2,4-triazol-3-yl)ethanesulfonamide, Example 49.0. To a solution of 2-(5-chloropyrimidin-2-yl)-N-(4-(2,6-dimethoxyphenyl)-5-(furan-2-yl)-4H-1,2,4-triazol-3-yl)-N-(2-(trimethylsilyl)ethyl)ethane sulfonamide (Example 49.2, 12.1 mg, 0.020 mmol) in DMF (1 mL) was added tris(dimethylamino)sulfur trimethylsilyl difluoride (35 mg, 0.13 mmol, 6.4 equiv). The resulting amber solution was heated at 60° C. overnight. The reaction mixture was then cooled to RT. The material was purified by reverse-phase preparative HPLC using an Agilent SB C8 column, 0.1% TFA in ACN/H 2 O, gradient 20% to 75% over 25 min. The desired fraction was lyophilized to give Example 49.0 (3.5 mg, 7.13 μmol, 2.88% yield). 1 H NMR (500 MHz, CDCl 3 ) δ 3.39-3.48 (m, 2H) 3.54-3.63 (m, 2H) 3.76 (app s, 6H) 6.01 (dd, J=3.67, 0.49 Hz, 1H) 6.34 (dd, J=3.55, 1.83 Hz, 1H) 6.68 (d, J=8.56 Hz, 2H) 7.42-7.50 (m, 2H) 8.62 (s, 2H). LCMS ESI (pos.) m/z: 491.1 (M+H) + .

Example 50.0. Preparation of 2-(5-chloro-3-cyano-2-pyridinyl)-N-(4-(2,6-dimethoxyphenyl)-5-(2-furanyl)-4H-1,2,4-triazol-3-yl)ethanesulfonamide

2-(5-Chloro-3-cyano-2-pyridinyl)-N-(4-(2,6-dimethoxyphenyl)-5-(2-furanyl)-4H-1,2,4-triazol-3-yl)ethanesulfonamide, Example 50.0. To a solution of 2-(3-bromo-5-chloropyridin-2-yl)-N-(4-(2,6-dimethoxyphenyl)-5-(furan-2-yl)-4H-1,2,4-triazol-3-yl)ethanesulfonamide (Example 27.3, 151.2 mg, 0.266 mmol) in DMF (2 mL) was added tetrakis(triphenylphosphine)palladium(0) (32 mg, 0.028 mmol) and zinc cyanide (38.1 mg, 0.324 mmol). Argon was bubbled through the mixture for one min and then the microwave vial was sealed. The resulting mixture was heated in a microwave for 8 min 120° C. The reaction was then filtered through a syringe filter, rinsed with MeOH, and concentrated in vacuo. The material thus obtained was purified by reverse-phase preparative HPLC using an Agilent SB C8 column, 0.1% TFA in ACN/H 2 O, gradient 30% to 60% over 25 min. The desired fractions were lyophilized to give Example 50.0 (107.1 mg, 0.208 mmol, 78% yield. 1 H NMR (400 MHz, CDCl 3 ) δ 3.42-3.54 (m, 2H) 3.54-3.64 (m, 2H) 3.76 (s, 3H) 3.76 (s, 3H) 6.01 (dd, J=3.62, 0.68 Hz, 1H) 6.33 (dd, J=3.52, 1.76 Hz, 1H) 6.69 (d, J=8.61 Hz, 2H) 7.41-7.51 (m, 2H) 7.87 (d, J=2.35 Hz, 1H) 8.66 (d, J=2.35 Hz, 1H) 10.94 (br. s., 1H). LCMS ESI (pos.) m/z: 515.1 (M+H) + .

Example 52.0. Preparation of (2R)—N-(4-(2,6-dimethoxyphenyl)-5-(2-furanyl)-4H-1,2,4-triazol-3-yl)-1-(5-fluoro-2-pyrimidinyl)-2-propanesulfonamide and (2S)—N-(4-(2,6-dimethoxyphenyl)-5-(2-furanyl)-4H-1,2,4-triazol-3-yl)-1-(5-fluoro-2-pyrimidinyl)-2-propanesulfonamide

(E)-N-(4-(2,6-Dimethoxyphenyl)-5-(furan-2-yl)-4H-1,2,4-triazol-3-yl)-1-(5-fluoropyrimidin-2-yl)-N-(2-(trimethylsilyl)ethyl)prop-1-ene-2-sulfonamide and (Z)—N-(4-(2,6-dimethoxyphenyl)-5-(furan-2-yl)-4H-1,2,4-triazol-3-yl)-1-(5-fluoropyrimidin-2-yl)-N-(2-(trimethylsilyl)ethyl)prop-1-ene-2-sulfonamide, Example 52.1. The title compound was prepared employing Example 366.0 and 5-fluoropyrimidine-2-carbaldehyde (commercially available from J & W PharmLab, Levittown, Pa., USA) using the procedure described for the synthesis of Example 4.0. LCMS-ESI (pos.) m/z: 587.2 (M+H) + .

(S)—N-(4-(2,6-Dimethoxyphenyl)-5-(furan-2-yl)-4H-1,2,4-triazol-3-yl)-1-(5-fluoropyrimidin-2-yl)-N-(2-(trimethylsilyl)ethyl)propane-2-sulfonamide and (R)—N-(4-(2,6-dimethoxyphenyl)-5-(furan-2-yl)-4H-1,2,4-triazol-3-yl)-1-(5-fluoropyrimidin-2-yl)-N-(2-(trimethylsilyl)ethyl)propane-2-sulfonamide, Example 52.2. The title compound was prepared employing 52.1, and the procedure described in Example 4.0. LCMS-ESI (pos.) m/z: 589.2 (M+H) + .

›EXAMPLES · 18 of 46

(2R)—N-(4-(2,6-Dimethoxyphenyl)-5-(2-furanyl)-4H-1,2,4-triazol-3-yl)-1-(5-fluoro-2-pyrimidinyl)-2-propanesulfonamide and (2S)—N-(4-(2,6-dimethoxyphenyl)-5-(2-furanyl)-4H-1,2,4-triazol-3-yl)-1-(5-fluoro-2-pyrimidinyl)-2-propanesulfonamide, Example 52.0. To a solution of N-(4-(2,6-dimethoxyphenyl)-5-(furan-2-yl)-4H-1,2,4-triazol-3-yl)-1-(5-fluoropyrimidin-2-yl)-N-(2-(trimethylsilyl)ethyl)propane-2-sulfonamide (Example 52.2, 145.3 mg, 0.247 mmol) in DMF (0.5 mL) was added tris(dimethylamino)sulfur trimethylsilyl difluoride (151 mg, 0.548 mmol). The resulting solution was heated at 60° C. over 4 h. The reaction mixture was then cooled to RT. The material was purified by reverse-phase preparative HPLC using an Agilent SB C8 column, 0.1% TFA in ACN/H 2 O, gradient 10% to 60% over 25 min. The desired fraction was lyophilized to give a mixture of (2R)—N-(4-(2,6-dimethoxyphenyl)-5-(2-furanyl)-4H-1,2,4-triazol-3-yl)-1-(5-fluoro-2-pyrimidinyl)-2-propanesulfonamide and (2S)—N-(4-(2,6-dimethoxyphenyl)-5-(2-furanyl)-4H-1,2,4-triazol-3-yl)-1-(5-fluoro-2-pyrimidinyl)-2-propanesulfonamide. 1 H NMR (500 MHz, CDCl 3 ) δ 1.32 (d, J=6.85 Hz, 3H) 3.09 (dd, J=14.67, 9.54 Hz, 1H) 3.68 (dd, J=14.92, 4.65 Hz, 1H) 3.76 (d, J=9.05 Hz, 6H) 3.79-3.85 (m, 1H) 6.01 (d, J=3.42 Hz, 1H) 6.34 (dd, J=3.42, 1.71 Hz, 1H) 6.68 (dd, J=8.56, 2.45 Hz, 2H) 7.43-7.51 (m, 2H) 8.56 (s, 2H). LCMS ESI (pos.) m/z: 489.1 (M+H) + .

Example 53.0. Preparation of (2R,3S)—N-(4-(2,6-dimethoxyphenyl)-5-(5-methyl-2-furanyl)-4H-1,2,4-triazol-3-yl)-3-(5-ethyl-2-pyrimidinyl)-2-butanesulfonamide or (2S,3R)—N-(4-(2,6-dimethoxyphenyl)-5-(5-methyl-2-furanyl)-4H-1,2,4-triazol-3-yl)-3-(5-ethyl-2-pyrimidinyl)-2-butanesulfonamide

(2S,3R)-3-(5-Ethylpyrimidin-2-yl)butane-2-sulfonamide or (2R,3S)-3-(5-ethylpyrimidin-2-yl)butane-2-sulfonamide, Example 53.1. To a stirred solution of (E)-3-(5-ethylpyrimidin-2-yl)but-2-ene-2-sulfonamide (0.20 g, 0.83 mmol) in IPA (8.3 mL) was added palladium hydroxide (0.012 g, 0.083 mmol). The reaction was then placed under an atmosphere of hydrogen and stirred overnight. To see partial hydrogenation, the products were separated from the starting material using a chiral AD-H column. The racemic mixture was separated on an AD-H column using 20% EtOH (+20 mM NH 3 ); Rf 2.32-peak one and Rf 2.83-peak two. The title compound (0.04 g, 0.164 mmol, 20%) was the second isomer to elute under these conditions. LCMS-ESI (pos.) m/z: 527.3 (M+H) + .

(2R,3S)—N-(4-(2,6-Dimethoxyphenyl)-5-(5-methyl-2-furanyl)-4H-1,2,4-triazol-3-yl)-3-(5-ethyl-2-pyrimidinyl)-2-butanesulfonamide or (2S,3R)—N-(4-(2,6-dimethoxyphenyl)-5-(5-methyl-2-furanyl)-4H-1,2,4-triazol-3-yl)-3-(5-ethyl-2-pyrimidinyl)-2-butanesulfonamide, Example 53.0. The title compound was prepared following the procedure described in Example 149.0 using Example 53.1 (0.020 g, 0.082 mmol), 5-methylfuran-2-carbohydrazide (0.014 g, 0.098 mmol), 2-isothiocyanato-1,3-dimethoxybenzene, Example 372.0 and TFA. The initial product was subjected to SFC purification. Separation conditions for Example 53.0 were a chiral purification using the following parameters: Run on a Thar 80 SFC with 250×21 mm AD-H column with 12.5 g/min MeOH (neat)+37.5 g/min CO 2 , 25% co-solvent at 50 g/min. Outlet pressure=100 bar; Temp.=RT; Wavelength=276 nm. Manually injected 0.25 mL of a solution from 3 mg sample dissolved in 0.8 mL of MeOH, c=3.75 mg/mL; 0.94 mg per injection. This separation gave the title compound (0.0009 g, 2%). 1 H NMR (500 MHz, CD 2 Cl 2 ) δ 11.22 (br. s., 1H), 8.53 (s, 2H), 7.54-7.49 (m, 1H), 7.52 (t, J=8.6 Hz, 1H), 6.76-6.69 (m, 2H), 5.93 (dd, J=1.0, 3.4 Hz, 1H), 5.85 (d, J=3.4 Hz, 1H), 3.75 (d, J=8.6 Hz, 7H), 3.68-3.59 (m, 1H), 2.62 (q, J=7.6 Hz, 2H), 2.29 (s, 3H), 1.32 (d, J=7.1 Hz, 3H), 1.29-1.24 (m, 9H). LCMS-ESI (pos.) m/z: 527.3 (M+H) + .

Example 54.0. Preparation of (1S,2S)—N-(4-(2,6-dimethoxyphenyl)-5-(5-methyl-2-furanyl)-4H-1,2,4-triazol-3-yl)-1-hydroxy-1-(2-methyl-1,3-oxazol-4-yl)-2-propanesulfonamide or (1R,2R)—N-(4-(2,6-dimethoxyphenyl)-5-(5-methyl-2-furanyl)-4H-1,2,4-triazol-3-yl)-1-hydroxy-1-(2-methyl-1,3-oxazol-4-yl)-2-propanesulfonamide

(1R,2R)—N-(4-(2,6-Dimethoxyphenyl)-5-(5-methyl-2-furanyl)-4H-1,2,4-triazol-3-yl)-1-hydroxy-1-(2-methyl-1,3-oxazol-4-yl)-2-propanesulfonamide and (1S,2S)—N-(4-(2,6-dimethoxyphenyl)-5-(5-methyl-2-furanyl)-4H-1,2,4-triazol-3-yl)-1-hydroxy-1-(2-methyl-1,3-oxazol-4-yl)-2-propanesulfonamide, Example 54.1. The title compound was prepared using Example 369.0 and 2-methyloxazole-4-carboxaldehyde following the general procedure described in Example 281.0. 1 H NMR (400 MHz, DMSO-d 6 ) δ 13.31 (s, 1H), 7.74 (s, 1H), 7.57 (t, J=8.5 Hz, 1H), 6.89 (d, J=8.6 Hz, 2H), 6.13 (d, J=2.5 Hz, 1H), 5.82 (d, J=3.1 Hz, 1H), 4.96-5.08 (m, 1H), 4.68 (dd, J=7.2, 2.9 Hz, 1H), 3.73 (s, 3H), 3.74 (s, 3H), 3.19-3.29 (m, 1H), 2.36 (s, 3H), 2.25 (s, 3H), 1.02 (d, J=7.0 Hz, 3H). LCMS-ESI (pos.) m/z: 504.1 (M+H) + .

(1S,2S)—N-(4-(2,6-Dimethoxyphenyl)-5-(5-methyl-2-furanyl)-4H-1,2,4-triazol-3-yl)-1-hydroxy-1-(2-methyl-1,3-oxazol-4-yl)-2-propanesulfonamide or (1R,2R)—N-(4-(2,6-dimethoxyphenyl)-5-(5-methyl-2-furanyl)-4H-1,2,4-triazol-3-yl)-1-hydroxy-1-(2-methyl-1,3-oxazol-4-yl)-2-propanesulfonamide, Example 54.0. The racemic mixture Example 54.1 was separated by SFC (250×30 mm IC column with 36 g/min MeOH (+20 mM NH 3 )+44 g/min CO 2 , 45% co-solvent at 80 g/min on Thar 80 SFC. Two enantiomers were obtained. The title compound was the second isomer to elute under these conditions. 1 H NMR (500 MHz, CD 2 Cl 2 ) δ 7.51 (t, J=8.6 Hz, 1H), 7.47 (s, 1H), 6.73 (d, J=8.6 Hz, 2H), 5.94 (d, J=2.7 Hz, 1H), 5.88 (d, J=2.9 Hz, 1H), 4.74 (d, J=8.8 Hz, 1H), 3.78 (s, 3H), 3.78 (s, 3H), 3.47-3.39 (m, 1H), 2.40 (s, 3H), 2.29 (s, 3H), 1.09 (d, J=7.1 Hz, 3H). LCMS-ESI (pos.) m/z: 504.2 (M+H) + .

Example 55.0. Preparation of (1S,2S)—N-(4-(2,6-dimethoxyphenyl)-5-(5-methyl-2-furanyl)-4H-1,2,4-triazol-3-yl)-1-hydroxy-1-(2-methyl-1,3-oxazol-4-yl)-2-propanesulfonamide or (1R,2R)—N-(4-(2,6-dimethoxyphenyl)-5-(5-methyl-2-furanyl)-4H-1,2,4-triazol-3-yl)-1-hydroxy-1-(2-methyl-1,3-oxazol-4-yl)-2-propanesulfonamide

›EXAMPLES · 19 of 46

(1S,2S)—N-(4-(2,6-Dimethoxyphenyl)-5-(5-methyl-2-furanyl)-4H-1,2,4-triazol-3-yl)-1-hydroxy-1-(2-methyl-1,3-oxazol-4-yl)-2-propanesulfonamide or (1R,2R)—N-(4-(2,6-dimethoxyphenyl)-5-(5-methyl-2-furanyl)-4H-1,2,4-triazol-3-yl)-1-hydroxy-1-(2-methyl-1,3-oxazol-4-yl)-2-propanesulfonamide, Example 55.0. The racemic mixture (Example 54.1) was separated by SFC (250×30 mm IC column with 36 g/min MeOH (+20 mM NH 3 )+44 g/min CO 2 , 45% co-solvent at 80 g/min on Thar 80 SFC. Two enantiomers were obtained. The title compound was the first isomer to elute under these conditions. 1 H NMR (500 MHz, CD 2 Cl 2 ) δ 7.52 (t, J=8.4 Hz, 1H), 7.47 (s, 1H), 6.73 (d, J=8.6 Hz, 2H), 5.97-5.87 (m, 2H), 4.73 (d, J=8.8 Hz, 1H), 3.78 (s, 3H), 3.78 (s, 3H), 3.47-3.38 (m, 1H), 2.40 (s, 3H), 2.29 (s, 3H), 1.09 (d, J=7.1 Hz, 3H). LCMS-ESI (pos.) m/z: 504.2 (M+H) + .

Example 56.0. Preparation of (2S,3R)—N-(4-(2,6-dimethoxyphenyl)-5-(5-methyl-2-furanyl)-4H-1,2,4-triazol-3-yl)-3-(5-fluoro-2-pyrimidinyl)-2-butanesulfonamide

(E)-2-(But-2-en-2-yl)-5-fluoropyrimidine, Example 56.1. 2-Chloro-5-fluoro-pyrimidine (14.45 mL, 117 mmol), potassium (Z)-but-2-en-2-yltrifluoroborate (24.63 g, 152 mmol), tricyclohexylphosphine (6.56 g, 23.39 mmol), and Pd 2 (dba) 3 (10.71 g, 11.70 mmol) were added to a vial which was then degassed and backfilled with nitrogen. 1,4-Dioxane (195 mL) and aqueous potassium phosphate tribasic (29.0 mL, 351 mmol) were then added by syringe. The resulting reaction was heated at 100° C. for 16 h. The reaction was then cooled to RT. The organics were concentrated in vacuo. The residue was filtered through a plug of silica gel and then loaded onto a silica gel column (0-20% EtOAc in hexanes) to afford Example 56.1 (14.24 g, 94 mmol, 80% yield). LCMS-ESI (pos.) m/a: 153.1 (M+H) + .

2-(2-Chloro-3-(pyrimidin-2-ylthio)butan-2-yl)-5-fluoropyrimidine, Example 56.2. To a solution of pyrimidine-2-thiol (13.27 g, 118 mmol) in DCM (329 mL) was added sulfuryl dichloride (9.62 mL, 118 mmol). The reaction was stirred at 0° C. for 1 h and for a further 1 h at RT. To the initial cloudy reaction was added Example 56.1 (15 g, 99 mmol) dropwise. The reaction was further stirred for 1 h. Next, the reaction mixture was concentrated in vacuo. A saturated aqueous solution of sodium bicarbonate was added to the mixture to neutralize the reaction mixture. The reaction was then extracted with EtOAc and concentrated in vacuo. The residue was purified on silica gel with 0-25% EtOAc in hexanes to give the desired product (Example 56.2, 21 g, 70.3 mmol, 71.3% yield). LCMS-ESI (pos.) m/z: 291.1 (M+H) + .

2-(2-Chloro-3-(pyrimidin-2-ylsulfonyl)butan-2-yl)-5-fluoropyrimidine, Example 56.3. To a solution of Example 56.2 (21 g, 70.3 mmol) in DCM (201 mL) was added 3-chlorobenzoperoxoic acid (24.26 g, 141 mmol) at 0° C. The reaction was then stirred at RT for 1 day. The reaction was concentrated in vacuo and an aqueous solution of sodium bicarbonate and sodium thiosulfate was added. The mixture was extracted with EtOAc and concentrated in vacuo. The material thus was obtained was then purified on silica gel eluting with 0-100% EtOAc in hexanes to give the desired product (18 g, 54.4 mmol, 77% yield). LCMS-ESI (pos.) m/z: 331.1 (M+H) + .

(E)-3-(5-Fluoropyrimidin-2-yl)but-2-ene-2-sulfonamide, Example 56.4. To a stirred solution of Example 56.3 (18 g, 54.4 mmol) in MeOH (136 mL) was added potassium carbonate (15.04 g, 109 mmol). The reaction was stirred at RT for 16 h. Next, the reaction was concentrated in vacuo. The initial sulfinate was dissolved in water (231 mL, 46.3 mmol) and potassium acetate (4.54 g, 46.3 mmol) was added followed by (aminooxy)sulfonic acid (10.47 g, 93 mmol). The reaction was stirred at RT for 3 h. The reaction was then extracted with EtOAc and the combined organic layers were concentrated in vacuo. The product was purified on silica gel eluting with 0-80% EtOAc in hexanes to give the desired product (11.77 g, 46.3 mmol). LCMS-ESI (pos.) m/z: 232.1 (M+H) + .

(2S,3R)-3-(5-Fluoropyrimidin-2-yl)butane-2-sulfonamide, Example 56.5. To a solution of Example 56.4 (0.77 g, 3.33 mmol) in EtOH (8.32 mL) was added zinc(II) trifluoromethanesulfonate (0.121 g, 0.33 mmol), and (R)-(−)-4,12-bis(diphenylphosphino)[2.2]paracyclophane (1,5-cyclooctadiene)rhodium(I) tetrafluoroborate (Strem chemicals, 0.116 g, 0.133 mmol). The reaction mixture was placed under an atmosphere of hydrogen and stirred for 16 h. The reaction was then filtered to give the desired product and the mother liquor was concentrated in vacuo and purified on silica gel eluting with 0-80% EtOAc in hexanes to give the desired product. The combined product was recrystallized from EtOH to give the desired product (0.46 g, 60%, 99% ee). LCMS-ESI (pos.) m/z: 234.2 (M+H) + .

(2S,3R)—N-(4-(2,6-Dimethoxyphenyl)-5-(5-methyl-2-furanyl)-4H-1,2,4-triazol-3-yl)-3-(5-fluoro-2-pyrimidinyl)-2-butanesulfonamide, Example 56.0. The title compound was prepared following the procedure described in Example 92.0 using Example 56.5 and Example 364.1. 1 H NMR (500 MHz, CD 2 Cl 2 ) δ 10.90 (s, 1H), 8.54 (s, 2H), 7.52 (t, J=8.6 Hz, 1H), 6.76-6.70 (m, 2H), 5.95-5.92 (m, 1H), 5.85 (d, J=3.9 Hz, 1H), 3.75 (s, 3H), 3.75 (s, 3H), 3.74-3.67 (m, 2H), 2.29 (s, 3H), 1.32 (d, J=6.8 Hz, 3H), 1.28 (d, J=6.8 Hz, 3H). LCMS-ESI (pos.) m/z: 517.3 (M+H) + .

Example 57.0. Preparation of (1S,2S)—N-(4-(2,6-dimethoxyphenyl)-5-(5-methyl-2-furanyl)-4H-1,2,4-triazol-3-yl)-1-(5-fluoro-2-pyridinyl)-1-hydroxy-2-propanesulfonamide and (1R,2R)—N-(4-(2,6-dimethoxyphenyl)-5-(5-methyl-2-furanyl)-4H-1,2,4-triazol-3-yl)-1-(5-fluoro-2-pyridinyl)-1-hydroxy-2-propanesulfonamide or (1R,2S)—N-(4-(2,6-dimethoxyphenyl)-5-(5-methyl-2-furanyl)-4H-1,2,4-triazol-3-yl)-1-(5-fluoro-2-pyridinyl)-1-hydroxy-2-propanesulfonamide and (1S,2R)—N-(4-(2,6-dimethoxyphenyl)-5-(5-methyl-2-furanyl)-4H-1,2,4-triazol-3-yl)-1-(5-fluoro-2-pyridinyl)-1-hydroxy-2-propanesulfonamide

(1S,2S)—N-(4-(2,6-Dimethoxyphenyl)-5-(5-methylfuran-2-yl)-4H-1,2,4-triazol-3-yl)-1-(5-fluoropyridin-2-yl)-1-hydroxy-N-(2-(trimethylsilyl)ethyl)propane-2-sulfonamide and (1R,2R)—N-(4-(2,6-dimethoxyphenyl)-5-(5-methylfuran-2-yl)-4H-1,2,4-triazol-3-yl)-1-(5-fluoropyridin-2-yl)-1-hydroxy-N-(2-(trimethylsilyl)ethyl)propane-2-sulfonamide or (1R, 2S)—N-(4-(2,6-dimethoxyphenyl)-5-(5-methylfuran-2-yl)-4H-1,2,4-triazol-3-yl)-1-(5-fluoropyridin-2-yl)-1-hydroxy-N-(2-(trimethylsilyl)ethyl)propane-2-sulfonamide and (1S,2R)—N-(4-(2,6-dimethoxyphenyl)-5-(5-methylfuran-2-yl)-4H-1,2,4-triazol-3-yl)-1-(5-fluoropyridin-2-yl)-1-hydroxy-N-(2-(trimethylsilyl)ethyl)propane-2-sulfonamide, Example 57.1. N-(4-(2,6-Dimethoxyphenyl)-5-(5-methylfuran-2-yl)-4H-1,2,4-triazol-3-yl)-N-(2-(trimethylsilyl)ethyl)ethanesulfonamide (Example 369.0, 325 mg, 0.66 mmol) was azeotroped with toluene. THF (2.5 mL) was added, and the mixture was cooled in a dry ice-acetone bath. n-BuLi (0.412 mL, 0.660 mmol) was added and the mixture was stirred for 10 min. A THF (1 mL) solution of 5-fluoropicolinaldehyde (99 mg, 0.79 mmol, Frontier Scientific Services Inc., flushed with nitrogen before adding THF) was added dropwise. The reaction mixture was then stirred in a dry ice-acetone bath for 45 mi. before warming to RT. The reaction was stirred overnight. The reaction was quenched with saturated NH 4 Cl and extracted with EtOAc. The EtOAc layer was dried, concentrated, and purified on reverse phase HPLC using an Agilent SB C8 column, 0.1% TFA in ACN/H 2 O) gradient (30-90%) in 2 batches. The two diastereomers (1.5:1 ratio) were separated. Fractions containing the major diastereomer were lyophilized to give 140 mg of the title compound (Example 57.1) as a TFA salt. LCMS-ESI (pos.) m/z: 618.0 (M+H) + .

›EXAMPLES · 20 of 46

Example 59.0. Preparation of (1S,2S)—N-(4-(2,6-dimethoxyphenyl)-5-(5-methyl-2-furanyl)-4H-1,2,4-triazol-3-yl)-1-(5-fluoro-2-pyridinyl)-1-hydroxy-2-propanesulfonamide and (1R,2R)—N-(4-(2,6-dimethoxyphenyl)-5-(5-methyl-2-furanyl)-4H-1,2,4-triazol-3-yl)-1-(5-fluoro-2-pyridinyl)-1-hydroxy-2-propanesulfonamide or (1R,2S)—N-(4-(2,6-dimethoxyphenyl)-5-(5-methyl-2-furanyl)-4H-1,2,4-triazol-3-yl)-1-(5-fluoro-2-pyridinyl)-1-hydroxy-2-propanesulfonamide and (1S,2R)—N-(4-(2,6-dimethoxyphenyl)-5-(5-methyl-2-furanyl)-4H-1,2,4-triazol-3-yl)-1-(5-fluoro-2-pyridinyl)-1-hydroxy-2-propanesulfonamide

(1S,2S)—N-(4-(2,6-Dimethoxyphenyl)-5-(5-methyl-2-furanyl)-4H-1,2,4-triazol-3-yl)-1-(5-fluoro-2-pyridinyl)-1-hydroxy-2-propanesulfonamide and (1R,2R)—N-(4-(2,6-dimethoxyphenyl)-5-(5-methyl-2-furanyl)-4H-1,2,4-triazol-3-yl)-1-(5-fluoro-2-pyridinyl)-1-hydroxy-2-propanesulfonamide or (1R,2S)—N-(4-(2,6-dimethoxyphenyl)-5-(5-methyl-2-furanyl)-4H-1,2,4-triazol-3-yl)-1-(5-fluoro-2-pyridinyl)-1-hydroxy-2-propanesulfonamide and (1S,2R)—N-(4-(2,6-dimethoxyphenyl)-5-(5-methyl-2-furanyl)-4H-1,2,4-triazol-3-yl)-1-(5-fluoro-2-pyridinyl)-1-hydroxy-2-propanesulfonamide, Example 59.0. A flask was charged with Example 57.1 (140 mg, 0.191 mmol, TFA salt) and azeotroped with toluene and then dried on a high vacuum pump. Tris(dimethylamino)sulfonium difluorotrimethylsilicate (IV) (158 mg, 0.57 mmol) was added to the flask. DMF (1.8 mL) was then added. The resulting solution was heated at 60° C. for 3 hr. LCMS showed incomplete conversion. More tris(dimethylamino)sulfonium difluorotrimethylsilicate (IV) was added, and the reaction was continued overnight. The reaction was then cooled to RT. The initial material was purified by reverse-phase preparative HPLC using an Agilent SB C8 column, 0.1% TFA in ACN/H 2 O, gradient 20% to 75% over 25 min (the peaks that were visible at 220 nm were collected). The desired fractions were lyophilized to provide the title compound (Example 59.0, 119 mg) as a TFA salt. 1 H NMR (400 MHz, CD 3 OD) δ 8.42 (d, J=2.54 Hz, 1H) 7.59-7.67 (m, 2H) 7.56 (t, J=8.51 Hz, 1H) 6.85 (dd, J=8.51, 2.45 Hz, 2H) 6.01-6.04 (m, 1H) 5.97 (d, J=3.52 Hz, 1H) 5.35-5.39 (m, 1H) 3.78 (s, 3H) 3.76 (s, 3H) 3.60 (qd, J=7.04, 2.15 Hz, 1H) 2.26 (s, 3H) 1.10 (d, J=6.85 Hz, 3H). LCMS-ESI (pos.) m/z: 518.0 (M+H) + .

(1S,2S)—N-(4-(2,6-Dimethoxyphenyl)-5-(5-methyl-2-furanyl)-4H-1,2,4-triazol-3-yl)-1-(5-fluoro-2-pyridinyl)-1-hydroxy-2-propanesulfonamide or (1R,2R)—N-(4-(2,6-dimethoxyphenyl)-5-(5-methyl-2-furanyl)-4H-1,2,4-triazol-3-yl)-1-(5-fluoro-2-pyridinyl)-1-hydroxy-2-propanesulfonamide or (1R,2S)—N-(4-(2,6-dimethoxyphenyl)-5-(5-methyl-2-furanyl)-4H-1,2,4-triazol-3-yl)-1-(5-fluoro-2-pyridinyl)-1-hydroxy-2-propanesulfonamide or (1S,2R)—N-(4-(2,6-dimethoxyphenyl)-5-(5-methyl-2-furanyl)-4H-1,2,4-triazol-3-yl)-1-(5-fluoro-2-pyridinyl)-1-hydroxy-2-propanesulfonamide, Example 57.0. Example 59.0 was purified by SFC (Lotus Inc) to give two enantiomers. Chiral separation conditions were as follows: IA (2×15 cm), 25% MeOH/CO 2 , 100 bar, 60 mL/min, 220 nm. Inj volume: 0.75 mL, 11 mg/mL 2:1 MeOH:DCM. The title compound (Example 57.0) was the first peak (faster-eluting) off the chiral column 1 H NMR (400 MHz, CD 3 OD) δ 8.40 (t, J=1.47 Hz, 1H) 7.53-7.61 (m, 3H) 6.85 (dd, J=8.61, 2.74 Hz, 2H) 6.02 (dd, J=3.52, 0.98 Hz, 1H) 5.97 (d, J=3.52 Hz, 1H) 5.36-5.39 (m, 1H) 3.78 (s, 3H) 3.76 (s, 3H) 3.61 (qd, J=6.98, 1.96 Hz, 1H) 2.22-2.29 (m, 3H) 1.09 (d, J=7.04 Hz, 3H). LCMS-ESI (pos.) m/z: 518.0 (M+H) + .

Example 58.0. Preparation of (2R)-2-(5-cyano-2-pyridinyl)-N-(4-(2,6-dimethoxyphenyl)-5-(5-methyl-2-furanyl)-4H-1,2,4-triazol-3-yl)-2-hydroxyethanesulfonamide or (2S)-2-(5-cyano-2-pyridinyl)-N-(4-(2,6-dimethoxyphenyl)-5-(5-methyl-2-furanyl)-4H-1,2,4-triazol-3-yl)-2-hydroxyethanesulfonamide

2-(5-Bromopyridin-2-yl)-N-(4-(2,6-dimethoxyphenyl)-5-(5-methylfuran-2-yl)-4H-1,2,4-triazol-3-yl)-2-hydroxyethanesulfonamide, Example 58.1. The title compound was prepared as a TFA salt following the procedure described in Example 57.0 employing Example 368.0 and 5-bromopicolinaldehyde. LCMS-ESI (pos.) m/z: 565.9 (M+H) + .

(2R)-2-(5-Cyano-2-pyridinyl)-N-(4-(2,6-dimethoxyphenyl)-5-(5-methyl-2-furanyl)-4H-1,2,4-triazol-3-yl)-2-hydroxyethanesulfonamide and (2S)-2-(5-cyano-2-pyridinyl)-N-(4-(2,6-dimethoxyphenyl)-5-(5-methyl-2-furanyl)-4H-1,2,4-triazol-3-yl)-2-hydroxyethanesulfonamide, Example 58.2. A microwave tube was charged with dicyanozinc (58.2 mg, 0.50 mmol, Alfa Aesar), Pd(PPh 3 ) 4 (69.8 mg, 0.060 mmol, Strem Chemicals Inc.), and Example 58.1 (205 mg, 0.302 mmol). Argon-degassed DMF (2.5 mL) was added, and the reaction was degassed again with argon. The reaction mixture was then heated to 120° C. for 1 h in a microwave. Water was added, and the reaction was extracted with EtOAc. The EtOAc layer was washed with brine, dried, concentrated in vacuo, and purified on reverse phase HPLC in 2 batches using an Agilent SB C8 column, 0.1% TFA in ACN/H 2 O, gradient 30-70% over 25 min and collecting peaks at 220 nM to provide the title compound (Example 58.2, 97 mg) as a white solid. 1 H NMR (400 MHz, CD 3 OD) δ 8.83-8.85 (m, 1H) 8.15 (dd, J=8.22, 2.15 Hz, 1H) 7.72 (d, J=8.22 Hz, 1H) 7.56 (t, J=8.51 Hz, 1H) 6.86 (d, J=0.98 Hz, 1H) 6.83 (d, J=0.78 Hz, 1H) 6.02 (dd, J=4.81 Hz, 1H) 5.96 (d, J=3.52 Hz, 1H) 5.21 (dd, J=8.71, 3.23 Hz, 1H) 3.77 (s, 3H) 3.77 (s, 3H) 3.69 (dd, J=14.28, 3.33 Hz, 1H) 3.31 (m, 1H) 2.26 (s, 3H). LCMS-ESI (pos.) m/z: 511.0 (M+H) + .

›EXAMPLES · 21 of 46

(2R)-2-(5-Cyano-2-pyridinyl)-N-(4-(2,6-dimethoxyphenyl)-5-(5-methyl-2-furanyl)-4H-1,2,4-triazol-3-yl)-2-hydroxyethanesulfonamide or (2S)-2-(5-cyano-2-pyridinyl)-N-(4-(2,6-dimethoxyphenyl)-5-(5-methyl-2-furanyl)-4H-1,2,4-triazol-3-yl)-2-hydroxyethanesulfonamide, Example 58.0. The racemate Example 58.2 was separated by SFC to give two single enantiomers. Chiral separation conditions were as follows: Run on Thar 80 SFC with 250×30 mm IC column with 44 g/min MeOH (neat)+36 g/min CO 2 , 55% co-solvent at 80 g/min. Outlet pressure=100 bar; Temp.=27° C.; Wavelength=222 nm. injected 0.2 mL of a solution from 29 mg sample dissolved in 3 mL of MeOH/DCM (50% DCM), c=9.6 mg/mL; 1.9 mg per injection. Cycle time 5.2 min, run time 12 min. The title compound was the first peak (faster-eluting) from the chiral separation. 1 H NMR (400 MHz, CD 3 OD) δ 8.82-8.85 (m, 1H) 8.15 (dd, J=8.22, 215 Hz, 1H) 7.72 (d, J=8.22 Hz, 1H) 7.56 (t, J=8.30 Hz, 1H) 6.84 (dd, J=8.51, 0.88 Hz, 2H) 6.02 (d, J=3.79 Hz, 1H) 5.96 (d, J=3.52 Hz, 1H) 5.21 (dd, J=8.71, 3.23 Hz, 1H) 3.77 (s, 3H) 3.77 (s, 3H) 3.69 (dd, J=14.08, 3.33 Hz, 1H) 3.27-3.35 (m, 1H) 2.26 (s, 3H). LCMS-ESI (pos.) m/z: 511.0 (M+H) + .

Example 60.0. Preparation of (2R)—N-(4-(2,6-dimethoxyphenyl)-5-(5-methyl-2-furanyl)-4H-1,2,4-triazol-3-yl)-2-(5-fluoro-2-pyridinyl)-2-hydroxyethanesulfonamide and (2S)—N-(4-(2,6-dimethoxyphenyl)-5-(5-methyl-2-furanyl)-4H-1,2,4-triazol-3-yl)-2-(5-fluoro-2-pyridinyl)-2-hydroxyethanesulfonamide

(2R)—N-(4-(2,6-Dimethoxyphenyl)-5-(5-methyl-2-furanyl)-4H-1,2,4-triazol-3-yl)-2-(5-fluoro-2-pyridinyl)-2-hydroxyethanesulfonamide and (2S)—N-(4-(2,6-dimethoxyphenyl)-5-(5-methyl-2-furanyl)-4H-1,2,4-triazol-3-yl)-2-(5-fluoro-2-pyridinyl)-2-hydroxyethanesulfonamide, Example 60.0. The title compound was prepared according to the procedure described in Example 59.0 using Example 368.0 and 5-fluoropicolinaldehyde. 1 H NMR (400 MHz, CD 3 OD) δ 8.43 (d, J=2.35 Hz, 1H) 7.59-7.69 (m, 2H) 7.55 (t, J=8.51 Hz, 1H) 6.84 (d, J=8.61 Hz, 2H) 6.02 (d, J=3.93 Hz, 1H) 5.96 (d, J=3.33 Hz, 1H) 5.20 (dd, J=8.51, 3.42 Hz, 1H) 3.77 (s, 3H) 3.76 (s, 3H) 3.63 (dd, J=14.18, 3.42 Hz, 1H) 3.32-3.37 (m, 1H) 2.25 (s, 3H). LCMS-ESI (pos.) m/z: 504.0 (M+H) + .

Example 61.0. Preparation of (1R,2S)-1-(4-cyano-2-fluorophenyl)-N-(4-(2,6-dimethoxyphenyl)-5-(5-methyl-2-furanyl)-4H-1,2,4-triazol-3-yl)-1-hydroxy-2-propanesulfonamide or (1S,2R)-1-(4-cyano-2-fluorophenyl)-N-(4-(2,6-dimethoxyphenyl)-5-(5-methyl-2-furanyl)-4H-1,2,4-triazol-3-yl)-1-hydroxy-2-propanesulfonamide or (1S,2S)-1-(4-cyano-2-fluorophenyl)-N-(4-(2,6-dimethoxyphenyl)-5-(5-methyl-2-furanyl)-4H-1,2,4-triazol-3-yl)-1-hydroxy-2-propanesulfonamide or (1R,2R)-1-(4-cyano-2-fluorophenyl)-N-(4-(2,6-dimethoxyphenyl)-5-(5-methyl-2-furanyl)-4H-1,2,4-triazol-3-yl)-1-hydroxy-2-propanesulfonamide

(1S,2S)-1-(4-Bromo-2-fluorophenyl)-N-(4-(2,6-dimethoxyphenyl)-5-(5-methylfuran-2-yl)-4H-1,2,4-triazol-3-yl)-1-hydroxy-N-(2-(trimethylsilyl)ethyl)propane-2-sulfonamide and (1R,2R)-1-(4-bromo-2-fluorophenyl)-N-(4-(2,6-dimethoxyphenyl)-5-(5-methylfuran-2-yl)-4H-1,2,4-triazol-3-yl)-1-hydroxy-N-(2-(trimethylsilyl)ethyl)propane-2-sulfonamide and (1S,2R)-1-(4-bromo-2-fluorophenyl)-N-(4-(2,6-dimethoxyphenyl)-5-(5-methylfuran-2-yl)-4H-1,2,4-triazol-3-yl)-1-hydroxy-N-(2-(trimethylsilyl)ethyl)propane-2-sulfonamide and (1R,2S)-1-(4-bromo-2-fluorophenyl)-N-(4-(2,6-dimethoxyphenyl)-5-(5-methylfuran-2-yl)-4H-1,2,4-triazol-3-yl)-1-hydroxy-N-(2-(trimethylsilyl)ethyl)propane-2-sulfonamide, Example 61.1. The title compound was prepared from Example 369.0 following the procedure described in Example 59.0. The initial product was purified by chromatography on a Redi-Sep pre-packed gold silica gel column with 0-50% gradient EtOAc in hexanes to provide the title compound (Example 61.1) as a 2.3:1 ratio of diastereomers.

(1R,2S)-1-(4-Bromo-2-fluorophenyl)-N-(4-(2,6-dimethoxyphenyl)-5-(5-methyl-2-furanyl)-4H-1,2,4-triazol-3-yl)-1-hydroxy-2-propanesulfonamide and (1S,2R)-1-(4-bromo-2-fluorophenyl)-N-(4-(2,6-dimethoxyphenyl)-5-(5-methyl-2-furanyl)-4H-1,2,4-triazol-3-yl)-1-hydroxy-2-propanesulfonamide and (1S,2S)-1-(4-bromo-2-fluorophenyl)-N-(4-(2,6-dimethoxyphenyl)-5-(5-methyl-2-furanyl)-4H-1,2,4-triazol-3-yl)-1-hydroxy-2-propanesulfonamide and (1R,2R)-1-(4-bromo-2-fluorophenyl)-N-(4-(2,6-dimethoxyphenyl)-5-(5-methyl-2-furanyl)-4H-1,2,4-triazol-3-yl)-1-hydroxy-2-propanesulfonamide, Example 75.0. The title compound was prepared from Example 61.1 following the procedure described in Example 58.2 to install the cyano group followed by removal of the silyl protecting group following the procedure described in Example 59.0 employing tris(dimethylamino)sulfonium difluorotrimethylsilicate (IV). 1 H NMR (400 MHz, CD 3 OD) δ 7.61-7.73 (m, 1H) 7.54-7.59 (m, 2H) 7.48-7.54 (m, 1H) 6.87 (d, J=3.52 Hz, 1H) 6.84 (d, J=3.52 Hz, 1H) 6.03 (dd, J=3.52, 0.98 Hz, 1H) 5.96 (d, J=3.52 Hz, 1H) 5.65-5.18 (m, 1H) 3.79-3.81 (m, 3H) 3.76-3.78 (m, 3H) 3.37-3.20 (m, 1H) 2.26 (s, 3H) 1.05-1.19 (m, 3H). LCMS-ESI (pos.) m/z: 542.3 (M+H) + .

(1R,2S)-1-(4-Cyano-2-fluorophenyl)-N-(4-(2,6-dimethoxyphenyl)-5-(5-methyl-2-furanyl)-4H-1,2,4-triazol-3-yl)-1-hydroxy-2-propanesulfonamide or (1S,2R)-1-(4-cyano-2-fluorophenyl)-N-(4-(2,6-dimethoxyphenyl)-5-(5-methyl-2-furanyl)-4H-1,2,4-triazol-3-yl)-1-hydroxy-2-propanesulfonamide or (1S,2S)-1-(4-cyano-2-fluorophenyl)-N-(4-(2,6-dimethoxyphenyl)-5-(5-methyl-2-furanyl)-4H-1,2,4-triazol-3-yl)-1-hydroxy-2-propanesulfonamide or (1R,2R)-1-(4-cyano-2-fluorophenyl)-N-(4-(2,6-dimethoxyphenyl)-5-(5-methyl-2-furanyl)-4H-1,2,4-triazol-3-yl)-1-hydroxy-2-propanesulfonamide, Example 61.0. Example 75.0 was separated by SFC into four isomers. Separation condition were as follows: Stage 1: Run with 250×30 mm IC column with 30 mL/min EtOH(Neat)+90 g/min CO 2 on Thar 200 SFC, 120 g/min at 25% co-solvent. Outlet pressure=100 bar; Temp.=20° C.; Wavelength=225 nm. Used 0.35 mL injections of 30 mg/5 mL (16.6 mg/mL) sample solution MeOH and DCM (1:1), i.e. 5.8 mg/injection. Cycle time 14.5 min. Run time=30 min. Stage 2: Peak 3 from stage 1 was dried down and re-screened for separation. Run with 250×30 mm AS-H column with 24 mL/min MeOH (Neat)+96 g/min CO 2 on Thar 200 SFC, 120 g/min at 20% co-solvent. Outlet pressure=100 bar; Temp.=20° C.; Wavelength=225 nm. Used 1 mL injections sample dissolved in 8 mL MeOH (30% DCM), Cycle time 10.0 min. Run time=12.5 min. The title compound was the second peak of the major diastereomer pair (stage 2, peak 2) to elute on subjecting Example 75.0 to the SFC conditions described above. 1 H NMR (400 MHz, CDCl 3 ) δ 10.83 (s, 1H) 7.67 (t, J=7.53 Hz, 1H) 7.51 (t, J=8.51 Hz, 1H) 7.45-7.48 (m, 1H) 7.32 (dd, J=9.78, 1.17 Hz, 1H) 6.73 (d, J=8.61 Hz, 1H) 6.70 (d, J=8.61 Hz, 1H) 5.90-6.02 (m, 1H) 5.88 (d, J=3.52 Hz, 1H) 5.76 (s, 1H) 4.13 (s, 1H) 3.86 (s, 3H) 3.77 (s, 3H) 3.45-3.53 (m, 1H) 3.22-3.32 (m, 1H) 2.33 (s, 3H) 1.15 (d, J=7.04 Hz, 3H). LCMS-ESI (pos.) m/z: 542.0 (M+H) + .

›EXAMPLES · 22 of 46

Example 62.0. Preparation of (3S,4R)—N-(4-(2,6-dimethoxyphenyl)-5-(5-methyl-2-furanyl)-4H-1,2,4-triazol-3-yl)-1-hydroxy-4-(5-methyl-2-pyrimidinyl)-3-pentanesulfonamide or (3R,4S)—N-(4-(2,6-dimethoxyphenyl)-5-(5-methyl-2-furanyl)-4H-1,2,4-triazol-3-yl)-1-hydroxy-4-(5-methyl-2-pyrimidinyl)-3-pentanesulfonamide or (3S,4S)—N-(4-(2,6-dimethoxyphenyl)-5-(5-methyl-2-furanyl)-4H-1,2,4-triazol-3-yl)-1-hydroxy-4-(5-methyl-2-pyrimidinyl)-3-pentanesulfonamide or (3R,4R)—N-(4-(2,6-dimethoxyphenyl)-5-(5-methyl-2-furanyl)-4H-1,2,4-triazol-3-yl)-1-hydroxy-4-(5-methyl-2-pyrimidinyl)-3-pentanesulfonamide

2-(1-Ethoxyvinyl)-5-methylpyrimidine, Example 62.1. A flask was charged with 2-chloro-5-methylpyrimidine (5.0 g, 38.9 mmol, Indofine Inc.), Pd(PPh 3 ) 4 (4.49 g, 3.89 mmol, Strem Chemicals Inc.) and purged with nitrogen. Degassed 1,4-dioxane (90 mL) was added followed by tributyl(1-ethoxyvinyl)stannane (19.71 mL, 58.3 mmol). The reaction was heated to 100° C. for 16 h. The reaction mixture was concentrated and directly purified by chromatography through a Redi-Sep pre-packed gold silica gel column, eluting with a gradient of 0% to 40% EtOAc in hexanes to provide the title compound (Example 62.1, 3.3 g, 52%). LCMS-ESI (pos.) m/z: 165.1 (M+H) + .

1-(5-Methylpyrimidin-2-yl)ethanone, Example 62.2. 2-(1-Ethoxyvinyl)-5-methylpyrimidine (Example 62.1, 3.3 g, 20.10 mmol) was dissolved in 1,4-dioxane (20 mL). HCl (8.04 mL, 40.2 mmol, 5 M, Macron Chemicals) was added, and the reaction was heated at 80° C. for 15 min. The reaction was carefully neutralized with 5N NaOH to pH neutral and concentrated to dryness. The mixture was diluted with 30% IPA in CHCl 3 and filtered. The filtrate was purified by chromatography through a Redi-Sep pre-packed gold silica gel column eluting with a gradient of 0-80% EtOAc in heptanes and then 2-5% MeOH/DCM to provide the title compound (Example 62.2, 1.69 g) as a white solid. LCMS-ESI (pos.) m/z: 159.1 (M+Na) + .

(3-Bromopropoxy)(tert-butyl)diphenylsilane, Example 62.3. A flask was charged with 1H-imidazole (10.78 g, 158 mmol), and DCM (250 mL) was added followed by 3-bromopropan-1-ol (6.51 mL, 71.9 mmol) and tert-butylchlorodiphenylsilane (18.78 mL, 73.4 mmol). The reaction was stirred overnight under nitrogen. Next, water was added and the reaction was extracted with DCM. The DCM layer was washed with brine, dried, and purified by chromatography through a Redi-Sep pre-packed gold silica gel column eluting with a gradient of 0-5% EtOAc in hexanes to give Example 62.3, (21.72 g, 80%). 1 H NMR (400 MHz, CDCl 3 ) δ 7.66-7.70 (m, 4H) 7.38-7.47 (m, 6H) 3.80 (t, J=5.77 Hz, 2H) 3.60 (t, J=6.55 Hz, 2H) 2.09 (quin, J=6.16 Hz, 2H) 1.03-1.11 (m, 9H).

(3-((tert-Butyldiphenylsilyl)oxy)propyl)triphenylphosphonium bromide, Example 62.4. (3-Bromopropoxy)(tert-butyl)diphenylsilane (Example 62.3, 21.94 g, 58.1 mmol) was azeotroped with toluene. To this was added triphenylphosphine (12.2 g, 46.5 mmol) followed by benzene (31 mL). The resulting mixture was heated overnight at reflux. A white precipitate formed and was removed by filteration. The filtrate was heated to reflux. More precipitate formed which was collected and combined with the previous batch. The solids were dried to yield (3-((tert-butyldiphenylsilyl)oxy)propyl)triphenylphosphonium bromide (Example 62.4, 18.83 g) which was directly used in the next step.

(E)-2-(5-((tert-Butyldiphenylsilyl)oxy)pent-2-en-2-yl)-5-methylpyrimidine, Example 62.5. (3-((tert-Butyldiphenylsilyl)oxy)propyl)triphenylphosphonium bromide (Example 62.4, 15.09 g, 23.58 mmol) was azeotroped with toluene and dried on a high vacuum pump overnight. The material was suspended in THF (100 mL) under nitrogen. The suspension was cooled in an ice-bath and sodium bis(trimethylsilyl)amide (1.0 M, 25.2 mL, 25.2 mmol) was added dropwise. After 30 min., 1-(5-methylpyrimidin-2-yl)ethanone (Example 62.2, 1.97 g, 14.47 mmol) in THF (5 mL) was added. The mixture was stirred overnight. A saturated NH 4 Cl solution was then added, and the reaction was extracted with EtOAc. The EtOAc layer was dried, concentrated in vacuo, and purified by chromatography through a Redi-Sep pre-packed gold silica gel column eluting with a gradient 0-10% EtOAc in hexanes to obtain the desired product (3.99 g) that contained an impurity but was carried on to the next step without further purification. LCMS-ESI (pos.) m/z: 417.2 (M+H) + .

(E)-4-(5-Methylpyrimidin-2-yl)pent-3-en-1-ol, Example 62.6. To a flask containing (E)-2-(5-((tert-butyldiphenylsilyl)oxy)pent-2-en-2-yl)-5-methylpyrimidine (Example 62.5, 3.99 g, 9.58 mmol) was added THF (28 mL) and then TBAF (3.54 mL, 3.54 mmol). The reaction was stirred overnight. Next, the reaction was concentrated and then dry-loaded onto a silica gel column (80 g) and purified with gradient 0-85% EtOAc in hexanes then gradient 0-10% MeOH/DCM to obtain Example 62.6 (1.43 g, 84%) as a white solid. LCMS-ESI (pos.) m/z: 179.2 (M+H) + .

(3S,4R)—N-(4-(2,6-Dimethoxyphenyl)-5-(5-methyl-2-furanyl)-4H-1,2,4-triazol-3-yl)-1-hydroxy-4-(5-methyl-2-pyrimidinyl)-3-pentanesulfonamide and (3R,4S)—N-(4-(2,6-dimethoxyphenyl)-5-(5-methyl-2-furanyl)-4H-1,2,4-triazol-3-yl)-1-hydroxy-4-(5-methyl-2-pyrimidinyl)-3-pentanesulfonamide and (3S,4S)—N-(4-(2,6-dimethoxyphenyl)-5-(5-methyl-2-furanyl)-4H-1,2,4-triazol-3-yl)-1-hydroxy-4-(5-methyl-2-pyrimidinyl)-3-pentanesulfonamide and (3R,4R)—N-(4-(2,6-dimethoxyphenyl)-5-(5-methyl-2-furanyl)-4H-1,2,4-triazol-3-yl)-1-hydroxy-4-(5-methyl-2-pyrimidinyl)-3-pentanesulfonamide, Example 77.0. The title compound was prepared from Example 62.6 following the procedure described in Example 70.0. 1 H NMR (400 MHz, CD 3 OD) δ 8.59 (m, 2H) 7.54 (m, 1H) 6.82 (m, 2H) 6.01 (m, 1H) 5.93 (m, 1H) 3.77 (m, 7H) 3.58 (m, 3H) 2.32 (m, 3H) 2.26 (s, 3H) 1.98 (m, 2H) 1.41 (m, 3H). LCMS-ESI (pos.) m/z: 543.0 (M+H) + .

›EXAMPLES · 23 of 46

(3S,4R)—N-(4-(2,6-Dimethoxyphenyl)-5-(5-methyl-2-furanyl)-4H-1,2,4-triazol-3-yl)-1-hydroxy-4-(5-methyl-2-pyrimidinyl)-3-pentanesulfonamide or (3R,4S)—N-(4-(2,6-dimethoxyphenyl)-5-(5-methyl-2-furanyl)-4H-1,2,4-triazol-3-yl)-1-hydroxy-4-(5-methyl-2-pyrimidinyl)-3-pentanesulfonamide or (3S,4S)—N-(4-(2,6-dimethoxyphenyl)-5-(5-methyl-2-furanyl)-4H-1,2,4-triazol-3-yl)-1-hydroxy-4-(5-methyl-2-pyrimidinyl)-3-pentanesulfonamide or (3R,4R)—N-(4-(2,6-dimethoxyphenyl)-5-(5-methyl-2-furanyl)-4H-1,2,4-triazol-3-yl)-1-hydroxy-4-(5-methyl-2-pyrimidinyl)-3-pentanesulfonamide, Example 62.0. Example 77.0 was separated by SFC into four peaks. Separation conditions were as follows: 250×30 mm CC 4 column with 54 mL/min MeOH (20 mM Ammonia)+66 g/min CO 2 on Thar 350 SFC, 45% co-solvent at 120 g/min. Outlet pressure=100 bar; Temp.=20° C.; Wavelength=276 nm. Used 0.8 mL injections of 140 mg/17 mL (8.2 mg/mL) sample solution in MeOH:DCM (14:3), i.e. 6.6 mg/injection. Cycle time=18 min., Run time=19 min. The title compound was the first peak (faster-eluting) from the chiral separation. 1 H NMR (400 MHz, CD 3 OD) δ 8.57 (s, 2H) 7.53 (t, J=8.51 Hz, 1H) 6.82 (dd, J=8.61, 0.98 Hz, 2H) 6.01 (dd, J=3.52, 0.98 Hz, 1H) 5.93 (d, J=3.52 Hz, 1H) 3.90 (m, 1H) 3.78 (m, 1H) 3.75 (s, 3H) 3.74 (s, 3H) 3.49 (m, 1H) 3.40 (m, 1H) 2.30 (s, 3H) 2.26 (s, 3H) 2.08 (m, 1H) 1.82 (m, 1H) 1.37 (d, J=7.04 Hz, 3H). LCMS-ESI (pos.) m/z: 543.0 (M+H) + .

Example 63.0. Preparation of (1S,2S)—N-(4-(2,6-dimethoxyphenyl)-5-(5-methyl-2-furanyl)-4H-1,2,4-triazol-3-yl)-1-hydroxy-1-(5-methyl-2-pyridinyl)-2-propanesulfonamide or (1R,2R)—N-(4-(2,6-dimethoxyphenyl)-5-(5-methyl-2-furanyl)-4H-1,2,4-triazol-3-yl)-1-hydroxy-1-(5-methyl-2-pyridinyl)-2-propanesulfonamide or (1R,2S)—N-(4-(2,6-dimethoxyphenyl)-5-(5-methyl-2-furanyl)-4H-1,2,4-triazol-3-yl)-1-hydroxy-1-(5-methyl-2-pyridinyl)-2-propanesulfonamide or (1S,2R)—N-(4-(2,6-dimethoxyphenyl)-5-(5-methyl-2-furanyl)-4H-1,2,4-triazol-3-yl)-1-hydroxy-1-(5-methyl-2-pyridinyl)-2-propanesulfonamide

(1S,2S)-1-Hydroxy-1-(5-methylpyridin-2-yl)propane-2-sulfonamide and (1R,2R)-1-hydroxy-1-(5-methylpyridin-2-yl)propane-2-sulfonamide, or (1R,2S)-1-hydroxy-1-(5-methylpyridin-2-yl)propane-2-sulfonamide and (1S,2R)-1-hydroxy-1-(5-methylpyridin-2-yl)propane-2-sulfonamide, Example 63.1. The title compound was prepared according to the procedure described in Example 356.04 using Example 361.0 and 5-methylpicolinaldehyde. Example 63.1 is the major diastereomer pair isolated after purification on silica gel.

(1S,2S)-1-Hydroxy-1-(5-methylpyridin-2-yl)propane-2-sulfonamide and (1R,2R)-1-hydroxy-1-(5-methylpyridin-2-yl)propane-2-sulfonamide, or (1R,2S)-1-hydroxy-1-(5-methylpyridin-2-yl)propane-2-sulfonamide and (1S,2R)-1-hydroxy-1-(5-methylpyridin-2-yl)propane-2-sulfonamide, Example 63.2. The title compound was prepared according to the procedure described in Example 63.1. Example 63.2 is the minor diastereomer pair isolated after silica gel chromatography.

(Z)—N′-(2,6-Dimethoxyphenyl)-N-(((1S,2S)-1-hydroxy-1-(5-methylpyridin-2-yl)propan-2-yl)sulfonyl)-2-(5-methylfuran-2-carbonyl)hydrazinecarboximidamide and (Z)—N′-(2,6-dimethoxyphenyl)-N-(((1R,2R)-1-hydroxy-1-(5-methylpyridin-2-yl)propan-2-yl)sulfonyl)-2-(5-methylfuran-2-carbonyl)hydrazinecarboximidamide or (Z)—N′-(2,6-dimethoxyphenyl)-N-(1R,2S)-1-hydroxy-1-(5-methylpyridin-2-yl)propan-2-yl)sulfonyl)-2-(5-methylfuran-2-carbonyl)hydrazinecarboximidamide and (Z)—N′-(2,6-dimethoxyphenyl)-N-(((1S,2R)-1-hydroxy-1-(5-methylpyridin-2-yl)propan-2-yl)sulfonyl)-2-(5-methylfuran-2-carbonyl)hydrazinecarboximidamide, Example 63.3. The title compound was prepared according to the general procedure described in the synthesis of Example 149.0 using Example 63.1, Example 372.0, and 5-methyl-2-furohydrazide (commercially available from Chembridge Corporation, San Diego, Calif., USA).

Example 65.0. Preparation of (1S,2S)—N-(4-(2,6-dimethoxyphenyl)-5-(5-methyl-2-furanyl)-4H-1,2,4-triazol-3-yl)-1-hydroxy-1-(5-methyl-2-pyridinyl)-2-propanesulfonamide and (1R,2R)—N-(4-(2,6-dimethoxyphenyl)-5-(5-methyl-2-furanyl)-4H-1,2,4-triazol-3-yl)-1-hydroxy-1-(5-methyl-2-pyridinyl)-2-propanesulfonamide or (1R,2S)—N-(4-(2,6-dimethoxyphenyl)-5-(5-methyl-2-furanyl)-4H-1,2,4-triazol-3-yl)-1-hydroxy-1-(5-methyl-2-pyridinyl)-2-propanesulfonamide and (1S,2R)—N-(4-(2,6-dimethoxyphenyl)-5-(5-methyl-2-furanyl)-4H-1,2,4-triazol-3-yl)-1-hydroxy-1-(5-methyl-2-pyridinyl)-2-propanesulfonamide

(1S,2S)—N-(4-(2,6-Dimethoxyphenyl)-5-(5-methyl-2-furanyl)-4H-1,2,4-triazol-3-yl)-1-hydroxy-1-(5-methyl-2-pyridinyl)-2-propanesulfonamide and (1R,2R)—N-(4-(2,6-dimethoxyphenyl)-5-(5-methyl-2-furanyl)-4H-1,2,4-triazol-3-yl)-1-hydroxy-1-(5-methyl-2-pyridinyl)-2-propanesulfonamide and (1R,2S)—N-(4-(2,6-dimethoxyphenyl)-5-(5-methyl-2-furanyl)-4H-1,2,4-triazol-3-yl)-1-hydroxy-1-(5-methyl-2-pyridinyl)-2-propanesulfonamide and (1S,2R)—N-(4-(2,6-dimethoxyphenyl)-5-(5-methyl-2-furanyl)-4H-1,2,4-triazol-3-yl)-1-hydroxy-1-(5-methyl-2-pyridinyl)-2-propanesulfonamide, Example 65.0. Example 63.3 (215 mg, 0.404 mmol) was azeotroped with toluene. DMF (0.6 mL) was added followed by TFA (0.156 mL, 2.02 mmol). The resulting mixture was heated at 100° C. under nitrogen for 6 hr. Next, more TFA (0.156 mL, 2.022 mmol) was added and heating was continued overnight. The reaction was then cooled to RT and concentrated in vacuo and directly purified on reverse phase HPLC (Agilent SB C8 column, 0.1% TFA in ACN/water, 10-60% gradient over 25 min) to give title compound. 1 H NMR (400 MHz, CD 3 OD) δ 8.48 (s, 1H) 8.12 (d, J=8.22 Hz, 1H) 7.58 (m, 2H) 6.87 (dd, J=8.71, 1.66 Hz, 2H) 6.03 (dd, J=3.52, 0.98 Hz, 1H) 5.98 (d, J=3.52 Hz, 1H) 5.36 (d, J=3.72 Hz, 1H) 3.78 (m, 6H) 3.47 (m, 1H) 2.47 (m, 3H) 2.26 (s, 3H) 1.22 (m, 3H). LCMS-ESI (pos.) m/z: 514.0 (M+H) + .

›EXAMPLES · 24 of 46

(1S,2S)—N-(4-(2,6-Dimethoxyphenyl)-5-(5-methyl-2-furanyl)-4H-1,2,4-triazol-3-yl)-1-hydroxy-1-(5-methyl-2-pyridinyl)-2-propanesulfonamide or (1R,2R)—N-(4-(2,6-dimethoxyphenyl)-5-(5-methyl-2-furanyl)-4H-1,2,4-triazol-3-yl)-1-hydroxy-1-(5-methyl-2-pyridinyl)-2-propanesulfonamide or (1R,2S)—N-(4-(2,6-dimethoxyphenyl)-5-(5-methyl-2-furanyl)-4H-1,2,4-triazol-3-yl)-1-hydroxy-1-(5-methyl-2-pyridinyl)-2-propanesulfonamide or (1S,2R)—N-(4-(2,6-dimethoxyphenyl)-5-(5-methyl-2-furanyl)-4H-1,2,4-triazol-3-yl)-1-hydroxy-1-(5-methyl-2-pyridinyl)-2-propanesulfonamide, Example 63.0. Example 65.0 was separated by SFC (separation condition: Run on Thar 80 SFC with 250×21 mm IC column with 27 g/min MeOH (neat)+33 g/min CO 2 , 45% co-solvent at 60 g/min. Outlet pressure=100 bar; Temp.=22° C.; Wavelength=275 nm. Injected 0.5 mL of a solution from 23 mg sample dissolved in 4 mL of MeOH, c=5.8 mg/mL; 2.4 mg per injection.) Two enantiomers were obtained. The title compound was the first peak to elute off the chiral column. 1 H NMR (400 MHz, CD 3 OD) δ 8.32 (s, 1H) 7.65 (dd, J=8.02, 1.76 Hz, 1H) 7.56 (t, J=8.51 Hz, 1H) 7.46 (d, J=8.02 Hz, 1H) 6.85 (dd, J=8.61, 2.54 Hz, 2H) 6.02 (dd, J=3.52, 0.78 Hz, 1H) 5.96 (d, J=3.33 Hz, 1H) 5.38 (s, 1H) 3.77 (s, 3H) 3.76 (s, 3H) 3.55 (m, 1H) 2.33 (s, 3H) 2.26 (s, 3H) 1.07 (d, J=7.04 Hz, 3H). LCMS-ESI (pos.) m/z: 514.0 (M+H) + .

Example 64.0. Preparation of (2R)—N-(4-(2,6-dimethoxyphenyl)-5-(5-methyl-2-furanyl)-4H-1,2,4-triazol-3-yl)-2-(5-fluoro-2-pyridinyl)-2-hydroxyethanesulfonamide or (2S)—N-(4-(2,6-dimethoxyphenyl)-5-(5-methyl-2-furanyl)-4H-1,2,4-triazol-3-yl)-2-(5-fluoro-2-pyridinyl)-2-hydroxyethanesulfonamide

(2R)—N-(4-(2,6-Dimethoxyphenyl)-5-(5-methyl-2-furanyl)-4H-1,2,4-triazol-3-yl)-2-(5-fluoro-2-pyridinyl)-2-hydroxyethanesulfonamide or (2S)—N-(4-(2,6-dimethoxyphenyl)-5-(5-methyl-2-furanyl)-4H-1,2,4-triazol-3-yl)-2-(5-fluoro-2-pyridinyl)-2-hydroxyethanesulfonamide, Example 64.0. Example 60.0 was purified by SFC to give two enantiomers. Chiral separation conditions were as follows: Run on Thar 200 with 250×30 mm AD-H column with 36 g/min EtOH (neat) and 84 g/min CO 2 , 30% co-solvent at 120 g/min. Wavelength 275 nm. Injected 0.5 mL of 90 mg dissolved in 7.0 mL MeOH (25% DCM); 12.8=x/mL, 6.4 mg/injection. Cycle time 9.0 min, run time 21 min. The title compound was the second peak to elute. 1 H NMR (400 MHz, CD 3 OD) δ 8.33-8.44 (m, 1H) 7.52-7.62 (m, 3H) 6.84 (d, J=8.66 Hz, 2H) 6.02 (dd, J=3.87 Hz, 1H) 5.96 (d, J=3.52 Hz, 1H) 5.17 (dd, J=8.71, 3.03 Hz, 1H) 3.78 (s, 3H) 3.77 (s, 3H) 3.63 (dd, J=14.18, 3.23 Hz, 1H) 3.26-3.36 (m, 13H) 2.26 (s, 3H). LCMS-ESI (pos.) m/z: 504.0 (M+H) + .

Example 66.0. Preparation of (2R)-2-(5-cyano-2-pyridinyl)-N-(4-(2,6-dimethoxyphenyl)-5-(5-methyl-2-furanyl)-4H-1,2,4-triazol-3-yl)-2-hydroxyethanesulfonamide or (2S)-2-(5-cyano-2-pyridinyl)-N-(4-(2,6-dimethoxyphenyl)-5-(5-methyl-2-furanyl)-4H-1,2,4-triazol-3-yl)-2-hydroxyethanesulfonamide

(S)-2-(5-Bromopyridin-2-yl)-N-(4-(2,6-dimethoxyphenyl)-5-(5-methylfuran-2-yl)-4H-1,2,4-triazol-3-yl)-2-hydroxyethanesulfonamide and (R)-2-(5-bromopyridin-2-yl)-N-(4-(2,6-dimethoxyphenyl)-5-(5-methylfuran-2-yl)-4H-1,2,4-triazol-3-yl)-2-hydroxyethanesulfonamide, Example 66.1. The title compound (Example 66.1) was prepared as a TFA salt following procedures described in Example 57.0 and Example 59.0 using 5-bromopicolinaldehyde and Example 365.2. LCMS-ESI (pos.) m/z: 565.9 (M+H) + .

(2R)-2-(5-Cyano-2-pyridinyl)-N-(4-(2,6-dimethoxyphenyl)-5-(5-methyl-2-furanyl)-4H-1,2,4-triazol-3-yl)-2-hydroxyethanesulfonamide and (2S)-2-(5-cyano-2-pyridinyl)-N-(4-(2,6-dimethoxyphenyl)-5-(5-methyl-2-furanyl)-4H-1,2,4-triazol-3-yl)-2-hydroxyethanesulfonamide, Example 66.2. A microwave tube was charged with dicyanozinc (58.2 mg, 0.50 mmol, Alfa Aesar), Pd(PPh 3 ) 4 (69.8 mg, 0.060 mmol, Strem Chemicals Inc.), and Example 66.1 (205 mg, 0.302 mmol). Argon-degassed DMF (2.5 mL) was added, and the reaction was degassed again with argon. The reaction was heated to 120° C. for 1 h in a microwave. Water was added and the reaction was extracted with EtOAc. The EtOAc layer was washed with brine, dried, concentrated in vacuo, and purified on reverse phase HPLC in 2 batches using an Agilent SB C8 column, 0.1% TFA in ACN/H 2 O, gradient 30-70% over 25 min and collecting peaks at 220 nM to provide the title compound (97 mg) as a white solid. 1 H NMR (400 MHz, CD 3 OD) δ 8.83-8.85 (m, 1H) 8.15 (dd, J=8.22, 2.15 Hz, 1H) 7.72 (d, J=8.22 Hz, 1H) 7.56 (t, J=8.51 Hz, 1H) 6.86 (d, J=0.98 Hz, 1H) 6.83 (d, J=0.78 Hz, 1H) 6.02 (dd, J=4.81 Hz, 1H) 5.96 (d, J=3.52 Hz, 1H) 5.21 (dd, J=8.71, 3.23 Hz, 1H) 3.77 (s, 3H) 3.77 (s, 3H) 3.69 (dd, J=14.28, 3.33 Hz, 1H) 3.31 (m, 1H) 2.26 (s, 3H). LCMS-ESI (pos.) m/z: 511.0 (M+H) + .

(2R)-2-(5-Cyano-2-pyridinyl)-N-(4-(2,6-dimethoxyphenyl)-5-(5-methyl-2-furanyl)-4H-1,2,4-triazol-3-yl)-2-hydroxyethanesulfonamide or (2S)-2-(5-cyano-2-pyridinyl)-N-(4-(2,6-dimethoxyphenyl)-5-(5-methyl-2-furanyl)-4H-1,2,4-triazol-3-yl)-2-hydroxyethanesulfonamide, Example 66.0. Example 66.2 was separated by SFC into two enantiomers. Chiral separation conditions were as follows: Run on Thar 80 SFC with 250×30 mm IC column with 44 g/min MeOH (neat)+36 g/min CO 2 , 55% co-solvent at 80 g/min. Outlet pressure=100 bar; Temp.=27° C.; Wavelength=222 nm. injected 0.2 mL of a solution from 29 mg sample dissolved in 3 mL of MeOH/DCM (50% DCM), c=9.6 mg/mL; 1.9 mg per injection. Cycle time 5.2 min, run time 12 min. The title compound was the second peak to elute on subjecting Example 66.2 to the SFC conditions described above. 1 H NMR (400 MHz, CD 3 OD) δ 8.82-8.90 (m, 1H) 8.15 (dd, J=8.22, 2.15 Hz, 1H) 7.72 (d, J=8.02 Hz, 1H) 7.56 (t, J=8.34 Hz, 1H) 6.85 (br. s, 1H) 6.83 (br. s, 1H) 6.01-6.04 (m, 1H) 5.96 (d, J=3.33 Hz, 1H) 5.21 (dd, J=8.80, 3.13 Hz, 1H) 3.77 (s, 3H) 3.77 (s, 3H) 3.69 (dd, J=14.18, 3.23 Hz, 1H) 3.26-3.36 (m, 1H) 2.26 (s, 3H). LCMS-ESI (pos.) m/z: 511.0 (M+H) + .

Example 67.0. Preparation of (3S,4R)—N-(4-(2,6-dimethoxyphenyl)-5-(5-methyl-2-furanyl)-4H-1,2,4-triazol-3-yl)-4-(5-fluoro-2-pyrimidinyl)-1-methoxy-3-pentanesulfonamide or (3R,4S)—N-(4-(2,6-dimethoxyphenyl)-5-(5-methyl-2-furanyl)-4H-1,2,4-triazol-3-yl)-4-(5-fluoro-2-pyrimidinyl)-1-methoxy-3-pentanesulfonamide or (3R,4R)—N-(4-(2,6-dimethoxyphenyl)-5-(5-methyl-2-furanyl)-4H-1,2,4-triazol-3-yl)-4-(5-fluoro-2-pyrimidinyl)-1-methoxy-3-pentanesulfonamide or (3S,4S)—N-(4-(2,6-dimethoxyphenyl)-5-(5-methyl-2-furanyl)-4H-1,2,4-triazol-3-yl)-4-(5-fluoro-2-pyrimidinyl)-1-methoxy-3-pentanesulfonamide

›EXAMPLES · 25 of 46

(3R,4S)-4-(5-Fluoropyrimidin-2-yl)-1-methoxypentane-3-sulfonic acid and (3S,4S)-4-(5-fluoropyrimidin-2-yl)-1-methoxypentane-3-sulfonic acid and (3R,4R)-4-(5-fluoropyrimidin-2-yl)-1-methoxypentane-3-sulfonic acid and (3S,4R)-4-(5-fluoropyrimidin-2-yl)-1-methoxypentane-3-sulfonic acid, Example 67.1. The title compound was prepared following the procedures described in Example 72.0 with heating at 60° C. over three days. The initial sulfonic acid was purified further on reverse phase HPLC (Gemini column, the mobile phase was 0.1% TFA in ACN/H 2 O; the method was 2.5% isocratic for 5 min, then grading to 70% over 10 min, then 95% isocratic for 3 min (collected the peaks that were visible at 220 nm). The desired fractions were lyophilized to obtain the title compound. LCMS-ESI (pos.) m/z: 279.0 (M+H) + .

Example 74.0. Preparation of (3S,4R)—N-(4-(2,6-dimethoxyphenyl)-5-(5-methyl-2-furanyl)-4H-1,2,4-triazol-3-yl)-4-(5-fluoro-2-pyrimidinyl)-1-methoxy-3-pentanesulfonamide and (3R,4S)—N-(4-(2,6-dimethoxyphenyl)-5-(5-methyl-2-furanyl)-4H-1,2,4-triazol-3-yl)-4-(5-fluoro-2-pyrimidinyl)-1-methoxy-3-pentanesulfonamide and (3R,4R)—N-(4-(2,6-dimethoxyphenyl)-5-(5-methyl-2-furanyl)-4H-1,2,4-triazol-3-yl)-4-(5-fluoro-2-pyrimidinyl)-1-methoxy-3-pentanesulfonamide and (3S,4S)—N-(4-(2,6-dimethoxyphenyl)-5-(5-methyl-2-furanyl)-4H-1,2,4-triazol-3-yl)-4-(5-fluoro-2-pyrimidinyl)-1-methoxy-3-pentanesulfonamide

(3S,4R)—N-(4-(2,6-Dimethoxyphenyl)-5-(5-methyl-2-furanyl)-4H-1,2,4-triazol-3-yl)-4-(5-fluoro-2-pyrimidinyl)-1-methoxy-3-pentanesulfonamide and (3R,4S)—N-(4-(2,6-dimethoxyphenyl)-5-(5-methyl-2-furanyl)-4H-1,2,4-triazol-3-yl)-4-(5-fluoro-2-pyrimidinyl)-1-methoxy-3-pentanesulfonamide and (3R,4R)—N-(4-(2,6-dimethoxyphenyl)-5-(5-methyl-2-furanyl)-4H-1,2,4-triazol-3-yl)-4-(5-fluoro-2-pyrimidinyl)-1-methoxy-3-pentanesulfonamide and (3S,4S)—N-(4-(2,6-dimethoxyphenyl)-5-(5-methyl-2-furanyl)-4H-1,2,4-triazol-3-yl)-4-(5-fluoro-2-pyrimidinyl)-1-methoxy-3-pentanesulfonamide, Example 74.0. The title compound (Example 74.0) was prepared following the same procedure described in Example 72.0 using Example 67.1. 1 H NMR (400 MHz, CD 3 OD) δ 8.66 (s, 1H) 8.60 (s, 1H) 7.54 (m, 1H) 6.83 (m, 2H), 6.02 (dd, J=3.42, 0.88 Hz, 1H) 5.93 (m, 1H) 3.93-3.77 (m, 1H) 3.79 (s, 3H) 3.77 (m, 3H) 3.63 (m, 1H) 3.44 (t, J=6.94 Hz, 1H) 3.28 (m, 1H) 3.11 (m, 3H) 2.26 (s, 3H) 1.99 (m, 2H) 1.39 (m, 3H). LCMS-ESI (pos.) m/z: 561.0 (M+H) + .

(3S,4R)—N-(4-(2,6-Dimethoxyphenyl)-5-(5-methyl-2-furanyl)-4H-1,2,4-triazol-3-yl)-4-(5-fluoro-2-pyrimidinyl)-1-methoxy-3-pentanesulfonamide or (3R,4S)—N-(4-(2,6-dimethoxyphenyl)-5-(5-methyl-2-furanyl)-4H-1,2,4-triazol-3-yl)-4-(5-fluoro-2-pyrimidinyl)-1-methoxy-3-pentanesulfonamide or (3R,4R)—N-(4-(2,6-dimethoxyphenyl)-5-(5-methyl-2-furanyl)-4H-1,2,4-triazol-3-yl)-4-(5-fluoro-2-pyrimidinyl)-1-methoxy-3-pentanesulfonamide or (3S,4S)—N-(4-(2,6-dimethoxyphenyl)-5-(5-methyl-2-furanyl)-4H-1,2,4-triazol-3-yl)-4-(5-fluoro-2-pyrimidinyl)-1-methoxy-3-pentanesulfonamide, Example 67.0. The racemate Example 74.0 was separated by SFC into four isomers. Separation conditions were as follows: On Thar 350 SFC with 250×30 mm+150×30 mm CC4 columns in series and 45 mL/min MeOH (neat)+55 g/min CO 2 , 45% co-solvent. Outlet pressure=100 bar; Temp.=20° C.; Wavelength=277 nm. Used 0.8 mL injections of 104 mg/12 mL (8.7 mg/mL) sample solution in MeOH:DCM (8:4) for 6.9 mg/injection. Cycle time=5.5 min, Run time=15.5 min. Example 67.0 was the first peak (faster-eluting) off the chiral column 1 H NMR (400 MHz, CD 3 OD) δ 8.66 (s, 2H), 7.54 (t, J=8.51 Hz, 1H), 6.83 (dd, J=8.61, 2.15 Hz, 2H), 6.01 (d, J=3.52 Hz, 1H), 5.94 (d, J=3.33 Hz, 1H), 3.92 (m, 1H), 3.75 (m, 7H), 3.27 (m, 2H), 3.03 (s, 3H), 2.26 (s, 3H), 2.10 (m, 1H), 1.89 (m, 1H), 1.37 (d, J=7.04 Hz, 3H). LCMS-ESI (pos.) m/z: 561.0 (M+H) + .

Example 68.0. Preparation of (1R,2S)-1-(5-cyano-3-fluoro-2-pyridinyl)-N-(4-(2,6-dimethoxyphenyl)-5-(5-methyl-2-furanyl)-4H-1,2,4-triazol-3-yl)-1-hydroxy-2-propanesulfonamide or (1S,2R)-1-(5-cyano-3-fluoro-2-pyridinyl)-N-(4-(2,6-dimethoxyphenyl)-5-(5-methyl-2-furanyl)-4H-1,2,4-triazol-3-yl)-1-hydroxy-2-propanesulfonamide or (1S,2S)-1-(5-cyano-3-fluoro-2-pyridinyl)-N-(4-(2,6-dimethoxyphenyl)-5-(5-methyl-2-furanyl)-4H-1,2,4-triazol-3-yl)-1-hydroxy-2-propanesulfonamide or (1R,2R)-1-(5-cyano-3-fluoro-2-pyridinyl)-N-(4-(2,6-dimethoxyphenyl)-5-(5-methyl-2-furanyl)-4H-1,2,4-triazol-3-yl)-1-hydroxy-2-propanesulfonamide

(1R,2S)-1-(5-Bromo-3-fluoropyridin-2-yl)-N-(4-(2,6-dimethoxyphenyl)-5-(5-methylfuran-2-yl)-4H-1,2,4-triazol-3-yl)-1-hydroxy-N-(2-(trimethylsilyl)ethyl)propane-2-sulfonamide and (1S,2R)-1-(5-bromo-3-fluoropyridin-2-yl)-N-(4-(2,6-dimethoxyphenyl)-5-(5-methylfuran-2-yl)-4H-1,2,4-triazol-3-yl)-1-hydroxy-N-(2-(trimethylsilyl)ethyl)propane-2-sulfonamide or (1S,2S)-1-(5-bromo-3-fluoropyridin-2-yl)-N-(4-(2,6-dimethoxyphenyl)-5-(5-methylfuran-2-yl)-4H-1,2,4-triazol-3-yl)-1-hydroxy-N-(2-(trimethylsilyl)ethyl)propane-2-sulfonamide and (1R,2R)-1-(5-bromo-3-fluoropyridin-2-yl)-N-(4-(2,6-dimethoxyphenyl)-5-(5-methylfuran-2-yl)-4H-1,2,4-triazol-3-yl)-1-hydroxy-N-(2-(trimethylsilyl)ethyl)propane-2-sulfonamide, Example 68.1. The title compound was the less polar diastereomer isolated from the reaction using 5-bromo-3-fluoropicolinaldehyde (Combi-Blocks inc) and Example 369.0 following the procedure described in Example 10.0. LCMS-ESI (pos.) m/z: 698.0 (M+H) + .

(1R,2S)-1-(5-Bromo-3-fluoropyridin-2-yl)-N-(4-(2,6-dimethoxyphenyl)-5-(5-methylfuran-2-yl)-4H-1,2,4-triazol-3-yl)-1-hydroxy-N-(2-(trimethylsilyl)ethyl)propane-2-sulfonamide and (1S,2R)-1-(5-bromo-3-fluoropyridin-2-yl)-N-(4-(2,6-dimethoxyphenyl)-5-(5-methylfuran-2-yl)-4H-1,2,4-triazol-3-yl)-1-hydroxy-N-(2-(trimethylsilyl)ethyl)propane-2-sulfonamide or (1S,2S)-1-(5-bromo-3-fluoropyridin-2-yl)-N-(4-(2,6-dimethoxyphenyl)-5-(5-methylfuran-2-yl)-4H-1,2,4-triazol-3-yl)-1-hydroxy-N-(2-(trimethylsilyl)ethyl)propane-2-sulfonamide and (1R,2R)-1-(5-bromo-3-fluoropyridin-2-yl)-N-(4-(2,6-dimethoxyphenyl)-5-(5-methylfuran-2-yl)-4H-1,2,4-triazol-3-yl)-1-hydroxy-N-(2-(trimethylsilyl)ethyl)propane-2-sulfonamide, Example 68.2. The title compound is the diastereomer of Example 68.1. It was the more polar diastereomer isolated from the reaction described in Example 68.1.

›EXAMPLES · 26 of 46

(1R,2S)-1-(5-Bromo-3-fluoropyridin-2-yl)-N-(4-(2,6-dimethoxyphenyl)-5-(5-methylfuran-2-yl)-4H-1,2,4-triazol-3-yl)-1-hydroxypropane-2-sulfonamide and (1S,2R)-1-(5-bromo-3-fluoropyridin-2-yl)-N-(4-(2,6-dimethoxyphenyl)-5-(5-methylfuran-2-yl)-4H-1,2,4-triazol-3-yl)-1-hydroxypropane-2-sulfonamide or (1S,2S)-1-(5-bromo-3-fluoropyridin-2-yl)-N-(4-(2,6-dimethoxyphenyl)-5-(5-methylfuran-2-yl)-4H-1,2,4-triazol-3-yl)-1-hydroxypropane-2-sulfonamide and (1R,2R)-1-(5-bromo-3-fluoropyridin-2-yl)-N-(4-(2,6-dimethoxyphenyl)-5-(5-methylfuran-2-yl)-4H-1,2,4-triazol-3-yl)-1-hydroxypropane-2-sulfonamide, Example 68.3. The title compound was obtained after removal of the trimethylsilyl ethyl group starting from Example 68.1 following the procedure described in Example 57.0. LCMS-ESI (pos.) m/z: 598.0 (M+H) + .

(1R,2S)-1-(5-Cyano-3-fluoro-2-pyridinyl)-N-(4-(2,6-dimethoxyphenyl)-5-(5-methyl-2-furanyl)-4H-1,2,4-triazol-3-yl)-1-hydroxy-2-propanesulfonamide and (1S,2R)-1-(5-cyano-3-fluoro-2-pyridinyl)-N-(4-(2,6-dimethoxyphenyl)-5-(5-methyl-2-furanyl)-4H-1,2,4-triazol-3-yl)-1-hydroxy-2-propanesulfonamide or (1S,2S)-1-(5-cyano-3-fluoro-2-pyridinyl)-N-(4-(2,6-dimethoxyphenyl)-5-(5-methyl-2-furanyl)-4H-1,2,4-triazol-3-yl)-1-hydroxy-2-propanesulfonamide and (1R,2R)-1-(5-cyano-3-fluoro-2-pyridinyl)-N-(4-(2,6-dimethoxyphenyl)-5-(5-methyl-2-furanyl)-4H-1,2,4-triazol-3-yl)-1-hydroxy-2-propanesulfonamide, Example 68.4. A 10 mL microwave tube was charged with Example 68.4 (36 mg, 0.060 mmol), dicyanozinc (11.62 mg, 0.10 mmol), and Pd(PPh 3 ) 4 (13.95 mg, 0.012 mmol). Argon-degassed DMF (1 mL) was added and the microwave tube was degassed again with argon. The mixture was heated at 120° C. for 1 h in a microwave. The reaction mixture was directly purified on reverse phase HPLC using an Agilent SB C8 column, 0.1% TFA in ACN/H 2 O, gradient 20% to 90% over 25 min (collected the peaks that were visible at 220 nm) to give the title compound (Example 68.4, 13 mg) as a TFA salt. 1 H NMR (400 MHz, CD 3 OD) δ 8.74 (s, 1H) 8.04 (dd, J=9.49, 1.66 Hz, 1H) 7.56 (t, J=8.51 Hz, 1H) 6.85 (dd, J=8.61, 0.98 Hz, 2H) 6.02 (dd, J=3.52, 0.98 Hz, 1H) 5.95 (d, J=3.52 Hz, 1H) 5.27 (d, J=7.83 Hz, 1H) 3.80 (s, 3H) 3.78 (s, 3H) 3.56-3.65 (m, 1H) 2.26 (s, 3H) 1.12 (d, J=7.04 Hz, 3H). LCMS-ESI (pos.) m/z: 543.0 (M+H) + .

(1R,2S)-1-(5-Cyano-3-fluoro-2-pyridinyl)-N-(4-(2,6-dimethoxyphenyl)-5-(5-methyl-2-furanyl)-4H-1,2,4-triazol-3-yl)-1-hydroxy-2-propanesulfonamide and (1S,2R)-1-(5-cyano-3-fluoro-2-pyridinyl)-N-(4-(2,6-dimethoxyphenyl)-5-(5-methyl-2-furanyl)-4H-1,2,4-triazol-3-yl)-1-hydroxy-2-propanesulfonamide or (1S,2S)-1-(5-cyano-3-fluoro-2-pyridinyl)-N-(4-(2,6-dimethoxyphenyl)-5-(5-methyl-2-furanyl)-4H-1,2,4-triazol-3-yl)-1-hydroxy-2-propanesulfonamide and (1R,2R)-1-(5-cyano-3-fluoro-2-pyridinyl)-N-(4-(2,6-dimethoxyphenyl)-5-(5-methyl-2-furanyl)-4H-1,2,4-triazol-3-yl)-1-hydroxy-2-propanesulfonamide, Example 68.5. Example 68.5 is the diastereomer of Example 68.4. It was prepared from Example 68.2 employing the chemistry described in Example 68.4 and Example 68.3 via installation of the cyanide first and then removal of the trimethylsilyl ethyl protecting group. 1 H NMR (400 MHz, CD 3 OD) δ 8.71 (d, J=0.98 Hz, 1H) 7.99 (dd, J=9.49, 1.66 Hz, 1H) 7.56 (t, J=8.61 Hz, 1H) 6.85 (d, J=8.61 Hz, 2H) 6.02 (dd, J=3.42, 1.08 Hz, 1H) 5.95 (d, J=3.13 Hz, 1H) 5.37 (dd, J=6.26, 1.17 Hz, 1H) 3.79 (s, 3H) 3.78 (s, 3H) 3.67 (t, J=6.75 Hz, 1H) 2.26 (s, 3H) 1.41 (d, J=6.85 Hz, 3H). LCMS-ESI (pos.) m/z: 543.0 (M+H) + .

(1R,2S)-1-(5-Cyano-3-fluoro-2-pyridinyl)-N-(4-(2,6-dimethoxyphenyl)-5-(5-methyl-2-furanyl)-4H-1,2,4-triazol-3-yl)-1-hydroxy-2-propanesulfonamide or (1S,2R)-1-(5-cyano-3-fluoro-2-pyridinyl)-N-(4-(2,6-dimethoxyphenyl)-5-(5-methyl-2-furanyl)-4H-1,2,4-triazol-3-yl)-1-hydroxy-2-propanesulfonamide or (1S,2S)-1-(5-cyano-3-fluoro-2-pyridinyl)-N-(4-(2,6-dimethoxyphenyl)-5-(5-methyl-2-furanyl)-4H-1,2,4-triazol-3-yl)-1-hydroxy-2-propanesulfonamide or (1R,2R)-1-(5-cyano-3-fluoro-2-pyridinyl)-N-(4-(2,6-dimethoxyphenyl)-5-(5-methyl-2-furanyl)-4H-1,2,4-triazol-3-yl)-1-hydroxy-2-propanesulfonamide, Example 68.0. The racemic compound Example 68.4 was separated by SFC. The separation conditions were as follows: Run on Thar 80 SFC with 250×21 mm IC column with 24 g/min MeOH (+20 mM NH 3 )+30 g/min CO 2 , 45% co-solvent at 55 g/min. Outlet pressure=100 bar; Temp.=22° C.; Wavelength=220 nm. Injected 0.3 mL of a solution from 10.5 mg sample dissolved in 3 mL of MeOH (25% DCM), c=3.5 mg/mL; 1.05 mg per injection. Cycle time 10 min, run time 14 min. The title compound was the second peak to elute on subjecting Example 68.4 to the SFC conditions described herein. 1 H NMR (400 MHz, CD 3 OD) δ 8.74 (s, 1H) 8.04 (dd, J=9.39, 1.57 Hz, 1H) 7.56 (t, J=8.61 Hz, 1H) 6.84 (dd, J=8.61, 0.98 Hz, 2H) 6.00-6.04 (m, 1H) 5.94 (d, J=3.33 Hz, 1H) 5.27 (d, J=7.83 Hz, 1H) 3.80 (s, 3H) 3.77 (s, 3H) 3.57-3.66 (m, 1H) 2.26 (s, 3H) 1.12 (d, J=7.04 Hz, 3H). LCMS-ESI (pos.) m/z: 543.0 (M+H) + .

Example 70.0. Preparation of (2R)—N-(4-(2,6-dimethoxyphenyl)-5-(5-methyl-2-furanyl)-4H-1,2,4-triazol-3-yl)-4-hydroxy-1-(5-methyl-2-pyrimidinyl)-2-butanesulfonamide and (2S)—N-(4-(2,6-dimethoxyphenyl)-5-(5-methyl-2-furanyl)-4H-1,2,4-triazol-3-yl)-4-hydroxy-1-(5-methyl-2-pyrimidinyl)-2-butanesulfonamide

(E)-2-(4-((tert-Butyldimethylsilyl)oxy)but-1-en-1-yl)-5-methylpyrimidine, Example 70.1. A flask was charged with trans-4-(tert-butyldimethylsiloxy)-1-buten-1-ylboronic acid pinacol ester (3.37 mL, 9.61 mmol), cesium carbonate (6.89 g, 21.13 mmol), triphenylphosphine (1.01 g, 3.84 mmol), 2-bromo-5-methylpyrimidine (1.70 g, 9.80 mmol), ACN (60 mL), and water (15 mL). Argon was bubbled through the reaction mixture. Diacetoxypalladium (0.216 g, 0.96 mmol) was then added and Argon was bubbled through the reaction again. The mixture was then heated at 85° C. for 16 h. Water was added to the mixture which was then extracted with EtOAc. The EtOAc layer was dried, concentrated, and purified by silica gel column chromatography with gradient hexanes/EtOAc solvent system to give (E)-2-(4-((tert-butyldimethylsilyl)oxy)but-1-en-1-yl)-5-methylpyrimidine (Example 70.1, 2.3 g 86%) as a yellow oil. LCMS-ESI (pos.) m/z: 279.2 (M+H) + .

›EXAMPLES · 27 of 46

(E)-4-(5-Methylpyrimidin-2-yl)but-3-en-1-ol, Example 70.2. To a flask with (E)-2-(4-((tert-butyldimethylsilyl)oxy)but-1-en-1-yl)-5-methylpyrimidine (Example 70.1, 2.3 g, 8.26 mmol) was added THF (25 mL) and then TBAF (1.0 M, 3.06 mL, 3.06 mmol). The reaction was stirred overnight and then concentrated. The reaction mixture was directly loaded onto a silica gel column (80 g) and purified with a gradient elution of 0-85% EtOAc in hexanes first, and then a gradient elution of 0-10% MeOH in DCM to give 1.2 g (88%) of the title compound as a white solid. LCMS-ESI (pos.) m/z: 165.1 (M+H) + .

(E)-2-(4-(Benzyloxy)but-1-en-1-yl)-5-methylpyrimidine, Example 70.3. (E)-4-(5-methylpyrimidin-2-yl)but-3-en-1-ol (Example 70.2, 1.20 g, 7.31 mmol) was azeotroped with toluene and purged with nitrogen. DMF (15 mL) was added and the reaction was cooled in an ice bath. Sodium hydride (0.322 g, 8.04 mmol) was added, and the mixture was stirred for 15 min at 0° C. Benzyl bromide (1.30 mL, 10.96 mmol) was then added and the reaction was stirred overnight. Water was added, and the mixture was extracted with EtOAc. The EtOAc layer was dried, concentrated, and purified by silica gel column chromatography to give (E)-2-(4-(benzyloxy)but-1-en-1-yl)-5-methylpyrimidine (Example 70.3, 1.15 g, 62%). LCMS-ESI (pos.) m/z: 255.1 (M+H) + .

4-(Benzyloxy)-1-(5-methylpyrimidin-2-yl)butane-2-sulfonic acid, Example 70.4. To a vial containing Example 70.3 (1.35 g, 5.30 mmol) in THF (1 mL) and EtOH (1 mL) was added sodium hydrogensulfite (1.65 g, 15.90 mmol) in water (4 mL). The vial was heated at 85° C. overnight. The mixture was then concentrated in vacuo. The pH of the mixture was then adjusted to pH 5-6 with 1 N HCl. A small amount of DCM was added to extract the nonpolar impurity and was discarded. The aqueous layer was lyophilized and the resulting solid was dissolved in hot EtOH and filtered. The EtOH layer was concentrated and purified on reverse phase HPLC in 2 batches using 2.5%-70% gradient (5 min at 2.5%). The product fractions were lyophilized to give 4-(benzyloxy)-1-(5-methylpyrimidin-2-yl)butane-2-sulfonic acid (1.2 g, 67%) as a white solid. LCMS-ESI (pos.) m/z: 337.1 (M+H) + .

4-(Benzyloxy)-1-(5-methylpyrimidin-2-yl)butane-2-sulfonyl fluoride, Example 70.5. Example 70.4 (700 mg, 2.08 mmol) was azeotroped with toluene and dried on a vacuum pump. DCM (10 mL) was added followed by slow addition of DAST (0.66 mL, 4.99 mmol). The reaction was stirred for 70 min at RT and LCMS showed the reaction was not complete. Thus, more DAST was added. After 1 h, silica gel was added and the reaction mixture was concentrated in vacuo and dry loaded onto a silica gel column. The material was purified by gradient elution of EtOAc in hexanes to give 4-(benzyloxy)-1-(5-methylpyrimidin-2-yl)butane-2-sulfonyl fluoride (Example 70.5, 375 mg, 53%). LCMS-ESI (pos.) m/z: 337.1 (M+H) + .

(2R)-4-(Benzyloxy)-N-(4-(2,6-dimethoxyphenyl)-5-(5-methyl-2-furanyl)-4H-1,2,4-triazol-3-yl)-1-(5-methyl-2-pyrimidinyl)-2-butanesulfonamide and (2S)-4-(benzyloxy)-N-(4-(2,6-dimethoxyphenyl)-5-(5-methyl-2-furanyl)-4H-1,2,4-triazol-3-yl)-1-(5-methyl-2-pyrimidinyl)-2-butanesulfonamide, Example 70.6. Example 70.5 (374 mg, 1.11 mmol) was azeotroped with toluene and dried on a pump. THF (2 mL) was then added under nitrogen. In a separate flask, Example 367.0 (431 mg, 1.44 mmol) was flushed with nitrogen on a high vacuum pump. THF (2 mL) was added followed by KHMDS (1.0 M, 2.21 mL, 2.21 mmol). The reaction was stirred at RT for 20 min. The sulfonyl fluoride solution was then added dropwise to the reaction at RT. The reaction was stirred overnight and then quenched with an aqueous solution of NH 4 Cl followed by addition of water and extraction with EtOAc. The reaction mixture was purified on reverse phase HPLC using an Agilent SB C8 column, 0.1% TFA in ACN/H 2 O, with a 20-85% gradient in 3 batches. The product fractions were lyophilized to give the title compound (157 mg, 23%). 1 H NMR (400 MHz, CD 3 OD) δ 8.52 (s, 2H) 7.52 (t, J=8.26 Hz, 1H) 7.26 (m, 3H) 7.17 (m, 2H) 6.81 (dd, J=8.61, 1.17 Hz, 2H) 6.02 (dd, J=3.52, 0.98 Hz, 1H) 5.94 (d, J=3.33 Hz, 1H) 4.21 (m, 2H) 3.87 (m, 1H) 3.75 (s, 3H) 3.73 (s, 3H) 3.56 (m, 1H) 3.45 (m, 2H) 3.07 (m, 1H) 2.26 (m, J=3.10 Hz, 7H) 1.86 (m, 1H). LCMS-ESI (pos.) m/z: 669.1 (M+H) + .

(2R)—N-(4-(2,6-Dimethoxyphenyl)-5-(5-methyl-2-furanyl)-4H-1,2,4-triazol-3-yl)-4-hydroxy-1-(5-methyl-2-pyrimidinyl)-2-butanesulfonamide and (2S)—N-(4-(2,6-dimethoxyphenyl)-5-(5-methyl-2-furanyl)-4H-1,2,4-triazol-3-yl)-4-hydroxy-1-(5-methyl-2-pyrimidinyl)-2-butanesulfonamide, Example 70.0. Example 70.6 (34 mg, 0.055 mmol) was azeotroped with toluene. DCM (1 mL) was added followed by boron trifluoride etherate (0.056 mL, 0.440 mmol) and ethanethiol (0.5 mL, 6.75 mmol, Alfa Aesar). The reaction was stirred for 3 d. LCMS indicated the reaction was complete. Water was added and the mixture was extracted with EtOAc. The EtOAc layer was dried and concentrated in vacuo. The material was then purified by reverse phase HPLC with 10-70% gradient elution. The pure fractions were lyophilized to give the title compound (13 mg, 45%) as a white solid. 1 H NMR (400 MHz, CD 3 OD) δ 8.57 (s, 2H), 7.54 (t, J=8.22 Hz, 1H), 6.83 (dd, J=8.51, 1.27 Hz, 2H), 6.01 (m, 1H), 5.94 (d, J=4.11 Hz, 1H), 3.76 (m, 7H), 3.55 (m, 3H), 3.06 (dd, J=15.26, 9.00 Hz, 1H), 2.31 (s, 3H), 2.25 (s, 3H), 2.13 (m, 1H), 1.74 (m, 1H). LCMS-ESI (pos.) m/z: 529.0 (M+H) + .

Example 69.0. Preparation (2R)-4-(benzyloxy)-N-(4-(2,6-dimethoxyphenyl)-5-(5-methyl-2-furanyl)-4H-1,2,4-triazol-3-yl)-1-(5-methyl-2-pyrimidinyl)-2-butanesulfonamide and (2S)-4-(benzyloxy)-N-(4-(2,6-dimethoxyphenyl)-5-(5-methyl-2-furanyl)-4H-1,2,4-triazol-3-yl)-1-(5-methyl-2-pyrimidinyl)-2-butanesulfonamide

(2R)-4-(Benzyloxy)-N-(4-(2,6-dimethoxyphenyl)-5-(5-methyl-2-furanyl)-4H-1,2,4-triazol-3-yl)-1-(5-methyl-2-pyrimidinyl)-2-butanesulfonamide and (2S)-4-(benzyloxy)-N-(4-(2,6-dimethoxyphenyl)-5-(5-methyl-2-furanyl)-4H-1,2,4-triazol-3-yl)-1-(5-methyl-2-pyrimidinyl)-2-butanesulfonamide, Example 69.0. Example 70.0 was separated into two enantiomers by SFC. Separation conditions were as follows: Run on Thar 80 SFC with 250×30 mm AS-H column with 15 g/min EtOH (neat)+55 g/min CO 2 , 22% co-solvent at 70 g/min. Outlet pressure=100 bar; Temp.=21° C.; Wavelength=276 nm. Injected 0.5 mL of a solution from 60 mg sample dissolved in 5 mL of MeOH, c=12.0 mg/mL; 6.0 mg per injection. Cycle time 8 min. runtime 15 min. The title compound was the second peak from chiral separation. 1 H NMR (400 MHz, CD 3 OD) δ 8.56 (s, 2H) 7.53 (t, J=8.31 Hz, 1H) 6.83 (dd, J=8.51, 1.27 Hz, 2H) 6.01 (m, 1H) 5.94 (d, J=3.33 Hz, 1H) 3.76 (m, 7H) 3.54 (m, 3H) 3.04 (m, 1H) 2.31 (s, 3H) 2.26 (s, 3H) 2.11 (d, J=6.46 Hz, 1H) 1.74 (m, 1H). LCMS-ESI (pos.) m/z: 529.0 (M+H) + .

›EXAMPLES · 28 of 46

Example 71.0. Preparation of (2R)—N-(4-(2,6-dimethoxyphenyl)-5-(5-methyl-2-furanyl)-4H-1,2,4-triazol-3-yl)-4-methoxy-1-(5-methyl-2-pyrimidinyl)-2-butanesulfonamide or (2S)—N-(4-(2,6-dimethoxyphenyl)-5-(5-methyl-2-furanyl)-4H-1,2,4-triazol-3-yl)-4-methoxy-1-(5-methyl-2-pyrimidinyl)-2-butanesulfonamide

(E)-2-(4-((tert-Butyldimethylsilyl)oxy)but-1-en-1-yl)-5-methylpyrimidine, Example 71.1. A 30 mL microwave tube was charged with trans-4-(tert-butyldimethylsiloxy)-1-buten-1-ylboronic acid pinacol ester (3.37 mL, 9.61 mmol), cesium carbonate (6.89 g, 21.13 mmol), triphenylphosphine (1.01 g, 3.84 mmol) and 2-bromo-5-methylpyrimidine (1.70 g, 9.80 mmol, Combiphos) in ACN (60 mL) and water (15.00 mL). Argon was bubbled through the mixture and diacetoxypalladium (0.216 g, 0.961 mmol) was added. The mixture was heated at 85° C. for 16 h in a microwave. Water was added, and the reaction was extracted with EtOAc. The EtOAc layer was dried, concentrated in vacuo, and purified by silica gel chromatography eluting with a gradient of EtOAc in hexanes to give title compound (2.3 g, 86%). LCMS-ESI (pos.) m/z: 279.2 (M+H) + .

(E)-4-(5-Methylpyrimidin-2-yl)but-3-en-1-ol, Example 71.2. A flask with Example 71.1 (3.37 g, 12.10 mmol) was azeotroped with toluene. THF (40 mL) was added followed by TBAF (1.0 M, 12.10 mL, 12.10 mmol). The reaction was stirred at RT for 75 min. The reaction mixture was then concentrated in vacuo. Water was added followed by extraction with EtOAc. The EtOAc layer was dried and concentrated in vacuo. The material was purified by reverse phase HPLC to give the title compound (632 mg) as a white solid. LCMS-ESI (pos.) m/z: 165.1 (M+H) + .

(E)-2-(4-Methoxybut-1-en-1-yl)-5-methylpyrimidine, Example 71.3. Example 71.2 (320 mg, 1.95 mmol) was azeotroped with toluene. NaH (94 mg, 2.34 mmol) was added and after stirring the mixture for 15 min, methyl iodide (0.244 mL, 3.90 mmol) was added. The reaction was stirred overnight, after which a saturated solution of NH 4 Cl was added to quench the reaction followed by EtOAc extraction. The EtOAc layer was dried, concentrated, and purified by silica gel chromatography with a gradient 0-70% EtOAc in hexanes to afford 2-(4-methoxybut-1-en-1-yl)-5-methylpyrimidine (170 mg) as a colorless oil. LCMS-ESI (pos.) m/z: 179.1 (M+H) + .

Example 76.0. Preparation of (2R)—N-(4-(2,6-dimethoxyphenyl)-5-(5-methyl-2-furanyl)-4H-1,2,4-triazol-3-yl)-4-methoxy-1-(5-methyl-2-pyrimidinyl)-2-butanesulfonamide and (2S)—N-(4-(2,6-dimethoxyphenyl)-5-(5-methyl-2-furanyl)-4H-1,2,4-triazol-3-yl)-4-methoxy-1-(5-methyl-2-pyrimidinyl)-2-butanesulfonamide

(2R)—N-(4-(2,6-dimethoxyphenyl)-5-(5-methyl-2-furanyl)-4H-1,2,4-triazol-3-yl-4-methoxy-1-(5-methyl-2-pyrimidinyl)-2-butanesulfonamide and (2S)—N-(4-(2,6-dimethoxyphenyl)-5-(5-methyl-2-furanyl)-4H-1,2,4-triazol-3-yl)-4-methoxy-1-(5-methyl-2-pyrimidinyl)-2-butanesulfonamide, Example 76.0. The title compound was prepared following the procedure as described in Example 72.0 using 2-(4-methoxybut-1-en-1-yl)-5-methylpyrimidine (Example 71.3). 1 H NMR (400 MHz, CD 3 OD) δ 8.60 (s, 2H) 7.55 (t, J=8.61 Hz, 1H) 6.84 (d, J=8.61 Hz, 2H) 6.02 (dd, J=3.52, 0.98 Hz, 1H) 5.94 (d, J=3.33 Hz, 1H) 3.82 (m, 1H) 3.77 (s, 3H) 3.76 (s, 3H) 3.55 (dd, J=14.87, 4.89 Hz, 1H) 3.38 (m, 2H) 3.09 (m, 4H) 2.32 (s, 3H) 2.26 (s, 3H), 2.16 (m, 1H) 1.79 (m, 1H). LCMS-ESI (pos.) m/z: 543.1 (M+H) + .

(2R)—N-(4-(2,6-Dimethoxyphenyl)-5-(5-methyl-2-furanyl)-4H-1,2,4-triazol-3-yl)-4-methoxy-1-(5-methyl-2-pyrimidinyl)-2-butanesulfonamide or (2S)—N-(4-(2,6-dimethoxyphenyl)-5-(5-methyl-2-furanyl)-4H-1,2,4-triazol-3-yl)-4-methoxy-1-(5-methyl-2-pyrimidinyl)-2-butanesulfonamide, Example 71.0. The racemate Example 76.0 was purified by SFC with the following conditions: Run on Thar 80 SFC with 250×30 mm AD-H column with 28 g/min MeOH (neat)+52 g/min CO 2 , 35% co-solvent at 80 g/min. Outlet pressure=100 bar; Temp.=24° C.; Wavelength=276 nm. Injected 0.4 mL of a solution in each injection from 43 mg sample dissolved in 4.0 mL of MeOH and 2.0 mL of DCM. Two enantiomers were obtained. Example 71.0 was the first peak off the column. 1 H NMR (400 MHz, CDCl 3 ) δ 8.51 (s, 2H), 7.45 (t, J=8.51 Hz, 1H), 6.66 (d, J=8.41 Hz, 2H), 5.91 (d, J=2.54 Hz, 1H), 5.79 (d, J=3.33 Hz, 1H), 3.89 (m, 1H), 3.77 (s, 3H), 3.73 (s, 3H), 3.59 (dd, J=15.16, 5.77 Hz, 1H), 3.48 (m, 2H), 3.18 (m, 4H), 2.33 (s, 3H), 2.29 (m, 4H), 1.84 (m, 1H). LCMS-ESI (pos.) m/z: 543.1 (M+H) + .

Example 72.0. Preparation of (2R)—N-(4-(2,6-dimethoxyphenyl)-5-(5-methyl-2-furanyl)-4H-1,2,4-triazol-3-yl)-1-(5-fluoro-2-pyrimidinyl)-3-methoxy-2-propanesulfonamide or (2S)—N-(4-(2,6-dimethoxyphenyl)-5-(5-methyl-2-furanyl)-4H-1,2,4-triazol-3-yl)-1-(5-fluoro-2-pyrimidinyl)-3-methoxy-2-propanesulfonamide

(E)-5-Fluoro-2-(3-methoxyprop-1-en-1-yl)pyrimidine, Example 72.1. A flask was charged with (E)-2-(3-methoxy-1-propen-1-yl)-4,4,5,5-tetramethyl-(1,3,2)-dioxaborolane (0.193 mL, 0.91 mmol), cesium carbonate (0.651 g, 2.0 mmol), triphenylphosphine (0.095 g, 0.36 mmol), and 2-chloro-5-fluoro-pyrimidine (0.121 mL, 0.98 mmol, Matrix Scientific) in ACN (9 mL) and water (2.25 mL). Argon was bubbled through the mixture and diacetoxypalladium (0.020 g, 0.091 mmol, Strem) was added. The reaction mixture was placed under an atmosphere of Argon and the mixture was heated at 85° C. for 16 h. Water was then added and the reaction was extracted with EtOAc. The EtOAc layer was dried, concentrated in vacuo, and purified by silica gel chromatography with a gradient of EtOAc in hexanes to give the title compound (122 mg) as an yellow oil. LCMS-ESI (pos.) m/z: 169.0 (M+H) + .

(S)-1-(5-Fluoropyrimidin-2-yl)-3-methoxypropane-2-sulfonic acid and (R)-1-(5-fluoropyrimidin-2-yl)-3-methoxypropane-2-sulfonic acid, Example 72.2. A flask was charged with Example 72.1 (988 mg, 5.88 mmol) and THF (0.8 mL), followed by a solution of sodium bisulfite (673 mg, 6.46 mmol) in water (3 mL). The mixture was stirred in a vial at RT overnight. The contents of the vial were then concentrated to remove the THF. Water was added followed by 4 drops of 1 N HCl. The mixture was extracted with DCM to remove any organic impurities. The aqueous layer was concentrated and then azeotroped with toluene and dried on a high vacuum to give a foamy oil. EtOH was added to the mixture, and it was then heated to reflux. The solution was filtered hot to remove any solid impurities. After rinsing the solids with hot EtOH, the combined filtrate was concentrated to give 1-(5-fluoropyrimidin-2-yl)-3-methoxypropane-2-sulfonic acid (1.65 g) as a foamy white solid which was used without further purification. LCMS-ESI (pos.) m/z: 251.0 (M+H) + .

›EXAMPLES · 29 of 46

(S)-1-(5-Fluoropyrimidin-2-yl)-3-methoxypropane-2-sulfonyl chloride and (R)-1-(5-fluoropyrimidin-2-yl)-3-methoxypropane-2-sulfonyl chloride, Example 72.3. Example 72.2 (358 mg, 1.43 mmol) was azeotroped with toluene. DCM (4.5 mL) was added and the flask was cooled to 0° C. An oxalyl chloride solution (2.0 M in DCM, 0.98 mL, 1.97 mmol) was added followed by 2 drops of DMF. The reaction was then stirred at 0° C. for 2 h. The reaction mixture was concentrated in vacuo, azeotroped with toluene, and dried on a high vacuum pump. The title compound was directly used in the next step. LCMS-ESI (pos.) m/z: 265.0 (M-Cl+HOMe) + .

(2R)—N-(4-(2,6-Dimethoxyphenyl)-5-(5-methyl-2-furanyl)-4H-1,2,4-triazol-3-yl)-1-(5-fluoro-2-pyrimidinyl)-3-methoxy-2-propanesulfonamide or (2S)—N-(4-(2,6-dimethoxyphenyl)-5-(5-methyl-2-furanyl)-4H-1,2,4-triazol-3-yl)-1-(5-fluoro-2-pyrimidinyl)-3-methoxy-2-propanesulfonamide, Example 72.0. A flask with 4-(2,6-dimethoxyphenyl)-5-(5-methylfuran-2-yl)-4H-1,2,4-triazol-3-amine (Example 367.0, 210 mg, 0.70 mmol) was purged with nitrogen. THF (4 mL) was added, and the flask was cooled to 0° C. KHMDS (2.10 mL, 2.098 mmol) was added and the reaction was stirred for 18 min at 0° C. A 0° C., a THF (3 mL) solution of 1-(5-fluoropyrimidin-2-yl)-3-methoxypropane-2-sulfonyl chloride (Example 72.3, 376 mg, 1.40 mmol) was added slowly to the reaction. The reaction was then allowed to warm to RT and stirred overnight. The reaction was quenched with a minimal amount of water and purified on reverse phase HPLC in two batches, using an Agilent SB C8 column, 0.1% TFA in ACN/H 2 O, 20-70% gradient elution over 25 min. Two mixed fractions were obtained. Both fractions were re-purified using the following SFC chiral separation conditions: IA column (2×15 cm), 20% MeOH/CO 2 , 100 bar, 60 mL/min, 220 nm, injection volume: 0.7 mL, 3 mg/mL MeOH. The title compound (Example 72.0) was the first peak (faster-eluting) to elute under these conditions. 1 H NMR (400 MHz, CDCl 3 ) δ 11.10 (br. s, 1H), 8.53 (s, 2H), 7.46 (t, J=8.51 Hz, 1H), 6.68 (d, J=8.61 Hz, 2H), 5.92 (dd, J=3.42, 0.88 Hz, 1H), 5.80 (d, J=3.33 Hz, 1H), 4.08 (dq, J=7.60, 4.30 Hz, 1H), 3.85 (dd, J=10.27, 4.21 Hz, 1H), 3.78 (s, 3H), 3.75 (s, 3H), 3.64 (dd, J=10.17, 7.82 Hz, 1H), 3.55 (dd, J=15.45, 6.06 Hz, 1H), 3.41 (m, 1H), 3.23 (s, 3H), 2.33 (s, 3H). LCMS-ESI (pos.) m/z: 533.0 (M+H) + .

Example 78.0. Preparation of (2R)—N-(4-(2,6-dimethoxyphenyl)-5-(5-methyl-2-furanyl)-4H-1,2,4-triazol-3-yl)-1-(5-fluoro-2-pyrimidinyl)-3-methoxy-2-propanesulfonamide or (2S)—N-(4-(2,6-dimethoxyphenyl)-5-(5-methyl-2-furanyl)-4H-1,2,4-triazol-3-yl)-1-(5-fluoro-2-pyrimidinyl)-3-methoxy-2-propanesulfonamide

Example 73.0. Preparation of (1R,2S)—N-(4-(2,6-dimethoxyphenyl)-5-(5-methyl-2-furanyl)-4H-1,2,4-triazol-3-yl)-1-(4-fluoro-2-(hydroxymethyl)phenyl)-1-hydroxy-2-propanesulfonamide and (1S,2R)—N-(4-(2,6-dimethoxyphenyl)-5-(5-methyl-2-furanyl)-4H-1,2,4-triazol-3-yl)-1-(4-fluoro-2-(hydroxymethyl)phenyl)-1-hydroxy-2-propanesulfonamide or (1S,2S)—N-(4-(2,6-dimethoxyphenyl)-5-(5-methyl-2-furanyl)-4H-1,2,4-triazol-3-yl)-1-(4-fluoro-2-(hydroxymethyl)phenyl)-1-hydroxy-2-propanesulfonamide and (1R,2R)—N-(4-(2,6-dimethoxyphenyl)-5-(5-methyl-2-furanyl)-4H-1,2,4-triazol-3-yl)-1-(4-fluoro-2-(hydroxymethyl)phenyl)-1-hydroxy-2-propanesulfonamide

(1R,2R)-1-(2-Bromo-4-fluorophenyl)-N-(4-(2,6-dimethoxyphenyl)-5-(5-methylfuran-2-yl)-4H-1,2,4-triazol-3-yl)-1-hydroxy-N-(2-(trimethylsilyl)ethyl)propane-2-sulfonamide and (1S,2S)-1-(2-bromo-4-fluorophenyl)-N-(4-(2,6-dimethoxyphenyl)-5-(5-methylfuran-2-yl)-4H-1,2,4-triazol-3-yl)-1-hydroxy-N-(2-(trimethylsilyl)ethyl)propane-2-sulfonamide or (1S,2R)-1-(2-bromo-4-fluorophenyl)-N-(4-(2,6-dimethoxyphenyl)-5-(5-methylfuran-2-yl)-4H-1,2,4-triazol-3-yl)-1-hydroxy-N-(2-(trimethylsilyl)ethyl)propane-2-sulfonamide and (1R,2S)-1-(2-bromo-4-fluorophenyl)-N-(4-(2,6-dimethoxyphenyl)-5-(5-methylfuran-2-yl)-4H-1,2,4-triazol-3-yl)-1-hydroxy-N-(2-(trimethylsilyl)ethyl)propane-2-sulfonamide, Example 73.1. The title compound was prepared using Example 369.0 and 2-bromo-4-fluorobenzaldehyde following the procedure described in Example 57.1. LCMS-ESI (pos.) m/z: 697.0 (M+H) + .

(1R,2R)-1-(2-Cyano-4-fluorophenyl)-N-(4-(2,6-dimethoxyphenyl)-5-(5-methylfuran-2-yl)-4H-1,2,4-triazol-3-yl)-1-hydroxy-N-(2-(trimethylsilyl)ethyl)propane-2-sulfonamide and (1S,2S)-1-(2-cyano-4-fluorophenyl)-N-(4-(2,6-dimethoxyphenyl)-5-(5-methylfuran-2-yl)-4H-1,2,4-triazol-3-yl)-1-hydroxy-N-(2-(trimethylsilyl)ethyl)propane-2-sulfonamide or (1S,2R)-1-(2-cyano-4-fluorophenyl)-N-(4-(2,6-dimethoxyphenyl)-5-(5-methylfuran-2-yl)-4H-1,2,4-triazol-3-yl)-1-hydroxy-N-(2-(trimethylsilyl)ethyl)propane-2-sulfonamide and (1R,2S)-1-(2-cyano-4-fluorophenyl)-N-(4-(2,6-dimethoxyphenyl)-5-(5-methylfuran-2-yl)-4H-1,2,4-triazol-3-yl)-1-hydroxy-N-(2-(trimethylsilyl)ethyl)propane-2-sulfonamide, Example 73.2. A microwave tube was charged with Example 73.1 (250 mg, 0.359 mmol), dicyanozinc (69.2 mg, 0.59 mmol, Alfa Aesar), and Pd(PPh 3 ) 4 (83 mg, 0.072 mmol, Strem Chemicals Inc). Degassed DMF (3 mL) was added, and the reaction was again degassed with argon. The reaction was then heated at 120° C. for 1 h in a microwave. Water was added to quench the reaction mixture which was then extracted with EtOAc. The EtOAc layer was dried, concentrated in vacuo, and purified on reverse phase HPLC using an Agilent SB C8 column, 0.1% TFA in ACN/H 2 O, gradient 30% to 90% over 25 min (collected the peaks that were visible at 220 nm) in 2 batches. The product fractions were lyophilized and the material was repurified on a Redi-Sep pre-packed gold silica gel column, eluting with a gradient EtOAc/hexanes 0-70% and then 2-8% MeOH/DCM to give the title compound (56 mg). LCMS-ESI (pos.) m/z: 642.0 (M+H) + .

›EXAMPLES · 30 of 46

(1R,2S)—N-(4-(2,6-Dimethoxyphenyl)-5-(5-methylfuran-2-yl)-4H-1,2,4-triazol-3-yl)-1-(5-fluoro-3-oxo-1,3-dihydroisobenzofuran-1-yl)-N-(2-(trimethylsilyl)ethyl)ethanesulfonamide and (1S,2R)—N-(4-(2,6-dimethoxyphenyl)-5-(5-methylfuran-2-yl)-4H-1,2,4-triazol-3-yl)-1-(5-fluoro-3-oxo-1,3-dihydroisobenzofuran-1-yl)-N-(2-(trimethylsilyl)ethyl)ethanesulfonamide, or (1R,2R)—N-(4-(2,6-dimethoxyphenyl)-5-(5-methylfuran-2-yl)-4H-1,2,4-triazol-3-yl)-1-(5-fluoro-3-oxo-1,3-dihydroisobenzofuran-1-yl)-N-(2-(trimethylsilyl)ethyl)ethanesulfonamide and (1S,2S)—N-(4-(2,6-dimethoxyphenyl)-5-(5-methylfuran-2-yl)-4H-1,2,4-triazol-3-yl)-1-(5-fluoro-3-oxo-1,3-dihydroisobenzofuran-1-yl)-N-(2-(trimethylsilyl)ethyl)ethanesulfonamide, Example 73.3. A by-product formed from Example 73.2 was isolated after HPLC reverse phase purification to yield the title compound (43 mg). LCMS-ESI (pos.) m/z: 643.0 (M+H) + .

(1R,2S)—N-(4-(2,6-Dimethoxyphenyl)-5-(5-methylfuran-2-yl)-4H-1,2,4-triazol-3-yl)-1-(4-fluoro-2-(hydroxymethyl)phenyl)-1-hydroxy-N-(2-(trimethylsilyl)ethyl)propane-2-sulfonamide and (1S,2R)—N-(4-(2,6-dimethoxyphenyl)-5-(5-methylfuran-2-yl)-4H-1,2,4-triazol-3-yl)-1-(4-fluoro-2-(hydroxymethyl)phenyl)-1-hydroxy-N-(2-(trimethylsilyl)ethyl)propane-2-sulfonamide, or (1S,2S)—N-(4-(2,6-dimethoxyphenyl)-5-(5-methylfuran-2-yl)-4H-1,2,4-triazol-3-yl)-1-(4-fluoro-2-(hydroxymethyl)phenyl)-1-hydroxy-N-(2-(trimethylsilyl)ethyl)propane-2-sulfonamide and (1R,2R)—N-(4-(2,6-dimethoxyphenyl)-5-(5-methylfuran-2-yl)-4H-1,2,4-triazol-3-yl)-1-(4-fluoro-2-(hydroxymethyl)phenyl)-1-hydroxy-N-(2-(trimethylsilyl)ethyl)propane-2-sulfonamide, Example 73.4. Example 73.3 (43 mg, 0.067 mmol) was azeotroped with toluene. THF (2 mL) was added under nitrogen followed by lithium borohydride (2.0 M solution in THF, 0.100 mL, 0.201 mmol). The reaction was heated at reflux for 2.5 h. 1 N HCl was added to quench the reaction and both EtOAc and water were added to the mixture. The mixture was washed with brine and the EtOAc layer was dried and concentrated in vacuo to give the title compound (43 mg) which was carried to the next step without further purification. LCMS-ESI (pos.) m/z: 647.0 (M+H) + .

(1R,2S)—N-(4-(2,6-Dimethoxyphenyl)-5-(5-methyl-2-furanyl)-4H-1,2,4-triazol-3-yl)-1-(4-fluoro-2-(hydroxymethyl)phenyl)-1-hydroxy-2-propanesulfonamide and (1S,2R)—N-(4-(2,6-dimethoxyphenyl)-5-(5-methyl-2-furanyl)-4H-1,2,4-triazol-3-yl)-1-(4-fluoro-2-(hydroxymethyl)phenyl)-1-hydroxy-2-propanesulfonamide or (1S,2S)—N-(4-(2,6-dimethoxyphenyl)-5-(5-methyl-2-furanyl)-4H-1,2,4-triazol-3-yl)-1-(4-fluoro-2-(hydroxymethyl)phenyl)-1-hydroxy-2-propanesulfonamide and (1R,2R)—N-(4-(2,6-dimethoxyphenyl)-5-(5-methyl-2-furanyl)-4H-1,2,4-triazol-3-yl)-1-(4-fluoro-2-(hydroxymethyl)phenyl)-1-hydroxy-2-propanesulfonamide, Example 73.0. To a solution of Example 73.4 (43 mg, 0.066 mmol) was added tris(dimethylamino)sulfonium difluorotrimethylsilicate (IV) (54.9 mg, 0.20 mmol). DMF (1 mL) was added, and the resulting solution was heated at 70° C. for 3 h. The reaction was cooled to RT. Water was added to the mixture and it was extracted with EtOAc. The EtOAc layer was dried, concentrated in vacuo, and purified by silica gel chromatography to give the title compound (26 mg). 1 H NMR (400 MHz, DMSO-d 6 ) δ 13.24 (s, 1H) 7.56 (t, J=8.51 Hz, 1H) 7.43 (dd, J=8.61, 6.06 Hz, 1H) 7.18 (dd, J=10.37, 2.93 Hz, 1H) 7.05 (td, J=8.51, 2.74 Hz, 1H) 6.90 (d, J=3.13 Hz, 1H) 6.88 (d, J=3.13 Hz, 1H) 6.02-6.23 (m, 1H) 5.82 (d, J=3.33 Hz, 1H) 5.75 (br. s, 1H) 5.37 (br. s., 1H) 5.27 (t, J=5.38 Hz, 1H) 4.68 (br. s., 1H) 4.44 (qd, J=14.02, 5.09 Hz, 2H) 3.72 (s, 3H) 3.73 (d, J=7.24 Hz, 6H) 2.97 (q, J=7.04 Hz, 1H) 2.25 (s, 3H) 0.92-1.16 (m, 3H). LCMS-ESI (pos.) m/z: 547.0 (M+H) + .

Example 79.0. Preparation of (1S,2S)—N-(4-(2,6-dimethoxyphenyl)-5-(5-methyl-2-furanyl)-4H-1,2,4-triazol-3-yl)-1-(5-fluoro-2-pyridinyl)-1-hydroxy-2-propanesulfonamide and (1R,2R)—N-(4-(2,6-dimethoxyphenyl)-5-(5-methyl-2-furanyl)-4H-1,2,4-triazol-3-yl)-1-(5-fluoro-2-pyridinyl)-1-hydroxy-2-propanesulfonamide or (1R,2S)—N-(4-(2,6-dimethoxyphenyl)-5-(5-methyl-2-furanyl)-4H-1,2,4-triazol-3-yl)-1-(5-fluoro-2-pyridinyl)-1-hydroxy-2-propanesulfonamide and (1S,2R)—N-(4-(2,6-dimethoxyphenyl)-5-(5-methyl-2-furanyl)-4H-1,2,4-triazol-3-yl)-1-(5-fluoro-2-pyridinyl)-1-hydroxy-2-propanesulfonamide

Example 80.0. Preparation of (2R)-4-(benzyloxy)-N-(4-(2,6-dimethoxyphenyl)-5-(5-methyl-2-furanyl)-4H-1,2,4-triazol-3-yl)-1-(5-methyl-2-pyrimidinyl)-2-butanesulfonamide and (2S)-4-(benzyloxy)-N-(4-(2,6-dimethoxyphenyl)-5-(5-methyl-2-furanyl)-4H-1,2,4-triazol-3-yl)-1-(5-methyl-2-pyrimidinyl)-2-butanesulfonamide

(2R)-4-(Benzyloxy)-N-(4-(2,6-dimethoxyphenyl)-5-(5-methyl-2-furanyl)-4H-1,2,4-triazol-3-yl)-1-(5-methyl-2-pyrimidinyl)-2-butanesulfonamide and (2S)-4-(benzyloxy)-N-(4-(2,6-dimethoxyphenyl)-5-(5-methyl-2-furanyl)-4H-1,2,4-triazol-3-yl)-1-(5-methyl-2-pyrimidinyl)-2-butanesulfonamide, Example 80.0. Example 70.0 was chirally separated into two enantiomers by SFC. The separation conditions were as follows: Run on Thar 80 SFC with 250×30 mm AS-H column with 15 g/min EtOH (neat)+55 g/min CO 2 , 22% co-solvent at 70 g/min. Outlet pressure=100 bar; Temp.=21° C.; Wavelength=276 nm. Injected 0.5 mL of a solution from 60 mg sample dissolved in 5 mL of MeOH, c=12.0 mg/mL; 6.0 mg per injection. Cycle time 8 min. runtime 15 min. The title compound was the first peak (faster-eluting) from chiral separation. 1 H NMR (400 MHz, CD 3 OD) δ 8.56 (s, 2H) 7.53 (t, J=8.31 Hz, 1H) 6.83 (dd, J=8.51, 1.27 Hz, 2H) 6.01 (m, 1H) 5.94 (d, J=3.33 Hz, 1H) 3.76 (m, 7H) 3.54 (m, 3H) 3.04 (m, 1H) 2.31 (s, 3H) 2.26 (s, 3H) 2.11 (d, J=6.46 Hz, 1H) 1.74 (m, 1H). LCMS-ESI (pos.) m/z: 529.0 (M+H) + .

›EXAMPLES · 31 of 46

Example 81.0. Preparation of (1R,2S)-1-(3-cyano-4-fluorophenyl)-N-(4-(2,6-dimethoxyphenyl)-5-(5-methyl-2-furanyl)-4H-1,2,4-triazol-3-yl)-1-hydroxy-2-propanesulfonamide and (1S,2R)-1-(3-cyano-4-fluorophenyl)-N-(4-(2,6-dimethoxyphenyl)-5-(5-methyl-2-furanyl)-4H-1,2,4-triazol-3-yl)-1-hydroxy-2-propanesulfonamide or (1S,2S)-1-(3-cyano-4-fluorophenyl)-N-(4-(2,6-dimethoxyphenyl)-5-(5-methyl-2-furanyl)-4H-1,2,4-triazol-3-yl)-1-hydroxy-2-propanesulfonamide and (1R,2R)-1-(3-cyano-4-fluorophenyl)-N-(4-(2,6-dimethoxyphenyl)-5-(5-methyl-2-furanyl)-4H-1,2,4-triazol-3-yl)-1-hydroxy-2-propanesulfonamide

(1R,2S)-1-(3-Bromo-4-fluorophenyl)-N-(4-(2,6-dimethoxyphenyl)-5-(5-methylfuran-2-yl)-4H-1,2,4-triazol-3-yl)-1-hydroxy-N-(2-(trimethylsilyl)ethyl)propane-2-sulfonamide and (1S,2R)-1-(3-bromo-4-fluorophenyl)-N-(4-(2,6-dimethoxyphenyl)-5-(5-methylfuran-2-yl)-4H-1,2,4-triazol-3-yl)-1-hydroxy-N-(2-(trimethylsilyl)ethyl)propane-2-sulfonamide or (1S,2S)-1-(3-bromo-4-fluorophenyl)-N-(4-(2,6-dimethoxyphenyl)-5-(5-methylfuran-2-yl)-4H-1,2,4-triazol-3-yl)-1-hydroxy-N-(2-(trimethylsilyl)ethyl)propane-2-sulfonamide and (1R,2R)-1-(3-bromo-4-fluorophenyl)-N-(4-(2,6-dimethoxyphenyl)-5-(5-methylfuran-2-yl)-4H-1,2,4-triazol-3-yl)-1-hydroxy-N-(2-(trimethylsilyl)ethyl)propane-2-sulfonamide, Example 81.1. Example 81.1 was prepared using Example 369.0 and 3-bromo-4-fluorobenzaldehyde following the procedure described in Example 57.1. The reaction mixture was purified by silica gel chromatography eluting with a gradient of 0-40% EtOAc in hexanes to give two diastereomers in a 3:1 ratio. The title compound (Example 81.1) was the major diastereomer (less polar) from this reaction.

(1R,2S)-1-(3-Bromo-4-fluorophenyl)-N-(4-(2,6-dimethoxyphenyl)-5-(5-methylfuran-2-yl)-4H-1,2,4-triazol-3-yl)-1-hydroxy-N-(2-(trimethylsilyl)ethyl)propane-2-sulfonamide and (1S,2R)-1-(3-bromo-4-fluorophenyl)-N-(4-(2,6-dimethoxyphenyl)-5-(5-methylfuran-2-yl)-4H-1,2,4-triazol-3-yl)-1-hydroxy-N-(2-(trimethylsilyl)ethyl)propane-2-sulfonamide or (1S,2S)-1-(3-bromo-4-fluorophenyl)-N-(4-(2,6-dimethoxyphenyl)-5-(5-methylfuran-2-yl)-4H-1,2,4-triazol-3-yl)-1-hydroxy-N-(2-(trimethylsilyl)ethyl)propane-2-sulfonamide and (1R,2R)-1-(3-bromo-4-fluorophenyl)-N-(4-(2,6-dimethoxyphenyl)-5-(5-methylfuran-2-yl)-4H-1,2,4-triazol-3-yl)-1-hydroxy-N-(2-(trimethylsilyl)ethyl)propane-2-sulfonamide, Example 81.2. The title compound (Example 81.2) was the minor diastereomer (more polar) isolated from the same reaction described in Example 81.1.

(1R,2S)-1-(3-Cyano-4-fluorophenyl)-N-(4-(2,6-dimethoxyphenyl)-5-(5-methyl-2-furanyl)-4H-1,2,4-triazol-3-yl)-1-hydroxy-2-propanesulfonamide and (1S,2R)-1-(3-cyano-4-fluorophenyl)-N-(4-(2,6-dimethoxyphenyl)-5-(5-methyl-2-furanyl)-4H-1,2,4-triazol-3-yl)-1-hydroxy-2-propanesulfonamide or (1S,2S)-1-(3-cyano-4-fluorophenyl)-N-(4-(2,6-dimethoxyphenyl)-5-(5-methyl-2-furanyl)-4H-1,2,4-triazol-3-yl)-1-hydroxy-2-propanesulfonamide and (1R,2R)-1-(3-cyano-4-fluorophenyl)-N-(4-(2,6-dimethoxyphenyl)-5-(5-methyl-2-furanyl)-4H-1,2,4-triazol-3-yl)-1-hydroxy-2-propanesulfonamide, Example 81.0. The title compound was prepared from Example 81.1 following the procedure described in Example 68.0. 1 H NMR (400 MHz, CDCl 3 ) δ 10.86 (br. s, 1H) 7.64 (dd, J=5.97, 2.05 Hz, 1H) 7.45-7.59 (m, 2H) 7.18 (t, J=8.61 Hz, 1H) 6.74-6.79 (m, 1H) 6.69-6.74 (m, 1H) 5.95 (dd, J=3.52, 0.98 Hz, 1H) 5.89 (d, J=3.52 Hz, 1H) 5.49 (s, 1H) 3.87 (s, 3H) 3.78 (s, 3H) 3.10 (m, J=6.94, 1.27 Hz, 1H) 2.33 (s, 3H) 1.14 (d, J=6.85 Hz, 3H). LCMS-ESI (pos.) m/z: 542.0 (M+H) + .

Example 82.0. Preparation of (1R,2R)—N-(4-(2,6-dimethoxyphenyl)-5-(5-methyl-2-furanyl)-4H-1,2,4-triazol-3-yl)-1-(2,4-dimethyl-1,3-oxazol-5-yl)-1-hydroxy-2-propanesulfonamide, and (1S,2S)—N-(4-(2,6-dimethoxyphenyl)-5-(5-methyl-2-furanyl)-4H-1,2,4-triazol-3-yl)-1-(2,4-dimethyl-1,3-oxazol-5-yl)-1-hydroxy-2-propanesulfonamide, and (1R,2S)—N-(4-(2,6-dimethoxyphenyl)-5-(5-methyl-2-furanyl)-4H-1,2,4-triazol-3-yl)-1-(2,4-dimethyl-1,3-oxazol-5-yl)-1-hydroxy-2-propanesulfonamide, and (1S,2R)—N-(4-(2,6-dimethoxyphenyl)-5-(5-methyl-2-furanyl)-4H-1,2,4-triazol-3-yl)-1-(2,4-dimethyl-1,3-oxazol-5-yl)-1-hydroxy-2-propanesulfonamide

(1R,2R)—N-(4-(2,6-Dimethoxyphenyl)-5-(5-methyl-2-furanyl)-4H-1,2,4-triazol-3-yl)-1-(2,4-dimethyl-1,3-oxazol-5-yl)-1-hydroxy-2-propanesulfonamide and (1S,2S)—N-(4-(2,6-dimethoxyphenyl)-5-(5-methyl-2-furanyl)-4H-1,2,4-triazol-3-yl)-1-(2,4-dimethyl-1,3-oxazol-5-yl)-1-hydroxy-2-propanesulfonamide and (1R,2S)—N-(4-(2,6-dimethoxyphenyl)-5-(5-methyl-2-furanyl)-4H-1,2,4-triazol-3-yl)-1-(2,4-dimethyl-1,3-oxazol-5-yl)-1-hydroxy-2-propanesulfonamide and (1S,2R)—N-(4-(2,6-dimethoxyphenyl)-5-(5-methyl-2-furanyl)-4H-1,2,4-triazol-3-yl)-1-(2,4-dimethyl-1,3-oxazol-5-yl)-1-hydroxy-2-propanesulfonamide, Example 82.0. The title compound was prepared using Example 369.0 and 2,4-dimethyl-oxazole-5-carbaldehyde following the procedures described in Example 86.0 and Example 59.0 to deliver the title compound as a mixtures of diasteromers in a 3:1 diastereomeric ratio. 1 H NMR (400 MHz, CD 3 OD) δ 7.53-7.60 (m, 1H) 6.83-6.89 (m, 2H) 6.02 (dd, J=5.49 Hz, 1H) 5.96 (d, J=3.52 Hz, 1H) 4.95-5.08 (m, 1H) 3.76-3.83 (m, 6H) 3.26-3.47 (m, 1H) 2.43-2.48 (m, 3H) 2.25 (s, 3H) 1.87-2.05 (m, 3H) 1.15-1.50 (m, 3H). LCMS-ESI (pos.) m/z: 518.0 (M+H) + .

Example 83.0. Preparation of 2-(4-chlorophenyl)-N-(5-(furan-2-yl)-4-(pyridin-2-yl)-4H-1,2,4-triazol-3-yl)ethanesulfonamide

2-(4-Chlorophenyl)-N-(5-(furan-2-yl)-4-((1R,2R)-2-methoxycyclopentyl)-4H-1,2,4-triazol-3-yl)ethanesulfonamide and 2-(4-chlorophenyl)-N-(5-(furan-2-yl)-4-((1S,2S)-2-methoxycyclopentyl)-4H-1,2,4-triazol-3-yl)ethanesulfonamide, Example 84.0. Following the procedure described in Example 112.0 employing (1R,2R)-2-methoxycyclopentanamine and (1S,2S)-2-methoxycyclopentanamine (commercially available from Aurum Pharmatech) yielded the title compound as a white solid. 1 H NMR (400 MHz, DMSO-d 6 ) δ 1.33 (s, 1H), 1.54-1.67 (m, 2H), 1.79-1.80 (m, 1H), 2.01-2.06 (m, 2H), 2.07-2.15 (m, 1H), 2.97-3.01 (m, 2H), 3.10 (s, 3H), 3.33-3.39 (m, 1H), 4.28-4.32 (m, 1H), 4.48-4.54 (m, 1H), 6.74 (s, 1H), 7.06-7.09 (m, 1H), 7.28 (d, 2H, J=8.4), 7.33 (d, 2H, J=8), 7.99 (s, 1H), 13.02 (s, 1H); LCMS-ESI (pos.), m/z, 450.94 (M+H) + .

›EXAMPLES · 32 of 46

Example 84.0. Preparation of 2-(4-chlorophenyl)-N-(5-(furan-2-yl)-4-(pyridin-2-yl)-4H-1,2,4-triazol-3-yl)ethanesulfonamide

2-(4-Chlorophenyl)-N-(5-(furan-2-yl)-4-(pyridin-2-yl)-4H-1,2,4-triazol-3-yl)ethanesulfonamide, Example 84.0. Following the procedure described in Example 112.0 employing pyridin-2-amine yielded the title compound as a white solid. 1 H NMR (400 MHz, DMSO-d 6 ) δ 2.92 (t, 2H, J=8.4), 3.26 (t, 2H, J=7.6), 6.23 (d, 1H, J=3.2), 6.55 (s, 1H), 7.26 (d, 2H, J=8), 7.32 (d, 2H, J=8.4), 7.65-7.68 (m, 1H), 7.73 (d, 1H, J=8), 7.78 (s, 1H), 8.14 (t, 1H, J=7.2), 8.64 (d, 1H, J=4), 13.45 (s, 1H). LCMS-ESI (pos.) m/z: 429.88 (M+H) + .

Example 86.0. Preparation of (1R,2S)-1-(5-cyano-6-methylpyridin-2-yl)-N-(4-(2,6-dimethoxyphenyl)-5-(5-methylfuran-2-yl)-4H-1,2,4-triazol-3-yl)-1-hydroxypropane-2-sulfonamide

(1R,2R)-1-(5-Bromo-6-methylpyridin-2-yl)-N-(4-(2,6-dimethoxyphenyl)-5-(5-methylfuran-2-yl)-4H-1,2,4-triazol-3-yl)-1-hydroxy-N-(2-(trimethylsilyl)ethyl)propane-2-sulfonamide compound and (1R,2S)-1-(5-bromo-6-methylpyridin-2-yl)-N-(4-(2,6-dimethoxyphenyl)-5-(5-methylfuran-2-yl)-4H-1,2,4-triazol-3-yl)-1-hydroxy-N-(2-(trimethylsilyl)ethyl)propane-2-sulfonamide and (1S,2R)-1-(5-bromo-6-methylpyridin-2-yl)-N-(4-(2,6-dimethoxyphenyl)-5-(5-methylfuran-2-yl)-4H-1,2,4-triazol-3-yl)-1-hydroxy-N-(2-(trimethylsilyl)ethyl)propane-2-sulfonamide and (1S,2S)-1-(5-bromo-6-methylpyridin-2-yl)-N-(4-(2,6-dimethoxyphenyl)-5-(5-methylfuran-2-yl)-4H-1,2,4-triazol-3-yl)-1-hydroxy-N-(2-(trimethylsilyl)ethyl)propane-2-sulfonamide, Example 86.1. To a solution of Example 369.0 (0.524 g, 1.06 mmol) in THF (5.32 mL) was added n-butyllithium (1.6 M solution in hexanes, 1.33 mL, 2.13 mmol) at −78° C. dropwise. The resulting mixture was stirred at the same temperature for 20 min and then a solution of 3-bromo-2-methyl-pyridine-6-carbaldehyde (AOBChem USA, 0.426 g, 2.13 mmol) in THF (2 mL) was added. The resulting mixture was allowed to stir overnight while gradually warming to RT. The mixture was quenched with a saturated aqueous solution of NH 4 Cl and extracted with EtOAc. The EtOAc layer was dried and concentrated in vacuo. The residue was then purified by an Isco CombiFlash on a Redi Gold 40 g silica gel column using a 0-100% EtOAc gradient in hexanes to give Example 86.1 (335 mg, 45%). LCMS-ESI (pos.) m/z: 693.6 (M+H) + .

(1R,2R)-1-(5-Cyano-6-methylpyridin-2-yl)-N-(4-(2,6-dimethoxyphenyl)-5-(5-methylfuran-2-yl)-4H-1,2,4-triazol-3-yl)-1-hydroxy-N-(2-(trimethylsilyl)ethyl)propane-2-sulfonamide and (1R,2S)-1-(5-cyano-6-methylpyridin-2-yl)-N-(4-(2,6-dimethoxyphenyl)-5-(5-methylfuran-2-yl)-4H-1,2,4-triazol-3-yl)-1-hydroxy-N-(2-(trimethylsilyl)ethyl)propane-2-sulfonamide and (1S,2R)-1-(5-cyano-6-methylpyridin-2-yl)-N-(4-(2,6-dimethoxyphenyl)-5-(5-methylfuran-2-yl)-4H-1,2,4-triazol-3-yl)-1-hydroxy-N-(2-(trimethylsilyl)ethyl)propane-2-sulfonamide and (1S,2S)-1-(5-cyano-6-methylpyridin-2-yl)-N-(4-(2,6-dimethoxyphenyl)-5-(5-methylfuran-2-yl)-4H-1,2,4-triazol-3-yl)-1-hydroxy-N-(2-(trimethylsilyl)ethyl)propane-2-sulfonamide, Example 86.2. Argon was bubbled through a mixture of zinc cyanide (0.092 mL, 1.45 mmol) and Example 86.1 (0.335 g, 0.484 mmol) in DMF (2.5 mL) for 5 min. Tetrakis(triphenylphosphine)palladium (0.056 g, 0.048 mmol) was then added and argon was further bubbled through the mixture for an additional 1 min. The mixture was then placed under an atmosphere of argon and stirred at 115° C. overnight. The mixture was cooled to RT and then directly loaded onto a silica gel cartridge and purified by Isco CombiFlash on a Redi 40 g gold column using a 0-100% EtOAc gradient in hexanes as the eluent to give Example 86.2 (220 mg, 71%). LCMS-ESI (pso.) m/z: 639.2 (M+H) + .

(1R,2R)-1-(5-Cyano-6-methylpyridin-2-yl)-N-(4-(2,6-dimethoxyphenyl)-5-(5-methylfuran-2-yl)-4H-1,2,4-triazol-3-yl)-1-hydroxypropane-2-sulfonamide and (1R,2S)-1-(5-cyano-6-methylpyridin-2-yl)-N-(4-(2,6-dimethoxyphenyl)-5-(5-methylfuran-2-yl)-4H-1,2,4-triazol-3-yl)-1-hydroxypropane-2-sulfonamide and (1S,2R)-1-(5-cyano-6-methylpyridin-2-yl)-N-(4-(2,6-dimethoxyphenyl)-5-(5-methylfuran-2-yl)-4H-1,2,4-triazol-3-yl)-1-hydroxypropane-2-sulfonamide and (1S,2S)-1-(5-cyano-6-methylpyridin-2-yl)-N-(4-(2,6-dimethoxyphenyl)-5-(5-methylfuran-2-yl)-4H-1,2,4-triazol-3-yl)-1-hydroxypropane-2-sulfonamide, Example 88.0. To a solution of Example 86.2 (0.220 g, 0.344 mmol) in DMF (2.5 mL) was added tris(dimethylamino)sulfonium difluorotrimethylsilicate (0.285 g, 1.03 mmol) in portions at RT. The resulting mixture was stirred at 60° C. overnight. The mixture was cooled to RT and then was directly loaded onto a silica gel cartridge and purified by Isco CombiFlash on a Redi 40 g gold silica gel column using a 0-100% EtOAc gradient in hexanes as the eluent to give Example 88.0 (118 mg, 63%). LCMS-ESI (pos.): 539.2 (M+H) + .

(1R,2R)-1-(5-Cyano-6-methylpyridin-2-yl)-N-(4-(2,6-dimethoxyphenyl)-5-(5-methylfuran-2-yl)-4H-1,2,4-triazol-3-yl)-1-hydroxypropane-2-sulfonamide or (1R,2S)-1-(5-cyano-6-methylpyridin-2-yl)-N-(4-(2,6-dimethoxyphenyl)-5-(5-methylfuran-2-yl)-4H-1,2,4-triazol-3-yl)-1-hydroxypropane-2-sulfonamide or (1S,2R)-1-(5-cyano-6-methylpyridin-2-yl)-N-(4-(2,6-dimethoxyphenyl)-5-(5-methylfuran-2-yl)-4H-1,2,4-triazol-3-yl)-1-hydroxypropane-2-sulfonamide or (1S,2S)-1-(5-cyano-6-methylpyridin-2-yl)-N-(4-(2,6-dimethoxyphenyl)-5-(5-methylfuran-2-yl)-4H-1,2,4-triazol-3-yl)-1-hydroxypropane-2-sulfonamide, Example 86.0. Example 88.0 was separated by SFC (250×30 AD-H column with 31.5 g/min EtOH (20 mM NH 3 )+59 g/min CO 2 , 35% co-solvent at 90 g/min. Temp.=20° C., Outlet pressure=100 bar, Wavelength=275 nm. Injected 1.2 mL of 115 mg sample dissolved in 10 mL MeOH, c=11.5 mg/mL and 13.8 mg per injection. Cycle time=14 min, run time=16 min.). Four enantiomers were obtained. The title compound (Example 86.0) was the third isomer to elute under these conditions. 1 H NMR (400 MHz, CDCl 3 ) δ 10.97 (br s, 1H), 7.87 (d, J=8.0 Hz, 1H), 7.48-7.52 (m, 2H), 6.71 (t, J=10 Hz, 2H), 5.93 (br s, 1H), 5.88 (br s, 1H), 5.45 (br s, 1H), 4.08 (br s, 1H), 3.82-3.86 (obscured m, 1H), 3.81 (s, 3H), 3.76 (s, 3H), 2.72 (s, 3H), 2.32 (s, 3H), 1.08 (d, J=6.7 Hz, 3H). LCMS-ESI (pos.): 539.2 (M+H) + .

›EXAMPLES · 33 of 46

The compounds set forth in the following table were synthesized following the procedure in Example 10.0 using the starting materials as described.

Example 89.0. Preparation of (R)—N-(4-(2,6-dimethoxyphenyl)-5-(4,5-dimethylfuran-2-yl)-4H-1,2,4-triazol-3-yl)-1-(5-fluoropyrimidin-2-yl)propane-2-sulfonamide compound or (S)—N-(4-(2,6-dimethoxyphenyl)-5-(4,5-dimethylfuran-2-yl)-4H-1,2,4-triazol-3-yl)-1-(5-fluoropyrimidin-2-yl)propane-2-sulfonamide

(R)—N-((2,6-Dimethoxyphenyl)carbamothioyl)-1-(5-fluoropyrimidin-2-yl)propane-2-sulfonamide and (S)—N-((2,6-dimethoxyphenyl)carbamothioyl)-1-(5-fluoropyrimidin-2-yl)propane-2-sulfonamide, Example 89.1. To a solution of (S)-1-(5-fluoropyrimidin-2-yl)propane-2-sulfonamide and (R)-1-(5-fluoropyrimidin-2-yl)propane-2-sulfonamide (Example 353.0, 1.8 g, 8.21 mmol) in DMF (10 mL) was added cesium carbonate (4.01 g, 12.32 mmol) in portions. The mixture was stirred at RT for 5 min before 2-isothiocyanato-1,3-dimethoxybenzene (Example 372.0, 1.683 g, 8.62 mmol) was added in portions. The resulting mixture was stirred at RT and monitored by LCMS. Upon completion of reaction, 20 mL of water was added, and the mixture was acidified by addition of aqueous HCl solution, 2.0 N (6.16 mL, 12.32 mmol) to a pH of about 5. The precipitate was collected and washed with water three times and dried under vacuum to give Example 89.1 (3.37 g, 8.13 mmol, 99% yield). LCMS-ESI (pos.) m/z: 415.1 (M+H) + .

4,5-Dimethylfuran-2-carbohydrazide, Example 89.2. To a mixture of 4,5-dimethyl-2-furoic acid (2.0 g, 14.27 mmol) and cesium carbonate (5.58 g, 17.13 mmol) in ACN (28.5 mL) was added iodomethane (1.773 mL, 28.5 mmol) at 0° C. The resulting mixture was stirred at RT for 24 h. The mixture was concentrated in vacuo to give methyl 4,5-dimethylfuran-2-carboxylate (1.33 g, 60%). The residue (1.33 g, 8.63 mmol) was dissolved in MeOH (8.5 mL) and hydrazine (1.38 g, 43.1 mmol) was added. The resulting mixture was stirred at RT. Upon completion of reaction as determined by LCMS, the mixture was concentrated. The residue was dissolved in 100 mL of water. The aqueous solution was then lyophilized to give Example 89.2 (1.25 g, 94%). LCMS-ESI (pos.) m/z: 155.1 (M+H) + .

(R)—N-(4-(2,6-Dimethoxyphenyl)-5-(4,5-dimethylfuran-2-yl)-4H-1,2,4-triazol-3-yl)-1-(5-fluoropyrimidin-2-yl)propane-2-sulfonamide and (S)—N-(4-(2,6-dimethoxyphenyl)-5-(4,5-dimethylfuran-2-yl)-4H-1,2,4-triazol-3-yl)-1-(5-fluoropyrimidin-2-yl)propane-2-sulfonamide, Example 89.3. To a mixture of Example 89.1 (0.300 g, 0.72 mmol) and Example 89.2 (0.335 g, 2.17 mmol) in DMF (3.5 mL) was added mercuric acetate (0.074 mL, 0.760 mmol) in portions. The mixture was stirred at RT for 1 h. TFA (0.335 mL, 4.34 mmol) and AcOH (0.418 mL, 7.24 mmol) were then added. The resulting mixture was then stirred at 100° C. for two days. Additional AcOH (0.418 mL, 7.24 mmol) was added, and the resulting mixture was stirred at 100° C. for an additional 24 h. The mixture was cooled to RT and was then directly purified by Isco CombiFlash on a Redi 24 g silica gel column using 0-100% EtOAc gradient in hexanes as eluent to give the product which was further purified by reverse phase HPLC to give Example 89.3 (121 mg). LCMS-ESI (pos.) m/z: 517.1 (M+H) + .

(R)—N-(4-(2,6-Dimethoxyphenyl)-5-(4,5-dimethylfuran-2-yl)-4H-1,2,4-triazol-3-yl)-1-(5-fluoropyrimidin-2-yl)propane-2-sulfonamide or (S)—N-(4-(2,6-dimethoxyphenyl)-5-(4,5-dimethylfuran-2-yl)-4H-1,2,4-triazol-3-yl)-1-(5-fluoropyrimidin-2-yl)propane-2-sulfonamide, Example 89.0. Example 89.3 was separated by SFC (2×15 cm IA column with 80 mL/min 15% MeOH/CO 2 . Outlet pressure=100 bar; wavelength=220 nm; injection volumn=1 mL, 6 mg/mL MeOH). Two enantiomers were obtained. The title compound was the first isomer to elute under these conditions. 1 H NMR (400 MHz, CDCl 3 ) δ 8.52 (s, 2H), 7.46 (t, J=8.5 Hz, 1H), 6.68 (dd, J=8.6, 2.2 Hz, 2H), 5.68 (s, 1H), 3.78-3.82 (m, 1H), 3.77 (s, 3H), 3.75 (s, 3H), 3.65-3.70 (m, 1H), 3.07 (dd, J=14.7, 9.8 Hz, 1H), 2.22 (s, 3H), 1.82 (s, 3H), 1.29 (d, J=6.8 Hz, 3H). LCMS-ESI (pos.): 517.1 (M+H) + .

Example 91.0. Preparation of (R)—N-(4-(2,6-dimethoxyphenyl)-5-(4,5-dimethylfuran-2-yl)-4H-1,2,4-triazol-3-yl)-1-(5-fluoropyrimidin-2-yl)propane-2-sulfonamide or (S)—N-(4-(2,6-dimethoxyphenyl)-5-(4,5-dimethylfuran-2-yl)-4H-1,2,4-triazol-3-yl)-1-(5-fluoropyrimidin-2-yl)propane-2-sulfonamide

(R)—N-(4-(2,6-Dimethoxyphenyl)-5-(4,5-dimethylfuran-2-yl)-4H-1,2,4-triazol-3-yl)-1-(5-fluoropyrimidin-2-yl)propane-2-sulfonamide or (S)—N-(4-(2,6-dimethoxyphenyl)-5-(4,5-dimethylfuran-2-yl)-4H-1,2,4-triazol-3-yl)-1-(5-fluoropyrimidin-2-yl)propane-2-sulfonamide, Example 91.0. Example 91.0 is the enantiomer of Example 89.0. The title compound was the second isomer to elute on subjecting Example 89.3 to the SFC conditions described in Example 89.0. 1 H NMR (400 MHz, CDCl 3 ) δ 8.52 (s, 2H), 7.46 (t, J=8.5 Hz, 1H), 6.68 (dd, J=8.6, 2.2 Hz, 2H), 5.68 (s, 1H), 3.78-3.84 (m, 1H), 3.77 (s, 3H), 3.75 (s, 3H), 3.65-3.70 (m, 1H), 3.07 (dd, J=14.7, 9.8 Hz, 1H), 2.22 (s, 3H), 1.83 (s, 3H), 1.29 (d, J=6.7 Hz, 3H). LCMS-ESI (pos.): 517.1 (M+H) + .

Example 51.0. Preparation of (2S)—N-(4-(2,6-dimethoxyphenyl)-5-(2-furanyl)-4H-1,2,4-triazol-3-yl)-1-(5-fluoro-2-pyrimidinyl)-2-propanesulfonamide or (2R)—N-(4-(2,6-dimethoxyphenyl)-5-(2-furanyl)-4H-1,2,4-triazol-3-yl)-1-(5-fluoro-2-pyrimidinyl)-2-propanesulfonamide

(E)-N-(4-(2,6-Dimethoxyphenyl)-5-(furan-2-yl)-4H-1,2,4-triazol-3-yl)-1-(5-fluoropyrimidin-2-yl)-N-(2-(trimethylsilyl)ethyl)prop-1-ene-2-sulfonamide and (Z)—N-(4-(2,6-dimethoxyphenyl)-5-(furan-2-yl)-4H-1,2,4-triazol-3-yl)-1-(5-fluoropyrimidin-2-yl)-N-(2-(trimethylsilyl)ethyl)prop-1-ene-2-sulfonamide, Example 51.0. The title compound was prepared employing Example 366.0 and 5-fluoropyrimidine-2-carbaldehyde (commercially available from J & W PharmLab, Levittown, Pa., USA) following the procedure described in Example 4.0. LCMS-ESI (pos.) m/z: 587.2 (M+H) + .

(S)—N-(4-(2,6-Dimethoxyphenyl)-5-(furan-2-yl)-4H-1,2,4-triazol-3-yl)-1-(5-fluoropyrimidin-2-yl)-N-(2-(trimethylsilyl)ethyl)propane-2-sulfonamide and (R)—N-(4-(2,6-dimethoxyphenyl)-5-(furan-2-yl)-4H-1,2,4-triazol-3-yl)-1-(5-fluoropyrimidin-2-yl)-N-(2-(trimethylsilyl)ethyl)propane-2-sulfonamide, Example 51.2. The title compound was prepared employing Example 51.2 following the procedure described in Example 4.0. LCMS-ESI (pos.) m/z: 589.2 (M+H) + .

›EXAMPLES · 34 of 46

(2S)—N-(4-(2,6-Dimethoxyphenyl)-5-(2-furanyl)-4H-1,2,4-triazol-3-yl)-1-(5-fluoro-2-pyrimidinyl)-2-propanesulfonamide and (2R)—N-(4-(2,6-dimethoxyphenyl)-5-(2-furanyl)-4H-1,2,4-triazol-3-yl)-1-(5-fluoro-2-pyrimidinyl)-2-propanesulfonamide, Example 51.3. The title compound was prepared employing Example 51.2 following the procedure described in Example 4.0. 1 H NMR (500 MHz, CDCl 3 ) δ 8.56 (s, 2H) 7.43-7.51 (m, 2H) 6.68 (dd, J=8.56, 2.45 Hz, 2H) 6.34 (dd, J=3.42, 1.71 Hz, 1H) 6.01 (d, J=3.42 Hz, 1H) 3.79-3.85 (m, 1H) 3.76 (d, J=9.05 Hz, 6H) 3.68 (dd, J=14.92, 4.65 Hz, 1H) 3.09 (dd, J=14.67, 9.54 Hz, 1H) 1.32 (d, J=6.85 Hz, 3H). LCMS-ESI (pos.) m/z: 489.2 (M+H) + .

(2S)—N-(4-(2,6-Dimethoxyphenyl)-5-(2-furanyl)-4H-1,2,4-triazol-3-yl)-1-(5-fluoro-2-pyrimidinyl)-2-propanesulfonamide or (2R)—N-(4-(2,6-dimethoxyphenyl)-5-(2-furanyl)-4H-1,2,4-triazol-3-yl)-1-(5-fluoro-2-pyrimidinyl)-2-propanesulfonamide, Example 51.0. Purification of Example 51.3 by SFC [4.6×250 mm AD-H column with 22% MeOH (neat) in CO 2 at 100 bar] afforded two enantiomers. The title compound was the first isomer to elute under these conditions. 1 H NMR (500 MHz, CDCl 3 ) δ 11.07 (br. s., 1H) 8.53 (s, 2H) 7.40-7.51 (m, 2H) 6.68 (dd, J=8.56, 2.93 Hz, 2H) 6.33 (dd, J=3.42, 1.71 Hz, 1H) 6.00 (d, J=3.42 Hz, 1H) 3.78-3.84 (m, 1H) 3.76 (d, J=9.78 Hz, 6H) 3.69 (dd, J=14.79, 4.28 Hz, 1H) 3.08 (dd, J=14.67, 9.78 Hz, 1H) 1.31 (d, J=6.60 Hz, 3H). LCMS-ESI (pos.) m/z: 489.2 (M+H) + .

Example 92.0. Preparation of (2S)—N-(4-(2,6-dimethoxyphenyl)-5-(5-ethyl-2-furanyl)-4H-1,2,4-triazol-3-yl)-1-(5-fluoro-2-pyrimidinyl)-2-propanesulfonamide and (2R)—N-(4-(2,6-dimethoxyphenyl)-5-(5-ethyl-2-furanyl)-4H-1,2,4-triazol-3-yl)-1-(5-fluoro-2-pyrimidinyl)-2-propanesulfonamide

(2S)—N-(4-(2,6-Dimethoxyphenyl)-5-(5-ethyl-2-furanyl)-4H-1,2,4-triazol-3-yl)-1-(5-fluoro-2-pyrimidinyl)-2-propanesulfonamide and (2R)—N-(4-(2,6-dimethoxyphenyl)-5-(5-ethyl-2-furanyl)-4H-1,2,4-triazol-3-yl)-1-(5-fluoro-2-pyrimidinyl)-2-propanesulfonamide, Example 92.0. A suspension of Example 364.2 (60 mg, 0.16 mmol), Example 353.0 (70 mg, 0.32 mmol), rac-trans-N,N′-dimethylcyclohexane-1,2-diamine (49 μL, 0.32 mmol), cesium carbonate (129 mg, 0.40 mmol) and 4 Å dried and crushed molecular sieves (60 mg) in dioxane (0.3 mL) was sparged with argon for 3 min. Copper(I) iodide (15 mg, 0.079 mmol) was added and the mixture was briefly degassed. The reaction vessel was then heated in a microwave at 90° C. until LCMS analysis indicated that the reaction was complete (12 h). Thereafter, the mixture was cooled to RT, diluted with water, filtered, and extracted with EtOAc (3×). The combined organic layers were dried over MgSO 4 , filtered, and concentrated in vacuo. The residue was purified on a silica gel column employing a gradient of 0-5% IPA in DCM to afford Example 92.0 (13 mg, 16%). 1 H NMR (400 MHz, CDCl 3 ) δ 11.00 (br. s., 1H) 8.56 (br. s., 2H) 7.45 (t, J=8.5 Hz, 1H) 6.67 (dd, J=8.5, 2.1 Hz, 2H) 5.81-5.99 (m, 2H) 3.75 (d, J=7.8 Hz, 7H) 3.68 (d, J=13.1 Hz, 1H) 2.97-3.17 (m, 1H) 2.65 (q, J=7.6 Hz, 2H) 1.30 (d, J=6.7 Hz, 3H) 1.18 (t, J=7.6 Hz, 3H). LCMS-ESI (pos.) m/z: 517.2 (M+H) + .

Example 97.0. Preparation of (2S)—N-(4-(2,6-dimethoxyphenyl)-5-(5-ethyl-2-furanyl)-4H-1,2,4-triazol-3-yl)-1-(5-fluoro-2-pyrimidinyl)-2-propanesulfonamide or (2R)—N-(4-(2,6-dimethoxyphenyl)-5-(5-ethyl-2-furanyl)-4H-1,2,4-triazol-3-yl)-1-(5-fluoro-2-pyrimidinyl)-2-propanesulfonamide

(2S)—N-(4-(2,6-Dimethoxyphenyl)-5-(5-ethyl-2-furanyl)-4H-1,2,4-triazol-3-yl)-1-(5-fluoro-2-pyrimidinyl)-2-propanesulfonamide or (2R)—N-(4-(2,6-dimethoxyphenyl)-5-(5-ethyl-2-furanyl)-4H-1,2,4-triazol-3-yl)-1-(5-fluoro-2-pyrimidinyl)-2-propanesulfonamide, Example 97.0. Purification of Example 92.0 by SFC [20×250 mm IA column with 30 g/min MeOH (20 mM NH 3 ) in 90 g/min CO 2 at 100 bar] afforded two enantiomers. The title compound was the first isomer to elute under these conditions. 1 H NMR (400 MHz, CDCl 3 ) δ 8.54 (s, 2H), 7.39-7.54 (m, 1H), 6.69 (dd, J=8.5, 1.3 Hz, 2H), 5.86-6.01 (m, 2H), 3.63-3.91 (m, 8H), 3.09 (dd, J=14.7, 9.8 Hz, 1H), 2.66 (q, J=7.4 Hz, 2H), 1.31 (d, J=6.8 Hz, 3H), 1.19 (t, J=7.6 Hz, 3H). LCMS-ESI (pos.) m/z: 517.1 (M+H) + .

Example 99.0. Preparation of (2S)—N-(4-(2,6-dimethoxyphenyl)-5-(5-ethyl-2-furanyl)-4H-1,2,4-triazol-3-yl)-1-(5-fluoro-2-pyrimidinyl)-2-propanesulfonamide or (2R)—N-(4-(2,6-dimethoxyphenyl)-5-(5-ethyl-2-furanyl)-4H-1,2,4-triazol-3-yl)-1-(5-fluoro-2-pyrimidinyl)-2-propanesulfonamide

(2S)—N-(4-(2,6-Dimethoxyphenyl)-5-(5-ethyl-2-furanyl)-4H-1,2,4-triazol-3-yl)-1-(5-fluoro-2-pyrimidinyl)-2-propanesulfonamide or (2R)—N-(4-(2,6-dimethoxyphenyl)-5-(5-ethyl-2-furanyl)-4H-1,2,4-triazol-3-yl)-1-(5-fluoro-2-pyrimidinyl)-2-propanesulfonamide, Example 99.0. Example 99.0 is the enantiomer of Example 97.0. The title compound was the second isomer to elute on subjecting racemic Example 92.0 to the SFC conditions described in Example 97.0. 1 H NMR (400 MHz, CDCl 3 ) δ 11.03 (br. s., 1H), 8.55 (s, 2H), 7.47 (t, J=8.5 Hz, 1H), 6.69 (dd, J=8.5, 2.1 Hz, 2H), 5.91-5.96 (m, 2H), 3.76-3.85 (m, 7H), 3.70 (dd, J=14.4, 4.2 Hz, 1H), 3.10 (dd, J=14.7, 9.8 Hz, 1H), 2.67 (q, J=7.5 Hz, 2H), 1.32 (d, J=6.7 Hz, 3H), 1.20 (t, J=7.5 Hz, 3H). LCMS-ESI (pos.) m/z: 517.1 (M+H) + .

Example 96.0. Preparation of (1R,2S)—N-(4-(2,6-dimethoxyphenyl)-5-(5-methyl-2-furanyl)-4H-1,2,4-triazol-3-yl)-1-(5-fluoro-2-pyrimidinyl)-1-hydroxy-2-propanesulfonamide and (1S,2R)—N-(4-(2,6-dimethoxyphenyl)-5-(5-methyl-2-furanyl)-4H-1,2,4-triazol-3-yl)-1-(5-fluoro-2-pyrimidinyl)-1-hydroxy-2-propanesulfonamide

(1R,2S)—N-(4-(2,6-Dimethoxyphenyl)-5-(5-methyl-2-furanyl)-4H-1,2,4-triazol-3-yl)-1-(5-fluoro-2-pyrimidinyl)-1-hydroxy-2-propanesulfonamide and (1S,2R)—N-(4-(2,6-dimethoxyphenyl)-5-(5-methyl-2-furanyl)-4H-1,2,4-triazol-3-yl)-1-(5-fluoro-2-pyrimidinyl)-1-hydroxy-2-propanesulfonamide, Example 93.1. The title compound was prepared employing Example 364.1 and Example 355.1 using the procedure described in Example 94.0. The reaction was diluted with a small volume of water and stirred vigorously. EtOAc was added followed by dropwise addition of concentrated HCl. Any precipitants were removed by filtration through Celite® brand filter aid. The organics were dried on MgSO 4 , filtered, and evaporated. The filtrate was purified by silica gel using an eluent of 0-5% IPA/DCM. The material was repurified by preparatory RP-HPLC (25 to 65% ACN, water, 0.1% TFA, gradient elution) over 20 min using Eclipse Plus Prep C18 column, 5 μm, 30×150 mm (Agilent Technologies, Inc., Santa Clara, Calif.) at 50 mLs/min and provided Example 96.0 (34 mg, 12%) as a white amorphous solid. 1 H NMR (500 MHz, CDCl 3 ) δ 8.64 (s, 2H) 7.49 (t, J=8.4 Hz, 1H) 6.71 (dd, J=14.9, 8.6 Hz, 2H) 5.92-5.99 (m, 1H) 5.85 (d, J=3.4 Hz, 1H) 5.63 (s, 1H) 3.71-3.91 (m, 7H) 2.34 (s, 3H) 1.24 (d, J=6.8 Hz, 3H). LCMS-ESI (pos.), m/z: 519.0 (M+H) + .

›EXAMPLES · 35 of 46

Example 93.0. Preparation of (1R,2S)—N-(4-(2,6-dimethoxyphenyl)-5-(5-methyl-2-furanyl)-4H-1,2,4-triazol-3-yl)-1-(5-fluoro-2-pyrimidinyl)-1-hydroxy-2-propanesulfonamide or (1S,2R)—N-(4-(2,6-dimethoxyphenyl)-5-(5-methyl-2-furanyl)-4H-1,2,4-triazol-3-yl)-1-(5-fluoro-2-pyrimidinyl)-1-hydroxy-2-propanesulfonamide

(1R,2S)—N-(4-(2,6-Dimethoxyphenyl)-5-(5-methyl-2-furanyl)-4H-1,2,4-triazol-3-yl)-1-(5-fluoro-2-pyrimidinyl)-1-hydroxy-2-propanesulfonamide or (1S,2R)—N-(4-(2,6-dimethoxyphenyl)-5-(5-methyl-2-furanyl)-4H-1,2,4-triazol-3-yl)-1-(5-fluoro-2-pyrimidinyl)-1-hydroxy-2-propanesulfonamide, Example 93.0. Example 96.0 was separated via chiral purification techniques to deliver the title compound. 1 H NMR (500 MHz, CDCl 3 ) δ 10.85 (br. s., 1H) 8.53 (s, 2H) 7.39 (t, J=8.4 Hz, 1H) 6.62 (d, J=8.3 Hz, 1H) 6.60 (d, J=8.6 Hz, 1H) 5.80-5.90 (m, 1H) 5.75 (d, J=3.4 Hz, 1H) 5.53 (br. s., 1H) 3.70 (s, 4H) 3.68 (s, 3H) 2.24 (s, 3H) 1.15 (d, J=6.8 Hz, 3H). LCMS-ESI (pos.) m/z: 519.0 (M+H) + .

Example 94.0. Preparation of (2S)—N-(4-(2,6-dimethoxyphenyl)-5-(5-methyl-2-furanyl)-4H-1,2,4-triazol-3-yl)-1-(5-fluoro-2-pyrimidinyl)-2-propanesulfonamide and (2R)—N-(4-(2,6-dimethoxyphenyl)-5-(5-methyl-2-furanyl)-4H-1,2,4-triazol-3-yl)-1-(5-fluoro-2-pyrimidinyl)-2-propanesulfonamide

(2S)—N-(4-(2,6-Dimethoxyphenyl)-5-(5-methyl-2-furanyl)-4H-1,2,4-triazol-3-yl)-1-(5-fluoro-2-pyrimidinyl)-2-propanesulfonamide and (2R)—N-(4-(2,6-dimethoxyphenyl)-5-(5-methyl-2-furanyl)-4H-1,2,4-triazol-3-yl)-1-(5-fluoro-2-pyrimidinyl)-2-propanesulfonamide, Example 94.0. A suspension of Example 364.1 (64 mg, 0.18 mmol), Example 353.0 (77 mg, 0.35 mmol), rac-trans-N,N′-dimethylcyclohexane-1,2-diamine (54 μL, 0.35 mmol), cesium carbonate (143 mg, 0.44 mmol) and 5 Å dried and crushed molecular sieves (100 mg) in dioxane (0.4 mL) was sparged with argon for 3 min. Copper(I) iodide (17 mg, 0.089 mmol) was then added and the mixture was briefly degassed. The reaction vessel was then heated in a microwave at 90° C. until LCMS analysis indicated that the reaction was complete (12 h). Thereafter, the mixture was cooled to RT, filtered, diluted with 10% aqueous NH 4 OH, and stirred vigorously for 20 min. The mixture was then acidified with concentrated HCl, filtered, and extracted with EtOAc (3×). The organic layers were then combined, dried over MgSO 4 , filtered, and concentrated in vacuo. The residue was purified on a reverse-phase column employing a gradient of 20-70% ACN in water (0.1% TFA in both eluents) to afford Example 94.0 (62 mg, 70%). 1 H NMR (400 MHz, CDCl 3 ) δ 8.57 (br. s., 2H) 7.46 (t, J=8.4 Hz, 1H) 6.68 (d, J=8.4 Hz, 2H) 5.87-5.98 (m, 1H) 5.82 (d, J=3.3 Hz, 1H) 3.71-3.88 (m, 7H) 3.67 (d, J=14.1 Hz, 1H) 2.96-3.19 (m, 1H) 2.32 (s, 3H) 1.32 (d, J=5.9 Hz, 3H). LCMS-ESI (pos.) m/z: 503.0 (M+H) + .

Example 108.0. Preparation of (2S)—N-(4-(2,6-dimethoxyphenyl)-5-(5-methyl-2-furanyl)-4H-1,2,4-triazol-3-yl)-1-(5-fluoro-2-pyrimidinyl)-2-propanesulfonamide or (2R)—N-(4-(2,6-dimethoxyphenyl)-5-(5-methyl-2-furanyl)-4H-1,2,4-triazol-3-yl)-1-(5-fluoro-2-pyrimidinyl)-2-propanesulfonamide

(2S)—N-(4-(2,6-Dimethoxyphenyl)-5-(5-methyl-2-furanyl)-4H-1,2,4-triazol-3-yl)-1-(5-fluoro-2-pyrimidinyl)-2-propanesulfonamide or (2R)—N-(4-(2,6-dimethoxyphenyl)-5-(5-methyl-2-furanyl)-4H-1,2,4-triazol-3-yl)-1-(5-fluoro-2-pyrimidinyl)-2-propanesulfonamide, Example 108.0. Purification of Example 94.0 was accomplished using SFC [21×250 mm IA column with 24 g/min MeOH (20 mM NH 3 ) in 56 g/min CO 2 at 100 bar] and afforded two enantiomers. The title compound (Example 108.0) was the first isomer to elute under these conditions. 1 H NMR (400 MHz, CDCl 3 ) δ 8.57 (br. s., 2H) 7.48 (t, J=8.5 Hz, 1H) 6.70 (dd, J=8.5, 2.2 Hz, 2H) 5.93 (dd, J=3.4, 0.9 Hz, 1H) 5.83 (d, J=3.3 Hz, 1H) 3.76-3.83 (m, 7H) 3.71 (d, J=14.7 Hz, 1H) 3.10 (dd, J=14.3, 10.0 Hz, 1H) 2.34 (s, 3H) 1.33 (d, J=6.7 Hz, 3H). LCMS-ESI (pos.) m/z: 503.1 (M+H) + .

Example 95.0. Preparation of (1R,2R)—N-(4-(2,6-dimethoxyphenyl)-5-(5-methyl-2-furanyl)-4H-1,2,4-triazol-3-yl)-1-(5-fluoro-2-pyrimidinyl)-1-hydroxy-2-propanesulfonamide or (1S,2S)—N-(4-(2,6-dimethoxyphenyl)-5-(5-methyl-2-furanyl)-4H-1,2,4-triazol-3-yl)-1-(5-fluoro-2-pyrimidinyl)-1-hydroxy-2-propanesulfonamide

(1R,2R)—N-(4-(2,6-Dimethoxyphenyl)-5-(5-methyl-2-furanyl)-4H-1,2,4-triazol-3-yl)-1-(5-fluoro-2-pyrimidinyl)-1-hydroxy-2-propanesulfonamide and (1S,2S)—N-(4-(2,6-dimethoxyphenyl)-5-(5-methyl-2-furanyl)-4H-1,2,4-triazol-3-yl)-1-(5-fluoro-2-pyrimidinyl)-1-hydroxy-2-propanesulfonamide, Example 95.1. The title compound was prepared employing Example 364.1 and Example 355.0 using the procedure described in Example 94.0 (using 1.5 eq of Example 364.1 and 1 eq Example 355.0, and the reaction was heated to 90° C. for 12 h in a microwave reactor). The reaction was then diluted with a small volume of water and stirred vigorously. EtOAc was added followed by dropwise addition of concentrated HCl. Any precipitants were removed by filtration through a a pad of Celite® brand filter aid. The organics were dried on MgSO 4 , filtered, and evaporated. Purification by flash chromatography on 40 g Redisep Gold pre-packed spherical silica gel column (Teledyne Isco Inc., Lincoln, Nebr.) (eluent: 3-5% IPA/DCM, gradient elution) provided the title compound (26 mg, 28%) as a light-yellow powder. 1 H NMR (500 MHz, CDCl 3 ) δ 10.84 (br. s., 1H) 8.60 (s, 2H) 7.50 (t, J=8.6 Hz, 1H) 6.71 (dd, J=8.6, 3.4 Hz, 2H) 5.94 (dd, J=3.4, 1.0 Hz, 1H) 5.86 (d, J=3.4 Hz, 1H) 5.07 (d, J=6.4 Hz, 1H) 3.81 (d, J=1.5 Hz, 6H) 2.34 (s, 3H) 1.29 (d, J=7.1 Hz, 3H). LCMS-ESI (pos.), m/z: 519.2 (M+H) + .

(1R,2R)—N-(4-(2,6-Dimethoxyphenyl)-5-(5-methyl-2-furanyl)-4H-1,2,4-triazol-3-yl)-1-(5-fluoro-2-pyrimidinyl)-1-hydroxy-2-propanesulfonamide or (1S,2S)—N-(4-(2,6-dimethoxyphenyl)-5-(5-methyl-2-furanyl)-4H-1,2,4-triazol-3-yl)-1-(5-fluoro-2-pyrimidinyl)-1-hydroxy-2-propanesulfonamide, Example 95.0. Example 95.1 was separated via chiral purification techniques to deliver the title compound as peak 2. 1 H NMR (500 MHz, CDCl 3 ) δ 10.84 (br. s., 1H) 8.58 (s, 2H) 7.48 (t, J=8.4 Hz, 1H) 6.69 (dd, J=8.4, 3.5 Hz, 2H) 5.90-5.94 (m, 1H) 5.84 (d, J=3.4 Hz, 1H) 5.05 (d, J=6.4 Hz, 1H) 3.74-3.81 (m, 7H) 3.72 (s, 1H) 2.32 (s, 3H) 1.27 (d, J=7.1 Hz, 3H). LCMS-ESI (pos.) m/z: 519.0 (M+H) + .

›EXAMPLES · 36 of 46

Example 98.0. Preparation of N-(4-(2,6-dimethoxyphenyl)-5-(5-ethyl-2-furanyl)-4H-1,2,4-triazol-3-yl)-2-(5-fluoro-2-pyrimidinyl)ethanesulfonamide

N-(4-(2,6-dimethoxyphenyl)-5-(5-ethyl-2-furanyl)-4H-1,2,4-triazol-3-yl)-2-(5-fluoro-2-pyrimidinyl)ethanesulfonamide, Example 98.0. A suspension of Example 364.2 (35 mg, 0.093 mmol), Example 351.0 (76 mg, 0.37 mmol), rac-trans-N,N′-dimethylcyclohexane-1,2-diamine (26 μL, 0.19 mmol), cesium carbonate (151 mg, 0.46 mmol), and 5 Å dried and crushed molecular sieves (75 mg) in dioxane (0.9 mL) was sparged with argon for 3 min. Copper(I) iodide (18 mg, 0.093 mmol) was then added, the mixture was briefly degassed, and the reaction vessel was heated in a microwave at 100° C. until LCMS analysis indicated that the reaction was complete (4 h). Thereafter, the mixture was cooled to RT, filtered, and concentrated in vacuo. The residue was purified on a reverse-phase column, employing a gradient of 25-75% ACN in water (0.1% TFA in both eluents) to afford Example 98.0 (10 mg, 22%). 1 H NMR (400 MHz, CDCl 3 ) δ 8.54 (s, 2H), 7.46 (t, J=8.5 Hz, 1H), 6.67 (d, J=8.4 Hz, 2H), 5.90-5.95 (m, 2H), 3.75 (s, 3H), 3.75 (s, 3H), 3.53-3.66 (m, 2H), 3.38-3.53 (m, 2H), 2.64 (q, J=7.6 Hz, 2H), 1.18 (t, J=7.6 Hz, 3H). LCMS-ESI (pos.) m/z: 503.1 (M+H) + .

Example 100.0. Preparation of (1R,2S)—N-(4-(2,6-dimethoxyphenyl)-5-(5-methyl-2-furanyl)-4H-1,2,4-triazol-3-yl)-2-(5-fluoro-2-pyrimidinyl)cyclopentanesulfonamide and (1S,2R)—N-(4-(2,6-dimethoxyphenyl)-5-(5-methyl-2-furanyl)-4H-1,2,4-triazol-3-yl)-2-(5-fluoro-2-pyrimidinyl)cyclopentanesulfonamide

2-(Cyclopent-1-en-1-yl)-5-fluoropyrimidine, Example 100.1. A slurry of cyclopentene-1-boronic acid (Combi-Blocks, 2.05 g, 18.3 mmol), sodium carbonate (3.88 g, 36.6 mmol), and 2-chloro-5-fluoro-pyrimidine (2.26 mL, 18.3 mmol) in a mixture of THF (24 mL) and water (12 mL) was deoxygenated with an Ar stream. Tetrakis(triphenylphosphine)palladium (2.12 g, 1.8 mmol) was added and the slurry was again deoxygenated with an Ar stream. The reaction was heated under Ar at 100° C. for 3 d. The reaction mixture was extracted with DCM (3×). The combined organic layers were dried over anhydrous magnesium sulfate and concentrated. The residue was purified by silica gel chromatography (eluent: DCM) to provide 100.1 (2.6 g, 86% yield) as a colorless oil. LCMS-ESI (pos.) m/z: 165.2 (M+H) + .

(1S,2S)-2-(5-Fluoropyrimidin-2-yl)cyclopentane-1-sulfonic acid and (1R,2R)-2-(5-fluoropyrimidin-2-yl)cyclopentane-1-sulfonic acid and (1R,2S)-2-(5-fluoropyrimidin-2-yl)cyclopentane-1-sulfonic acid and (1S,2R)-2-(5-fluoropyrimidin-2-yl)cyclopentane-1-sulfonic acid, Example 100.2. To a microwave vial containing a suspension of 100.1 (2.6 g, 15.8 mmol) in 4 M aqueous sodium bisulfite solution (3.76 mL, 15.0 mmol) was added EtOH (4 mL). The vial was sealed and the resulting slurry was heated at 90° C. in the microwave for 12 h. The reaction was filtered and the filtrate was directly purified by reverse phase preparatory HPLC (Sunfire 5 μM C18 column, eluent: 0-40% ACN in water over a 15 min period where both solvents contain 0.1% TFA) to provide 100.2 (3.09 g, 79% yield). LCMS-ESI (pos.) m/z: 247.2 (M+H) + .

(1R,2R)-2-(5-Fluoropyrimidin-2-yl)-N-(4-methoxybenzyl)cyclopentane-1-sulfonamide and (1S,2S)-2-(5-fluoropyrimidin-2-yl)-N-(4-methoxybenzyl)cyclopentane-1-sulfonamide, Example 100.3. To a suspension of 100.2 (1.24 g, 5.0 mmol) in DCM (50 mL) was added oxalyl chloride (1.34 mL, 15.1 mmol) via syringe followed by a catalytic amount of DMF via syringe. Vigorous bubbling was observed. The resulting white slurry was stirred at RT for 2 h and then was concentrated. The residue was azeotroped to dryness with cyclopentylmethyl ether and then was suspended in DCM (50 mL). 2,4-Dimethoxybenzylamine (2.53 mL, 15.1 mmol) and TEA (3.51 mL, 25.2 mmol) were added sequentially via syringe. The resulting slurry was then stirred at RT overnight. The reaction mixture was partitioned between water and DCM (3×). The combined organic layers were dried over anhydrous magnesium sulfate and concentrated. The residue was purified by silica gel chromatography (eluent: 10-40% EtOAc in hexanes over a 30 min period) to provide Example 100.3 (21%) as a clear colorless oil. LCMS-ESI (pos.), m/z: 366.0 (M+H) + .

(1R,2S)-2-(5-Fluoropyrimidin-2-yl)-N-(4-methoxybenzyl)cyclopentane-1-sulfonamide and (1S,2R)-2-(5-fluoropyrimidin-2-yl)-N-(4-methoxybenzyl)cyclopentane-1-sulfonamide, Example 100.4. Further elution under the conditions described in Example 100.3 delivered the title compound (1.07 g, 54%) as a colorless oil.

(1R,2S)-2-(5-Fluoropyrimidin-2-yl)cyclopentane-1-sulfonamide and (1S,2R)-2-(5-fluoropyrimidin-2-yl)cyclopentane-1-sulfonamide, Example 100.5. An ice-cooled solution of Example 100.4 (1.09 g, 2.7 mmol) in DCM (14 mL) was treated sequentially with anisole (899 μL, 8.3 mmol) via syringe and TFA (2.05 mL, 27.6 mmol) via syringe. The resulting solution was stirred at 0° C. for 30 min and then was warmed to RT and stirred for an additional 3 h. The reaction was directly concentrated and the residue was purified by silica gel chromatography (eluent: 30-100% EtOAc in hexanes over a 30 min period) to provide Example 100.5 (540 mg, 80% yield) as a white solid. LCMS-ESI (pos.) m/z: 246.1 (M+H) + .

(1S,2S)-2-(5-Fluoropyrimidin-2-yl)cyclopentane-1-sulfonamide and (1R,2R)-2-(5-fluoropyrimidin-2-yl)cyclopentane-1-sulfonamide, Example 100.6. An ice-cooled solution of Example 100.3 (408 mg, 1.0 mmol) in DCM (5 mL) was treated sequentially with anisole (336 μL, 3.1 mmol) via syringe and TFA (767 μL, 10.3 mmol) via syringe. The resulting solution was stirred at 0° C. for 30 min and then was warmed to RT and stirred for an additional 3 h. The reaction was directly concentrated and the residue was purified by silica gel chromatography (eluent: 30-100% EtOAc in hexanes over a 30 min period) to provide Example 100.6 (60 mg, 24% yield) as a white solid. LCMS-ESI (pos.) m/z: 246.2 (M+H) + .

(1R,2S)—N-(4-(2,6-Dimethoxyphenyl)-5-(5-methyl-2-furanyl)-4H-1,2,4-triazol-3-yl)-2-(5-fluoro-2-pyrimidinyl)cyclopentanesulfonamide and (1S,2R)—N-(4-(2,6-dimethoxyphenyl)-5-(5-methyl-2-furanyl)-4H-1,2,4-triazol-3-yl)-2-(5-fluoro-2-pyrimidinyl)cyclopentanesulfonamide, Example 100.0. The title compound was prepared employing Example 364.1 and Example 100.5 as the sulfonamide coupling partner using the Cut coupling procedure described in Example 94.0 (the reaction was heated to 90° C. for 16 h). The reaction was then diluted with a small volume of water and stirred vigorously. EtOAc was added followed by dropwise addition of concentrated HCl. Any precipitants were removed by filtration through a pad of Celite® brand filter aid. The organics were dried over MgSO 4 , filtered, evaporated, and then triturated in MeOH. Purification by preparatory reverse phase HPLC (20 to 55% ACN, water, 0.1% TFA, gradient elution) over 20 min using Sunfire™ Prep C18 OBD column, 10 μm, 30×150 mm (Waters, Milford, Mass.) at 50 mLs/min provided Example 100.0 (90 mg, 42%). 1 H NMR (500 MHz, CDCl 3 ) δ 8.52 (s, 2H) 7.46 (t, J=8.3 Hz, 1H) 6.66 (d, J=7.9 Hz, 2H) 5.90 (dd, J=3.3, 0.9 Hz, 1H) 5.77 (d, J=3.4 Hz, 1H) 4.20 (q, J=7.8 Hz, 1H) 3.86 (q, J=8.0 Hz, 1H) 3.75 (s, 3H) 3.75 (s, 3H) 2.32 (s, 3H) 2.14-2.30 (m, 3H) 1.75-1.88 (m, 3H). LCMS-ESI (pos.), m/z: 529.1 (M+H) + .

›EXAMPLES · 37 of 46

Example 101.0. Preparation of (1R,2S)—N-(4-(2,6-dimethoxyphenyl)-5-(5-methyl-2-furanyl)-4H-1,2,4-triazol-3-yl)-2-(5-fluoro-2-pyrimidinyl)cyclopentanesulfonamide or (1S,2R)—N-(4-(2,6-dimethoxyphenyl)-5-(5-methyl-2-furanyl)-4H-1,2,4-triazol-3-yl)-2-(5-fluoro-2-pyrimidinyl)cyclopentanesulfonamide

(1R,2S)—N-(4-(2,6-Dimethoxyphenyl)-5-(5-methyl-2-furanyl)-4H-1,2,4-triazol-3-yl)-2-(5-fluoro-2-pyrimidinyl)cyclopentanesulfonamide or (1S,2R)—N-(4-(2,6-dimethoxyphenyl)-5-(5-methyl-2-furanyl)-4H-1,2,4-triazol-3-yl)-2-(5-fluoro-2-pyrimidinyl)cyclopentanesulfonamide, Example 101.0. Chiral purification of Example 100.0 was performed using the following preparative SFC method: Column: 250×30 mm Phenomenex Lux-2 Cell, 60 mL/min MeOH+60 g/min CO 2 , 100 bar, 215 nm, Inj volume: 4.0 mL of a 5.0 mg/mL solution of sample in MeOH provided the initial peak as the title compound. 1 H NMR (500 MHz, CDCl 3 ) δ 10.98 (br. s., 1H) 8.51 (s, 2H) 7.45 (t, J=8.6 Hz, 1H) 6.66 (d, J=8.6 Hz, 2H) 5.90 (dd, J=3.4, 1.0 Hz, 1H) 5.76 (d, J=3.4 Hz, 1H) 4.19 (q, J=7.8 Hz, 1H) 3.86 (q, J=8.1 Hz, 1H) 3.76 (s, 3H) 3.75 (s, 3H) 2.32 (s, 3H) 2.14-2.29 (m, 3H) 1.73-1.89 (m, 3H). LCMS-ESI (pos.) m/z: 529.1 (M+H) + .

Example 102.0. Preparation of (1R,2S)—N-(4-(2,6-dimethoxyphenyl)-5-(5-methyl-2-furanyl)-4H-1,2,4-triazol-3-yl)-2-(5-fluoro-2-pyrimidinyl)cyclopentanesulfonamide or (1S,2R)—N-(4-(2,6-dimethoxyphenyl)-5-(5-methyl-2-furanyl)-4H-1,2,4-triazol-3-yl)-2-(5-fluoro-2-pyrimidinyl)cyclopentanesulfonamide

(1R,2S)—N-(4-(2,6-Dimethoxyphenyl)-5-(5-methyl-2-furanyl)-4H-1,2,4-triazol-3-yl)-2-(5-fluoro-2-pyrimidinyl)cyclopentanesulfonamide or (1S,2R)—N-(4-(2,6-dimethoxyphenyl)-5-(5-methyl-2-furanyl)-4H-1,2,4-triazol-3-yl)-2-(5-fluoro-2-pyrimidinyl)cyclopentanesulfonamide, Example 102.0. Chiral purification of Example 100.0 was conducted using the following preparative SFC method: Column: 250×30 mm Phenomenex Lux-2 Cell, 60 mL/min MeOH+60 g/min CO 2 , 100 bar, 215 nm, Inj volume: 4.0 mL of a 5.0 mg/mL solution of sample in MeOH provided the second peak as the title compound. 1 H NMR (500 MHz, CDCl 3 ) δ 10.97 (s, 1H) 8.51 (s, 2H) 7.45 (t, J=8.6 Hz, 1H) 6.66 (d, J=8.6 Hz, 2H) 5.90 (dd, J=3.4, 1.0 Hz, 1H) 5.76 (d, J=3.4 Hz, 1H) 4.19 (q, J=7.8 Hz, 1H) 3.86 (q, J=8.2 Hz, 1H) 3.76 (s, 3H) 3.75 (s, 3H) 2.32 (s, 3H) 2.12-2.29 (m, 3H) 1.75-1.91 (m, 3H). LCMS-ESI (pos.) m/z: 529.1 (M+H) + .

Example 103.0. Preparation of (1S,2S)—N-(4-(2,6-dimethoxyphenyl)-5-(2-furanyl)-4H-1,2,4-triazol-3-yl)-2-(5-fluoro-2-pyrimidinyl)cyclohexanesulfonamide or (1R,2R)—N-(4-(2,6-dimethoxyphenyl)-5-(2-furanyl)-4H-1,2,4-triazol-3-yl)-2-(5-fluoro-2-pyrimidinyl)cyclohexanesulfonamide

2-(Cyclohex-1-en-1-yl)-5-fluoropyrimidine, Example 103.1. A slurry of cyclohexene-1-boronic acid (CombiPhos Catalysts, 4.00 g, 31.8 mmol), sodium carbonate (6.73 g, 63.5 mmol) and 2-chloro-5-fluoro-pyrimidine (3.92 mL, 31.8 mmol) in a mixture of ACN (53 mL) and water (26.5 mL) was deoxygenated with an Ar stream. Tetrakis(triphenylphosphine)palladium (1.84 g, 1.6 mmol) was added and the slurry was again deoxygenated with an Ar stream. The reaction was heated under Ar at 95° C. for 3 d. The reaction mixture was then extracted with DCM (3×). The combined organic layers were dried over anhydrous magnesium sulfate and concentrated. The residue was purified by silica gel chromatography (eluent: 0-50% DCM in hexanes over a 30 min period) to provide Example 103.1 (2.8 g, 50% yield) as a colorless oil. LCMS-ESI (pos.) m/z: 179.1 (M+H) + .

(1R,2S)-2-(5-Fluoropyrimidin-2-yl)cyclohexane-1-sulfonic acid and (1R,2R)-2-(5-fluoropyrimidin-2-yl)cyclohexane-1-sulfonic acid and (1S,2S)-2-(5-fluoropyrimidin-2-yl)cyclohexane-1-sulfonic acid and (1S,2R)-2-(5-fluoropyrimidin-2-yl)cyclohexane-1-sulfonic acid, Example 103.2. To a microwave vial containing a suspension of Example 103.1 (2.8 g, 15.7 mmol) in 4 M aqueous sodium bisulfite solution (9.82 mL, 39.3 mmol) was added EtOH (3.9 mL). The vial was sealed and the resulting slurry was heated at 90° C. in the microwave for 3 h. The reaction was concentrated and then the residue was suspended in EtOH (30 mL). The mixture was heated, filtered, and the filtered solids were rinsed with more EtOH. The filtrate was concentrated to provide Example 103.2 (2.03 g, 50% yield). LCMS-ESI (pos.) m/z: 261.2 (M+H) + .

(1R,2R)—N-(2,4-Dimethoxybenzyl)-2-(5-fluoropyrimidin-2-yl)cyclohexane-1-sulfonamide and (1S,2S)—N-(2,4-dimethoxybenzyl)-2-(5-fluoropyrimidin-2-yl)cyclohexane-1-sulfonamide, Example 103.3. To a suspension of Example 03.2 (565 mg, 2.2 mmol) in DCM (11 mL) was added oxalyl chloride (578 μL, 6.5 mmol) via syringe followed by a catalytic amount of DMF via syringe. Vigorous bubbling was observed. The resulting white slurry was stirred at RT for 2 h and then was concentrated. The residue was azeotroped to dryness with cyclopentylmethyl ether and then was suspended in DCM (11 mL). 2,4-Dimethoxybenzylamine (423 μL, 6.5 mmol) and TEA (1.51 mL, 10.9 mmol) were added sequentially via syringe. The resulting slurry was stirred at RT overnight. The reaction mixture was then partitioned between water and DCM (3×). The combined organic layers were dried over anhydrous magnesium sulfate and concentrated. The residue was purified by silica gel chromatography (eluent: 30-50% EtOAc in hexanes over a 30 min period) to provide the title compound (84 mg, 10%). LCMS-ESI (pos.) m/z: 432.0 (M+Na) + .

(1R,2S)—N-(2,4-Dimethoxybenzyl)-2-(5-fluoropyrimidin-2-yl)cyclohexane-1-sulfonamide and (1S,2R)—N-(2,4-dimethoxybenzyl)-2-(5-fluoropyrimidin-2-yl)cyclohexane-1-sulfonamide, Example 103.4. Further elution under the conditions described in Example 103.3 delivered the title compound (52 mg, 5.8%). LCMS-ESI (pos.) m/z: 432.0 (M+Na) + .

(1R,2R)-2-(5-Fluoropyrimidin-2-yl)cyclohexane-1-sulfonamide and (1S,2S)-2-(5-fluoropyrimidin-2-yl)cyclohexane-1-sulfonamide, Example 103.5. An ice-cooled solution of Example 103.3 (84 mg, 0.21 mmol) in DCM (2 mL) was treated sequentially with anisole (67 μL, 0.62 mmol) via syringe and TFA (227 μL, 3.0 mmol) via syringe. The resulting solution was warmed to RT and stirred for 2 h. The reaction was directly concentrated and the residue was purified by reverse phase preparatory HPLC (Sunfire 5 μM C18 column, eluent: 0-65% ACN in water over a 20 min period where both solvents contain 0.1% TFA) to provide Example 103.5 (15 mg, 28% yield) as a white solid. LCMS-ESI (pos.) m/z: 260.1 (M+H) + .

›EXAMPLES · 38 of 46

(1R,2S)-2-(5-Fluoropyrimidin-2-yl)cyclohexane-1-sulfonamide and (1S,2R)-2-(5-fluoropyrimidin-2-yl)cyclohexane-1-sulfonamide, Example 103.5. An ice-cooled solution of Example 103.4 (52 mg, 0.13 mmol) in DCM (2 mL) was treated sequentially with anisole (67 μL, 0.62 mmol) via syringe and TFA (227 μL, 3.0 mmol) via syringe. The resulting solution was warmed to RT and stirred for 2 h. The reaction was directly concentrated and the residue was purified by reverse phase preparatory HPLC (Sunfire 5 μM C18 column, eluent: 0-65% ACN in water over a 20 min period where both solvents contain 0.1% TFA) to provide Example 103.6 (33 mg, 100% yield) as a white solid. LCMS-ESI (pos.) m/z: 260.1 (M+H) + .

(1S,2S)—N-(4-(2,6-Dimethoxyphenyl)-5-(2-furanyl)-4H-1,2,4-triazol-3-yl)-2-(5-fluoro-2-pyrimidinyl)cyclohexanesulfonamide and (1R,2R)—N-(4-(2,6-dimethoxyphenyl)-5-(furan-2-yl)-4H-1,2,4-triazol-3-yl)-2-(5-fluoropyrimidin-2-yl)cyclohexane-1-sulfonamide, Example 103.7. The title compound was prepared employing 3-bromo-4-(2,6-dimethoxyphenyl)-5-(furan-2-yl)-4H-1,2,4-triazole, Example 364.3 and Example 103.5 using the general procedure described in Example 94.0 (employing 2 eq Example 364.3, 1 eq of Example 103.5, 0.35M in dioxane, no molecular sieves, and the reaction was heated to 90° C. for 4 h in a microwave reactor). The reaction was then diluted with a small volume of water and stirred vigorously. EtOAc was added followed by dropwise addition of concentrated HCl. Any precipitants were removed by filtration through a pad of Celite® brand filter aid. The organics were dried over MgSO 4 , filtered, and concentrated in vacuo. The residue was dissolved in DMF and purified by preparatory reverse phase HPLC (20 to 90% ACN, water, 0.1% TFA, gradient elution) over 20 min using an Eclipse Plus Prep C18 column, 5 μm, 30×150 mm (Agilent Technologies, Inc., Santa Clara, Calif.) at 50 mLs/min. This provided Example 103.7 (17 mg, 56%) as a yellow solid. 1 H NMR (500 MHz, C 6 D 6 ) δ 8.03 (s, 2H) 7.05 (t, J=8.4 Hz, 1H) 6.75 (d, J=1.2 Hz, 1H) 6.20 (dd, J=8.3, 4.9 Hz, 2H) 6.14 (d, J=3.7 Hz, 1H) 5.69 (dd, J=3.4, 1.7 Hz, 1H) 3.89 (d, J=4.6 Hz, 1H) 3.54-3.62 (m, 1H) 3.16 (d, J=13.2 Hz, 6H) 2.73-2.85 (m, 1H) 1.90-2.18 (m, 4H) 1.56-1.68 (m, 1H) 1.07-1.25 (m, 2H). LCMS-ESI (pos.), m/z: 529.1 (M+H) + .

(1S,2S)—N-(4-(2,6-Dimethoxyphenyl)-5-(2-furanyl)-4H-1,2,4-triazol-3-yl)-2-(5-fluoro-2-pyrimidinyl)cyclohexanesulfonamide or (1R,2R)—N-(4-(2,6-dimethoxyphenyl)-5-(furan-2-yl)-4H-1,2,4-triazol-3-yl)-2-(5-fluoropyrimidin-2-yl)cyclohexane-1-sulfonamide, Example 103.0. The title compound was isolated from the racemic material by chiral HPLC purification on a 250×30 mm IC column with 50 g/min MeOH+(20 mM NH 3 )+60 g/min CO 2 on Thar 200 SFC. Outlet pressure=100 bar; Temp.=29° C.; Wavelength=266 nm. Used 5.0 mL injections of 28 mg/15 mL (1.87 mg/mL) sample solution in MeOH, i.e. 9.3 mg/injection. Run time=14 min. This delivered the title compound. 1 H NMR (500 MHz, C 6 D 6 ) δ 8.05 (br. s., 2H) 6.98-7.07 (m, 1H) 6.68-6.86 (m, 1H) 6.04-6.31 (m, 3H) 5.70 (br. s., 1H) 3.95 (br. s., 1H) 3.64 (br. s., 1H) 3.15 (d, J=19.1 Hz, 6H) 2.87 (d, J=7.8 Hz, 1H) 1.91-2.26 (m, 4H) 1.66 (br. s., 1H) 1.22 (br. s., 2H). LCMS-ESI (pos.) m/z: 529.1 (M+H) + .

Example 104.0. Preparation of (1R,2S)—N-(4-(2,6-dimethoxyphenyl)-5-(2-furanyl)-4H-1,2,4-triazol-3-yl)-2-(5-fluoro-2-pyrimidinyl)cyclopentanesulfonamide and (1S,2R)—N-(4-(2,6-dimethoxyphenyl)-5-(2-furanyl)-4H-1,2,4-triazol-3-yl)-2-(5-fluoro-2-pyrimidinyl)cyclopentanesulfonamide

(1R,2S)—N-(4-(2,6-Dimethoxyphenyl)-5-(2-furanyl)-4H-1,2,4-triazol-3-yl)-2-(5-fluoro-2-pyrimidinyl)cyclopentanesulfonamide and (1S,2R)—N-(4-(2,6-dimethoxyphenyl)-5-(2-furanyl)-4H-1,2,4-triazol-3-yl)-2-(5-fluoro-2-pyrimidinyl)cyclopentanesulfonamide, Example 104.1. The title compound was prepared employing 3-bromo-4-(2,6-dimethoxyphenyl)-5-(furan-2-yl)-4H-1,2,4-triazole, Example 364.3 and 100.5 as the sulfonamide coupling partner using the CuI coupling procedure described in Example 94.0 (employing 1 eq of Example 364.3, 1 eq of Example 100.5, no molecular sieves, and the reaction was heated to 90° C. for 15 h in a microwave reactor). The reaction was diluted with a small volume of water and stirred vigorously. EtOAc was added followed by dropwise addition of concentrated HCl. Any precipitants were removed by filtration through a pad of Celite® brand filter aid. The organics were dried on MgSO 4 , filtered, and evaporated. Trituration in ether removed the majority of the impurities. Further trituration in MeOH yielded a tan solid (107 mg, 43%), which was carried forward as such to the chiral separation. 1 H NMR (500 MHz, CDCl 3 ) δ 8.56 (s, 2H) 7.43-7.51 (m, 2H) 6.67 (d, J=8.6 Hz, 2H) 6.33 (dd, J=3.5, 1.8 Hz, 1H) 5.99 (d, J=3.7 Hz, 1H) 4.21 (q, J=7.9 Hz, 1H) 3.85 (q, J=8.2 Hz, 1H) 3.76 (d, J=1.0 Hz, 7H) 2.15-2.31 (m, 3H) 1.76-1.88 (m, 3H). LCMS-ESI (pos.), m/z: 515.0 (M+H) + .

(1R,2S)—N-(4-(2,6-Dimethoxyphenyl)-5-(2-furanyl)-4H-1,2,4-triazol-3-yl)-2-(5-fluoro-2-pyrimidinyl)cyclopentanesulfonamide or (1S,2R)—N-(4-(2,6-dimethoxyphenyl)-5-(2-furanyl)-4H-1,2,4-triazol-3-yl)-2-(5-fluoro-2-pyrimidinyl)cyclopentanesulfonamide, Example 104.0. The title compound was isolated from the racemic material by chromatography using a 250 mm×21 mm Lux2 column with 36 g/min MeOH (20 mM NH 3 )+44 g/min CO 2 on Thar 80 SFC. Outlet pressure=100 bar; Temperature=25° C.; Wavelength=267 nm. Used 2.0 mL injections of 108 mg/40 mL (2.7 mg/mL) sample solution in MeOH:DCM (1:1) i.e. 5.4 mg/injection. Run time=9 min, Cycle time=6 min. This delivered the title compound as the second eluting compound. 1 H NMR (400 MHz, CDCl 3 ) δ 11.04 (s, 1H) 8.51 (s, 2H) 7.39-7.55 (m, 2H) 6.67 (d, J=8.6 Hz, 2H) 6.33 (dd, J=3.5, 1.8 Hz, 1H) 5.97 (dd, J=3.5, 0.6 Hz, 1H) 4.20 (q, J=7.8 Hz, 1H) 3.82-4.03 (m, 1H) 3.76 (s, 3H) 3.75 (s, 3H) 2.08-2.34 (m, 3H) 1.75-1.90 (m, 3H). LCMS-ESI (pos.) m/z: 515.2 (M+H) + .

Example 105.0. Preparation of (1R,2S)—N-(4-(2,6-dimethoxyphenyl)-5-(2-furanyl)-4H-1,2,4-triazol-3-yl)-2-(5-fluoro-2-pyrimidinyl)cyclohexanesulfonamide or (1S,2R)—N-(4-(2,6-dimethoxyphenyl)-5-(2-furanyl)-4H-1,2,4-triazol-3-yl)-2-(5-fluoro-2-pyrimidinyl)cyclohexanesulfonamide

›EXAMPLES · 39 of 46

(1R,2S)—N-(4-(2,6-Dimethoxyphenyl)-5-(2-furanyl)-4H-1,2,4-triazol-3-yl)-2-(5-fluoro-2-pyrimidinyl)cyclohexanesulfonamide and (1S,2R)—N-(4-(2,6-dimethoxyphenyl)-5-(2-furanyl)-4H-1,2,4-triazol-3-yl)-2-(5-fluoro-2-pyrimidinyl)cyclohexanesulfonamide, Example 105.1. The title compound was prepared employing 3-bromo-4-(2,6-dimethoxyphenyl)-5-(furan-2-yl)-4H-1,2,4-triazole, Example 364.3 and Example 103.6 as the sulfonamide coupling partner using the CuI coupling procedure described in Example 94.0 (employing 2 eq Example 364.3, 1 eq Example 103.6, 0.35M in dioxane, no molecular sieves, and the reaction was heated to 90° C. for 4 h in a microwave reactor). The reaction was diluted with a small volume of water and stirred vigorously. EtOAc was added followed by dropwise addition of concentrated HCl. Any precipitants were removed by filtration through a pad of Celite® brand filter aid. The organics were dried on MgSO 4 , filtered, and evaporated. Purification by preparatory reverse phase HPLC (12 to 85% ACN, water, 0.1% TFA, gradient elution) over 20 min using Eclipse Plus Prep C18 column, 5 μm, 30×150 mm (Agilent Technologies, Inc., Santa Clara, Calif.) at 50 mLs/min. This provided Example 105.1 (34 mg, 51%) as a yellow solid. 1 H NMR (500 MHz, CD 3 CN) δ 8.56 (s, 2H) 7.54-7.61 (m, 2H) 6.84 (t, J=8.5 Hz, 2H) 6.42 (dd, J=3.5, 1.8 Hz, 1H) 6.06 (d, J=3.4 Hz, 1H) 3.79 (s, 3H) 3.75 (s, 3H) 3.49 (td, J=11.6, 3.9 Hz, 1H) 3.14 (td, J=11.6, 4.3 Hz, 1H) 2.17-2.23 (m, 1H) 1.91 (d, J=2.9 Hz, 1H) 1.81-1.88 (m, 1H) 1.75 (d, J=13.0 Hz, 1H) 1.49-1.63 (m, 2H) 1.40 (dt, J=12.9, 3.2 Hz, 1H) 1.26-1.36 (m, 1H). LCMS-ESI (pos.), m/z: 529.1 (M+H) + .

(1R,2S)—N-(4-(2,6-Dimethoxyphenyl)-5-(2-furanyl)-4H-1,2,4-triazol-3-yl)-2-(5-fluoro-2-pyrimidinyl)cyclohexanesulfonamide or (1S,2R)—N-(4-(2,6-dimethoxyphenyl)-5-(2-furanyl)-4H-1,2,4-triazol-3-yl)-2-(5-fluoro-2-pyrimidinyl)cyclohexanesulfonamide, Example 105.0. The title compound was isolated from the racemic material on a 250×30 mm Lux2 column with 40 g/min MeOH+(20 mM NH 3 )+60 g/min CO 2 on Thar 200 SFC. Outlet pressure=100 bar; Temp.=20° C.; Wavelength=267 nm. Used 4.0 mL injections of 28 mg/18 mL (1.56 mg/mL) sample solution in MeOH, i.e. 6.2 mg/injection. Run time=16 min.; Cycle time=7 min. This delivered the title compound as the first compound from the column. 1 H NMR (500 MHz, CD 3 CN) δ 8.60 (s, 2H) 7.57-7.62 (m, 2H) 6.87 (t, J=8.4 Hz, 2H) 6.44 (dd, J=3.4, 1.7 Hz, 1H) 6.07 (d, J=3.7 Hz, 1H) 3.82 (s, 3H) 3.78 (s, 3H) 3.53 (td, J=11.6, 3.8 Hz, 1H) 3.19 (td, J=11.5, 4.2 Hz, 1H) 2.24 (dd, J=13.3, 3.1 Hz, 1H) 1.91-1.95 (m, 1H) 1.84-1.91 (m, 1H) 1.78 (d, J=12.7 Hz, 1H) 1.59 (m, 2H) 1.28-1.49 (m, 2H). LCMS-ESI (pos.) m/z: 529.1 (M+H) + .

Example 106.0 Preparation of 2-(4-chlorophenyl)-N-(4-(2,6-dimethoxyphenyl)-5-(3-methyl-2-furanyl)-4H-1,2,4-triazol-3-yl)ethanesulfonamide

2-(4-Chlorophenyl)-N-(4-(2,6-dimethoxyphenyl)-5-(3-methyl-2-furanyl)-4H-1,2,4-triazol-3-yl)ethanesulfonamide, Example 106.0. The title compound was prepared employing Example 363.4 and 2-(4-chloro-phenyl)-ethanesulfonyl chloride (commercially available from Synchem Inc., IL, USA) and following the procedure described in Example 111.0 except for the addition of a catalytic quantity of DMAP to the reaction mixture. This yielded the title compound (Example 106.0, 31 mg, 29%) as an off-white solid. 1 H NMR (400 MHz, CD 3 OD) δ 7.38 (t, J=8.5 Hz, 1H), 7.22-7.26 (m, 1H), 7.05-7.14 (m, 3H), 6.61 (d, J=8.4 Hz, 2H), 6.28 (d, J=1.8 Hz, 1H), 3.71 (app s, 6H), 3.23-3.33 (m, 2H), 3.04-3.11 (m, 2H), 2.25 (s, 3H). LCMS-ESI (pos.) m/z: 503.0 (M+H) + .

Example 107.0. Preparation of N-(4-(2,6-dimethoxyphenyl)-5-(5-(trifluoromethyl)-2-furanyl)-4H-1,2,4-triazol-3-yl)-2-(5-fluoro-2-pyrimidinyl)ethanesulfonamide

N-(4-(2,6-Dimethoxyphenyl)-5-(5-(trifluoromethyl)-2-furanyl)-4H-1,2,4-triazol-3-yl)-2-(5-fluoro-2-pyrimidinyl)ethanesulfonamide, Example 107.0. A suspension of Example 364.0 (55 mg, 0.13 mmol), Example 351.0 (108 mg, 0.53 mmol), rac-trans-N,N′-dimethylcyclohexane-1,2-diamine (37 μL, 0.26 mmol), cesium carbonate (171 mg, 0.53 mmol) and 5 Å dried and crushed molecular sieves (75 mg) in dioxane (1.3 mL) was sparged with argon for 3 min. Copper(I) iodide (20 mg, 0.11 mmol) was then added. The mixture was briefly degassed and the reaction vessel was then heated in a microwave at 100° C. until LCMS analysis indicated that the reaction was complete (3 h). Thereafter, the mixture was cooled to RT, diluted with saturated aqueous Na 2 CO 3 , and extracted with EtOAc (3×). The EtOAc layers were combined, dried over MgSO 4 , filtered, and concentrated in vacuo. The residue was purified on a reverse-phase column, employing a gradient of 30-60% ACN in water (0.1% TFA in both eluents) to afford the title compound. 1 H NMR (400 MHz, CDCl 3 ) δ 8.52 (s, 2H), 7.47 (t, J=8.5 Hz, 1H), 6.73-6.75 (m, 1H), 6.67 (d, J=8.6 Hz, 2H), 6.29 (d, J=3.8 Hz, 1H), 3.76 (s, 3H), 3.76 (3H), 3.56-3.62 (m, 2H), 3.43-3.48 (m, 2H). LCMS-ESI (pos.) m/z: 543.0 (M+H) + .

Example 111.0. Preparation of 2-(4-chlorophenyl)-N-(4-(2,6-dimethoxyphenyl)-5-(furan-2-yl)-4H-1,2,4-triazol-3-yl)ethanesulfonamide

2-(4-Chlorophenyl)-N-(4-(2,6-dimethoxyphenyl)-5-(furan-2-yl)-4H-1,2,4-triazol-3-yl)ethanesulfonamide, Example 111.0. To a 50 mL RBF was added Example 362.03 (1.3 g, 4.0 mmol) and TEA (2.8 mL, 20.2 mmol) in DCM (20 mL). At RT, 2-(4-chloro-phenyl)-ethanesulfonyl chloride (commercially available from Synchem Inc., IL, USA), 1.3 g, 5.3 mmol) was added. The reaction mixture was stirred at RT for 6 h. LCMS analysis showed a small amount of starting material remained 2-(4-Chloro-phenyl)-ethanesulfonyl chloride (200 mg) was then added. The reaction mixture was stirred at RT for 6 h. LCMS analysis showed the reaction was complete. The reaction mixture was diluted with water and extracted with DCM. The combined organic layers were washed with brine and dried over Na 2 SO 4 . The solution was filtered and concentrated in vacuo to give as a light-yellow glass. The initial material was absorbed onto a plug of silica gel and purified by chromatography through a Redi-Sep pre-packed silica gel column (40 g) eluting with a gradient of 20% to 100% EtOAc in hexanes to provide the title compound (1.2 g, 2.5 mmol, 61% yield) as an off-white solid. 1 H NMR (400 MHz, CD 3 OD) δ 7.82 (d, J=1.2 Hz, 1H), 7.56 (t, J=8.6 Hz, 1H), 7.29-7.35 (m, 2H), 7.17-7.24 (m, 2H), 6.89 (d, J=8.4 Hz, 2H), 6.51 (dd, J=3.5, 1.8 Hz, 1H), 6.02 (d, J=3.5 Hz, 1H), 3.70 (s, 3H), 3.70 (s, 3H), 3.13-3.21 (m, 2H), 2.84-2.91 (m, 2H). LCMS-ESI (pos.) m/z: 489.1 (M+H) + .

›EXAMPLES · 40 of 46

The compounds set forth in the following table were synthesized following the procedure in Example 127.0 using the starting materials as described.

Example 112.0. Preparation of (P)-2-(4-chlorophenyl)-N-(5-(furan-2-yl)-4-(2-methoxy-6-methylphenyl)-4H-1,2,4-triazol-3-yl)ethanesulfonamide or (M)-2-(4-chlorophenyl)-N-(5-(furan-2-yl)-4-(2-methoxy-6-methylphenyl)-4H-1,2,4-triazol-3-yl)ethanesulfonamide

5-(Furan-2-yl)-4-(2-methoxy-6-methylphenyl)-4H-1,2,4-triazol-3-amine, Example 112.1. Employing 2-methoxy-6-methylaniline (commercially available from CombiBlocks, San Diego, Calif., USA) and the procedures described in Example 363.0 yielded Example 112.1 (0.31 g, 1.16 mmol, 9% over 4 steps). LCMS-ESI (pos.), m/z: 271.2 (M+H) + .

(P)-2-(4-Chlorophenyl)-N-(5-(furan-2-yl)-4-(2-methoxy-6-methylphenyl)-4H-1,2,4-triazol-3-yl)ethanesulfonamide and (M)-2-(4-chlorophenyl)-N-(5-(furan-2-yl)-4-(2-methoxy-6-methylphenyl)-4H-1,2,4-triazol-3-yl)ethanesulfonamide Example 112.2. To a 5 mL RBF was added Example 112.1 (0.10 g, 0.38 mmol) and TEA (0.21 mL, 1.48 mmol) in DCM (7.4 mL). Subsequently, 2-(4-chlorophenyl)ethanesulfonyl chloride (commercially available from Oakwood Products, Inc., SC, USA, 0.10 g, 0.41 mmol) was added at 0° C. After 30 min, the reaction was removed from the ice bath and maintained at RT for 90 min. The mixture was then cooled to 0° C. and a second aliquot of TEA (0.21 mL, 1.48 mmol) and 2-(4-chlorophenyl)ethanesulfonyl chloride (0.10 g, 0.41 mmol) was added. The reaction was then warmed to RT and stirred overnight. The mixture was then diluted with water and extracted with EtOAc. The combined organic layers were then washed with brine, dried over Na 2 SO 4 , filtered, and concentrated in vacuo to give a residue. The residue was then purified on a 12 g silica gel column employing a gradient of 1-3% MeOH in DCM affording Example 112.2 (94 mg, 0.20 mmol, 53% yield) as an off-white solid. 1 H NMR (400 MHz, CDCl 3 ) δ 10.95 (s, 1H) 7.51 (d, J=1.76 Hz, 1H) 7.47 (t, J=8.02 Hz, 1H) 7.24-7.31 (m, 2H) 7.10 (d, J=8.22 Hz, 2H) 7.02 (d, J=7.83 Hz, 1H) 6.91 (d, J=8.22 Hz, 1H) 6.35 (dd, J=3.52, 1.76 Hz, 1H) 5.89 (d, J=3.52 Hz, 1H) 3.66-3.74 (m, 3H) 3.22-3.33 (m, 2H) 3.03-3.13 (m, 2H) 2.14-2.23 (m, 3H). LCMS-ESI (pos.), m/z: 473.0 (M+H) + .

(P)-2-(4-Chlorophenyl)-N-(5-(furan-2-yl)-4-(2-methoxy-6-methylphenyl)-4H-1,2,4-triazol-3-yl)ethanesulfonamide or (M)-2-(4-chlorophenyl)-N-(5-(furan-2-yl)-4-(2-methoxy-6-methylphenyl)-4H-1,2,4-triazol-3-yl)ethanesulfonamide, Example 112.0. Purification of Example 112.2 was performed by SFC [250×30 mm OJ column with 20 g/min IPA (+20 mM NH 3 )+60 g/min CO 2 on Thar 80 SFC. Outlet pressure=100 bar; Temp.=22° C.; Wavelength=270 nm. Used 0.5 mL injections of 90 mg/15 mL (6 mg/mL) sample solution in MeOH, i.e. 3 mg/injection. Run time=10 min, Cycle time 6 min]. This afforded two atropisomers. The title compound was the first isomer to elute under these conditions. 1 H NMR (400 MHz, CDCl 3 ) δ 11.11 (br. s., 1H) 7.50 (d, J=1.37 Hz, 1H) 7.46 (t, J=8.02 Hz, 1H) 7.23-7.31 (m, 2H) 7.07-7.14 (m, 2H) 7.01 (d, J=7.83 Hz, 1H) 6.91 (d, J=8.22 Hz, 1H) 6.35 (dd, J=3.52, 1.76 Hz, 1H) 5.90 (d, J=3.52 Hz, 1H) 3.70 (s, 3H) 3.24-3.32 (m, 2H) 3.03-3.12 (m, 2H) 2.18 (s, 3H). LCMS-ESI (pos.), m/z: 473.0 (M+H) + . Specific Optical Rotation: [α]=−22.5 (c=1.395 g/100 mL, CHCl 3 , ee=99%).

Example 113.0. Preparation of (P)-2-(4-chlorophenyl)-N-(5-(furan-2-yl)-4-(2-methoxy-6-methylphenyl)-4H-1,2,4-triazol-3-yl)ethanesulfonamide or (M)-2-(4-chlorophenyl)-N-(5-(furan-2-yl)-4-(2-methoxy-6-methylphenyl)-4H-1,2,4-triazol-3-yl)ethanesulfonamide

(P)-2-(4-Chlorophenyl)-N-(5-(furan-2-yl)-4-(2-methoxy-6-methylphenyl)-4H-1,2,4-triazol-3-yl)ethanesulfonamide or (M)-2-(4-chlorophenyl)-N-(5-(furan-2-yl)-4-(2-methoxy-6-methylphenyl)-4H-1,2,4-triazol-3-yl)ethanesulfonamide, Example 113.0. Example 113.0 is the atropisomer of Example 112.0. The title compound was the second isomer to elute on subjecting Example 112.2 to the SFC conditions described in Example 112.0. 1 H NMR (400 MHz, CDCl 3 ) δ 11.11 (br. s., 1H) 7.50 (d, J=1.76 Hz, 1H) 7.42-7.49 (m, 1H) 7.23-7.31 (m, 2H) 7.07-7.14 (m, 2H) 7.01 (d, J=7.63 Hz, 1H) 6.91 (d, J=8.41 Hz, 1H) 6.32-6.37 (m, 1H) 5.90 (d, J=3.52 Hz, 1H) 3.66-3.71 (m, 3H) 3.24-3.31 (m, 2H) 3.03-3.12 (m, 2H) 2.18 (s, 3H). LCMS-ESI (pos.), m/z: 473.0 (M+H) + . Specific Optical Rotation: [α]=+24.7 (c=1.450 g/100 mL, CHCl 3 , ee=96%).

Example 114.0. Preparation of (3-(4-chlorophenyl)-N-(4-(2,6-dimethoxyphenyl)-5-(2-furanyl)-4H-1,2,4-triazol-3-yl)-1-propanesulfonamide

3-(4-Chlorophenyl)-N-(4-(2,6-dimethoxyphenyl)-5-(2-furanyl)-4H-1,2,4-triazol-3-yl)-1-propanesulfonamide, Example 114.0. The title compound was prepared employing 3-(4-chlorophenyl)propane-1-sulfonyl chloride (commercially available from Sigma-Aldrich Corp., St. Louis, Mo., USA) using the procedure described for the synthesis of Example 210.0 (employing the use of 2 eq of sulfonyl chloride and 8 eq of TEA). 1 H NMR (400 MHz, CDCl 3 ) δ 10.92 (br. s., 1H) 7.41-7.50 (m, 2H) 7.19-7.26 (m, 2H) 7.06 (d, J=8.41 Hz, 2H) 6.62-6.69 (m, 2H) 6.33 (dd, J=3.52, 1.76 Hz, 1H) 5.98 (d, J=3.52 Hz, 1H) 3.68 (s, 3H) 3.68 (s, 3H) 2.96-3.07 (m, 2H) 2.70 (t, J=7.63 Hz, 2H) 2.03-2.14 (m, 2H). LCMS-ESI (pos.) m/z: 503.0 (M+H) + .

The compounds set forth in the following table were synthesized following the procedure in Example 127.0 using the starting materials as described.

Example 119.0. Preparation of 2-(2-cyano-4-fluorophenyl)-N-(4-(2,6-dimethoxyphenyl)-5-(5-methylfuran-2-yl)-4H-1,2,4-triazol-3-yl)ethanesulfonamide

2-(2-Bromo-4-fluorophenyl)-N-(4-(2,6-dimethoxyphenyl)-5-(5-methylfuran-2-yl)-4H-1,2,4-triazol-3-yl)ethanesulfonamide, Example 119.1. To a solution of 362.0 (45 mg, 0.15 mmol) and TEA (83 μL, 0.60 mmol) in DCM (2.3 mL) was added 2-(2-bromo-4-fluorophenyl)ethanesulfonyl chloride (Synchem, 68 mg, 0.22 mmol). The resulting orange solution was stirred at RT for 1.5 h and then was quenched with water (5 mL) and extracted with DCM (3×). The combined organic layers were dried over anhydrous sodium sulfate and concentrated. The residue was purified by reverse phase preparatory HPLC (Sunfire 5 μM C18 column, eluent: 45-70% ACN in water where both solvents contain 0.1% TFA) to provide Example 119.1 (17.4 mg, 21% yield) as a white solid. LCMS-ESI (pos.) m/z: 565.0 (M+H) + .

›EXAMPLES · 41 of 46

2-(2-Cyano-4-fluorophenyl)-N-(4-(2,6-dimethoxyphenyl)-5-(5-methylfuran-2-yl)-4H-1,2,4-triazol-3-yl)ethanesulfonamide, Example 20.0. To a vial containing a solution of Example 119.1 (8.5 mg, 0.02 mmol) in DMF (1.4 mL) was added copper cyanide (35 mg, 0.39 mmol). The resulting yellow slurry was capped and heated at 130° C. for 23 h. After this period, more copper cyanide (35 mg, 0.39 mmol) was added. After an additional 23 h at 130° C., the reaction mixture was diluted with MeOH/DMSO and filtered. A small amount of ACN containing 0.1% TFA was added, and the solution was directly purified by reverse phase preparatory HPLC (Sunfire 5 μM C18 column, eluent: 45-65% ACN in water where both solvents contain 0.1% TFA) to provide Example 119.0 (0.6 mg, 8% yield) as a white solid. 1 H NMR (400 MHz, CD 3 OD) δ 7.44-7.60 (m, 3H), 7.35-7.43 (m, 1H), 6.86 (d, J=8.6 Hz, 2H), 6.03 (d, J=3.3 Hz, 1H), 5.93 (d, J=3.3 Hz, 1H), 3.79 (s, 3H), 3.36-3.42 (m, 2H), 3.24-3.31 (m, 2H), 2.28 (s, 3H). LCMS-ESI (pos.) m/z: 512.2 (M+H) + .

Example 120.0. Preparation of (1R,2S)—N-(4-(2,6-dimethoxyphenyl)-5-(5-methylfuran-2-yl)-4H-1,2,4-triazol-3-yl)-1-(2-methoxyethoxy)-1-(5-methylpyrimidin-2-yl)propane-2-sulfonamide

(1R,2S)-1-(Allyloxy)-N,N-bis(4-methoxybenzyl)-1-(5-methylpyrimidin-2-yl)propane-2-sulfonamide, Example 120.1. To a −78° C. solution of Example 377.2 (1.76 g, 3.7 mmol) in THF (40 mL) was added potassium bis(trimethylsilyl)amide (1.0 M solution in THF, 5.0 mL, 5.0 mmol) slowly via syringe. After 7 min, allyl bromide (1.3 mL, 15.0 mmol) was added slowly via syringe. The resulting bright yellow solution was stirred at −78° C. for 6 min and then was warmed to 0° C. and stirred for an additional 40 min. The reaction mixture was quenched with a 5.5:1 mixture of saturated aqueous ammonium chloride and water (65 mL) and then was extracted with EtOAc (4×). The combined organic layers were dried over anhydrous sodium sulfate and concentrated. The residue was purified by silica gel chromatography (eluent: 5-75% EtOAc in hexanes) to provide Example 120.1 (1.33 g, 70% yield) as a light yellow oil. LCMS-ESI (pos.) m/z: 512.2 (M+H) + .

(1R,2S)-1-((S)-2,3-Dihydroxypropoxy)-N,N-bis(4-methoxybenzyl)-1-(5-methylpyrimidin-2-yl)propane-2-sulfonamide and (1R,2S)-1-((R)-2,3-dihydroxypropoxy)-N,N-bis(4-methoxybenzyl)-1-(5-methylpyrimidin-2-yl)propane-2-sulfonamide, Example 120.2. To a solution of Example 120.1 (1.33 g, 2.6 mmol) in a mixture of acetone (45 mL) and water (15 mL) was added a catalytic amount of osmium tetroxide and then 4-methylmorpholine-N-oxide (1.07 g, 9.1 mmol). The resulting brown solution was stirred at RT for 24 h and then was partially concentrated to remove the acetone. The aqueous residue was diluted with water and extracted with DCM (7×). The combined organic layers were dried over anhydrous sodium sulfate and concentrated. The residue was purified by silica gel chromatography (eluent: 0-10% MeOH in DCM) to provide Example 120.2 (1.32 g, 93% yield) as a tan solid. LCMS-ESI (pos.) m/z: 546.2 (M+H) + .

(1R,2S)-1-(2-Hydroxyethoxy)-N,N-bis(4-methoxybenzyl)-1-(5-methylpyrimidin-2-yl)propane-2-sulfonamide, Example 120.3. To a solution of Example 120.2 (1.32 g, 2.4 mmol) in a mixture of THF (30 mL) and water (10 mL) was added sodium periodate (1.44 g, 6.8 mmol). The resulting yellow slurry was stirred at RT for 3.75 h and then was filtered and the filtrate rinsed with DCM. The mixture was partially concentrated to remove the organic solvents and then was diluted with water and extracted with DCM (4×). The combined organic layers were dried over anhydrous sodium sulfate and concentrated to afford the initial aldehyde as a pink solid. To an ice-cooled solution of the initial aldehyde in MeOH (60 mL) was added sodium borohydride (728 mg, 19.2 mmol). The resulting yellow solution was stirred at 0° C. for 2 h and then was quenched with 1 N HCl solution (35 mL). The mixture was partially concentrated to remove the MeOH and then was extracted with DCM (4×). The combined organic layers were dried over anhydrous sodium sulfate and concentrated. The residue was purified by silica gel chromatography (eluent: 0-15% MeOH in DCM) to provide Example 120.3 (965 mg, 78% yield) as a tan solid. LCMS-ESI (pos.) m/z: 516.0 (M+H) + .

(1R,2S)—N,N-Bis(4-methoxybenzyl)-1-(2-methoxyethoxy)-1-(5-methylpyrimidin-2-yl)propane-2-sulfonamide, Example 120.4. To a −78° C. solution of Example 120.3 (964 mg, 1.9 mmol) in THF (50 mL) was added potassium bis(trimethylsilyl)amide, (1.0 M solution in THF, 3.93 mL, 3.9 mmol) slowly via syringe. After stirring for 10 min at −78° C., the reaction was warmed to −40° C. and stirred for an additional 8 min. The reaction was then recooled to −78° C. and MeOTf (307 μL, 2.0 mmol) was added slowly via syringe. The resulting red solution was stirred at −78° C. for 25 min and then was quenched with a 2:1 mixture of saturated aqueous ammonium chloride and water (30 mL). The resulting mixture was extracted with DCM (4×). The combined organic layers were dried over anhydrous sodium sulfate and concentrated. The residue was purified by silica gel chromatography (eluent: 0-12% MeOH in DCM) to provide Example 120.4 (376 mg, 38% yield) as an orange oil. LCMS-ESI (pos.) m/z: 530.2 (M+H) + .

(1R,2S)-1-(2-Methoxyethoxy)-1-(5-methylpyrimidin-2-yl)propane-2-sulfonamide, Example 120.05. Example 120.4 (376 mg, 0.71 mmol) was dissolved in TFA (5 mL). Anisole (170 μL, 1.5 mmol) was then added via syringe. The resulting orange solution was stirred at RT for 7 h and then concentrated. The residue was purified by silica gel chromatography (eluent: 0-7% MeOH in DCM) to provide Example 120.5 (143 mg, 70% yield) as a light yellow solid. LCMS-ESI (pos.) m/z: 290.1 (M+H) + .

(1R,2S)—N-(4-(2,6-Dimethoxyphenyl)-5-(5-methylfuran-2-yl)-4H-1,2,4-triazol-3-yl)-1-(2-methoxyethoxy)-1-(5-methylpyrimidin-2-yl)propane-2-sulfonamide, Example 120.0. Following the procedure described in Example 94.0, Example 364.1 (70 mg, 0.19 mmol) and Example 120.5 (40 mg, 0.14 mmol) were coupled to provide Example 120.0 (65 mg, 82% yield) as a light yellow solid. 1 H NMR (400 MHz, CDCl 3 ) δ 11.37 (br. s., 1H), 8.60 (s, 2H), 7.44 (t, J=8.5 Hz, 1H), 6.66 (dd, J=3.4, 0.9 Hz, 2H), 5.90 (dd, J=3.4, 0.9 Hz, 1H), 5.79 (d, J=5.3 Hz, 1H), 5.07 (d, J=3.5 Hz, 1H), 3.79-3.89 (m, 1H), 3.76 (s, 3H), 3.76 (s. 3H), 3.67-3.74 (m, 1H), 3.54-3.62 (m, 2H), 3.46-3.53 (m, 1H), 3.34 (s, 3H), 2.32 (s, 3H), 1.42 (d, J=7.0 Hz, 3H). LCMS-ESI (pos.) m/z: 573.0 (M+H) + .

›EXAMPLES · 42 of 46

Example 121.0. Preparation of (1S,2S)—N-(4-(2,6-dimethoxyphenyl)-5-(5-methylfuran-2-yl)-4H-1,2,4-triazol-3-yl)-1-(2-hydroxyethoxy)-1-(5-methylpyrimidin-2-yl)propane-2-sulfonamide

(1S,2S)-1-(Allyloxy)-N,N-bis(4-methoxybenzyl)-1-(5-methylpyrimidin-2-yl)propane-2-sulfonamide and (1R,2R)-1-(allyloxy)-N,N-bis(4-methoxybenzyl)-1-(5-methylpyrimidin-2-yl)propane-2-sulfonamide, Example 121.1. To a −78° C. solution of Example 356.05 (401 mg, 0.85 mmol) in THF (10 mL) was added potassium bis(trimethylsilyl)amide (1.0 M solution in THF, 1.15 mL, 1.15 mmol) slowly via syringe. After 6 min, allyl iodide (313 μL, 3.40 mmol) was added slowly via syringe. The resulting bright yellow solution was stirred at −78° C. for 5 min and then was warmed to 0° C. and stirred for an additional 2.5 h. The reaction mixture was quenched with saturated aqueous ammonium chloride (35 mL) and then was extracted with EtOAc (4×). The combined organic layers were dried over anhydrous sodium sulfate and concentrated. The residue was purified by silica gel chromatography (eluent: 5-65% EtOAc in hexanes) to provide Example 121.1 (197 mg, 45% yield) as a colorless oil. LCMS-ESI (pos.) m/z: 512.2 (M+H) + .

(1S,2S)-1-(Allyloxy)-1-(5-methylpyrimidin-2-yl)propane-2-sulfonamide and (1R,2R)-1-(allyloxy)-1-(5-methylpyrimidin-2-yl)propane-2-sulfonamide, Example 121.2. Example 121.1 (197 mg, 0.39 mmol) was dissolved in TFA (5 mL) and anisole (209 μL, 1.93 mmol) was added via syringe. The resulting yellow solution was stirred at RT for 22.5 h and then was concentrated in vacuo. The residue was purified by silica gel chromatography (eluent: 0-4.5% MeOH in DCM) to provide Example 121.2 (92 mg, 88% yield) as a white solid. LCMS-ESI (pos.) m/z: 277.1 (M+H) + .

(1S,2S)-1-(Allyloxy)-N-(4-(2,6-dimethoxyphenyl)-5-(5-methylfuran-2-yl)-4H-1,2,4-triazol-3-yl)-1-(5-methylpyrimidin-2-yl)propane-2-sulfonamide and (1R,2R)-1-(allyloxy)-N-(4-(2,6-dimethoxyphenyl)-5-(5-methylfuran-2-yl)-4H-1,2,4-triazol-3-yl)-1-(5-methylpyrimidin-2-yl)propane-2-sulfonamide, Example 121.3. Following the procedure described in Example 94.0, Example 364.1 (173 mg, 0.48 mmol) and Example 121.2 (92 mg, 0.34 mmol) were coupled to provide Example 121.3 (43 mg, 23% yield) as a light yellow solid. LCMS-ESI (pos.) m/z: 555.2 (M+H) + .

(1S,2S)-1-((R)-2,3-Dihydroxypropoxy)-N-(4-(2,6-dimethoxyphenyl)-5-(5-methylfuran-2-yl)-4H-1,2,4-triazol-3-yl)-1-(5-methylpyrimidin-2-yl)propane-2-sulfonamide and (1S,2S)-1-((S)-2,3-dihydroxypropoxy)-N-(4-(2,6-dimethoxyphenyl)-5-(5-methylfuran-2-yl)-4H-1,2,4-triazol-3-yl)-1-(5-methylpyrimidin-2-yl)propane-2-sulfonamide and (1R,2R)-1-((R)-2,3-dihydroxypropoxy)-N-(4-(2,6-dimethoxyphenyl)-5-(5-methylfuran-2-yl)-4H-1,2,4-triazol-3-yl)-1-(5-methylpyrimidin-2-yl)propane-2-sulfonamide and (1R,2R)-1-((S)-2,3-dihydroxypropoxy)-N-(4-(2,6-dimethoxyphenyl)-5-(5-methylfuran-2-yl)-4H-1,2,4-triazol-3-yl)-1-(5-methylpyrimidin-2-yl)propane-2-sulfonamide, Example 121.4. To a solution of Example 121.3 (43 mg, 0.08 mmol) in a mixture of acetone (2.85 mL) and water (1 mL) was added a catalytic amount of osmium tetroxide followed by 4-methylmorpholine-N-oxide (32 mg, 0.27 mmol). The resulting dark yellow solution was stirred at RT for 5 h and then was partially concentrated to remove the acetone. The aqueous residue was diluted with water and extracted with DCM (3×). The combined organic layers were dried over anhydrous sodium sulfate and concentrated. The residue was purified by silica gel chromatography (eluent: 0-8% MeOH in DCM) to provide Example 121.4 (32 mg, 70% yield) as a light yellow solid. LCMS-ESI (pos.) m/z: 589.1 (M+H) + .

(1S,2S)—N-(4-(2,6-Dimethoxyphenyl)-5-(5-methylfuran-2-yl)-4H-1,2,4-triazol-3-yl)-1-(5-methylpyrimidin-2-yl)-1-(2-oxoethoxy)propane-2-sulfonamide and (1R,2R)—N-(4-(2,6-dimethoxyphenyl)-5-(5-methylfuran-2-yl)-4H-1,2,4-triazol-3-yl)-1-(5-methylpyrimidin-2-yl)-1-(2-oxoethoxy)propane-2-sulfonamide, Example 121.5. To a solution of Example 121.4 (32 mg, 0.05 mmol) in a mixture of THF (2.9 mL) and water (1 mL) was added sodium periodate (32.5 mg, 0.15 mmol). The resulting yellow slurry was stirred at RT for 4 h and then was filtered rinsing the filtered solids with DCM. The filtrate was partially concentrated to remove the organic solvents and then was diluted with water and extracted with DCM (3×). The combined organic layers were dried over anhydrous sodium sulfate and concentrated to afford Example 121.5 (26 mg, 86% yield) as a white solid. LCMS-ESI (pos.) m/z: 557.2 (M+H) + .

(1S,2S)—N-(4-(2,6-Dimethoxyphenyl)-5-(5-methylfuran-2-yl)-4H-1,2,4-triazol-3-yl)-1-(2-hydroxyethoxy)-1-(5-methylpyrimidin-2-yl)propane-2-sulfonamide and (1R,2R)—N-(4-(2,6-dimethoxyphenyl)-5-(5-methylfuran-2-yl)-4H-1,2,4-triazol-3-yl)-1-(2-hydroxyethoxy)-1-(5-methylpyrimidin-2-yl)propane-2-sulfonamide, Example 121.6. To an ice-cooled solution of Example 121.5 (26 mg, 0.05 mmol) in MeOH (6 mL) was added sodium borohydride (5 mg, 0.13 mmol). The resulting light yellow solution was stirred at 0° C. for 1 h and then more sodium borohydride (5 mg, 0.13 mmol) was added. After an additional 4 h, another portion of sodium borohydride (5 mg, 0.13 mmol) was added. The reaction mixture was stirred for an additional 20 min and then quenched with 1 N HCl (5 mL). The reaction was partially concentrated to remove MeOH and was extracted with DCM (3×). The combined organic layers were dried over anhydrous sodium sulfate and concentrated to afford Example 121.6 (27 mg, 93% yield) as an off-white solid. LCMS-ESI (pos.) m/z: 559.1 (M+H) + .

(1S,2S)—N-(4-(2,6-Dimethoxyphenyl)-5-(5-methylfuran-2-yl)-4H-1,2,4-triazol-3-yl)-1-(2-hydroxyethoxy)-1-(5-methylpyrimidin-2-yl)propane-2-sulfonamide or (1R,2R)—N-(4-(2,6-dimethoxyphenyl)-5-(5-methylfuran-2-yl)-4H-1,2,4-triazol-3-yl)-1-(2-hydroxyethoxy)-1-(5-methylpyrimidin-2-yl)propane-2-sulfonamide, Example 121.0. Example 121.6 was separated by preparative SFC (column: 250×21 mm Chiralpak AD, 19 g/min MeOH+41 g/min CO 2 , 100 bar, 275 nm, Inj volume: 0.4 mL of a 9.0 mg/mL solution of sample in 2:1 MeOH/DCM). The title compound Example 121.0 was the first eluting peak (9.7 mg). 1 H NMR (500 MHz, CDCl 3 ) δ 11.68 (br. s., 1H), 8.61 (s, 2H), 7.45 (t, J=8.4 Hz, 1H), 6.68 (d, J=8.6 Hz, 2H), 5.88-5.94 (m, 1H), 5.80 (d, J=3.2 Hz, 1H), 4.74 (d, J=7.1 Hz, 1H), 3.73-3.88 (m, 7H), 3.45-3.60 (m, 4H), 2.34 (s, 3H), 2.32 (s, 3H), 1.22 (d, J=7.1 Hz, 3H). LCMS-ESI (pos.) m/z: 559.1 (M+H) + .

›EXAMPLES · 43 of 46

The compounds set forth in the following table were synthesized following the procedure in Example 127.0 using the starting materials as described.

Example 123.0. Preparation of (S)—N-(4-(2,6-dimethoxyphenyl)-5-(5-methylfuran-2-yl)-4H-1,2,4-triazol-3-yl)-2-(5-fluoropyrimidin-2-yl)propane-1-sulfonamide or (R)—N-(4-(2,6-dimethoxyphenyl)-5-(5-methylfuran-2-yl)-4H-1,2,4-triazol-3-yl)-2-(5-fluoropyrimidin-2-yl)propane-1-sulfonamide

5-Fluoro-2-(prop-1-en-2-yl)pyrimidine, Example 123.1. To a solution of potassium isopropenyltrifluoroborate (4.19 g, 28.3 mmol) in THF (56 mL) were added oven-dried cesium carbonate (27.4 g, 84 mmol), triphenylphosphine (1.49 g, 5.7 mmol), 2-chloro-5-fluoropyrimidine (3.5 mL, 28.3 mmol) and water (14 mL). The slurry was degassed with an argon stream, and then palladium(II) chloride (603 mg, 3.4 mmol) was added. The slurry was again degassed with an argon stream, and the resulting mixture was heated at reflux under argon for 24 h. The reaction mixture was then filtered through a Whatman GF/F disposable plastic cup and was washed with water (1×) and brine (1×). The organic layer was dried over anhydrous sodium sulfate and partially concentrated on rotary evaporator at a pressure of 150 torr. The residue was purified by silica gel chromatography (eluent: pure DCM) to provide Example 123.1 (2.88 g, 74% yield) as a yellow oil. LCMS-ESI (pos.): 139.1 (M+H).

(S)-2-(5-Fluoropyrimidin-2-yl)propane-1-sulfonyl fluoride and (R)-2-(5-fluoropyrimidin-2-yl)propane-1-sulfonyl fluoride, Example 123.2. To a solution of 5-fluoro-2-(prop-1-en-2-yl)pyrimidine Example 123.1 (2.88 g, 20.9 mmol) in THF (30 mL) was added a solution of sodium bisulfite (6.51 g, 62.5 mmol) in water (11 mL) slowly via pipette. The resulting cloudy biphasic mixture was heated at 65° C. for 3 d and then partially concentrated to remove the THF. To the sulfonic acid slurry was added DCM (55 mL) followed by DAST (4.13 mL, 31.3 mmol) slowly via syringe. A mild exotherm was observed. The resulting yellow slurry was stirred for 18 h and then was directly purified by silica gel chromatography (eluent: pure DCM) to provide Example 123.2 (230 mg, 5% yield) as a white solid. LCMS-ESI (pos.): 223.1 (M+H).

(S)—N-(2,4-Dimethoxybenzyl)-2-(5-fluoropyrimidin-2-yl)propane-1-sulfonamide and (R)—N-(2,4-dimethoxybenzyl)-2-(5-fluoropyrimidin-2-yl)propane-1-sulfonamide, Example 123.3. To a solution of 2-(5-fluoropyrimidin-2-yl)propane-1-sulfonyl fluoride Example 123.2 (230 mg, 1.04 mmol) in ACN (10 mL) was added 2,4-dimethoxybenzylamine (544 μL, 3.62 mmol) via syringe followed by TEA (1.01 mL, 7.25 mmol) dropwise via syringe. The resulting white slurry was stirred at 50° C. for 17.5 h and then was partitioned between water and DCM (3×). The combined organic layers were dried over anhydrous sodium sulfate and concentrated. The residue was purified directly by silica gel chromatography (eluent: 10-50% EtOAc in hexanes) to provide Example 123.3 (327 mg, 86% yield) as a colorless oil. LCMS-ESI (pos.): 392.0 (M+Na).

(S)-2-(5-Fluoropyrimidin-2-yl)propane-1-sulfonamide and (R)-2-(5-fluoropyrimidin-2-yl)propane-1-sulfonamide, Example 123.4. To an ice-cooled flask containing N-(2,4-dimethoxybenzyl)-2-(5-fluoropyrimidin-2-yl)propane-1-sulfonamide (Example 123.3, 326 mg, 0.88 mmol) was added TFA (3.0 mL, 40.4 mmol) slowly via syringe. The resulting pink solution was stirred at 0° C. for 40 min and then was concentrated in vacuo. The residue was purified by silica gel chromatography (eluent: 0.8-5% MeOH in DCM) to provide Example 123.4 (176 mg, 90% yield) as a white solid. LCMS-ESI (pos.): 220.1 (M+H).

Example 127.0. Preparation of (S)—N-(4-(2,6-dimethoxyphenyl)-5-(5-methylfuran-2-yl)-4H-1,2,4-triazol-3-yl)-2-(5-fluoropyrimidin-2-yl)propane-1-sulfonamide and (R)—N-(4-(2,6-dimethoxyphenyl)-5-(5-methylfuran-2-yl)-4H-1,2,4-triazol-3-yl)-2-(5-fluoropyrimidin-2-yl)propane-1-sulfonamide

(S)—N-(4-(2,6-Dimethoxyphenyl)-5-(5-methylfuran-2-yl)-4H-1,2,4-triazol-3-yl)-2-(5-fluoropyrimidin-2-yl)propane-1-sulfonamide and (R)—N-(4-(2,6-dimethoxyphenyl)-5-(5-methylfuran-2-yl)-4H-1,2,4-triazol-3-yl)-2-(5-fluoropyrimidin-2-yl)propane-1-sulfonamide, Example 127.0. A microwave vial was charged with 3-bromo-4-(2,6-dimethoxyphenyl)-5-(5-methylfuran-2-yl)-4H-1,2,4-triazole (Example 364.1, 381 mg, 1.05 mmol), 2-(5-fluoropyrimidin-2-yl)propane-1-sulfonamide (Example 123.4, 164 mg, 0.75 mmol), cesium carbonate (609 mg, 1.87 mmol) and rac-trans-N,N′-dimethylcyclohexane-1,2-diamine (236 μL, 1.50 mmol). Dioxane (1.87 mL) was added, and the slurry was degassed with an argon strem. Copper(I) iodide (71 mg, 0.37 mmol) was added and then the slurry was again degassed with an argon strem. The resulting blue slurry was heated in a microwave at 90° C. for 15 h and then was filtered through a plug of Celite® brand filter aid rinsing with EtOAc. The filtrate was transferred to a RBF and concentrated HCl was added dropwise until the color changed to light brown. The mixture was then partitioned between water and EtOAc (2×). The combined organic layers were dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by silica gel chromatography (eluent: 20% EtOAc in hexanes grading to 100% EtOAc) to provide Example 127.0 (97 mg, 26% yield) as an off-white. LCMS-ESI (pos.): 503.1 (M+H).

(S)—N-(4-(2,6-Dimethoxyphenyl)-5-(5-methylfuran-2-yl)-4H-1,2,4-triazol-3-yl)-2-(5-fluoropyrimidin-2-yl)propane-1-sulfonamide or (R)—N-(4-(2,6-dimethoxyphenyl)-5-(5-methylfuran-2-yl)-4H-1,2,4-triazol-3-yl)-2-(5-fluoropyrimidin-2-yl)propane-1-sulfonamide, Example 123.0. Example 127.0 (91 mg, 0.18 mmol) was separated by chiral SFC; Preparative SFC method: Column: 2×25 cm Chiralpak AS-H, 35% i-PrOH/CO 2 , 100 bar, 65 mL/min, 220 nm, Inj volume: 0.75-1 mL of a 9.0 mg/mL solution of sample in 1:1 MeOH/DCM. This provided the title compound as peak two (36.2 mg, 40% yield, >99% ee) as a white solid. 1 H NMR (500 MHz, CDCl 3 ) δ: 10.89 (br. s., 1H), 8.53 (s, 2H), 7.46 (t, J=8.5 Hz, 1H), 6.68 (dd, J=8.5, 1.7 Hz, 2H), 5.91 (dd, J=3.5, 1.0 Hz, 1H), 5.75 (d, J=3.5 Hz, 1H), 3.70-3.86 (m, 8H), 3.29 (dd, J=13.8, 5.0 Hz, 1H), 2.32 (s, 3H), 1.42 (d, J=6.9 Hz, 3H). LCMS-ESI (pos.) m/z: 503.1 (M+H) + .

›EXAMPLES · 44 of 46

Example 126.0. Preparation of (S)—N-(4-(2,6-dimethoxyphenyl)-5-(5-methylfuran-2-yl)-4H-1,2,4-triazol-3-yl)-2-(5-fluoropyrimidin-2-yl)propane-1-sulfonamide or (R)—N-(4-(2,6-dimethoxyphenyl)-5-(5-methylfuran-2-yl)-4H-1,2,4-triazol-3-yl)-2-(5-fluoropyrimidin-2-yl)propane-1-sulfonamide

(S)—N-(4-(2,6-Dimethoxyphenyl)-5-(5-methylfuran-2-yl)-4H-1,2,4-triazol-3-yl)-2-(5-fluoropyrimidin-2-yl)propane-1-sulfonamide or (R)—N-(4-(2,6-dimethoxyphenyl)-5-(5-methylfuran-2-yl)-4H-1,2,4-triazol-3-yl)-2-(5-fluoropyrimidin-2-yl)propane-1-sulfonamide, Example 126.0. Example 127.0 (91 mg, 0.18 mmol) was separated by chiral SFC; Preparative SFC method: Column: 2×25 cm Chiralpak AS-H, 35% i-PrOH/CO 2 , 100 bar, 65 mL/min, 220 nm, Inj volume: 0.75-1 mL of a 9.0 mg/mL solution of sample in 1:1 MeOH/DCM. This provided the title compound as peak one (37.5 mg, 41% yield, >99% ee) as a white solid. 1 H NMR (500 MHz, CDCl 3 ) δ: 10.90 (br. s., 1H), 8.53 (s, 2H), 7.46 (t, J=8.5 Hz, 1H), 6.68 (dd, J=8.6, 1.7 Hz, 2H), 5.91 (dd, J=3.4, 0.9 Hz, 1H), 5.75 (d, J=3.5 Hz, 1H), 3.70-3.85 (m, 8H), 3.29 (dd, J=13.8, 5.0 Hz, 1H), 2.32 (s, 3H), 1.42 (d, J=7.0 Hz, 3H). LCMS-ESI (pos.) m/z: 503.1 (M+H) + .

Example 125.0. Preparation of N-(4-(2,6-dimethoxyphenyl)-5-(5-methylfuran-2-yl)-4H-1,2,4-triazol-3-yl)-2-(5-fluoropyrimidin-2-yl)ethanesulfonamide

N-(4-(2,6-Dimethoxyphenyl)-5-(5-methylfuran-2-yl)-4H-1,2,4-triazol-3-yl)-2-(5-fluoropyrimidin-2-yl)ethanesulfonamide, Example 125.0. A microwave vial containing Example 364.1 (49 mg, 0.14 mmol), Example 351.0 (110 mg, 0.54 mmol), copper(I) iodide (25.5 mg, 0.14 mmol), trans-N,N′-dimethyl-1,2-cyclohexanediamine (42 μL, 0.27 mmol), and cesium carbonate (219 mg, 0.67 mmol) was degassed and then backfilled with argon. Evacuation and backfilling were repeated three times. 1,4-Dioxane (1.4 mL) was then added and the dark blue-green slurry was heated in a microwave at 100° C. for 4 h. The reaction was concentrated in vacuo and the residue was dissolved in DCM (10 mL) and treated with 1 N citric acid solution (5 mL). The layers were separated and the aqueous layer was extracted with more DCM (4×). The combined organic layers were dried over anhydrous sodium sulfate and concentrated. The residue was purified by reverse phase preparatory HPLC (Sunfire 5 μM C18 column, eluent: 35-75% ACN in water where both solvents contain 0.1% TFA) to provide Example 25.0 (22 mg, 33% yield) as a light yellow solid. 1 H NMR (500 MHz, CD 3 OD) δ8.64 (s, 2H), 7.54 (t, J=8.3 Hz, 1H), 6.83 (d, J=8.3 Hz, 2H), 6.01-6.04 (m, 1H), 5.95 (d, J=3.4 Hz, 1H), 3.77 (s, 3H), 3.50-3.55 (m, 2H), 3.34-3.39 (m, 2H), 2.26 (s, 3H). LCMS-ESI (pos.) m/z: 489.0 (M+H) + .

The compounds set forth in the following table were synthesized following the procedure in Example 127.0 using the starting materials as described.

Example 131.0. Preparation of 2-(2-cyano-4-fluorophenyl)-N-(4-(2,6-dimethoxyphenyl)-5-(5-(trifluoromethyl)furan-2-yl)-4H-1,2,4-triazol-3-yl)ethanesulfonamide

2-(2-Cyano-4-fluorophenyl)-N-(4-(2,6-dimethoxyphenyl)-5-(5-(trifluoromethyl)furan-2-yl)-4H-1,2,4-triazol-3-yl)ethanesulfonamide, Example 131.0. To a solution of 363.0 (52 mg, 0.15 mmol) and TEA (82 μL, 0.59 mmol) in DCM (2.0 mL) was added 352.6 (51 mg, 0.21 mmol). The resulting orange solution was stirred at RT for 1.5 h and then was quenched with water (5 mL) and extracted with DCM (3×). The combined organic layers were dried over anhydrous sodium sulfate and concentrated. The residue was purified by reverse phase preparatory HPLC (Sunfire 5 μM C18 column, eluent: 45-70% ACN in water where both solvents contain 0.1% TFA) to provide Example 131.0 (36 mg, 41% yield) as a light yellow solid. 1 H NMR (500 MHz, CD 3 OD) δ 7.56 (t, J=8.5 Hz, 1H), 7.42-7.52 (m, 2H), 7.32-7.40 (m, 1H), 6.98-7.03 (m, 1H), 6.84 (d, J=8.6 Hz, 2H), 6.40 (d, J=3.9 Hz, 1H), 3.78 (s, 3H), 3.32-3.38 (m, 2H), 3.23-3.30 (m, 2H). LCMS-ESI (pos.) m/z: 566.0 (M+H) + .

The compounds set forth in the following table were synthesized following the procedure in Example 127.0 using the starting materials as described.

Example 134.0. Preparation of (R)—N-(4-(2,6-dimethoxyphenyl)-5-(5-methylfuran-2-yl)-4H-1,2,4-triazol-3-yl)-1-(5-fluoropyrimidin-2-yl)butane-2-sulfonamide or (S)—N-(4-(2,6-dimethoxyphenyl)-5-(5-methylfuran-2-yl)-4H-1,2,4-triazol-3-yl)-1-(5-fluoropyrimidin-2-yl)butane-2-sulfonamide

(R)—N-(4-(2,6-Dimethoxyphenyl)-5-(5-methylfuran-2-yl)-4H-1,2,4-triazol-3-yl)-1-(5-fluoropyrimidin-2-yl)butane-2-sulfonamide and (S)—N-(4-(2,6-dimethoxyphenyl)-5-(5-methylfuran-2-yl)-4H-1,2,4-triazol-3-yl)-1-(5-fluoropyrimidin-2-yl)butane-2-sulfonamide, Example 134.1. A microwave vial was charged with 3-bromo-4-(2,6-dimethoxyphenyl)-5-(5-methylfuran-2-yl)-4H-1,2,4-triazole (Example 364.1, 120 mg, 0.33 mmol), 1-(5-fluoropyrimidin-2-yl)butane-2-sulfonamide (Example 358.0, 96 mg, 0.412 mmol), cesium carbonate (268 mg, 0.82 mmol), rac-trans-N,N′-dimethylcyclohexane-1,2-diamine (104 μL, 0.66 mmol) and crushed, powdered 4 A molecular sieves (125 mg). Dioxane (720 μL) was added and the slurry was degassed with an argon stream. Copper(I) iodide (31.5 mg, 0.17 mmol) was added and then the slurry was again degassed with an argon strem. The resulting blue slurry was heated in a microwave at 90° C. for 15 h and then was filtered through a pad of Celite® brand filter aid rinsing with EtOAc. The filtrate was partitioned between water and EtOAc (4×). The combined organic layers were dried over anhydrous sodium sulfate and concentrated. The residue was purified twice by reverse phase preparatory HPLC (eluent: 30% ACN in water grading to 60% ACN in water where both solvents contain 0.1% TFA) to provide Example 134.1 (56 mg, 33% yield) as a tan solid. LCMS-ESI (pos.): 517.1 (M+H).

(R)—N-(4-(2,6-Dimethoxyphenyl)-5-(5-methylfuran-2-yl)-4H-1,2,4-triazol-3-yl)-1-(5-fluoropyrimidin-2-yl)butane-2-sulfonamide or (S)—N-(4-(2,6-dimethoxyphenyl)-5-(5-methylfuran-2-yl)-4H-1,2,4-triazol-3-yl)-1-(5-fluoropyrimidin-2-yl)butane-2-sulfonamide, Example 133.0. Example 131.1 (51 mg, 0.10 mmol) was separated by chiral SFC using the following preparative SFC method: Column: 2×15 cm Chiralpak AD-H, 35% i-PrOH/CO 2 , 100 bar, 60 mL/min, 220 nm, Inj volume: 1.0 mL of a 4.6 mg/mL solution of sample in 4:1 EtOH/DCM. This delivered the title compound as peak two (16.4 mg, 32% yield, >99% ee) as an off-white solid. 1 H NMR (500 MHz, CDCl 3 ) δ: 8.54 (s, 2H), 7.46 (t, J=8.4 Hz, 1H), 6.67 (d, J=8.4 Hz, 2H), 5.91 (d, J=3.1 Hz, 1H), 5.79 (d, J=3.5 Hz, 1H), 3.76 (s, 3H), 3.58-3.75 (m, 4H), 3.58 (dd, J=15.1, 6.3 Hz, 1H), 3.21 (dd, J=14.9, 7.2 Hz, 1H), 2.32 (s, 3H), 1.95-2.06 (m, 1H), 1.65-1.75 (m, 1H), 0.95 (t, J=7.5 Hz, 3H). LCMS-ESI (pos.) m/z: 517.1 (M+H) + .

›EXAMPLES · 45 of 46

Example 135.0. Preparation of (2S,3R)—N-(4-(2,6-dimethoxyphenyl)-5-(5-methylfuran-2-yl)-4H-1,2,4-triazol-3-yl)-3-(5-fluoropyrimidin-2-yl)butane-2-sulfonamide and (2R,3S)—N-(4-(2,6-dimethoxyphenyl)-5-(5-methylfuran-2-yl)-4H-1,2,4-triazol-3-yl)-3-(5-fluoropyrimidin-2-yl)butane-2-sulfonamide and (2S,3S)—N-(4-(2,6-dimethoxyphenyl)-5-(5-methylfuran-2-yl)-4H-1,2,4-triazol-3-yl)-3-(5-fluoropyrimidin-2-yl)butane-2-sulfonamide and (2R,3R)—N-(4-(2,6-dimethoxyphenyl)-5-(5-methylfuran-2-yl)-4H-1,2,4-triazol-3-yl)-3-(5-fluoropyrimidin-2-yl)butane-2-sulfonamide

(2S,3R)—N-(4-(2,6-Dimethoxyphenyl)-5-(5-methylfuran-2-yl)-4H-1,2,4-triazol-3-yl)-3-(5-fluoropyrimidin-2-yl)butane-2-sulfonamide and (2R,3S)—N-(4-(2,6-dimethoxyphenyl)-5-(5-methylfuran-2-yl)-4H-1,2,4-triazol-3-yl)-3-(5-fluoropyrimidin-2-yl)butane-2-sulfonamide and (2S,3S)—N-(4-(2,6-dimethoxyphenyl)-5-(5-methylfuran-2-yl)-4H-1,2,4-triazol-3-yl)-3-(5-fluoropyrimidin-2-yl)butane-2-sulfonamide and (2R,3R)—N-(4-(2,6-dimethoxyphenyl)-5-(5-methylfuran-2-yl)-4H-1,2,4-triazol-3-yl)-3-(5-fluoropyrimidin-2-yl)butane-2-sulfonamide, Example 135.0. A microwave vial containing Example 364.1 (70 mg, 0.19 mmol), Example 354.0 (50 mg, 0.21 mmol), copper(I) iodide (18.3 mg, 0.10 mmol), trans-N,N-dimethyl-1,2-cyclohexanediamine (60 μL, 0.38 mmol), and cesium carbonate (157 mg, 0.48 mmol) was degassed and then backfilled with argon. Evacuation and backfilling were repeated three times. 1,4-Dioxane (0.48 mL) was then added and the dark blue-green slurry was heated in a microwave at 90° C. for 15 h. The reaction was then filtered through a plug of Celite® brand filter aid rinsing with EtOAc and water. The filtrate was extracted with EtOAc (3×). The combined organic layers were dried over anhydrous sodium sulfate and concentrated. The residue was purified by reverse phase preparatory HPLC (Sunfire 5 μM C18 column, eluent: 35-55% ACN in water over a 35 min period where both solvents contain 0.1% TFA) to provide Example 135.0 (19.4 mg, 20% yield) as a white solid. 1 H NMR (500 MHz, CDCl 3 ) δ 8.55 (br. s, 2H), 7.46 (t, J=8.3 Hz, 1H), 6.67 (d, J=7.7 Hz, 2H), 5.83-5.91 (m, 1H), 5.77-5.81 (m, 1H), 3.76 (s, 3H, major diastereomer), 3.76 (s, 3H, major diastereomer), 3.75 (s, 3H, minor diastereomer), 3.74 (s, 3H, minor diastereomer), 3.62-3.70 (m, 1H), 3.53-3.60 (m, 1H), 2.32 (s, 3H), 1.49 (d, J=6.4 Hz, 3H, major diastereomer), 1.37 (d, J=6.2 Hz, 3H, minor diastereomer), 1.35 (d, J=6.2 Hz, 3H, minor diastereomer), 1.26 (d, J=6.2 Hz, 3H, major diastereomer). 1 H NMR analysis indicated that a 2.2:1 d.r. was obtained. LCMS-ESI (pos.) m/z: 517.1 (M+H) + .

Example 136.0. Preparation of (R)—N-(4-(2,6-dimethoxyphenyl)-5-(furan-2-yl)-4H-1,2,4-triazol-3-yl)-1-(5-fluoropyrimidin-2-yl)butane-2-sulfonamide or (S)—N-(4-(2,6-dimethoxyphenyl)-5-(furan-2-yl)-4H-1,2,4-triazol-3-yl)-1-(5-fluoropyrimidin-2-yl)butane-2-sulfonamide

(R)—N-(4-(2,6-Dimethoxyphenyl)-5-(furan-2-yl)-4H-1,2,4-triazol-3-yl)-1-(5-fluoropyrimidin-2-yl)butane-2-sulfonamide and (S)—N-(4-(2,6-dimethoxyphenyl)-5-(furan-2-yl)-4H-1,2,4-triazol-3-yl)-1-(5-fluoropyrimidin-2-yl)butane-2-sulfonamide, Example 136.1. A microwave vial was charged with 3-bromo-4-(2,6-dimethoxyphenyl)-5-(furan-2-yl)-4H-1,2,4-triazole (Example 364.3, 105 mg, 0.30 mmol), 1-(5-fluoropyrimidin-2-yl)butane-2-sulfonamide (Example 358.0, 80 mg, 0.35 mmol), cesium carbonate (244 mg, 0.75 mmol), rac-trans-N,N′-dimethylcyclohexane-1,2-diamine (95 μL, 0.60 mmol) and powdered 4 A molecular sieves (110 mg). Dioxane (650 μL) was added and the slurry was degassed with an argon stream. Copper(I) iodide (29 mg, 0.15 mmol) was then added and the slurry was again degassed with an argon stream. The resulting blue slurry was heated in a microwave at 90° C. for 12 h and then was filtered through a plug of Celite® brand filter aid rinsing with EtOAc. The filtrate was partitioned between water and EtOAc (4×). The combined organic layers were dried over anhydrous sodium sulfate and concentrated. The residue was purified twice by reverse phase preparatory HPLC (eluent: 30% ACN in water grading to 65% ACN in water where both solvents contain 0.1% TFA) to provide the title compound (38 mg, 25% yield) as a light pink solid. LCMS-ESI (pos.): 503.1 (M+H).

(R)—N-(4-(2,6-Dimethoxyphenyl)-5-(furan-2-yl)-4H-1,2,4-triazol-3-yl)-1-(5-fluoropyrimidin-2-yl)butane-2-sulfonamide or (S)—N-(4-(2,6-dimethoxyphenyl)-5-(furan-2-yl)-4H-1,2,4-triazol-3-yl)-1-(5-fluoropyrimidin-2-yl)butane-2-sulfonamide, Example 136.0. Example 136.1 (52 mg, 0.10 mmol) was separated by chiral SFC using the following preparative SFC method: Column: 250×21 mm Chirlpak IA 16.5 g/min MeOH containing 20 mM ammonia+38.5 g/min CO 2 , 100 bar, 215 nm, Inj volume: 0.2 mL of a 5.0 mg/mL solution of sample in 1:1 MeOH/DCM. This provided peak two as the title compound (10.7 mg, 53% yield, % ee not determined) as an off-white solid. 1 H NMR (500 MHz, CDCl 3 ) δ: 11.15 (br. s., 1H), 8.53 (s, 2H), 7.43-7.50 (m, 2H), 6.67 (d, J=8.4 Hz, 2H), 6.33 (dd, J=3.5, 1.8 Hz, 1H), 5.99 (d, J=3.5 Hz, 1H), 3.76 (s, 3H), 3.68-3.75 (m, 4H), 3.58 (dd, J=15.2, 6.0 Hz, 1H), 3.21 (dd, J=15.3, 7.6 Hz, 1H), 1.94-2.07 (m, 1H), 1.62-1.75 (m, 1H), 0.94 (t, J=7.5 Hz, 3H). LCMS-ESI (pos.) m/z: 503.1 (M+H) + .

Example 137.0. Preparation of 2-(4-chlorophenyl)-N-(4-(2,6-dimethoxyphenyl)-5-(5-methylfuran-2-yl)-4H-1,2,4-triazol-3-yl)ethanesulfonamide

2-(4-Chlorophenyl)-N-(4-(2,6-dimethoxyphenyl)-5-(5-methylfuran-2-yl)-4H-1,2,4-triazol-3-yl)ethanesulfonamide, Example 137.0. To a solution of Example 362.0 (14.5 mg, 0.05 mmol) and TEA (54 μL, 0.39 mmol) in DCM (1.8 mL) was added 2-(4-chlorophenyl)ethanesulfonyl chloride (35 mg, 0.15 mmol). The resulting yellow solution was stirred at RT for 5.25 h and then was quenched with water (5 mL) and extracted with DCM (3×). The combined organic layers were dried over anhydrous sodium sulfate and concentrated. The residue was purified by reverse phase preparatory HPLC (Sunfire 5 μM C18 column, eluent: 55-75% ACN in water where both solvents contain 0.1% TFA) and provided Example 137.0 (3.2 mg, 13% yield) as a light yellow solid. 1 H NMR (500 MHz, CD 3 OD) δ 7.55 (t, J=8.6 Hz, 1H), 7.27 (d, J=8.1 Hz, 2H), 7.18 (d, J=8.3 Hz, 2H), 6.85 (d, J=8.6 Hz, 2H), 6.01 (d, J=2.9 Hz, 1H), 5.93 (d, J=2.7 Hz, 1H), 3.75 (s, 3H), 3.21-3.28 (m, 2H), 2.96-3.06 (m, 2H), 2.25 (s, 3H). LCMS-ESI (pos.) m/z: 503.0 (M+H) + .

›EXAMPLES · 46 of 46

The compounds set forth in the following table were synthesized following the procedure in Example 137.0 using the starting material as described.

Example 142.0. Preparation of N-(5-(5-(tert-butyl)furan-2-yl)-4-(2,6-dimethoxyphenyl)-4H-1,2,4-triazol-3-yl)-2-(2-cyano-4-fluorophenyl)ethanesulfonamide

N-(5-(5-(tert-Butyl)furan-2-yl)-4-(2,6-dimethoxyphenyl)-4H-1,2,4-triazol-3-yl)-2-(2-cyano-4-fluorophenyl)ethanesulfonamide, Example 142.0. To a solution of 5-(5-(tert-butyl)furan-2-yl)-4-(2,6-dimethoxyphenyl)-4H-1,2,4-triazol-3-amine, Example 363.2 (48 mg, 0.14 mmol) in DCM (2 mL), was added TEA (78 μL, 0.56 mmol) via syringe followed by 2-(2-cyano-4-fluorophenyl)ethanesulfonyl chloride Example 352.6 (49 mg, 0.20 mmol) directly. The resulting orange solution was stirred at RT for 3 h and then was partitioned between water and DCM (3×). The combined organic layers were dried over anhydrous sodium sulfate and concentrated. The residue was purified by reverse phase preparatory HPLC (eluent: 50% ACN in water grading to 75% ACN in water where both solvents contain 0.1% TFA) to provide Example 142.0 (18 mg, 23% yield) as an off-white solid. 1 H NMR (500 MHz, DMSO-d 6 ) δ 13.34 (s, 1H), 7.80 (dd, J=2.69, 8.56 Hz, 1H), 7.46-7.59 (m, 3H), 6.89 (d, J=8.56 Hz, 2H), 6.40 (d, J=3.67 Hz, 1H), 6.16 (d, J=3.42 Hz, 1H), 3.71 (s, 3H), 3.71 (s, 3H), 3.24-3.30 (m, 2H), 3.07-3.14 (m, 2H), 1.06 (m, 9H). LCMS-ESI (pos.): 554.2 (M+H).

Example 143.0. Preparation of (1S,2R)-1-(2,4-dicyanophenyl)-N-(4-(2,6-dimethoxyphenyl)-5-(5-methyl-2-furanyl)-4H-1,2,4-triazol-3-yl)-1-methoxy-2-propanesulfonamide or (1R,2S)-1-(2,4-dicyanophenyl)-N-(4-(2,6-dimethoxyphenyl)-5-(5-methyl-2-furanyl)-4H-1,2,4-triazol-3-yl)-1-methoxy-2-propanesulfonamide

(1R,2R)-1-(2,4-Dibromophenyl)-1-hydroxy-N,N-bis(4-methoxybenzyl)propane-2-sulfonamide and (1R,2S)-1-(2,4-dibromophenyl)-1-hydroxy-N,N-bis(4-methoxybenzyl)propane-2-sulfonamide and (1S,2R)-1-(2,4-dibromophenyl)-1-hydroxy-N,N-bis(4-methoxybenzyl)propane-2-sulfonamide and (1S,2S)-1-(2,4-dibromophenyl)-1-hydroxy-N,N-bis(4-methoxybenzyl)propane-2-sulfonamide, Example 143.1. To a 250 mL RBF was added Example 361.0 (3.06 g, 8.76 mmol) in 2-methyltetrahydrofuran (22 mL). n-Butyllithium, (2.5M solution in hexanes, 4.20 mL, 10.51 mmol) was then added under N 2 at −78° C. The reaction mixture was stirred at −78° C. for 10 min and then left at RT for 20 min. 2,4-Dibromobenzaldehyde (2.54 g, 9.63 mmol) in 2-methyltetrahydrofuran (22 mL) was then added dropwise under N 2 at −78° C. The reaction mixture was stirred at −78° C. for 1 h. LCMS analysis indicated formation of the desired product. The reaction was quenched with a saturated aqueous solution of NH 4 Cl. The reaction mixture was diluted with a saturated solution of NH 4 Cl and extracted with EtOAc. The organic layer was washed with brine and dried over Na 2 SO 4 . The solution was filtered and concentrated in vacuo to give a light-yellow solid which was purified by silica gel chromatography (a gradient of 0% to 100% EtOAc in DCM). This provided the title compound Example 143.1 (4.9 g, 7.99 mmol, 91% yield) as a white solid which was a mixture of diastereomers. LCMS-ESI (pos.), m/z: 634.0 (M+Na) + .

(1R,2R)-1-(2,4-Dibromophenyl)-1-methoxy-N,N-bis(4-methoxybenzyl)propane-2-sulfonamide and (1R,2S)-1-(2,4-dibromophenyl)-1-methoxy-N,N-bis(4-methoxybenzyl)propane-2-sulfonamide and (1S,2R)-1-(2,4-dibromophenyl)-1-methoxy-N,N-bis(4-methoxybenzyl)propane-2-sulfonamide and (1S,2S)-1-(2,4-dibromophenyl)-1-methoxy-N,N-bis(4-methoxybenzyl)propane-2-sulfonamide, Example 143.2. To a 250 mL RBF was added Example 143.1 (4.9 g, 7.99 mmol) in 2-methyltetrahydrofuran (53.3 mL). Potassium bis(trimethylsilyl)amide, (1.0 M in THF, 8.79 mL, 8.79 mmol) was added under N 2 at −78° C. The reaction mixture was stirred at −78° C. for 10 min and then left at RT for 5 min. Iodomethane (0.546 mL, 8.79 mmol) was then added dropwise under N 2 at −78° C. The reaction mixture was stirred at −78° C. for 30 min and then the dry ice-acetone bath was removed. The mixture was then left at RT for 10 min. LCMS analysis indicated formation of the desired product but the reaction was not complete. The reaction mixture was stirred at RT for 16 h. The reaction mixture was cooled to −78° C. again and quenched with saturated aqueous NaHCO 3 . The reaction mixture was diluted with water and extracted with EtOAc. The combined organic layers were washed with brine and dried over Na 2 SO 4 . The solution was then filtered and concentrated in vacuo to give a light-yellow oil which was purified by silica gel chromatography (0% to 100% EtOAc in hexanes), to provide Example 143.2 (5.0 g, 7.97 mmol, 100% yield) as a white solid which was a mixture of diastereomers. LCMS-ESI (pos.), m/z: 626.0 (M+H) + .

(1R,2R)-1-(2,4-Dicyanophenyl)-1-methoxy-N,N-bis(4-methoxybenzyl)propane-2-sulfonamide and (1R,2S)-1-(2,4-dicyanophenyl)-1-methoxy-N,N-bis(4-methoxybenzyl)propane-2-sulfonamide and (1S,2R)-1-(2,4-dicyanophenyl)-1-methoxy-N,N-b

›Tables in the description — 27

TABLE 1

Example	Reagents	Structure, Name and Data
85.1	N-(4-(2,6-dimethoxyphenyl)- 5-(5-methylfuran-2-yl)-4H- 1,2,4-triazol-3-yl)-N-(2- (trimethylsilyl)ethyl)ethane- sulfonamide (Example 369.0) and 6-chloropicolinaldehyde (Bionet Research).
		(1R,2R)-1-(6-chloropyridin-2-yl)-N-(4-(2,6-
		dimethoxyphenyl)-5-(5-methylfuran-2-yl)-4H-1,2,4-
		triazol-3-yl)-1-hydroxypropane-2-sulfonamide
		compound and (1R,2S)-1-(6-chloropyridin-2-yl)-N-(4-
		(2,6-dimethoxyphenyl)-5-(5-methylfuran-2-yl)-4H-
		1,2,4-triazol-3-yl)-1-hydroxypropane-2-sulfonamide and
		(1S,2R)-1-(6-chloropyridin-2-yl)-N-(4-(2,6-
		dimethoxyphenyl)-5-(5-methylfuran-2-yl)-4H-1,2,4-
		triazol-3-yl)-1-hydroxypropane-2-sulfonamide and
		(1S,2S)-1-(6-chloropyridin-2-yl)-N-(4-(2,6-
		dimethoxyphenyl)-5-(5-methylfuran-2-yl)-4H-1,2,4-
		triazol-3-yl)-1-hydroxypropane-2-sulfonamide.
		LCMS (pos.) m/z: 534.1 (M + H) + .
85.0	The mixture (Example 85.1) was separated by SFC using the following methodology: (2 × 15 cm AD-H column with 65 mL/min 30% EtOH (0.2% NH 4 OH)/CO 2 . Outlet pressure = 100 bar; wavelength = 280 nm; injection volumn = 0.8 mL, 7 mg/mL 1:2 DCM:EtOH). Four isomers were obtained. This was the third isomer to elute under these conditions.
		(1R,2R)-1-(6-chloropyridin-2-yl)-N-(4-(2,6-
		dimethoxyphenyl)-5-(5-methylfuran-2-yl)-4H-1,2,4-
		triazol-3-yl)-1-hydroxypropane-2-sulfonamide
		compound or (1R,2S)-1-(6-chloropyridin-2-yl)-N-(4-
		(2,6-dimethoxyphenyl)-5-(5-methylfuran-2-yl)-4H-
		1,2,4-triazol-3-yl)-1-hydroxypropane-2-sulfonamide or
		(1S,2R)-1-(6-chloropyridin-2-yl)-N-(4-(2,6-
		dimethoxyphenyl)-5-(5-methylfuran-2-yl)-4H-1,2,4-
		triazol-3-yl)-1-hydroxypropane-2-sulfonamide or
		(1S,2S)-1-(6-chloropyridin-2-yl)-N-(4-(2,6-
		dimethoxyphenyl)-5-(5-methylfuran-2-yl)-4H-1,2,4-
		triazol-3-yl)-1-hydroxypropane-2-sulfonamide.
		1 H NMR (400 MHz, CDCl 3 ) δ 7.64 (dd, J = 7.7, 7.7 Hz,
		1 H), 7.46-7.51 (m, 2 H), 7.18 (d, J = 7.6 Hz, 1 H), 6.70
		(ddd, J = 11.3, 8.6, 0.78 Hz, 2 H), 5.93 (dd, J = 3.33, 0.98
		Hz, 1 H), 5.86 (d, J = 3.52 Hz, 1 H), 5.43 (s, 1 H), 4.03
		(br. s., 1 H), 3.80 (s, 3 H), 3.75-3.80 (m, 1 H), 3.77 (s,
		3 H), 2.32 (s, 3 H), 1.11 (d, J = 7.04 Hz, 3 H). LCMS-
		ESI (pos.): 534.0 (M + H) + .
87.1	N-(4-(2,6-dimethoxyphenyl)- 5-(5-methylfuran-2-yl)-4H- 1,2,4-triazol-3-yl)-N-(2- (trimethylsilyl)ethyl)ethane- sulfonamide (Example 369.0) and 6-methylpicolinaldehyde.
		(1R,2R)-N-(4-(2,6-dimethoxyphenyl)-5-(5-methylfuran-
		2-yl)-4H-1,2,4-triazol-3-yl)-1-hydroxy-1-(6-
		methylpyridin-2-yl)propane-2-sulfonamide compound
		and (1R,2S)-N-(4-(2,6-dimethoxyphenyl)-5-(5-
		methylfuran-2-yl)-4H-1,2,4-triazol-3-yl)-1-hydroxy-1-
		(6-methylpyridin-2-yl)propane-2-sulfonamide and
		(1S,2R)-N-(4-(2,6-dimethoxyphenyl)-5-(5-methylfuran-
		2-yl)-4H-1,2,4-triazol-3-yl)-1-hydroxy-1-(6-
		methylpyridin-2-yl)propane-2-sulfonamide and (1S,2S)-
		N-(4-(2,6-dimethoxyphenyl)-5-(5-methylfuran-2-yl)-
		4H-1,2,4-triazol-3-yl)-1-hydroxy-1-(6-methylpyridin-2-
		yl)propane-2-sulfonamide.
		LCMS (pos.) m/z: 514.1 (M + H) + .
87.0	The mixture (Example 87.1) was separated by SFC using the following methodology: (2 × 15 cm AD-H column with 65 mL/min 35% EtOH (0.2% NH 4 OH)/CO 2 . Outlet pressure = 100 bar; wavelength = 220 nm; injection volumn = 0.7 mL, 7 mg/mL 1:3 DCM:MeOH). Four isomers were obtained. This compound (Example 87.0) was the third isomer to elute under these conditions.
		(1R,2R)-N-(4-(2,6-dimethoxyphenyl)-5-(5-methylfuran-
		2-yl)-4H-1,2,4-triazol-3-yl)-1-hydroxy-1-(6-
		methylpyridin-2-yl)propane-2-sulfonamide compound
		or (1R,2S)-N-(4-(2,6-dimethoxyphenyl)-5-(5-
		methylfuran-2-yl)-4H-1,2,4-triazol-3-yl)-1-hydroxy-1-
		(6-methylpyridin-2-yl)propane-2-sulfonamide or
		(1S,2R)-N-(4-(2,6-dimethoxyphenyl)-5-(5-methylfuran-
		2-yl)-4H-1,2,4-triazol-3-yl)-1-hydroxy-1-(6-
		methylpyridin-2-yl)propane-2-sulfonamide or (1S,2S)-
		N-(4-(2,6-dimethoxyphenyl)-5-(5-methylfuran-2-yl)-
		4H-1,2,4-triazol-3-yl)-1-hydroxy-1-(6-methylpyridin-2-
		yl)propane-2-sulfonamide.
		1 H NMR (400 MHz, CDCl 3 ) δ 7.54 (t, J = 7.6 Hz, 1 H),
		7.47 (t, J = 8.2 Hz, 1 H), 7.27 (d, J = 6.8 Hz, 1 H), 7.00 (d,
		J = 7.6 Hz, 1 H), 6.70 (dd, J = 11.44, 8.51 Hz, 2 H), 5.92
		(dd, J = 3.4, 0.9 Hz, 1 H), 5.85 (d, J = 3.3 Hz, 1 H), 5.44
		(s, 1 H), 3.79 (s, 3 H), 3.77-3.80 (obscured m, 1 H),
		3.74 (s, 3 H), 3.70-3.75 (obscured m, 1 H), 2.49 (s, 3
		H), 2.12 (s, 3 H), 1.09 (d, J = 7.0 Hz, 3 H). LCMS-ESI
		(pos.): 514.1 (M + H) + .
90.1	N-(4-(2,6-dimethoxyphenyl)- 5-(5-methylfuran-2-yl)-4H- 1,2,4-triazol-3-yl)-N-(2- (trimethylsilyl)ethyl)ethane- sulfonamide (Example 369.0) and 2- pyridinecarboxaldehyde (Frontier Scientific Services Inc.). The mixture of the diastereomers was purified by ISCO CombiFlash on a Redi 24 g silica gel column using 0-100% EtOAc gradient in hexane as the eluent. Two peaks were collected. This was the second peak to elute under these conditions.
		((1R,2R)-N-(4-(2,6-dimethoxyphenyl)-5-(5-
		methylfuran-2-yl)-4H-1,2,4-triazol-3-yl)-1-hydroxy-1-
		(pyridin-2-yl)-N-(2-(trimethylsilyl)ethyl)propane-2-
		sulfonamide compound and (1S,2S)-N-(4-(2,6-
		dimethoxyphenyl)-5-(5-methylfuran-2-yl)-4H-1,2,4-
		triazol-3-yl)-1-hydroxy-1-(pyridin-2-yl)-N-(2-
		(trimethylsilyl)ethyl)propane-2-sulfonamide.
		LCMS (pos.) m/z: 600.2 (M + H) + .
90.0	Example 90.1.
		(1R,2R)-N-(4-(2,6-dimethoxyphenyl)-5-(5-methylfuran-
		2-yl)-4H-1,2,4-triazol-3-yl)-1-hydroxy-1-(pyridin-2-
		yl)propane-2-sulfonamide compound and (1S,2S)-N-(4-
		(2,6-dimethoxyphenyl)-5-(5-methylfuran-2-yl)-4H-
		1,2,4-triazol-3-yl)-1-hydroxy-1-(pyridin-2-yl)propane-2-
		sulfonamide.
		1 H NMR (400 MHz, CDCl 3 ) δ 8.54 (dt, J = 4.11, 0.78 Hz,
		1 H), 7.65 (td, J = 7.63, 1.76 Hz, 1 H), 7.46 (t, J = 8.51 Hz,
		1 H), 7.39 (d, J = 7.83 Hz, 1 H), 7.18 (ddd, J = 7.48, 4.84,
		1.17 Hz, 1 H), 6.67-6.70 (m, 2 H), 5.89-5.92 (m, 1 H),
		5.84 (d, J = 3.3 Hz, 1 H), 4.98 (d, J = 7.4 Hz, 2 H), 3.75-
		3.80 (obscured m, 1H), 3.78 (app s, 6 H), 3.54-3.61 (m,
		1 H), 2.32 (s, 3 H), 1.11 (d, J = 7.0 Hz, 3 H). LCMS
		(pos.) m/z: 500.1 (M + H) + .

TABLE 2

Example	Reagents	Structure, Name and Data
109.0 110.0	3-bromo-4-(2,6- dimethoxyphenyl)-5-(5- methylfuran-2-yl)-4H- 1,2,4-triazole (Example 364.1) and (2S,3R)-3- (5-fluoropyrimidin-2- yl)butane-2- sulfonamide, (2R,3S)- 3-(5-fluoropyrimidin-2- yl)butane-2- sulfonamide and (2R,3R)-3-(5- fluoropyrimidin-2- yl)butane-2- sulfonamide and (2S,3S)-3-(5- fluoropyrimidin-2- yl)butane-2- sulfonamide (Example 354.0). Preparative SFC method, stage one (separates Peak 1 from Peaks 2-4): Column: 250 × 21 mm Chiralpak AS-H, 30 g/min IPA containing 20 mM ammonia + 30 g/min CO 2 , 100 bar, 276 nm, Inj volume: 0.2 mL of a 4.5 mg/mL solution of sample in 33:7 MeOH/DCM. Preparative SFC method, stage two (separates Peaks 2-4): Column: 150 × 30 mm CC4, 39 g/min EtOH containing 20 mM ammonia + 91 g/min CO 2 , 100 bar, 276 nm, Inj volume: 0.4 mL of a 1.9 mg/mL solution of sample in 5:2 MeOH/DCM.

TABLE 3

Example	Reagents	Structure, Name and Data
116.0	3-bromo-4-(2,6- dimethoxyphenyl)-5-(5- methylfuran-2-yl)-4H- 1,2,4-triazole (Example 364.1), (1R,2S)-1-(5- fluoropyrimidin-2-yl)- 1-methoxypropane-2- sulfonamide and (1S,2R)-1-(5- fluoropyrimidin-2-yl)- 1-methoxypropane-2- sulfonamide (Example 359.0). Preparative SFC method: Column: 250 × 30 mm Chiralpak AS-H, 10.5 g/min MeOH + 59.5 g/min CO 2 , 100 bar, 277 nm, Inj volume: 0.5 mL of a 7.5 mg/mL solution of sample in 2:1 MeOH/DCM.
		(1R,2S)-N-(4-(2,6-dimethoxyphenyl)-5-(5-methylfuran-2-
		yl)-4H-1,2,4-triazol-3-yl)-1-(5-fluoropyrimidin-2-yl)-1-
		methoxypropane-2-sulfonamide or (1S,2R)-N-(4-(2,6-
		dimethoxyphenyl)-5-(5-methylfuran-2-yl)-4H-1,2,4-triazol-
		3-yl)-1-(5-fluoropyrimidin-2-yl)-1-methoxypropane-2-
		sulfonamide.
		1H NMR (400 MHz, CDCl 3 ) δ 10.95 (br. s., 1H), 8.61 (s,
		2H), 7.45 (t, J = 8.4 Hz, 1H), 6.67 (d, J = 8.6 Hz, 2H), 5.90
		(dd, J = 3.5, 0.8 Hz, 1H), 5.79 (d, J = 3.3 Hz, 1H), 4.96 (d,
		J = 4.9 Hz, 1H), 3.67-3.79 (m, 7H), 3.33 (s, 3H), 2.31 (s,
		3H), 1.38 (d, J = 7.0 Hz, 3H). LCMS-ESI (pos.) m/z: 533.2
		(M + H).
117.0	3-bromo-4-(2,6- dimethoxyphenyl)-5-(5- methylfuran-2-yl)-4H- 1,2,4-triazole (Example 364.1), (1S,2S)-1- ethoxy-1-(5- methylpyrimidin-2- yl)propane-2- sulfonamide and (1R,2R)-1-ethoxy-1-(5- methylpyrimidin-2- yl)propane-2- sulfonamide (Example 356.1). Preparative SFC method: Column: 2 × 15 cm Phenomenex Lux-2 Cell, 40% EtOH/CO 2 , 100 bar, 65 mL/min, 220 nm, Inj volume: 2.0 mL of a 5.0 mg/mL solution of sample in 5:1 MeOH/DCM.
		(1S,2S)-N-(4-(2,6-dimethoxyphenyl)-5-(5-methylfuran-2-
		yl)-4H-1,2,4-triazol-3-yl)-1-ethoxy-1-(5-methylpyrimidin-
		2-yl)propane-2-sulfonamide or (1R,2R)-N-(4-(2,6-
		dimethoxyphenyl)-5-(5-methylfuran-2-yl)-4H-1,2,4-
		triazol-3-yl)-1-ethoxy-1-(5-methylpyrimidin-2-yl)propane-
		2-sulfonamide
		1 H NMR (500 MHz, CDCl 3 ) δ 8.62 (s, 2H), 7.42 (t, J = 8.5
		Hz, 1H), 6.66 (t, J = 8.1 Hz, 2H), 5.89 (dd, J = 3.4, 0.9 Hz,
		1H), 5.73 (d, J = 3.5 Hz, 1H), 4.78 (d, J = 4.9 Hz, 1H), 3.80
		(s, 3H), 3.70-3.79 (m, 4H), 3.49-3.62 (m, 1H), 3.31-3.41
		(m, 1H), 2.33 (s, 3H), 2.33 (s, 3H), 1.39 (d, J = 7.0 Hz, 3H),
		1.08 (t, J = 6.9 Hz, 3H). LCMS-ESI (pos.) m/z: 543.2
		(M + H) + .
118.0	3-bromo-4-(2,6- dimethoxyphenyl)-5-(5- methylfuran-2-yl)-4H- 1,2,4-triazole (Example 364.1), (1S,2R)-1- ethoxy-1-(5- methylpyrimidin-2- yl)propane-2- sulfonamide and (1R,2S)-1-ethoxy-1-(5- methylpyrimidin-2- yl)propane-2- sulfonamide (Example 356.0). Preparative SFC method: Column: 2 × 15 cm Chiralpak AD- H, 30% EtOH/CO 2 , 100 bar, 220 um, Inj volume: 0.5 mL of a 5.0 mg/mL solution of sample in MeOH.
		(1R,2S)-N-(4-(2,6-dimethoxyphenyl)-5-(5-methylfuran-2-
		yl)-4H-1,2,4-triazol-3-yl)-1-ethoxy-1-(5-methylpyrimidin-
		2-yl)propane-2-sulfonamide.
		1H NMR (500 MHz, CDCl 3 ) δ 11.23 (br. s., 1H), 8.58 (s,
		2H), 7.44 (t, J = 8.6 Hz, 1H), 6.66 (d, J = 8.6 Hz, 2H), 5.90
		(br. s., 1H), 5.75-5.80 (m, 1H), 4.96 (d, J = 5.6 Hz, 1H),
		3.70-3.82 (m, 7H), 3.42-3.56 (m, 2H), 2.32 (s, 3H), 2.31 (s,
		3H), 1.43 (d, J = 7.0 Hz, 3H), 1.14 (t, J = 7.0 Hz, 3H).
		LCMS-ESI (pos.) m/z: 543.2 (M + H)+.

TABLE 4

Example	Reagents	Structure, Name and Data
122.0	3-bromo-4-(2,6- dimethoxyphenyl)-5-(5- methylfuran-2-yl)-4H- 1,2,4-triazole (Example 364.1), (1R,2R)-1-(5- fluoropyrimidin-2-yl)-1- methoxypropane-2- sulfonamide and (1S,2S)-1-(5- fluoropyrimidin-2-yl)-1- methoxypropane-2- sulfonamide (Example 359.1). Preparative SFC method: Column: 150 × 30 mm ChromegaChiral CC4, 28 g/min MeOH + 42 g/min CO 2 , 100 bar, 277 nm, Inj volume: 1.0 mL of a 4.0 mg/mL solution of sample in 3:1 MeOH/DCM.
		(1R,2R)-N-(4-(2,6-dimethoxyphenyl)-5-(5-methylfuran-2-
		yl)-4H-1,2,4-triazol-3-yl)-1-(5-fluoropyrimidin-2-yl)-1-
		methoxypropane-2-sulfonamide or (1S,2S)-N-(4-(2,6-
		dimethoxyphenyl)-5-(5-methylfuran-2-yl)-4H-1,2,4-
		triazol-3-yl)-1-(5-fluoropyrimidin-2-yl)-1-
		methoxypropane-2-sulfonamide.
		1 H NMR (500 MHz, CDCl 3 ) δ 11.25 (br. s., 1H), 8.62 (s,
		2H), 7.46 (t, J = 8.5 Hz, 1H), 6.67 (dd, J = 8.2, 5.0 Hz, 2H),
		5.91 (d, J = 2.7 Hz, 1H), 5.76 (d, J = 2.4 Hz, 1H), 4.80 (d,
		J = 6.1 Hz, 1H), 3.81 (s, 3H), 3.71-3.80 (m, 4H), 3.24 (s,
		3H), 2.32 (s, 3H), 1.24 (d, J = 6.6 Hz, 3H). LCMS-ESI
		(pos.) m/z: 533.2 (M + H) + .

TABLE 5

Example	Reagents	Structure, Name and Data
128.0	3-bromo-4-(2,6- dimethoxyphenyl)-5-(5- methylfuran-2-yl)-4H- 1,2,4-triazole (Example 364.1), and (S)-1-(5- fluoropyrimidin-2- yl)butane-2-sulfonamide and (R)-1-(5- fluoropyrimidin-2- yl)butane-2-sulfonamide (Example 358.0)
		(R)-N-(4-(2,6-dimethoxyphenyl)-5-(5-methylfuran-2-yl)-
		4H-1,2,4-triazol-3-yl)-1-(5-fluoropyrimidin-2-yl)butane-2-
		sulfonamide and (R)-N-(4-(2,6-dimethoxyphenyl)-5-(5-
		methylfuran-2-yl)-4H-1,2,4-triazol-3-yl)-1-(5-
		fluoropyrimidin-2-yl)butane-2-sulfonamide.
		1 H NMR (500 MHz, CDCl 3 ) δ: 8.53 (s, 2H), 7.46 (t, J = 8.5
		Hz, 1H), 6.67 (d, J = 8.4 Hz, 2H), 5.89-5.93 (m, 1H), 5.79
		(d, J = 3.3 Hz, 1H), 3.76 (s, 3H), 3.58-3.75 (m, 4H), 3.58
		(dd, J = 15.1, 6.1 Hz, 1H), 3.21 (dd, J = 15.3, 7.4 Hz, 1H),
		2.32 (s, 3H), 1.96-2.07 (m, 1H), 1.65-1.75 (m, 1H), 0.95 (t,
		J = 7.5 Hz, 3H). LCMS-ESI (pos.) m/z: 517.1 (M + H) + .
129.0	3-bromo-4-(2,6-3- bromo-4-(2,6- dimethoxyphenyl)-5- (furan-2-yl)-4H-1,2,4- triazole (Example 364.3), and (R)-2-(5- fluoropyrimidin-2- yl)propane-1- sulfonamide and (S)-2- (5-fluoropyrimidin-2- yl)propane-1- sulfonamide (Example 123.4).
		(S)-N-(4-(2,6-dimethoxyphenyl)-5-(furan-2-yl)-4H-1,2,4-
		triazol-3-yl)-2-(5-fluoropyrimidin-2-yl)propane-1-
		sulfonamide and (R)-N-(4-(2,6-dimethoxyphenyl)-5-
		(furan-2-yl)-4H-1,2,4-triazol-3-yl)-2-(5-fluoropyrimidin-2-
		yl)propane-1-sulfonamide.
		1 H NMR (500 MHz, CDCl 3 ) δ: 10.99 (br. s., 1H), 8.53 (s,
		2H), 7.44-7.50 (m, 2H), 6.68 (dd, J = 8.4, 3.1 Hz, 2H), 6.34
		(dd, J = 3.4, 1.7 Hz, 1H), 5.99 (d, J = 3.7 Hz, 1H), 3.70-3.86
		(m, 8H), 3.30 (dd, J = 14.0, 5.1 Hz, 1H), 1.42 (d, J = 7.1 Hz,
		3H). LCMS-ESI (pos.) m/z: 489.0 (M + H) + .
130.0	3-bromo-4-(2,6- dimethoxyphenyl)-5-(5- methylfuran-2-yl)-4H- 1,2,4-triazole (Example 364.1), and (1S,2S)-1- ethoxy-1-(5- methylpyrimidin-2- yl)propane-2- sulfonamide and (1R,2R)-1-ethoxy-1-(5- methylpyrimidin-2- yl)propane-2- sulfonamide (Example 356.1). Preparative SFC method: Column: 2 × 15 cm Phenomenex Lux-2 Cell, 40% EtOH/CO 2 , 100 bar, 65 mL/min, 220 nm, Inj volume: 2.0 mL of a 5.0 mg/mL solution of sample in 5:1 MeOH/DCM.
		(1R,2R)-N-(4-(2,6-dimethoxyphenyl)-5-(5-methylfuran-2-
		yl)-4H-1,2,4-triazol-3-yl)-1-ethoxy-1-(5-methylpyrimidin-
		2-yl)propane-2-sulfonamide or (1S,2S)-N-(4-(2,6-
		dimethoxyphenyl)-5-(5-methylfuran-2-yl)-4H-1,2,4-
		triazol-3-yl)-1-ethoxy-1-(5-methylpyrimidin-2-yl)propane-
		2-sulfonamide.
		1 H NMR (500 MHz, CDCl 3 ) δ 12.40 (br. s., 1H), 8.62 (s,
		2H), 7.43 (t, J = 8.5 Hz, 1H), 6.61-6.73 (m, 2H), 5.90 (dd,
		J = 3.3, 1.0 Hz, 1H), 5.73 (d, J = 3.3 Hz, 1H), 4.78 (d, J = 4.9
		Hz, 1H), 3.80 (s, 3H), 3.69-3.78 (m, 4H), 3.55 (dq, J = 8.8,
		7.0 Hz, 1H), 3.36 (dq, J = 8.9, 7.0 Hz, 1H), 2.33 (s, 3H),
		2.33 (s, 3H), 1.39 (d, J = 7.0 Hz, 3H), 1.08 (t, J = 7.0 Hz,
		3H). LCMS-ESI (pos.) m/z: 543.2 (M + H) + .

TABLE 6

Example	Reagents	Structure, Name and Data
132.0	3-bromo-4-(2,6- dimethoxyphenyl)-5-(5- methylfuran-2-yl)-4H- 1,2,4-triazole (Example 364.1), and (1R,2R)-1- (5-fluoropyrimidin-2- yl)-1-methoxypropane- 2-sulfonamide and (1S,2S)-1-(5- fluoropyrimidin-2-yl)-1- methoxypropane-2- sulfonamide (Example 359.1). Preparative SFC method: Column: 150 × 30 mm ChromegaChiral CC4, 28 g/min MeOH + 42 g/min CO 2 , 100 bar, 277 nm, Inj volume: 1.0 mL, of a 4.0 mg/mL solution of sample in 3:1 MeOH/DCM.
		(1S,2S)-N-(4-(2,6-dimethoxyphenyl)-5-(5-methylfuran-2-
		yl)-4H-1,2,4-triazol-3-yl)-1-(5-fluoropyrimidin-2-yl)-1-
		methoxypropane-2-sulfonamide or (1R,2R)-N-(4-(2,6-
		dimethoxyphenyl)-5-(5-methylfuran-2-yl)-4H-1,2,4-
		triazol-3-yl)-1-(5-fluoropyrimidin-2-yl)-1-
		methoxypropane-2-sulfonamide.
		1 H NMR (400 MHz, CDCl 3 ) δ 11.24 (br. s., 1H), 8.62 (s,
		2H), 7.46 (t, J = 8.4 Hz, 1H), 6.67 (dd, J = 8.5, 3.4 Hz, 2H),
		5.91 (dd, J = 3.4, 0.9 Hz, 1H), 5.76 (d, J = 3.5 Hz, 1H), 4.80
		(d, J = 6.5 Hz, 1H), 3.81 (s, 3H), 3.71-3.80 (m, 4H), 3.24 (s,
		3H), 2.32 (s, 3H), 1.24 (d, J = 7.0 Hz, 3H). LCMS-ESI
		(pos.) m/z: 533.2 (M + H) + .

TABLE 7

Example	Reagents	Structure, Name and Data
138.0	4-(2,6-dimethoxyphenyl)-5- (5-(methoxymethyl)furan- 2-yl)-4H-1,2,4-triazol-3- amine (Example 16.3).
		2-(4-chlorophenyl)-N-(4-(2,6-dimethoxyphenyl)-
		5-(5-(methoxymethyl)furan-2-yl)-4H-1,2,4-
		triazol-3-yl)ethanesulfonamide.
		1 H NMR (400 MHz, DMSO-d 6 ) δ 13.38 (s, 1H),
		7.57 (t, J = 8.5 Hz, 1H), 7.30-7.36 (m, 2H), 7.22
		(d, J = 8.6 Hz, 2H), 6.90 (d, J = 8.6 Hz, 2H), 6.47 (d,
		J = 3.5 Hz, 1H), 5.98 (d, J = 3.5 Hz, 1H), 4.31 (s,
		2H), 3.72 (s, 3H), 3.72 (s, 3H), 3.18 (s, 3H), 3.14-
		3.22 (m, 2H), 2.85-2.92 (m, 2H). LCMS-ESI
		(pos.) m/z: 533.0 (M + H) + .
139.0	4-(2,6-dimethoxyphenyl)-5- (5-(trifluoromethyl)furan-2- yl)-4H-1,2,4-triazol-3- amine (Example 363.0).
		2-(4-chlorophenyl)-N-(4-(2,6-dimethoxyphenyl)-
		5-(5-(trifluoromethyl)furan-2-yl)-4H-1,2,4-triazol-
		3-yl)ethanesulfonamide.
		1 H NMR (400 MHz, CD 3 OD) δ 7.57 (t, J = 8.41
		Hz, 1H), 7.26-7.33 (m, 2H), 7.14-7.21 (m, 2H),
		6.99-7.05 (m, 1H), 6.82-6.89 (d, J = 8.41 Hz, 2H),
		6.38-6.44 (m, 1H), 3.78 (s, 3H), 3.78 (s, 3H),
		3.22-3.28 (m, 2H), 2.97-3.05 (m, 2H). Mass
		spectrum (ESI) m/z = 557.0 (M + H).
140.0	5-(5-bromofuran-2-yl)-4- (2,6-dimethoxyphenyl)-4H- 1,2,4-triazol-3-amine (Example 362.04).
		N-(5-(5-bromofuran-2-yl)-4-(2,6-
		dimethoxyphenyl)-4H-1,2,4-triazol-3-yl)-2-(4-
		chlorophenyl)ethanesulfonamide.
		1 H NMR (400 MHz, DMSO-d 6 ) δ 13.46 (s, 1H),
		7.57 (t, J = 8.5 Hz, 1H), 7.31-7.36 (m, 2H), 7.18-
		7.24 (m, 2H), 6.90 (d, J = 8.6 Hz, 2H), 6.66 (d,
		J = 3.7 Hz, 1H), 6.06 (d, J = 3.7 Hz, 1H), 3.73 (s,
		3H), 3.73 (s, 3H), 3.16-3.23 (m, 2H), 2.85-2.92
		(m, 2H). LCMS-ESI (pos.) m/z: 567.0 (M + H) + .
141.0	5-(5-(tert-butyl)furan-2-yl)- 4-(2,6-dimethoxyphenyl)- 4H-1,2,4-triazol-3-amine (Example 16.2).
		N-(5-(5-(tert-butyl)furan-2-yl)-4-(2,6-
		dimethoxyphenyl)-4H-1,2,4-triazol-3-yl)-2-(4-
		chlorophenyl)ethanesulfonamide.
		1 H NMR (400 MHz, CD 3 OD) δ 7.53 (t, J = 8.5 Hz,
		1H), 7.24-7.32 (m, 2H), 7.13-7.21 (m, 2H), 6.85
		(d, J = 8.6 Hz, 2H), 6.41 (d, J = 3.5 Hz, 1H), 6.06 (d,
		J = 3.5 Hz, 1H), 3.73 (s, 3H), 3.73 (s, 3H), 3.20-
		3.26 (m, 2H), 2.97-3.05 (m, 2H), 1.11 (s, 9H).
		LCMS-ESI (pos.) m/z: 545.2 (M + H) + .

TABLE 8

Example	Reagents	Structure, Name and Data
211.0	3-bromo-4-(2,6-dimethoxyphenyl)-5- (5-methylfuran-2-yl)-4H-1,2,4-triazole (Example 364.1), (1R,2R)-1-(5- fluoropyrimidin-2-yl)-1- hydroxypropane-2-sulfonamide and (1S,2S)-1-(5-fluoropyrimidin-2-yl)-1- hydroxypropane-2-sulfonamide (Example 355.0) and (1S,2R)-1-(5- fluoropyrimidin-2-yl)-1- hydroxypropane-2-sulfonamide and (1S,2R)-1-(5-fluoropyrimidin-2-yl)-1- hydroxypropane-2-sulfonamide (Example 355.1).
	Chiral Purification by SFC, first stage:	(1S,2R)-N-(4-(2,6-dimethoxyphenyl)-5-(5-
	Run on Thar 80 SFC with 250 x	methylfuran-2-yl)-4H-1,2,4-triazol-3-yl)-1-(5-
	30 mm OJ-H column with 11 g/min	fluoropyrimidin-2-yl)-1-hydroxypropane-2-
	MeOH(neat)) + 59 g/min CO 2 ,	sulfonamide.
	16% co-solvent at 70 g/min. Outlet	1 H NMR (400 MHz, CD 3 OD) δ 8.65 (s, 2 H)
	pressure = 100 bar; Temp. = 21° C.;	7.55 (t, J = 8.61 Hz, 1 H) 6.84 (d, J = 8.61 Hz, 2
	Wavelength = 275 nm. Manually	H) 6.03 (d, J = 2.54 Hz, 1 H) 5.94 (d, J = 3.13 Hz,
	injected 0.7 mL of a solution from 47	1 H) 5.41 (s, 1 H) 4.59 (s, 1 H) 3.77 (app s, 6
	mg sample dissolved in 4.0 mL of	H) 2.34 (s, 3 H) 2.28 (s, 3 H). LCMS ESI
	MeOH, c = 11.8 mg/mL; 8.2 mg per	(pos.) m/z: 515.1 (M + H) + .
	injection to deliver Peak 1, of
	purification of major set of
	diastereomers.
115.0	3-bromo-4-(2,6-dimethoxyphenyl)-5- (5-methylfuran-2-yl)-4H-1,2,4-triazole (Example 364.1), (1R,2R)-1-(5- fluoropyrimidin-2-yl)-1- hydroxypropane-2-sulfonamide and (1S,2S)-1-(5-fluoropyrimidin-2-yl)-1- hydroxypropane-2-sulfonamide (Example 355.0) and (1S,2R)-1-(5- fluoropyrimidin-2-yl)-1- hydroxypropane-2-sulfonamide and (1S,2R)-1-(5-fluoropyrimidin-2-yl)-1- hydroxypropane-2-sulfonamide (Example 355.1).
	Chiral Purification by SFC, first	(1R,2S)-N-(4-(2,6-dimethoxyphenyl)-5-(5-
	stage: Run on Thar 80 SFC with 250 x	methylfuran-2-yl)-4H-1,2,4-triazol-3-yl)-1-(5-
	30 mm OJ-H column with 11 g/min	fluoropyrimidin-2-yl)-1-hydroxypropane-2-
	MeOH(neat)) + 59 g/min CO 2 ,	sulfonamide.
	16% co-solvent at 70 g/min. Outlet	1 H NMR (400 MHz, CD 3 OD) δ 8.64 (s, 2 H)
	pressure = 100 bar; Temp. = 21° C.;	7.55 (t, J = 8.61 Hz, 1 H) 6.84 (d, J = 8.61 Hz, 1
	Wavelength = 275 nm. Manually	H) 6.02 (d, J = 2.74 Hz, 1 H) 5.93 (d, J = 2.93 Hz,
	injected 0.7 mL of a solution from 47	1 H) 5.40 (s, 1 H) 4.59 (s, 1 H) 3.77 (app s, 6
	mg sample dissolved in 4.0 mL of	H) 2.34 (s, 1 H) 2.27 (s, 1 H). LCMS ESI
	MeOH, c = 11.8 mg/mL; 8.2 mg per	(pos.) m/z: 515.1 (M + H) + .
	injection to deliver Peak 2, only the
	major set of diastereomers were
	purified.
212.0	3-bromo-4-(2,6-dimethoxyphenyl)-5- (5-methylfuran-2-yl)-4H-1,2,4-triazole (Example 364.1), (1R,2R)-1-(5- chloropyrimidin-2-yl)-1- hydroxypropane-2-sulfonamide and (1S,2S)-1-(5-chloropyrimidin-2-yl)-1- hydroxypropane-2-sulfonamide and (1S,2R)-1-(5-chloropyrimidin-2-yl)-1- hydroxypropane-2-sulfonamide and (1R,2S)-1-(5-chloropyrimidin-2-yl)-1- hydroxypropane-2-sulfonamide. This material was prepared in analogous fashion to that described in Example 355.0 employing 5-chloropyrimidine- 2-carbaldehyde. Preparative SFC method: Column: Chiralpak AD-H (250 x 21 mm, 5 μm) Mobile Phase: 50:50 (A:B), A: Liquid CO2, B: EtOH, Flow Rate: 50 mL/min, 220 nm, 3 mg/injection to deliver Peak 2, only the major set of diastereomers were purified. .
		(1R,2S)-1-(5-chloro-2-pyrimidinyl)-N-(4-(2,6-
		dimethoxyphenyl)-5-(5-methyl-2-furanyl)-4H-
		1,2,4-triazol-3-yl)-1-hydroxy-2-
		propanesulfonamide or (1S,2R)-1-(5-chloro-2-
		pyrimidinyl)-N-(4-(2,6-dimethoxyphenyl)-5-(5-
		methyl-2-furanyl)-4H-1,2,4-triazol-3-yl)-1-
		hydroxy-2-propanesulfonamide.
		1 H NMR (400 MHz, CD 3 OD) δ 8.84 (s, 2H),
		7.58 (dd, J = 8.5, 8.5 Hz, 1H), 6.87 (d, J = 8.6
		Hz, 2H), 6.60 (d, J = 3.5 Hz, 1H), 5.99 (d, J =
		3.3 Hz, 1H), 5.39 (d, J = 3.5 Hz, 1H), 3.81 (s,
		3H), 3.80 (s, 3H), 2.75-2.78 (m, 1H), 2.29 (s,
		3H), 1.26 (d, J = 6.8 Hz, 3H). LCMS ESI
		(pos.) m/z: 535.1 (M + H) + .
213.0	3-bromo-4-(2,6-dimethoxyphenyl)-5- (5-methylfuran-2-yl)-4H-1,2,4-triazole (Example 364.1), (1R,2S)-1-hydroxy- 1-(5-methylpyrazin-2-yl)propane-2- sulfonamide and (1S,2S)-1-hydroxy- 1-(5-methylpyrazin-2-yl)propane-2- sulfonamide and (1R,2R)-1-hydroxy- 1-(5-methylpyrazin-2-yl)propane-2- sulfonamide and (1S,2S)-1-hydroxy- 1-(5-methylpyrazin-2-yl)propane-2- sulfonamide. This material was prepared in analogous fashion to that described in Example 355.0 employing 5-methylpyrazine-2- carbaldehyde. Preparative SFC method: Column: Chiralpak AS-H (250 x 21 mm, 5 μm), Mobile Phase: 80:20 (A:B), A: Liquid CO2, B: MeOH, Flow Rate: 70 mL/min, 220 nm, 22.4 mg/injection to deliver Peak 1, only the major set of diastereomers were purified.
		(1S,2R)-N-(4-(2,6-dimethoxyphenyl)-5-(5-
		methyl-2-furanyl)-4H-1,2,4-triazol-3-yl)-1-
		hydroxy-1-(5-methyl-2-pyrazinyl)-2-
		propanesulfonamide or (1R,2S)-N-(4-(2,6-
		dimethoxyphenyl)-5-(5-methyl-2-furanyl)-4H-
		1,2,4-triazol-3-yl)-1-hydroxy-1-(5-methyl-2-
		pyrazinyl)-2-propanesulfonamide.
		1 H NMR (500 MHz, CD 3 OD) δ 8.59 (s, 1H),
		8.51 (s, 1H), 7.6 (dd, J = 8.6, 8.6 Hz, 1H), 6.89
		(dd, J = 8.6, 4.3 Hz, 2H), 6.6 (d, J = 4.0 Hz,
		1H), 6.01 (d, J = 4.0 Hz, 1H), 5.42 (br s, 1H),
		3.82 (s, 3H), 3.80 (s, 3H), 3.64-3.70 (m, 1H),
		2.58 (s, 3H), 2.30 (s, 3H), 1.19 (d, J = 6.8 Hz,
		3H). LCMS ESI (pos.) m/z: 515.2 (M + H) + .
216.0	3-bromo-4-(2,6-dimethoxyphenyl)-5- (5-methylfuran-2-yl)-4H-1,2,4-triazole (Example 364.1), (1R,2R)-1-(5- chloropyrimidin-2-yl)-1- hydroxypropane-2-sulfonamide and (1S,2S)-1-(5-chloropyrimidin-2-yl)-1- hydroxypropane-2-sulfonamide and (1S,2R)-1-(5-chloropyrimidin-2-yl)-1- hydroxypropane-2-sulfonamide and (1R,2S)-1-(5-chloropyrimidin-2-yl)-1- hydroxypropane-2-sulfonamide. This material was prepared in analogous fashion to that described in Example 355.0 employing 5-chloropyrimidine- 2-carbaldehyde. Preparative SFC method: Column: Chiralpak AD-H (250 x 21 mm, 5 μm) Mobile Phase: 50:50 (A:B), A: Liquid CO2, B: EtOH, Flow Rate: 50 mL/min, 220 nm, 3 mg/injection to deliver Peak 1, only the major set of diastereomers were purified.
		(1R,2S)-1-(5-chloro-2-pyrimidinyl)-N-(4-(2,6-
		dimethoxyphenyl)-5-(5-methyl-2-furanyl)-4H-
		1,2,4-triazol-3-yl)-1-hydroxy-2-
		propanesulfonamide or (1S,2R)-1-(5-chloro-2-
		pyrimidinyl)-N-(4-(2,6-dimethoxyphenyl)-5-(5-
		methyl-2-furanyl)-4H-1,2,4-triazol-3-yl)-1-
		hydroxy-2-propanesulfonamide.
		1 H NMR (400 MHz, CD 3 OD ) δ 8.84 (s, 2H),
		7.58 (dd, J = 8.5, 8.5 Hz, 1H), 6.87 (d, J = 8.6
		Hz, 2H), 6.05-7.06 (m, 1H), 5.98 (d, J = 3.3 Hz,
		1H), 5.4 (d, J = 3.3 Hz, 1H), 3.80 (s, 3H), 3.80
		(s, 3H), 3.75-3.78 (m, 1H), 2.29 (s, 3H), 1.26
		(d, J = 6.8 Hz, 3H). LCMS ESI (pos.) m/z:
		535.1 (M + H) + .
217.0	3-bromo-4-(2,6-dimethoxyphenyl)-5- (5-methylfuran-2-yl)-4H-1,2,4-triazole (Example 364.1), (2S,3R)-3-hydroxy- 3-(5-methylpyrimidin-2-yl)butane-2- sulfonamide and (2R,3R)-3-hydroxy- 3-(5-methylpyrimidin-2-yl)butane-2- sulfonamide and (2S,3S)-3-hydroxy- 3-(5-methylpyrimidin-2-yl)butane-2- sulfonamide and (2R,3S)-3-hydroxy- 3-(5-methylpyrimidin-2-yl)butane-2- sulfonamide prepared employing 1-(5- methylpyrimidin-2-yl)ethanone and Example 361.0 following procedures described in Example 10.0. Preparative SFC method: 35 g/min EtOH(neat) + 65 g/min CO 2 on 250 x 30 mm AS-H column. Outlet pressure = 100 bar, Temp. = 20° C., Wavelength = 275 nm. Used 0.6 mL injections of 16 mg sample in 4 mL MeOH/DCM 1:1 (c = 4 mg/mL), resulting in 2.4 mg/injection. Run time 7.0 min., cycle time = 5.0 min to deliver Peak 1, only the major set of diastereomers were purified.
		(2S,3S)-N-(4-(2,6-dimethoxyphenyl)-5-(5-
		methyl-2-furanyl)-4H-1,2,4-triazol-3-yl)-3-
		hydroxy-3-(5-methyl-2-pyrimidinyl)-2-
		butanesulfonamide or (2R,3S)-N-(4-(2,6-
		dimethoxyphenyl)-5-(5-methyl-2-furanyl)-4H -
		1,2,4-triazol-3-yl)-3-hydroxy-3-(5-methyl-2-
		pyrimidinyl)-2-butanesulfonamide or (2S,3R)-
		N-(4-(2,6-dimethoxyphenyl)-5-(5-methyl-2-
		furanyl)-4H-1,2,4-triazol-3-yl)-3-hydroxy-3-(5-
		methyl-2-pyrimidinyl)-2-butanesulfonamide or
		(2R,3R)-N-(4-(2,6-dimethoxyphenyl)-5-(5-
		methyl-2-furanyl)-4H-1,2,4-triazol-3-yl)-3-
		hydroxy-3-(5-methyl-2-pyrimidinyl)-2-
		butanesulfonamide.
		1 H NMR (400 MHz, CD 3 OD) δ 8.65 (s, 2 H)
		7.58 (t, J = 8.61 Hz, 1 H) 6.87 (dd, J = 8.61, 0.98
		Hz, 2 H) 6.04 (dd, J = 3.68 Hz, 1 H) 5.97 (d,
		J = 3.52 Hz, 1 H) 4.87 (s, 15 H) 3.92 (q, J = 7.04
		Hz, 1 H) 3.82 (d, J = 2.74 Hz, 6 H) 2.37 (s, 3 H)
		2.28 (s, 3 H) 1.55 (s, 3 H) 1.46 (d, J = 7.04 Hz, 3
		H). LCMS ESI (pos.) m/z: 529.1 (M + H) + .
225.0	3-bromo-4-(2,6-dimethoxyphenyl)-5- (5-methylfuran-2-yl)-4H-1,2,4-triazole (Example 364.1), (2R,3S)-3-(5- fluoropyrimidin-2-yl)-3- hydroxybutane-2-sulfonamide and (2R,3R)-3-(5-fluoropyrimidin-2-yl)-3- hydroxybutane-2-sulfonamide and (2S,3S)-3-(5-fluoropyrimidin-2-yl)-3- hydroxybutane-2-sulfonamide and (2S,3R)-3-(5-fluoropyrimidin-2-yl)-3- hydroxybutane-2-sulfonamide prepared employing 1-(5- fluoropyrimidin-2-yl)ethanone and Example 361.0 following procedures described in Example 10.0. Preparative SFC method: 250 x 30 mm IC column with 55 mL/min EtOH(neat) + 55 g/min CO 2 on Thar 350 SFC. Outlet pressure = 100 bar; Temp. = 21 C.; Wavelength = 276 nm. Used 1.0 mL injections of 292 mg/35 mL (8.3 mg/mL) sample solution in MeOH:DCM (33:2), i.e. 8.3 mg/injection. Cycle time = 10.4 min, Runtime =18 min to deliver Peak 4.
		(2R,3S)-N-(4-(2,6-dimethoxyphenyl)-5-(5-
		methyl-2-furanyl)-4H-1,2,4-triazol-3-yl)-3-(5-
		fluoro-2-pyrimidinyl)-3-hydroxy-2-
		butanesulfonamide and (2R,3R)-N-(4-(2,6-
		dimethoxyphenyl)-5-(5-methyl-2-furanyl)-4H-
		1,2,4-triazol-3-yl)-3-(5-fluoro-2-pyrimidinyl)-
		3-hydroxy-2-butanesulfonamide and (2S,3S)-
		N-(4-(2,6-dimethoxyphenyl)-5-(5-methyl-2-
		furanyl)-4H-1,2,4-triazol-3-yl)-3-(5-fluoro-2-
		pyrimidinyl)-3-hydroxy-2-butanesulfonamide
		and (2S,3R)-N-(4-(2,6-dimethoxyphenyl)-5-(5-
		methyl-2-furanyl)-4H-1,2,4-triazol-3-yl)-3-(5-
		fluoro-2-pyrimidinyl)-3-hydroxy-2-
		butanesulfonamide.
		1 H NMR (400 MHz, CD 3 OD) δ 8.66 (s, 2 H)
		7.51 (t, J = 8.33 Hz, 1 H) 6.82 (dd, J = 8.61, 3.52
		Hz, 2 H) 5.97 (d, J = 3.13 Hz, 1 H) 5.82 (d,
		J = 3.33 Hz, 1 H) 4.03 (m, 1 H) 3.77 (app s, 6 H)
		2.27 (s, 3 H) 1.75 (s, 3 H) 1.32 (d, J = 7.04 Hz, 4
		H). LCMS ESI (pos.) m/z: 533.0 (M + H) + .
226.0	3-bromo-4-(2,6-dimethoxyphenyl)-5- (5-methylfuran-2-yl)-4H-1,2,4-triazole (Example 364.1), (1S,2S)-1-methoxy- 1-(5-methylpyrimidin-2-yl)propane-2- sulfonamide and (1R,2S)-1-methoxy- 1-(5-methylpyrimidin-2-yl)propane-2- sulfonamide and (1S,2R)-1-methoxy- 1-(5-methylpyrimidin-2-yl)propane-2- sulfonamide and (1R,2R)-1-methoxy- 1-(5-methylpyrimidin-2-yl)propane-2- sulfonamide was prepared following procedures described in Example 356.0 employing 2,4-dimethoxy- benzylamine, 5-methylpyrimidine- 2-carbaldehyde and MeI. Preparative SFC method: Chiral separation of the racemic mixture was conducted through a 2 step purification process. First purification step: Run on Thar 350 with 400x30 mm AD-H columns using 32 mL/min neat IPA and 58 g/min CO 2 on SFC, 35% co-solvent at 90 g/min. Outlet pressure = 100 bar; Temp. = 20° C.; Wavelength = 276 nm. Used 0.5 mL injections of 432
	mg sample dissolved in 70 mL of	(1R,2R)-N-(4-(2,6-dimethoxyphenyl)-5-(5-
	solvent (55 mL IPA, 10 mL MeOH, 5	methyl-2-furanyl)-4H-1,2,4-triazol-3-yl)-1-
	mL DCM); c = 6.5 mg/mL,	methoxy-1-(5-methyl-2-pyrimidinyl)-2-
	3.25 mg/injection. Cycle time =	propanesulfonamide or (1S,2S)-N-(4-(2,6-
	11 min; Run time = 20 min.	dimethoxyphenyl)-5-(5-methyl-2-furanyl)-4H-
	Separation conditions for step2: Run	1,2,4-triazol-3-yl)-1-methoxy-1-(5-methyl-2-
	on Thar 80 SFC with 250 x 30 mm	pyrimidinyl)-2-propanesulfonamide.
	AS-H column with 28 g/min	1 H NMR (500 MHz, CD 3 OD) δ 8.68 (s, 2 H)
	IPA(neat) + 52 g/min CO 2 , 35% co-	7.62 (t, J = 8.41 Hz, 1 H) 6.86 (d, J = 8.80 Hz, 2
	solvent at 80 g/min. Outlet pressure =	H) 6.03 (m, 1 H) 5.95 (d, J = 3.42 Hz, 1 H) 4.83
	100 bar; Temp. = 21° C.; Wavelength =	(m, 2 H) 4.58-4.68 (m, 1 H) 3.84 (s, 3 H) 3.81
	276 nm. Injected 0.8 mL of a	(s, 3 H) 3.63 (dd, J = 8.19, 7.21 Hz, 1 H) 3.11 (s,
	solution from 150 mg sample	3 H) 2.37 (s, 3 H) 2.27 (s, 3 H) 1.03 (d, J = 7.34
	dissolved in 40 mL of IPA:MeOH	Hz, 3 H). LCMS ESI (pos.) m/z: 529.0
	25:15 mL. c = 3.8 mg/mL; 3.0 mg per	(M + H) + .
	injection. Cycle time = 7.6 min, total
	elution time= 13 min to deliver peak 1
	from step 1.
227.0	3-bromo-4-(2,6-dimethoxyphenyl)-5- (5-methylfuran-2-yl)-4H-1,2,4-triazole (Example 364.1), (2R,3R)-3-(5- cyanopyridin-2-yl)-3-hydroxybutane- 2-sulfonamide and (2R,3S)-3-(5- cyanopyridin-2-yl)-3-hydroxybutane- 2-sulfonamide and (2S,3R)-3-(5-cyanopyridin-2-yl)-3- hydroxybutane-2-sulfonamide and (2S,3S)-3-(5-cyanopyridin-2-yl)-3- hydroxybutane-2-sulfonamide was prepared following the procedures described in Example 10.0, employing 1-(5-bromopyridin-2- yl)ethanone and Example 361.0. Preparative SFC method: Separation conditions Run on Thar 80 SFC with 250 x 30 mm OJ-H column with 9 g/min MeOH(neat)) + 61 g/min CO2, 13% co-solvent at 70 g/min. Outlet pressure = 101 bar; Temp. = 22 C.; Wavelength = 221 nm. Manually injected 0.5 mL of a solution from 29 mg sample dissolved in 2.5 mL of MeOH, c = 11.6 mg/mL; 5.8 mg per injection to deliver Peak 2, only the major set of diastereomers were purified.
		(2S,3S)-3-(5-cyano-2-pyridinyl)-N-(4-(2,6-
		dimethoxyphenyl)-5-(5-methyl-2-furanyl)-4H-
		1,2,4-triazol-3-yl)-3-hydroxy-2-
		butanesulfonamide.
		1 H NMR (500 MHz, CD 3 OD) δ 8.77 (s, 1 H)
		8.04 (dd, J = 8.31, 1.96 Hz, 1 H) 7.58-7.67 (m,
		2 H) 6.90 (t, J = 7.25 Hz, 2 H) 6.04 (s, 1 H) 5.98
		(d, J = 3.18 Hz, 1 H) 3.88 (m, 1 H) 3.84 (s, 3 H)
		3.82 (s, 3 H) 2.27 (s, 3 H) 1.43-1.47 (s, 3 H)
		1.46 (s, 3 H). LCMS ESI (pos.) m/z: 539.1
		(M + H) + .
228.0	3-bromo-4-(2,6-dimethoxyphenyl)-5- (5-methylfuran-2-yl)-4H-1,2,4-triazole (Example 364.1), (2R,3S)-3-(5- fluoropyrimidin-2-yl)-3- hydroxybutane-2-sulfonamide and (2R,3R)-3-(5-fluoropyrimidin-2-yl)-3- hydroxybutane-2-sulfonamide and (2S,3S)-3-(5-fluoropyrimidin-2-yl)-3- hydroxybutane-2-sulfonamide and (2S,3R)-3-(5-fluoropyrimidin-2-yl)-3- hydroxybutane-2-sulfonamide prepared employing 1-(5- fluoropyrimidin-2-yl)ethanone and Example 361.0 following procedures described in Example 10.0. Preparative SFC method: Run on 250x30 mm IC column with 55 mL/min EtOH (neat) + 55 g/min CO 2 on Thar 350 SFC. Outlet pressure = 100 bar; Temp. = 21° C.; Wavelength = 276 nm. Used 1.0 mL injections of 292 mg/35 mL (8.3 mg/mL) sample solution in MeOH:DCM (33:2), i.e. 8.3 mg/injection. Cycle time = 10.4 min, Runtime = 18 min to deliver a mixture of peak 3 and 4.
		(2R,3S)-N-(4-(2,6-dimethoxyphenyl)-5-(5-
		methyl-2-furanyl)-4H-1,2,4-triazol-3-yl)-3-(5-
		fluoro-2-pyrimidinyl)-3-hydroxy-2-
		butanesulfonamide or (2R,3R)-N-(4-(2,6-
		dimethoxyphenyl)-5-(5-methyl-2-furanyl)-4H-
		1,2,4-triazol-3-yl)-3-(5-fluoro-2-pyrimidinyl)-
		3-hydroxy-2-butanesulfonamide or (2S,3S)-N-
		(4-(2,6-dimethoxyphenyl)-5-(5-methyl-2-
		furanyl)-4H-1,2,4-triazol-3-yl)-3-(5-fluoro-2-
		pyrimidinyl)-3-hydroxy-2-butanesulfonamide
		or (2S,3R)-N-(4-(2,6-d
		methyl-2-furanyl)-4H-1,2,4-triazol-3-yl)-3-(5-
		fluoro-2-pyrimidinyl)-3-hydroxy-2-
		butanesulfonamide.
		LCMS ESI (pos.) m/z: 540.1 (M + H) + .
236.0	3-bromo-4-(2,6-dimethoxyphenyl)-5- (5-methylfuran-2-yl)-4H-1,2,4-triazole (Example 364.1), (2R,3S)-3-(5- fluoropyrimidin-2-yl)-3- hydroxybutane-2-sulfonamide and (2R,3R)-3-(5-fluoropyrimidin-2-yl)-3- hydroxybutane-2-sulfonamide and (2S,3S)-3-(5-fluoropyrimidin-2-yl)-3- hydroxybutane-2-sulfonamide and (2S,3R)-3-(5-fluoropyrimidin-2-yl)-3- hydroxybutane-2-sulfonamide prepared employing 1-(5- fluoropyrimidin-2-yl)ethanone and Example 361.0 following procedures described in Example 10.0. Preparative SFC method: Run on 250x30 mm IC column with 55 mL/min EtOH (neat) + 55 g/min CO 2 on Thar 350 SFC. Outlet pressure = 100 bar; Temp. = 21° C.; Wavelength = 276 nm. Used 1.0 mL injections of 292 mg/35 mL (8.3 mg/mL) sample solution in MeOH:DCM (33:2), i.e. 8.3 mg/injection. Cycle time =10.4 min, Runtime =18 min to deliver peak 1.
		(2R,3S)-N-(4-(2,6-dimethoxyphenyl)-5-(5-
		methyl-2-furanyl)-4H-1,2,4-triazol-3-yl)-3-(5-
		fluoro-2-pyrimidinyl)-3-hydroxy-2-
		butanesulfonamide or (2R,3R)-N-(4-(2,6-
		dimethoxyphenyl)-5-(5-methyl-2-furanyl)-4H-
		1,2,4-triazol-3-yl)-3-(5-fluoro-2-pyrimidinyl)-
		3-hydroxy-2-butanesulfonamide or (2S,3S)-N-
		(4-(2,6-dimethoxyphenyl)-5-(5-methyl-2-
		furanyl)-4H-1,2,4-triazol-3-yl)-3-(5-fluoro-2-
		pyrimidinyl)-3-hydroxy-2-butanesulfonamide
		or (2S,3R)-N-(4-(2,6-dimethoxyphenyl)-5-(5-
		methyl-2-furanyl)-4H-1,2,4-triazol-3-yl)-3-(5-
		fluoro-2-pyrimidinyl)-3-hydroxy-2-
		butanesulfonamide.
		LCMS ESI (pos.) m/z: 540.1 (M + H) + .
244.0	3-bromo-4-(2,6-dimethoxyphenyl)-5- (5-methylfuran-2-yl)-4H-1,2,4-triazole (Example 364.1), (1R,2R)-1-(5-fluoropyrimidin-2-yl)-1- hydroxypropane-2-sulfonamide and (1S,2S)-1-(5-fluoropyrimidin-2-yl)-1- hydroxypropane-2-sulfonamide (Example 355.0) and (1S,2R)-1-(5- fluoropyrimidin-2-yl)-1- hydroxypropane-2-sulfonamide and (1S,2R)-1-(5-fluoropyrimidin-2-yl)-1- hydroxypropane-2-sulfonamide (Example 355.1). Preparative SFC method: Run on Thar 200 with 250x30 mm AS-H column with 54 g/min MeOH (neat) and 66 g/min CO 2 , 45% co-solvent at 120 g/min. Wavelength 276 nm. Injected 1.0 mL of 80 mg dissolved in 10.0 mL MeOH; c = 8.0 mg/mL, 8.0 mg/injection. Cycle time 7.0 min, run time 11 min to provide peak 2 of the minor set of diastereomers.
		(1R,2R)-N-(4-(2,6-dimethoxyphenyl)-5-(5-
		methyl-2-furanyl)-4H-1,2,4-triazol-3-yl)-1-
		hydroxy-1-(5-methyl-2-pyrimidinyl)-2-
		propanesulfonamide or (1S,2S)-N-(4-(2,6-
		dimethoxyphenyl)-5-(5-methyl-2-furanyl)-4H-
		1,2,4-triazol-3-yl)-1-hydroxy-1-(5-methyl-2-
		pyrimidinyl)-2-propanesulfonamide.
		1 H NMR (400 MHz, CD 3 OD) δ 8.64 (s, 2 H)
		7.55 (t, J = 8.41 Hz, 1 H) 6.84 (d, J = 8.61 Hz, 2
		H) 6.02 (m, 1 H) 5.92 (m, 1 H) 4.99 (d, J = 7.43
		Hz, 2 H) 4.59 (br. s., 2 H) 3.82 (s, 3 H) 3.79 (s,
		3 H) 3.61-3.70 (m, 1 H) 2.35 (s, 3 H) 2.27 (s,
		3 H) 1.13 (d, J = 7.04 Hz, 3 H). LCMS ESI
		(pos.) m/z: 515.0 (M + H) + .
247.0	3-bromo-4-(2,6-dimethoxyphenyl)-5- (5-methylfuran-2-yl)-4H-1,2,4-triazole (Example 364.1), (1R,2S)-1-hydroxy- 1-(5-methylpyrazin-2-yl)propane-2- sulfonamide and (1S,2S)-1-hydroxy- 1-(5-methylpyrazin-2-yl)propane-2- sulfonamide and (1R,2R)-1-hydroxy- 1-(5-methylpyrazin-2-yl)propane-2- sulfonamide and (1S,2S)-1-hydroxy- 1-(5-methylpyrazin-2-yl)propane-2- sulfonamide. This material was prepared in an analogous fashion to that described in Example 355.0 employing 5-methylpyrazine-2- carbaldehyde. Preparative SFC method: Dissolved 112 mg in 2.5 mL DCM + 2.5 mL meoh (22.4 mg/mL). Column: Chiralpak AS-H (250 x 21 mm, 5 μm), Mobile Phase: 80:20 (A:B), A: Liquid CO 2 , B: MeOH, Flow Rate: 70 mL/min, 220 nm, 22.4 mg/injection to provide peak 2 of the major set of diastereomers.
		(1S,2R)-N-(4-(2,6-dimethoxyphenyl)-5-(5-
		methyl-2-furanyl)-4H-1,2,4-triazol-3-yl)-1-
		hydroxy-1-(5-methyl-2-pyrazinyl)-2-
		propanesulfonamide or (1R,2S)-N-(4-(2,6-
		dimethoxyphenyl)-5-(5-methyl-2-furanyl)-4H-
		1,2,4-triazol-3-yl)-1-hydroxy-1-(5-methyl-2-
		pyrazinyl)-2-propanesulfonamide.
		1 H NMR (500 MHz, CD 3 OD) δ 8.58 (s, 1H),
		8.51 (s, 1H), 7.60 (d, J = 8.5, 8.5 Hz, 1H), 6.89
		(dd, J = 8.4, 4.3 Hz, 2H), 6.07 (d, J = 3.5 Hz,
		1H), 6.01 (d, J = 3.5 Hz, 1H), 5.42 (br s, 1H),
		3.82 (s, 3H), 3.80 (s, 3H), 3.63-3.69 (m, 1H),
		2.58 (s, 3H), 2.29 (s, 3H), 1.18 (d, J = 7.0 Hz,
		3H). LCMS ESI (pos.) m/z: 515.2 (M + H) + .
250.0	3-bromo-4-(2,6-dimethoxyphenyl)-5- (5-methylfuran-2-yl)-4H-1,2,4-triazole (Example 364.1), (1S,2S)-1-methoxy- l-(5-methylpyrimidin-2-yl)propane-2- sulfonamide and (1R,2S)-1-methoxy- 1-(5-methylpyrimidin-2-yl)propane-2- sulfonamide and (1S,2R)-1-methoxy- 1-(5-methylpyriinidin-2-yl)propane-2- sulfonamide and (1R,2R)-1-methoxy- 1-(5-methylpyrimidin-2-yl)propane-2- sulfonamide was prepared following procedures described in Example 356.0 employing 2,4-dimethoxy- benzylamine, 5-methylpyrimidine- 2-carbaldehyde and MeI. Preparative SFC method: Chiral separation of the racemic mixture was conducted through a 2 step purification process. First purification step: Run on Thar 350 with 400x30 mm AD-H columns using 32 mL/min neat IPA and 58 g/min CO 2 on SFC, 35% co-solvent at 90 g/min. Outlet pressure = 100 bar; Temp. = 20° C.; Wavelength = 276 nm. Used 0.5 mL injections of 432
	mg sample dissolved in 70 mL of	(1R,2R)-N-(4-(2,6-dimethoxyphenyl)-5-(5-
	solvent (55 mL IPA, 10 mL MeOH, 5	methyl-2-furanyl)-4H-1,2,4-triazol-3-yl)-1-
	mL DCM); c = 6.5 mg/mL,	methoxy-1-(5-methyl-2-pyrimidinyl)-2-
	3.25 mg/injection. Cycle time = 11	propanesulfonamide or (1S,2S)-N-(4-(2,6-
	min; Run time = 20 min. Separation	dimethoxyphenyl)-5-(5-methyl-2-furanyl)-4H-
	conditions for step2: Run on Thar 80	1,2,4-triazol-3-yl)-1-methoxy-1-(5-methyl-2-
	SFC with 250 x 30 mm AS-H column	pyrimidinyl)-2-propanesulfonamide.
	with 28 g/min IPA(neat) + 52 g/min	1 H NMR (500 MHz, CD 3 OD) δ 8.68 (s, 2 H)
	CO 2 , 35% co-solvent at 80 g/min.	7.56 (t, J = 8.41 Hz, 1 H) 6.86 (d, J = 8.80 Hz, 2
	Outlet pressure = 100 bar; Temp. =	H) 6.03 (m, 1 H) 5.95 (d, J = 3.42 Hz, 1 H) 4.83
	21° C.; Wavelength = 276 nm. Injected	(m, 2 H) 4.58-4.68 (m, 1 H) 3.84 (s, 3 H) 3.81
	0.8 mL of a solution from 150 mg	(s, 3 H) 3.63 (dd, J = 8.19, 7.21 Hz, 1 H) 3.11 (s,
	sample dissolved in 40 mL of	3 H) 2.37 (s, 3 H) 2.27 (s, 3 H) 1.03 (d, J = 7.34
	IPA:MeOH 25:15 mL, c = 3.8	Hz, 3 H). LCMS ESI (pos.) m/z: 529.0
	mg/mL; 3.0 mg per injection. Cycle	(M + H) + .
	time = 7.6 min, total elution time =
	13 min to provide peak 3 from step 2.
261.0	3-bromo-4-(2,6-dimethoxyphenyl)-5- (5-methylfuran-2-yl)-4H-1,2,4-triazole (Example 364.1), (1S,2S)-1-methoxy- 1-(5-methylpyrimidin-2-yl)propane-2- sulfonamide and (1R,2S)-1-methoxy- 1-(5-methylpyrimidin-2-yl)propane-2- sulfonamide and (1S,2R)-1-methoxy- 1-(5-methylpyrimidin-2-yl)propane-2- sulfonamide and (1R,2R)-1-methoxy- 1-(5-methylpyrimidin-2-yl)propane-2- sulfonamide was prepared following procedures described in Example
	356.0 employing 2,4-dimethoxy-	(1R,2S)-N-(4-(2,6-dimethoxyphenyl)-5-(5-
	benzylamine, 5-methylpyrimidine-	methyl-2-furanyl)-4H-1,2,4-triazol-3-yl)-1-
	2-carbaldehyde and MeI.	methoxy-1-(5-methyl-2-pyrimidinyl-2-
	Preparative SFC method: Separation	propanesulfonamide: 1 H NMR (500 MHz,
	conditions for (step 1), chiral	CD 3 OD) δ 8.67 (d, J = 0.73 Hz, 2 H) 7.56 (t,
	purification (1000 + 3700 mg): Run on	J = 8.41 Hz, 1 H) 6.85 (d, J = 8.56 Hz, 2 H) 6.03
	Thar 350 SFC with 250x30 mm IC-H	(s, 1 H) 5.95 (d, J = 3.42 Hz, 1 H) 5.00 (d,
	column at 50 g/min MeOH (neat) + 50	J = 3.67 Hz, 1 H) 3.80 (s, 3 H) 3.77 (s, 3 H) 3.54-
	g/min CO 2 , 50% co-solvent, at 100	3.59 (m, 1 H) 3.28 (s, 3 H) 2.36 (s, 3 H) 2.27
	g/min. Outlet pressure = 100 bar;	(s, 3 H) 1.25 (d, J = 6.85 Hz, 3 H). LCMS ESI
	Temp. = 20° C.; Wavelength = 276 nm.	(pos.) m/z: 529.0 (M + H) + .
	Material was dissolved in batches of
	200-400 mg to avoid possible
	decomposition upon sitting in
	solution. Injected 2.0 mL of 400 mg
	sample in 17 mL, comprised of 10 mL
	DCM and 7 mL ACN. Solution
	concentration = 23.5 mg/mL, resulting
	in 47 mg per injection. Cycle time 8.5
	min; run time 16 min. Chiral
	separation of, step 2 (2500 mg) by
	preparative SFC. Run on Thar 200
	with 2x(250x35) mm AS-H column
	with 19 g/min MeOH (neat) + 91
	g/min CO 2 , 17% co-solvent at 110
	g/min. Temperature 21° C.,
	Wavelength 297 nm. Injected 1.0 mL
	of a solution of e.g. 855 mg of
	sample (step 1, peak 1) dissolved in 35
	mL (15 mL DCM = 20 mL ACN); c =
	24.5 mg/mL; 24.5 mg/injection. Cycle
	time 7 min; runtime 16 min to provide
	step 2, peak 2.

TABLE 9

251.0	1-(5-methylpyrimidin-2- yl)ethanone and Example 365.0. Preparative SFC method: chiral separation by prep. SFC: On Thar 200, conditions used were 30 g/min EtOH(neat) + 70 g/min CO 2 on 250 x 30 mm AS-H column. Outlet pressure = 100 bar, Temp. = 20° C., Wavelength = 270 nm. Used 1.0 mL injections of 173 mg sample in 10 mL MeOH/DCM (c = 17.3 mg/mL), resulting in 17 mg/injection. Run time 10.0 min., cycle time = 7.0 min to deliver peak 1.
		(2S)-N-(4-(2,6-dimethoxyphenyl)-5-(2-furanyl)-4H-
		1,2,4-triazol-3-yl)-2-(5-methyl-2-pyrimidinyl)-1-
		propanesulfonamide or (2R)-N-(4-(2,6-dimethoxy-
		phenyl)-5-(2-furanyl)-4H-1,2,4-triazol-3-yl)-2-
		(5-methyl-2-pyrimidinyl)-1-propanesulfonamide.
		1 H NMR (400 MHz, CD 3 OD) δ 8.56 (s, 2 H) 7.61
		(s, 1 H) 7.56 (t, J = 8.61 Hz, 1 H) 6.86 (d, J =
		8.61 Hz, 1 H) 6.84 (s, 1 H) 6.44 (dd, J = 3.52,
		1.76 Hz, 1 H) 6.14 (dd, J = 3.52, 0.78 Hz, 1 H)
		3.80 (app s, 6 H), 3.78 (m, 1 H) 3.29-3.34 (m, 2 H)
		2.31 (s, 3 H) 1.39 (d, J = 7.04 Hz, 3 H). LCMS
		ESI (pos.) m/z: 485.1 (M + H) + .

TABLE 10

Example	Reagents	Structure, Name and Data
222.0	4-pyridinylboronic acid (commercially available from Sigma-Aldrich Corp., St. Louis, MO, USA).
		2-(5-chloro-3,4′-bipyridin-2-yl)-N-(4-(2,6-
		dimethoxyphenyl)-5-(2-furanyl)-4H-1,2,4-
		triazol-3-yl)ethanesulfonamide.
		1 H NMR (400 MHz, CD 3 OD) δ 8.75 (d,
		J = 6.06 Hz, 2 H) 8.65 (d, J = 2.35 Hz, 1 H)
		7.77-7.90 (m, 3 H) 7.61 (d, J = 1.76 Hz, 1
		H) 7.55 (t, J = 8.51 Hz, 1 H) 6.81 (d, J = 8.41
		Hz, 2 H) 6.45 (dd, J = 3.62, 1.86 Hz, 1 H)
		6.13 (d, J = 3.66 Hz, 1 H) 3.72 (app s, 6 H)
		3.55 (t, J = 7.24 Hz, 2 H) 3.16 (t, J = 7.34 Hz,
		2 H). LCMS-ESI (pos.) m/z: 567.2 (M + H) + .
223.0	1H-pyrazole-5-boronic acid pinacol ester (commercially available from Sigma-Aldrich Corp., St. Louis, MO, USA).
		2-(5-chloro-3-(1H-pyrazol-3-yl)-2-pyridinyl)-N-(4-(2,6-
		dimethoxyphenyl)-5-(2-furanyl)-4H-1,2,4-triazol-3-
		yl)ethanesulfonamide.
		1 H NMR (500 MHz, CD 3 OD) δ 8.49 (d, J = 2.44 Hz, 1 H)
		7.98 (d, J = 2.45 Hz, 1 H) 7.71 (d, J = 2.20 Hz, 1 H) 7.60
		(d, J = 1.71 Hz, 1 H) 7.53 (t, J = 8.56 Hz, 1 H) 6.79 (d,
		J = 8.56 Hz, 2 H) 6.60 (d, J = 2.45 Hz, 1 H) 6.43 (dd,
		J = 3.55, 1.83 Hz, 1 H) 6.12 (d, J = 3.42 Hz, 1 H) 3.69
		(app s, 6 H) 3.41-3.55 (m, 4 H). LCMS-ESI (pos.)
		m/z: 556.2 (M + H) + .

TABLE 11

Example	Reagents	Structure, Name and Data
262.0	(2S,3R)-3-(5- methylpyrimidin-2- yl)butane-2-sulfonamide (Example 371.0) and 3- bromo-4-(2,6- dimethoxyphenyl)-5-(5- methylfuran-2-yl)-4H- 1,2,4-triazole (Example 364.1).
		(2S,3R)-N-(4-(2,6-dimethoxyphenyl)-5-(5-methylfuran-2-
		yl)-4H-1,2,4-triazol-3-yl)-3-(5-methylpyrimidin-2-
		yl)butane-2-sulfonamide.
		1 H NMR (500 MHz, DMSO-d 6 ) δ = 13.17 (s, 1H), 8.58 (d,
		J = 0.7 Hz, 2H), 7.55 (t, J = 8.6 Hz, 1H), 6.87 (dd, J = 2.1, 8.7
		Hz, 2H), 6.12 (dd, J = 1.0, 3.4 Hz, 1H), 5.79 (d, J = 3.4 Hz,
		1H), 3.71-3.63 (m, 7H), 3.59 (dq, J = 3.4, 6.9 Hz, 1H),
		2.25 (s, 3H), 2.23 (s, 3H), 1.23 (d, J = 7.1 Hz, 3H), 1.09 (d,
		J = 6.8 Hz, 3H). Mass Spectrum (pos.) m/z: 513.1
		(M + H) + .

TABLE 12

Example	Reagents	Structure, Name and Data
356.1	(1R,2R)-1-hydroxy-N,N- bis(4-methoxybenzyl)- 1-(5-methylpyrimidin- 2-yl)propane- 2-sulfonamide and (1S,2R)-1- hydroxy-N,N-bis(4- methoxybenzyl)-1-(5- methylpyrimidin- 2-yl)propane-2- sulfonamide, Example 356.05. Material prepared in an analagous mariner to that of Example 356.0 employing sulfonamide 356.05
		(1S,2S)-1-ethoxy-1-(5-
		methylpyrimidin-2-yl)propane-2-
		sulfonamide and(1R,2R)-1-ethoxy-1-
		(5-methylpyrimidin-2-yl)propane-2-
		sulfonamide. LCMS-ESI (pos.) m/z:
		260.0 (M + H) + .

TABLE 13

Example	Reagents	Structure, Name and Data
357.1	trans-1-propen-1- ylboronic acid (Sigma-Aldrich)
		(1S,2R)-1-((tert-Butyldimethylsilyl)oxy)-1-
		(5-fluoropyrimidin-2-yl)propane-2-
		sulfonamide and (1S,1R)-1-
		((tert-butyldimethylsilyl)oxy)-1-
		(5-fluoropyrimidin-2-yl)propane-2-
		sulfonamide.
		LCMS-ESI (pos.) mz: 350.1 (M + H) + .

TABLE 14

Example	Reagents	Structure, Name and Data
363.1	5-ethylfuran-2- carboxylic acid (Matrix Scientific).
		4-(2,6-dimethoxyphenyl)-5-
		(5-ethylfuran-2-y1)-4H-1,2,4-
		triazol-3-amine
		LCMS-ESI (pos.) m/z: 315.0 (M + H) + .
363.2	5-(tert-butylfuran)-2- carboxylic acid (Chembridge).
		5-(5-(tert-butyl)furan-2-y1)-
		4-(2,6-dimethoxyphenyl)-4H-
		1,2,4-triazol-3-amine.
		LCMS-ESI (pos.) m/z: 343.2 (M + H) + .
363.3	5-(methoxymethyl)-2- furoic acid (Sigma- Aldrich).
		4-(2,6-dimethoxyphenyl)-5-
		(5-(methoxymethyl)furan-2-
		yl)-4H-1,2,4-triazol-3-amine
		LCMS-ESI (pos.) m/z: 331.2 (M + H) + .
363.4	3-methyl-2-furoic acid (Sigma-Aldrich).
		4-(2,6-dimethoxyphenyl)-5-
		(3-methylfuran-2-yl)-4H-
		1,2,4-triazol-3-amine.
		LCMS-ESI (pos.) m/z: 301.1 (M + H) + .

TABLE 15

Example	Reagents	Structure, Name and Data
364.1	4-(2,6- dimethoxyphenyl)- 5-(5-methylfuran- 2-yl)- 4H-1,2,4- triazol-3-amine, Example 362.0.
		3-bromo-4-(2,6-dimethoxyphenyl)-
		5-(5-methylfuran-2-yl)-4H-
		1,2,4-triazole.
		LCMS-ESI (pos.) m/z: 364.0 (M + H) + .
364.2	4-(2,6- dimethoxyphenyl)- 5-(5-ethylfuran- 2-yl)-4H-1,2,4- triazol-3-amine, Example 363.1.
		3-bromo-4-(2,6-dimethoxyphenyl)-
		5-(5-ethylfuran-2-yl)-4H-1,2,4-triazole.
		LCMS-ESI (pos.) m/z: 378.0 (M + H) + .
364.3	4-(2,6- dimethoxyphenyl)- 5-(furan-2-yl)- 4H-1,2,4-triazol- 3-amine, Example 362.03.
		3-bromo-4-(2,6-dimethoxyphenyl)-
		5-(furan-2-yl)-4H-1,2,4-triazole.
		LCMS-ESI (pos.) m/z: 350.0 (M + H) + .

TABLE 16

Example	Reagents	Structure, Name and Data
371.1	2-chloro-5-fluoro-pyrimidine.
		(2S,3R)-3-(5-fluoropyrimidin-2-yl)butane-
		2-sulfonamide.
		LCMS ESI (pos.) m/z:
		234.4 (M + H) + .
371.2	2-bromo-5-methylpyrazine. The title compound was the first isomer to elute under the following SFC conditions: Run on Thar 200 SFC with 250 × 30 mm AD-H column with 20 mL/min MeOH (+ 20 mM NH 3 ) + 80 g/min CO 2 , 20% co-solvent at 100 g/min. Temperature. = 29° C., Outlet pressure = 100 bar, Wavelength = 271 nm. Injected 1.0 mL of 550 mg of the enantiomerically enriched product dissolved in 20 mL MeOH:DCM, 15:5; c = 27.5 mg/mL and
	27.5 mg per injection. Cycle time 5.0	(2S,3R)-3-(5-methylpyrazin-2-yl)butane-2-
	min, run time 13 min. \	sulfonamide.
		1 H NMR (400 MHz, DMSO-d 6 ) δ 8.46 (d, J =
		6.5 Hz, 2H), 6.84 (s, 2H), 3.63 (qd, J =
		7.0, 4.3 Hz, 1H), 3.44 (qd, J = 7.0, 4.3 Hz,
		1H), 2.47 (s, 3H), 1.31 (d, J = 7.0 Hz, 3H),
		1.23 (d, J = 7.0 Hz, 3H). LCMS (ESI, pos.)
		m/z; 230.0 (M + H) + .
371.3	2-bromo-5-methylpyrazine. The title compound is the enantioiner of Example 371.2. Example 371.3 is the second isomer to elute from the AD-H column on subjecting the cnantiomerically enriched product to the SFC conditions described in Example 371.2.
		(2R,3S)-3-(5-methylpyrazin-2-yl)butane-2-
		sulfonamide.
		LCMS-ESI (pos.) m/z: 230.0 (M + H) + .
371.4	2-chloro-5-chloro-pyrimidine. Recrystallization: Example 371.4 (38 g, 90% ce) was dissolved in IPA (400 mL) at 70° C..
		(2S,3R)-3-(5-chloropyrimidin-2-yl)butane-
		2-sulfonamide.
		1 H NMR (400 MHz, DMSO-d 6 ) δ 8.93-
		8.85 (m, 2H), 6.86 (d, J = 4.0 Hz, 2H),
		3.73-3.59 (m, 2H), 1.31 (dt, J = 7.3, 2.4 Hz,
		3H), 1.25-1.19 (m, 3H). LCMS (ESI
		pos.) m/z: 250.2 (M + H) + .
371.5	2-bromo-5-methoxypyrazine.
		(2S,3R)-3-(5-methoxypyrazin-2-yl)butane-
		2-sulfonamide.
		1 H NMR (400 MHz, DMSO-d 6 ) δ 8.26 (d,
		J = 1.4 Hz, 1H), 8.12 (d, J = 1.4 Hz, 1H),
		6.84 (s, 2H), 3.90 (d, J = 1.5 Hz, 3H), 3.62
		(dd, J = 7.1, 4.3 Hz, 1H), 3.42-3.38 (m,
		1H), 1.32 (d, J = 1.5 Hz, 3H), 1.23-1.21
		(m, 3H). LCMS (ESI pos.) m/z: 246.2
		(M + H) + .

TABLE 17

Example	Reagents	Structure, Name and Data
372.1	4,6-dimethoxypyrimidin-5- amine (D-L Chiral chemicals).
		5-isothiocyanato-4,6-dimethoxypyrimidine.
		LCMS-ESI (pos.) m/z: 198.1 (M + H) + .
372.2	2-methoxyaniline (Aldrich).
		1-isothiocyanato-2-methoxybenzene.
		1 H NMR (400 MHz, DMSO-d) δ 3.89 (s, 3H), 6.96
		(td, J = 7.68, 1.27 Hz, 1H), 7.16 (dd, J = 8.31, 1.27 Hz,
		1H), 7.30 (dd, J = 7.92, 1.66 Hz, 1H), 7.31-7.37 (m, 1H).
372.3	3,5-difluoropyridin-4-amine (commercially available from Ark Pharm Inc, Libertyville, IL).
		3,5-difluoro-4-isothiocyanatopyridine.
		LCMS-ESI (pos.) m/z: 173.0 (M + H) + .

TABLE 18

Example	Reagents	Structure, Name and Data
373.1	2-bromo-5-methyl pyrazine (NOWA pharmaceuticals).
		(1R,2S)-1-methoxy-1-(5-methylpyrazin-2-
		yl)propane-2-sulfonamide.
		LCMS-ESI (pos.) m/z: 246.2 (M + H) + .
373.2	2-chloro-5- fluoropyrimidine (Oakwood).
		(1R,2S)-1-(5-fluoropyrimidin-2-yl)-1-
		methoxypropane-2-sulfonamide.
		LCMS-ESI (pos.) m/z: 250.1 (M + H) + .
373.3	2,5-dichloropyrimidine (Oakwood).
		(1R,2S)-1-(5-chloropyrimidin-2-yl)-1-
		methoxypropane-2-sulfonamide.
		LCMS-ESI (pos.) m/z: 265.9 (M + H) + .
373.4	2-chloropyrimidine (Acros Organics).
		(1R,2S)-1-methoxy-1-(pyrimidin-2-yl)propane-2-
		sulfonamide.
		LCMS-ESI (pos.) m/z: 232.0 (M + H) + .
373.5	2-chloro-5- fluoropyrimidine (Oakwood) EtOTf used in place of MeOTf in Example 83.5.
		(1R,2S)-1-ethoxy-1-(5-fluoropyrimidin-2-
		yl)propane-2-sulfonamide.
		LCMS-ESI (pos.) m/z: 264.0(M + H) + .
373.6	2-chloro-5- fluoropyrimidine (Oakwood) TBSOTf used in place of MeOTf in Example 83.5.
		(1R,2S)-1-((tert-butyldimethylsilyl)oxy)-1-(5-
		fluoropyrimidin-2-yl)propane-2-sulfonamide.
		LCMS-ESI (pos.) m/z: 350.1 (M + H) + .
373.7	2,5-dichloropyrimidine (Oakwood), EtOTf used in place of MeOTf in Example 83.05.
		(1R,2S)-1-(5-chloropyrimidin-2-yl)-1-
		ethoxypropane-2-sulfonamide.
		LCMS-ESI (pos.) m/z: 279.9.

TABLE 19

Example	Reagents	Structure, Name and Data
374.1	2-chloro-5-chloro- pyrimidine.
		(1S,2S)-1-(5-chloropyrimidin-2-yl)-1-
		isopropoxypropane-2-sulfonamide.
		LCMS ESI (pos.) m/z: 294.2 (M + H) + .

TABLE 20

Example	Reagents	Structure, Name and Data
384.0	2-5-isothiocyanato-4,6- dimethoxypyrimidine (Example 372.1), 5- methylfuran-2- carbohydrazide, and (1R,2S)-1-(5- chloropyrimidin-2-yl)- 1-methoxypropane-2- sulfonamide Example 373.3.
		(1R,2S)-1-(5-chloro-2-pyrimidinyl)-N-(4-(4,6-dimethoxy-
		5-pyrimidinyl)-5-(5-methyl-2-furanyl)-4H-1,2,4-triazol-3-
		yl)-1-methoxy-2-propanesulfonamide.
		1 H NMR (500 MHz, DMSO-d 6 ) δ 13.35 (br s, 1 H) 8.93 (s,
		2 H) 8.73 (s, 1 H) 6.43 (br d, J = 3.37 Hz, 1 H) 6.22 (br d,
		J = 2.60 Hz, 1 H) 4.80 (br d, J = 3.89 Hz, 1 H) 3.94 (br s, 3
		H) 3.92 (br s, 3 H) 3.43 (br dd, J = 6.75, 4.15 Hz, 1 H) 3.14
		(s, 3 H) 2.21 (s, 3 H) 1.16 (br d, J = 7.01 Hz, 3 H). LCMS-
		ESI (pos.) m/z: 551.1 (M + H) + .
385.0	2-isothiocyanato-1,3- dimethoxypropane, Example 385.1, 5- methylfuran-2- carbohydrazide, and (1R,2S)-1-(5- chloropyrimidin-2-yl)- 1-methoxypropane-2- sulfonamide Example 373.3.
		(1R,2S)-1-(5-chloro-2-pyrimidinyl)-1-methoxy-N-(4-(1-
		(methoxymethyl)cyclopropyl)-5-(5-methyl-2-furanyl)-4H-
		1,2,4-triazol-3-yl)-2-propanesulfonamide.
		1 H NMR (500 MHz, DMSO-d 6 ) δ 12.94 (br s, 1 H) 8.94 (s,
		2 H) 6.34 (br d, J = 2.59 Hz, 1 H) 4.98 (br d, J = 3.63 Hz, 1
		H) 4.07 (br d, J = 3.89 Hz, 1 H) 2.85-3.68 (m, 11 H) 2.35
		(s, 3 H) 0.74-1.58 (m, 5 H). LCMS-ESI (pos.) m/z: 495.1
		(M + H) + .
386.0	(1R,2S)-1-(5- chloropyrimidin-2-yl)- 1-methoxypropane-2- sulfonamide, Example 373.3, 2-methoxyethyl isothiocyanate (commercially available from Sigma Aldrich),
	and 5-methylfuran-2-	(1R,2S)-1-(5-chloropyrimidin-2-yl)-1-methoxy-N-(4-(2-
	carbohydrazide	methoxyethyl)-5-(5-methylfuran-2-yl)-4H-1,2,4-triazol-3-
	(commercially available	yl)propane-2-sulfonamide.
	from Bellen).	1 H NMR (400 MHz, DMSO-d 6 ) δ 13.10 (s, 1H), 8.91 (s,
		2H), 7.06 (s, 1H), 6.35 (s, 1H), 4.87 (d, J = 3.5 Hz, 1H),
		4.03 (s, 2H), 3.64-3.52 (m, 3H), 3.18 (s, 3H), 3.15-3.08
		(m, 3H), 2.37 (s, 3H), 1.29 (d, J = 6.6 Hz, 3H). LCMS-ESI
		(pos.) m/z: 471.0 (M + H) + .
387.0	5-methylfuran-2- carbohydrazide (commercially available from Bellen), (1R,2S)- 1-(5-chloropyrimidin-2- yl)-1-methoxypropane- 2-sulfonamide, Example 373.3, and 2- isothiocyanato-1,3- dimethoxypropane, Example 385.1.
		(1R,2S)-1-(5-chloro-2-pyrimidinyl)-N-(4-(1,3-dimethoxy-
		2-propanyl)-5-(5-methyl-2-furanyl)-4H-1,2,4-triazol-3-yl)-
		1-methoxy-2-propanesulfonamide.
		1 H NMR (600 MHz, DMSO-d 6 ) δ 8.96 (s, 2 H) 6.90 (br d,
		J = 2.02 Hz, 1 H) 6.34 (d, J = 2.80 Hz, 1 H) 4.94 (d, J = 3.89
		Hz, 1 H) 4.71-4.80 (m, 1 H) 3.95-4.10 (m, 2 H) 3.54-
		3.66 (m, 3 H) 3.22 (s, 3 H) 3.20 (s, 3 H) 3.18 (s, 3 H) 2.37
		(s, 3 H) 1.26 (d, J = 7.01 Hz, 3 H). LCMS-ESI (pos.) m/z:
		515.2 (M + H) + .
388.0	5-methylfuran-2- carbohydrazide (commericially available from Chembridge, CA, USA), 2- isothiocyanatopropane (comercially avilable
	from Sigma-Aldrich	(1R,2S)-1-(5-chloropyrimidin-2-yl)-N-(4-isopropyl-5-(5-
	Inc.), and (1R,2S)-1-(5-	methylfuran-2-yl)-4H-1,2,4-triazol-3-yl)-1-
	chloropyrimidin-2-yl)-	methoxypropane-2-sulfonamide.
	1-methoxypropane-2-	1 H NMR (600 MHz, DMSO-d6) δ 8.88-8.98 (m, 2 H)
	sulfonamide (Example	6.86-6.94 (m, 1 H) 6.30-6.39 (m, 1 H) 4.88-4.94 (m, 1
	373.3).	H) 4.53-4.63 (m, 1 H) 3.56-3.62 (m, 1 H) 3.12-3.14 (m,
		3 H) 2.36-2.40 (m, 3 H) 1.35-1.44 (m, 6 H) 1.24-1.31
		(m, 3 H). LCMS-ESI (pos.) m/z: 455.2 (M + H) + .

TABLE 21

Example	Reagents	Structure, Name and Data
385.2	1-(methoxymethyl) cyclopropanamine hydrochloride (J&W Pharm Lab), DIEA (Sigma Aldrich).
		1-isothiocyanato-1-
		(methoxymethyl)cyclopropane.
		1 H NMR (400 MHz, CDCl 3 ) δ 3.47 (s, 2H),
		3.43 (s, 3H), 1.06-1.16 (m, 2H), 0.81-0.94
		(m, 2H).

TABLE 22

Example	Reagents	Structure, Name and Data
389.2	(3R)-oxan-3-amine hydrochloride (commerically available from Accela ChemBio Inc).
		(R)-3-isothiocyanatotetrahydro-2H-pyran.
		LCMS-ESI (pos.) m/z: 143.8 (M + H) + .

TABLE 23

Example	Reagents	Structure, Name and Data
390.0	5-methylfuran-2-carbohydrazide (commericially available from Enamine), (S)-3- isothiocyanatotetrahydro-2H- pyran (Example 389.1), and (1R,2S)-1-(5-chloropyrimidin-2- yl)-1-methoxypropane-2- sulfonamide (Example 373.3).
		(1R,2S)-1-(5-chloropyrimidin-2-yl)-1-methoxy-N-(5-
		(5-methylfuran-2-yl)-4-((S)-tetrahydro-2H-pyran-3-yl)-
		4H-1,2,4-triazol-3-yl)propane-2-sulfonamide.
		1 H NMR (600 MHz, DMSO-d 6 ) δ 13.20 (s, 1H), 8.95
		(s, 1H), 6.97 (d, J = 3.27 Hz, 1H), 6.38 (d, J = 2.80 Hz,
		1H), 4.94 (d, J = 3.74 Hz, 1H), 4.28-4.35 (m, 1H), 3.98
		(t, J = 10.67 Hz, 1H), 3.80-3.91 (m, 2H), 3.63 (s, 1H),
		3.45-3.52 (m, 1H), 3.20-3.27 (m, 1H), 3.11 (s, 3H),
		2.40 (s, 3H), 2.30 (br dd, J = 4.13, 12.53 Hz, 1H), 1.88
		(br d, J = 11.37 Hz, 1H), 1.71-1.77 (m, 1H), 1.59-1.70
		(m, 1H), 1.28 (d, J = 7.01 Hz, 3H). LCMS-ESI (pos.)
		m/z: 497.2 (M + H) +
391.0	5-methylfuran-2-carbohydrazide (commericially available from Enamine), (R)-3- isothiocyanatotetrahydro-2H- pyran (Example 389.2), and (1R,2S)-1-(5-chloropyrimidin-2- yl)-1-methoxypropane-2- sulfonamide (Example 373.3).
		(1R,2S)-1-(5-chloropyrimidin-2-yl)-1-methoxy-N-(5-
		(5-methylfuran-2-yl)-4-((R)-tetrahydro-2H-pyran-3-
		yl)-4H-1,2,4-triazol-3-yl)propane-2-sulfonamide.
		1 H NMR (600 MHz, DMSO-d6) δ 8.93 (s, 2H), 6.88
		(br s, 1H), 6.35 (d, J = 2.65 Hz, 1H), 4.90 (d, J = 4.20 Hz,
		1H), 4.22-4.29 (m, 1H), 3.93 (t, J = 10.59 Hz, 1H), 3.70-
		3.85 (m, 2H), 3.63 (s, 1H), 3.15-3.25 (m, 2H), 3.13 (s,
		3H), 2.38 (s, 3H), 2.24-2.36 (m, 1H), 1.78-1.86 (m,
		1H), 1.68-1.75 (m, 1H), 1.51-1.67 (m, 1H), 1.27 (d,
		J = 7.01 Hz, 3H). LCMS-ESI (pos.) m/z: 497.2 (M + H) +

TABLE 24

Example	Reagents	Structure, Name and Data
392.0	5-methylfuran-2- carbohydrazide (commercially available from Bellen), (1S,2S)-1- (5-chloropyrimidin-2- yl)-1- isopropoxypropane-2- sulfonamide (Example 374.1) and 2- isothiocyanato-1,3- dimethoxypropane (Example 385.1).
		(1S,2S)-1-(5-chloro-2-pyrimidinyl)-N-(4-(1,3-dimethoxy-2-
		propanyl)-5-(5-methyl-2-furanyl)-4H-1,2,4-triazol-3-yl)-1-(2-
		propanyloxy)-2-propanesulfonamide.
		1 H NMR (400 MHz, CDCl 3 ) δ 12.02 (br s, 1 H) 8.74 (s, 2 H)
		6.93 (d, J = 3.32 Hz, 1 H) 6.16 (dd, J = 3.32, 0.93 Hz, 1 H) 4.91 (d,
		J = 3.84 Hz, 1 H) 4.79 (tt, J = 8.40, 5.29 Hz, 1 H) 4.18 (t, J = 9.28
		Hz, 1 H) 4.10 (dd, J = 9.90, 8.24 Hz, 1 H) 3.82 (qd, J = 7.03, 3.89
		Hz, 1 H) 3.72 (ddd, J = 13.86, 9.98, 5.29 Hz, 2 H) 3.56 (m, 1 H)
		3.35 (s, 3 H) 3.31 (s, 3 H) 2.41 (s, 3 H) 1.57 (d, J = 7.05 Hz, 3 H)
		1.10 (d, J = 6.01 Hz, 3 H) 0.95 (d, J = 6.12 Hz, 3 H). LCMS-ESI
		(pos.) m/z: 543.0 (M + H) + .
393.0	(2S,3R)-3-(5- fluoropyrimidin-2- yl)butane-2-sulfonamide (Example 371.1), 2-5- isothiocyanato-4,6- dimethoxypyrimidine (Example 372.1), and 5- methylfuran-2- carbohydrazide (commercially available from Bellen).
		(2S,3R)-N-(4-(4,6-dimethoxy-5-pyrimidinyl)-5-(5-methyl-2-
		furanyl)-4H-1,2,4-triazol-3-yl)-3-(5-fluoro-2-pyrimidinyl)-2-
		butanesulfonamide.
		1 H NMR (400 MHz, DMSO-d 6 ) δ 13.38 (br s, 1H), 8.82 (d,
		J = 0.8 Hz, 2H), 8.72 (s, 1H), 6.41 (d, J = 3.1 Hz, 1H), 6.21 (dd,
		J = 0.8, 3.3 Hz, 1H), 3.93-3.88 (m, 6H), 3.73-3.66 (m, 1H),
		3.65-3.57 (m, 1H), 2.21 (s, 3H), 1.26 (d, J = 7.0 Hz, 3H), 1.12
		(d, J = 7.0 Hz, 3H). LCMS-ESI (pos.) m/z: 519.0 (M + H) + .
394.0	(2S,3R)-3-(5- fluoropyrimidin-2- yl)butane-2-sulfonamide (Example 371.1), 2-5- isothiocyanato-4,6- dimethoxypyrimidine (Example 372.1), and 5- bromofuran-2- carbohydrazide (commercially available from ChemBridge).
		(2S,3R)-N-(5-(5-bromo-2-furanyl)-4-(4,6-dimethoxy-5-
		pyrimidinyl)-4H-1,2,4-triazol-3-yl)-3-(5-fluoro-2-pyrimidinyl)-
		2-butanesulfonamide.
		1 H NMR (400 MHz, DMSO-d 6 ) δ 13.55 (s, 1H), 8.82 (d, J = 0.6
		Hz, 2H), 8.74 (s, 1H), 6.76-6.71 (m, 2H), 3.93-3.90 (m, 6H),
		3.71-3.64 (m, 1H), 3.62-3.55 (m, 1H), 1.25 (d, J = 7.0 Hz, 3H),
		1.13 (d, J = 6.8 Hz, 3H). LCMS-ESI (pos.) m/z: 582.8 (M + H) + .
396.0	5-methylfuran-2- carbohydrazide (commercially available from Bellen), (1S,2S)-1- (5-chloropyrimidin-2- yl)-1- isopropoxypropane-2- sulfonamide (Example 374.1), and isothiocyanatocyclopropane (commercially available from Sigma Aldrich).
		(1S,2S)-1-(5-chloro-2-pyrimidinyl)-N-(4-cyclopropyl-5-(5-
		methyl-2-furanyl)-4H-1,2,4-triazol-3-yl)-1-(2-propanyloxy)-2-
		propanesulfonamide.
		1 H NMR (600 MHz, DMSO-d 6 ) δ 12.74 (s, 1 H) 8.96 (s, 2 H)
		7.10 (d, J = 3.27 Hz, 1 H) 6.37 (dd, J = 3.35, 1.01 Hz, 1 H) 4.86 (d,
		J = 7.40 Hz, 1 H) 3.57 (quin, J = 7.18 Hz, 1 H) 3.30 (dt, J = 12.20,
		6.08 Hz, 1 H) 3.01-3.11 (m, 1 H) 2.37 (s, 3 H) 1.02-1.15 (m,
		6 H) 0.97 (d, J = 6.07 Hz, 3 H) 0.71-0.80 (m, 1 H) 0.66 (d,
		J = 6.15 Hz, 3 H). LCMS-ESI (pos.) m/z: 481.0 (M + H) + .
398.0	(2S,3R)-3-(5- chloropyrimidin-2- yl)butane-2-sulfonamide (Example 371.4), (S)-2- isothiocyanato-1- methoxypropane (Example 398.1), and 5- methylfuran-2- carbohydrazide (commercially available from Bellen).
		(2S,3R)-3-(5-chloro-2-pyrimidinyl)-N-(4-((2S)-1-methoxy-2-
		propanyl)-5-(5-methyl-2-furanyl)-4H-1,2,4-triazol-3-yl)-2-
		butanesulfonamide.
		1 H NMR (600 MHz, DMSO-d 6 ) δ 13.09 (br s, 1 H) 8.87 (s, 2 H)
		6.94 (br s, 1 H) 6.35 (d, J = 2.41 Hz, 1 H) 4.58-4.69 (m, 1 H)
		3.94 (br t, J = 9.54 Hz, 1 H) 3.67-3.78 (m, 2 H) 3.43 (dd,
		J = 10.08, 4.87 Hz, 1 H) 3.14 (s, 3 H) 2.37 (s, 3 H) 1.39 (d,
		J = 7.01 Hz, 3 H) 1.35 (d, J = 7.01 Hz, 3 H) 1.24 (d, J = 6.85 Hz, 3
		H). LCMS-ESI (pos.) m/z: 469.0 (M + H) + .
400.0	2-5-isothiocyanato-4,6- dimethoxypyrimidine (Example 372.1), 5- methylfuran-2- carbohydrazide (commercially available from Bellen), and (2S,3R)-3-(5- chloropyridin-2- yl)butane-2-sulfonamide (Example 375.0).
		(2S,3R)-3-(5-chloro-2-pyridinyl)-N-(4-(4,6-dimethoxy-5-
		pyrimidinyl)-5-(5-methyl-2-furanyl)-4H-1,2,4-triazol-3-yl)-2-
		butanesulfonamide.
		1 H NMR (600 MHz, DMSO-d 6 ) δ13.45 (s, 1 H) 8.74 (s, 1 H)
		8.54 (d, J = 2.34 Hz, 1 H) 7.86 (dd, J = 8.41, 2.57 Hz, 1 H) 7.30 (d,
		J = 8.41 Hz, 1 H) 6.43 (d, J = 3.43 Hz, 1 H) 6.23 (dd, J = 3.43, 0.93
		Hz, 1 H) 3.90 (s, 3 H) 3.90 (s, 3 H) 3.58 (qd, J = 7.03, 3.43 Hz, 1
		H) 3.41 (qd, J = 6.92, 3.46 Hz, 1 H) 2.21 (s, 3 H) 1.22 (d, J = 7.08
		Hz, 3 H) 1.08 (d, J = 7.01 Hz, 3 H). LCMS-ESI (pos.) m/z: 534.0
		(M + H) + .
401.0	2-5-isothiocyanato-4,6- dimethoxypyrimidine (Example 372.1), 5- methylfuran-2- carbohydrazide (commercially available from Bellen), and (1S,2S)-1-(5- chloropyrimidin-2-yl)-1- isopropoxypropane-2- sulfonamide (Example 374.1)
		(1S,2S)-N-(4-(4,6-dimethoxypyrimidin-5-yl)-5-(5-methylfuran-
		2-yl)-4H-1,2,4-triazol-3-yl)-1-isopropoxy-1-(5-
		methylpyrimidin-2-yl)propane-2-sulfonamide.
		1 H NMR (400 MHz, CDCl 3 ) δ 1.00 (d, J = 6.22 Hz, 3 H) 1.12 (d,
		J = 6.01 Hz, 3 H) 1.52 (d, J = 7.05 Hz, 3 H) 2.30 (s, 3 H) 2.36 (s,
		3H) 3.59 (s, 1 H) 3.68-3.78 (m, 1 H) 3.93 (s, 3 H) 4.02 (s, 3 H)
		4.88 (d, J = 3.52 Hz, 1 H) 5.97-6.04 (m, 1 H) 6.16 (s, 1 H) 8.54
		(s, 1 H) 8.65 (s, 2 H), 13.10 (br. s., 1 H). LCMS-ESI (pos.) m/z:
		559.2 (M + H) + .

TABLE 25

402.0	3-bromo-4-(2,6-dimethoxyphenyl)- 5-(5-methylfuran-2-yl)-4H-1,2,4- triazole (Example 364.1) and 4- hydroxytetrahydro-2H-pyran-3- sulfonamide (Example 402.1). The compound was purified by SFC chromatography: Chiralcel OZ-H, 2 × 25 cm, 40% MeOH Flow rate: 80 mL/min, UV Detector Wavelength: 277 nm. This was the first isomer to elute under these conditions.
		(3R,4S)-N-(4-(2,6-dimethoxyphenyl)-5-(5-methyl-2-
		furanyl)-4H-1,2,4-triazol-3-yl)-4-hydroxytetrahydro-
		2H-pyran-3-sulfonamide or (3S,4R)-N-(4-(2,6-
		dimethoxyphenyl)-5-(5-methyl-2-furanyl)-4H-1,2,4-
		triazol-3-yl)-4-hydroxytetrahydro-2H-pyran-3-
		sulfonamide or (3R,4R)-N-(4-(2,6-dimethoxyphenyl)-
		5-(5-methyl-2-furanyl)-4H-1,2,4-triazol-3-yl)-4-
		hydroxytetrahydro-2H-pyran-3-sulfonamide or
		(3S,4S)-N-(4-(2,6-dimethoxyphenyl)-5-(5-methyl-2-
		furanyl)-4H-1,2,4-triazol-3-yl)-4-hydroxytetrahydro-
		2H-pyran-3-sulfonamide.
		1 H NMR (500 MHz, CDCl 3 ) δ 10.59-10.98 (m, 1 H)
		7.45-7.54 (m, 1 H) 6.65-6.75 (m, 2 H) 5.92-5.97
		(m, 1 H) 5.86-5.92 (m, 1 H) 4.22-4.32 (m, 1 H) 4.06-
		4.16 (m, 1 H) 3.93-4.01 (m, 1 H) 3.78-3.82 (m, 6
		H) 3.37-3.49 (m, 2 H) 3.07-3.15 (m, 1 H) 2.31-2.36
		(m, 3 H) 1.98-2.04 (m, 1 H) 1.57-1.71 (m, 2 H)
		LCMS-ESI (pos.) m/z: 465.2 (M + H) + .
403.0	3-bromo-4-(2,6-dimethoxyphenyl)- 5-(5-methylfuran-2-yl)-4H-1,2,4- triazole (Example 364.1) and 4- hydroxytetrahydro-2H-pyran-3- sulfonamide (Example 402.1). The compound was purified by SFC chromatography: Chiralcel OZ-H, 2 × 25 cm, 40% MeOH, Flow rate: 80 mL/min, UV Detector Wavelength: 277 nm. This was the second isomer to elute under these conditions.
		(3R,4S)-N-(4-(2,6-dimethoxyphenyl)-5-(5-methyl-2-
		furanyl)-4H-1,2,4-triazol-3-yl)-4-hydroxytetrahydro-
		2H-pyran-3-sulfonamide or (3S,4R)-N-(4-(2,6-
		dimethoxyphenyl)-5-(5-methyl-2-furanyl)-4H-1,2,4-
		triazol-3-yl)-4-hydroxytetrahydro-2H-pyran-3-
		sulfonamide or (3R,4R)-N-(4-(2,6-dimethoxyphenyl)-
		5-(5-methyl-2-furanyl)-4H-1,2,4-triazol-3-yl)-4-
		hydroxytetrahydro-2H-pyran-3-sulfonamide or
		(3S,4S)-N-(4-(2,6-dimethoxyphenyl)-5-(5-methyl-2-
		furanyl)-4H-1,2,4-triazol-3-yl)-4-hydroxytetrahydro-
		2H-pyran-3-sulfonamide.
		1 H NMR (500 MHz, CDCl 3 ) δ 10.57-10.96 (m, 1 H)
		7.44-7.55 (m, 1 H) 6.65-6.76 (m, 2 H) 5.93-6.00
		(m, 1 H) 5.86-5.91 (m, 1 H) 4.23-4.33 (m, 1 H) 4.06-
		4.20 (m, 1 H) 3.97-4.04 (m, 1 H) 3.79-3.82 (m, 3
		H) 3.77-3.79 (m, 3 H) 3.36-3.50 (m, 2 H) 3.06-3.14
		(m, 1 H) 2.31-2.35 (m, 3 H) 1.98-2.05 (m, 1 H) 1.60-
		1.70 (m, 1 H) 1.23-1.36 (m, 1 H). LCMS-ESI (pos.)
		m/z: 465.2 (M + H) + .
404.0	3-bromo-4-(2,6-dimethoxyphenyl)- 5-(5-methylfuran-2-yl)-4H-1,2,4- triazole (Example 364.1) and 4- hydroxytetrahydro-2H-pyran-3- sulfonamide (Example 402.1). The compound was purified by SFC chromatography: Chiralcel OZ-H, 2 × 25 cm, 40% MeOH, Flow rate: 80 mL/min, UV Detector Wavelength: 277 nm. This was the third isomer to elute under these conditions.
		(3R,4S)-N-(4-(2,6-dimethoxyphenyl)-5-(5-methyl-2-
		furanyl)-4H-1,2,4-triazol-3-yl)-4-hydroxytetrahydro-
		2H-pyran-3-sulfonamide or (3S,4R)-N-(4-(2,6-
		dimethoxyphenyl)-5-(5-methyl-2-furanyl)-4H-1,2,4-
		triazol-3-yl)-4-hydroxytetrahydro-2H-pyran-3-
		sulfonamide or (3R,4R)-N-(4-(2,6-dimethoxyphenyl)-
		5-(5-methyl-2-furanyl)-4H-1,2,4-triazol-3-yl)-4-
		hydroxytetrahydro-2H-pyran-3-sulfonamide or
		(3S,4S)-N-(4-(2,6-dimethoxyphenyl)-5-(5-methyl-2-
		furanyl)-4H-1,2,4-triazol-3-yl)-4-hydroxytetrahydro-
		2H-pyran-3-sulfonamide.
		1 H NMR (500 MHz, CDCl 3 ) δ 10.57-10.96 (m, 1 H)
		7.44-7.55 (m, 1 H) 6.65-6.76 (m, 2 H) 5.93-6.00
		(m, 1 H) 5.86-5.91 (m, 1 H) 4.23-4.33 (m, 1 H) 4.06-
		4.20 (m, 1 H) 3.97-4.04 (m, 1 H) 3.79-3.82 (m, 3
		H) 3.77-3.79 (m, 3 H) 3.36-3.50 (m, 2 H) 3.06-3.14
		(m, 1 H) 2.31-2.35 (m, 3 H) 1.98-2.05 (m, 1 H) 1.60-
		1.70 (m, 1 H) 1.23-1.36 (m, 1 H). LCMS-ESI
		(pos.) m/z: 465.2 (M + H) + .
405.0	3-bromo-4-(2,6-dimethoxyphenyl)- 5-(5-methylfuran-2-yl)-4H-1,2,4- triazole (Example 364.1) and 4- hydroxytetrahydro-2H-pyran-3- sulfonamide (Example 402.1). The compound was purified by SFC chromatography: Chiralcel OZ-H, 2 × 25 cm, 40% MeOH, Flow rate: 80 mL/min, UV Detector Wavelength: 277 nm. This was the fourth isomer to elute under these conditions.
		(3R,4S)-N-(4-(2,6-dimethoxyphenyl)-5-(5-methyl-2-
		furanyl)-4H-1,2,4-triazol-3-yl)-4-hydroxytetrahydro-
		2H-pyran-3-sulfonamide or (3S,4R)-N-(4-(2,6-
		dimethoxyphenyl)-5-(5-methyl-2-furanyl)-4H-1,2,4-
		triazol-3-yl)-4-hydroxytetrahydro-2H-pyran-3-
		sulfonamide or (3R,4R)-N-(4-(2,6-dimethoxyphenyl)-
		5-(5-methyl-2-furanyl)-4H-1,2,4-triazol-3-yl)-4-
		hydroxytetrahydro-2H-pyran-3-sulfonamide or
		(3S,4S)-N-(4-(2,6-dimethoxyphenyl)-5-(5-methyl-2-
		furanyl)-4H-1,2,4-triazol-3-yl)-4-hydroxytetrahydro-
		2H-pyran-3-sulfonamide.
		1 H NMR (500 MHz, CDCl 3 ) δ 10.71-11.00 (m, 1 H)
		7.43-7.57 (m, 1 H) 6.63-6.82 (m, 2 H) 5.85-6.00
		(m, 2 H) 4.50-4.61 (m, 1 H) 4.09 (dd, J = 10.8, 4.1 Hz,
		1 H) 3.66-3.93 (m, 8 H) 3.25 (dd, J = 11.2, 4.0 Hz, 1
		H) 2.31-2.35 (m, 3 H) 1.71-1.85 (m, 2 H). LCMS-
		ESI (pos.) m/z: 465.2 (M + H) + .
406.0	3-bromo-4-(2,6-dimethoxyphenyl)- 5-(5-methylfuran-2-yl)-4H-1,2,4- triazole (Example 364.1) and (1S,3R,4R)-3,4- dihydroxycyclohexane-1- sulfonamide and (1R,3R,4R)-3,4- dihydroxycyclohexane-1- sulfonamide (Example 406.1). The final material was purified by SFC. Column: Chiralpak AD-H, 2 × 25 cm. Mobile Phase: 40% IPA. Flow rate: 80 mL/min. UV Detector Wavelength: 277 nm This was the first isomer to elute under these conditions.
		(1R,3R,4R)-N-(4-(2,6-dimethoxyphenyl)-5-(5-
		methylfuran-2-yl)-4H-1,2,4-triazol-3-yl)-3,4-
		dihydroxycyclohexane-1-sulfonamide OR (1S,3R,4R)-
		N-(4-(2,6-dimethoxyphenyl)-5-(5-methylfuran-2-yl)-
		4H-1,2,4-triazol-3-yl)-3,4-dihydroxycyclohexane-1-
		sulfonamide.
		1 H NMR (500 MHz, DMSO-d 6 ) δ 12.92-13.07 (m, 1
		H) 7.47-7.65 (m, 1 H) 6.84-6.99 (m, 2 H) 6.06-6.18
		(m, 1 H) 5.71-5.94 (m, 1 H) 4.69-4.81 (m, 1 H) 4.52-
		4.63 (m, 1 H) 3.71-3.77 (m, 6 H) 3.64-3.70 (m, 1
		H) 3.46-3.53 (m, 1 H) 2.91-3.02 (m, 1 H) 2.23-2.27
		(m, 3 H) 1.73-1.80 (m, 2 H) 1.59-1.70 (m, 3 H) 1.48-
		1.57 (m, 1 H). LCMS-ESI (pos.) m/z: 479.2 (M + H) + .
407.0	3-bromo-4-(2,6-dimethoxyphenyl)- 5-(5-methylfuran-2-yl)-4H-1,2,4- triazole (Example 364.1) and (1S,3R,4R)-3,4- dihydroxycyclohexane-1- sulfonamide and (1R,3R,4R)-3,4- dihydroxycyclohexane-1- sulfonamide (Example 406.1). The final material was purified by SFC. Column: Chiralpak AD-H, 2 × 25 cm. Mobile Phase: 40% IPA Flow rate: 80 mL/min. UV Detector Wavelength: 277 nm. This was the second isomer to elute under these conditions.
		(1R,3R,4R)-N-(4-(2,6-dimethoxyphenyl)-5-(5-
		methylfuran-2-yl)-4H-1,2,4-triazol-3-yl)-3,4-
		dihydroxycyclohexane-1-sulfonamide OR (1S,3R,4R)-
		N-(4-(2,6-dimethoxyphenyl)-5-(5-methylfuran-2-yl)-
		4H-1,2,4-triazol-3-yl)-3,4-dihydroxycyclohexane-1-
		sulfonamide.
		1 H NMR (500 MHz, DMSO-d 6 ) δ 12.99 (s, 1 H) 9.72-
		9.75 (m, 1 H) 7.50-7.63 (m, 1 H) 6.78-6.97 (m, 2 H)
		6.07-6.18 (m, 1 H) 5.79 (d, J = 3.4 Hz, 1 H) 4.74 (d,
		J = 3.9 Hz, 1 H) 4.58 (d, J = 3.0 Hz, 1 H) 3.73 (m, 6 H)
		3.63-3.69 (m, 1 H) 3.44-3.51 (m, 1 H) 2.91-3.01
		(m, 1 H) 2.24 (s, 3 H) 1.73-1.81 (m, 2 H) 1.60-1.69
		(m, 3 H) 1.48-1.56 (m, 1 H). LCMS-ESI (pos.)
		m/z: 479.2 (M + H) + .
409.0	3-bromo-4-(2,6-dimethoxyphenyl)- 5-(5-methylfuran-2-yl)-4H-1,2,4- triazole (Example 364.1) and 3- (hydroxymethyl)benzenesulfonamide (commercially available from Enamine).
		N-(4-(2,6-dimethoxyphenyl)-5-(5-methyl-2-furanyl)-
		4H-1,2,4-triazol-3-yl)-3-
		(hydroxymethyl)benzenesulfonamide
		1 H NMR (600 MHz, DMSO-d 6 ) δ 13.17-13.41 (m, 1
		H) 7.74 (s, 1 H) 7.58-7.67 (m, 1 H) 7.52-7.58 (m, 1
		H) 7.41-7.49 (m, 2 H) 6.83-6.89 (m, 2 H) 6.07-6.17
		(m, 1 H) 5.76-5.85 (m, 1 H) 5.29-5.40 (m, 1 H) 4.49-
		4.56 (m, 2 H) 3.59-3.66 (m, 6 H) 2.18-2.25 (m, 3
		H). LCMS-ESI (pos.) m/z: 471.2 (M + H) + .
410.0	3-bromo-4-(2,6-dimethoxyphenyl)- 5-(5-methylfuran-2-yl)-4H-1,2,4- triazole (Example 364.1) and 3-(1- hydroxyethyl)benzenesulfonamide (commercially available from Enamine). The final material was was separated by SFC: Column: Chiralpak AD-H, 2 × 25 cm Mobile Phase: 25% MeOH Flow rate: 80 mL/min UV Detector Wavelength: 215 nm. This was the first isomer to elute under these conditions.
		(R)-N-(4-(2,6-dimethoxyphenyl)-5-(5-methylfuran-2-
		yl)-4H-1,2,4-triazol-3-yl)-3-(1-
		hydroxyethyl)benzenesulfonamide or (S)-N-(4-(2,6-
		dimethoxyphenyl)-5-(5-methylfuran-2-yl)-4H-1,2,4-
		triazol-3-yl)-3-(1-hydroxyethyl)benzenesulfonamide.
		1 H NMR (500 MHz, CDCl 3 ) δ 10.52-11.29 (m, 1 H)
		7.83-7.99 (m, 1 H) 7.75-7.81 (m, 1 H) 7.50-7.55
		(m, 1 H) 7.36-7.47 (m, 2 H) 6.60-6.67 (m, 2 H) 5.89-
		5.92 (m, 1 H) 5.79-5.83 (m, 1 H) 4.94 (q, J = 6.5 Hz,
		1 H) 3.58-3.65 (m, 6 H) 2.27-2.36 (m, 3 H) 1.72-
		1.83 (m, 1 H) 1.48-1.52 (m, 3 H). LCMS-ESI (pos.)
		m/z: 485.0 (M + H) + .
411.0	3-bromo-4-(2,6-dimethoxyphenyl)- 5-(5-methylfuran-2-yl)-4H-1,2,4- triazole (Example 364.1) and 3-(1- hydroxyethyl)benzenesulfonamide (commercially available from Enamine). The final material was was separated by SFC: Column: Chiralpak AD-H, 2 × 25 cm Mobile Phase: 25% MeOH. Flow rate: 80 mL/min UV Detector Wavelength: 215 nm. This was the second isomer to elute under these conditions.
		(R)-N-(4-(2,6-dimethoxyphenyl)-5-(5-methylfuran-2-
		yl)-4H-1,2,4-triazol-3-yl)-3-(1-
		hydroxyethyl)benzenesulfonamide or (S)-N-(4-(2,6-
		dimethoxyphenyl)-5-(5-methylfuran-2-yl)-4H-1,2,4-
		triazol-3-yl)-3-(1-hydroxyethyl)benzenesulfonamide.
		1 H NMR (500 MHz, CDCl 3 ) δ 10.52-11.29 (m, 1 H)
		7.83-7.99 (m, 1 H) 7.75-7.81 (m, 1 H) 7.50-7.55
		(m, 1 H) 7.36-7.47 (m, 2 H) 6.60-6.67 (m, 2 H) 5.89-
		5.92 (m, 1 H) 5.79-5.83 (m, 1 H) 4.94 (q, J = 6.5 Hz,
		1 H) 3.58-3.65 (m, 6 H) 2.27-2.36 (m, 3 H) 1.72-
		1.83 (m, 1 H) 1.48-1.52 (m, 3 H). LCMS-ESI (pos.)
		m/z: 485.0 (M + H) + .

TABLE 26 — Biological Activity Information for Example Compounds. Activity hAPJ SPA

Example	EC 50 IP (μM)
1.0	—
2.0	13
3.0	0.00031
4.0	0.00077
5.0	0.00095
6.0	0.00098
7.0	0.0030
8.0	0.028
9.0	0.000091
10.0	0.00011
11.0	0.00014
12.0	0.00015
13.0	0.00019
14.0	0.00020
15.0	0.00021
16.0	0.00022
17.0	0.00026
18.0	0.00028
19.0	0.00029
20.0	0.00030
21.0	0.00031
22.0	0.00031
23.0	0.00036
24.0	0.00036
25.0	0.00037
26.0	0.00042
27.0	0.00046
28.0	0.00048
29.0	0.00082
30.0	0.0012
31.0	0.0019
32.0	0.0023
33.0	0.0024
34.0	0.0032
35.0	0.0035
36.0	0.0035
37.0	0.0036
38.0	0.0038
39.0	0.0066
40.0	0.011
41.0	0.012
42.0	0.012
43.0	0.025
44.0	0.044
45.0	0.072
46.0	0.30
47.0	—
48.0	—
49.0	—
50.0	—
51.0	0.0010
52.0	0.00029
53.0	0.0034
54.0	0.0083
55.0	0.028
56.0	0.000071
57.0	0.00011
58.0	0.00013
59.0	0.00016
60.0	0.00017
61.0	0.00020
62.0	0.00022
63.0	0.00024
64.0	0.00029
65.0	0.00031
66.0	0.00032
67.0	0.00036
68.0	0.00037
69.0	0.00039
70.0	0.00040
71.0	0.00047
72.0	0.00048
73.0	0.00049
74.0	0.00054
75.0	0.00055
76.0	0.00060
77.0	0.00077
78.0	0.00077
79.0	0.00098
80.0	0.0011
81.0	0.0011
82.0	0.018
83.0	—
84.0	—
85.0	0.00017
86.0	0.00023
87.0	0.00041
88.0	0.00051
89.0	0.0019
90.0	0.0039
91.0	0.0042
92.0	0.00013
93.0	0.00014
94.0	0.00017
95.0	0.00032
96.0	0.00034
97.0	0.00040
98.0	0.00045
99.0	0.0010
100.0	0.0020
101.0	0.0020
102.0	0.0028
103.0	0.0045
104.0	0.022
105.0	0.030
106.0	—
107.0	—
108.0	0.00025
109.0	0.00087
110.0	0.00097
111.0	0.0078
112.0	—
113.0	—
114.0	—
115.0	0.00020
116.0	0.000056
117.0	0.000061
118.0	0.000084
119.0	0.00015
120.0	0.00015
121.0	0.00015
122.0	0.00022
123.0	0.00024
125.0	0.00034
126.0	0.00045
127.0	0.00065
128.0	0.0011
129.0	0.0033
130.0	0.0035
131.0	0.0039
132.0	0.0068
134.0	0.010
135.0	0.016
136.0	.019
137.0	—
138.0	—
139.0	—
140.0	—
141.0	—
142.0	—
143.0	0.000072
144.0	0.000073
145.0	0.000090
146.0	0.00013
147.0	0.00014
148.0	0.00019
149.0	0.00021
150.0	0.00022
151.0	0.00024
152.0	0.00025
153.0	0.00026
154.0	0.00032
155.0	0.00035
156.0	0.00036
157.0	0.00039
158.0	0.00040
159.0	0.00048
160.0	0.00050
161.0	0.00067
162.0	0.00068
163.0	0.00070
164.0	0.00074
165.0	0.00075
166.0	0.00075
167.0	0.00094
168.0	0.00097
169.0	0.0010
170.0	0.0011
171.0	0.0012
172.0	0.0012
173.0	0.0016
174.0	0.0019
175.0	0.0019
176.0	0.0021
177.0	0.0028
178.0	0.0030
179.0	0.0032
180.0	0.0036
181.0	0.0059
182.0	0.026
183.0	0.028
184.0	0.028
185.0	0.033
186.0	0.037
187.0	0.051
188.0	0.075
189.0	0.11
190.0	—
191.0	0.015
192.0	0.0028
193.0	—
194.0	—
195.0	—
196.0	—
197.0	—
198.0	—
199.0	—
200.0	—
201.0	—
202.0	—
203.0	—
204.0	0.00026
205.0	0.0023
206.0	0.0048
207.0	—
208.0	—
209.0	—
210.0	0.0032
211.0	0.0041
212.0	0.000074
213.0	0.00012
214.0	0.00021
215.0	0.00022
216.0	0.00023
217.0	0.00024
218.0	0.00025
219.0	0.00026
220.0	0.00027
221.0	0.00030
222.0	0.00031
223.0	0.00032
224.0	0.00032
225.0	0.00033
226.0	0.00035
227.0	0.00035
228.0	0.00039
229.0	0.00039
230.0	0.00041
231.0	0.00044
232.0	0.00045
233.0	0.0005
234.0	0.00054
235.0	0.00056
236.0	0.00057
237.0	0.00058
238.0	0.00059
239.0	0.00060
240.0	0.00061
241.0	0.00065
242.0	0.00081
243.0	0.00087
244.0	0.00094
245.0	0.00095
246.0	0.0014
247.0	0.0015
248.0	0.0016
249.0	0.0025
250.0	0.0033
251.0	0.0067
252.0	0.0097
253.0	0.015
254.0	—
255.0	—
256.0	—
257.0	—
258.0	—
259.0	—
260.0	—
261.0	0.00013
262.0	0.000070
263.0	0.000086
264.0	0.000167
265.0	0.00018
266.0	0.00021
267.0	0.00043
268.0	0.00047
269.0	0.00049
270.0	0.00056
271.0	0.00062
272.0	0.00065
273.0	0.00072
274.0	0.00079
275.0	0.00085
276.0	0.00087
277.0	0.00096
278.0	0.00096
279.0	0.0010
280.0	0.0012
281.0	0.0012
282.0	0.0014
283.0	0.0014
284.0	0.0016
285.0	0.0025
286.0	0.0037
287.0	0.0041
288.0	0.0042
289.0	0.0049
290.0	0.0050
291.0	0.0050
292.0	0.0051
293.0	0.0055
294.0	0.0058
295.0	0.0061
296.0	0.0068
297.0	0.0088
298.0	0.011
299.0	0.011
300.0	0.012
301.0	0.013
302.0	0.013
303.0	0.013
304.0	0.016
305.0	0.016
306.0	0.018
307.0	0.028
308.0	0.033
309.0	0.061
310.0	0.083
311.0	0.19
312.0	0.21
313.0	0.23
314.0	0.23
315.0	0.27
316.0	0.27
317.0	0.31
318.0	0.42
319.0	0.61
320.0	0.00017
321.0	0.00018
322.0	0.00020
323.0	0.00020
324.0	0.00021
325.0	0.00023
326.0	0.00024
327.0	0.00025
328.0	0.00030
329.0	0.00038
330.0	0.00043
331.0	0.00045
332.0	0.00045
333.0	0.00045
334.0	0.00047
335.0	0.00052
336.0	0.00055
337.0	0.0013
338.0	0.019
339.0	0.062
340.0	0.075
341.0	0.081
342.0	0.121
343.0	0.20
344.0	—
345.0	—
346.0	—
347.0	—
348.0	—
349.0	—
350.0	—
383.0	0.000060
384.0	0.00015
385.0	0.00038
386.0	0.037
387.0	0.0021
388.0	0.037
390.0	0.013
391.0	0.0084
392.0	0.00055
393.0	0.00028
394.0	0.00031
395.0	0.00026
396.0	—
397.0	0.00051
398.0	0.010
400.0	0.00010
401.0	0.00053
402.0	0.065
403.0	0.057
404.0	0.036
405.0	0.064
406.0	0.067
407.0	0.18
409.0	0.043
410.0	0.011
411.0	0.032

TABLE 27 — Contractile Effects of Examples Observed in ex vivo (Isolated Heart Assay) and in vivo (MI Rat Model). MI Rat

Isolated Heart Assay	Model
Example(s)	dP/dt max (%)	dP/dt min (%)	dP/dt max (%)
26	10.20	11.1	58
41	22.1	22.7	nd*
51	40.6	33.8	38
56	23.0	24.9	30
108	38.8	30.1	nd*
111	19.5	24.9	97
115	32.6	34.7	30
204	24.6	29.0	No effect
205	18.8	20.5	nd*
210	25.9	34.0	95.6
261	34.5	53.8	30
*nd is not determined

description truncated at 500,000 characters

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Claims as granted

25 claims

Classifications

18 codes

IPC · International Patent Classification

Section A — Human necessities

A61K31/501
A61K31/506
A61K31/341
A61K31/4196
A61K31/437
A61P9/02
A61P9/00
A61K31/4439
A61K31/421

Section C — Chemistry; metallurgy

C07D307/54
C07D405/04
C07D413/12
C07F7/08
C07D405/12
C07D403/12
C07D239/26
C07D471/04
C07D405/14

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Matthew P Coughlin

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