NZ772098B2 - 4-methylsulfonyl-substituted piperidine urea compounds for the treatment of dilated cardiomyopathy (DCM) - Google Patents

Abstract

The present invention provides novel 4-methylsulphone-substituted piperidine urea compounds that are useful for the treatment of dilated cardiomyopathy (DCM) and conditions associated with left and/or right ventricular systolic dysfunction or systolic reserve. The synthesis and characterization of the compounds is described, as well as methods for treating DCM and other forms of heart disease.

Description

-METHYLSULFONYL-SUBSTITUTED PIPERIDINE UREA COMPOUNDS FOR THE ENT OF DILATED CARDIOMYOPATHY (DCM) CROSS-REFERENCES TO RELATED APPLICATIONS The present application is a divisional application of New Zealand Patent Application No. 734020, which is the national phase of International Application No. , which in turn claims ty to U.S. Provisional Application Serial No. 62/106,571, filed on January 22, 2015. Each of the aforementioned applications are incorporated herein by cross reference in their entireties. raph deliberately blank] BACKGROUND OF THE INVENTION Dilated cardiomyopathy (DCM) comprises a group of myocardial disorders that lead to left ventricular dilatation and systolic dysfunction (abnormality of contraction). DCM can be subdivided into ic (attributed due to coronary artery disease) or non-ischemic ry diseases of the myocardium). ter, DCM refers to non-ischemic primary diseases of the myocardium. DCM can be assigned a clinical diagnosis of "idiopathic" DCM if no identifiable cause (except genetic) can be found. Idiopathic DCM can be further subcategorized based upon whether a genetic cause can be identified. Mutations in over 30 genes, including sarcomere genes, perturb a diverse set of myocardial proteins to cause a DCM phenotype. Epidemiologic data indicate that approximately 1 in 2,500 duals in the general population have thic DCM. ere gene mutations that cause DCM are highly penetrant, but there is wide variability in clinical severity and clinical course. Some genotypes are associated with a more malignant course, but there is considerable variability between and even within families carrying the same mutation. While many ts with DCM report minimal or no ms for extended periods of time, DCM is a progressive disease with a significant cumulative burden of ity and mortality. The rk ofDCM is a dilated left cle, more spherical in shape than usual, and with decreased systolic function. Patients usually present with symptoms of heart failure: a, orthopnea, exercise intolerance, fatigue, abdominal discomfort and poor appetite. Signs include sinus tachycardia, a gallop rhythm, murmur of mitral regurgitation, rales, jugular venous distension, hepatomegaly, peripheral edema and cool extremities can be found. As with many other ers, symptoms tend to worsen with age. The t journey is punctuated by hospitalizations for decompensated heart failure and an increased risk for sudden arrhythmic death and death from pump failure.

Diagnosis is dependent upon patient history and physical ation. Plasma biomarkers such as B—type natriuretic peptide (BNP) or its inal pro-protein (NT- proBNP) can help with diagnosis and management of DCM, especially to distinguish heart failure from comorbid pulmonary disease. Coronary angiography can identify if heart failure is due to ischemic etiology. Endomyocardial biopsy can distinguish DCM from disease processes that might require alternative management strategy, such as myocarditis, storage disease, sarcoidosis or hemochromatosis.

Medical y remains the mainstay in patients with DCM and heart failure. Beta- blocker, ACE inhibitor or ARB, mineralcorticoid receptor blocker, and loop ics continue to be standard treatment options for the treatment of heart failure symptoms and reduction of risk for cardiovascular death and heart failure alization. Implantable verter defibrillators (ICD) for patients with left ventricular ejection fraction of less than % can reduce sudden hmic death. Additionally, cardiac resynchronization therapy (CRT) has been shown to improve heart failure-free survival in select patients. Despite these interventions, morbidity and mortality for heart failure remain high, and hospitalization for heart failure remains the most common reason for hospitalization in the y. The present invention provides new therapeutic agents and methods that remedy the unmet need for improved treatment of DCM and related cardiac disorders.

BRIEF SUMMARY OF THE INVENTION 3O [0007] In one aspect, provided is a compound having formula (I): O \S/Ar2 Ar —NH1 VNOFfR‘3 R2 R (I) or a pharmaceutically acceptable salt thereof.

In formula (1), Ar1 is a 5- to 6-membered heteroaryl having at least one nitrogen atom ring ; and is optionally substituted with from 1-3 Ra. Ar2 is a 5- to 10- membered aryl or heteroaryl which is optionally substituted with from 1—5 Rb. The symbols R1 and R2 are each independently a member ed from H, F, C1-C4 alkyl, C1-C4 deuteroalkyl, and C1-C4 haloalkyl, or optionally R1 and R2 can be combined to form a C3- to C5 carbocyclic ring which is optionally substituted with one or two F. The symbol R3 represents a member selected from H, F, OH and C1—C4 alkyl. id="p-9" id="p-9" id="p-9" id="p-9" id="p-9" id="p-9" id="p-9" id="p-9" id="p-9" id="p-9" id="p-9" id="p-9" id="p-9" id="p-9"

[0009] The substituents for each of Ar1 and Ar2 are as follows: each Ra is independently selected from the group consisting of halo, CN, hydroxyl, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 hydroxyalkyl, 01—04 alkoxy, C1-C4 haloalkoxy, -CORa1, -C02Ra1, 1, -SOzNRa1Ra2, and -CONRa1Ra2, wherein each Ra1 and R312 is independently selected from the group consisting ofH and C1-C4 alkyl or ally Ral and RaZ when attached to a nitrogen atom are combined to form a 4- to 6- membered ring; or optionally, two Ra substituents on adjacent ring members are combined to form a 5- or 6-membered ring having 0, l or 2 ring s selected from O, N and S; and each Rb is independently selected from the group consisting of halo, CN, hydroxyl, C1-C4 alkyl, C1-C4 deuteroalkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 haloalkoxy, C3-C6 cycloalkyl, -NRb1Rb2, 4:011", £0211", —sosz1, b1Rb2, — 2O CONRblRw, and a 5- or 6-membered heteroaryl which is optionally substituted with C1-C4 alkyl, and wherein each Rb1 and Rb2 is independently selected from the group ting ofH and C1-C4 alkyl or optionally Rb1 and Rb2 when attached to a nitrogen atom are combined to form a 4- to 6- membered ring; or optionally, two Rb substituents on adjacent ring members are combined to form a 5- or 6-membered ring having 0, 1 or 2 ring members selected from O, N and S.

In another aspect, the invention es a pharmaceutical composition containing a nd or a ceutically acceptable salt thereof as described herein and a ceutically acceptable excipient.

In r aspect, the invention provides a method of treating d cardiomyopathy. The method includes administering to a subject in need thereof an ive amount of a compound or pharmaceutically acceptable salt thereof as bed herein. [0011a] In one aspect, the invention provides a nd having formula (I): or a pharmaceutically acceptable salt thereof, wherein Ar1 is a 5- to 6-membered heteroaryl having at least one nitrogen atom ring member which is unsubstituted or substituted with from 1-3 Ra; Ar2 is a 5- to 10-membered aryl or heteroaryl which is unsubstituted or substituted with from 1-5 Rb; R1 and R2 are each independently a member selected from the group consisting of H, F, C1-C4 alkyl, C1-C4 deuteroalkyl, and C1-C4 haloalkyl; or alternatively, R1 and R2 are combined to form a C3- to C5 carbocyclic ring which is unsubstituted or substituted with one or two F; R3 is member selected from the group consisting of H, F, OH and C1-C4 alkyl; each Ra is independently selected from the group consisting of halo, CN, hydroxyl, C1-C4 alkyl, C1-C4 kyl, C1-C4 hydroxyalkyl, C1-C4 alkoxy, C1-C4 haloalkoxy, -CORa1, -CO2Ra1, -SO2Ra1, -SO2NRa1Ra2, and -CONRa1Ra2, wherein each Ra1 and Ra2 is independently selected from the group consisting of H and C1-C4 alkyl or wherein Ra1 and Ra2 when ed to a en atom are combined to form a 4- to 6- membered ring; or wherein two Ra substituents on adjacent ring members are combined to form a 5- or 6-membered ring having 0, 1 or 2 ring members selected from O, N and S; and each Rb is independently selected from the group consisting of halo, CN, hydroxyl, C1-C4 alkyl, C1-C4 deuteroalkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 haloalkoxy, C3-C6 cycloalkyl, -NRb1Rb2, -CORb1, 1, -SO2Rb1, -SO2NRb1Rb2, –CONRb1Rb2, and a - or 6-membered heteroaryl which is unsubstituted or substituted with C1-C4 alkyl, and wherein each Rb1 and Rb2 is independently selected from the group consisting of H and C1-C4 alkyl or wherein Rb1 and Rb2 when attached to a nitrogen atom are combined to form a 4- to 6- membered ring; or wherein two Rb substituents on adjacent ring members are combined to form a 5- or 6-membered ring having 0, 1 or 2 ring members selected from the group consisting of O, N and S; wherein each aryl is an aromatic hydrocarbon ring system; and wherein each heteroaryl is an ic ring system comprising one or more heteroatoms selected from the group consisting of O, N, and S.

] Throughout this specification and the claims which follow, unless the context requires otherwise, the word "comprise", and variations such as ises" and "comprising", will be understood to imply the inclusion of a stated r or step or group of integers or steps but not the exclusion of any other integer or step or group of integers or steps.

BRIEF PTION OF THE DRAWINGS Figures 1A, 1B, 1C, 1D and 1E shows schematic routes for the synthesis of the compounds or pharmaceutically acceptable salts described herein.

DETAILED DESCRIPTION OF THE INVENTION I. General A series of 4-methylsulfonyl-substituted piperidine ureas and pharmaceutically acceptable salts thereof has been found to increase contractility by ing phosphate release from myosin without ging systole or shortening diastole. As such, the compounds can improve systolic function in patients with DCM, helping them to me the debilitating exertional dyspnea and fatigue that often accompanies the disease. The compounds can also be used to treat other cardiac disorders characterized by diminished c output.

II. Definitions As used herein, the term "alkyl" refers to a straight or branched, saturated, aliphatic radical having the number of carbon atoms indicated. Alkyl can include any number of carbons, such as C1.2, C1.3, C1.4, C1.s, C1-6, C1.7, C1.s, C2.3, C2.4, C2.s, C2-6, C3.4, C3.s, C3-6, C4.s, C4-6 and Cs For example, C1-6 alkyl includes, but is not limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, tyl, hexyl, etc. Alkyl can refer to alkyl groups having up to 20 carbons atoms, such as, but not limited to heptyl, octyl, nonyl, decyl, etc. Unless stated otherwise, alkyl groups are unsubstituted. A "substituted alkyl" group can be substituted with one or more moieties selected from halo, hydroxy, amino, alkylamino, nitro, cyano, and alkoxy.

As used herein, the term "cycloalkyl" refers to a saturated or partially unsaturated, clic, fused bicyclic or bridged polycyclic ring assembly containing from 3 to 12 ring atoms, or the number of atoms ted. Cycloalkyl can include any number of carbons, such as C3-6, C4-6, Cs-6, C3.s, C4.s, Cs.s, and C6 Saturated monocyclic cycloalkyl rings 4b followed by page 5 include, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cyclooctyl. ted bicyclic and polycyclic cycloalkyl rings include, for example, norbornane, [2.2.2] bicyclooctane, decahydronaphthalene and adamantane. Cycloalkyl groups can also be partially unsaturated, having one or more double bonds in the ring. Representative cycloalkyl groups that are partially unsaturated e, but are not limited to, cyclobutene, cyclopentene, cyclohexene, cyclohexadiene (1,3- and 1,4-isomers), cycloheptene, cycloheptadiene, cyclooctene, cyclooctadiene (1,3—, 1,4- and 1,5—isomers), norbornene, and norbornadiene. Unless otherwise stated, cycloalkyl groups are unsubstituted. A "substituted cycloalkyl" group can be substituted with one or more moieties ed from halo, hydroxy, amino, alkylamino, nitro, cyano, and alkoxy.

As used herein, the term "heterocycloalkyl" refers to a saturated ring system having from 3 to 12 ring members and from 1 to 4 atoms selected from N, O and S.

Additional heteroatoms including, but not limited to, B, Al, Si and P can also be present in a heterocycloalkyl group. The atoms can be oxidized to form moieties such as, but not limited to, -S(O)- and -S(O)2-. Heterocycloalkyl groups can include any number of ring atoms, such as, 3 to 6, 4 to 6, 5 to 6, or 4 to 7 ring s. Any suitable number of heteroatoms can be included in the heterocycloalkyl groups, such as l, 2, 3, or 4, or 1 to 2, l to 3, l to 4, 2 to 3, 2 to 4, or 3 to 4. Examples of heterocycloalkyl groups include, but are not limited to, ine, azetidine, pyrrolidine, piperidine, azepane, azocane, quinuclidine, 2O pyrazolidine, imidazolidine, piperazine (1,2—, 1,3- and 1,4-isomers), oxirane, oxetane, tetrahydrofuran, oxane (tetrahydropyran), oxepane, thiirane, ne, thiolane (tetrahydrothiophene), thiane hydrothiopyran), oxazolidine, isoxazolidine, thiazolidine, azolidine, dioxolane, dithiolane, morpholine, thiomorpholine, dioxane, or dithiane.

Heterocycloalkyl groups are unsubstituted, but can be described, in some embodiments as substituted. "Substituted heterocycloalkyl" groups can be tuted with one or more moieties selected from halo, hydroxy, amino, mino, nitro, cyano, and alkoxy.

The term "aryl" or "aromatic ring" means, unless otherwise stated, a polyunsaturated, typically aromatic, hydrocarbon group which can be a single ring or multiple rings (up to three rings) which are fused together or linked covalently. Non-limiting examples of aryl groups e phenyl, naphthyl and yl.

As used herein, the term "heteroaryl" refers to a monocyclic or fused bicyclic or tricyclic aromatic ring assembly containing 5 to 16 ring atoms, where from 1 to 5 of the ring atoms are a heteroatom such as N, O or S. Additional heteroatoms including, but not limited to, B, Al, Si and P can also be present in a heteroaryl group. The heteroatoms can be oxidized to form moieties such as, but not limited to, -S(O)— and -S(O)2-. Heteroaryl groups can include any number of ring atoms, such as, 5 to 6, 5 to 8, 6 to 8, 5 to 9, 5 to 10, 5 to 11, or to 12 ring members. Any suitable number of heteroatoms can be included in the heteroaryl groups, suchas 1, 2, 3, 4, or 5, or 1 to2, 1 to3, 1 to4, 1 toS, 2to3, 2to4, 2to 5, 3 to4, or3 to 5. aryl groups can have from 5 to 8 ring members and from 1 to 4 heteroatoms, or from 5 to 8 ring s and from 1 to 3 heteroatoms, or from 5 to 6 ring members and from 1 to 4 atoms, or from 5 to 6 ring s and from 1 to 3 heteroatoms. Examples of heteroaryl groups include, but are not d to, pyrrole, pyridine, imidazole, pyrazole, triazole, ole, pyrazine, pyrimidine, pyridazine, triazine (1,2,3-, 1,2,4- and 1,3,5- isomers), thiophene, furan, thiazole, isothiazole, oxazole, and isoxazole, Heteroaryl groups are unsubstituted, but can be described, in some embodiments as substituted. "Substituted heteroaryl" groups can be substituted with one or more moieties selected from halo, hydroxy, amino, alkylamino, nitro, cyano, and alkoxy.

As used , the term "alkoxy" refers to an alkyl group having an oxygen atom that connects the alkyl group to the point of attachment: i.e., alkyl-O-. As for the alkyl portions, alkoxy groups can have any suitable number of carbon atoms, such as C1-6 or C1.4.

Alkoxy groups include, for example, methoxy, ethoxy, propoxy, iso-propoxy, butoxy, 2O 2-butoxy, iso-butoxy, sec-butoxy, tert-butoxy, pentoxy, , etc. Alkoxy groups are unsubstituted, but can be described, in some embodiments as substituted. "Substituted alkoxy" groups can be substituted with one or more moieties selected from halo, hydroxy, amino, alkylamino, nitro, cyano, and alkoxy.

As used herein, the terms "halo" and "halogen" refer to ?uorine, chlorine, bromine and iodine.

As used herein, the term "pharmaceutically acceptable" refers to a substance that is compatible with a compound of the invention, as well as with any other ingredients with which the nd is formulated. Furthermore, a pharmaceutically acceptable substance is not deleterious to the recipient of the substance. id="p-22" id="p-22" id="p-22" id="p-22" id="p-22" id="p-22" id="p-22" id="p-22" id="p-22" id="p-22" id="p-22" id="p-22" id="p-22" id="p-22"

[0022] As used herein, the term "salt" refers to an acid or base salt of a compound of the invention. aceutically acceptable salts can be derived, for e, from mineral acids (hydrochloric acid, hydrobromic acid, phosphoric acid, and the like), c acids (acetic acid, propionic acid, glutamic acid, citric acid and the like), and nary um ions.

It is tood that the pharmaceutically acceptable salts are non-toxic. Additional information on suitable pharmaceutically acceptable salts can be found in Remington's Pharmaceutical Sciences, 17th ed, Mack Publishing Company, , Pa, 1985, which is incorporated herein by nce.

The neutral form of a compound may be regenerated by ting the salt with a base or acid and isolating the parent compound in the conventional manner. The parent form of the compound differs from the various salt forms in certain physical ties, such as solubility in polar solvents, but otherwise the salts are equivalent to the parent form of the compound for the purposes of the invention.

Certain compounds of the present invention possess asymmetric carbon atoms (optical centers) or double bonds; the racemates, diastereomers, geometric isomers, regioisomers and individual isomers (e.g., separate enantiomers) are all ed to be encompassed within the scope of the present invention. When a stereochemical depiction is shown, it is meant to refer the compound in which one of the isomers is present and substantially free of the other isomer. "Substantially free of’ another isomer indicates at least a 70/30 ratio of the two isomers at the stereochemical center shown, more preferably 80/20, 90/10, or 95/5 or more. In some embodiments, one of the isomers will be t in an amount of at least 99%. id="p-25" id="p-25" id="p-25" id="p-25" id="p-25" id="p-25" id="p-25" id="p-25" id="p-25" id="p-25" id="p-25" id="p-25" id="p-25" id="p-25"

[0025] The compounds of the present invention may also contain unnatural proportions of atomic isotopes at one or more of the atoms that constitute such compounds. Unnatural tions of an isotope may be de?ned as ranging from the amount found in nature to an amount consisting of 100% of the atom in question. For example, the compounds may orate radioactive isotopes, such as m (3H), iodine-125 (1251) or carbon-l4 (14C), or non-radioactive isotopes, such as deuterium (2H) or carbon-l3 (13C). Such isotopic variations can provide additional utilities to those described elsewhere within this application. For instance, isotopic variants of the compounds of the invention may ?nd additional utility, including but not d to, as diagnostic and/or imaging reagents, or as cytotoxic/radiotoxic therapeutic agents. Additionally, isotopic variants of the compounds of the invention can 3O have altered pharmacokinetic and pharmacodynamic characteristics, which can bute to enhanced safety, tolerability or cy during treatment. All isotopic variations of the compounds of the present invention, whether radioactive or not, are intended to be encompassed within the scope of the present invention. When speci?cally referred to, such as, C1-C4 deuteroalkyl — the term refers to an alkyl group with the indicated number of carbon atoms and having en atoms replaced by deuterium in a number of from one to a per- deutero form, wherein the deuterium replacement is greater than the natural abundance of deuterium — typically 50%, 60%, 70%, 80%, 90%, 95% or more deuterium replacement.

Examples of C1-C4 deuteroalkyl are -CD3, —CH2CD3, -CD2CD3, 2CH2D, and the like.

As used herein, the term "pharmaceutical composition" refers to a t comprising a compound of the invention, an excipient as de?ned herein, and other optional ingredients in ied amounts, as well as any product which results ly or indirectly from combination of the speci?ed ingredients in the speci?ed amounts.

As used herein, the term "excipient" refers to a substance that aids the administration of an active agent to a t. Pharmaceutical excipients useful in the present invention include, but are not limited to, binders, ?llers, disintegrants, lubricants, gs, sweeteners, ?avors and colors. One of skill in the art will recognize that other excipients can be useful in the present invention.

As used herein, the terms "treat," "treating" and "treatment" refer to any indicia of success in the treatment or amelioration of a pathology, injury, condition, or symptom related to dilated cardiomyopathy, including any objective or subjective parameter such as abatement, remission, diminishing of symptoms; making the ogy, injury, condition, or m more tolerable to the patient; decreasing the frequency or duration of the pathology, injury, condition, or symptom; or, in some situations, ting the onset of the pathology, injury, condition, or symptom. Treatment or amelioration can be based on any objective or subjective parameter; including, e.g., the result of a physical examination.

III. nds id="p-29" id="p-29" id="p-29" id="p-29" id="p-29" id="p-29" id="p-29" id="p-29" id="p-29" id="p-29" id="p-29" id="p-29" id="p-29" id="p-29"

[0029] In one aspect, provided herein are nds having the formula: O OQg/Arz Ar —NH1 VOW3 2 R R (I) or a pharmaceutically acceptable salt thereof, wherein Ar1 is a 5- to 6-membered heteroaryl having at least one en atom ring member, and which is optionally substituted with from 1-3 Ra; Ar2 is a 5- to lO-membered aryl or heteroaryl which is optionally substituted with from 1-5 R1 and R2 are each ndently a member selected from the group consisting of H, F, C1-C4 alkyl, C1-C4 deuteroalkyl, and C1-C4 haloalkyl, or optionally R1 and R2 can be combined to form a C3- to C5 carbocyclic ring which is ally tuted with one or two F, R3 is a member selected from the group consisting of H, F, OH and C1-C4 alkyl; each R8 is independently selected from the group ting of halo, CN, yl, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 yalkyl, C1-C4 alkoxy, C1-C4 haloalkoxy, -CORa1, -C02Ra1, -s02Ra1, -SOzNRa1R32, and -CONRa1Ra2, wherein each Ral and Ra2 is independently selected from the group consisting ofH and C1-C4 alkyl or optionally Ral and R212 when attached to a nitrogen atom are combined to form a 4- to 6- membered ring; or optionally, two Rb substituents on adjacent ring s are combined to form a 5- or 6-membered ring having 0, l or 2 ring members selected from O, N and S; and each Rb is independently selected from the group consisting of halo, CN, hydroxyl, C1-C4 alkyl, C1-C4 oalkyl, C1-C4 kyl, C1-C4 alkoxy, C1-C4 haloalkoxy, C3-C6 cycloalkyl, -NRb1Rb2, -CORb1, 430211", —SOszl, -SOzNRb1Rb2, —CONRb1Rb2, and a - or 6-membered aryl which is optionally substituted with C1-C4 alkyl, and 2O wherein each Rb1 and sz is independently selected from the group consisting ofH and C1-C4 alkyl or optionally Rb1 and RI32 when attached to a nitrogen atom are combined to form a 4- to 6- membered ring; or optionally, two Rb tuents on adjacent ring members are combined to form a 5- or 6-membered ring having 0, l or 2 ring members selected from O, N and S. id="p-30" id="p-30" id="p-30" id="p-30" id="p-30" id="p-30" id="p-30" id="p-30" id="p-30" id="p-30" id="p-30" id="p-30" id="p-30" id="p-30"

[0030] In some embodiments, compounds are provided of Formula I, or a ceutically acceptable salt thereof, wherein Ar1 is selected from the group consisting of pyridyl, pyridazinyl, oxazolyl, isoxazolyl, pyrazolyl, 1,2,3-thiadiazolyl, isothiazolyl, and thiazolyl, each of which is optionally substituted with from 1 or 2 Ra.

In other embodiments, compounds are provided of Formula I, or a pharmaceutically acceptable salt thereof, wherein Ar2 is selected from the group consisting of phenyl, pyridyl and pyrazolyl, each of which is optionally substituted with from 1 to 3 Rb. In some of these embodiments, Rb is selected from the group consisting of halo, CN, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy and C1-C4 haloalkoxy.

In yet other embodiments, compounds are provided of Formula I, or a pharmaceutically acceptable salt f, wherein R1 is selected from the group consisting of H, F and CH3.

In still other embodiments, compounds are provided of Formula I, or a pharmaceutically acceptable salt thereof, wherein R2 is selected from the group consisting of H, F and CH3.

In some embodiments, compounds are provided of a I, or a pharmaceutically acceptable salt f, R1 and R2 taken together with the carbon atom to which each is attached to form a cyclopropane or cyclobutane ring. id="p-35" id="p-35" id="p-35" id="p-35" id="p-35" id="p-35" id="p-35" id="p-35" id="p-35" id="p-35" id="p-35" id="p-35" id="p-35" id="p-35"

[0035] In other ments, compounds are provided of Formula I, or a pharmaceutically acceptable salt thereof, wherein R1 and R2 are each F.

In other embodiments, compounds are provided of a I, or a pharmaceutically acceptable salt thereof, wherein R1 75 R2, and one of R1 or R2 is selected from F and CH3 to form a quaternary chiral center. id="p-37" id="p-37" id="p-37" id="p-37" id="p-37" id="p-37" id="p-37" id="p-37" id="p-37" id="p-37" id="p-37" id="p-37" id="p-37" id="p-37"

[0037] In other embodiments, compounds are provided of Formula I, or a pharmaceutically acceptable salt thereof, wherein R1 75 R2, and one of R1 or R2 is selected from F and CH3 to form a quaternary chiral center having a R con?guration.

In yet other ments, compounds are provided of a I, or a pharmaceutically acceptable salt thereof, wherein R3 is H or F. id="p-39" id="p-39" id="p-39" id="p-39" id="p-39" id="p-39" id="p-39" id="p-39" id="p-39" id="p-39" id="p-39" id="p-39" id="p-39" id="p-39"

[0039] In some particular embodiments, compounds are ed of Formula I, or a pharmaceutically acceptable salt thereof, wherein Arl is 4-pyridinyl and Ar2 is phenyl, optionally substituted with from 1 to 3 Rb. In still other embodiments, R3 is H, and each of R1 and R2 is F. In yet other embodiments, R3 is H, and each of R1 and R2 is CH3. In other embodiments, R3 is H, R1 is CH3, and R2 is F. id="p-40" id="p-40" id="p-40" id="p-40" id="p-40" id="p-40" id="p-40" id="p-40" id="p-40" id="p-40" id="p-40" id="p-40" id="p-40" id="p-40"

[0040] In other particular embodiments, compounds are provided of Formula I, or a pharmaceutically acceptable salt thereof, wherein Arl is daziny1 and Ar2 is , optionally substituted with from 1 to 3 Rb. In still other embodiments, R3 is H, and each of R1 and R2 are F. In yet other embodiments, R3 is H, and each of R1 and R2 are CH3. In other embodiments, R3 is H, R1 is CH3, and R2 is F.

In still other particular embodiments, compounds are provided of Formula I, or a pharmaceutically acceptable salt f, wherein Ar1 is selected from the group consisting of oxazol-S-yl, isoxazolyl, isoxazolyl, pyrazolyl, pyrazolyl, 1,2,3-thiadiazolyl, azol-S-yl, and l-S-yl, each of which is ally substituted with one Ra. In still other embodiments, R3 is H, and each of R1 and R2 are F. In yet other embodiments, R3 is H, and each of R1 and R2 are CH3. In other embodiments, R3 is H, R1 is CH3, and R2 is F.

In other selected embodiments, compounds are provided of Formula I, or a pharmaceutically acceptable salt thereof, wherein R1 and R2 are not the same, and at least one of R1 and R2 is F or CH3 to form a chiral center at the carbon atom bearing R1 and R2 that has a R—conflguration.

In some selected embodiments, compounds are provided of a I, or a pharmaceutically acceptable salt thereof, selected from Table 2 and having an activity level of ++ or +++, In some embodiments, compounds are provided of Formula I, or a pharmaceutically acceptable salt thereof, selected from: F F o o N/ \ N / \ N N N\ N — H H F F ON? 0%,? O>‘- CH8 0 / N / \ >—WN \ N N F N N \ F H \_ F N— N F F o 0°59 {N F o 0%? {N O/ N\ >_N g" N\ / N\ N ’ \ N N>—N<:>?/l"’ \ F F H — H F F O 0°91? C1 \| \\'ll O 0%? O’N\ yNO?/ F I / \ F F >?/I, \ F F o \‘N/ o o (N, F, O’N\ yN \ 0’N\ >LN F NH F NH F \ \ The compounds or their ceutically acceptable salts provided herein can have any combination of the Arl, Arz, R1, R2, R3, Ra, Ral, Raz, Rb, Rb1 and sz groups recited above. Selected embodiments recited for R2, for example, can be combined with any of the selected embodiments recited for R1 which, in turn, can be combined with any of the selected embodiments recited for R3 or Ar1 or Arz.

The compounds of a (I) can be prepared by methods as generally outlined in Figures 1A, 1B and 1C, or as provided in the Examples and ed in Table 1. One skilled in the art will appreciate that the nds of invention can be prepared using other synthetic methods, including transformations as described in, for example, LaRock (Comprehensive Organic Transformations: A Guide to Functional Group Preparations, Wiley, 1999), as substitutes for transformations provided in the Examples.

IV. Compositions In another aspect, provided herein is a pharmaceutical composition containing a compound of formula I or a ceutically acceptable salt f and a pharmaceutically acceptable excipient. The compositions are useful for treating dilated cardiomyopathy in humans and other subjects. id="p-48" id="p-48" id="p-48" id="p-48" id="p-48" id="p-48" id="p-48" id="p-48" id="p-48" id="p-48" id="p-48" id="p-48" id="p-48" id="p-48"

[0048] The pharmaceutical compositions for the administration of the compounds or their pharmaceutically acceptable salts provided herein may conveniently be presented in unit dosage form and may be prepared by any of the methods known in the art of pharmacy and drug delivery. All methods include the step of bringing the active ingredient into association with a carrier containing one or more accessory ingredients. In l, the pharmaceutical compositions are prepared by uniformly and intimately bringing the active ingredient into association with a liquid carrier or a ?nely divided solid carrier or both, and then, if necessary, shaping the product into the desired formulation. In the pharmaceutical composition, the active agent is generally included in an amount suf?cient to increase myocardial contractility (i.e. to improve the ic dysfunction in DCM) and to e or not worsen left ventricular tion in diastole. Such improved relaxation can alleviate symptoms in dilated cardiomyopathy and other gies of diastolic ction, such as heart failure with preserved ejection fraction (HFpEF). It can also ameliorate the effects of diastolic dysfunction causing impairment of coronary blood flow, improving the latter as an adjunctive agent in angina pectoris and ischemic heart disease, It can also confer bene?ts on salutary left ventricular remodeling in DCM and other causes of left ventricular dysfunction due to ischemic heart disease or chronic volume or pressure overload from, e.g., myocardial infarction, valvular heart disease or systemic hypertension The pharmaceutical compositions ning 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 es, syrups, elixirs, solutions, buccal patch, oral gel, chewing gum, chewable tablets, effervescent powder and effervescent tablets. Compositions intended for oral use may be ed ing to any method known to the art for the manufacture of pharmaceutical compositions and such compositions may n one or more agents selected from the group consisting of ning agents, ?avoring agents, coloring agents, antioxidants and preserving agents in order to provide pharmaceutically elegant and palatable preparations. Tablets contain the active ingredient in admixture with non-toxic pharmaceutically acceptable excipients which are suitable for the cture of tablets. These excipients may be for example, inert diluents, such as cellulose, silicon dioxide, aluminum oxide, m carbonate, sodium carbonate, e, mannitol, sorbitol, lactose, calcium phosphate or sodium phosphate; granulating and 3O disintegrating agents, for e, corn starch, or alginic acid; binding agents, for example PVP, cellulose, PEG, starch, gelatin or acacia, and lubricating agents, for example ium stearate, stearic acid or talc. The tablets may be uncoated or they may be coated, enterically or otherwise, 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 to form osmotic therapeutic tablets for controlled release.

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

Additionally, emulsions can be prepared with a non-water miscible ingredient such as oils and stabilized with surfactants such as mono-diglyceiides, PEG esters and the like. s suspensions n the active materials in admixture with excipients suitable for the cture of aqueous sions. 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 ?avoring agents, and one or more sweetening , such as sucrose or rin. id="p-52" id="p-52" id="p-52" id="p-52" id="p-52" id="p-52" id="p-52" id="p-52" id="p-52" id="p-52" id="p-52" id="p-52" id="p-52" id="p-52"

[0052] 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 paraf?n. The oily suspensions may contain a thickening agent, for example beeswax, hard paraf?n or cetyl alcohol. Sweetening agents such as those set forth above, and ?avoring agents may be added to provide a palatable oral preparation. These itions 3O may be preserved by the addition of an anti—oxidant such as ascorbic acid.

Dispersible s and granules suitable for preparation of an aqueous sion 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 sing or g agents and suspending agents are i?ed by those already mentioned above.

Additional excipients, for example sweetening, ?avoring and coloring agents, may also be present.

The pharmaceutical compositions provided herein 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 paraf?n or mixtures of these. Suitable emulsifying agents may be naturally-occurring gums, for e gum acacia or gum tragacanth, naturally- occurring phosphatides, for example soy bean, lecithin, and esters or l 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 ?avoring agents.

Syrups and elixirs may be formulated with sweetening agents, for e glycerol, propylene glycol, sorbitol or sucrose. Such formulations may also contain a ent, a preservative and ?avoring and coloring agents. Oral solutions can be prepared in combination with, for example, cyclodextrin, PEG and surfactants.

The pharmaceutical compositions may be in the form of a sterile injectable aqueous or oleagenous suspension. This suspension may be formulated ing 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 on 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 on and isotonic sodium chloride solution. In addition, e, ?xed oils are tionally employed as a solvent or suspending medium. For this purpose any bland ?xed oil may be employed including synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid ?nd use in the ation of injectables.

The compounds or their pharmaceutically acceptable salts provided herein may also be stered 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 cocoa butter and hylene glycols. Additionally, the compounds can be stered via ocular delivery by means of solutions or ointments. Still further, transdermal delivery of the subject compounds can be accomplished by means of iontophoretic patches and the like. For topical use, creams, ointments, jellies, solutions or suspensions, etc, containing the compounds or their pharmaceutically acceptable salts provided herein are employed. As used , topical ation is also meant to include the use of mouth washes and s.

The compounds of this invention may also be coupled to a carrier that is a suitable polymer for targetable drug carriers. Such polymers can e polyvinylpyrrolidone, pyran copolymer, polyhydroxy-propyl-methacrylamide-phenol, polyhydroxyethyl-aspartamidephenol , or polyethyleneoxide-polylysine substituted with palmitoyl residues. Furthermore, the compounds or their pharmaceutically acceptable salts provided herein may be coupled to a carrier that is a radable polymer useful in achieving controlled e of a drug, such as polylactic acid, polyglycolic acid, copolymers of ctic and polyglycolic acid, polyepsilon caprolactone, polyhydroxy butyric acid, polyorthoesters, polyacetals, polydihydropyrans, polycyanoacrylates and cross linked or amphipathic block copolymers of hydrogels. Polymers and semipermeable polymer matrices may be formed into shaped articles, such as valves, stents, tubing, eses and the like.

V. Methods of treating cardiac disorders The mutations that lead to DCM cause cant perturbations in myosin mechanics. These ons exert their effects via distinct mechanisms depending on their locations in the myosin gene. Without wishing to be bound by any particular theory, it is believed that the compounds or their pharmaceutically acceptable salts provided herein can bind directly to the mutant sarcomeric proteins and correct for their aberrant function, either in cis (by affecting the same speci?c function) or in trans (by altering a complementary on). As such, they can provide therapeutic benefit for DCM ts by racting the hypocontractile and/or impaired relaxation associated with this disease. Additionally, these compounds that increase systolic function hold promise of treating a wide spectrum of disorders in which symptoms and/or clinical outcomes are attributable to systolic dysfunction (left or right sided heart failure) or a reduction in systolic e (eg. HFpEF).

Accordingly, the invention provides a method of ng dilated cardiomyopathy (DCM) or a cardiac disorder having one or more pathophysiological features associated with DCM, such as disorders with systolic dysfunction or a reduction in systolic reserve. The method es administering to a subject in need thereof an effective amount of a compound provided herein.

The compounds of the invention or their pharmaceutically acceptable salts can alter the natural history of DCM and other diseases rather than merely palliating symptoms. The mechanisms conferring clinical bene?t to DCM ts can extend to patients with other forms of heart disease sharing similar pathophysiology, with or without trable genetic in?uence. For example, an effective ent for DCM, by improving ventricular contraction, can also be ive in a broader tion characterized by systolic dysfunction. The compounds of the invention or their pharmaceutically acceptable salts can speci?cally target the root causes of the conditions or act upon other ream ys. Accordingly, the compounds of the invention or their pharmaceutically acceptable salts can also confer benefit to patients suffering from heart failure with reduced ejection fraction (HFrEF), HFpEF, chronic congestive heart failure, acute heart failure, right-sided (or right ventricular) heart failure, genic shock and inotropic support after cardiac surgery. nds of the ion or their pharmaceutically acceptable salts can potentially improve cardiac function in the following t segments: idiopathic dilated cardiomyopathy, genetically defined or al dilated cardiomyopathy, ischemic or post- infarction mardiomyopathy, viral cardiomyopathy or myocarditis, toxic cardiomyopathies (eg. post-anthracycline anticancer therapy), metabolic cardiomyopathies (in conjunction with enzyme replacement therapy), diastolic heart failure (with diminished systolic reserve), right heart failure due to pulmonary hypertension, and cular dysfunction due to on-bypass cardiovascular surgery. Compounds of the ion or their pharmaceutically acceptable salts can also promote salutary ventricular reverse remodeling of left ventricular dysfunction due to ischemia or volume or pressure overload; e.g, myocardial infarctions, chronic mitral regurgitation, chronic aortic stenosis, or chronic systemic hypertension. By reducing left ventricular ?lling pressures the compounds could improve the symptom of dyspnea and reduce the risk of pulmonary edema and respiratory failure. Reducing or eliminating onal mitral regurgitation and/or lowering left atrial pressures may reduce the risk of paroxysmal or permanent atrial fibrillation, and with it reduce the attendant risk of arterial thromboembolic cations including but not limited to cerebral arterial embolic stroke.

The compounds or their pharmaceutically acceptable salts may reduce the severity of the chronic ischemic state associated with DCM and thereby reduce the risk of Sudden Cardiac Death (SCD) or its equivalent in ts with implantable cardioverter-de?brillators (frequent and/or repeated ICD discharges) and/or the need for potentially toxic antiarrhythmic medications. The nds or their pharmaceutically acceptable salts could be valuable in reducing or eliminating the need for concomitant medications with their attendant potential toxicities, drug-drug interactions, and/or side effects. The nds or their pharmaceutically acceptable salts may reduce interstitial myocardial s and/or slow the progression, , or e left ventricular stiffness and diastolic dysfunction.

Depending on the disease to be treated and the subject’s condition, the compounds or their pharmaceutically acceptable salts provided herein may be stered by oral, parenteral (e.g., intramuscular, intraperitoneal, intravenous, ICV, intracisternal injection or infusion, subcutaneous injection, or implant), by implantation (e.g., as when the compound is coupled to a stent device), by inhalation spray, nasal, vaginal, rectal, sublingual, or topical routes of administration and may be formulated, alone or together, in le dosage unit formulations containing conventional non—toxic pharmaceutically acceptable carriers, adj uvants and vehicles appropriate for each route of administration. id="p-63" id="p-63" id="p-63" id="p-63" id="p-63" id="p-63" id="p-63" id="p-63" id="p-63" id="p-63" id="p-63" id="p-63" id="p-63" id="p-63"

[0063] In the treatment or prevention of conditions which require improved ventricular contraction without ment of diastolic tion, an appropriate dosage level will generally be about 0.001 to 100 mg per kg patient body weight per day which can be administered in single or multiple doses. Preferably, the dosage level will be about 0.01 to about 25 mg/kg per day, more preferably about 0.05 to about 10 mg/kg per day. A suitable dosage level may be about 0.01 to 25 mg/kg per day, about 0.05 to 10 mg/kg per day, or about 0.1 to 5 mg/kg per day. Within this range the dosage may be 0.005 to 0.05, 0.05 to 0.5 or 0.5 to 5.0 mg/kg per day. For oral administration, the compositions are preferably provided in the form of tablets containing 1.0 to 1000 milligrams of the active ingredient, particularly 1.0, 5.0, 10.0, 15.0, 20.0, 25.0, 50.0, 75.0, 100.0, 150.0, 200.0, 250.0, 300.0, 400.0, 500.0, 600.0, 750.0, 800.0, 900.0, and 1000.0 milligrams ofthe active ingredient for the symptomatic adjustment of the dosage to the patient to be treated. The compounds may be stered on a regimen of l to 4 times per day, ably once or twice per day.

It will be understood, however, that the speci?c dose level and frequency of dosage for any particular patient may be varied and will depend upon a variety of factors including the activity of the speci?c compound employed, the metabolic stability and length of action of that compound, the age, body weight, hereditary characteristics, l health, sex and diet of the subject, as well as the mode and time of administration, rate of excretion, drug combination, and the ty of the particular condition for the t undergoing therapy.

Compounds and compositions provided herein may be used in combination with other drugs that are used in the treatment, prevention, suppression or amelioration of the diseases or conditions for which compounds and compositions provided herein are useful.

Such other drugs may be stered, by a route and in an amount ly used therefor, contemporaneously or sequentially with a nd or composition provided herein. When a compound or composition provided herein is used contemporaneously with one or more other drugs, a pharmaceutical composition containing such other drugs in addition to the compound or composition ed herein is preferred. Accordingly, the pharmaceutical compositions provided herein include those that also contain one or more other active ingredients or therapeutic , in addition to a compound or ition provided herein.

Suitable additional active agents include, for example: therapies that retard the progression of heart failure by down-regulating neurohormonal stimulation of the heart and attempt to t cardiac remodeling (e.g., ACE inhibitors, angiotensin receptor blockers (ARBs), [3- blockers, aldosterone receptor antagonists, or neural endopeptidase inhibitors), therapies that e cardiac function by ating cardiac contractility (e.g., positive inotropic agents, such as the B-adrenergic agonist dobutamine or the phosphodiesterase inhibitor milrinone), and therapies that reduce cardiac preload (e.g., diuretics, such as furosemide) or afterload (vasodilators of any class, including but not limited to calcium channel blockers, phosphodiesterase inhibitors, endothelin receptor antagonists, renin inhibitors, or smooth muscle myosin modulators). The compounds or their pharmaceutically acceptable salts may be used in combination with a beta-blocker (a drug class with known side-effects due to ve inotropic effect) to confer unique tolerability of beta-blocker titration to target doses.

The nds or their pharmaceutically acceptable salts may be used in combination with a lusitropic agent for the treatment of lic heart failure (or HFpEF, a disorder with diastolic dysfunction and reduced systolic e). The weight ratio of the compound provided herein to the second active ingredient may be varied and will depend upon the effective dose of each ingredient. Generally, an effective dose of each will be used. 3O VI. Examples aq: aqueous; BBr3: boron tribromide; BTC: Bis(t1ichloromethyl) carbonate; CH2C12: dichloromethane; CH3CN: acetonitrile; CH3OH: methanol, DAST: Diethylaminosulfur tri?uoride; DIAD: diisopropyl azodicarboxylate; DIEA: diisopropyl ethylamine; DMF: dimethyl formamide; DMSO: dimethyl ide; dppf: [1;1’- Bis(diphenylphosphino)ferrocene]dichloropalladium(II); complex with dichloromethane; DPPA: Diphenylphosphoryl azide; equiv.: equivalent(s); Et3N: trimethylamine; EtzO: diethyl ether; EtOH: ethanol; h; hr: hour(s); HATU: (1-[Bis(dimethylamino)methylene]—1H-1;2;3- triazolo[4;5-b]pyridinium 3-oxid hexa?uorophosphate); HCl: en de; H20: water; K2C03: potassium carbonate; KHSO4: potassium bisulfate; KNCO: potassium isocyanate; LDA: lithium diisopropylamide; mCPBA: meta-chloroperbenzoic acid; MgSO4: magnesium sulfate; mL: milliliter(s); MW: ave (reaction done in a microwave reactor); NaCl: sodium chloride; NaH: sodium hydride; NaHCO3: sodium bicarbonate; NaOEt: sodium de; NaOH: sodium hydroxide; NaOMe: sodium methoxide; NaZSO4: sodium sulfate; Na2803: sodium sul?te; NBS: N—Bromosuccinimide; NFSI: robenzenesulfonimide; NH4Cl: ammonium chloride; NMP: n—methyl pyrrolidinone; pH: -log [H+]; POCl3: phosphoryl trichloride; PPTS: pyridinium p—toluenesulfonate; RP-HPLC: reversed phase high pressure liquid chromatography; RT: room temperature; RTX: retention time; SFC: Supercritical ?uid chromatography; TEBAC: triethylbenzylammonium chloride; TFA: tri?uoroacetic acid; and THF: tetrahydrofuran.

Exam le 1. Pre aration of 4- 1-iso r0 l-lH— razol lsulfon lmeth l-N- ridin l i eridine—l-carboxamide.

TsCI, Et3N BocN —> BocN OH DMAP, CHZCIZ OTS Compound 1.1. tert—Butyl 4-((tosyloxy)methyl)piperidine—1-carboxylate.

A on of tert-butyl 4-(hydroxymethyl)piperidine—1-carboxylate (50 g; 232.25 mmol; 1.00 equiv); triethylamine (35.2 g; 347.86 mmol; 1.50 equiv); 4- dimethylaminopyridine (2.8 g; 22.92 mmol, 0.10 equiv) and 4-methylbenzene—1-su1fony1 chloride (53 g, 278.00 mmol, 1.20 equiv) in CH2C12 (500 mL) was d under argon overnight at room ature. The solids were removed by ?ltration, and the ?ltrate was concentrated under reduced pressure. The resulting residue was puri?ed by silica gel column (Ethyl Acetate/Petroleum ether = 1/3 9v/v)) to provide 78 g (91%) as a yellow solid. 1H- NMR (400 MHz; DMSO-d6): 6 7.78 (d, J=8.4Hz, 2H); 7.48 (d, J=8.4Hz; 2H); 3.87 (m; 4H); 2.49 (m; 2H); 2.42 (s; 3H); 1.76 (m; 1H), 1.53 (m; 2H); 1.36 (s; 9H); 0.96 (m; 2H) ppm.

HZN NH2 B NC>_\00 3°CNC>1 OT3 Kl, CH3OH (NH Compound 1.2. tert—Butyl 4-((carbamimidoylthio)methyl)piperidine—l-carboxylate.

A solution of tert-butyl 4-((tosyloxy)methyl)piperidine-l-carboxylate (1.1, 11 g, 29.77 mmol, 1.00 equiv), thiourea (4.5 g, 59.13 mmol, 2.00 equiv) and potassium iodide (2.47 g, 14.88 mmol, 0.50 equiv) in CH3OH (110 mL) was stirred overnight at 70 °C under argon. The reaction mixture was cooled to room temperature and trated under reduced pressure. The resulting product (15 g, crude) was used as is in the next on without further puri?cation.

BOCN NH H o2 SH NH2 Compound 1.3. tert—Butyl 4-(mercaptomethyl)piperidine—l-carboxylate.

A on of tert-butyl 4-((carbamimidoylthio)methyl)piperidinecarboxylate (1.2, 15 g, 1.00 equiv, crude) and sodium ide (2.2 g, 55.00 mmol, 1.00 equiv) in 1:2 (v/v) CH3OH/H20 (150 mL) was stirred for 2 h at 60 °C under argon. Then the reaction mixture was cooled to room temperature. The pH value of the solution was adjusted to 7 with HCl(aq) (35 %). The resulting solution was ted with EtOAc (3x50 mL) and the organic layers were ed. The organic layer was washed with brine (2x50 mL). The mixture was dried over anhydrous Na2804, ?ltered and concentrated under reduced pressure. The resulting residue was puri?ed by silica gel chromatography (EtOAc/petroleum ether = 1:8 (v/v)) to provide 5.6 g (44%) as yellow oil. 1H-NMR (400 MHz, CDC13): 5 4.13 (m, 2H), 2.69 (m, 2H), 2.46 (m, 2H), 1.82 (m, 2H), 1.50 (s, 9H), 1.32 (m,1H), 1.18 (m, 2H) ppm.

Y my -0. so-N SH Xantphos,DIPEA,Pd2(dba)3, 1,4-dioxane 7/ Compound 1.4. utyl 4-(((1-isopropyl-lH-pyrazolyl)thio)methyl)piperidine carboxylate.

A solution of tert—butyl 4-(mercaptomethyl)piperidine-l-carboxylate (1.3, 300 mg, 1.30 mmol, 1.00 equiv), Xantphos (123 mg, 0.21 mmol, 0.20 equiv), Pd2(dba)3-CHCl3 (144 mg, 0.10 , 4-bromo-l(propanyl)-lH-pyrazole (246 mg, 1.30 mmol, 1.00 equiv) and N,N—diisopropylethylamine (195 mg, 1.51 mmol, 1.50 equiv) in 1,4-dioxane (5 mL) was stirred overnight at 90 0C under argon. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The resulting residue was puri?ed by silica gel tography (EtOAc/petroleum ether = 7:3 (v/V)) to e 400 mg (crude) of a yellow oil. The product was used directly in the next step without further ation.

BOCN/\:>—\s\\37/ Oxone BOCNC>_’\84<:I?J0’|l \ N DMF 0 Compound 1.5. tert—Butyl 4-(((1-isopropyl-lH-pyrazolyl)sulfonyl)methyl)piperidine- 1-carboxylate.

A solution of tert-butyl -isopropyl—1H-pyrazolyl)thio)methyl)piperidine carboxylate (1.4, 400 mg, 1.18 mmol, 1.00 equiv) and Oxone (2.17 g, 3.00 equiv) in DMF (10 mL) was stirred overnight at room temperature under argon. The solids were d by ?ltration, and the ?ltrate was diluted with EtOAc (25 mL). The ?ltrate was washed with H20 (3x15 mL), dried over anhydrous Na2804, ?ltered, and concentrated under reduced pressure to provide 200 mg (crude) of a yellow oil. The product was used directly in the next step without further puri?cation.

BOCQso\ HQso\ Compound 1.6. 4-(((1-Isopropyl-1H-pyrazol-4—yl)sulfonyl)methyl)piperidine.

A solution of tert-butyl 4—(((l—isopropyl—1H—pyrazol yl)sulfonyl)methyl)piperidine-l-carboxylate (1.5, 200 mg, 0.54 mmol, 1.00 equiv) in tri?uoroacetic HzClz (1 :1 (v/v), 10 mL) was stirred for 2 h at room temperature under argon, and then was concentrated under reduced pressure to provide 100 mg (crude) of a yellow oil. The product was used directly used in the next step without further puri?cation. my 4 MEN— o /\ >\—~ \N H \ —> N_ 03% \ O 7/ BTC, DIPEA, THF 0 7/ Compound 1. 4-(((1-Isopropyl-1H-pyrazolyl)sulfonyl)methyl)-N-(pyridin eridine—l-carboxamide.

To a solution of pyridin—4—amine (34.7 mg, 0.368mmol, 1.00 equiv.) and BTC (43.7 mg, 0.40 equiv.) in THF (3 mL) under argon was added N,N—diisopropylethylamine (143 mg, 1.11 mmol, 3.00 equiv) dropwise with stirring at 0 °C. The resulting solution was stirred for min at 0 °C before a solution of 4—(((1—isopropyl—1H-pyrazol yl)sulfonyl)methyl)piperidine (1.6, 100 mg, 0.37 mmol, 1.00 equiv.) in THF (1 mL) was added dropwise with stirring at 0 °C. The resulting solution was stirred for 1 h at 0 0C before being quenched by the addition of saturated Na2C03(aq) (10 mL). The resulting solution was extracted with EtOAc (2X20 mL), and the combined organic layers were concentrated under reduced re. The residue was d by Prep-HPLC [Column: X Bridge C18, 19*150 mm, 5 um, Mobile Phase A: Water/10mmol/L NH4HCO3, Mobile Phase B: ACN; Flow rate: mL/min, Gradient: 25%B to 65%B in 8 min; Detector UV, 254nm] to e 8.7 mg (6%) of a white solid. LC-MS (ES, m/z): 392 [M+H]+, 1H-NMR (400 MHz, g): 6 8.89 (s, 1H), 8.48 (s, 1H), 8.29 (d, J=6.4Hz, 2H), 7.91 (s, 1H), 7.46 (m, 2H), 4.60 (m, 1H), 4.01 (m, 2H), 3.29 (m, 2H), 2.87 (m, 2H), 2.07 (m, 1H), 1.81 (m, 2H), 1.45 (m, 6H), 1.27 (m, 2H) ppm.

Exam le 2. Pre aration of N- trifluoromethox hen lsulfon lc clo ro l i eridine—l-carboxamide. _ CI HS‘Q—OCQ _ sgiom=3 \ / K2C03, DMF, rt Compound 2.1. 4-(((4-(Trifluoromethoxy)phenyl)thio)methyl)pyridine.

A solution of of 4-(chloromethyl)pyridine (625 mg, 4.90 mmol, 1.00 equiv), K2C03 (1.35 g, 9.70 mmol, 2.00 equiv) and 4-(tri?uoromethoxy)benzenethiol (950 mg, 4.89 mmol, 1.00 equiv) in DMF (10 mL) was stirred overnight at room temperature under argon, and the solids were removed by ion. The ?ltrate was diluted with H20 (30 mL), and the ing solution was extracted with EtOAc (3x20 mL). The ed organic layers were washed with brine (2x20 mL), dried over anhydrous NaZSO4, ?ltered and concentrated under reduced pressure. The resulting residue was puri?ed on silica gel (EtOAc/petroleum ether) to provide 1.3 g (93%) ofa light yellow oil. 3~~om=3 O\I _ mCPBA ‘SI—QOCFg N\ / DCM, Compound 2.2. 4-(((4-(Trifluoromethoxy)phenyl)sulfonyl)methyl)pyridine.

A solution of 4-(((4-(tri?uoromethoxy)phenyl)thio)methyl)py1idine (2.1, 800 mg, 2.80 mmol, 1.00 equiv) and mCPBA (1.07 g, 6.17 mmol, 2.20 equiv) in CH2C12 (20 mL) was stirred for 2 h at room ature under argon. The on was then washed with saturated Na2C03(aq) (2x20 mL) and brine (20 mL). The organic layer was dried over anhydrous Na2804, ?ltered and concentrated under reduced pressure. The resulting residue was puri?ed on silica gel (EtOAc/petroleum ether = 1/1 (v/v)) to provide 900 mg (96%) of a white solid.

MS (ES, m/z): 318 [M+H]+. 0 Br 0 O\I‘sLroa V\ Cl x‘ _ S—QOCFSu N/\\:/>—/ N \ / 032003, TBAB, DMSO, Compound 2.3. 4-(l-((4-(Tri?uoromethoxy)phenyl)sulfonyl)cyclopropyl)pyridine.

A solution of 4-((4-(tri?uoromethoxy)phenylsulfonyl)methyl)pyridine (2.2, 770 mg, 2.43 mmol, 1.00 equiv), 1-bromochloroethane (1.47 g, 10.25 mmol, 3.00 equiv), CS2CO3 (2.37 g, 7.27 mmol, 3.00 equiv) and tetrabutylammonium bromide (157 mg, 0.49 mmol, 0.20 equiv) in DMSO (20 mL) was stirred for 2 h at room temperature under argon. The reaction was then quenched by the addition of H20 (30 mL), and was extracted with EtOAc (2x30 mL). The ed organic layers were washed with bline (2x20 mL), dried over anhydrous , d, and concentrated under reduced pressure, The resulting residue was puri?ed on silica gel (EtOAc/petroleum ether = 2/3 (v/v)) to provide 600 mg (72%) of a light yellow solid. Ms (ES, m/z): 344 [M+H]+, 1H—NMR (300 MHz, : 5 8.51 (d, J=6.0 Hz, 2H), 7.55 (d, J=7.6 Hz. 2H), 7.25 (d, J=7.6 Hz. 2H), 7.13 (d, J=6.0 Hz, 2H), 1.97—2.09 (m, 2H), 1.28-1.34 (m, 2H) ppm.

O O _ OQSH‘Q’OCFa PtOZ, H2(g), 3N HCI o°S"~©700B dioxane, 5 atm, rt Compound 2.4. 4-(1-((4-(Tri?uoromethoxy)phenyl)sulfonyl)cyclopropyl)piperidine.

A mixture of 4-(1-((4-(tri?uoromethoxy)phenyl)sulfonyl)cyclopropyl)pyridine (2.3, 400 mg, 1.17 mmol, 1.00 equiv) and PtOz (80 mg) in 3N HCl/dioxane (10 mL) was stirred for 5 h at room ature in a sealed tube under an atmosphere of Hm) (5 atm). [Cautionz the reaction ?ask was purged with N2(g) prior to being purged with H2(g).] The solids were removed by ?ltration. The ?ltrate was concentrated under reduced pressure to provide 400 mg (98%) ofa light yellow solid. 1H-NMR (300 MHz, DMSO-d6): 6 8.08 (d, J=8.1 Hz, 2H), 7.65 (d, J=8.1 Hz. 2H), 3.16 (m, 2H), 2.76 (m, 2H), 2.08 (m, 1H), 1.65 (m, 2H), 1.46 (m, 2H), 1.29 (m, 2H), 1.07 (m, 2H) ppm. ".1 \ 0 O\IIO N / NAG 0 II0 H04;‘SQOCF3 DIEA, DMSO, 70 °c N" \ Compound 2. N-(Pyridazinyl)(1-((4- (trifluoromethoxy)phenyl)sulfonyl)cyclopropyl) piperidine-l-carboxamide.

A solution of 4-(1-((4-(tri?uoromethoxy)phenyl)sulfonyl)cyclopropyl)piperidine (2.4, 58 mg, 0.17 mmol, 1.00 , phenyl pyridazinylcarbamate (5.1, 36 mg, 0.17 mmol, 1.00 equiv) and N-ethyl-N-isopropylpropanamine (65 mg, 0.50 mmol, 3.00 equiv) in DMSO (1 mL) was stirred for 2 h at 70 0C under argon. After cooling to room temperature the reaction was quenched by the addition of H20 (10 mL), and the resulting e was extracted with CH2C12 (3X20 mL). The combined organic layers were washed with brine (2X10 mL), dried over anhydrous MgSO4, ?ltered, and concentrated under reduced pressure.

The resulting e was puri?ed by PLC [Column: )?3ridge Prep C18 OBD Column 19*150mm 5um 13nm;Mobile Phase A:Water with 10mmolNH4HCO3, Mobile Phase B: ACN, Gradient: 25% B to 55% B in 10 min; or, UV 254 nm] to provide 32.0 mg (41%) of a white solid. MS (ES, m/z): 471 [M+H]+, 1H—NMR (300 MHz, DMSO-d6): 5 9.23 (d, J=1.8 Hz, 1H), 9.08 (s, 1H), 8.85 (d, J=6.0 Hz, 1H), 8.08 (d, J=8.7 Hz, 2H), 7.72 (dd, J=1.8 Hz, 6.0 Hz. 1H), 7.67 (d, J=8.7 Hz, 1H),4.03-4.14 (m, 2H), 2.73-2.86 (m, 2H), 1.97— 2.08 (m, 1H), 1.41—1.52 (m, 4H), 0.92—1.13 (m, 4H) ppm.

Exam le 3. Pre aration of 4- 2—C ano—4— tri?uorometh l hen lsulfon l- di?uorometh l ‘ ‘ i eridine—l-carboxamide.

— CI ASK S—\< N\ / N\ / O HCI K2003, DMF Compound 3.1. S-(Pyridinylmethyl) ethanethioate.

To a mixture of oromethyl)pyridine hydrochloride (9 g, 54.87 mmol, 1.00 equiv) and K2C03 (7.6 g, 54.99 mmol, 1.50 equiv) in DMF (50 mL) under argon was added potassium thioacetate (9.38 g, 82.13 mmol, 1.00 equiv) in several batches at 0 oC. The resulting mixture was d for 1 h at 50 0C in an oil bath. After cooling to room temperature the reaction was quenched by the addition of ice water (500 mL). The resulting solution was ted with EtOAc (3x300 mL). The combined organic layers were washed with brine (2x500 mL), dried over anhydrous Na2SO4, ?ltered, and concentrated under d pressure to provide 9 g (98%) of a brown liquid. MS (ES, m/z): 168 [M+H]+. s~< Br CF3 N\ N:/>—/S E: CPS / O szdba3, K2CO3,xantphos dioxane, MeOH, 85 °C Compound 3.2. 4-(((2-Bromo(tri?uoromethyl)phenyl)thio)methyl)pyridine.

A mixture of S-(pyridinylmethyl) ethanethioate (3.1, 4.75 g, 28.40 mmol, 1.20 equiv), Pd2(dba)3-CHC13 (2.94 g, 2.84 mmonl, 0.10 equiv), ium carbonate (9.8 g, 70.91 mmol, 2.50 equiv), 2—bromo—1—iodo—4—(tri?uoromethyl)benzene (8.3 g, 23.65 mmol, 1.00 equiv) and Xantphos (3.29 g, 5.69 mmol, 0.20 equiv) in oxane (50 mL) was stirred for min at 85 0C in an oil bath in a sealed tube. This was followed by the addition ofMeOH (9.1 g, 284.02 mmol, 10.00 equiv) dropwise at 85°C. The resulting mixture was stirred for 2 h at 85°C in an oil bath. After cooling to room temperature the solids were removed by ?ltration, and the ?ltrate was concentrated under reduced pressure. The resulting e was puri?ed by silica gel chromatography (EtOAc/petroleum ether = 1/1 (v/v)) to provide 6 g (73%) ofbrown oil. MS (ES, m/z): 349 [M+H]+, 388 [M+H+CH3CN]+. 8470F3 0xone o 9Q — S CF3 Nx / MeOH, H20 \ / Compound 3.3. 4-(((2-Bromo(trifluoromethyl)phenyl)sulfonyl)methyl)pyridine.

A solution of 4—(((2—bromo—4—(tri?uoromethyl)phenyl)thio)methyl)pyridine (3.2, 4.6 g, 13.21 mmol, 1.00 equiv) and Oxone (20.35 g, 33.02 mmol, 2.5 equiv) in methanol/water (1 : 1, 50 mL) was stirred overnight at room temperature. The mixture was ved with water (800 mL), and the pH value of the solution was adjusted to 9-10 with K2CO3(aq,) The solids were collected by ion to provide 5 g (100%) of a yellow solid. 1H-NMR (400MHz, DMSO-d6, ppm): 5 8.53 (d, J=6.0Hz, 2H), 8.40(m, 1H), 7.97 (m, 2H), 7.24—7.25 (d, J=6.0 Hz, 2H), 5.03 (s, 2H).

Br 00 Br 05'? Ph’ ‘2) on ‘Ph 05.

NC/>—/_ ‘s CF3 — S CF3 tBuOK,THF N \ / F Compound 3.4. 4-(((2-bromo (trifluoromethyl)phenyl)sulfonyl)di?uoromethyl)pyridine.

To a solution of 4-(((2-bromo(tri?uoromethyl)phenyl)sulfonyl)methyl)pyridine (3.3, 2.45 g, 6.44 mmol, 1.00 equiv) in THF (40 mL) was added dropwise t-BuOK (1M in THF, 19.4 mL, 1932 mmol, 3 equiv) at -10 °C under argon. The resulting solution was stirred for 30 min at -10 °C. This was followed by the addition of N- Fluorobenzenesulfonimide (5.1 g, 16.17 mmol, 2.50 equiv) in THF (5 mL) dropwise with stirring at -10°C. The resulting solution was stirred for 1 hour at -10°C. The reaction was then ed by the addition of NH4Cl(sat,) (50 mL). The resulting mixture was extracted with EtOAc (3x50 mL) and the organic layers were combined. The solution was concentrated under vacuum. The ing e was puri?ed by Flash-Prep-HPLC [Column, C18; mobile phase, CH3CN:H20=0: 100 increasing to CH3CN:H20=100:0 within 35 min, Detector, UV 254 nm] to provide 1 g (37%) of as a yellow solid. MS (ES, m/z): [M+H+CH3CN]+ 458.

Br Br 0 O O\l| PtO,H O\|l N\ HOAc, TFA / F F HNOjF Compound 3.5. 4-(((2-Bromo(trifluoromethyl)phenyl)sulfonyl)difluoromethyl) piperidine.

To a mixture of 4—(((2—bromo—4—(tri?uoromethyl)phenyl)sulfonyl)di?uoromethyl)- pyridine (3.4, 500 mg, 1.20 mmol, 1.00 equiv) and PtOz (200 mg, 40%) in a pressure tank reactor was added HOAc (6 mL) and roacetic acid (6 mL). The reaction mixture was purged with Hm) (20 atm) and the solution was stirred for 2 days at 60 0C in an oil bath.

[Cautionz the reaction ?ask was purged with N2(g) prior to being purged with H2(g).] The solids were removed by ?ltration. A second aliquot of PtOz (200m g, 40%) was added and the ing on was stirred for another 2 days at 60 0C in an oil bath. The solids were removed by ?ltration and the e was concentrated under d pressure to provide 500 mg (crude) of a brown solid. The product was used to next step directly without further puri?cation.

B. 0 ° Q Oj? N / Nio O\\II o s CF3 HNC>74‘s CF3 H ,N N \ N>—N::>—?F F — H F DIEA,DMSO Compound 3.6. -Bromo(tri?uoromethyl)phenyl)sulfonyl)di?uoromethyl)—N- (pyridazinyl)piperidine-l-carboxamide.

A solution of 4-(((2-bromo(tri?uoromethyl)phenyl)sulfonyl)di?uoromethyl)- piperidine (3.5, 0.5 g, 1.15 mmol, 1.00 equiv), DIEA (1.5 g, 5.75 mmol, 5.00 equiv) and phenyl pyridazinylcarbamate (5.1, 0.5 g, 2.30 mmol, 2.00 equiv) in DMSO (10 mL) was stirred for 3 h at 70 0C in an oil bath under argon. The mixture was puri?ed directly by Flash- Prep-HPLC [Column, C18; mobile phase, CH3CN:H20=0: 100 increasing to CH3CN:H20=100:0 within 35 min; Detector, UV 254 nm] to provide 240 mg (36%) of a brown solid. MS (ES, m/z): [M+H]+ 543, [M+H+CH3CN]+ 584.

O O O\II CuCN, dppf O\II S CF3—> O N N M \S‘©70F3 g, dioxane Compound 3. 4-(((2-Cyano(trifluoromethyl)phenyl)sulfonyl)difluoromethyl)-N- (pyridazinyl)piperidine-l-carboxamide.

A mixture of 4—(((2—bromo—4—(tri?uoromethyl)phenyl)sulfonyl)di?uoromethyl)—N— (pyridazinyl)piperidine—l—carboxamide (3.6, 190 mg, 0.35 mmol, 1.00 , CuCN (125 mg, 1.4 mmol, 4.00 equiv), dppf(156 mg, 0.28 mmol, 0.80 equiv) and Pd2(dba)3CHCl3 (145 mg, 0.14 mmol, 0.40 equiv) in 1,4—dioxane (10 mL) was stirred for 1 hour at 100 °C in an oil bath under argon. After cooling to room temperature, the resulting mixture was diluted with H20 (40 mL) and was extracted with EtOAc (2x50 mL). The combined organic layers were washed with FeSO4(sat,) (30 mL) and dried over anhydrous magnesium sulfate. The solution was concentrated under vacuum, and the resulting residue was puri?ed by PLC [Column, SUNFTRE, 19*150 mm, 5 um, mobile phase, Mobile Phase A: Water/10 mM NH4HCO3, Mobile Phase B: CH3CN, Flow rate: 20 mL/min, Gradient: B in 8 min, Detector, 254nm] to e 53.1 mg (31%) ofa light yellow solid. MS (ES, m/z): [M+H]+ 490, [M+Na]+ 512, 1H—NMR (400MHz, DMSO-d6, ppm): 5 9.28 (m, 2H), 8.88 (m, 2H), 8.45 (m, 2H), 7.75 (d, J=3.2Hz, 1H), 4.26 (m, 2H), 2.93—3.04 (m, 3H), 2.05 (m, 2H), 1.51— 1.60 (m, 2H). 19F—NMR (400MHz, DMSO-d6, ppm): 62.107, 104.437.

Exam le 4. Pre n of 4- 2— di?uorometh l hen lsulfon ldi?uorometh l-N- ridazin l i eridine—l-carboxamide.

O H F F Br —>Br Compound 4.1. 1-bromo-2—(di?uoromethyl)benzene.

To a solution of 2—bromobenzaldehyde (10.0 g, 54.05 mmol, 1.00 equiv) in CH2C12 (100 mL) under argon was added DAST (17.4 g, 107.95 mmol, 2.00 equiv) dropwise with stirring at 0 0C. The resulting solution was stirred for 3 h at room temperature. The reaction was then ed by the slow and careful addition of NaHCO3(sat.) (200 mL). The resulting mixture was extracted with CH2C12 (3x100 mL) and the combined organic layers were washed with brine (150 mL), dried over anhydrous sodium sulfate, ?ltered, and concentrated under reduced pressure. The resulting residue was puri?ed by silica gel tography (EtOAc/petroleum ether (1:40)) to provide 9.0 g (80%) of a colorless oil. 1H-NMR (CDCl3,400MHz, ppm): 5 7.68 (m, 1H), 7.61 (m, 1H), 7.42 (m, 1H), 7.33 (m, 1H), 6.79-7.05 (t, J=52 Hz, 1H). 19F-Nl\/lR(CDCl3,400MHz, ppm): 6 114.63.

BOC-N/\:>—/8—< F F F o F O S szdba3, K2C03, xantphos dioxane, MeOH >—N E 0 Compound 4.2. tert-Butyl 4-(((2-(di?uoromethyl)phenyl)thio)methyl)piperidine—1- carboxylate.

A mixture of l-bromo(difluoromethyl)benzene (4.1, 3.0 g, 14.49 mmol, 1.00 equiv), Pd2(dba)3-CHC13 (750 mg, 0.82 mmol, 0.05 equiv), potassium carbonate (6.04 g, 43.70 mmol, 3.00 equiv), Xantphos (838 mg, 1.45 mmol, 0.10 equiv) and tert-butyl 4- [(acetylsulfanyl)methyl]piperidine-l-carboxylate (3.96 g, 14.48 mmol, 1.00 equiv) in 1,4- dioxane (80 mL) was stirred for 10 min at 80 °C in an oil bath under argon. This was followed by the on of methanol (4.6 g, 143.57 mmol, 10.00 equiv) dropwise at 80 0C.

The resulting solution was stirred for l h at 80 0C in an oil bath. The on mixture was cooled to room temperature, and then was concentrated under reduced re. The resulting residue was d by silica gel chromatography /petroleum ether (1:10)) to provide 3.0 g (58%) ofa colorless oil. 1H-NMR (400MHz, CDCl3, ppm): 8 7.65 (m, 1H), 7.35-7.48 (m, 3H), 6.97-7.24 (t, J=52 Hz, 1H), 4.10 (m, 2H) 2.83 (m, 2H) 2.66 (m, 2H), 1.57 (m, 2H) , , 1.45 (s, 9H), 1.16-1.27(m, 3H). mCPBA O‘l'l S \S CHZCIZ Boc—N Boc—N Compound 4.3. tert-Butyl 4-(((2-(difluoromethyl)phenyl)sulfonyl)methyl)piperidine carboxylate.

To a solution of tert-butyl 4-(((2-(di?uoromethyl)phenyl)thio)methyl)piperidine carboxylate (4.2, 2.0 g, 5.60 mmol, 1.00 equiv) in CHzClz (40 mL) was added mCPBA(4.8 g, 27.82 mmol, 4.00 equiv) in several batches at 0 °C. The resulting solution was stirred for 2 h at room ature. The reaction was then quenched by the addition of NaHCO3(sat,) (150 mL). The resulting solution was extracted with CH2C12 (3x100 mL). The combined organic layers were washed with H20 (2x100 mL) and brine (150 mL),dried over anhydrous sodium e and concentrated under reduced pressure. The ing residue was d by silica gel tography (EtOAc/petroleum ether (1:10)) to provide 800 mg (37%) of a colorless oil. 1H-NMR (400MHz, CDC13, ppm): 5 8.09 (m, 1H), 7.92 (m, 1H) ,7.79 (m, 1H) ,7.71 (m, 1H), 7.49—7.70 (t, J=44 Hz, 1H), 4.07 (m, 2H) 3.10 (m, 2H) 2.74 (m, 2H) 2.23 (m, 1H), , , , 1.87 (m, 2H), 1.47 (s, 9H), 1.26 (m, 2H).

F q‘ ,N\ 00 F F Ph/ \ F "0 6’ Ph 0 0 Ogu —> S O¢él F Compound 4.4. tert-Butyl 4-(((2-(di?uoromethyl)phenyl)sulfonyl)difluoromethyl) piperidinecarboxylate.

To a mixture of tert-butyl 4-(((2— (di?uoromethyl)phenyl)sulfonyl)methyl)piperidine-1—carboxylate (4.3, 800 mg, 2.05 mmol, 1.00 equiv) and NFSI (3.2 g, 5.00 equiv) in THF (20 mL) under argon was added a solution ofNaHMDS (2.0M in THF, 8 mL, 800 equiv) dropwise with stirring at -78 0C. The resulting solution was d for 1 hour at -78 OC, and the reaction was then quenched by the addition of NH4C1(sat‘) (100 mL). The resulting solution was extracted with EtOAc (3x100 mL) and the combined organic layers were washed with H20 (2x100 mL), brine (150 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting residue was puri?ed by silica gel chromatography (EtOAc/petroleum ether =1/3 (v/V)) to provide 600 mg (69%) of a ess oil. 1H—NMR (400MHz, CDCl3): 6 8.006 (m, 2H),7.90 (m, 1H),7.74 (m, 1H), 7.26-7.48 (t, J=44 Hz, 1H), 4.26 (m, 2H), 2.76 (m, 3H), 2.07 (m, 2H), 1.61 (m, 2H), 1.47 (s, 9H) ppm. 19F—NMR (376 MHz, CDC13): 5 0, —109,33 ppm.

F F 0 TFA TFA Odo B —/ OC DCM F F F Compound 4.5. 4-(((2-(Di?uoromethyl)phenyl)sulfonyl)difluoromethyl)piperidine tri?uoroacetic acid salt.

A solution of teIt-butyl 4-(((2— (di?uoromethyl)phenyl)sulfonyl)di?uoromethyl)piperidinecarboxy1ate (4.4, 600 mg, 1.41 mmol, 1.00 equiv) and roacetic acid (4 mL) in CH2C12 (4 mL) was d for 1 hour at room temperature under argon. The resulting mixture was concentrated under reduced pressure to provide 600 mg of crude of a brown oil. The product was used to next step directly without further puri?cation. MS (ES, m/z): 325 [M+H]+ 367 [M+CH3CN+H]+.

F F 0 N / Q N O DIEA, DMSO — Compound 4. 4-(((2-(Di?uoromethyl)phenyl)sulfonyl)di?uoromethyl)—N-(pyridazin yl)piperidine—1-carboxamide.

A e of4-(((2-(di?uoromethyl)phenyl)su1fony1)di?uoromethy1)piperidine tri?uoroacetic acid salt (4.5, 460 mg, 1.05 mmol, 1.00 equiv), DIEA (731 mg, 5.66 mmol, 4.00 equiv) and phenyl pyridazinylcarbamate (5.1, 609 mg, 2.83 mmol, 2.00 equiv) in DMSO (5 mL) was stirred for 1 hour at 80 0C in an oil bath under argon. The reaction mixture was cooled to room temperature and was directly d by Flash-Prep-HPLC [Column, C18; mobile phase, CH3CN:H20=0: 100 (v/v) increasing to CH3CN:H20=100:0 (v/v) within 35 min; Detector, UV 254 nm] to provide 350 mg (75%) of an off-white solid.

LC-MS (ES, m/z): 447 [M+H]+, 488 [M+CH3CN+H]+ ; 1H-NMR (400MHz, CD3OD): 8 9.24 (m, 1H), 8.87 (m, 1H), 8.02-8.14 (m, 3H), 7.88 (m, 2H), 7.37-7.64 (t, J=56 Hz, 1H), 4.34 (m, 2H), 2.91-3.13 (m, 3H), 2.18 (m, 2H), 1.74 (m, 2H) ppm.

Exam le 5. Pre aration of 4- difluoro 3—fluoro hen l sulfon l meth l -N- ridazin l i eridine—l-carboxamide.

\ NH2 0 O Y pyrI me'd' N N O + P )r N / CI THF/CH3CN N / 0 Compound 5.1. Phenyl pyridazin-4—ylcarbamate.

To a suspension of opyridazine (1.00g, 10.51 mmol) in a 1:1 mix of THF ) and acetonitrile (lOmL) at 0 0C was added pyridine (1.03 mL, 12.62 mmol), followed by the dropwise addition of phenyl chloroformate (1.58 mL, 12.62 mmol) over a period of 10 minutes. The reaction mixture was stirred for 2 h while warming to room temperature. The precipitate was isolated by ion and dried for 1 h under high vacuum to provide the desired t as an off—white powder (0.923g, 41%). LC-MS (ES, m/z): 216 [M+H]+, 1H- NMR (400 MHz, CDC13): 6 1100 (br. s., 1H), 9.25 (d, J = 1.96 Hz, 1H), 9.03 (d, J = 5.87 Hz, 1H), 7.76 (dd, J: 5.87, 2.74 Hz, 1H), 7.38 — 7.51 (m, 2H), 7.19 — 7.35 (m, 3H) ppm. 0 H301: A)CJ: >LOANOVBrW O NOVEUF Compound 5.2. utyl 4-(((3—?uorophenyl)—l3—sulfanyl)methyl)piperidine—1- carboxylate.

To a solution of tert-butyl 4-(bromomethyl)piperidinecarboxylate (10.0g, 35.94 mmol) in DMF (100 mL) was added potassium carbonate (7.45g, 53.90 mmol), followed by 3-?uorothiophenol (3.20 mL, 37.87 mmol). The reaction mixture was stirred at room 2O temperature for 24 h. The on mixture was diluted with H20, and extracted with EtOAc.

The organic layer was washed with H20, saturated NaCl, dried over NaZSO4, ?ltered and concentrated. The desired product was obtained as a clear oil (11.8 g) and was used without puri?cation. LC-MS (ES, m/z): 324 [M-H]'. >L JOK >L i o IO\/H Oxone o —> [\OVO o\v/ S Compound 5.3. tert—Butyl 4-(((3-fluorophenyl)sulfonyl)methyl)piperidine—1- carboxylate.

To a solution of tert-butyl 4-(((3-?uorophenyl)—l3-sulfanyl)methyl)piperidine ylate (5.2, 11.8 g) in DMF (110 mL) was added Oxone (66.4 g, 107.9 mmol). The reaction mixture was stirred at room temperature for 18h. The reaction mixture was diluted with H20, and extracted into EtOAc. The organic layer was washed with 0.5 N NaOH, saturated NaCl, dried with Na2804, d and concentrated. The resulting residue was puri?ed by ?ash chromatography (20% - 40% EtOAc in s) to provide the desired product as a white solid (7.48 g, 56% over two steps). LC-MS (ES, m/z): 302 [M-56+H]+; 1H-NMR (400 MHz, CDC13): 6 7.72 (d, J= 7.83 Hz, 1H), 7.54 - 7.65 (m, 2H), 7.37 (td, J= 8.22, 2.74 Hz, 1H), 3.97 = 6.26 Hz, 2H), 2.74 (m, 2H), 2.13 — 4.20 (m, 2H), 3.02 (d, J — 2.26 (m, 1H), 1.89 — 1.86 (m, 2H), 1.44 (s, 9 H), 1.19 — 1.33 (m, 2H) ppm. ‘3’ F —, s F U i. LDA, THF, -78°C F F 0 ii. NaHMDS Compound 5.4. tert—Butyl 4-(di?uoro((3-?uorophenyl)sulfonyl)methyl)piperidine—1- carboxylate.

To a solution of tert-butyl 4-(((3-?uorophenyl)sulfonyl)methyl)piperidine carboxylate (5.3, 1.00g, 2.80 mmol) and N-?uorobenzene sul?nimde , 11.1 mmol) in dry THF (50 mL) at -78 0C under nitrogen was added LDA (2.0M in THF, 3.5 mL, 3.50 mmol)) dropwise. The reaction e was stirred for 25 minutes at -78 0C. A second aliquot of LDA (2.0M in THF, 20 mL, 200 mmol) was added dropwise, and the reaction e was stirred at -78 0C for 40 minutes. The NaHMDS (1.0M in THF, 7.0 mL, 7.00 mmol) was added slowly and the reaction mixture was stirred at -78 0C for 1.5 h. Hexanes (150 mL) was added to the reaction mixture, and the precipitate was d by ?ltration.

The ?ltrate was washed with saturated NaHCO3, saturated NaCl, dried with Na2S04, ?ltered and concentrated. The resulting residue was puri?ed by ?ash chromatography (0 — 20% EtOAc in s) to provide the desired product as a white solid (06 g, 54%). LC-MS (ES, m/z): 338 [M-56+H]+; 1H—NMR (400 MHz, CDC13): 6 7.77 (d, J = 7.83 Hz, 1H), 7.65 — 7.70 (m, 1H), 7.62 (m, 1H), 7.46 (m, 1H), 4.25 (br. s., 2H), 2.60 — 2.87 (m, 3H), 2.07 (d, .1: 13.30 Hz, 2H), 1.55 — 1.67 (m, 2H), 1.46 (s, 9H) ppm. i A0 1. 4N HCIDioxane o W"? NaHC0325% EtOH 80F HO???:FU Compound 5.5. 4-(Difluoro((3-?uorophenyl)sulfonyl)methyl)piperidine.

To a solution of tert-butyl uoro((3-?uorophenyl)sulfonyl)methyl)piperidine- 1-carboxylate (5.4, 8.0 g, 20.35 mmol) in dioxane (30 mL) was added 4N HCl/dioxane (30 mL). The reaction mixture was d at room temperature for lb, and then was concentrated.

The resulting residue was dissolved in EtOH (30mL) and 150 mL 5% NaHCO3 in water was added. The crashed solid was stirred at room temperature for 30 minutes. The solid was d, washed with water and dried to provide the desired product as a white solid which was used without further puri?cation (4.68 g). LC-MS (ES, m/z): 294 [M+H]+.

N \ "1° F HN H O\\//O N / O O\IIO S F O ‘S . N F F U ACN/TEA,6O C N. \ F NH>801F Compound 5. 4-(Difluoro((3-?uorophenyl)sulfonyl)methyl)—N-(pyridazin yl)piperidine—1-carboxamide.

To a solution of 4-(di?uoro((3-?uorophenyl)sulfonyl)methyl)piperidine (5.5, 4.68 g, 15.95 mmol) and yl(pyridazine—4-yl)urea (3.50 g, 16.27 mmol) in acetonitrile (50 mL) was added triethylamine (31.9 mmol, 3.22 g) in sealed tube. The reaction mixture was heated at 60°C for 2h behind a blast shield. The resulting residue was puri?ed by ?ash chromatography (0-7% (v/v) MeOH/DCM) to e the desired product as white solid (6.2 g). LC-MS (ES, m/z): 415 [M+H]+; 1H N1VIR (400 MHz, CD3OD): 6 9.23 (dd, J=2.7, 0.8 Hz, 1H), 8.80-8.94 (m, 1H), 7.82-7.96 (m, 2H), 7.70-7.80 (m, 2H), 7.58-7.68 (m, 1H), 4.32 (d, J=14.1 Hz, 2H), 3.03 (t, J=12.3 Hz, 2H), 2.83-2.97 (m, 1H), 2.16 (d, J=12.9 Hz, 2H), 1.63- 1.78 (m, 2H) ppm. >LOJJ\I\O\E oo XOANo CH3I, LDA \\ I/ —> \\ // SUP -78 0C, THF SUF Compound 6.1. tert—Butyl 4-(1-((3-?uorophenyl)sulfonyl)ethyl)piperidine—1- carboxylate.

To a solution of tert-butyl 4-(((3-?uorophenyl)sulfonyl)methyl)piperidine carboxylate (5.3, 0.10 g, 0.279 mmol) in dry THF (1 mL) at -78 0C was added LDA (2.0M in THF, 0.168 mL, 0.336 mmol). The reaction mixture was stirred at -78 0C under nitrogen for 15 minutes before methyl iodide (0017 mL, 0.279 mmol) was added. The on mixture was allowed to stir for 18 h while warming to room temperature. The reaction mixture was diluted with H20 and extracted into EtOAc. The organic layer was dried with Na2SO4, ?ltered and concentrated. The resulting residue was puri?ed by ?ash chromatography (20% EtOAc in hexanes) to provide the desired t as a colorless oil (0.103 g, 98%). LC-MS (Es, m/z): 316 [M-56+H]+; 1H—NMR (400 MHz, CDC13): 6 7.66 — 7.71 (m, 1H), 7.53 — 7.62 (m, 2H), 7.33 — 7.40 (m, 2H), 3.98 — 4.33 (m, 2H), 3.00 — 2.94 (m, 1H), 2.63 — 2.80 (m, 2H), 2.44 — 2.37 (m, 1H), 1.96 — 1.92 (m, 1H), 1.45 (s, 9H), 1.23 — 1.42 (m, 2H), 1.20 (d, .1: 7.04 Hz, 3H) ppm.

SU—)F LDA THF, -78 °C Compound 6.2. tert-Butyl uoro((3-?uorophenyl)sulfonyl)ethyl)piperidine carboxylate.

To a solution of tert—butyl 4—(1—((3—?uorophenyl)sulfonyl)ethyl)piperidine carboxylate (6.1, 0.103 g, 0.277 mmol) in dry THF (lmL) at -78 0C was added LDA (2.0M in THF, 0.173 mL, 0.346 mmol). The reaction mixture was stirred at -78 0C for 15 minutes before obenzene mde (0.087 g, 0.277 mmol) was added. The reaction mixture was stirred for 2 h at -78 0C. A second aliquot of both LDA (2.0M in THF, 0.173 mL, 0.346 mmol) and N—?uorobenzene sul?nimde (0.087 g, 0.277 mmol) were added, and the reaction mixture was stirred for an additional 30 s at -78 0C. The reaction mixture was d with H20, warmed to room temperature and extracted into EtOAc. The organic layer was dried with Na2804, ?ltered and concentrated. The resulting residue was puri?ed by ?ash tography (20% EtOAc in hexanes to provide the desired product as a colorless oil (0.028 g, 26%). LC-MS (ES, m/z): 334 [M-56+H]+; 1H—NMR (400 MHz, CDC13): 5 7.74 — 7.72 (m, 1H), 7.54 - 7.67 (m, 2H), 7.42 (ddt, J= 8.27, 6.99, 1.37, 1.37 Hz, 1H), 4.30 — 4.15 (m, 2H), 2.77 — 2.64 (m, 3H), 2.40 - 2.53 (m, 1H), 2.21 — 2.17 (m, 1H), 1.81 — 1.78 (m, 2H), 1.48 - 1.58 (m, 3H), 1.46 (s, 9H) ppm. i A0 1 TFA CHZCIZ o N O O 2. MP-Carbonate EtOH S F F U PU Compound 6.3. 4-(1-Fluoro((3-?uorophenyl)sulfonyl)ethyl)piperidine.

To a solution of tert-butyl 4-(1-?uoro—l—((3-?uorophenyl)sulfonyl)ethyl)piperidine- 1-carboxylate (6.2, 0.046 g, 0.119 mmol) in CH2C12 (1 mL) was added TFA (0.20 mL). The reaction mixture was stirred at room temperature for 18h, and then was concentrated. The resulting residue was dissolved in EtOH (1mL) and bonate (0.376 g, 1.19 mmol) was added. The reaction mixture was stirred for 30 minutes at room temperature. The solid was d by ?ltration and the ?ltrate was concentrated to provide the desired t as a colorless oil which was used without further puri?cation (0.026 g, 75%). LC-MS (ES, m/z): 290 [M+H]+.

HO?<\\SIO HN o o HN o o SFC chiral separation F 0V? F + 0);? F Compound 6.3a. (R)(l-fluoro((3-fluorophenyl)sulfonyl)ethyl)piperidine and Compound 6.3b. (S)—4—(1—?uoro—l-((3—fluorophenyl)sulfonyl)ethyl)piperidine.

The enantiomers of 4—(1—fluoro—l—((3—?uorophenyl)sulfonyl)ethyl)piperidine (6.3, 1.89 g) were separated using by Prep—SFC (Column: Phenomenex Lux® 3u Celloluse-2, 46* 100mm, 3um, Mobile Phase A:C02, Mobile Phase B: EtO H(0.1%DEA) gradient 10% to 50% in 40min, hold 20min at 50%; Flow rate: 150 mL/min, 220 nm) to provide RT1 = 2.16 min (6.321, 0.938 g, 98%) as a white solid and RTg- = 2.75 min (6.3b, 0.948 g, 98%) as a white solid. 0 F HN 1. \ 1r 0 O\\//0 N / O O Oég s F / >_N . \ F DIEA. DMSO, 80 C N\ NH F Compound 6. lu0ro((3-fluorophenyl)sulfonyl)ethyl)-N-(pyridazin yl)piperidine-l-carboxamide trifluoroacetic acid salt.

To a solution of 4—(1—?uoro—1—((3—?uorophenyl)sulfonyl)ethyl)piperidine (6.3, 0.026 g, 0.089 mmol) in in DMSO (1 mL) was added phenyl pyridazinylcarbamate (5.1, 0.028 g, 0.132 mmol), followed by DIEA (0055 mL, 0.309 mmol). The reaction mixture was plunged into a preheated 80 °C oil bath and was stirred for 2 h, The reaction mixture was cooled to room temperature and diluted with EtOAc and H20. The two layers were separated.

The organic layer was dried with Na2804, ?ltered and concentrated. The ing residue was puri?ed using reverse phase high pressure liquid chromatography (0 - 90% (v/v) CH3CN in H20 (both containing 0.1%TFA)) to provide the d t as a white solid (0.015 g, 42%). LC-MS- (ES, m/z): 411 [M+H]+, 1H—NMR (400 MHz, CDC13): 5 10.55 (s, 1H), 9.60 (d, J = 1.96 Hz, 1H), 8.77 (d, J = 7.04 Hz, 1H), 8.67 (dd, J = 6.85, 2.15 Hz, 1H), 7.74 (d, J = 7.43 Hz, 1H), 7.56 — 7.67 (m, 2H), 7.43 (td, J = 8.12, 2.15 Hz, 1H), 4.49 (t, J = 12.91 Hz, 2H), 2.96 (br. s., 2H), 2.55 — 2.68 (m, 1H), 2.33 (d, J=12.91 Hz, 1H), 1.96 (d, 0 Hz, 1H), 1.42 - 1.59 (m, 5H) ppm.

Exam le 7. Pre aration of 4- 2— 3-Fluoro hen lsulfon 1 r0 an l-N- ridazin >L O O OJJWOVO o >L CH3I, NaHMDS \V/ —> OJLW 0\V/S\©/F Compound 7.1. tert-butyl 4—(2—((3—flu0r0phenyl)sulfonyl)pr0panyl)piperidine carboxylate Compound 7.1 was prepared in a similar manner as compound 6.1 with the exception of the substitution of sodium bis(trimethylsi1y1)amide for LDA and the use of 3.5 equivalents of methyl iodide to provide the desired product as a white solid (1.8 g, 83%) which was used without puri?cation in the next reaction. i AO 1. 4N HCI Dioxane O N 2. 5% NaHCO3, EtOH HN \\ ’l —> \\ // SUI: SUI: Compound 7.2. 4-(2-((3-Fluorophenyl)sulfonyl)propanyl)piperidine.

Compound 7.2 was ed in a similar manner as compound 5.5 to provide the desired product which was used t puri?cation in the next reaction, N \ "To F HN H OW/O N / O O\ICI) o N 30%N ACN/TEA, 60 C N, \ Compound 7. 4-(2-((3-?uorophenyl)sulfonyl)propanyl)—N-(pyridazin yl)piperidine—1-carboxamide.

Compound 7 was prepared in a r manner as compound 5 to provide the desired product as a white solid (0.56 g, 72%). LC-MS (ES, m/z): 407 [M+H]+; 1H-NMR (400MHz, DMSO-d6, ppm): 6 9.28 (s, 1H), 9.17 (s, 1H), 8.88 (d, J = 6.0 Hz, 1H), 7.78 — 7.66 (m, 5H), 4.23 — 4.20 (m, 2H), 2.83 — 2.77 (m, 2H), 2.08 — 1.94 (m, 3H), 1.40 — 1.37 (m, 2H), 1.19 (s, 6H) ppm.

Exam le 8. Pre n of 4- l-?uoro-l- 4- tri?uorometh l hen l sulfon l eth l -N- isoxazol l i eridine-l-carboxamide ‘s NaHCO ,Na so3 2 3 / CI’ +Na'O CF CF Compound 8.1. Sodium 4-(tri?uoromethyl)benzenesulfinate To a solution of 4-(tri?uoromethyl)benzenesulfonyl chloride (0.424 g, 1.73 mmol) in H20 (2.5 mL) was added NaHCO3 (0.291 g, 3.46 mmol) and Na2SO3 (0.437 g, 3.46 mmol). The reaction mixture was plunged into a preheated 80 °C oil bath and was stirred for 3h. The on mixture was cooled to room temperature and was concentrated under reduced pressure. The resulting residue was suspended in EtOH (5 mL) and the solids were removed by ?ltration. The ?ltrate was concentrated under d pressure to provide the desired product as a white solid which was used without further puri?cation (0.40 g, 99%).

LC-MS (ES, m/z): 232 [M+H]+. + _ /S O >k JL 0 @/Br NOVOP K2C03,DMF 0CF Compound 8.2. tert-Butyl 4-(((4-(triflu0r0methyl)phenyl)sulfonyl)methyl)piperidine—1- carboxylate.

To a solution of tert-butyl 4-(((4- (trifluoromethyl)phenyl)sulfonyl)methyl)piperidinecarboxylate (8.1, 0.40 g, 1.79 mmol) in DMF (10 mL) was added K2C03 (0.495 g, 3.58 mmol) and utyl 4- (bromomethyl)piperidinecarboxylate (0.499 g, 1.79 mmol). The reaction e was d into a preheated 80 oC oil bath and was stirred for 3h. The reaction mixture was then stirred overnight while g to room temperature. The solids were removed by ?ltration.

The ?ltrate was diluted with EtOAc (15 mL) and H20 (10 mL) and the two layers were separated. The organic layer was dried with Na2SO4, d and concentrated. The resulting residue was puri?ed by ?ash chromatography (20% EtOAc in hexanes to provide the desired product as a colorless oil (0.21 g, 73%). LC-MS (ES, m/z): 222 [M-56+H]+; 1H-N1VIR (400 MHz, CDC13): 6 8.09 (d, J=8.07 Hz, 2H), 7.88 (d, J=8.19 Hz, 2H), 4.10 (d, J=13.69 Hz, 2H), 3.05 (d, J=6.36 Hz, 2H), 2.77 (t, J=12.72 Hz, 2H), 2.24 (br. s., 1H), 1.92 (d, J=12.23 Hz, 2H), 1.47 (s, 9H), 1.22-1.38 (m, 2H) ppm.

\\ ,NS/p #91039 Gal);(D >k0$0ng LDA THF -78 °C Compound 8.3. utyl 4-(?uoro((4- (tri?uoromethyl)phenyl)sulfonyl)methyl)piperidine—l-carboxylate To a solution of tert-butyl 4-(((4- (tri?uoromethyl)phenyl)sulfonyl)methyl)piperidine-l-carboxylate (8.2, 0.207 g, 0.508 mmol) in THF (3 mL) at -78 °C was added LDA (2.0 M in THF, 0279 mL, 0.559 mmol). The reaction mixture was stirred for 25 minutes before NFSI (0.241 g, 0.762 mmol) was added.

The reaction mixture was d for 4h at —78 °C, then was diluted with EtOAc (5mL) and was warmed to room temperature. The reaction mixture was diluted with H20 (5mL) and the two layers were separated. The organic layer was dried with Na2S04, ?ltered and then concentrated. The resulting residue was d by ?ash chromatography (20% EtOAc in hexanes to provide the desired product as a colorless oil (0.16 g, 21%) which was used as is in the next on. LC-MS (ES, m/z): 370 [M-56+H]+.

A it >L ft 0 N o o LDA,CH3| O N o o S S THE-78°C F F CF3 CF Compound 8.4. utyl 4-(1-?uoro-l-((4- (tri?uoromethyl)phenyl)sulfonyl)ethyl)piperidine-l-carboxylate To a solution of utyl 4-(((4- (tri?uoromethyl)phenyl)sulfonyl)methyl)piperidine-l-carboxylate (8.3, 0.160 g, 0.377 mmol) in THF (3 mL) at -78 0C was added LDA (2.0 M in THF, 0.235 mL, 0.471 mmol). The reaction mixture was stirred for 20 minutes before the iodomethane (0.094 g, 0.659 mmol) was added. The reaction mixture was diluted with EtOAc (6 mL) and H20 (2 mL) and was warmed to room temperature. The two layers were separated and the organic layer was dried with Na2S04, ?ltered and then concentrated. The ing residue was puri?ed by ?ash chromatography (20% (V/V) EtOAc in hexanes to provide the desired product as a colorless oil (0.09 g, 55%), which was used as is in the next reaction. LC-MS (ES, m/z): 384 [M- 56+H]+.

XOJLo 1. TFA. CH2C|2 HN N O\\//0 Q\S,,0 2. MP-Carbonate, EtOH 3 F : F ‘CF Compound 8.5. 4-(1-Fluoro((4-(trifluoromethyl)phenyl)sulfonyl)ethyl)piperidine Compound 8.5 was prepared in a similar manner as compound 6.3 to provide the desired product which was used t puri?cation in the next reaction.

,N N O HN O 0 OJ 131/ \© 059 "3" o a Compound 8. 4-(1-Fluoro((4-(trifluoromethyl)phenyl)sulfonyl)ethyl)—N-(isoxazol yl)piperidine—1-carboxamide Compound 8 was prepared in a similar manner as compound 6 to provide the desired product as a white solid (0.010 g, 33%). LC—MS (ES, m/z): 450.1 [M+H]+, 1H NMR (400 MHz, CDCl3): 5 8.41 (s, 1H), 8.16 (s, 1H), 8.00 (d, J=7.95 Hz, 2H), 7.80 (d, J=8. 19 Hz, 2H), 6.92 (s, 1H), .30 (m, 2H), 2.83-2.95 (m, 2H), 2.51-2.61 (m, 1H), 2.25 (d, 0 Hz, 1H), 1.86 (d, 1:12.96 Hz, 1H), 1.35—1.54 (m, 5H) ppm.

Exam le 9. Pre aration of 4- l-?uoro-l- 6-methox ridin l sulfon l eth l -N- ridazin l i eridine—l-carboxamide O $—O¥NC>_/ SK @ O swig szdbag K2C03 xantphos dioxane MeOH $40OWN? Compound 9.1. tert-Butyl 4-(((6-methoxypyridinyl)thio)methyl)piperidine—1- carboxylate id="p-112" id="p-112" id="p-112" id="p-112" id="p-112" id="p-112" id="p-112" id="p-112" id="p-112" id="p-112" id="p-112" id="p-112" id="p-112" id="p-112"

[0112] Compound 9.1 was prepared in a similar manner to compound 4.2 to e the desired product as a yellow solid (1.78 g, 48%). 1H NMR (400 MHz, CDC13) 6 8.17 — 8.23 (dd, J=2.4, 0.7Hz, 1H), 7.59 — 7.67 (dd, J=8.6, 2.5Hz, 1H), 6.68 — 6.75 (dd, J=8.6, 0.7Hz, 1H), 4.05 — 4.15 (m, 2H), 3.94 (s, 3H), 2.59 — 2.75 (m, 4H), 1.76 — 1.87 (m, 2H), 1.50 — 1.64 (m, 1H), 1.42 — 1.48 (s, 9H), 1.06 — 1.21 (m, 2H) ppm. ):>\—~©f@o 3+3:)wy??_ 9 _ Compound 9.2. tert-Butyl 4-(((6-methoxypyridinyl)sulfonyl)methyl)piperidine—1- ylate id="p-113" id="p-113" id="p-113" id="p-113" id="p-113" id="p-113" id="p-113" id="p-113" id="p-113" id="p-113" id="p-113" id="p-113" id="p-113" id="p-113"

[0113] Compound 9.2 was prepared in a similar manner to compound 4.3 to provide the desired product as a white solid (0.20 g, 81%). 1H NMR (400 MHz, CDC13) 5 ppm 8.63 — 8.70 (d, J=2.5Hz, 1H), 7.91 — 8.04 (dd, J=8.8, 2.6Hz, 1H), 6.79 — 6.89 (d, J=8.8Hz, 1H), 3.97 — 4.11 (m, 5H), 2.94 — 3.02 (d, J=6.3Hz, 2H), 2.63 — 2.79 (m, 2H), 2.08 — 2.22 (m, 1H), 1.72 — 1.91 (m, 2H), 1.41 (s, 9H), 1.15 — 1.34 (m, 2H) ppm. 0\\SN:S//0 ow @abO/l —N $7:>\‘_N<:>—/S049R NaHMDS THF -78°C O>\‘—N/\:>—<:Ova Compound 9.3. tert-Butyl 4-(fluoro((6-methoxypyridinyl)sulfonyl)methyl)piperidine— 1-carboxylate To a solution of tert-butyl methoxypyridinesulfonyl)methyl]piperidine carboxylate (9.2, 1.00 g, 2.70 mmol) in THF (10 mL) at -78 °C was added dropwise NaHlVlDS (2.0 M in THF, 1.4 mL, 0.700 mmol) followed by the dropwise addition of a solution of NFSI (840 mg, 2.66 mmol) in THF (5 mL). The resulting solution was stirred for 2 h while warming to room temperature. The resulting solution was d with s (100 mL), and the solids were removed by ?ltration. The e was washed with saturated NaCl (50 mL), dried over anhydrous Na2SO4, and was concentrated. The resulting residue was puri?ed by silica gel chromatography (EtOAc/petroleum ether (1 : 10-1 :5 ) to provide the desired product as an off-white solid (0.75 g, 72%). LC-MS (ES, m/z): 288.9 [M- 56+H]+. o Os's' of? " \,CH3| NaHMDS 20+ \ / $70 N THF -78 °c Compound 9.4. tert-Butyl 4-(1-?uoro((6-methoxypyridin-3— fonyl)ethyl)piperidine—1-carboxylate To a solution of tert-butyl 4-[?uoro(6-methoxypyridine sulfonyl)methyl]piperidine-l-carboxylate (9.3, 0.700 g, 1.80 mmol) in THF (15 mL) at -78 0C was added NaHMDS (2.0 M in THF, 1 mL, 2.00 mmol) followed by the dropwise addition of iodomethane (0.282 g, 1.98 mmol). The resulting solution was stirred for 2 h while warming to room temperature. The reaction was then quenched by the addition of saturated NH4Cl(aq) (40 mL). The resulting solution was extracted with EtOAc (3X10 mL) and the ed organic layers were washed with ted NaCl (50 mL), dried over Na2804, ?ltered and trated. The resulting residue was puri?ed by silica gel column with (EtOAc/petroleum ether (1:10—l:5 (V/V))) to provide the desired product as a yellow oil (0.600 g, 83%). 1H NMR (300 MHz, DMSO-d6) 6 8.64 (d, z, 1H), 8.10 (dd, J=8.7, 1.5Hz, 1H), 7.10 (d, J=8.7Hz, 1H), 4.03 (m, 2H), 3.99 (s, 3H), 2.71 (s, 1H), 2.32 (m, 1H), 2.02 (m, 1H), 1.62 (m, 1H), 1.52 (d, J=22.8Hz, 1H), 1.40 (s, 9H), 1.24—1.39 (m, 5H) ppm.

HC] WOiQR $70O>—NC>::4<\:/)¥O\H1,4—dioxane nd 9.5. 5-(1-Fluoro(piperidin-4—yl)ethylsulfonyl)methoxypyridine hydrochloride To a solution of tert-butyl 4-[1—?uoro(6-methoxypyridine sulfonyl)ethyl]piperidine-l-carboxylate (9.4, 0.600 g, 1.49 mmol) in 1,4-dioxane (5 mL) was added 4N HCl in oxane (5 mL) dropwise. The resulting solution was stirred for l h at room temperature and then was concentrated. The resulting residue (0.500 g, crude) was used as is in the next reaction without puri?cation. LC-MS (ES, m/z): 302.7 [M+H]+.

N o 09 Elj 1; \© —N 0 0°53? 78F \ >\—N \ / O c / \ HN ,N Et3N, DMSO 70°C N’ \ F Compound 9. 4-(1-Fluoro((6-methoxypyridin-3—yl)sulfonyl)ethyl)—N-(pyridazin yl)piperidine—1-carboxamide To a solution of 5-(l-?uoro—l—(piperidin—4—yl)ethylsulfonyl)methoxypy1idine hydrochloride (9.5, 0.300 g, crude) in DMSO (7 mL) was added triethylamine (0.400 g, 3.95 mmol) and phenyl N—(pyridazinyl)carbamate (0.312 mg, 1.45 mmol). The reaction mixture was stirred for 1 h at 70 oC. The reaction e was cooled to room temperature and was then quenched by the addition of H20 (20 mL). The resulting on was extracted with EtOAc (3x10 mL) and the ed organic layers were washed with saturated NaCl (50 mL), dried over Na2SO4, ?ltered and trated. The resulting residue was puri?ed by Prep-HPLC (Column: X Bridge RP, 19*150 mm, 5 pm; Mobile Phase A: H20/10mM NH4HC03, Mobile Phase B: ACN; Flow rate: 20 mL/min; Gradient: 24%B to 33%B in 10 min; 254nm) to provide the desired product as a white solid (0.216 g, 39%). LC-MS (ES, m/z): 424.1 [M+H]+; 1H-NMR (300 MHz, CD30D): 6 9.24 (d, J=2.7Hz, 1H), 8.86 (d, J=6.0Hz, 1H), 8.65 (d, J=2.4Hz, 1H), 8.09 (d, J=8.7Hz, 1H), 7.86 (dd, J=2.7, 6.0Hz, 1H), 7.02 (d, J=9.0Hz, 1H), 4.40—4.25 (m, 2H), 4.05 (s, 3H), 2.96 (t, J=13.2Hz, 2H), 2.68-2.48 (m, 1H), 2.27 (d, J=12.9Hz, 1H), 1.89 (d, J=12.9Hz, 1H), 1.65-1.45 (m, 2H), 1.58 (d, J=22.5Hz, 3H) ppm.

Exam le 10. Pre n of 1- 4- 1-flu0r0—1- 3—fluoro hen lsulfon leth l i eridin-l- l ridazin l ethan-l-one FNw F W 0 04,4? x \ 0+ HATU ET3N, DMF N\ F 2O nd 10. 1-(4-(1-Fluoro((3-?uorophenyl)sulfonyl)ethyl)piperidinyl)—2- (pyridazinyl)ethan0ne To a solution of 4-(1-?uoro—1-((3—?uorophenyl)sulfonyl)ethyl)piperidine (6.3, 0.025 g, 0.086 mmol) and sodium 2-(pyridazinyl)acetate (0.014 g, 0.086 mmol) in DMF (1 mL) was added yl amine (0.024 mL, 0.172 mmol) and HATU (0.039 g, 0.103 mmol). The reaction mixture was stirred for 18 h at room temperature and the reaction mixture was d with EtOAc (5 mL) and H20 (2 mL). The two layers were separated and the organic layer was dried with Na2S04, ?ltered and concentrated. The resulting residue was puri?ed using reverse phase high pressure liquid chromatography (0 - 90% CH3CN in H20 (both containing O.1%TFA)) to provide the desired product as a white solid (0.015 g, 42%). LC-MS (ES, m/z): 410 [M+H]+; 1H—NMR (400 MHz, CDC13): 5 9.28 (m, 2H), 7.73 (t, J = 6.04 Hz, 1H), 7.66 (d, J = 7.83 Hz, 1H), 7.60 (m, 3H), 7.41 - 7.32 (m, 1H), 4.73 - 4.61 (m, 1H), 4.00 - 3.86 (m, 1H), 3.80 (s, 2H), 3.04 (m, 1H), 2.39 - 2.15 (m, 2H), 1.79 (m, 1H), 1.52 - 1.27 (m, 5H) ppm.

Exam le 11. Pre aration of 4- l-?uoro-l- 3-?uor0 hen l sulfon l eth l -N- isoxazol-S- yl )piperidine—1-carboxamide O F NIO/Q_NH2 check00013 0 085 ,0 99+ DIEA, THF UNH F nd 11. luoro((3-flu0r0phenyl)sulfonyl)ethyl)—N-(isoxazol-S- yl)piperidine—1-carb0xamide To a on of 4-(1-?uoro—1—((3—?uorophenyl)sulfonyl)ethyl)piperidine (6.3, 0.050 g, 0.172 mmol) in THF (1 mL) at 0 °C was added DIEA (0.184 mL, 1.03 mmol) followed by triphosgene (0.017 g, 0.057 mmol). The reaction mixture was stirred for 15 minutes before the isoxazolamine (0.014 g, 0.172 mmol) was added. The reaction mixture was stirred overnight at room temperature and then was diluted with EtOAc (5 mL) and was quenched with H20 (2 mL). The two layers were separated, and the organic layer was concentrated.

The resulting residue was puri?ed using reverse phase high pressure liquid chromatography (0 - 90% CH3CN in H20 (both containing 0.1%TFA)) to e the desired product as a white solid (0.015 g, 42%). LC-MS (ES, m/z): 400 [M+H]+; 1H NMR (400 MHz, CDCl3): 6 8.06 (d, J = 1.8 Hz, 1H), 7.70 — 7.62 (m, 1H), 7.60 — 7.48 (m, 2H), 7.30 (m, 2H), 6.14 (m, 1H), 4.18 — 4.00 (m, 2H), 2.99 — 2.83 (m, 2H), 2.62 — 2.49 (m, 1H), 2.30 (m, 1H), 1.94 (m, 1H), 1.51 - 1.33 (m, 5H) ppm.

Exam le 12. Pre aration of 4- l-?uoro-l- 3-?uoro hen l sulfon l eth l -N- 6- meth l ridazin l i eridine—l-carboxamide o 1. (PhO)2PON3, Et3N, DMF, 90 °C 0 (I? 2. HN ,DMF N / O O / \ N N NH F S F \ Compound 12. 4-(l-Fluoro((3-?uorophenyl)sulfonyl)ethyl)—N-(6-methylpyridazin yl)piperidine—1-carboxamide To a solution of 6-methylpyridazine-4—carboxylic acid (0.060 g, 0.345 mmol) and triethyl amine (0.058 mL, 0.414 mmol) in DMF (1 mL) was added DPPA (0.082 mL, 0.372 mmol). The reaction mixture was plunged into a preheated 90 OC oil bath and was stirred for minutes. A solution of 4-(1-?uoro—l-((3—?uorophenyl)sulfonyl)ethyl)piperidine (6.3, 0.025 g, 0.086 mmol) in DMF (1 mL) was added slowly. The reaction mixture was stirred for 3.5 h while cooling to room temperature. The reaction e was diluted with EtOAc (5 mL) and H20 (2 mL) and the two layers were separated. The organic layer was concentrated and the ing residue was d using reverse phase high pressure liquid chromatography (0 — 90% CH3CN in H20 (both containing 0.1%TFA)) to provide the d product as a white solid (0.047 g, 4%). LC-MS (ES, m/z): 425 [M+H]+; 1H NMR (400 MHz, CDCl3): (br s, 1H), 9.44 (m, 1H), 8.53 (m, 1H), 7.76 (d, J = 8.19 Hz, 1H), 7.65 (s, 1H), 7.45 (dt, J = 1.83, 8.19 Hz, 1H), 7.15 (m, 1H), 4.57 — 4.38 (m, 2H), 2.94 — 2.78 (m, 2H), 2.71 (s, 3H), 2.43 (m, 1H), 2.37 (m, 1H), 1.96 — 1.84 (m, 1H), 1.58 — 1.37 (m, 5H) ppm.

Exam le 13. Pre aration of 4- 1-fluoro—1- 3—?uoro hen l sulfon l eth l -N- 1-meth [- 1H- razoll i eridine-l-carboxamide F F O O 9 o O/U\N o o W >_N —> >_N 13W CHZC'Z HN F 13W F nd 13.1. 4-(1-Fluoro((3-?uorophenyl)sulfonyl)ethyl)—N-(1H-pyrazol yl)piperidinecarboxamide To a solution of tert-butyl 4-(4-(1-?uoro—1-((3- ?uorophenyl)sulfonyl)ethyl)piperidinecarboxamido)—lH—pyrazole-l-carboxylate (0.093 g, 0.185 mmol) was dissolved in DCM (2 mL) and tri?uoroactetic acid (0.20 mL, 2.61 mmol) was added slowly. The reaction mixture was stirred at room temperature overnight. The reaction mixture was trated and the resulting residue was puii?ed using reverse phase high pressure liquid chromatography (0 — 90% (v/v) CH3CN in H20 (both containing 0.1%TFA)) to provide the desired product as a white solid (0.032 g, 70%). LC-MS (ES, m/z): 499.1 [M+H]+, 1H NMR (400 MHz, CDC13): 5 8.31 (s, 1H), 7.78 (m, 1H), 7.71 (s, 1H), 7.69 (m, 2H), 7.49 (m, 1H), 6.33 (br s, 1H), 4.29 — 4.06 (m, 2H), 3.05 — 2.88 (m, 2H), 2.54 (m, 1H), 2.27 (m, 1H), 2.02 (m, 1H), 1.72 — 1.40 (m, 14H) ppm. 0.9 K2C03, CH3I 0‘9, 0 \s —> o ‘s >\_N DMF \ >_N Compound 13. 4-(l-Fluoro((3-fluorophenyl)sulfonyl)ethyl)—N-(1-methyl-1H-pyrazol— 4-yl)piperidinecarboxamide To a solution of 4—(1—?uoro—1—((3—?uorophenyl)sulfonyl)ethyl)-N-(1H—pyrazol yl)piperidinecarboxamide (13.1, 0.030 g, 0.075 mmol) and K2C03 (0,026 g, 0.188 mmol) in DMF (1 mL) was added iodomethane (0005 mL, 0.090 mmol), The reaction mixture was plunged into a ted 60 °C oil bath and was stirred for 18 h. The reaction mixture was cooled to room temperature and ?ltered. The ?ltrate was trated the resulting residue was puri?ed using reverse phase high pressure liquid chromatography (0 - 90% (v/v) CH3CN in H20 (both containing O.1%TFA)) to provide the desired product as a white solid (0.032 g, 70%). LC-MS (ES, m/z): 399.1 [M+H]+, 1H NMR (400 MHz, CDC13): 5 7.88 (br s, 2H), 7.68 (d, J = 7.70 Hz, 1H), 7.62 — 7.51 (m, 2H), 7.49 — 7.32 (m, 2H), 4.28 — 4.02 (m, 2H), 2.95 (m, 2H), 2.59 (m, 2H), 2.20 (d, J = 11.86 Hz, 1H), 1.85 (d, J = 12.35 Hz, 1H), 1.54 — 1.31 (m, 5H) s~\< / _N B \ OH 0 "Q H? o s >—~ \ / OH %—o o szdba3,K2C03,xantphos,Kl $70 dioxane, MeOH Compound 14.1. tert-Butyl 4-(((6-hydroxypyridinyl)thio)methyl)piperidine—1- carboxylate Compound 14.1 was ed in a similar manner to compound 4.2 to provide the d product as a yellow solid (4.00 g, 72%). 1H NMR (400 MHz, CDC13) 6 7.50 — 7.65 (m, 3H), 6.62 — 6.70 (m, 1H), 6.53 — 6.60 (d, J=10.4Hz, 1H), 2.60 — 2.73 (m, 4H), 1.76 — 1.84 (m, 2H), 1.50 — 1.63 (m, 1H), 1.41 — 1.46 (s, 9H), 1.22 — 1.32 (m, 3H), 1.06 — 1.20 (m, 2H) $7:>_NC>—/S?<\:/)—OH‘N RuCl NaIO TH: H20 4 % éTOO>\‘_N<:>—/S\ Compound 14.2. utyl 4-(((6-hydroxypyridinyl)sulfonyl)methyl)piperidine carboxylate To a solution of tert—butyl 4—[[(6—hydroxypyridinyl)sulfanyl]methyl]piperidine carboxylate (14.1, 4.00 g,12.33 mmol) and ruthenium (III) chloride (0.80 g, 3.85 mmol) in THF/H20(1 :1 (V/V), 60 mL) was added dropwise a solution of NaIO4 (12.0 g, 49.3 mmol) in water (5 mL). The resulting solution was stirred for 1 h at room temperature. The reaction was then quenched by the addition ofH20 (30 mL) and was extracted with EtOAc (3X20 mL), dried over anhydrous NaZSO4, ?ltered and concentrated. The resulting residue was puri?ed by silica gel column with /petroleum ether (100: 1)) to provide the desired product as a white solid (2.40 g, 55%). 1H NMR (400 MHz, DMSO-d6): 5 12.35 (s, 1H), 7.89 — 7.95 (d, J=2.8Hz, 1H), 7.67 — 7.75 (m, 1H), 6.41 — 6.48 (d, z, 1H), 3.78 — 3.86 (d, J=13.3Hz, 2H), 3.23 — 3.28 (d, J=6.3Hz, 4H), 2.73 (s, 1H), 1.91 — 2.02 (m, 1H), 1.70 — 1.78 (m, 2H), 1.34 — 1.39 (s, 9H), 1.07 — 1.20 (m, 2H) ppm.

O\S/OOH . $70O>\—N/\:>—/S— K2C03, CHgCN $70O>TN/\:>_/SA<\:/)TO Compound 14.3. tert-Butyl -(difluoromethoxy)pyridin yl)sulfonyl)methyl)piperidine-l-carboxylate To a solution of tert—butyl 4—(((6—hydroxypy1idinyl)sulfonyl)methyl)pipen'dine- l-carboxylate (14.2, 1.00 g, 2.81 mmol) and K2C03 (0.590 g, 5.57 mmol) in CH3CN (20 mL) was added 2,2-difluoro-2 (?uorosulfonyl)acetic acid (0.550 g, 3.09 mmol). The resulting solution was stirred for 2 h at room ature. The reaction was then quenched by the addition of H20 (50 mL) and was extracted with EtOAc (3X30 mL). The combined organic layers were washed with brine (50 mL), dried over NaZSO4, ?ltered and concentrated. The resulting residue was puri?ed by silica gel column with (EtOAc/petroleum ether (1:10 — 1:3 (v/v))) to e the d product as a white solid (1.00 g, 88%). 1H NMR (300 MHz, CDC13): 5 8.74 (d, J = 2.4, 1H) 8.21 (dd, J = 2.4 Hz, 8.7 Hz, 1H) 7.31-7.78 , , (t, J = 71.7 Hz, 1H), 7.08 (d, J = 8.4 Hz, 1H), 4.08 (d, J = 13.5 Hz, 2H), 3.04 (d, J = 6.3 Hz, 2H), 2.72-2.81 (m, 2H), 2.22 (m, 1H), 1.92 (d, J = 12.9 Hz, 2H), 1.46 (s, 9H), .37 (m, 2H) ppm.

\\N\ l/ F>—F 08%) 0/0©/S F _N >—F $,:>_N<:>:/S2&0\Il Q? NaHMDS THF -78 °c 9,:>—N<:>:<:_QO Compound 14.4. tert-Butyl 4-(((6-(di?uoromethoxy)pyridin yl)sulfonyl)?uoromethyl)piperidine—l-carboxylate Compound 14.4 was prepared in a similar manner to nd 9.3 to provide the desired product as a yellow oil (0.20 g, 34%). 1H NMR (300 MHz, CDCl3) 5 8.74 (d, J: 2.4, 1H), 8.22 (m, 1H), 7.31-7.80 (t, J: 71.7Hz, 1H), 7.15 (d, J: 8.4Hz, 1H), 4.77—4.95 (dd, J = 6.0, 18.0 Hz, 1H), 4.19 (m, 2H), 2.79 (m, 2H), 2.40-2.60 (m, 1H) 2.00 (m, 1H), 1.50-1.60 (m, 3H), 1.47 (s, 9H) ppm.

(I? _N >—F )OHCHo \s \ / o %—»:>\_©?{kCH3|NaHMDS \ / o Compound 14.5. tert-Butyl 4-(1-((6-(di?uoromethoxy)pyridinyl)sulfonyl)—1- ?uoroethyl)piperidine-l-carboxylate Compound 14.5 was prepared in a similar manner to compound 9.4 to provide the desired product as a yellow oil (0.100 g, 48%). 1H NMR (300 MHz, CDCl3) 6 8,70 (d, J=2.4, 1H), 8.20 (m, 1H), 7.37—7.73 (t, J = 71.6Hz, 1H), 7.08 (d, J = 8.4Hz, 1H), 4.24 (m, 2H), 2.69- 2.77 (m, 2H), 2.43—2.59 (m, 1H), 2.18 (m, 1H), 1.81 (d, J = 12.0 Hz, 1H), 1.55 (d, J = 22 Hz, 3H), 1.50 (s, 9H), 1.31—1.40 (m, 2H) ppm. o (I? _N >7F O\9 —N >_F Q8&0 —.TFA ‘s o o \ / >—N HN CH2CI2 F Compound 14.6. 2-(Difluoromethoxy)—5—((l-?uoro-l-(piperidin yl)ethyl)sulfonyl)pyridine id="p-128" id="p-128" id="p-128" id="p-128" id="p-128" id="p-128" id="p-128" id="p-128" id="p-128" id="p-128" id="p-128" id="p-128" id="p-128" id="p-128"

[0128] Compound 14.6 was prepared in a similar manner to compound 4.5 to e the desired t as a yellow oil (0.300 g). The d product was used as is in the next reaction t puri?cation. LC-MS (ES, m/z): 339.0 [M+H]+.

\ F F [ii \?/ 0 O —N Ow s~<\:/)ro_N > F N / O >—F >_N O§§4OO\ / F Et3N, DMSO, 70 °C NC\>,NHN F Compound 14. 4-(1-((6-(Difluoromethoxy)pyridinyl)sulfonyl)—1-fluoroethyl)—N- (pyridazinyl)piperidine—1-carboxamide id="p-129" id="p-129" id="p-129" id="p-129" id="p-129" id="p-129" id="p-129" id="p-129" id="p-129" id="p-129" id="p-129" id="p-129" id="p-129" id="p-129"

[0129] Compound 14 was prepared in a similar manner to compound 9 to provide the desired product as a white solid (0.116 g, 29%). LC-MS (ES, m/z): 460.1 [M+H]+; 1H NMR (400 MHz, DMSO-dé): 6 9.28 (d, J=2.0Hz, 1H), 9.21 (s, 1H), 8.88 (d, J=6.0Hz, 1H), 8.77 (d, J=2.4Hz, 1H), 8.37 (dd, J=8.4, 1.6Hz, 1H), 7.83 (t, J=71.6Hz, 1H), 7.77 (d, J=2.4Hz, 1H), 7.41 (d, J=8.8Hz, 1H), 4.23 — 4.31 (m, 2H), 2.89 (m, 2H), 2.47 (m, 1H), 2.10 (m, 1H), 1.73 (m, 1H), 1.57 (d, J=22.8Hz, 3H), 1.40 (m, 2H) ppm. sulfon l TsCl, Et3N Csz —> 0sz OH DIVIAP, CHZCIZ OTs Compound 15.1. Benzyl 4-((tosyloxy)methyl)piperidine—l-carboxylate nd 15.1 was prepared in a similar manner to compound 1.1 to provide the desired product as a white solid (13.0 g, 80%). LC-MS (ES, m/z): 404.2 [M+H]+; 1H NMR (300 MHz, CDC13): 5 7.78 (d, J = 8.4Hz, 2H), 7.38-7.78 (m, 7H), 5.10 (s, 2H), 4.20—4.15 (m, 2H), 3.85 (d, J = 6.3Hz, 2H), 2.77-2.69 (m, 2H), 2.41 (s, 3H), .79 (m, 1H), 1.69-1.64 (m, 2H), 1.19-1.15 (m, 2H) ppm.

—’ CbZN:>_\S_ OTS K2C03, DMF Compound 15.2. Benzyl 4-((carbamimidoylthio)methyl)piperidine—l-carboxylate Compound 15.2 was prepared in a similar manner to compound 3.1 to provide the desired product as a brown oil (25.0 g). The material was used as is in the next reaction without further puri?cation. LC-MS (ES, m/z): 308.1 [M+H]+.

M" ‘N _\< H2N 0—»mySMNH szdbag, K2C03, xantphos, KI e, MeOH Compound 15.3. Benzyl 4-(((3-aminomethyl-1H-pyrazolyl)thio)methyl)piperidine— 1-carboxylate Compound 15.3 was prepared in a similar manner to compound 4.2 to provide the desired product as a yellow oil (8.3 g, 59%). 1H NMR (400 MHz, CDCl3) 6 7.29-7 .39 (m, 5H), 5.65 (s, 1H), 5.12 (s, 2H), 4.05-4.19 (m, 2H), 3.71 (s, 3H), 2.66-2.79 (m, 2H), 2.64 (m, 2H), .85 (m, 2H), 1.60-1.72 (m, 1H), 1.10-1.35 (m, 2H) ppm.

\ \ SMNH NaNo2 CuCl N~N oszC>—/ HCI AcOH H20 oszC>—/SMCI nd 15.4. benzyl 4-(((3-chloro—l-methyl-lH-pyrazolyl)thio)methyl)piperidine— 1-carboxylate To a solution of benzyl 4—(((3—amino—1—methyl-1H-pyrazol yl)thio)methyl)piperidinecarboxylate (1.9 g, 5.27 mmol) in concentrated HCl (9.5 mL) and AcOH (57 mL) at 0 0C was added dropwise a solution of sodium nitrate (0.551 g, 7.99 mmol) in H20 (9.5 mL). The resulting solution was d for 30 minutes at 0 oC. The temperature was increased to 80 0C, and a solution of copper (I) chloride (2.09 g, 21.1 mmol) in concentrated HCl (9.5 mL) and AcOH (19 mL) was added dropwise. The resulting solution was stirred for an additional 10 min while the temperature was maintained at 70 °C. The resulting solution was extracted with EtOAc (100 mL) and the organic layers combined. The resulting solution was washed with brine (50 mL), dried over anhydrous NaZSO4, ?ltered, and then concentrated. The resulting residue was puri?ed by silica gel column with (EtOAc/petroleum ether (1 :2 (v/v))) to provide the desired product as a white solid (0.700 g, 35%). 1H NMR (300 MHz, : 6 7.29-7.39 (m, 5H), 6.19 (s, 1H), 5.12 (s, 2H), 4.23- 4.19 (m, 2H), 3.83 (s, 3H), 2.68-2.80 (m, 3H), 1.69-1.85 (m, 2H), 1.60 (m, 1H), 1.22 (m, 2H) \ \ N‘ O N Oxone O N\N CbZN/\:>—/SM —> ‘SM\ll Cl D|V|F CbZN Cl Compound 15.5. Benzyl 4-(((3-chlor0-l-methyl—lH-pyrazol-S- yl)sulfonyl)methyl)piperidine—l-carboxylate Compound 15.5 was prepared in a r manner to nd 5.3 to provide the desired product as a yellow oil (8.3 g, 59%). 1H NMR (400 MHz, CDC13): 5 7.26-7.39 (m, 5H), 6.14 (s, 1H), 5.12 (s, 2H), 4.17-4.28 (m, 2H), 4.09 (s, 3H), 3.09 (m, 2H), 2.84 (m, 2H), .29 (m, 1H), 1.91 (m, 2H), 1.27—1.40 (m, 2H) ppm.

\ \ O N\ O N\ 0% IN 1.NFS|,t-BuOK,THF,—78°C 0% N \ —> \ 0sz CbZN Cl 2. CH3I, t-BUOK, THF, —78 °C Compound 15.6. Benzyl 4-(1-((3-chlor0-l-methyl-1H-pyrazol-S-yl)sulfonyl) ?uoroethyl)piperidine-l-carboxylate id="p-135" id="p-135" id="p-135" id="p-135" id="p-135" id="p-135" id="p-135" id="p-135" id="p-135" id="p-135" id="p-135" id="p-135" id="p-135" id="p-135"

[0135] To a solution of benzyl 4—[(3—chloro—1—methyl—1H—pyrazole sulfonyl)methyl]piperidine—1—carboxylate (15.5, 2.9 g, 7.04 mmol) in THF (120 mL) at -78 °C was added t-BuOK (7 mL, 7.04 mmol, 1M in THF) dropwise, followed by a solution of NFSI (1.33 g, 4.22 mmol) in THF (20 mL) dropwise. The resulting solution was stirred for 1h at -78 0C before onal t-BuOK (21.1 mL, 21.12 mmol, 1M in THF) was added dropwise.

The resulting solution was stirred for 30 min at -78 °C before iodomethane (3.00 g, 21.14 mmol) was added dropwise. The resulting solution was stirred for an additional 30 min at -78 0C before being quenched by the addition of n—hexane (50 mL). The reaction mixture was warmed to room ature, the solids were removed by ?ltration, and the ?ltrate was concentrated. The resulting residue was puri?ed by prep-HPLC (ACN/HZO 10:90 (v/v) sing to ACN/HZO 80:20 (v/v) within 50 min; Detector, UV 254nm) to provide the product as a white solid (1.5 g, 83%). 1H NMR (400 MHz, CDCl3): 8 7.35 (m, 5H), 6.80 (s, 1H), 5.13 (s, 2H), 4.09-4.33 (m, 2H), 4.07 (s, 3H), 2.56-2.82 (m, 2H), 2.52 (m, 1H), 2.12 (m, 1H), 1.84 (m, 1H), 1.59 (d, J = 24.0 Hz, 3H), 1.40 (m, 2H) ppm. (kg? conc. HCI (kg—Q Cl CH3OH C, ': %F Compound 15.7. 4-(1-((3-Chloro-l-methyl-1H-pyrazolyl)sulfonyl)—1- fluoroethyl)piperidine hydrochloride To a solution of benzyl 4-[1-(3—chloro—l—methyl-lH- pyrazolesulfonyl) ?uoroethyl]piperidinecarboxylate (15.6, 1.00 g, 2.25 mmol, 1.00) in methanol (5 mL) was added concentrated HCl (15 mL). The resulting on was stirred for 3 h at 70 0C in an oil bath, and then was concentrated. The resulting residue was precipitated with methanol (2 mL). The crude product was puri?ed by re—crystallization from ether to provide the desired product as a white solid (0.429 g, 55%). LC-MS (ES, m/z): 310.1 [M+H]+, 1H NMR (400 MHz, CD3OD): 6 7.05 (s, 1H), 4.09 (s, 3H), 3.50 (m, 2H), 3.03-3.13 (m, 2H), 2.64-2.73 (m, 1H), 2.35 (m, 1H), 2.10 (m, 2H), 1.70-1.85 (m, 2H), 1.65 (d, J = 24.0 Hz, 3H) ppm, 19F NMR (376 MHz, CD3OD)I 6 -146.30 ppm.

HCI.HNC>—?FS | Cl NI" \ NZ‘" F DIEA, DMSO, 80 °c Compound 15. 4-(1-((3-Chloro-l-methyl-lH-pyrazol-S-yl)sulfonyl)—1-fluoroethyl)—N- (pyridazinyl)piperidine—l-carboxamide Compound 15 was ed in a similar manner to compound 6 to provide the desired product as an off-white solid (0.012 g, 8%). LC-MS (ES, m/z): 430.1 [M+H]+, 1H NMR (300 MHz, CD30D): 6 9.20 (m, 1H), 8.84 (d, J = 8.0 Hz, 1H), 7.83 (m, 1H), 6.99 (s, 1H), 4.33 (m, 2H), 4.03 (s, 3H), 2.99 (m, 2H), 2.56 (m, 1H), 2.17 (m, 1H), 1.90 (m, 1H), 1.66 — 1.42 (m, 5H) ppm; 19F NMR (376 MHz, CD3OD): 6 —77.12, 4 ppm.

Exam le 16. Pre aration of 4- l-fluoro-l- l-meth l trifluorometh 1 -1H- razol Compound 16.1. 4-Bromomethyl(tri?uoromethyl)-1H-pyrazole Into a lO—mL sealed tube purged and maintained with an inert atmosphere of argon, was placed a solution of l—methyl—3—(tri?uoromethyl)—lH—pyrazole (10.0 g, 66.62 mmol) and NBS (16.2 g, 66.62 mmol) in DMF (100 mL). The resulting solution was stirred overnight at 50 0C in an oil bath. The reaction was then ed by the addition of ice water (1 L). The resulting on was extracted with ether (3x200 mL), the organic layers combined and dried over anhydrous NaZSO4, ?ltered and then trated to provide the desired product as a yellow oil (12.0 g, crude), which was used as is without further puri?cation. 1H NMR (400 MHz, : 5 7.46 (s, 1H), 3.94 (s, 3H) ppm. $7Z>~NC>_/S— szdba3, K2C03, xantphos, O>—N::>—/S: dioxane, MeOH Compound 16.2. tert-Butyl 4-(((1-methyl(tri?uoromethyl)-1H-pyrazol yl)thio)methyl)piperidine-l-carboxylate Compound 16.2 was prepared in a similar manner to compound 4.2 to provide the desired product as a yellow solid (0.200 g, crude). The desired product was used as is in the next reaction without further puri?cation. LC-MS (ES, m/z): 279.9 [M+H—Boc]+.

F3C F3C \N O\\\ \N o 8&1 RuCI3, Na IO4 o ‘8&1 >—N \ \ THF,H20 $70 $~o>~N Compound 16.3. tert-Butyl 4-(((1-methyl(tri?uoromethyl)-1H-pyrazol yl)sulfonyl)methyl)piperidine—1-carboxylate nd 16.3 was prepared in a similar manner to nd 14.2 to provide the desired product as a yellow solid (0.200 g, 15%). The desired product was used as is in the next reaction without further puri?cation. lH NlVIR (400 MHz, CDCl3): 6 7.96 (s, 1H), 4.07 (m, 2H), 4.02 (s, 3H), 3.14 (d, J=6.4Hz, 2H), 2.74 (m, 1H), 2.22 (m, 2H), 1.90 (m, 2H), 1.46 (s, 9H), .35 (m, 2H) ppm.

F3C F3C 08" o 0%" 4&0 o NFSI, t-BuOK >—/\ o THF -78 °c —< o o F Compound 16.4. tert-Butyl 4-(fluoro((1-methyl-3—(trifluoromethyl)—1H—pyrazol yl)sulfonyl)methyl)piperidine—1-carboxylate To a solution of tert-butyl 4—[[1—methyl—3—(tri?uoromethyl)—lH-pyrazole sulfonyl]methyl]piperidine-l-carboxylate (16.3, 0.450 mg, 1.09 mmol) in THF (20 mL) at - 78 0C was added dropwise a solution oft—BuOK (11 mL, 1.0M in THF, 5.54 mmol). The resulting on was stirred for 0.5 h before a solution of NFSI (2.42 g, 7.63 mmol) in THF (2 mL) was added. The resulting solution was stirred for an additional 1 h at -78 0C before being quenched by the addition of ice water (50 mL). The resulting mixture was extracted with EtOAc (3x50 mL), and the organic layers combined, then dried over NaZSO4 and concentrated. The resulting residue was puri?ed by prep-HPLC (ACN/HzO 0:100 (V/V) increasing to ACN/HzO 100:0 (V/V) within 50 min; Detector, UV 254nm) to provide the product as a white solid (0.200 g, 43%). 1H NMR (400 MHz, CDCl3): 6 7.99 (s, 1H), 4.87- .00 (m, 1H), 4.18 (d, J = 13.2 Hz, 2H), 4.03 (s, 3H), 2.71-2.82 (m, 2H), 2.42 — 2.54 (m, 1H), 1.93-2.01 (m, 2H), 1.40-1.60 (m, 11H) ppm.

F3C F30 o 09% CH3I t-BuOK 03 46171 >—N N\ \ THF -78°C >\—N N\ > o E F Compound 16.5. utyl 4-(l-?uoro((1-methyl-3—(trifluoromethyl)-1H—pyrazol yl)sulfonyl)ethyl)piperidine—1-carboxylate To a solution of tert-butyl 4-[fluoro[1-methyl(t1i?uoromethyl)—lH-pyrazole sulfonyl]methyl]piperidine-l-carboxylate (16.4, 0.060 g, 0.14 mmol) in THF (3 mL) at -78 0C was added a solution of t-BuOK (0.45 mL, 1.0M in THF, 0.56 mmol). The reaction mixture was stirred for 0.5 h at -78 0C before iodomethane (0.052 g, 0.37 mmol) was added dropwise. The reaction mixture was stirred for an additional 4 hours at -78 0C before being quenched by the addition of ice water (30 mL). The resulting solution was extracted with EtOAc (3x30 mL). The combined organic layers were dried over NaZSO4, ?ltered and concentrated to provide the d product as a solid (0.040g, crude) which was used as is in the next reaction without further puri?cation. LC-MS (ES, m/z): 344 oc]+.

O>—N::>74F —>HCI.HN<:>74F \ > \ 14-dioxane N\ Compound 16.6. 4-(1-Fluoro((1-methyl-3—(tri?uoromethyl)—1H-pyrazol yl)sulfonyl)ethyl)piperidine hloride Compound 16.4 was prepared in a similar manner to compound 9.5 to provide the desired product as a white (0.104 g, 93%). LC-MS (ES, m/z): 343.9 [M+H]+, 1H NMR (400 MHz, D20): 8 8.39 (s, 1H), 3.93 (s, 3H), 3.38-3.50 (m, 2H), 2.88-3.02 (m, 2H), 2.53 (m, 1H), 2.21 (d, J = 14.5 Hz, 1H), 2.01 (dt, J = 14.4, 3.0 Hz, 1H), .77 (m, 4H), 1.55 (s, 2H) F30 JT0 3 03 O\\\ \N 0 o \s{' O’N 3 N N\ HCI. HN Et3N DMSO, 70°C \ F Compound 16. 4-(1-Fluoro((1-methyl(trifluoromethyl)-1H-pyrazol yl)sulfonyl)ethyl)—N-(isoxazolyl)piperidine—l-carboxamide Compound 16 was prepared in a similar manner to compound 9 to e the desired product as a white solid (0.09 g, 22%). LC-MS (ES, m/z): 454.1 [M+H]+; 1H NMR (400 MHz, CD3OD): 6 8.39 (d, J = 1.5 Hz, 2H), 6.68 (d, J = 1.8 Hz, 1H), 4.00-4.30 (m, 2H), 3.98 (s, 3H), 2.84-2.93 (m, 2H), 2.48-2.58 (m, 1H), 2.18 (d, J = 1.5 Hz, 1H), 1.84 (d, J = 12.6 Hz, 1H), 1.33-1.61 (m, 5H) ppm; 19F NMR (376 MHz, CD3OD): 6 —61,149, 2, — 144.269, —144.300 ppm.

Exam le 17. Pre aration of 4- 1- 3— difluorometh l meth l-1H- razol-S- lsulfon l-l-fluoroeth l-N- ridazin-4— l i eridine-l-carboxamide N—— DAST NI / —> 54-— / CH20|2 /N / Compound 17.1. uoromethyl)—l-methyl-lH-pyrazole To a solution of l-methyl—lH—pyrazole—3-carbaldehyde (4.00 g, 36.33 mmol) in CH2C12 (50 mL) at 0 °C was added DAST (23.4 g, 145.17 mmol, 4.00 equiv) dropwise. The reaction mixture was stirred overnight at room ature and then was quenched by the on of saturated NaHCO3 (100 mL), and extracted with CHzClz (3x200 mL). The combined organic layers were dried over anhydrous MgSO4, ?ltered and concentrated to provide the desired product as an oil (4.8 g, crude) which was used in the next reaction without further puri?cation. 1H NMR (400 MHz, CDC13): 6 7.32—7.37 (m, 1H), 6.44-6.45 (t, 1H), 6.80 (m, 1H), 3.90 (s, 3H) ppm.

F |2 N .— N—— —> I : , THF N / | Compound 17.2. 3-(Difluoromethyl)—5-iodo—l-methyl-lH-pyrazole To a solution of 3-(di?uoromethyl)—l—methyl-lH-pyrazole (17.1, 4.8 g, 36.33 mmol) in THF (50 mL) at -78 °C was added n-BuLi (20.0 mL, 2.5 M in n-hexane) dropwise.The resulting on was stirred for 30min at -78 0C before a solution of 12 (13.8 g, 54.49 mmol) in THF (50 mL) was added dropwise. The reaction mixture was stirred for 2 h at -78 0C before being quenched by the addition of NH4Cl(sat‘) (100 mL). The resulting solution was extracted Et2O (2x200 mL) and the combined organic layers were washed with saturated Na2S203(aq.) (2x100 mL), dried over anhydrous MgSO4, ?ltered and trated to provide the desired product (9.0 g, crude), which was used as is in the next reaction without further puri?cation. 1H NMR (400 MHz, CDC13): 6 651-678 (m, 2H), 3.97 (s, 3H) ppm.

O>¥ s—< I 970 O>\_N szdba3 K2C03 xantphos, dioxane MeOH $70 Compound 17.3. tert—Butyl -(di?uoromethyl)—l-methyl-lH-pyrazol-S- yl)thio)methyl)piperidine—1-carboxylate Compound 17.3 was prepared in a similar manner to compound 4.2 to provide the desired product as a dark red oil (0.370 g, 38%). The desired product was used as is in the next on without further puri?cation. 1H NMR (400 MHz, CDC13): 8 6.44-6.74 (m, 2H), .17 (m, 2H), 3.83-3.96 (m, 3H), 2.62-2.76 (m, 4H), 1.82 (d, J = 13.2 Hz, 2H), 1.60 (m, 2H), 1.46 (s, 8H), 1.09—1.28 (m, 2H) ppm.

\ \ N\ O N O RUCI3, NaIO4 O\\ H\\S \lN MyS \ l F >—~ THF, H20 $70 $70 Compound 17.4. tert—Butyl 4-(((3-(difluoromethyl)—l-methyl-lH-pyrazol-S- yl)sulfonyl)methyl)piperidine—l-carboxylate Compound 17.4 was ed in a similar manner to compound 14.2 to provide the desired product as a dark red oil (0.200 g, 68%). The desired product was used as is in the next reaction without further puri?cation. 1H NMR (400 MHz, CDCl3): 5 7.05 (s, 1H), 6.67 (t, J = 54.7 Hz, 1H), 4.17 (m, 5H), 3.11 (d, J = 6.4 Hz, 2H), 2.68-2.84 (m, 2H), 2.24 (m, 1H), 1.90 (d, J = 13.5 Hz, 2H), 1.45 (s, 9H), 1.22—1.41 (m, 2H) ppm. o ‘N ok 065 ‘N ‘N 0 NFSI t-BuOK 0" >—N\/:>—/ \ I I THF -78 °c :>\‘N<:>—<: F Compound 17.5. tert-Butyl 4-(((3-(difluoromethyl)methyl-1H-pyrazol yl)sulfonyl)?uoromethyl)piperidine—l-carboxylate Compound 17.5 was prepared in a similar manner to nd 16.4 to provide the desired product as a yellow oil (0.900 g, 29%). 1H NMR (400 MHz, CDCl3): 6 7.11 (s, 1H), 6.68 (t, J = 54.7 Hz, 1H), 5.03 (d, J = 6.4 Hz, 0.5H), 4.87 (d, J = 6.4 Hz, 0.5H), 4.16 (s, 5H), 2.86 — 2.69 (m, 2H), 2.45 (s, 1H), 2.04 — 1.91 (m, 2H), 1.59 — 1.50 (m, 2H), 1.46 (s, 9H) ppm. o\N o\N :>—<:4<\/S/F0|| 0|| CH3I, t-BuOK THF, -78 °c O)\-—N > >0 SWF Compound 17.6. tert-Butyl 4-(1-((3-(difluoromethyl)—l-methyl-lH-pyrazol-S- yl)sulfonyl)—1-fluoroethyl)piperidine—l-carboxylate Compound 17.6 was prepared in a similar manner to compound 16.5 to e the desired t as a clear oil (0.900 g, 29%). 1H NMR (400 MHz, CDC13): 8 7.11 (s, 1H), 6.70 (t, J = 54.7 Hz, 1H), 4.25 (m, 2H), 4.14 (s, 3H), 2.74 (m, 2H), 2.51 (m, 1H), 2.13 (d, J = 12.2 Hz, 1H), 1.81 (m, 1H), 1.53-1.65 (m, 4H), 1.47 (s, 9H) ppm.

\ \ O N O Ow ‘N N\ o ‘s I TFA Osg > \ _’ \ N TFAHN F F CHZCIZ F $70 F Compound 17.7. 4-[1-[3-(Difluoromethyl)—1-methyl-lH-pyrazole-S-sulfonyl]1- fluoroethyl]piperidine trifluoroacetic acid Compound 17.7 was prepared in a similar manner to compound 4.5 to provide the desired product as a white solid (0.496 g, 69%). The desired product was used as is in the next reaction t further puri?cation. LC-MS (ES, m/z): 326.1 [M+H]+, 367.1 [M+H+CH3CN]+, 1H NMR (300 MHz, CD3OD): 8 7.24 (s, 1H), 6.80 (t, J = 54.5 Hz, 1H), 4.11 (s, 3H), 3.47 (m, 2H), 3.05 (m, 2H), 2.69 (m, 1H), 2.28-2.40 (m, 1H), 2.09 (m, 1H), 1.57-1.87 (m, 5H) ppm.

\ \H/ o N :H N 0(98' O 0*" N‘N \ l O S \ | TFA"ND—fl: Et3N DMSO 70°C «5" \ NHyN<:>_?F N Compound 17. 4-(1-((3-(Difluoromethyl)—l-methyl-lH-pyrazol-S-yl)sulfonyl)—1- fluoroethyl)—N-(pyridazinyl)piperidine—l-carboxamide fluoroethyl]piperidine tri?uoroacetic acid Compound 17 was ed in a similar manner to compound 9 to provide the desired product as a white solid (0.068 g, 60%). LC-MS (ES, m/z): 447.0 [M+H]+, 1H NMR (300 MHz, CD3OD): 5 9.20 (d, J = 2.1 Hz, 1H), 8.84 (d, J = 6.0 Hz, 1H), 7.84 — 7.81 (m, 1H), 7.21 (s, 1H), 6.79 (t, J = 54.3 Hz, 1H), 4.34 — 4.26 (m, 2H), 4.11 (s, 3H), 3.03 — 2.94 (m, 2H), 2.64 — 2.53 (m, 1H), 2.19 — 2.15 (m, 1H), 1.90 — 1.86 (m, 1H), 1.65 — 1.48 (m, 5H) ppm.

Exam le 18. Pre aration of R l-?uoro—l- l-meth l-3— orometh 1 -1H- razol-S- lsulfon leth l-N— isoxazol l i eridine—l-carboxamide H H2804 F3C o/\ \ Et3N, MeOH N Compound 18.1. 1-Methyl(tri?uoromethyl)—1H-pyrazole id="p-153" id="p-153" id="p-153" id="p-153" id="p-153" id="p-153" id="p-153" id="p-153" id="p-153" id="p-153" id="p-153" id="p-153" id="p-153" id="p-153"

[0153] To a on of (3E)—4—ethoxy—1,1,1—tri?uorobut—3-enone (29.0 g, 172.50 mmol) in methanol (300 mL) was added methylhydrazine sulfuric acid (39.8 g, 276.10 mmol) portionwise, followed by the addition of triethylamine (18.0 g, 177.88 mmol) portionwise.

The resulting solution was stirred overnight at 40 °C. The resulting mixture was then cooled to room temperature and trated under vacuum. The reaction was then ed by the addition of ice water (200 mL) and was extracted with EtzO (3x200 mL). The combined organic layers were washed with brine (2x200 mL), dried over anhydrous MgSO4, ?ltered and concentrated to provide the desired product as a light brown oil (29.0 g, crude) which was used as is in the next reaction. LC-MS (ES, m/z): 151.0 [M+H]+, 192.0 [M+H+CH3CN]+, 1H NMR (300 MHz, CDC13): 5 7.37 (m, 1H), 6.48 (d, J = 2.2 Hz, 1H), 3.94 2O (s, 3H) ppm. "n—» "m N n-BuLi THF N Compound 18.2. methyl(tri?uoromethyl)-1H-pyrazole To a solution of l-methyl(tri?uoromethyl)-lH-pyrazole (18.1, 3.7 g, 24.65 mmol) in THF (40 mL) at -78 °C was added n-BuLi (2.5M in n-hexane, 11.2 mL, 27.11 mmol) dropwise. The resulting on was stirred for 10 min at -78 °C before a solution of solution of 12 (10.0 g, 39.44 mmol) in THF (10 mL) was added dropwise. The on mixture was stirred at -78 °C for 30 minutes before being quenched by the addition of saturated NH4Cl(aq) (100 mL) and extracted with EtzO (3x200 mL). The combined organic layers were washed with saturated Na28203(aq) (2x100 mL) and brine (2x50 mL), dried over anhydrous MgSO4, d and concentrated to provide the desired t as a yellow solid (8.0 g, crude) that was used as is in the next on. LC-MS (ES, m/z): 276.8 [M+H]+, 317.8 [M+H+CH3CN]+, 1H NMR (300 MHz, CDC13): 5 6.67 (s, 1H), 3.96 (s, 3H) ppm. 0 s—< N\N 3*" \ OMyS 0 \ | o szdba3, K2C03, xantphos, +0 F dioxane, MeOH F Compound 18.3. utyl 4-(((1-methyl-3—(trifluoromethyl)—1H-pyrazol yl)thio)methyl)piperidine-l-carboxylate Compound 18.3 was prepared in a similar manner to compound 4.2 to provide the desired product as a dark red oil (2.20 g, 85%). The desired product was used as is in the next reaction without further puri?cation. 1H NMR (300 MHz, CDCl3): 6 6.53 (s, 1H), 4.13 (d, J = 13.1 Hz, 2H), 3.94 (s, 3H), 2.60-2.78 (m, 4H), 1.82 (d, J = 13.5 Hz, 2H), 1.53—1.70 (m, 1H), 1.46 (s, 9H), 1.07—1.29 (m, 2H) ppm.

\ \ N‘N N O S I RUCI3, Na|04 09 $70MyRF My \ F THF, H20 F $70 Compound 18.4. tert—Butyl 4-(((1-methyl(tri?uoromethyl)—1H-pyrazol yl)sulfonyl)methyl)piperidine—l-carboxylate Compound 18.4 was prepared in a similar manner to compound 14.2 to provide the desired t as a dark red oil (3.5 g, 92%). The desired product was used as is in the next reaction without further puri?cation. 1H NMR (400 MHz, CD3OD): 8 7.09 (s, 1H), 4.20 (s, 3H), 4.12 (m, 2H), 3.12 (d, J = 6.4 Hz, 2H), 2.71-2.83 (m, 2H), 2.27 (m, 1H), 1.90 (d, J = 12.9 Hz, 2H), 1.45 (s, 9H), 1.30 (m, 2H) ppm. 0 Z/ o\u ‘N NFS|,tBuOK 0% ‘N o _ \ I o \s | 0My o>903 F F F F F Compound 18.5. tert—Butyl 4-(fluoro((1-methyl(trifluoromethyl)—1H-pyrazol yl)sulfonyl)methyl)piperidine—l-carboxylate Compound 18.5 was prepared in a similar manner to compound 16.4 to provide the desired t as a yellow oil (0.100 g, 27%). 1H NMR (400 MHz, CDCl3): 5 7.15 (s, 1H), 4.97 (dd, J = 48.0, 6.5 Hz, 1H), 4.21 (m, 5H), 2.71-2.82 (m, 2H), 2.48 (m, 1H), 1.97 (t, J = 12.8 Hz, 2H), 1.48 (m, 2H), 1.46 (s, 9H) ppm.

\ \ N. O N o>_ ‘5 "CH \ IN -BuOK 0% THF,-78 0. o>_ > o F F F > NQ—? Compound 18.6. tert—Butyl 4-(1-fluoro—1-((l-methyl(trifluoromethyl)—1H-pyrazol fonyl)ethyl)piperidine—1-carboxylate Compound 18.6 was prepared in a similar manner to compound 16.5 to provide the desired product as a clear oil (10.0 g, 86%). 1H NMR (400 MHz, CDCl3)I 6 7.12 (s, 1H), 4.25 (d, J = 15.2 Hz, 2H), 4.15 (s, 3H), 2.70 (a, J = 129,26 Hz, 2H), 2.48 (m, 1H), 2.08 (d, J = 13.2 Hz, 1H), 1.79 (d, J = 13.3 Hz, 1H), 1.58 (d, J = 22.4 Hz, 3H), 1.44 (s, 9H), 1.19—1,40 (m, 2H) ppm.

O\" \N O \S \ | E F O \N\ > 804o F O\\" N SFC chiral separation O>_04S + F \ #0 F F 0 9 N‘N Compound 18.6a. tert-Butyl (R)(1-?uoro((1-methyl(trifluoromethyl)-1H- pyrazol-S-yl)sulfonyl)ethyl)piperidine—l-carboxylate and Compound 18.6b. utyl (S)—4-(1-fluoro((1-methyl-3—(trifluoromethyl)—1H-pyrazol yl)sulfonyl)ethyl)piperidine—l-carboxylate The enantiomers of tert—butyl 4—(1—?uoro—1—((l-methyl(tri?uoromethyl)-1H- pyrazol-S-yl)sulfonyl)ethyl)piperidine—l—carboxylate (18.6, 3.3g) were separated using by Prep-SFC (Column: Phenomenex Lux 5u Cellulose—4250*50mm; Mobile Phase A: C0180, Mobile Phase B: MeOHz20, Flow rate: 150 mL/min; 220 nm) to provide RT1 = 3.04 min (18.621, 1.3 g, 78%) as a white solid and RT2 = 3.59 min (18.6b, 1.3 g, 78%) as a white solid.

\ \ OH N S 4N HCI 0‘," ‘N \ I S \ | 2%O>—NC>—4F CHgOH HCl-HN F Compound 18.7. (R)—4-(1-Fluoro-l-((l-methyl(trifluoromethyl)—1H-pyrazol yl)sulfonyl)ethyl)piperidine hydrochloride To a solution of tert-butyl 4-[(1R)?uoro[1-methyl-3 -(tri?uoromethyl)-1H- pyrazole-5—sulfonyl]ethyl]piperidine—l—carboxylate (18.63, 1.3 g, 2.93 mmol) in CHzClz (10 mL) was added 4N HCl in CH3OH (10 mL). The resulting on was stirred for 1h at room ature and then was concentrated. The resulting residue was dissolved in CH3OH (5 mL) and was precipitated by the addition of 320 (8 mL) to provide the desired product (1.03 g, 92%) as a white solid. LC-MS (ES, m/z): 344.0 , 385.0 [M+H+CH3CN]+, 1H NMR (400 MHZ, CDgOD): 5 7.42 (s, 1H), 4.16 (s, 3H), 3.46 (d, J = 8.9 Hz, 2H), 3.06 (dt, J = 14.0, 10.5 Hz, 2H), 2.62-2.79 (m, 1H), 2.34 (d, J = 14.6 Hz, 1H), 2.09 (d, J = 14.5 Hz, 1H), 1.77 (t, J = 12.8 Hz, 2H), 1.66 (d, J = 22.9 Hz, 3H) ppm.

Compound 18. (R)(1-Fluoro((1-methyl(trifluoromethyl)—1H-pyrazol yl)sulfonyl)ethyl)—N-(isoxazolyl)piperidine—l-carboxamide Compound 18 was prepared in a similar manner to compound 9 to e the desired t as a white solid (0.09 g, 22%). LC-MS (ES, m/z): 454.1 [M+H]+; 1H NMR (400 MHz, CD3CN): 6 8.36 (s, 1H), 8.01-8.16 (m, 1H), 8.09 (br. s., 1H), 7.39 (s, 1H), 6.85 (s, 1H), 4.17 (s, 5H), 2.82-3.00 (m, 2H), 2.45-2.61 (m, 1H), 2.05-2.17 (m, 1H), 1.76-1.90 (m, 1H), 1.59-1.72 (m, 3H), 1.41-1.58 (m, 2H) ppm.

Exam le 19. Pre aration of 4- 1- 3—chloro—l-meth l-1H- razol l sulfon l fluoroeth l-N- isoxazol l i eridine—l-carboxamide 1. HCI, NaNOZ, 0 °C NH2 2. CuCI, HCI, 80 °C ’N\ ’N\ ’N ’N / / Compound 19.1. 3-Chloro-l-methyl-lH-pyrazole To a solution of l-methyl-1H-pyrazol-3—amine (5.0 g, 51.48 mmol) in trated HCl(aq) (50 mL) at 0 °C was added NaNOz (3.56 g, 51.59 mmol). The ing solution was stirred for 30 min at 0 °C before being added to a solution of CuCl (5.1 g, 51.48 mmol) in concentrated HCl(aq) (50 mL). The reaction mixture was stirred overnight at 80 °C and then was quenched by the on of H20 (100 mL). The resulting solution was extracted with EtOAc (50 mL), washed with brine (3x50 mL), dried over anhydrous MgSO4, ?ltered and was concentrated. The resulting residue was puri?ed by ?ash chromatography (CHzClz/petroleum ether = 1:1 (v/v)) to provide the desired product as a solid (1.9 g, 32%). 1H NMR (400 MHz, CDgOD): 5 7.57 (d, J = 2.3 Hz, 1H), 6.22 (d, J = 2.3 Hz, 1H), 3.85 (s, 3H) ppm.

Cl 'N‘ NT —>3 ’NCISO H /N’ / .CI / 1,5" Compound 19.2. 3-Chloromethyl-1H-pyrazole—4-sulfonyl chloride 3-Chloromethyl-1H-pyrazole (19.1, 3.0 g, 25.74 mmol) was added to chlorosulfuric acid (20 mL) and the reaction mixture was stirred overnight at 100 °C. The reaction was then quenched by the addition of ice (200 mL), ted with EtOAc (3x200 mL), washed with brine (3x200 mL), dreied over MgSO4, ?ltered and concentrated.

The resulting residue was puri?ed by ?ash tography (10% (v/v) CH3OH in CHZCIZ) to provide the desired product as a white solid (4.2 g, 76%). 1H NMR (400 MHz, CDC13): 8 12.48 (d, J = 6.1 Hz, 1H), 7.90 (d, J = 3.0 Hz, 3H) ppm.

N\ / Br ’N O§SI94_/ N\ l/ \\ NaH003, N82303, 0 0 dioxane, H20, 50 °c Compound 19.3. 4-(((3-Chloro-l-methyl-lH-pyrazolyl)sulfonyl)methyl)pyridine To a on ofNaHCO3 (5.86 g, 69.75 mmol) and Na2803 (5.86 g, 69.75 mmol) in H20 (7.5 mL) at 50 0C was added a solution of 3-chloromethy1—1H—pyrazolesulfonyl chloride (19.2, 5.0 g, 23.25 mmol) in dioxane (2.5 mL). The reaction mixture was tirred for 15h at 50 °C and then was concentrated. The resulting residue was then added to a solution of 4-(bromomethyl)pyridine hydrobromide (4.94 g, 19.53 mmol) in DMF (100 mL). The resulting solution was stirred for 15 min at room temperature and then was heated to 50 °C for an additional 2h. The reaction was then quenched by the on of H20 (200 mL), extracted with EtOAc (3x100 mL), washed with brine (100 mL), dried over NaSO4, ?ltered and concentrated to provide the desired product as a white solid (3.7 g, crude), which was used as is in the next on without puri?cation. LC-MS (ES, m/z): 271.9 [M+H]+, 312.9 [M+CH3CN]+, 1H NMR (400 MHz, DMSO-d6): 5 8.56 (m, 2H), 8.31 (s, 1H), 7.24 (m, 2H), 4.72 (s, 2H), 3.84 (s, 3H) ppm.

CI CI 0 O O\\é’ \N 038" \ NFSI,t—BuOK N / \ \ / \ N —> \ N N \ N THF, -78 °c \ _ F Compound 19.4. -Chloromethyl-lH-pyrazol yl)sulfonyl)?uoromethyl)pyridine To a solution of 4-[(3 -chloro—1—methyl-1H-pyrazolesulfonyl)methyl]pyridine (19.3, 200 mg, 0.74 mmol) in THF (5 mL) at —78 0C was added t-BuOK (0.44 mL, 0.44 2O mmol, 1M in THF) and NFSI (127 mg, 0.41 mmol). The reaction mixture was stirred for 2 h at -78 oC, and then was quenched by the addition of H20 (20 mL). The resulting solution was ted with EtOAc (3x20 mL), washed with brine (3x20 mL), dried over anhydrous MgSO4, ?ltered and concentrated to provide the desired product as a white solid (0.100 g, 47%). LC-MS (ES, m/z): 290.0 [M+H]+, 331.2 [M+CH3CN]+.

Cl CI 0 O Os" \N \ CH3I,t—BuOK Oes’,’ N / \ \ / N —> \ \ N N \ THE-78°C N_ \ Compound 19.5. 4-(1-((3-Chloromethyl-lH-pyrazolyl)sulfonyl)—1- ?uoroethyl)pyridine To a solution of chloro—1-methyl—1H—pyrazole sulfonyl)(?uoromethyl)pyridine (19.4, 0.100 g, 0.35 mmol) in THF (5 mL) at -78 CC was added t-BuOK (0.42 mL, 042 mmol, 1M in THF) and iodomethane (0.58 g, 0.41 mmol). The reaction mixture was stirred for 2 h at -78 OC, and then was quenched by the addition of H20 (20 mL). The resulting solution was extracted with EtOAc (3x20 mL), washed with brine (3x20 mL), dried over ous MgSO4, ?ltered and concentrated. The resulting residue was d by silica gel column chromatography (EtOAc/petroleum ether = 4:1 (v/v)) to provide the desired product as a white solid (0.80 g, 76%). LC-MS (ES, m/z): 303.9 [M+H]+; 1H NMR (400 MHz, CD3OD): 6 8.70 — 8.59 (m, 2H), 8.15 (s, 1H), 7.59 — 7.48 (m, 2H), 3.89 (s, 3H), 2.14 (d, J = 22.8 Hz, 3H) ppm. ?fth: P102, H2(g), H019) 0. {0‘II 1 4-dioxane, 5 atm Compound 19.6. 4-(1-((3-Chloromethyl-1H—pyrazolyl)sulfonyl)—1- fluoroethyl)piperidine To a pressure tank reactor containing a on of 4-(1-((3-chloromethyl-1H- pyrazolyl)sulfonyl)—l-?uoroethyl)pyridine (0.150 g, 0.49 mmol) in 4N HCl in dioxane (3mL) was added PtOz (0.75 g, 0.245 mmol). The system was purged and then maintained with an atmosphere of H2(g) (5 atm), and stirred for 2 h at 35 °C. The reaction mixture was then cooled to room ature, evacuated and the purged with Nag). The solids were removed by ion and the reaction mixture was concentrated to provide the desired product as a yellow solid (0.120 g, crude). The material was used as is in the next reaction.

LC-MS (ES, m/z): 310.0 [M+H]+, 351.1 [M+CH3CN]+.

CI N N O SIo O’ \ \?/ \ \ N ,N HN o >\—N F \ F Et3N, DMSO, 50 °c NH \ Compound 19. 4-(1-((3-Chloro-l-methyl-1H-pyrazolyl)sulfonyl)fluoroethyl)—N- (isoxazolyl)piperidine—1-carboxamide Compound 19 was prepared in a similar manner to compound 9 to provide the desired product as a white solid (0.011 g, 7%). LC-MS (ES, m/z): 420.2 [M+H]+, 465.3 [M+Na+CH3CN]+, 1H NMR (400 MHz, CD3OD): 6 8.45 (d, J = 1.8 Hz, 1H), 8.30 (s, 1H), 6.76 (d, J = 1.8 Hz, 1H), 4.30 (t, J=16.4Hz, 2H), 3.95 (s, 3H), 2.93 (m, 2H), 2.52 (m, 1H), 2.25 (d, J = 13.4 Hz, 1H), 1.88 (d, J = 13.0 Hz, 1H), 1.66 (d, J=23.0Hz, 3H), 1.52 (m, 2H) NBS, DIVIF N \N’N\ \N, \ 0 — _ 2h, 50°C nd 20.1. 4-Bromomethyl-1H—pyrazole—3—carbaldehyde To a solution of 1-methyl-1H—pyrazole—3—carbaldehyde (150 g, 1.36 mol) in DMF (1000 mL) was added NBS (240 g, 1.35 mol). The resulting solution was stirred for 2 h at 50 oC and then was quenched by the addition of ice water (2000 mL). The reaction mixture was cooled to -10 0C with an lt bath, and the solids were collected by ?ltration to provide the desired product as a white solid (200 g, 78%). 1H N1VIR (300 MHz, CDCl3): 5 9.90 (d, J = 0.7 Hz, 1H), 7.46 (s, 1H), 3.96 (s, 3H) ppm. o, O $70>\—N o—> o s \ I Pd2dba3, K2C03, xantphos, KI, N\ 1,4-dioxane, MeOH, 85 °C >_NC>_/ +0 Compound 20.2. tert-Butyl 4-(((3-formyl-l-methyl-1H-pyrazol yl)thio)methyl)piperidine-l-carboxylate To a solution of 4—bromo—1—methyl—1H—pyrazolecarbaldehyde (20.1, 20 g, 105.81 mmol), in 1,4-dioxane (300 mL) was added Pd2(dba)3'CHCl3 (5.4 g, 5.22 mmol), K2C03 (36 g, 260.47 mmol), Xantphos (6.1 g, 10.54 mmol), KI (1.7 g, 10.58 mmol) and tert-butyl 4- [(acetylsulfanyl)methyl]piperidine—1—carboxylate (34 g, 124.36 mmol). The reaction mixture was heated to 80 °C and MeOH (40 g, 1.25 mol) was added dropwise. The on mixture was stirred for 12h at 85 oC. The on mixture was cooled to room temperature with ice water bath, and the solids were removed by ?ltration. The ?ltrate was trated and the resulting residue was puri?ed by ?ash column chromatography /petroleum ether = 1/2 (v/v)) to provide the desired product as a yellow solid (24 g, 60%). 1H NMR (400 MHz, CDC13): 5 10.02 (d, J = 0.8 Hz, 1H), 7.35 (s, 1H), 4.11 (m, 2H), 4.00 (s, 3H), 2.77 (d, J = 6.9 Hz, 2H), 2.68 (t, J = 12.9 Hz, 2H), 1.89 — 1.79 (m, 2H), 1.70 — 1.58 (m, 1H), 1.47 (s, 9H), 1.32 — 1.11 (m, 2H) ppm. 0 F H F \N \N O S \ S \ I /\:>—/ N\ CHzclz %0O>~N/\:>—/ Compound 20.3. tert—Butyl 4-(((3-(di?uoromethyl)—l-methyl-lH-pyrazol yl)thio)methyl)piperidine—l-carboxylate To a solution of tert-butyl 4-(((3—formyl—1—methyl-1H-pyrazol yl)thio)methyl)piperidinecarboxylate (20.2, 50 g, 147.30 mmol) in dichloromethane (500 mL) at 0 0C was added DAST (95 g, 589.37 mmol) dropwise. The reaction mixture was stirred overnight at 30 oC. The temperature was sed to 0 OC and the reaction e was quenched with saturated NaHC03(aq). The resulting solution was extracted with EtOAc (3x1000 mL). The combined organic layers were washed with brine (500 mL), dried over anhydrous Na2804, ?ltered and concentrated. The resulting residue was puri?ed by ?ash chromatography (EtOAc/petroleum ether = 1/5 (v/v)) to provide the desired product as a 2O yellow solid (35 g, 66%). 1H NMR (300 MHz, CD3OD): 5 7.73 (s, 1H), 6.74 (t, J = 53.9 Hz, 1H), 4.07 — 3.95 (m, 2H), 3.87 (d, J = 1.1 Hz, 3H), 2.66 (d, J = 12.6 Hz, 2H), 2.58 (d, J = 6.9 Hz, 2H), 1.81 (d, J = 13.0 Hz, 2H), 1.54 (m, 1H), 1.41 (s, 9H), 1.07 (m, 2H) ppm.

F Cl CICI F ClCl Cl O S \\N —> I >\. N/\:>_/ N\ o :SC>\._N<:>_/\ n-BuLi THF, 78 c N\ Compound 20.4. tert—Butyl 4—(((5—chloro—3—(di?uoromethyl)—l-methyl-lH-pyrazol yl)thio)methyl)piperidine—l-carboxylate To a solution of tert-butyl 4-(((3—(di?uoromethyl)methyl-1H-pyrazol yl)thio)methyl)piperidine-l-carboxylate (20.3, 30 g, 83.00 mmol) in THF (400mL) at -78 CC was added dropwise a solution of n-BuLi (50 mL, 1245 mmol, 2.5M in n-hexane). The reaction mixture was stirred for 20 minutes before a solution of perchloroethane (23.6 g, 99.72 mmol) in THF (30 mL) was added dropwise. The reaction mixture was stirred for 30 min at -78 0C before being quenched by the addition of saturated NH4Cl(aq) (100 mL). The ing solution was extracted with EtOAc (3x500 mL), washed with brine (300 mL), dried over ous Na2804, d and then concentrated to provide the d product as a white solid (30 g, crude) which was used as is in the next reaction without further puri?cation. 1H NMR (400 MHz, CDC13): 6 6.68 (t, J = 53.8 Hz, 1H), 4.16 — 4.04 (m, 2H), 3.90 (t, J = 0.9 Hz, 3H), 2.71 — 2.56 (m, 4H), 1.91 — 1.75 (m, 2H), 1.45 (m, 10H), 1.19 — 1.04 (m, 2H) ppm.

RuC|3 Na|O4 of O>_N \N 970 :>—/8%E\ THF, H20 O>_ N N Cl $70 (:>—/§CI Compound 20.5. tert—Butyl 4-(((5-chloro—3—(difluoromethyl)—1-methyl-1H-pyrazol yl)sulfonyl)methyl)piperidine—l-carboxylate Compound 20.5 was prepared in a similar manner to compound 14.2 to provide the desired product as a white solid (28 g, 86%). 1H NMR (400 MHz, CDCl3): 5 7.03 (t, J = 53.8 Hz, 1H), 4.12 — 4.03 (m, 2H), 3.96 (s, 3H), 3.10 (d, J = 6.3 Hz, 2H), 2.74 (m, 2H), 1.90 (m, 2H), 1.44 (s, 9H), 1.36 — 1.18 (m, 3H) ppm.

F F OF OF 0(PSI \N LDA, NFSI 03831 \Nl \ :>\_N \ 3 :>\—N::>—/SC N THF, -78°C N Compound 20.6. tert-Butyl 4-(((5-chl0r0-3—(difluoromethyl)-l-methyl-1H-pyrazol yl)sulfonyl)?uoromethyl)piperidine—l-carboxylate To a solution of tert—butyl -chloro—3-(di?uoromethyl)methyl-1H-pyrazol yl)sulfonyl)methyl)piperidine—l—carboxylate (20.5, 25 g, 58.43 mmol) in THF (300 mL) at - 78 0C was added LDA (43 mL, 87.64 mmol, 20 M in THF) se, followed by the dropwise addition of a solution of NFSI (22 g, 58.43 mmol) in THF (100 mL). The reaction mixture was stirred for 30 min at -78 OC and then was ed by the addition of saturated aq) (500 mL). The reaction mixture was extracted with EtOAc (3x500 mL), washed with brine (500 mL), dried over anhydrous Na2804, d, and concentrated. The resulting residue was puri?ed by ?ash chromatography (EtOAc/petroleum ether = 1/4 (V/V)) to provide the desired product as a white solid (18 g, 69%). 1H N1VIR (300 MHz, CD3OD): 6 6.96 (t, J: 53.2 Hz, 1H), 5.27 (d, J = 6.4 Hz, 1H), 5.11 (d, J = 6.4 Hz, 1H), 4.16 — 4.02 (m, 2H), 3.94 (s, 3H), 2.80 (s, 2H), 2.42 (m, 1H), 1.92 (m, 2H), 1.43 (s, 9H), 0.95 — 0.74 (m, 2H) ppm.

F F F F O 0.53? \ry L O Oils? \w \ N\ \ t-BuOK, THF N\ é—O>_N 9’0>4" F Cl F CI nd 20.7. tert—Butyl 4-(1-((5-chloro—3—(di?uoromethyl)—1-methyl-1H-pyrazol yl)sulfonyl)—1-?uoroethyl)piperidine—1-carboxylate To a solution of tert-butyl 4-(((5-chloro—3—(di?uoromethyl)—1-methyl-1H-pyrazol fonyl)fluoromethyl)piperidinecarboxylate (20.6, 15.6 g, 34.99 mmol) in THF (250 mL) at -78 0C was added dropwise a solution of t—BuOK (70 mL, 69.98 mmol, 1.0 M in THF). The reaction mixture was stirred for 5 minutes before iodomethane (7.4 g, 52.14 mmol) was dded dropwise. The reaction mixture was stirred for 15 min at -78 0C before being quenched by the addition of saturated NH4Cl(aq) (500 mL). The resulting solution was extracted with EtOAc (3x500 mL), washed with brine (300 mL), dried over anhydrous Na2804, ?ltered and then concentrated to provide the desired product as a white solid (15 g, crude), which was used directly to next step without puri?cation.

F F 0:"3 \N n-BuLi OQII \ N O S I O S I >_N \ N\ THF, H20 >\_N/\:>_’/\ \ N\ +0 F a 40 F nd 20.8. utyl 4-(1-((3-(difluoromethyl)—l-methyl-lH-pyrazol yl)sulfonyl)—1-fluoroethyl)piperidine—l-carboxylate To a solution of tert-butyl 4-(1-((5-chloro—3-(di?uoromethyl)—1-methyl-1H-pyrazol- 4-yl)sulfonyl)?uoroethyl)piperidine—l—carboxylate (20.7, 25 g, 54.36 mmol) in THF (400 mL) at -78 CC was added n-BuLi (28 mL, 70.66 mmol, 2.5 M in hexanes) dropwise. The reaction mixture was stirred for 30 min at -78 0C before being quenched by the addition of ice water (200 mL). The resulting mixture was extracted with EtOAc (3x500 mL), washed withbrine (300 mL), dried over anhydrous Na2SO4, ?ltered, and then trated. The resulting residue was puri?ed by Flash-Prep—HPLC (Column, C18 silica gel; mobile phase, ACN2H20=20280 (V/V) increasing to ACN:H20=95:5 (V/V) within 60 min, or, UV 254 nm) to provide the desired product as a white solid (15 g, 65%). 1H NMR (300 MHz, CDC13): 6 7.85 (s, 1H), 6.95 (t, J = , 1H), 4.18 (m, 2H), 4.01 (s, 3H), 2.79 — 2.59 (m, 2H), 2.43 (m, 1H), 2.16 — 2.05 (m, 1H), 1.77 (m, 1H), 1.53 (d, J = 22.2 Hz, 3H), 1.43 (s, 9H), 1.32 (m, 2H) ppm. 0 Dis? "3 >404\ ~x F 90 0:3 \N SFC chiral separation + F Compound 20.821. tert-Butyl (R)—4-(1-((3-(difluoromethyl)—1-methyl-1H-pyrazol fonyl)—1-fluoroethyl)piperidine—l-carboxylate and Compound 20.8b. tert-Butyl (S)- 4-(1-((3-(difluoromethyl)—l-methyl-1H-pyrazolyl)sulfonyl)—1-fluoroethyl)piperidine—1- carboxylate The enantiomers of tert-butyl 4-(1-((3-(di?uoromethyl)methyl-1H-pyrazol yl)sulfonyl)?uoroethyl)piperidine—l-carboxylate (20.8, 63.6 g) were separated using by FC (Column: Phenomenex Lux Cellulose—4 (5*25cm, 5pm); Mobile Phase A:C02:70, Mobile Phase B: EtOH230, Flow rate: 150 mL/min; 220 nm) to provide RT1 = 1.448 min (20.821, 24.0 g, 91%, [0t] — -26.9 (C=0.37g/100mL, T=23.6°C, MeOH)) as a white solid and RT2 = 1744 min (20.8b, 24.0 g, 91%, [0t]= +234 (C=0.33g/100mL, T=24.6°C,MeOH)) as a white solid.

F F O 4N HCI O " \ \\ N O S —> 08 \N I >_N \ \ N\ CH3OH O—EQFS \ ,{l %o F \ Compound 20.9. (1-((3-(Di?uoromethyl)—l-methyl-1H-pyrazolyl)sulfonyl) fluoroethyl)piperidine hydrochloride Compound 20.9 was prepared in a similar manner to compound 18.7 to provide the desired product as a white solid (15.0 g, 85%). LC-MS (ES, m/z): 326.0 [M+H]+; 1H NIVIR (300 MHz, CD3OD): 6 8.29 (s, 1H), 6.92 (t, J = 53.1 Hz, 1H), 4.01 (s, 3H), 3.19 — 3.07 (m, 2H), 2.62 — 2.52 (m, 1H),2.41— 2.38 (m, 1H), 2.10 — 2.03 (m, 1H), 1.76 —1.73 (m, 1H), 1.56 — 1.38 (m, 5H) ppm.

ClCOOPh, Pyridine, /N 0 ’N o \ j: Q \ CH3CN,-20 Ctort o VNHZ V" Compound 20.10. Phenyl isoxazol-3—ylcarbamate To a solution of 3-amino-isoxazole (25 g, 0.297 mmol) and pyridine (29.0 mL, 0.356 mmol) in acetonitrile (600 mL) was added phenyl chloroformate (39.1 mL, 0.312 mmol) dropwise at -20 0C over 15 min. The reaction e was lly warmed to rt and stirred at rt overnight. Subsequently, the reaction e was concentrated and the residue was added ice water (500 mL). The suspension was ?ltered and the solid was washed with water and dried in vacuo to give the desired product as a white solid (58.76 g, 97% yield).

O\l(l) O \ N \ H S \ | S \ j N HN N 0’N\ N\ \ CH3CN, 65 °C \ ? F Compound 20. (R)—4-(1-((3-(Difluoromethyl)—l-methyl-lH-pyrazolyl)sulfonyl) fluoroethyl)-N-(isoxazolyl)piperidine—l-carboxamide To a solution of (R)—4—(1—((3—(di?uoromethyl)—1-methyl-1H-pyrazolyl)sulfonyl)— 1-?uoroethyl)piperidine (20.9, 20.0 g, 61.46 mmol) in acetonitrile (246 mL, 0.5 M) was added 3-aminoisoxazole phenyl carbamate (13.18 g, 64.54 mmol) portion-wise at 65 0C over minutes. After stirring at 65 OC overnight, the reaction mixture was concentrated and the residue was d by silica gel column chromatography (ISCO CombiFlash, 330 g , CAT# 69330) using MeOH/DCM = 0% to 2% (v/v) as the eluent to give the desired t as a white solid (25.6 g, 96% yield). LC-MS- (ES, m/z): 436.0 [M+H]+, 1H NMR (400 MHz, CDCl3): 5 8.23 (s, 1H), 8.11 (s, 1H), 7.89 (s, 1H), 6.98 (t, J = 53.1 Hz, 1H), 6.98 (s, 1H), 4.32 — 4.25 (m, 2H), 4.04 (s, 3H), 2.99 — 2.90 (m, 2H), 2.62 — 2.54 (m, 1H), 2.27 — 2.24 (m, 1H), 1.94 — 1.91 (m, 1H), 1.53 — 1.47 (m, 5H) ppm; 19F NMR (376 MHz, CDC13): 6 -114.3 to -117.1 (m, 2F), -144.8 (5, IF) ppm.

Exam le 21. Pre aration of S 1- 3— difluorometh l-l-meth l-lH- razol Compound 21.1. (1-((3-(Difluoromethyl)—l-methyl-1H-pyrazolyl)sulfonyl) fluoroethyl)piperidine hydrochloride Compound 21.1 was prepared in a similar manner to compound 18.7 to provide the desired product as a white solid (15.0 g, 85%). LC-MS (ES, m/z): 326.0 [M+H]+, 1H NMR (300 MHz, CD3OD): 6 8.29 (s, 1H), 6.92 (t, J = 53.1Hz, 1H), 4.01 (s, 3H), 3.19 — 3.07 (m, 2H), 2.62 —2.52 (m, 1H), 2.41 —2.38 (m, 1H), 2.10— 2.03 (m, 1H), 1.76 — 1.73 (m, 1H), 1.56 — 1.38 (m, 5H) ppm.

Compound 21. (S)—4-(1-((3-(Difluoromethyl)—l-methyl-lH-pyrazolyl)sulfonyl) ?uoroethyl)-N-(isoxazolyl)piperidine—l-carboxamide To a solution of (S)(1-((3-(difluoromethyl)—l-methyl-lH-pyrazolyl)sulfonyl)- l-?uoroethyl)piperidine (21.1, 0.20 g, 0.553 mmol) in acetonitrile (2 mL) was added 3- aminoisoxazole phenyl carbamate (0.118 g, 0.580 mmol) followed by trimethylamine (0.167 g, 1.65 mmol). After stirring at 65 oC overnight, the on mixture was concentrated and the residue was puri?ed by reverse phase high pressure liquid chromatography (0 - 90% CH3CN in H20 (both containing A)) to provide the desired t as a white solid (0.162 g, 67%). LC-MS (ES, m/z): 436.0 [M+H]+; lH NlVIR (400 MHZ, CDCl3)I 6 8.60 (s, 1H), 8.22 (s, 1H), 7.89 (s, 1H), 6.99 (t, J = 52.0 Hz, 1H), 6.99 (s, 1H), 4.37 — 4.25 (m, 2H), 4.04 (s, 3H), 2.99 — 2.90 (m, 2H), 2.62 — 2.54 (m, 1H), 2.27 — 2.24 (m, 1H), 1.94 — 1.91 (m, 1H), 1.53 — 1.47 (m, 5H) ppm; 19F NMR (376 MHz, CDC13): 8 -114.3 to -117.1 (m, 2F), - 144.8 (s, 1F) ppm.

Exam le 22. Pre aration of 4- difluoro imidazo 1 2-a ridin lsulfon l meth l -N- ridazin l i eridine—l-carboxamide S~< I CI O N/ éioyNC>—/ Cl _N szdbag, K2CO3, xantphoso, KI, 1,4-dloxane, MeOH, 85 C $~OO>_NC>_/S@ nd 22.1 utyl 4-(((2-chloropyridinyl)thio)methyl)piperidine carboxylate Compound 22.1 was prepared in a similar manner to compound 4.2 to provide the desired product as a yellow solid (1.99 g, 55%). 1H NMR (300 MHz, DMSO-d6): 5 8.16-8.18 (dd, J =44, 1.6Hz, 1H), 85 (dd, J = 8.0, 1.6Hz, 1H), 7.39-7.42 (dd, J = 8.0, 4.8 Hz, 1H), 3.92-3.95 (d, J=12.0Hz, 2H), 2.99-3.00 (d, J=6.8Hz, 2H), 2.70 (m, 2H), 1.79-1.82 (d, J =12.8Hz, 2H), 1.68-1.75(m, 1H), 1.39 (s, 9H), 1.10-1.14 (m, 2H) ppm. 7Q>L~QP®—N ""53: $90538E6\ / 25 Compound 22.2 tert-Butyl 4-(((2—chloropyridin-3—yl)sulfonyl)methyl)piperidine carboxylate Compound 22.2 was prepared in a similar manner to compound 4.3 to provide the desired product as a yellow solid (0.72 g, 53%). 1H N1VIR (400 MHz, DMSO-d6): 5 8.74-8.76 (dd, J =48, 1.6Hz, 1H), .46 (dd, J = 8.0, 2.0Hz, 1H), 7.73-7.76 (dd, J = 7.6, 4.8 Hz, 1H), 3.84-3.87 (d, J =8.4Hz, 2H), 3.56—3.57 (d, J =6.4Hz, 2H), 2.65 (m, 2H), , 1H), 1.72—1.75 (d, J =12.0Hz, 2H), 1.38 (s, 9H), 1.17-1.26 (m, 2H) ppm.

CI o\\ ,N. 30 O —N 00 \\ Ph/S\‘ VSPh O O\\S OO NO—/ \ / NaHMDS,THF > o>—O>_ O\\S\ Compound 22.3. tert—Butyl 4-(((2-chl0r0pyridin-3— yl)sulfonyl)difluoromethyl)piperidine—l-carboxylate id="p-185" id="p-185" id="p-185" id="p-185" id="p-185" id="p-185" id="p-185" id="p-185" id="p-185" id="p-185" id="p-185" id="p-185" id="p-185" id="p-185"

[0185] Compound 22.3 was prepared in a similar manner to compound 4.4 to provide the desired product as a yellow solid (0.36 g, 66%). 1H NMR (400 MHz, CDC13): 6 8.70-8.71 (dd, J=4.8, 2.0Hz, 1H), 8.41-8.43 (dd, J: 8.0, 2.0Hz, 1H), 7.51—7.54 (dd, J: 7.6, 4.8, 4.8 Hz, 1H), 4.27 (s, 2H), 2.74-2.77 (m, 3H), 2.06-2.09 (d, J = 13.6 Hz, 2H), 1.60-1.64(m, 2H), 1.47 (s, 9H) ppm. 0)— Qéj©_>NH3 EtOH 0.3 )0 NQEE9 30Wo>\_ C>_EF:N{\:> nd 22.4. tert—Butyl -aminopyridin yl)sulfonyl)difluoromethyl)piperidine—l-carboxylate To a solution of tert-butyl 4-(((2—chloropyridin yl)sulfonyl)di?uoromethyl)piperidine—1-carboxylate (22.3, 0.360 g, 0.88 mmol) in EtOH (2 mL) was added saturated NH3 in EtOH (10 mL). The resulting solution was stirred for 2 h at room temperature and then was concentrated. The ing residue was d by ?ash chromatography (EtOAc/petroleum ether = 1/1 (v/v)) to provide the desired product as a light yellow solid (0.100 g, 29%). 1H NMR (400 MHz, CDC13): 6 .33 (d, J =36 Hz, 1H), 7.94-7.96 (d, J = 7.8 Hz, 1H), 6.76-6.80 (dd, J = 7.5, 48 Hz, 1H), 6.15 (s, 2H), 4.22—4.25 (d, J = 8.7Hz, 2H), 2.62-2.78(m, 3H), 204-208 ((1, J = 12.9 Hz, 2H), 1.61-1.66(m, 2H), 1.46 (s, 9H) ppm. $7:>_N<:>—FH:© 04<——C| NaOAc, HCI EtOH H20 $70O>—NC>_I::;2L_\> Compound 22.5. tert-Butyl 4-(di?uoro(imidazo[1,2-a]pyridinylsulfonyl)methyl)— piperidine—l-carboxylate To a on of tert-butyl 4-(((2-aminopyridiny1)sulfony1)di?uoromethyl)- piperidine-l-carboxylate (22.4, 0.100 g, 0.26 mmol) in EtOH (1.2 mL) and H20 (1.4 mL) was added NaOAc (0.526 g, 2.52 equiv), 2—chloro-1,1-dimethoxyethane (0.59 g, 047 mmol), and 6N HCl (0.1 mL). The resulting on was stirred overnight at 75 °C, The EtOH was removed under vacuum and the resulting solution was extracted with EtOAc (3x5 mL). The combined organic layers were washed with brine (2X5 mL), diied over anhydrous Na2804, ?ltered and concentrated. The resulting residue was puri?ed by ?ash column chromatography (EtOAc/petroleum ether = 1/1 (v/v)) to provide the d product as a light yellow solid (0.75 g, 71%). LC-MS (ES, m/z): 316 [M+H]+. >—N/\:>—y/\Fl:\\1,4-dioxane W HCI'HNC>_FF \ / Compound 22.6. 8-((Di?uoro(piperidin-4—yl)methyl)sulfonyl)imidazo[1,2-a]pyridine hydrochloride Compound 22.6 was prepared in a similar manner to compound 9.5 to provide the d product as a yellow solid (0.51 g, crude). LC-MS (ES, m/z): 316 [M+H]+. :j/H\n/OOE) O N Et N DMSO 70°C N N N" \ NH F Compound 22. 4-(Dif1uoro(imidazo[1,2-a]pyridin-8—ylsulfonyl)methyl)-N-(pyridazin yl)piperidine—1-carboxamide Compound 22 was prepared in a similar manner to compound 9 to provide the desired product as a yellow solid (0.33 g, 47%). LC-MS (ES, m/z): 437 [M+H]+, 1H NMR (300 MHz, DMSO-d6): 6 9.25-9.26 (m, 1H), 9.23 (s, 1H), 9.04-9.06 (dd, J = 6.9, 1.2 Hz, 1H), 8.84-8.86 (dd, J = 6.0, 0.6 Hz, 1H), 8.22-8.23 (d, J = 1.5 Hz, 1H), 8.03-8.05 (dd, J = 7.2, 0.9 Hz, 1H), .78 (d, J = 1.5 Hz, 1H), 7.73-7.76 (dd, J = 6.0, 2.8 Hz, 1H), 7.18-7.20(t, J = 7.0 Hz, 1H), 4.22—4.27 (d, J = 14.1 Hz, 2H), 2.89-2.97(t, J = 12.8 Hz, 3H), 2.08-2.10 (d, J = .4 Hz, 2H), 1.48-1.54 (m, 2H) ppm.

Exam le 23. Pre aration of 4- 1 3-dimeth l-lH- l sulfon l difluorometh l - N- ridazinl i eridine—l-carboxamide Et3N, toluene Compound 23.1. 2,5-Dimethyl-2,4-dihydro—3H-pyrazolone To a solution of methylhydrazine sulfuric acid (5.47 g, 37.95 mmol) in toluene (100 mL) at 0 0C was added ylamine (30.7 g, 303.39 mmol) dropwise. The resulting solution was d for 30 min at 0 0C before ethyl 3-oxobutanoate (5 g, 38.42 mmol) was added dropwise followed by the portionwise addition of magnesium sulfate (9.12 g, 2.00 equiv.) The resulting solution was allowed to react, with stirring, for an additional 2 days at room temperature. The solids were removed by ion and the e was trated. The 2O resulting residue was puri?ed by ?ash column chromatography (6% (v/v) of CH3OH in CHzClz) to provide the desired product as a yellow solid (8 g, crude). 1H NMR (300 MHz, CDCl3): 6 3.28 (s, 3H), 3.19 (s, 2H), 2.10 (s, 3H) ppm.

Wo—>m Wow szo CH2012 Compound 23.2. 1,3-Dimethyl-4,5—dihydro—lH-pyrazol-S-yl trifluoromethanesulfonate To a solution of 2,5—dimethyl—2,4—dihydro—3H—pyrazolone (23.1, 2 g, 17.84 mmol) in dichloromethane (20 mL) at 0 °C was added 2,6-dimethylpyridine (2.86 g, 26.76 mmol) dropwise, followed by the dropwise addition of tn'?ic anhydride (6.54 g, 23.18 mmol).

The resulting solution was stirred for 2 h at room temperature and then was quenched by the on of H20 (20 mL). The resulting solution was extracted with dichloromethane (2X25 mL) and the ed organic layers were dried over anhydrous MgSO4, ?ltered and concentrated. The resulting residue was puri?ed by ?ash chromatography (9% (v/v) EtOAc in petroleum ether) to provide the desired t as a yellow oil (0.750 g, 17%). 1H NMR (300 MHz, CDCl3): 6 5.93 (s, 1H), 3.75 (s, 3H), 2.24 (s, 3H) ppm.

BOCN/\:>j \ BocNC>? / SH 8 ' szdbag, K2003, N’N os, 1,4-dioxane / Compound 23.3. tert—Butyl 4-(((1,3-dimethyl-1H-pyrazol-S-yl)thio)methyl)piperidine—1- carboxylate To a solution of methyl—4,5—dihydro—1H—pyrazolyl tri?uoromethanesulfonate (23.2, 1.9 g, 7.78 mmol) in 1,4-dioxane (50 mL) was added tert- butyl captomethyl)piperidine—1-carboxylate (1.3, 1.8 g, 7.78 mmol), potassium carbonate (2.69 g, 19.46 mmol), Xantphos (0.450 g, 0.78 mmol), and Pd2(dba)3 (0.403 g, 0.44 mmol). The resulting solution was stirred for 4 h at 100 OC. The reaction mixture was cooled to room temperature, the solids were removed by ?ltration, and the ?ltrate was concentrated.

The resulting e was puri?ed by ?ash chromatography (22% EtOAc in petroleum ether) to provide the desired product as a yellow oil (1.95 g, 77%). 1H NMR (300 MHz, CDCl3): 5 6.08 (s, 1H), .09 (m, 2H), 3.84 (s, 3H),2.71-2.63 (m, 4H), 2.25 (s, 3H), 1.82 (d, J = 12.9 Hz, 2H), 1.60-1.50 (m, 1H), 1.45 (s, 9H), 1.23—1.12 (m,2H) ppm.

My RuCI3, Na|O4 o Osg?0 $23 / THF,H20 3 o>‘—NC>4 / Compound 23.4. tert—Butyl 4-(((1,3--dimethyl-1H-pyrazol-5—- yl)sulfonyl)methyl)piperidine-l-carboxylate id="p-193" id="p-193" id="p-193" id="p-193" id="p-193" id="p-193" id="p-193" id="p-193" id="p-193" id="p-193" id="p-193" id="p-193" id="p-193" id="p-193"

[0193] Compound 23.4 was prepared in a similar manner to compound 14.2 to provide the desired product as a yellow oil (1.60 g, 7%). LC-MS (ES, m/z): 437 [M+H]+, 1H NMR (300 MHz, DMSO-d6): 6 6.61 (s, 1H), 4.16-4.06 (m, 5H), 3.07 (d, J = 6.3 Hz, 2H), 2.79—2.70 (m, 2H), 2.28 (s, 3H), 2.19-2.10 (m, 1H), 1.87 (d, J = 13.5 Hz, 2H), 1.45 (s, 9H), 1.31-1.24 (m, 2H) ppm. 065W0 s s. 0 Ph/ ‘b 0/, Ph o 0 065W > Myo / NaHMDS,THF > >604o / Compound 23.5. tert-Butyl4-(((1,3-dimethyl-1H-pyrazolyl)sulfonyl)di?uoromethyl)- piperidine-l-carboxylate Compound 23.5 was prepared in a similar manner to compound 4.4 to provide the desired t as a yellow solid , crude), which was used as is in the next reaction without puri?cation. 1H NMR (400 MHz, CDC13): 6 6.77 (s, 1H), 422—427 (d, J: 13.2 Hz, 3H), 4.06 (s, 3H), 2.67-2.79 (m, 3H), 2.31 (s, 03-2.07 (d, J = 12.9 Hz, 2H), 1.57-1.67 (m, 2H), 1.46 (s, 9H), 1.28 (m, 2H) ppm. 0 043W HCI 023W éioyNO—FFF /'\rN 1,4-dioxane HCI-HNC>_FFF /N/N Compound 23.6. 4-(((1,3-Dimethyl-1H-pyrazol-5—yl)sulfonyl)difluoromethyl)piperidine hydrochloride Compound 23.6 was prepared in a similar manner to compound 9.5 to provide the desired product as a yellow solid (0.51 g, crude). LC-MS (ES, m/z): 294 [M+H]+.

C>_?= ’N HC|.HN N N N, a \ >— F / N NH "0—14 / Et3N, DMSO, 70 °C Compound 23. 4-(((1,3-Dimethyl-1H-pyrazol-S-yl)sulfonyl)difluoromethyl)—N- (pyridazinyl)piperidine—1-carboxamide Compound 23 was prepared in a similar manner to compound 9 to provide the d product as a yellow solid (0.33 g, 47%). LC-MS (ES, m/z): 415 [M+H]+; 1H NMR (300 MHz, DMSO-d6): 6 9.27-9.23 (m, 2H), 8.88 (m, 1H), 7.45 (m, 1H), 7.03 (s, 1H). 4.24 (d, J = 13.2 Hz, 2H), 4.00 (s, 3H), 3.02—2.88 (m, 3H), 2.25 (s, 3H), 2.01 (d, J = 12.0 Hz, 2H), 1.59-1.46 (m, 2H) ppm.

Exam le 24. Pre aration of 4- 3-c clo ro l-l-meth l-1H- razol-S- lsulfon orometh l-N- n-4— l i eridine—l-carboxamide Compound 24.1. 3—Cyclopropyl-l-methyl-lH-pyrazol-S-ol id="p-197" id="p-197" id="p-197" id="p-197" id="p-197" id="p-197" id="p-197" id="p-197" id="p-197" id="p-197" id="p-197" id="p-197" id="p-197" id="p-197"

[0197] Compound 24.1 was prepared in a similar manner to compound 23.1 to provide the desired product as a yellow solid (1.60 g, 45%). LC-MS (ES, m/z): 139 [M+H]+; 1H NMR (300 MHz, DMSO-d6): 6 10.61(s, 1H), 5.02 (s, 1H), 3.58 (s, 3H), 1.62-1.73 (m, 1H), 0.72— 0.81 (m, 2H), 0.53-0.67 (m, 2H) ppm.

MOH—g>MSHLawesson's reaent N toluene ‘N \ \ Compound 24.2. 3-Cyclopropyl-l-methyl-lH-pyrazole—S-thiol To a solution of 3-cyclopropyl—1-methyl-1H-pyrazolol (1.6 g, 11.58 mmol) in toluene (30 mL) was added Lawesson’s reagent (4.68 g, 11.58 mmol). The resulting solution was stirred overnight at 60 0C, cooled to room temperature and then trated. The ing residue was d by ?ash chromatography (chloroform/methanol = 20/1 (v/v)) to provide the desired product as a yellow oil (1.1 g, 62%). LC-MS (ES, m/z): 155 [M+H]+. 0»— Qa p" > N o s 0 ms 032003, DMF o>~N/\:>—/ ,N Compound 24.3. tert—Butyl 4-(((3-cyclopropyl-l-methyl-1H-pyrazolyl)thio)methyl)— piperidine—l-carboxylate To a solution of 3-cyclopropyl—1-methyl-lH-pyrazole-S-thiol (24.2, 1.1 g, 7.13 mmol) in DMF (20 mL) was added utyl 4-((tosyloxy)methyl)piperidine-l-carboxylate (1.1, 2.63 g, 7.12 mmol), and CS2CO3 (4.6 g, 14.12 mmol). The reaction e was stirred for 3 h at room temperature, and then was quenched by the addition of H20 (100 mL) and extracted with EtOAc (3x30 mL). The combined organic layers were dried over anhydrous Na2804, ?ltered and concentrated to provide the desired product as a yellow oil (1.5 g, 60%).

LC-MS (ES, m/z): 352 . 0 SMRuCI3,NaIO4 o ,N O§§M ,N , My ~ N o / THF,H20 9 69o / Compound 24.4. tert—Butyl 4-(((3-cyclopropyl-l-methyl-lH-pyrazol-S- yl)sulfonyl)methyl)piperidine—l-carboxylate Compound 24.4 was prepared in a r manner to compound 14.2 to provide the desired product as a yellow oil (1.60 g, 7%). LC—MS (ES, m/z): 406 [M+Na]+, 1H NMR (300 MHz, DMSO-d6): 5 6.66 (s, 1H), 3.96 (s, 3H), 3.83-3.87 (d, J:18.6Hz, 2H), 3.40—3.42 (d, J:6.3Hz, 2H), 2.74 (s, 1H), 1.99—2.03 (m, 1H), .93 (m, 1H), 1.72—1.75 (d, J:11.1Hz, 2H), 1.38 (s, 9H), 1.15—1.25 (m, 2H), 0.80-0.90 (m, 2H),0.65-0.7O (m, 2H) ppm. o QijnS/P o 0% / Ph’ bd/‘Ph / O | O 0% | > Myo / NaHMDS,THF 0+. o / , nd 24.5. tert-Butyl 4-(((3-cyclopropyl-l-methyl-IH-pyrazol-S- yl)sulfonyl)difluoromethyl)piperidine-l-carboxylate Compound 24.5 was prepared in a similar manner to compound 4.4 to provide the desired product as a yellow solid (0.70g, 64%). LC-MS (ES, m/z): 406 [M-CH3+H]+.

O S I >— , ,N é’ N o [NO—VLF IN 1,4-dioxane HCI.HN/\:>_¥/\F / Compound 24.6. 4-(((3-Cyclopropyl-l-methyl-lH-pyrazol-S- yl)sulfonyl)difluoromethyl)—piperidine hloride Compound 24.6 was prepared in a similar manner to compound 9.5 to provide the desired product as a red solid (0.40 g, crude). LC-MS (ES, m/z): 320 [M+H]+. 05.; N. \ T \s / | N / O 0 (lawo HCI.HN/\:>—FF N’N y / \ >\—N<:>—FFS N NH /N F Et3N, DMSO, 70 °c F Compound 24. 4-(((3-Cyclopropylmethyl-lH-pyrazol-S-yl)sulfonyl)difluoromethyl)- N-(pyridazinyl)piperidine—l-carboxamide Compound 24 was prepared in a similar manner to compound 9 to provide the desired product as a yellow solid (0.33 g, 47%). LC-MS (ES, m/z): 441 ; 1H NMR (300 MHz, CDC13): 6 9.13-9.14 (d, J =2.4Hz, 1H), 8.88-8.90 (d, J =6.3Hz, 1H), 8.63(s, 1H), 8.02-8.05 (m, 1H), 6.66 (s, 1H), 4.39-4.43 (d, J =13.5Hz, 2H), 4.03 (s, 3H), 2.92-3.00 (m, 2H), 2.71-2.79 (m, 1H), 2.12-2.16(d, J =2.4Hz, 2H), 1.88-1.96 (m,1H), .76 (m, 2H), 0.99 (m, 2H), 0.98 (m, 2H) ppm.

Exam le 25. Pre aration of 4- di?uoro 2- h drox meth l hen lsulfon lmeth l-N- ridazin l i e-l-carboxamide O>_ —> 0 0%? +N n-BuLi THF +0>_ O—FN F nd 25.1. tert—Butyl 4-(difluoro((2—formylphenyl)sulfonyl)methyl)piperidine—1- carboxylate To a solution of tert-butyl 4-[[(2— bromobenzene)sulfonyl]di?uoromethyl]piperidine-l-carboxylate (600 mg, 1.32 mmol) in THF (15 mL) at -78 0C was added n-BuLi (0.52 mL, 2.5M in n-hexane, 2.64 mmol) dropwise. The reaction mixture was d for 30 minutes at -78 °C before DMF (0.300 g, 4.10 mmol) was added. The resulting solution was allowed to react, with stirring, for an additional 5 min while the temperature was maintained at -78 OC. The on was then quenched by the on of NH4C1(5at,) (2 mL). The resulting solution was extracted with EtOAc (3x100 mL) and the organic layers combined and dried over anhydrous sodium sulfate and concentrated under vacuum to provide (0.600 g, crude) of the desired product as yellow oil which was used t further puri?cation. LC-MS (ES, m/z): 425.9 [M+H]+.

O o / / O\|| TFA O o ‘s _> 0% >‘N F CHZCIZ O F TFA.HN/\:>—FF Compound 25.2. 2-((Difluoro(1-(2,2,2-trifluoroacetyl)—114-piperidin hyl)sulfonyl)benzaldehyde id="p-205" id="p-205" id="p-205" id="p-205" id="p-205" id="p-205" id="p-205" id="p-205" id="p-205" id="p-205" id="p-205" id="p-205" id="p-205" id="p-205"

[0205] Compound 25.2 was prepared in a similar manner to compound 4.5 to provide the desired product as a yellow solid (0.40 g, crude) which was used as is without further puri?cation. LC-MS (ES, m/z): 304 [M+H]+. \ o O O 1311K) /N o o\n :0 H 0%" ‘s s F 0% TFAHN DIEA, DMSO l" \ F N NH F F Compound 25.3. 4-(Difluoro((2-formylphenyl)sulfonyl)methyl)-N-(pyridazin yl)piperidinecarboxamide Compound 25.2 was prepared in a similar manner to compound 4 to provide the desired t as a yellow solid (0.150 g, 27%). LC-MS (ES, m/z): 425 [M+H]+, 1H NMR (300 MHz, DMSO-d6): 6 10.57 (s, 1H), 9.33 — 9.15 (m, 2H), 8.87 (m, 1H), 8.17 — 7.88 (m, 4H), 7.81 — 7.69 (m, 1H), 4.24 (d, J = 13.2 Hz, 2H), 3.01 (m, 3H), 2.00 (d, J = 19.3 Hz, 2H), 1.54 (m, 2H) ppm. 0 OH O O O\|| NaBl"l4 O\II z—~Q+S 0+S N\:>7N F N\)NH Compound 25. 4-(Difluoro((2-(hydroxymethyl)phenyl)sulfonyl)methyl)-N-(pyridazin yl)piperidinecarboxamide To a solution of luoro((2—formylphenyl)sulfonyl)methyl)-N-(pyridazin yl)piperidinecarboxamide (25.3, 0.150 g, 0.35 mmol) in methanol (10.0 g, 312.09 mmol) at 0 °C was added NaBH4 (0.017 g, 0.45 mmol). The resulting solution was stirred for 1 h at room temperature. The reaction was then quenched by the addition of NH4Cl(satv) (20 mL).

The ing solution was extracted with EtOAc (3X50 mL) and the organic layers were combined, dried over ous sodium e and concentrated. The resulting residue was puri?ed by Prep-HPLC (Column: X Bridge C18, 19*250 mm, 10 um, Mobile Phase A: Water/10 mM 3 Mobile Phase B: ACN; Flow rate: 30 mL/min; Gradient: 15-60%B in 6 min; 254nm) to provide (0.0356 g, 24%) of the desired product as a white solid. LC-MS (ES, m/z): 427 [M+H]+; 1H NMR (300 MHz, : 5 9.22-9.26 (m, 2H), 8.87-8.89 ( m, 1H), 7.89-7.99 (m, 3H), 7.73—7.75 (m, 1H), 6.60-6.64 (m, 1H), 5.56-5.58 (t, J=5.6Hz, 1H), 4.90—4.92 (d, J=5.6Hz, 2H),4.22-4.25 (m, 2H), 2.88-2.97 (m,3H), 2.00—2.07 (m, 2H), 1.46- 1.57 (m, 2H) ppm.

Exam le 26. N- Isoxazol l 2- l-meth l tri?uorometh 1 -1H- razol lsulfon 1 r0 an l i eridine—l-carboxamide 08 \N CH3I 08‘ F30\ O>—N/\:>_/S \ | %o \ tBuOK, THF #0OyNO—?\N Compound 26.1. tert-Butyl 4-(2—((1-methyl-3—(tri?uoromethyl)-1H-pyrazol yl)sulfonyl)propan-Z-yl)piperidine—l-carboxylate To a solution of tert-butyl 4-(((1—methyl(tri?uoromethyl)-lH-pyrazol yl)sulfonyl)methyl)piperidine-l-carboxylate (16.3, 1.0 g, 2.43 mmol) in THF (20 mL) at -78 0C was added se a solution oft-BuOK (1N in THF, 7.2 mL, 7.29 mmol). The resulting solution was stirred for 20 min at -78 °C before a solution of Mel (858 mg, 6.07 mmol) in THF (2 mL) was added se. The resulting solution was allowed to react, with stirring, for an additional 1 h while the temperature was maintained at —60 0C in a liquid nitrogen bath.

The on was then quenched by the addition of NH4Cl(satp) (50 mL). The resulting solution was extracted with EtOAc (3x100 mL), washed with brine (2X100 mL), dried over anhydrous sodium sulfate, ?ltered and trated. The resulting residue was puri?ed by Flash-Prep- HPLC ((IntelFlash-l): Column, C18 silica gel; mobile phase, CH3CN:H20=20:80 (v/v) increasing to CH3CN:H20=95:5 (v/v) within 35 min; Detector, UV 254 nm) to provide the desired product as a white solid (0.150 g, 14%). LC-MS (ES, m/z): 462.1 [M+H]+. 0 4C 3 O\\\ \N O ‘ l O\\\ >~N \ N\—> OACE\ $~o CHzClz TFA.HN Compound 26.2. 4-(2-((1-Methyl(tri?uoromethyl)-lH-pyrazolyl)sulfonyl)propan- 2-yl)piperidine Compound 26.2 was prepared in a similar manner to compound 4.5 to provide the desired t as a yellow solid (0.25 g, crude) which was used as is without further puri?cation. LC-MS (ES, m/z): 340.0 [M+H]+.

Compound 26. N-(Isoxazolyl)(2-((l-methyl(trifluoromethyl)-1H-pyrazol yl)sulfonyl)propanyl)piperidine—l-carboxamide Compound 26 was prepared in a similar manner to compound 9 to provide the desired product as a yellow solid (0.024 g, 13%). LC-MS (ES, m/z): 448.0 [M+H]+; 1H NMR (300 MHz, CDgOD): 5 8.40 (s, 1H), 8.33 (s,1H), 6.70 (s, 1H), 4.21 (d, J=13.8Hz, 2H), 3.99 (s 2.90-2.81 , 2.22—2.03 (m, 3H), 1.49—1.44 (m, 2H), 1.27 (s,6H) ppm. , 3H), Oil? 0 \N CH3I 0%" \N S \ | _ I _ \ N N N\ \ \ / NaH, DMF N\ / Compound 27.1. 4-(2-((3-Chloro-l-methyl-1H-pyrazolyl)sulfonyl)propan yl)pyridine To a solution of 4—[(3—chloro—1—methyl—1H—pyrazole sulfonyl)methyl]pyridine (680 mg, 2.50 mmol) in DMF (10 mL) at 0 °C was added sodium hydride (200 mg, 8.33 mmol), followed by Mel (713 mg, 5.00 mmol). The resulting on was stirred for 2 h at 0 0C in an ice/salt bath. The reaction was then quenched by the addition of water (20 mL). The resulting solution was extracted with EtOAc (3x20 mL), washed with brine (3x20 mL), dried over anhydrous magnesium sulfate, ?ltered and concentrated. The resulting e was puri?ed by ?ash chromatography (dichloromethane/methanol (20: 1)) to e the desired product as a yellow solid (0.650 g, 87%). LC-MS (ES, m/z): 299.9 [M+H]+, 1H NMR (300 MHz, DMSO-d6): 5 8.60 — 8.53 (m, 2H), 8.25 (s, 1H), 7.47 - 7.40 (m, 2H), 3.84 (s, 3H), 1.73 (s, 6H) ppm.

CI CI 0 O — S \ [ll —> S \ N N\ / \ 1, 4-di0xane, 5 atm HN \ nd 27.2. 4-(2-((3-Chloro-l-methyl-lH-pyrazolyl)sulfonyl)propan yl)piperidine To a solution of (3 -chloro-l-methyl-1H-pyrazolyl)sulfonyl)propan yl)pyridine (27.1, 0.200 g, 0.67 mmol) in 4N HCl in 1, 4-dioxane (3 mL) was added PtOz (0.80 g, 0.27 mmol). Then Hm) was introduced in the mixture and a pressure of 5 atm was maintained while the reaction mixture was stirred at 35 °C for 48 h. The reaction mixture was cooled to room temperature and ?ltered. The ?ltrate was concentrated and the resulting residue was puri?ed by Prep-HPLC (Column: e Prep C18 OBD Column, Sum, 19*150m, Mobile Phase A: H20 (10 mmol/L NH4HCO3), Mobile Phase B: ACN; Flow rate: mL/min, Gradient: 20% B to 40% B in 8 min; Detector, UV 254nm) to provide the desired product as a white solid (0.20 g, 10%). LC-MS (ES, m/z): 306.0 [M+H]+.

N 0 CI Cl \?/ O\\\ \N OJ,N 0 / on \N O O \\S I "074 \ [i1 \ Et3N, DMSO, 70 °C \ NH Compound 27. 4-(2-((3-Chlor0-l-methyl-lH-pyrazolyl)sulfonyl)propanyl)—N- (isoxazolyl)piperidine-l-carboxamide Compound 27 was prepared in a r manner to compound 9 to provide the desired t as a yellow solid (0.038 g, 16%). LC-MS (ES, m/z): 416.1 [M+H]+; 1H NMR (400 MHz, : 6 8.45 (d, J: 1.8 Hz, 1H), 8.23 (s, 1H), 6.76 (d, J: 1.8 Hz, 1H), 4.26 (m, 2H), 3.94 (s, 3H), 2.97 — 2.85 (m, 2H), 2.15 (m, 3H), 1.55 — 1.39 (m, 2H), 1.33 (s, 6H) Exam 1e 28. Pre aration of 4- 3 3-di?u0r0-l- 3—?uoro hen l sulfon l c clobut l -N- ridazin l i eridine—l-carboxamide Compound 28.1. utyl 4-(1-((3-?uorophenyl)sulfonyl) hydroxycyclobutyl)piperidine—l-carboxylate To a solution of tert-butyl 4-(((3-?uorophenyl)sulfonyl)methyl)piperidine carboxylate (5.3, 2.0 g, 5.60 mmol) in THF (100 mL) at 10 0C was added n-BuLi (2.5M, 6.7 mL, 168 mmol) se. The resulting solution was stirred for 30 min at -10 °C before 2- (chloromethyl)oxirane (1.04 g, 11.24 mmol) was added dropwise. The reaction mixture was stirred overnight while warming to room temperature, and then was ed by the addition of water (30 mL). The resulting solution was extracted with EtOAc (2X50 mL), dried over anhydrous sodium sulfate, ?ltered and concentrated. The resulting residue was puri?ed by Prep-HPLC ((IntelFlash-l): Column, C18 silica gel; Mobile Phase A: Water with 10mmol NH4HCO3, Mobile Phase B: ACN; Flow rate: 50 mL/min; Gradient: 0% B to 100% B in 40min, Detector, UV 254 nm) to provide the d product as a yellow solid (1 .l g, 47%).

LC-MS (ES, m/z): 414.1 . 9 fr 9 fr 0 N Cox/0 0 N 0N9 S\©/F IBX, EtOAc ? SUI: Compound 28.2. tert-Butyl 4-(1-((3-?uorophenyl)sulfonyl)oxocyclobutyl)piperidine- l-carboxylate To a on of tert—butyl 4—(1—((3—?uorophenyl)sulfonyl)—3- hydroxycyclobutyl)piperidine—l—carboxylate (28.1, 1.1 g, 2.66 mmol) in EtOAc (40 mL) was added IBX (1.49 g, 5.32 mmol). The resulting solution was stirred overnight at 750C. The reaction mixture was cooled to room temperature and the solids were removed by ?ltration.

The ?ltrate was washed with brine (2X30 mL), dried over anhydrous sodium e, ?ltered and concentrated to provide the desired product as a yellow oil (1.0g, , which was used as is without further puri?cation. LC-MS (ES, m/z): 397.0 [M-CH3+H]+.

RANO OO >LJOL ‘3' FM ©5140: ,F F F Compound 28.3. utyl 4-(3,3-di?uoro((3-fluorophenyl)sulfonyl)cyclobutyl)— piperidine—l-carboxylate To a solution of tert-butyl 4-(1-((3-?uorophenyl)sulfonyl)—3- oxocyclobutyl)pipe1idine-l-carboxylate (0.300 g, 0.73 mmol) in dichloromethane (10 mL) was added DAST (1.17 g, 7.26 mmol). The resulting solution was stirred for 3 days at room temperature. The reaction was then quenched by the addition of water (10 mL), and the pH of the solution was adjusted to 7 with the addition of sodium bicarbonate, The resulting solution was extracted with DCM (2X20 mL), dried over anhydrous magnesium sulfate, ?ltered and concentrated. The resulting residue was puri?ed by preparative thin layer chromatography (petroleum ether/ethyl acetate = 1/1 (v/v)) to provide the desired product as a yellow solid (0.150 g, 47%). 1H NMR (400 MHz, DMSO-d6): 6 7.72-7.86 (m, 4H), 3.92—4.02 (m, 2H), 3.22—3.32 (m, 4H), 3.08-3.15 (m, 2H), 1.75—1.79 (m, 3H), 1.36 (s, 9H), 1.18-1.20 (m, 2H) iJOL HN HCI Q Q O N O\\ 00 —> "31/ F S\©/F 1,4-dioxane O F F F F nd 28.4. 4-(3,3-Difluoro-l-((3—fluorophenyl)sulfonyl)cyclobutyl)piperidine nd 28.4 was prepared in a similar manner to compound 9.5 to e the desired product as a red solid (0.140 g, crude). LC-MS (ES, m/z): 334 [M+H]+.

O ,N N \"J \(IDr O N’ O HN I A O\\//0 \ s F N N o o s F Et3N, DMSO,70 c. U F F Compound 28. 4-(3,3-Di?uoro((3-fluorophenyl)sulfonyl)cyclobutyl)—N-(pyridazin yl)piperidine—1-carboxamide Compound 28 was prepared in a similar manner to compound 4 to provide the desired product as a white solid (0.027 g, 14%). LC-MS (ES, m/z): 455 [M+H]+; 1H NMR (300 MHz, 6): 6 9.18 (d, J = 0.9 Hz, 1H), 8.83(dd,J1 = 0.9 Hz, J2 = 6.0 Hz, 1H), 7.84-7.66 (m, 4H), 7.57-7.54 (m, 1H), 4.22 (d, J = 13.8 Hz, 2H), 3.33-3.23 (m, 2H), 3.04-2.94 (m, 2H), 2.81-2.73 (m, 2H), 2.00-1.92 (m, 3H), 1.47-1.42 (m, 2H) ppm. i eridine—l- carboxamide N\ CN HZNJkOtBu N CN l I /’ // Pd(OAc)2, XPhos, Br C82C03, 1,4-dioxane NHBoc Example 29.1. tert—Butyl (2-cyan0pyridin-4—yl)carbamate To a solution of 4-bromopyridine—2-carbonitrile (20 g, 109.29 mmol) in oxane (300 mL) was added Pd(OAc)2 (2.98 g, 13.27 mmol), XPhos (18.9 g, , C52 C03 (50.3 g, 154.38 mmol). The resulting solution was d for 1 h at 100 °C. The reaction was cooled to room temperature and the solids were removed by ?ltration. The ?ltrate was concentrated and the resulting residue was puri?ed by ?ash column chromatography (EtOAc/petroleum ether = 1/3 (v/v)) to provide the desired product as a yellow solid (23 g, 95%). LC-MS (ES, m/z): 220 [M+H]+. 1H NMR (300 MHz, CDC13): 6 8.49 (d, J: 5.6 Hz, 1H), 7.87 (d, J = 2.2 Hz, 1H), 7.43 (dd, J = 5.6, 2.2 Hz, 1H), 6.90 (s, 1H), 1.54 (s, 9H) ppm.

N CN I MeMgBr \ NHBoc NHBoc Example 29.2. tert—Butyl tylpyridin-4—yl)carbamate To a solution of tert-butyl (2-cyanopyridinyl)carbamate (29.1, 23.0 g, 104.91 mmol) in THF (200 mL) at 0 0C was added a solution of MeMgBr (1M in THF, 125.4 mmol, 125.4 mL) dropwise. The resulting solution was stirred for 1 h and then was quenched by the addition of ice water (1000 mL). The resulting on was extracted with EtOAc (3x500 mL) and the organic layers combined, washed with brine (2x200 mL) of brine, dried over anhydrous sodium sulfate and trated. The resulting residue was puri?ed by ?ash column chromatography (EtOAc/petroleum ether = 1/4 (v/v)) to provide the desired product as a white solid (21 g, 85%). LC-MS (ES, m/z): 237 [M+H]+. 1H NTVIR (300 MHz, CDC13): 6 8.49 (d, J = 5.4 Hz, 1H),7.81— 7.71 (m, 2H), 6.89 (s, 1H), 2.68 (s, 3H), 1.51 (s, 9H) ppm. 0 o N N \ \ | TFA, CHZCIZ | // "’ // NHBoc NH2 Example 29.3. 1-(4-Aminopyridin-2—yl)ethanone To a solution of tert-butyl cetylpyridinyl)carbamate (29.2, 2.3 g, 9.73 mmol) in dichloromethane (5 mL) was added tri?uoroacetic acid (15 g, 132.70 mmol). The resulting solution was stirred overnight at room temperature and then was concentrated. The crude product was precipitated from ether, and the solids were collected by ?ltration to provide the desired product as a white solid (2.0 g, 82%). 1H NMR (300 MHz, DMSO-d6): 5 13.33 (s, 1H), 8.28 (s, 2H), 8.08 (d, J: 6.8 Hz, 1H), 7.44 (d, J: 2.4 Hz, 1H), 6.86 (dd, J: 68,24 Hz, 1H), 2.46 (m, 3H) ppm.

Py, THF, ACN o NH2 Example 29.4. Phenyl (2-acetylpyridin-4—yl)carbamate To a solution of 1-(4-aminopyridin—2—yl)ethanone (29.3, 5 g, 36.72 mmol) in ACN/THF (1 :1 (v/v), 50 mL) and pyridine (4.74 g, 59.92 mmol) at 0 0C was added dropwise phenyl chloroformate (4.68 g, 29.89 mmol). The resulting solution was stirred for 2 h at room temperature. The resulting mixture was concentrated under vacuum and washed with ether (2X30 mL) to provide the desired t as a yellow solid (9 g, crude), which was used as is t r ation. LC—MS (ES, m/z): 257 [M+H]+.

O F PhO H \H/ \ O | 08 \N OQ'S' \F}! o /N o o ‘s \ I \ "\ HO-HN - "\ "F N/\ NHHCHIIF Et3N, DMSO, 70 °c Example 29.5. (S)-N-(2-Acetylpyridinyl)(1-((3-(diflu0romethyl)-l-methyl-1H- pyrazolyl)sulfonyl)?uoroethyl)piperidine-l-carboxamide Compound 29.5 was prepared in a similar manner to compound 4 to provide the desired product as a white solid (0.28 g, 37%). LC-MS (ES, m/z): 488 [M+H]+, 1H NMR (300 MHZ, DMSO-d6): 6 9.15 (s, 1H), 8.62 (s, 1H), 8.42 (d, J = 5.6 Hz, 1H), 8.05 (d, J = 2.1 Hz, 1H), 7.73 (dd, J = 5.7, 2.2 Hz, 1H), 6.92 (d, J = 53.0 Hz, 1H), 4.20 (d, J = 12.6 Hz, 2H), 3.96 (s, 3H), 2.81 (m, 2H), 2.56 (s, 3H), 2.46 (m, 1H), 1.99 (d, J =13.2 Hz, 1H), 1.69 (d, J = 12.5 Hz, 1H), 1.53 (d, J = 22.8 Hz, 3H), 1.42 — 1.30 (m, 2H) ppm. osn \N (R)Me—CBS BH3 o." \N O O S \ | —>HO 8F\ | N N Example 29. 4-((S)((3-(Difluoromethyl)-l-methyl-1H-pyrazolyl)sulfonyl) fluoroethyl)-N-(2-((S)hydroxyethyl)pyridinyl)piperidine—l-carboxamide To a solution of 4—((S)—l—((3—(di?uoromethyl)—1-methyl-1H-pyrazoly1)sulfony1)- 1-?uoroethyl)-N—(2-((S)—1—hydroxyethyl)pyridin—4—yl)piperidinecarboxamide (29.5, 0.120 g, 0.25 mmol) in THF (2 mL) at 0 °C was added (R)—Me-CBS (0.074 mL, 0.75 mmol) se, followed by the dropwise addition of BH3-THF (0.37 mL, 0.375 mmol). The resulting solution was stirred for 1 h at 0 °C in a water/ice bath and then was quenched by the addition of methanol (2 mL). The reaction mixture was concentrated and the ing residue was puri?ed by Prep-HPLC lFlash-l): Column, C18 silica gel; mobile phase, CH3 CN:H2 O=5:95 increasing to CH3 CN:H2 O=95:5 within 30 min, Detector, UV 254 nm) to provide the desired product as a racemate. The racemate (50 mg) was puri?ed by Prep-SFC ((Prep ): Column, CHIRALPAK—AD—H-SL002, 20*250mm; Mobile Phase A: C02 :50, Mobile Phase B: IPA:50; Flow rate: 40 mL/min; 220 nm; RT1 = 4.68 min, RT2 = 5.98 min) to provide the desired product as a white solid (0.029, 24%). LC-MS (ES, m/z): 490.2 [M+H]+, 1H NMR (300 MHz, CD3OD): 6 8.33 (s, 1H), 8.18 (d, J = 5.8 Hz, 1H), 7.59 (d, J = 2.1 Hz, 1H), 7.38 (dd, J = 5.8, 2.2 Hz, 1H), 6.94 (t, J = 53.1 Hz, 1H), 4.76 (m, 1H), 4.27 (m, 2H), 4.00 (s, 3H), 3.00 — 2.80 (m, 2H), 2.51 (s, 1H), 2.18 (d, J = 13.2 Hz, 1H), 1.84 (d, J = 13.3 Hz, 1H), 1.65 — 1.36 (m, 8H) ppm.

Exam le 30. Pre aration of 4-flu0r0 n l i eridine—l-carboxamide F. : SH CHzBrz, K2003 F. :S\/SF: Example 30.1. Bis((3-fluorophenyl)thi0)methane To a solution of 3-?uorobenzene—1—thiol (2 g, 15.60 mmol) and potassium carbonate (3.23 g, 23.37 mmol) in DMF (10 mL) was added CHzBrz (1.5 g, 8.58 mmol). The resulting solution was d overnight at 70 0C, cooled to room temperature and then was concentrated. The resulting residue was puri?ed by ?ash column chromatography (EtOAc/petroleum ether = 1/10 (v/v)) to provide the desired product as a solid (2.1 g, 50%). 1H NMR (300 MHz, CD3OD): 5 7.30—7.40 (m, 4H), 7.21—7.23 (m, 2H), .09 (m, 2H), 4.82 (s, 2H) ppm. 0M0 o o F RuClg Nalo4 \V/ F svs F THF H20 Example 30.2. Bis((3-?u0r0phenyl)sulfonyl)methane To a solution of —?uorophenyl)sulfonyl)methane (30.1, 0.200 g, 0.75 mmol) in THF/HzO (1 :1 (v/v), 10 mL) was added NaIO4 (1.6 g, 7.5 mmol) and RuCl3 (0.15 g, 0.075 mmol). The resulting solution was stirred for l h at room temperature and then was quenched by the addition of water (20 mL). The resulting on was extracted with EtOAc (3X20 mL), washed with brine (3x20 mL), dried over anhydrous magnesium sulfate, ?ltered and was concentrated to provide the desired product as a yellow solid (0.180 g, 73%), which was used without further puri?cation. 1H NMR (400 MHz, DMSO-d6): 6 7.63-7 .76 (m, 8H), 6.13 (s, 2H) ppm. 0 OO\S’/O o 00 F "s" NaH CH3| *3" "s" USVU—*U6U Example 30.3. 3,3'-(Pr0pane-2,2-diyldisulfonyl)bis(fluorobenzene) To a solution of bis((3-?uorophenyl)sulfonyl)methane (30.2, 2.0 g, 6.02 mmol) in DMSO (15 mL) was added sodium hydride (0.600 g, 15.00 mmol), followed by the addition of MeI (2.55 g, 17.96 mmol) over 30 minutes. The resulting solution was stirred for 2 h at room temperature and then was quenched by the addition of water (80 mL). The resulting solution was extracted with EtOAc (3x30 mL), washed with brine (2X30 mL), dried over anhydrous sodium sulfate, ?ltered and concentrated. The resulting residue was puri?ed by ?ash column chromatography (EtOAc/petroleum ether = 1/1 (v/v)) to e the desired product as a white solid (1.8 g, 83%). 1H NMR (400 MHz, DMSO-d6): 6 7.72-7.88 (m, 8H), 1.65 (s, 6H) ppm. 08300 Q‘s/9 :<:/\NBOC OI-{égggO5 e 30.4. tert-Butyl 4-(2-((3-?uorophenyl)sulfonyl)propanyl)—4- hydroxypiperidine-l-carboxylate To a solution of 3,3’-(propane-2,2-diyldisulfonyl)bis(?uorobenzene) (30.3, 1.0 g, 2.77 mmol) and tert—butyl 4—oxopiperidinecarboxylate (1.6 g, 8.03 mmol) in THF (5 mL) was added SmIz (83 mL, 8.31 mmol). The resulting solution was stirred for 1 h at room temperature and then quenched by the addition of saturated NH4C1 (400 mL) and water (10 mL). The resulting solution was extracted with EtOAc (3X150 mL), washed with brine (2x100 mL), dried over anhydrous sodium sulfate, ?ltered and concentrated. The resulting residue was puri?ed by ?ash chromatography (EtOAc/petroleum ether = 1/3 (v/v)) to provide the desired product as a white solid (0.830 g, 75%). 1H NMR (400 MHz, DMSO-d6): 6 7.57- 7.70 (m, 4H), 4.97 (m, 1H), 3.77-3.79( d,J=10.8, 2H), 2.95-2.97 (m, 2H), 1.76-1.97 (m, 4H), 1.41 (s, 9H), 1.22 (s, 6H) ppm. so2O O O\II DAST, CH Cl2 O\IIso BocN BocN Example 30.5. tert-Butyl 4-fluoro(2-((3-?uorophenyl)sulfonyl)propan 2O yl)piperidine—l-carboxylate To a solution of tert-butyl 4-?uoro—4—(2-((3-?uorophenyl)sulfonyl)propan yl)piperidinecarboxylate (30.4, 0.040 g, 0.10 mmol) in DCM (3 mL) at -30 °C was added DAST (0.024 g, 0.15 mmol). The resulting solution was stirred ght while g to 0 °C. The on was then ed by the on of water (10 mL), ted with EtOAc (3x10 mL), washed with brine (2x10 mL), dried over anhydrous sodium sulfate, ?ltered and was concentrated. The resulting residue was puri?ed by ?ash column chromatography (ethyl acetate/petroleum ether = 1/3 (v/v)) to provide the desired product as a white solid (0.025 g).

LC-MS (ES, m/z): 389 [M-CH3+H]+.

O\|I HCI O\\(PSI BOCNM 1 ,4-dioxane HCIHN<:>F—: Example 30.6. 4-Fluoro(2—((3-?uorophenyl)sulf0nyl)propanyl)piperidine hydrochloride Compound 30.6 was prepared in a similar manner to compound 9.5 to provide the d product as a white solid (0.350 g, crude) which was used as is t further ation. LC-MS (ES, m/z): 304 [M+H]+.

HCI-HN " >\—N Et3N, DMSO, 70 °C F F Example 30. 4-Fluor0(2-((3-?u0r0phenyl)sulfonyl)propanyl)—N-(pyridazin yl)piperidine—1-carb0xamide Compound 30 was prepared in a similar manner to compound 4 to provide the desired product as a white solid (0.070 g, 14%). LC-MS (ES, m/z): 425 [M+H]+; 1H NMR (300 MHz, DMSO-d6): 6 9.26-9.28 (m, 2H), 8.87-8.89 (d, J=6.0Hz, 1H), 7.62-7.77 (m,5H), 4.10-4.15 (d, J=14.8Hz, 2H), 2.96-3.32 (m, 2H), 2.22-2.52 (m, 2H), 1.359 (s, 6H) ppm.

The compounds in Table 1 were prepared according to the examples as described above.

Table 1. Re resentative com ounds of the Invention and Anal tical Data Cmpd. Ref.

Structure Name Mass 1H NMR N0. Example M+ + 1H-NMR(400MHz, 6): 8 9.10 (s, 1H), 8.33 (d, J = 6.4 Hz, 2H), 7.76 - 7.72 (m, 3H), 7.68 - 7.64 (m, 1H), 7.53 - 7.52 ?uo:35161:313qu (m, 2H), 4.19 - 4.18 (m, onyl)ethyl)—N- 31 2H), 3.50 - 3.47 (m, 1H), (py?din_4_ 2.86 - 2.76 (m, 2H), 2.28 - yl)pipeIidine_1_ 2.24 (m, 1H), 1.84 - 1.80 carboxamide (m, 1H), 1.65 - 1.62 (m, 1H), 1.40 - 1.32 (m, 2H), 1.10 (d, J = 7.2Hz, 3H) 1H-NMR(400MHZ, 6): 8 8.98 (s, 1H), 4—(2-<<3- 8.31 (d, J — 6.4 Hz, 2H),— ?ggrgplrlgnznbfgf 7.78 - 7.65 (m, 4H), 7.50 DEV-Fr) Edin—4- 32 (d, J = 6.4 Hz, 2H), 4.22 - yy1)piperyidine_1_ 4.18 (m, 2H), 2.80 - 2.73 (m, 2H), 2.07 - 1.93 (m, carboxamlde 3H), 1.38 - 1.35 (m, 2H), 1.19 (s, 6H) 0 III lH-NMR z, DMSO-d6): 8 8.87 (s, 1H), 8.29 - 8.27 (m, 2H), 7.80 - 4_(((3_ 7.72 (m, 3H), 7.66 - 7.64 ?uoropheny1)sulf (m, 1H), 7.46 - 7.44 (m, ony1)methy1)-N- 33 2H), 4.04 - 4.00 (m, 2H), (py?din_4_ 3.43 - 3.42 (m, 2H), 2.88 - V pp1) 1 en.dine_1_ 2.82 (m, 2H), 2.10 - 2.06 carboxamlde (m, 1H), 1.80 - 1.77 (m, 2H), 1.29 - 1.24 (m, 2H) lH-NMR (400MHz, DMSO-d6): 5 9.25 (d, J = 2.4 Hz, 1H), 9.13 (s, 1H), 4_(((3_ 8.86 - 8.85 (m, 1H), 7.80 - ?uor°phenyl)sulf 7.71 (m, 4H), 7.66 - 7.62 onyl??thylZN‘ 34 5 (m, 1H), 4.04 - 4.01 (m, $213223; 2H), 3.43 (d, J = 6.4 Hz, xaMde 2H), 2.92 - 2.86 (m, 2H), 2.08 - 2.04 (m, 1H), 1.82 - 1.79 (m, 2H), 1.31-1.22 lH-NMR (300MHz, CDC13): 5 8.83 - 8,29 (m, 2H), 7.71 - 7,68 (m, 1H), 4_(1_((3_ 7.61 - 7,57 (m, 4H), 7.41 - ?uorophenyl)sulf 7 36 (m 1H) 4 18 _ 4 11 onymycbpmpyl 35 5 (m, 2H), 2.83 -'2.75 (m, gii'igg‘il?g?: 2H), 2.15 - 2.08 (m, 1H), 1.74 - 1.70 (m, 2H), 1.61 - carboxamide 1.56 (m, 3H), 1.37 - 1.26 (m, 2H), 1.00 - 0.95 (m, 2H) . .m lH-NMR (400MHz, CD3OD): 8 8.44 (s, 1H), 4-(((3- 7.82 - 7.80 (m, 1H), 7.75 - ?uoropheny1)sulf 7.68 (m, 2H), 7.54 - 7.50 onyl)methy1)-N- (m, 2H), 4.14 - 4.10 (m, (thiazol-S- 2H), 3.15 - 3.00 (m, 2H), y1)pipen'dine-l- 2.97 - 2.94 (m, 2H), 2.26 - amide 2.20 (m, 1H), 1.98 - 1.95 (m, 2H), 1.40 - 1.37 (m, lH-NMR (400MHz, CDC13): 8 8.14 (s, 1H), 4-(1-((3- 7.72 - 7.70 (m, 1H), 7.62 - ?uorophenyl)sulf 7.57 (m, 4H), 7.42 - 7.40 onyl)cyclopropyl (m, 1H), 4.10 - 4.07 (m, )-N-(thiazol 2H), 2.85 - 2.79 (m, 2H), yl)piperidine-l- 2.13 - 2.05 (m, 1H), 1.62 - carboxamide 1.35 (m, 4H), 1.00 — 0.93 (m, 2H), 0.89 — 0.85 (m, 2H) ppm lH-NMR (300 MHz, 6): 8 8.86 (s, 1H), 8.28 (d, J = 4.8 Hz, 2H), N-(py?din—4-yl)— 7.81 (d, J = 6.3 Hz, 2H), 7.48 — 7.44 (m, 4H), 4.02 — (tosylmethy1)pip 3.99 (m, 2H), 3.31 — 3.29 en'dine (m, 2H), 2.82 (m, 2H), 2.52 carboxamide — 2.49 (m, 3H), 2.00 (m, 1H), 1.78 — 1.75 (m, 2H), 1.23 (m, 2H) . .m lH-NMR (300MHz, DMSO-d6): 8 8.86 (s, 1H), 8.28 — 8.26 (m, 2H), 7.92 — N—(pyn'din—4-y1)— 7.89 (m, 1H), 7.63 — 7.60 4-((o- (m, 1H), 7.50 — 7.44 (m, tolylsulfony1)met 4H), 4.05 — 4.00 (m, 2H), peridine— 1 - 3.32 — 3.28 (m, 2H), 2.85 — amide 2.82 (m, 2H), 2.64 (s, 3H), 2.08 — 2.00 (m, 1H), 1.79 — 1.75 (m, 2H), 1.32 — 1.25 (m, 2H) . .m lH-NMR (400MHz, DMSO-d6): 8 9.23 (s, 1H), 4-(1-((3- 9.05 (s, 1H), 8.85 (d, J = ?uorophenyl)sulf 6.0 Hz, 1H), 7.80 — 7.65 onyl)cyclopropyl (m, 5H), 4.08 - 4.05 (m, )-N-(pyn'dazin 2H), 2.74 - 2.68 (m, 2H), yl)piperidine-l- 2.08 - 2.05 (m, 1H), 1.48 - carboxamide 1.41 (m,4H), 1.10 - 1.08 (m, 2H), 1.05 - 1.01 (m, 1H-NMR (400MHz, CD3OD): 8 8.29 - 8.27 (m, 4-(((2- 2H), 7.93 - 7.90 (m, 1H), methoxyphenyl)s 7.74 - 7.69 (m, 1H), 7.49 - ulfonyl)methyl)— 7.47 (m, 2H), 7.30 - 7.28 N-(pyridin—4- (m, 1H), 7.21 - 7.14 (m, y1)piperidine 1H), 4.11 - 4.10 (m, 2H), carboxamide 4.01 (s, 3H), 3.43 - 3.41 (m, 2H), 2.95 - 2.88 (m, 2H), 2.16 - 2.13 (m, 1H), 2.03 - 1.89 (m, 2H), 1.45 - 1.36 (m, 2H) ppm lH-NMR (400MHz, DMSO-d6): 5 10.21 (s, 1H), 8.55 (d, J = 7.2 Hz, 4-(1-((3- 2H), 7.91 (d, J = 7.2 Hz, henyl)sulf 2H), 7.79 - 7.65 (m, 4H), yclobutyl)- 4.21- 4.17 (m, 2H), 2.81 - N-(pyridin 2.74 (m, 2H), 2.62 - 2.54 yl)pipetidine-l- (m, 2H), 2.29 - 2.22 (m, carboxamide 2H), 1.91 - 1.88 (m, 3H), 1.77 - 1.362 (m, 2H), 1.45 - 1.39 (m, 2H) lH-NMR (400MHz, DMSO-d6): 5 9.27 (s, 1H), 441 9.14 (s, 1H), 8.88 - 8.86 ?uorophenyl)sulf (m, 1H), 7.79 - 7.66 (m, onyl)cyclobutyl)- 5H), 4.20 - 4.17 (m, 2H), N-(py?dazin—4- 2.75 - 2.69 (m, 2H), 2.63 - y1)piperidine 2.60 (m, 2H), 2.31 - 2.23 carboxamide (m, 2H), 1.88 - 1.85 (m, 3H), 1.78 - 1.71 (m, 2H), 1.69 - 1.66 (m, 2H) . .m 1H mvm (400 MHz, 4-(di?uoro((3- DMSO-d6): 5 10.97 (s, ?uoropheny1)sulf 1H), 8.53 (s, 1H), 7.76- ony1)methy1)-N- 7.89 (m, 4H), 4.21 (d, (1,2,3 -thiadiazol- J=13.3 Hz, 2H), 2.78-3.15 -y1)pipen'dine- (m, 3H), 1.94-2.11 (m, 1-carboxamide 2H), 1.40-1.65 (m, 2H) 1Hm (400 MHz, CDC13): 5 9.29 (s, 1H), 8.55 (s, 1 H), 7.73 (d, 4-(1-?uoro—1- J=7.83 Hz, 1 H), 7.56 - ((3 - 7.67 (m, 2 H), 7.44 (td, ?uoropheny1)8qu J=8.22, 1.96 Hz, 1 H), 4.24 thy1)-N- - 4.44 (m, 2 H), 2.96 - 3.13 (1,2,3 -thiadiazol- (m, 2 H), 2.55 - 2.84 (m, -y1)piperidine- 3H), 2.35 (d, J=13.30 Hz, 1 1-carboxamide H), 1.99 ((1, 1:12.13 Hz, 1 H), 1.43 - 1.59 (m, 3H) 1H NMR (400 MHz, 4-(di?uoro((4- : 5 8.49 (s, 1H), (tri?uoromethyl) 8.20 (d, J=8.22 Hz, 2H), phenyl)sulfonyl) 8.05 (d, J=8.22 Hz, 2H), methy1)-N- 4.31 (d, J=13.69 Hz, 2H), (1,2,3-thiadiazol- 3.03 - 3.15 (m, 2H), 2.86 yl)piperidine- 3.03 (m, 1H), 2.18 (d, 1-carb0xamide J=13.30 Hz, 2H), 1.68 (qd, J=12.78, 4.30 Hz, 2H) ppm 1H 10411 (400 MHz, CD3CN): 5 9.19 - 9.22 (m, 4-«(4— 1 H) 8.84 - 8.88 (m, 1 H) cyanopheny1)su]f 8.12 - 8.17 (m, 2 H) 8.05 - i?uoromet 8.09 (m, 2 H) 7.77 (dd, hy1)-N- J=5.87, 2.74 Hz, 1 H) 7.69 (pyIidazin (br. s., 1 H) 4.21 - 4.28 (m, y1)pipetidine 2 H) 2.94 - 3.03 (m, 2 H) carboxamide 2.79 - 2.92 (m, 1 H) 2.08 - 2.14 (m, 2 H) 1.60 - 1.71 1H NMR (400 MHz, CD3CN): 8 9.18 - 9.21 (m, 4-(di?uoro((4- 1 H) 8.84 - 8.88 (m, 1 H) (tri?uoromethox 8.10 (d, J=9.00 Hz, 2 H) y)phenyl)sulf0ny 7.78 (dd, J=5.87, 2.74 Hz, l)methy1)-N- 1 H) 7.68 (br. s., 1 H) 7.61 (pyridazin—4— (d, J=7.83 Hz, 2 H) 4.20 - yl)piperidine 4.28 (m, 2 H) 2.94 - 3.03 carboxamide (m, 2 H) 2.79 - 2.93 (m, 1 H) 2.09 - 2.13 (m, 2 H) 1.59 - 1.71 (m, 2 H) . .m 1H NMR (400 MHz, CD3OD): 5 9.21 - 9.26 (m, 4-(di?u0r0((3- 1H), 8.83 - 8.89 (m, 1H), (tn'?uoromethyl) 8.27 (d, J=7.83 Hz, 1H), pheny1)su1fony1) 8.17 - 8.24 (m, 2H), 7.96 (t, methyD-N- J=8.22 Hz, 1H), 7.87 (dd, (pyn'dazin—4— J=6.26, 2.74 Hz, 1H), 4.33 y1)pipen'dine (d, J=13.69 Hz, 2H), 2.88 - carboxamide 3.10 (m, 3H), 2.17 (d, 3 Hz, 2H), 1.69 (qd, J=12.72, 4.11 Hz, 2H) . .m 1Hm (400 MHz, CD3OD): 8 9.27 (d, J=2.35 Hz, 1 H) 9.10 (d, J=7.04 Hz, 1 H) 8.91 (d, J=2.35 4-(di?uoro((6— Hz, 1 H) 8.36 (dd, J=7.04, py?din—3- 2.74 Hz, 1 H) 8.23 (dd, y1)su1fony1)meth J=8.61, 2.35 Hz, 1 H) 7.62 yl)-N-(pyn'dazin- (d, J=8.22 Hz, 1 H) 4.31 - 4-y1)pipen'dine- 4.39 (m, 2 H) 3.06 - 3.15 l-carboxamide (m, 2 H) 2.92 - 3.03 (m, 1 H) 2.69 (s, 3 H) 2.16 - 2.24 (m, 2 H) 1.65 - 1.79 (m, 2 1H NMR (400 MHz, CDC13): 5 10.46 (s, 1 H), 9.56 (d, J=2.35 Hz, 1H), 8.77 (d, J=7.04 Hz, 1H), 4-(2-((4-cyan0- 8.65 (dd, J=6.85, 2.54 Hz, 1H), 8.09 (d, J=8.22 Hz, methylphenyl)sul 1H), 7,63 — 7.75 (m, 2H), f0nyl)pr0pan—2- 7,19 — 7.27 (m, 1H), 4.43 yl)-N—(pyridazin— (d, J=13.30 Hz, 2H), 3.07 — iperidine- 3.24 (m, 1H), 2.86 — 3.09 l-carboxamide (m, 3H), 2.54 (d, J=3.13 Hz, 1H), 2.13 (d, J=12.91 Hz, 1H), 1.74 (d, J=12.91 Hz, 1H), 1.43 — 1.63 (m, 2H), 1.35 (t, J=7.43 Hz, 3H), 1.15 (d, J=7.04 Hz, 1H NMR (400 MHz, CDC13): 5 10.46 (s, 1H), 9.58 (d, J=2.74 Hz, 1H), 4-(((4-cyano 8.81 (d, J=6.65 Hz, 1H), methylphenyl)sul 8.69 (dd, J=6.85, 2.54 Hz, fonyl)di?uor0me 1H), 8.11 (d, J=8.22 Hz, thyl)-N- 1H), 7.64 - 7.75 (m, 2H), (pyridazin 4.51 (d, J=13.69 Hz, 2H), yl)piperidine-l- 3.02 (t, J=12.91 Hz, 2H), carboxamide 2.85 (t, J=13,11 Hz, 1H), 2,75 (s, 3H), 2.21 (d, J=12.13 Hz, 2H), 1.72 (qd, 8, 3.91 Hz, 2H) lH-NMR (300 MHz, CD30D): 5 9.20 (dd, J=0.9, 2.7Hz, 1H), 8.83 (dd, J=0.9, 3.0Hz, 1H), 7.94 (d, J=7.2Hz, 1H), 7.83 uoro(o- (dd, J=3.0, 6.0Hz, 1H), tolylsulfo11y1)eth 7.65-7.58 (m, 1H), 7.48- yl)-N-(pyn'dazin— 7.40 (m, 2H), 4.38-4.22 4-y1)pipen'dine- (m,2H), 2.92 (t, J=12.9Hz, l-carboxamide 2H), 2.66 (s, 3H), 2.62- 2.45 (m, 1H), 2.25 (d, J=13.5Hz, 1H), 1.88 (d, J=12.6Hz, 1H), 1.60-1.40 (m, 2H), 1.50 (d, J=22.5Hz, 3H) . .m lH-NMR (400 MHz, DMSO-d6): 5 10.20 (br.s, 4-(((2- 1H), 9.29 (d, J=2.4Hz, 1H), cyanopheny1)sulf 9.13 (d, J=6.4Hz, 1H), onyl)di?uoromet 8.38-8.30 (m, 1H), 8.28- hy1)-N- 8.20 (m, 1H), 8.16-8.08 (m, (pyIidazin 3H), 4.25 (d, J=13.6Hz, yl)pipetidine 2H), 3.15-2.98 (m, 3H), carboxamide 2.08 (d, J=12.0Hz, 2H), 1.66-1.50 (m, 2H) lH-NMR (400 MHz, CD30D): 5 9.27 (s, 1H), 9.10 (d, J=6.8Hz, 1H), 8.51 4-(1-?uoro (dd, J=1.8, 5.0Hz, 1H), ((2- 8.36 (dd, J=2.8, 7,2Hz, ypyridin- 1H), 8.25 (dd, J=1.6, 3_ 7.6Hz, 1H), 7.22 (dd, f0nyl)ethyl J=5.0, 7.8Hz, 1H), 4.42- )-N-(pyridazin—4- 4.28 (m, 2H), 4.06 (s, 3H), y1)piperidine 3.02 (t, J=12.6Hz, 2H), carboxamide 2.66-2.53 (m, 1H), 2.32 (d, J=13.2Hz, 1H), 1.93 (d, J=13.2Hz, 1H), .48 (m, 2H), 1.63 (d, J=23.2Hz, lH-NMR (400 MHz, DMSO-d6): 8 10.26 (br. s, 1H), 9.31 (d, J=2.4Hz, 1H), 4-( 1 -((2- 9.20-9.10 (m, 1H), 8.30- cyanophenyl)sulf 8.23 (m, 1H), 8.22-8.12 (m, onyl) 2H), 8.10-8.02 (m, 2H), ?uoroethy1)-N- 4.28 (d, J=13.2Hz, 2H), azin 3.00 (q, J=11.2Hz, 2H), yl)piperidine 2.67-2.49 (m, 1H), 2.15 (d, carboxamide J=12.4Hz, 1H), 1.80 (d, J=12.4Hz, 1H), 1.59 (d, J=23,2Hz, 3H), 1.57-1.43 lH-NMR (300 MHz, CD3OD): 5 9.22-9.18 (m, 1H), 8.83 (dd, J=0.9, 4-(1-?u0r0 6.0Hz, 1H), 8.27-8.20 (m, ((2 - 1H), .00 (m, 1H), oromethyl) 7.97-7.88 (m, 2H), 7.85- pheny1)sulfony1) 7.81 (m, 1H), 4.35-4.23 (m, ethy1)-N- 2H), 3.02-2.88 (m, 2H), azin 2.72-2.55 (m, 1H), 2.20 (d, y1)pipen'dine J=12.9Hz, 1H), 1.88 (d, carboxamide J=13.2Hz, 1H), 1.56 (d, J=22.5Hz, 3H), 1.60-1.43 (m, 2H) . .m lH-NMR (300 MHz, CDC13): 5 9.27 (d, J=2.4Hz, 1H), 8.92 (d, 4-(di?uoro((4- J=6Hz, 1H), 8.11-8.08 (m, ( 1 -methy1-1H- 1H), 8.05 (d, J=8.4Hz, 2H), pyrazol—S— 7.69 (d, J=8.4Hz, 2H), 7.56 y1)pheny1)sulfon (d, J=1.8Hz, 1H), 6.44 (d, y1)methy1)-N- J=1.8Hz, 1H), 4.42 (d, azin J=14.4Hz, 2H), 3.95 (s, yl)pipetidine 3H), 3.02 (t, J=12Hz, 2H), carboxamide 2.89-2.81 (m, 1H), 2.37 (br. s, 1H), 2.26 (d, , 2H), 1.82-1.68 (m, lH-NMR (300 MHz, CD3OD): 8 9.23 (d, N-(pyridazin J=2.1Hz, 1H), 8.84 (d, y1)<2-<(2- J=6.0Hz, 1H), 8.25-8.18 (tri?uoromethyl) (m, 1H), 8.10-8.00 (m, phenyl)sulf0nyl) 1H), 7.95-7.80 (m, 3H), propan-Z- 4.30 (d, J=13.5Hz, 2H), y1)piperidine 2.95 (t, J=12.6Hz, 2H), carboxamide 2.45-2.30 (m, 1H), 2.10 (d, Hz, 2H), 1.60-1.40 (m, 2H), 1.30 (s, 6H) . .m 1H-NMR (300 MHz, 6): 8 10.16 (br. s, 1H), 9.28 (d, z, 1H), 9.12 (d, J=6.3Hz, 1H), 8.87 ropylpyrid (d, J=2.4Hz, 1H), 8.20 (d, in J=2.4Hz, 1H), 8.18-8.08 y1)su1fony1)di?u (m, 1H), 7.72 (d, J=8.7Hz, oromethy1)-N- 1H), 4.25 (d, J=13.5Hz, (pyIidazin 2H), 3.12-2.85 (m, 3H), y1)pipetidine 2.40-2.30 (m, 1H), 2.05 (d, carboxamide J=12.6Hz, 2H), 1.65-1.45 (m, 2H), 1.20-1.07 (m, 4H) lH-NMR (400 MHz, CD3OD): 8 9.29 (d, J=2.4Hz, 1H), 9.09 (d, 4-(di?uoro((3- J=7.2Hz, 1H), 8.33 (dd, ?u0r0 J=2.8, 6.8Hz, 1H), 7.75 (d, methoxyphenyl)s J=80Hz, 1H), 7.70-7.64 ulfonyl)methyl)- (m, 1H), 7.41-7.35 (m, N-(pyridazin 1H), 4.36 (d, J=14Hz, 2H), y1)piperidine 4.05 (s, 3H), 3.10 (t, carboxamide Hz, 2H), 3.00-2.85 (m, 1H), 2.21 (d, J=12.8Hz, 2H), 1.80-1.60 (m, 2H) 1H-NMR (300 MHz, DMSO-d6): 8 9.26 (dd, J=0.9, 2.7Hz, 1H), 9.22 (s, 4-(di?uoro((2- 1H), 8.88 (dd, J=0.9, 6Hz, methoxypheny1)s 1H), 7.90-7.81 (m, 2H), 1)methy1)- 7.75 (dd, J=2.7, 6.0Hz, idazin 1H), 7.37 (d, J=8.1Hz, 1H), y1)piperidine-1— 7.25 (t, J=7.5Hz, 1H), 4.25 carboxamide (d, J=13.2Hz, 2H), 3.92 (s, 3H), 3.05-2.70 (m, 3H), 2.03 (d, J=12.0Hz, 2H), 1.57-1.40 (m, 2H) 0 m 1H NMR (400 MHz, DMSO-d6): 8 10.00 (br. s., 4-(di?uoro((5- 1 H) 9.26 (d, J=2.74 Hz, 1 ?uoro H) 9.07 (d, J=6.65 Hz, 1 H) methylphenyl)sul 8.03 (dd, J=6.65, 2.74 Hz, fony1)methyl)-N- 1 H) 7.60 - 7.73 (m, 3 H) (pyridazin 4.19 - 4.28 (m, 2 H) 2.89 - yl)piperidine-l- 3.08 (m, 3 H) 2.60 (s, 3 H) carboxamide 1.99 - 2.08 (m, 2 H) 1.47 - 1.60 (m, 2 H) lH-NMR (400 MHz, DMSO-d6) 8 ppm 9.56 (s, 4-(((4-(1H-1,2,4- 1H), 9.25 (d, J=13.2Hz, tn'azol 2H), 8.88 (d, J=6.0Hz, 1H), yl)phenyl)sulf0n 8.38 (s, 1H), 8,29 (d, N yl)di?u0r0methy J=8.8Hz, 2H), 8.18 (d, V" 1)-N-(pyridazin- J=8.4Hz, 2H), 7.75 (dd, 4-y1)piperidine- J=2.4, 6.0Hz, 1H), 4.26 (d, 1-carb0xamide J=12.8Hz, 2H), 3.05-2.85 (m, 3H), 2.05 (d, J=11.2Hz, 2H), 1.60-1.48 (m, 2H). 1H-NMR (300 MHz, DMSO-d6): 8 10.20 (br. s, 4-(di?uoro((2- 1H), 9.29 (d, J=1.8Hz, 1H), methyl 9.13 (d, J=6.0Hz, 1H), 8.17 (tri?uoromethyl) (d, J=8.4Hz, 1H), 8.15-8.06 pheny1)su1fonyl) (m, 1H), 8.04 (s, 1H), 7.95 methy1)-N- (d, J=8.4Hz, 1H), 4.27 (d, azin J=13.2Hz, 2H), 3.15-2.90 y1)pipen'dine (m, 3H), 2.74 (s, 3H), 2.05 carboxamide (d, J=11.7Hz, 2H), 1.68- 1.48 (m, 2H) 1H-N1VIR (400 MHz, CD3OD): 8 9.23 (d, J=2.4 4-(di?uoro(( 1- Hz, 1H), 8.86 (d, J=6.0Hz, methyl-1H- 1H), 8.29 (s, 1H), 8.10 (d, indazol J=8.8Hz, 1H), 7.90-7.85 yl)sulfonyl)meth (m, 2H), 7.69 (dd, J=7.2, yl)-N-(pyridazin— 8.4Hz, 1H), 4.33 (d, iperidine- J=13.6Hz, 2H), 4.17 (s, 1-carb0xamide 3H), 3.10-2.85 (m, 3H), 2.20 (d, J=11.6Hz, 2H), 1.78-1.62 (m, 2H) - um 1H-NMR (300 MHz, DMSO-d6): 5 9.26 (d, J=2.4Hz, 1H), 9.22 (s, 1H), 4-(((6-(azetidin— 8.88 (d, z, 1H), 8.43 1-y1)pyn'din—3 - (d, z, 1H), 7.85-7.72 y1)su1fony1)di?u (In, 2H), 6.47 (d, z, hy1)-N- 1H), 4.25 (d, J=13.8Hz, (pyn'dazin-4— 2H), 4.14 (t, J=7.7Hz, 4H), y1)pipen'dine 3.00-2.70 (m, 3H), 2.45- carboxamide 2.35 (m, 2H), 2.00 (d, J=12.9Hz, 2H), 1.58-1.40 (m, 2H) o um 1H-NMR (300 MHz, DMSO-d6): 5 9.26 (dd, J=0.9, 2.7Hz, 1H), 9.22 (s, 4-(di?uoro((5— 1H), 8.88 (dd, J=0.9, ?uoro 6.0Hz, 1H), 7.83-7.70 (m, methoxyphenyl)s 2H), 7.64 (dd, J=3.3, ulfony1)methyl)- 7.8Hz, 1H), 7.44 (dd, N-(pyn'dazin J=3.9, 9.3Hz, 1H), 4.25 (d y1)pipetidine-l- J=13.5Hz, 2H), 3.92 (s, carboxamide 3H), 3.05-2.70 (m, 3H), 2.00 (d, J=12.0Hz, 2H), 1.60-1.40 (m, 2H) 1H-N1V[R (300 MHz, CD3OD): 8 9.20 (dd, uoro((3- J=0.9, 2.7Hz, 1H), 8.83 ?uoro (dd, J=0.9, 6.0Hz, 1H), 8.12-8.05 (m, 1H), 7.98 (d, J=8.4Hz, 2H), 7.84 (dd, J=2.9, 6.2Hz, 1H), 4.30 (d, (pyridazin—4— J=13.5Hz, 2H), 3.10-2.80 y1)piperidine (m, 3H), 2.13 (d, J=12.6Hz, carboxamide 2H), 1.66 (qd, J=4.0, 8.9Hz, 2H) ppm lH-NMR (300 MHz, CD3OD): 5 9.20 (dd, uoro((3— J=0.9, 2.7Hz, 1H), 8.83 methylpy?din—4- (dd, J=0.9, 6.0Hz, 1H), y1)su1fony1)meth 8.78-8.70 (m, 2H), 7.88- yl)-N-(pyn'dazin- 7.80 (m, 2H), 4.30 (d, 4-y1)pipen'dine- J=13.8Hz, 2H), .80 l-carboxamide (m, 3H), 2.67 (s, 3H), 2.13 (d, J=12.3Hz, 2H), 1.75— 1.57 (m, 2H) lH-NMR (400 MHz, DMSO-d6): 5 10.10 (br. s, 1H), 9.29 (d, J=2.4Hz, 1H), 4-(((1,3- 9.10 (d, J=6.8Hz, 1H), dihydroisobenzof .04 (m, 1H), 7.89 (d, uran J=7.6Hz, 1H), 7.83 (d, yl)sulfony1)dj?u J=7.6Hz, 1H), 7.71 (t, oromethyl)-N- z, 1H), 5.24 (s, 2H), (pyridazin—4— .11 (s, 2H), 4.25 (d, yl)piperidine J=13.2Hz, 2H), 3.10-2.88 carboxamide (m, 3H), 2.05 (d, J=17.2Hz, 2H), 1.64-1.47 (m, 2H) lH-NMR (400 MHz, CD3OD): 8 9.23 (dd, J=1.0, 3.0Hz, 1H), 8.86 4-(((2-ch10r0 (dd, J=0.8, 6.0Hz, 1H), methoxypheny1)s 7.87 (dd, J=2.8, 6.0Hz, ulfony1)di?uoro 1H), 7.63-7.55 (m, 2H), methy1)-N- 3.35 (dd, J=2.8, 8.8Hz, (pyn'dazin—4— 1H), 4.32 (d, J=14.0Hz, y1)pipeI1'dine 2H), 3.89 (s, 3H), 3.08- carboxamide 2.85 (m, 3H), 2.16 (d, J=12.8Hz, 2H), 1.75-1.60 (m, 2H) 0 um 1H NMR (400 MHz, CDC13): 8 10.50 (s, 1H), 9.61 (d, J=2.35 Hz, 1H), 4-(di?uoro((2— 8.79 (d, J=7.04 Hz, 1H), methyl 8.70 (dd, J=6.85, 2.54 Hz, 1H), 8.04 (d, J=9.00 Hz, y)pheny1)sulfony 1H), 7.15 - 7.28 (m, 2H), 1)methy1)-N- 4.51 (d, J=12.52 Hz, 2H), (pyIidazin 3.01 (t, J=11.54 Hz, 2H), y1)p1petidine 2.77 - 2.92 (m, 1H), 2.67 - carboxamide 2.76 (m, 3H), 2.22 (d, J=12.52 Hz, 2H), 1.64 - 1.82 (m, 2H) lH-NMR (300 MHz, 4-(((2-chloro DMSO-d6): 8 8.44 (br.s, (tri?uoromethox 1H), 8.06 (d, J=8.4Hz, 1H), y)phenyl)sulf0ny 7.19 (br, s, 1H), .02 0r0methyl) (m, 2H), 6.98-6.90 (m, -N-(pyridazin—4- 1H), 3.53 (d, J=21.2Hz, y1)piperidine 2H), 2.32-2.08 (m, 3H), carboxamide 1.36 (d, J=15.2Hz, 2H), 0.98-0.75 (m, 2H) ppm 1H-NMR (300 MHz, DMSO-d6): 5 9.25 (dd, 4-(((2-chloro—3— J=0.9, 2.7Hz, 1H), 8.88 ypheny1)s (dd, J=0.9, 6.0Hz, 1H), ulfony1)di?uor0 7.74 (dd, J=2.7, 6.0Hz, methy1)-N- 1H), 7.70-7.65 (m, 3H), (pyridazin 4.24 (d, J=13.5Hz, 2H), y1)pipetidine 3.97 (s, 3H), 3.05-2.80 (m, carboxamide 3H), 2.02 (d, J=10.8Hz, 2H), 1.62-1.42 (m,2H) lH-NMR (300 MHz, DMSO-d6): 8 9.27-9.20 -chloro (m, 2H), 8.88 (d, J=6.0Hz, cyanophenyl)su1f 1H), 8.50 (d, J=1.5Hz, 1H), onyl)di?uoromet 8.30-8.25 (m, 1H), 8.20- hyl)-N- 8.15 (m, 1H), 7.74 (dd, (pyridazin J=2.7, 6.0Hz, 1H), 4.24 (d, yl)piperidine-l- J=12.6Hz, 2H), 2.98 (t, carboxamide J=11.8Hz, 3H), 2.02 (d, J=13.2Hz, 2H), 1.64-1.45 1H NMR (400 MHz, : 5 10.45 (s, 1H), 9.53 (d, J=2.35 Hz, 1H), 8.81 (d, J=7.04 Hz, 1H), 8.63 (dd, J=7.04, 2.35 Hz, 4-(1-?uor0 1H), 7.73 (d, J=7.83 Hz, 1H), 7.55 - 7.66 (m, 2H), ?uoropheny1)sulf 7.42 (td, J=8.22, 1.96 Hz, ony1)propy1)-N- 1H), 4.46 (d, J=13.30 Hz, (pyn'dazin—4- 2H), 2.89 (t, J=12.33 Hz, y1)pipeI1'dine 2H), 2.44 - 2.59 (m, 1H), carboxamide 2.19 (d, J=13.69 Hz, 1H), 1.98 (td, J=15.16, 8.41 Hz, 3H), 1.61 - 1.79 (m, 2H), 0.95 (t, J=7.63 Hz, 3H) 1H NMR (400 MHz, MeOH-d4) 8 ppm 8.90 (d, N-(6- J = 2.45 Hz, 1 H), 8.38 (s, 1 cyanopyn'din H), 8.29 (dd, J1 =8.80, J2 = y1)(<<3- 2.45 Hz, 1 H), 7.69 (d, J = romethyl)- 8.93 Hz, 1 H), 6.84 (t, J = 1 -methyl- 1H- 52.0 Hz, 1H), 4.24 (br d, J pyrazol = 13.69 Hz, 2 H), 3.94 (s, 3 yl)sulfonyl)di?u H), 2.92 (br t, J = 12.17 Hz, 2 H), 2.72 - 2.87 (m, 1 H), dine 2.61 (5,3 H), 2.05 (br d, J = carboxamide 11.62 Hz, 2 H), 1.56 (qd, J1 = 12.76, J2 = 4.16 Hz, 2 4-(((3- 1H NMR (400 MHZ, (di?uoromethyl)- MeOH-d4) 5 ppm 8.63 (d, 1-methy1— 1H- J = 2.20 Hz, 1 H), 8.37 (s, 1 pyrazol H), 7.99 (dd, J1 =8.68, J2 = y1)su1f0nyl)di?u 2.57 Hz, 1 H), 7.66 (d, J = oromethyl)—N—(2- 8.68 Hz, 1 H), 6.67 - 7.04 ?uoropyridin (In, 1 H), 4.21 (br 01, J = 13.69 Hz, 2 H), 3.90 - 3.96 (In, 3 H), 2.87 - 2.96 (m, 2 H), 2.64 - 2.85 (m, 1 H), 2.04 (br 01, J = 11.74 Hz, 2 H), 1.56 (qd, J1 = 12.76, J2 = 4.16 Hz, 2 H) ppm 1H NMR (400 MHz, MeOH-d4) 8 ppm 8.90 (d, J = 2.45 Hz, 1 H), 8.38 (s, 1 (di?uoromethyl)- H), 8.29 (dd, J1 =8.80, J2 = 1 l- 1H- 2.45 Hz, 1 H), 7.69 (d, J = pyrazol 8.93 Hz, 1 H), 6.84 (t, J = yl)sulfonyl)dj?u 52.0 Hz, 1H), 4.24 (br d, J = 13.69 Hz, 2 H), 3.94 (s, 3 pyridin H), 2.92 (br t, J = 12.17 Hz, yl)piperidine-l- 2 H), 2.71 - 2.87 (m, 1 H), carboxamide 2.61 (s, 3 H), 2.05 (br d, J = 11.62 Hz, 2 H), 1.56 (qd, J = 12.76, 4.16 Hz, 2 H) 1H N1V1R (400 MHz, MeOH-d4) 5 ppm 8.37 (s, 1 H), 8.09 (dd, J1 =2.63, J2 (di?uoromethyl)— = 0.92 Hz, 1 H), 7.88 (ddd, 1-methy1—1H- J1 = 8.86, J2 = 7.03, J3 = pyrazol 2.81 Hz, 1 H), 6.65 - 7.01 fony1)di?u (m, 2 H), 4.19 (br 01, J = 13.82 Hz, 2 H), 3.93 (s, 3 ?uoropyn'din H), 2.84 - 2.96 (m, 2 H), y1)pipen'dine 2.64 - 2.82 (m, 1 H), 1.98 - carboxamide 2.08 (m, 2 H), 1.55 (qd, J1 = 12.76, J2 = 4.16 Hz, 2 H) 1H NMR (400 MHz, 4-(((3 - ACETONITRILE-d3) 8 (di?uor0methy1)- ppm 8.36 (s, 1 H), 8.26 (s, 1 l-1H- 1 H), 8.04 (s, 1 H), 7.00 (t, pyrazol—4— J = 52 Hz, 1 H), 6.84 (s, y1)su1fony1)di?u 1H), 4.21 (d, J=13.69 Hz, 2 oromethyl)-N- H), 4.00 (s, 3 H), 2.95 (t, (isoxazol-3 - J=12.96 Hz, 2 H), 2.65 - y1)pipen'dine 2.88 (m, 1 H), 2.08 (d, carboxamide J=12.72 Hz, 2 H), 1.62 (qd, J=12.67, 3.79 Hz, 2 H) 1H NMR (300 MHZ, 4-(((3 - CD3OD) 8 ppm 9.24 — (di?uoromethyl)- 9.16 (m, 1H), 8.83 (d, J = 1 -methyl- 1H- 6.0 Hz, 1H), 8.43 (s, 1H), pyrazol 7.84 (m, 1H), 6.91 (t, J = yl)sulfonyl)dj?u 53.1 Hz, 1H), 4.29 (d, J = oromethyl)-N- 13.6 Hz, 2H), 4.00 (s, 3H), (pyridazin 3.07 — 2,91 (m, 2H), 2.84 yl)piperidine (s, 1H), 2.12 (d, J = 13.4 carboxamide Hz, 2H), 1.75 — 1.54 (m, 4-(di?u0r0(( 1- 1H NMR (300 MHz, methyl-1H- CD3OD) 5 ppm 9.20 - 9.19 imidaz01 (m, 1H), 8.84 - 8.81 (m, y1)su1f0ny1)meth 1H), 8.05 (d, J = 1.2 Hz, 1)-N-( o ridazin— 1H), 7.87 - 7.82 (m, 2H), 4-y1)piperidine- 4.29 - 4.25 (m, 2H), 3.81 l-caIboxamide (s, 3H), 3.00 - 2.92 (m, 2H), 2.81 - 2.73 (m, 1H), 2.14 - 2.10 (m, 2H), 1.68 - 1.53 (m, 2H) 1H NMR (300 MHz, CDC13) 8 ppm 9.11 (d, J = 2.4 Hz, 1H), 8.83 (d, J = 4-(((1-ethyl-1H- 6.3 Hz, 1H), 8.01 - 7.98 pyrazol-S- (m, 1H), 7.62 (d, J = 2.1 y1)su1fonyl)di?u Hz, 1H), 6.95 (d, J = 2.1 oromethyl)-N- Hz, 1H), 4.49 - 4.38 (In, (pyridazin 4H), 2.95 - 2.87 (In, 2H), etidine-l- 2.80 - 2.76 (In, 1H), 2.23 - amide 2.20 (In, 2H), 1.71 - 1.67 (In, 2H), 1.47 (t, J = 7.2 Hz, 1H NMR (300 MHZ, CD3OD) 8 ppm 9.23 (dd, J = 2.7, 1.0 Hz, 1H), 8.87 4-(((2-(1H-1,2,4- (dd, J = 6.1, 1.0 Hz, 1H), t?azol 8.77 (s, 1H), 8.29 (dd, J = y1)phenyl)sulf0n 7.9, 1.5 Hz, 1H), 8.19 (s, y1)di?u0r0methy 1H), 8.07 (In, 1H), 7.84 — 1)-N-(pyridazin— 8.00 (In, 2H), 7.73 (In, 1H), 4-y1)piperidine- 4.28 (d, J = 13.8 Hz, 2H), l-carboxamide 2.99 (In, 2H), 2.69 — 2.87 (In, 1H),1.59 (In, 2H), 81.99 — 2.09 (In, 2H) 1H NMR (400 MHz, CDC13) 8 ppm 10.48 (s, 4-(di?uoro(( 1 - 1H), 9.58 (s, 1H), 8.86 - isopropy1 8.85 (In, 1H), 8.70 - 8.69 methyl-1H- (In, 1H), 6.74 (s, 1H), 5.12 pyrazol-5— - 5.05 (In, 1H), 4.53 - 4.49 y1)su1fony1)meth (In, 2H), 3.05 - 2.99 (In, yl)-N-(pyIidazin- 2H), 2.84 - 2.78 (In, 1H), 4-y1)pipeIidine- 2.35 (s, 3H), 2.23 - 2.20 l-carboxamide (In, 2H), 1.78 - 1.69 (In, 2H), 1.51 (d, J = 6.4 Hz, 1H NMR (400 MHz, CD3OD) 8 ppm 9.23 - 9.22 4-(di?uoro((6- (m, 1H), 8.87 - 8.85 (m, ypyridin- 1H), 8.19 - 8.18 (In, 1H), 3- 7.88 - 7.85 (In, 1H), 7.75 - yl)sulfonyl)meth 7.72 (In, 1H), 6.56 (d, J = yl)-N-(pyridazin- 9.6 Hz, 1H), 4.33 - 4.29 4-yl)piperidine- (In, 2H), 3.04 - 3.01 (m, 1-carboxamide 2H), 2.92 - 2.82 (m, 1H), 2.20 - 2.16 (m, 2H), 1.71 - 1.60 (m, 2H) 4-(((3-(tert- 1H NMR (400 MHZ, butyl)methyl- DMSO-d6) 8 ppm 9.27 - 1H-pyrazol 9.24 (m, 2H), 8.89 - 8.87 y1)su1f0nyl)di?u (m, 1H), 7.76 - 7.3 (m, hyl)-N- 1H), 7.11 (m, 1H), 4.26 - (pyridazin—4— 4.22 (m, 2H), 4.02 (m, 3H), y1)pipen'dine 3.02 - 2.93 (m, 3H), 2.02 - carboxamide 1.99 (m, 2H), 1.55 - 1.49 (m, 2H), 1.27 (s, 9H) 1H NMR (300 MHZ, 4-(((1- DMSO-d6) 8 ppm 9.26 - cyclopropy1 9.23 (m, 2H), 8.89 - 8.87 methyl-1H- (m, 1H), 7.76 - 7.73 (m, pyrazol-S- 1H), 7.02 (s, 1H), 4.26 - y1)sulfonyl)dj?u 4.22 (In, 2H), 4.08 - 4.03 oromethyl)-N- (In, 1H), 3.02 - 2.94 (In, azin 3H), 2.22 (s, 3H), 2.03 - yl)piperidine-l- 2.00 (In, 2H), 1.60 - 1.47 carboxamide (In, 2H), 1.23 - 1.20 (m, 2H), 1.19 - 1.18 (m, 2H) 1H NMR (300 MHZ, DMSO-d6) 8 ppm 9.44 - 4_ 9.43 (m, 1H), 9.26 - 9.23 (di?u0r0(pyrazol (m, 2H), 8.89 - 8.86 (m, 0[1,5-a]pyridin— 1H), 8.41 - 8.40 (m, 1H), 6- 8.00 (d, J = 9.0 HZ, 1H), ylsulfony1)methy 7.76 - 7.73 (In, 1H), 7.49 - 1)-N-(pyridaZin- 7.46 (In, 1H), 6.94 - 6.93 4-y1)piperidine- (m, 1H), 4.26 - 4.22 (m, 1-carboxamide 2H), 3.02 - 2.94 (m, 3H), 2.06 - 2.02 (In, 2H), 1.60 - 1.50 (m, 2H) 1H NMR (400 MHZ, 6) 8 ppm 10.1 - 4-(((2-chlor0 10.0 (m, 1H), 9.27 (s, 1H), hydroxypheny1)s 9.12 - 9.10 (m, 1H), 8.10 - 1)di?uoro 8.07 (m, 1H), 7.92 - 7.90 )-N- (m, 1H), 7.21 (s, 1H), 7.03 (pyIidaZin - 7.01 (m, 1H), 4.26 - 4.22 y1)pipeIidine-1 - (m, 2H), 3.06 - 3.00 (m, carboxamide 2H), 2.94 - 2.91 (m, 1H), 2.07 - 2.03 (m, 2H), 1.58 - 1.49 (m, 2H) 1H NMR (300 MHZ, DMSO-d6) 8 ppm 9.26 - 4- 9.23 (m, 2H), 9.08 - 9.06 (di?uoro(pyrazol (m, 1H), 8.89 - 8.87 (m, o[1,5-a]pyridin- 1H), 8.65 (s, 1H), 7.94 - 3- 7.92 (In, 1H), 7.84 - 7.81 ylsulfonyl)methy (In, 1H), 7.76 - 7.73 (In, l)-N-(pyn'dazin- 1H), 7.40 - 7.35 (In, 1H), 4-y1)piperidine- 4.25 - 4.21 (In, 2H), 3.00 - 1-carboxamide 2.82 (In, 3H), 2.07 - 2.02 (m, 2H), 1.58 - 1.44 (m, 1H NMR (300 MHZ, 4-(di?u0r0(( 1- DMSO-d6) 8 ppm 9.26 - methyl-1H- 9.23 (m, 2H), 8.89 - 8.87 pyrazol-S- (m, 1H), 7.84 - 7.83 (m, y1)su1f0nyl)meth 1H), 7.76 - 7.73 (m, 1H), yl)-N-(pyridazin— 7.25 - 7.24 (In, 1H), 4.26 - 4-y1)piperidine- 4.22 (m, 2H), 4.09 (s, 3H), 1-carboxamide 2.98 - 2.89 (In, 3H), 2.03 - 1.99 (In, 2H), 1.59 - 1.46 1H NMR (300 MHz, CD3OD) 8 ppm 9.23 (s, 1H), 8.92 - 8.86 (m, 1H), 4-(((2-(1H- 8.25 - 8.23 (m, 1H), 8.02 - pyrazol 8.00 (m, 2H), 7.99 - 7.94 y1)phenyl)sulfon (m, 2H), 7.75 (s, 1H), 7.63 y1)di?uoromethy - 7.60 (m, 1H), 6.51 - 6.49 pyridazin- (m, 1H), 4.29 - 4.25 (m, 4-yl)pipetidine- 2H), 3.00 - 2.94 (m, 2H), 1-carboxamide 2.81 - 2.78 (m, 1H), 2.08 - 2.01 (m, 2H), 1.62 - 1.52 (m, 2H) 1H NMR (300 MHZ, DMSO-d6) 5 ppm 9.25(d, 4-(((2- J=1.8Hz, 1H), 9.21(s, 1H), (dimethylamino) 8.88(m, 1H), 8.49(m, 1H), pyridin—3- 8.13(d, J=7.8Hz, 1H), y1)su1f0nyl)di?u 7.74(m, 1H), 7.07(m, 1H), oromethy1)-N- 4.22(d, J=12.9Hz, 2H), (pyridazin—4— 4.23(d, J=13.2Hz, 2H), y1)pipen'dine , 6H), 2.72-2.96(m, carboxamide 3H), 1.97(d, J=12.9Hz, 2H), 1.42-1.51(m, 2H) (S) 1H NMR (300 MHz, (di?uoro((3- CD3OD) 8 ppm 8.19 - 8.17 (m, 1H), 7.81 - 7.59 (m, ony1)methy1)-N- 5H), 7.39 - 7.37 (m, 1H), (2-(1- 4.79 - 4.73 (m, 1H), 4.30 - hydroxyethy1)pyr 4.25 (m, 2H), 3.03 - 2.81 idin—4- (m, 3H), 2.14 (m, 2H), 1.69 y1)piperidine - 1.56 (m, 2H), 1.26 -1.24 carboxamide (m, 3H) (R) 1H NMR (300 MHz, (di?uoro((3— CD3OD) 8 ppm 8.19 - 8.17 (m, 1H), 7.81 - 7.59 (m, onyl)methy1)-N- 5H), 7.39 - 7.37 (m, 1H), (2-(1- 4.79 - 4.73 (m, 1H), 4.30 - hydroxyethyl)pyr 4.25 (m, 2H), 3.03 - 2.81 idin (m, 3H), 2.14 (m, 2H), 1.69 y1)piperidine - 1.56 (m, 2H), 1.26 - 1.24 carboxamide (m, 3H) 1H NNIR (300 MHZ, (S)(((3- CD3OD) 6 ppm 8.43 (s, romethyl)- 1H), 8.19 - 8.17 (m, 2H), 1 -methyl- 1H- 7.9 - 7.58 (m, 1H), 7.39 - F pyrazol °S'~(\\[INF 7.36 (m, 1H), 6.74 (t, J = 0,0 fony1)dj?u 53.1Hz, 1H), 4.79 - 4.72 HO 0 oromethyl)—N-(2- (m, 1H), 4.29 - 4.25 (m, /\ H379 N N NH ( 1 - F \ 2H), 4.03 (s, 3H), 3.04 - yethyl)pyr 2.74 (m, 3H), 2.13 - 2.08 idin—4- (m, 2H), 1.69 - 1.55 (m, y1)piperidine 2H), 1.42 (d, J = 6.6 Hz, carboxamide 1H NMR (300 MHz, (R)(((3 - CD3OD) 8 ppm 8.43 (s, (di?uor0methy1)- 1H), 8.19 - 8.17 (m, 2H), 1 -methy1-1H- 7.9 - 7.58 (m, 1H), 7.39 - pyrazol—4— 7.36 (m, 1H), 6.74 (t, J = y1)su1fony1)di?u 53.1 Hz, 1H), 4.79 - 4.72 oromethy1)-N-(2- (m, 1H), 4.29 - 4.25 (m, ( 1 - 2H), 4.03 (s, 3H), 3.04 - hydroxyethyl)pyr 2.74 (m, 3H), 2.13 - 2.08 idin (m, 2H), 1.69 - 1.55 (m, y1)pipetidine 2H), 1.42 (d, J = 6.6 Hz, amide 1H N1V[R (300 MHZ, 4-(((3 - Acetonitrile-d3) 8 ppm (di?uoromethyl)- 8.69 (s, 1H), 8.18 - 8.14 1 -methyl- 1H- (m, 2H), 7.77 - 7.76 (m, pyrazol 1H), 7.67 - 7.64 (m, 1H), yl)sulfonyl)dj?u 6.88 (t, J = 56.1 Hz, 1H), oromethyl)-N-(2- 4.70 (s, 2H), 4.17 - 4.14 (hydroxymethyl) (m, 2H), 3.88 (s, 3H), 2.92 pyridin—4- - 2.86 (m, 2H), 2.76 - 2.69 y1)piperidine (m, 1H), 2.02 - 1.99 (m, carboxamide 2H), 1.60 - 1.49 (m, 2H) 1H NMR (400 MHz, DMSO-d6) 8 ppm 9.64 (s, 4-(2-((4- 1H), 8.61 (d, J = 1.5 Hz, cyanopheny1)sulf 1H), 8.12 (d, J = 8.7 Hz, ony1)propan 2H), 7.99 (d, J = 8.7 Hz, yl)-N-(isoxazol- 2H), 6.72 (s, 1H), 4.19 y1)pipen'dine- 4.14 (m, 2H), 2.72 - 2.64 l-carboxamide (m, 2H), 1.94 - 1.85 (m, 3H), 1.32 - 1.24 (m, 2H), 1.12 (s, 6H) 1H NMR (400 MHz, 4-(2-((3 -chloro- CD3OD) 8 ppm 9.30 (br s, 1 -methyl-1H- 1H), 9.12 (d, J = 6.8 Hz, 1H), 8.38 - 8.36 (m, 1H), y1)su1fony1)propa 8.23 (s, 1H), 4.35 - 4.31 n—2-y1)-N- (m, 2H), 3.94 (s, 3H), 3.04 (pyridazin - 2.97 (m, 2H), 2.20 - 2.17 y1)pipen'dine (m, 3H), 1.58 - 1.49 (m, carboxamide 2H), 1.34 (s, 6H) 1H NMR (400 MHz, N-(6- CDC13) 8 ppm 9.19 (s, ?uoropyridin 1H), 8.39 (d, J=7.83 Hz, yl)(2-((6- 1H), 8.11 (br. s., 2H), 7.95 oromethyl) (d,J=8.31Hz, 1H), 6.94 pytidin—3- (br. s., 1H), 4.23 - 4.20 (m, yl)sulfony1)pr0pa 2H), 3.11 - 3.00 (m, 2H), 2.38 - 2.33 (m, 1H), 2.20 - yl)piperidine-l- 2.18 (m, 2H), 1.31 - 1.28 carboxamide (s, 8H) 4-(2-((3 - 1H NMR (400 MHZ, (di?uor0methyl)— CD3OD) 8 ppm 798-8. 15 1 l- 1H- (m, 1H), 7.39-7.51 (m, pyrazol 2H), 7.13 (s, 1H), 6.83 (t, f0nyl)pr0pa J=56.0 Hz, 1H), 4.26-4.39 n—2-y1)-N-(2- (m, 2H), 4.20 (s, 3H), 2.87- ?uoropyridin—4- 3.06 (m, 2H), 2.21-2.37 (m, 1) o i o en'dine 1H), 2.04-2.18 (m, 2H), carboxamide 1.43-1.66 (m, 2H), 1.34 (s, 1H NMR (400 MHz, 4-(2-((3 - CD3OD) 8 ppm 8.05-8.13 (di?uoromethyl)- (m, 1H), 7.83-7.91 (m, 1 -methyl- 1H- 1H), 7.01 (s, 1H), 6.88- pyrazol-S- 6.95 (m, 1H), 6.72 (t, yl)su1fonyl)pr0pa J=56.00 Hz, 1H), 4.12-4.23 n—2-yl)-N-(6- (m, 2H), 4.09 (s, 3H), 2.74- ?uoropyridin—3 - 2.88 (m, 2H), 2.10-2.23 (m, yl)piperidine 1H), 1.93-2.03 (m, 2H), carboxamide 1.34-1.51(m,2H), 1.23 (s, 1H NMR (400 MHZ, 4-(2-((3 - CD3OD) 8 ppm 9.01 (s, r0methyl)- 1H), 8.34-8.43 (m, 1H), 1 -methyl- 1H- 7.76-7.85 (m, 1H), 7.08- pyrazol-S- 7.16 (m, 1H), 6.82 (t, yl)su1fonyl)pr0pa J=56.00 Hz, 1H), 4.27-4.39 n—2-y1)-N-(6- (m, 2H), 4.20 (s, 3H), 2.90- methylpyn’din-3 - 3.03 (m, 2H), 2.72 (s, 3H), y1)piperidine 2.23-2.36 (m, 1H), 2.07- carboxamide 2.17 (m, 2H), 1.47-1.64 (m, 2H), 1.35 (s, 6H) 1H mvm (400 MHz, DMSO-d6) 8 ppm 9.74 (S, (di?uoromethy1)- 1H), 8.67 (s, 1H), 7.24 (s, yl-lH- s, - Ybsulgonf'DNpmpa 108 , . , . 4.27 (m, 2H), 4.13 (s, 3H), (1:0XZZ)01- 2.69-2.85 (m, 2H), 2.05- 2.18 (m, 1H), 1.84-1.96 (m, y1)piperidine 2H), 1.27-1.44 (m, 2H), carboxamide 1.24 (s, 6H) 1Hm (400 MHz, CHLOROFORM-d) 8 ppm (4- 8.06 (br. s., 2H), 7.93 (d, cyanophenyl)sulf J=8.07 Hz, 2H), 7.81 (d, ony1)propan J=8.07 Hz, 2H), 6.81-6.95 yl)-N-(6- (m, 2H), 4.12 (d, J=13.20 ?uoropyridin Hz, 2H), 2.89 (t, J=12.65 y1)piperidine Hz, 2H), 2.21 (t, 0 carboxamide Hz, 1H), 2.07 (d, J=12.96 Hz, 2H), 1.44 ((1, 1:12.10 Hz, 2H), 1.16 (s, 6H) 1H NMR (400 MHz, 4-(2-((1-methyl- ACETONITRILE-d3) d ppm 8.13 (s, 1 H) 7,62 (s, 2 (tri?uoromethyl) H) 7.19 (br, s., 1 H) 4.11 -1H-pyrazol (d, 3 Hz, 2 H) 3.97 yl)sulfonyl)pr0pa (s, 3 H) 2.81 (t, J=12.84 nyl)—N—( 1H- Hz, 2 H) 2.14 (t, J=11.98 pyrazol Hz, 1 H) 1.99 - 2.05 (m, 2 eridine H) 1.39 (qd, J=12.49, 3.36 carboxamide Hz, 2 H) 1.27 (s, 6 H) 1H NMR (400 MHz, ACETONITRILE-d3) (1 N-(6- ppm 8.21 (br. s., 1 H) 8.13 ?uoropyridin—3 - (s, 1 H) 7.99 (t, J=8.07 Hz, yl)(2-((1- 1 H) 7.37 (br. s., 1 H) 6.95 methyl-3 - (dd, J=8.80, 2.69Hz, 1 H) (t??uoromethyl) 4.17 (d, J=13.45 Hz, 2 H) -1H-pyrazol 3.98 (s, 3 H) 2.86 (t, y1)sulfony1)propa J=12.90 Hz, 2 H) 2.18 (t, J=11.98 Hz, 1 H) 2.04 (d, y1)pipetidine J=12.96 Hz, 2 H) 1.44 (qd, amide J=12.55, 3.30 Hz, 2 H) 1.29 (s, 6 H) 1H NMR (300 MHz, DMSO-d6) 8 ppm 9.65 (s, 4-(2-((3- 1H), 8.61 (s, 1H), 8.25 - henyl)sulf 8.21 (m, 2H), 8.13 - 8.10 0ny1)pr0pan—2- (m, 1H), 7.87 - 7.81 (m, yl)-N—(isoxazol- 1H), 6.72 (d, J = 1.5 Hz, 3 -yl)piperidine- 1H), 4.19 - 4.15 (m, 2H), 1-carb0xamide 2.73 - 2.65 (m, 2H), 2.00 - 1.86 (m, 3H), 1.33 - 1.22 (m, 2H), 1.13 (s, 6H) 1H NMR (300 MHz, DMSO-d6) 8 ppm 9.70 (br N-(isoxazol s, 1H), 9.17 (d, J = 1.2 Hz, (2-((6- 1H), 8.65 (d, J = 1.5 Hz, (tn'?uoromethyl) 1H), 8.57 - 8.53 (m, 1H), pyn'din-3 - 8.22 (d, J = 8.4 Hz, 1H), y1)su1fony1)propa 6.77 (d, J = 1.8 Hz, 1H), 4.24 - 4.20 (m, 2H), 2.80 - y1)pipen'dine 2.71 (m, 2H), 2.08 - 1.92 amide (m, 3H), 1.40 - 1.27 (m, 2H), 1.22 (s, 6H) 1H NMR (400 MHz, 4-(2-((3 -chloro- CDC13) 8 ppm 8.03 (br. s., 1 -methy1-1H- 1H), 7.18 (s, 1H), 6.89 (d, pyrazol-5— J=8.31 Hz, 1H), 6.64 (s, y1)su1fony1)propa 1H), 4.11 (d, J=13.08 Hz, n—2-y1)-N-(6- 2H), 4.03 (s, 3H), 2.82- yridin—3 - 2.95 (m, 2H), 2.16-2.29 (m, y1)pipetidine-l- 1H), 1.99-2.12 (m, 2H), carboxamide 1.36-1.53 (m, 2H), 1.23 (s, 1H NMR (400 MHz, CDC13) 8 ppm 7.89-8.01 4-(2-((3 -chlor0- (m, 1H), 7.49-7.59 (m, 1 -methyl- 1H- 1H), 7.38-7.48 (m, 1H), pyrazol-S- 7.18 (s, 1H), 6.64 (s, 1H), yl)sulfony1)pr0pa 4.11-4.47 (m, 2H), 4.03 (s, nyl)-N-(2- 3H), 2.89 (t, J=12.65 Hz, ?uoropyridin 2H), 2.17-2.32 (m, 1H), yl)piperidine 2.05 (d, J=12.84 Hz, 2H), amide 1.34-1.54 (m, 2H), 1.22 (s, 1H NMR (400 MHz, CD3OD) 8 ppm 8.31 (s, 1 4-(2-((3 - H), 7.96 (d, J=5.62 Hz, 1 (di?uor0methy1)- H), 7.31 (d, J=5.62 Hz, 1 1 -methy1-1H- H), 7.27 (s, 1H), 7.07 (t, pyrazol—4- J=54 Hz, 1 H) 4.28 (d, y1)su1fony1)propa J=13.45 Hz, 2 H) 4.04 (s, 3 n—2-y1)-N-(2- H) 2.92 (t, J=12.84 Hz, 2 ?uoropyridin—4- H) 2.21 (t, J=12.10 Hz,1 y1)piperidine H) 2.12 (d, J=13 Hz, 2 H) amide 1.40 - 1.61 (m, 2 H) 1.31 (s, 6 H) 1H N1V1R (400 MHZ, 4-(2-((3 - MeOH-d4) 8 ppm 8.32 (s, (di?uoromethyl)- 1 H), 8.20 (s, 1 H), 7.92 methyl- 1H- 8.06 (m, 1 H), 6.91 - 7.26 pyrazol (m, 2 H), 4.27 (br (1, J = yl)su1fonyl)pr0pa 13.20 Hz, 2 H), 4.04 (s, 3 n—2-yl)—N—(6- H), 2.91 (br t, J = 12.90 Hz, ?uor0pyridin—3 - 2 H), 2.06 - 2.27 (m, 3 H), yl)piperidine 1.42 - 1.58 (m, 2 H), 1.25 - carboxamide 1.38 (m, 7 H) 1H NMR (400 MHz, (3- CD3OD) 5 ppm 8.62 (s, romethyl)— 1H), 8.29 (s, 1H), 8.18 (d, 1 -methy1-1H- J=4.65 Hz, 1H), 7.90-7.98 pyrazol (m, 1H), 7.35-7.45 (m, y1)su1fony1)propa 1H), 7.03 (t, J=54.00 Hz, n—2-y1)-N- 1H), 4.21-4.32 (m, 2H), (pyn'din—3- 4.01 (s, 3H), 2.83-2.95 (m, y1)pipen'dine 2H), 2.13-2.24 (m, 1H), carboxamide 2.03-2.13 (m, 2H), 1.40- 1.58 (m, 2H), 1.29 (s, 6H) 1H NMR (400 MHz, 4-(2-((3- CD3OD) 8 ppm 8.37-8.43 heny1)sulf (m, 1H), 8.03-8.09 (m, ropan 1H), 7.82-7.90 (m, 1H), yl)-N-(5- 7.60-7.76 (m, 3H), 7.48- ?uoropyridin 7.58 (m, 1H), 4.20-4.31 (m, y1)piperidine 2H), .95 (m, 2H), carboxamide 2.04-2.22 (m, 3H), 1.41- 1.58 (m, 2H), 1.26 (s, 6H) 1H NMR (400 MHz, 4-(2-((1-methyl- ACETONITRILE-d3) 5 3- ppm 9.17 (s, 1 H) 8.78 - (tri?uoromethyl) 8.96 (m, 2 H) 8.17 (d, -1H-pyrazol J=6.72 Hz, 1 H) 8.02 (s, 1 yl)sulfonyl)pr0pa H) 4.13 (d, J=13.69 Hz, 2 ny1)-N- H) 3.86 (s, 3 H) 2.84 (t, (pyridazin J=12.65 Hz, 2 H) 2.11 (t, yl)piperidine J=11.98 Hz, 1 H) 1.98 (d, carboxamide J=12.84 Hz, 2 H) 1.30 - 1.43 (m, 2 H) 1.18 (s, 6 H) 4-(2-((3- 1H NMR (400 MHZ, F ?uorophenyl)sulf DMSO-d6) 5 ppm 10.62 0ny1)pr0pan—2- (br s, 1 H), 8.34 (d, J = 9.29 yl)-N-(6- Hz, 1 H), 7.95 (d, J = 9.29 pyridazin— Hz, 1 H), 7.51 - 7.78 (m, 4 3 -y1)piperidine- H), 4.22 (br d, J = 13.20 1-carboxamide Hz, 2 H), 2.76 (br t, J = 12.53 Hz, 2 H), 2.59 (s, 2 H), 2.56 - 2.64 (m, 1 H), 1.83 - 2.06 (m, 3 H), 1.24 - 1.40 (m, 2 H), 1.11 (s, 6 H) 1H NMR (400 MHz, 4-(2-((3 - CD3OD) 5 ppm 9.20 (d, J (di?uoromethyl)- = 2.4 Hz, 1H), 8.83 (d, J = 1 -methyl- 1H- 6.0 Hz, 1H), 7.84 - 7.81 pyrazol-S- (m, 1H), 7.07 (s, 1H), 6.77 F fonyl)pr0pa (t, J = 54.6 Hz, 1H), 4.29 - n—2-y1)-N- 4.24 (In, 2H), 4.15 (s, 3H), (pyridazin 2.96 - 2.87 (In, 2H), 2.28 - yl)piperidine 2.20 (In, 1H), 2.09 - 2.05 carboxamide (In, 2H), 1.56 - 1.44 (In, 2H), 1.29 (s, 6H) N-(6- 1H NMR (400 MHZ, ?uoropyridin DMSO-d6) 5 ppm 8.78 (s, yl)<2-<(1- 1H), 8.21 (s, 1H), 7.97 (t, J methyl = 7.5 Hz, 1H), 7.51 (s, 1H), (tn'?uoromethyl) 4.17 (d, J: 13.1 HX, 2), razol 4.11 (s, 3H), 2.73 (t, J = F y1)su1f0nyl)pr0pa 12.5 Hz, 2H), 2.07 (t, J = n—2- 11.9 Hz, 1H), 1.86 (d, J = y1)pipeI1'dine 12.4 Hz, 2H), 1.33 (In, 2H), carboxamide 1.20 (s, 6H) 1H NMR (400 MHz, DMSO-d6) 8 ppm 8.56 (s, N-(6- 1H), 8.28 (s, 1H), 8.04 (t, J ?uoropyII'din = 7.6 Hz, 1H), 7.72 (d, J = yl)(2-((1- 1.2 Hz, 1H), 7.06 (dd, J1 = methyl-1H- 8.8 Hz, J2 = 3.1 Hz, 1H), pyrazol-S- 6.96 (s, 1H), 4.23 (d, J = fony1)propa 13.2 Hz, 2H), 4.08 (s, 3H), 2.78 (t, J = 12.6 Hz, 2H), y1)pipeIidine-1 - 2.09 (t, J =11.9 Hz, 1H), carboxamide 1.91 (d, J = 12.6 Hz, 2H), 1.35 (In, 2H), 1.22 (s, 6H) 1H NMR (400 MHz, 4-(2-((3 - DMSO-d6) 8 ppm 9.53 (s, F ?uorophenyl)sulf 1H), 8.92 (s, 1H), 8.26 (s, ony1)propan 1H), 7.76 — 7.65 (m, 4H), yl)-N-(S- 4.25 (d, J = ,2H), methylpyIazin 2.75 (t, J = 12.8 Hz, 2H), yl)piperidine 2.43 (s, 3H), 2.04 — 1.91 carboxamide (In, 3H), 1.33 (In, 2H), 1.17 (s, 6H) N-(isoxazol 1H NMR (400 MHZ, yl)<2-<(1- DMSO-d6): 9.75 (s, 1H), methyl-3 - 8.67 (s, 1H), 7.57 (s, 1H), (tri?uoromethyl) 6.78 (s, 1H), 4.23 (d, J = -1H-pyrazol 13.2 Hz, 2H), 4.17 (s, 3H), F yl)sulfonyl)pr0pa 2.78 (t, J = 12.4 Hz, 2H), n—2- 2.12 (t, J = 12.0 Hz, 1H), y1)piperidine 1.90 (d, J = 12.8 Hz, 2H), carboxamide 1.34 (m, 2H), 1.25 (s, 6H) 1H NMR (400 MHz, N-(2- MeOH-d4) 8 ppm 8.08 (br ?uoropyridin—4- (1, J = 5.99 Hz, 1 H), 7.42 - (2-((1- 7.55 (m, 2 H), 7.30 (s, 1 methyl-3 - H), 4.32 (br (1, J =13.20 (t??uoromethyl) Hz, 2 H), 4.24 (s, 3 H), -1H-pyrazol 2.97 (brt, J = 12.78 Hz, 2 y1)su1fony1)propa H), 2.30 (br t, J = 11.86 Hz, 1 H), 2.12 (br (1, J = 12.84 y1)pipetidine Hz, 2 H), 1.46 - 1.64 (m, 2 carboxamide H), 1.35 (s, 6 H) 1H N1V[R (400 MHz, DMSO-d6) 8 ppm 9.66 (s, N-(isoxazol 1 H), 8.60 (s, 1 H), 7.65 (d, yl)<2-<(1- J = 1.96 Hz, 1 H), 6.88 (d, -1H- J= 1.83 Hz, 1 H), 6.70 (s, 1 pyrazol-S- H), 4.16 (br d, J = 13.33 yl)su1fonyl)pr0pa Hz, 2 H), 4.00 (s, 3 H), n—2- 2.69 (br t, J: 12.65 Hz, 2 yl)piperidine H), 2.01 (brt, J = 11.92 Hz, carboxamide 1 H), 1.83 (br d, J = 12.59 Hz, 2 H), 1.20 - 1.37 (m, 2 H), 1.14 (s, 6 H) 1H NMR (400 MHz, 4-(2-((3-ch10r0- DMSO-d6) 8 ppm 9.65 (s, 1-methy1—1H- 1 H), 8.59 (s, 1 H), 7.07 (s, \ l 1 H), 6.70 (s, 1 H), 4.15 (br o\\,,0 N\N O s I y1)su1fony1)propa 01, J = 13.20 Hz, 2 H), 3.97 n—2-y1)-N- (s, 3 H), 2.70 (br t, J = N N%MCI (isoxazol 12.53 Hz, 2 H), 1.97 - 2.11 y1)pipen'dine (m, 2 H), 1.82 (br (1, J = carboxamide 12.47 Hz, 2 H), 1.20 - 1.34 (m, 2 H), 1.17 (s, 7 H) 1H NMR (400 MHz, MeOH-d4) 8 ppm 8.93 (d, 4-(2-((1-methy1- J = 2.20 Hz, 1 H), 8.31 (dd, 3 _ J = 8.80, 2.32 Hz, 1 H), (tri?uoromethyl) 7.73 (d, J = 8.80 Hz, 1 H), -1H-pyrazol 7.22 (s, 1 H), 4.26 (br (1, J = y1)su1fony1)propa 13.45 Hz, 2 H), 4.16 (s, 3 n—2-y1)-N-(6- H), 2.90 (br t, J=12.65 Hz, 2 H), 2.64 (s, 3 H), 2.22 (br y1)piperidine t, J = 12.04 Hz, 1 H), 2.05 carboxamide (br (1, J =12.84 Hz, 2 H), 1.48 (qd, J = 12.57, 3.61 Hz, 2 H), 1.27 (s, 6 H) 1H NIVIR (400 MHz, CD3OD) 8 ppm 9.02 (s, 4-(2-((3- 1H), 8.24-8.33 (m, 1H), ?uorophenyl)sulf 8.12-8.18 (m, 1H), 7.59- onyl)propan 7.78 (m, 3H), 7.44-7.58 (m, yl)-N-(pyrazin 1H), 4.20-4.39 (m, 2H), yl)piperidine 2.81-2.98 (m, 2H), 2.02- carboxamide 2.22 (m, 3H), .60 (m, 2H), 1.27 (s, 6H) <3- 1H NMR (400 MHz, ?uorophenyl)sulf CD3OD) 8 ppm 8.88 (s, ony1)pr0pan 1H), 8.76 (s, 1H), 7.59- 7.78 (m, 5H), 7.46-7.58 (m, 1H), 4.18-4.32 (m, 2H), y1)piperidine-1 - 2.83-2.97 (m, 2H), 2.02- amide 2.24 (m, 3H), 1.42-1.57 (m, 2H), 1.27 (s, 6H) 1H N1V[R (400 MHZ, CD30D) 5 ppm 8.60-8.66 4-(2-((3- (m, 1H), 8.15-8.21 (m, ?uorophenyl)sulf 1H), 7.91-8.01 (m, 1H), ony1)propan 7.60-7.79 (In, 3H), 7.47- yl)-N-(pyridin 7.59 (m, 1H), 7.36-7.46 (m, y1)piperidine-l- 1H), 4.21-4.32 (m, 2H), carboxamide 2.79-2.96 (m, 2H), 2.03- 2.22 (In, 3H), 1.39-1.58 (m, 2H), 1.27 (s, 6H) 1H NMR (400 MHZ, MeOH-d4) 8 ppm 8.01 (br N-(2- d, J = 6.24 Hz, 1 H), 7.54 yridin (d, J =1.96 Hz, 1 H), 7.40 - yl)<2-<(1- 7.50 (m, 2 H), 6.80 (d, J = methyl-1H- 1.96 Hz, 1 H), 4.21 (br (1, J pyrazol-S- = 13.20 Hz, 2 H), 4.04 (s, 3 y1)su1fonyl)pr0pa H), 2.85 (br t, J = 12.78 HZ, 2 H), 2.11 - 2.22 (m, 1 H), y1)piperidine 2.00 (br d, J = 13.08 HZ, 2 carboxamide H), 1.37 - 1.55 (m, 2 H), 1.20 (s, 6 H) 1H NMR (400 MHZ, MeOH-d4) 8 ppm 9.02 (d, J = 2.20 Hz, 1 H), 8.41 (dd, J1 = 8.93, J2 = 2.32 HZ, 1 4-(2-((1-methy1- H), 7.81 (d, J = 8.93 HZ, 1 1H-pyrazol H), 7.66 (d, J = 2.08 Hz, 1 y1)su1fony1)propa H), 6.92 (d, J = 1.96 Hz, 1 ny1)-N-(6- H), 4.34 (br (1, J = 13.45 methylpyridin Hz, 2 H), 4.16 (s, 3 H), eridine 2.96 (br t, J =12.84 Hz, 2 carboxamide H), 2.73 (s, 3 H), 2.27 (br t, J = 12.10 Hz, 1 H), 2.12 (br d, J = 13.08 Hz, 2 H), 1.54 (qd, J1 = 12.70, J2 = 3.85 Hz, 2 H), 1.28 (m, 6 H) 1H NMR (400 MHZ, MeOH-d4) 8 ppm 9.02 (d, J = 2.20 Hz, 1 H), 8.41 (dd, J1 = 8.93, J2 = 2.32 HZ, 1 H), 7.81 (d, J = 8.93 Hz,1 4-(2-((3 - H), 7.66 (d, J = 2.08 HZ, 1 ?uorophenyl)sulf H), 6.92 (d, J = 1.96 HZ, 1 onyl)propan H), 4.34 (br (1, J =13.45 yl)-N-( 1 -methyl- Hz, 2 H), 4.16 (s, 3 H), 1H-pyrazol-S- 2.96 (br t, J = 12.84 HZ, 2 yl)piperidine H), 2.73 (s, 3 H), 2.27 (br t, amide J =12,10 Hz, 1 H), 2.12 (br d, J = 13.08 Hz, 2 H), 1.54 (qd, J1 =12.70, J2 = 3.85 Hz, 2 H), 1.28 - 1.37 (m, 6 1H NMR (400 MHz, (1-methy1- CD3OD) 8 ppm 9.23 (d, J = 1.5 Hz, 1H), 8.86 (d, J = (tri?uoromethyl) 4.5 Hz, 1H), 7.87 - 7.85 -1H-pyrazol (m, 1H), 7.27 (s, 1H), 4.31 y1)su1fony1)propa - 4.28 (m, 2H), 4.22 (s, n—2-y1)-N- 3H), 2.98 - 2.92 (m, 2H), (pyIidazm 2.31 - 2.24 (m, 1H), 2.11 - y1)pipen'dine 2.03 (m, 2H), 1.58 - 1.48 carboxamide (m, 2H), 1.33 (s, 6H) 1H NMR (400 MHz, 4-(2-((3 - DMSO-d6) 8 ppm 9.20 (br henyl)sulf s, 1 H), 7.55 - 7.84 (m, 5 onyl)propan H), 4.21 (br (1, J = 12.84 yl)-N-( 1 -methyl- Hz, 2 H), 3.73 (s, 3 H), 1H-pyrazol-3 - 2.68 (br t, J =12.41Hz,2 yl)piperidine H), 1.83 - 2.06 (m, 3 H), carboxamide 1.22 -1,38(m,2 H), 1.17 (s, 6 H) 1H NMR (400 MHZ, 4-(2-((3 - 6) 8 ppm 7.53 - ?uorophe11yl)5qu 7.74 (m, 5 H), 7.34 (s, 1 0ny1)pr0pan—2- H), 4.08 (br (1, J = 13.20 yl)-N-( 1 -methyl- Hz, 2 H), 3.70 (s, 3 H), azol 2.61 (br t, J = 12.23 Hz, 2 y1)pipen'dine H), 1.78 - 1.99 (m, 3 H), carboxamide 1.22 (qd, J1 = 12.37, J2 = 3.24 Hz, 2 H), 1.11 (s, 6 H) 1H NMR (300 MHz, DMSO-d6) 8 ppm 9.96 (br 4-(2-((3 -chloro- s, 1H), 9.29 (d, J = 2.4 Hz, 1 -methyl-1H- 1H), 9.08 (d, J = 6.6 Hz, pyrazol 1H), 8.06 - 8.03 (m, 1H), y1)su1fony1)propa 7.14 (s, 1H), 4.25 - 4.21 n—2-y1)-N- (m, 2H), 4.05 (s, 3H), 2.94 (pyridazin—4— - 2.86 (m, 2H), 2.19 - 2.11 y1)piperidine-1 - (m, 1H), 2.07 - 1.98 (m, amide 2H), 1.45 - 1.34 (m, 2H), 1.25 (s, 6H) 1H NMR (400 MHz, 4-(2-((3- DMSO-d6) 8 ppm 8.82 - F ?uorophenyl)sulf 8.90 (m, 2 H), 7.53 - 7.77 ony1)propan (m, 5 H), 4.17 (br (1, J = yl)-N-(Z- 13.08 Hz, 2 H), 2.71 (br t, J methylpyrimidin = 12.41 Hz, 2 H), 2.52 (s, 3 yl)piperidine- H), 1.83 - 2.03 (m, 3 H), 1-carboxamide 1.22 - 1.38 (m, 2 H), 1.12 (5,6 H) 1H NMR (400 MHz, 4-(2-((3- DMSO-d6) 8 ppm 9.50 (s, F ?uorophenyl)sulf 1 H), 7.50 - 7.77 (m, 4 H), 0ny1)pr0pan—2- 6.40 (s, 1 H), 4.13 (br (1, J = yl)-N-(5- 13.20 Hz, 2 H), 2.64 (br t, J methylisoxazol- = 12.53 Hz, 2 H), 2.26 (s, 3 3 -y1)piperidine- H), 1.77 - 2.01 (m, 3 H), 1-carb0xamide 1.15 - 1.36 (m, 2 H), 1.10 (s, 6 H) 1H NMR (400 MHz, 4-(2-((3- DMSO-d6) 8 9.06 (s, 1 H), (di?uoromethy1)- 8.89 (s, 2 H), 8.56 (s, 1 H), 1 -methy1-1H- 7.12 (t, J = 52.0 Hz, 1H), pyrazol—4— 4.23 (br 01, J = 13.20 Hz, 2 y1)su1fony1)propa H), 3.99 (s, 3 H), 2.73 - ny1)-N-(2- 2.89 (m, 2 H), 2.58 (s, 3 methylpytimidin H), 2.03 - 2.13 (m, 1 H), y1)piperidine- 1.96 (br (1, J = 12.47 Hz, 2 1 -carboxamide H), 1.27 - 1.45 (m, 2 H), 1.20 (s, 6 H) 1H NMR (400 MHz, 6) 8 ppm 9.57 (s, 4-(2-((3 - 1 H), 8.55 (s, 1 H), 7.11 (t, (di?uoromethyl)- J = 65.0 Hz, 1H), 7.29 (m, 1 -methyl- 1H- 1 H), 6.47 (s, 1 H), 4.20 (b1 pyrazol (1, J = 13.20 Hz, 2 H), 3.98 yl)su1fonyl)propa (s, 3 H), 2.72 (br t, J = nyl)-N-(5- 12.41 Hz, 2 H), 2.33 (s, 3 methylisoxazol- H), 2.02 (br t, J = 11.80 Hz, 3 -yl)piperidine- 1 H), 1.91 (br d, J = 12.10 1-carb0xamide Hz, 2 H), 1.25 - 1.38 (m, 2 H), 1.18 (s, 6 H) 1H NMR (400 MHz, (di?uoromethyl)- CD30D) 8 ppm 8.47-8.71 1-methy1—1H- (m, 1H), 8.29 (s, 1H), 7.04 pyrazol (t, J=56.00 Hz, 1H), 4.16- y1)su1fony1)propa 4.41 (m, 2H), 4.01 (s, 3H), ny1)-N-(1,3,4- 2.75-3.00 (m, 2H), 2.01- oxadiazol 2.23 (m, 3H), 1.37-1.54 (m, y1)pipeI1'dine 2H), 1.28 (s, 6H) carboxamide 1H NMR (400 MHz, 4-(2-((3- 6) 8 ppm 8.46 (s, heny1)sulf 1 H), 7.56 - 7.73 (m, 4 H), ony1)propan 7.53 (s, 2 H), 4.07 (br 01, J = yl)-N-( 1H- 13.33 Hz, 2 H), 2.61 (br t, J pyrazol—4— = 12.17 Hz, 2 H), 1.77 y1)piperidine 2.01 (m, 3 H), 1.15 - 1.31 carboxamide (m, 2 H), 1.11 (s, 6 H) 1H NMR (400 MHz, 4-(2-((3- MeOH-d4) 5 ppm 7.94 (br ?uorophenyl)sulf s, 1 H), 7.40 - 7.69 (m, 4 ony1)propan H), 6.21 (br s, 1 H), 4.18 yl)-N-( 1H- (br (1, J = 12.59 Hz, 2 H), pyrazol 2.82 (br t, J = 12.53 Hz, 2 yl)pipetidine-l- H), 1.96 - 2.16 (m, 3 H), carboxamide 1.40 (q, J = 10.88 Hz, 2 H), 1.17 (s, 6 H) 1H NMR (400 MHZ, ACETONITRILE-d3) (1 4-(2-((1-methyl- ppm 9.28 (d, J=2.69 Hz, 1 1H-imidazol H) 8.96 (d, J=6.97 Hz, 1 H) yl)sulfonyl)pr0pa 8.40 (br. s., 1 H) 8.34 (dd, )-N- J=6.97, 2.81 Hz, 1H) 7.91 (pyridazin (br. s., 1 H) 4.26 (d, yl)piperidine J=12.23 Hz, 2 H) 3.96 (s, 3 carboxamide H) 2.98 (t, 5 Hz, 2 H) 2.24 (ft, J=12.03, 3.07 Hz, 1 H) 2.08 (d, J=13.20 Hz, 2 H) 1.52 (qd, J=12.70, 3.73 Hz, 2 H) 1.32 (s, 6 H) 4-(2-((3 - 1H NMR (400 MHz, (di?uoromethyl)- CD3OD) 6 ppm 8.43 (s, 1 -methyl- 1H- 1H), 8.29 (s, 1H), 7.05 (t, pyrazol J=56.00 Hz, 1H), 6.73 (s, yl)su1fonyl)pr0pa 1H), 4.22 (br. s., 2H), 4.01 nyl)-N- (s, 3H), 2.80-2.96 (m, 3H), zol-3 - 2.12-2.24 (m, 1H), 2.02- yl)piperidine 2.11(m,2H), 1.38-1.54 (m, carboxamide 2H), 1.28 (s, 6H) 1H NMR (400 MHz, MeOH-d4) 8 ppm 8.36 (br s, 1 H), 7,58 - 7.67 (m, 2 4-(2-((3- H), 7.50 - 7.56 (m, 1 H), ?uorophenyl)sulf 7.38 - 7.49 (m, 1 H), 6.65 0nyl)pr0pan—2- (s, 1 H), 4.15 (br d, J = yl)-N-(isoxazol- 13.33 Hz, 2 H), 2.77 (br t, J 3 -y1)piperidine- = 12.59 Hz, 2 H), 1.93 l-carboxamide 2.11 (m, 3 H), 1.37 (qd, J1 =12.51, J2 = 2.93 Hz, 2 H), 1.16 (s, 6 H) 1H NMR (400 MHz, MeOH-d4) 8 ppm 8.10 (dd, 4—(2-((3- J1 = 6.30, J2 =1.16 Hz,1 F ?uoropheny1)sulf H), 7.69 - 7.78 (m, 2 H), ony1)propan 7.63 - 7.67 (m, 1 H), 7.46 - yl)-N-(2- 7.59 (m, 3 H), 4.30 (br d, J ?uoropyridin—4- = 13.57 Hz, 2 H), 2.94 (br y1)pipen'dine t, J = 12.35 Hz, 2 H), 2.08 - carboxamide 2.22 (m, 3 H), 1.48 - 1.60 (m, 2 H), 1.29 (s, 6 H) 1H NMR (400 MHz, 4) 8 ppm 8.19 (d, 4-(2-((3- J = 1.47 Hz, 1 H), 7.94 - ?uorophenyl)sulf 8.04 (m, 1 H), 7.63 - 7.79 ony1)propan (m, 3 H), 7.50 - 7.61 (m,1 yl)-N-(6- H), 7.02 (dd, J1 = 8.86, J2 ?uoropyridin = 2.87 Hz, 1 H), 4.27 (br d, y1)piperidine J = 13.45 Hz, 2 H), 2.89 (br carboxamide t, J = 12.17 Hz, 2 H), 2.05 - 2.23 (m, 3 H), 1.43 - 1.60 (m, 2 H), 1.29 (s, 6 H) 1H NMR (400 MHz, 4-(2-((3- CD3OD) 8 ppm 8.60-8.64 ?uorophenyl)sulf (m, 1H), 7.61-7.75 (m, ropan 3H), 7.47-7.56 (m, 1H), yl)-N-(1,3,4- 4.21-4.38 (m, 2H), 2.78- oxadiazol-Z- 2.94 (m, 2H), .19 (m, yl)piperidine 3H), 1.38-1.54 (m, 2H), carboxamide 1.26 (s, 6H) 4-(2-((3- 1H NMR (400 MHz, (di?uoromethyl)— CDC13) 5 ppm 8.18-8.30 1-methy1—1H- (m, 1H), 7.68 (s, 1H), 6.79- l 7.29 (m, 3H), 4.21-4.35 (m, 1)su1fon 1) oro a 1H), 3.94 (s, 3H), 2.46- n—2-y1)-N-(6- 2.64 (m, 3H), 2.41 (s, 3H), methylpyridazin— 1.92-2.12 (m, 3H), 1.13- 4-y1)piperidine- 1.31 (m, 1H), 1.08 (s, 6H) 1-carboxamide 1H N1V[R (400 MHZ, MeOH-d4) 8 ppm 9.01 (d, 4-(2-((3 - J = 2.45 Hz, 1 H), 8.37 (dd, (di?uoromethyl)- J1 = 8.86, J2 = 2.51 HZ, 1 1 -methyl- 1H- H), 8.32 (s, 1 H), 7.81 (d, J pyrazol = 8.93 Hz, 1 H), 7.07 (t, J = y1)sulfonyl)propa 52.0 HZ, 1H), 4.31 (br (1, ny1)-N-(6- J=13.45 HZ, 2 H), 4.04 (s, 3 methylpyridin-3 - H), 2.88 - 3.03 (m, 2 H), yl)pipetidine 2.06 - 2.28 (m, 3 H) 2.72 carboxamide (5,3 H), 1.52 (qd, J=12.53, 3.97 Hz, 2 H), 1.32 (s, 6 H) 1H NMR (400 MHZ, MeOH-d4) 8 ppm 7.51 - 4-(2-((3- 7.81 (m, 5 H), 7.37 (br s, 1 ?uorophenyl)sulf H), 4.31 (br d, J = 12.84 r0pan—2- Hz, 2 H), 3.03 (br t, J = yl)-N—(thiazol 12.59 HZ, 2 H), 2.11 - 2.28 y1)piperidine (m, 3 H), 1.56 (qd, J1 = carboxamide 12.70, J2 = 3.00 Hz, 2 H), 1.29 (s, 6 H) 1H NMR (400 MHZ, (3- 4) 8 ppm 8.63 (s, (di?uoromethyl)- 1 H), 8.34 (s, 1 H), 8.19 (s, 1-methy1-1H- 1 H), 6.95 (t, J =54.0 Hz, pyrazol 1H), 4.09 (br (1, J = 13.57 y1)su1fony1)propa Hz, 2 H), 3.92 - 3.96 (m,1 n—2-y1)-N- H), 2.78 (br t, J = 12.17 Hz, zol 2 H), 1.91 - 2.17 (m, 3 H), y1)piperidine-1— 1.35 (qd, J = 12.59, 3.91 carboxamide Hz, 2 H), 1.16 - 1.24 (m, 8 1H NMR (400 MHZ, 4-(2-((3- MeOH-d4) 8 ppm 8.70 - ?uoropheny1)sulf 8.82 (m, 1 H), 8.45 (s, 1 ony1)propan H), 7.49 - 7.80 (m, 4 H), yl)-N-(isoxazol- 4.21 (brd, J = 13.45 Hz, 2 4-y1)pipen'dine- H), 2.81 - 2.97 (m, 2 H), l-carboxamide 2.01- 2.24 (m, 3 H), 1.36 - 1.56 (m, 2 H), 1.28 (s, 6 H) 1H NMR (400 MHZ, MeOH-d4) 8 ppm 8.55 (d, J=2.45 HZ, 1 H), 8.01 (dd, N-(6- J1= 8.80, J2 = 2.81 HZ, 1 chloropyridin H), 7.62 - 7.80 (m, 3 H), yl)<2-<(3- 7.51- 7.61 (m, 1 H), 7.48 ?uorophenyl)sulf (d, J = 8.68 HZ, 1 H), 4.28 onyl)propan (br (1, J =13.57 Hz, 2 H), yl)piperidine 2.90 (br t, J = 12.29 Hz, 2 carboxamide H), 2.07 - 2.23 (m, 3 H), 1.42 - 1.61 (m, 2 H), 1.29 (s, 6 H) 1H NMR (400 MHz, MeOH-d4) 8 ppm 8.35 (d, N-(2- J = 6.72 Hz, 1 H), 8.02 (d, chloropyridin—4- J = 2.08 Hz, 1 H), 7.51 - y1)(2-((3- 7.81 (m, 5 H), 4.32 (br (1, J heny1)sulf = 13.45 Hz, 2 H), 2.96 (br ropan t, J = 12.65 Hz, 2 H), 2.09 - y1)pipen'dine 2.27 (m, 3 H), 1.54 (qd, J1 carboxamide = 12.72, J2 = 2.93 Hz, 2 H), 1.29 (s, 6 H) 1H NMR (400 MHz, MeOH-d4) 8 ppm 7.93 (d, 4-(2-((3- J = 7.09 Hz, 1 H), 7.50 - F ?uorophenyl)sulf 7.66 (m, 4 H), 7.40 - 7.49 ropan (m, 1 H), 7.33 (dd, J1 yl)-N-(6- =7.09, J2 = 1.83 Hz, 1 H), ypyridin- 4.22 (br d, J =13.45 Hz, 2 3 -y1)piperidine- H), 4.03 (s, 3 H), 2.84 (br t, 1-carb0xamide J =12.90 Hz, 2 H), 2.01 - 2.16 (m, 3 H), 1.36 - 1.51 (m, 2 H), 1.17 (s, 6 H) 1H NMR (400 MHz, CD3OD) 8 ppm 9.01 (d, J = 2.20 Hz, 1 H), 8.38 (dd, 4-(2-((3- J1 = 8.93, J2 = 2.45 Hz, 1 F ?uoropheny1)sulf H), 7.69 - 7.85 (m, 3 H), ony1)propan 7.62 - 7.68 (m, 1 H), 7.50 - y1)-N-(6- 7.61 (m, 1 H), 4.32 (br (1, J methylpyn'din—3- = 13.45 Hz, 2 H), 2.94 (br y1)pipen'dine t, J = 12.41 Hz, 2 H), 2.72 carboxamide (s, 3 H), 2.09 - 2.27 (m, 3 H), 1.44 - 1.61 (m, 2 H), 1.29 (s, 6 H) 1H NMR (400 MHz, 4-(2-((3- DMSO-d6) 8 ppm 9.27- F ?uoropheny1)sulf 9.28(s, 1H), 9.18-9.27 (s, ony1)propan 1H), 8.86-8.88(d, J , y1)hydroxy—N- 1H), 7.58-7.77 (m, 5H), (pyridazin—4- 5.07 (s, 1H), 4.00-4.04 (d, J y1)piperidine =13.2Hz, 2H), 3.06-3.13 carboxamide (m, 2H), 1.85-1.99 (m, 4H), 1.26 (s, 6H) 1H NMR (400 MHz, CD3OD) 8 ppm 9.25 (d, J = 0.8 Hz, 1H), 8.88 - 8.87 4-( 1 -((4- (In, 1H), 8.15 - 8.13 (m, cyanophenyl)sulf 31" 2H), 8.06 - 8.04 (m, 2H), onyl)cyclobutyl)- 7.88 - 7.86 (In, 1H), 4.29 - N-(pyridazin 4.26 (m, 2H), 2.87 - 2.81 yl)piperidine (m, 2H), 2.77 - 2.69 (m, carboxamide 2H), 2.38 - 2.31 (m, 2H), 2.05 -1.81(m,5H),1.61- 1.55 (m, 2H) N—(pyridazin—4— 1H NMR (300 MHZ, y1)(1-<(4- DMSO-d6) 8 ppm 9.27 - (tn'?uoromethyl) 9.26 (m, 1H), 9.15 (s, 1H), pheny1)sulf0nyl) 8.88 - 8.86 (m, 1H), 8.17 - cyclobutyl)piperi 8.14 (m, 2H), 8.07 - 8.04 dine (m, 2H), 7.76 - 7.73 (m, carboxamide 1H), 4.21 - 4.16 (m, 2H), 3.33 - 3.16 (m, 2H), 2.77 - 2.72 (m, 2H), 2.60 - 2.57 (m, 2H), 1.91 - 1.62 (m, 5H), 1.46 - 1.34 (m, 2H) 1H NMR (400 MHZ, DMSO-d6) 8 ppm 9.26 - 4-?uoro( 1- 9.25 (m, 1H), 8.88 - 8.86 ((3 - (m, 1H), 7.83 - 7.65 (m, ?uorophenyl)sulf 5H), 4.12 - 4.10 (m, 2H), onyl)cyclobutyl)- 3.00 - 2.94 (m, 2H), 2.71 - N-(pyridazin 2.63 (m, 2H), 2.52 - 2.48 yl)pipetidine (m, 2H), 2.16 - 2.10 (m, carboxamide 2H), 1.98 - 1.75 (m, 3H), 1.57 - 1.55 (m, 2H) 1H N1\/[R (400 MHZ, DMSO-d6) 8 ppm 9.27 - 4-( 1-((3 ,5- 9.26 (m, 1H), 9.15 (s, 1H), di?uorophenyl)s 8.87 - 8.86 (m, 1H), 7.84 - ulfonyl)cyclobut 7.68 (m, 4H), 4.20 - 4.16 yl)-N-(pyridazin— (m, 2H), 2.76 - 2.70 (m, 4-y1)piperidine- 2H), 2.65 - 2.62 (m, 2H), 1-carb0xamide 2.32 - 2.24 (m, 2H), 1.88 - 1.69 (In, 5H), 1.58 -1.55 (m, 2H) 1H NMR (400 MHZ, 4-(2-((3- CD30D) 5 ppm 9.23 - 9.22 (di?uoromethyl)- (m, 1H), 8.86 - 8.84 (m, 1-methy1-1H- 1H), 8.29 (s, 1H), 7.87 - pyrazol 7.84 (m, 1H), 7.05 (t, J = yl)sulfony1)propa 53.2 HZ, 1H), 4.29 - 4.26 n—2-y1)-N- (m, 2H), 4.01 (s, 3H), 2.95 (pyridaZin - 2.89 (m, 2H), 2.22 - 2.03 y1)piperidine-1— (m, 3H), 1.54 - 1.147 (m, carboxamide 2H), 1.43 (s, 6H) 1H NMR (400 MHZ, DMSO-d6) 5 ppm 9.28 (d, 4-(2-((3,5- J = 2.0 HZ, 1H), 9.17 (s, di?uoropheny1)s 1H), 8.88 (d, J = 6.0 HZ, ulfony1)propan- 1H), 7.83 - 7.74 (m, 2H), 2-y1)-N- 7.62 - 7.59 (m, 2H), 4.23 - (pyIidaZin 4.19 (m, 2H), 2.84 - 2.78 etidine (m, 2H), 2.09 - 2.06 (m, carboxamide 1H), 1.97 - 1.94 (m, 2H), 1.41 - 1.32 (m, 2H), 1.21 (s, 6H) 1H NW (400 MHZ, CDC13) 8 ppm 9.38 (s, 4-( 1 -((3 - 1H), 8.94 - 8.92 (m, 1H), romethyl)- 8.16 - 8.14 (m, 1H), 7.94 1 -methyl- 1H- (s, 1H), 702 (t, J = 53.6 pyrazol Hz, 1H), 4.40 - 4.36 (m, yl)sulf0nyl)cyclo 2H), 4.06 (s, 3H), 2.95 - buty1)-N- 2.91 (m, 2H), 2.79 - 2.68 (pyridaZin (m, 2H), 2.63 - 2.57 (m, y1)piperidine 2H), 2.31 - 2.24 (m, 3H), carboxamide 2.11 - 2.05 (2H), 1.93 - 1.82 (m, 2H), .68 - 1.62 (m, 1H NMR (300 MHz, DMSO-d6) 8 ppm 9.28 - N-(pyridazin—4- 9.27 (m, 1H), 9.19 - 9.17 yl)(2-((6- (m, 2H), 8.88 - 8.86 (m, (tri?uoromethyl) 1H), 8.58 - 8.54 (m, 1H), pyridin—3- 8.23 - 8.20 (m, 1H), 7.77 - y1)su1fony1)propa 7.74 (m, 1H), 4.24 - 4.20 (m, 2H), 2.87 - 2.79 (m, y1)pipen'dine 2H), 2.13 - 1.97 (m, 3H), carboxamide 1.44 - 1.40 (m, 2H), 1.23 (s, 6H) 1H N1V1R (300 MHZ, 4-(2-((1-methyl- CD3OD) 8 ppm 9.23 - 9.22 1H-imidazol (m, 1H), 8.86 - 8.84 (m, yl)sulfony1)pr0pa 1H), 7.86 - 7.82 (m, 3H), nyl)-N- 4.28 - 4.24 (m, 2H), 3.82 (pyridazin (s, 3H), 2.92 - 2.86 (m, yl)piperidine 2H), 2.17 - 2.09 (m, 3H), carboxamide 1.50 - 1.46 (m, 2H), 1.30 (s, 6H) 1H NMR (300 MHz, CDC13) 5 ppm 9.23 - 9.22 4-(1-((1-methyl- (m, 1H), 8.89 (d, J = 6.3 1H-imidazol Hz, 1H), 8.30 (br s, 1H), y1)sulfony1)cyclo 8.00 - 7.97 (m, 1H), 7.60 - butyl)-N- 7.56 (m, 2H), 4.32 - 4.27 (pyn'dazin-4— (m, 2H), 3.80 (s, 3H), 2.87 en'dine - 2.70 (m, 4H), 2.24 - 2.18 carboxamide (m, 3H), 2.16 - 2.11 (m, 2H), 1.90 - 1.82 (m, 2H), 1.79 - 1.59 (m, 2H) 1H NMR (400 MHz, CDC13) 8 ppm 9.21 (d, J = 2.4 Hz, 1H), 8.92 - 8.90 4-(1-((1-methy1- (m, 1H), 8.05 - 8.03 (m, azol—5— 1H), 7.60 (s, 1H), 6.87 (s, y1)su1fony1)cyclo 1H), 4.36 - 4.32 (m, 2H), butyl)-N- 4.17 (s, 3H), 2.91 -2.85 (m, (pyridazin—4— 2H), 2.59 - 2.53 (m, 2H), y1)piperidine 2.31 - 2.26 (m, 2H), 2.11 - carboxamide 2.02 (m, 3H), 1.83 - 1.81 (m, 2H), 1.79 - 1.74 (m, 1H NMR (300 MHz, 4-(1-((1-methyl- CDC13) 8 ppm 8.70 (br s, azol 1H), 7.69 (s, 1H), 6.89 - yl)su.lfonyl)cyclo 6.82 (In, 2H), 4.37 - 4.33 butyl)-N-(1,2,3- (m, 2H), 4.18 (s, 3H), 2.96 thiadiazol-S- - 2.84 (m, 2H), 2.63 - 2.53 yl)piperidine-l- (m, 2H), 2.30 - 2.23 (m, carboxamide 2H), 2.10 - 2.02 (m, 3H), 1.79 - 1.63 (m, 4H) 1H NMR (400 MHZ, N—(3- MeOH-d4) 5 ppm 8.82 (s, pyridin—4- 1 H), 8.44 - 8.52 (m, 1 H), yl)(2-((3- 8.37 - 8.43 (m, 1 H), 7.48 - ?uorophenyl)sulf 7.78 (m, 4 H), 4.26 (br 01, J 0ny1)pr0pan—2- = 12.91 Hz, 2 H), 2.93 y1)piperidine 3.13 (m, 2 H), 2.07 - 2.26 carboxamide (m, 3 H), 1.49 - 1.70 (m, 2 H), 1.27 (s, 5 H) 1H NMR (400 MHz, 4-(2-((3- MeOH-d4) 8 ppm 8.74 (br ?uorophenyl)sulf s, 1 H), 8.33 - 8.48 (m, 2 ony1)pIopan H), 7.49 - 7.79 (m, 4 H), y1)-N-(3- 4.27 (br (1, J =12.91Hz,2 yridin H), 2.97 (br t, J = 12.91 yl)piperidine-l- Hz, 2 H), 2.08 - 2.24 (In, 3 carboxamide H), 1.50 - 1.65 (In, 2 H), 1.33 (s, 1 H) 1.27 (s, 6 H) 1H NMR (400 MHz, CDC13) 8 ppm 10.41 (br. 4-(3,3-di?uor0- s., 1H), 9.56 (s, 1H), 8.74- 2-((3- 8.82 (m, 1H), 8.60-8.72 (In, ?uorophenyl)sulf 1H), .95 (In, 3H), 0nyl)butan—2-yl)— 7.52 (t, J=9.20 Hz, 1H), N-(pyridazin—4— 4.36-4.53 (In, 2H), 2.87- y1)piperidine 3.05 (In, 2H), 2.27-2.41 (In, carboxamide 1H), 2.06-2.19 (In, 2H), 1.42-1.60 (In, 2H), 1.24 (s, 4-(2-((4- 1H NMR (300 MHz, cyanopheny1)su1f CD3OD) 8 ppm 8.46 (s, ony1)propan 1H), 8.05 - 7.9 (m, 4H), (1,2,3- 4.25 - 4.21 (m, 2H), 2.97 - thiadiazol-S- 2.89 (m, 2H), 2.18 - 2.08 y1)pipeII'dine (m, 3H), 1.53 - 1.44 (m, amide 2H), 1.23 (s, 6H) 1H NMR (400 MHz, CD3OD) 8 ppm 9.23 - 9.22 4-(2-((4- (m, 1H), 8.86 - 8.84 (m, cyanopheny1)su]f 1H), 8.07 - 8.01 (m, 4H), ony1)propan 7.87 - 7.84 (m, 1H), 4.29 - y1)-N-(pyIidazin- 4.26 (m, 2H), 2.94 - 2.88 4-y1)pipeIidine- (m, 2H), 2.19 - 2.09 (m, 1-carboxamide 3H), 1.56 - 1.45 (m, 2H), 1.26 (s, 6H) 1H NMR (400 MHz, N—(pyIidazin DMSO-d6) 8 ppm 9.28 - y1)(2-((4- 9.27 (m, 1H), 9.17 (s, 1H), F (tri?uoromethyl) 8.88 - 8.86 (In, 1H), 8.09 - phenyl)sulfonyl) 8.04 (In, 4H), 7.76 - 7.74 propan (m, 1H), 4.23 - 4.20 (In, yl)piperidine 2H), 2.84 - 2.78 (In, 2H), amide 2.08 - 1.96 (In, 3H), 1.41 - 1.33 (In, 2H), 1.19 (s, 6H) N-(1,2,3- 1H NMR (400 MHZ, thiadiazol-S-yl)- DMSO-d6) 8 ppm 10.9 (In, 4-(2-((4- 1H), 8.53 (s, 1H), 8.09 - F (tn?uoromethyl) 8.04 (In, 4H), 4.22 - 4.18 phenyl)sulf0nyl) (In, 2H), 2.92 - 2.85 (In, propan—2- 2H), 2.09 - 2.01 (In, 3H), y1)pipeIIdine 1.42 - 1.35 (In, 2H), 1.18 carboxamide (6H) 1H NMR (400 MHz, DMSO-d6) 8 ppm 10.8 (br 4-(2-((1-ethy1- s, 1H), 8.53 (s, 1H), 7.77 - 1H-pyrazol—5— 7.76 (m, 1H), 6.94 - 6.93 y1)su1fony1)propa (m, 1H), 4.47 - 4.41 (m, n—2-y1)-N-(1,2,3 - 2H), 4.23 - 4.20 (m, 2H), thiadiazol-S- 2.93 - 2.87 (m, 2H), 2.17 - y1)pipen'dine 2.08 (m, 1H), 1.96 - 1.93 carboxamide (m, 2H), 1.41 - 1.33 (m, 5H), 1.20 (6H) 1H NMR (400 MHz, DMSO-d6) 8 ppm 8.92 (m, (1-ethyl- 1H), 8.30 - 8.29 (m, 2H), 1H-pyrazol 7.76 (s, 1H), 7.48 - 7.46 y1)su1fony1)pr0pa (m, 2H), 6.93 (s, 1H), 4.47 ny1)-N- - 4.42 (m, 2H), 4.23 - 4.20 (pyridin (m, 2H), 2.82 - 2.76 (m, yl)piperidine-l- 2H), 2.13 - 2.08 (m, 1H), carboxamide 1.93 -1.89(m,2H),1.41- 1.30 (m, 5H), 1.18 (s, 6H) 1H NMR (300 MHz, 6) 8 ppm 9.27 (s, (1-ethyl- 1H), 9.17 (s, 1H), 8.88 (d, J 1H-pyrazol = 5.7 Hz, 1H), 7.76 - 7.73 y1)su1fonyl)pr0pa (m, 2H), 6.93 - 6.92 (m, n—2-y1)-N- 1H), 4.47 - 4.40 (m, 2H), azin-4— 4.24 - 4.19 (m, 2H), 2.86 - y1)pipen'dine 2.78 (m, 2H), 2.16 - 2.08 carboxamide (m, 1H), 1.94 - 1.90 (m, 2H), 1.41 - 1.35 (m, 5H), 1.21 (s, 6H) 1H NMR (300 MHz, 4-(2-((1,3 - DMSO-d6) 8 ppm 8.87 (s, dimethyl-lH- 1H), 8.25 - 8.23 (m, 2H), pyrazol 7.43 - 7.41 (m, 2H), 6.67 y1)su1fony1)propa (s, 1H), 4.18 - 4.14 (m, n—2-y1)-N- 2H), 3.94 (s, 3H), 2.79 - (pyridin—4- 2.70 (m, 2H), 2.17 (s, 3H), y1)piperidine 2.09 - 2.01 (m, 1H), 1.89 - carboxamide 1.84 (m, 2H), 1.35 - 1.27 (m, 2H), 1.23 (s, 6H) 1H NMR (300 MHz, DMSO-d6) 8 ppm 9.23 - 4-(2-(( 1 ,3 - 9.22 (m, 1H), 9.12 (br s, dimethyl- 1H- 1H), 8.83 - 8.81 (m, 1H), pyrazol-S- 7.72 - 7.69 (m, 1H), 6.68 yl)sulfonyl)pr0pa (s,1H),4.19 - 4.15 (m, ny1)-N- 2H), 3.94 (s, 3H), 2.83 - (pyridazin 2.75 (m, 2H), 2.17 (s, 3H), yl)piperidine 2.11 - 2.03 (m, 1H), 1.90 - carboxamide 1.86 (m, 2H), 1.38 - 1.29 (m, 2H), 1.17 (s, 6H) 4-(2-(( 1 ,3 - 1H NMR (300 MHZ, dimethyl- 1H- DMSO-d6) 8 ppm 10.8 (br pyrazol s, 1H), 8.49 (s, 1H), 6.68 yl)su1f0nyl)pr0pa (s, 1H), 4.18 - 4.14 (m, n—2-y1)-N-(1,2,3 - 2H), 3.94 (s, 3H), 2.90 - azol 2.82 (m, 2H), 2.17 (s, 3H), y1)piperidine 2.12 - 2.03 (m, 1H), 1.92 - carboxamide 1.88 (m, 2H), 1.38 - 1.30 (m, 2H), 1.16 (s, 6H) 1H NMR (300 MHz, DMSO-d6) 8 ppm 9.27 (s, 4-(2- 1H) 9.16 - 9.14 (m, 2H), (pyrazolo[l,5- 8.88 - 8.86 (m, 1H), 8.31 - din 8.30 (M, 1H), 7.92 - 7.89 ylsulfonyl)pr0pa (m, 1H), 7.76 - 7.73 (m, n—2-yl)-N- 1H), 7.46 - 7.43 (In, 1H), (pyIidazin 6.86 (s, 1H), 4.23 - 4.19 yl)piperidine-l- (In, 2H), 2.86 - 2.78 (In, carboxamide 2H), 2.10 - 1.98 (m, 3H), 1.38 - 1.30 (m, 2H), 1.25 (s, 6H) 1H NMR (300 MHZ, CD3OD) 5 ppm 9.23 - 9.22 (m, 1H), 8.86 - 8.84 (m, methoxypyridin— 1H), 8.48 - 8.46 (m, 1H), 8.22 - 8.20 (m, 1H), 7.87 - yl)su1fonyl)pr0pa 7.84 (m, 1H), 7.21 - 7.18 n—2-y1)-N- (m, 1H), 4.30 - 4.26 (In, (pyridazin—4— 2H), 4.05 (s, 3H), 2.93 - y1)piperidine 2.87 (In, 2H), 2.22 - 2.11 carboxamide (In, 3H), 1.53 - 1.42 (In, 2H), 1.30 (s, 6H) 1H NMR (300 MHz, DMSO-d6) 8 ppm 9.27 - 4-(2- 9.26 (In, 1H), 9.16 (br s, (pyrazolo[1,5- 1H), 8.91 - 8.85 (In, 2H), a]pyridin—5- 8.35 (s, 1H), 8.24 - 8.23 ylsulfony1)propa (In, 1H), 7.76 - 7.73 (In, n—2-y1)-N- 1H), 7.16 - 7.13 (In, 1H), (pyIidazin—4— 7.05 - 7.04 (In, 1H), 4.23 - y1)pipeIidine 4.19 (In, 2H), 2.85 - 2.77 carboxamide (In, 2H), 2.12 - 1.97 (In, 3H), 1.42 - 1.30 (In, 2H), .24 (s, 6H) 1H NMR (300 MHz, DMSO-d6) 8 ppm 9.27 - (1-methyl- 9.26 (m, 1H), 9.17 (s, 1H), 1H-pyrazol 8.88 - 8.85 (m, 1H), 7.76 - y1)su1fonyl)propa 7.71 (m, 2H), 6.96 - 6.95 ny1)-N- (In, 1H), 4.24 - 4.19 (In, (pyIidazin 2H), 4.07 (s, 3H), 2.87 - yl)piperidine-l- 2.72 (In, 2H), 2.15 - 2.08 carboxamide (In, 1H), 1.95 - 1.91 (m, 2H), 1.43 - 1.30 (m, 2H), 1.22 (s, 6H) 1H NMR (300 MHZ, 4-(2-((1-methyl- DMSO-d6) 5 ppm 10.9 (br lH-pyrazol-S- s, 1H), 8.53 (s, 1H), 7.71 y1)sulfonyl)pr0pa (d, J = 1.8 Hz, 1H), 6.96 (d, n—2-y1)-N—(1,2,3 - J = 2.1 Hz, 1H), 4.23 - 4.18 thiadiazol-S- (m, 2H), 4.07 (s, 3H), 2.95 y1)piperidine - 2.86 (m, 2H), 2.17 - 2.09 carboxamide (m, 1H), 1.97 - 1.92 (m, 2H), 1.43 - 1.32 (m, 2H), 1.21 (s, 6H) 1H NMR (300 MHz, DMSO-d6) 8 ppm 8.91 (s, 4-(2-((1-methyl- 1H), 8.30 - 8.28 (m, 2H), 1H-pyrazol 7.72 - 7.71 (m, 1H), 7.47 - fonyl)propa 7.45 (m, 2H), 6.95 (s, 1H), nyl)-N- 4.23 - 4.18 (m, 2H), 4.07 (pyridin (s, 3H), 2.83 - 2.75 (In, yl)piperidine 2H), 2.14 - 2.07 (In, 1H), carboxamide 1.93 - 1.89 (In, 2H), 1.40 - 1.29 (In, 2H), 1.21 (s, 6H) 1H NMR (300 MHZ, CD3OD) 8 ppm 9.23 - N-(pyridazin 9.22 (m, 1H), 8.85 - 8.83 yl)<2-<(2- (m, 1H), 8.20 - 8.17 (In, (tn?uoromethyl) 1H), 8.06 - 8.02 (In, 1H), phenyl)sulf0nyl) 7.93 - 7.83 (In, 3H), 4.30 - propan—2- 4.26 (In, 2H), 2.98 - 2.90 y1)pipeIIdine (In, 2H), 2.41 - 2.34 (In, amide 1H), 2.10 - 2.00 (In, 2H), 1.56 - 1.46 (In, 2H), 1.23 (s, 6H) 1H NMR (400 MHz, CDC13) 8 ppm 9.56 (d, J=2.35 Hz, 1H), 8.77 (d, J=7.04 Hz, 1H), 8.65 (dd, J=2.54, 6.85 Hz, 1H), 8.09 4-(2-((4-cyano- (d, J=8.22 Hz, 1H), 7.63- 7.75 (m, 2H), .27 (m, methylpheny1)su1 1H), 6.77-6.87 (m, 1H), fony1)propan 4.37-4.54 (m, 2H), 3.07- yl)-N-(pyIidazin- _N_ 3.24 (m, 1H), 2.86-3.09 (m, 4-y1)pipeIidine- 3H), 2.48-2.62 (m, 1H), 1-carboxamide 2.06-2.20 (m, 1H), 1.69- 1.80 (m, 1H), 1.43-1.63 (m, 2H), 1.35 (t, J=7.43 Hz, 3H), 1.15 (d, J=7.04 Hz, 1H NMR (300 MHz, CD3OD) 8 ppm 9.20 - 9.19 4-(2-((2- (m, 1H), 8.83 - 8.81 (m, chlorophenyl)sul 1H), 8.04 - 8.01 (In, 1H), fonyl)propan 7.84 - 7.81 (In, 1H), 7.69 - yl)-N-(pyridazin- 7.52 (In, 3H), 4.27 - 4.23 4-yl)piperidine- (In, 2H), 2.94 - 2.86 (m, oxamide 2H), 2.29 - 2.21 (m, 1H), 2.12 - 2.08 (m, 2H), 1.53 - 1.40 (m, 2H), 1.20 (s, 6H) 1H NMR (300 MHZ, 4-(2-((1-methyl- CD3OD) 5 ppm 8.43 (d, J 1H-pyrazol = 7.5 Hz, 2H), 8.16 (s, 1H), y1)su1fonyl)pr0pa 7.93 (d, J = 7.5 Hz, 2H), n—2-y1)-N- 7.75 (s, 1H), 4.28 - 4.23 (pyIidin—4- (In, 2H), 3.94 (s, 3H), 2.96 y1)piperidine - 2.88 (In, 2H), 2.12 - 2.05 carboxamide (In, 3H), 1.54 - 1.41 (m, 2H), 1.25 (s, 6H) 1H NMR (400 MHz, CD3OD) 8 ppm 9.25 (d, J 4-(2-((1-methyl- = 2.8 Hz, 1H), 8.87 (d, J = 1H-pyrazol 6.0 Hz, 1H), 8.21 (s, 1H), y1)su1fony1)propa 7.88 - 7.86 (m, 1H), 7.80 nyl)-N- (s, 1H), 4.30 - 4.27 (m, (pyridazin 2H), 3.99 (s, 3H), 2.96 - y1)piperidine 2.89 (In, 2H), 2.14 - 2.09 carboxamide (In, 3H), 1.54 - 1.44 (In, 2H), 1.30 (s, 6H) 1H NMR (400 MHZ, CD3OD) 8 ppm 9.27 (s, 1H), 9.11 - 9.09 (m, 1H), 4-( 1 -((2- 8.35 - 8.33 (m, 1H), 8.22 - cyanophenyl)sulf 8.20 (m, 1H), 8.11 - 8.09 0nyl)cyclopr0pyl (m, 1H), 7.99 - 7.91 (In, )-N-(pyridazin—4— 2H), 4.23 - 4.19 (In, 2H), y1)piperidine 2.94 - 2.88 (In, 2H), 2.28 - carboxamide 2.22 (In, 1H), 1.81 - 1.78 (In, 2H), 1.70 - 1.67 (In, 2H), 1.26 - 1.16 (In, 4H) 1H NMR (400 MHz, 4-(2-((2- DMSO-d6) 8 ppm 8.21 - cyanopheny1)su1f 8.18 (m, 1H), 8.11 - 8.07 ony1)propan (m, 2H), 8.01 - 7.95 (m, yl)-N- 2H), 6.80 (s, 1H), 4.23 - (isothiazol-S- 4.19 (m, 2H), 2.90 - 2.82 y1)piperidine (2H), 2.17 - 2.13 (m, 1H), carboxamide 2.02 - 1.98 (m, 2H), 1.45 - 1.30 (m, 2H), 1.24 (s, 6H) 1H NMR (400 MHz, CD3OD) 8 ppm 8.28 (d, J N—(pyIidin—4-y1)- = 6.4 Hz, 2H), 8.03 - 8.01 4-( 1 -(o- (m, 1H), 7.62 - 7.58 (m, tolylsulfony1)cyc 1H), 7.46 - 7.44 (m, 4H), lopropy1)piperidi 4.13 - 4.10 (m, 2H), 2.73 - ne 2.67 (m, 5H), 2.01 - 1.98 carboxamide (m, 1H), 1.68 - 1.65 (m, 2H), 1.50 - 1.47 (m, 2H), 1.19 - 1.09 (4H) 1H NMR (300 MHz, CD3OD) 8 ppm 8.06 (s, 4-(1-((3,5- 1H), 7.60 - 7.53 (In, 2H), di?uorophenyl)s 7.42 - 7.35 (In, 1H), 6.78 ulfonyl)cyclopr0 (s, 1H), 4.12 - 4.08 (m, pyl)-N- 2H), 2.87 - 2.78 (m, 2H), iazol-S- 2.14 - 2.04 (m, 1H), 1.69 - yl)piperidine 1.65 (m, 2H), 1.53 - 1.49 carboxamide (m, 2H), 1.18 - 1.04 (In, 4-(2-((2- 1H NMR (300 MHz, henyl)sulf CD3OD) 8 ppm 9.25 (d, J r0pan—2- = 2.1 Hz, 1H), 8.87 - 8.85 yl)-N-(pyridazin— (In, 1H), 8.15 - 8.07 (In, 4-y1)piperidine- 2H), 7.99 - 7.85 (In, 3H), 1-carboxamide 4.32 - 4.28 (In, 2H), 3.08 - 2.92 (m, 2H), 2.31 - 2.15 (m, 3H), 1.60 - 1.47 (m, 2H), 1.29 (s, 6H) 1H NMR (300 MHz, DMSO-d6) 8 ppm 9.23 (d, N-(pyn'dazin-4— J = 1.8 Hz, 1H), 9.09 (br s, (1-((4- 1H), 8.85 - 8.83 (m, 1H), (t??uoromethox 8.09 -8.06 (m, 2H), 7.72 - y)pheny1)sulfony 7.64 (m, 3H), 4.20 - 4.18 1)cyclopropyl)pip (m, 2H), 3.71 - 2.58 (m, eridine 2H), 2.10 - 2.08 (m, 1H), carboxamide 1.41 - 1.37 (m, 4H), 1.11 - 1.06 (m, 4H) 1H NMR (300 MHZ, DMSO-d6) 8 ppm 8.80 (s, N-(pyridinyl)- 1H), 8.28 - 8.26 (m, 2H), 4-( 1 -((4- 8.09 - 8.06 (m, 2H), 7.66 - (tri?uoromethox 7.63 (m, 2H), 7.44 - 7.42 y)phenyl)sulf0ny (m, 2H), 4.20 - 4.16 (m, 1)Cyclopr0pyl)pip 2H), 2.70 - 2.66 (m, 2H), eridine 2.11 - 2.06 (m, 1H), 1.43 - carboxamide 1.40 (m, 4H), 1.11 - 0.98 (m, 4H) 1H NMR (300 MHz, N-(isothiazol-S- DMSO-d6) 8 ppm 10.4 (br F F y1)(1-((4- s, 1H), 8.09 - 8.05 (m, 3H), >LF (tn'?uoromethox 7.66 - 7.63 (m, 2H), 6.78 y1)su1fony (s, 1H), 4.08 - 4.04 (m, opr0pyl)pip 2H), 2.77 - 2.69 (m, 2H), e 2.10 - 2.02 (m, 1H), 1.50 - carboxamide 1.38 (m, 4H), 1.14 - 1.07 (m, 4H) 1H NMR (400 MHz, CD3OD) 8 ppm 8.21 - 8.20 4-(2-((2- (m, 1H), 8.08 - 8.06 (m, chloropheny1)su1 1H), 7.73 - 7.67 (m, 2H), fony1)propan 7.61 - 7.57 (m, 1H), 6.89 y1)-N- (s, 1H), 4.29 - 4.6=26 (m, (isothiazol-S- 2H), 3.02 - 2.95 (m, 2H), y1)pipen'dine 2.34 - 2.28 (m, 1H), 2.17 - carboxamide 2.14 (m, 2H), 1.56 - 1.45 (m, 2H), 2.28 (s, 6H) 1H NMR (400 MHz, DMSO-d6) 8 ppm 8.90 (s, 1H), 8.29 - 8.28 (m, 2H), 4-(2-((2- 8.21- 8.19 (m, 1H), 8.10 - cyanophenyl)sulf 8.08 (m, 1H), 8.02 - 7.98 onyl)propan (m, 2H), 7.47 - 7.46 (m, yl)-N-(pyridin 2H), 4.23 - 4.19 (m, 2H), yl)piperidine-l- 2.83 - 2.76 (m, 2H), 2.12 - carboxamide 2.10 (m, 1H), 1.99 - 1.96 (m, 2H), 1.40 - 1.35 (m, 2H), 1.24 (s, 6H) 4-(2-((3,5- 1H NMR (400 MHz, di?uorophenyl)s CD3OD) 8 ppm 8.13 (s, ulfony1)pr0pan- 1H), 7.55 - 7.54 (m, 2H), 2-y1)-N- 7.48 - 7.43 (m, 1H), 6.86 (isothiazol-S- (s, 1H), 4.29 - 4.26 (m, 1) mien'dine-l- 2H), 2.99 - 2.93 (m, 2H), amide .- 2.24 - 2.11 (m, 3H), 1.55 - 1.46 (m, 2H), 1.28 (s, 6H) 1H NMR (400 MHz, 4-(2-((3 - CD3OD) 8 ppm 8.55 (s, ?uoropheny1)5qu 1H), 7.62-7.78 (m, 3H), ony1)propan 7.49-7.60 (m, 1H), 4.23- y1)-N-(1,2,3 - 4.35 (m, 2H), 2.92-3.06 (m, thiadiazol-S- 2H), 2.10-2.27 (m, 3H), y1)piperidine .60 (m, 2H), 1.28 (s, carboxamide 1H NIVIR (300 MHZ, DMSO-d6) 8 ppm 8.90 (s, 1H), 8.30 - 8.27 (m, 2H), N-(pyridinyl)- 7.83 - 7.80 (m, 1H), 7.64 - 4-(2-(0- 7.61 (m, 1H), 7.50 - 7.45 tolylsulfonyl)pr0 (m, 4H), 4.22 - 4.18 (m, pan 2H), 2.77 - 2.73 (m, 2H), yl)piperidine 2.65 (s, 3H), 2.20 - 2.18 carboxamide (m, 1H), 1.96 - 1.92 (m, 2H), 1.36 - 1.30 (m, 2H), 1.14 (s, 6H) 1H NMR (300 MHz, DMSO-d6) 8 ppm 10.5 (s, 1H), 8.12 - 8.11 (m, 1H), N-(isothiazol-S- 7.83 - 7.80 (m, 1H), 7.66 - y1)(2-(o- 7.61 (m, 1H), 7.50 - 7.45 tolylsulfony1)pro (m, 2H), 6.82 (s, 1H), 4.21 pan - 4.17 (m, 2H), 2.89 - 2.80 y1)pipen'dine (m, 2H), 2.58 (s, 3H), 2.20 carboxamide - 2.17 (m, 1H),1.98 - 1.94 (m, 2H), 1.39 - 1.35 (m, 2H), 1.15 (s, 6H) 1H NMR (400 MHz, 4-(2-((3- DMSO-d6) 8 ppm 8.25 - ?uoropheny1)sulf 8.20 (m, 2H), 8.06 (s, 1H), ony1)propan 7.77 - 7.65 (m, 4H), 7.43 - y1)-N-(3- 7.42 (m, 1H), 4.17 - 4.13 methylpyn'din (m, 2H), 2.80 - 2.74 (m, en'dine 2H), 2.16 (s, 3H), 2.07 - carboxamide 1.92(m,3H), 1.41 - 1.30 (m, 2H), 1.18 (s, 6H) 1H NMR (300 MHz, CD3OD) 8 ppm 8.12 (s, 1H), 7.86 - 7.83 (m, 1H), N-(isothiazol-S- 7.73 - 7.68 (m, 1H), 7.28 - y1)(2-((2- 7.26 (m, 1H), 7.19 - 7.14 methoxyphenyl)s (m, 1H), 6.85 - 6.84 (m, ulfonyl)propan- 1H), 4.27 - 4.22 (m, 2H), 2-y1)piperidine- 3.94 (s, 3H), 2.95 - 2.87 1-carboxamide (m, 2H), 2.24 - 2.0 (m, 3H), 1.51 - 1.40 (m, 2H), 1.23 (s, 6H) 4-(2-((2- 1H NMR (300 MHz, methoxyphenyl)s CD3OD) 8 ppm 8.29 - 8.27 ulfony1)pr0pan- (m, 2H), 7.87 - 7.84 (m, N-(pyridin— 1H), 7.74 - 7.69 (m, 1H), 4-y1)piperidine- 7.50 - 7.48 (m, 2H), 7.28 - 1-carboxamide 7.26(m,1H),7.19 - 7.14 (m, 1H), 4.29 - 4.24 (m, 2H), 3.94 (s, 3H), 2.91 - 2.82 (m, 2H), 2.22 - 2.09 (m, 3H), 1.51 - 1.40 (m, 2H), 1.29 (s, 6H) 1H NMR (400 MHz, CD3OD) 8 ppm 8.18 (s, 4-(1-((3 - 1H), 7.81 - 7.79 (m, 1H), ?uorophenyl)sulf 7.73 - 7.68 (m, 2H), 7.55 - ony1)cyclopropyl 7.51 (m, 1H), 6.86 (s, 1H), )-N-(isothiazol- 4.15 - 4.12 (m, 2H), 2.89 - -yl)piperidine- 2.83 (m, 2H), 2.16 - 2.09 1-carboxamide (m, 1H), 1.70 - 1.67 (m, 2H), 1.56 - 1.55 (m, 2H), 1.20 - 1.10 (m, 4H) 1H NMR (400 MHZ, 4-(2-((3- 6) 8 ppm 10.5 (s, ?uorophenyl)sulf 1H), 8.11 (s, 1H), 7.75 - 0nyl)pr0pan—2- 7.65 (m, 4H), 6.82 (s, 1H), yl)-N- 4.20 - 4.16 (m, 2H), 2.85 - (isothiazol-S- 2.79 (m, 2H), 2.03 - 1.93 y1)piperidine (m, 3H), 1.35 - 1.31 (m, carboxamide 2H), 1.17 (s, 6H) 1H NMR (300 MHz, 4-(2-((3- DMSO-d6) 8 ppm 8.33 - ?uoropheny1)sulf 8.31 (m, 2H), 7.77 - 7.63 ony1)propan (m, 4H), 6.92 - 6.90 (m, yl)-N-methyl-N- 2H), 3.85 - 3.80 (m, 2H), (pyn'din—4- 3.11 (s, 3H), 2.82 - 2.74 y1)pipen'dine (m, 2H), 1.99 - 1.87 (m, amide 3H), 1.38 - 1.23 (m, 2H), 1.16 (s, 6H) 1H NMR (300 MHz, xazol-3— DMSO-d6) 8 ppm 9.70 (s, yl)(2-((6- 1H), 9.18 - 9.17 (m, 1H), (tri?uoromethyl) 8.65 (s, 1H), 8.57 - 8.56 pyridin—3— (m, 1H), 8.22 - 8.19 (m, y1)su1fony1)propa 1H), 6.77 (s, 1H), 4.24 - n—2- 4.20 (m, 2H), 2.80 - 2.71 y1)piperidine (m, 2H), 2.08 - 1.92 (m, carboxamide 3H), 1.40 - 1.27 (m, 2H), 1.22 (s, 6H) 1H NMR (300 MHz, 6) 8 ppm 9.28 - N-(pyridazin 9.27 (m, 1H), 9.19 - 9.17 yl)(2-((6- (m, 2H), 8.88 - 8.86 (m, (tri?uoromethyl) 1H), 8.58 - 8.54 (m, 1H), pytidin—3- 8.23 - 8.20 (In, 1H), 7.77 - yl)sulfony1)pr0pa 7.74 (m, 1H), 4.24 - 4.20 (m, 2H), 2.87 - 2.79 (m, yl)piperidine-l- 2H), 2.13 - 1.97 (m, 3H), carboxamide 1.44 - 1.32 (m, 2H), 1.23 (s, 6H) 4-(1-?u0r0 1H NMR (400 MHZ, ((3 - CD3OD) 8 ppm 8.45-8.58 ?uorophe11yl)5qu (m, 1H), 7.77 (s, 3H), 7.52- ony1)ethyl)-N- 7.62 (m, 1H), 4.25-4.45 (m, (1,3 ,4-0xadiazol- 2H), 2.79-2.95 (m, 2H), 2-y1)piperidine- 2.44-2.56 (m, 1H), 2.16- 1-carboxamide 2.28 (m, 1H), 1.76-1.90 (m, 1H), 1.40-1.64 (m, 5H) 1H NMR (400 MHz, CD3OD) 8 ppm 8.40 (s, 4-(1-?uor0 1H), .10 (m, 1H), ((3 - 7.83-7.90 (m, 1H), 7.64- ?uoIopheny1)sulf 7.81(m,3H),7.53-7.62(m, ony1)ethyl)-N-(5- 1H), 4.23-4.35 (m, 2H), ?uoropyridin-3 - .97 (m, 2H), 2.46- yl)piperidine 2.59 (In, 1H), 2.20-2.29 (In, carboxamide 1H), 1.81-1.91 (In, 1H), .63 (In, 5H) 1H NMR (400 MHZ, CD3OD) 8 ppm 8.54-8.61 4-(1-?uoro (m, 1H), 8.16 (d, J=4.77 ((3- Hz, 1H), 7.86-7.94 (m, ?uorophenyl)sulf 1H), 7.77 (m, 3H), 7.52- 0nyl)ethyl)—N- 7.63 (m, 1H), 7.30-7.40 (m, (pyridin—3- 1H), 4.22-4.36 (m, 2H), y1)piperidine 2.84-2.97 (m, 2H), 2.45- amide 2.60 (m, 1H), 2.19-2.30 (m, 1H), 1.81-1.92 (In, 1H), 1.41-1.65 (In, 5H) 1H NMR (400 MHz, CD3OD) 8 ppm 8.97 (s, 4-(1-?uor0 1H), 8.30 (d, J=9.06 Hz, ((1-methy1-1H- 1H), 7.76 (d, J=8.80 Hz, pyrazol-S- 1H), 7.66 (s, 1H), 7.01 (s, y1)su1fony1)ethy1 1H), 4.31 (t, J=14.31 Hz, )-N-(6- 2H), 4.10 (s, 3H), 2.96 (t, methylpyn'din—3- J=12.96 Hz, 2H), 2.68 (s, y1)pipeIidine-1— 3H), 2.59 (d, J=7.95 Hz, carboxamide 1H), 2.21 (d, J=12.84 Hz, 1H), 1.90 (d, J=12.96 Hz, 1H), 1.45-1.67 (m, 5H) 1H NMR (400 MHz, CD3OD) 8 ppm 7.91-7.97 uor0—1- (m, 1H), 7.63-7.68 (m, ((1-methy1-1H- 1H), 7.27-7.31 (m, 1H), pyrazol-S- 7.23-7.27 (m, 1H), 6.98- y1)sulfony1)ethyl 7.03 (m, 1H), 4.22-4.36 (m, )-N-(2- 2H), 4.10 (s, 3H), 2.88- ?uoropyridin 2.99 (m, 2H), 2.50-2.64 (m, yl)piperidine 1H), 2.14-2.25 (In, 1H), amide 1.84-1.92 (In, 1H), 1.42- 1.67 (In, 5H) 1H NMR (400 MHZ, CD3OD) 8 ppm 9.13-9.20 4-(1-?uoro (m, 1H), 8.37-8.47 (m, ((1-methyl-1H- 2H), 7.89-7.98 (m, 1H), pyrazol-S- 7.66 (s, 1H), 6.97-7.05 (m, f0nyl)ethyl 1H), 4.26-4.41 (m, 2H), )-N-(pyridin—3 - 4.10 (s, 3H), 2.90-3.04 (m, y1)piperidine 2H), 2.53-2.67 (m, 1H), carboxamide 2.15-2.26 (m, 1H), 1.85- 1.96 (m, 1H), 1.45-1.70 (m, 1H NMR (400 MHz, uoro—1- CD3OD) 8 ppm 8.15-8.20 (( 1 -methy1-1H- (m, 1H), 7.92-8.00 (m, pyrazol—S— 1H), 7.60-7.71 (m, 1H), y1)su1fony1)ethy1 6.97-7.05 (m, 2H), 4.22- )-N-(6- 4.37 (m, 2H), 4.10 (s, 3H), ?uoropyn'din-3 - 2.86-2.98 (m, 2H), 2.48- en'dine 2.62 (m, 1H), 2.14-2.23 (m, carboxamide 1H), 1.82-1.93 (m, 1H), 1.59 (s, 5H) 1H NMR (400 MHz, (S)(1-?uor0- CD3OD) 8 ppm 8.43 (s, 1-((1-methyl-3 - 1H), 7.43 (s, 1H), 6.73 (s, (tri?uoromethyl) 1H), 4.22-4.39 (m, 2H), -1H-pyrazol 4.18 (s, 3H), 2.85-3.05 (m, y1)sulfonyl)ethyl 2H), 2.54-2.70 (m, 1H), )-N-(isoxazol-3 - 2.10-2.23 (m, 1H), 1.84- eridine 1.94 (m, 1H), 1.38-1.73 (m, carboxamide 1H NMR (400 MHZ, (S)(1-?u0r0- CD3OD) 8 ppm 7.94 (d, 1-((1-methyl-3 - J=5.87 Hz, 1H), 7.43 (s, (tn'?uoromethyl) 1H), .30 (m, 1H), -1H-pyrazol 7.24 (s, 1H), 4.23-4.43 (m, y1)su1f0ny1)ethyl 2H), 4.18 (s, 3H), 2.88- )-N-(2- 3.04 (m, 2H), 2.55-2.71 (m, ?uoropyn'din—4- 1H), 2.11-2.23 (m, 1H), y1)pipen'dine 1.84-1.97 (m, 1H), 1.39- carboxamide 1.72 (m, 5H) 1H NMR (400 MHz, (1-((3- CD3OD) 8 ppm 8.36 (s, (di?uoromethy1)- 1H), 7.93 (d, J=5.75 Hz, 1-methy1-1H- 1H), 7.26-7.30 (m, 1H), pyrazol 7.24 (s, 1H), 6.97 (t, J=52.0 y1)su1fony1) Hz, 1H), 4.17-4.41 (m, ?uoroethy1)-N- 2H), 4.02 (s, 3H), 2.92 (br. (2-?uoropy1idin— s., 2H), 2.42-2.63 (m, 1H), 4-y1)piperidine- 2.12-2.29 (m, 1H), 1.79- 1-carboxamide 1.92 (m, 1H), 1.37-1.68 (m, (R)(1-?uor0- 1H NMR (400 MHz, 1-((1-methyl-3 - CD3OD) 5 ppm 8.31 (d, (t??uoromethyl) J=7.21 Hz, 1H), 7.77 (s, -1H-pyrazol 2H), 7.42 (s, 1H), 4.25- y1)sulfony1)ethyl 4.42 (m, 2H), 4.18 (s, 3H), )-N-(2- 2.92-3.10 (m, 2H), 2.58- pyIidin 2.72 (In, 4H), 2.15-2.27 (m, yl)piperidine 1H), 1.87-2.00 (m, 1H), carboxamide 1.46-1.73 (m, 5H) 1H N1\/[R (400 MHz, (R)(1-((3 - CD3OD) 8 ppm 8.36 (s, (di?uoromethyl)- 1H), 8.31 (d, J=7.34 Hz, 1 -methyl- 1H- 1H), 7.73-7.80 (m, 2H), pyrazol 6.80-7.12 (t, J = 52.4 Hz, y1)sulf0nyl) 1H), 4.23-4.38 (m, 2H), ?uor0ethyl)-N- 4.02 (s, 3H), 2.91-3.05 (m, 2H), .67 (m, 4H), py?din—4- 2.19-2.30 (m, 1H), 1.85- y1)piperidine 1.95 (m, 1H), 1.43-1.67 (m, carboxamide 1H NMR (400 MHz, CDC13) 8 ppm 7.93 (s, 4-(1-?uoro—1- 1H),7.13-7.31(m,3H), ((3 - 7.08 (t, J = 8.41 Hz, 1H), ?uoropheny1)sulf 6.23 (s, 1H), 3.78 (t, J = onyl)ethy1)-N- 10.96 Hz, 2H), 2.81 (s, (isoxazol-3 - 3H), 2.40 (t, J = 13.11 Hz, y1)pipen'dine 2H), 1.91-2.13 (m, 1H), carboxamide 1.73 (d, J = 13.30 Hz,1H), 1.35 (d, J =13.30 Hz,1H), 0.87-1.16 (m, 3H) 1H N1V1R (400 MHZ, 4-(1-?uoro CD3OD) 8 ppm 8.73 (s, ((3 - 1H), 8.43 (s, 1H), 7.77 (s, ?uorophenyl)sulf 3H), 7.58 (s, 1H), 4.23 (t, onyl)ethyl)-N- J=12.13 Hz, 2H), 2.90 (t, (isoxazol J=12.91Hz,2H),2‘44-2.60 eridine (m, 1H), 2.23 (d, J=12.91 carboxamide Hz, 1H), 1.85 (d, J=12.91 Hz, 1H), 1.37-1.66 (m, 5H) 1H NMR (400 MHz, CDC13) 8 ppm 8.06 (d, J = .8 Hz, 1H), 7.76 (dd, J = 1.16, 7.89 Hz, 1H), 7.70 - 4-(1-?u0r0 7.59 (m, 2H), 7.47 (ddt, J = ((3 - 0.86, 2.57, 8.25 Hz, 1H), ?uoropheny1)$qu 7.33 (d, J = 15.16 Hz, 2H), ony1)ethy1)-N-(2- 7.19 (d, J = 5.62 Hz, 1H), ?uoropyn'din—4- 4.35 - 4.16 (m, 2H), 3.06 - y1)pipen'dine 2.93 (m, 2H), 2.60 - 2.72 carboxamide (m, 1H), 2.35 (d, J = 13.33 Hz, 1H), 1.99 (d, J = 13.20 Hz, 1H), 1.62 - 1.42 (m, 1H NMR (400 MHz, tert-butyl 4-(4- CDC13) 8 ppm 8.31 (s, (1-?uoro((3 - 1H), 7.78 (m, 1H), 7.71 (s, ?uoropheny1)5qu 1H), 7.69 (m, 2H), 7.49 (m, ony1)ethy1)piperi 1H), 6.33 (br s, 1H), 4.29 - dine 4.06 (m, 2H), 3.05 - 2.88 carboxamido)- (m, 2H), 2.54 (m, 1H), 2.27 azole (m, 1H), 2.02 (m, 1H), 1.72 carboxylate - 1.40 (m, 14H) 1H NMR (400 MHz, CDC13) 8 ppm 8.63 (s, 4-(1-?uoro 1H), 7.66 (d, J = 7.70 Hz, ((3 - 1H), 7.60 - 7.48 (m, 2H), ?uorophenyl)sulf 7.32-7.41 (m, 1H), 5.78 (s, onyl)ethy1)-N-(3- 1H), 3.94-4.18 (m, 2H), isoxazol- 2.81-2.99 (m, 2H), 2.47- 4-yl)piperidine- 2.61 (m, 1H), 2.16-2.30 (m, 1-carboxamide 3H), 1.80-2.08 (m, 2H), 1.34-1.52 (m, 5H) 4-(1-?u0r0 1H NMR (400 MHZ, ((3 - CD3OD) 8 ppm 8.19 (d, ?uorophe11yl)5qu J=1.47 Hz, 1H), 7.95-8.03 onyl)ethyl)—N—(6- (m, 1H), 7.67-7.84 (m, ?uoropyridin—3 - 3H), 7.56-7.66 (m, 1H), y1)piperidine 7.02 (dd, J=2.93, 8.80 Hz, amide 1H), 4.25-4.37 (m, 2H), 2.87-3.00 (m, 2H), 2.48- 2.61 (m, 1H), 2.22-2.31 (m, 1H), 1.83-1.93 (m, 1H), 1.46-1.65 (m, 5H) 1H NMR (400 MHz, 4-(1-((4- CDC13) 8 ppm 8.05 (br s, cyanophenyl)sulf 2H), 7.99 (d, J = 8.07 Hz, ony1) 2H), 7.84 (d, J = 8.19 Hz, ?uoroethyl)-N- 2H), 6.91 (d, J = 8.44 Hz, (6-?uoropyridin- 1H), 6.75 (br s, 1H), 4.09 3 -yl)piperidine- (m, 2H), 2.91 (m, 2H), 2.58 1-carboxamide (m, 1H), 2.24 (m, 1H), 1.88 (m, 1H), 1.34-1.55 (m, 5H) 1H NIVIR (400 MHz, CDC13) 8 ppm 8.25 (s, 4-( 1 -((3 - 1H), 8.09-8.22 (m, 3H), CN cyanophenyl)sulf 8.03 (d, J=7.58 Hz, 1H), 0nyl) 6,96 (d,J=8.31Hz, 1H), ?uor0ethyl)-N- 6.74 (s, 1H), 4.17-4.37 (m, (6-?u0ropyridin- 2H), 2.90-3.08 (m, 2H), 3 -y1)piperidine- 2.61-2.75 (m, 1H), 2.33 (d, 1-carb0xamide 8 Hz, 1H), 1.81-2.09 (m, 2H), 1.45-1.62 (m, 5H) 1H NMR (400 MHz, 4-(1-?uor0 CDC13) 8 ppm 7.97-8.08 ((4- (m, 4H), 7.81 (d, J=8.19 (tn'?uoromethyl) Hz, 2H), 6.89 (d, J=9.29 pheny1)su1fony1) Hz, 1H), 6.77 (br. s., 1H), ethyl)-N-(6- 4.06-4.26 (m, 2H), 2.83- ?uoropyridin—3- 2.99 (m, 2H), 2.51-2.65 (m, en'dine 1H), .31 (m, 1H), carboxamide 1.83-1.93 (m, 1H), 1.36- 1.53 (m, 5H) 1H NMR (400 MHz, 4-(1-?uoro—1- CDC13) 8 ppm 8.76 (br. s., ((4- 1H), 7.90-8.04 (m, 3H), (tIi?uoromethyl) 7.80 (d, J=7.95 Hz, 2H), pheny1)sulfony1) 7.64 (br. s., 1H), 7.58 (br. ethyl)-N-(2- s., 1H), 4.25-4.39 (m, 2H), ?uoropyridin—4- 2.84-3.00 (m, 2H), 2.52- y1)pipetidine 2.66 (m, 1H), 2.21-2.32 (m, carboxamide 1H), 1.84-1.94 (m, 1H), 1.36-1.52 (m, 5H) 1H NMR (400 MHz, 4-(1-?uoro CDC13) 8 ppm 8.04 (br. s., ((1-methyl-3 - 2H), 7.88 (s, 1H), 6.88 (d, (tri?uoromethyl) J=8.19 Hz, 1H), 6.69 (br. -1H-pyrazol ., 1H), 4.00-4.28 (m, 2H), y1)sulfonyl)ethyl 3.97 (s, 3H), 2.79-2.97 (m, )-N-(6- 2H), 2.51 (d,J=10151Hz, ?uoropyridin-3 - 1H), 2.21 (d, J=12.96 Hz, yl)piperidine 1H), 1.87 (d, J=11.98 Hz, amide 1H), 1.31-1.59 (m, 5H) 4-(1-?u0r0 1H NMR (400 MHz, ((1-methyl-3 - CDC13) 8 ppm 8.44 (br. s., (tn'?uoromethyl) 1H), 7.88-8.01 (m, 2H), -1H-pyrazol 7.45-7.63 (m, 2H), 4.35 (d, fony1)ethyl 8 Hz, 1H), 4.23 (d, - J=12.35 Hz, 1H), 3.97 (s, ?uoropyn‘din—4- 3H), 2.81-2.99 (m, 2H), y1)pipeIidine—1— 2.54 (br. s., 1H), 2.20 (d, carboxamide J=13.45 Hz, 1H), 1.89 (d, J=12.35 Hz, 1H), 1.32-1.58 (m, 5H) 1H NMR (400 MHz, CDC13) 8 ppm 8.60 (s, 4-(1-?uoro 1H), 8.55 (s, 1H), 8.15 (s, 1H), 7.92 (d, J=8.68 Hz, 1H), 6.97 (s, 1H), 6.82 (d, 3- J=8.80 Hz, 1H), 4.12-4.29 yl)sulfonyl)ethyl (In, 2H), 3.97 (s, 3H), 2.89 )-N-(isoxazol (q, 0 Hz, 2H), 2.46- yl)piperidine-l- 2.61 (In, 1H), 2.26 (d, carboxamide J=13.20 Hz, 1H), 1.87 (d, J=13.20 Hz, 1H), 1.29-1154 (m, 5H) 1H NMR (400 MHZ, 4-(1-?u0r0 CDC13) 5 ppm 9.14 (br. s., ((1-methyl-3 - 1H), 9.05 (br. s., 1H), 8.92 oromethyl) (d, J=8.56 Hz, 1H), 7.93 (s, -1H-pyrazol 1H), 7.42 (d, J=8.80 Hz, y1)su1f0nyl)ethyl 1H), .47 (In, 2H), )-N-(6- 3.96 (s, 3H), 2.75-2.94 (In, methylpyn’din—3 - 2H), 2.67 (s, 3H), 2.46- y1)pipeII'dine 2.59 (In, 1H), 2.10-2.21 (m, carboxamide 1H), 1.79-1.91 (m, 1H), 1.29-1.57 (m, 5H) (R)(1-((3 - 1H NMR (400 MHz, (di?uoIomethy1)- CDC13) 8 ppm 8.17 (s, 1 -methyl-1H- 1H), 7.82 (m, 3H), 6.75- pyrazol 7.06 (m, 1H), 4.61-5.07 (m, fony1)-1 - 2H), 3.97 (s, 3H), 2.87 thyl)-N- (m,3H), 2.21 (d, J=12.84 (oxazol Hz, 1H), 1.88 (d, J=12.35 y1)pipeIidine-1 - Hz, 1H), 1.32-1.58 (m, 5H) carboxamide 1H NMR (400 MHz, 4-(1-?uoro—1- DMSO-d6) 8 ppm 9.78 (s, ((1-methy1-3 - 1H), 8.67 (s, 1H), 7.75 (s, (tIi?uoromethyl) 1H), 6.77 (s, 1H), 4.29 - -1H-pyrazol 4.26 (m, 2H), 4.14 (s, 3H), y1)sulfony1)ethyl 2.87 - 2.81 (m, 2H), 1.99 - )-N-(isoxazol-3 - 1.96 (m, 1H), 1.75 - 1.60 y1)pipen'dine (m, 4H), 1.47 - 1.35 (m, carboxamide 1H N1V1R (400 MHz, DMSO-d6) 8 ppm 9.77 (s, 4-(1-?uoro 1H), 8.98 (s, 1H), 8.54 (d, J ((1-methyl-3 - = 8.8 Hz, 1H), 7.80 - 7.75 (tri?uoromethyl) (In, 2H), 4.37 - 4.34 (In, razol 2H), 4.15 (s, 3H), 2.95 - yl)sulf0nyl)ethyl 2.84 (m, 2H), 2.64 (s, 3H), )-N-(6- 2.58 - 2.50 (In, 1H), 2.07 - methylpyridin—3 - 2.00 (In, 1H), 1.77 - 1.74 y1)piperidine (In, 1H), 1.61 (d, J: 23.2 carboxamide Hz, 3H), 1.48 - 1.39 (In, 1H NMR (400 MHz, DMSO-d6) 8 ppm 9.41 (s, 4-(1-?uoro—1- 1H), 7.97 (d, J = 5.7 Hz, ((1-methy1-3 - 1H), 7.75 (s, 1H), 7.40 - (tri?uoromethyl) 7.38 (m, 1H), 7.31 (s, 1H), -1H-pyrazol 4.31 - 4.26 (m, 2H), 4.41 yl)sulfony1)ethyl (s, 3H), 2.92 - 2.82 (m, )-N-(2- 2H), 2.56 - 2.50 (m, 1H), ?uoropyridin 2.02 - 1.99 (m, 1H), 1.76 - y1)pipetidine 1.73 (m, 1H), 1.61 (d, J= amide 23.2 Hz, 3H), 1.47 - 1.39 (m, 2H) 1H N1V[R (400 MHz, 4-(1-?uoro DMSO-d6) 8 ppm 8.80 (s, ((1-methyl-3 - 1H), 8.26 (s, 1H), 8.04 - (tri?uoromethyl) 7.99 (m, 1H), 7.76 (s, 1H), -1H-pyrazol 7.09 - 7.06 (m, 1H), 4.27 - fonyl)ethyl 4.21 (m, 2H), 4.15 (s, 3H), )-N-(6- 2.91- 2.80 (m, 2H), 2.52 - ?uor0pyridin—3 - 2.50 (m, 1H), 2.02 - 1.99 y1)piperidine (m, 1H), 1.76 - 1.72 (m, carboxamide 1H), 1.62 (d, J = 23.1 Hz, 3H), 1.49 - 1.38 (m, 2H) 1H NMR (400 MHz, 4—(1-(<3- CD3OD) 8 ppm 9.77 (s, (di?uoromethyl)— 1H), 8.66 (s, 1H), 7.42 (s, 1 -methy1-1H- 1H), 7.12 (t, J = 54.1 Hz, pyrazol 1H), 6.77 (s, 1H), 4.29 - fony1)-1 - 4.23 (m, 2H), 4.10 (s, 3H), thy1)-N- 2.87 - 2.77 (m, 2H), 2.50 - (isoxazol 2.47 (m, 1H), 1.99 - 1.96 y1)pipen'dine (m, 1H), 1.72 - 1.69 (m, carboxamide 1H), 1.58 (d, J = 23.2 Hz, 3H), 1.49 - 1.35 (m, 2H) 1H NMR (400 MHz, 4-( 1 -((3 - CD3OD) 8 ppm 8.21 (s, (di?uor0methy1)- 1H), 8.02 - 7.97 (m, 1H), 1 -methy1-1H- 7.26 (s, 1H), 7.04 - 7.01 pyrazol—5— (m, 1H), 6.84 (t, J = 54.5 yl)sulfony1) Hz, 1H), 4.36 - 4.29 (m, ?uor0ethyl)-N- 2H), 4.16 (s, 3H), 2.98 - (6-?uoropyn'din- 2.92 (m, 2H), 2.63 - 2.61 3 -y1)piperidine- (m, 1H), 2.22 - 2.18 (m, 1-carboxamide 1H), 1.92 - 1.89 (m, 1H), 1.69 - 1.52 (m, 5H) 1H N1V1R (400 MHz, 4-( 1 -((3 - CD3OD) 8 ppm 8.03 (d, J (di?uoromethyl)- = 6.4 Hz, 1H), 7.48 - 7.41 1 -methyl- 1H- (m, 2H), 7.14 (s, 1H), 6.72 pyrazol-S- (t, J = 54.3 Hz, 1H), 4.27 - yl)sulfony1) 4.20 (m, 2H), 3.21 (s, 3H), ?uoroethy1)-N- 2.92 - 2.85 (m, 2H), 2.53 - (2-?u0ropyridin- 2.48 (m, 1H), 2.12 - 2.09 4-yl)piperidine- (m, 1H), 1.84 - 1.80 (m, 1-carb0xamide 1H), 1.57 - 1.42 (m, 5H) 1H NMR (400 MHz, 4-(1-((3- CD3OD) 8 ppm 9.02 (s, (di?uoromethy1)- 1H), 8.42 (d, J = 8.8 Hz, 1-methy1—1H- 1H), 7.82 (d, J = 8.8 Hz, pyrazol-S- 1H), 7.26 (s, 1H), 6.85 (t, J = 54.5 Hz, 1H), 4.41 \ y1)su1fony1) - 4.34 M NxN ?uoroethyl)-N- (m, 2H), 4.16 (s, 3H), 3.02 OVNO—AS \ | F (6- - 2.96 (m, 2H), 2.72 (s, @NH F methylpyridin 3H), 2.68 - 2.60 (m, 1H), N_ y1)pipetidine 2.23 - 2.20 (m, 1H), 1.95 - carboxamide 1.92 (m, 1H), 1.69 - 1.51 (m, 5H) 1H N1V[R (400 MHZ, (1-((3- CD3OD) 8 ppm 8.77 (s, (di?uoromethyl)- 1H), 8.60 (s, 1H), 8.20 (s, 1-methyl-1H- 1H), 7.98 - 7.94 (m, 1H), pyrazol 711 - 6.84 (m, 2H), 4.21 - f0nyl)—1- 4.13 (m, 2H), 3.93 (s, 3H), \ ?uoroethyl)-N- 2.80 - 2,70 (m, 2H), 2.43 - (6-?u0r0pyridin— 2,35 (m, 1H), 1.97 - 1.94 3-yl)piperidine- (1H), 1.66 - 1.63 (m, 1H), 1-carb0xamide 1.47 (d, J = 23.0 Hz, 3H), 1.39 - 1.26 (m, 2H) 1H NMR (400 MHz, (S)(1-((3- DMSO-d6) 8 ppm 9.01 (s, (di?uor0methyl)- 1H), 8.41 - 8.39 (m, 2H), 1 -methy1-1H- 7.82 - 7.80 (m, 2H), 6.98 (t, pyrazol J = 53.1 Hz, 1H), 4.39 - y1)su1fony1) 4.31 (m, 2H), 4.05 (s, 3H), thyl)-N- 3.00 - 2.94 (m, 2H), 2.72 (s, 3H), 2.57 - 2.56 (m, methylpyn'din—3 - 1H), 1.92 - 1.89 (m, 1H), y1)piperidine 1.65 - 1.61 (m, 1H), 1.59 - carboxamide 1.50 (m, 5H) 1H NMR (400 MHz, (R)(1-((3 - DMSO-d6) 8 ppm 8.26 (s, r0methy1)- 1H), 8.07 - 8.06 (m, 1H), 1 -methyl-1H- 7.89 - 7.84 (m, 1H), 7.00 - pyrazol—4— 6.74 (m, 2H), 4.23 - 4.17 y1)su1fony1) (m, 2H), 3.92 (s, 3H), 2.85 \ ?uoroethy1)-N- - 2.74 (m, 2H), 2.45 - 2.41 ropyn'din- (m, 1H), 2.12 - 1.93 (m, 3 -y1)piperidine- 1H), 1.78 - 1.75 (m, 1H), 1-carboxamide 1.53 - 1.36 (m, 5H) (R)(1-((3- 1H NMR (400 MHz, (di?uoromethyl)- CD3OD) 8 ppm 8.38 (s, 1-methyl-1H- 1H), 8.21 (s, 1H), 8.02 - pyrazol 7.97 (m, 2H), 7.12 - 6.86 yl)sulfonyl) (m, 2H), 4.34 - 4.26 (m, ?uoroethyl)-N- 2H), 4.04 (s, 3H), 2.97 - (6- 2.90 (m, 2H), 2.55 - 2.52 methylpyridin (m, 1H), 2,24 - 2.20 (m, yl)piperidine-l- 1H), 1,90 - 1.87 (m, 1H), carboxamide 1.65 - 1.46 (m, 5H) (R)(1-((3- 1H NMR (400 MHz, (di?uoromethyl)— CD3OD) 8 ppm 8.63 (d, J 1-methyl-1H- = 2.4 Hz, 1H), 8.26 (s, 1H), pyrazol 8.02 - 7.99 (m, 1H), 7.61 y1)su1fony1) (d, J = 8.64 Hz, 1H), 6.87 ?uoroeth 1)-N- (t, J = 53.1 Hz, 1H), 4.26 - 4.21 (m, 2H), 3.92 (s, 3H), (tri?uoromethyl) 2.87 - 2.80 (m, 2H), 2.46 - n—3 - 2.41 (m, 1H), 2.13 - 2.10 y1)piperidine—1— (m, 1H), 1.79 - 1.76 (m, carboxamide 1H), 1.53 - 1.38 (m, 5H) lH-NMR (300 MHZ, 4-(1-?uoro DMSO-d6) 8 ppm 9.28 - 9.20 (m, 3H), 8.88 (m, 1H), (tIi?uoromethyl) 8.62 (m, 1H), 8.29 (m, 1H), pytidin-3 - 7.75 (m, 1H), 4.23 (m, 2H), y1)sulfony1)ethyl 2.90 (m, 2H), 2.50 (m, 1H), )-N-(pyridazin 2.11 (m, 1H), 1.76 (m, 1H), yl)pipetidine 1.64 (d, J = 23.1 HZ, 3H), carboxamide 1.54 - 1.43 (m, 2H) 1H NIVIR (400 MHZ, CD3OD) 8 ppm 9.23 (d, J 4-( 1 -((2- = 2.0 Hz, 1H), 8.86 (d, J = chlor0phenyl)sul 60 Hz, 1H), 8.10 (d, J = f011y l) 1.2 Hz, 1H), 7.86 (m, 1H), ?uor0ethyl)-N— 7.71 - 7.69 (m, 2H), 7.62 - aZin 7.57 (m, 2H), 4.32 (m, 2H), y1)piperidine 2.95 (m, 2H), 2.62 (m, 1H), carboxamide 2.28 (m, 1H), 1.92 (m, 1H), 1.63 - 1.50 (m, 5H) 1H NMR (400 MHZ, DMSO-d6) 8 ppm 9.27 (d, 4—(1-<<3- J = 2 HZ, 1H), 9.20 (s, 1H), chloropheny1)su1 8.87 (d, J = 6 HZ, 1H), 7.97 f0my1) (d, J = 0.8HZ, 1H), 7.89 ?uoroethy1)-N- (m, 2H), 7.77 (m, 2H), 4.24 (pyridaZin (d, J = 13.2 HZ, 2H), 2.87 y1)piperidine-l- (m, 2H), 2.43 (m, 1H), 2.07 carboxamide (m, 1H), 1.73 (m, 1H), 1.53 (d, J = 21 Hz, 3H), 1.41 (m, 1H NMR (2300 MHZ, 6) 8 ppm 9.22 (d, 4-(1-((3 - J = 2.7 Hz, 1H), 9.16 (br. cyanophenyl)su]f s., 1H), 8.82 (d, J = 6.0 Hz, ony1) 1H), 8.32 - 8.28 (m, 2H), ?uoroethyl)-N- 8.18 (m, 1H), 7.89 (m, 1H), (pyIidaZin 7.70 (m, 1H), 4.23 (m, 2H), y1)piperidine 2.83 (m, 2H), 2.45 (m, 1H), carboxamide 2.03 (m, 1H), 1.69 (m, 1H), 1.47 - 1.32 (m, 5H) 1H-N1V[R (400 MHZ, 4-(1-?uoro 6) 6 ppm 9.28 (m, ((4- 1H), 9.19 (br s, 1H), 8.88 (tri?uoromethyl) (m, 1H), 8.15 - 8.10 (m, phenyl)sulfonyl) 4H), 7.76 (M, 1H), 4.26 ethy1)-N- (m, 2H), 2,91 - 2.83 (m, (pyridazin—4— 2H), 2,47 (m, 1H), 2.10 (m, yl)piperidine 1H), 1.74 (m, 1H), 1.58 (d, carboxamide J = 23.2 Hz, 3H), 1.49 (m, lH-NMR (400 MHZ, 4-(1-?uoro—1- DMSO-d6) 8 ppm 10.96 (( 1 -methy1-1H- (br s, 1H), 8.54 (s, 1H), pyrazol—S— 7.78 (d, J = 2.4 Hz, 1H), y1)su1fony1)ethy1 7.12 (d, J = 2.4 Hz, 1H), )-N-( 1,2,3 - 4.23 (m, 2H), 4.08 (s, 3H), azol-S- 2.93 (m, 2H), 2.49 (m, 1H), eHdine 2.06 (m, 1H), 1.77 (m, 1H), carboxamide 1.61 (d, J = 23.2 Hz, 3H), 1.54 - 1.46 (m, 2H) 4-(1-?uoro 1H-NMR (400 MHZ, ((4- DMSO-d6) 8 ppm 10.97 (tri?uoromethyl) (br s, 1H), 8.54 (s, 1H), F phenyl)sulfonyl) 8.13 (m, 4H), 4.25 (m, 2H), ethyl)-N-( 1,2,3 - 2.94 (m, 2H), 2.44 (m, 1H), thiadiazol-S- 2.09 (m, 1H), 1.75 (m, 1H), yl)piperidine 1.58 (d, J = 22.8 HZ, 3H), carboxamide 1.50 - 1.41 (m, 2H) lH-NMR (300 MHZ, DMSO-d6) 5 ppm 9.27 (m, 4-(1-((1-ethyl- 2H), 8.89 (d, J = 6.0 Hz, 1H-pyrazol 1H), 7.82 (d, J = 1.5 Hz, yl)su1f0nyl)— 1- 1H), 7.76 (m, 1H), 7.10 (d, ?uor0ethyl)-N- J = 1.5 Hz, 1H), 4.43 (m, (pyIidaZin 2H), 4.27 (m, 2H), 2.90 (m, y1)pipen'dine 2H), 2.46 (m, 1H), 2.05 (m, carboxamide 1H), 1.76 (m, 1H), 1.63 (d, J = 23.1 HZ, 3H), 1.39 - 1.17 (m, 5H) lH-NMR (400 MHZ, 4-(1-((4- CD3OD) 8 ppm 9.25 (d, J cyanopheny1)su1f = 2.4 Hz, 1H), 8.88 (m, ony1) 1H), 8.14 (m, 2H), 8.08 (m, ?uoroethy1)-N- 2H), 7.88 (m, 1H), 4.33 (m, (pyIidaZin-4— 2H), 2.94 (m, 2H), 2.59 (m, y1)piperidine 1H), 2.29 (m, 1H), 1.90 (m, carboxamide 1H), 1.62 - 1.57 (m, 5H) lH-NMR (400 MHZ, DMSO-d6) 5 ppm 9.28 (d, 4-(1-?uor0 J = 2.4 Hz, 1H), 9.20 (s, thy1-1H- 1H), 8.88 (d, J = 6.0 Hz, pyrazol-S- 1H), 7.77 (m, 2H), 7.12 (d, y1)su1fonyl)ethyl J = 2.4 Hz, 1H), 4.27 (m, yridazin 2H), 4.07 (s, 3H), 2.86 (m, y1)piperidine 2H), 2.46 (m, 1H), 2.05 (m, carboxamide 1H), 1.79 (m, 1H), 1.62 (d, J = 23.2 HZ, 3H), 1.53 - 1.46 (In, 2H) 1H-NMR (400 MHZ, CD3OD) 8 ppm 9.25 (d, J 4-(1-?uoro = 2.4 Hz, 1H), 8.88 (m, ((1-methyl-1H- 1H), 7.96 (d, J = 1.2 HZ, imidazol 1H), 7.88 (m, 2H), 4.36 (m, yl)sulf0nyl)ethyl 2H), 3.86 (s, 3H), 2.94 (m, )-N-(pyridaZin 2H), 2.54 (m, 1H), 2.32 (m, y1)piperidine 1H), 1.90 (m, 1H), 1.69 (d, carboxamide J = 22.4 HZ, 3H), 1.56 - 1.48 (m, 2H) 1H-NMR (400 MHZ, 6) 8 ppm 9.26 (d, 4-(1-?uoro—1- J = 2.0 Hz, 1H), 9.19 (br s, ((2 - 1H), 8.85 (m, 1H), 7.81 - methoxypheny1)s 7.74 (m, 3H), 7.34 (d, J = ulfonyl)ethyl)-N- 10.8 Hz, 1H), 7.17 (m, 1H), (pyIidaZin 4.27 (m, 2H), 3.90 (s, 3H), y1)pipen'dine- l - 2.85 (m, 2H), 2.38 (m, 1H), carboxamide 2.10 (m, 1H), 1.73 (m, 1H), 1.49 (d, J = 23.2 Hz, 3H), 1.42 - 1.34 (m, 2H) [R (400 MHZ, DMSO-d6) 8 ppm 10.93 4-( 1 -((4- (br s, 1H), 8.54 (s, 1H), cyanophenyl)sulf 8.22 (d, J = 8.4 Hz, 2H), onyl) 8.10 (d, J = 8.4 Hz, 2H), ?uoroethy1)-N- 4.24 (m, 2H), 2.92 (m, 2H), (1,2,3-thiadiazol- 2.44 (m, 1H), 2.10 (m, 1H), -yl)piperidine- 1.73 (m, 1H), 1.57 (d, J = 1-carb0xamide 22.8 Hz, 3H), 1.49 - 1.36 (m, 2H) 1H-NMR (400 MHZ, 4-( 1-((3 ,5 - DMSO-d6) 5 ppm 9.28 (d, di?uorophenyl)s J = 2.0 Hz, 1H), 8.87 (m, ulfomy1) 1H), 7.90 (m, 1H), 7.77 (m, ?uor0ethyl)-N- 1H), 7.67 (m, 2H), 4.27 (m, (pyn'daZin 2H), 2.90 (m, 2H), 2.47 (m, y1)pipen'dine 1H), 2.08 (m, 1H), 1.75 (m, amide 1H), 1.61 (d, J = 22.8 Hz, 3H), 1.49 - 1.40 (m, 2H) 1H-NMR (400 MHZ, 4-( 1 -((3 - CD3OD) 8 ppm 9.23 (d, J (di?uor0methy1)- = 2.0 Hz, 1H), 8.86 (d, J = 1 -methy1-1H- 6.4 Hz, 1H), 8.36 (s, 1H), pyrazol 7.85 (m, 1H), 6.97 (t, J = y1)su1fony1) 53.2 Hz, 1H), 4.31 (m, 2H), ?uor0ethyl)-N- 4.02 (s, 3H), 2.94 (m, 2H), (pyIidaZin—4- 2.56 (m, 1H), 2.23 (m, 1H), y1)pipeIidine- l - 1.90 (m, 1H), 1.63 - 1.53 carboxamide (m, 5H) 1H-NMR (400 MHZ, 4-( l -?uoro- l - CD3OD) 5 ppm 9.20 (d, J (( l -methyl-3 - = 2.0 Hz, 1H), 8.84 (d, J = (tIi?uor0methyl) 8.0 Hz, 1H), 7.84 (m, 1H), - lH-pyrazol-S- 7.39 (s, 1H), 4.34 (m, 2H), y1)sulfonyl)ethyl 3.91 (s, 3H), 2.99 (m, 2H), )-N-(pyridazin 2.62 (m, 1H), 2.19 (m, 1H), yl)pipetidine 1.91 (m, 1H), 1.67 - 1.45 amide (m, 5H) lH-NMR (400 MHZ, (R)(1-?uor0- CD3OD) 8 ppm 9.23 (d, J 1-((3 - = 2 Hz, 1H), 8.86 (d, J = 6 ?uorophenyl)sulf Hz, 1H), 7.87 (m, 1H), 7.79 0nyl)ethyl)—N- - 7.66 (m, 3H), 7.60 (m, (pyridaZin 1H), 4.33 (m, 2H), 2.94 (m, y1)piperidine 2H), 2.52 (m, 1H), 2.27 (m, carboxamide 1H), 1.89 (m, 1H), 1.59 - 1.49 (m, 5H) 1H-NMR (400 MHz, (S)(1-?uoro- CD3OD) 8 ppm 9.23 (d, J 1-((3 - = 2 Hz, 1H), 8.86 (d, J = 6 ?uoropheny1)5qu Hz, 1H), 7.87 (m, 1H), 7.79 ony1)ethy1)-N- - 7.66 (m, 3H), 7.60 (m, (pyridazin 1H), 4.33 (m, 2H), 2.94 (m, y1)pipen'dine 2H), 2.52 (m, 1H), 2.27 (m, carboxamide 1H), 1.89 (m, 1H), 1.59 - 1.49 (m, 5H) lH-NMR (400 MHz, CD3OD) 8 ppm 8.45 (d, J 4-(1-?uoro = 1.6 Hz, 1H), 7.68 (d, J = ((1-methyl-1H- 2.0 Hz, 1H), 7.03 (d, J = pyrazol-S- 2.0 Hz, 1H), 6.75 (d, J = yl)sulfonyl)ethyl 1.4 Hz, 1H), 4.31 (m, 2H), soxazol-3 - 4.12 (s, 3H), 2.93 (m, 2H), yl)piperidine 2.56 (m, 1H), 2.22 (m, 1H), carboxamide 1.95 (m, 1H), 1.67 (d, J = 22.8 Hz, 3H), 1.58 (m, 2H) 1H-NMR (400 MHZ, 4-(1-?u0r0 CD3OD) 5 ppm 9.23 (d, J ((1-methyl-3 - = 2.0 Hz, 1H), 8.86 (d, J = (tn'?uoromethyl) 6.0 Hz, 1H), 8.43 (s, 1H), -1H-pyrazol 7.86 (m, 1H), 4.31 (m, 2H), f0ny1)ethyl 3.91 (s, 3H), 2.95 (m, 2H), )-N-(pyn'dazin—4— 2.57 (m, 1H), 2.22 (m, 1H), y1)pipen'dine 1.91 (m, 1H), 1.63 - 1.55 carboxamide (m, 5H) 1H-NMR (300 MHz, DMSO-d6) 8 ppm 9.69 (s, 4-(1-((3 - 1H), 8.61 (d, J = 1.8 Hz, cyanopheny1)su1f 1H), 8.31 - 8.28 (m, 2H), ony1) 8.18 - 8.15 (m, 1H), 7.92 - ?uoroethy1)-N- 7.86 (m, 1H), 6.73 (s, 1H), (isoxazol 4.22 - 4.18 (m, 1H), 2.80 - y1)piperidine 2.72 (m, 2H), 2.46 - 2.45 carboxamide (m, 1H), 2.03 - 1.97 (m, 1H), 1.61 - 1.54 (m, 1H), 1.40 - 1.32 (m, 5H) lH-NMR (400 MHz, DMSO-d6) 8 ppm 9.74 (s, 4-( 1 -((4- 1H), 8.66 (d, J = 1.8 Hz, cyanophenyl)sulf 1H), 8.22 (d, J = 8.4 Hz, onyl) 2H), 8.10 (d, J = 8.1 Hz, ?uoroethy1)-N- 2H), 6.77 (d, J = 1.5 Hz, (isoxazol-3 - 1H), 4.30 (m, 2H), 2.79 (m, yl)pipetidine 2H), 2.50 (m, 1H), 2.19 (m, amide 1H), 1.63 (In, 1H), 1.58 (d, J = 22.8 Hz, 3H), 1.47 (m, 1H-NMR (400 MHZ, DMSO-d6) 8 ppm 9.74 (s, (R)(1-?u0r0- 1H), 8.66 (d, J = 2.0 Hz, 1-((3 - 1H), 7.83 - 7.70 (m, 4H), henyl)sulf 6.77 (d, J = 1.6 Hz, 1H), 0ny1)ethyl)—N- 4.25 (m, 2H), 2.78 (m, 2H), (isoxazol-3 - 2.40 (m, 1H), 2.05 (m, 1H), y1)piperidine 1.69 (m, 1H), 1.56 (d, J = carboxamide 22.8 Hz, 3H), 1.45 - 1.34 (m, 2H) 1H-NMR (400 MHz, DMSO-d6) 8 ppm 9.74 (s, (1-?uoro- 1H), 8.66 (d, J = 2.0 Hz, 1-((3 - 1H), 7.83 - 7.70 (m, 4H), ?uoropheny1)5qu 6.77 (d, J = 1.6 Hz, 1H), ony1)ethy1)-N- 4.25 (m, 2H), 2.78 (m, 2H), (isoxazol-3 - 2.40 (m, 1H), 2.05 (m, 1H), y1)pipetidine 1.69 (m, 1H), 1.56 (d, J= carboxamide 22.8 Hz, 3H), 1.45 - 1.34 (m, 2H) lH-NMR (400 MHz, (R)(1-?uor0- DMSO-d6) 8 ppm 8.65 (s, 1-((3- 1H), 8.52 (d, J = 2.4 Hz, ?uorophenyl)sulf 1H), 7.86 - 7.71 (m, 5H), onyl)ethyl)-N-(6- 7.30 (m, 1H), 5.26 (m, 1H), (hydroxymethyl) 4.48 (m, 2H), 4.25 (m, 2H), pyridin 2.84 (m, 2H), 2.49 (m, 1H), yl)piperidine-l- 2.07 (m, 1H), 1.68 (m, 1H), carboxamide 1.52 (d, J = 22.8 Hz, 3H), 1.14 - 1.02 (m, 2H) 1H-NMR (400 MHz, DMSO-d6) 5 ppm 8.95 (s, (R)(1-?u0r0- 1H), 8.19 (d, J = 5.6 Hz, 1-((3- 1H), 7.82 - 7.71 (m, 4H), F heny1)sulf 7.56 (d, J = 2.0 Hz, 1H), ony1)ethy1)-N-(2- 7.39 (m, 1H), 5.32 (m, 1H), (hydroxymethyl) ' 4.45 (d, J = 6.0 Hz, 2H), pyn'din—4- 4.26 (m, 2H), 2.81 (m, 2H), y1)pipen'dine 2.46 (m, 1H), 2.07 (m, 1H), amide 1.71 (m, 1H), 1.57 (d, J = 23.0 Hz, 3H), 1.47 - 1.35 (m, 2H) 1H NMR (400 MHz, DMSO-d6) 8 ppm 9.24 (s, 1H), 8.92 (d, J=2.45 Hz, (R)(1-((3 - 1H), 8.59 (s, 1H), 8.32- (di?uor0methy1)- 8.38 (m, 1H), 8.22-8.29 (m, 1 -methy1-1H- 1H), 7.72 (dd, , 8.62 pyrazol—4— Hz, 1H), 6.98 (t, J=52.00 y1)su1fony1) Hz, 1H), 4.12-4.27 (m, ?uor0ethyl)-N- 2H), 2.74-2.94 (m, 2H), in-3 - 2.47 (s, 3H), 2.33-2.41 (m, y1)pipen'dine 1H), 1.91-2.04 (m, 1H), carboxamide 1.64-1.74 (m, 1H), 1.50 (d, J=23.00 Hz, 3H), 1.25-1.45 (m, 2H) 1H NNIR (400 MHz, (R)(1-((3- DMSO-d6) 5 ppm 8.59 (s, (di?uoromethyl)- 1H), 8.47 (s, 1H), 7.51 (s, 1-methyl-1H- 2H), 6.97 (t, J=52.00 Hz, l 1H), 4.04-4.18 (m, 23H), yl)sulfonyl) 3.93 (s, 3H), 2.59-2.76 (m, ?uoroethyl)-N- 2H), 2.23-2.39 (m, 1H), (1H-pyrazol 1.87-1.98 (m, 1H), 1.57- y1)piperidine 1.66 (m, 1H), 1.49 (d, carboxamide J=23.00 Hz, 3H), 1.18-1.39 (m, 2H) 1H NMR (400 MHz, (R)(1-((3 - DMSO-d6) 8 ppm 8.59 (s, (di?uor0methy1)- 1H), 8.47 (s, 1H), 7.51 (s, 1 -methy1-1H- 2H), 6.97 (t, J=52.00 Hz, pyrazol—4— 1H), .18 (m, 23H), yl)sulfony1) 3.93 (s, 3H), 2.59-2.76 (m, ?uor0ethyl)-N- 2H), 2.23-2.39 (m, 1H), (1H-pyrazol-3 - 1.87-1.98 (m, 1H),1.57- y1)piperidine 1.66 (m, 1H), 1.49 (d, carboxamide J=23.00 Hz, 3H), 1.18-1.39 (m, 2H) 1H N1V[R (400 MHZ, DMSO-d6) 8 ppm 9.24 (s, 1H), 8.81 (d, J=2.45 Hz, cyanopyn’din 1H), 8.11 (dd, J=2.57, 8.68 yl)(1-?uor0- Hz, 1H), 7.89 (d, J=8.68 1-((3 - Hz, 1H), 7.68-7.85 (m, ?uorophenyl)sulf 4H), .31 (m, 2H), 0nyl)ethyl)piperi 2.79-2.95 (m, 2H), 2.38- dine 2.48 (m, 1H), 2.03-2.13 (m, amide 1H), 1.68-1.77 (m, 1H), 1.34-1.62 (m, 5H) 1H NMR (400 MHz, 6) 5 ppm 9.24 (s, (R)-N-(6- 1H), 8.81 (d, J=2.45 Hz, cyanopy?din—3- 1H), 8.11 (dd, J=2.57, 8.68 y1)( 1 -?u0r0— Hz, 1H), 7.89 (d, J=8.68 1-((3 - Hz, 1H), 7.69-7.85 (m, ?uoropheny1)sulf 4H), 4.19-4.32 (m, 2H), ony1)ethy1)pipen' 2.79-2.94 (m, 2H), 2.37- dine 2.49 (m, 1H), 2.03-2.14 (m, carboxamide 1H), 1.67-1.77 (m, 1H), 1.35-1.62 (m, 5H) 1H NMR (400 MHz, (R)-N-(2- DMSO-d6) 8 ppm 9.38 (s, cyanopyridin—4- 1H), 8.47 (d, J=5.75 Hz, yl)(1-?uoro- 1H), 8.05 (d, J=2.08 Hz, 1-((3 - 1H), 7.68-7.86 (m, 5H), ?uoropheny1)sulf 4.18-4.30 (m, 3H), 2.80- ony1)ethy1)piperi 2.94 (m, 2H), .48 (m, dine 1H), 2.04-2.14 (m, 1H), carboxamide 1.67-1.78 (m, 1H), 1.34- 1.62 (m, 5H) 1H NMR (400 MHz, 6) 8 ppm 9.37 (s, (R)-N-(2- 1H), 8.67 (s, 1H), 8.47 (d, cyanopyIidin J=5.75 Hz, 1H), 8.06 (d, yl)(1-<<3 - J=2.20 Hz, 1H), 7.72 (dd, (di?uoromethyl)- J=2.20, 5.75 Hz, 1H), 7.05 1 -methyl- 1H- (t, J=52.00 Hz, 1H), 4.16- pyrazol 4.33 (m, 2H), 4.00 (s, 3H), yl)sulfonyl) 2.79-2.96 (m, 2H), 2.39- ?uoroethyl)piper 2.49 (m, 1H), 2.00-2.10 (m, idine 1H), 1.69-1.79 (m, 1H), carboxamide 1.57 (d, J=23.00 Hz, 3H), 1.32-1.52 (m, 2H) 1H NMR (400 MHz, DMSO-d6) 8 ppm 9.20 (s, 4-(1-?uoro—1- 1H), 8.80 (d, J=2.45 Hz, ((3 - 1H), 8.20 (dd, J=2.45, 8.80 ?uoropheny1)5qu Hz, 1H), 7.56-7.81 (m, ony1)ethy1)-N-(6- 4H), .24 (m, 2H), methylpyn'din-3 - 2.72-2.90 (m, 3H), 2.30- y1)pipetidine 2.49 (m, 4H), 1.95-2.06 (m, carboxamide 1H), 1.62-1.75 (m, 1H), .56 (m, 5H) 1H N1V1R (400 MHZ, (R)(1-?uor0- CD3CN) 8 ppm 7.97 (d, 1-((1-methyl-3 - J=5.99 Hz, 1H), 7.82 (br. (tri?uoromethyl) ., 1H), 7.39 (s, 1H), 7.26 razol (s, 2H), 4.20-4.31 (m, 2H), yl)sulf0nyl)ethyl 4.17 (s, 3H), 2.82-3.00 (m, )-N-(2- 2H), 2.47-2.63 (m, 1H), ?uoropyridin 2.06-2.18 (m, 1H), 1.79- yl)piperidine 1.90 (m, 1H), .73 (m, carboxamide 1H NMR (400 MHz, CD3OD) 5 ppm 8.38 (s, (R)(1-((3- 1H), 7.96 (d, J=5.87 Hz, (di?uoromethyl)— 1H), 7.30 (td, J=1.60, 5.84 1-methy1—1H- Hz, 1H), 7.26 (d, J=1.83 pyrazol Hz, 1H), 6.99 (t, J=52.00 yl)sulfony1) Hz, 1H), 4.24-4.39 (m, ?uoroethy1)-N- 2H), 4.05 (s, 3H), 2.95 (dt, (2-?uoropyn'din- J=2.57, 13.08 Hz, 2H), 4-y1)pipen'dine- 2.49-2.63 (m, 1H), 2.18- 1-carboxamide 2.29 (m, 1H), 1.84-1.94 (m, 1H), .69 (m, 5H) 1H NMR (400 MHz, (S)(1-((3- CD3CN) 8 ppm 8.63 (br. (di?uor0methy1)- s., 1H), 8.23 (d, J=6.85 Hz, 1 -methyl-1H- 1H), 8.16 (s, 1H), 7.78 (s, pyrazol-4— 1H), 7.71 (d, J=6.97 Hz, yl)sulfony1) 1H), 7.02 (t, J=52.00 Hz, ?uor0ethyl)-N- 1H), 4.18-4.33 (m, 2H), (2- 4.00 (s, 3H), 2.87-3.04 (m, methy1py1idin 2H), 2.62 (s, 3H), 2.46- y1)pipen'dine 2.58 (m, 1H), 2.11-2.22 (m, carboxamide 1H), 1.80-1.91 (m, 1H), 1.41-1.66 (m, 5H) 1H N1V1R (400 MHZ, (R)-N-(6- CD3OD) 8 ppm 9.03-9.09 cyanopyIidin-3 - (In, 1H), 8.71-8.77 (m, yl)(1-<<3 - 1H), 8.38 (s, 1H), 8.10 (dd, (di?uoromethyl)- J=2.57, 8.68 Hz, 1H), 7.78 1 -methyl- 1H- (d, J=8.68 Hz, 1H), 6.99 (t, pyrazol J=52.00 Hz, 1H), 4.24-4.40 yl)sulf0ny1) (m, 2H), 4.05 (s, 3H), 2.96 ?uoroethyl)piper (dt, J=2.57, 13.08 Hz, 2H), idine 2.51-2.64 (m, 1H), 2.20- amide 2.29 (m, 1H), 1.84-1.95 (m, 1H), 1.44-1.68 (m, 5H) 1H NMR (400 MHz, (R)(4-(1-((3- METHANOL-d4) 8 ppm (di?uoromethy1)- 8.70 (t, J=1.47 Hz, 1H), y1—1H- 8.27 (s, 1H), 7.99 (d, pyrazol—4— J=1.47 Hz, 2H), 6.88 (t, yl)sulfony1) J=52.00 Hz, 1H), 4.14-4.30 ?uoroethy1)piper (m, 2H), 3.93 (s, 3H), 2.85 idine (dt, J=2.38, 13.05 Hz, 2H), carboxamido)pic 2.39-2.52 (m, 1H), 2.07- olinamide 2.18 (m, 1H), 1.74-1.84 (m, 1H), .57 (m, 5H) 1H N1V[R (400 MHz, (R)(1-?uor0- DMSO-d6) 8 ppm 9.03 (s, 1-((3 - 1H), 8.69 - 8.66 (m, 2H), ?uorophenyl)sulf 8.19 - 8.19 (m, 1H), 7.80 - ony1)ethy1)-N-(7- 7.71 (m, 4H), 4.32 - 4.25 0x0-6,7-dihydr0- (m, 4H), 2.85 - 2.83 (m, 5H-pyrrolo [3 ,4- 2H), 2.50 - 2.49 (m, 1H), b]pyridin-3 - 2.07 - 2.02 (m, 1H), 1.70 - eridine 1.166 (m, 1H), 1.58 - 1.44 carboxamide (m, 5H) 1H NMR (400 MHz, DMSO-d6) 8 ppm 8.95 (s, 4-((R)?u0r0- 1H), 8.19 - 8.18 (m, 1H), 1-((3 - 7.83 - 7.71 (m, 4H), 7.58 ?uoropheny1)sulf (s, 1H), 7.41 - 7.40 (m, onyl)ethy1)—N—(2- 1H), 5.27 - 526 (m, 1H), ((S) 4.65 - 4.59 (m, 1H), 4.26 - hydroxyethyl)pyr 4.23 (m, 2H), 2.84 - 2.77 idin (m, 2H), 2.43 - 2.38 (m, y1)pipen'dine 1H), 2.07 - 2.04 (m, 1H), carboxamide 1.71 - 1.68 (m, 1H), 1.57 - 1.41 (m, 8H) 1H NMR (400 MHz, DMSO-d6) 8 ppm 8.95 (s, 4-((R)?uoro- 1H), 8.19 - 8.18 (m, 1H), 1-((3 - 7.80 - 7.71 (m, 4H), 7.58 ?uoropheny1)5qu ,7.41- 7.39 (m, ony1)ethy1)-N-(2- 1H), 5.27 - 5.26 (m, 1H), ((R) 4.63 - 4.61 (m, 1H), 4.26 - hydroxyethyl)pyr 4.23 (m, 2H), 2.81 - 2.79 idin (m, 2H), 2.50 - 2.49 (m, y1)pipen'dine 1H), 2.07 - 2.04 (m, 1H), carboxamide 1.71 - 1.68 (m, 1H), 1.52 - 1.23 (m, 8H) 1H N1V[R (400 MHz, ((3 - CD3OD) 8 ppm 8.33 (s, (di?uoromethyl)- 1H), 8.18 (d, J = 5.8 Hz, 1 -methyl- 1H- 1H), 7.59 (d, J = 2.2 Hz, pyrazol 1H), 7.38 (dd, J = 5.8, 22 yl)sulfony1) Hz, 1H), 6.94 (t, J = 53.1 ?uoroethy1)-N- Hz, 1H), 4,76 (m, 1H), 4.27 (2-((R) (t, J = 14.0 Hz, 2H), 4.00 hydroxyethyl)pyr (s, 3H), 3.00 — 2.80 (m, idin—4- 2H), 2.52 (s, 1H), 2.18 (d, J y1)piperidine = 13.4 Hz, 1H), 1.84 (d, J = carboxamide 13.1 Hz, 1H), 1.65 — 1.36 (m, 8H).

(S)(1-((3- 1H NMR (400 MHz, (di?uor0methy1)- CD3OD) 8 ppm 8.33 (s, 1-(methy1-d3)- 1H), 8.25 (s, 1H), 6.87 (t, J 1H-pyrazol—4— = 53.1 Hz, 1H), 6.63 (s, yl)sulfony1) 1H), 4.21 - 4.17 (m, 2H), ?uoroethyl- 2.84 - 2.77 (m, 2H), 2.47 - 2,2,2-d3)-N- 2.37 (m, 1H), 2.11 - 2.07 (isoxazol-3 - (m, 1H), 1.77 - 1.73 (m, y1)piperidine 1H), 1.77 - 1.31 (m, 2H) carboxamide (R)(1-((3 - 1H NMR (400 MHz, (di?uoromethyh- CD3OD) 8 ppm 8.33 (s, 1 -(methy1-d3 )- 1H), 8.25 (s, 1H), 6.87 (t, J 1H-pyrazol = 53.1 Hz, 1H), 6.63 (s, yl)sulfony1) 1H), 4.21 - 4.17 (m, 2H), ?uoroethyl- 2.84 - 2.77 (m, 2H), 2.47 - 2,2,2-d3)-N- 2.37 (m, 1H), 2.11 - 2.07 (isoxazol-3 - (m, 1H), 1.77 - 1.73 (m, yl)piperidine 1H), 1.77 - 1.31 (m, 2H) carboxamide 1H NMR (300 MHz, 6) 8 ppm 9.73 (br (S)(1-?u0r0- s, 1H), 8.65 (s, 2H), 8.11 - 1-((6- 8.09 (m, 1H), 7.12 (d, J = 8.8 Hz, 1H), 6.77 (d, J = 3 _ 1.6 Hz, 1H), 4.26 - 4.24 yl)sulfony1)ethy1 (m, 2H), 3.99 (s, 3H), 2.83 )-N-(isoxazol - 2.75 (m, 2H), 2.41 - 2.40 y1)pipen'dine (m, 1H), 2.07 - 2.02 (m, amide 1H), 1.69 - 1.65 (m, 1H), 1.56 (d, J = 22.8 Hz, 3H), 1.42 - 1.35 (m, 2H) 1H NMR (300 MHz, 6) 8 ppm 9.71 (br (R)( 1 -?uor0- s, 1H), 8.63 (s, 2H), 8.10 ((6- 8.07 (m, 1H), 7.10 (d, J = 8.7 Hz, 1H), 6.75 - 6.74 / ypyridin— 3 _ (m, 1H), 4.25 - 4.20 (m, yl)sulfony1)ethy1 2H), 3.97 (s, 3H), 2.87 - )-N-(isoxazol-3 - 2.73 (m, 2H), 2.48 - 2.37 y1)pipen'dine (m, 1H), 2.05 - 2.00 (m, carboxamide 1H), 1.67 - 1.63 (m, 1H), 1.55 (d, J = 23.0 Hz, 3H), 1.44 - 1.27 (m, 2H) 1H NMR (400 MHZ, (S)(1-?uor0- DMSO-d6) 8 ppm 9.73 (s, 1 -((6- 1H), 9.24 - 9.21 (In, 1H), (tri?uoromethyl) 8.68 - 8.59 (m, 2H), 8.26 - pyridin-3 - 8.24 (m, 1H), 6.75 (s, 1H), yl)sulfonyl)ethyl 4.25 - 4.22 (m, 2H), 2.83 - )-N-(isoxazol-3 - 2.77 (m, 2H), 2.65 - 2.59 yl)piperidine (m, 1H), 2.05 - 2.00 (m, carboxamide 1H), 1.68 - 1.51 (m, 4H), 1.47 - 1.34 (m, 2H) (R)(1-?u0r0- 1H NMR (400 MHz, 1-((6- DMSO-d6) 8 ppm 9.73 (s, F (tn'?uoromethyl) 1H), 9.21 (s, 1H), 8.64 - py?din—3 - 8.59 (m, 2H), 8.26 - 8.24 yl)sulfony1)ethyl (m, 1H), 6.75 (s, 1H), 4.25 )-N-(isoxazol-3 - - 4.22 (m, 2H), 2.83 - 2.77 yl)pipeIidine-1— (m, 2H), 2.65 - 2.59 (m, amide 1H), 2.05 - 2.00 (m, 1H), 1.68 - 1.51 (m,4H), 1.47 - 1.34 (m, 2H) 1H NMR (400 MHz, DMSO-d6) 8 ppm 9.88 (s, 1H), 8.73 (d, J = 2.4 Hz, (S)(1-((6- 1H), 8.64 (s, 1H), 8.36 - (di?uoromethox 8.33 (m, 1H), 7.80 (t, J = y)pyridin-3 - 71.6 Hz, 1H), 7.40 (d, J = fonyl) 8.8 Hz, 1H), 6.75 (s, 1H), ?uoroethyl)-N- 4.24 - 4.22 (In, 2H), 2.82 - (isoxazol-3 - 2.76 (In, 2H), 2.49 - 2.31 yl)piperidine (In, 1H), 2.05 - 2.00 (m, carboxamide 1H), 1.67 - 1.64 (m, 1H), 1.51 (d, J = 23.0 Hz, 3H), 1.42 -1,31(m,2H) 1H NMR (400 MHz, DMSO-d6) 5 ppm 9.88 (s, 1H), 8.73 (d, J = 2.4 Hz, (R)(1-((6- 1H), 8.64 (s, 1H), 8.36 - (di?uoromethox 8.33 (In, 1H), 7.80 (t, J = y)pyn'din-3 - 71.6 Hz, 1H), 7.40 (d, J = yl)sulfonyl)— 1 - 8.8 Hz, 1H), 6.75 (s, 1H), ?uor0ethyl)-N- 4.24 - 4.22 (In, 2H), 2.82 - (isoxazol-3 - 2.76 (In, 2H), 2.49 - 2.31 yl)pipeIidine- l - (In, 1H), 2.05 - 2.00 (m, carboxamlde 1H), 1.67 - 1.64 (m, 1H), 1.51 (d, J = 23.0 Hz, 3H), 1.42 - 1.31 (m, 2H) Exam le 8. M osin Activation Assa Small molecule agents were assessed for their ability to activate the enzymatic activity of bovine cardiac myosin using a biochemical assay that couples the release of ADP sine diphosphate) from c myosin to an tic coupling system consisting of pyruvate kinase and lactate dehydrogenase (PK/LDH) and monitoring the absorbance se ofNADH (at 340 nm) as a function of time. PK converts ADP to ATP (adenosine triphosphate) by converting PEP (phosphoenolpyruvate) to pyruvate. Pyruvate is then converted to lactate by LDH by converting NADH (nicotinamide adenine dinucleotide) to NAD (oxidized nicotinamide adenine dinucleotide). The source of cardiac myosin was from bovine heart in the form of skinned myo?biils. Prior to testing small molecule agents, the bovine myo?brils were assessed for their m responsiveness and the calcium concentration that achieves either a 50% (pCaso or pCa = ~ 6) or < 5% (pCa= 10) activation of the myo?bril system was chosen as the ?nal condition for assessing the activation ty of the small molecule agents. All enzymatic activity was measured in a buffered solution containing 12 mM PIPES (piperazine—N,N'—bis(2—ethanesulfonic acid), 2 mM magnesium chloride at pH 6.8 (PM12 buffer). Final assay conditions were 1 mg/mL of bovine cardiac myo?brils, 0.4 mM PK/LDH, 50 uM ATP, 01 mg/mL BSA (bovine serum n), 10 ppm antifoam, 2 mM BME, 0.5 mM NADH, 1.5 mM PEP at the desired free calcium concentration required to achieve either 50% or < 5% activation of the myo?brils.

A dilution series of compound was created in DMSO such that the ?nal desired concentration of nd would be achieved in a volume of 100 uL with a ?xed DMSO concentration of 3.3% (v/v). lly a 1 HL of the dilution series was added to a 384 well plate to achieve a 10 point dose response. ing the addition of 14 uL of a solution containing bovine cardiac myo?brils, PK/LDH and a solution of m (that achieved the desired activation), the enzymatic reaction was started with the on of 15 uL of a solution containing ATP, PEP and NADH. The reaction progress was followed in a PerkinElmer Envision plate reader at ambient temperature using clear bottom . The plate reader was con?gured to read absorbance at 340 nm in kinetics mode for 15 minutes.

Data were recorded as the slope of the ance response to time. The slopes of the absorbance response as a on of time were normalized to slopes on the plate containing DMSO. This normalized rate was then plotted as a function of small molecule concentration and the data was ?tted to a four-parameter ?t using EXCEL XL?t. The concentration at which the total response is increased by twenty or ?fty percent is reported as ACzo or AC50.

Any agent that failed to achieve the corresponding percent activation at the highest concentration tested is reported as an AC20 or AC50 greater than the highest concentration tested (ie. AC50 > 50 uM).

Table 2. Myosin Activation of Selected Compoundsa Compound No. Myosin Activation 56700901234 ——————++++++H+++++++++++ 3333 + 444444555 012 +++++++++H+++++++ + + 6 + 6 + 6 + 6 + 6 + 7 + 7 + 7 + 7777777 9 ++++++H+++ 88888 12345 + 88 78 99999 12345 + 1 4 1 — 1 4 5 +++ represents myosin activation value AC20 < 2 uM; ++ represents myosin activation value ACzo from 2 uM - 5 M; + ents myosin activation value ACzo > 5 M.

Selectivity against rabbit skeletal myo?brils was assessed as described above with the exception that the source of myosin was that of fast skeletal myosin from rabbit in the form of myo?brils. Dose responses against rabbit skeletal myofibrils were also determined as described above.

Example 9. myocyte contractility assay.

Contractility of adult rat ventricular myocytes is determined by edge detection with an IonOptix contractility system. Aliquots of myocytes in Tyrode buffer (137 mM NaCl, 3.7 mM KCl, 0.5 mM MgCl2, 1.5 mM CaClz, 4 mM HEPES, 11 mM glucose) are placed in a perfusion chamber (Series 20 RC-27NE; Warner Instruments), d to adhere to the coverslip, and then ed with 37°C Tyrode buffer. Myocytes are filed stimulated at le and 10V. Only myocytes with clear striations, quiescent prior to pacing, with a cell length of 120-180 microns, a basal fractional ning equal to 3—8% of the cell length, and a contraction ty greater than 100 microns per second are used for contractility experiments. To determine the response to compounds, myocytes are first perfused for 60 seconds with Tyrodes buffer followed by 5 minutes of compound and a 140 second washout with Tyrodes buffer. Data is continuously recorded using ix software. Contractility data is ed using Ionwizard software (IonOptix). For each cell, 10-20 contractility transients were averaged and compared under basal (no compound) and compound-treated conditions. Compound activity is measured by effects on fractional shortening (F S), where fractional shortening is the ratio of the peak length of the cell at contraction divided by the basal cell length normalized to 100% for an untreated cell.

Table 3. Activation of Cardiomyocyte Contraction by Selected Compoundsa Compound Activity at 10 Activity at Activity at No. . 1.0 uM a + represents fractional shorting activation <20% over basal. ++ represents onal shorting activation values from 20% to 50% over basal. +++ represents fractional shortening activation values greater than 50% over basal.

Although the foregoing invention has been described in some detail by way of illustration and example for purposes of clarity of understanding, one of skill in the art will appreciate that certain s and modifications may be practiced within the scope of the appended . In on, each reference provided herein is incorporated by reference in its entirety to the same extent as if each reference was individually incorporated by reference.

Where a con?ict exists between the t application and a reference ed herein, the instant application shall dominate.

Claims (56)

WHAT IS CLAIMED IS:

1. A compound having formula (I): or a ceutically acceptable salt thereof, wherein Ar1 is a 5- to 6-membered heteroaryl having at least one nitrogen atom ring member which is tituted or substituted with from 1-3 Ra; Ar2 is a 5- to 10-membered aryl or heteroaryl which is unsubstituted or substituted with from 1-5 Rb; R1 and R2 are each independently a member selected from the group consisting of H, F, C1-C4 alkyl, C1-C4 deuteroalkyl, and C1-C4 haloalkyl; or alternatively, R1 and R2 are combined to form a C3- to C5 carbocyclic ring which is unsubstituted or substituted with one or two F; R3 is member selected from the group consisting of H, F, OH and C1-C4 alkyl; each Ra is independently selected from the group consisting of halo, CN, hydroxyl, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 hydroxyalkyl, C1-C4 alkoxy, C1-C4 koxy, -CORa1, -CO2Ra1, -SO2Ra1, -SO2NRa1Ra2, and -CONRa1Ra2, wherein each Ra1 and Ra2 is independently selected from the group consisting of H and C1-C4 alkyl or wherein Ra1 and Ra2 when attached to a nitrogen atom are combined to form a 4- to 6- membered ring; or wherein two Ra substituents on adjacent ring members are combined to form a 5- or ered ring having 0, 1 or 2 ring members selected from O, N and S; and each Rb is independently selected from the group consisting of halo, CN, yl, C1-C4 alkyl, C1-C4 deuteroalkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 haloalkoxy, C3-C6 cycloalkyl, -NRb1Rb2, , -CO2Rb1, -SO2Rb1, -SO2NRb1Rb2, –CONRb1Rb2, and a 5- or 6-membered heteroaryl which is unsubstituted or substituted with C1-C4 alkyl, and n each Rb1 and Rb2 is independently selected from the group consisting of H and C1-C4 alkyl or n Rb1 and Rb2 when attached to a nitrogen atom are combined to form a 4- to 6- membered ring; or wherein two Rb substituents on adjacent ring s are combined to form a 5- or 6-membered ring having 0, 1 or 2 ring members selected from the group consisting of O, N and S; wherein each aryl is an aromatic hydrocarbon ring system; and n each heteroaryl is an aromatic ring system comprising one or more heteroatoms ed from the group consisting of O, N, and S.

2. The compound of claim 1, or a pharmaceutically acceptable salt f, wherein Ar1 is a 5-membered heteroaryl having at least one nitrogen atom ring member; and which is unsubstituted or substituted with from 1-3 Ra.

3. The compound of claim 2, or a pharmaceutically acceptable salt thereof, wherein Ar1 is isoxazolyl.

4. The nd of any one of claims 1-3, or a pharmaceutically acceptable salt thereof, wherein Ar2 is a 5-membered heteroaryl, which is unsubstituted or substituted with from 1-5

5. The compound of claim 4, or a pharmaceutically acceptable salt f, n Ar2 is pyrazolyl, which is unsubstituted or substituted with from 1 to 3 Rb.

6. The compound of claim 5, or a pharmaceutically acceptable salt thereof, wherein Rb is selected from the group consisting of halo, CN, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy and C1-C4 haloalkoxy.

7. The compound of claim 1, or a ceutically acceptable salt thereof, wherein R1 is selected from the group consisting of H, F and CH3.

8. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R1 and R2 are not the same and at least one of R1 and R2 is selected from F and CH3.

9. The compound of claim 5, or a pharmaceutically acceptable salt thereof, wherein R3 is H, R1 is CH3 and R2 is F.

10. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein the carbon atom bearing R1 and R2 has a stereochemical R-configuration.

11. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein Ar1 is selected from the group consisting of l, pyridazinyl, oxazolyl, isoxazolyl, 1,2,3- thiadiazolyl, isothiazolyl, and thiazolyl, each of which is unsubstituted or substituted with from 1 to 2 Ra.

12. The compound of claim 1 or 11, or a pharmaceutically acceptable salt thereof, wherein Ar2 is selected from the group consisting of phenyl, l and pyrazolyl, each of which is unsubstituted or substituted with from 1 to 3 Rb.

13. The compound of claim 12, or a pharmaceutically acceptable salt thereof, wherein Rb is selected from the group consisting of halo, CN, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy and C1-C4 haloalkoxy.

14. The compound of claim 13, or a ceutically acceptable salt thereof, wherein R1 is selected from the group consisting of H, F and CH3.

15. The compound of claim 14, or a pharmaceutically able salt thereof, wherein R2 is selected from the group ting of H, F and CH3.

16. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R1 and R2 taken together with the carbon atom to which each is attached form a cyclopropane or cyclobutane ring.

17. The compound of claim 14 or 15, or a pharmaceutically acceptable salt thereof, wherein R1 and R2 are not the same and at least one of R1 and R2 is selected from F and CH3.

18. The compound of claim 14 or 15, or a pharmaceutically acceptable salt thereof, wherein the carbon atom bearing R1 and R2 has a R configuration.

19. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R3 is H or F.

20. The nd of claim 1, or a ceutically acceptable salt thereof, wherein Ar1 is 4-pyridinyl and Ar2 is phenyl, optionally substituted with from 1 to 3 Rb.

21. The compound of claim 1, or a pharmaceutically acceptable salt f, n Ar1 is 4-pyridazinyl and Ar2 is phenyl, which is unsubstituted or substituted with from 1 to 3 Rb.

22. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein Ar1 is selected from the group consisting of thiadiazolyl, isothiazolyl, and thiazolyl, each of which is unsubstituted or substituted with one Ra.

23. The compound of any one of claims 20-22, or a pharmaceutically acceptable salt thereof, n R3 is H, and each of R1 and R2 is F.

24. The compound of any one of claims 20-22, or a pharmaceutically acceptable salt thereof, wherein R3 is H, and each of R1 and R2 is CH3.

25. The compound of any one of claims 20-22, or a pharmaceutically acceptable salt thereof, wherein R3 is H, R1 is CH3 and R2 is F.

26. The compound of any one of claims 20-22, or a pharmaceutically acceptable salt thereof, wherein the carbon atom g R1 and R2 has a stereochemical R-configuration.

27. The compound of claim 1, selected from the group consisting of , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , O S N N O H , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , and , or a pharmaceutically able salt thereof.

28. The compound of claim 1 selected from the group consisting of or a pharmaceutically acceptable salt thereof.

29. The compound of claim 1 selected from the group consisting of , or a pharmaceutically acceptable salt thereof.

30. The nd of claim 1 having the structure: or a pharmaceutically acceptable salt thereof.

31. The compound of claim 1 having the structure: or a pharmaceutically acceptable salt thereof.

32. The compound of claim 31, wherein the compound is:

33. A pharmaceutical composition comprising the compound or pharmaceutically able salt thereof of any one of claims 1-30 and a pharmaceutically acceptable excipient.

34. A pharmaceutical composition comprising the compound or pharmaceutically acceptable salt thereof of claim 31 and a pharmaceutically acceptable excipient.

35. A ceutical composition sing the compound of claim 32 and a pharmaceutically acceptable excipient.

36. Use of the compound or pharmaceutically acceptable salt thereof of any one of claims 1-32 in the manufacture of a medicament for treating dilated cardiomyopathy (DCM), or a cardiac disorder having a pathophysiological feature of DCM.

37. The use of claim 36, wherein the DCM is terized by systolic dysfunction or reduction in systolic reserve.

38. Use of the compound or ceutically acceptable salt thereof of any one of claims 1-32 in the manufacture of a medicament for treating a disease or disorder selected from the group consisting of systolic dysfunction, diastolic dysfunction, heart failure with reduced ejection fraction ), heart failure with ved ejection fraction (HFpEF), chronic heart failure and acute heart failure.

39. The use of claim 38, wherein the compound is for use in an IV formulation for the ent of acute heart failure.

40. Use of the nd or pharmaceutically acceptable salt thereof of any one of claims 1-32 in the manufacture of medicament for treating a disease or disorder characterized by left ventricular systolic dysfunction or symptoms or reduced exercise capacity due to systolic ction; in conjunction with therapies aimed at treating heart failure.

41. Use of the compound or pharmaceutically acceptable salt thereof of any one of claims 1-32 in the manufacture of a medicament, for treating dilated myopathy (DCM), or a cardiac er having a pathophysiological feature associated with DCM, wherein the medicament is for use in combination with: i. a therapy that retards the progression of heart e by down-regulating neurohormonal stimulation of the heart and attempt to prevent cardiac remodeling ii. a therapy that improves cardiac function by stimulating cardiac ctility; or iii. a therapy that reduces c d or afterload.

42. The use of claim 41, wherein the compound is for use in combination with a betablocker.

43. The use of claim 41, wherein the nd is for use with ACE inhibitors, angiotensin receptor blockers (ARBs), ß-blockers, aldosterone receptor antagonists, or neural ptidase inhibitors.

44. The use of claim 41, wherein the compound is for use with positive inotropic agents sing the nergic agonist dobutamine or the odiesterase inhibitor milrinone.

45. The use of claim 41, wherein the compound is for use with diuretics or vasodilators.

46. The use of claim 41, wherein the diuretic is furosemide; or wherein the vasodilator comprises calcium channel blockers, phosphodiesterase inhibitors, endothelin receptor antagonists, renin inhibitors, or smooth muscle myosin modulators.

47. Use of the compound or pharmaceutically acceptable salt thereof of claim 31 in the manufacture of a medicament for treating dilated cardiomyopathy (DCM).

48. Use of the compound or pharmaceutically acceptable salt thereof of claim 31 in the manufacture of a medicament for treating systolic dysfunction.

49. Use of the compound or pharmaceutically acceptable salt thereof of claim 31 in the manufacture of a medicament for treating heart failure with reduced ejection on (HFrEF).

50. Use of the compound or pharmaceutically acceptable salt thereof of claim 31 in the manufacture of a medicament for treating chronic heart failure or acute heart failure.

51. The use of any one of claims 47-50, in combination with a therapeutic agent ed from the group consisting of an ACE inhibitor, an angiotensin or blocker (ARB), a er , an aldosterone receptor antagonist, a neural endopeptidase inhibitor, a positive inotropic agent, a diuretic, a vasodilator, a m channel blocker, a phosphodiesterase inhibitor, an endothelin receptor antagonist, a renin inhibitor, a smooth muscle myosin modulator, and combinations thereof.

52. Use of the nd of claim 32 in the manufacture of a medicament for treating dilated cardiomyopathy (DCM).

53. Use of the compound of claim 32 in the manufacture of a medicament for treating systolic dysfunction.

54. Use of the compound of claim 32 in the manufacture of a medicament for treating heart e with reduced ejection on (HFrEF).

55. Use of the compound of claim 32 in the manufacture of a medicament for treating chronic heart failure or acute heart failure.

56. The use of any one of claims 52-55, in combination with a therapeutic agent selected from the group consisting of an ACE inhibitor, an angiotensin receptor blocker (ARB), a ßblocker , an erone receptor antagonist, a neural endopeptidase inhibitor, a positive inotropic agent, a diuretic, a vasodilator, a calcium channel blocker, a phosphodiesterase inhibitor, an endothelin receptor nist, a renin inhibitor, a smooth muscle myosin modulator, and combinations thereof.