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Electronically Filed on J ovemDert 3, ζυιν

CYCLOALKYL SUBSTITUTED TRIAZOLE COMPOUNDS AS AGONISTS

OF THE APJ RECEPTOR

CROSS REFERENCES TO RELATED APPLICATIONS

[001] This application claims the benefit of U.S. Provisional

Application No. 62/422,901, filed on November 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

[002] 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

[003] 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.

[004] 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.

[005] 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.

[006] 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. US 7,635,751.

[007] 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.

[008] A shortened 12 amino acid-apelin peptide having ligand activity on APJ was reported in a 2009 patent (US 7,635,751). The peptide could have a substitution of one non-canonical amino acid. In another application, WO 2013/111110 A2 and US 8,673,848, cyclic mimetics of apelin have also been reported. [009] 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. ChemMedChem 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 alia, the potency of the molecule. The increased potency can be a result of increased half-life or decreased degradation relative to wild- type apelin.

[010] 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.

[011] 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

[012] In one aspect, the invention provides a compound of Formula I or

Formula II:

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 monocyclic C3-C8 cycloalkyl, an unsubstituted Cs-Cg polycyclic cycloalkyl, an unsubstituted monocyclic C4-C8 cycloalkenyl, a monocyclic C3- Cg cycloalkyl substituted with 1, 2, 3, or 4 R ^la substituents, a Cs-Cg polycyclic cycloalkyl substituted with 1, 2, or 3 R ^la substituents, or a monocyclic C4-Cg cycloalkenyl substituted with 1, 2, or 3 R ^la substituents;

R ^la in each instance is independently selected from -F, -CI, -Br, -I, -CN, -OH, =0, -0-(Ci-C ₆ alkyl), -0-(Ci-C ₆ haloalkyl), -0-(Ci-C ₆ perhaloalkyl), -Ci-C ₆ alkyl, -Ci-C ₆ haloalkyl, -Ci-C ₆ perhaloalkyl, -C ₂ -C ₄ alkenyl, alkyl), -(Ci-C ₆ alkyl)- OH, -(Ci-Cg alkyl)-0-(Ci-C ₆ alkyl), -(Ci-C ₆ haloalkyl)-OH, -(Ci-C ₆ haloalkyl)-0-(Ci-C ₆ alkyl), -(Ci-Ce perhaloalkyl)-OH, -(Ci-C ₆ perhaloalkyl)-0-(Ci-C ₆ alkyl), -0-(Ci-C ₆ alkyl)-OH, -0-(Ci-C ₆ alkyl)-0-(Ci-C ₆ alkyl), -0-(Ci-C ₆ haloalkyl)-OH, -0-(Ci-C ₆ haloalkyl)-0-(Ci-C ₆ alkyl), -0-(Ci-C ₆ perhaloalkyl)-OH, -0-(Ci-C ₆ perhaloalkyl)-0-(Ci- C ₆ alkyl), -NH ₂ , -NH(Ci-C ₆ alkyl), -N(Ci-C ₆ alkyl) ₂ , -C(=0)-(Ci-C ₆ alkyl), -C(=0)OH, alkyl) ₂ , -NHS(=0) ₂ -(Ci-C6 alkyl), -S(=0) ₂ -(Ci-C6 alkyl), a phenyl group, or a monocyclic heteroaryl group with 5 or 6 ring members containing 1, 2, or 3 heteroatoms

independently selected from N, O, or S, wherein the R ^la phenyl and R ^la heteroaryl groups are unsubstituted or are substituted with 1, 2, or 3, R ^la substituents; and further wherein two R ^la groups on a single carbon atom of a monocyclic C3-Cg cycloalkyl R ¹ group may join together with the carbon atom to which they are attached to form a heterocyclic ring having 3 to 6 members of which 1 or 2 are heteroatoms independently selected from O, N, and S; R ^la is in each instance, independently selected from -F, -CI, -Br, -I, -CN, -OH, O- (Ci-Cg alkyl), -0-(Ci-C ₆ haloalkyl), -0-(Ci-C ₆ perhaloalkyl), -Ci-C ₆ alkyl, -Ci-C ₆ haloalkyl, -Ci-C ₆ perhaloalkyl, -C ₂ -C ₄ alkenyl, -(Ci-C ₆ alkyl)-OH, -(Ci-C ₆ alkyl)-0-(Ci- C ₆ alkyl), -(Ci-C ₆ haloalkyl)-OH, -(Ci-C ₆ haloalkyl)-0-(Ci-C ₆ alkyl), -(Ci-C ₆ perhaloalkyl)-OH, -(Ci-C ₆ perhaloalkyl)-0-(Ci-C ₆ alkyl), -0-(Ci-C ₆ alkyl)-OH, -0-(Ci- C ₆ alkyl)-0-(Ci-C ₆ alkyl), -0-(Ci-C ₆ haloalkyl)-OH, -0-(Ci-C ₆ haloalkyl)-0-(Ci-C ₆ alkyl), -0-(Ci-C ₆ perhaloalkyl)-OH, -0-(Ci-C ₆ perhaloalkyl)-0-(Ci-C ₆ alkyl), -NH ₂ , - NH(Ci-C ₆ alkyl), -N(Ci-C ₆ alkyl) ₂ , -C(=0)-(Ci-C ₆ alkyl), -C(=0)OH,

alkyl), -C(=0)NH ₂ , alkyl) ₂ ,

alkyl), or alkyl);

R ² is selected from -H, or C1-C4 alkyl or is absent in the compounds of Formula

II;

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(=0)-Q, a group of formula -(CR ^3d R ^3e )-(CR ^3f R ^¾ )-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, or a group of formula -(heterocyclyl)-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 ^substituted or is substituted with 1, 2, or 3 R ^3h substituents, and further wherein the C3-C8 cycloalkyl of the -(C3-C8 cycloalkyl)-Q group is unsubstituted or is substituted with 1 or 2 R ^3h substituents;

R ^3b and R ^3c are independently selected from -H, -F, -CI, -CN, -Ci-C ₆ alkyl, -Ci- C ₆ haloalkyl, -Ci-C ₆ perhaloalkyl, -OH, -0-(Ci-C ₆ alkyl), -0-(Ci-C ₆ haloalkyl), -0-(Ci-C ₆ perhaloalkyl), -0-(Ci-C ₆ alkyl)-OH, -0-(Ci-C ₆ alkyl)-0-(Ci-C ₆ alkyl), -NH ₂ , -NH(Ci-C ₆ alkyl), or -N(Ci-C ₆ alkyl) ₂ ;

R ^3d and R ^3e are independently selected from -H, -F, -CI, -CN, -Ci-C ₆ alkyl, -Ci- C ₆ haloalkyl, -Ci-C ₆ perhaloalkyl, -OH, -(Ci-C ₆ alkyl)-OH, -(Ci-C ₆ alkyl)-0-(Ci-C ₆ alkyl), -(Ci-Ce alkyl)-0-(Ci-C ₆ alkyl)-phenyl, -0-(Ci-C ₆ alkyl), -0-(Ci-C ₆ haloalkyl), -O- (Ci-Cg perhaloalkyl), -0-(Ci-C ₆ alkyl)-OH, -0-(Ci-C ₆ alkyl)-0-(Ci-C ₆ alkyl), -NH ₂ , - NH(Ci-C ₆ alkyl), or -N(Ci-C ₆ alkyl) ₂ ;

R ^3f and R ^3g are independently selected from -H, -F, -CI, -CN, -Ci-C ₆ alkyl, -Ci- C ₆ haloalkyl, -Ci-C ₆ perhaloalkyl, -OH, -(Ci-C ₆ alkyl)-OH, -(Ci-C ₆ alkyl)-0-(Ci-C ₆ alkyl), -0-(Ci-C ₆ alkyl), -0-(Ci-C ₆ haloalkyl), -0-(Ci-C ₆ perhaloalkyl), -0-(C ₂ -C ₆ alkenyl), -0-(Ci-C ₆ alkyl)-OH, -0-(Ci-C ₆ alkyl)-0-(Ci-C ₆ alkyl), -NH ₂ , -NH(Ci-C ₆ alkyl), or -N(Ci-C ₆ alkyl) ₂ ;

R ^3h in each instance is independently selected from -F, -CI, -CN, -Ci-Ce alkyl, -Ci-Cg haloalkyl, -Ci-C ₆ perhaloalkyl, -OH, -0-(Ci-C ₆ alkyl), -0-(Ci-C ₆ haloalkyl), -O- (Ci-Cg perhaloalkyl), -0-(Ci-C ₆ alkyl)-OH, -0-(Ci-C ₆ alkyl)-0-(Ci-C ₆ alkyl), -NH ₂ , - NH(Ci-C ₆ alkyl), -N(Ci-C ₆ alkyl) ₂ , cycloalkyl), - C(=0)-0-(Ci-C6 alkyl), oxo, or -C(=0)-(heterocyclyl), wherein the heterocyclyl group of the R ^h -C(=0)-(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 Ce-Cw 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 C3-C8 cycloalkyl group, a 3 to 10 membered heterocyclyl group containing 1, 2, or 3 heteroatoms independently selected from N, O, or S, wherein the Ce-Cw aryl, the heteroaryl, the cycloalkyl, and the heterocyclyl Q groups are unsubstituted or are substituted with 1, 2, 3, or 4 R ^Q substituents; and further 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;

R ^Q in each instance is independently selected from -F, -CI, -Br, -I, -CN, -Ci-Ce alkyl, -Ci-C ₆ haloalkyl, -Ci-C ₆ perhaloalkyl, -C ₂ -C ₆ alkenyl, -C ₂ -C ₆ alkynyl, -OH, -0-(Ci- C ₆ alkyl), -0-(Ci-C ₆ haloalkyl), -0-(Ci-C ₆ perhaloalkyl), -NH ₂ , -NH(Ci-C ₆ alkyl), -N(Ci- C ₆ alkyl) ₂ , alkyl), -C(=0)OH

alkyl), alkyl) ₂ ,

alkyl), -(Ci-Ce alkyl)-OH, -(Ci-C ₆ alkyl)-0-(Ci-C ₆ alkyl), -(Ci-C ₆ alkyl)-NH ₂ , -(Ci-C ₆ alkyl)-NH-(Ci-C ₆ alkyl), -(Ci-C ₆ alkyl)-N-(Ci-C ₆ alky 1) ₂ , phenyl, a heterocyclyl group, a -(Ci-Ce 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 -(Ci-Ce alkyl)heterocyclyl groups have 3 to 6 ring members of which 1 or 2 are heteroatoms independently selected from N, O, or S, and further wherein the heterocyclyl and the heterocyclyl of the -(Ci-Ce alkyl)heterocyclyl R ^Q groups may be further substituted with one or two oxo substituents and a substituent selected from -F, -CI, -Br, -I, -CN, -OH, -Ci-C ₆ alkyl, or -C(=0)-(Ci-C ₆ alkyl);

R ⁴ is selected from a monocyclic or bicyclic Ce-Cw 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 Ci- Ce alkyl group, wherein the Ce-Cioaryl, 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 Ci-Ce 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, -CI, -Br, -I, -CN, -Ci-Ce alkyl, -Ci-C ₆ haloalkyl, -Ci-C ₆ perhaloalkyl, -(Ci-C ₆ alkyl)-OH, -(Ci-C ₆ alkyl)-0-(Ci-C ₆ alkyl), -OH, -0-(Ci-C ₆ alkyl), -0-(Ci-C ₆ haloalkyl), -0-(Ci-C ₆ perhaloalkyl), -NH ₂ , - NH(Ci-C ₆ alkyl), -N(Ci-C ₆ alkyl) ₂ , NH(Ci-C ₆ alkyl-OH), -N(Ci-C ₆ alkyl-OH) ₂ , -C(=0)- (Ci-Cg alkyl), -C(=0)OH, -C(=0)-0-(Ci-C ₆ alkyl), -C(=0)NH ₂ , alkyl), alkyl) ₂ , phenyl, alkyl), -(Ci-C ₆ alkyl)-heterocyclyl, or heterocyclyl wherein the heterocyclyl of the -(Ci-Ce 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 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, -CI, -Br, -I, -CN, -OH, -0-(Ci-C ₆ alkyl), -0-(Ci-C ₆ haloalkyl), -0-(Ci-C ₆ perhaloalkyl), -NH ₂ , -NH(Ci-C ₆ alkyl), -N(Ci-C ₆ alkyl) ₂ , NH(Ci-C ₆ alkyl-OH), -N(Ci-C ₆ alkyl-OH) ₂ , -C(=0)-(Ci-C ₆ alkyl), -C(=0)OH, -C(=0)- 0-(Ci-C ₆ alkyl), alkyl) ₂ , or, - S(=0) ₂ -(d-C ₆ alkyl);

wherein if R ¹ is an unsubstituted cyclopropyl, if R ⁴ is an unsubstituted cyclopropyl group, or if R ⁴ is a substituted or unsubstituted straight or branched chain Ci- Ce alkyl group, then at least one of the following is true:

(a) if R ⁴ is an unsubstituted cyclopropyl group, then R ³ is a group of formula

-(heterocyclyl)-Q or R ³ is a group of formula -(CR ^3d R ^3e )-(CR ^3f R ^3g )-Q and at least one of R ^3d , R ^3e , R ^3f , or R ^3g is not -H;

(b) if R ¹ is an unsubstituted cyclopropyl, then R ⁴ is a substituted or unsubstituted monocyclic or bicyclic Ce-Cw aryl group, a substituted or unsubstituted monocyclic or bicyclic heteroaryl group with 5 to 10 ring members containing 1, 2, or 3 heteroatoms independently selected from N, O, or S, or is a substituted or unsubstituted 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

(c) if R ⁴ is a substituted or unsubstituted straight or branched chain Ci-Ce alkyl group, then R ³ is a group of formula -(heterocyclyl)-Q or R ³ is a group of formula

-(CR ^3d R ^3e )-(CR ^3f R ^3g )-Q and at least one of R ^3d , R ^3e , R ^3f , or R ^3g is not -H.

[013] Numerous other embodiments of the compound of Formula I and

Formula II are set forth herein.

[014] 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.

[015] 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.

[016] 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.

[017] 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.

[018] 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 or chronic kidney disease.

[019] 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.

[020] 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.

[021] 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.

[022] 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 or chronic kidney disease.

[023] 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

[024] FIG. 1 is a graph plotting different concentrations of angiotensin

(Angll) with fixed concentration of pyr apelin-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 pyr apelin-13 induces the positive cooperativity on the AT1R upon activation by APJ receptor.

[025] FIG. 2 is a graph plotting different concentrations of angiotensin

(Angll) with fixed concentration of pyr apelin-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 pyr apelin-13 when the human APJ receptor is expressed alone.

[026] FIG. 3 is a graph plotting different concentrations of angiotensin

(Angll) with fixed concentration of pyr apelin-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 pyr apelin-13 in the absence of APJ expression. DETAILED DESCRIPTION OF THE INVENTION

[027] 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.

[028] 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.

[029] 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.

[030] 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.

[031] 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.

[032] 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, IN, 1972).

[033] 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.

[034] 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:

Tautomer A Tautomer B

[035] 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.

[036] 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 (Ci- C^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.

[037] 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.

[038] 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).

[039] "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-l-yl and propan-2-yl, butyls such as butan-l-yl, butan-2-yl, 2-methyl-propan-l-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 (Ci-C6)alkyl group and an alkyl group having 1 to 4 carbon atoms may be referred to as a (Ci-C4)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 -0-(Ci-Ce alkyl)-OH will be recognized as a group where an -O atom is bonded to a Ci-Ce alkyl group and one of the H atoms bonded to a C atom of the Ci-Ce alkyl group is replaced with a bond to the O atom of an -OH group. As another example, a group -0-(Ci-Ce alkyl)-0-(Ci-C6 alkyl) will be recognized as a group where an -O atom is bonded to a first Ci-Ce alkyl group and one of the H atoms bonded to a C atom of the first Ci-Ce alkyl group is replaced with a bond to a second O atom that is bonded to a second Ci-Ce alkyl group.

[040] "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-l-en-l-yl, prop-l-en-2-yl, prop-2-en-l-yl (allyl), and prop-2-en-2-yl; butenyls such as but-l-en-l-yl, but-l-en-2-yl, 2-methyl-prop-l-en-l-yl, but-2-en-l-yl, but-2-en-l-yl, but-2-en-2-yl, buta-l,3-dien-l-yl, and buta-l,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 (C2-C6)alkenyl group.

[041] "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 -C6)alkynyl group.

[042] " 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-(Ci-Ce) alkyl or as -0-(Ci-Ce alkyl) groups. In some embodiments, an alkoxy group may include 1 to 4 carbon atoms and may be designated as -0-(Ci-C4) alkyl or as -0-(Ci-C4 alkyl) groups group.

[043] "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 Ce-Cw 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.

[044] "Carbonyl" refers to the radical -C(0) which may also be referred to as -C(=0) group.

[045] "Carboxy" refers to the radical -C(0)OH which may also be referred to as -C(=0)OH.

[046] "Cyano" refers to the radical -CN.

[047] "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 -Cg)cycloalkyl, a cycloalkyl group having 3 to 7 ring members may be referred to as a (C ₃ -Cv)cycloalkyl and a cycloalkyl group having 4 to 7 ring members may be referred to as a (C ₄ -Cv)cycloalkyl. In certain embodiments, the cycloalkyl group can be a (C ₃ -Cio)cycloalkyl, a (C ₃ -Cg)cycloalkyl, a (C ₃ -Cv)cycloalkyl, a (C ₃ -C6)cycloalkyl, or a (C4-Cv)cycloalkyl group and these may be referred to as C3-C10 cycloalkyl, C3-C8 cycloalkyl, C3-C7 cycloalkyl, C3-C6 cycloalkyl, or C4-C7 cycloalkyl groups using alternative language. Cycloalkyl groups may be monocyclic or polycyclic. For the purposes of this application, the term "polycyclic" when used with respect to cycloalkyl will include bicyclic cycloalkyl groups such as, but not limited to, norbornane, bicyclo[l. l. l]pentane, and bicyclo[3.1.0]hexane, and cycloalkyl groups with more ring systems such as, but not limited to, cubane. The term "polycyclic" when used with respect to cycloalkyl will also include spirocyclic ring systems such as, but not limited to, spiro[2.2]pentane, spiro[2.3]hexane, spiro[3.3]heptane, and spiro[3.4]octane.

[048] "Heterocyclyl" and "heterocyclic" refer 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-lH-pyrolyl, 2,3-dihydro-lH-pyrolyl, lH-azirinyl, 1,2-dihydroazetenyl, and the like. Substituted heterocyclyl also includes ring systems substituted with one or more oxo

(=0) or oxide (-0 ^" ) substituents, such as piperidinyl N-oxide, morpholinyl-N-oxide, 1- oxo-l-thiomorpholinyl, pyridinonyl, benzimidazolonyl, benzo[d]oxazol-2(3H)-only, 3,4- dihydroisoquinolin-l(2H)-only, indolin-only, lH-imidazo[4,5-c]pyridin-2(3H)-only, 7H- purin-8(9H)-only, imidazolidin-2-only, lH-imidazol-2(3H)-only, 1,1-dioxo-l- thiomorpholinyl, and the like. In heterocyclyl group containing a sulfur atom, the sulfur atom may be bonded to 0, 1, or 2 O atoms in addition to the adjacent ring members such that the sulfur may in various oxidation states. For example, a saturated 5-membered hetereocycle containing one heteroatom which is a S may include the following heterocycles.

[049] "Disease" refers to any disease, disorder, condition, symptom, or indication.

[050] "Halo" or "halogen" refers to a fluoro, chloro, bromo, or iodo group.

[051] "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, l,l,l-trifluoro-2-bromo-2-chloroethyl, and the like.

[052] "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][l,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][l,2,3]triazole benzofuran, indole, pyridine, quinoline, imidazole, benzimidazole, oxazole, tetrazole, and pyrazine.

[053] "Pharmaceutically acceptable" refers to generally recognized for use in animals, and more particularly in humans.

[054] "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.

[055] "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.

[056] "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."

[057] "Subject" includes mammals and humans. The terms "human" and

"subject" are used interchangeably herein.

[058] "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.

[059] "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.

[060] 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

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

[062] 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 monocyclic C3-C8 cycloalkyl, an unsubstituted Cs-Cg polycyclic cycloalkyl, an unsubstituted monocyclic C4-C8 cycloalkenyl, a monocyclic C3- Cg cycloalkyl substituted with 1, 2, 3, or 4 R ^la substituents, a Cs-Cg polycyclic cycloalkyl substituted with 1, 2, or 3 R ^la substituents, or a monocyclic C4-Cg cycloalkenyl substituted with 1, 2, or 3 R ^la substituents;

R ^la in each instance is independently selected from -F, -CI, -Br, -I, -CN, -OH, =0, -0-(Ci-C ₆ alkyl), -0-(Ci-C ₆ haloalkyl), -0-(Ci-C ₆ perhaloalkyl), -Ci-C ₆ alkyl, -Ci-C ₆ haloalkyl, -Ci-C ₆ perhaloalkyl, -C ₂ -C ₄ alkenyl, alkyl), -(Ci-C ₆ alkyl)- OH, -(Ci-Cg alkyl)-0-(Ci-C ₆ alkyl), -(Ci-C ₆ haloalkyl)-OH, -(Ci-C ₆ haloalkyl)-0-(Ci-C ₆ alkyl), -(Ci-Ce perhaloalkyl)-OH, -(Ci-C ₆ perhaloalkyl)-0-(Ci-C ₆ alkyl), -0-(Ci-C ₆ alkyl)-OH, -0-(Ci-C ₆ alkyl)-0-(Ci-C ₆ alkyl), -0-(Ci-C ₆ haloalkyl)-OH, -0-(Ci-C ₆ haloalkyl)-0-(Ci-C ₆ alkyl), -0-(Ci-C ₆ perhaloalkyl)-OH, -0-(Ci-C ₆ perhaloalkyl)-0-(Ci- C ₆ alkyl), -NH ₂ , -NH(Ci-C ₆ alkyl), -N(Ci-C ₆ alkyl) ₂ , -C(=0)-(Ci-C ₆ alkyl), -C(=0)OH, alkyl) ₂ , -NHS(=0) ₂ -(Ci-C6 alkyl), -S(=0) ₂ -(Ci-C6 alkyl), a phenyl group, or a monocyclic heteroaryl group with 5 or 6 ring members containing 1, 2, or 3 heteroatoms

independently selected from N, O, or S, wherein the R ^la phenyl and R ^la heteroaryl groups are unsubstituted or are substituted with 1, 2, or 3, R ^la substituents; and further wherein two R ^la groups on a single carbon atom of a monocyclic C3-Cg cycloalkyl R ¹ group may join together with the carbon atom to which they are attached to form a heterocyclic ring having 3 to 6 members of which 1 or 2 are heteroatoms independently selected from O, N, and S;

R ^la is in each instance, independently selected from -F, -CI, -Br, -I, -CN, -OH, O- (Ci-Cg alkyl), -0-(Ci-C ₆ haloalkyl), -0-(Ci-C ₆ perhaloalkyl), -Ci-C ₆ alkyl, -Ci-C ₆ haloalkyl, -Ci-C ₆ perhaloalkyl, -C ₂ -C ₄ alkenyl, -(Ci-C ₆ alkyl)-OH, -(Ci-C ₆ alkyl)-0-(Ci- C ₆ alkyl), -(Ci-C ₆ haloalkyl)-OH, -(Ci-C ₆ haloalkyl)-0-(Ci-C ₆ alkyl), -(Ci-C ₆ perhaloalkyl)-OH, -(Ci-C ₆ perhaloalkyl)-0-(Ci-C ₆ alkyl), -0-(Ci-C ₆ alkyl)-OH, -0-(Ci- C ₆ alkyl)-0-(Ci-C ₆ alkyl), -0-(Ci-C ₆ haloalkyl)-OH, -0-(Ci-C ₆ haloalkyl)-0-(Ci-C ₆ alkyl), -0-(Ci-C ₆ perhaloalkyl)-OH, -0-(Ci-C ₆ perhaloalkyl)-0-(Ci-C ₆ alkyl), -NH ₂ , - NH(Ci-C ₆ alkyl), -N(Ci-C ₆ alkyl) ₂ , -C(=0)-(Ci-C ₆ alkyl), -C(=0)OH,

alkyl), alkyl) ₂ ,

alkyl), or alkyl);

R ² is selected from -H, or C1-C4 alkyl or is absent in the compounds of Formula

II; 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(=0)-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 ^3s )-(CR ^3f R ^3s )-Q, a group of formula -(C ₃ -C ₈ cycloalkyl)-Q, or a group of formula -(heterocyclyl)-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 ^substituted or is substituted with 1, 2, or 3 R ^3h substituents, and further wherein the C3-C8 cycloalkyl of the -(C3-C8 cycloalkyl)-Q group is ^substituted or is substituted with 1 or 2 R ^3h substituents;

R ^3b and R ^3c are independently selected from -H, -F, -CI, -CN, -Ci-C ₆ alkyl, -Ci- C ₆ haloalkyl, -Ci-C ₆ perhaloalkyl, -OH, -0-(Ci-C ₆ alkyl), -0-(Ci-C ₆ haloalkyl), -0-(Ci-C ₆ perhaloalkyl), -0-(Ci-C ₆ alkyl)-OH, -0-(Ci-C ₆ alkyl)-0-(Ci-C ₆ alkyl), -NH ₂ , -NH(Ci-C ₆ alkyl), or -N(Ci-C ₆ alkyl) ₂ ;

R ^3d and R ^3e are independently selected from -H, -F, -CI, -CN, -Ci-C ₆ alkyl, -Ci- C ₆ haloalkyl, -Ci-C ₆ perhaloalkyl, -OH, -(Ci-C ₆ alkyl)-OH, -(Ci-C ₆ alkyl)-0-(Ci-C ₆ alkyl), -(Ci-Ce alkyl)-0-(Ci-C ₆ alkyl)-phenyl, -0-(Ci-C ₆ alkyl), -0-(Ci-C ₆ haloalkyl), -O- (Ci-Cg perhaloalkyl), -0-(Ci-C ₆ alkyl)-OH, -0-(Ci-C ₆ alkyl)-0-(Ci-C ₆ alkyl), -NH ₂ , - NH(Ci-C ₆ alkyl), or -N(Ci-C ₆ alkyl) ₂ ;

R ^3f and R ^3g are independently selected from -H, -F, -CI, -CN, -Ci-C ₆ alkyl, -Ci- C ₆ haloalkyl, -Ci-C ₆ perhaloalkyl, -OH, -(Ci-C ₆ alkyl)-OH, -(Ci-C ₆ alkyl)-0-(Ci-C ₆ alkyl), -0-(Ci-C ₆ alkyl), -0-(Ci-C ₆ haloalkyl), -0-(Ci-C ₆ perhaloalkyl), -0-(C ₂ -C ₆ alkenyl), -0-(Ci-C ₆ alkyl)-OH, -0-(Ci-C ₆ alkyl)-0-(Ci-C ₆ alkyl), -NH ₂ , -NH(Ci-C ₆ alkyl), or -N(Ci-C ₆ alkyl) ₂ ;

R ^3h in each instance is independently selected from -F, -CI, -CN, -Ci-Ce alkyl, -Ci-Cg haloalkyl, -Ci-C ₆ perhaloalkyl, -OH, -0-(Ci-C ₆ alkyl), -0-(Ci-C ₆ haloalkyl), -O- (Ci-Cg perhaloalkyl), -0-(Ci-C ₆ alkyl)-OH, -0-(Ci-C ₆ alkyl)-0-(Ci-C ₆ alkyl), -NH ₂ , - NH(Ci-C ₆ alkyl), -N(Ci-C ₆ alkyl) ₂ , -C(=0)-(Ci-C ₆ alkyl), -C(=0)-(C ₃ -C ₆ cycloalkyl), - C(=0)-0-(Ci-C6 alkyl), oxo, or -C(=0)-(heterocyclyl), wherein the heterocyclyl group of the R ^h -C(=0)-(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 Cs-Cio 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 C3-C8 cycloalkyl group, a 3 to 10 membered heterocyclyl group containing 1, 2, or 3 heteroatoms independently selected from N, O, or S, wherein the Ce-Cw aryl, the heteroaryl, the cycloalkyl, and the heterocyclyl Q groups are unsubstituted or are substituted with 1, 2, 3, or 4 R ^Q substituents; and further 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;

R ^Q in each instance is independently selected from -F, -CI, -Br, -I, -CN, -Ci-Ce alkyl, -Ci-C ₆ haloalkyl, -Ci-C ₆ perhaloalkyl, -C ₂ -C ₆ alkenyl, -C ₂ -C ₆ alkynyl, -OH, -0-(Ci- C ₆ alkyl), -0-(Ci-C ₆ haloalkyl), -0-(Ci-C ₆ perhaloalkyl), -NH ₂ , -NH(Ci-C ₆ alkyl), -N(Ci- C ₆ alkyl) ₂ , alkyl), -C(=0)OH

alkyl), alkyl) ₂ ,

alkyl), -(Ci-Ce alkyl)-OH, -(Ci-C ₆ alkyl)-0-(Ci-C ₆ alkyl), -(Ci-C ₆ alkyl)-NH ₂ , -(Ci-C ₆ alkyl)-NH-(Ci-C ₆ alkyl), -(Ci-C ₆ alkyl)-N-(Ci-C ₆ alky 1) ₂ , phenyl, a heterocyclyl group, a -(Ci-Ce 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 -(Ci-Ce alkyl)heterocyclyl groups have 3 to 6 ring members of which 1 or 2 are heteroatoms independently selected from N, O, or S, and further wherein the heterocyclyl and the heterocyclyl of the -(Ci-Ce alkyl)heterocyclyl R ^Q groups may be further substituted with one or two oxo substituents and a substituent selected from -F, -CI, -Br, -I, -CN, -OH, -Ci-C ₆ alkyl, or -C(=0)-(Ci-C ₆ alkyl);

R ⁴ is selected from a monocyclic or bicyclic Ce-Cw 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 Ci- Ce alkyl group, wherein the Ce-Cioaryl, 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 Ci-Ce 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, -CI, -Br, -I, -CN, -Ci-Ce alkyl, -Ci-C ₆ haloalkyl, -Ci-C ₆ perhaloalkyl, -(Ci-C ₆ alkyl)-OH, -(Ci-C ₆ alkyl)-0-(Ci-C ₆ alkyl), -OH, -0-(Ci-C ₆ alkyl), -0-(Ci-C ₆ haloalkyl), -0-(Ci-C ₆ perhaloalkyl), -NH ₂ , - NH(Ci-C ₆ alkyl), -N(Ci-C ₆ alkyl) ₂ , NH(Ci-C ₆ alkyl-OH), -N(Ci-C ₆ alkyl-OH) ₂ , -C(=0)- (Ci-Cg alkyl), -C(=0)OH, -C(=0)-0-(Ci-C ₆ alkyl), alkyl), alkyl) ₂ , phenyl, alkyl), -(Ci-C ₆ alkyl)-heterocyclyl, or heterocyclyl wherein the heterocyclyl of the -(Ci-Ce 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 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, -CI, -Br, -I, -CN, -OH, -0-(Ci-C ₆ alkyl), -0-(Ci-C ₆ haloalkyl), -0-(Ci-C ₆ perhaloalkyl), -NH ₂ , -NH(Ci-C ₆ alkyl), -N(Ci-C ₆ alkyl) ₂ , NH(Ci-C ₆ alkyl-OH), -N(Ci-C ₆ alkyl-OH) ₂ , -C(=0)-(Ci-C ₆ alkyl), -C(=0)OH, -C(=0)- 0-(Ci-C ₆ alkyl), -C(=0)NH ₂ , alkyl) ₂ , or, - S(=0) ₂ -(d-C ₆ alkyl);

wherein if R ¹ is an unsubstituted cyclopropyl, if R ⁴ is an unsubstituted cyclopropyl group, or if R ⁴ is a substituted or unsubstituted straight or branched chain Ci- Ce alkyl group, then at least one of the following is true:

(a) if R ⁴ is an unsubstituted cyclopropyl group, then R ³ is a group of formula

-(heterocyclyl)-Q or R ³ is a group of formula -(CR ^3d R ^3e )-(CR ^3f R ^3g )-Q and at least one of R ^3d , R ^3e , R ^3f , or R ^3g is not -H;

(b) if R ¹ is an unsubstituted cyclopropyl, then R ⁴ is a substituted or unsubstituted monocyclic or bicyclic Ce-Cw aryl group, a substituted or unsubstituted monocyclic or bicyclic heteroaryl group with 5 to 10 ring members containing 1, 2, or 3 heteroatoms independently selected from N, O, or S, or is a substituted or unsubstituted 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

(c) if R ⁴ is a substituted or unsubstituted straight or branched chain Ci-Ce alkyl group, then R ³ is a group of formula -(heterocyclyl)-Q or R ³ is a group of formula -(CR ^3d R ^3e )-(CR ^3f R ^3g )-Q and at least one of R ^3d , R ^3e , R ^3f , or R ^3g is not -H.

In some embodiments, if R ⁴ is a substituted or unsubstituted straight or branched chain Ci-Ce alkyl group or if R ⁴ is an unsubstituted cyclopropyl group, then R ³ is a group of formula -(heterocyclyl)-Q or R ³ is a group of formula -(CR ^3d R ^3e )-(CR ^3f R ^3g )-Q and at least one of R ^3d , R ^3e , R ^3f , or R ^3g is not -H and Q is selected from an unsubstituted or substituted monocyclic or bicyclic heteroaryl group with 5 to 10 ring members containing 1, 2, or 3 heteroatoms independently selected from N, O, or S, an unsubstituted or substituted C3-C8 cycloalkyl group, or an unsubstituted or substituted 3 to 10 membered heterocyclyl group containing 1, 2, or 3 heteroatoms independently selected from N, O, or S.

In some embodiments, if R ⁴ is a substituted or unsubstituted straight or branched chain Ci-Ce alkyl group or if R ⁴ is an unsubstituted cyclopropyl group, then R ³ is a group of formula -(heterocyclyl)-Q or R ³ is a group of formula -(CR ^3d R ^3e )-(CR ^3f R ^3g )-Q and at least one of R ^3d , R ^3e , R ^3f , or R ^3g is not -H and Q is selected from an unsubstituted or substituted monocyclic or bicyclic heteroaryl group with 5 to 10 ring members containing 1, 2, or 3 heteroatoms independently selected from N, O, or S.

In some embodiments, if R ⁴ is a substituted or unsubstituted straight or branched chain Ci-Ce alkyl group or if R ⁴ is an unsubstituted cyclopropyl group, then R ³ is a group of formula -(heterocyclyl)-Q or R ³ is a group of formula -(CR ^3d R ^3e )-(CR ^3f R ^3g )-Q and at least one of R ^3d , R ^3e , R ^3f , or R ^3g is not -H and Q is selected from an unsubstituted or substituted monocyclic heteroaryl group with 6 ring members containing 1, 2, or 3 heteroatoms independently selected from N, O, or S.

[063] 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 ³ is selected from a group of formula -(CR ^3d R ^3e )-(CR ^3f R ^3g )-Q, or a group of formula -(heterocyclyl)-Q.

[064] 3. The compound of 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 ³ is a group of formula -(CR ^3d R ^3e )-(CR ^3f R ^3g )-Q.

[065] 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 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, -Ci-C ₆ alkyl, -(Ci-C ₆ alkyl)-OH, or -(Ci-Cg alkyl)-0-(Ci-C ₆ alkyl); and

R ^3f and R ^3g are independently selected from -H, -F, -Ci-Ce alkyl, -Ci-Ce haloalkyl, -Ci-C ₆ perhaloalkyl, -OH, -0-(Ci-C ₆ alkyl), -0-(Ci-C ₆ haloalkyl), -0-(Ci-C ₆ perhaloalkyl), or -0-(C2-C6 alkenyl).

[066] 5. 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 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, or -Ci-Ce alkyl; and

R ^3f and R ^3g are independently selected from -H, -Ci-C ₆ alkyl, -OH, or -0-(Ci-C ₆ alkyl).

[067] 6. The compound of any one of embodiments 3-5 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 at least one of R ^3d , R ^3e , R ^3f , or R ^3g is not -H.

[068] 7. The compound of any one of embodiments 3-5 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 at least one of R ^3d , R ^3e , R ^3f , or R ^3g is a -Ci-C ₆ alkyl.

[069] 8. The compound of 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 ³ is a group of formula -(heterocyclyl)-Q.

[070] 9. The compound of embodiment 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 the heterocyclyl of the -(heterocyclyl)-Q R ³ group is a piperidinyl that is unsubstituted or is substituted with 1 or 2 R ^3h substituent.

[071] 10. The compound of embodiment 8 or 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 the heterocyclyl of the -(heterocyclyl)-Q R ³ group is a piperidinyl that is unsubstituted or is substituted with 1 or 2 R ^3h substituent independently selected from -OH, or -0-(Ci-C6 alkyl).

[072] 11. The compound of any one of embodiments 1, 2, or 8-10 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 ³ is selected from [073] 12. The compound of any one of embodiments 1, 2, or 8-10 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

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

[074] 13. The compound of any one of embodiments 1, 2, or 8-10 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

wherein the symbol , when drawn across a bond, indicates the point of attachment to the rest of the molecule. [075] 14. 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 ³ is selected from

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

[076] 15. 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 ³ is selected from

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

[077] 16. 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 ³ is

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

[078] 17. 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 ³ is

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

[079] 18. 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 ³ is

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

[080] 19. 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 ³ is selected from

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

[081] 20. 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 ³ is

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

[082] 21. The compound of any one of embodiments 1-20 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, pyridinyl, or phenyl, any of which may be unsubstituted or substituted with 1, 2, or 3 R ^Q substituents.

[083] 22. The compound of any one of embodiments 1-20 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, 2, or 3 R ^Q substituents.

[084] 23. The compound of any one of embodiments 1-20 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. [085] 24. The compound of any one of embodiments 1-20 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, 2, or 3 R ^Q substituents.

[086] 25. The compound of any one of embodiments 1-20 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 group and Q is unsubstituted or is substituted with 1, 2, or 3 R ^Q substituents.

[087] 26. The compound of any one of embodiments 1-25 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 ^Q in each instance is independently selected from -F, -CI, -Br, -CN, - Ci-Ce alkyl, -Ci-C ₆ haloalkyl, -Ci-C ₆ perhaloalkyl, -0-(Ci-C ₆ alkyl), -0-(Ci-C ₆ haloalkyl), or -0-(Ci-C6 perhaloalkyl).

[088] 27. The compound of any one of embodiments 1-25 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 ^Q in each instance is independently selected from -F, -CI, -Br, -CN, or - CH ₃ .

[089] 28. The compound of any one of embodiments 1-20 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

-39-

wherein the symbol «ΛΛ/ν _^ when drawn across a bond, indicates the point of attachment to the rest of the molecule.

[090] 29. The compound of any one of embodiments 1-20 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.

[091] 30. The compound of embodiment 29 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 >ΛΛΛ^ _} when drawn across a bond, indicates the point of attachment to the rest of the molecule.

[092] 31. The compound of embodiment 29 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 /w r _} when drawn across a bond, indicates the point of attachment to the rest of the molecule.

[093] 32. The compound of embodiment 29 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 ^vwr when drawn across a bond, indicates the point of attachment to the rest of the molecule.

[094] 33. The compound of embodiment 29 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 */vwo , when drawn across a bond, indicates the point of attachment to the rest of the molecule.

[095] 34. The compound of embodiment 29 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 /wvr· _^ when drawn across a bond, indicates the point of attachment to the rest of the molecule.

[096] 35. The compound of any one of embodiments 1-34 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.

[097] 36. The compound of any one of embodiments 1-35 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, or pyrimidinyl, any of which may be

^substituted or substituted with 1, 2, or 3 R ^4a substituents.

[098] 37. The compound of any one of embodiments 1-35 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 cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or tetrahydropyranyl, any of which may be unsubstituted or substituted with 1, 2, or 3 R ^4a substituents.

[099] 38. The compound of any one of embodiments 1-37 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 ^4a is in each instance independently selected from -F, -Br, -CN, -Ci-Ce alkyl, -Ci-C ₆ haloalkyl, -Ci-C ₆ perhaloalkyl, -(Ci-C ₆ alkyl)-OH, -OH, -0-(Ci-C ₆ alkyl), - 0-(Ci-C ₆ haloalkyl), -0-(Ci-C ₆ perhaloalkyl), -C(=0)OH, -C(=0)-0-(Ci-C ₆ alkyl), -NH ₂ , -NH(Ci-C ₆ alkyl), -N(Ci-C ₆ alkyl) ₂ , -NH(Ci-C ₆ alkyl-OH), -C(=0)NH ₂ ,

C ₆ alkyl), or alkyl) ₂ .

[0100] 39. The compound of embodiment 38 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, -CI, -Br, -CN, -CF ₃ , -OCH ₃ , or -OCHF ₂ .

[0101] 40. The compound of embodiment 38 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 or , -OCH ₃ .

[0102] 41. The compound of any one of embodiments 1-35 or the pharmaceutically acceptable salt thereof, the stereoisomer of any of the foregoing, or the m

-45 -

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

[0103] 42. The compound of any one of embodiments 1-35 or the pharmaceutically acceptable salt thereof, the stereoisomer of any of the foregoing, or the

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

[0104] 43. The compound of any one of embodiments 1-35 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 or pyrimidinyl substituted with 1 or 2 R ^4a substituents.

[0105] 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 R ^4a substituents are -0-(Ci-C2 alkyl) groups. [0106] 45. 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 R ⁴ is

wherein the symbol »A/WP _^ when drawn across a bond, indicates the point of attachment to the rest of the molecule.

[0107] 46. The compound of any one of embodiments 1-45 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 ¹ is an unsubstituted monocyclic C3-C8 cycloakyl or is a monocyclic C3-C8 cycloakyl substituted with 1, 2, 3, or 4 R ^la substituents.

[0108] 47. The compound of any one of embodiments 1-45 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 ¹ is an unsubstituted cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl group or is a cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl group substituted with 1, 2, 3, or 4 R ^la substituents.

[0109] 48. The compound of any one of embodiments 1-45 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 ¹ is an unsubstituted Cs-Cg polycyclic cycloalkyl or is a Cs-Cg polycyclic cycloalkyl substituted with 1, 2, or 3 R ^la substituents.

[0110] 49. The compound of any one of embodiments 46-49 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 ^la is absent or R ^la is independently selected from -F, -CN, -CH ₃ , -CF ₃ , -CHF ₂ , -CH ₂ F, -CH2CHF2, =CH ₂ , =0, -OH, -OCH3, -OCHF ₂ , -OCH ₂ CH ₃ , or -CH ₂ OH.

[0111] 50. The compound of any one of embodiments 1-45 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 ¹ is selected from

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

[0112] 51. The compound of embodiment 1 , wherein the compound has the

Formula IA

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 ¹ is as defined in embodiment 1;

X is selected from CH or N;

Z is selected from CH or N;

R ^3d and R ^3e are independently selected from -H, -Ci-C ₆ alkyl, -(Ci-C ₆ alkyl)-OH, or -(Ci-Cg alkyl)-0-(Ci-C ₆ alkyl); and R ^3f and R ^3g are independently selected from -H, -F, -Ci-Ce alkyl, -Ci-Ce haloalkyl, -Ci-C ₆ perhaloalkyl, -OH, -0-(Ci-C ₆ alkyl), -0-(Ci-C ₆ haloalkyl), -0-(Ci-C ₆ perhaloalkyl), or -0-(C2-C6 alkenyl).

Q is a phenyl group or a monocyclic heteroaryl group with 6 ring members containing 1 or 2 N heteroatoms, wherein the phenyl and the monocyclic heteroaryl Q groups are unsubstituted or are substituted with 1, 2, or 3 R ^Q substituent; and

R ^Q is independently selected from -F, -CI, -Br, -CN, -Ci-C ₆ alkyl, -Ci-C ₆ haloalkyl, -Ci-C ₆ perhaloalkyl, -0-(Ci-C ₆ alkyl), -0-(Ci-C ₆ haloalkyl), -0-(Ci-C ₆ perhaloalkyl), -(Ci-C ₆ alkyl)-NH ₂ or alkyl).

[0113] 52. The compound of embodiment 51 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 ^3d and R ^3e are independently selected from -H, -Ci-Ce alkyl, or -(Ci-Ce alkyl)- OH; and

R ^3f and R ^3g are independently selected from -H, -Ci-C ₆ alkyl, -OH, or -0-(Ci-C ₆ alkyl).

[0114] 53. The compound of embodiment 51 or 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 at least one of R ^3d , R ^3e , R ^3f , or R ^3g is not -H.

[0115] 54. The compound of any one of embodiments 51-53 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 at least one of R ^3d , R ^3e , R ^3f , or R ^3g is -CH ₃ .

[0116] 55. The compound of any one of embodiments 51-54 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 ^Q in each instance is independently selected from -F, -CI, -Br, -CN, or - CH ₃ .

[0117] 56. The compound of embodiment 1 , wherein the compound has the

Formula IB

IB

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 ¹ is as defined in embodiment 1;

X is selected from CH or N;

Z is selected from CH or N;

R ^3h is independently selected from -OH, or -0-(Ci-C6 alkyl);

the subscript p is selected from 0, 1, 2, or 3;

Q is a phenyl group or a monocyclic heteroaryl group with 6 ring members containing 1 or 2 N heteroatoms, wherein the phenyl and the monocyclic heteroaryl Q groups are unsubstituted or are substituted with 1, 2, or 3 R ^Q substituent; and

R ^Q is independently selected from -F, -CI, -Br, -CN, -Ci-C ₆ alkyl, -Ci-C ₆ haloalkyl, -Ci-C ₆ perhaloalkyl, -0-(Ci-C ₆ alkyl), -0-(Ci-C ₆ haloalkyl), -0-(Ci-C ₆ perhaloalkyl), -(Ci-C ₆ alkyl)-NH ₂ or alkyl).

[0118] 57. The compound of embodiment 56 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 p is 0 or 1 and R ^3h is selected from -OH, -OCH ₃ , -OCH ₂ CH ₃ , or -OCH(CH ₃ ) ₂ .

[0119] 58. The compound of any one of embodiments 51-57 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:

X is CH;

Z is CH; and Q is a phenyl, a pyrimidinyl, a pyridinyl, or a pyrazinyl any of which are unsubstituted or are substituted with 1, 2, or 3 R ^Q substituent.

[0120] 59. The compound of any one of embodiments 51-57 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:

X is N;

Z is N; and

Q is a phenyl, a pyrimidinyl, a pyridinyl, or a pyrazinyl any of which are unsubstituted or are substituted with 1, 2, or 3 R ^Q substituent.

[0121] 60. The compound of any one of embodiments 51-59 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 monocyclic C3-C8 cycloakyl or is a monocyclic C3-C8 cycloakyl substituted with 1, 2, 3, or 4 R ^la substituents.

[0122] 61. The compound of any one of embodiments 51-59 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 cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl group or is a cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl group substituted with 1, 2, 3, or 4 R ^la substituents.

[0123] 62. The compound of any one of embodiments 51-59 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 Cs-Cg polycyclic cycloalkyl or is a Cs-Cg polycyclic cycloalkyl substituted with 1, 2, or 3 R ^la substituents.

[0124] 63. The compound of any one of embodiments 51-59 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 ^la is absent or R ^la is independently selected from -F, -CN, -CH ₃ , -CF ₃ , -CHF ₂ , -CH ₂ F, -CH2CHF2, =CH ₂ , =0, -OH, -OCH3, -OCHF ₂ , -OCH ₂ CH ₃ , or -CH ₂ OH.

[0125] 64. The compound of any one of embodiments 51-59 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 selected from

-57-

wherein the symbol /w r ^> _^ when drawn across a bond, indicates the point of attachment to the rest of the molecule.

[0126] 65. The compound of embodiment 1, wherein the compound is selected from

2-(4-chlorophenyl)-N-(5-cyclobutyl-4-(2,6-dimethoxyphenyl)-4 H-l,2,4-triazol-3- yl)ethanesulfonamide;

2-(4-chlorophenyl)-N-(5-cyclopentyl-4-(2,6-dimethoxyphenyl)- 4H-l,2,4-triazol- 3-yl)ethanesulfonamide;

(2S,3R)-N-(5-cyclopropyl-4-(4,6-dimethoxy-5-pyrimidinyl)-4H- l,2,4-triazol-3- yl)-3-(5-methyl-2-pyrimidinyl)-2-butanesulfonamide;

(2S,3R)-N-(5-cyclobutyl-4-(4,6-dimethoxy-5-pyrimidinyl)-4H-l ,2,4-triazol-3- yl)-3-(5-methyl-2-pyrimidinyl)-2-butanesulfonamide; (2S,3R)-N-(5-cyclohexyl-4-(4,6-dimethoxy-5^yrimidinyl)-4H-l, 2,4-triazol-3- yl)-3-(5-methyl-2-pyrimidinyl)-2-butanesulfonamide;

(lR,2S)-l-(5-chloro-2-pyrimidinyl)-N-(5-cyclohexyl-4-(4,6-di methoxy-5- pyrimidiny 1)-4H- 1 ,2,4-triazol-3 -y 1)- 1 -methoxy -2-propanesulfonamide ;

(lR,2S)-l-(5-chloro-2-pyrimidinyl)-N-(5-cyclobutyl-4-(4,6-di methoxy-5- pyrimidiny 1)-4H- 1 ,2,4-triazol-3 -y 1)- 1 -methoxy -2-propanesulfonamide ;

N-(4-(2-bromo-6-methoxyphenyl)-5-cyclopentyl-4H-l,2,4-triazo l-3-yl)-l-(4- chlorophenyl)methanesulfonamide;

l-(4-chlorophenyl)-N-(5-cyclopentyl-4-(2,6-dibromophenyl)-4H -l,2,4-triazol-3- yl)methanesulfonamide;

(lR,2S)-l-(5-chloro-2-pyrimidinyl)-N-(5-cyclopentyl-4-(4,6-d imethoxy-5- pyrimidiny 1)-4H- 1 ,2,4-triazol-3 -y 1)- 1 -methoxy -2-propanesulfonamide ;

(lR,2S)-l-(5-chloro-2-pyrimidinyl)-N-(5-((lR)-2,2-dimethylcy clopropyl)-4- (tetrahydro-2H-pyran-4-yl)-4H-l,2,4-triazol-3-yl)-l-methoxy -2-propanesulfonamide;

(lR,2S)-l-(5-chloro-2-pyrimidinyl)-N-(5-((lS)-2,2-dimethylcy clopropyl)-4- (tetrahydro-2H-pyran-4-yl)-4H-l,2,4-triazol-3-yl)-l-methoxy -2-propanesulfonamide;

(lR,2S)-l-(5-chloro-2-pyrimidinyl)-N-(4-(2,6-dimethoxyphenyl )-5-((lR)-2,2- dimethy Icy clopropy 1)-4H- 1 ,2,4-triazol-3 -y 1)- 1 -methoxy-2-propanesulfonamide ;

(lR,2S)-l-(5-chloro-2-pyrimidinyl)-N-(4-(2,6-dimethoxyphenyl )-5-((lS)-2,2- dimethy Icy clopropy 1)-4H- 1 ,2,4-triazol-3 -y 1)- 1 -methoxy-2-propanesulfonamide ;

(lR,2S)-l-(5-chloro-2-pyrimidinyl)-N-(5-cyclopropyl-4-(4,6-d imethoxy-5- pyrimidiny 1)-4H- 1 ,2,4-triazol-3 -y 1)- 1 -methoxy -2-propanesulfonamide ;

(lR,2S)-l-(5-chloro-2-pyrimidinyl)-N-(4-(4,6-dimethoxy-5-pyr imidinyl)-5- ((lR)-2,2-dimethylcyclopropyl)-4H-l,2,4-triazol-3-yl)-l-meth oxy -2-propanesulfonamide;

(lR,2S)-l-(5-chloro-2-pyrimidinyl)-N-(4-(4,6-dimethoxy-5-pyr imidinyl)-5-((lS)- 2,2-dimethylcyclopropyl)-4H-l,2,4-triazol-3-yl)-l-methoxy-2- propanesulfonamide;

(lR,2S)-l-(5-chloro-2-pyrimidinyl)-N-(4-(4,6-dimethoxy-5-pyr imidinyl)-5- ((2r,3S,5S,6r,7S,8r)-pentacyclo[4.2.0.0~2,5~.0~3,8~.0~4,7~]o ct-l-yl)-4H-l,2,4-triazol-3- yl)-l-methoxy -2-propanesulfonamide;

(lR,2S)-N-(5-cyclobutyl-4-(4,6-dimethoxy-5-pyrimidinyl)-4H-l ,2,4-triazol-3- yl)-l-methoxy-l-(5-methyl-2-pyrazinyl)-2-propanesulfonamide;

(lS,2S)-N-(5-cyclobutyl-4-(4,6-dimethoxy-5-pyrimidinyl)-4H-l ,2,4-triazol-3-yl)- l-(5-methyl-2-pyrimidinyl)-l-(2-propanyloxy)-2-propanesulfon amide; (2S,3R)-N-(5-cyclobutyl-4-(4,6-dimethoxy-5-pyrimidinyl)-4H-l ,2,4-triazol-3- yl)-3-(5-fluoro-2-pyrimidinyl)-2-butanesulfonamide;

(2S,3R)-3-(5-chloro-2-pyrimidinyl)-N-(5-cyclobutyl-4-(4,6-di methoxy-5- pyrimidinyl)-4H-l,2,4-triazol-3-yl)-2-butanesulfonamide;

(lS,2S)-N-(5-cyclobutyl-4-(4,6-dimethoxy-5-pyrimidinyl)-4H-l ,2,4-triazol-3-yl)- l-(5-methyl-2-pyrazinyl)-l-(2-propanyloxy)-2-propanesulfonam ide;

(2S,3R)-3-(5-chloro-2-pyridinyl)-N-(5-cyclobutyl-4-(4,6-dime thoxy-5- pyrimidinyl)-4H-l,2,4-triazol-3-yl)-2-butanesulfonamide;

(2S,3R)-N-(5-cyclobutyl-4-(4,6-dimethoxy-5-pyrimidinyl)-4H-l ,2,4-triazol-3- yl)-3-(5-methyl-2-pyrazinyl)-2-butanesulfonamide;

(lS,2S)-l-(5-chloro-2-pyrimidinyl)-N-(5-cyclobutyl-4-(4,6-di methoxy-5- pyrimidinyl)-4H-l,2,4-triazol-3-yl)-l-(2-propanyloxy)-2-prop anesulfonamide;

(lR,2S)-N-(5-cyclobutyl-4-(4,6-dimethoxypyrimidin-5-yl)-4H-l ,2,4-triazol-3- yl)-l-methoxy-l-(5-methylpyrimidin-2-yl)propane-2-sulfonamid e;

(lR,2S)-l-(5-chloropyridin-2-yl)-N-(5-cyclobutyl-4-(4,6-dime thoxypyrimidin-5- yl)-4H-l,2,4-triazol-3-yl)-l-methoxypropane-2-sulfonamide;

(lR,2S)-N-(5-cyclobutyl-4-(4,6-dimethoxypyrimidin-5-yl)-4H-l ,2,4-triazol-3- yl)-l-methoxy-l-(5-methoxypyrimidin-2-yl)propane-2-sulfonami de;

(lR,2S)-l-(5-chloropyrimidin-2-yl)-N-(5-cyclobutyl-4-(2,6-di methoxyphenyl)- 4H-l,2,4-triazol-3-yl)-l-methoxypropane-2-sulfonamide;

(lR,2S)-l-(5-chloropyrimidin-2-yl)-N-(5-cyclobutyl-4-(2,6-di fluorophenyl)-4H- l,2,4-triazol-3-yl)-l-methoxypropane-2-sulfonamide;

(1 R,2S)- 1 -(5-chloropyrimidin-2-y l)-N-(5 -cy clobuty l-4-( 1 ,3 -dimethoxypropan-2- yl)-4H-l,2,4-triazol-3-yl)-l-methoxypropane-2-sulfonamide;

(lR,2S)-l-(5-chloropyrimidin-2-yl)-N-(5-cyclobutyl-4-(l- (methoxymethyl)cyclopropyl)-4H-l,2,4-triazol-3-yl)-l-methoxy propane-2-sulfonamide;

(lR,2S)-l-(5-chloropyrimidin-2-yl)-N-(5-cyclobutyl-4-(tetrah ydro-2H-pyran-4- yl)-4H-l,2,4-triazol-3-yl)-l-methoxypropane-2-sulfonamide;

(lR,2S)-l-(5-chloro-2-pyrimidinyl)-N-(5-((lR)-2,2-difluorocy clopropyl)-4-(4,6- dimethoxy-5-pyrimidinyl)-4H-l,2,4-triazol-3-yl)-l-methoxy-2- propanesulfonamide;

(lR,2S)-l-(5-chloro-2-pyrimidinyl)-N-(5-((lS)-2,2-difluorocy clopropyl)-4-(4,6- dimethoxy-5-pyrimidinyl)-4H-l,2,4-triazol-3-yl)-l-methoxy-2- propanesulfonamide;

(lR,2S)-l-(5-chloro-2-pyrimidinyl)-N-(4-(4,6-dimethoxy-5-pyr imidinyl)-5- ((lR)-6-oxaspiro[2.5]oct-l-yl)-4H-l,2,4-triazol-3-yl)-l-meth oxy-2-propanesulfonamide; (lR,2S) -(5-chloro-2-pyrimidinyl)-N-(4-(4,6-dimethoxy-5^yrimidinyl)- 5-((lS)- 6-oxaspiro[2.5]oct-l-yl)-4H-l,2,4-triazol-3-yl)-l-methoxy-2- propanesulfonamide;

(lR,2S) -(5-chloro-2-pyrimidinyl)-N-(4-(4,6-dimethoxy-5^yrimidinyl)- 5-((lS)- spiro[2.2]pent-l-yl)-4H-l,2,4-triazol-3-yl)-l-methoxy-2-prop anesulfonamide;

(lR,2S)-l-(5-chloro-2-pyrimidinyl)-N-(4-(4,6-dimethoxy-5-pyr imidinyl)-5- ((lR)-spiro[2.2]pent-l-yl)-4H-l,2,4-triazol-3-yl)-l-methoxy- 2-propanesulfonamide;

(lR,2S)-l-(5-chloro-2-pyrimidinyl)-N-(4-(2,6-dimethoxyphenyl )-5-((lS,2R)-2- ethoxycyclopropyl)-4H-l,2,4-triazol-3-yl)-l-methoxy-2-propan esulfonamide;

(lR,2S)-l-(5-chloro-2-pyrimidinyl)-N-(4-(2,6-dimethoxyphenyl )-5-((lR,2S)-2- ethoxycyclopropyl)-4H-l,2,4-triazol-3-yl)-l-methoxy-2-propan esulfonamide;

(lR,2S)-l-(5-chloro-2-pyrimidinyl)-N-(4-(2,6-dimethoxyphenyl )-5-((lS,2S)-2- ethoxycyclopropyl)-4H-l,2,4-triazol-3-yl)-l-methoxy-2-propan esulfonamide;

(lR,2S)-l-(5-chloro-2-pyrimidinyl)-N-(4-(2,6-dimethoxyphenyl )-5-((lR,2R)-2- ethoxycyclopropyl)-4H-l,2,4-triazol-3-yl)-l-methoxy-2-propan esulfonamide;

(lR,2S)-l-(5-chloro-2-pyrimidinyl)-N-(4-(4,6-dimethoxy-5-pyr imidinyl)-5-(3- methylidenecyclobutyl)-4H-l,2,4-triazol-3-yl)-l-methoxy-2-pr opanesulfonamide;

(lR,2S)-l-(5-chloro-2-pyrimidinyl)-N-(4-(2,6-dimethoxyphenyl )-5-(3,3- dimethylcyclobutyl)-4H-l,2,4-triazol-3-yl)-l-methoxy-2-propa nesulfonamide;

(lR,2S) -(5-chloro-2-pyrimidinyl)-N-(4-(4,6-dimethoxy-5-pyrimidinyl) -5-(3,3- dimethylcyclobutyl)-4H-l,2,4-triazol-3-yl)-l-methoxy-2-propa nesulfonamide;

(lR,2S)-l-(5-chloro-2-pyrimidinyl)-N-(5-(cis-3-cyanocyclobut yl)-4-(2,6- dimethoxyphenyl)-4H-l,2,4-triazol-3-yl)-l-methoxy-2-propanes ulfonamide;

(lR,2S)-l-(5-chloro-2-pyrimidinyl)-N-(5-(trans-3-cyanocyclob utyl)-4-(2,6- dimethoxyphenyl)-4H-l,2,4-triazol-3-yl)-l-methoxy-2-propanes ulfonamide;

(lR,2S)-l-(5-chloro-2-pyrimidinyl)-N-(4-(2,6-dimethoxyphenyl )-5-(cis-3- (¾ydroxymethyl)cyclobutyl)-4H-l,2,4-triazol-3-yl)-l-methoxy -2-propanesulfonamide;

(lR,2S)-l-(5-chloro-2-pyrimidinyl)-N-(4-(2,6-dimethoxyphenyl )-5-(trans-3- (¾ydroxymethyl)cyclobutyl)-4H-l,2,4-triazol-3-yl)-l-methoxy -2-propanesulfonamide;

(2S,3R)-3-(5-chloro-2-pyrimidinyl)-N-(4-(2,6-dimethoxyphenyl )-5-(l-(2- pyridiny l)cy clopropy 1)-4H- 1 ,2,4-triazol-3 -y l)-2-butanesulfonamide ;

(2S,3R)-N-(4-(2,6-dimethoxyphenyl)-5-(l-(2-pyridinyl)cyclopr opyl)-4H-l,2,4- triazol-3-yl)-3-(5-methyl-2-pyrimidinyl)-2-butanesulfonamide ;

(2S,3R)-N-(4-(2,6-dimethoxyphenyl)-5-(l-(3-pyridinyl)cyclobu tyl)-4H-l,2,4- triazol-3-yl)-3-(5-methyl-2-pyrimidinyl)-2-butanesulfonamide ; (lR,2S)-l-(5-chloro-2-pyrimidinyl)-N-(5-cyclobut l-4-(2-propanyl)-4H-l,2,4- triazol-3 -y 1) - 1 -methoxy -2-propanesulfonamide ;

(lR,2S)-l-(5-chloro-2-pyrimidinyl)-N-(5-(cis-3-(hydroxymethy l)cyclobutyl)-4- (l-(methoxymethyl)cyclopropyl)-4H-l,2,4-triazol-3-yl)-l-meth oxy-2- propane sulfonamide ;

(lR,2S)-l-(5-chloro-2-pyrimidinyl)-N-(5-(trans-3-(¾ydroxyme thyl)cyclobutyl)-4- (l-(methoxymethyl)cyclopropyl)-4H-l,2,4-triazol-3-yl)-l-meth oxy-2- propane sulfonamide ;

(lR,2S)-l-(5-chloro-2-pyrimidinyl)-N-(4-(l,3-dimethoxy-2-pro panyl)-5-(trans-3- (hydroxymethyl)cyclobutyl)-4H-l,2,4-triazol-3-yl)-l-methoxy -2-propanesulfonamide; or

(lR,2S)-l-(5-chloro-2-pyrimidinyl)-N-(4-(l,3-dimethoxy-2- propanyl)-5-(cis-3- (hydroxymethyl)cyclobutyl)-4H-l,2,4-triazol-3-yl)-l-methoxy -2-propanesulfonamide; 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.

[0127] 66. The compound of embodiment 1, wherein the compound is selected from

(lR,2S)-l-(5-chloropyrimidin-2-yl)-N-(4-(4,6-dimethoxypyrimi din-5-yl)-5-(2- fluorocy clopropy 1)-4H- 1 ,2,4-triazol-3 -y 1)- 1 -methoxypropane-2-sulfonamide;

(lR,2S)-l-(5-chloropyrimidin-2-yl)-N-(5-(2,2-difluorocyclopr opyl)-4-(4,6- dimethoxypyrimidin-5-yl)-4H-l,2,4-triazol-3-yl)-l-methoxypro pane-2-sulfonamide;

(lR,2S)-l-(5-chloropyrimidin-2-yl)-N-(4-(4,6-dimethoxypyrimi din-5-yl)-5-(2- (trifluoromethyl)cyclopropyl)-4H-l,2,4-triazol-3-yl)-l-metho xypropane-2-sulfonamide;

(lR,2S)-l-(5-chloropyrimidin-2-yl)-N-(5-(2,2-difluoro-3-meth ylcyclopropyl)-4- (4,6-dimethoxypyrimidin-5-yl)-4H-l,2,4-triazol-3-yl)-l-metho xypropane-2-sulfonamide;

(lR,2S)-l-(5-chloropyrimidin-2-yl)-N-(5-(2-(difluoromethyl)c yclopropyl)-4-(4,6- dimethoxypyrimidin-5-yl)-4H-l,2,4-triazol-3-yl)-l-methoxypro pane-2-sulfonamide;

(lR,2S)-l-(5-chloropyrimidin-2-yl)-N-(5-(l-(2,2-difluoroethy l)cyclopropyl)-4- (4,6-dimethoxypyrimidin-5-yl)-4H-l,2,4-triazol-3-yl)-l-metho xypropane-2-sulfonamide;

(lR,2S)-l-(5-chloropyrimidin-2-yl)-N-(4-(4,6-dimethoxypyrimi din-5-yl)-5-(l- (trifluoromethyl)cyclopropyl)-4H-l,2,4-triazol-3-yl)-l-metho xypropane-2-sulfonamide;

(lR,2S)-l-(5-chloropyrimidin-2-yl)-N-(5-(3,3-difluorocyclobu tyl)-4-(4,6- dimethoxypyrimidin-5-yl)-4H-l,2,4-triazol-3-yl)-l-methoxypro pane-2-sulfonamide; (lR,2S)-l-(5-chloropyrimidin-2-yl)-N-(4-(4,6-dimethoxypyrimi din-5-yl)-5-(3- hy droxy cyclobuty 1)-4H- 1 ,2,4-triazol-3 -y 1)- 1 -methoxypropane-2-sulfonamide;

(lR,2S)-l-(5-chloropyrimidin-2-yl)-N-(4-(4,6-dimethoxypyrimi din-5-yl)-5-(3- (¾ydroxymethyl)cyclobutyl)-4H-l,2,4-triazol-3-yl)-l-methoxy propane-2-sulfonamide;

(lR,2S)-l-(5-chloropyrimidin-2-yl)-N-(4-(4,6-dimethoxypyrimi din-5-yl)-5-(3- oxocyclobutyl)-4H-l,2,4-triazol-3-yl)-l-methoxypropane-2-sul fonamide;

(lR,2S)-l-(5-chloropyrimidin-2-yl)-N-(5-(3-cyanocyclobutyl)- 4-(4,6- dimethoxypyrimidin-5-yl)-4H-l,2,4-triazol-3-yl)-l-methoxypro pane-2-sulfonamide;

(lR,2S)-l-(5-chloropyrimidin-2-yl)-N-(4-(4,6-dimethoxypyrimi din-5-yl)-5-(2- fluorocy clobuty 1)-4H- 1 ,2,4-triazol-3 -y 1)- 1 -methoxypropane-2-sulfonamide;

(lR,2S)-l-(5-chloropyrimidin-2-yl)-N-(4-(4,6-dimethoxypyrimi din-5-yl)-5-(l- fluorocy clobuty 1)-4H- 1 ,2,4-triazol-3 -yl)- 1 -methoxypropane-2-sulfonamide;

(lR,2S)-l-(5-chloropyrimidin-2-yl)-N-(4-(4,6-dimethoxypyrimi din-5-yl)-5-(l- hy droxy cyclobuty 1)-4H- 1 ,2,4-triazol-3 -yl)- 1 -methoxypropane-2-sulfonamide;

(lR,2S)-l-(5-chloropyrimidin-2-yl)-N-(4-(4,6-dimethoxypyrimi din-5-yl)-5-(4- (trifluoromethy l)bicy clo [1.1.1 ]pentan-2-y 1)-4H- 1 ,2,4-triazol-3 -y 1)- 1 -methoxypropane-2- sulfonamide;

(lR,2S)-l-(5-chloropyrimidin-2-yl)-N-(5-(3-(difluoromethoxy) cyclobutyl)-4- (4,6-dimethoxypyrimidin-5-yl)-4H-l,2,4-triazol-3-yl)-l-metho xypropane-2-sulfonamide;

(lR,2S)-l-(5-chloropyrimidin-2-yl)-N-(4-(4,6-dimethoxypyrimi din-5-yl)-5-(2- (fluoromethy l)cy clobuty 1)-4H- 1 ,2,4-triazol-3 -y 1)- 1 -methoxypropane-2-sulfonamide;

(lR,2S)-l-(5-chloropyrimidin-2-yl)-N-(5-(2-(difluoromethyl)c yclobutyl)-4-(4,6- dimethoxypyrimidin-5-yl)-4H-l,2,4-triazol-3-yl)-l-methoxypro pane-2-sulfonamide;

(lR,2S)-l-(5-chloropyrimidin-2-yl)-N-(5-(l-(difluoromethyl)c yclobutyl)-4-(4,6- dimethoxypyrimidin-5-yl)-4H-l,2,4-triazol-3-yl)-l-methoxypro pane-2-sulfonamide;

(lR,2S)-l-(5-chloropyrimidin-2-yl)-N-(4-(4,6-dimethoxypyrimi din-5-yl)-5-(l- (trifluoromethyl)cyclobutyl)-4H-l,2,4-triazol-3-yl)-l-methox ypropane-2-sulfonamide;

(lR,2S)-l-(5-chloropyrimidin-2-yl)-N-(5-(2,2-difluorocyclobu tyl)-4-(4,6- dimethoxypyrimidin-5-yl)-4H-l,2,4-triazol-3-yl)-l-methoxypro pane-2-sulfonamide;

(lR,2S)-l-(5-chloropyrimidin-2-yl)-N-(4-(4,6-dimethoxypyrimi din-5-yl)-5-(l- hy droxy cyclopentyl)-4H-l,2,4-triazol-3-yl)-l-methoxypropane-2-sulfo namide;

(lR,2S)-l-(5-chloropyrimidin-2-yl)-N-(5-(cyclopent-3-en-l-yl )-4-(4,6- dimethoxypyrimidin-5-yl)-4H-l,2,4-triazol-3-yl)-l-methoxypro pane-2-sulfonamide; (lR,2S)-l-(5-chloropyrimidin-2-yl)-N-(5-(3,3-difluorocyclope ntyl)-4-(4,6- dimethoxypyrimidin-5-yl)-4H-l,2,4-triazol-3-yl)-l-methoxypro pane-2-sulfonamide;

(lR,2S)-l-(5-chloropyrimidin-2-yl)-N-(5-(2,2-difluorocyclope ntyl)-4-(4,6- dimethoxypyrimidin-5-yl)-4H-l,2,4-triazol-3-yl)-l-methoxypro pane-2-sulfonamide;

(lR,2S)-l-(5-chloropyrimidin-2-yl)-N-(4-(4,6-dimethoxypyrimi din-5-yl)-5-(3- methoxycyclopentyl)-4H-l,2,4-triazol-3-yl)-l-methoxypropane- 2-sulfonamide;

(lR,2S)-l-(5-chloropyrimidin-2-yl)-N-(5-(l-(difluoromethyl)c yclopentyl)-4-(4,6- dimethoxypyrimidin-5-yl)-4H-l,2,4-triazol-3-yl)-l-methoxypro pane-2-sulfonamide;

(lR,2S)-l-(5-chloropyrimidin-2-yl)-N-(4-(4,6-dimethoxypyrimi din-5-yl)-5-(3- fluorocy clopenty 1)-4H- 1 ,2,4-triazol-3 -y 1)- 1 -methoxypropane-2-sulfonamide;

(lR,2S)-N-(5-(bicyclo[3.1.0]hexan-3-yl)-4-(4,6-dimethoxypyri midin-5-yl)-4H- l,2,4-triazol-3-yl)-l-(5-chloropyrimidin-2-yl)-l-methoxyprop ane-2-sulfonamide;

(lR,2S)-l-(5-chloropyrimidin-2-yl)-N-(4-(4,6-dimethoxypyrimi din-5-yl)-5-(2- (hy droxymethy l)cyclohexy 1)-4H- 1 ,2,4-triazol-3 -yl)- 1 -methoxypropane-2-sulfonamide;

(lR,2S)-l-(5-chloropyrimidin-2-yl)-N-(4-(4,6-dimethoxypyrimi din-5-yl)-5-(4- (hy droxymethy l)cyclohexy 1)-4H- 1 ,2,4-triazol-3 -yl)- 1 -methoxypropane-2-sulfonamide;

(lR,2S)-l-(5-chloropyrimidin-2-yl)-N-(4-(4,6-dimethoxypyrimi din-5-yl)-5-(2- hydroxycyclohexyl)-4H-l,2,4-triazol-3-yl)-l-methoxypropane-2 -sulfonamide;

(lR,2S)-l-(5-chloropyrimidin-2-yl)-N-(4-(4,6-dimethoxypyrimi din-5-yl)-5-(4- oxocyclohexyl)-4H-l,2,4-triazol-3-yl)-l-methoxypropane-2-sul fonamide;

(lR,2S)-l-(5-chloropyrimidin-2-yl)-N-(5-(4-(difluoromethoxy) cyclohexyl)-4- (4,6-dimethoxypyrimidin-5-yl)-4H-l,2,4-triazol-3-yl)-l-metho xypropane-2-sulfonamide;

N-(5-cyclobutyl-4-(2,6-dimethoxyphenyl)-4H-l,2,4-triazol-3-y l)-l-(5- methylpyrimidin-2-yl)piperidine-3-sulfonamide;

N-(5-cyclobutyl-4-(2,6-dimethoxyphenyl)-4H-l,2,4-triazol-3-y l)-5-methoxy-l- (5-methylpyrimidin-2-yl)piperidine-3-sulfonamide;

(lR,2S)-l-(5-chloropyrimidin-2-yl)-N-(5-cyclobutyl-4-(2-meth oxyethyl)-4H- l,2,4-triazol-3-yl)-l-methoxypropane-2-sulfonamide;

(lR,2S)-l-(5-chloropyrimidin-2-yl)-N-(4-(4,6-dimethoxypyrimi din-5-yl)-5-((S)- 2,2-dimethylcyclobutyl)-4H-l,2,4-triazol-3-yl)-l-methoxyprop ane-2-sulfonamide; or

(lR,2S)-l-(5-chloropyrimidin-2-yl)-N-(4-(4,6-dimethoxypyr imidin-5-yl)-5-((R)- 2,2-dimethylcyclobutyl)-4H-l,2,4-triazol-3-yl)-l-methoxyprop ane-2-sulfonamide; 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.

[0128] 67. The compound of embodiment 1, wherein the compound is selected from

(lR,2S)-l-(5-chloro-2-pyrimidinyl)-N-(5-cyclopentyl-4-(4,6-d imethoxy-5- pyrimidiny 1)-4H- 1 ,2,4-triazol-3 -y 1)- 1 -methoxy -2-propanesulfonamide ;

(2S,3R)-N-(5-cyclopentyl-4-(2,6-dimethoxyphenyl)-4H-l,2,4-tr iazol-3-yl)-3-(5- methyl-2-pyrimidinyl)-2-butanesulfonamide;

(2S,3R)-N-(5-cyclopentyl-4-(4,6-dimethoxy-5-pyrimidinyl)-4H- l,2,4-triazol-3- yl)-3-(5-methyl-2-pyrimidinyl)-2-butanesulfonamide;

(lR,2S)-l-(5-chloro-2-pyrimidinyl)-N-(5-cyclohexyl-4-(4,6-di methoxy-5- pyrimidiny 1)-4H- 1 ,2,4-triazol-3 -y 1)- 1 -methoxy -2-propanesulfonamide ;

(2S,3R)-N-(5-cyclohexyl-4-(4,6-dimethoxy-5-pyrimidinyl)-4H-l ,2,4-triazol-3- yl)-3-(5-methyl-2-pyrimidinyl)-2-butanesulfonamide;

(lR,2S)-l-(5-chloro-2-pyrimidinyl)-N-(5-cyclobutyl-4-(4,6-di methoxy-5- pyrimidiny 1)-4H- 1 ,2,4-triazol-3 -y 1)- 1 -methoxy -2-propanesulfonamide ;

(2S,3R)-N-(5-cyclobutyl-4-(4,6-dimethoxy-5-pyrimidinyl)-4H-l ,2,4-triazol-3- yl)-3-(5-methyl-2-pyrimidinyl)-2-butanesulfonamide;

(lR,2S)-N-(5-cyclopropyl-4-(2,6-dimethoxyphenyl)-4H-l,2,4-tr iazol-3-yl)-l- methoxy-l-(5-methyl-2-pyrimidinyl)-2-propanesulfonamide;

(2S,3R)-N-(5-cyclopropyl-4-(4,6-dimethoxy-5-pyrimidinyl)-4H- l,2,4-triazol-3- yl)-3-(5-methyl-2-pyrimidinyl)-2-butanesulfonamide;

(lR,2S)-l-(5-chloro-2-pyrimidinyl)-N-(5-cyclopropyl-4-(4,6-d imethoxy-5- pyrimidiny 1)-4H- 1 ,2,4-triazol-3 -y 1)- 1 -methoxy -2-propanesulfonamide; or

(lR,2S)-l-(5-chloropyrimidin-2-yl)-N-(5-((2R,3S,4S,5S,6S,7R, 8S)-cuban-l-yl)- 4-(4,6-dimethoxypyrimidin-5-yl)-4H-l,2,4-triazol-3-yl)-l-met hoxypropane-2- sulfonamide; 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.

[0129] 68. The compound of embodiment 1, wherein the compound is selected from

(lR,2S)-l-(5-chloro-2-pyrimidinyl)-N-(5-(tjans-3-(¾ydroxyme thyl)cyclobutyl)-4- (l-(methoxymethyl)cyclopropyl)-4H-l,2,4-triazol-3-yl)-l-meth oxy-2- propane sulfonamide ;

(lR,2S)-l-(5-chloro-2-pyrimidinyl)-N-(5-(cis-3-(hydroxymethy l)cyclobutyl)-4- (l-(methoxymethyl)cyclopropyl)-4H-l,2,4-triazol-3-yl)-l-meth oxy-2- propane sulfonamide ;

(lR,2S)-l-(5-chloro-2-pyrimidinyl)-N-(4-cyclopropyl-5-(trans -3- (¾ydroxymethyl)cyclobutyl)-4H-l,2,4-triazol-3-yl)-l-methoxy -2-propanesulfonamide;

(lR,2S)-l-(5-chloro-2-pyrimidinyl)-N-(4-cyclopropyl-5-(cis-3 - (¾ydroxymethyl)cyclobutyl)-4H-l,2,4-triazol-3-yl)-l-methoxy -2-propanesulfonamide;

(lR,2S)-l-(5-chloro-2-pyrimidinyl)-N-(5-(tjans-3-(¾ydroxyme thyl)cyclobutyl)-4- (2-propany 1)-4H- 1 ,2,4-triazol-3-y 1)- 1 -methoxy -2-propanesulfonamide ;

(lR,2S)-l-(5-chloro-2-pyrimidinyl)-N-(5-(cis-3-(hydroxymethy l)cyclobutyl)-4- (2-propanyl)-4H- 1 ,2,4-triazol-3-y 1)- 1 -methoxy -2-propanesulfonamide ;

(lR,2S)-N-(5-cyclobutyl-4-(2,6-dimethoxyphenyl)-4H-l,2,4-tri azol-3-yl)-l- methoxy - 1 -(5 -methy 1-2-py raziny l)-2 -propane sulfonamide ;

(2S,3R)-N-(5-cyclobutyl-4-(2,6-dimethoxyphenyl)-4H-l,2,4-tri azol-3-yl)-3-(5- methyl-2-pyrazinyl)-2-butanesulfonamide;

(lS,2S)-N-(5-cyclobutyl-4-(2,6-dimethoxyphenyl)-4H-l,2,4-tri azol-3-yl)-l-(5- methyl-2-pyrazinyl)-l-(2-propanyloxy)-2-propanesulfonamide;

(lR,2S)-N-(5-cyclobutyl-4-(2,6-dimethoxyphenyl)-4H-l,2,4-tri azol-3-yl)-l- methoxy-l-(5-methyl-2-pyrimidinyl)-2-propanesulfonamide;

(lS,2S)-N-(5-cyclobutyl-4-(2,6-dimethoxyphenyl)-4H-l,2,4-tri azol-3-yl)-l-(5- methyl-2-pyrimidinyl)-l-(2-propanyloxy)-2-propanesulfonamide ; (lR,2S)-l-(5-chloro-2-pyrimidinyl)-N-(5-(cis-4-(difluorometh yl)cyclohexyl)-4- (4,6-dimethoxy-5-pyrimidinyl)-4H-l,2,4-triazol-3-yl)-l-metho xy-2-propanesulfonamide;

(lR,2S)-l-(5-chloro-2-pyrimidinyl)-N-(5-(trans-4-(difluorome thyl)cyclohexyl)-4- (4,6-dimethoxy-5-pyrimidinyl)-4H-l,2,4-triazol-3-yl)-l-metho xy-2-propanesulfonamide;

(lR,2S)-l-(5-chloropyrimidin-2-yl)-N-(5-((lR,2S)-2- (difluoromethyl)cyclobutyl)-4-(4,6-dimethoxypyrimidin-5-yl)- 4H-l,2,4-triazol-3-yl)-l- methoxypropane-2-sulfonamide;

(lR,2S)-l-(5-chloropyrimidin-2-yl)-N-(5-((lS,2R)-2- (difluoromethyl)cyclobutyl)-4-(4,6-dimethoxypyrimidin-5-yl)- 4H-l,2,4-triazol-3-yl)-l- methoxypropane-2-sulfonamide;

(lR,2S)-l-(5-chloropyrimidin-2-yl)-N-(5-((lR,2R)-2- (difluoromethyl)cyclobutyl)-4-(4,6-dimethoxypyrimidin-5-yl)- 4H-l,2,4-triazol-3-yl)-l- methoxypropane-2-sulfonamide;

(lR,2S)-l-(5-chloropyrimidin-2-yl)-N-(5-((lS,2S)-2- (difluoromethyl)cyclobutyl)-4-(4,6-dimethoxypyrimidin-5-yl)- 4H-l,2,4-triazol-3-yl)-l- methoxypropane-2-sulfonamide;

(lR,2S)-l-(5-chloro-2-pyrimidinyl)-N-(5-(3,3-difluorocyclobu tyl)-4-(2,6- dimethoxyphenyl)-4H-l,2,4-triazol-3-yl)-l-methoxy-2-propanes ulfonamide;

(lR,2S)-l-(5-chloropyrimidin-2-yl)-N-(4-(2,6-dimethoxyphenyl )-5-((lr,3S)-3- methy Icy clobuty 1)-4H- 1 ,2,4-triazol-3 -y 1)- 1 -methoxypropane-2-sulfonamide ;

(lR,2S)-l-(5-chloropyrimidin-2-yl)-N-(4-(2,6-dimethoxyphenyl )-5-((ls,3R)-3- methy Icy clobuty 1)-4H- 1 ,2,4-triazol-3 -yl)- 1 -methoxypropane-2-sulfonamide ;

(lR,2S)-l-(5-chloropyrimidin-2-yl)-N-(4-(2,6-dimethoxyphenyl )-5-((lr,3S)-3- (trifluoromethyl)cyclobutyl)-4H-l,2,4-triazol-3-yl)-l-methox ypropane-2-sulfonamide;

(lR,2S)-l-(5-chloropyrimidin-2-yl)-N-(4-(2,6-dimethoxyphenyl )-5-((ls,3R)-3- (trifluoromethyl)cyclobutyl)-4H-l,2,4-triazol-3-yl)-l-methox ypropane-2-sulfonamide;

(lR,2S)-l-(5-chloropyrimidin-2-yl)-N-(4-(2,6-dimethoxyphenyl )-5-((lr,3S)-3- fluorocy clobuty 1)-4H- 1 ,2,4-triazol-3 -yl)- 1 -methoxypropane-2-sulfonamide;

(lR,2S)-l-(5-chloropyrimidin-2-yl)-N-(4-(2,6-dimethoxyphenyl )-5-((ls,3R)-3- fluorocy clobuty 1)-4H- 1 ,2,4-triazol-3 -yl)- 1 -methoxypropane-2-sulfonamide; (lR,2S)-l-(5-chloropyrimidin-2-yl)-N-(4-(2,6-dimethoxyphenyl )-5-((lr,3S)-3- chlorocyclobutyl)-4H-l,2,4-triazol-3-yl)-l-methoxypropane-2- sulfonamide;

(lR,2S)-l-(5-chloropyrimidin-2-yl)-N-(4-(2,6-dimethoxyphenyl )-5-((ls,3R)-3- chlorocyclobutyl)-4H-l,2,4-triazol-3-yl)-l-methoxypropane-2- sulfonamide;

(lR,2S)-l-(5-chloropyrimidin-2-yl)-N-(4-(2,6-dimethoxyphenyl )-5-((lr,3S)-3- methoxycyclobutyl)-4H-l,2,4-triazol-3-yl)-l-methoxypropane-2 -sulfonamide;

(lR,2S)-l-(5-chloropyrimidin-2-yl)-N-(4-(2,6-dimethoxyphenyl )-5-((ls,3R)-3- methoxycyclobutyl)-4H-l,2,4-triazol-3-yl)-l-methoxypropane-2 -sulfonamide;

(lR,2S)-l-(5-chloropyrimidin-2-yl)-N-(5-((R)-2,2-difluorocyc lobutyl)-4-(2,6- dimethoxypheny 1)-4H- 1 ,2,4-triazol-3-y 1)- 1 -methoxypropane-2-sulfonamide ;

(lR,2S)-l-(5-chloropyrimidin-2-yl)-N-(5-((S)-2,2-difluorocyc lobutyl)-4-(2,6- dimethoxypheny 1)-4H- 1 ,2,4-triazol-3-y 1)- 1 -methoxypropane-2-sulfonamide ;

(lR,2S)-l-(5-chloropyrimidin-2-yl)-N-(4-(4,6-dimethoxypyrimi din-5-yl)-5- ((ls,3R)-3-fluorocyclobutyl)-4H-l,2,4-triazol-3-yl)-l-methox ypropane-2-sulfonamide;

(lR,2S)-l-(5-chloropyrimidin-2-yl)-N-(4-(4,6-dimethoxypyrimi din-5-yl)-5- ((lr,3S)-3-fluorocyclobutyl)-4H-l,2,4-triazol-3-yl)-l-methox ypropane-2-sulfonamide;

(lR,2S)-l-(5-chloropyrimidin-2-yl)-N-(4-(4,6-dimethoxypyrimi din-5-yl)-5- ((ls,3R)-3-chlorocyclobutyl)-4H-l,2,4-triazol-3-yl)-l-methox ypropane-2-sulfonamide;

(lR,2S)-l-(5-chloropyrimidin-2-yl)-N-(4-(4,6-dimethoxypyrimi din-5-yl)-5- (( lr,3 S)-3 -chlorocy clobuty 1)-4H- 1 ,2,4-triazol-3-y 1)- 1 -methoxypropane-2-sulfonamide;

(2S,3R)-3-(5-chloropyrimidin-2-yl)-N-(5-((lR,2S)-2- (difluoromethyl)cy clobuty l)-4-(4,6-dimethoxypyrimidin-5-yl)-4H- 1,2, 4-triazol-3- yl)butane-2-sulfonamide;

(2S,3R)-3-(5-chloropyrimidin-2-yl)-N-(5-((lS,2R)-2- (difluoromethyl)cy clobuty l)-4-(4,6-dimethoxypyrimidin-5-yl)-4H- 1,2, 4-triazol-3- yl)butane-2-sulfonamide;

(2S,3R)-3-(5-chloropyrimidin-2-yl)-N-(5-((lR,2R)-2- (difluoromethyl)cy clobuty l)-4-(4,6-dimethoxypyrimidin-5-yl)-4H- 1,2, 4-triazol-3- yl)butane-2-sulfonamide; (2S,3R)-3-(5-chloropyrimidin-2-yl)-N-(5-((lS,2S)-2- (difluoromethyl)cy clobuty l)-4-(4,6-dimethoxypyrimidin-5-yl)-4H- 1,2, 4-triazol-3- yl)butane-2-sulfonamide;

(lS,2S)-l-(5-chloropyrimidin-2-yl)-N-(5-((lR,2S)-2- (difluoromethyl)cyclobutyl)-4-(4,6-dimethoxypyrimidin-5-yl)- 4H-l,2,4-triazol-3-yl)-l- isopropoxypropane-2-sulfonamide;

(lS,2S)-l-(5-chloropyrimidin-2-yl)-N-(5-((lS,2R)-2- (difluoromethyl)cyclobutyl)-4-(4,6-dimethoxypyrimidin-5-yl)- 4H-l,2,4-triazol-3-yl)-l- isopropoxypropane-2-sulfonamide;

(lR,2S)-l-(5-chloropyrimidin-2-yl)-N-(5-((lR,2S)-2-cyanocycl obutyl)-4-(2,6- dimethoxypheny 1)-4H- 1 ,2,4-triazol-3-y 1)- 1 -methoxypropane-2-sulfonamide ;

(lR,2S)-l-(5-chloropyrimidin-2-yl)-N-(5-((lS,2R)-2-cyanocycl obutyl)-4-(2,6- dimethoxypheny 1)-4H- 1 ,2,4-triazol-3-y 1)- 1 -methoxypropane-2-sulfonamide ;

(lR,2S)-l-(5-chloropyrimidin-2-yl)-N-(5-((lR,2R)-2-cyanocycl obutyl)-4-(2,6- dimethoxypheny 1)-4H- 1 ,2,4-triazol-3-y 1)- 1 -methoxypropane-2-sulfonamide ;

(lR,2S)-l-(5-chloropyrimidin-2-yl)-N-(4-(4,6-dimethoxypyrimi din-5-yl)-5- ((ls,4R)-4-fluorocyclohexyl)-4H-l,2,4-triazol-3-yl)-l-methox ypropane-2-sulfonamide;

(lR,2S)-l-(5-chloropyrimidin-2-yl)-N-(4-(4,6-dimethoxypyrimi din-5-yl)-5- ((lr,4S)-4-fluorocyclohexyl)-4H-l,2,4-triazol-3-yl)-l-methox ypropane-2-sulfonamide;

(lR,2S)-l-(5-chloropyrimidin-2-yl)-N-(4-(4,6-dimethoxypyrimi din-5-yl)-5- ((ls,3R)-3-(trifluoromethyl)cyclobutyl)-4H-l,2,4-triazol-3-y l)-l-methoxypropane-2- sulfonamide;

(lR,2S)-l-(5-chloropyrimidin-2-yl)-N-(4-(4,6-dimethoxypyrimi din-5-yl)-5- (( lr,3 S)-3-(trifluoromethyl)cy clobuty 1)-4H- 1 ,2,4-triazol-3 -yl)- 1 -methoxypropane-2- sulfonamide;

(lR,2S)-l-(5-chloropyrimidin-2-yl)-N-(4-(4,6-dimethoxypyrimi din-5-yl)-5- (( 1 S,2S)-2-fluorocy clobuty 1)-4H- 1 ,2,4-triazol-3 -y 1)- 1 -methoxypropane-2-sulfonamide;

(lR,2S)-l-(5-chloropyrimidin-2-yl)-N-(4-(4,6-dimethoxypyrimi din-5-yl)-5- ((lR,2R)-2-fluorocyclobutyl)-4H-l,2,4-triazol-3-yl)-l-methox ypropane-2-sulfonamide; (lR,2S)-l-(5-chloropyrimidin-2-yl)-N-(4-(4,6-dimethoxypyrimi din-5-yl)-5- ((lR,2S)-2-fluorocyclobutyl)-4H-l,2,4-triazol-3-yl)-l-methox ypropane-2-sulfonamide;

(lR,2S)-l-(5-chloropyrimidin-2-yl)-N-(4-(4,6-dimethoxypyrimi din-5-yl)-5- ((lS,2R)-2-fluorocyclobutyl)-4H-l,2,4-triazol-3-yl)-l-methox ypropane-2-sulfonamide;

(lR,2S)-l-(5-chloropyrimidin-2-yl)-N-(4-(4,6-dimethoxypyrimi din-5-yl)-5- ((lS,2S)-2-methylcyclobutyl)-4H-l,2,4-triazol-3-yl)-l-methox ypropane-2-sulfonamide;

(lR,2S)-l-(5-chloropyrimidin-2-yl)-N-(4-(4,6-dimethoxypyrimi din-5-yl)-5- ((lR,2R)-2-methylcyclobutyl)-4H-l,2,4-triazol-3-yl)-l-methox ypropane-2-sulfonamide;

(lR,2S)-l-(5-chloropyrimidin-2-yl)-N-(4-(4,6-dimethoxypyrimi din-5-yl)-5- ((lS,2R)-2-methylcyclobutyl)-4H-l,2,4-triazol-3-yl)-l-methox ypropane-2-sulfonamide;

(lR,2S)-l-(5-chloropyrimidin-2-yl)-N-(4-(4,6-dimethoxypyrimi din-5-yl)-5- ((lR,2S)-2-methylcyclobutyl)-4H-l,2,4-triazol-3-yl)-l-methox ypropane-2-sulfonamide;

(lR,2S)-N-(5-((lr,3S)-3-chlorocyclobutyl)-4-(2,6-dimethoxyph enyl)-4H-l,2,4- triazol-3 -y 1)- 1 -methoxy- 1 -(5 -methy lpyrimidin-2-y l)propane-2-sulfonamide;

(lR,2S)-N-(5-((ls,3R)-3-chlorocyclobutyl)-4-(2,6-dimethoxyph enyl)-4H-l,2,4- triazol-3 -y 1)- 1 -methoxy- 1 -(5 -methy lpyrimidin-2-y l)propane-2-sulfonamide;

(2S,3R)-N-(5-((lr,3S)-3-chlorocyclobutyl)-4-(2,6-dimethoxyph enyl)-4H-l,2,4- triazol-3-yl)-3-(5-methylpyrimidin-2-yl)butane-2-sulfonamide ;

(2S,3R)-N-(5-((ls,3R)-3-chlorocyclobutyl)-4-(2,6-dimethoxyph enyl)-4H-l,2,4- triazol-3-yl)-3-(5-methylpyrimidin-2-yl)butane-2-sulfonamide ;

(lR,2S)-N-(4-(2,6-dimethoxyphenyl)-5-(spiro[2.3]hexan-5-yl)- 4H-l,2,4-triazol- 3-yl)-l-methoxy-l-(5-methylpyrimidin-2-yl)propane-2-sulfonam ide;

(lR,2S)-N-(4-(4,6-dimethoxypyrimidin-5-yl)-5-(spiro[2.3]hexa n-5-yl)-4H-l,2,4- triazol-3 -y 1)- 1 -methoxy- 1 -(5 -methy lpyrimidin-2-y l)propane-2-sulfonamide;

(2S,3R)-N-(4-(4,6-dimethoxy-5-pyrimidinyl)-5-(spiro[2.3]hexa n-5-yl)-4H-l,2,4- triazol-3-yl)-3-(5-methyl-2-pyrimidinyl)-2-butanesulfonamide ;

(lR,2S)-l-(5-chloropyrimidin-2-yl)-N-(4-(2,6-dimethoxyphenyl )-5-((lR,2R)-2- methy Icy clobuty 1)-4H- 1 ,2,4-triazol-3 -y 1)- 1 -methoxypropane-2-sulfonamide ; (lR,2S)-l-(5-chloropyrimidin-2-yl)-N-(4-(2,6-dimethoxyphenyl )-5-((lS,2R)-2- methy Icy clobuty 1)-4H- 1 ,2,4-triazol-3 -y 1)- 1 -methoxypropane-2-sulfonamide ;

(lR,2S)-l-(5-chloropyrimidin-2-yl)-N-(4-(2,6-dimethoxyphenyl )-5-((lS,2S)-2- methy Icy clobuty 1)-4H- 1 ,2,4-triazol-3 -yl)- 1 -methoxypropane-2-sulfonamide ;

(lR,2S)-l-(5-chloropyrimidin-2-yl)-N-(4-(2,6-dimethoxyphenyl )-5-((lR,2S)-2- methy Icy clobuty 1)-4H- 1 ,2,4-triazol-3 -yl)- 1 -methoxypropane-2-sulfonamide ;

(lR,2S)-N-(5-cyclobutyl-4-(2,6-dimethoxyphenyl)-4H-l,2,4-tri azol-3-yl)-l-(2,2- difluoroethoxy)-l-(5-methyl-2-pyrimidinyl)-2-propanesulfonam ide;

(lR,2S)-l-(5-chloropyrimidin-2-yl)-N-(4-(4,6-dimethoxypyrimi din-5-yl)-5- ((ls,4R)-4-methoxycyclohexyl)-4H-l,2,4-triazol-3-yl)-l-metho xypropane-2-sulfonamide;

(lR,2S)-l-(5-chloropyrimidin-2-yl)-N-(4-(4,6-dimethoxypyrimi din-5-yl)-5- ((lr,4S)-4-methoxycyclohexyl)-4H-l,2,4-triazol-3-yl)-l-metho xypropane-2-sulfonamide;

(lR,2S)-l-(5-chloropyrimidin-2-yl)-N-(4-(4,6-dimethoxypyrimi din-5-yl)-5- ((ls,4R)-4-(trifluoromethyl)cyclohexyl)-4H-l,2,4-triazol-3-y l)-l-methoxypropane-2- sulfonamide;

(lR,2S)-l-(5-chloropyrimidin-2-yl)-N-(4-(4,6-dimethoxypyrimi din-5-yl)-5- ((lr,4S)-4-(trifluoromethyl)cyclohexyl)-4H-l,2,4-triazol-3-y l)-l-methoxypropane-2- sulfonamide;

(lR,2S)-l-(5-chloro-2-pyrimidinyl)-N-(4-(4,6-dimethoxy-5-pyr imidinyl)-5- (spiro[2.3]hexan-5-yl)-4H-l,2,4-triazol-3-yl)-l-methoxy-2-pr opanesulfonamide;

(lR,2S)-l-(5-chloro-2-pyrimidinyl)-N-(4-(4,6-dimethoxy-5-pyr imidinyl)-5- (spiro[3.3]heptan-2-yl)-4H-l,2,4-triazol-3-yl)-l-methoxy-2-p ropanesulfonamide;

(lR,2S)-l-(5-chloro-2-pyrimidinyl)-N-(4-(4,6-dimethoxy-5-pyr imidinyl)-5- (trans-3-methylcyclobutyl)-4H-l,2,4-triazol-3-yl)-l-methoxy- 2-propanesulfonamide;

(lR,2S)-l-(5-chloro-2-pyrimidinyl)-N-(4-(4,6-dimethoxy-5-pyr imidinyl)-5-(cis- 3-methylcyclobutyl)-4H-l,2,4-triazol-3-yl)-l-methoxy-2-propa nesulfonamide;

(lR,2S)-l-(5-chloropyrimidin-2-yl)-N-(4-(2,6-dimethoxyphenyl )-5-((ls,3R)-3- fluoro-3-methylcyclobutyl)-4H-l,2,4-triazol-3-yl)-l-methoxyp ropane-2-sulfonamide;

(lR,2S)-l-(5-chloropyrimidin-2-yl)-N-(4-(2,6-dimethoxyphenyl )-5-((lr,3S)-3- fluoro-3-methylcyclobutyl)-4H-l,2,4-triazol-3-yl)-l-methoxyp ropane-2-sulfonamide; (lR,2S)-l-(5-chloropyrimidin-2-yl)-N-(4-(2,6-dimethoxyphenyl )-5-((R)-2,2- dimethyl-3-oxocyclobutyl)-4H-l,2,4-triazol-3-yl)-l-methoxypr opane-2-sulfonamide;

(lR,2S)-l-(5-chloropyrimidin-2-yl)-N-(4-(2,6-dimethoxyphenyl )-5-((S)-2,2- dimethyl-3-oxocyclobutyl)-4H-l,2,4-triazol-3-yl)-l-methoxypr opane-2-sulfonamide;

(lR,2S)-l-(5-chloropyrimidin-2-yl)-N-(5-((lr,4R)-4-cyanocycl ohexyl)-4-(2,6- dimethoxypheny 1)-4H- 1 ,2,4-triazol-3-y 1)- 1 -methoxypropane-2-sulfonamide ;

(lR,2S)-l-(5-chloropyrimidin-2-yl)-N-(5-((ls,4R)-4-cyanocycl ohexyl)-4-(2,6- dimethoxypheny 1)-4H- 1 ,2,4-triazol-3-y 1)- 1 -methoxypropane-2-sulfonamide ;

(lR,2S)-l-(5-chloropyrimidin-2-yl)-N-(5-(3,3-dichlorocyclobu tyl)-4-(4,6- dimethoxypyrimidin-5-yl)-4H-l,2,4-triazol-3-yl)-l-methoxypro pane-2-sulfonamide;

(lR,2S)-l-(5-chloropyrimidin-2-yl)-N-(5-((3R,5s)-l,l-difluor ospiro[2.3]hexan-5- yl)-4-(4,6-dimethoxypyrimidin-5-yl)-4H-l,2,4-triazol-3-yl)-l -methoxypropane-2- sulfonamide;

(lR,2S)-l-(5-chloropyrimidin-2-yl)-N-(5-((3S,5r)-l,l-difluor ospiro[2.3]hexan-5- yl)-4-(4,6-dimethoxypyrimidin-5-yl)-4H-l,2,4-triazol-3-yl)-l -methoxypropane-2- sulfonamide;

2-(5-chloro-2-pyrimidinyl)-N-(5-cyclobutyl-4-(2,6-dimethoxyp henyl)-4H- 1,2,4- triazol-3 -y l)ethanesulfonamide ;

(lS,2S)-l-(5-chloro-2-pyrimidinyl)-N-(5-cyclobutyl-4-(tetrah ydro-2H-pyran-4- yl)-4H-l,2,4-triazol-3-yl)-l-(2-propanyloxy)-2-propanesulfon amide;

(lR,2S)-l-(5-chloro-2-pyrimidinyl)-N-(4-(2,6-dimethoxyphenyl )-5-((lS,3S)-3- methoxycyclopentyl)-4H-l,2,4-triazol-3-yl)-l-methoxy-2-propa nesulfonamide;

(lR,2S)-l-(5-chloro-2-pyrimidinyl)-N-(4-(2,6-dimethoxyphenyl )-5-((lR,3R)-3- methoxycyclopentyl)-4H-l,2,4-triazol-3-yl)-l-methoxy-2-propa nesulfonamide;

(lR,2S)-l-(5-chloro-2-pyrimidinyl)-N-(4-(2,6-dimethoxyphenyl )-5-((lR,3S)-3- methoxycyclopentyl)-4H-l,2,4-triazol-3-yl)-l-methoxy-2-propa nesulfonamide;

(lR,2S)-l-(5-chloro-2-pyrimidinyl)-N-(4-(2,6-dimethoxyphenyl )-5-((lS,3R)-3- methoxycyclopentyl)-4H-l,2,4-triazol-3-yl)-l-methoxy-2-propa nesulfonamide;

(lR,2S)-N-(5-(bicyclo[l. l. l]pentan-l-yl)-4-(2,6-dimethoxyphenyl)-4H-l,2,4- triazol-3 -y 1)- 1 -(5 -chloropyrimidin-2-y 1)- 1 -methoxypropane-2-sulfonamide; (lR,2S)-l-(5-chloropyrimidin-2-yl)-N-(4-(2,6-dimethoxyphenyl )-5-((R)-3- oxocyclopentyl)-4H-l,2,4-triazol-3-yl)-l-methoxypropane-2-su lfonamide;

(lR,2S)-l-(5-chloropyrimidin-2-yl)-N-(4-(2,6-dimethoxyphenyl )-5-((S)-3- oxocyclopentyl)-4H-l,2,4-triazol-3-yl)-l-methoxypropane-2-su lfonamide;

(2S,3R)-3-(5-chloropyrimidin-2-yl)-N-(4-(2,6-dimethoxyphenyl )-5-((S)- spiro[2.2]pentan-l-yl)-4H-l,2,4-triazol-3-yl)butane-2-sulfon amide;

(2S,3R)-3-(5-chloropyrimidin-2-yl)-N-(4-(2,6-dimethoxyphenyl )-5-((R)- spiro[2.2]pentan-l-yl)-4H-l,2,4-triazol-3-yl)butane-2-sulfon amide;

(2S,3R)-3-(5-chloropyrimidin-2-yl)-N-(5-((R)-2,2-difluorocyc lopropyl)-4-(2,6- dimethoxyphenyl)-4H-l,2,4-triazol-3-yl)butane-2-sulfonamide;

(2S,3R)-3-(5-chloropyrimidin-2-yl)-N-(5-((S)-2,2-difluorocyc lopropyl)-4-(2,6- dimethoxyphenyl)-4H-l,2,4-triazol-3-yl)butane-2-sulfonamide;

(lR,2S)-l-(5-chloropyrimidin-2-yl)-N-(4-(2,6-dimethoxyphenyl )-5-((S)- spiro[2.2]pentan-l-yl)-4H-l,2,4-triazol-3-yl)-l-methoxypropa ne-2-sulfonamide;

(lR,2S)-l-(5-chloropyrimidin-2-yl)-N-(4-(2,6-dimethoxyphenyl )-5-((R)- spiro[2.2]pentan-l-yl)-4H-l,2,4-triazol-3-yl)-l-methoxypropa ne-2-sulfonamide;

(lS,2S)-N-(4-(2,6-dimethoxyphenyl)-5-(trans-3-methoxycyclobu tyl)-4H-l,2,4- triazol-3-yl)-l-(5-methyl-2-pyrimidinyl)-l-(2-propanyloxy)-2 -propanesulfonamide;

(lS,2S)-N-(4-(2,6-dimethoxyphenyl)-5-(cis-3-methoxycyclobuty l)-4H-l,2,4- triazol-3-yl)-l-(5-methyl-2-pyrimidinyl)-l-(2-propanyloxy)-2 -propanesulfonamide;

(lS,2S)-N-(4-(2,6-dimethoxyphenyl)-5-(cis-4-hydroxybicyclo[l . l. l]pentan-2-yl)- 4H-l,2,4-triazol-3-yl)-l-isopropoxy-l-(5-methylpyrimidin-2-y l)propane-2-sulfonam

(lS,2S)-N-(4-(2,6-dimethoxyphenyl)-5-(trans-4-hydroxybicy clo[l. l. l]pentan-2- yl)-4H-l,2,4-triazol-3-yl)-l-isopropoxy-l-(5-methylpyrimidin -2-yl)propane-2- sulfonamide;

(lS,2S)-N-(4-(2,6-dimethoxyphenyl)-5-((R)-3-oxocyclopenty l)-4H-l,2,4-triazol- 3-yl)-l-isopropoxy-l-(5-methylpyrimidin-2-yl)propane-2-sulfo namide;

(lS,2S)-N-(4-(2,6-dimethoxyphenyl)-5-((S)-3-oxocyclopenty l)-4H-l,2,4-triazol- 3-yl)-l-isopropoxy-l-(5-methylpyrimidin-2-yl)propane-2-sulfo namide; (lS,2S)-N-(4-(2,6-dimethoxyphenyl)-5-(trans-3-hydroxy-3-meth ylcyclobutyl)- 4H-l,2,4-triazol-3-yl)-l-(5-methyl-2-pyrimidinyl)-l-(2-propa nyloxy)-2- propane sulfonamide ;

(lS,2S)-N-(4-(2,6-dimethoxyphenyl)-5-(cis-3-hydroxy-3-met hylcyclobutyl)-4H- l,2,4-triazol-3-yl)-l-(5-methyl-2-pyrimidinyl)-l-(2-propanyl oxy)-2-propanesulfonamide;

(lS,2S)-N-(5-((lR)-3,3-difluorocyclopentyl)-4-(2,6-dimeth oxyphenyl)-4H-l,2,4- triazol-3-yl)-l-(5-methyl-2-pyrimidinyl)-l-(2-propanyloxy)-2 -propanesulfonamide;

(lS,2S)-N-(5-((lS)-3,3-difluorocyclopentyl)-4-(2,6-dimeth oxyphenyl)-4H-l,2,4- triazol-3-yl)-l-(5-methyl-2-pyrimidinyl)-l-(2-propanyloxy)-2 -propanesulfonamide;

(lS,2S)-N-(4-(2,6-dimethoxyphenyl)-5-((lR,2S)-2-methoxycy clopentyl)-4H- l,2,4-triazol-3-yl)-l-isopropoxy-l-(5-methylpyrimidin-2-yl)p ropane-2-sulfonamide;

(lS,2S)-N-(4-(2,6-dimethoxyphenyl)-5-((lS,2R)-2-methoxycy clopentyl)-4H- l,2,4-triazol-3-yl)-l-isopropoxy-l-(5-methylpyrimidin-2-yl)p ropane-2-sulfonamide;

(lS,2S)-N-(4-(2,6-dimethoxyphenyl)-5-((lR,2R)-2-methoxycy clopentyl)-4H- l,2,4-triazol-3-yl)-l-isopropoxy-l-(5-methylpyrimidin-2-yl)p ropane-2-sulfonamide;

(lS,2S)-N-(4-(2,6-dimethoxyphenyl)-5-((lS,2S)-2-methoxycy clopentyl)-4H- l,2,4-triazol-3-yl)-l-isopropoxy-l-(5-methylpyrimidin-2-yl)p ropane-2-sulfonamide;

(lR,2S)-l-(5-chloro-2-pyrimidinyl)-N-(4-(2,6-dimethoxyphe nyl)-5- (spiro[3.3]heptan-2-yl)-4H-l,2,4-triazol-3-yl)-l-methoxy-2-p ropanesulfonamide;

(lR,2S) -(5-chloro-2-pyrimidinyl)-N-(5-(3,3-dimethoxycyclobutyl)-4-( 4,6- dimethoxy-5-pyrimidinyl)-4H-l,2,4-triazol-3-yl)-l-methoxy-2- propanesulfonamide;

(lR,2S)-l-(5-chloropyrimidin-2-yl)-N-(4-(4,6-dimethoxypyr imidin-5-yl)-5- (( 1 s,3 S)-3-fluoro-3 -methy Icy clobuty 1)-4H- 1 ,2,4-triazol-3 -y 1)- 1 -methoxypropane-2- sulfonamide;

(lR,2S)-l-(5-chloropyrimidin-2-yl)-N-(4-(4,6-dimethoxypyr imidin-5-yl)-5- ((lr,3S)-3-fluoro-3-methylcyclobutyl)-4H-l,2,4-triazol-3-yl) -l-methoxypropane-2- sulfonamide; (lR,2S) -(5-chloro-2-pyrimidinyl)-N-(4-(2,6-dimethoxyphenyl)-5- (spiro[2 ]hexan-5-yl)-4H-l,2,4-triazol-3-yl)-l-methoxy-2-propanesulfo namide;

(lR,2S)-l-(5-chloro-2-pyrimidinyl)-N-(4-(4,6-dimethoxy-5- pyrimidinyl)-5-(2- oxaspiro[3 ]heptan-6-yl)-4H-l,2,4-triazol-3-yl)-l-methoxy-2-propanesulf onamide; or

(lR,2S)-l-(5-chloro-2-pyrimidinyl)-N-(5-cyclopentyl-4-(2, 6-dimethoxyphenyl)- 4H-l,2,4-triazol-3-yl)-l-methoxy-2-propanesulfonamide; 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.

[0130] 69. A pharmaceutical composition, comprising the compound of any one of embodiments 1-68 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.

[0131] 70. A pharmaceutical composition, comprising the compound of any one of embodiments 1-68 or the pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable excipient.

[0132] 71. A pharmaceutical composition, comprising the compound of any one of embodiments 1-68 and at least one pharmaceutically acceptable excipient.

[0133] 72. A pharmaceutical composition, comprising the pharmaceutically acceptable salt of the compound of any one of embodiments 1-68 and at least one pharmaceutically acceptable excipient.

[0134] 73. The pharmaceutical composition of any one of embodiments 69-

72, further comprising a therapeutic agent selected from an a-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.

[0135] 74. The pharmaceutical composition of any one of embodiments 69-

72, further comprising a therapeutic agent selected from an angiotensin converting enzyme (ACE) inhibitor or an angiotensin-receptor blocker (ARB).

[0136] 75. 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 1-68 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 69-74.

[0137] 76. The method of embodiment 75, wherein the cardiovascular condition is heart failure.

[0138] 77. The method of embodiment 75, wherein the cardiovascular condition is heart failure with reduced ejection fraction.

[0139] 78. The method of embodiment 75, wherein the cardiovascular condition is heart failure with preserved ejection fraction.

[0140] 79. The method of embodiment 75, wherein the cardiovascular condition is chronic systolic heart failure or chronic diastolic heart failure.

[0141] 80. The method of embodiment 75, wherein the cardiovascular condition is acute heart failure.

[0142] 81. The method of embodiment 75, wherein the cardiovascular condition is hypertension.

[0143] 82. 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 1-68 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 69-74, wherein cardiac contractility is improved in the subject after administration.

[0144] 83. 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 1-68 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 69-74, wherein the ejection fraction is increased in the subject after administration.

[0145] 84. 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 1-68 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 69-74.

[0146] 85. The method of embodiment 84, wherein the condition is obesity or diabetes. [0147] 86. The method of embodiment 84, wherein the condition is diabetic nephropathy or chronic kidney disease.

[0148] 87. The method of any one of embodiments 75-86, wherein the method includes administering at least one additional therapeutic agent to the subject, wherein the additional therapeutic agent is selected from an a-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.

[0149] 88. The method of any one of embodiments 75-86, 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).

[0150] 89. A compound of any one of embodiments 1-68 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 69-74 for use in treating a cardiovascular condition.

[0151] 90. The compound of embodiments 89, wherein the cardiovascular condition is heart failure.

[0152] 91. The compound of embodiment 89, wherein the cardiovascular condition is heart failure with reduced ejection fraction.

[0153] 92. The compound of embodiment 89, wherein the cardiovascular condition is heart failure with preserved ejection fraction.

[0154] 93. The compound of embodiment 89, wherein the cardiovascular condition is chronic systolic heart failure or chronic diastolic heart failure.

[0155] 94. The compound of embodiment 89, wherein the cardiovascular condition is acute heart failure.

[0156] 95. The compound of embodiment 89, wherein the cardiovascular condition is hypertension.

[0157] 96. A compound of any one of embodiments 1-68 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 69-74 for use in activating the APJ Receptor or for treating a condition where it is desirable to activate the APJ Receptor. [0158] 97. The compound of embodiment 96, wherein the condition is obesity or diabetes.

[0159] 98. The compound of embodiment 96, wherein the condition is diabetic nephropathy or chronic kidney disease.

[0160] 99. A use of the compound of any one of embodiments 1-68 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.

[0161] 100. The use of embodiment 99, further comprising a therapeutic agent selected from an a-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.

[0162] 101. The use of embodiment 99, further comprising a therapeutic agent selected from an angiotensin converting enzyme (ACE) inhibitor or an angiotensin- receptor blocker (ARB).

[0163] 102. The use of the compound of any one of embodiments 99-101, wherein the cardiovascular condition is heart failure.

[0164] 103. The use of the compound of any one of embodiments 99-101, wherein the cardiovascular condition is heart failure with reduced ejection fraction.

[0165] 104. The use of the compound of any one of embodiments 99-101, wherein the cardiovascular condition is heart failure with preserved ejection fraction.

[0166] 105. The use of the compound of any one of embodiments 99-101, wherein the cardiovascular condition is chronic systolic heart failure or chronic diastolic heart failure.

[0167] 106. The use of the compound of any one of embodiments 99-101, wherein the cardiovascular condition is acute heart failure.

[0168] 107. The use of the compound of any one of embodiments 99-101, wherein the cardiovascular condition is hypertension.

[0169] 108. A use of the compound of any one of embodiments 1-68 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. [0170] 109. The use of embodiment 108, wherein the condition is obesity or diabetes.

[0171] 110. The use of embodiment 108, wherein the condition is diabetic nephropathy or chronic kidney disease.

[0172] 111. A treatment regimen for a cardiovascular disease, the regimen comprising: the compound of any one of embodiments 1-68 or the pharmaceutically acceptable salt thereof, the stereoisomer of any of the foregoing, or the mixture thereof.

[0173] 112. The treatment regimen of embodiment 111, wherein the regimen further comprises a therapeutic agent selected from an a-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.

[0174] 113. The treatment regimen of embodiment 111, wherein the regimen further comprises a therapeutic agent selected from an angiotensin converting enzyme (ACE) inhibitor or an angiotensin-receptor blocker (ARB).

[0175] 114. A kit, the kit comprising: the compound of any one of embodiments 1-68 or the pharmaceutically acceptable salt thereof, the stereoisomer of any of the foregoing, or the mixture thereof.

[0176] 115. The kit of embodiment 114, wherein the kit further comprises a therapeutic agent selected from an a-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.

[0177] 116. The kit of embodiment 114, wherein the kit further comprises a therapeutic agent selected from an angiotensin converting enzyme (ACE) inhibitor or an angiotensin-receptor blocker (ARB).

[0178] 117. In another aspect, the invention provides a compound of Formula

V, a salt thereof, a tautomer thereof, or a salt of the tautomer:

R ⁴

V

wherein:

R ¹ is an unsubstituted monocyclic C3-C8 cycloalkyl, an unsubstituted Cs-Cg polycyclic cycloalkyl, an unsubstituted monocyclic C4-C8 cycloalkenyl, a monocyclic C3- Cg cycloalkyl substituted with 1, 2, 3, or 4 R ^la substituents, a Cs-Cg polycyclic cycloalkyl substituted with 1, 2, or 3 R ^la substituents, or a monocyclic C4-Cg cycloalkenyl substituted with 1, 2, or 3 R ^la substituents;

R ^la in each instance is independently selected from -F, -CI, -Br, -I, -CN, -OH, =0, -0-(Ci-C ₆ alkyl), -0-(Ci-C ₆ haloalkyl), -0-(Ci-C ₆ perhaloalkyl), -Ci-C ₆ alkyl, -Ci-C ₆ haloalkyl, -Ci-C ₆ perhaloalkyl, -C ₂ -C ₄ alkenyl, alkyl), -(Ci-C ₆ alkyl)- OH, -(Ci-Cg alkyl)-0-(Ci-C ₆ alkyl), -(Ci-C ₆ haloalkyl)-OH, -(Ci-C ₆ haloalkyl)-0-(Ci-C ₆ alkyl), -(Ci-Ce perhaloalkyl)-OH, -(Ci-C ₆ perhaloalkyl)-0-(Ci-C ₆ alkyl), -0-(Ci-C ₆ alkyl)-OH, -0-(Ci-C ₆ alkyl)-0-(Ci-C ₆ alkyl), -0-(Ci-C ₆ haloalkyl)-OH, -0-(Ci-C ₆ haloalkyl)-0-(Ci-C ₆ alkyl), -0-(Ci-C ₆ perhaloalkyl)-OH, -0-(Ci-C ₆ perhaloalkyl)-0-(Ci- C ₆ alkyl), -NH ₂ , -NH(Ci-C ₆ alkyl), -N(Ci-C ₆ alkyl) ₂ , -C(=0)-(Ci-C ₆ alkyl), -C(=0)OH, alkyl) ₂ , -NHS(=0) ₂ -(Ci-C6 alkyl), -S(=0) ₂ -(Ci-C6 alkyl), a phenyl group, or a monocyclic heteroaryl group with 5 or 6 ring members containing 1, 2, or 3 heteroatoms

independently selected from N, O, or S, wherein the R ^la phenyl and R ^la heteroaryl groups are unsubstituted or are substituted with 1, 2, or 3, R ^la substituents; and further wherein two R ^la groups on a single carbon atom of a monocyclic C3-Cg cycloalkyl R ¹ group may join together with the carbon atom to which they are attached to form a heterocyclic ring having 3 to 6 members of which 1 or 2 are heteroatoms independently selected from O, N, and S;

R ^la is in each instance, independently selected from -F, -CI, -Br, -I, -CN, -OH, O- (Ci-Cg alkyl), -0-(Ci-C ₆ haloalkyl), -0-(Ci-C ₆ perhaloalkyl), -Ci-C ₆ alkyl, -Ci-C ₆ haloalkyl, -Ci-C ₆ perhaloalkyl, -C ₂ -C ₄ alkenyl, -(Ci-C ₆ alkyl)-OH, -(Ci-C ₆ alkyl)-0-(Ci- C ₆ alkyl), -(Ci-C ₆ haloalkyl)-OH, -(Ci-C ₆ haloalkyl)-0-(Ci-C ₆ alkyl), -(Ci-C ₆

perhaloalkyl)-OH, -(Ci-C ₆ perhaloalkyl)-0-(Ci-C ₆ alkyl), -0-(Ci-C ₆ alkyl)-OH, -0-(Ci- C ₆ alkyl)-0-(Ci-C ₆ alkyl), -0-(Ci-C ₆ haloalkyl)-OH, -0-(Ci-C ₆ haloalkyl)-0-(Ci-C ₆ alkyl), -0-(Ci-C ₆ perhaloalkyl)-OH, -0-(Ci-C ₆ perhaloalkyl)-0-(Ci-C ₆ alkyl), -NH ₂ , - NH(Ci-C ₆ alkyl), -N(Ci-C ₆ alkyl) ₂ , -C(=0)-(Ci-C ₆ alkyl), -C(=0)OH,

alkyl), alkyl) ₂ ,

alkyl), or alkyl); R ³ is selected from a group of formula -(CR ^3d R ^3e )-(CR ^3f R ^3g )-Q, a group of formula -(CR ^3d R ^3e )-(CR ^3f R ^¾ )-C(=0)-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 -(C3-C8 cycloalkyl)-Q, or a group of formula -(heterocyclyl)-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 C3-C8 cycloalkyl of the -(C3-C8 cycloalkyl)-Q group is unsubstituted or is substituted with 1 or 2 R ^3h substituents;

R ^3d and R ^3e are independently selected from -H, -F, -CI, -CN, -Ci-C ₆ alkyl, -Ci- C ₆ haloalkyl, -Ci-C ₆ perhaloalkyl, -OH, -(Ci-C ₆ alkyl)-OH, -(Ci-C ₆ alkyl)-0-(Ci-C ₆ alkyl), -(Ci-Ce alkyl)-0-(Ci-C ₆ alkyl)-phenyl, -0-(Ci-C ₆ alkyl), -0-(Ci-C ₆ haloalkyl), -O- (Ci-Cg perhaloalkyl), -0-(Ci-C ₆ alkyl)-OH, -0-(Ci-C ₆ alkyl)-0-(Ci-C ₆ alkyl), -NH ₂ , - NH(Ci-C ₆ alkyl), or -N(Ci-C ₆ alkyl) ₂ ;

R ^3f and R ^3g are independently selected from -H, -F, -CI, -CN, -Ci-C ₆ alkyl, -Ci- C ₆ haloalkyl, -Ci-C ₆ perhaloalkyl, -OH, -(Ci-C ₆ alkyl)-OH, -(Ci-C ₆ alkyl)-0-(Ci-C ₆ alkyl), -0-(Ci-C ₆ alkyl), -0-(Ci-C ₆ haloalkyl), -0-(Ci-C ₆ perhaloalkyl), -0-(C ₂ -C ₆ alkenyl), -0-(Ci-C ₆ alkyl)-OH, -0-(Ci-C ₆ alkyl)-0-(Ci-C ₆ alkyl), -NH ₂ , -NH(Ci-C ₆ alkyl), or -N(Ci-C ₆ alkyl) ₂ ;

R ^3h in each instance is independently selected from -F, -CI, -CN, -Ci-Ce alkyl, -Ci-Cg haloalkyl, -Ci-C ₆ perhaloalkyl, -OH, -0-(Ci-C ₆ alkyl), -0-(Ci-C ₆ haloalkyl), -O- (Ci-Cg perhaloalkyl), -0-(Ci-C ₆ alkyl)-OH, -0-(Ci-C ₆ alkyl)-0-(Ci-C ₆ alkyl), -NH ₂ , - NH(Ci-C ₆ alkyl), -N(Ci-C ₆ alkyl) ₂ , -C(=0)-(Ci-C ₆ alkyl), -C(=0)-(C ₃ -C ₆ cycloalkyl), - C(=0)-0-(Ci-C6 alkyl), oxo, or -C(=0)-(heterocyclyl), wherein the heterocyclyl group of the R ^h -C(=0)-(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 Ce-Cio 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 -Cg cycloalkyl group, a 3 to 10 membered heterocyclyl group containing 1, 2, or 3 heteroatoms independently selected from N, O, or S, wherein the Cs-Cio aryl, the heteroaryl, the cycloalkyl, and the heterocyclyl Q groups are unsubstituted or are substituted with 1, 2, 3, or 4 R ^Q substituents; and further 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;

R ^Q in each instance is independently selected from -F, -CI, -Br, -I, -CN, -Ci-Ce alkyl, -Ci-C ₆ haloalkyl, -Ci-C ₆ perhaloalkyl, -C ₂ -C ₆ alkenyl, -C ₂ -C ₆ alkynyl, -OH, -0-(Ci- C ₆ alkyl), -0-(Ci-C ₆ haloalkyl), -0-(Ci-C ₆ perhaloalkyl), -NH ₂ , -NH(Ci-C ₆ alkyl), -N(Ci- C ₆ alkyl) ₂ , alkyl), -C(=0)OH

alkyl), alkyl) ₂ ,

alkyl), -(Ci-Ce alkyl)-OH, -(Ci-C ₆ alkyl)-0-(Ci-C ₆ alkyl), -(Ci-C ₆ alkyl)-NH ₂ , -(Ci-C ₆ alkyl)-NH-(Ci-C ₆ alkyl), -(Ci-C ₆ alkyl)-N-(Ci-C ₆ alky 1) ₂ , phenyl, a heterocyclyl group, a -(Ci-Ce 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 -(Ci-Ce alkyl)heterocyclyl groups have 3 to 6 ring members of which 1 or 2 are heteroatoms independently selected from N, O, or S, and further wherein the heterocyclyl and the heterocyclyl of the -(Ci-Ce alkyl)heterocyclyl R ^Q groups may be further substituted with one or two oxo substituents and a substituent selected from -F, -CI, -Br, -I, -CN, -OH, -Ci-C ₆ alkyl, or -C(=0)-(Ci-C ₆ alkyl);

R ⁴ is selected from a monocyclic or bicyclic Ce-Cw 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 Ci- Ce alkyl group, wherein the Ce-Cioaryl, 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 Ci-Ce 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, -CI, -Br, -I, -CN, -Ci-Ce alkyl, -Ci-C ₆ haloalkyl, -Ci-C ₆ perhaloalkyl, -(Ci-C ₆ alkyl)-OH, -(Ci-C ₆ alkyl)-0-(Ci-C ₆ alkyl), -OH, -0-(Ci-C ₆ alkyl), -0-(Ci-C ₆ haloalkyl), -0-(Ci-C ₆ perhaloalkyl), -NH ₂ , - NH(Ci-C ₆ alkyl), -N(Ci-C ₆ alkyl) ₂ , NH(Ci-C ₆ alkyl-OH), -N(Ci-C ₆ alkyl-OH) ₂ , -C(=0)- (Ci-Cg alkyl), -C(=0)OH, -C(=0)-0-(Ci-C ₆ alkyl), alkyl), alkyl) ₂ , phenyl, alkyl), -(Ci-C ₆ alkyl)-heterocyclyl, or heterocyclyl wherein the heterocyclyl of the -(Ci-Ce 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 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, -CI, -Br, -I, -CN, -OH, -0-(Ci-C ₆ alkyl), -0-(Ci-C ₆ haloalkyl), -0-(Ci-C ₆ perhaloalkyl), -NH ₂ , -NH(Ci-C ₆ alkyl), -N(Ci-C ₆ alkyl) ₂ , NH(Ci-C ₆ alkyl-OH), -N(Ci-C ₆ alkyl-OH) ₂ , -C(=0)-(Ci-C ₆ alkyl), -C(=0)OH, -C(=0)- 0-(Ci-C ₆ alkyl), -C(=0)NH ₂ , alkyl) ₂ , or, - alkyl).

[0179] 118. The compound of embodiment 117, the salt thereof, the tautomer thereof, or the salt of the tautomer, wherein the compound has any of the R ¹ , R ^la , R ³ , R ^3d , R ^3e , R ^3f , R ^3g , R ^3h , R ⁴ , R ^4a , Q, or R ^Q , values or combinations of values of any one of embodiments 2-64.

[0180] 119. In yet another aspect, the invention provides a method for preparing a compound of Formula VI, a salt thereof, a tautomer thereof, or a salt of the tautomer:

VI

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,

V

wherein:

R ¹ is an unsubstituted monocyclic C3-C8 cycloalkyl, an unsubstituted Cs-Cg poly cyclic cycloalkyl, an unsubstituted monocyclic C4-C8 cycloalkenyl, a monocyclic C3- Cg cycloalkyl substituted with 1, 2, 3, or 4 R ^la substituents, a Cs-Cg polycyclic cycloalkyl substituted with 1, 2, or 3 R ^la substituents, or a monocyclic C4-Cg cycloalkenyl substituted with 1, 2, or 3 R ^la substituents;

R ^la in each instance is independently selected from -F, -CI, -Br, -I, -CN, -OH, =0, -0-(Ci-C ₆ alkyl), -0-(Ci-C ₆ haloalkyl), -0-(Ci-C ₆ perhaloalkyl), -Ci-C ₆ alkyl, -Ci-C ₆ haloalkyl, -Ci-C ₆ perhaloalkyl, -C ₂ -C ₄ alkenyl, alkyl), -(Ci-C ₆ alkyl)- OH, -(Ci-Cg alkyl)-0-(Ci-C ₆ alkyl), -(Ci-C ₆ haloalkyl)-OH, -(Ci-C ₆ haloalkyl)-0-(Ci-C ₆ alkyl), -(Ci-Ce perhaloalkyl)-OH, -(Ci-C ₆ perhaloalkyl)-0-(Ci-C ₆ alkyl), -0-(Ci-C ₆ alkyl)-OH, -0-(Ci-C ₆ alkyl)-0-(Ci-C ₆ alkyl), -0-(Ci-C ₆ haloalkyl)-OH, -0-(Ci-C ₆ haloalkyl)-0-(Ci-C ₆ alkyl), -0-(Ci-C ₆ perhaloalkyl)-OH, -0-(Ci-C ₆ perhaloalkyl)-0-(Ci- C ₆ alkyl), -NH ₂ , -NH(Ci-C ₆ alkyl), -N(Ci-C ₆ alkyl) ₂ , -C(=0)-(Ci-C ₆ alkyl), -C(=0)OH, alkyl) ₂ , -NHS(=0) ₂ -(Ci-C6 alkyl), -S(=0) ₂ -(Ci-C6 alkyl), a phenyl group, or a monocyclic heteroaryl group with 5 or 6 ring members containing 1, 2, or 3 heteroatoms

independently selected from N, O, or S, wherein the R ^la phenyl and R ^la heteroaryl groups are ^substituted or are substituted with 1, 2, or 3, R ^la substituents; and further wherein two R ^la groups on a single carbon atom of a monocyclic C3-Cg cycloalkyl R ¹ group may join together with the carbon atom to which they are attached to form a heterocyclic ring having 3 to 6 members of which 1 or 2 are heteroatoms independently selected from O, N, and S;

R ^la is in each instance, independently selected from -F, -CI, -Br, -I, -CN, -OH, O- (Ci-Cg alkyl), -0-(Ci-C ₆ haloalkyl), -0-(Ci-C ₆ perhaloalkyl), -Ci-C ₆ alkyl, -Ci-C ₆ haloalkyl, -Ci-C ₆ perhaloalkyl, -C ₂ -C ₄ alkenyl, -(Ci-C ₆ alkyl)-OH, -(Ci-C ₆ alkyl)-0-(Ci- C ₆ alkyl), -(Ci-C ₆ haloalkyl)-OH, -(Ci-C ₆ haloalkyl)-0-(Ci-C ₆ alkyl), -(Ci-C ₆ perhaloalkyl)-OH, -(Ci-C ₆ perhaloalkyl)-0-(Ci-C ₆ alkyl), -0-(Ci-C ₆ alkyl)-OH, -0-(Ci- C ₆ alkyl)-0-(Ci-C ₆ alkyl), -0-(Ci-C ₆ haloalkyl)-OH, -0-(Ci-C ₆ haloalkyl)-0-(Ci-C ₆ alkyl), -0-(Ci-C ₆ perhaloalkyl)-OH, -0-(Ci-C ₆ perhaloalkyl)-0-(Ci-C ₆ alkyl), -NH ₂ , - NH(Ci-C ₆ alkyl), -N(Ci-C ₆ alkyl) ₂ , -C(=0)-(Ci-C ₆ alkyl), -C(=0)OH,

alkyl), alkyl) ₂ ,

alkyl), or alkyl);

R ³ is selected from 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(=0)-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 -(C3-Cg cycloalkyl)-Q, or a group of formula -(heterocyclyl)-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 C3-C8 cycloalkyl of the -(C3-C8 cycloalkyl)-Q group is unsubstituted or is substituted with 1 or 2 R ^3h substituents;

R ^3d and R ^3e are independently selected from -H, -F, -CI, -CN, -Ci-C ₆ alkyl, -Ci- C ₆ haloalkyl, -Ci-C ₆ perhaloalkyl, -OH, -(Ci-C ₆ alkyl)-OH, -(Ci-C ₆ alkyl)-0-(Ci-C ₆ alkyl), -(Ci-Ce alkyl)-0-(Ci-C ₆ alkyl)-phenyl, -0-(Ci-C ₆ alkyl), -0-(Ci-C ₆ haloalkyl), -O- (Ci-Cg perhaloalkyl), -0-(Ci-C ₆ alkyl)-OH, -0-(Ci-C ₆ alkyl)-0-(Ci-C ₆ alkyl), -NH ₂ , - NH(Ci-C ₆ alkyl), or -N(Ci-C ₆ alkyl) ₂ ;

R ^3f and R ^3g are independently selected from -H, -F, -CI, -CN, -Ci-C ₆ alkyl, -Ci- C ₆ haloalkyl, -Ci-C ₆ perhaloalkyl, -OH, -(Ci-C ₆ alkyl)-OH, -(Ci-C ₆ alkyl)-0-(Ci-C ₆ alkyl), -0-(Ci-C ₆ alkyl), -0-(Ci-C ₆ haloalkyl), -0-(Ci-C ₆ perhaloalkyl), -0-(C ₂ -C ₆ alkenyl), -0-(Ci-C ₆ alkyl)-OH, -0-(Ci-C ₆ alkyl)-0-(Ci-C ₆ alkyl), -NH ₂ , -NH(Ci-C ₆ alkyl), or -N(Ci-C ₆ alkyl) ₂ ;

R ^3h in each instance is independently selected from -F, -CI, -CN, -Ci-Ce alkyl, -Ci-Cg haloalkyl, -Ci-C ₆ perhaloalkyl, -OH, -0-(Ci-C ₆ alkyl), -0-(Ci-C ₆ haloalkyl), -O- (Ci-Cg perhaloalkyl), -0-(Ci-C ₆ alkyl)-OH, -0-(Ci-C ₆ alkyl)-0-(Ci-C ₆ alkyl), -NH ₂ , - NH(Ci-C ₆ alkyl), -N(Ci-C ₆ alkyl) ₂ , -C(=0)-(Ci-C ₆ alkyl), -C(=0)-(C ₃ -C ₆ cycloalkyl), - C(=0)-0-(Ci-C6 alkyl), oxo, or -C(=0)-(heterocyclyl), wherein the heterocyclyl group of the R ^h -C(=0)-(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 Cs-Cio 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 C3-C8 cycloalkyl group, a 3 to 10 membered heterocyclyl group containing 1, 2, or 3 heteroatoms independently selected from N, O, or S, wherein the Cs-Cio aryl, the heteroaryl, the cycloalkyl, and the heterocyclyl Q groups are unsubstituted or are substituted with 1, 2, 3, or 4 R ^Q substituents; and further 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;

R ^Q in each instance is independently selected from -F, -CI, -Br, -I, -CN, -Ci-Ce alkyl, -Ci-C ₆ haloalkyl, -Ci-C ₆ perhaloalkyl, -C ₂ -C ₆ alkenyl, -C ₂ -C ₆ alkynyl, -OH, -0-(Ci- C ₆ alkyl), -0-(Ci-C ₆ haloalkyl), -0-(Ci-C ₆ perhaloalkyl), -NH ₂ , -NH(Ci-C ₆ alkyl), -N(Ci- C ₆ alkyl) ₂ , alkyl), -C(=0)OH

alkyl), -C(= 0)NH ₂ , alkyl) ₂ ,

alkyl), -(Ci-Ce alkyl)-OH, -(Ci-C ₆ alkyl)-0-(Ci-C ₆ alkyl), -(Ci-C ₆ alkyl)-NH ₂ , -(Ci-C ₆ alkyl)-NH-(Ci-C ₆ alkyl), -(Ci-C ₆ alkyl)-N-(Ci-C ₆ alky 1) ₂ , phenyl, a heterocyclyl group, a -(Ci-Ce 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 -(Ci-Ce alkyl)heterocyclyl groups have 3 to 6 ring members of which 1 or 2 are heteroatoms independently selected from N, O, or S, and further wherein the heterocyclyl and the heterocyclyl of the -(Ci-Ce alkyl)heterocyclyl R ^Q groups may be further substituted with one or two oxo substituents and a substituent selected from -F, -CI, -Br, -I, -CN, -OH, -Ci-C ₆ alkyl, or -C(=0)-(Ci-C ₆ alkyl);

R ⁴ is selected from a monocyclic or bicyclic Ce-Cw 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 Ci- Ce alkyl group, wherein the Ce-Cioaryl, 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 Ci-Ce 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, -CI, -Br, -I, -CN, -Ci-Ce alkyl, -Ci-C ₆ haloalkyl, -Ci-C ₆ perhaloalkyl, -(Ci-C ₆ alkyl)-OH, -(Ci-C ₆ alkyl)-0-(Ci-C ₆ alkyl), -OH, -0-(Ci-C ₆ alkyl), -0-(Ci-C ₆ haloalkyl), -0-(Ci-C ₆ perhaloalkyl), -NH ₂ , - NH(Ci-C ₆ alkyl), -N(Ci-C ₆ alkyl) ₂ , NH(Ci-C ₆ alkyl-OH), -N(Ci-C ₆ alkyl-OH) ₂ , -C(=0)- (Ci-Cg alkyl), -C(=0)OH, -C(=0)-0-(Ci-C ₆ alkyl), alkyl), alkyl) ₂ , phenyl, alkyl), -(Ci-C ₆ alkyl)-heterocyclyl, or heterocyclyl wherein the heterocyclyl of the -(Ci-Ce 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 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, -CI, -Br, -I, -CN, -OH, -0-(Ci-C ₆ alkyl), -0-(Ci-C ₆ haloalkyl), -0-(Ci-C ₆ perhaloalkyl), -NH ₂ , -NH(Ci-C ₆ alkyl), -N(Ci-C ₆ alkyl) ₂ , NH(Ci-C ₆ alkyl-OH), -N(Ci-C ₆ alkyl-OH) ₂ , -C(=0)-(Ci-C ₆ alkyl), -C(=0)OH, -C(=0)- 0-(Ci-C ₆ alkyl), -C(=0)NH ₂ , alkyl) ₂ , or, - alkyl).

[0181] 120. The method of embodiment 119, wherein R ¹ , R ^la , R ³ , R ^3d , R ^3e ,

R ^3f , R ^3g , R ^3h , R ⁴ , R ^4a , Q, or R ^Q , have any of the values or combination of values of any one of embodiments 2-64.

[0182] 121. The method of embodiment 119 or embodiment 120, 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.

[0183] 122. The method of embodiment 121, 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.

[0184] 123. The method of embodiment 121, 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.

[0185] 124. The method of any one of embodiments 119-123, 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.

[0186] 125. The method of any one of embodiments 119-124, wherein the base is a metal hydroxide.

[0187] 126. The method of embodiment 125, wherein the metal hydroxide is selected from NaOH or LiOH.

[0188] 127. The method of any one of embodiments 124-126, wherein the cyclizing is carried out in an alcohol solvent.

[0189] 128. The method of embodiment 127, wherein the alcohol is isopropanol.

[0190] 129. The method of any one of embodiments 119-123, 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.

[0191] 130. The method of embodiment 129, wherein the acid is selected from a sulfonic acid, a carboxylic acid, polyphosphoric acid, phosphoric acid, sulfuric acid, or hydrochloric acid.

[0192] 131. The method of embodiment 130, wherein the sulfonic acid is methanesulfonic acid. [0193] 132. The method of embodiment 130, wherein the acid is trifluoroacetic acid, acetic acid, or trichloroacetic acid.

[0194] 133. The method of any one of embodiments 129-132, wherein the cyclizing is carried out in a cyclic ether, an acyclic ether, Ν,Ν-dimethylformamide, or acetonitrile.

[0195] 134. The method of embodiment 133, wherein the cyclizing is carried out in a cyclic ether.

[0196] 135. The method of embodiment 134, wherein the cyclic ether is selected from tetrahydrofuran, tetrahydropyran, or 1,4-dioxane.

[0197] 136. The method of embodiment 134, wherein the cyclic ether is 1,4- dioxane.

[0198] 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.

[0199] 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.

[0200] 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.

[0201] 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.

[0202] 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. Patent Nos. 4,256,108, 4,160,452, and 4,265,874 to form osmotic therapeutic tablets for control release.

[0203] 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.

[0204] 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.

[0205] 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.

[0206] 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.

[0207] 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.

[0208] 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.

[0209] 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.

[0210] 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.

[0211] 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.

[0212] 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.

[0213] 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.

[0214] 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.

[0215] 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. [0216] 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.

[0217] 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.

[0218] 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.

[0219] 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. [0220] 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.

[0221] 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.

[0222] 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.

[0223] 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 (A VP) regulation and in angiotensin receptor (AT1R) regulation.

[0224] 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.

[0225] 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.

[0226] 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 a-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 ( EP) 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 a-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.

[0227] Therapeutic agents such as a-blockers may be used in conjunction with the compounds of the invention. Examples of a-blockers include, but are not limited to, doxazosin, prazosin, tamsulosin, and terazosin and their pharmaceutically acceptable salts. [0228] 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.

[0229] 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.

[0230] 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.

[0231] 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.

[0232] 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.

[0233] 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.

[0234] 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.

[0235] 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.

[0236] 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.

[0237] Inhibitors of the funny current (If) 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.

[0238] Myosin activators may also be used in conjunction with the compounds of the invention. Examples of myosin activators include cardiac myosin activators.

[0239] 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.

[0240] 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 coadministration 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.

[0241] 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.

[0242] 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

[0243] Unless otherwise noted, all materials were obtained from commercial suppliers and were used without further purification. Anhydrous solvents were obtained from Sigma- Aldrich (Milwaukee, WI) 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 x 150 mm, 5 micron, 5 to 100% ACN in H ₂ 0 with 0.1% TFA for 15 min at 1.5 mL/min; System B: Zorbax SB-C8, 4.6 x 75 mm, 10 to 90% ACN in H ₂ 0 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). ¾ 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 μΕ 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).

[0244] 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.

[0245] The following Abbreviations are used to refer to various reagents and solvents:

ACN Acetonitrile

AcOH Acetic Acid

d day or days

CV Column volume

DCM Dichloromethane

DEA Diethylamine

DMF N,N-Dimethylformamide

DMSO Dimethylsulfoxide

EtOAc Ethyl Acetate

EtOH Ethanol

EtOTf: Ethyl triflate or ethyl trifluoromethane sulfonate

h hour or hours

IPA Isopropanol

LAH Lithium aluminum hydride

min minute or minutes

MeOH Methanol

MeOTf: Methyl triflate or methyl trifluoromethanesulfonate

MS Mass spectrum

MSA Methane sulfonic acid

RT Room temperature

SFC Supercritical fluid chromatography TBS t-Butyldimethylsilane

TBSOTf: t-Butyldimethylsilyl triflate or t-butyldimethylsilyl

trifluoromethanesulfonate

TEA Triethylamine

TFA Trifluoroacetic acid

THF Tetrahydrofuran

TLC Thin Layer Chromatography

[0246] Example 1.0. Preparation of 2-(4-chlorophenyl)-N-(5-cyclobutyl-4-

(2,6-dimethoxyphenyl)-4 /-l,2,4-triazol-3-yl)ethanesulfonamide.

1.01

[0247] N-(2,6-Dimethoxyphenyl)cyclobutanecarboxamide, Example 1.01.

To an ice-cooled solution of 2,6-dimethoxyaniline (Amfinecom Inc., 2.0 g, 13.1 mmol) in DCM (65 mL) was added N-diisopropylethylamine (6.8 mL, 39.2 mmol) followed by cyclobutanecarbonyl chloride (Sigma-Aldrich, 1.56 mL, 13.7 mmol) slowly via syringe. The resulting solution was warmed to RT and stirred for 48 h, then was partitioned between water and DCM (2X). The combined organic layers were dried over anhydrous sodium sulfate and concentrated in vacuo to provide Example 1.01 (2.92 g, 95% yield). LCM ⁺ .

1.01 1.02

[0248] N-(2,6-Dimethoxyphenyl)cyclobutanecarbothioamide, Example

1.02. To a suspension of Example 1.01 (2.92 g, 12.4 mmol) in toluene (41.5 mL) was added Lawesson's reagent (2.76 g, 6.8 mmol). The resulting light yellow slurry was heated at reflux for 9 h and then was allowed to cool to RT. The reaction was quenched with water and extracted with EtOAc (2X). The combined organic layers were dried over anhydrous magnesium sulfate and concentrated in vacuo. The residue was purified by silica gel chromatography (eluent: 0-100% EtOAc in hexanes) to provide 1.02 (3.12 g, 100% yie ⁺ .

1.02 1.03

[0249] N-(2,6-Dimethoxyphenyl)cyclobutanecarbohydrazonamide, Example 1.03. To a solution of 1.02 (1.80 g, 7.2 mmol) in THF (48 mL) was added hydrazine hydrate solution (80% solution in water, 2.79 mL, 47.0 mmol) via syringe. The resulting slurry was heated at 60 °C for 30 min and then was partitioned between brine and EtOAc (3X). The combined organic layers were dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by flash chromatography on neutral alumina (eluent: 0-3% MeOH in DCM) to provide 1.03 (510 mg, 29% yield) as a yellow solid. L ⁺ .

1.03 1.04

[0250] 5-Cyclobutyl-4-(2,6-dimethoxyphenyl)-4I-l,2,4-triazol-3-amin e, Example 1.04. To a solution of 1.03 (373 mg, 1.50 mmol) in EtOH (7.5 mL) was added cyanogen bromide (5.0 M solution in ACN, 658 μΕ, 3.30 mmol) slowly via syringe. The reaction was heated at 70 °C for 4.5 h and then was quenched with water and concentrated in vacuo. The residue was purified by reverse phase preparatory HPLC (Sunfire 5 μΜ CI 8 column, eluent: 10-60% ACN in water over a 20 min period where both solvents contained 0.1% TFA) to provide 1.04 (199 mg, 49% yield) as a white solid. LCMS-ESI (pos.) m/z: 275.2 (M+H) ⁺ .

[0251] 2-(4-Chlorophenyl)-N-(5-cyclobutyl-4-(2,6-dimethoxyphenyl)-4 i7- l,2,4-triazol-3-yl)ethanesulfonamide, Example 1.0. To a solution of 1.04 (80 mg, 0.29 mmol) and TEA (203 μΐ,, 1.46 mmol) in DCM (2.9 mL) was added 2-(4- chlorophenyl)ethanesulfonyl chloride (Synchem Inc., 91 mg, 0.38 mmol). The reaction was stirred at RT overnight and additional 2-(4-chlorophenyl)ethanesulfonyl chloride (182 mg, 0.76 mmol) was added. After stirring for an additional 4 h, the reaction was quenched with a saturated aqueous sodium bicarbonate solution (10 mL) and brine (10 mL). The mixture was extracted with EtOAc (3X). The combined organic layers were dried over anhydrous magnesium sulfate and concentrated in vacuo. The residue was purified by reverse phase preparatory HPLC (Sunfire 5 μΜ C18 column, eluent: 20-80% ACN in water over a 20 min period where both solvents contain 0.1% TFA) to provide Example 1.0 (5.9 mg, 4% yield) as an off-white solid. ¾ NMR (CDC1 ₃ ) δ 7.40 (m, 1H), 7.19-7.26 (m, 2H), 7.02-7.14 (m, 2H), 6.63 (d, 2H), 3.74 (s, 3H), 3.74 (s, 3H), 3.16-3.38 (m, 2H), 2.95-3.13 (m, 3H), 2.21-2.39 (m, 2H), 1.81-2.10 (m, 4H). LCMS-ESI (pos.) m/z: 477.0 (M+H) ⁺ .

[0252] The compounds set forth in the following table were synthesized following the procedure in Example 1.0 using the known starting material as described.

Table 1

7.25-7.31 (m, 2H), 7.14-7.20 (m, 2H), 6.83 (d, J=8.56

Hz, 2H), 3.81 (s, 3 H), 3.81 (s, 3H), 3.17-3.23 (m, 2H), 2.95-3.01 (m, 2H), 2.63-2.71 (m, IH), 1.75-1.84 (m, 2H), 1.66-1.75 (m, 4H), 1.48-1.59 (m, 2H). LCMS-ESI (pos.) m/z: 491.0 (M+H).

[0254] Example 8.0. Preparation of N-(4-(2-bromo-6-methoxyphenyl)-5- cyclopentyl-4H-l,2,4-triazol-3- l)-l-(4-chlorophenyl)methanesulfonamide.

8.1

[0255] N-(2-Bromo-6-methoxyphenyl)cyclopentanecarboxamide, Example

8.1. To a 500 mL round-bottom flask was added 2-bromo-6-methoxyaniline

(commercially available from Apollo Scientific Ltd., Manchester, UK, 8.60 g, 42.6 mmol) and N,N-diisopropylethylamine (14.81 mL, 85 mmol) in DCM (142 mL). At 0 °C cyclopentanecarbonyl chloride (5.69 mL, 46.8 mmol) in DCM (50 mL) was added dropwise via syringe. The reaction mixture was stirred at 0 °C -RT. The reaction mixture was diluted with 1.0 N HCl and extracted with DCM. The organic extract was washed with a saturated NaCl solution and dried over Na2S04. The solution was filtered and concentrated in vacuo to the title compound (12 g, 40.2 mmol, 95 % yield) as a white solid, which was of >85% purity by ¾ NMR and LCMS. The material was directly used in the next step without purifi -ESI (pos.), m/z: 298.0 (M+H) ⁺ .

8.2

[0256] N-(2-Bromo-6-methoxyphenyl)cyclopentanecarbohydrazonamide, Example 8.2. To a 500 mL round-bottom flask was added N-(2-bromo-6- methoxyphenyl)cyclopentanecarboxamide (11.98 g, 40.2 mmol) and thionyl chloride (50 mL, 685 mmol). The reaction mixture was stirred at 66 °C for 30 mins and then at RT overnight. The reaction mixture was concentrated in vacuo to give (Z)-N-(2-bromo-6- methoxyphenyl)cyclopentanecarbimidoyl chloride. The initial product was directly used in the next step without purification.

[0257] To a cooled 500 mL round-bottom flask at 0 °C containing hydrazine

(23.79 mL, 758 mmol) in toluene (95 mL) was added a solution of (Z)-N-(2-bromo-6- methoxyphenyl)cyclopentanecarbimidoyl chloride (12 g, 37.9 mmol) in toluene (95 mL). The reaction mixture was then stirred at RT for 20 h. Next, the reaction mixture was diluted with water and extracted with Et20. The insoluble solid was removed by filtration. The organic extract was washed with a saturated NaHCC solution and brine and then dried over Na2S04. The solution was filtered and concentrated in vacuo to give the title compound (10.2 g, 32.7 mmol, 86 % yield). The material was directly used in the next step without purification. m/z: 312.0 (M+H) ⁺ .

8.3

[0258] 5-Cyclopentyl-4-(2,6-dibromophenyl)-4H-l,2,4-triazol-3-amine , Example 8.3. To a 500 mL round-bottom flask was added Example 8.2 (10.22 g, 32.7 mmol) and cyanogen bromide (6.55 mL, 32.7 mmol) in MeOH (149 mL). The reaction mixture was stirred at 70 °C for 18 h. The reaction was not complete. Thus, more cyanogen bromide, (5.0 M in ACN, 6.55 mL, 32.7 mmol) was added, and the reaction mixture was stirred at 90 °C for 18 h. The solution was allowed to cool to RT and concentrated in vacuo. The reaction mixture was diluted with a saturated solution of NaHCC and extracted with DCM. The organic extract was washed with a saturated solution of NaCl and dried over Na2S04. The solution was filtered and concentrated in vacuo to give the title compound as a tan glass. The material was absorbed onto a plug of silica gel and purified by chromatography through a Redi-Sep pre-packed silica gel column (220g, gold), eluting with a gradient of 60% to 100% EtOAc in DCM (w/ 0.5% saturated NH ₃ -H ₂ 0 and 2% MeOH in EtOAc) and then repurified by eluting with a gradient of 0% to 40% MeOH in DCM, to provide the title compound Example 8.3 (3.2

+.

8.0

[0259] (P)-N-(4-(2-Bromo-6-methoxyphenyl)-5-cyclopentyl-4H-l,2,4- triazol-3-yl)-l-(4-chlorophenyl)methanesulfonamide and ( )-N-(4-(2-bromo-6- methoxyphenyl)-5-cyclopentyl-4H-l,2,4-triazol-3-yl)-l-(4- chlorophenyl)methanesulfonamide, Example 8.0. A glass microwave reaction vessel was charged with Example 8.3 (0.148 g, 0.44 mmol) and (4-chloro-phenyl)- methanesulfonyl chloride (0.148 g, 0.66 mmol) in pyridine (2.19 mL, 0.44 mmol). The reaction mixture was stirred and heated in a Discover model microwave reactor (CEM, Matthews, NC) at 120 °C for 120 min (200 watts, Powermax feature off, ramp time 1 min). The reaction mixture was then concentrated in vacuo to give a tan solid. The 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 50% EtOAc in hexanes, to provide the title compound (0.047 g, 0.089 mmol, 20 % yield) as a white solid. ¾ NMR (400 MHz, CDC1 ₃ ) δ 7.38 - 7.44 (m, 1 H) 7.32 - 7.38 (m, 3 H) 7.25 - 7.32 (m, 2 H) 7.05 (dd, J=8.22, 1.17 Hz, 1 H) 4.21 (d, J=2.15 Hz, 2 H) 3.79 - 3.96 (m, 3 H) 3.88 (s, 3 H) 2.58 (t, J=7.83 Hz, 1 H) 1.64 - 1.92 (m, 6 H) 1.48 - 1.63 (m, 2 H). LCMS-ESI (pos.) m/z: 524.9 527.0.

[0260] Example 9.0. Preparation of l-(4-chlorophenyl)-N-(5-cyclopentyl-

4-(2,6-dibromophenyl)-4H- -triazol-3-yl)methanesulfonamide.

9.1

[0261] 5-Cyclopentyl-4-(2,6-dibromophenyl)-4H-l,2,4-triazol-3-amine , Example 9.1. The title compound was prepared from 2,6-dibromoaniline and cyclopentanecarbonyl chloride using the procedures described in Example 8.3. LCMS- ESI (pos.), m/z: 386 ⁺ .

9.0

[0262] l-(4-Chlorophenyl)-N-(5-cyclopentyl-4-(2,6-dibromophenyl)-4H - l,2,4-triazol-3-yl)methanesulfonamide, Example 9.0. The title compound was prepared from Example 9.1 using the procedure described in Example 8.0. ¾ NMR

(400 MHz, CDC1 ₃ ) δ 10.39 (br. s., 1 H) 7.73 - 7.79 (m, 2 H) 7.26 - 7.40 (m, 5 H) 4.22 (s, 2 H) 2.59 (quin, J=l .91 Hz, 1 H) 1.52 - 1.92 (m, 8 H). LCMS-ESI (pos.) m/z: 572.8, 574.8 and 576.8.

[0263] Example 10.0. Preparation of ( )-N-(4-(2-bromo-6- methoxyphenyl)-5-cyclopentyl-4H-l,2,4-triazol-3-yl)-2-(4- chlorophenyl)ethanesulfonamide and ( )-N-(4-(2-bromo-6-methoxyphenyl)-5- cyclopentyl-4H-l,2,4-triazol-3-yl)-2-(4-chlorophenyl)ethanes ulfonamide.

10.0

[0264] ( )-N-(4-(2-Bromo-6-methoxyphenyl)-5-cyclopentyl-4H-l,2,4- triazol-3-yl)-2-(4-chlorophenyl)ethanesulfonamide and ( )-N-(4-(2-bromo-6- methoxyphenyl)-5-cyclopentyl-4H-l,2,4-triazol-3-yl)-2-(4- chlorophenyl)ethanesulfonamide, Example 10.0. To a 10 mL vial containing Example 8.3 (106 mg, 0.32 mmol) and TEA (88 μΐ,, 0.63 mmol) in DCM (3.1 mL) was added 2- (4-chlorophenyl)ethanesulfonyl chloride (83 mg, 0.35 mmol) at RT. The reaction mixture was stirred at RT for 96 h. The reaction mixture was diluted with water and extracted with DCM. The organic extracts were washed with a saturated NaCl solution and dried over Na2S04. The solution was filtered and concentrated in vacuo to give a tan oil. 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, to provide Example 10.0 (40 mg, 0.074 mmol, 24 % yield) as an off-white solid. ¾ NMR (400 MHz, CDC1 ₃ ) δ 10.58 (br. s, 1 H) 7.22 - 7.35 (m, 2 H) 7.14 - 7.22 (m, 2 H) 7.03 (d, J=7.67 Hz, 2 H) 6.94 (dd, J=8.31, 1.27 Hz, 1 H) 3.73 - 3.76 (m, 3 H) 3.09 - 3.21 (m, 2 H) 2.96 - 3.05 (m, 2 H) 2.46 - 2.60 (m, 1 H) 1.58 - 1.83 (m, 6 H) 1.40 - 1.50 (m, 2 H). LCMS-ESI (pos.), m/z: 538.8 (M+H) ⁺ .

[0265] Example 11.0. Preparation of 2-(4-chlorophenyl)-N-(5-cyclopentyl-

4-(2,6-dibromophenyl)-4H-l,2,4-triazol-3-yl)ethanesulfona mide.

11.0

[0266] 2-(4-Chlorophenyl)-N-(5-cyclopentyl-4-(2,6-dibromophenyl)-4H - l,2,4-triazol-3-yl)ethanesulfonamide, Example 11.0. The title compound was prepared from Example 9.1 using the procedure described in Example 10.0. ¾ NMR (400 MHz, CDCI ₃ ) δ 10.61 (br. s., 1 H) 7.66 (d, J=8.02 Hz, 2 H) 7.10 - 7.30 (m, 3 H) 7.03 (d, J=6.33

Hz, 2 H) 3.09 - 3.25 (m, 2 H) 2.93 - 3.09 (m, 2 H) 2.53 (quin, J=7.97 Hz, 1 H) 1.63 - 1.87

(m, 6 H) 1.50 (br. s., 2 H). LCMS-ESI (pos.), m/z: 586.8, 589.0 and 590.9.

[0267] Example 12.0. Preparation of N-(4-(5-bromo-2-methoxyphenyl)-5- cyclopentyl-4H-l,2,4-triazol- -yl)-2-(4-chlorophenyl)ethanesulfonamide.

12.1

[0268] 4-(5-Bromo-2-methoxyphenyl)-5-cyclopentyl-4H-l,2,4-triazol-3 - amine, Example 12.1. The title compound was prepared from 5-bromo-2- methoxyaniline and cyclopentanecarbonyl chloride using the procedures described in Example 8.3. LCMS-ESI (pos.), m/z: 337.0 339.0.

12.0

[0269] N-(4-(5-Bromo-2-methoxyphenyl)-5-cyclopentyl-4H-l,2,4-triazo l-3- yl)-2-(4-chlorophenyl)ethanesulfonamide, Example 12.0. The title compound was prepared from Example 12.1 using the procedure described in Example 10.0. ¾ NMR (400 MHz, CDCI ₃ ) δ 7.52 (dd, J=8.90, 2.45 Hz, 1 H) 7.15 - 7.22 (m, 3 H) 6.99 - 7.06 (m, 2 H) 6.86 (d, J=8.80 Hz, 1 H) 3.70 (s, 3 H) 3.13 - 3.22 (m, 2 H) 2.92 - 3.02 (m, 2 H) 2.57 (d, J=7.82 Hz, 1 H) 1.31 - 1.78 (m, 8 H). LCMS-ESI (pos.), m/z: 539.0 541.0.

[0270] Example 13.0. Preparation of 2-(4-chlorophenyl)-N-(4-(2-

(difluoromethoxy)phenyl)-5-(5-fluoro-2-thiophenyl)-4H-l,2 ,4-triazol-3- yl)ethanesulfonamide.

- I l l -

13.1

[0271] 5-Cyclopentyl-4-(2-methoxyphenyl)-4H-l,2,4-triazol-3-amine, Example 13.1. To a 150 mL round-bottom flask was added Example 12.1 (0.2 g, 0.593 mmol) in EtOH (30 mL). The solution was flushed with N ₂ . Palladium on activated carbon (10% Pd, 0.063 g, 0.59 mmol) was added under N ₂ . The flask was closed with a septum and the system was placed under vacuum. The reaction mixture was then stirred at RT under an atmosphere of hydrogen gas for 2 h. The mixture was filtered through a silica gel pad, rinsed with MeOH and concentrated in vacuo to give the initial material Example 13.1 as a tan glass, which was directly used in the next step without further purification. LCMS- ⁺ .

13.0

[0272] 2-(4-Chlorophenyl)-N-(4-(2-(difluoromethoxy)phenyl)-5-(5-flu oro- 2-thiophenyl)-4H-l,2,4-triazol-3-yl)ethanesulfonamide, Example 13.0. The title compound was prepared from Example 13.1 using the procedure described in Example 10.0. ¾ NMR (400 MHz, CDC1 ₃ ) δ 10.62 (br. s., 1 H) 7.52 (t, J=7.84 Hz, 1 H) 7.23 -

7.29 (m, 2 H) 7.20 (dd, J=7.73, 1.66 Hz, 1 H) 7.06 - 7.15 (m, 4 H) 3.81 (s, 3 H) 3.22 -

3.30 (m, 2 H) 3.03 - 3.12 (m, 2 H) 2.69 (t, J=7.83 Hz, 1 H) 1.48 - 1.87 (m, 8 H). LCMS- ESI (pos.), m/z: 461.0 (M+H) ⁺ .

[0273] Example 14.0. Preparation of (P)-N-(4-(2-bromo-6- methoxyphenyl)-5-cyclopentyl-4H-l,2,4-triazol-3-yl)-2-(4- chlorophenyl)ethanesulfonamide or ( )-N-(4-(2-bromo-6-methoxyphenyl)-5- cyclopentyl-4H-l,2,4-triazol-3-yl)-2-(4-chlorophenyl)ethanes ulfonamide.

[0274] (P)-N-(4-(2-Bromo-6-methoxyphenyl)-5-cyclopentyl-4H-l,2,4- triazol-3-yl)-2-(4-chlorophenyl)ethanesulfonamide or ( )-N-(4-(2-bromo-6- methoxyphenyl)-5-cyclopentyl-4H-l,2,4-triazol-3-yl)-2-(4- chlorophenyl)ethanesulfonamide, Example 14.0. Example 14.0 was the first isomer to elute under the following conditions to separate the racemic compound Example 10.0. 250 x 30 mm Lux-2 column with 44 g/min MeOH (20 mM NH ₃ ) + 36 g/min C0 ₂ on Thar 80 SFC. Outlet pressure = 100 bar; Temp. = 29 °C; Wavelength = 220 nm. Used 1.5 mL injections of 50 mg/10 mL (5 mg/mL) sample solution in MeOH, i.e. 7.5 mg/injection. Run time = 18 min, Cycle time = 10 min. ¾ NMR (400 MHz, CDC1 ₃ ) δ 10.62 (br. s, 1 H) 7.14 - 7.33 (m, 4 H) 7.03 (d, J=7.74 Hz, 2 H) 6.94 (dd, J=8.31, 1.08 Hz, 1 H) 3.73 - 3.77 (m, 3 H) 3.11 - 3.23 (m, 2 H) 2.97 - 3.05 (m, 2 H) 2.52 (quin, J=7.87 Hz, 1 H) 1.57 - 1.83 (m, 6 H) 1.39 - 1.56 (m, 2 H). LCMS-ESI (pos.), m/z: 539.0 541.0.

[0275] Example 15.0. Preparation of ( )-N-(4-(2-bromo-6- methoxyphenyl)-5-cyclopentyl-4H-l,2,4-triazol-3-yl)-2-(4- chlorophenyl)ethanesulfonamide or ( )-N-(4-(2-bromo-6-methoxyphenyl)-5- cyclopentyl-4H-l,2,4-triazol-3-yl)-2-(4-chlorophenyl)ethanes ulfonamide.

[0276] ( )-N-(4-(2-Bromo-6-methoxyphenyl)-5-cyclopentyl-4H-l,2,4- triazol-3-yl)-2-(4-chlorophenyl)ethanesulfonamide or ( )-N-(4-(2-bromo-6- methoxyphenyl)-5-cyclopentyl-4H-l,2,4-triazol-3-yl)-2-(4- chlorophenyl)ethanesulfonamide, Example 14.0. Example 15.0 is the enantiomer of Example 14.0. The title compound Example 15.0 was the second isomer to elute on subjecting Example 10.0 to the SFC conditions described in Example 14.0. ¾ NMR (400 MHz, CDCI ₃ ) δ 10.74 (br. s, 1 H) 7.31 - 7.43 (m, 2 H) 7.25 - 7.31 (m, 2 H) 7.13 (d, J=7.26 Hz, 2 H) 7.04 (dd, J=8.22, 1.17 Hz, 1 H) 3.84 (s, 3 H) 3.19 - 3.32 (m, 2 H) 3.07 - 3.14 (m, 2 H) 2.62 (t, J=7.83 Hz, 1 H) 1.69 - 1.92 (m, 6 H) 1.50 - 1.62 (m, 2 H). LCMS- ESI (pos.), m/z: 539.0, 541.0.

[0277] Example 16.0: Preparation of (lR,2S)-N-(5-cyclopropyl-4-(2,6- dimethoxyphenyl)-4H-l,2,4-triazol-3-yl)-l-methoxy-l-(5-methy l-2-pyrimidinyl)-2- propanesulfonamide.

28.0 29.0 16.1

[0278] (E)-N'-(2,6-Dimethoxyphenyl)-N-(((lR,2S)-l-methoxy-l-(5- methylpyrimidin-2-yl)propan-2-yl)sulfonyl)carbamimidothioic acid, Example 16.1. Example 29.0 (0.203 g, 0.83 mmol) was suspended in ACN (8 mL) in a vial. The vial was warmed in a warm water bath to give a clear solution. To the solution, at RT, was added 28.0 (0.168 g, 0.859 mmol) followed by portion-wise addition of cesium carbonate (0.37 g, 1.13 mmol). The slightly cloudy mixture was stirred at RT for 15 h to obtain a suspension. LCMS-ESI (pos.) m/z: 440.9 (M+H) ⁺ . This suspension of 16.1 was used as

16.1 16.0

[0279] (lR,2S)-N-(5-Cyclopropyl-4-(2,6-dimethoxyphenyl)-4H-l,2,4- triazol-3-yl)-l-methoxy-l-(5-methyl-2-pyrimidinyl)-2-propane sulfonamide, Example 16.0. To a 20 mL scintillation vial was added 16.1 (2.50 mL, 0.250 mmol) and cyclopropanecarbohydrazide (0.025 g, 0.25 mmol, Frontier Scientific Services, Inc., Newark, DE). The mixture was cooled in an ice-water bath and silver(I) nitrate (0.085 g, 0.50 mmol) was added. The cold bath was removed, and the brown mixture was stirred at RT. After 15 min, the mixture was filtered through a pad of diatomaceous earth (flushing with ACN). The filtrate was concentrated in a Gene Vac into a 20 mL scintillation vial. Dioxane (2 mL) was added to the yellow residue followed by MSA (0.073 g, 0.76 mmol). The mixture was stirred at 80 °C for overnight. The reaction mixture was then allowed to cool to RT and concentrated in vacuo. The residue was dissolved in MeOH (~2 mL ) and the mixture was passed through a PS-carbonate column, eluting with MeOH. The filtrate was concentrated in vacuo and purified by mass-triggered HPLC to afford 16.0 (0.082 g, 0.11 mmol, 67% yield). ¾ NMR (500 MHz, DMSO-d ₆ ) δ 12.57 (br. s., 1H), 8.64 (s, 2H), 7.50 (t, J=8.50 Hz, 1H), 6.86 (dd, .7=1.39, 8.53 Hz, 2H), 4.79 (d, .7=3.50 Hz, 1H), 3.76 (m, 6H), 3.34-3.42 (m, 1H), 3.14 (s, 3H), 2.26 (s, 3H), 1.27-1.36 (m, 1H), 1.11 (d, .7=7.01 Hz, 3H), 0.73-0.83 (m, 4H). LCMS (pos.) m/z: 489.1 (M+H) ⁺ .

[0280] The compounds set forth in the following table were synthesized following the procedure in Example 16.0 using the known starting material as described.

Table 3

(lR,2S)-l-(5-cWoropyrirnidin-2-yl)-l- methoxypropane-2-sulfonamide

(Example 29.3), (S)-2,2- dimethylcyclopropanecarbohydrazide

hydrocliloride and (R)-2,2- dimethylcyclopropanecarbohydrazide

hydrocliloride (commercially available

from Chembridge), and 4- isothiocyanatooxane (commercially

available from Oakwood Products

Inc.).

The mixture obtained was purified by

(lR,2S)-l-(5-chloropyrimidin-2-yl)-N-(5-((R)- preparative SFC method: Column:

2,2-dimethylcyclopropyl)-4-(tetrahydro-2H- AD-H (2 x 25 cm) Mobile Phase: 60:40

pyran-4-yl)-4H-l,2,4-triazol-3-yl)-l- (A:B) A: Liquid C0 ₂ , B: MeOH, Flow

methoxypropane-2-sulfonamide or (1R,2S)-1- Rate: 80 mL/min, 220 nm, 100 bar inlet

(5-chloropyrimidin-2-yl)-N-(5-((S)-2,2- pressure to deliver Peak 1.

dimethylcyclopropyl)-4-(tetrahydro-2H-pyran- 4-yl)-4H- 1 ,2,4-triazol-3 -yl)- 1 - methoxypropane-2-sulfonamide.

¾ NMR (500MHz, DMSO-d ₆ ) δ 12.60 (br s, IH), 8.94 (s, 2H), 4.91 (d, J=3.6 Hz, IH), 4.30 (tt, J=3.8, 12.2 Hz, IH), 4.00 (d, J=11.4 Hz, 2H), 3.47 - 3.36 (m, 3H), 3.09 (s, 3H), 2.49 - 2.42 (m, 2H), 1.97 (dd, J=5.6, 8.4 Hz, IH), 1.74 ( d, J=11.2 Hz, IH), 1.62 (d, J=11.2 Hz, IH), 1.27 - 1.21 (m, 6H), 1.09 (t, J=4.9 Hz, IH), 0.94 (dd, J=4.4, 8.3 Hz, IH), 0.85 (s, 3H). LCMS-ESI (pos.), m/z: 485.2 (M+H) ⁺ .

(lR,2S)-l-(5-cWoropyrirnidin-2-yl)-l- methoxypropane-2-sulfonamide

(Example 29.3), (S)-2,2- dimethylcyclopropanecarbohydrazide

hydrochloride and (R)-2,2- dimethylcyclopropanecarbohydrazide

hydrocliloride (commercially available

from Chembridge), and 4- isothiocyanatooxane (commercially

available from Oakwood Products

Inc.).

The mixture obtained was purified by

(lR,2S)-l-(5-chloropyrimidin-2-yl)-N-(5-((R)- preparative SFC method: Column: AD- 2,2-dimethylcyclopropyl)-4-(tetrahydro-2H- H (2 x 25 cm) Mobile Phase: 60:40

pyran-4-yl)-4H-l,2,4-triazol-3-yl)-l- (A:B) A: Liquid C0 ₂ , B: MeOH, Flow

methoxypropane-2-sulfonamide or (1R,2S)-1- Rate: 80 mL/min, 220 nm, 100 bar inlet

(5-chloropyrimidin-2-yl)-N-(5-((S)-2,2- pressure to deliver Peak 2.

dimethylcyclopropyl)-4-(tetrahydro-2H-pyran- 4-yl)-4H- 1 ,2,4-triazol-3 -yl)- 1 - methoxypropane-2-sulfonamide.

¾ NMR (500MHz, DMSO-d ₆ ) δ 12.59 (br s, IH), 8.92 (s, 2H), 4.90 (d, J=3.9 Hz, IH), 4.25 (t, J=12.1 Hz, IH), 4.04 - 3.95 (m, 2H), 3.51 - 3.45 (m, IH), 3.43 - 3.36 (m, 2H), 3.12 (s, 3H), 2.50 - 2.45 (m, 2H), 1.96 (dd, J=5.4, 8.0 Hz, IH), 1.71 (d, J=11.4 Hz, IH), 1.57 (d, J=11.4 Hz, IH), 1.29 - 1.22 (m, 6H), 1.08 (t, J=4.7 Hz, IH), 0.94 (dd, J=4.3, 8.4 Hz, IH), 0.91 - 0.83 (m, 3H). LCMS-ESI (pos.), m/z: 485.2 (M+H) ⁺ . (lR,2S)-l-(5-cWoropyrirnidin-2-yl)-l- methoxypropane-2-sulfonamide

(Example 29.3), (S)-2,2- dimethylcyclopropanecarbohydrazide

hydrocliloride and (R)-2,2- dimethylcyclopropanecarbohydrazide

hydrocliloride (commercially available

from Chembridge), and 2- isothiocy anato- 1 ,3 -dimethoxybenzene

(Example 28.0).

The mixture was purified by

preparative SFC method: Column: AD-

(lR,2S)-l-(5-chloropyrimidin-2-yl)-N-(4-(2,6- H (2 x 25 cm) Mobile Phase: 75:25

dimethoxyphenyl)-5-((R)-2,2- (A:B) A: Liquid C0 ₂ , B: MeOH, Flow

dimethylcyclopropyl)-4H-l ,2,4-triazol-3 -yl)- 1 - Rate: 60 mL/min, 215 nm, 100 bar inlet

methoxypropane-2-sulfonamide or pressure to deliver Peak 1.

(lR,2S)-l-(5-chloropyrimidin-2-yl)-N-(4-(2,6- dimefhoxyphenyl)-5-((S)-2,2- dimethylcyclopropyl)-4H-l ,2,4-triazol-3 -yl)- 1 - methoxypropane-2-sulfonamide.

¾ NMR (500MHz, DMSO-d ₆ ) δ 12.61 (br s, 1H), 8.93 (s, 2H), 7.51 (t, .7=8.4 Hz, 1H), 6.87 (dd, .7=3.4, 8.3 Hz, 2H), 4.79 (d, .7=4.2 Hz, 1H), 3.77 (s, 3H), 3.76 - 3.72 (m, 3H), 3.42 - 3.34 (m, 1H), 3.14 (s, 3H), 1.14 (d, .7=7.0 Hz, 3H), 1.12 - 1.08 (m, 1H), 1.01 (t, .7=4.9 Hz, 1H), 0.89 (s, 3H), 0.87 - 0.83 (m, 4H). LCMS- ESI (pos.), m/z: 537.2 (M+H) ⁺ .

sulfonamide.

[0281] Example 27.0: Preparation of (2S,3R)-3-(5-methylpyrimidin-2- yl)butane-2-sulfonamide.

27.01 [0282] (E)-2-(But-2-en-2-yl)-5-methylpyrimidine, Example 27.01. 2-

Chloro-5-methyl-pyrimidine (18 mL, 151 mmol), potassium (Z)-but-2-en-2- yltrifluoroborate (Sigma Aldrich, 31 g, 191 mmol), tricyclohexylphosphine (8.5 g, 30.2 mmol), and Pd ₂ (dba)3 (13.82 g, 15.09 mmol) were added to a flask which was then degassed and backfilled with nitrogen. To the flask was added 1,4-dioxane (252 mL) and aqueous potassium phosphate tribasic (37.5 mL, 453 mmol). The resulting reaction was heated at 100 °C for 16 h. The reaction was then cooled to RT. The residue was filtered through a plug of silica gel and then loaded onto silica gel (0-20% EtOAc in heptanes) to afford (E)-2-(but-2-en-2-yl)-5-methylpyrimidine 27.1 (19 g, 125 mmol, 83% yield).

27.01 27.02

[0283] 2-(2-Chloro-3-(pyrimidin-2-ylthio)butan-2-yl)-5-methylpyrimi dine,

Example 27.02. To a solution of pyrimidine-2 -thiol (14.8 g, 132 mmol) in DCM (440 mL) was added sulfuryl chloride (10.73 mL, 132 mmol). The reaction was stirred at 0 °C for 1 h and a further 1 h at RT. To the cloudy reaction mixture was added (Z?)-2-(but-2- en-2-yl)-5-methylpyrimidine 27.01 (20 g, 132 mmol) dropwise, and the mixture was further stirred for 2 h. The reaction mixture was concentrated in vacuo. An aqueous sodium bicarbonate solution was added to the mixture to neutralize the reaction mixture. The reaction was 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 2-(2- chloro-3-(pyrimidin-2-ylthio)butan-2-yl)-5-methylpyrimidine 27.02 (30 g, 76% yield).

27.02 27.03 [0284] 2-(2-Chloro-3-(pyrimidin-2-ylsulfonyl)butan-2-yl)-5- methylpyrimidine, Example 27.03. To a solution of 2-(2-chloro-3-(pyrimidin-2- ylthio)butan-2-yl)-5-methylpyrimidine 27.02 (30 g, 100 mmol) in DCM (201 mL) was added meta-chloroperoxy benzoic acid (45.0 g, 201 mmol). The reaction was stirred at RT for 1 d. The reaction was concentrated in vacuo and aqueous sodium bicarbonate and sodium thiosulfate were added. The mixture was extracted with EtOAc and concentrated in vacuo to give the desired product 2-(2-chloro-3-(pyrimidin-2-ylsulfonyl)butan-2-yl)-5- methylpyrimidi g, 100 mmol, 100% yield).

27.03 27.04

[0285] Potassium (E)-3-(5-methylpyrimidin-2-yl)but-2-ene-2-sulfinate,

Example 27.04. To a solution of 2-(2-chloro-3-(pyrimidin-2-ylsulfonyl)butan-2-yl)-5- methylpyrimidine 27.03 (33 g, 100 mmol) in MeOH (249 mL) was added potassium carbonate (27.6 g, 200 mmol). The reaction was stirred at RT for 16 h. The reaction was concentrated in vacuo to give the desired product, potassium (£)-3-(5-methylpyrimidin-2- yl)but-2-ene-2-sulfinate 27.04 (21.57 g, 100% yield) which was used without further purification.

27.04 27.05

[0286] (E)-3-(5-Methylpyrimidin-2-yl)but-2-ene-2-sulfonamide, Example

27.05. To a solution of potassium (ii)-3-(5-methylpyrimidin-2-yl)but-2-ene-2-sulfinate (Example 27.04, 21.57 g, 85 mmol) in water (424 mL, 85 mmol) was added potassium acetate (5.30 mL, 85 mmol) followed by amidoperoxymonosulfuric acid (19.18 g, 170 mmol). The reaction was stirred at RT for 24 h. The reaction was extracted with EtOAc and concentrated in vacuo. The product thus obtained was purified on silica gel eluting with 0-50% EtOAc in hexanes to give the desired product (E)-3-(5-methylpyrimidin-2- yl)but-2-ene-2-sulfonamide 27.05 12 61% ield .

27.05 27.0

[0287] (2S,3R)-3-(5-Methylpyrimidin-2-yl)butane-2-sulfonamide, Example

27.0. A 900 mL pressure reactor was charged under nitrogen flow with (E)-3-(5- methylpyrimidin-2-yl)but-2-ene-2-sulfonamide, Example 27.05 (40.00 g, 0.1760 mol, 1 equiv), zinc trifluoromethane sulfonate (12.79 g, 0.0352 mol, 0.2 equiv, Aldrich), bis(l,5- cyclooctadiene)rhodium(I) tetrafluoroborate (1.43 g, 0.00352 mol, 0.02 equiv, Strem Chemicals, Inc.), (S)-l-[(R)-2-(di-l-naphthylphosphino)ferrocenyl]-ethyl-di-te rt.- butylphosphine (2.60 g, 0.00405 mol, 0.023 equiv, Solvias) and MeOH (520 mL). The mixture was purged with nitrogen and then with hydrogen and the media was stirred under 3-4 bars of hydrogen for 20 h. The reaction was monitored by HPLC and showed a complete conversion. The reactor was purged with nitrogen and the resulting suspension was concentrated at 35 °C under industrial vacuum to give initial material as an orange solid. The initial material was mixed with EtOH (742 mL) and the resulting suspension was stirred at 20-25 °C for 40 mins. The solid was filtered, washed with EtOH (2 x 97 mL) and dried at 40 °C under vacuum to give the title compound as a white powder (85.2% yield, 99%ee). ¾ NMR (400 MHz, DMSO-d ₆ ): δ 8.61 (s, 2H), 6.84 (s, 2H), 3.69 (tt, J = 12.4, 4.5 Hz, 2H), 2.25 (s, 3H), 1.32 (d, J = 6.9 Hz, 3H), 1.20 (d, J= 7.0 Hz, 3H). LCMS ESI (pos.) m/z; 230.1 (M+H) ⁺ .

[0288] The compounds in the following table were synthesized following the procedure in Example 27.0 using the known starting material as described.

Table 4

Example Reagents Structure, Name and Data

13 min.

LCMS-ESI (pos.) m/z: 246.2 (M+H) ⁺ . 27.6 2-chloro-5- methoxypy rimidine .

(2S,3R)-3-(5-methoxypyrimidin-2-yl)butane-2- sulfonamide.

LCMS-ESI (pos.) m/z: 246.2 (M+H)+.

[0289] Example 28.0. Preparation of 2-isothiocyanato-l,3- dimethoxybenzene.

28.0

[0290] 2-Isothiocyanato-l,3-dimethoxybenzene, Example 28.0. To a solution of 2,6-dimethoxyaniline (500 g, 3.25 mol, 1 eq) in DCM (5.0 L) was added 2,6- lutidine (1.5 L, 13.0 mol, 4 eq). The reaction mixture was cooled to 0 °C (internal temperature) and CSCI2 (374 mL, 4.88 mol, 1.5 eq) was added drop-wise. The reaction mixture was allowed to stir for 2 h. The solvent was then evaporated in vacuo, and the initial mass was purified by S1O2 column to provide 2-isothiocyanato-l,3- dimethoxybenzene, Example 28.0 as white solid. LCMS-ESI (pos.) m/z: (M+H) ⁺ = 196. ¾ NMR (400 MHz, CDC1 ₃ ) δ 7.16 (t, J = 8.48 Hz, 1H), 6.55 (d, J= 8.48 Hz, 2H), 3.90 (app s, 6H).

[0291] The compounds set forth in the following table were synthesized following the procedure in Example 28.0 using the known starting material as described.

Table 5

LCMS-ESI (pos.) m/z: 198.1 (M+H) ⁺ .

28.2 Commercially available

from CombiBlocks.

1 -isothiocyariato-2-methoxybenzene.

¾ NMR (400 MHz, DMSO-c¾) 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).

3,5-difluoropyridin-4- N

amine (commercially

available from Ark Pharm

Inc, Libertyville, IL). F ^' y F

NCS

3,5-difluoro-4-isotriiocyariatopyridine.

LCMS-ESI (pos.) m/z: 173.0 (M+H) ⁺ .

[0292] Example 29.0. Preparation of (lR,2S)-l-methoxy-l-(5- methylpyrimidin-2-yl)propane-2-sulfonamide.

29.01

[0293] (E)-5-Methyl-2-(prop-l-en-l-yl)pyrimidine, Example 29.01. To a

500 mL round bottom flask was added 2-chloro-5-methylpyrimidine (12 g, 93 mmol), potassium (E)-trifluoro(prop-l-en-l-yl)borate (17.27 g, 117 mmol), and potassium phosphate (59.4 g, 280 mmol). The flask was purged with N ₂ (5x) and then 1,4-dioxane (200 mL) and water (20 mL) were added. The resulting yellow suspension was bubbled with Ar for 15 min and then l,l-bis[(di-t-butyl-p-methylaminophenyl]palladium(II) chloride (Amphos, commercially available from Strem, 2.64 g, 3.73 mmol) was added, a reflux condenser was attached and the reaction was warmed to 90 °C in an oil bath and stirred under N ₂ for 16.5 h. The reaction was then cooled to RT. The reaction was diluted with water (250 mL), and extracted with EtOAc (2 x 250 mL). The organic layers were combined, dried (MgSC ), and concentrated in vacuo. The residue was purified by flash chromatography on silica gel eluting with 0-20% EtOAc/hexanes) to afford (E)-5- methyl-2-(prop-l-en-l-yl)pyrimidine 29.01 (12.96 g, 97 mmol, 100% yield) as a yellow/orange oily solid. ¾ NMR (300 MHz, CDC1 ₃ ) δ 8.49 (s, 2H), 7.01-7.20 (m, 1H), 6.57 (dd, J= 15.6, 1.7 Hz, 1H), 2.29 (s, 3H), 1.97 (dd, J= 6.8, 1.6 Hz, 3H). LCMS-ESI (pos.) ⁺ .

29.01 29.02

[0294] (lR,2R)-l-(5-Methylpyrimidin-2-yl)propane-l,2-diol, Example

29.02. Racemic conditions. To a solution of (E)-5-methyl-2-(prop-l-en-l-yl)pyrimidine, 29.01 (5.75 g, 42.9 mmol) and 4-methylmoφholine-4-oxide (7.53 g, 64.3 mmol) in acetone (60 mL) and water (6 mL) was added osmium tetroxide, 4 wt.%, in water (0.681 mL, 0.111 mmol). The resulting reaction mixture was stirred at RT under N2 for 21.5 h. LCMS showed complete conversion to a product corresponding to the mass of the desired product (M+H) ⁺ = 169. The reaction was passed through a Varian Chem-Elut cartridge to remove water and concentrated in vacuo. Water was still presen, and the residue was dissolved in DCM, dried (MgSC ), and concentrated in vacuo. The residue was purified by flash chromatography (120 g Si0 ₂ , 0-10% MeOH/DCM) to give the racemic syn-diol (lS,2S)-l-(5-methylpyrimidin-2-yl)propane-l,2-diol and (2R,2R)-l-(5-methylpyrimidin- 2-yl)propane-l,2-diol (5.85 g, 34.8 mmol, 81% yield) as a light yellow solid. ¾ NMR (300 MHz, CDCI ₃ ) δ 8.59 (s, 2H), 4.67 (br. s., 1H), 4.33 (br. s., 1H), 4.09-4.25 (m, 1H), 2.86 (d, J=7.2 Hz, 1H), 2.36 (s, 3H), 1.30 (d, J=6.6 Hz, 3H). LCMS-ESI (pos.) m/z: 169.2 (M+H). Chiral conditions. A batch of AD-mix-beta was prepared from:

K ₂ Os0 ₂ (OH) ₄ (26 mg, 0.07 mmol); K ₃ Fe(CN) ₆ (16.4 g, 49.9 mmol); K ₂ CO (6.89 g, 49.9 mmol) 3; and (DHQD) ₂ PHAL (125 mg, 0.16 mmol). In a 50 mL round bottom flask was added t-BuOH (5 mL), water (5.00 mL), 1.4 g of AD-mix-beta (prepared above) and methanesulfonamide (95 mg, 1.00 mmol). The mixture was stirred at RT until clear and then cooled to 0 °C. (E)-5-Methyl-2-(prop-l-en-l-yl)pyrimidine (intermediate 29.01 168 mg, 1 mmol) in t-BuOH (1 mL) was added, and the slurry was stirred at 0 °C 2 h. LCMS (1.5 h) showed -10% conversion. The reaction was allowed to warm slowly to RT as the ice bath melted, and the mixture was stirred an additional 22 h. LCMS showed -90% conversion. The reaction was quenched with saturated aqueous sodium sulfite (10 mL), and extracted with EtOAc (2x20 mL). The combined organic layers were washed with 2 N NaOH (10 mL), dried (MgSC ), and concentrated. The aqueous layer was extracted with DCM (2x50 mL), EtOAc (2x50 mL), and 10% iPrOH in CHC1 ₃ (2x50 mL). The combined organic layers were concentrated, and the residue was purified by flash column chromatography (12 g Si0 ₂ , 5-100% 3: 1 EtOAc :EtOH/heptane) to give (lR,2R)-l-(5- methylpyrimidin-2-yl)propane-l,2-diol (Example 29.02, 88.6 mg, 0.527 mmol, 52.7% yield) as a clear, colorless oil. Chiral Analysis: SFC Chiral Analysis showed the %ee to be 94.8% using an AS-H (100x2. lmm, 3um), 10% organic modifier (IPA with 20mM ammonia), 90% carbon dioxide. F=1.0 mL/min, column temperature=RT, BRP=105 bar.

29.02 29.03

[0295] 5-Methyl-2-((2R,3R)-3-methyloxiran-2-yl)pyrimidine, Example

29.03. To a solution of syn-diol (lR,2R)-l-(5-methylpyrimidin-2-yl)propane-l,2-diol 11.2 (1.46 g, 8.68 mmol) in DCM (25 mL) (cooled with a RT water bath) was added 1,1,1-trimethoxy ethane (2.50 mL, 2.29 mmol). Chlorotrimethylsilane (2.50 mL, 19.7 mmol) was then added in 2 portions 5 min apart. The reaction had a small exotherm on the first portion of addition of TMSC1 (23-28 °C). The reaction was stirred at RT under N ₂ for 23 h. LCMS indicated incomplete conversion. Thus, an additional 1.25 equiv. of 1,1,1-trimethoxy ethane (1.25 mL, 9.95 mmol) and chlorotrimethylsilane (1.25 mL, 9.85 mmol) were added, and the reaction was stirred for an additional 24 h. LCMS; ((M+H) ⁺ = 229). The reaction was then concentrated in vacuo. The residue was dissolved in MeOH (20 mL) and potassium carbonate (1.50 g, 10.85 mmol) was added and the reaction stirred at RT for 4 h. LCMS (4 h) showed complete conversion to product corresponding to desired epoxide LCMS; ((M+H) ⁺ =151). The reaction was filtered, the filter cake washed with DCM (5 mL), and the combined filtrates concentrated in vacuo. The residue was purified by flash column chromatography on silica gel eluting with 0- 100% EtOAc/hexanes) to afford 5-methyl-2-((2R,3R)-3-methyloxiran-2-yl)pyrimidine 29.03 (1.00 g, 6.6 mmol, 77%) as a clear, light yellow oil. ¾ NMR (300 MHz, CDC1 ₃ ) δ 8.54 (s, 2H), 3.81 (d, J=1.9 Hz, 1H), 3.32-3.53 (m, 1H), 2.31 (s, 3H), 1.50 (d, J=5.1 Hz, 3 ⁺ .

29.03 29.04

[0296] (lR,2S)-2-(Benzo[d]thiazol-2-ylthio)-l-(5-methylpyrimidin-2- yl)propan-l-ol, Example 29.04. To a solution of Example 29.03 (250 mg, 1.33 mmol) in DCM (5 mL) was added benzo[d]thiazole-2-thiol (245 mg, 1.465 mmol), followed by tris(((trifluoromethyl)sulfonyl)oxy)ytterbium (83 mg, 0.133 mmol). The suspension was heated in a 35 °C heating block for 17 h and showed 100% conversion to the desired product. The reaction was cooled to RT, loaded on a plug of silica, and purified by flash chromatography (12 g Si0 ₂ , 5-100% 3: 1 EtOAc:EtOH/heptane) to afford (lR,2S)-2- (benzo[d]thiazol-2-ylthio)-l-(5-methylpyrimidin-2-yl)propan- l-ol 29.04 (428 mg, 1.35 mmol, 100% yield) as a clear colorless oil. ¾ NMR (300 MHz, CDC1 ₃ ) δ 8.60 (s, 2H), 7.88 (d, J=7.6 Hz, 1H), 7.71-7.81 (m, 1H), 7.42 (td, J=7.7, 1.3 Hz, 1H), 7.27-7.35 (m, 1H), 5.31 (s, 1H), 4.70 (qd, J=7. l, 3.1 Hz, 1H), 2.32 (s, 3H), 1.33 (d, J=7.0 Hz, 3H).

+.

29.04 29.05

[0297] 2-(((lR,2S)-l-Methoxy-l-(5-methylpyrimidin-2-yl)propan-2- yl)thio)benzo[d]thiazole, Example 29.05. To a 50 mL flask equipped with a magnetic stirrer was charged Example 29.04 (350 mg, 1.103 mmol) in 2-methyltetrahydrofuran (1.1 mL). The reaction mixture was cooled to -78 °C and potassium

bis(trimethylsilyl)amide (1.0 M solution in THF, 1.32 μΕ, 1.32 mmol)) was added dropwise (total addition time: 2 min., turned to yellow solution). The resulting mixture was stirred for 1 h and then methyl trifluoromethane sulfonate (374 μΕ, 3.31 mmol) was added dropwise (turned to a lighter yellow solution). The reaction mixture was stirred at - 78 °C for 15 min. LCMS showed complete conversion to the product. The reaction mixture was quenched with a saturated aqueous NH ₄ C1 solution (30 mL) at -78 °C. The reaction was allowed to warm to RT and the aqueous layer was back extracted with EtOAc (3x75 mL). The combined organic layers were washed with brine, dried (Na2S04), and concentrated in vacuo. The material thus obtained was purified by chromatography through a Biotage 50g ultra silica gel column, eluting with a gradient of 0-25% EtOAc in hexanes, to provide 2-(((lR,2S))-l-methoxy-l-(5-methylpyrimidin-2- yl)propan-2-yl)thio)benzo[d]thiazole 29.05 (0.32 g, 75% for two runs) as a light-yellow oil.

[0298] 2-(((lR,2S)-l-Methoxy-l-(5-methylpyrimidin-2-yl)propan-2- yl)sulfonyl)benzo[d]thiazole, Example, Example 29.06. A solution of 2-(((lR,2S)-l- methoxy-l-(5-methylpyrimidin-2-yl)propan-2-yl)thio)benzo[d]t hiazole 29.05 (313 mg, 0.94 mmol) in DCM (2.8 mL) at 0 °C was treated with 3 -chloroperoxy benzoic acid, 77% max. (476 mg, 2.13 mmol). The reaction was stirred at 0 °C for 1 h before the ice bath was removed. LCMS showed desired product, sulfoxide, and the presumed

sulfoxide/sulfone. The mixture was allowed to warm to ambient temperature and stirred for an additional 40 h. The reaction was quenched with saturated aqueous sodium bisulfite (6 mL), saturated aqueous sodium bicarbonate (5 mL), and was then stirred for 10 min. The reaction was extracted with EtOAc (2x20 mL) and the organic layers were combined, washed with saturated aqueous NaHC0 ₃ (10 mL), brine (10 mL), dried (MgSC ) and filtered. Iodide/starch strip indicator showed no peroxide was present. The filtrates were concentrated to give a clear, colorless oil (360 mg). Purification of the residue by flash chromatography (40 g S1O2, 0-100% 3: 1 EtOAc :EtOH/heptane) gave 2- (((lR,2S)-l-methoxy-l-(5-methylpyrimidin-2-yl)propan-2-yl)su lfonyl)benzo[d]thiazole 11.6 (285 mg, 0.78 mmol, 83% yield, 77% purity) as a white foam. ¾ NMR (300 MHz, CDCI ₃ ) δ 8.57 (s, 2H), 8.18-8.28 (m, 1H) 7.97-8.05 (m, 1H), 7.54-7.67 (m, 2H), 5.25-5.34 (m, 1H), 4.23 (qd, J=7.2, 3.1 Hz, 1H), 3.41 (s, 3H), 2.31 (s, 3H), 1.49 (d, J=7.2 Hz, 3H). LCMS-ESI (pos.) m/z: 364.0 (M+H).

29.06 29.07

[0299] Potassium (lR,2S)-l-methoxy-l-(5-methylpyrimidin-2-yl)propane-

2-sulfinate, Example 29.07. To a solution of 2-(((lR,2S)-l-methoxy-l-(5- methylpyrimidin-2-yl)propan-2-yl)sulfonyl)benzo[d]thiazole 29.06 (268 mg, 0.74 mmol) in MeOH (1843 μΚ) was added potassium carbonate (204 mg, 1.48 mmol). The reaction was stirred at RT for 17 h. LCMS showed desired product formation as the sulfuric acid. LCMS-ESI (pos.) m/z: (M+H) ⁺ =231.1). The reaction was concentrated in vacuo (yellow solid) and used directly in the following step. Note: Some epimerization occurred in this reaction (-15%).

29.07 29.0

[0300] (lR,2S)-l-Methoxy-l-(5-methylpyrimidin-2-yl)propane-2- sulfonamide, Example 29.0. To a suspension of potassium (lR,2S)-l-methoxy-l-(5- methylpyrimidin-2-yl)propane-2-sulfinate (Example 29.07, 198 mg, 0.74 mmol) in water (3.7 mL) was added potassium acetate (72.4 mg, 0.74 mmol), followed by

hydroxylamine-o-sulfonic acid, 97% (167 mg, 1.476 mmol). The reaction mixture was stirred at RT for 4.5 h. LCMS showed desired product formation plus a small peak that corresponded to the stereoisomer. The reaction mixture was extracted with EtOAc (2 ^χ ) and the organic layers were combined, dried (Na2S04), and concentrated in vacuo. The residue was loaded onto a silica gel column eluting with 0-30% (3: 1 EtOAc:EtOH)/DCM to afford (lR,2S)-l-methoxy-l-(5-methylpyrimidin-2-yl)propane-2-sulfon amide 29.0 (114 mg, 0.465 mmol, 63% yield) as a white solid (contained -15% other diastereomer).

¾ NMR (300 MHz, CDC1 ₃ ) δ 8.63 (s, 2H), 5.10 (d, J=33 Hz, 1H), 4.78 (br. s., 2H), 3.74 (qd, J=7. \, 3.3 Hz, 1H), 3.51 (s, 3H), 2.36 (s, 3H), 1.33 (d, J=7. \ Hz, 3H). LCMS-ESI (pos.) m/z: 246.1 (M+H) ⁺ . [0301] The compounds set forth in the following table were synthesized following the procedure in Example 29.0 using the known starting material as described. Table 6

LCMS-ESI (pos.) m/z: 232.0 (M+H) ⁺ .

[0302] Example 29.8. Preparation of Example (lR,2S)-l-methoxy-l-(5- methoxypyrimidin-2-yl)propane-2-sulfonamide.

29.8

[0303] (lR,2S)-l-Methoxy-l-(5-methoxypyrimidin-2-yl)propane-2- sulfonamide, Example 29.8. The title compound was obtained as a by-product of the synthesis of ( 1R,2S)- 1 -methoxy - 1 -(5-fluoropy rimidin-2-y l)propane-2-sulfonamide (Example 29.2) during step 29.07 and isolated in the final step of the synthesis of

Example 29.2 to give the title compound 29.8 (240 mg, 10.2% yield) as a white solid. ¾ NMR (CDC1 ₃ ) δ 8.46 (s, 2H), 5.11 (d, J=3A Hz, 1H), 4.77 (br. s, 2H), 3.97 (s, 3H), 3.67- 3.77 (m, 1H), 3.50 (s, 3H), 1.35 (d, J=7.0 Hz, 3H). LCMS-ESI (pos.) m/z: 284.1 (M+Na) ⁺ .

[0304] Example 30.0. Preparation of /VyV-bis(4- methoxybenzyl)ethanesulfonamide.

30.1

[0305] Bis(4-methoxybenzyl)amine, Example 30.1. 4-Methoxybenzylamine

(neat, 600 g, 4.37 mol, 1 eq) and 4-methoxybenzaldehyde (532 mL, 4.37 mol, 1 eq) were added to a 10 L round bottom flask at ambient temperature with stirring. The reaction spontaneously warmed and a white precipitate was observed. The mixture was stirred for 1 h. To the above mixture was added anhydrous EtOH (4.8 L) and stirring was continued at RT for 15-30 min. This was followed by the addition of sodium borohydride granules (99 g, 2.62 mol, 0.6 eq) portionwise over ~ 2 h (Note : During the addition of NaBH ₄ , the internal temperature of the reaction rose to 42 °C), and the mixture was further stirred at ambient temperature overnight. The reaction was quenched slowly with water (600 mL). The mixture was then concentrated on a rotary evaporator at 50°C. The residue was partitioned between water (4 L) and DCM (4 L). The aqueous layer was extracted with more DCM (2 x 2 L). The combined organic layers were dried over Na2S04, filtered and concentrated in vacuo to give bis(4-methoxybenzyl)amine 30.1 (1112 g, 99% yield) as a semi-solid. The material was used directly in the next step without further purification. ¾-NMR (400 MHz, CDC1 ₃ ) δ 7.28 (t, J = 7.12 Hz, 4H), 6.89 (d, J = 8.60 Hz, 4H), 3.83 (app s, 6H), 3.76 (s, 4H) (-NH proton not observed). LCMS-ESI (pos.) m/z: = 258.4 ( ⁺ .

30.1 30.0

[0306] N^V-Bis(4-methoxybenzyl)ethanesulfonamide, Example 30.0. To a solution of bis(4-methoxybenzyl)amine 30.1 (900 g, 3.49 mol, 1 eq) in DCM (9 L) was added TEA (634 mL, 4.55 mol, 1.3 eq) followed by dropwise addition of ethanesulfonyl chloride (399 mL, 4.19 mol, 1.2 eq). (The internal temperature was kept between 5-10 °C during the addition of the ethanesulfonyl chloride). Once the addition was complete, the cooling bath was removed. After 1.5 h, TLC showed complete loss of starting material. The reaction was quenched by the addition of water (4 L) to the reaction mixture. The layers were separated and the aqueous layer extracted with DCM (2x 2 L). The combined organic layers were washed with brine (2x 1 L), dried over Na2S04, and concentrated in vacuo. The material thus obtained was adsorbed onto a plug of silica gel and purified by chromatography (silica gel (60-120 mesh) eluting with a gradient of 10-80% EtOAc in hexanes) to provide the title compound 30.0 (1125 g, 3.22 mol, 92%) as white solid. ¾- NMR (400 MHz, CDC1 ₃ ) δ 7.23 (dd, J = 2.08, 6.62 Hz, 4H), 6.90 (dd, J = 2.12, 6.60 Hz, 4H), 4.29 (s, 4H), 3.83 (app s, 6H), 2.92 (q, J = 7.40 Hz, 2H), 1.33 (t, J = 7.40 Hz, 3H). GC-MS (ESI pos. ion) m/z: = 372.2 (M+Na) ⁺ .

[0307] Example 31.0: Preparation of (lS,2S)-l-isopropoxy-l-(5- methylpyrimidin-2-yl)propane-2-sulfonamide.

31.1

[0308] 5-Methylpyrimidine-2-carbonitrile, Example 31.1. A solution of 2- chloro-5-methylpyrimidine (500 g, 3889 mmol, 1.0 equiv) in DMF (5000 mL) was degassed with N ₂ for 20 min and dppf (108 g, 194 mmol, 0.05 equiv) and Pd ₂ (dba) ₃ (178 g, 194 mmol, 0.05 equiv) were added to the reaction mixture. Zn(CN) ₂ (685 g, 5834 mmol, 1.5 equiv) was added, and the reaction mixture was heated at 100 °C for 16h. The reaction was quenched with water (5 L) and stirred for 10 min. The reaction mixture was then filtered through a pad of Celite® brand filter aid. Filtrate was diluted with water (4 L) and extracted with EtOAc (2 x 4 L). The combined organic layers were washed with brine (4 L), dried over Na ₂ S04, filtered and concentrated in vacuo to give the initial product which was further purified by column chromatography using silica gel (60-120 mesh) and 0-10 % EtOAc in hexanes to obtain Example 31.1 (330 g, 71 %) as and off white solid. ¾ NMR (400 MHz, DMSO-i¾) δ 8.89 (s, 2H), 2.39 (s, 3H).

31.2

[0309] (R)-N,N-Bis(4-methoxybenzyl)-l-(5-methylpyrimidin-2-yl)-l- oxopropane-2-sulfonamide and (S)-N,N-bis(4-methoxybenzyl)-l-(5- methylpyrimidin-2-yl)-l-oxopropane-2-sulfonamide, Example 31.2. A solution of Example 30.0 (293 g, 839 mmol, 2.0 equiv) in THF (2 L) was added

isopropylmagnesium chloride (420 mL, 839 mmol, 2.0 equiv, 2.0 M in diethyl ether) at 0 °C. The reaction mixture was stirred at RT for 3 h. To the reaction mixture was added 5- methylpyrimidine-2-carbonitrile (50 g, 420 mmol, 1.0 equiv) in THF (100 mL) at 0 °C, and themixture was stirred at RT for 2h. The reaction was then quenched with 1.5 N HCl (500 mL) and water (2 L) and stirred for 10 min. The mixture was extracted with EtOAc (2 x 1 L), and the combined organic layers were washed with brine (500 mL), dried over Na ₂ S04 and filtered. The organic layer was concentrated in vacuo to give the initial compound which was purified by column chromatography using silica gel (100-200 mesh) and 0-50% EtOAc in hexanes as eluent to obtain Example 31.2 (60 g, 30 % yield) as a brown liquid. ¾ NMR (400 MHz, DMSO-d ₆ ) δ 8.90 (s, 2H), 7.15 - 7.09 (m, 4H), 6.85 - 6.80 (m, 4H), 4.34 - 4.18 (m, 5H), 3.71 (app s, 6H), 2.39 (s, 3H), 1.50 (d, J = 6.9 Hz, 3H). LCMS-ESI (pos.) m/z: (M+H) ⁺ : 470.0.

31.3 [0310] (E)-l-Isopropoxy-N,N-bis(4-methoxybenzyl)-l-(5-methylpyrimid in- 2-yl)prop-l-ene-2-sulfonamide, Example 31.3. A solution of Example 31.2 (120 g, 256 mmol, 1.0 equiv) in DMF (1.2 L) was added 2-iodopropane (129 mL, 1278 mmol, 5.0 equiv) and potassium carbonate (70.6 g, 511 mmol, 2.0 equiv). The reaction mixture was stirred at 60 °C for 14 h. The reaction was then quenched with water (1 L), stirred for 10 min and extracted with EtOAc (2 x 1 L). The combined organic layers were washed with brine (1 L), dried over Na2S04, filtered and concentrated in vacuo to give the initial material. The initial product was purified by column chromatography using silica gel (100-200 mesh) and 0-50% EtOAc in hexanes as eluent to obtain Example 31.3 (75 g, 57.4 % yield) as an off white solid. ¾ NMR (400 MHz, DMSO-rf ₆ ) δ 8.72 (s, 2H), 7.09 (d, J = 8.3 Hz, 4H), 6.86 (d, J= 8.3 Hz, 4H), 4.16 (s, 4H), 3.73 (s, 3H), 3.73 (s, 3H), 3.71 - 3.67 (m, 1H), 2.31 (s, 3H), 1.87 (s, 3H), 1.19 - 1.16 (m, 6H). LCMS-ESI (pos.) m/z: (M+H) ⁺ : 512.1.

31.4

[0311] (lS,2R)-l-Isopropoxy-N,N-bis(4-methoxybenzyl)-l-(5- methylpyrimidin-2-yl)propane-2-sulfonamide, Example 31.4. To a solution of

Example 31.3 (180 g, 352 mmol, 1.0 equiv) in MeOH (1.8 L) was added zinc triflate (256 g, 704 mmol, 2.0 equiv) and (S)-RuCl[(p-cymene(BINAP)]Cl (6.54 g,7.04 mmol, 0.02 equiv) were added, and the mixture was heated at 60 °C under H ₂ pressure (60 psi) for 16h. The reaction mixture was concentrated in vacuo to obtain the initial product which was further purified by column chromatography using silica gel (60-120 mesh) and 0-50% EtOAc in DCM as eluent to obtain Example 31.4 (140 g, 77 %, 92% ee) as an off white solid. ¾ NMR (400 MHz, DMSO-i¾) δ 8.71 (s, 2H), 7.25 - 7.15 (m, 4H), 6.95 - 6.75 (m, 4H), 4.82 (dd, J= 7.8, 1.8 Hz, 1H), 4.39 (d, J = 15.6 Hz, 2H), 4.13 (d, J = 15.7 Hz, 2H), 3.82 (qd, J = 8.5, 7.9, 6.0 Hz, 1H), 3.65 (m, 6H), 3.41 - 3.35 (m, 1H), 2.27 (s, 3H), 1.12 (dd, J = 6.2, 1.8 Hz, 3H), 1.02 (dd, J = 7.1, 2.0 Hz, 3H), 0.96 (dd, J = 6.3, 1.8 Hz, 3H). LCMS-ESI (pos. ⁺ : 514.2.

31.0

[0312] (lS,2S)-l-Isopropoxy-l-(5-methylpyrimidin-2-yl)propane-2- sulfonamide, Example 31.0, Example 31.0. To a solution of Example 31.4 (140.0 g, 273 mmol, 1.0 equiv) in DCM (500 mL) was added TFA (250 mL) at 0 °C, and the reaction mixture was allowed to stir at RT for 16 h. The reaction mixture was concentrated in vacuo to obtain the initial material which was dissolved in DCM (1 L) and washed with a saturated aqueous NaHC0 ₃ solution (1 L). The organic layer was dried over Na2S04, filtered and concentrated in vacuo to obtain the initial material which was further purified by column chromatography using silica gel (60-120 mesh) and 0-2% MeOH in DCM to obtain Example 31.0 (72 g, 97 % yield, 90% ee) as an off white solid. Example 31.0 (72 g, 90% ee) was suspended in IPA (500 mL) and heated to 70 °C until the mixture became homogeneous. Once the solution became homogeneous, the mixture was cooled to RT overnight. The white solid thus obtained was filtered and dried under vacuum to obtain compound-6 (30 g, >99%ee). The mother liquor was concentrated and the solid obtained was recrystallized again following the same procedure. ¾ NMR (400 MHz, DMSO-i¾) δ 8.70 (d, J = 2.3 Hz, 2H), 6.45 (d, J = 2.4 Hz, 2H), 4.68 (dd, J = 8.8, 2.5 Hz, 1H), 3.59 - 3.52 (m, 1H), 3.48 (ddd, J = 9.7, 7.4, 4.9 Hz, 1H), 2.29 (d, J = 2.6 Hz, 3H), 1.13 (dd, J = 6.1, 2.5 Hz, 3H), 0.93 (dd, J = 7.1, 2.5 Hz, 3H), 0.88 (dd, J = 63, 2.5 Hz, 3H). LCMS-ESI (pos.) m/z: (M+H) ⁺ : 274.1.

[0313] The compounds in the following table were synthesized following the procedure in Example 31.0 using the known starting material as described.

Table 7

Example Reagents Structure, Name and Data

LCMS ESI (pos.) m/z: 274.1 (M+H) ⁺ .

[0314] Example 32.0. Preparation of (2S,3R)-3-(5-chloropyridin-2- yl)but

32.0

[0315] (2S,3R)-3-(5-Chloropyridin-2-yl)butane-2-sulfonamide, Example

32.0. To a solution of (E)-2-(5-chloropyridin-2-yl)ethenesulfonamide (10 g, 40.5 mmol) in MeOH (100 mL) was added zinc trifluoromethane sulfonate (2.95 g,8.11 mmol), bis(l,5-cyclooctadiene)rhodium(I) tetrafluroborate (0.329 g,0.811 mmol) and (S)-1-[(R)- 2-(di-l-naphthylphosphino)ferrocenyl]-ethyl-di-tert-butylpho sphine (0.651 g, 1.013 mmol). The reaction mixture was degassed with argon and hydrogen three times and charged with hydrogen (50 Psi) in 200 mL. The reaction was mini-claved at RT for 16 h followed by heating at 65 °C for 16 h checked by TLC for completion of reaction. The reaction mass was concentrated in vacuo to give the initial product which was purified by column chromatography (silica gel 60-120 mesh) using 40-45 % of EtOAc in petroleum ether as an eluent to obtain the desired product Example 32.0 (9 g,36.2 mmol, 89 %) as a brownish solid in 82% ee. Recrystallization from i-PrOH yielded >97% ee material. 1H NMR (400 MHz, DMSO-d ₆ ) δ 1.19 (d, J=7.05 Hz, 3 H) 1.29 (d, J=7.05 Hz, 3 H) 3.46 (qd, J=7.08, 3.84 Hz, 1 H) 3.63 (qd, J=7.08, 3.84 Hz, 1 H) 6.82 (s, 2 H) 7.36 (d, J=8.50 Hz, 1 H) 7.88 (dd, J=8.50, 2.70 Hz, 1 H) 8.56 (d, J=2.28 Hz, 1 H). LCMS-ESI (pos.) m/z: 249.0 (M+H) ⁺ .

[0316] Example 33.0. Preparation of (lR,2R)-l-isopropoxy-l-(5- methylpyrazin-2-yl)propane-2-sulfonamide or (1 S,2S)-1 -isopropoxy-1 -(5- methylpyrazin-2-yl)propane- -sulfonamide.

33.1

[0317] 5-Methylpyrazine-2-carbaldehyde, Example 33.1. A solution of

LAH (164.0 mL, 0.164 mol, 1.0 M in THF, 0.5 equiv.) was added to a suspension of methyl 5-methylpyrazine-2-carboxylate (50 g, 0.328 mol, 1.0 equiv.) in anhydrous THF (750 mL) at -78°C. The internal temperature was kept below -72 °C during the addition of LAH. On completion of addition, the reaction mixture was left, to stir at -78 °C for a further 20 min and then quenched with glacial AcOH (50.0 mL) at the same temperature. The resulting mixture was warmed to RT and the volatile s were removed by evaporation under pressure. The residue was dissolved in hydrochloric acid (1.5N, 500 mL) and extracted with DCM (2 x 2 L). The extracts were combined, washed with a saturated aqueous sodium hydrogen carbonate solution (2 x 500 mL), (Note: no product was observed in the HC1 or aqueous sodium hydrogen carbonate solution) dried over anhydrous Na ₂ S04, and concentrated in vacuo to yield a brown oil. The initial product was purified by column chromatography (silica gel 60-120 mesh) eluting with a gradient of 10% EtOAc in petroleum ether to provide the title compound as a pale yellow liquid (21.3 g, 53 %). TLC Info: (9.0/1.0 petroleum ether/EtOAc). ¾ NMR (400 MHz, CDC1 ₃ ) δ 10.14 (s, 1H), 9.07 (d, J = 1.5 Hz, 1H), 8.63 (d, J= 1.4 Hz, 1H), and 2.70 (s, 3H).

+.

33.2

[0318] (lR,2S)-l-Hydroxy-N,N-bis(4-methoxybenzyl)-l-(5-methylpyrazi n- 2-yl)propane-2-sulfonamide and (lS,2R)-l-hydroxy-N,N-bis(4-methoxybenzyl)-l-(5- methylpyrazin-2-yl)propane-2-sulfonamide, Example 33.2. To a solution of N,N- bis(4-methoxybenzyl)ethanesulfonamide (Example 12.0, 73.13 g, 0.209 mol, 1.2 equiv.) in anhydrous THF (600 mL) at -78 °C was added n-butyl lithium (83.71 mL, 0.209 mol, 2.5 M solution in hexanes, 1.2 equiv.) via additional funnel slowly, and the resulting mixture was stirred for 10 min. Then a solution of 5-methylpyrazine-2-carbaldehyde (Example 33.1, 21.3 g, 0.174 mol, 1.0 equiv.) in anhydrous THF (150 mL) was added, and the resulting mixture was stirred at the same temperature for 45 min and then allowed to warm to RT for 2 h. The reaction mixture was quenched by the addition of aqueous ammonium chloride (200 mL) and extracted with EtOAc (2 x 2 L). The combined organic layers were washed with brine (2 x 500 mL) (Note: no productwas observed in the ammonium chloride or brine layer). After drying over anhydrous Na ₂ S0 ₄ , the filtrate was concentrated in vacuo, to afford an oil. The oil was purified by flash column chromatography (silica gel, 230-400 mesh) to afford the two isomers. The faster moving isomer (32 g as a white solid) was obtained from the column with a gradient of 10 % to 30 % EtOAc in petroleum ether. ¾ NMR (400 MHz, DMSO-rf ₆ ) δ 8.61 (d, J= 1.5 Hz, 1H), 8.51 (d, J = 1.5 Hz, 1H), 7.22 - 7.11 (m, 4H), 6.90 - 6.80 (m, 4H), 6.10 (d, J = 5.9 Hz, 1H), 5.29 (dd, J= 5.9, 2.2 Hz, 1H), 4.36 - 4.16 (m, 4H), 3.73 (m, 6H), 3.70-3.66 (m, 1H) 2.50 (merged with solvent peak, 3H) and 1.10 (d, J = 7.0 Hz, 3H). LCMS-ESI (pos.) m/z:472.4 (M+H) ⁺ .

33.3

[0319] (1 S,2S)-1 -Hydroxy-N,N-bis(4-methoxybenzyl)-l -(5-methyl-pyrazin-

2-yl)propane-2-sulfonamide and (lR,2R)-l-hydroxy-N,N-bis(4-methoxybenzyl)-l-(5- methyl-pyrazin-2-yl)propane-2-sulfonamide, Example 28.3. Further elution of the mixture with a gradient of 30 % to 35 % EtOAc in petroleum ether yielded Example 33.3 (16 g, pale yellow gummy liquid). ¾ NMR (400 MHz, CDC1 ₃ ) δ 8.62 (d, J= 1.6 Hz, 1H), 8.44 (d, J = 1.5 Hz, 1H), 7.25 - 7.12 (m, 4H), 6.93 - 6.82 (m, 4H), 5.17 (d, J = 7.1 Hz, lH), 4.47 (d, J = 15.2 Hz, 3H), 4.14 (d, J = 15.4 Hz, 2H), 3.82 (d, J= 1.8 Hz, 6H), 3.66 - 3.61 (m, 1H), 2.60 (d, J = 2.0 Hz, 3H), and 1.08 (dd, J = 7.2, 2.1 Hz, 3H). LCMS- ESI (p ⁺ .

33.4

[0320] (lS,2S)-l-Isopropoxy-N,N-bis(4-methoxybenzyl)-l-(5- methylpyrazin-2-yl)propane-2-sulfonamide and (lR,2R)-l-isopropoxy-N,N-bis(4- methoxybenzyl)-l-(5-methylpyrazin-2-yl)propane-2-sulfonamide , Example 33.4. To a flask containing (lS,2S)-l-hydroxy-N,N-bis(4-methoxybenzyl)-l-(5-methylpyrazi n-2- yl)propane-2-sulfonamide and (lR,2R)-l-hydroxy-N,N-bis(4-methoxybenzyl)-l-(5- methylpyrazin-2-yl)propane-2-sulfonamide (Example 33.3, 4.16 g, 8.81 mmol) and isopropyl iodide (12.3 mL, 123 mmol) in anhydrous toluene (35 mL) was added silver(I) oxide (4.17 g, 18.0 mmol) carefully in portions. Upon complete addition of silver oxide, the reaction was protected from light and heated to an internal temperature of 72 °C. After 60 h, the mixture was cooled to RT and then filtered through a Chemglass disposable filter that was rinsed with EtOAc. The filtrate was concentrated in vacuo. The dark brown residue was loaded onto a silica gel column (10-55 % EtOAc in heptanes). Fractions containing the product were combined and then concentrated in vacuo to afford (lS,2S)-l-isopropoxy-N,N-bis(4-methoxybenzyl)-l-(5-methylpyr azin-2-yl)propane-2- sulfonamide and ( 1 R,2R) - 1 -isopropoxy -N,N-bis(4-methoxy benzyl) - 1 -(5 -methy lpy razin- 2-yl)propane-2-sulfonamide (Example 33.4, 1.52 g, 2.97 mmol, 34 % yield) as a dark brown oil that was used without further purification. ¾ NMR (400MHz, DMSO-d ₆ ) δ 8.58 (d, J=1.5 Hz, 1H), 8.54 (d, J=0.8 Hz, 1H), 7.20 - 7.15 (m, 4H), 6.89 - 6.85 (m, 4H),

4.81 (d, J=7.0 Hz, 1H), 4.35 - 4.29 (m, 2H), 4.20 - 4.13 (m, 2H), 3.76 - 3.71 (m, 7H), 3.39 (quin, J=6.1 Hz, 1H), 2.51 (s, 3H), 1.13 (d, J=6.0 Hz, 3H), 1.05 (d, J=7.3 Hz, 3H), 0.99 (d, J=6 ⁺ .

33.5

[0321] (lR,2R)-l-Isopropoxy-l-(5-methylpyrazin-2-yl)propane-2- sulfonamide and (lS,2S)-l-isopropoxy-l-(5-methylpyrazin-2-yl)propane-2- sulfonamide, Example 33.5. Anisole (1.3 mL, 11.9 mmol) was added to a flask containing Example 33.4 (1.5 g, 3 mmol) and DCM (7.5 mL). The homogeneous solution was cooled in an ice-water bath. After 15 mins, TFA (7.6 mL, 99 mmol) was added dropwise to the reaction solution. Upon complete addition of TFA, the reaction was allowed to warm to RT. After 20 h, the brownish reaction solution was concentrated in vacuo. The residue was loaded onto a silica gel column (15-85% EtOAc in heptanes). Fractions containing the product were concentrated in vacuo to afford Example 33.5 (714 mg, 2.6 +H) ⁺ .

33.6

[0322] (lR,2R)-l-Isopropoxy-l-(5-methylpyrazin-2-yl)propane-2- sulfonamide or (lS,2S)-l-isopropoxy-l-(5-methylpyrazin-2-yl)propane-2- sulfonamide, Example 33.6. Example 33.5 (714 mg, 2.6 mmol) was purified by preparative SFC using the following method: Column: IC (2 x 25 cm) Mobile Phase: 70:30 (A:B) A: Liquid C0 ₂ , B: iPrOH to afford peak 1 as Example 33.6 (293 mg, 1.07 mmol, 36 % yield). ¾ NMR (400MHz, DMSO-d ₆ ) δ 8.60 (d, J=1.5 Hz, 1H), 8.53 (d, J=0.8 Hz, 1H), 6.52 (s, 2H), 4.77 (d, J=7.0 Hz, 1H), 3.56 - 3.45 (m, 2H), 1.15 (d, J=6.0 Hz, 3H), 1.05 (d, J=7.0 Hz, 3H), 0.96 (d, J=6.2 Hz, 3H). (Obscured CH ₃ in DMSO peak) LCMS-ESI (pos.), m/z: 274.2 (M+H) ⁺ .

33.0

[0323] (lR,2R)-l-Isopropoxy-l-(5-methylpyrazin-2-yl)propane-2- sult ^' onamidc or (lS,2S)-l-isopropoxy-l-(5-methylpyrazin-2-yl)propane-2- sulfonamide Example 33.0. Further elution under the conditions described in Example 33.5 delivered the second eluting peak as Example 33.0 (303 mg, 1.11 mmol, 37 % yield). ¾ NMR (400MHz, DMSO-d ₆ ) δ 8.60 (d, J=1.5 Hz, 1H), 8.53 (d, J=1.0 Hz, 1H), 6.52 (s, 2H), 4.77 (d, J=7.0 Hz, 1H), 3.58 - 3.44 (m, 2H), 1.27 - 1.14 (m, 3H), 1.05 (d, J=7.0 Hz, 3H), 1.00 - 0.91 (m, 3H). (Obscured CH ₃ in DMSO peak). LCMS-ESI (pos.), m/z: 274.2 (M+H) ⁺ .

[0324] Example 34.0. Preparation of (lR,2S)-l-((tert- butyldimethylsilyl)oxy)-N,N-bis(4-methoxybenzyl)-l-(5-methyl pyrimidin-2- yl)propane-2-sulfonamide.

34.1

[0325] 5-Methyl-2-vinylpyrimidine, Example 34.1. A 3 L 3 -necked round bottom flask was fitted with a reflux condenser, a temperature controller and a septum and was charged with 2-chloro-5-methylpyrimidine (81 mL, 778 mmol), potassium vinyltrifluoroborate (156g, 1167 mmol), triphenylphosphine (18.02 mL, 78 mmol), cesium carbonate (156 mL, 1945 mmol) and a large stir bar. Water (1565 mL) was added and the mixture was stirred for several min and then THF (244 mL) was added. Argon was bubbled through the mixture for 5 min and then palladium (II) chloride (1.72 g, 38.9 mmol) was added. The reaction was further sparged with argon for 5 mins. The temperature was raised to 62 °C and stirring was continued to completion. The reaction was then cooled to RT and filtered through two Whatman GF/F filter cups, rinsing with ether. The mixture was transferred to a separatory funnel, and the layers were separated. The aqueous layer was further extracted with diethyl ether (4 x 200 mL). The organic layers were combined and dried over anhydrous MgSC and then filtered. The mixture was partially concentrated on the rotory evaporator at 20 °C and 115 torr for an extended period of time to give an orange liquid. The material was further purified by Kugelrohr distillation to isolate the title compound (65.4g, 70%) as a light yellow oil. ¾ NMR (400 MHz, CDC1 ₃ ) δ 2.31 (s, 3H), 5.68 (d, J=10.56 Hz, 1H), 6.55 (d, J=17.22 Hz, 1H), 6.86 (dd, J=17. -ESI (pos.) m/z: 121.1 (M+H) ⁺ .

34.1 34.2

[0326] l-(5-Methylpyrimidin-2-yl)ethane-l,2-diol, Example 34.2. To a 2 L round-bottom flask was added 5-methyl-2-vinylpyrimidine (64.5 g, 537 mmol), osmium tetroxide (0.204 mL, 3.93 mmol), 1,4-dioxane (537 mL, 537 mmol), 4- methylmorpholine-N-oxide, 50% wt. in water (40 mL, 341 mmol) and 4- methylmorpholine-4-oxide (94 g, 805 mmol). The reaction mixture was stirred over 2 d. LCMS showed that the reaction was complete and the solvent was removed in vacuo. The compound was purified by silica gel. The gradient was 100% heptanes for 3CV's, then 0-100% EtOAc-EtOH(3: l) in heptanes for 6 CV's, then 100% EtOAc:EtOH(3: l) for 5 CV's. The desired compound was collected and concentrated in vacuo. The material was triturated with 40% EtOAc in hexanes to give a solid, which was filtered. The solid was washed with 20% EtOAc in hexanes several times and then dried to give the title compound (67.3g). ¾ NMR (400 MHz, CDC1 ₃ ) δ 8.59 (s, 2H), 4.81 - 4.98 (m, 1H), 3.88 - 4.19 (m, 2H), 2.36 (s, 3H).

34.2 34.3

[0327] 5-Methylpyrimidine-2-carbaldehyde, Example 34.3. A 5 L flask equipped with a mechanical stirrer was charged with l-(5-methylpyrimidin-2-yl)ethane- 1,2-diol (64.3 g, 417 mmol), 1,4-dioxane (1043 mL) and water (261 mL). The reaction was cooled in an ice-water bath. Sodium periodate (223 g, 1043 mmol) was added and the internal temperature was monitored until it returned to RT. The reaction was further stirred at RT for 2 hr and 20 min. DCM (2 L) was then added. The resulting solution was filtered through a plug of dried MgSC (700g). The plug was washed with DCM (7 L). The solvent was concentrated in vacuo and the aldehyde was azeotroped with toluene to deliv 122.8 (M+H) ⁺ .

34.4 [0328] (lR,2S)-l-Hydroxy-N,N-bis(4-methoxybenzyl)-l-(5- methylpyrimidin-2-yl)propane-2-sulfonamide and (1 S,2S)-1 -hydroxy-N,N-bis(4- methoxybenzyl)-l-(5-methylpyrimidin-2-yl)propane-2-sulfonami de and (1R,2R)-1- hydroxy-N,N-bis(4-methoxybenzyl)-l-(5-methylpyrimidin-2-yl)p ropane-2- sulfonamide and (lS,2R)-l-hydroxy-N,N-bis(4-methoxybenzyl)-l-(5- methylpyrimidin-2-yl)propane-2-sulfonamide Example 34.4. A 3 L flask was charged with N,N-bis(4-methoxybenzyl)ethanesulfonamide (Example 30.0, 151 g, 432 mmol) and anhydrous THF (1200 mL) under nitrogen and then equipped with a pre-dried addition funnel under nitrogen. The flask was cooled in a dry ice-acetone bath, n- Butyllithium (1.6 M, 270 mL, 432 mmol) was first cannulated into the additional funnel. It was added slowly into the reaction flask and stirred for 10 min. 5-Methylpyrimidine-2- carbaldehyde (34.3, 44 g, 360 mmol) in THF (300 mL) was then cannulated into the reaction. The reaction continued at -78 °C for 45 min and then was warmed to RT and stirred for 2 h and 10 min. A saturated solution of ammonium chloride was then added to quench the reaction, and the mixture was extracted with EtOAc and concentrated in vacuo to give the product.

34.5

[0329] (lR,2S)-l-Hydroxy-N,N-bis(4-methoxybenzyl)-l-(5- methylpyrimidin-2-yl)propane-2-sulfonamide and (lS,2R)-l-hydroxy-N,N-bis(4- methoxybenzyl)-l-(5-methylpyrimidin-2-yl)propane-2-sulfonami de, Example 34.5.

The mixture of diastereomers was separated and purified on silica gel eluting with 0-50% EtOAc gradient in DCM to give the title compound (56.4 g). LCMS-ESI (pos.) m/z:472.1 (M+H) ⁺ .

34.6

[0330] (1 S,2S)-1 -Hydroxy-N,N-bis(4-methoxybenzyl)-l -(5- methylpyrimidin-2-yl)propane-2-sulfonamide and (lR,2R)-l-hydroxy-N,N-bis(4- methoxybenzyl)-l-(5-methylpyrimidin-2-yl)propane-2-sulfonami de Example 34.6.

Further elution under the conditions described in Example 34.5 delivered the title

+.

34.6 34.7

[0331] (lR,2S)-2-(N,N-Bis(4-methoxybenzyl)sulfamoyl)-l-(5- methylpyrimidin-2-yl)propyl 4-nitrobenzoate, Example 34.7. To a stirred solution of Example 34.6 (22.7 g, 48.1 mmol) in toluene (241 mL) was added 4-nitrobenzoic acid (12.07 g, 72.2 mmol), and triphenylphosphine (18.94 g, 72.2 mmol) followed by dropwise addition of (E)-diisopropyl diazene-l,2-dicarboxylate (14.22 mL, 72.2 mmol). The mixture was stirred at RT overnight and showed the desired product by LCMS. The reaction was concentrated in vacuo and purified on silica gel eluting with 0-50% EtOAc/hexanes to give the desired compound (lR,2S)-2-(N,N-bis(4- methoxybenzyl)sulfamoyl)-l-(5-methylpyrimidin-2-yl)propyl 4-nitrobenzoate (29.9 g, 48.1 mmol, 100% yield). LCMS-ESI (pos.) m/z: 621.3 (M+H) ⁺ .

34.7 34.9

[0332] (lR,2S)-2-(N,N-Bis(4-methoxybenzyl)sulfamoyl)-l-(5- methylpyrimidin-2-yl)propyl 4-nitrobenzoate, Example 34.9. To a stirred solution of 34.7 (76 g, 122 mmol) in MeOH (612 mL) at 0 °C was added potassium carbonate (16.92 g, 122 mmol). The mixture was allowed to warm to RT over 1 h and then showed the desired product by LCMS. The reaction was concentrated in vacuo and purified on silica gel eluting with 0-40% EtOAc in hexanes to give (lR,2S)-l-hydroxy-N,N-bis(4- methoxybenzyl)-l-(5-methylpyrimidin-2-yl)propane-2-sulfonami de. LCMS-ESI (pos.)

+.

34.9 34.0

[0333] (lR,2S)-l-((tert-Butyldimethylsilyl)oxy)-N,N-bis(4-methoxybe nzyl)- l-(5-methylpyrimidin-2-yl)propane-2-sulfonamide, Example 34.0. To a stirred solution of (lR,2S)-l-hydroxy-N,N-bis(4-methoxybenzyl)-l-(5-methylpyrimi din-2- yl)propane-2-sulfonamide (34.9, 28 g, 59.4 mmol) in DCM (297 mL, 59.4 mmol) at 0 °C was added tert-butyldimethylsilyl trifluoromethane sulfonate (15.00 mL, 65.3 mmol), followed by TEA (9.12 mL, 65.3 mmol). The mixture was allowed to warm to RT over 1 h and showed the desired product by LCMS. The reaction was concentrated in vacuo, and the product thus obtained was purified on silica gel eluting with 0-30% EtOAc in hexanes to give the desired compound (lR,2S)-l-((tert-butyldimethylsilyl)oxy)-N,N- bis(4-methoxybenzyl)-l-(5-methylpyrimidin-2-yl)propane-2-sul fonamide (15 g, 25.6 mmol, 43.1% yield). LCMS-ESI (pos.) m/z: 586.0 (M+H) ⁺ .

[0334] Example 35.0. Preparation of (2R,3R)-N-(4-(2,6-dimethoxyphenyl)-

5-(3-pyridinyl)-4H-l,2,4-triazol-3-yl)-3-(5-methoxy-2-pyr azinyl)-2- butanesulfonamide and (2R,3S)-N-(4-(2,6-dimethoxyphenyl)-5-(3-pyridinyl)-4H- l,2,4-triazol-3-yl)-3-(5-methoxy-2-pyrazinyl)-2-butanesulfon amide and (2S,3R)-N- (4-(2,6-dimethoxyphenyl)-5-(3-pyridinyl)-4H-l,2,4-triazol-3- yl)-3-(5-methoxy-2- pyrazinyl)-2-butanesulfonamide and (2S,3S)-N-(4-(2,6-dimethoxyphenyl)-5-(3- pyridinyl)-4H-l,2,4-triazol-3-yl)-3-(5-methoxy-2-pyrazinyl)- 2-butanesulfonamide.

35.0

[0335] (2R,3R)-3-(5-methoxypyrazin-2-yl)butane-2-sulfonamide and

(2R,3S)-3-(5-methoxypyrazin-2-yl)butane-2-sulfonamide and (2S,3R)-3-(5- methoxypyrazin-2-yl)butane-2-sulfonamide and (2S,3S)-3-(5-methoxypyrazin-2- yl)butane-2-sulfonamide, Example 35.0. Example 35.0 was synthesized following the procedure in Example 32.0 using 2-bromo-5-methoxypyrazine (commercially available from Ark Pharm, Inc.). LCMS-ESI (pos.) m/z: 246.2 (M+H) ⁺ .

[0336] Example 36.0. Preparation of (2S,3R)-N-(4-(2,6-dimethoxyphenyl)-

5-((2R)-l,4-dioxan-2-yl)-4H-l,2,4-triazol-3-yl)-3-(5-meth oxy-2-pyrimidinyl)-2- butanesulfonamide or (2S,3R)-N-(4-(2,6-dimethoxyphenyl)-5-((2R)-l,4-dioxan-2-yl)- 4H-l,2,4-triazol-3-yl)-3-(5-methoxy-2-pyrimidinyl)-2-butanes ulfonamide.

36.1

[0337] (2S,3R)-3-(5-Methoxypyrimidin-2-yl)butane-2-sulfonamide, Example 36.1. A round bottom flask was charged with (2S,3R)-3-(5-fluoropyrimidin-2- yl)butane-2-sulfonamide (575 mg, 2.47 mmol, Example 27.1), MeOH (7 mL), and potassium carbonate (679 mg, 4.91 mmol). The reaction was stirred at RT. After 48 h, the reaction was heated to 50 °C and stirred for 24 h. The temperature rwas then aised to 65 °C and the reaction was stirred for 48 h. LCMS-ESI showed the reaction was 75% complete. The reaction was allowed to cool to RT and filtered. The solids were rinsed with MeOH (2 x 5 mL). The filtrate was concentrated in vacuo and adsorbed onto a plug of silica gel and chromatographed through a RediSep® pre-packed silica gel column, eluting with 0-40% EtOAc:EtOH (3: 1) in heptanes. The organic layers from several fractions were concentrated in vacuo to give a mixture of starting material and the title compound (56 mg, 0.23 mmol, 9% yield) as an off-white solid. The fractions were washed with an aqueous saturated solution of NaCl and extracted with CHC¾:IPA (9: 1, 3 x 15 mL). The combined organic layers were dried over MgSC and concentrated in vacuo to give more title compound (114 mg). The material was carried forward as obtained. LCMS-ESI (pos.) m/z: 246.1 (M+H) ⁺ .

[0338] Example 37.0. Preparation of (3R,5S)-N-(4-(4,6-dimethoxy-5- pyrimidinyl)-5-((2R)-l,4-dioxan-2-yl)-4H-l,2,4-triazol-3-yl) -l-(5-fluoro-2- pyrimidinyl)-5-(l-methylethoxy)-3-piperidinesulfonamide or (3R,5S)-N-(4-(4,6- dimethoxy-5-pyrimidinyl)-5-((2S)-l,4-dioxan-2-yl)-4H-l,2,4-t riazol-3-yl)-l-(5-fluoro- 2-pyrimidinyl)-5-(l-methylethoxy)-3-piperidinesulfonamide or (3S,5R)-N-(4-(4,6- dimethoxy-5-pyrimidinyl)-5-((2R)-l,4-dioxan-2-yl)-4H-l,2,4-t riazol-3-yl)-l-(5- fluoro-2-pyrimidinyl)-5-(l-methylethoxy)-3-piperidinesulfona mide or (3S,5R)-N-(4- (4,6-dimethoxy-5-pyrimidinyl)-5-((2S)-l,4-dioxan-2-yl)-4H-l, 2,4-triazol-3-yl)-l-(5- fluoro-2-pyrimidinyl)-5-(l-methylethoxy)-3-piperidinesulfona mide.

37.1

[0339] 5-Hydroxypyridine-3-sulfonamide, Example 37.1. To a 100 mL round-bottom flask was added 5-bromopyridine-3-sulfonamide (commercially available from Enamine, KIEV, Ukraine) (0.486 g, 2.05 mmol), 2-di-t-butylphosphino-3, 4,5,6- tetramethyl-2',4',6'-tri-i-isopropylbiphenyl (commercially available from Strem

Chemicals, Inc., MA, USA) (0.079 g, 0.16 mmol) and Pd ₂ (dba) ₃ (Sigma-Aldrich Chemical Company, Inc.) (0.038 g, 0.041 mmol). The flask was placed under vacuum and back-filled with potassium hydroxide (0.345 g, 6.15 mmol) solution in dioxane (5 mL) and water (5 mL). The reaction mixture was then stirred at 100 °C under N ₂ for 17 h. LCMS analysis indicated the reaction was complete. The reaction mixture was allowed to cool to RT. The reaction mixture was diluted with 1 N HC1 and washed with Et20. The aqueous phase was concentrated in vacuo to afford the title compound 37.1 (0.387 g, 2.22 mmol, 100% yield) as a white solid, which was directly used in the next step without fu (M+H) ⁺ .

37.1 37.2

[0340] 5-Isopropoxypyridine-3-sulfonamide, Example 37.2. To a suspension of 5-hydroxypyridine-3-sulfonamide, Example 37.1 (1.1 g, 6.32 mmol) in THF (16 mL) and IPA (16 mL) was added triphenylphosphine (1.99 g, 7.58 mmol). The mixture was bubbled with argon for 3 min before diisopropyl azodicarboxylate (1.49 mL, 7.58 mmol) was added dropwise at 0 °C under N ₂ stream. The reaction was then stirred at 0 °C to RT for 15 h. The reaction mixture was concentrated in vacuo. The material was absorbed onto a plug of silica gel and purified by chromatography through a RediSep-Sep pre-packed silica gel column (40 g), eluting with a gradient of 0% to 100% EtOAc in heptane, to provide the enriched product fractions which were combined and extracted with IN HC1. The desired product was enriched in acidic aqueous solution which was then modified by a saturated aqueous NaHC0 ₃ to pH>8. The basic aqueous solution was then extracted with DCM. The organic extract was washed with brine and dried over Na2S04. The solution was filtered and concentrated in vacuo to give Example 37.2, 5- isopropoxypyridine-3-sulfonamide (0.95 g, 70 % yield) as awhite solid. LCMS-ESI (pos.), m/z: 217.2 (M+H) ⁺ .

37.3

[0341] (3S,5R)-5-Isopropoxypiperidine-3-sulfonamide and (3R,5R)-5- isopropoxypiperidine-3-sulfonamide and (3S,5S)-5-isopropoxypiperidine-3- sulfonamide and (3R,5S)-5-isopropoxypiperidine-3-sulfonamide, Example 37.3. A solution of Example 37.2 (1.8 g, 8.32 mmol) in AcOH (41.6 mL) was bubbled with argon gas for 2 min before platinum (IV) oxide (1.89 g, 8.32 mmol) was added under argon stream. The above reaction mixture was then stirred at RT under 45 psi of hydrogen gas for two d. Celite® brand filter aid (5g) was then added to the reaction mixture. The mixture was stirred at RT for 10 min. The mixture was then filtered and the solution was concentrated in vacuo to give the initial product mixture as a light yellow oil, which was used as such in the next step. LCMS-ESI (pos.), m/z: 223.3 (M+H) ⁺ .

37.4

[0342] (3R,5R)-l-(5-Fluoropyrimidin-2-yl)-5-isopropoxypiperidine-3- sult ^' onamidc and (3S,5R)-l-(5-fluoropyrimidin-2-yl)-5-isopropoxypiperidine-3- sulfonamide and (3S,5S)-l-(5-fluoropyrimidin-2-yl)-5-isopropoxypiperidine-3- sult ^' onamidc and (3R,5S)-l-(5-fluoropyrimidin-2-yl)-5-isopropoxypiperidine-3- sulfonamide, Example 37.4. To a 40 mL vial (with pressure release septa) was added Example 37.3 (2.0 g, 4.96 mmol) and 2-chloro-5-fluoropyrimidine (3.29 g, 24.79 mmol). The reaction mixture was stirred at 90 °C for 21 h. LCMS indicated the reaction was complete. The reaction mixture was then concentrated in vacuo. The initial material was absorbed onto a plug of silica gel and purified by chromatography through RediSep-Sep pre-packed silica gel column (40 g), eluting with a gradient of 0% to 100% EOAc in heptane, to provide Example 37.4 as a mixture of diastereomers (0.5 g, 1.6 mmol, 32 % yield) ⁺ .

37.5 [0343] (3S,5R)-l-(5-Fluoropyrimidin-2-yl)-5-isopropoxypiperidine-3- sulf onamide or (3R,5S)-1 -(5-fluoropyrimidin-2-yl)-5-isopropoxypiperidine-3- sulfonamide, Example 37.5. Example 37.4 was separated by SFC on a Chiralpak AS-H column using 15% MeOH/C0 ₂ . Example 37.5 and Example 37.6 are a pair of enantiomers, Example 37.5 was the second peak among 4 isomers (earlier peak vs. its opposite enantiomer) on the AS-H column. ¾ NMR (400 MHz, CD ₃ OD) δ 1.96 (ddd, J=13.39, 12.45, 2.93 Hz, 1 H) 2.44 (dt, J=13.48, 1.89 Hz, 1 H) 2.97 (dd, J=14.33, 1.58 Hz, l H) 3.08 (dd, J=13.01, 11.14 Hz, 1 H) 3.28 - 3.35 (m, 1 H) 3.60 - 3.72 (m, 1 H) 4.87 - 5.00 (m, l H) 5.16 (dt, J=13.02, 1.91 Hz, 1 H) 8.27 (d, =0.67 Hz, 2 H). LCMS-ESI (pos.) m/ ⁺ .

37.6

[0344] (3S,5R)-l-(5-Fluoropyrimidin-2-yl)-5-isopropoxypiperidine-3- sulf onamide or (3R,5S)-1 -(5-fluoropyrimidin-2-yl)-5-isopropoxypiperidine-3- sulfonamide, Example 37.6. Further elution under the conditions described in Example 37.5 gave Example 37.6 as the third peak. ¾ NMR (400 MHz, CD ₃ OD) δ 1.96 (ddd, J=13.39, 12.45, 2.93 Hz, 1 H) 2.44 (dt, J=13.48, 1.89 Hz, 1 H) 2.97 (dd, J=14.33, 1.58 Hz, l H) 3.08 (dd, J=13.01, 11.14 Hz, 1 H) 3.28 - 3.35 (m, 1 H) 3.60 - 3.72 (m, 1 H) 4.87 - 5.00 (m, l H) 5.16 (dt, J=13.02, 1.91 Hz, 1 H) 8.27 (d, =0.67 Hz, 2 H). LCMS-ESI (pos.) m/z ⁺ .

37.7 [0345] (3R,5R)-l-(5-Fluoropyrimidin-2-yl)-5-isopropoxypiperidine-3- sult ^' onamidc or (3S,5S)-l-(5-fluoropyrimidin-2-yl)-5-isopropoxypiperidine-3- sulfonamide, Example 37.7. Examples 37.7 and 37.8 are a pair of enantiomers.

Example 37.7 was the first peak among 4 isomers (earlier peak vs. its opposite enantiomer) to elute on an AS-H column under the conditions described in Example 37.5.

¾ NMR (400 MHz, CD ₃ OD) δ 0.92 (d, J=6.12 Hz, 3 H) 1.08 (d, J=6.01 Hz, 3 H) 1.98 (ddd, J=13.19, 12.15, 2.95 Hz, 1 H) 2.33 (dtdd, J=13.26, 3.68, 3.68, 1.97, 1.87 Hz, 1 H) 3.01 (dd, J=14.10, 1.66 Hz, 1 H) 3.13 (dd, J=13.06, 10.99 Hz, 1 H) 3.33 - 3.45 (m, 1 H) 3.74 (dt, J=12.13, 6.06 Hz, 1 H) 3.86 - 3.93 (m, 1 H) 4.77 - 4.83 (m, 1 H) 5.11 (ddt, J=13.05, 3.69, 1.79, 1.79 Hz, 1 H) 8.27 (d, J=0.62 Hz, 2 H). LCMS-ESI (pos.) m/z: 319.2 ( ⁺ .

37.8

[0346] (3R,5R)-l-(5-Fluoropyrimidin-2-yl)-5-isopropoxypiperidine-3- sulfonamide or (3S,5S)-l-(5-fluoropyrimidin-2-yl)-5-isopropoxypiperidine-3- sulfonamide, Example 37.8. Further elution under the conditions described in Example 37.5 gave Example 37.8 as the fourth peak. ¾ NMR (400 MHz, CD ₃ OD) δ 0.92 (d, J=6.12 Hz, 3 H) 1.08 (d, J=6.01 Hz, 3 H) 1.98 (ddd, J=13.19, 12.15, 2.95 Hz, 1 H) 2.33 (dtdd, J= 13.26, 3.68, 3.68, 1.97, 1.87 Hz, 1 H) 3.01 (dd, J=14.10, 1.66 Hz, 1 H) 3.13 (dd, J=13.06, 10.99 Hz, 1 H) 3.33 - 3.45 (m, 1 H) 3.74 (dt, J=12.13, 6.06 Hz, 1 H) 3.86 - 3.93 (m, 1 H) 4.77 - 4.83 (m, 1 H) 5.11 (ddt, J=13.05, 3.69, 1.79, 1.79 Hz, 1 H) 8.27 (d, J=0.62 Hz, 2 H). LCMS-ESI (pos.) m/z: 319.2 (M+H) ⁺ .

[0347] Example 38.0. Preparation of (S)-tert-butyl 3-sulfamoylpiperidine-

1-carbox late and (R)-tert-butyl 3-sulfamoylpiperidine-l-carboxylate.

38.1 [0348] (S)-Piperidine-3-sulfonamide hydrochloride and (R)-piperidine-3- sult ^' onamidc hydrochloride, Example 38.1. A solution of 4-chloropyridine-3- sulfonamide (5.0 g, 25.9 mmol) in AcOH (150 mL) was placed in a Parr bottle. The solution was bubbled with nitrogen gas for 5 mins. To this solution was added a suspension of platinum (IV) oxide (5.9 g, 25.9 mmol) in AcOH (30 mL). The reaction was stirred under hydrogen (50 psi) for 72 h. The reaction mixture was then filtered through a pad of Celite® brand filter aid and the pad was washed with MeOH (2 x 50 mL). The combined filtrate was concentrated in vacuo to provide initial Example 38.1 (6.0 g) as an oil which was used in the next step without further purification. LCMS-ESI (pos.) m/z: 165 (M+H) ⁺ .

38.0

[0349] (S)-tert-Butyl 3-sulfamoylpiperidine-l-carboxylate and (R)-tert- butyl 3-sulfamoylpiperidine-l-carboxylate, Example 38.0. To a mixture of 38.1 (12.0 g, 59.8 mmol) and TEA (41.6 mL, 298.9 mmol) in DCM (215 mL) was added a solution of boc anhydride (15.7 mL, 71.8 mmol) in DCM (70 mL) at RT. The reaction mixture was stirred for 16 h at RT. The reaction mixture was washed with water (2 x 200 mL). The combined organic layer was washed with brine (100 mL), dried over sodium sulfate and evaporated in vacuo to obtain the product which was purified by column chromatography (silica: 100-200 mesh; elution: 0-30% EtOAc in DCM) to provide the title compound- (4.6 g, 34%, over two steps) as a white solid. ¾ NMR (400 MHz, CD ₃ CN) δ 5.30 (s, 2H), 4.36 (d, J = 11.8 Hz, 1H), 3.94 (d, J = 13.3 Hz, 1H), 3.01 - 2.84 (m, 2H),2.64-2.58 (s, 1H), 2.20 (d, J = 13.3 Hz, 1H), 1.78 (d, J = 13.5 Hz, 1H), 1.74 - 1.57 (m, 2H), 1.43 (s, 9H). LCMS-ESI (pos.) m/z: 263 (M-H) ⁺ .

[0350] Example 39.0: Preparation of (3S,5S)-l-(5-fluoropyrimidin-2-yl)-5- hydroxypiperidine-3- sulfonamide and (3S,5R)-l-(5-fluoropyrimidin-2-yl)-5- hydroxypiperidine-3- sulfonamide and (3R,5S)-l-(5-fluoropyrimidin-2-yl)-5- hydroxypiperidine-3-sulfonamide and (3R,5R)-l-(5-fluoropyrimidin-2-yl)-5- hydroxypiperidine-3-sulfonamide.

39.1

[0351] 5-Hydroxypyridine-3-sulfonamide, Example 39.1. To a 100 mL round-bottom flask was added 5-bromopyridine-3-sulfonamide (commercially available from Enamine, KIEV, Ukraine) (0.486 g, 2.05 mmol), 2-di-t-butylphosphino-3, 4,5,6- tetramethyl-2',4',6'-tri-i-isopropylbiphenyl (commercially available from Strem Chemicals, Inc., MA, USA) (0.079 g, 0.16 mmol) and Pd ₂ (dba) ₃ (Sigma-Aldrich Chemical Company, Inc.) (0.038 g, 0.041 mmol). The flask was placed under vacuum and back-filled with potassium hydroxide (0.345 g, 6.15 mmol) solution in dioxane (5 mL) and water (5 mL). The reaction mixture was then stirred at 100 °C under N ₂ for 17 h. LCMS analysis indicated the reaction was complete. The reaction mixture was allowed to cool to RT. The reaction mixture was then diluted with 1 N HC1 and washed with Et ₂ 0. The aqueous phase was concentrated in vacuo to afford the title compound 39.1 (0.387 g, 2.22 mmol, 100% yield) as a white solid, which was used directly in the next step without further purification. LCMS-ESI (pos.), m/z: 175.1 (M+H) ⁺ .

AND

OH OH

39.2 [0352] (3R,5R)-5-Hydroxypiperidine-3-sulfonamide acetate and (3S,5R)-5- hydroxypiperidine-3-sulfonamide acetate and (3R,5S)-5-hydroxypiperidine-3- sulfonamide acetate and (3S,5S)-5-hydroxypiperidine-3-sulfonamide acetate, Example 39.2. To a 1 L hydrogenation flask was added 39.1 (6.46 g, 37.1 mmol) and AcOH (250 mL, 4330 mmol). Water (20 mL) was added as a co-solvent. The mixture was bubbled with N ₂ for 2 min before platinum (iv) oxide hydrate (8.42 g, 37.1 mmol) was added under N ₂ flow. The flask was set up on a Parr shaker, vacuumed and backfilled with N ₂ two times, and then placed under vacuum and back-filled with hydrogen gas (tank). The reaction mixture was stirred at RT under 50 psi of hydrogen gas for 24 h. LCMS analysis indicated that the reaction was complete. Celite® brand filter agent (20 g) was added to the mixture with stirring. The solid was removed by filtration after 10 min of stirring. The filter cake was then rinsed with MeOH. The combined organics were concentrated in vacuo to afford 39.2 (8.91 g, 100% yield) as a light-yellow oil, which was directly used in the next step without purification. LCMS-ESI (pos.), m/z: 181.1 (M+H) ⁺ .

39.0

[0353] (3S,5S)-l-(5-Fluoropyrimidin-2-yl)-5-hydroxypiperidine-3- sulfonamide and (3S,5R)-l-(5-fluoropyrimidin-2-yl)-5-hydroxypiperidine-3- sulfonamide and (3R,5S)-l-(5-fluoropyrimidin-2-yl)-5-hydroxypiperidine-3- sulfonamide and (3R,5R)-1 -(5-fluoropyrimidin-2-yl)-5-hydroxypiperidine-3- sulfonamide, Example 39.0. To a 500 mL round-bottom flask was added 39.2 (8.91 g, 37.1 mmol) and Hunig's base (32.3 mL, 185 mmol) in DMF (80 mL). 2-Chloro-5-fTuoro- pyrimidine (18.32 mL, 148 mmol) was then added with stirring. The reaction mixture was stirred at 120 °C for 18 h. LCMS analysis indicated the reaction was complete. The reaction mixture was allowed to cool to RT and then was diluted with water and extracted with DCM. The organic layers were washed with brine and dried over Na ₂ S0 ₄ . The solution was filtered and concentrated in vacuo to give the initial material as an orange oil. The material thus obtained was purified by silica gel chromatography (a gradient of 0-100% EtOAc in DCM), to provide 39.0 (3.7 g, 10.93 mmol, 36% yield) as a light- yellow solid. LCMS-ESI (pos.), m/z: 277.0 (M+H) ⁺ .

[0354] Example 40.3. Preparation of (3S,5R)-l-(5-fluoropyrimidin-2-yl)-5- methoxypiperidine-3-sulfonamide and (3R,5S)-l-(5-fluoropyrimidin-2-yl)-5- methoxypiperidine-3-sulfonamide.

40.1

[0355] 5-Methoxypyridine-3-sulfonamide, Example 40.1. The reaction mixture of 5-methoxypyridine-3-sulfonyl chloride (commercially available from

Enamine, KIEV, Ukraine) (1.0 g, 4.82 mmol) and ammonia, (0.5 M solution in 1,4- dioxane, 96 mL, 48.2 mmol) was stirred at 0 to RT for 30 min. LCMS indicated the reaction was complete. The reaction was filtered and the cake was rinsed with dioxane. The combined solution was concentrated in vacuo to give the title compound (0.91 g, 100 % yield) as a light yellow foam which was used as such in the next step without purification. LCMS-ESI (pos.) m/z: 189.2 (M+H) ⁺ .

AND

40.1 40.2

[0356] (3R,5R)-5-Methoxypiperidine-3-sulfonamide acetate and (3R,5S)- 5-methoxypiperidine-3-sulfonamide acetate and (3S,5R)-5-methoxypiperidine-3- sulfonamide acetate and (3S,5S)-5-methoxypiperidine-3-sulfonamide acetate, Example 40.2. The solution of 5-methoxypyridine-3-sulfonamide (0.9 g, 4.78 mmol) in AcOH (31.9 mL) was bubbled with argon gas for 2 min before platinum (iv) oxide ((1.09 g, 4.78 mmol) was added under an argon stream. The reaction mixture was then stirred at RT under 45 psi of hydrogen gas for 38 h. The mixture was filtered and the filtrate was concentrated in vacuo to give the title compound (1.22 g, 100 % yield) as a light yellow foam w 195.2 (M+H) ⁺ .

40.3

[0357] (3S,5R)-l-(5-Fluoropyrimidin-2-yl)-5-methoxypiperidine-3- sulfonamide and (3R,5S)-l-(5-fluoropyrimidin-2-yl)-5-methoxypiperidine-3- sulfonamide, Example 40.3. To a 40 mL vial (with pressure release septa) was added 5- methoxypiperidine-3-sulfonamide acetate, 40.2 (2.45 g, 9.62 mmol), N-ethyl-N- isopropylpropan-2 -amine (16.75 mL, 96 mmol) and 2-chloro-5-fluoropyrimidine (6.37 g, 48.1 mmol) in DMSO (48 mL). The reaction mixture was then stirred at 100 °C for 23 h. LCMS indicated formation of the desired product. The reaction mixture was diluted with water and extracted with DCM. The organic extract was washed with saturated aqueous NaCl, brine and dried over Na2S04. The solution was filtered and concentrated in vacuo to give the initial material as an orange oil. The initial material was absorbed onto a plug of silica gel and purified by chromatography through a RediSep-Sep pre-packed silica gel column (40 g), eluting with a gradient of 0% to 100% 1/3 EtOH/EtOAc in heptanes to provide the title compound, 40.3 (0.51 g, 18 % yield) as white solid, LCMS-ESI (pos.) m/z: 291. ⁺ .

40.4

[0358] (3S,5S)-l-(5-Fluoropyrimidin-2-yl)-5-methoxypiperidine-3- sulfonamide and (3R,5R)-1 -(5-fluoropyrimidin-2-yl)-5-methoxypiperidine-3- sulfonamide, Example 40.4. Further elution under the conditions described in Example 40.3 delivered 40.4 (0.24 g, 0.832 mmol, 8.65 % yield) as a light yellow solid. LCMS- ESI (pos.) ⁺ .

40.5

[0359] (3S,5R)-l-(5-Fluoropyrimidin-2-yl)-5-methoxypiperidine-3- sulf onamide or (3R,5S)-1 -(5-fluoropyrimidin-2-yl)-5-methoxypiperidine-3- sulfonamide, Example 40.5. Example 40.5 was obtained by chiral separation of 40.3 on SFC: Chiralpak AD-H column, 30% MeOH / C0 ₂ , with 0.2% DEA. Example 40.5 was the earlier peak to elute on the Chiralpak AD-H column. ¾ NMR (400 MHz, CD ₃ OD) δ 1.65 (td, J=12.28, 10.88 Hz, 1 H) 2.57 - 2.72 (m, 2 H) 2.98 (dd, J=13.06, 11.40 Hz, 1 H) 3.14 (ddt, 1 H) 3.27 - 3.36 (m, 1H) 3.45 (s, 3 H) 4.97 (ddt, 1 H) 5.17 (ddt, 1 H) 8.32 (d, J=0.62 Hz, 2 H). LCMS-ESI (pos.) m/z: 291.0 (M+H) ⁺ .

40.6

[0360] (3S,5R)-l-(5-Fluoropyrimidin-2-yl)-5-methoxypiperidine-3- sulf onamide or (3R,5S)-1 -(5-fluoropyrimidin-2-yl)-5-methoxypiperidine-3- sulfonamide, Example 40.6. Further elution under the conditions described in Example 40.5 delivered Example 40.6. ¾ NMR (400 MHz, CD ₃ OD) δ 1.65 (td, J=12.28, 10.88 Hz, 1 H) 2.57 - 2.71 (m, 2 H) 2.94 - 3.04 (m, 1 H) 3.14 (ddt, 1 H) 3.31 - 3.36 (m, 1 H) 3.45 (s, 3 H) 4.97 (ddt, 1 H) 5.17 (ddt, 1 H) 8.32 (s, 2 H). LCMS-ESI (pos.) m/z: 291.0 (M+H) ⁺ .

40.7

[0361] (3S,5S)- 1 - (5-Fluoropyrimidin-2-yl)-5-methoxypiperidine-3- sult ^' onamidc or (3R,5R)-l-(5-fluoropyrimidin-2-yl)-5-methoxypiperidine-3- sulfonamide, Example 40.7. Example 40.7 was obtained by chiral separation of 40.4 on a SFC: Chiralpak AD-H column, 25% MeOH / C0 ₂ , with 0.2% DEA. Example 40.7 was the earlier peak to elute on the Chiralpak AD-H column. ¾ NMR (400 MHz, CD ₃ OD) δ 1.98 (ddd, J=13.42, 12.39, 3.01 Hz, 1 H) 2.41 - 2.51 (m, 1 H) 2.98 (dd, J=14.31, 1.66 Hz, 1 H) 3.10 (dd, J=13.06, 11.20 Hz, 1 H) 3.29 - 3.36 (m, 1 H) 3.32 (s, 3H) 3.66 - 3.71 (m, 1 H) 4.98 (dq, J=14.38, 2.19 Hz, 1 H) 5.18 (ddt, 1 H) 8.29 (d, J=0.83 Hz, 2 H) LCMS-ESI (pos.) m/z: 291.0 (M+H) ⁺ .

40.8

[0362] (3R,5R)-l-(5-Fluoropyrimidin-2-yl)-5-methoxypiperidine-3- sult ^' onamidc or (3S,5S)-l-(5-fluoropyrimidin-2-yl)-5-methoxypiperidine-3- sulfonamide, Example 40.8. Further elution under the conditions described in Example 40.6 delivered Example 40.8. ¾ NMR (400 MHz, CD ₃ OD) δ 1.96 (ddd, J=13.39, 12.45, 2.93 Hz, 1 H) 2.44 (dt, J=13.48, 1.89 Hz, 1 H) 2.97 (dd, J=14.33, 1.58 Hz, 1 H) 3.08 (dd, J=13.01, 11.14 Hz, 1 H) 3.28 - 3.35 (m, 1 H) 3.32 (s, 3H) 3.60 - 3.72 (m, 1 H) 4.87 - 5.00 (m, 1 H) 5.16 (dt, J=13.02, 1.91 Hz, 1 H) 8.27 (d, J=0.67 Hz, 2 H). LCMS-ESI (pos.) m/z: 291.0 (M+H) ⁺ .

[0363] Example 41.0. Preparation of Examples (lR,2S)-l-ethoxy-l-(5- methylpyrimidin-2-yl)propane-2-sulfonamide and (lS,2R)-l-ethoxy-l-(5- methylpyrimidin-2-yl)propane-2-sulfonamide.

34.5 41.1

[0364] (lR,2S)-l-Ethoxy-N,N-bis(4-methoxybenzyl)-l-(5-methylpyrimid in- 2-yl)propane-2-sulfonamide and (lS,2R)-l-ethoxy-N,N-bis(4-methoxybenzyl)-l-(5- methylpyrimidin-2-yl)propane-2-sulfonamide, Example 41.1. To a -78 °C solution of 34.5 (1.62 g, 3.4 mmol) in THF (70 mL) was added potassium bis(trimethylsilyl)amide (1.0 M solution in THF, 10.6 mL, 10.6 mmol) slowly via syringe. After 1.25 h, ethyl trifluoromethane sulfonate (1.4 mL, 10.6 mmol) was added slowly via syringe. The resulting orange solution was stirred at -78 °C for 45 min and then was quenched with a 2: 1 mixture of saturated aqueous ammonium chloride solution and water (75 mL). The resulting mixture was extracted with EtOAc (4X). The combined organic layers were dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by silica gel chromatography (eluent: 10- 65% EtOAc in hexanes) to provide 41.1 (1.02 g, 60% yield) as a light yellow oil. LCMS-ESI (pos.) m/z: 500.1 (M+H) ⁺ .

AND AND

41.1 41.0

[0365] (l ?,2 )-l-Ethoxy-l-(5-methylpyrimidin-2-yl)propane-2- sult ^' onamidc and (lS,2 ?)-l-ethoxy-l-(5-methylpyrimidin-2-yl)propane-2- sulfonamide, Example 41.0. Example 41.1 (1.02 g, 2.0 mmol) was dissolved in TFA (14 mL) and anisole (466 μΕ, 4.3 mmol) was added via syringe. The resulting orange solution was stirred at RT for 16.5 h and was then concentrated in vacuo. The residue was purified by silica gel chromatography (eluent: pure DCM grading to 4.5% MeOH in DCM) to provide the title compound Example 41.0 (495 mg, 93% yield) as a white solid. LCMS-ESI (pos.) m/z: 260.0 (M+H) ⁺ .

[0366] The compounds set forth in the following table were synthesized following the procedure in Example 41.0 using the known starting material as described. Table 8

Example Reagents Structure, Name and Data

AND AND

Ths mat

that of Example 34.2 employing the cis olefin.

(lR,2R)-l-ethoxy-l-(5- methylpyrimidin-2-yl)propane-2- sulfonamide and (lS,2S)-l-ethoxy-l- (5-methylpyrimidin-2-yl)propane-2- sulfonamide.

LCMS-ESI (pos.) m/z: 260.0 (M+H) ⁺

I 5-chloropicolinaldehyde (commercially available

from Combi-Blocks), methyl

trifluoromethanesulfonate (commercially

available from Combi-Blocks).

AND

( 1R,2S)- 1 -(5-chloropyridin-2-yl)- 1- methoxy propane -2 -sulfonamide and ( 1 S,2R)- 1 -(5-chloropyridin-2-yl)- 1- methoxypropane-2-sulfonamide. LCMS-ESI (pos.) m/z: 265.0 (M+H) ⁺ . 116.0 Example 116.0 was purified by preparative SFC

using the following method: Column: Chiral Pak

IC (250 X 4.6)mm 5u, Mobile Phase: 0.1% DEA H ₂ N

in hexanes : EtOH (80:20), Flow : 1.0 niL/min. to ^{0 0}

provide peak 1.

OR

( 1R,2S)- 1 -(5-chloropyridin-2-yl)- 1- methoxypropane-2-sulfonamide or ( 1 S,2R)- 1 -(5-chloropyridin-2-yl)- 1- methoxypropane-2-sulfonamide. ¾ NMR (400 MHz, DMSO-c¾) δ 8.64 (d, J = 2.5 Hz, 1H), 7.99 (dt, J = 8.4, 2.3 Hz, 1H), 7.44 (d, J = 8.4 Hz, 1H), 6.81 (s, 2H), 4.89 (d, J = 2.5 Hz, 1H), 3.33 (m, 4H), 1.10 (dd, J = 7.0, 1.9 Hz, 3H). LCMS-ESI (pos.) m/z: 265.0 (M+H) ⁺ .

117.0 Example 117.0 was purified by preparative SFC

using the following method: Column: CHIRAL

PAK IC (250 X 4.6)mm 5u, Mobile Phase: 0.1%

DEA in hexane : EtOH (80:20), Flow : 1.0

mL/min. to provide peak 2.

OR

( 1R,2S)- 1 -(5-chloropyridin-2-yl)- 1- methoxypropane-2-sulfonamide or ( 1 S,2R)- 1 -(5-chloropyridin-2-yl)- 1- methoxypropane-2-sulfonamide. ¾ NMR (400 MHz, DMSO-c¾) δ 8.64 (d, J = 2.4 Hz, 1H), 7.99 (dd, J = 8.3, 2.4 Hz, 1H), 7.44 (d, J = 8.4 Hz, 1H), 6.81 (s, 2H), 4.89 (d, J = 2.3 Hz, 1H), 3.33 (m, 4H), and 1.10 (d, J = 7.0 Hz, 3H). LCMS-ESI (pos.) m/z: 265.0 (M+H) ⁺ .

[0367] Example 42.0. Preparation of (lR,2S)-N-(l-cubane-4-(4,6- dimethoxy-5-pyrimidinyl)-4H-l,2,4-triazol-3-yl)-l-(5-chloro- 2-pyrimidinyl)-l- methoxy-2-propanesulfonamide.

42.1

[0368] Methyl cubane-l-carboxylate, Example 42.1. To a solution of cubane-l-carboxylic acid (Pharmablock, 0.5 g, 3.37 mmol) in MeOH (6.75 mL) was added sulfuric acid (0.018 mL, 0.34 mmol), and the reaction was heated at 60 °C for 4 h after which LCMS indicated complete conversion to product. The solvent was removed in vacuo and the mixture was dissolved in DCM, washed with a saturated solution of NaHC0 ₃ , dried over Na2S04, and concentrated in vacuo to yield methyl cubane-l- carboxylate (0.525 g, 3.24 mmol, 96 % yield). ¾ NMR (500 MHz, CDC1 ₃ ) δ 4.21 - 4.30 (m, 3 H) 3.95 - 4.07 (m, 4 H) 3.68 - 3.74 (m, 3 H). LCMS-ESI (pos.) m/z: 163.2 (M+H) ⁺ .

42.2 [0369] Cubane-l-carbohydrazide, Example 42.2. To methyl cubane-1- carboxylate (0.52 g, 3.21 mmol) in MeOH (4.86 mL) was added hydrazine, monohydrate (0.494 mL, 6.41 mmol), and the reaction was heated at 60 °C for 5 h. After 5 h, LCMS indicated complete conversion to the hydrazide. EtOAc was added, and the mixture was stirred at RT for 1 h resulting in a white precipitate. The mixture was filtered and the filtrate was washed with heptane s/EtO Ac (1: 1) to yield cubane-l-carbohydrazide (0.52 g, 3.21 mmol, 100 % yield). ¾ NMR (400 MHz, CDC1 ₃ ) δ 6.62 - 6.87 (m, 1 H) 4.19 - 4.28 (m, 3 H) 3.99 - 4.08 (m, 4 H). LCMS-ESI (pos.) m/z: 163.2 (M+H) ⁺ .

42.3

[0370] (Z)-N-(((lR,2R)-2-(5-Chloropyrimidin-2-yl)-l- methoxypropyl)sulfonyl)-2-(cubane-l-carbonyl)-N'-(4,6-dimeth oxypyrimidin-5- yl)hydrazinecarboximidamide, Example 42.3. To a solution of (lR,2S)-l-(5- chloropyrimidin-2-yl)-l-methoxypropane-2-sulfonamide (Example 29.3, 0.2 g, 0.75 mmol) in ACN (7.53 mL) was added 5-isothiocyanato-4,6-dimethoxypyrimidine

(Example 28.1, 0.148 g, 0.75 mmol) and cesium carbonate (0.312 g, 0.98 mmol). The resulting mixture was then stirred at RT. After 12 h, LCMS showed complete coonsumption of SM and conversion to the thiourea intermediate. To this white slurry was added cubane-l-carbohydrazide (Example 42.2, 0.122 g, 0.75 mmol) followed by silver(I) nitrate (0.256 g, 1.51 mmol), and the resulting mixture was stirred at RT. After 30 min, the mixture had turned brown and LCMS indicated conversion to product. The mixture was loaded directly onto silica gel and purified (30-100% EtOAc :EtOH 3: 1 in heptanes) to yield the desired product as an off white solid (0.4 g, 0.68 mmol, 90 % yield).

42.3 42.0

[0371] (lR,2S)-N-(l-Cubane-4-(4,6-dimethoxy-5-pyrimidinyl)-4H-l,2,4 - triazol-3-yl)-l-(5-chloro-2-pyrimidinyl)-l-methoxy-2-propane sulfonamide, Example 42.0. To a solution of Example 42.3 (0.4 g, 0.677 mmol) in IPA (2.26 mL) and water (1.123 mL) was added a solution of sodium hydroxide (1.0 M, 0.880 mL, 0.880 mmol). The resulting mixture was then heated at 80 °C. After 2 h, the reaction was complete as determined by by LCMS. The mixture was neutralized to pH 7 with 1.0 N HCl, extracted with DCM, dried over sodium sulfate and concentrated in vacuo. The product was purified by silica gel 30-100% (EtOH:EtOAc 1 :3 in heptanes) to yield Example 42.0 (0.32 g, 0.56 mmol, 83 % yield). ¾ NMR (400 MHz, CDC1 ₃ ) δ 10.77 (br s, 1 H) 8.69 - 8.75 (m, 2 H) 8.47 - 8.53 (m, 1 H) 5.29 - 5.32 (m, 1 H) 4.90 - 4.97 (m, 1 H) 4.07 - 4.12 (m, 3 H) 4.00 - 4.05 (m, 6 H) 3.92 - 3.99 (m, 1 H) 3.85 - 3.91 (m, 3 H) 3.68 - 3.77 (m, 1 H) 3.33 - 3.37 (m, 3 H) 1.34 - 1.40 (m, 3 H). LCMS-ESI (pos.) m/z:573.2 (M+H) ⁺ .

[0372] The compounds set forth in the following table were synthesized following the procedure in Example 42.0 using the known starting material as described. Table 9

[0373] Following the procedure in Example 42.0 the following compounds may be synthesized using the intermediates and conditions described in the following table.

Table 10

5-yl)-5-((lR,2R)-2-(trifluoromethyl)cyclopropyl)-4H- 1 ,2,4-triazol-3 -yl)- 1 -methoxypropane-2-sulfonamide and ( 1R,2S)- 1 -(5-cMoropyrimidin-2-yl)-N-(4-(4,6- dimethoxypyrimidin-5-yl)-5-((lR,2S)-2- (trifluoromethyl)cyclopropyl)-4H- 1 ,2,4-triazol-3 -yl)- 1 - methoxypropane-2-sulfonamide and (lR,2S)-l-(5- cWoropyrimidin-2-yl)-N-(4-(4,6-dimethoxypyrimidin- 5-yl)-5-((lS,2R)-2-(trifluoromethyl)cyclopropyl)-4H- 1 ,2,4-triazol-3 -yl)- 1 -methoxypropane-2-sulfonamide.

( 1R,2S)- 1 -(5-chloropyrimidin-2- N ^ N

yl)-l-mefhoxypropane-2- sulfonamide (Example 29.3), 5- isofhiocyanato-4,6- dimethoxypyrimidine (Example / N-N ⁰

28.1), and 2,2-difluoro-3-

AND

methylcyclopropanecarbohydrazi

de (material may be prepared in

an analogous manner to that of

Example 42.2 employing 2,2- difluoro-3- methylcyclopropanecarboxylic

acid (commercially available

from Enamine).

( 1R,2S)- 1 -(5-cMoropyrimidin-2-yl)-N-(5-(( 1 S,3R)-2,2- difluoro-3-methylcyclopropyl)-4-(4,6- dimethoxypyrimidin-5-yl)-4H- 1 ,2,4-triazol-3 -yl)- 1- methoxypropane-2-sulfonamide and (lR,2S)-l-(5- cliloropyrimidin-2-yl)-N-(5-((lR,3S)-2,2-difluoro-3- methylcyclopropyl)-4-(4,6-dimethoxypyrimidin-5-yl)- 4H- 1 ,2,4-triazol-3 -yl)- l-methoxypropane-2- sulfonamide and (lR,2S)-l-(5-cliloropyrimidin-2-yl)- N-(5-((lR,3R)-2,2-difluoro-3-methylcyclopropyl)-4- (4,6-dimethoxypyrimidin-5-yl)-4H-l,2,4-triazol-3-yl)- l-methoxypropane-2-sulfonamide and (lR,2S)-l-(5- cliloropyrimidin-2-yl)-N-(5-((lS,3S)-2,2-difluoro-3- methylcyclopropyl)-4-(4,6-dimethoxypyrimidin-5-yl)- 4H- 1 ,2,4-triazol-3 -yl)- l-methoxypropane-2- sulfonamide.

( 1R,2S)- 1 -(5-chloropyrimidin-2- N ^ N

yl)-l-meflioxypropane-2- sulfonamide (Example 29.3), 5- isofhiocyanato-4,6- dimethoxypyrimidine (Example F ₂ HC N-N ° O l ^

28.1), and 2- AND

(difluoromethyl)cyclopropanecar

bohydrazide (material may be N ^ N

prepared in an analogous manner

to that of Example 42.2

employing 2-

(difluoromethyl)cyclopropanecar F ₂ HC ^{" N"N} ° ° 0,

boxy lie acid (commercially AND

available from Enamine). N ^ N

F ₂ HC °\

AND

( 1R,2S)- 1 -(5-cMoropyrimidin-2-yl)-N-(5-(( 1 S,2S)-2- (difluoromethyl)cyclopropyl)-4-(4,6- dimethoxypyrimidin-5-yl)-4H- 1 ,2,4-triazol-3 -yl)- 1- methoxypropane-2-sulfonamide and (lR,2S)-l-(5- cliloropyrimidin-2-yl)-N-(5-((lR,2R)-2- (difluoromethyl)cyclopropyl)-4-(4,6- dimethoxypyrimidin-5-yl)-4H- 1 ,2,4-triazol-3 -yl)- 1- methoxypropane-2-sulfonamide and (lR,2S)-l-(5- cliloropyrimidin-2-yl)-N-(5-((lR,2S)-2- (difluoromethyl)cyclopropyl)-4-(4,6- dimethoxypyrimidin-5-yl)-4H- 1 ,2,4-triazol-3 -yl)- 1- methoxypropane-2-sulfonamide and (lR,2S)-l-(5- cliloropyrimidin-2-yl)-N-(5-((lS,2R)-2- (difluoromethyl)cyclopropyl)-4-(4,6- dimethoxypyrimidin-5-yl)-4H- 1 ,2,4-triazol-3 -yl)- 1- methoxypropane -2 -sulfonamide .

( 1R,2S)- 1 -(5-chloropyrimidin-2-

N ^ N

yl)-l-meflioxypropane-2- sulfonamide (Example 29.3), 5- isofhiocyanato-4,6- dimethoxypyrimidine (Example )— ' N-N ° ° A

28.1), and l-(2,2- F ^

difluoroethyl)cyclopropanecarboh ( 1R,2S)- 1 -(5-cMoropyrimidin-2-yl)-N-(5-( 1 -(2,2- ydrazide (material may be difluoroethyl)cyclopropyl)-4-(4,6-dimethoxypyrimidin- prepared in an analogous manner 5-yl)-4H-l,2,4-triazol-3-yl)-l-methoxypropane-2- to that of Example 42.2 sulfonamide.

employing l-(2,2- difluoroethyl)cyclopropanecarbox

ylic acid (commercially available

from Enamine).

( 1R,2S)- 1 -(5-chloropyrimidin-2-

N ^ N

yl)-l-methoxypropane-2- sulfonamide (Example 29.3), 5- isofhiocyanato-4,6- dimethoxypyrimidine (Example

28.1), and 1-

( 1R,2S)- 1 -(5-cMoropyrimidin-2-yl)-N-(4-(4,6-

(trifluoromethyl)cyclopropanecar cWoropyrimidin-2-yl)-N-(4-(4,6-dimethoxypyrimidin- 5-yl)-5-((lr,3R)-3-(hydroxymethyl)cyclobutyl)-4H- 1 ,2,4-triazol-3 -yl)- 1 -methoxypropane-2-sulfonamide.

( 1R,2S)- 1 -(5-chloropyrirnidin-2-

N ^N

yl)-l-meflioxypropane-2- sulfonamide (Example 29.3), 5- isofhiocyanato-4,6- dimethoxypyrimidine (Example N-N ° ° A

28.1), and 3-

( 1R,2S)- 1 -(5-chloropyrimidin-2-yl)-N-(4-(4,6- oxocyclobutanecarbohydrazide

dimethoxypyrimidin-5-yl)-5-(3-oxocyclobutyl)-4H- (material may be prepared in an

1 ,2,4-triazol-3 -yl)- 1 -methoxypropane-2-sulfonamide. analogous manner to that of

Example 42.2 employing methyl

3 -oxocy clobutanecarboxylate

(commercially available from

Combi-Blocks Inc).

( 1R,2S)- 1 -(5-chloropyrimidin-2-

N^ N

yl)-l-methoxypropane-2- sulfonamide (Example 29.3), 5- isothiocyanato-4,6- dimethoxypyrimidine (Example N-N ° ° o

28.1), and 3- AND

cyanocyclobutanecarbohydrazide N ^ N

(material may be prepared in an

analogous manner to that of

Example 42.2 employing methyl

3 -cy anocyclobutanecarboxylate N-N ° ° A

(commercially available from ( 1R,2S)- 1 -(5-chloropyrimidin-2-yl)-N-(5-(( 1 s,3 S)-3 - AstaTech, Inc). Methansulfonic cyanocyclobutyl)-4-(4,6-dimethoxypyrimidin-5-yl)- acid will be used instead of 4H- 1 ,2,4-triazol-3 -yl)- l-methoxypropane-2- sodium hydroxide. sulfonamide and (lR,2S)-l-(5-chloropyrimidin-2-yl)- N-(5-((lr,3S)-3-cyanocyclobutyl)-4-(4,6- dimethoxypyrimidin-5-yl)-4H- 1 ,2,4-triazol-3 -yl)- 1- methoxypropane -2 -sulfonamide .

3 -yl)- 1 -methoxypropane-2-sulfonamide.

( 1R,2S)- 1 -(5-chloropyrimidin-2-

N^N

yl)-l-meflioxypropane-2- sulfonamide (Example 29.3), 5- isofhiocyanato-4,6- dimethoxypyrimidine (Example F N-N ^{0 0} A

28.1), and 1-

( 1R,2S)- 1 -(5-chloropyrimidin-2-yl)-N-(4-(4,6- fluorocyclobutanecarbohydrazide

dimethoxypyrimidin-5-yl)-5-(l-fluorocyclobutyl)-4H- (material may be prepared in an

1 ,2,4-triazol-3 -yl)- 1 -methoxypropane-2-sulfonamide. analogous manner to that of

Example 42.2 employing 1- fluorocyclobutanecarboxylic acid

(commercially available from

Enamine).

( 1R,2S)- 1 -(5-chloropyrimidin-2- N^N

yl)-l-methoxypropane-2- sulfonamide (Example 29.3), 5- isofhiocyanato-4,6- dimethoxypyrimidine (Example OHN-N ^{ϋ ϋ} A

28.1), and 1- ^\

( 1R,2S)- 1 -(5-chloropyrimidin-2-yl)-N-(4-(4,6- hydroxycyclobutanecarbohydrazi

dimethoxypyrimidin-5-yl)-5-(l-hydroxycyclobutyl)- de (material may be prepared in

4H- 1 ,2,4-triazol-3 -yl)- l-methoxypropane-2- an analogous manner to that of

sulfonamide.

Example 42.2 employing 1- hydroxycyclobutanecarboxylic

acid (commercially available

from Enamine).

( 1R,2S)- 1 -(5-chloropyrimidin-2- N^N

yl)-l-methoxypropane-2- sulfonamide (Example 29.3), 5- isothiocyanato-4,6- dimethoxypyrimidine (Example N-N ° ° A

28.1), and 4-

( 1R,2S)- 1 -(5-chloropyrimidin-2-yl)-N-(4-(4,6-

(trifluoromethy l)bicyclo [ 1.1.1 ]pe

dimethoxypyrimidin-5-yl)-5-(4- ntane-2-carbohydrazide (material

(trifluoromethyl)bicyclo[l.l. l]pentan-2-yl)-4H-l,2,4- may be prepared in an analogous

triazol-3-yl)-l-methoxypropane-2-sulfonamide. manner to that of Example 42.2

methoxypropane -2 -sulfonamide .

(difluoromethyl)cyclobutyl)-4-(4,6-

available from Enamine).

dimethoxypyrimidine (Example A

methoxypropane -2 -sulfonamide .

1 - -yl)- 1-

dimethoxypyrimidin-5-yl)-5-((lR,3R)-3-

available from Enamine).

I (lR,2S)-l-(5-cWoropyrirnidin-2- yl)-l-meflioxypropane-2- sulfonamide (Example 29.3), 5- isofhiocyanato-4,6- dimethoxypyrimidine (Example

28.1), and 2- hydroxycyclohexanecai ohydrazi

de (material may be prepared in

an analogous manner to that of

Example 42.2 employing ethyl 2- hydroxycyclohexanecarboxylate

(commercially available from Ark

Pharm).

( 1R,2S)- 1 -(5-chloropyrimidin-2-yl)-N-(4-(4,6- dimethoxypyrimidin-5-yl)-5-((lR,2S)-2- hydroxycyclohexyl)-4H- l,2,4-triazol-3 -yl)- 1- methoxypropane-2-sulfonamide and (lR,2S)-l-(5- cWoropyrimidin-2-yl)-N-(4-(4,6-dimethoxypyrimidin- 5-yl)-5-((lS,2R)-2 -hydroxy cyclohexyl)-4H-l,2,4- triazol-3-yl)-l-methoxypropane-2-sulfonamide and ( 1R,2S)- 1 -(5-chloropyrimidin-2-yl)-N-(4-(4,6- dimethoxypyrimidin-5-yl)-5-((lS,2S)-2- hydroxycyclohexyl)-4H- l,2,4-triazol-3 -yl)- 1- methoxypropane-2-sulfonamide and (lR,2S)-l-(5- cWoropyrimidin-2-yl)-N-(4-(4,6-dimethoxypyrimidin- 5-yl)-5-((lR,2R)-2 -hydroxy cyclohexyl)-4H- 1,2,4- triazol-3-yl)-l-methoxypropane-2-sulfonamide.

methoxypropane -2 -sulfonamide .

[0374] Example 98.1. Preparation of (R)-l-(5-fluoropyrimidin-2- yl)piperidine-3-sulfonamide and (S)-l-(5-fluoropyrimidin-2-yl)piperidine-3- sulfonamide.

98.11

[0375] (+)-Pipei"idine-3-sulfonamide hydrochloride, Example 98.11. To a

100-mL round-bottomed flask was added 4-chloro-3-pyridinesulfonamide (commercially available from Alfa Aesar, 0.56 g, 2.91 mmol) in AcOH (25 mL). N ₂ was bubbled through the suspension for 5 mins before platinum (iv) oxide (commercially available from Sigma- Aldrich, USA, 0.330 g, 1.454 mmol) was added under N ₂ flow. The flask was then sealed with a septum and vacuumed. Hydrogen gas was back-filled from a balloon. The reaction mixture was stirred at 23 °C under hydrogen gas for 3 days.

Celite ^® brand filter aid (20 g) was then added to the reaction mixture with stirring. The solution was filtered through a short pad of Celite ^® brand filter aid. The cake was rinsed with MeOH. The combined organics were concentrated in vacuo to give the initial material as a light-yellow glass. The residue was triturated with DCM to afford Example 98.11 (0.6 g, 2.99 mmol, 103 % yield) as a light yellow solid. LCMS-ESI (pos.), m/z: 165.2 ( ⁺ .

98.12

[0376] (R)-l-(5-Fluoropyrimidin-2-yl)piperidine-3-sulfonamide and (S)-l-

(5-fluoropyrimidin-2-yl)piperidine-3-sulfonamide, Example 98.12. To a 50-mL vial was added Example 98.11 (200 mg, 0.997 mmol) and 2-chloro-5-fluoro-pyrimidine (Matrix Scientific, SC, USA, 0.66 mL, 4.98 mmol) in DMSO (5 mL). Hunig's base (0.867 mL, 4.98 mmol) was then added with stirring. The reaction mixture was stirred at 100 °C for 2 h. LCMS analysis indicated the reaction was complete. The reaction mixture was allowed to cool to room temperature. The reaction mixture was then diluted with water and extracted with DCM. The organic extract was washed with brine and dried over Na2S04. The solution was filtered and concentrated in vacuo to give the initial material as a light-yellow glass, which was triturated with IPA to afford Example 98.12 (240 mg, 93 % yield) as an off-white solid. ¾ NMR (500 MHz, CDC1 ₃ ) δ 8.21 (s, 2 H) 4.98 - 5.07 (m, 1 H) 4.76 (s, 2 H) 4.49 - 4.59 (m, 1 H) 3.31 (dd, .7=12.96, 10.27 Hz, 1 H) 3.15 (tt, .7=10.51, 3.91 Hz, 1 H) 3.04 (ddd, .7=13.69, 11.49, 2.69 Hz, 1 H) 2.32 - 2.43 (m, 1 H) 1.87 - 2.02 (m, 2 H) 1.51 - 1.63 (m, 1 H). LCMS-ESI (pos.), m/z: 261.2 (M+H) ⁺ .

[0377] The compounds set forth in the following table were synthesized following the procedure in Example 42.0 using the known starting material as described. Table 11

I (lR,2S)-l-(5-cWoropyrirnidin-2- yl)-l-meflioxypropane-2- sulfonamide (Example 29.3), 5- isothiocyanato-4,6- dimethoxypyrimidine (Example

28.1), (R)-spiro[2.2]pentane-l- carbohydrazide hydrocliloride and OR

(S)-spiro[2.2]pentane-l- carbohydrazide hydrocliloride

(Example 105.2).

The racemic mixture was purified

using the following preparative

SFC method: Column: AD-H (3

( 1R,2S)- 1 -(5-chloropyrimidin-2-yl)-N-(4-(4,6- x 25 cm) Mobile Phase: 85: 15

dimethoxypyrimidin-5-yl)-5-((R)-spiro[2.2]pentan-l- (A:B) A: Liquid C0 ₂ , B: MeOH,

yl)-4H- 1 ,2,4-triazol-3-yl)- 1 -methoxypropane-2- Flow Rate: 200 niL/min, 254 iim,

sulfonamide or (lR,2S)-l-(5-chloropyrimidin-2-yl)-N- 100 bar inlet pressure to deliver

(4-(4,6-dimethoxypyrimidin-5-yl)-5-((S)- Peak 2.

spiro [2.2]pentan- 1 -yl)-4H- 1 ,2,4-triazol-3 -yl)-l- methoxypropane -2 -sulfonamide .

¾ NMR (400MHz, DMSO-d ₆ ) δ = 12.85 (s, IH), 8.93 (s, 2H), 8.68 (s, IH), 4.78 (d, .7=4.1 Hz, IH), 3.96 (s, 3H), 3.93 (s, 3H), 3.43 - 3.36 (m, IH), 3.13 (s, 3H), 1.93 (dd, .7=4.5, 7.8 Hz, IH), 1.49 (t, .7=4.3 Hz, IH), 1.41 (dd, .7=4.1, 7.9 Hz, IH), 1.13 (d, .7=7.0 Hz, 3H), 0.90 - 0.83 (m, IH), 0.83 - 0.74 (m, 2H), 0.71 - 0.65 (m, IH). LCMS-ESI (pos.) m/z: 537.0 (M+H) ⁺ .

l-methoxypropane-2-sulfonamide or (lR,2S)-l-(5- cWoropyrimidin-2-yl)-N-(4-(2,6-dimethoxyphenyl)-5-

((lS,2R)-2-ethoxycyclopropyl)-4H-l,2,44riazol-3-yl)-

1 -methoxypropane-2-sulforiamide.

¾ NMR (400MHz, CD ₂ C1 ₂ ) δ 10.97 - 10.34 (m, 1H),

8.71 (s, 2H), 7.48 (t, .7=8.5 Hz, 1H), 6.76 - 6.71 (m,

2H), 4.86 (d, .7=4.8 Hz, 1H), 3.83 (s, 3H), 3.78 (s, 3H),

3.57 (dq, .7=4.8, 7.0 Hz, 1H), 3.46 - 3.31 (m, 3H), 3.25

(s, 3H), 1.49 - 1.40 (m, 2H), 1.26 (d, .7=6.8 Hz, 3H),

1.11 - 1.02 (m, 4H). LCMS-ESI (pos.) m/z: 553.2

(M+H) ⁺ .

1 -

( 1R,2S)- 1 -(5-cMoropyrimidin-2-yl)-N-(4-(2,6- dimethoxyphenyl)-5-((lR,2R)-2-ethoxycyclopropyl)- 4H- 1 ,2,4-triazol-3 -yl)- l-methoxypropane-2- sulfonamide or (lR,2S)-l-(5-cWoropyrimidin-2-yl)-N- (4-(2,6-dimethoxyphenyl)-5-((lS,2S)-2- ethoxycyclopropyl)-4H- 1 ,2,4-triazol-3 -yl)- 1 - methoxypropane-2-sulforiamide or (lR,2S)-l-(5- cWoropyrimidin-2-yl)-N-(4-(2,6-dimethoxyphenyl)-5- ((lR,2S)-2-ethoxycyclopropyl)-4H-l,2,4-triazol-3-yl)- l-methoxypropane-2-sulforiamide or (lR,2S)-l-(5- cWoropyrimidin-2-yl)-N-(4-(2,6-dimethoxyphenyl)-5- ((lS,2R)-2-ethoxycyclopropyl)-4H-l,2,4-triazol-3-yl)- 1 -methoxypropane-2-sulfonamide.

¾ NMR (400MHz, DMSO-d ₆ ) δ 12.66 (s, IH), 8.92 (s, 2H), 7.52 (t, .7=8.5 Hz, IH), 6.87 (t, .7=7.6 Hz, 2H), 4.76 (d, J=4.4 Hz, IH), 3.79 (s, 3H), 3.75 (s, 3H), 3.44 - 3.36 (m, IH), 3.31 - 3.28 (m, IH), 3.20 (qd, .7=7.0, 9.5 Hz, IH), 3.14 (s, 3H), 2.99 (qd, .7=7.0, 9.5 Hz, IH), 1.40 - 1.34 (m, IH), 1.27 - 1.21 (m, IH), 1.20 - 1.15 (m, IH), 1.14 (d, .7=7.0 Hz, 3H), 0.94 (t, .7=7.0 Hz, 3H). LCMS-ESI (pos.) m/z: 553.2 (M+H) ⁺ .

cWoropyrimidin-2-yl)-N-(4-(2,6-dimethoxyphenyl)-5- ((lS,2R)-2-ethoxycyclopropyl)-4H-l,2,4-triazol-3-yl)- 1 -methoxypropane-2-sulfonamide.

¾ NMR (400MHz, DMSO-d ₆ ) δ = 12.66 (br s, 1H), 8.92 (s, 2H), 7.52 (t, .7=8.5 Hz, 1H), 6.88 (d, .7=8.7 Hz, 1H), 4.77 (d, .7=4.1 Hz, 1H), 3.81 - 3.77 (m, 3H), 3.77 - 3.75 (m, 3H), 3.43 - 3.36 (m, 1H), 3.31 - 3.29 (m, 1H), 3.21 (qd, .7=7.0, 9.5 Hz, 1H), 3.14 (s, 3H), 3.05 - 2.96 (m, 1H), 1.40 - 1.35 (m, 1H), 1.26 - 1.21 (m, 1H), 1.21 - 1.16 (m, 1H), 1.13 (d, .7=7.0 Hz, 3H), 0.94 (t, .7=6.9 Hz, 3H). LCMS-ESI (pos.) m/z: 553.0 (M+H) ⁺ .

[0378] Example 100.2. Preparation of (R)-2,2- difluorocyclopropanecarbohydrazide hydrochloride and (S)-2,2- difluorocyclopropanecarbohydrazide hydrochloride.

100.1

[0379] tert-Butyl 2-(2,2- difluorocyclopropanecarbonyl)hydrazinecarboxylate Example 100.1. A flask

containing 2,2-difluorocyclopropanecarboxylic acid (1.01 g, 8.2 mmol) (commercially available from Alfa Aesar, a Johnson Mathey Company) in anhydrous DCM (16.5 mL) was cooled in an ice bath. After 20 mins, l-(3-dimethylaminopropyl)-3- ethylcarbodiimide hydrochloride (1.62 g, 8.5 mmol) and then tert-butyl carbazate (1.14 g, 8.6 mmol) were carefully added in portions to the homogeneous solution. Upon complete addition of tert-butyl carbazate, the solution was allowed to warm to RT. After 19 h, the reaction was carefully quenched with water and then extracted three times with DCM.

The organic layers were pooled and then washed once with brine. The organic layer was dried over anhydrous magnesium sulfate and was then filtered and concentrated in vacuo. The colorless film was identified as tert-butyl 2-(2,2-difluorocyclopropanecarbonyl) hydrazinecarboxylate, Example 100.1 (1.95 g, 8.2 mmol, 100 % yield), and was used without purification. ¾ NMR (400MHz, CD ₂ C1 ₂ ) δ = 8.02 - 7.81 (m, 1H), 6.72 - 6.53 (m, 1H), 2.44 - 2.34 (m, 1H), 2.15 - 2.08 (m, 1H), 1.80 - 1.73 (m, 1H), 1.46 (s, 9H AND

100.2

[0380] (R)-2,2-Difluorocyclopropanecarbohydrazide hydrochloride and

(S)-2,2-difluorocyclopropanecarbohydrazide hydrochloride Example 100.2. A flask containing tert-butyl 2-(2,2-difluorocyclopropanecarbonyl)hydrazinecarboxylate (1.95 g, 8.2 mmol) in EtOH (8.3 mL) was cooled in an ice water bath. After 20 mins, hydrogen chloride (EtOH solution 1.25 M in EtOH (26.5 mL, 33.1 mmol)) was added carefully dropwise. Upon complete addition of acid, the mixture was allowed to warm to RT. After 22 h, the reaction was diluted with EtOAc and then carefully concentrated in vacuo. The solid was suspended in EtOAc and a few drops of EtOH. The subsequent white solid was filtered and identified as Example 100.2 and was used without purification. LCMS- ESI (pos.) m/z: 137.4 (M+H) ⁺ .

[0381] Example 105.2. Preparation of (R)-spiro[2.2]pentane-l- carbohydrazide hydrochloride and (S)-spiro[2.2]pentane-l-carbohydrazide hydrochloride.

105.1

[0382] tert- Butyl 2-(spiro[2.2]pentane-l-carbonyl)hydrazinecarboxylate,

Example 105.1. A flask containing spiro[2.2]pentane-l-carboxylic acid (904 mg, 8.1 mmol) (commercially available from ChemBridge) in anhydrous DCM (16 mL) was cooled in an ice bath. After 20 mins, N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride, EDCI (1.55 g, 8.1 mmol), and then tert-butyl carbazate (1.08 g, 8.15 mmol) were carefully added in portions to the homogeneous solution. Upon complete addition of tert-butyl carbazate, the homogeneous solution was allowed to warm to RT. After 22 h, the reaction was carefully quenched with water and then extracted three times with DCM. The organic layers were pooled and then washed once with brine. The organic layer was dried over anhydrous magnesium sulfate and then filtered and concentrated in vacuo. The colorless residue was identified as Example 105.1 (1.8 g, 8.0 mmol, 99 % yield) that was used without purification. LCMS-ESI (pos.) m/z: 225.3 (M- H)-.

105.2

[0383] (R)-Spiro[2.2]pentane-l-carbohydrazide hydrochloride and (S)- spiro[2.2]pentane-l-carbohydrazide hydrochloride, Example 105.2. A flask containing tert-butyl 2-(spiro[2.2]pentane-l-carbonyl)hydrazinecarboxylate, Example 105.1 (1.8 g, 8.0 mmol) in EtOH (8 mL), was cooled in an ice water bath. After 20 mins, hydrogen chloride (1.25M in EtOH (32 mL, 32.0 mmol)) was added carefully dropwise. Upon complete addition of acid, the mixture was allowed to warm to RT. After 19 h, the reaction was diluted with EtOAc and then carefully concentrated in vacuo. The white solid was suspended in EtOAc and then sonicated. The subsequent white solid was filtered and identified as Example 105.2 (1.11 g, 6.8 mmol, 86 % yield) and was used without purification. LCMS-ESI (pos.) m/z: 127.2 (M+H) ⁺ .

[0384] The compounds set forth in the following table were synthesized following the procedure in Example 42.0 using the known starting material as described. Table 12

Example Reagents Structure, Name and Data

ChemBridge Corporation). pyrimidinyl)-4H- 1 ,2,4-triazol-3-yl)- 1 -(5-mefhyl-2- pyrazinyl)- 1 -(2-propanyloxy)-2-propanesulfonamide. ¾ NMR (500 MHz, CDC1 ₃ ) δ 11.10 (br s, IH), 8.60 (s, IH), 8.50 (s, IH), 8.43 (s, IH), 4.97 (d, .7=5.19 Hz, IH), 3.95-4.04 (m, 6H), 3.52-3.66 (m, 2H), 3.01-3.10 (m, IH), 2.58-2.63 (m, 3H), 2.26-2.38 (m, 2H), 2.06 (s, 2H), 1.89-2.03 (m, 2H), 1.24 (d, .7=7.14 Hz, 3H), 1.17 (d, .7=5.97 Hz, 3H), 1.03 (d, .7=6.10 Hz, 3H). LCMS- ESI (pos.) m/z: 533.2 (M+H) ⁺ .

87.0 (2S,3R)-3-(5-chloropyridin-2-

N ^ N

yl)butane-2-sulforiamide

(Example 32.0), 5- isofhiocyanato-4,6- dimethoxypyrimidine (Example N-N ° ° 1

28.1), and (2S,3R)-3-(5-chloro-2-pyridinyl)-N-(5-cyclobutyl-4- cyclobutanecarbohydrazide (4,6-dimethoxy-5-pyrimidinyl)-4H-l,2,4-triazol-3-yl)- (commercially available from 2 -butane sulfonamide .

ChemBridge Corporation). ¾ NMR (500 MHz, CDC1 ₃ ) δ 10.70 (br s, IH), 8.48- 8.52 (m, 2H), 7.60 (dd, .7=2.40, 8.37 Hz, IH), 7.17 (d, .7=8.30 Hz, IH), 3.97 (s, 3H), 3.97 (s, 3H), 3.72 (dd, J=4.35, 7.07 Hz, IH), 3.61 (br dd, .7=4.41, 6.88 Hz, IH), 3.08 (quin, .7=8.40 Hz, IH), 2.28-2.40 (m, 2H), 1.90-2.13 (m, 4H), 1.36 (d, .7=7.14 Hz, 3H), 1.31 (d, .7=7.01 Hz, 3H). LCMS-ESI (pos.) m/z: 508.0 (M+H) ⁺ .

88.0 (2S,3R)-3-(5-methylpyrazin-2-

N ^ N

yl)butane-2-sulfonamide

(Example 27.2), 5- isofhiocyanato-4,6- dimethoxypyrimidine (Example

28.1), and

(2S,3R)-N-(5-cyclobutyl-4-(4,6-dimethoxy-5- cyclobutanecarbohydrazide

pyrimidinyl)-4H-l,2,4-triazol-3-yl)-3-(5-methyl-2- (commercially available from

pyrazinyl)-2-butanesulfonamide.

ChemBridge Corporation).

¾ NMR (500 MHz, CDC1 ₃ ) δ 10.72 (br s, IH), 8.49 (s,

IH), 8.36 (d, .7=3.63 Hz, 2H), 3.93-4.00 (m, 6H), 3.70-

3.78 (m, IH), 3.51-3.58 (m, IH), 3.07 (quin, J=8.37

Hz, IH), 2.53 (s, 3H), 2.28-2.44 (m, 2H), 1.87-2.10 (m,

ChemBridge Corporation).

LCMS-ESI (pos.) m/z: 499.0 (M+H) ⁺ .

ChemBridge Corporation). methoxypropane -2 -sulfonamide . ¾ NMR (500 MHz, CDC1 ₃ ) δ 10.76 (br s, 1H), 8.74 (s,

2H), 5.12 (d, .7=3.50 Hz, 1H), 4.09-4.20 (m, 4H), 3.66- 3.75 (m, 1H), 3.44 (dt, .7=3.50, 11.68 Hz, 2H), 3.36 (s, 3H), 2.54-2.64 (m, 2H), 2.37-2.48 (m, 4H), 2.09-2.20 (m, 1H), 1.98-2.05 (m, 1H), 1.69 (br d, .7=10.12 Hz, 2H), 1.40 (d, .7=7.14 Hz, 3H). LCMS-ESI (pos.) m/z: 471.2 (M+H) ⁺ .

[0385] Example 113.0. Preparation of 2-isothiocyanato-l,3- dimethoxypropane.

113.0

[0386] 2-Isothiocyanato-l,3-dimethoxypropane, Example 113.0. To a dry

200 round-bottom flask was added di(2-pyridyl) thionocarbonate (5.34 g, 23.00 mmol) in DCM (73.0 mL). 2-Amino-l,3-dimethoxypropane in DCM (15 mL) was added dropwise via an addition funnel over 5 mins. The reaction mixture was then stirred at RT for 3.5 h.

The reaction mixture was concentrated in vacuo. The 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 0% to 50% EtOAc in heptanes, to provide 2- isothiocyanato-l,3-dimethoxypropane (3.28 g, 20.34 mmol, 93 % yield) as a colorless oil. LCMS-ESI (pos.) m/z: 162.2 (M+H) ⁺ .

[0387] The compound set forth in the following table was synthesized

following the procedure in Example 113.0 using the known starting material as

described.

Table 13

1 -isothiocyanato- 1 -

(methoxymethyl)cyclopropane.

¾ NMR (400 MHz, CDC1 ₃ ) δ 3.47 (s, 2H),

3.43 (s, 3H), 1.06-1.16 (m, 2H), 0.81-0.94

(m, 2H).

[0388] The compounds set forth in the following table were synthesized following the procedure in Example 42.0 using the known starting material as described.

Table 14

LCMS-ESI (pos.) m/z: 548.2 (M+H) ⁺ .

dimethoxyphenyl)-5-(cis-3-

ESI (pos.) m/z: 519.0 (M+H) ⁺ .

[0389] The compounds set forth in the following table were synthesized following the procedure in Example 42.0 using the known starting material as described. Table 15

Example Reagents Structure, Name and Data

2-(difluoromethyl)cyclobutanecarboxylic

acid (commercially available from

Enamine).

NH;

AND

AND

( lR,2S)-2-(difluoromethyl)cyclobutane- 1 - carbohydrazide and (lS,2R)-2- (difluoromethyl)cyclobutane-l-carbohydrazide and ( 1 S,2S)-2-(difluoromethyl)cyclobutane- 1 - carbohydrazide and (lR,2R)-2- (difluoromethyl)cyclobutane-l-carbohydrazide.

LCMS-ESI (pos.) m/z: 165.2 (M+H) ⁺ . 147.1 3 ,3 -difluorocy clobutane- 1 -carboxy lie

acid (commercially available from

Synthonix).

NH ₂

3,3 -difluorocyclobutane- l-carbohy drazide.. LCMS-ESI (pos.) m/z: 151.0 (M+H) ⁺ .

148.1 3 -methy Icy clobutane- 1 -carboxy lie acid

(commercially available from

Synthonix).

^ΗΝ -ΝΗ,

AND

^ΗΝ -ΝΗ,

( 1 s,3 s) -3 -methy Icyclobutane- 1 -carbohydrazide and ( lr,3r)-3 -methy Icy clobutane- 1 -carbohydrazide.

LCMS-ESI (pos.) m/z: 129.0 (M+H) ⁺ . 149.1 3 -(trifluoromethy l)cy clobutane- 1 - carboxylic acid (commercially available

from Synthonix).

^H H ₂

AND

^H H ₂

( ls,3 s)-3 -(trifluoromethy l)cy clobutane- 1 - carbohydrazide and (lr,3r)-3- (trifluoromethyl)cyclobutane-l-carbohy drazide.

LCMS-ESI (pos.) m/z: 183.2 (M+H) ⁺ .

151.1 3 -fluorocy clobutane- 1 -carboxylic acid

(commercially available from

Synthonix).

^HN -N¾

AND

^HN -N¾

( 1 s,3 s) -3 -fluorocy clobutane- 1 -carbohydrazide and ( lr,3r)-3-fluorocyclobutane- 1 -carbohydrazide.

LCMS-ESI (pos.) m/z: 133.2 (M+H) ⁺ . 153.1 3 -chlorocyclobutane- 1 -carboxylic acid

(commercially available from

Synthonix).

^H H ₂ AND

^H H ₂

( 1 s,3 s) -3 -chlorocyclobutane- 1 -carbohy drazide and (lr,3r)-3-chlorocyclobutane-l-carbohy drazide.

LCMS-ESI (pos.) m/z: 149.0 (M+H) ⁺ .

154.1 3 -methoxycy clobutane- 1 -carboxylic acid

(commercially available from

Synthonix.)

^H H ₂ AND

( 1 s,3 s) -3 -methoxycy clobutane- 1 -carbohy drazide and (lr,3r)-3-mefhoxycyclobutane-l- carbohy drazide. LCMS-ESI (pos.) m/z: 145.2 (M+H) ⁺ .

2,2-difluorocyclobutane- 1 -carboxylic

acid (commercially available from

Enamine).

^{F H} H ₂ AND

F HISk

NH ₂

(S)-2,2-difluorocyclobutane-l-carboliydrazide and (R)-2,2-difluorocyclobutane-l-carbohydrazide.

LCMS-ESI (pos.) m/z: 151.2 (M+H) ⁺ .

LCMS-ESI (pos.) m/z: 140.2 (M+H) ⁺ .

2-methylcyclobutane-l-carboxylic acid

(commercially available from Enamine).

AND

AND

AND

H

(lR,2S)-2-metliylcyclobutane-l-carboliydrazide and (lS,2R)-2-methylcyclobutane-l- carbohydrazide and (lS,2S)-2-methylcyclobutane- 1 -carbohydrazide and (lR,2R)-2- methylcyclobutane-l-carbohydrazide.

LCMS-ESI (pos.) m/z: 129.2 (M+H) ⁺ . 200.1 spiro[2.3]hexane-5-carboxylic acid

(commercially available from Enamine) spiro [2.3] hexane-5 -carbohydrazide . LCMS-ESI (pos.) m/z: 141.2 (M+H) ⁺ .

175.1 4-fluorocyclohexane-l-carboxylic acid

(commercially available from Enamine)

^H H ₂

AND

( 1 s,4s) -4-fluorocyclohexane- 1 -carbohydrazide and ( lr,4r)-4-fluorocyclohexane- 1 -carbohydrazide.

LCMS-ESI (pos.) m/z: 161.2 (M+H) ⁺ .

238.1 3 ,3 -dimethoxy cyclobutane- 1 -carboxylic

acid (commercially available from

Frontier Scientific Services Inc.).

3,3 -dimethoxy cyclobutane- 1 -carbohydrazide. LCMS-ESI (pos.) m/z: 197.2 (M+Na) ⁺ . [0390] The compounds set forth in the following table were synthesized

following the procedure in Example 42.0 using the known starting material as described. Table 16

Example Reagents Structure, Name and Data

132.0 ( 1R,2 S) - 1 -(5 -chloropyrimidin-2- yl)- 1 -methoxypropane-2- sulfonamide (Example 29.3), 5-1- isothiocyanato-1- (methoxymethyl)cyclopropane

(Example 114.0), and 3- hydroxycyclobutanecarbohydrazid

e (material was prepared in an

analogous manner to that of

Example 42.2 employing ethyl 3- hydroxycyclobutanecarboxylate

(commercially available from

Synthonix)).

(lR,2S)-l-(5-chloro-2-pyrimidinyl)-N-(5-(trans-3- (hydroxymethyl)cyclobutyl)-4-( 1 - (methoxymethyl)cyclopropyl)-4H- l,2,4-triazol-3 -yl)- 1 - methoxy-2-propanesulfonamide or (lR,2S)-l-(5-chloro-2- pyrimidinyl)-N-(5-(cis-3-(hydroxymethyl)cyclobutyl)-4- ( 1 -(methoxymethyl)cyclopropyl)-4H- l,2,4-triazol-3 -yl)- 1- methoxy -2 -propanesulf onamide .

¾ NMR (500 MHz, DMSO-c*) δ 12.34 - 12.74 (m, 1 H) 8.85 - 9.03 (m, 2 H) 4.89 - 4.96 (m, 1 H) 4.59 - 4.66 (m, 1 H) 4.02 - 4.12 (m, 1 H) 3.46 - 3.52 (m, 2 H) 3.38 - 3.46 (m, 2 H) 3.29 (s, 1 H) 3.21 (s, 3 H) 3.15 - 3.18 (m, 3 H) 3.05 - 3.12 (m, 3 H) 2.37 - 2.41 (m, 1 H) 2.07 - 2.17 (m, 2 H) 1.25 (d, J=7.0 Hz, 3 H) 1.07 - 1.11 (m, 1 H) 1.06 - 1.11 (m, 1 H). LCMS-ESI (pos.) m/z: 501.2 (M+H) ⁺ . 1R,2 S) - 1 -(5 -chloropy rirnidin-2- yl)-l -methoxypropane-2- sulfonamide (Example 29.3), 5-1- isotliiocyanato-1- (methoxymethyl)cyclopropane

(Example 114.0), and 3- hydroxycyclobutanecarbohydrazid OR

e (material was prepared in an

analogous manner to that of

Example 42.2 employing ethyl 3- hydroxycyclobutanecarboxylate

(commercially available from

Synthonix)).

(lR,2S)-l-(5-chloro-2-pyrimidinyl)-N-(5-(trans-3- (hydroxymethyl)cyclobutyl)-4-( 1 - (methoxymethyl)cyclopropyl)-4H- l,2,4-triazol-3 -yl)- 1 - methoxy-2-propanesulfonamide or (lR,2S)-l-(5-chloro-2- pyrimidinyl)-N-(5-(cis-3-(hydroxymethyl)cyclobutyl)-4- ( 1 -(methoxymethyl)cyclopropyl)-4H- l,2,4-triazol-3 -yl)- 1- methoxy -2 -propanesulf onamide .

¾ NMR (500 MHz, DMSO-c¾) δ 12.39 - 12.62 (m, 1 H) 8.86 - 9.02 (m, 2 H) 4.87 - 4.99 (m, 1 H) 4.43 - 4.54 (m, 1 H) 4.02 - 4.21 (m, 1 H) 3.58 - 3.66 (m, 1 H) 3.39 - 3.46 (m, 1 H) 3.35 (t, J=5.6 Hz, 2 H) 3.29 - 3.29 (m, 1 H) 3.22 (s, 3 H) 3.15 - 3.18 (m, 3 H) 3.04 - 3.12 (m, 3 H) 2.35 - 2.42 (m, 1 H) 2.25 - 2.34 (m, 1 H) 1.23 - 1.27 (m, 3 H) 1.04 - 1.16 (m, 3 H). LCMS-ESI (pos.) m/z: 501.2 (M+H) ⁺ .

I (lR,2S)-l-(5-cMoropyrimidin-2- yl)-l -methoxypropane-2- sulfonamide (Example 29.3), 5-1- HO ^'

isothiocyariatocyclopropane

OMe

(commercially available from

Sigma- Aldrich), and 3- OR

hydroxycyclobutanecarbohydrazid

e (material was prepared in an

analogous manner to that of

Example 42.2 employing ethyl 3- hydroxycyclobutanecarboxylate

(commercially available from

Synthonix)). (lR,2S)-l-(5-chloro-2-pyrimidinyl)-N-(4-cyclopropyl-5- (trans-3 -(hydro xymethyl)cyclobutyl)-4H- l,2,4-triazol-3 - yl)-l-methoxy-2-propanesulfonamide or (lR,2S)-l-(5- chloro-2-pyrimidinyl)-N-(4-cyclopropyl-5-(cis-3- (hydroxymethyl)cyclobutyl)-4H-l,2,4-triazol-3-yl)-l- methoxy -2 -propanesulf onamide .

¾ NMR (500 MHz, CDC1 ₃ ) δ 10.22 - 11.14 (m, 1 H) 8.63 - 8.84 (m, 2 H) 4.99 - 5.11 (m, 1 H) 3.76 - 3.81 (m, 2 H) 3.68 - 3.75 (m, 1 H) 3.60 - 3.68 (m, 1 H) 3.32 (s, 3 H) 2.73 (br s, 2 H) 2.43 - 2.55 (m, 2 H) 2.26 - 2.39 (m, 2 H) 1.42 - 1.46 (m, 3 H) 0.99 - 1.17 (m, 4 H). LCMS-ESI (pos.) m/z: 457.2 (M+H) ⁺ .

hydroxycyclobutanecarboxylate ° _Me (commercially available from (lR,2S)-l-(5-chloro-2-pyrimidinyl)-N-(5-(trans-3- Synthonix)). (hydroxymethyl)cyclobutyl)-4-(2-propanyl)-4H- 1 ,2,4- triazol-3-yl)-l-methoxy-2-propanesulfonamide or (1R,2S)- l-(5-chloro-2-pyrimidinyl)-N-(5-(cis-3- (hydroxymethyl)cyclobutyl)-4-(2-propanyl)-4H- 1 ,2,4- triazol-3-yl)-l-methoxy-2-propanesulfonamide.

¾ NMR (500 MHz, CDC1 ₃ ) δ 10.53 - 10.88 (m, 1 H) 8.74 (s, 2 H) 5.02 - 5.12 (m, 1 H) 4.18 - 4.35 (m, 1 H) 3.78 (d, .7=6.1 Hz, 2 H) 3.69 - 3.75 (m, 1 H) 3.51 (s, 4 H) 3.36 (s, 3 H) 2.58 - 2.71 (m, 1 H) 2.45 - 2.56 (m, 2 H) 2.24 - 2.35 (m, 2 H) 1.54 - 1.56 (m, 3 H) 1.42 (d, .7=7.0 Hz, 3 H). LCMS-ESI (pos.) m/z: 459.2 (M+H) ⁺ .

( 1R,2 S) - 1 -(5 -chloropyrimidin-2- yl)- 1 -methoxypropane-2- sulfonamide (Example 29.3), 5-1- 2-isothiocyanatopropane -N ^{0 0} £ _M e

(commercially available from

Sigma- Aldrich), and 3- OR

(hydroxymefhyl)cyclobutane-l- carbohydrazide (material was

prepared in an analogous manner

to that of Example 42.2 employing

ethyl 3-

hydroxycyclobutanecarboxylate

(commercially available from (lR,2S)-l-(5-chloro-2-pyrimidinyl)-N-(5-(trans-3- Synthonix)). (hydroxymethyl)cyclobutyl)-4-(2-propanyl)-4H- 1 ,2,4- triazol-3-yl)-l-methoxy-2-propanesulfonamide or (1R,2S)- l-(5-chloro-2-pyrimidinyl)-N-(5-(cis-3- (hydroxymethyl)cyclobutyl)-4-(2-propanyl)-4H- 1 ,2,4- triazol-3-yl)-l-methoxy-2-propanesulfonamide.

¾ NMR (500 MHz, CDC1 ₃ ) δ 10.49 - 10.92 (m, 1 H) 8.64 - 8.85 (m, 2 H) 4.89 - 5.17 (m, 1 H) 4.28 - 4.37 (m, 1 H) 3.68 - 3.75 (m, 1 H) 3.63 - 3.68 (m, 2 H) 3.50 - 3.52 (m, 3 H) 3.33 - 3.43 (m, 4 H) 2.60 - 2.71 (m, 1 H) 2.43 - 2.53 (m, 2 H) 2.17 - 2.30 (m, 2 H) 1.55 - 1.57 (m, 3 H) 1.40 - ( 1R,2 S) - 1 -(5 -chloropyrimidin-2- yl)-l -methoxypropane-2- sulfonamide (Example 29.3), 5- CI isothiocyanato-4,6- F

dimethoxypyrimidine (Example

28.1), and (ls,4s)-4- OMe

(difluoromethy l)cy clohexane- 1 -

OR

carbohydrazide and (lr,4r)-4-

(difluoromethy l)cy clohexane- 1 - carbohydrazide (Example 145.1)

(lR,2S)-l-(5-chloro-2-pyrimidinyl)-N-(5-(cis-4-

(difluoromethyl)cyclohexyl)-4-(4,6-dimethoxy-5- pyrimidinyl)-4H- 1 ,2,4-triazol-3 -yl)- l-methoxy-2- propanesulfonamide or (lR,2S)-l-(5-chloro-2- pyrimidinyl)-N-(5-(trans-4-(difluoromethyl)cyclohexyl)-4- (4,6-dimethoxy-5-pyrimidinyl)-4H-l,2,4-triazol-3-yl)-l- methoxy -2 -propanesulf onamide .

¾ NMR (500 MHz, DMSO-c*) δ 12.87 - 13.06 (m, 1 H) 8.93 (s, 2 H) 8.70 (s, 1 H) 5.80 (d, .7=4.2 Hz, 1 H) 4.77 (d, .7=4.0 Hz, 1 H) 3.96 (m, 6 H) 3.34 - 3.41 (m, 1 H) 3.12 (s, 3 H) 2.23 - 2.32 (m, 1 H) 1.71 - 1.83 (m, 5 H) 1.39 - 1.51 (m, 2 H) 1.12 (m, 5 H). LCMS-ESI (pos.) m/z: 603.0 (M+H) ⁺ .

dimethoxypyrimidin-5-yl)-4H- 1 ,2,4-triazol-3 -yl)-l - methoxypropane-2-sulfonamide and (lR,2S)-l-(5- cliloropyrimidin-2-yl)-N-(5-((lR,2R)-2- (difluoromethyl)cyclobutyl)-4-(4,6-dimethoxypyrimidin- 5-yl)-4H-l,2,4-triazol-3-yl)-l-methoxypropane-2- sulfonamide and (lR,2S)-l-(5-cWoropyrimidin-2-yl)-N- (5-((lS,2S)-2-(difluoromethyl)cyclobutyl)-4-(4,6- dimethoxypyrimidin-5-yl)-4H- 1 ,2,4-triazol-3 -yl)-l - methoxy propane -2 -sulfonamide .

¾ NMR (500 MHz, DMSO-c¾) δ 12.98 - 13.14 (m, 1 H) 8.91 - 9.00 (m, 2 H) 8.66 - 8.74 (m, 1 H) 6.02 (d, .7=4.4 Hz, 1 H) 4.72 - 4.88 (m, 1 H) 3.94 (m, 6 H) 3.39 (br d, .7=7.0 Hz, 1 H) 3.15 - 3.22 (m, 1 H) 3.13 (d, .7=4.4 Hz, 3 H) 3.00 - 3.11 (m, 1 H) 1.99 (s, 3 H) 1.83 - 1.95 (m, 1 H) 1.13 (d, .7=7.0 Hz, 3 H). LCMS-ESI (pos.) m/z: 575.0 (M+H) ⁺ .

( 1R,2 S) - 1 -(5 -chloropyrimidin-2- yl)-l -methoxypropane-2- sulfonamide (Example 29.3), Jfl

isothiocy anato- 1 ,3 - dimethoxybenzene (Example

28.0), and 3,3- -N ⁰ ° <?)Me

difluorocyclobutane-1-

( 1R,2S)- 1 -(5-cMoro-2-pyrimidinyl)-N-(5-(3 ,3- carbohydrazide (Example 147.1).

difluorocyclobutyl)-4-(2,6-dimethoxyphenyl)-4H- 1 ,2,4- triazol-3-yl)-l-methoxy-2-propanesulfonamide.

¾ NMR (500 MHz, DMSO-c¾) δ 12.74 - 13.05 (m, 1 H) 8.83 - 8.96 (m, 2 H) 7.39 - 7.65 (m, 1 H) 6.69 - 7.02 (m, 2 H) 4.68 - 4.85 (m, 1 H) 3.72 - 3.79 (m, 6 H) 3.36 - 3.45 (m, 1 H) 3.11 - 3.17 (m, 3 H) 2.89 - 3.00 (m, 1 H) 2.68 - 2.81 (m, 4 H) 1.10 - 1.16 (m, 3 H). LCMS-ESI (pos.) m/z: 559.0 (M+H) ⁺ .

(pos.)m/z: 541.0 (M+H) ⁺ .

(pos.)m/z: 553.2 (M+H) ⁺ .

H). LCMS-ESI (pos.) m/z: 559.2 (M+H) ⁺ .

I (lR,2S)-l-(5-cMoropyrimidin-2- yl)-l -methoxypropane-2- sulfonamide (Example 29.3),

isothiocy anato- 1 ,3 - dimethoxybenzene (Example

28.0), and (S)-2,2- OMe

difluorocyclobutane-1- OR

carbohydrazide and (R)-2,2- difluorocyclobutane-1- carbohydrazide (Example 159.1).

The sample was purified by Chiral

SFC: Column: Chiralpak AD-H

2x25 cm + Chiralpak AD-H 2x25

using 35% MeOH, 40 niL/min,

(lR,2S)-l-(5-chloropyrimidin-2-yl)-N-(5-((R)-2,2- Wavelength: 215 nm.

difluorocyclobutyl)-4-(2,6-dimethoxyphenyl)-4H- 1 ,2,4-

Under these conditions, this was triazol-3-yl)-l-methoxypropane-2 -sulfonamide or (1R,2S)- the second peak to elute. l-(5-chloropyrimidin-2-yl)-N-(5-((S)-2,2- difluorocyclobutyl)-4-(2,6-dimethoxyphenyl)-4H- 1 ,2,4- triazol-3 -yl)-l -methoxypropane-2-sulfonamide.

¾ NMR (400 MHz, CDC1 ₃ ) δ 8.64 - 8.72 (m, 2 H) 7.33 - 7.45 (m, 1 H) 6.56 - 6.68 (m, 2 H) 4.93 - 5.01 (m, 1 H) 3.76 - 3.81 (m, 3 H) 3.73 - 3.76 (m, 3 H) 3.64 - 3.73 (m, 1 H) 3.50 (br d, J=2.4 Hz, 1 H) 3.32 (s, 3 H) 2.39 - 2.60 (m, 3 H) 2.01 - 2.13 (m, 1 H) 1.31 - 1.39 (m, 3 H). LCMS-ESI (pos.) m/z: 559.2 (M+H) ⁺ .

pos. mz: . + .

- pos. mz: . + .

I (lR,2S)-l-(5-cMoropyrimidin-2- yl)-l -methoxypropane-2- sulfonamide (Example 29.3), 5- isothiocyanato-4,6- dimethoxypyrimidine (Example

28.1), and (ls,3s)-3- N-N OMe

clilorocy clobutane- 1 - carbohydrazide and (lr,3r)-3- OR

clilorocy clobutane- 1 - carbohydrazide (Example 153.1).

( 1R,2S)- 1 -(5-cMoropyrimidin-2-yl)-N-(4-(4,6- dimethoxypyrimidin-5-yl)-5-((ls,3R)-3-clilorocyclobutyl)- 4H- 1 ,2,4-triazol-3 -yl)- l-methoxypropane-2-sulfonamide or (lR,2S)-l-(5-cMoropyrimidin-2-yl)-N-(4-(4,6- dimethoxypyrimidin-5-yl)-5-((lr,3S)-3-clilorocyclobutyl)- 4H- 1 ,2,4-triazol-3 -yl)- 1 -methoxypropane-2-sulfonamide.

¾ NMR (500 MHz, DMSO-c¾) δ 12.97 - 13.16 (m, 1 H) 8.85 - 9.03 (m, 2 H) 8.64 - 8.85 (m, 1 H) 4.70 - 4.82 (m, 1 H) 4.56 - 4.70 (m, 1 H) 3.95 (m, 6 H) 3.36 - 3.51 (m, 2 H) 3.12 - 3.16 (m, 3 H) 2.74 - 2.82 (m, 2 H) 2.43 - 2.48 (m, 2 H) 1.08 - 1.16 (m, 3 H). LCMS-ESI (pos.) m/z: 559.0 (M+H) ⁺ .

I (2S,3R)-3-(5-cMoropyrimidin-2- y l)butane -2 -sulfonamide

(Example 27.4), 5-isothiocyanato- 4,6-dimethoxypyrimidine

(Example 28.1), and 2- (difluoromethyl)cyclobutanecarboh

ydrazide (Example 146.1).

(2S,3R)-3-(5-cMoropyrimidin-2-yl)-N-(5-((lR,2S)-2- (difluoromethyl)cyclobutyl)-4-(4,6-dimethoxypyrimidin- 5-yl)-4H-l,2,4-triazol-3-yl)butane-2-sulfonamide and (2S,3R)-3-(5-cMoropyrimidin-2-yl)-N-(5-((lS,2R)-2- (difluoromethyl)cyclobutyl)-4-(4,6-dimethoxypyrimidin- 5-yl)-4H-l,2,4-triazol-3-yl)butane-2-sulfonamide and (2S,3R)-3-(5-cMoropyrimidin-2-yl)-N-(5-((lR,2R)-2- (difluoromethyl)cyclobutyl)-4-(4,6-dimethoxypyrimidin- 5-yl)-4H-l,2,4-triazol-3-yl)butane-2-sulfonamide and

(pos.) m/z: 603.1 (M+H) ⁺ . ( 1R,2 S) - 1 -(5 -chloropyrimidin-2- yl)-l -methoxypropane-2- sulfonamide (Example 29.3), CI isothiocy anato- 1 ,3 - dimethoxybenzene (Example

28.0), and 2-cyanocyclobutane-l- carbohydrazide (Example 169.1). OR

The sample was purified by Chiral

SFC Chiralpak AS-H 2x25 cm.

Mobile Phase: 25% MeOH, Flow

rate: 80 mL/min, Pressure Drop:

92 bar, BPR: 100 bar, UV Detector

Wavelength: 215 nm. Under these

conditions, this was the first peak

( 1R,2S)- 1 -(5-chloropyrimidin-2-yl)-N-(5-(( lR,2S)-2- to elute.

cyanocyclobutyl)-4-(2,6-dimethoxyphenyl)-4H-l,2,4- triazol-3-yl)-l-methoxypropane-2 -sulfonamide or (1R,2S)- l-(5-chloropyrimidin-2-yl)-N-(5-((lS,2R)-2- cyanocyclobutyl)-4-(2,6-dimethoxyphenyl)-4H-l,2,4- triazol-3 -yl)-l -methoxypropane-2-sulfonamide.

¾ NMR (500 MHz, CDC1 ₃ ) δ 10.82 - 11.12 (m, 1 H) 8.71 (s, 2 H) 7.41 - 7.49 (m, 1 H) 6.68 (dd, .7=17.5, 8.6 Hz, 2 H) 4.92 - 4.96 (m, 1 H) 3.78 - 3.87 (m, 6 H) 3.66 - 3.76 (m, 1 H) 3.36 - 3.41 (m, 2 H) 3.29 - 3.34 (m, 3 H) 2.45 - 2.60 (m, 1 H) 2.26 - 2.42 (m, 2 H) 2.07 - 2.23 (m, 1 H) 1.36 (d, .7=7.0 Hz, 3 H). LCMS-ESI (pos.) m/z: 548.2 (M+H) ⁺ .

I (lR,2S)-l-(5-cMoropyrimidin-2- yl)-l -methoxypropane-2- sulfonamide (Example 29.3),

isothiocy anato- 1 ,3 - dimethoxybenzene (Example

28.0), and 2-cyanocyclobutane-l- carbohydrazide (Example 169.1).

The sample was purified by Chiral

SFC Chiralpak AS-H 2x25 cm.

Mobile Phase: 25% MeOH,

Flowrate: 80 mL/min, Pressure

Drop: 92 bar, BPR: 100 bar

UV Detector Wavelength: 215 nm.

Under these conditions, this was ( 1R,2S)- 1 -(5-chloropyrimidin-2-yl)-N-(5-(( lR,2R)-2- the second peak to elute. cyanocyclobutyl)-4-(2,6-dimethoxyphenyl)-4H-l,2,4- triazol-3-yl)-l-methoxypropane-2 -sulfonamide or (1R,2S)- l-(5-chloropyrimidin-2-yl)-N-(5-((lR,2R)-2- cyanocyclobutyl)-4-(2,6-dimethoxyphenyl)-4H-l,2,4- triazol-3 -yl)-l -methoxypropane-2-sulfonamide.

¾ NMR (500 MHz, CDC1 ₃ ) δ 10.76 - 11.12 (m, 1 H) 8.57 - 8.95 (m, 2 H) 7.34 - 7.71 (m, 1 H) 6.67 (dd, .7=12.3, 8.5 Hz, 2 H) 4.80 - 5.09 (m, 1 H) 3.83 - 3.89 (m, 3 H) 3.78 - 3.83 (m, 3 H) 3.67 - 3.73 (m, 1 H) 3.36 - 3.43 (m, 2 H) 3.34 (s, 3 H) 2.51 (br d, .7=9.7 Hz, 1 H) 2.26 - 2.43 (m, 2 H) 2.10 - 2.23 (m, 1 H) 1.36 (d, .7=6.9 Hz, 3 H). LCMS- ESI (pos.) m/z: 548.2 (M+H) ⁺ .

( 1R,2 S) - 1 -(5 -cMoropyrimidin-2-

N^N

yl)-l -methoxypropane-2- sulfonamide (Example 29.3), 5- isothiocyanato-4,6- dimethoxypyrimidine (Example

28.1), and (ls,4s)-4- -N ⁰ ° (*,Me fluorocyclohexane-1-

OR

carbohydrazide and (lr,4r)-4- fluorocyclohexane-1- carbohydrazide (Example 175.1).

( 1R,2S)- 1 -(5-cMoropyrimidin-2-yl)-N-(4-(4,6- dimethoxypyrimidin-5-yl)-5-((ls,4R)-4-fluorocyclohexyl)-

4H- 1 ,2,4-triazol-3 -yl)- l-methoxypropane-2-sulfonamide or (lR,2S)-l-(5-cliloropyrimidin-2-yl)-N-(4-(4,6- dimethoxypyrimidin-5-yl)-5-((lr,4S)-4-fluorocyclohexyl)-

4H- 1 ,2,4-triazol-3 -yl)- 1 -methoxypropane-2-sulfonamide.

¾ NMR (500 MHz, DMSO-c¾) δ 8.88 - 9.05 (m, 2 H)

8.63 - 8.80 (m, 1 H) 4.77 (d, .7=4.0 Hz, 1 H) 4.37 - 4.71

(m, 1 H) 3.89 - 4.04 (m, 6 H) 3.36 - 3.44 (m, 1 H) 3.12 (s,

3 H) 2.31 - 2.39 (m, 1 H) 1.99 (br d, .7=3.9 Hz, 2 H) 1.73 -

1.83 (m, 2 H) 1.47 (br s, 4 H) 1.11 (d, .7=7.0 Hz, 3 H)

LCMS-ESI (pos.) m/z: 571.0 (M+H) ⁺ .

( 1R,2 S) - 1 -(5 -chloropyrimidin-2- yl)-l -methoxypropane-2- sulfonamide (Example 29.3), 5- Cl isothiocyanato-4,6- dimethoxypyrimidine (Example

28.1), and 2-fluorocyclobutane-l- carbohydrazide (Example 179.1).

OR

The sample was purified by Chiral

SFC Chiralcel OX-H 2x25 cm,

Mobile Phase: 40% IP A, Flowrate:

80 niL/min, Pressure Drop: 98

bar, BPR: 100 bar, UV Detector

Wavelength: 218 nm. Under these

conditions, this was the first peak

to elute.

( 1R,2S)- 1 -(5-chloropyrimidin-2-yl)-N-(4-(4,6- dimethoxypyrimidin-5-yl)-5-((lR,2S)-2-fluorocyclobutyl)- 4H- 1 ,2,4-triazol-3 -yl)- l-methoxypropane-2-sulfonamide or (lR,2S)-l-(5-chloropyrimidin-2-yl)-N-(4-(4,6- dimethoxypyrimidin-5-yl)-5-((lS,2R)-2-fluorocyclobutyl)- 4H- 1 ,2,4-triazol-3 -yl)- 1 -methoxypropane-2-sulfonamide.

¾ NMR (500 MHz, DMSO-c¾) δ 12.96 - 13.24 (m, 1 H) 8.82 - 9.00 (m, 2 H) 8.68 (s, 1 H) 4.87 - 5.06 (m, 1 H) 4.77 (d, .7=4.2 Hz, 1 H) 3.94 (m, 6 H) 3.33 - 3.45 (m, 2 H) 3.13 (s, 3 H) 2.15 - 2.28 (m, 1 H) 1.86 - 2.11 (m, 2 H) 1.58 - 1.71 (m, 1 H) 1.14 (d, .7=7.0 Hz, 3 H). LCMS-ESI (pos.) m/z: 543.0 (M+H) ⁺ .

( 1R,2 S) - 1 -(5 -chloropyrimidin-2- yl)-l -methoxypropane-2- sulfonamide (Example 29.3), 5- CI isothiocyanato-4,6- dimethoxypyrimidine, (Example

28.1), and 2-fluorocyclobutane-l- F OMe

carbohydrazide (Example 179.1).

OR

The sample was purified by Chiral

SFC Chiralcel OX-H 2x25 cm,

Mobile Phase: 40% IP A, Flowrate:

80 niL/min, Pressure Drop: 98

bar, BPR: 100 bar, UV Detector

Wavelength: 218 nm. Under these

conditions, this was the second

peak to elute.

( 1R,2S)- 1 -(5-chloropyrimidin-2-yl)-N-(4-(4,6- dimethoxypyrimidin-5-yl)-5-((lR,2S)-2-fluorocyclobutyl)- 4H- 1 ,2,4-triazol-3 -yl)- l-methoxypropane-2-sulfonamide or (lR,2S)-l-(5-chloropyrimidin-2-yl)-N-(4-(4,6- dimethoxypyrimidin-5-yl)-5-((lS,2R)-2-fluorocyclobutyl)- 4H- 1 ,2,4-triazol-3 -yl)- 1 -methoxypropane-2-sulfonamide.

¾ NMR (500 MHz, DMSO-c¾) δ 12.99 - 13.16 (m, 1 H) 8.83 - 8.99 (m, 2 H) 8.56 - 8.73 (m, 1 H) 4.83 - 5.10 (m, 1 H) 4.66 - 4.83 (m, 1 H) 3.96 (s, 3 H) 3.93 (s, 3 H) 3.32 - 3.46 (m, 2 H) 3.13 (s, 3 H) 2.16 - 2.27 (m, 1 H) 1.88 - 2.13 (m, 2 H) 1.58 - 1.74 (m, 1 H) 1.14 (d, .7=7.0 Hz, 3 H). LCMS-ESI (pos.) m/z: 543.0 (M+H) ⁺ .

LCMS-ESI (pos.) m/z: 539.1 (M+H) ⁺ .

LCMS-ESI (pos.) m/z: 537.2 (M+H) ⁺ .

LCMS-ESI (pos.) m/z: 537.2 (M+H) ⁺ .

(pos.)m/z: 521.2 (M+H) .

5-yl)-4H-l,2,4-triazol-3-yl)-l-methoxy-l-(5- 1.70 - 1.83 (m, 1 H) 1.10 - 1.15 (m, 3 H). LCMS-ESI

(pos.) m/z: 553.2 (M+H) ⁺ .

[0391] Example 209.2. Preparation of (lR,2S)-l-(2,2-difluoroethoxy)-l-(5- methylpyrimidin-2-yl)propane-2-sulfonamide.

209.11

[0392] N-Methoxy-N,5-dimethylpyrimidine-2-carboxamide, Example

209.1. To a solution of 5-methylpyrimidine-2-carboxylic acid (1 g, 7.24 mmol) in DMF (72.4 mL) was added 5-methylpyrimidine-2-carboxylic acid (1 g, 7.24mmol), and Ν,Ο- dimethylhydroxylamine hydrochloride (0.777 g, 7.96 mmol). The mixture was cooled to 0 °C and 1-propanephosphonic acid cyclic anhydride, 50 wt. % solution in EtOAc (9.21 mL, 14.48 mmol) was added dropwise. The mixture was allowed to warm to RT overnight. LCMS indicated complete conversion to product. The mixture was diluted with water, extracted with CHCl3:IPA (3: 1) and washed with brine and NaHC03. The mixture was then dried over Na2S04, concentrated in vacuo and purified by silica gel chromatography (0-100% heptane s:EtO Ac) to yield Example 209.11 (0.7 g, 3.86 mmol, 53.4 % yield). ¾ NMR (500 MHz, CDC1 ₃ ) δ 8.61 - 8.69 (m, 2 H) 3.61 - 3.79 (m, 3 H) 3.27 - 3.47 (m, 3 H) 2.34 - 2.45 (m, 3 H). LCMS-ESI (pos) m/z: 182.2 (M+H) ⁺ .

31.2

[0393] (R)-N,N-Bis(4-methoxybenzyl)-l-(5-methylpyrimidin-2-yl)-l- oxopropane-2-sulfonamide and (S)-N,N-bis(4-methoxybenzyl)-l-(5- methylpyrimidin-2-yl)-l-oxopropane-2-sulfonamide, Example 31.2. A solution of N,N-bis(4-methoxybenzyl)ethanesulfonamide (azeotroped three times with toluene before use) (Example 30.0, 0.771 g, 2.21 mmol) was dissolved in THF (3.68 mL) and then cooled to -78 °C using a dry ice acetone bath (internal reaction temperature/bath temperature not monitored). To this was added a solution of n-butyllithium (0.883 mL, 2.21 mmol, 2.5 M in hexanes). The reaction turned pink immediately and then slowly faded to yellow upon stirring at -78 °C for 30 mins. This solution was then added quickly to a solution of N-methoxy-N,5-dimethylpyrimidine-2-carboxamide (Example 209.11, 0.2 g, 1.104 mmol) in THF (0.5 mL) at RT. The reaction was stirred at RT for ~20 mins after which LCMS indicated complete consumption of Weinreb amide and conversion to product. The reaction was quenched by addition to separation funnel that contained 1M HC1 (~15 mL). The mixture was extracted with DCM, dried over Na2S04 and concentrated in vacuo. The mixture was purified by silica gel chromatography 0-100% EtOAc:heptanes to yield Example 31.2 (0.36 g, 0.767 mmol, 69.5 % yield). ¾ NMR (500 MHz, DMSO-d ₆ ) δ 8.86 - 8.93 (m, 2 H) 7.06 - 7.15 (m, 4 H) 6.79 - 6.87 (m, 4 H) 5.87 - 5.95 (m, 1 H) 4.20 - 4.34 (m, 4 H) 3.67 - 3.73 (m, 6 H) 2.38 - 2.42 (m, 3 H) 1.46 - +.

31.2 209.12

[0394] (lR,2S)-l-Hydroxy-N,N-bis(4-methoxybenzyl)-l-(5- methylpyrimidin-2-yl)propane-2-sulfonamide, Example 209.12. To a solution of Example 31.2 (1.0 g, 2.130 mmol) in DMF (22.18 mL) was added (N-((1S,2S)-1,2- diphenyl-2-((3-phenylpropyl)amino)ethyl)-4-methylphenylsulfo namido)ruthenium(II) chloride (9.91 mg, 0.016 mmol). The mixture was then degassed by placing under vacuum and backfilling with N ₂ three times. To this was added a solution of HCOOH:Et ₃ N (5:2 v/v) (0.55mL), and the reaction was stirred at RT for 12 hrs after which LCMS indicated complete conversion to product and 7: 1 d.r. (syn:anti). The mixture was then washed with 5% LiCl (aq), extracted with DCM and then with CHC1 ₃ :IPA (3: 1). The organic layer was dried over Na2S04 and concentrated in vacuo. The mixture was loaded directly onto a silica gel column and purified using a gradient of 0-100% heptane s:EtO Ac. DMF caused both syn and anti to co-elute. The factions were combined and concentrated in vacuo. The mixture was repurified using the same gradient to yield (lR,2S)-l-hydroxy-N,N-bis(4-methoxybenzyl)-l-(5-methylpyrimi din-2- yl)propane-2-sulfonamide (0.77 g, 1.63 mmol, 77 % yield) as an off white solid. ¾ NMR (500 MHz, DMSO-d ₆ ) δ 8.85 - 8.93 (m, 2 H) 7.08 - 7.15 (m, 4 H) 6.78 - 6.86 (m, 4 H) 5.86 - 5.96 (m, 1 H) 4.20 - 4.35 (m, 4 H) 3.68 - 3.75 (m, 6 H) 3.28 - 3.34 (m, 2 H) 2.37 - 2.42 (m, 3 H) 1.47 - 1.54 (m, 3 H). LCMS-ESI (pos) m/z: 572.2 (M+H) ⁺ .

209.1

[0395] (lR,2S)-l-(2,2-Difluoroethoxy)-N,N-bis(4-methoxybenzyl)-l-(5 - methylpyrimidin-2-yl)propane-2-sulfonamide, Example 209.1. A solution of

Example 209.12 (0.5g, 1.06 mmol) in THF (5.30 mL) was cooled to -78 °C. To this was added potassium bis(trimethylsilyl)amide solution, (1M in THF, 1.27 mL, 1.27 mmol) dropwise, and the reaction was stirred at -78 °C for 15 mins. 2,2-Difluoroethyl trifluoromethane sulfonate (0.056 mL, 0.42 mmol) was added to the mixture dropwise. The reaction was then stirred for another 15 mins at -78 °C after which LCMS indicated complete conversion to product. The mixture was poured onto a solution of NH ₄ C1 and extracted with DCM, dried over Na2S04 and concentrated in vacuo. The material was purified by silica gel 0-75% EtOAc:Heptanes to yield Example 209.1 (0.4 g, 0.75 mmol, 70 % yield). LCMS-ESI (pos.) m/z: 472.2 (M+H) ⁺ .

209.2

[0396] (lR,2S)-l-(2,2-Difluoroethoxy)-l-(5-methylpyrimidin-2-yl)pro pane- 2- sulfonamide, Example 209.2. To a solution of Example 209.1 (0.8 g, 1.494 mmol) in DCM (7.47 mL) was added anisole (0.808 mL, 7.47 mmol), and the mixture was cooled to 0 °C. To this was added 1,1,1-trifluoroacetic acid (2.226 mL, 29.9 mmol), and the mixture was allowed to warm to RT and stirred at RT for 24 h. LCMS indicated incomplete conversion to product and so a second portion of TFA was added and the mixture stirred for a further 12 h after which the reaction didn't progress any further. The mixture was quenched by addition to an aqueous solution of NaHCC and extracted with DCM, dried over Na2S04 and concentrated in vacuo. The mixture was purified using a gradient of 0-100 Heptanes:EtOAc. to yield Example 209.2 (0.4 g, 1.36 mmol, 91 % yield). LCMS-ESI (pos.) m/z: 296.0 (M+H) ⁺ .

[0397] Example 161.0. Preparation of (lR,2S)-l-(5-chloropyrimidin-2-yl)-

N-(4-(4,6-dimethoxypyrimidin-5-yl)-5-((ls,4R)-4-methoxycy clohexyl)-4H-l,2,4- triazol-3-yl)-l -methoxypropane-2-sulf onamide or (1 R,2S)-1 -(5-chloropyrimidin-2- yl)-N-(4-(4,6-dimethoxypyrimidin-5-yl)-5-((lr,4S)-4-methoxyc yclohexyl)-4H-l,2,4- triazol-3-yl)-l-methoxypropane-2-sulfonamide.

161.1

[0398] (Z)-N-(((lR,2S)-l-(5-Chloropyrimidin-2-yl)-l-methoxypropan-2 - yl)sulfonyl)-N'-(2,6-dimethoxyphenyl)hydrazinecarboximidamid e, Example 161.1. To a solution of Example 29.3 (0.30 g, 1.13 mmol), in ACN (11.29 mL) was added 2- isothiocyanato-l,3-dimethoxybenzene (0.22 g, 1.13 mmol) followed by cesium carbonate (0.48 mL, 1.47 mmol). The mixture was then stirred at RT for 12 h. LCMS indicated complete loss of starting material. To the reaction was added 2,2- hydrazine hydrate (0.057 g, 1.13 mmol) followed by silver nitrate (0.088 mL, 2.26 mmol). The mixture was stirred at RT for 15 mins. LCMS indicated conversion to product. The mixture was loaded directly onto silica gel and purified by chromatography 0-100 heptanes- EtOAc:EtOH (3: 1) to yield Example 161.1 (0.5 g, 1.09 mmol, 97 % yield) as a white solid. LCMS-ESI (po ⁺ .

161.2

[0399] (Z)-N-(((lR,2S)-l-(5-Chloropyrimidin-2-yl)-l-methoxypropan-2 - yl)sulfonyl)-N'-(4,6-dimethoxypyrimidin-5-yl)hydrazinecarbox imidamide, Example 161.2. To a vial containing Example 29.3 (2 g, 7.53 mmol) was added ACN (75 mL). After 10 minutes, 5-isothiocyanato-4,6-dimethoxypyrimidine (1.48 g, 7.53 mmol) was added carefully in portions. The mixture was cooled in an ice-bath and then cesium carbonate (4.90 g, 15.05 mmol) was added carefully in portions to the homogeneous solution. Upon complete addition of cesium carbonate, the mixture was allowed to warm to 23 °C and monitored with LC-MS. After 12 h, complete loss of starting material was observed. After 20 mins, hydrazine, monohydrate (0.45 mL, 5.75 mmol) and then silver nitrate (2.56 g, 15.05 mmol) were carefully added in portions. The mixture was allowed to warm to 23 °C and monitored with LC-MS. After 30 mins. conversion to product was observed by LCMS. The mixture was loaded directly onto silica and purified with a gradient of 0-100% EtOH:EtOAc (3: 1) in heptanes to yield Example 161.2 (1.58 g, 3.43 mmol, 46 % yield). LCMS-ESI (pos.) m/z: 461.0 (M+H) ⁺ .

[0400] The compounds set forth in the following table were synthesized following the procedures described in Example 214.0 using the known starting material as described.

Table 17

(pos.)mz: 621.0 (M+H) .

spiro[2.3]hexane-5-carboxylic acid (commercially available from

Enamine).

(lR,2S)-l-(5-cMoro-2-pyrimidinyl)-N-(4-(4,6- dimethoxy-5 -pyrimidinyl)-5 -(spiro [2.3] hexan-5 -y 1)-4H- 1 ,2,4-triazol-3-yl)- 1 -methoxy-2-propanesulfonamide.

¾ NMR (500 MHz, DMSO-c¾) δ 12.84 - 13.04 (m, 1 H) 8.89 - 9.03 (m, 2 H) 8.60 - 8.82 (m, 1 H) 4.70 - 4.86 (m, 1 H) 3.94 (m, 6 H) 3.37 - 3.45 (m, 1 H) 3.31 - 3.37 (m, 1 H) 3.09 - 3.19 (m, 3 H) 2.38 - 2.44 (m, 2 H) 2.06 - 2.15 (m, 2 H) 1.12 - 1.15 (m, 3 H) 0.38 - 0.48 (m, 2 H) 0.29 - 0.38 (m, 2 H). LCMS-ESI (pos.) m/z: 551.2 (M+H) ⁺ .

(Z)-N-(((lR,2S)-l-(5- N^N

cliloropyrimidin-2-yl)- 1 - mefhoxypropan-2-yl)sulfonyl)-N'-

(4,6-dimethoxypyrimidin-5- yl)hydrazinecarboximidamide

(Example 161.2), N-N ⁰ ° i _M e spiro [3.3 ] heptane-2-carboxy lie

acid (commercially available from (lR,2S)-l-(5-cMoro-2-pyrimidinyl)-N-(4-(4,6-

Enamine). dimethoxy-5-pyrimidinyl)-5-(spiro[3.3]heptan-2-yl)-4H- 1 ,2,4-triazol-3-yl)- 1 -methoxy-2-propanesulfonamide.

¾ NMR (500 MHz, DMSO-c¾) δ 12.82 - 13.07 (m, 1 H) 8.84 - 9.03 (m, 2 H) 8.63 - 8.84 (m, 1 H) 4.66 - 4.86 (m, 1 H) 3.92 - 3.97 (m, 6 H) 3.36 - 3.44 (m, 1 H) 3.10 - 3.16 (m, 3 H) 3.01 (quin, J=8.4 Hz, 1 H) 2.06 - 2.18 (m, 4 H) 1.92 - 1.98 (m, 2 H) 1.80 - 1.89 (m, 2 H) 1.66 - 1.75 (m, 2 H) 1.10 - 1.14 (m, 3 H). LCMS-ESI (pos.) m/z: 565.2 (M+H) ⁺ .

H). LCMS-ESI (pos.) m/z: 555.2 (M+H) ⁺ .

(pos.)m/z: 565.1 (M+H) ⁺ .

LCMS-ESI (pos.) m/z: 565.1 (M+H) ⁺ .

ESI (pos.) m/z: 587.1 (M+H) ⁺ .

[0401] The compounds set forth in the following table were synthesized following the procedure in Example 42.0 using the known starting material as described.

Table 18

J=5.99 Hz, 3 H) 0.79 (d, J=6.07 Hz, 3 H). LCMS-ESI

(pos.) m/z: 499.2 (M+H) ⁺ .

[0402] Example 210.1. Preparation of 2-(5-chloropyrimidin-2- yl)ethanesulfonamide.

210.11

[0403] 5-Chloro-2-vinylpyrimidine, Example 210.11. To a stirred solution of 2,5-dichloropyrimidine (Combi-blocks, 20 g, 134 mmol, 1.0 equiv) in DMF (200 mL) was added tri-«-butyl(vinyl)stannane (Reddy & Reddy, 42.6 g, 134 mmol, 1.0 equiv) at RT. The reaction mixture was degassed and purged with nitrogen for 5 mins. To the above reaction mixture was added Pd(PPh ₃ ) ₄ (4.65 g, 4.03 mmol, 0.03 equiv), and the mixture was stirred at 100 °C for 16 h. The reaction mixture was cooled to RT, quenched with ice cold water (150 mL) and extracted with diethyl ether (2 x 300 mL). The combined organic layers were washed with brine (200 mL), dried over anhydrous

Na2S04, filtered and concentrated in vacuo to give Example 210.11 (50 g) as a yellow oil. This material was utilized in the next step without further purification. LCMS-ESI (pos.) m/z: 141.3 (M+H) ⁺ .

210.12

[0404] 2-(5-Chloro pyrimidin-2-yl)ethanesulfonic acid sodium salt,

Example 210.12. A solution of Example 210.11 (20 g, 142 mmol, 1.0 equiv) in a saturated aqueous sodium bisulfite solution ((Spectrochem, 80 mL) was stirred at RT for 12 h. The reaction mixture was concentrated in vacuo and the residue was purified by reverse phase flash chromatography (120 g, Redi Sep) eluting with 100% water to give Example 210.12 (17.5 g, 55% yield) as a white solid. ¾ NMR (400 MHz, DMSO-cfe) δ 8.83 (s, 2H), 3.16 (t, J= 8.0 Hz, 2H), 2.85 (t, J= 8.0 Hz, 2H). LCMS-ESI (pos.) m/z: 223.1 (M+H) ⁺ .

210.13

[0405] 2-(5-Chloropyrimidin-2-yl)-N-(4- methoxybenzyl)ethanesulfonamide, Example 210.13. To a stirred solution of Example 210.12 (15.0 g, 67.4 mmol) in DCM (375 mL) were added oxalyl chloride (17.69 mL, 202 mmol) and DMF (0.2 mL, catalytic) at 0 °C. The reaction mixture was stirred at RT for 1 h and concentrated in vacuo. The residue was azeotroped with

cyclopentylmethylether (200 mL) to give the acid chloride (17 g, crude) which was dissolved in DCM (375 mL). 4-Methoxybenzylamine (27.7 g, 202 mmol, 3.0 equiv) and TEA (34.1 g, 337 mmol, 5.0 equiv) were added at 0 °C, and the mixture was stirred at RT for 12 h. The reaction mixture was quenched with water (500 mL) and extracted with DCM (2 x 750 mL). The combined organic layers were washed with brine (500 mL), dried over anhyrous Na ₂ S04, filtered, and concentrated in vacuo. The residue was absorbed onto a plug of silica gel (60-120 mesh) and purified by flash chromatography through a Redi-Sep pre-packed silica gel column (120 g), eluting with a gradient of 55% to 60% EtOAc in hexanes, to give Example 210.13 (7.0 g, 30% yield) as an off-white solid. ¾ NMR (400 MHz, DMSO-cfe): δ 8.86 (s, 2H), 7.69 (t, J = 6.4 Hz, 1H), 7.23 (d, J = 8.4 Hz, 2H), 6.86 (d, J = 8.4 Hz, 2H), 4.08 (d, J = 6.4 Hz, 2H), 3.71 (s, 3H), 3.39 (t, J = 6.8 Hz, 2H), 3.24 (t, J = 6.8 Hz, 2H). LCMS-ESI (pos.) m/z: 342.1 (M+H) ⁺ .

210.1

[0406] Synthesis of 2-(5-chloropyrimidin-2-yl) ethanesulfonamide,

Example 210.1. To a stirred solution of Example 210.13 (16 g, 46.8 mmol, 1.0 equiv) in DCM (300 mL) was added TFA (220 mL, 2856 mmol) at 0 °C, and the mixture was stirred at room temperature for 16 h. The reaction mixture was then concentrated in vacuo. The residue was absorbed onto a plug of silica gel (60-120 mesh) and purified by flash chromatography through a Redi-Sep pre-packed silica gel (120 g) eluting with a gradient of 55% to 70% EtOAc in hexanes to give Example 210.1 (8.0 g, 77% yield) as an off-white solid. ¾ NMR (400 MHz, DMSO-rf ₆ ) δ 8.90 (s, 2H), 6.95 (s, 2H), 3.47 (t, J = 6.8 Hz, 2H), 3.33 (t, J = 6.8 Hz, 2H). LCMS-ESI (pos.) m/z: 222.0 (M+H) ⁺ .

[0407] Example 214.0: Preparation of (lR,2S)-l-(5-chloro-2-pyrimidinyl)-

N-(4-(2,6-dimethoxyphenyl)-5-((lS,3S)-3-methoxycyclopenty l)-4H-l,2,4-triazol-3-yl)- l-methoxy-2-propanesulfonamide or (lR,2S)-l-(5-chloro-2-pyrimidinyl)-N-(4-(2,6- dimethoxyphenyl)-5-((lR,3R)-3-methoxycyclopentyl)-4H-l,2,4-t riazol-3-yl)-l- methoxy-2-propanesulfonamide or (lR,2S)-l-(5-chloro-2-pyrimidinyl)-N-(4-(2,6- dimethoxyphenyl)-5-((lR,3S)-3-methoxycyclopentyl)-4H-l,2,4-t riazol-3-yl)-l- methoxy-2-propanesulfonamide or (lR,2S)-l-(5-chloro-2-pyrimidinyl)-N-(4-(2,6- dimethoxyphenyl)-5-((lS,3R)-3-methoxycyclopentyl)-4H-l,2,4-t riazol-3-yl)-l- methoxy-2-propanesulfonamide.

214.2 [0408] (Z)-N-(((lR,2S)-l-(5-Chloropyrimidin-2-yl)-l-methoxypropan-2 - yl)sulfonyl)-N'-(2,6-dimethoxyphenyl)-2-((lS,3R)-3- methoxycyclopentanecarbonyl)hydrazinecarboximidamide and (Z)-N-(((1R,2S)-1- (5-chloropyrimidin-2-yl)-l-methoxypropan-2-yl)sulfonyl)-N'-( 2,6-dimethoxyphenyl)- 2-((lR,3R)-3-methoxycyclopentanecarbonyl)hydrazinecarboximid amide and (Z)-N- (((lR,2S)-l-(5-chloropyrimidin-2-yl)-l-methoxypropan-2-yl)su lfonyl)-N'-(2,6- dimethoxyphenyl)-2-((l S,3S)-3- methoxycyclopentanecarbonyl)hydrazinecarboximidamide and (Z)-N-(((1R,2S)-1- (5-chloropyrimidin-2-yl)-l-methoxypropan-2-yl)sulfonyl)-N'-( 2,6-dimethoxyphenyl)- 2-((lR,3S)-3-methoxycyclopentanecarbonyl)hydrazinecarboximid amide, Example 214.2. To a vial containing 3-methoxycyclopentane-l-carboxylic acid (commercially available from Enamine, 167.3 mg, 1.16 mmol)) in EtOAc (3 mL) was added diisopropylethylamine (0.3 mL, 1.8 mmol) and then 1-propanephosphonic acid cyclic anhydride, (50 wt. % solution in EtOAc, T3P, 1.1 mL, 1.8 mmol) carefully dropwise at 23 °C. After 30 minutes, Example 161.1 (406 mg, 0.82 mmol) was added in one portion at 23 °C. After 19 h, the reaction was concentrated in vacuo. The residue was then loaded onto a silica gel column (30-60% 3: 1 EtOAc: EtOH in heptane). Fractions containing product were combined and then concentrated in vacuo to afford Example 214.2 (360.2 mg, 0.68 mmol, 89 % yield) as a white foam that was used without further purification.

+.

214.3

[0409] (lR,2S)-l-(5-Chloro-2-pyrimidinyl)-N-(4-(2,6-dimethoxyphenyl )-5- ((1 S,3S)-3-methoxycyclopentyl)-4H-l ,2,4-triazol-3-yl)-l -methoxy-2- propanesulfonamide and (lR,2S)-l-(5-chloro-2-pyrimidinyl)-N-(4-(2,6- dimethoxyphenyl)-5-((lR,3R)-3-methoxycyclopentyl)-4H-l,2,4-t riazol-3-yl)-l- methoxy-2-propanesulfonamide and (lR,2S)-l-(5-chloro-2-pyrimidinyl)-N-(4-(2,6- dimethoxyphenyl)-5-((lR,3S)-3-methoxycyclopentyl)-4H-l,2,4-t riazol-3-yl)-l- methoxy-2-propanesulfonamide and (lR,2S)-l-(5-chloro-2-pyrimidinyl)-N-(4-(2,6- dimethoxyphenyl)-5-((lS,3R)-3-methoxycyclopentyl)-4H-l,2,4-t riazol-3-yl)-l- methoxy-2-propanesulfonamide, Example 214.3. To a vial containing Example 214.2. (293 mg, 0.50 mmol) in IPA (1.3 mL) and water (0.66 mL) was added sodium hydroxide (IN, 0.66 mL, 0.66 mmol) carefully dropwise to the reaction mixture. Upon complete addition, the mixture was heated on a preheated stir plate at 80 °C. After 1.5 h, the reaction was cooled to RT and then diluted with water. The pH was adjusted with dropwise addition of 1 N aqueous citric acid solution to pH~7. The reaction mixture was extracted three times with DCM. The organic layers were combined and then dried over anhydrous magnesium sulfate. After filtration and concentration in vacuo, the residue was loaded onto a silica gel column (40-90% 3: 1 EtOAc: EtOH in heptane). Fractions containing product were combined and then concentrated in vacuo to afford a white foam as Example 214.3. LCMS-ESI (pos.), m/z: 567.2 (M+H) ⁺ .

[0410] The compounds set forth in the following table were synthesized following the procedure in Example 214.3 using the known starting material as described.

Table 19

Example Reagents Structure, Name and Data

-yl)- 1-

1 ,2,4- or -N-(4-(2,6- -yl)- 1- 5-(( 1 S,3R)-3 -methoxycyclopentyl)-4H- 1 ,2,4- triazol-3 -yl)-l -methoxy-2-propanesulfonamide.

¾ NMR (400MHz, CD ₂ C1 ₂ ) δ 10.68 (br s, IH), 8.71 (s, 2H), 7.48 (t, .7=8.5 Hz, IH), 6.72 (d, .7=8.5 Hz, 2H), 4.85 (d, .7=4.6 Hz, IH), 3.88 - 3.83 (m, IH), 3.82 - 3.80 (m, 3H), 3.80 - 3.79 (m, 3H), 3.60 - 3.53 (m, IH), 3.25 (s, 3H), 3.15 (s, 3H), 2.84 (quin, .7=8.3 Hz, IH), 1.96 - 1.72 (m, 5H), 1.66 - 1.61 (m, IH), 1.25 (d, .7=6.8 Hz, 3H). Mass Spectrum (pos.) m/e: 567.0 (M+H) ⁺ . LCMS-ESI (pos.), m/z: 567.0 (M+H) ⁺ .

-yl)- 1- or -yl)- 1- cWoro-2-pyrimidinyl)-N-(4-(2,6-dimethoxyphenyl)- 5-(( 1 S,3R)-3 -methoxycyclopentyl)-4H- 1 ,2,4- triazol-3 -yl)-l -methoxy-2-propanesulfonamide.

¾ NMR (400MHz, CD ₂ C1 ₂ ) δ 10.68 (br s, IH), 8.71 (s, 2H), 7.48 (t, .7=8.5 Hz, IH), 6.72 (d, .7=8.5 Hz, 2H), 4.85 (d, .7=4.6 Hz, IH), 3.87 - 3.83 (m, IH), 3.83 - 3.81 (m, 3H), 3.80 - 3.78 (m, 3H), 3.60 - 3.53 (m, IH), 3.24 (s, 3H), 3.15 (s, 3H), 2.84 (quin, .7=8.2 Hz, IH), 1.98 - 1.72 (m, 5H), 1.67 - 1.60 (m, IH), 1.25 (d, .7=7.0 Hz, 3H). LCMS-ESI (pos.), m/z: 567.0 (M+H) ⁺ .

[0411] The compounds set forth in the following table were synthesized following the procedure in Example 42.0 using the known starting material as described. Table 20

(pos.)m/z: 519.2 (M+H) ⁺ . (2S,3R)-3-(5-cMoropyrimidin-2- yl)butane-2 -sulfonamide (Example

27.4), 2-isothiocyanato-l,3- dimethoxybenzene (Example 28.0),

and (R)-spiro[2.2]pentane-l- carbohydrazide hydrocliloride and (S)- spiro [2.2] pentane- 1 -carbohydrazide

hydrocliloride (Example 105.2).

The racemic mixture was purified

using the following preparative SFC

method: Column: AD-H (2 x 25 cm)

Mobile Phase: 70:30 (A:B) A: Liquid

(2S,3R)-3-(5-chloropyrimidin-2-yl)-N-(4-(2,6- CO2, B: MeOH, Flow Rate: 80

dimethoxyphenyl)-5-((S)-spiro[2.2]pentan-l-yl)- mL/min, 215 nm, 100 bar inlet pressure

4H- 1 ,2,4-triazol-3-yl)butane-2-sulfonamide or to deliver Peak 2.

(2S,3R)-3-(5-chloropyrimidin-2-yl)-N-(4-(2,6- dimethoxyphenyl)-5-((R)-spiro[2.2]pentan-l-yl)- 4H- 1 ,2,4-triazol-3 -yl)butane-2-sulfonamide.

¾ NMR (500MHz, DMSO-d ₆ ) δ 12.66 (s, IH), 8.85 (s, 2H), 7.49 (t, .7=8.6 Hz, IH), 6.84 (br d, J=8.6 Hz, IH), 6.83 - 6.81 (m, IH), 3.76 (s, 3H), 3.71 (s, 3H), 3.68 - 3.62 (m, IH), 3.56 - 3.50 (m, IH), 1.64 (dd, .7=4.7, 7.8 Hz, IH), 1.46 (t, .7=4.4 Hz, IH), 1.37 (dd, .7=4.2, 7.8 Hz, IH), 1.23 (d, .7=7.0 Hz, 3H), 1.10 (d, .7=7.0 Hz, 3H), 0.83 - 0.78 (m, IH), 0.78 - 0.73 (m, 2H), 0.58 - 0.53 (m, IH). LCMS-ESI (pos.) m/z: 519.2 (M+H) ⁺ .

(2S,3R)-3-(5-cMoropyrimidin-2- yl)butane-2 -sulfonamide (Example

27.4), 2-isothiocyanato-l,3- dimethoxybenzene (Example 28.0),

and (R)-2,2- difluorocyclopropanecarbohydrazide

hydrocliloride and (S)-2,2- difluorocyclopropanecarbohydrazide

hydrocliloride (Example 100.2).

The racemic mixture was purified

using the following preparative SFC

method: Column: AS-H (2 x 25 cm) +

AS-H (2 x 25cm), Mobile Phase: (2S,3R)-3-(5-chloropyrimidin-2-yl)-N-(5-((R)- 80:20 (A:B) A: Liquid C0 ₂ , B: MeOH, 2,2-difluorocyclopropyl)-4-(2,6- Flow Rate: 80 niL/min, 220 nm, 100 dimethoxyphenyl)-4H- 1 ,2,4-triazol-3 -yl)butane- bar inlet pressure to deliver Peak 2. 2-sulfonamide or (2S,3R)-3-(5-chloropyrimidin- 2-yl)-N-(5-((S)-2,2-difluorocyclopropyl)-4-(2,6- dimethoxyphenyl)-4H- 1 ,2,4-triazol-3 -yl)butane- 2-sulfonamide.

¾ NMR (500MHz, DMSO-d ₆ ) δ 12.97 (br s, IH), 8.86 (s, 2H), 7.52 (t, .7=8.6 Hz, IH), 6.87 (d, .7=8.6 Hz, 2H), 3.76 (s, 3H), 3.75 - 3.73 (m, 3H), 3.68 - 3.62 (m, IH), 3.58 - 3.52 (m, IH), 2.55 - 2.50 (m, IH), 2.07 - 2.00 (m, 2H), 1.24 (d, .7=7.0 Hz, 3H), 1.12 (d, .7=7.0 Hz, 3H). LCMS-ESI (pos.) m/z: 529.2 (M+H) ⁺ .

( 1R,2 S) - 1 -(5 -cMoropyrimidin-2-y 1) - 1 - methoxypropane-2 -sulfonamide

(Example 29.3), 2-isofhiocyanato-l,3- dimethoxybenzene (Example 28.0),

and (R)-spiro[2.2]pentane-l- carbohydrazide hydrocliloride and (S)- spiro [2.2] pentane- 1 -carbohydrazide

hydrocliloride (Example 105.2).

The racemic mixture was purified

using the following three preparative

SFC methods: Column: AD-H (2 x 25

cm) and AD-H (2 x 25 cm) and AD-H

(2 x 25 cm), Mobile Phase: 65:35

( 1R,2S)- 1 -(5-chloropyrimidin-2-yl)-N-(4-(2,6- (A:B) A: Liquid C0 ₂ , B: IPA, Flow

dimethoxyphenyl)-5-((S)-spiro[2.2]pentan-l-yl)- Rate: 40 niL/min, 215 nm, 100 bar inlet

4H- 1 ,2,4-triazol-3 -y 1)- 1 -methoxypropane-2- pressure to deliver Peak 1.

sulfonamide or (lR,2S)-l-(5-chloropyrimidin-2- yl)-N-(4-(2,6-dimethoxyphenyl)-5-((R)- spiro [2.2]pentan- 1 -yl)-4H-l ,2,4-triazol-3 -yl)-l - methoxypropane-2-sulfonamide.

¾ NMR (500MHz, DMSO-d ₆ ) δ 12.66 (s, 1H), 8.93 (s, 2H), 7.49 (t, J=8.6 Hz, 1H), 6.84 (dd, .7=8.4, 16.5 Hz, 2H), 4.78 (d, .7=4.2 Hz, 1H), 3.76 (s, 3H), 3.75 - 3.71 (m, 3H), 3.42 - 3.36 (m, 1H), 3.14 (s, 3H), 1.66 - 1.63 (m, 1H), 1.48 (t, .7=4.3 Hz, 1H), 1.37 (dd, .7=4.2, 8.0 Hz, 1H), 1.13 (d, .7=7.0 Hz, 3H), 0.83 - 0.78 (m, 1H), 0.77 - 0.71 (m, 2H), 0.54 (dt, .7=3.9, 7.0 Hz, 1H). LCMS- ESI (pos.) m/z: 535.1 (M+H) ⁺ . ( 1R,2 S) - 1 -(5 -cMoropyrimidin-2-y 1) - 1 - methoxypropane-2 -sulfonamide

(Example 29.3), 2-isofhiocyanato-l,3- dimethoxybenzene (Example 28.0),

and (R)-spiro[2.2]pentane-l- carbohydrazide hydrocliloride and (S)- spiro [2.2] pentane- 1 -carbohydrazide

hydrochloride (Example 105.2).

The racemic mixture was purified

using the following three preparative

SFC methods: Columns: AD-H (2 x

25 cm) and AD-H (2 x 25 cm) and AD- H (2 x 25 cm), Mobile Phase: 65:35

(A:B) A: Liquid C0 ₂ , B: IPA, Flow ( 1R,2S)- 1 -(5-chloropyrimidin-2-yl)-N-(4-(2,6- Rate: 40 niL/min, 215 nm, 100 bar inlet dimethoxyphenyl)-5-((S)-spiro[2.2]pentan-l-yl)- pressure to deliver Peak 2. 4H- 1 ,2,4-triazol-3 -y 1)- 1 -methoxypropane-2- sulfonamide or (lR,2S)-l-(5-chloropyrimidin-2- yl)-N-(4-(2,6-dimethoxyphenyl)-5-((R)- spiro [2.2]pentan- 1 -yl)-4H-l ,2,4-triazol-3 -yl)-l - methoxypropane-2-sulfonamide.

¾ NMR (500MHz, DMSO-d ₆ ) δ 12.65 (s, 1H), 8.93 (s, 2H), 7.49 (t, .7=8.6 Hz, 1H), 6.86 - 6.81 (m, 2H), 4.77 (d, .7=4.4 Hz, 1H), 3.77 (s, 3H), 3.72 (s, 3H), 3.42 - 3.37 (m, 1H), 3.14 (s, 3H), 1.65 (dd, .7=4.7, 8.0 Hz, 1H), 1.48 (t, .7=4.4 Hz, 1H), 1.37 (dd, .7=4.2, 8.0 Hz, 1H), 1.14 (d, .7=7.0 Hz, 3H), 0.84 - 0.78 (m, 1H), 0.76 - 0.70 (m, 2H), 0.56 - 0.51 (m, 1H). LCMS-ESI (pos.) m/z: 535.1 (M+H) ⁺ .

[0412] Example 226.0: Preparation of (1 S,2S)-N-(4-(2,6- dimethoxyphenyl)-5-(trans-3-methoxycyclobutyl)-4H-l,2,4-tria zol-3-yl)-l-(5-methyl- 2-pyrimidinyl)-l-(2-propanyloxy)-2-propanesulfonamide or (lS,2S)-N-(4-(2,6- dimethoxyphenyl)-5-(cis-3-methoxycyclobutyl)-4H-l,2,4-triazo l-3-yl)-l-(5-methyl-2- pyrimidinyl)-l-(2-propanyloxy)-2-propanesulfonamide.

31.0 28.0 226.1

[0413] (Z)-N'-(2,6-Dimethoxyphenyl)-N-(((l S,2S)-1 -isopropoxy-1 -(5- methylpyrimidin-2-yl)propan-2-yl)sulfonyl)hydrazinecarboximi damide, Example 226.1. The title compound was repared in a similar manner to Example 161.1 using Example 31.0 and Example 28.0. This afforded Example 226.1 as a white solid. LCMS-ESI (pos.), m/z: 467.1 (M+H) ⁺ .

[0414] The compounds set forth in the following table were synthesized following the procedure in Example 214.3 using the known starting material as described.

Table 21

(pos.)m/z: 561.2 (M+H) ⁺ . (Z)-N'-(2,6-dimethoxyphenyl)-N- ((( 1 S,2S)- 1 -isopropoxy- l-(5- methylpyrimidin-2-yl)propan-2- yl)sulfonyl)hydrazinecarboximidamide

(Example 226.1) and 3,3- difluorocyclopentanecaiboxylic acid

(commercially available from

Synthonix).

( 1 S,2S)-N-(5-(( lR)-3 ,3 -difluorocyclopentyl)-4- (2,6-dimethoxyphenyl)-4H- 1 ,2,4-triazol-3 -yl)- 1 - (5-methyl-2-pyrimidinyl)-l-(2-propanyloxy)-2- propanesulfonamide and (lS,2S)-N-(5-((lS)-3,3- difluorocyclopentyl)-4-(2,6-dimethoxyphenyl)- 4H-l,2,4-triazol-3-yl)-l-(5-methyl-2- pyrimidinyl)- 1 -(2-propanyloxy)-2- propanesulfonamide.

¾ NMR (500MHz, DMSO-d ₆ ) δ 12.81 (br s, IH), 8.65 (s, 2H), 7.52 (t, .7=8.4 Hz, IH), 6.87 (d, .7=8.6 Hz, 2H), 4.69 (dd, .7=0.9, 7.4 Hz, IH), 3.81 (s, 3H), 3.80 - 3.78 (m, 3H), 3.45 - 3.34 (m, 2H), 2.96 (quin, .7=8.4 Hz, IH), 2.34 - 2.19 (m, 5H), 2.19 - 2.03 (m, 2H), 1.92 - 1.77 (m, 2H), 0.98 (d, .7=6.0 Hz, 3H), 0.91 (dd, .7=4.2, 7.0 Hz, 3H), 0.79 (dd, J=3.1, 6.2 Hz, 3H). LCMS-ESI (pos.) m/z: 581.3 (M+H) ⁺ .

2-sulfonamide or (lS,2S)-N-(4-(2,6- dimethoxyphenyl)-5-((lR,2R)-2- methoxycyclopentyl)-4H- 1 ,2,4-triazol-3 -yl)-l - isopropoxy- l-(5-methylpyrimidin-2-yl)propane- 2-sulfonamide or (lS,2S)-N-(4-(2,6- dimethoxyphenyl)-5-((lS,2S)-2- methoxycyclopentyl)-4H- 1 ,2,4-triazol-3 -yl)-l - isopropoxy- l-(5-methylpyrimidin-2-yl)propane- 2-sulfonamide.

¾ NMR (500MHz, CD ₂ C1 ₂ ) δ 12.32 (s, 1H), 8.64 (s, 2H), 7.48 (t, .7=8.6 Hz, 1H), 6.73 (t, .7=8.7 Hz, 2H), 4.80 (d, .7=4.2 Hz, 1H), 3.94 - 3.91 (m, 1H), 3.87 (s, 3H), 3.81 (s, 3H), 3.63 - 3.58 (m, 1H), 3.57 - 3.52 (m, 1H), 2.98 (s, 3H), 2.71 - 2.66 (m, 1H), 2.34 (s, 3H), 1.91 - 1.82 (m, 3H), 1.80 - 1.73 (m, 1H), 1.70 - 1.61 (m, 2H), 1.36 (d, .7=7.0 Hz, 3H), 1.09 (d, .7=6.0 Hz, 3H), 0.98 (d, .7=6.2 Hz, 3H). LCMS-ESI (pos.) m/z: 575.2 (M+H) ⁺ .

I (Z)-N'-(2,6-dimeflioxyphenyl)-N- ((( 1 S,2S)- 1 -isopropoxy- 1 -(5 - methylpyrimidin-2-yl)propan-2- yl)sulfonyl)hydrazinecarboximidamide

(Example 226.1) and 2- methoxycyclopentane-l-carboxylic

acid (commercially available from

Enamine). The racemic mixture was

purified using the following two

preparative SFC methods: Column:

AD-H (2 x 25 cm) + AD-H (2 x 25

cm), Mobile Phase: 75:25 (A:B) A:

Liquid C0 ₂ , B: IPA, Flow Rate: 60

niL/min, 215 nm, 100 bar inlet

pressure to deliver fraction 1 that was

resubjected to preparative SFC

method: Column: AD-H (2 x 25 cm)

+ AD-H (2 x 25 cm), Mobile Phase:

80: 20 (A:B) A: Liquid C0 ₂ , B: IPA,

Flow Rate: 60 mL/min, 215 nm, 100

bar inlet pressure to deliver Peak 2.

(lS,2S)-N-(4-(2,6-dimethoxyphenyl)-5-((lR,2S)- 2-methoxycyclopentyl)-4H- 1 ,2,4-triazol-3 -yl)- 1 - isopropoxy- l-(5-methy lpyrimidin-2-yl)propane- 2-sulfonamide or (lS,2S)-N-(4-(2,6- dimethoxyphenyl)-5-(( 1 S,2R)-2- methoxycyclopentyl)-4H- 1 ,2,4-triazol-3 -yl)- 1 - isopropoxy-l-(5-methylpyrimidin-2-yl)propane- 2-sulfonamide or (lS,2S)-N-(4-(2,6- dimethoxyphenyl)-5-((lR,2R)-2- methoxycyclopentyl)-4H- 1 ,2,4-triazol-3 -yl)- 1 - isopropoxy- l-(5-methylpyrimidin-2-yl)propane- 2-sulfonamide or (lS,2S)-N-(4-(2,6- dimethoxyphenyl)-5-((lS,2S)-2- methoxycyclopentyl)-4H- 1 ,2,4-triazol-3 -yl)- 1 - isopropoxy- l-(5-methy lpyrimidin-2-yl)propane- 2-sulfonamide.

¾ NMR (500MHz, CD ₂ C1 ₂ ) δ 12.28 (s, 1H), 8.63 (s, 2H), 7.48 (t, .7=8.4 Hz, 1H), 6.73 (t, .7=8.2 Hz, 2H), 4.80 (d, .7=4.4 Hz, 1H), 4.13 - 4.08 (m, 1H), 3.88 - 3.84 (m, 3H), 3.83 - 3.80 (m, 3H), 3.62 - 3.56 (m, 1H), 3.56 - 3.50 (m, 1H), 3.13 - 3.04 (m, 3H), 2.71 - 2.64 (m, 1H), 2.34 (s, 3H), 1.96 - 1.87 (m, 1H), 1.84 - 1.78 (m, 1H), 1.72 - 1.62 (m, 4H), 1.34 (d, .7=7.0 Hz, 3H), 1.08 (d, .7=6.0 Hz, 3H), 0.96 (d, .7=6.0 Hz, 3H). LCMS-ESI (pos.) m/z: 575.2 (M+H) ⁺ .

I (Z)-N'-(2,6-dimeflioxyphenyl)-N- ((( 1 S,2S)- 1 -isopropoxy- 1 -(5 - methylpyrimidin-2-yl)propan-2- yl)sulfonyl)hydrazinecarboximidamide

(Example 226.1) and 2- methoxycyclopentane-l-carboxylic

acid (commercially available from

Enamine). The racemic mixture was

purified using the following two

preparative SFC methods: Column:

AD-H (2 x 25 cm) + AD-H (2 x 25

cm), Mobile Phase: 75:25 (A:B) A:

Liquid C0 ₂ , B: IPA, Flow Rate: 60

niL/min, 215 nm, 100 bar inlet

pressure to deliver fraction 3.

(lS,2S)-N-(4-(2,6-dimethoxyphenyl)-5-((lR,2S)- 2-methoxycyclopentyl)-4H- 1 ,2,4-triazol-3 -yl)- 1 - isopropoxy- l-(5-methy lpyrimidin-2-yl)propane- 2-sulfonamide or (lS,2S)-N-(4-(2,6- dimethoxyphenyl)-5-(( 1 S,2R)-2- methoxycyclopentyl)-4H- 1 ,2,4-triazol-3 -yl)- 1 - isopropoxy- l-(5-methy lpyrimidin-2-yl)propane- 2-sulfonamide or (lS,2S)-N-(4-(2,6- dimethoxyphenyl)-5-((lR,2R)-2- methoxycyclopentyl)-4H- 1 ,2,4-triazol-3 -yl)-l - isopropoxy-l-(5-methylpyrimidin-2-yl)propane- 2-sulfonamide or (lS,2S)-N-(4-(2,6- dimethoxyphenyl)-5-((lS,2S)-2- methoxycyclopentyl)-4H- 1 ,2,4-triazol-3 -yl)-l - isopropoxy-l-(5-methylpyrimidin-2-yl)propane- 2-sulfonamide.

¾ NMR (500MHz, CD ₂ C1 ₂ ) δ 12.19 (br s, 1H),

8.65 - 8.60 (m, 2H), 7.50 - 7.44 (m, 1H), 6.73 (t, J=9.0 Hz, 2H), 4.86 - 4.79 (m, 1H), 3.88 - 3.84 (m, 3H), 3.84 - 3.81 (m, 3H), 3.61 - 3.51 (m, 2H), 3.37 - 3.31 (m, 1H), 3.11 - 3.01 (m, 3H),

2.66 - 2.60 (m, 1H), 2.36 - 2.32 (m, 3H), 2.31 - 2.21 (m, 1H), 1.94 - 1.78 (m, 4H), 1.58 - 1.49 (m, 2H), 1.31 - 1.26 (m, 3H), 1.08 (d, J=6.0 Hz, 3H), 0.97 (d, J=6.2 Hz, 3H). LCMS-ESI (pos.) m/z: 575.2 (M+H) ⁺ .

[0415] The compounds set forth in the following table were synthesized following the procedure in Example 42.0 using the known starting material as described.

Table 22

[0416] The compounds set forth in the following table were synthesized following the procedure in Example 214.3 using the known starting material as described.

Table 23

Example Reagents Structure, Name and Data

-fluoro-3 -

(br s, IH), Hz, IH), 3.32 - (m, 4H), Hz, 3H).

-N-(4-(2,6- -y 1)-4H- Enamine). l,2,44riazol-3-yl)-l-methoxy-2- propanesulfonamide .

¾ NMR (400MHz, DMSO-d ₆ ) δ 12.74 (s, IH),

8.93 (s, 2H), 7.49 (t, .7=8.5 Hz, IH), 6.83 (d, .7=8.5

Hz, 2H), 4.77 (d, .7=4.4 Hz, IH), 3.74 (s, 3H), 3.73

(s, 3H), 3.56 - 3.36 (m, IH), 3.19 - 3.11 (m, IH),

3.15 (s, 3H), 2.47 - 2.36 (m, 2H), 2.04 - 1.95 (m,

2H), 1.14 (d, .7=6.8 Hz, 3H), 0.42 - 0.30 (m, 4H).

Mass Spectrum (pos.) m/z: 549.2 (M+H) ⁺ .

[0417] Example 240.0: Preparation of (lR,2S)-l-(5-chloro-2-pyrimidinyl)-

N-(4-(4,6-dimethoxy-5-pyrimidinyl)-5-(2-oxaspiro[3.3]hept an-6-yl)-4H-l,2,4-triazol- 3-yl)-l-methoxy-2-propanesulfonamide.

240.1

[0418] (lR,2S)-l-(5-Chloro-2-pyrimidinyl)-N-(4-(4,6-dimethoxy-5- pyrimidinyl)-5-(2-oxaspiro[3.3]heptan-6-yl)-4H-l,2,4-triazol -3-yl)-l-methoxy-2- propanesulfonamide, Example 240.0. To a flask containing Example 161.2 (434 mg, 0.742 mmol) in water (3.7 mL) was added potassium hydroxide (6M, 0.09 mL, 0.54 mmol) dropwise. Upon complete addition, the mixture was heated to 90 °C. After 1 h, the reaction was cooled to RT and then diluted with water. The pH was carefully adjusted to pH~7 by dropwise addition of 1 N aqueous citric acid solution. The mixture was then extracted three times with DCM. The organic layers were combined and then dried over anhydrous magnesium sulfate. After filtration and concentration in vacuo, the residue was loaded onto a silica gel column (25-70% 3: 1 EtOAc: EtOH in heptane) to provide

Example 240.0 (421 mg, 0.354 mmol, 47.7%). ¾ NMR (400MHz, DMSO-d ₆ ) δ 12.94 (s, IH), 8.93 (s, 2H), 8.69 (s, IH), 4.76 (d, .7=4.1 Hz, IH), 4.53 (s, 2H), 4.43 (s, 2H), 3.95 (s, 3H), 3.94 (s, 3H), 3.52 - 3.34 (m, IH), 3.34 - 3.25 (m, IH), 3.13 (s, 3H), 3.03 (m, 2.34 (s, 3H), 1.13 (d, J=7.0 Hz, 3H). Mass Spectrum (pos.) m/e: 567.0 (M+H) ⁺ .

[0419] The compounds set forth in the following table were synthesized following the procedure in Example 240.0 using the known starting material as described.

Table 24

[0420] Biological Activity

[0421] [ ³⁵ S]GTPyS Binding

[0422] The human APJ receptor was cloned by polymerase chain reaction and the gene encoding the receptor was subcloned in pFLAG-CMV™-3 expression vector (Sigma, Saint Louis, MO USA) in-house at Amgen. A GTPyS binding assay was performed on membranes prepared from CHO cells stably expressing human APJ receptor. The optimum experimental conditions for the concentrations of GDP, MgC¾, and NaCl in the assay buffer were initially determined. The assay was performed in 9 μΐ, assay buffer [20 mM HEPES, pH 7.5, 5 mM MgCl ₂ , 100 mM NaCl and 0.1% (w/v) BSA], 1 μΐ. of diluted test compound (starting with 0.75 mM, 2-fold serial dilution with DMSO, total 22 points), 10 μΐ. of 18 μΜ GDP (final concentration of 3 μΜ GDP), 20 μΐ. of 0.25 μg/mL membrane protein expressing human APJ receptor captured with WGA PS beads (final concentration of 5 μg per well), and 20 μΐ. of 0.3 nM [ ³⁵ S]GTPyS (final concentration is 0.1 nM [ ³⁵ S]GTPYS)(Perkin Elmer Life and Analytical Sciences, Waltham USA). One column of the plate was 1 μΐ. of DMSO as background and another column of the plate was 1 μΐ. of 180 μΜ Pyr-Apelin-13 which was used as control at a final concentration of 3 μΜ. Incubation was at RT for 90 min and the microplate was read using a ViewLux™ ultra HTS Microplate Imager (PerkinElmer, Inc.). All the results presented are means of several independent experiments and analyzed by nonlinear regression methods using the commercially available program Prism (GraphPad, San Diego, CA) providing the EC50 values detailed in Table 25.

[0423] Evidence for load independent inotropic effects with APJ agonists using ex vivo assay (isolated perfused rat hearts)

[0424] Naive Sprague Dawley ^® SD rats (Harlan laboratories (Livermore, CA

USA)) were anaesthetized and hearts were excised followed by cannulation in the Langendorff apparatus (Harvard apparatus, Holliston, MA USA) via aorta. The heart was perfused retrograde with modified oxygenated Krebs-Henseleit buffer (Skrzypiec-Spring M et al., (2007) J. Pharmacol Toxicol Methods 55: 113-126). The pressure of the solution causes the aortic valve to shut and the perfusate is then forced into the ostium and the coronary vessels. This allows the heart to beat for several hours. A balloon was inserted into the left ventricle (LV) to measure (derivative of left ventricular pressure) as an index of cardiac contractility. The APJ agonist was perfused constantly in a dose dependent manner into the heart to examine cardiac contractility. Administration of APJ agonist showed a dose-dependent increase in inotropic and lusitropic effects at varying degrees (Table 26). APJ agonists of the present invention showed improvement in cardiac contractility and relaxation when perfused into the heart as described above.

[0425] Evidence for improvement in cardiac contractility in vivo in heart failure rat model

[0426] Based on the ex vivo findings in isolated heart assay, APJ agonists may be dosed in vivo to investigate the translation of cardiac contractility in in vivo settings. Male Lewis rats (Charles River, USA) at 2-3 months of age are used for the study. Heart failure is induced by permanent ligation of the left descending coronary artery which results in injury to the heart with an ejection fraction of <35%. APJ agonists are administered dose dependently acutely for a period of 30 min. Administration of example compounds will be found to lead to an increase in cardiac contractility as measured by dP/dtmax (derivative of left ventricular pressure).

[0427] The following table includes biological activity data obtained using the procedures and assays set forth above for the Example compounds described herein. Table 25. Biological Activity Information for Example Compounds.

43.0 Prophetic

44.0 Prophetic

45.0 Prophetic

46.0 Prophetic

47.0 Prophetic

48.0 Prophetic

49.0 Prophetic

54.0 Prophetic

55.0 Prophetic

56.0 Prophetic

57.0 Prophetic

This compound has been prepared (see Example 179.0,

58.0 Example 180.0, Example 181.0, and Example 182.0)

59.0 Prophetic

60.0 Prophetic

61.0 Prophetic

62.0 Prophetic

63.0 Prophetic

64.0 This compound has been prepared (see Example 146.0)

65.0 Prophetic

66.0 Prophetic

67.0 Prophetic

68.0 Prophetic

69.0 Prophetic

70.0 Prophetic

71.0 Prophetic

72.0 Prophetic

73.0 Prophetic

74.0 Prophetic

75.0 Prophetic

76.0 Prophetic

77.0 Prophetic

78.0 Prophetic

79.0 Prophetic

80.0 Prophetic

81.0 Prophetic 82.0 0.050

83.0 0.0060

84.0 0.0108

85.0 0.0017

86.0 0.036

87.0 0.0020

88.0 0.042

89.0 0.00074

90.0 0.0092

91.0 0.0029

92.0 0.0057

93.0 0.00091

94.0 0.00072

95.0 0.043

96.0 0.030

97.0 0.37

98.0 Prophetic

99.0 Prophetic

100.0 0.14

101.0 0.060

102.0 0.16

103.0 0.039

105.0 0.00092

106.0 0.019

107.0 —

108.0 —

109.0 —

110.0 —

111.0 Prophetic

112.0 Prophetic

118.0 0.0010

119.0 0.00079

120.0 0.0031

121.0 0.0054

122.0 0.028

123.0 0.0051 124.0 0.049

125.0 0.40

126.0 4.20

127.0 —

128.0 0.33

129.0 —

130.0 1.50

131.0 0.11

132.0 1.27

133.0 0.12

134.0 1.33

135.0 1.81

136.0 3.2

137.0 0.34

138.0 0.027

139.0 0.029

140.0 0.031

141.0 0.033

142.0 0.0051

143.0 0.0041

144.0 0.62

145.0 0.0048

146.0 0.026

147.0 0.0064

148.0 0.0011

149.0 0.0042

150.0 0.0068

151.0 0.0054

152.0 0.0042

153.0 0.0015

154.0 0.00018

155.0 0.0094

156.0 0.011

159.0 0.0080

160.0 0.027

161.0 0.019 162.0 0.0140

163.0 0.046

164.0 0.00054

165.0 0.0097

166.0 0.020

167.0 0.013

168.0 0.0080

169.0 0.021

170.0 0.018

172.0 0.37

173.0 0.013

174.0 1.2

175.0 0.059

176.0 0.017

177.0 0.023

178.0 0.0065

179.0 0.046

180.0 0.024

181.0 0.032

182.0 0.010

183.0 0.0014

184.0 0.0011

185.0 0.0027

186.0 0.00089

187.0 0.0088

188.0 0.014

191.0 0.0075

192.0 0.0029

193.0 0.010

194.0 0.0025

195.0 0.0026

196.0 0.33

197.0 0.87

198.0 0.0037

199.0 0.0081

200.0 0.0046 201.0 0.011

202.0 0.0042

203.0 0.010

204.0 0.034

205.0 0.0055

208.0 0.0027

209.0 0.018

210.0 0.015

211.0 0.42

214.0 0.020

215.0 0.066

216.0 0.015

217.0 0.0074

218.0 0.0011

219.0 0.029

220.0 0.039

221.0 0.018

222.0 0.024

223.0 0.0012

224.0 0.038

225.0 0.16

226.0 0.021

227.0 0.0027

228.0 0.19

229.0 0.030

230.0 0.19

231.0 0.22

232.0 0.042

233.0 0.094

234.0 0.012

235.0 0.15

236.0 0.00099

237.0 0.030

238.0 0.12

239.0 0.00064

240.0 0.071 241.0 0.0012

[0428] The following table includes data obtained using the procedures and assays set forth above for the Example compounds described herein.

Table 26. Contractile Effects of Examples Observed in ex vivo (Isolated Heart Assay) and in vivo (MI Rat Model).

^* nd is not determined.

[0429] APJ is a G-protein coupled receptor that is closely related to the

Angiotensin II Type 1 receptor (ATIR) with 50% homology in the transmembrane domain. Apelin is a known endogenous ligand for APJ and recently another ligand named ELABELA has been identified as another potential ligand for the APJ receptor (Tatemoto, K. et al., Biochem. Biophys. Res. Commun., 251, pp. 471-476 (1998); Pauli, A. et al., Science, 343, pp. 1248636 (2014)). Since its discovery, there is accumulating evidence indicating the role of the apelin-APJ receptor in the pathophysiology of cardiovascular diseases. Pre-clinical and clinical studies have shown that acute infusion of apelin or APJ agonists improve cardiac function under heart failure settings (Berry, M. F., et al., Circulation, 110(11) pp. 11187-11193 (2004); Japp, A. G. et al., Circulation, 121, pp. 1818-1827 (2010)).

[0430] A key emerging aspect of the apelin-APJ system is its interaction with the renin-angiotensin system. Apelin is also known to counter-regulate the

vasoconstriction actions of Angll. Apelin knockout mice show a strong increased vasopressor response to Angll indicating that the apelin/APJ system exerts the hypotensive effect in vivo against the pressor action of Angll. In addition, the apelin activated APJ pathway inhibited angiotensin-mediated formation of atherosclerosis through interaction with the ATIR (Chun, H. J., et al., J. Clin. Invest., 118, pp. 3343-3354 (2008), Siddiquee, K. et al., J. Hypertens., 29, pp. 724-731 (2011), Sun, X. et al., Hypertens. Res., 34, pp. 701-706 (2011)). This could be mediated by convergence of two independent intracellular signaling pathways or via direct physical interaction of APJ with ATIR to form a heterodimer. Siddiquee et al. showed that the Angll signaling is antagonized through apelin-dependent heterodimerization and APJ mediated negative allosteric modulation of ATIR function (Siddiquee, K. et al., Br. J. Pharmacol., 168, pp. 1104-1117 (2013).

[0431] We were interested to understand if the heterodimerization of APJ-

AT1R upon activation by APJ agonists would have any beneficial outcome clinically in heart failure patients considering most of these patients are on standard of care drugs such as angiotensin blockers (angiotensin II receptor antagonists or angiotensin receptor blockers (ARBs)) and angiotensin converting enzyme (ACE) inhibitors. In order to explore the cross-talk between APJ and the ATIR receptor, we examined IP1 signaling mediated by ATIR upon activation with APJ agonists. Surprisingly and contrary to the findings by Siddique et al., activation of the APJ pathway resulted in positive cooperativity of Angll by shifting its potency to the left and also increasing the efficacy of the IP response (see methods and results section below). Conversely, blocking the ATIR receptor by an ARB such as losartan relieved the inhibition of the APJ receptor and up regulates its signaling which is observed as synergistic effects in both ex-vivo and in vivo studies. This work establishes a new paradigm for cross-talk

interaction/heterodimerization between APJ & ATIR which might have implications for approaches to pharmacological interventions in heart failure populations.

[0432] The interaction between acetyl cholinesterase (ACE2) and Apelin biology is complicated. To investigate the interaction between the Apelin-APJ and ACE signalling pathways, we examined the improvement in cardiac function with APJ small molecule agonists in the presence of ACE inhibitor captopril in heart failure rats in vivo. Captopril alone, under acute settings, does not show a marked improvement in contractility or ejection fraction acutely. However, in the presence of an APJ agonist, there was a shift in potency to the left with marked improvement in contractility and ejection fraction without changes in heart rate. These findings provide a new reference for the understanding of the regulation of ACE2 for the renin angiotensin aldosterone system (RAAS), independent of ATIR signaling and offer new potential drug targets for the treatment of diseases such as hypertension and heart failure. This work clearly establishes that combination of an agonist of the APJ receptor with an ARB such as losartan and/or with an ACE inhibitor such as captopril which may play an important role in providing greater efficacy in treating heart failure patients, for example in improving contractility and ejection fraction without changing the heart rate.

[0433] Evidence for Allosteric Interaction between APJ and ATIR using

IP assay [0434] Methods

[0435] Single and double stable recombinant cell lines were generated for human APJ and the AT1R receptor in CHO Kl cells tagged either with FLAG or hemagglutinin (HA) tag. Briefly, the CHO-K1 APJ/AT1R cells were seeded in culture medium of DMEM-F12 and 10% FBS at a density of 15k/well in a 96 well plate overnight. The next day, the culture medium was replaced with medium containing no serum for 4 hours. The compound Angll at a range of concentrations (1 pM-10 μΜ) with or without different concentrations of APJ agonists were diluted in stimulation buffer and added to the cell plate. The plate was sealed and incubated for lhour. This was followed by addition of IP-d2 conjugate followed by europium cryptate antibody conjugate into the wells. The plate was sealed, followed with incubation for 2 hours at RT. Time-resolved fluorescence resonance energy (TR-FRET) at 620 nm and 665 nm was measured after 2 hours with an Envision reader. The signal ratios and delta F were calculated and the amount of IP1 produced was inversely proportional to the TR-FRET ratio, 665/620 nm.

[0436] Results

[0437] In cells expressing both APJ and the AT1R receptor, addition of APJ agonists at different concentrations increased the maximal response of Angll and also shifted the potency to the left. The increase in IP1 response reached a maximal effect both in potency and Emax indicating a ceiling effect which is a hallmark for allosteric cooperativity between the AT1R and APJ receptor (FIG. 1). However, this effect of cooperativity was not observed in either APJ or AT1R recombinant stable cell lines indicating that there is functional cross-talk between the two receptors through physical interaction or with downstream effectors (FIG. 2 and FIG. 3). Based on the above findings of cooperativity, we rationalized that if an APJ agonist can induce

heterodimerization of APJ with AT1R, blocking the AT1R with losartan would enhance the activation of APJ upon addition of small molecule agonists. We observed that APJ small molecule agonists induced positive cooperativity in the presence of Angll and addition of losartan relieved this cooperativity and resulted in synergistic effects of enhancing the efficacy of the APJ receptor. This work clearly establishes that combination of an agonist of the APJ receptor with an ARB such as losartan or an ACE inhibitor such as captopril may play an important role in providing greater efficacy in treatment of heart failure patients.

[0438] All publications and patent applications cited in this specification are hereby incorporated by reference herein in their entireties and for all purposes as if each individual publication or patent application were specifically and individually indicated as being incorporated by reference and as if each reference was fully set forth in its entirety. Although the foregoing invention has been described in some detail by way of illustration and example for purposes of clarity of understanding, it will be readily apparent to those of ordinary skill in the art in light of the teachings of this invention that certain changes and modifications may be made thereto without departing from the spirit or scope of the appended claims.