N-(pyridin-2-yl)pyridine-sulfonamide Derivatives and their Use in the Treatment of Disease

FIELD OF THE INVENTION

The present invention relates to N-(pyridin-2-yl)pyridine-sulfonamide derivatives and pharmaceutically acceptable salts thereof, compositions of these compounds, either alone or in combination with at least one additional therapeutic agent, processes for their preparation, their use in the treatment of diseases, their use, either alone or in combination with at least one additional therapeutic agent and optionally in combination with a pharmaceutically acceptable carrier, for the manufacture of pharmaceutical preparations, use of the pharmaceutical preparations for the treatment of diseases, and a method of treatment of said diseases, comprising administering the N-(pyridin-2-yl)pyridine-sulfonamide derivatives to a warm-blooded animal, especially a human.

BACKGROUND OF THE INVENTION

Cystic fibrosis (CF) is an autosomal genetic disease that affects approximately 30,000 people in the United States and approximately 70,000 people worldwide. Approximately 1 ,000 new cases of CF are diagnosed each year. Most patients are diagnosed with CF by the age of two, and more than half of the CF population is 18 years in age or older. Despite progress in the treatment of CF, there is no cure.

Cystic fibrosis (CF) is caused by loss-of-function mutations in the CF transmembrane conductance regulator (CFTR) protein, a cAMP-regulated chloride channel expressed primarily at the apical plasma membrane of secretory epithelia in the airways, pancreas, intestine, and other tissues. CFTR is a large, multidomain glycoprotein consisting of two membrane-spanning domains, two nucleotide-binding domains (NBD1 and NBD2) that bind and hydrolyze ATP, and a regulatory (R) domain that gates the channel by phosphorylation. Nearly 2000 mutations in the CFTR gene have been identified that produce the loss-of- function phenotype by impairing its translation, cellular processing, and/or chloride channel gating. The F508del mutation, which is present in at least one allele in -90% of CF patients, impairs CFTR folding, stability at the endoplasmic reticulum and plasma membrane, and chloride channel gating (Dalemans et al. 1991 ; Denning et al. 1992; Lukacs et al. 1993; Du et al. 2005). Other mutations primarily alter channel gating (e.g., G551 D), conductance (e.g., R1 17H), or translation (e.g., G542X) (Welsh and Smith 1993). The fundamental premise of CFTR corrector and potentiator therapy for CF is that correction of the underlying defects in the cellular processing and chloride channel function of CF-causing mutant CFTR alleles will be of clinical benefit. Correctors are principally targeted at F508del cellular misprocessing, whereas potentiators are intended to restore cAMP-dependent chloride channel activity to mutant CFTRs at the cell surface. In contrast to current therapies, such as antibiotics, anti- inflammatory agents, mucolytics, nebulized hypertonic saline, and pancreatic enzyme replacement, which treat CF disease manifestations, correctors and potentiators correct the underlying CFTR anion channel defect.

In view of the above, CFTR correctors of formula (I) are considered to be of value in the treatment and/or prevention of CF and related disorders.

SUMMARY OF THE INVENTION

In a first aspect, the invention relates to a compound of formula (I),

wherein:

ring A is a C ₆ . ₁₀ aryl ring;

ring B is pyridinyl;

R ¹ and R ² are each independently hydrogen, nitrile, C^alkoxy, halogen, C ₁ _ ₄ alkyl _, halo- substituted-C^alkyl, C ₃ . ₆ cycloalkyl or halo-substituted-C^alkoxy;

R ³ and R ⁴ are each independently hydrogen, nitrile, CD ₃ , C ₃ . ₆ cycloalkyl, C ₄ . ₆ heterocycle, C^

4alkoxy, halogen, Ci _-4 alkyl, halo-substituted-C^alkyl, hydroxy-substituted-C^alkyl or halo-substituted-C^alkoxy;

n is 0, 1 or 2;

R ⁵ is -NR ⁷ R ⁸ , -OR ⁹ or R ¹⁰ ;

R ⁶ is hydrogen, hydroxy, C _1-2 alkyl, C^alkoxy, hydroxy-substituted-C^alkyl, halogen or amino;

m is 0, 1 or 2;

R ⁷ is hydrogen, Ci _-6 alkyl, C ₃ . ₆ cycloalkyl, a fully or partially saturated 4 to 7-membered

heterocycle, wherein said 4 to 7-membered heterocycle is optionally substituted with 1 to 4 substituents each independently selected from halogen, hydroxy, C _1-4 alkyl, C _1-4 alkoxy, halo-substituted-C^alkyl, hydroxy-substituted-C^alkyl, halo-substituted-C^alkoxy, oxo, nitrile, C _M cycloalkyl, C ₄ . ₆ heterocycle, NHR ¹¹ , -C(0)-R ¹³ , -C(0)NHR ¹¹ , C _1-3 alkyl- C(0)NHR ¹¹ and -C(0)0-R ¹² ;

R ⁸ is hydrogen or Ci- alkyl;

R ⁹ is hydrogen, C ₃ . ₆ cycloalkyl or a fully or partially saturated 4 to 7-membered heterocycle, each ring is optionally substituted with one to four substituents each independently selected from halogen, hydroxy, C _1-4 alkyl, d_ ₄ alkoxy, halo-substituted-d_ ₄ alkyl, hydroxy- substituted-d. ₄ alkyl, halo-substituted-d. ₄ alkoxy, oxo, nitrile, C ₃ . ₆ cycloalkyl, C ₄ . ₆ heterocycle, NHR ¹¹ , -C(0)-R ¹³ , -C(0)NHR ¹¹ , d_3alkyl-C(0)NHR ¹¹ and -C(0)0-R ¹² ;

R ¹⁰ is a fully or partially saturated 4 to 10-membered heterocycle optionally substituted with one to four substituents each independently selected from halogen, hydroxy, C _ ₄ alkyl, d_ 4alkoxy, halo-substituted-d_ ₄ alkyl, hydroxy-substituted-d_ ₄ alkyl, halo-substituted-d_ 4alkoxy, oxo, nitrile, C ₃ . ₆ cycloalkyl, C ₄ . ₆ heterocycle, NHR ¹¹ , -C(0)-R ¹³ , -C(0)NHR ¹¹ , d_ 3alkyl-C(0)NHR ¹¹ , -C(0)d_3alkyl-NHR ¹¹ and -C(0)0-R ¹² ,wherein said C ₃ - ₆ cycloalkyl and C ₄ _6 heterocycle are optionally substituted with 1 to 3 substituents each independently selected from hydroxy, halogen, amino, -C(0)0-R ¹⁴ , C _1-4 alkyl, halo-substituted-d_ ₄ alkyl and hydroxy-substituted-d_ ₄ alkyl;

R ¹¹ is hydrogen, d. ₄ alkyl or C ₀ - ₃ alkyl-C(O)O-R ¹⁴ ;

R ¹² is hydrogen, d_ ₄ alkyl or d_3alkyl-C(0)-NHR ¹⁴ ;

R ¹³ is Ci _-4 alkyl, wherein said alkyl is optionally substituted with amino; and

R ¹⁴ is hydrogen or d _-4 alkyl;

or a pharmaceutically acceptable salt thereof.

Another aspect of the invention relates to pharmaceutical compositions comprising compounds of the invention or pharmaceutically acceptable salts thereof, and a pharmaceutical carrier. Such compositions can be administered in accordance with a method of the invention, typically as part of a therapeutic regimen for treatment or prevention of conditions and disorders related to Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) activity. In a particular aspect, the pharmaceutical compositions may additionally comprise further one or more therapeutically active ingredients suitable for use in combination with the compounds of the invention. In a more particular aspect, the further therapeutically active ingredient is an agent for the treatment of cystic fibrosis.

Another aspect of the invention relates to pharmaceutical combinations comprising compounds of the invention and other therapeutic agents for use as a medicament in the treatment of patients having disorders related to Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) activity. Such combinations can be administered in accordance with a method of the invention, typically as part of a therapeutic regimen for treatment or prevention of CF.

DETAILED DESCRIPTION OF THE INVENTION

The present invention provides compounds and pharmaceutical formulations thereof that may be useful in the treatment or prevention of CFTR mediated diseases, such as cystic fibrosis, and conditions and/or disorders through the mediation of CFTR function. In a first embodiment, the invention provides a compound of formula (I),

0)

wherein:

ring A is a C ₆ . ₁₀ aryl ring;

ring B is pyridinyl;

R ¹ and R ² are each independently hydrogen, nitrile, C^alkoxy, halogen, C ₁ _ ₄ alkyl _, halo- substituted-C^alkyl, C ₃ . ₆ cycloalkyl or halo-substituted-C^alkoxy;

R ³ and R ⁴ are each independently hydrogen, nitrile, CD ₃ , C ₃ . ₆ cycloalkyl, C ₄ . ₆ heterocycle, 4alkoxy, halogen, halo-substituted-C^alkyl, hydroxy-substituted-C^alkyl or halo-substituted-C^alkoxy;

n is 0, 1 or 2;

R ⁵ is -NR ⁷ R ⁸ , -OR ⁹ or R ¹⁰ ;

R ⁶ is hydrogen, hydroxy, C _ ₂ alkyl, C^alkoxy, hydroxy-substituted-C^alkyl, halogen or amino;

m is 0, 1 or 2;

R ⁷ is hydrogen, Chalky!, C ₃ . ₆ cycloalkyl, a fully or partially saturated 4 to 7-membered

heterocycle, wherein said 4 to 7-membered heterocycle is optionally substituted with 1 to 4 substituents each independently selected from halogen, hydroxy, C ₁ _ ₄ alkyl, C^alkoxy, halo-substituted-C^alkyl, hydroxy-substituted-C^alkyl, halo-substituted-C^alkoxy, oxo, nitrile, C ₃ . ₆ cycloalkyl, C ₄ - ₆ heterocycle, NHR ¹¹ , -C(0)-R ¹³ , -C(0)NHR ¹¹ , d.salkyl-

C(0)NHR ¹¹ and -C(0)0-R ¹² ;

R ⁸ is hydrogen or C ₁ _ ₄ alkyl;

R ⁹ is hydrogen, C ₃ . ₆ cycloalkyl or a fully or partially saturated 4 to 7-membered heterocycle each ring is optionally substituted with one to four substituents each independently selected from halogen, hydroxy, C ₁ _ ₄ alkyl, C^alkoxy, halo-substituted-C^alkyl, hydroxy- substituted-C^alkyl, halo-substituted-C^alkoxy, oxo, nitrile, C ₃ . ₆ cycloalkyl, C ₄ . ₆ heterocycle, NHR ¹¹ , -C(0)-R ¹³ , -C(0)NHR ¹¹ , C^alkyl-CCC NHR ¹¹ and -C(0)0-R ¹² ; R ¹⁰ is a fully or partially saturated 4 to 10-membered heterocycle optionally substituted with one to four substituents each independently selected from halogen, hydroxy, C ₁ _ ₄ alkyl, 4alkoxy, halo-substituted-C^alkyl, hydroxy-substituted-C^alkyl, halo-substituted-C^ 4alkoxy, oxo, nitrile, C ₃ . ₆ cycloalkyl, C ₄ . ₆ heterocycle, NHR ¹¹ , -C(0)-R ¹³ , -C(0)NHR ¹¹ , ₃ alkyl-C(0)NHR ¹¹ , -C^d.salkyl-NHR ¹¹ and -C(0)0-R ¹² ,wherein said C ₃ - ₆ cycloalkyl and C ₄ -6 heterocycle are optionally substituted with 1 to 3 substituents each independently selected from hydroxy, halogen, amino, -C(0)0-R ¹⁴ , C _1-4 alkyl, halo-substituted-C^alkyl and hydroxy-substituted-C^alkyl;

R ¹¹ is hydrogen, C^alkyl or C ₀ - ₃ alkyl-C(O)O-R ¹⁴ ;

R ¹² is hydrogen, C^alkyl or d.salkyl-C^-NHR ¹⁴ ;

R ¹³ is C _1-4 alkyl, wherein said alkyl is optionally substituted with amino; and

R ¹⁴ is hydrogen or C ₁ _ ₄ alkyl;

or a pharmaceutically acceptable salt thereof.

A second embodiment of the invention provides a compound according to the first embodiment of formula (la), (lb) or (lc):

(lc) wherein:

at least one of R ¹ or R ² is not hydrogen;

Y ¹ is N and Y ² is CR ⁶ ; or Y ² is N and Y ¹ is CR ⁶ ;

or a pharmaceutically acceptable salt thereof.

A third embodiment of the invention provides a compound according to the second embodiment of formula (la), (lb) or (lc):

Y ¹ is N and Y ² is CR ⁶ ;

or a pharmaceutically acceptable salt thereof.

A fourth embodiment of the invention provides a compound according to the second embodiment of formula (la), (lb) or (lc); wherein:

Y ¹ is CR ⁶ and Y ² is N; or a pharmaceutically acceptable salt thereof. A fifth embodiment of any of the preceding embodiments wherein:

m is 0 or 1 ; and

n is 0 or 1 ;

or a pharmaceutically acceptable salt thereof.

A sixth embodiment of the invention provides a compound according to the second embodiment of formula (la) wherein:

R ¹ is hydrogen, halogen or CF ₃ ;

R ² is hydrogen, halogen, -OCH ₃ or CF ₃ ;

m is 0;

n is 0;

Y ¹ is N and Y ² is CH; and

ring A is phenyl;

or a pharmaceutically acceptable salt thereof.

A seventh embodiment of the invention provides a compound according to the second embodiment of formula (la) wherein:

R ¹ is selected from hydrogen, halogen and CF ₃ ;

R ² is selected from hydrogen, halogen, -OCH ₃ and CF ₃ ;

m is 1 ;

R ⁶ is selected from hydrogen, hydroxy, C _ ₂ alkyl, C _1-2 alkoxy, hydroxy-substituted-C^alkyl, halogen and amino;

Y ¹ is N and Y ² is CH; and

ring A is phenyl;

or a pharmaceutically acceptable salt thereof.

An eighth embodiment of the invention provides a compound according to the second embodiment of formula (la) wherein:

R ¹ is selected from hydrogen, halogen and CF ₃ ;

R ² is selected from hydrogen, halogen, -OCH ₃ and CF ₃ ;

m is O oM ;

Y ¹ is N and Y ² is CH; and

ring A is phenyl;

or a pharmaceutically acceptable salt thereof.

A ninth embodiment of the invention provides a compound according to any of the previous embodiments, of formula (la) wherein: R ⁵ is R ¹⁰ and R ¹⁰ is a fully or partially saturated 4 to 10-membered heterocycle optionally substituted with one to four substituents each independently selected from halogen, hydroxy, C _1-4 alkyl, C^alkoxy, halo-substituted-C^alkyl, hydroxy-substituted-C^alkyl, halo- substituted-C^alkoxy, oxo, nitrile, C ₃ . ₆ cycloalkyl, C ₄ . ₆ heterocycle, NHR ¹¹ , -C(0)-R ¹³ , - C(0)NHR ¹¹ , Ci- ₃ alkyl-C(0)NHR ¹¹ , -C^d.salkyl-NHR ¹¹ and -C(0)0-R ¹² ,wherein said C ₃ - ₆ cycloalkyl and C ₄ . ₆ heterocycle are optionally substituted with 1 to 3 substituents each independently selected from hydroxy, halogen, amino, C ₁ _ ₄ alkyl, halo-substituted-C^alkyl and hydroxy-substituted-C^alkyl; or a pharmaceutically acceptable salt thereof. A tenth embodiment of the invention provides a compound according to any of the previous embodiments, of formula (la) wherein:

R ⁵ is R ¹⁰ and R ¹⁰ is a fully saturated 4 to 10-membered heterocycle optionally substituted with one to four substituents each independently selected from halogen, hydroxy, C _1-4 alkyl, C^alkoxy, halo-substituted-C^alkyl, hydroxy-substituted-C^alkyl, halo-substituted-C^- ₄ alkoxy, oxo, nitrile, C ₃ - ₆ cycloalkyl, C ₄ . ₆ heterocycle, NHR ¹¹ , -C(0)-R ¹³ , -C(0)NHR ¹¹ , Ci _-3 alkyl- C(0)NHR ¹¹ , -C(0)C _1-3 alkyl-NHR ¹¹ and -C(0)0-R ¹² ,wherein said C ₃ - ₆ cycloalkyl and C ₄ . ₆ heterocycle are optionally substituted with 1 to 3 substituents each independently selected from hydroxy, halogen, amino, C ₁ _ ₄ alkyl, halo-substituted-C^alkyl and hydroxy-substituted- C _1-4 alkyl; or a pharmaceutically acceptable salt thereof.

An eleventh embodiment of the invention provides a compound according to the ninth embodiment, wherein:

R ⁵ is R ¹⁰ ; R ¹⁰ is 4,5,6,7-tetrahydro-3H-imidazo[4,5-c]pyridine, 8-azabicyclo[3.2.1 ]octan-3-ol, octahydropyrrolo[1 ,2-a]pyrazine, 6-oxa-1 -azaspiro[3.3]heptane, 5,6,7,8- tetrahydroimidazo[1 ,2-a]pyrazine, 3,8 diazabicyclo[3.2.1 ]octane, 8-oxa-3- azabicyclo[3.2.1 ]octane, 2-oxa-6-azaspiro[3.3]heptane, 1 H-pyrazole, 2,6- diazaspiro[3.3]heptane, 1 ,6-diazaspiro[3.3]heptane, 5-oxa-2-azaspiro[3.4]octane, 7- azaspiro[3.5]nonane, 2,6-diazaspiro[3.4]octane, 2,5-diazabicyclo[2.2.1 ]heptane, 8- azaspiro[4.5]decane, 5-azaspiro[2.5]octane, 4,7-diazaspiro[2.5]octane, 5,6,7,8-tetrahydro- [1 ,2,4]triazolo[4,3-a]pyrazine or 3-azabicyclo[3.1 .0]hexane; wherein R ¹⁰ is optionally substituted by 1 to 3 substituents each independently selected from amino, oxo, halogen, ₄ alkyl, hydroxy-substituted C _1-4 alkyl and halo-substituted C _1-4 alkyl; or a pharmaceutically acceptable salt thereof. A twelfth embodiment of the invention provides a compound according to the second embodiment of formula (la) wherein:

R ¹ is F, CI or CF ₃ ; R ² is hydrogen, -OCH ₃ or CF ₃ ;

Y ¹ is N and Y ² is CH;

m is 0;

n is 0 or 1 ;

ring A is phenyl;

R ⁵ is -NR ⁷ R ⁸ ; and

R ⁸ is hydrogen;

or a pharmaceutically acceptable salt thereof.

A thirteenth embodiment of the invention provides a compound according to the second embodiment of formula (la) wherein:

R ¹ is F, CI or CF ₃ ;

R ² is hydrogen, -OCH ₃ or CF ₃ ;

Y ¹ is N and Y ² is CH;

m is 0;

ring A is phenyl; and

R ⁵ is -OR ⁹ ;

or a pharmaceutically acceptable salt thereof.

A fourteenth embodiment of the invention provides a compound according to the first embodiment of formula (II):

wherein:

R ¹ is F, CI or CF ₃ ;

or a pharmaceutically acceptable salt thereof.

A fifteenth embodiment of the invention provides a compound according to embodiment fourteen wherein:

R ¹ is F, CI or CF ₃ ;

R ⁵ is R ¹⁰ ; and

R ¹⁰ is a fully or partially saturated 4 to 10-membered heterocycle optionally substituted with one to four substituents each independently selected from the group consisting of halogen, hydroxy, C _1-4 alkyl, C^alkoxy, halo-substituted-C^alkyl, hydroxy-substituted-C _! . 4alkyl, halo-substituted-C^alkoxy, oxo, nitrile, C ₃ . ₆ cycloalkyl, C ₄ . ₆ heterocycle, NHR ¹¹ , - C(0)-R ¹³ , -C(0)NHR ¹¹ , C _1-3 alkyl-C(0)NHR ¹¹ , -C^d.salkyl-NHR ¹¹ and -C(0)0-R ¹² ; wherein said C ₃ . ₆ cycloalkyl or C ₄ . ₆ heterocycle, are optionally substituted with 1 to 3 substituents each independently selected from hydroxy, halogen, amino, C ₁ _ ₄ alkyl, halo- substituted-C^alkyl and hydroxy-substituted-C^alkyl;

or a pharmaceutically acceptable salt thereof.

A sixteenth embodiment of the invention provides a compound of the second embodiment of formula (la), wherein:

R ¹ is F, CI or CF ₃ ;

R ² is H;

Y ¹ is N and Y ² is CH;

m is 0;

n is 0 or 1 ;

ring A is

wherein * represents the carbon atom to which ring A is attached to formula (la);

R ³ and R ⁴ are each independently hydrogen, CI, F, CH ₃ , CD ₃ , nitrile, cyclopropyl, -OCH ₃ , - OCF ₃ or CF ₃ , where at least one of R ³ or R ⁴ is not hydrogen;

R ⁵ is R ¹⁰ ;

R ¹¹ is hydrogen or Ci _-4 alkyl;

R ¹² is hydrogen or C _1-4 alkyl; and

R ¹³ is d. ₄ alkyl;

or a pharmaceutically acceptable salt thereof. A seventeenth embodiment of the invention provides a compound of embodiment fifteen wherein R ³ is CH ₃ , cyclopropyl, CI, -OCH ₃ , CD ₃ , -CF ₃ or -OCF ₃ and R ⁴ is hydrogen, CI, - OCH ₃ , F, CH ₃ , CD ₃ , nitrile, or -CF ₃ ; or a pharmaceutically acceptable salt thereof. An eighteenth embodiment of the invention provides a compound of embodiment fifteen, wherein:

R ¹ is F;

or a pharmaceutically acceptable salt thereof.

A nineteenth embodiment of the invention provides a compound of embodiment fifteen, wherein:

R ¹ is CI;

or a pharmaceutically acceptable salt thereof.

A twentieth embodiment of the invention provides a compound of embodiment fifteen, wherein:

R ¹ is CF ₃ ;

or a pharmaceutically acceptable salt thereof.

A twenty-first embodiment of the invention provides a compound of embodiment fifteen, wherein:

n is 0;

or a pharmaceutically acceptable salt thereof.

A twenty-second embodiment of the invention provides a compound of embodiment fifteen, wherein:

1 ⁰ is

wherein *N represents the ring attachment nitrogen and X is O, C or N; wherein each R ¹⁰ ring is substituted with 1 or 2 substituents each independently selected from hydrogen, flouro, hydroxy, C ₁ _ ₄ alkyl, C _1-2 alkoxy, halo-substituted-C^alkyl, hydroxy- substituted-C^alkyl, halo-substituted-C^alkoxy, oxo, nitrile, C ₃ . ₆ cycloalkyl, C ₄ . ₆ heterocycle, NHR ¹¹ , -C(0)NHR ¹¹ , C _1-3 alkyl-C(0)NHR ¹¹ , -C^d.salkyl-NHR ¹¹ and - C(0)0-R ¹² , wherein said C ₃ . ₆ cycloalkyl and C ₄ . ₆ heterocycle are optionally substituted with 1 or 2 substituents each independently selected from hydroxy, halogen, amino, d. 4alkyl, halo-substituted-d_ ₄ alkyl and hydroxy-substituted-d_ ₄ alkyl;

R ¹¹ is selected from hydrogen and d. ₄ alkyl; and

R ¹² is selected from hydrogen and C ₁ _ ₄ alkyl;

or the pharmaceutically acceptable salt thereof.

A twenty-third embodiment of the invention provides a compound of embodiment two of formula (la), wherein:

R ¹ is selected from F, CI or CF ₃ ;

R ² is H;

Y ¹ is N and Y ² is CH;

m is 0;

ring A is

wherein * represents the carbon atom to which ring A is attached to formula (la);

R ³ and R ⁴ are each independently selected from hydrogen, CI, F, CH ₃ , CD ₃ , nitrile,

cyclopropyl, -OCH ₃ , -OCF ₃ and CF ₃ ; where at least one of R ³ or R ⁴ is not hydrogen; R ⁵ is -NR ⁷ R ⁸ ;

R ⁸ is hydrogen;

-NR ⁷ R ⁸ is selected from the group consisting of:

X is O, C or N;

wherein R ⁷ is substituted with 1 to 2 substituents each independently selected from hydrogen, halogen, hydroxy, C _ ₄ alkyl, C _1-4 alkoxy, halo-substituted-d^alkyl, hydroxy- substituted-C^alkyl, halo-substituted-C^alkoxy, oxo, nitrile, C ₃ . ₆ cycloalkyl, C ₄ . ₆ heterocycle, NHR ¹¹ , -C(0)-R ¹³ , -C(0)NHR ¹¹ , d.salkyl-C^NHR ¹¹ and -C(0)0-R ¹² ; R ¹¹ is selected from hydrogen and d^alkyl; and

R ¹² is selected from hydrogen and C ₁ _ ₄ alkyl;

or the pharmaceutically acceptable salt thereof.

A twenty-fourth embodiment of the invention provides a compound of according to embodiment two of formula (la), wherein:

R ¹ is selected from F, CI and CF ₃ ;

R ² is H;

Y ¹ is N and Y ² is CH;

m is 0;

ring A is

wherein * represents the carbon atom to which ring A is attached to formula (la);

R ³ and R ⁴ are each independently selected from hydrogen, CI, F, CH ₃ , CD ₃ , nitrile, cyclopropyl, -OCH ₃ , -OCF ₃ and CF ₃ ; where at least one of R ³ or R ⁴ is not hydrogen; R ⁵ is R ¹⁰ ;

R ¹⁰ is selected from the group consisting of:

wherein:

*N represents the ring attachment nitrogen:

XisO, CorN;

Zis N, orCH; wherein said R ¹⁰ heterocycle is substituted with 1 to 2 substituents each independently selected from hydrogen, flouro, hydroxy, C ₁ _ ₄ alkyl, C _1-2 alkoxy, halo-substituted-d^alkyl, hydroxy-substituted-C^alkyl, halo-substituted-C^alkoxy, oxo, nitrile, C ₃ . ₆ cycloalkyl, C ₄ . ₆ heterocycle, NHR ¹¹ , -C(0)NHR ¹¹ and -C(0)0-R ¹² ; wherein said C ₃ . ₆ cycloalkyl and C ₄ . ₆ heterocycle are optionally substituted with 1 or 2 substituents each independently selected from hydroxy, halogen, amino, C _1-4 alkyl, halo-substituted-C^alkyl and hydroxy- substituted-C^alkyl;

R ¹¹ is selected from hydrogen and d^alkyl; and

R ¹² is selected from hydrogen and C ₁ _ ₄ alkyl;

or the pharmaceutically acceptable salt thereof.

A twenty-fifth embodiment of the invention provides a compound according to embodiment fifteen, wherein:

R ¹⁰ is selected from the group consisting of:

X is O, C or N;

*N represents the ring attachment nitrogen:

wherein said heterocycle is optionally substituted with 1 to 2 substituents each independently selected from hydrogen, fluoro, hydroxy, C _1-2 alkyl, cyclopropyl, oxetane, halo-substituted-C^alkyl, hydroxy-substituted-C^alkyl, oxo, NHR ¹¹ , -C(0)NHR ¹¹ , d_ 3alkyl-C(0)NHR ¹¹ , -C^d.salkyl-NHR ¹¹ and -C(0)0-R ¹² ;

R ¹¹ is selected from hydrogen and C ₁ _ ₄ alkyl;

R ¹² is selected from hydrogen and C^alkyl; and

Rin

wherein * represents the carbon atom to which ring A is attached to formula (II);

R ³ is selected from CI, CH ₃ and CD ₃ , and R ⁴ is selected from hydrogen, CH ₃ , CI and F; or a pharmaceutically acceptable salt thereof. A twenty-sixth embodiment of the invention provides a compound according to any of the preceding embodiments wherein:

R ³ is CH3, or CI, and R ⁴ is hydrogen or F;

or a pharmaceutically acceptable salt thereof.

A twenty-seventh embodiment of the invention provides a compound according to embodiment twenty-three, wherein:

said R ¹⁰ heterocycle is substituted with 1 to 2 substituents each independently selected from hydrogen, fluoro, hydroxyl and C _1-4 alkyl;

or a pharmaceutically acceptable salt thereof.

A twenty-eighth embodiment of the invention provides a compound according to embodiment twenty-four, wherein:

said R ¹⁰ heterocycle is substituted with 1 to 2 substituents each independently selected from hydrogen, fluoro, hydroxyl and C ₁ _ ₄ alkyl;

or a pharmaceutically acceptable salt thereof.

A twenty-ninth embodiment of the invention is a compound selected from the group consisting of:

6-amino-N-(6-(5-fluoro-2-methylphenyl)-5-(trifluoromethyl)py ridin-2-yl)pyridine-2- sulfonamide;

6-Amino-N-(5-chloro-6-(o-tolyl)pyridin-2-yl)pyridine-2-sulfo namide;

6-amino-N-(6-(2,6-dimethylphenyl)-5-(trifluoromethyl)pyridin -2-yl)pyridine-2-sulfonamide; 6-amino-N-(5-bromo-6-(2,6-dimethylphenyl)pyridin-2-yl)pyridi ne-2-sulfonamide;

2-amino-N-(5-chloro-6-(2,6-dimethylphenyl)pyridin-2-yl)pyrid ine-4-sulfonamide;

6-amino-N-(6-(2,6-dimethylphenyl)-4-(trifluoromethyl)pyridin -2-yl)pyridine-2-sulfonamide; 6-amino-N-(5-chloro-6-(5-fluoro-2-methylphenyl)pyridin-2-yl) pyridine-2-sulfonamide; 6-amino-N-(6-(3-fluoro-2-methylphenyl)-5-(trifluoromethyl)py ridin-2-yl)pyridine-2- sulfonamide;

6-amino-N-(5-chloro-6-(2,6-dimethylphenyl)-4-(trifluoromethy l)pyridin-2-yl)pyridine-2- sulfonamide;

6-amino-N-(6-(2,6-dimethylphenyl)-5-fluoropyridin-2-yl)pyrid ine-2-sulfonamide;

6-amino-N-(4-chloro-6-(2,6-dimethylphenyl)pyridin-2-yl)pyrid ine-2-sulfonamide;

6-amino-N-(5-chloro-6-(2,6-dimethylphenyl)pyridin-2-yl)pyrid ine-2-sulfonamide;

6-amino-N-(5-chloro-6-(3-fluoro-2-methylphenyl)pyridin-2-yl) pyridine-2-sulfonamide;

6-amino-N-(5-chloro-6-(2-chloro-6-methylphenyl)pyridin-2- yl)pyridine-2-sulfonamide; 6-amino-N-(6-(o-tolyl)-5-(trifluoromethyl)pyridin-2-yl)pyrid ine-2-sulfonamide; 6-amino-N-(5-chloro-6-(5-chloro-2-cyclopropylphenyl)pyridin- 2-yl)pyridine-2-sulfonam 6-amino-N-(6-(2-chlorophenyl)-5-(trifluoromethyl)pyridin-2-y l)pyridine-2-sulfonami 6-amino-N-(5-(trifluoromethyl)-6-(2-(trifluoromethyl)phenyl) pyridin-2-yl)pyridin sulfonamide;

6-amino-N-(5-chloro-6-(2-cyclopropylphenyl)pyridin-2-yl)pyri dine-2-sulfonamide;

6-amino-N-(5-chloro-6-(2-(methyl-d3)phenyl)pyridin-2-yl)pyri dine-2-sulfonamide;

6-amino-N-(5-chloro-6-(2-cyclopropyl-5-fluorophenyl)pyridin- 2-yl)pyridine-2-sulfonamide 6-amino-N-(5-chloro-6-(o-tolyl)-4-(trifluoromethyl)pyridin-2 -yl)pyridine-2-sulfonam 6-amino-N-(5-bromo-6-(o-tolyl)pyridin-2-yl)pyridine-2-sulfon amide;

6-amino-N-(5-chloro-6-(2-chlorophenyl)pyridin-2-yl)pyridine- 2-sulfonamide;

2-amino-N-(6-(2,6-dimethylphenyl)-5-(triflu

2-amino-N-(5-chloro-6-(2-(methyl-d3)phenyl)pyridin-2-yl)pyri dine-4-sulfonamide;

6-amino-N-(5-chloro-6-(2-cyclopropyl-4-fluorophenyl)pyridin- 2-yl)pyridine-2-sulfonami^

6-amino-N-(6-(2-cyclopropyl-4-fluorophenyl)-5-(trifluorom ethyl)pyridin-2-yl)pyridine-2 sulfonamide;

6-amino-N-(5-chloro-6-(2-ethylphenyl)pyridin-2-yl)pyridine-2 -sulfonamide;

6-amino-N-(5-chloro-6-(4-fluoro-2,6-dimethylphenyl)pyridin-2 -yl)pyridine-2-sulfonamide;

6-amino-N-(5-chloro-6-(2-fluoro-6-methylphenyl)pyridin-2- yl)pyridine-2-sulfonamide;

6-amino-N-(5-chloro-6-mesitylpyridin-2-yl)pyridine-2-sulf onamide;

6-amino-N-(5-chloro-6-(o-tolyl)pyridin-2-yl)-3-fluoropyridin e-2-sulfonamide;

6-amino-N-(5-chloro-6-(2-methyl-3-(trifluoromethyl)phenyl)py ridin-2-yl)pyridine-2- sulfonamide;

6-amino-N-(5-fluoro-6-(2-isopropylphenyl)pyridin-2-yl)pyridi ne-2-sulfonamide;

6-amino-5-methyl-N-(6-(o-tolyl)-5-(trifluoromethyl)pyridin-2 -yl)pyridine-2-sulfonamide; 6-amino-N-(5-chloro-6-(4-fluoro-2-methylphenyl)pyridin-2-yl) pyridine-2-sulfonamide; 6-amino-N-(5-chloro-6-(6-chloro-2-fluoro-3-methylphenyl)pyri din-2-yl)pyridine-2- sulfonamide;

6-amino-N-(5-chloro-6-(2-chloro-6-fluorophenyl)pyridin-2-yl) pyridine-2-sulfonamide; 6-amino-N-(5-chloro-6-(o-tolyl)pyridin-2-yl)pyridine-3-sulfo namide;

6-amino-N-(6-(2-chloro-4-fluorophenyl)-5-(trifluoromethyl)py ridin-2-yl)pyridine-2- sulfonamide;

2-amino-N-(6-(5-fluoro-2-methylphenyl)-5-(trifluoromethyl)py ridin-2-yl)pyridine-4- sulfonamide;

6-amino-N-(5-chloro-6-(2-chloro-5-(trifluoromethyl)phenyl)py ridin-2-yl)pyridine-2- sulfonamide;

6-amino-N-(5-chloro-6-(5-fluoro-2-methylphenyl)pyridin-2-yl) pyridine-3-sulfonamide; 6-amino-N-(5-chloro-6-(2-isopropylphenyl)pyridin-2-yl)pyridi ne-3-sulfonamide; 2-amino-N- 5-chloro-6-(5-fluoro-2-methylphenyl)pyridin-2-yl)pyridine-4- sulfonamide; 6-amino-N- 5-chloro-6-(2,6-dimethylphenyl)pyridin-2-yl)pyridine-3-sulfo namide;

6-amino-N- 5-chloro-6-(2-(1 ,1 -difluoroethyl)phenyl)pyridin-2-yl)pyridine-2-sulfonamide; 2-amino-N- 5-chloro-6-(2-methyl-5-(trifluoromethyl)phenyl)pyridin-2-yl) pyridine-4- sulfonamide;

6-amino-N- 5-chloro-6-(2-isopropylphenyl)pyridin-2-yl)pyridine-2-sulfon amide;

6-amino-N- 5-chloro-6-(2-methyl-5-(trifluoromethyl)phenyl)pyridin-2-yl) pyridine-2- sulfonamide;

6-amino-N- 5-chloro-6-(2-chloro-6-(trifluoromethyl)phenyl)pyridin-2-yl) pyridine-2- sulfonamide;

6-amino-N- 5-chloro-6-(2-methyl-6-(trifluoromethyl)phenyl)pyridin-2-yl) pyridine-2- sulfonamide;

6-amino-N- 5-chloro-6-(2-cyclopropylphenyl)pyridin-2-yl)pyridine-3-sulf onamide; 6-amino-N- 5-chloro-6-(2-(trifluoromethyl)phenyl)pyridin-2-yl)pyridine- 2-sulfonamide; 6-amino-N- 5-chloro-6-(2-chloro-4-fluorophenyl)pyridin-2-yl)pyridine-2- sulfonamide; 2-amino-N- 5-chloro-6-(o-tolyl)pyridin-2-yl)pyridine-4-sulfonamide;

6-amino-N- 5-chloro-6-(2-chloro-6-fluoro-3-methylphenyl)pyridin-2-yl)py ridine-2- sulfonamide;

6-amino-N- 5-chloro-6-(2-(trifluoromethoxy)phenyl)pyridin-2-yl)pyridine -2-sulfonamide; 6-amino-N- 5-chloro-6-(2-fluoro-6-methylphenyl)pyridin-2-yl)pyridine-3- sulfonamide; 2-amino-N- 5-chloro-6-(2-(trifluoromethyl)phenyl)pyridin-2-yl)pyridine- 4-sulfonamide; 6-amino-N- 5- chloro-6-(5-fluoro-2-methoxyphenyl)pyridin-2-yl)pyridine-2-s ulfonamide; 6-amino-N- 6- (2,6-dimethylphenyl)-4-methylpyridin-2-yl)pyridine-2-sulfona mide;

2-amino-N- 6-(5-cyano-2-methylphenyl)-5-(trifluoromethyl)pyridin-2-yl)p yridine-4- sulfonamide;

6-amino-N- 5-chloro-6-(2-(difluoromethyl)phenyl)pyridin-2-yl)pyridine-2 -sulfonamide; 6-amino-N- 5-cyclopropyl-6-(o-tolyl)pyridin-2-yl)pyridine-2-sulfonamide ;

6-amino-N- 5- chloro-6-(3-cyano-2-methylphenyl)pyridin-2-yl)pyridine-2-sul fonamide; 6-amino-N- 6- (2,6-dimethylphenyl)pyridin-2-yl)pyridine-2-sulfonamide;

6-amino-N- 5-chloro-6-(2-fluorophenyl)pyridin-2-yl)pyridine-2-sulfonami de;

6-amino-N- 5-fluoro-6-(o-tolyl)pyridin-2-yl)pyridine-2-sulfonamide;

6-amino-N- 5- chloro-6-(4-fluoro-2-methylphenyl)pyridin-2-yl)pyridine-3-su lfonamide; 6-amino-N- 6- (2,6-dimethylphenyl)-5-methoxypyridin-2-yl)pyridine-2-sulfon amide; 6-amino-N- 5-chloro-6-(3-(trifluoromethyl)phenyl)pyridin-2-yl)pyridine- 2-sulfonamide; 2-amino-N- 5-chloro-6-(2,6-dimethylphenyl)pyridin-2-yl)pyridine-3-sulfo namide;

6-amino-N- 5-methyl-6-(o-tolyl)pyridin-2-yl)pyridine-2-sulfonamide;

6-amino-N- 5-chloro-6-(2-methoxyphenyl)pyridin-2-yl)pyridine-2-sulfonam ide; 6-amino-N-(6-(2-chlorophenyl)-5-methylpyridin-2-yl)pyridine- 2-sulfonamide;

6-amino-N-(5-chloro-6-(2,3,6-trifluorophenyl)pyridin-2-yl)py ridine-2-sulfonamide;

6-amino-N-(5-(trifluoromethyl)-6-(3-(trifluoromethyl)phenyl) pyridin-2-yl)pyridi sulfonamide;

6-amino-N-(5-chloro-6-(2,6-difluorophenyl)pyridin-2-yl)pyrid ine-2-sulfonamide;

6-amino-5-bromo-N-(5-chloro-6-(2,6-dimethylphenyl)pyridin-2- yl)pyridine-2-sulfonam 6-amino-N-(6-(2-methyl-5-(trifluoromethoxy)phenyl)-5-(triflu oromethyl)pyrid

yl)pyridine-2-sulfonamide;

6-amino-N-(6-(5-cyano-2-methylphenyl)-5-(trifluoromethyl)pyr idin-2-yl)pyridine-2^ sulfonamide;

6-amino-N-(5-chloro-6-(5-cyano-2-methylphenyl)pyridin-2-yl)p yridine-2-sulfonamide; 2-amino-N-(5-chloro-6-(5-cyano-2-methylphenyl)pyridin-2-yl)p yridine-4-sulfonamide; 6-amino-N-(5-chloro-6-(2,4,6-trifluorophenyl)pyridin-2-yl)py ridine-2-sulfonamide;

2-amino-N-(5-chloro-6-(3-cyano-2-methylphenyl)pyridin-2-yl)p yridine-4-sulfonamide; 2-amino-N-(5-chloro-6-(o-tolyl)pyridin-2-yl)pyridine-3-sulfo namide;

6-amino-N-(5-chloro-6-(2-methyl-5-(trifluoromethoxy)phenyl)p yridin-2-yl)pyridine-2- sulfonamide;

6-amino-N-(5-chloro-6-(2-cyanophenyl)pyridin-2-yl)pyridine-2 -sulfonamide;

6-amino-N-(5-chloro-6-(4-cyano-2-methylphenyl)pyridin-2-yl)p yridine-2-sulfonamide; 2-amino-N-(5-chloro-6-(4-cyano-2-methylphenyl)pyridin-2-yl)p yridine-4-sulfonamide;

6-amino-N-(6-(2,6-dimethylphenyl)-3-fluoropyridin-2-yl)py ridine-2-sulfonamide;

6-amino-N-(5-chloro-6-(4-(trifluoromethyl)phenyl)pyridin-2-y l)pyridine-2-sulfonamide;

6-amino-N-(5-chloro-6-(2,6-dimethylphenyl)-3-fluoropyridi n-2-yl)pyridine-2-sulfonamide;

6-amino-N-(3-chloro-6-(2,6-dimethylphenyl)pyridin-2-yl)py ridine-2-sulfonamide;

(R)-6-(3-aminopiperidin-1 -yl)-N-(6-(o-tolyl)-5-(trifluoromethyl)pyridin-2-yl)pyridine -2- sulfonamide;

(S)-6-(3-aminopiperidin-1 -yl)-N-(6-(o-tolyl)-5-(trifluoromethyl)pyridin-2-yl)pyridine -2- sulfonamide;

(R)-6-(piperidin-3-ylamino)-N-(6-(o-tolyl)-5-(trifluoromethy l)pyridin-2-yl)pyridine-2- sulfonamide;

(S)-6-(piperidin-3-ylamino)-N-(6-(o-tolyl)-5-(trifluoromethy l)pyridin-2-yl)pyridine-2- sulfonamide;

6-(((3R,4S)-4-methoxypiperidin-3-yl)amino)-N-(6-(o-tolyl)-5- (trifluoromethyl)pyridin-2- yl)pyridine-2-sulfonamide;

6-(6-amino-3-azabicyclo[3.1 .0]hexan-3-yl)-N-(6-(o-tolyl)-5-(trifluoromethyl)pyridin-2- yl)pyridine-2-sulfonamide; 6-(4-aminopiperidin-1 -yl)-N-(6-(o-tolyl)-5-(trifluoromethyl)pyridin-2-yl)py sulfonamide;

6-(4-(methylamino)piperidin-1 -yl)-N-(6-(o-tolyl)-5-(trifluoromethyl)pyridin

sulfonamide;

6-(4-amino-4-methylpiperidin-1 -yl)-N-(6-(o-tolyl)-5-(trifluoromethyl)pyridin-2-yl)pyridine -2- sulfonamide;

6-((3S,4R)-4-amino-3-fluoropiperidin-1 -yl)-N-(6-(o-tolyl)-5-(trifluoromethyl)pyridin-2- yl)pyridine-2-sulfonamide;

6-(piperidin-4-ylamino)-N-(6-(o-tolyl)-5-(trifluoromethyl)py ridin-2-yl)pyridine-2- sulfonamide;

6-(((3S,4R)-3-hydroxypiperidin-4-yl)amino)-N-(6-(o-tolyl)-5- (trifluoromethyl)pyridin-2- yl)pyridine-2-sulfonamide;

6-(((3R,4R)-3-hydroxypiperidin-4-yl)amino)-N-(6-(o-tolyl)-5- (trifluoromethyl)pyridin-2- yl)pyridine-2-sulfonamide;

6-(((3S,4R)-3-methoxypiperidin-4-yl)amino)-N-(6-(o-tolyl)-5- (trifluoromethyl)pyridin-2- yl)pyridine-2-sulfonamide;

6-(((3R,4R)-3-methoxypiperidin-4-yl)amino)-N-(6-(o-tolyl)-5- (trifluoromethyl)pyridin-2- yl)pyridine-2-sulfonamide;

6-(((3S,4R)-3-fluoropiperidin-4-yl)amino)-N-(6-(o-tolyl)-5-( trifluoromethyl)pyridin-2- yl)pyridine-2-sulfonamide;

6-((3 ,4 )-4'-hydroxy-[1 ,3'-bipyrrolidin]-1 '-yl)-N-(6-(o-tolyl)-5-(trifluoromethyl)pyridin yl)pyridine-2-sulfonamide;

(R)-6-(3-aminopyrrolidin-1 -yl)-N-(6-(o-tolyl)-5-(trifluoromethyl)pyridin-2-yl)pyridine -2- sulfonamide;

(S)-6-(3-aminopyrrolidin-1 -yl)-N-(6-(o-tolyl)-5-(trifluoromethyl)pyridin-2-yl)pyridine -2- sulfonamide;

(R)-6-(3-(methylamino)pyrrolidin-1 -yl)-N-(6-(o-tolyl)-5-(trifluoromethyl)pyridin-2- yl)pyridine-2-sulfonamide;

(S)-6-(3-(methylamino)pyrrolidin-1 -yl)-N-(6-(o-tolyl)-5-(trifluoromethyl)pyridin-2- yl)pyridine-2-sulfonamide;

(R)-6-(pyrrolidin-3-ylamino)-N-(6-(o-tolyl)-5-(trifluorometh yl)pyridin-2-yl)pyridine-2- sulfonamide;

(S)-6-(pyrrolidin-3-ylamino)-N-(6-(o-tolyl)-5-(trifluorometh yl)pyridin-2-yl)pyridine-2- sulfonamide;

N-(5-chloro-6-(2-(trifluoromethyl)phenyl)pyridin-2-yl)-6-((( 3S,4R)-4- hydroxytetrahydrofuran-3-yl)amino)pyridine-2-sulfonamide; N-(5-chloro-6-(2-(trifluoromethyl)phenyl)pyridin-2-yl)-6-((( 3R,4S)-4- hydroxytetrahydrofuran-3-yl)amino)pyridine-2-sulfonamide;

N-(5-chloro-6-(5-fluoro-2-methylphenyl)pyridin-2-yl)-6-(((3R ,4S)-4- hydroxytetrahydrofuran-3-yl)amino)pyridine-2-sulfonamide;

N-(5-chloro-6-(5-fluoro-2-methylphenyl)pyridin-2-yl)-6-(((1 S,2R,3R,4R)-3- (hydroxymethyl)-7-oxabicyclo[2.2.1 ]heptan-2-yl)amino)pyridine-2-sulfonamide;

(1 S,4S)-4-((6-(N-(5-chloro-6-(2,6-dimethylphenyl)pyridin-2-yl) sulfamoyl)pyridin-2- yl)oxy)cyclohexane-1 -carboxylic acid;

(1 R,4R)-4-((6-(N-(5-chloro-6-(2,6-dimethylphenyl)pyridin-2-yl) sulfamoyl)pyridin-2- yl)oxy)cyclohexane-1 -carboxylic acid;

N-(5-chloro-6-(2,6-dimethylphenyl)pyridin-2-yl)-6-(3-oxopipe razin-1 -yl)pyridine-2- sulfonamide;

tert-butyl 4-(6-(N-(6-(2,6-dimethylphenyl)-4-(trifluoromethyl)pyridin-2 -yl)sulfamoyl)pyridin- 2-yl)piperazine-1 -carboxylate;

N-(6-(2,6-dimethylphenyl)-4-(trifluorom

sulfonamide;

N-(5-chloro-6-(5-fluoro-2-methylphenyl)pyridin-2-yl)-6-((7S, 8aR)-7- fluorohexahydropyrrolo[1 ,2-a]pyrazin-2(1 H)-yl)pyridine-2-sulfonamide;

N-(5-chloro-6-(5-fluoro-2-methylphenyl)pyridin-2-yl)-6-((1 S,7S)-7-fluoro-1 - methylhexahydropyrrolo[1 ,2-a]pyrazin-2(1 H)-yl)pyridine-2-sulfonamide;

(S)-6-(7,7-difluorohexahydropyrrolo[1 ,2-a]pyrazin-2(1 H)-yl)-N-(6-(o-tolyl)-5- (trifluoromethyl)pyridin-2-yl)pyridine-2-sulfonamide;

6-((7S,8aS)-7-fluorohexahydropyrrolo[1 ,2-a]pyrazin-2(1 H)-yl)-N-(6-(o-tolyl)-5- (trifluoromethyl)pyridin-2-yl)pyridine-2-sulfonamide;

6-((7S,8aR)-7-fluorohexahydropyrrolo[1 ,2-a]pyrazin-2(1 H)-yl)-N-(6-(o-tolyl)-5-

(trifluoromethyl)pyridin-2-yl)pyridine-2-sulfonamide;

N-(6-(2,6-dimethylphenyl)-4-methoxypyridin-2-yl)-6-(piperazi n-1 -yl)pyridine-2- sulfonamide;

6-(4-(tert-butyl)piperazin-1 -yl)-N-(5-chloro-6-(3-fluoro-2-methylphenyl)pyridin-2- yl)pyridine-2-sulfonamide;

N-(5-chloro-6-(3-fluoro-2-methylphenyl)pyridin-2-yl)-6-(4-cy clopropylpiperazin-1 - yl)pyridine-2-sulfonamide;

6-(4-(tert-butyl)piperazin-1 -yl)-N-(6-(3-fluoro-2-methylphenyl)-5-(trifluoromethy ^ yl)pyridine-2-sulfonamide;

6-(4-(tert-butyl)piperazin-1 -yl)-N-(6-(5-fluoro-2-m

yl)pyridine-2-sulfonamide; 6-(4-cyclopropylpiperazin-1 -yl)-N-(6-(3-fluoro-2-methylphenyl)-5-(trifluoromethyl)pyrid i yl)pyridine-2-sulfonamide;

6-(4-cyclopropylpiperazin-1 -yl)-N-(6-(5-fluoro-2-methylphenyl)-5-(trifluoromethyl)pyrid in-2- yl)pyridine-2-sulfonamide;

N-(5-chloro-6-(3-fluoro-2-methylphenyl)pyridin-2-yl)-6-(5,6- dihydro-[1 ,2,4]triazolo[4,3- a]pyrazin-7(8H)-yl)pyridine-2-sulfonamide;

tert-butyl 4-(6-(N-(6-(2-cyclopropylphenyl)-5-(trifluoromethyl)pyridin- 2- yl)sulfamoyl)pyridin-2-yl)piperazine-1 -carboxylate;

N-(6-(2-cyclopropylphenyl)-5-(trifluoromethyl)pyridin-2-yl)- 6-(piperazin-1 -yl)pyridine-2- sulfonamide;

6-(4-(tert-butyl)piperazin-1 -yl)-N-(6-(5-fluoro-2-methoxyphenyl)-5-(trifluoromethyl)pyri 2-yl)pyridine-2-sulfonamide;

N-(6-(2-chlorophenyl)-5-(trifluoromethyl)pyridin-2-yl)-6-(pi perazin-1 -yl)pyridine-2^ sulfonamide;

N-(6-(3-fluoro-2-methylphenyl)-5-(trifluoromethyl)pyridin-2- yl)-6-(piperazin-1 -yl)pyridine-2- sulfonamide;

N-(6-(5-fluoro-2-methylphenyl)-5-(trifluoromethyl)pyridin-2- yl)-6-(piperazin-1 -yl)pyridine-2- sulfonamide;

N-(6-(2-chloro-4-fluorophenyl)-5-(trifluoromethyl)pyridin-2- yl)-6-(piperazin-1 -yl)pyridine-2- sulfonamide;

N-(6-(2-chloro-5-methoxyphenyl)-5-(trifluoromethyl)pyridin-2 -yl)-6-(piperazin-1 - yl)pyridine-2-sulfonamide;

N-(6-(2-chloro-3-fluorophenyl)-5-(trifluoromethyl)pyridin-2- yl)-6-(piperazin-1 -yl)pyridine-2- sulfonamide;

N-(5-chloro-6-(2-chlorophenyl)pyridin-2-yl)-6-(piperazin-1 -yl)pyridine-2-sulfonamide; N-(5-chloro-6-(2-chloro-4-fluorophenyl)pyridin-2-yl)-6-(pipe razin-1 -yl)pyridine-2- sulfonamide;

N-(5-chloro-6-(2-chloro-5-methoxyphenyl)pyridin-2-yl)-6-(pip erazin-1 -yl)pyridine-2- sulfonamide;

N-(5-chloro-6-(2-chloro-3-fluorophenyl)pyridin-2-yl)-6-(pipe razin-1 -yl)pyridine-2- sulfonamide;

6-(piperazin-1 -yl)-N-(6-(o-tolyl)-5-(trifluoromethyl)pyridin-2-yl)pyridine -2-sulfonamide; tert-butyl 4-(6-(N-(6-(o-tolyl)-5-(trifluoromethyl)pyridin-2-yl)sulfamo yl)pyridin-2- yl)piperazine-1 -carboxylate;

tert-butyl 4-(6-(N-(5-chloro-6-(2,6-dimethylphenyl)pyridin-2-yl)sulfamo yl)pyridin-2- yl)piperazine-1 -carboxylate;

N-(5-chloro-6-(2,6-dimethylphenyl)pyridin-2-yl)-6-(piperazin -1 -yl)pyridine-2-sulfonamide; tert-butyl (R)-2-(hydroxymethyl)-4-(6-(N-(6-(o-tolyl)-5-(trifluoromethy l)pyridin-2- yl)sulfamoyl)pyridin-2-yl)piperazine-1 -carboxylate;

(R)-6-(3-(hydroxymethyl)piperazin-1 -yl)-N-(6-(o-tolyl)-5-(trifluoromethyl)pyridin-2 yl)pyridine-2-sulfonamide;

tert-butyl (R)-2-methyl-4-(6-(N-(6-(o-tolyl)-5-(trifluoromethyl)pyridin -2-yl)sulfamoyl)pyridin- 2-yl)piperazine-1 -carboxylate;

(R)-6-(3-methylpiperazin-1 -yl)-N-(6-(o-tolyl)-5-(trifluoromethyl)pyridin-2-yl)pyridin sulfonamide;

tert-butyl 4-(6-(N-(5-chloro-6-(2-methyl-5-(trifluoromethyl)phenyl)pyri din-2- yl)sulfamoyl)pyridin-2-yl)piperazine-1 -carboxylate;

N-(5-chloro-6-(2-methyl-5-(trifluoromethyl)phenyl)pyridin-2- yl)-6-(piperazin-1 -yl)^ 2-sulfonamide;

(S)-6-(2-methylpiperazin-1 -yl)-N-(6-(o-tolyl)-5-(trifluoromethyl)pyridin-2-yl)pyridm sulfonamide;

(R)-6-(2-methylpiperazin-1 -yl)-N-(6-(o-tolyl)-5-(trifluoromethyl)pyridin-2-yl)pyridine -2- sulfonamide;

(R)-N-(6-(2,6-dimethylphenyl)-5-(trifluoromethyl)pyridin-2-y l)-6-(3- (hydroxymethyl)piperazin-1 -yl)pyridine-2-sulfonamide;

(S)-N-(6-(2,6-dimethylphenyl)-5-(trifluoromethyl)pyridin-2-y l)-6-(3- (hydroxymethyl)piperazin-l -yl)pyridine-2-sulfonamide;

(R)-N-(6-(5-fluoro-2-methylphenyl)-5-(trifluoromethyl)pyridi n-2-yl)-6-(3- (hydroxymethyl)piperazin-1 -yl)pyridine-2-sulfonamide;

(S)-N-(6-(5-fluoro-2-methylphenyl)-5-(trifluoromethyl)pyridi n-2-yl)-6-(3- (hydroxymethyl)piperazin-1 -yl)pyridine-2-sulfonamide;

(R)-N-(6-(5-fluoro-2-methylphenyl)-5-(trifluoromethyl)pyridi n-2-yl)-6-(3-methylpiperazin-1 - yl)pyridine-2-sulfonamide;

(S)-N-(6-(5-fluoro-2-methylphenyl)-5-(trifluoromethyl)pyridi n-2-yl)-6-(3-methylpiperazin-1 - yl)pyridine-2-sulfonamide;

6-((3S,5R)-3,5-dimethylpiperazin-1 -yl)-N-(6-(5-fluoro-2-methylphenyl)-5- (trifluoromethyl)pyridin-2-yl)pyridine-2-sulfonamide;

N-(6-(5-fluoro-2-methylphenyl)-5-(trifluoromethyl)pyridin-2- yl)-6-(4-methylpiperazin-1 - yl)pyridine-2-sulfonamide;

6-(4-acetylpiperazin-1 -yl)-N-(6-(5-fluoro-2-methylphenyl)-5-(trifluoromethyl)pyrid in-2- yl)pyridine-2-sulfonamide;

6-(3,8-diazabicyclo[3.2.1 ]octan-3-yl)-N-(6-(o-tolyl)-5-(trifluoromethyl)pyridin-2-yl) pyridine- 2-sulfonamide; 6-(4-(2-hydroxyethyl)piperazin-1-yl)-N-(6-(o-tolyl)-5-(trifl uoromethyl)pyridin-2-yl)py 2-sulfonamide;

2-(4-(6-(N-(6-(o-tolyl)-5-(trifluoromethyl)pyridin-2-yl)sulf amoyl)pyridin-2-yl)piperazin-1^ yl)acetamide;

4-(6-(N-(6-(o-tolyl)-5-(trifluoromethyl)pyridin-2-yl)sulfamo yl)pyridin-2-yl)piperazine-1- carboxamide;

6-(4-(2,2-difluoroethyl)piperazin-1-yl)-N-(6-(o-tolyl)-5-(tr ifluoromethyl)pyridin-2-yl)pyri^ 2-sulfonamide;

N-(6-(o-tolyl)-5-(trifluoromethyl)pyridin-2-yl)-6-(4-(2,2,2- trifluoroethyl)piperazin-1- yl)pyridine-2-sulfonamide;

6-(4-(oxetan-3-yl)piperazin-1-yl)-N-(6-(o-tolyl)-5-(trffl^

sulfonamide;

tert-butyl 4-(6-(N-(5-chloro-6-(2,6-dimethylphenyl)pyridin-2-yl)sulfamo yl)pyridin-2-yl)-3- oxopiperazine-1 -carboxylate

6-(4-methylpiperazin-1-yl)-N-(6-(o-tolyl)-5-(trifluoromethyl )pyridin-2-yl)pyridine-2- sulfonamide;

6-(3-oxopiperazin-1-yl)-N-(6-(o-tolyl)-5-(trifluoromethyl)py ridin-2-yl)pyridine-2- sulfonamide;

6-(4-glycylpiperazin-1 -yl)-N-(6-(o-tolyl)-5-(trifluoromethyl)pyridin-2-yl)pyridine -2- sulfonamide;

N-(5-chloro-6-(2,6-dimethylphenyl)pyridin-2-yl)-6-(2-oxopipe razin-1-yl)pyridine-2- sulfonamide;

N-(5-chloro-6-(5-fluoro-2-methylphenyl)pyridin-2-yl)-6-(pipe razin-1-yl)pyridine-2- sulfonamide;

N-[5-chloro-6-(3-fluoro-2-methylphenyl)pyridin-2-yl]-6-(pipe razin-1-yl)pyridine-2- sulfonamide;

N-(5-chloro-6-(o-tolyl)pyridin-2-yl)-6-(piperazin-1-yl)pyrid ine-2-sulfonamide;

6-(4-methyl-3-oxopiperazin-1 -yl)-N-(6-(o-tolyl)-5-(trifluoromethyl)pyridin-2-yl)pyridine -2- sulfonamide;

N-(5-chloro-6-(2,6-dimethylphenyl)pyridin-2-yl)-6-(4-methyl- 2-oxopiperazin-1-yl)pyridine- 2-sulfonamide;

N-(5-chloro-6-(2,6-dimethylphenyl)pyridin-2-yl)-6-(5,6-dihyd roimidazo[1 ,2-a]pyrazin- 7(8H)-yl)pyridine-2-sulfonamide;

N-(5-chloro-6-(2,6-dimethylphenyl)pyridin-2-yl)-6-(2-(triflu oromethyl)-5,6- dihydroimidazo[1 ,2-a]pyrazin-7(8H)-yl)pyridine-2-sulfonamide;

6-((1 S,4S)-2,5-diazabicyclo[2.2.2]octan-2-yl)-N-(6-(5-fluoro-2-me thylphenyl)-5- (trifluoromethyl)pyridin-2-yl)pyridine-2-sulfonamide; 6-(2,5-diazabicyclo[2.2.2]octan-2-yl)-N-(6-(5-fluoro-2-methy lphenyl)-5- (trifluoromethyl)pyridin-2-yl)pyridine-2-sulfonamide;

6-((5S)-1 ,4-diazabicyclo[3.2.1 ]octan-4-yl)-N-(6-(5-fluoro-2-methylphenyl)-5- (trifluoromethyl)pyridin-2-yl)pyridine-2-sulfonamide;

6-((1 S,4S)-2,5-diazabicyclo[2.2.1 ]heptan-2-yl)-N-(6-(o-tolyl)-5-(trifluoromethyl)pyridin-2- yl)pyridine-2-sulfonamide;

6-(3-hydroxy-3-(trifluoromethyl)azetidin-1 -yl)-N-(6-(o-tolyl)-5-(trifluoromethyl)pyridin-^ yl)pyridine-2-sulfonamide;

N-(6-(2,6-dimethylphenyl)-4-(trifluoromethyl)pyridin-2-yl)-6 -(3-hydroxyazetidin-1 - yl)pyridine-2-sulfonamide;

N-(6-(2,6-dimethylphenyl)-4-methoxypyridin-2-yl)-6-(3-hydrox y-3-methylazetidin-1 - yl)pyridine-2-sulfonamide;

N-(5-bromo-6-(o-tolyl)pyridin-2-yl)-6-(3-hydroxy-3-methylaze tidin-1 -yl)pyridine-2- sulfonamide;

N-(6-(2-cyclopropylphenyl)-5-(trifluoromethyl)pyridin-2-yl)- 6-(3-hydroxyazetidin-1 - yl)pyridine-2-sulfonamide;

N-(6-(5-fluoro-2-methoxyphenyl)-5-(trifluoromethyl)pyridin-2 -yl)-6-(3-hydroxyazetidin-1 - yl)pyridine-2-sulfonamide;

N-(5-chloro-6-(2,6-dimethylphenyl)pyridin-2-yl)-6-(3-hydroxy -3-methylazetidin-1 - yl)pyridine-2-sulfonamide;

N-(5-chloro-6-(2,6-dimethylphenyl)pyridin-2-yl)-6-(3-cyclopr opyl-3-hydroxyazetidin-1 - yl)pyridine-2-sulfonamide;

N-(5-chloro-6-(2-methyl-5-(trifluoromethyl)phenyl)pyridin-2- yl)-6-(3-hydroxy-3- methylazetidin-1 -yl)pyridine-2-sulfonamide;

N-(5-chloro-6-(2-chloro-4-fluorophenyl)pyridin-2-yl)-6-(3-hy droxy-3-methylazetidin-1 - yl)pyridine-2-sulfonamide;

N-(5-chloro-6-(2-chloro-4-fluorophenyl)pyridin-2-yl)-6-(3-hy droxyazetidin-1 -yl)pyridine-2- sulfonamide;

N-(6-(3-fluoro-2-methylphenyl)-5-(trifluoromethyl)pyridin-2- yl)-6-(3-hydroxy-3- methylazetidin-1 -yl)pyridine-2-sulfonamide;

N-(6-(3-fluoro-2-methylphenyl)-5-(trifluoromethyl)pyridin-2- yl)-6-(3-hydroxyazetidin-1 - yl)pyridine-2-sulfonamide;

N-(6-(4-fluoro-2-methylphenyl)-5-(trifluoromethyl)pyridin-2- yl)-6-(3-hydroxy-3- methylazetidin-1 -yl)pyridine-2-sulfonamide;

N-(6-(4-fluoro-2-methylphenyl)-5-(trifluoromethyl)pyridin-2- yl)-6-(3-hydroxyazetidin-1 - yl)pyridine-2-sulfonamide; N-(6-(5-fluoro-2-methylphenyl)-5-(trifluoromethyl)pyridin-2- yl)-6-(3-hydroxy-3- methylazetidin-1 -yl)pyridine-2-sulfonamide;

N-(6-(5-fluoro-2-methylphenyl)-5-(trifluoromethyl)pyridin-2- yl)-6-(3-hydroxyazetidin-1 - yl)pyridine-2-sulfonamide;

N-(6-(2-chlorophenyl)-5-(trifluoromethyl)pyridin-2-yl)-6-(3- hydroxy-3-methylazetidin-1 - yl)pyridine-2-sulfonamide;

N-(6-(2-chlorophenyl)-5-(trifluoromethyl)pyridin-2-yl)-6-(3- hydroxyazetidin-1 -yl)pyridi sulfonamide;

N-(5-chloro-6-(2-methyl-5-(trifluoromethyl)phenyl)pyridin-2- yl)-6-(3-hydroxyazetidin-1 - yl)pyridine-2-sulfonamide;

6-(3-hydroxyazetidin-1 -yl)-N-(5-(trifluoromethyl)-6-(2-(trifluoromethyl)phenyl)pyr idin yl)pyridine-2-sulfonamide;

N-(6-(2-chloro-4-fluorophenyl)-5-(trifluoromethyl)pyridin-2- yl)-6-(3-hydroxyazetidin-1 - yl)pyridine-2-sulfonamide;

N-(6-(2-chloro-5-methoxyphenyl)-5-(trifluoromethyl)pyridin-2 -yl)-6-(3-hydroxyazetidin-1 - yl)pyridine-2-sulfonamide;

N-(5-chloro-6-(2-chlorophenyl)pyridin-2-yl)-6-(3-hydroxyazet idin-1 -yl)pyridine-2- sulfonamide;

N-(5-chloro-6-(2-chloro-5-methoxyphenyl)pyridin-2-yl)-6-(3-h ydroxyazetidin-1 -yl)pyridine- 2-sulfonamide;

N-(5-chloro-6-(2-chloro-3-fluorophenyl)pyridin-2-yl)-6-(3-hy droxyazetidin-1 -yl)pyridine-^^ sulfonamide;

N-(6-(2-chloro-3-fluorophenyl)-5-(trifluoromethyl)pyridin-2- yl)-6-(3-hydroxyazetidin-1 - yl)pyridine-2-sulfonamide;

N-(5-chloro-6-(2,6-dimethylphenyl)pyridin-2-yl)-6-(3-hydroxy azetidin-1 -yl)pyridine-2- sulfonamide;

N-(5-chloro-6-(3-fluoro-2-methylphenyl)pyridin-2-yl)-6-(3-hy droxyazetidin-1 -yl)pyridine-2- sulfonamide;

6-(3-hydroxyazetidin-1 -yl)-N-(6-(o-tolyl)-5-(trifluoromethyl)pyridin-2-yl)pyridine -2- sulfonamide;

N-(5-chloro-6-(5-fluoro-2-methylphenyl)pyridin-2-yl)-6-(3-hy droxyazetidin-1 -yl)pyridine-2- sulfonamide;

N-(5-chloro-6-(5-fluoro-2-methylphenyl)pyridin-2-yl)-6-(3-hy droxy-3- (hydroxymethyl)azetidin-1 -yl)pyridine-2-sulfonamide;

methyl 1 -(6-(N-(6-(2-cyclopropylphenyl)-5-(trifluoromethyl)pyridin-2 -yl)sulfamoyl)pyridin-2- yl)-4-methylpiperidine-4-carboxylate; 1 -(6-(N-(6-(2-cyclopropylphenyl)-5-(trifluoromethyl)pyridin-2 -yl)sulfamoyl)pyridin-2 methylpiperidine-4-carboxylic acid;

1 -(6-(N-(6-(2-chlorophenyl)-5-(trifluoromethyl)pyridin-2-yl)s ulfamoyl)pyridin-2-yl)-4- methylpiperidine-4-carboxylic acid;

1 -(6-(N-(5-chloro-6-(2-chlorophenyl)pyridin-2-yl)sulfamoyl)py ridin-2-yl)-4- methylpiperidine-4-carboxylic acid;

1 -(6-(N-(6-(2-chloro-4 1uorophenyl)-5-(trifluor^

4-methylpiperidine-4-carboxylic acid;

1 -(6-(N-(6-(2-chloro-5-methoxyphenyl)-5-(trifluoromethyl)pyri din-2-yl)sulfamoyl)pyridin yl)-4-methylpiperidine-4-carboxylic acid;

1 -(6-(N-(6-(2-chloro-3 1uorophenyl)-5-(trifluoro

4-methylpiperidine-4-carboxylic acid;

1 -(6-(N-(5-chloro-6-(2-chloro-4-fluorophenyl)pyridin-2-yl)sul famoyl)pyridin-2-yl)-4- methylpiperidine-4-carboxylic acid;

1 -(6-(N-(5-chloro-6-(2-chloro-5-methoxyphenyl)pyridin-2-yl)su lfamoyl)pyridin-2-yl)-4- methylpiperidine-4-carboxylic acid;

1 -(6-(N-(5-chloro-6-(2-chloro-3-fluorophenyl)pyridin-2-yl)sul famoyl)pyridin-2-yl)-4- methylpiperidine-4-carboxylic acid;

methyl 1 -(6-(N-(5-chloro-6-(2,6-dimethylphenyl)pyridin-2-yl)sulfamoy l)pyridin-2- yl)piperidine-4-carboxylate;

1 -(6-(N-(5-chloro-6-(2,6-dimethylphenyl)pyridin-2-yl)sulfamoy l)pyridin-2-yl)piperidine-4- carboxylic acid;

1 -(6-(N-(5-chloro-6-(2,6-dimethylphenyl)pyridin-2-yl)sulfamoy l)pyridin-2-yl)-4- ethylpiperidine-4-carboxylic acid;

ethyl 1 -(6-(N-(5-chloro-6-(2,6-dimethylphenyl)pyridin-2-yl)sulfamoy l)pyridin-2-yl)-4- methylpiperidine-4-carboxylate;

1 -(6-(N-(5-chloro-6-(2,6-dimethylphenyl)pyridin-2-yl)sulfamoy l)pyridin-2-yl)-4- methylpiperidine-4-carboxylic acid;

ethyl 1 -(6-(N-(6-(5-fluoro-2-methylphenyl)-5-(trifluoromethyl)pyrid in-2-yl)sulfamoyl)pyridin- 2-yl)-4-methylpiperidine-4-carboxylate;

ethyl 1 -(6-(N-(5-chloro-6-(3-fluoro-2-methylphenyl)pyridin-2-yl)sul famoyl)pyridin-2-yl)-4- methylpiperidine-4-carboxylate;

1 -(6-(N-(5-chloro-6-(3-fluoro-2-methylphenyl)pyridin-2-yl)sul famoyl)pyridin-2-yl)-4- methylpiperidine-4-carboxylic acid;

ethyl 1 -(6-(N-(5-chloro-6-(o-tolyl)pyridin-2-yl)sulfamoyl)pyridin-2 -yl)-4-methylpiperidine-4- carboxylate; 1 -(6-(N-(5-chloro-6-(o-tolyl)pyridin-2-yl)sulfamoyl)pyridin-2 -yl)-4-methylpiperid carboxylic acid;

ethyl 1 -(6-(N-(5-chloro-6-(5-fluoro-2-methylphenyl)pyridin-2-yl)sul famoyl)pyridin-2-yl)-4- methylpiperidine-4-carboxylate;

1 -(6-{[5-chloro-6-(5-fluoro-2-methylphenyl)pyridin-2-yl]sulfa moyl}pyridin-2-yl)-4- methylpiperidine-4-carboxylic acid;

ethyl 1 -(6-{[6-(3-fluoro-2-methylphenyl)-5-(trifluoromethyl)pyridin -2-yl]sulfamoyl}pyridin-2- yl)-4-methylpiperidine-4-carboxylate;

ethyl 4-methyl-1 -(6-{[6-(2-methylphenyl)-5-(trifluoromethyl)pyridin-2-yl]sul famoyl}pyridin- 2-yl)piperidine-4-carboxylate;

methyl 1 -(6-{[5-chloro-6-(2,6-dimethylphenyl)pyridin-2-yl]sulfamoyl} pyridin-2-yl)-4- hydroxypiperidine-4-carboxylate;

1 -(6-{[5-chloro-6-(2,6-dimethylphenyl)pyridin-2-yl]sulfamoyl} pyridin-2-yl)-4- hydroxypiperidine-4-carboxylic acid;

1 -(6-{[6-(5-fluoro-2-methylphenyl)-5-(trifluoro

methylpiperidine-4-carboxylic acid;

1 -(6-(N-(6-(3-fluoro-2-methylphenyl)-5-(trifluoromethyl)pyrid in-2-yl)sulfamoyl)pyridin-2-y ^ 4-methylpiperidine-4-carboxylic acid;

4-methyl-1 -(6-(N-(6-(o-tolyl)-5-(trifluoromethyl)pyridin-2-yl)sulfamoy l)pyridin-2- yl)piperidine-4-carboxylic acid;

1 -(6-{[6-(3-fluoro-2-methylphenyl)-5-(trifluoromethyl)pyridin -2-yl]sulfamoyl}pyridin-2-yl)-4^ methylpiperidine-4-carboxylic acid;

4-methyl-1 -(6-{[6-(2-methylphenyl)-5-(trifluoromethyl)pyridin-2-yl]sul famoyl}pyridin-2- yl)piperidine-4-carboxylic acid;

1 -(6-{[6-(2,6-dimethylphenyl)-5-(trifluoromethyl)pyridin-2-yl ]sulfamoyl}pyridin-2-yl)-4- methylpiperidine-4-carboxylic acid;

ethyl 1 -(6-{[6-(2,6-dimethylphenyl)-5-(trifluoromethyl)pyridin-2-yl ]sulfamoyl}pyridin-2-yl)-4- methylpiperidine-4-carboxylate;

methyl 4-{[(tert-butoxy)carbonyl]amino}-1 -(6-{[5-chloro-6-(2,6-dimethylphenyl)pyridin-2- yl]sulfamoyl}pyridin-2-yl)piperidine-4-carboxylate;

4-{[(tert-butoxy)carbonyl]amino}-1 -(6-{[5-chloro-6-(2,6-dimethylphenyl)pyridin-2- yl]sulfamoyl}pyridin-2-yl)piperidine-4-carboxylic acid;

4-amino-1 -(6-{[5-chloro-6-(2,6-dimethylphenyl)pyridin-2-yl]sulfamoyl} pyridin-2- yl)piperidine-4-carboxylic acid;

methyl 4-amino-1 -(6-{[5-chloro-6-(2,6-dimethylphenyl)pyridin-2-yl]sulfamoyl} pyridin-2- yl)piperidine-4-carboxylate; N-[5-chloro-6-(2,6-dimethylphenyl)pyridin-2-yl]-6-[(oxan-4-y l)amino]pyridine-2- sulfonamide;

rac-N-[5-chloro-6-(5-fluoro-2-methylphenyl)pyridin-2-yl]-6-{ [(3R,4R)-3-hydroxyoxan-4- yl]amino}pyridine-2-sulfonamide;

N-[5-chloro-6-(5-fluoro-2-methylphenyl)pyridin-2-yl]-6-{[(3S ,4R)-3-hydroxyoxan-4- yl]amino}pyridine-2-sulfonamide;

rac-6-{[(3R,4R)-3-hydroxyoxan-4-yl]amino}-N-[6-(2-methylphen yl)-5- (trifluoromethyl)pyridin-2-yl]pyridine-2-sulfonamide;

6-{[(3S,4R)-3-hydroxyoxan-4-yl]amino}-N-[6-(2-methylphenyl)- 5-(trifluoromethyl)pyridin-2- yl]pyridine-2-sulfonamide;

6-{[(3R,4R)-3-hydroxyoxan-4-yl]amino}-N-[6-(2-methylphenyl)- 5-(trifluoromethyl)pyridin-2- yl]pyridine-2-sulfonamide;

6-{[(3S,4S)-3-hydroxyoxan-4-yl]amino}-N-[6-(2-methylphenyl)- 5-(trifluoromethyl)pyridin-2- yl]pyridine-2-sulfonamide;

N-[5-chloro-6-(5-fluoro-2-methylphenyl)pyridin-2-yl]-6-{[(3R ,4R)-4-hydroxyoxan-3- yl]amino}pyridine-2-sulfonamide;

6-{[(3R,4R)-4-hydroxyoxan-3-yl]amino}-N-[6-(2-methylphenyl)- 5-(trifluoromethyl)pyridin-2- yl]pyridine-2-sulfonamide;

rac-6-{[(3R,4S)-4-hydroxyoxan-3-yl]amino}-N-[6-(2-methylphen yl)-5- (trifluoromethyl)pyridin-2-yl]pyridine-2-sulfonamide;

6-{[(3R,4S)-4-hydroxyoxan-3-yl]amino}-N-[6-(2-methylphenyl)- 5-(trifluoromethyl)pyridin-2- yl]pyridine-2-sulfonamide;

6-{[(3S,4R)-4-hydroxyoxan-3-yl]amino}-N-[6-(2-methylphenyl)- 5-(trifluoromethyl)pyridin-2- yl]pyridine-2-sulfonamide;

N-[6-(2-methylphenyl)-5-(trifluoromethyl)pyridin-2-yl]-6-{[( 1 s,3s)-3- hydroxycyclobutyl]amino}pyridine-2-sulfonamide;

N-[6-(2-methylphenyl)-5-(trifluoromethyl)pyridin-2-yl]-6-{[( 1 r,3r)-3- hydroxycyclobutyl]amino}pyridine-2-sulfonamide;

N-[5-chloro-6-(2,6-dimethylphenyl)pyridin-2-yl]-6-{[(1 r,3s)-3-hydroxy-3- methylcyclobutyl]amino}pyridine-2-sulfonamide;

N-[5-chloro-6-(2,6-dimethylphenyl)pyridin-2-yl]-6-{[(1 s,3s)-3- hydroxycyclobutyl]amino}pyridine-2-sulfonamide;

N-[5-chloro-6-(2,6-dimethylphenyl)pyridin-2-yl]-6-{[(1 r,3r)-3- hydroxycyclobutyl]amino}pyridine-2-sulfonamide;

N-[5-chloro-6-(2,6-dimethylphenyl)pyridin-2-yl]-6-{[(3S,5S)- 5-(hydroxymethyl)oxolan-3- yl]oxy}pyridine-2-sulfonamide; N-[5-chloro-6-(5-fluoro-2-methylphenyl)pyridin-2-yl]-6-{[(3R ,4S)-4-hydroxyoxolan-3- yl]oxy}pyridine-2-sulfonamide;

rac-N-[5-chloro-6-(2,6-dimethylphenyl)pyridin-2-yl]-6-{[(3R, 4S)-4-hydroxyoxolan-3- yl]oxy}pyridine-2-sulfonamide;

rac-6-{[(3RS,4SR)-4-hydroxyoxolan-3-yl]oxy}-N-[6-(2-methylph enyl)-5- (trifluoromethyl)pyridin-2-yl]pyridine-2-sulfonamide;

rac-N-[6-(2-methylphenyl)-5-(trifluoromethyl)pyridin-2-yl]-6 -[(4-oxooxolan-3- yl)oxy]pyridine-2-sulfonamide;

rac-6-{[(3RR,4SR)-4-hydroxy-4-methyloxolan-3-yl]oxy}-N-[6-(2 -methylphenyl)-5- (trifluoromethyl)pyridin-2-yl]pyridine-2-sulfonamide;

6-{[(3R,4R)-4-hydroxy-4-methyloxolan-3-yl]oxy}-N-[6-(2-methy lphenyl)-5- (trifluoromethyl)pyridin-2-yl]pyridine-2-sulfonamide;

6-{[(3R,4S)-4-hydroxy-4-methyloxolan-3-yl]oxy}-N-[6-(2-methy lphenyl)-5- (trifluoromethyl)pyridin-2-yl]pyridine-2-sulfonamide;

6-{[(3R,4S)-4-hydroxyoxolan-3-yl]oxy}-N-[6-(2-methylphenyl)- 5-(trifluoromethyl)pyridin-2- yl]pyridine-2-sulfonamide;

ethyl 1 -(4-(6-(N-(6-(5-fluoro-2-methylphenyl)-5-(trifluoromethyl)py ridin-2- yl)sulfamoyl)pyridin-2-yl)piperazin-1 -yl)cyclopropane-1 -carboxylate;

tert-butyl 4-(6-(N-(5-chloro-6-(5-fluoro-2-methylphenyl)pyridin-2-yl)su lfamoyl)pyridin-2- yl)piperazine-1 -carboxylate;

A/-(6-(5-cyano-2-methylphenyl)-5-(trifluoromethyl)pyridin-2- yl)-6-(3-hydroxy-3- methylazetidin-1 -yl)pyridine-2-sulfonamide;

1 -(6-(N-(6-(5-fluoro-2-methylphenyl)-5-(trifluoromethyl) pyridin-2-yl) sulfamoyi) pyridin-2- yl) pyrrolidine-3-carboxylic acid;

tert-butyl 1 -(6-(N-(6-(o-tolyl)-5-(trifluoromethyl)pyridin-2-yl)sulfamoy l)pyridin-2-yl)-1 ,6- diazaspiro[3.3]heptane-6-carboxylate;

6-(47-diazaspiro[2.5]octan-7-yl)-N-(6-(o-tolyl)-5-(trifluoro methyl)pyridin-2-yl)pyridine-2- sulfonamide;

6-(8-amino-5-oxa-2-azaspiro[3 ]octan-2-yl)-N-(6-(o-tolyl)-5-(trifluoromethyl)pyridin-2- yl)pyridine-2-sulfonamide;

(R)-6-(1 -amino-8-azaspiro[4.5]decan-8-yl)-N-(6-(o-tolyl)-5-(trifluor omethyl)pyridin-2- yl)pyridine-2-sulfonamide;

A/-(5-chloro-6-(5-cyano-2-methylphenyl)pyridin-2-yl)-6-(3-hy droxy-3-methylazetidin-1 ^ yl)pyridine-2-sulfonamide;

(S)-6-(1 -amino-7-azaspiro[3.5]nonan-7-yl)-N-(6-(o-tolyl)-5-(trifluor omethyl)pyridin-2- yl)pyridine-2-sulfonamide; 6-((1 R)-1 -amino-2-(hydroxymethyl)-8-azaspiro[4.5]decan-8-yl)-N-(6-(o- tolyl)-5- (trifluoromethyl)pyridin-2-yl)pyridine-2-sulfonamide;

A/-(6-(3-cyano-2-methylphenyl)-5-(trifluoromethyl)pyridin-2- yl)-6-(3-hydroxy-3- methylazetidin-1 -yl)pyridine-2-sulfonamide;

N-(5-chloro-6-(3-cyano-2-methylphenyl)pyridin-2-yl)-6-(3-hyd roxy-3-methylazetidin-1 - yl)pyridine-2-sulfonamide;

N-(5-chloro-6-(5-fluoro-2-methylphenyl)pyridin-2-yl)-6-(1 ,6-diazaspiro[3.3]heptan-1 - yl)pyridine-2-sulfonamide;

A/-(6-(5-cyano-2-methylphenyl)-5-(trifluoromethyl)pyridin-2- yl)-6-(piperazin-1 -yl)pyridi 2-sulfonamide;

A/-(5-chloro-6-(5-cyano-2-methylphenyl)pyridin-2-yl)-6-(pipe razin-1 -yl)pyridine-2- sulfonamide;

6-(1 ,6-diazaspiro[3.3]heptan-1 -yl)-N-(6-(o-tolyl)-5-(trifluoromethyl)pyridin-2-yl)pyridine -2- sulfonamide;

6-((2R,3S)-3-hydroxy-2-methylpyrrolidin-1 -yl)-N-(6-(o-tolyl)-5-(trifluoromethyl)pyridin-2- yl)pyridine-2-sulfonamide;

1 -(6-(A/-(6-(5-fluoro-2-methylphenyl)-5-(trifluorom

3- hydroxypyrrolidine-2-carboxylic acid;

6-{[(3S,4R)-4-hydroxyoxolan-3-yl]oxy}-N-[6-(2-methylphenyl)- 5-(trifluoromethyl)pyridin-2- yl]pyridine-2-sulfonamide;

A/-(6-(5-cyano-2-methylphenyl)-5-(trifluoromethyl)pyridin-2- yl)-2-(3-hydroxy-3- methylazetidin-1 -yl)pyridine-4-sulfonamide;

(R)-A/-(5-chloro-6-(5-fluoro-2-methylphenyl)pyridin-2-yl)-2- (3-methylmorpholino)pyrid

4- sulfonamide;

(R)-A/-(5-chloro-6-(3-fluoro-2-methylphenyl)pyridin-2-yl)-2- (3-methylmorpholino)pyrid 4-sulfonamide;

A/-(6-(5-fluoro-2-methylphenyl)-5-(trifluoromethyl)pyridin-2 -yl)-2-(3-hydroxy-3- methylazetidin-1-yl)pyridine-4-sulfonamide;

(R)-A/-(6-(5-fluoro-2-methylphenyl)-5-(trifluoromethyl)pyrid in-2-yl)-2-(3- methylmorpholino)pyridine-4-sulfonamide;

A/-(5-chloro-6-(5-fluoro-2-methylphenyl)pyridin-2-yl)-2-(3-h ydroxyazetidin-1 -yl)pyridin sulfonamide;

A/-(5-chloro-6-(3-fluoro-2-methylphenyl)pyridin-2-yl)-2-(3-h ydroxyazetidin-1 -yl)pyridine-4- sulfonamide;

A/-(6-(5-fluoro-2-methylphenyl)-5-(trifluoromethyl)pyridin-2 -yl)-2-(3-hydroxyazetidin-1 - yl)pyridine-4-sulfonamide; 2- (3-hydroxyazetidin-1 -yl)-A/-(5-(trifluoromethyl)-6-(2-(trifluoromethyl)phenyl)py yl)pyridine-4-sulfonamide;

A/-(6-(5-fluoro-2-methylphenyl)-5-(trifluoromethyl)pyridin-2 -yl)-2-(piperazin-1 -yl)pyri^ sulfonamide;

A/-(5-chloro-6-(5-fluoro-2-methylphenyl)pyridin-2-yl)-2-(pip erazin-1 -yl)pyridine-4- sulfonamide;

(R)-1 -(6-(N-(6-(2-ethoxyphenyl)-5-(trifluoromethyl)pyridin-2-yl)s ulfamoyl)pyridin-2-^ methylpiperidine-3-carboxylic acid;

(R)-3-methyl-1 -(6-(N-(6-(2-propoxyphenyl)-5-(trifluoromethyl)pyridin-2- yl)sulfamoyl)pyridin-2-yl)piperidine-3-carboxylic acid;

1 -(6-(N-(6-(o-tolyl)-5-(trifluoromethyl)pyridin-2-yl)sulfamoy l)pyridin-2-yl)azetidine^ carboxylic acid;

3- ((6-(N-(6-(o-tolyl)-5-(trifluoromethyl)pyridin-2-yl)sulfamoy l)pyridin-2- yl)oxy)cyclobutanecarboxylic acid;

(3R)-1 -(6-{[6-(2-methylphenyl)-5-(trifluoromethyl)pyridin-2-yl]sul famoyl}pyridin-2- yl)piperidine-3-carboxylic acid;

(3S)-1 -(6-{[6-(2-methylphenyl)-5-(trifluorom

yl)piperidine-3-carboxylic acid;

(2S)-1 -[(tert-butoxy)carbonyl]-4-(6-{[6-(2-methylphenyl)-5-(triflu oromethyl)pyridin-2- yl]sulfamoyl}pyridin-2-yl)piperazine-2-carboxylic acid;

(2S)-4-(6-{[6-(2-methylphenyl)-5-(trifluorom

yl)piperazine-2-carboxylic acid;

3-methyl-1 -(6-{[6-(2-methylphenyl)-5-(trifluoromethyl)pyridin-2-yl]sul famoyl}pyri yl)pyrrolidine-3-carboxylic acid;

3-methyl-1 -(6-{[6-(2-methylphenyl)-5-(trifluoromethyl)pyridin-2-yl]sul famoyl}pyri yl)piperidine-3-carboxylic acid;

(2R)-1 -[(tert-butoxy)carbonyl]-4-(6-{[6-(2-methylphenyl)-5-(triflu oromethyl)pyridin-2- yl]sulfamoyl}pyridin-2-yl)piperazine-2-carboxylic acid;

(2R)-4-(6-{[6-(2-methylphenyl)-5-(trifluoromethyl)pyridin-2- yl]sulfamoyl}pyridin-2- yl)morpholine-2-carboxylic acid;

(1 R,2S,5S)-3-(6-{[6-(2-methylphenyl)-5-(trifluoromethyl)pyridi n-2-yl]sulfamoyl}pyridin-2^ yl)-3-azabicyclo[3.1 .0]hexane-2-carboxylic acid;

(2R)-4-(6-{[6-(2-methylphenyl)-5-(trifluoromethyl)pyridin-2- yl]sulfamoyl}pyridin-2- yl)piperazine-2-carboxylic acid;

4-((6-(N-(6-(o-tolyl)-5-(trifluoromethyl)pyridin-2-yl)sulfam oyl)pyridin-2- yl)oxy)cyclohexanecarboxylic acid; 4-methyl-1 -(6-(N-(6-(2-morpholinophenyl)-5-^

2-yl)piperidine-4-carboxylic acid;

1 -(6-{[6-(2-methylphenyl)-5-(trifluoromethyl)pyridin-2-yl]sul famoyl}pyridin-2-yl)pipen^ 4-carboxylic acid;

9-(6-{[6-(2-methylphenyl)-5-(trifluoromethyl)pyridin-2-yl]su lfamoyl}pyridin-2-yl)-9- azabicyclo[3.3.1 ]nonane-3-carboxylic acid;

8-(6-{[6-(2-methylphenyl)-5-(trifluoromethyl)pyridin-2-yl]su lfamoyl}pyridin-2-yl)-8- azabicyclo[3.2.1 ]octane-3-carboxylic acid;

(2R)-4-[(tert-butoxy)carbonyl]-1 -(6-{[6-(2-methylphenyl)-5-(trifluoromethyl)pyridin-2- yl]sulfamoyl}pyridin-2-yl)piperazine-2-carboxylic acid;

(3S)-1 -(6-{[6-(2-methylphenyl)-5-(trifluoromethyl)pyridin-2-yl]sul famoyl}pyridin-2- yl)pyrrolidine-3-carboxylic acid;

(3R)-1 -(6-{[6-(2-methylphenyl)-5-(trifluoromethyl)pyridin-2-yl]sul famoyl}pyridin-2- yl)pyrrolidine-3-carboxylic acid;

(2S)-4-[(tert-butoxy)carbonyl]-1 -(6-{[6-(2-methylphenyl)-5-(trifluoromethyl)pyridin-2- yl]sulfamoyl}pyridin-2-yl)piperazine-2-carboxylic acid;

1 -(6-{[6-(2-ethylphenyl)-5-(trifluoromethyl)pyridin-2-yl]sulf amoyl}pyridin-2-yl)-4- propylpiperidine-4-carboxylic acid;

1 -(6-{[6-(2-ethylphenyl)-5-(trifluoromethyl)pyridin-2-yl]sulf amoyl}pyridin-2-yl)-3- propylpiperidine-3-carboxylic acid;

(2R)-1 -(6-{[6-(2-methylphenyl)-5-(trifluoromethyl)pyridin-2-yl]sul famoyl}pyridin-2- yl)piperazine-2-carboxylic acid;

(2S)-1 -(6-{[6-(2-methylphenyl)-5-(trifluoromethyl)pyridin-2-yl]sul famoyl}pyridin-2- yl)piperazine-2-carboxylic acid;

(1 r,3r)-3-((6-(N-(6-(o-tolyl)-5-(trifluoromethyl)pyridin-2-yl) sulfamoyl)pyridin-2- yl)amino)cyclobutanecarboxylic acid;

(1 s,3s)-1 -methyl-3-((6-(N-(6-(o-tolyl)-5-(trifluoromethyl)pyridin-2-y l)sulfamoyl)pyridi yl)amino)cyclobutanecarboxylic acid;

(3R)-1 -(6-{[6-(5-fluoro-2-methylphenyl)-5-(trifluoromethyl)pyridin -2-yl]sulfamoyl}pyrid yl)piperidine-3-carboxylic acid;

(3R)-1 -(6-{[6-(3-fluoro-2-methylphenyl)-5-(trifluoromethyl)pyridin -2-yl]sulfamoyl}pyrid yl)piperidine-3-carboxylic acid;

(3S)-1 -(6-{[6-(5-fluoro-2-methylphenyl)-5-(trifluoromethyl)pyridin -2-yl]sulfamoyl}pyridin^ yl)piperidine-3-carboxylic acid;

(3S)-1 -(6-{[6-(3-fluoro-2-methylphenyl)-5-(trifluoromethyl)pyridin -2-yl]sulfamoyl}pyridin^ yl)piperidine-3-carboxylic acid; 1 -(6-{[6-(5-fluoro-2-methylphenyl)-5-(trifluoromethyl)pyridin -2-yl]sulfamoyl}pyridi methylpiperidine-3-carboxylic acid;

1 -(6-{[6-(3-fluoro-2-methylphenyl)-5-(trifluoromethyl)pyridin -2-yl]sulfamoyl}pyridin-2-y ^ methylpiperidine-3-carboxylic acid;

1 -(6-(N-(6-(2-cyclobutylphenyl)-5-(trifluoromethyl)pyridin-2- yl)sulfamoyl)pyridin-2-yl)-4- methylpiperidine-4-carboxylic acid;

(1 r,4r)-4-((6-(N-(6-(o-tolyl)-5-(trifluoromethyl)pyridin-2-yl) sulfamoyl)pyridin-2- yl)amino)cyclohexanecarboxylic acid;

(1 r,3s)-1 -methyl-3-[(6-{[6-(2-methylphenyl)-5-(trifluoromethyl)pyridi n-2- yl]sulfamoyl}pyridin-2-yl)amino]cyclobutane-1 -carboxylic acid;

(R)-1 -(6-(N-(6-(2-cyclobutylphenyl)-5-(trifluoromethyl)pyridin-2- yl)sulfamoyl)pyridin-2- yl)piperidine-3-carboxylic acid;

(S)-1 -(6-(N-(6-(2-cyclobutylphenyl)-5-(trifluoromethyl)pyridin-2- yl)sulfamoyl)pyridin-2- yl)piperidine-3-carboxylic acid;

1 -(6-(N-(6-(2-cyclobutylphenyl)-5-(trifluoromethyl)pyridin-2- yl)sulfamoyl)pyridin-2-yl)-3- methylpiperidine-3-carboxylic acid;

(R)-1 -(6-(N-(6-(2-ethylphenyl)-5-(trifluoromethyl)pyridin-2-yl)su lfamoyl)pyridin-2- yl)piperidine-3-carboxylic acid;

(S)-1 -(6-(N-(6-(2-ethylphenyl)-5-(trifluoromethyl)pyridin-2-yl)su lfamoyl)pyridin-2- yl)piperidine-3-carboxylic acid;

1 -(6-(N-(6-(2-ethylphenyl)-5-(trifluoromethyl)pyridin-2-yl)su lfamoyl)pyridin-2-yl)-3- methylpiperidine-3-carboxylic acid;

4-((6-(N-(6-(o-tolyl)-5-(trifluoromethyl)pyridin-2-yl)sulfam oyl)pyridin-2- yl)amino)cyclohexanecarboxylic acid;

(S)-1 -(6-(N-(6-(2-cyclobutylphenyl)-5-(trifluoromethyl)pyridin-2- yl)sulfamoyl)pyridin-2-yl)- 3-methylpiperidine-3-carboxylic acid;

1 -(4-(N-(6-(2-ethylphenyl)-5-(trifluoromethyl)pyridin-2-yl)su lfamoyl)pyridin-2-yl)-4- methylpiperidine-4-carboxylic acid;

(R)-1 -(6-(N-(6-(2-isopropylphenyl)-5-(trifluoromethyl)pyridin-2-y l)sulfamoyl)pyridin-2^ yl)piperidine-3-carboxylic acid;

(S)-1 -(6-(N-(6-(2-isopropylphenyl)-5-(trifluoromethyl)pyridin-2-y l)sulfamoyl)pyridin-2- yl)piperidine-3-carboxylic acid;

1 -(6-(N-(6-(2-isopropylphenyl)-5-(trifluoromethyl)pyridin-2-y l)sulfamoyl)pyridin-2-yl)-3- methylpiperidine-3-carboxylic acid;

1 -(4-(N-(6-(2-cyclobutylphenyl)-5-(trifluoromethyl)pyridin-2- yl)sulfamoyl)pyridin-2-yl)-4- methylpiperidine-4-carboxylic acid; 1 -(6-(N-(6-(2-cyclopentylphenyl)-5-(trifluo^

methylpiperidine-4-carboxylic acid;

1 -(6-(6-(2-ethylphenyl)-5-(trifluoromethyl)pyridine-2-sulfona mido)pyridin-2-yl)-4- methylpiperidine-4-carboxylic acid;

4-methyl-1 -(6-(N-(6-(2-(2,2,2-trifluoroethoxy)phenyl)-5-(trifluorometh yl)pyridin-2- yl)sulfamoyl)pyridin-2-yl)piperidine-4-carboxylic acid;

1 -(6-(N-(6-(2-isobutoxyphenyl)-5-(trifluoromethyl)pyridin-2-y l)sulfamoyl)pyridin-2-yl)-4- methylpiperidine-4-carboxylic acid;

(R)-1 -(6-(N-(6-(2-cyclobutylphenyl)-5-(trifluoromethyl)pyridin-2- yl)sulfamoyl)pyridin-2-yl)- 3-methylpiperidine-3-carboxylic acid;

(R)-1 -(6-(N-(6-(2-isopropylphenyl)-5-(trifluoro

methylpiperidine-3-carboxylic acid;

(S)-1 -(6-(N-(6-(2-isopropylphenyl)-5-(trifluoromethyl)pyridin-2-y l)sulfamoyl)pyridin-2-y methylpiperidine-3-carboxylic acid;

1 -(6-(N-(6-(2-isobutoxyphenyl)-5-(trifluoromethyl)pyridin-2-y l)sulfamoyl)pyridin-2-yl)-3- methylpiperidine-3-carboxylic acid;

1 -(6-(N-(5-chloro-6-(2-ethylphenyl)pyridin-2-yl)sulfamoyl)pyr idin-2-yl)-3-methylpiperidin 3-carboxylic acid;

1 -(6-(N-(5-chloro-6-(2-isopropylphenyl)pyridin-2-yl)sulfamoyl )pyridin-2-yl)-3- methylpiperidine-3-carboxylic acid;

1 -(6-(N-(5-chloro-6-(2-cyclobutylphenyl)pyridin-2-yl)sulfamoy l)pyridin-2-yl)-3- methylpiperidine-3-carboxylic acid;

1 -(6-(N-(6-(2-(tert-butyl)phenyl)-5-chloropyridin-2-yl)sulfam oyl)pyridin-2-yl)-3- methylpiperidine-3-carboxylic acid;

(R)-1 -(6-(N-(5-chloro-6-(2-cyclobutylphenyl)pyridin-2-yl)sulfamoy l)pyridin-2-yl)-3- methylpiperidine-3-carboxylic acid;

(R)-1 -(6-(N-(5-chloro-6-(2-isopropylphenyl)pyridin-2-yl)sulfamoyl )pyridin-2-yl)-3- methylpiperidine-3-carboxylic acid;

(R)-1 -(6-(N-(5-chloro-6-(2-ethylphenyl)pyridin-2-yl)sulfamoyl)pyr idin-2-yl)-3- methylpiperidine-3-carboxylic acid;

(R)-1 -(6-(N-(6-(2-ethylphenyl)-5-(trifluoromethyl)pyridin-2-yl)su lfamoyl)pyridin-2-yl)-3- methylpiperidine-3-carboxylic acid;

rac-(1 RS,3RS,4SR)-3-((6-(N-(6-(o-tolyl)-5-(trifluoromethyl)pyridin -2-yl)sulfamoyl)pyridin- 2-yl)amino)-7-oxabicyclo[2.2.1 ]heptane-1 -carboxylic acid;

(R)-1 -(6-(N-(6-(2-isobutoxyphenyl)-5-(trifluoromethyl)pyridin-2-y l)sulfamoyl)pyridin-2-y^ methylpiperidine-3-carboxylic acid; 1 -(6-(N-(5-chloro-6-(2-isobutoxyphenyl)pyridin-2-yl)sulfamoyl )pyridin-2-yl)-4- methylpiperidine-4-carboxylic acid;

4-methyl-1 -(6-(N-(6-(2^ropylphenyl)-5-(trifluoro

yl)piperidine-4-carboxylic acid;

1 -(6-(N-(6-(2-chlorophenyl)-5-(trifluoromethyl)pyridin-2-yl)s ulfamoyl)pyridin-2-yl)-3- methylpiperidine-3-carboxylic acid;

1 -(6-(N-(5-chloro-6-(2-isobutoxyphenyl)pyridin-2-yl)sulfamoyl )pyridin-2-yl)-3- methylpiperidine-3-carboxylic acid;

3-methyl-1 -(6-(N-(6-(2^ropylphenyl)-5-(trifluoromethyl)pyridin-2-yl)su lfamoyl)pyridin-2- yl)piperidine-3-carboxylic acid;

1 -(6-(N-(6-(2-cyclopropylphenyl)-5-(trifluoromethyl)pyridin-2 -yl)sulfamoyl)pyridin-2-yl)-3- methylpiperidine-3-carboxylic acid;

rac-(1 RS,3RS,4SR)-3-((6-(N-(6-(2-isopropylphenyl)-5-(trifluorometh yl)pyridin-2- yl)sulfamoyl)pyridin-2-yl)amino)-7-oxabicyclo[2.2.1 ]heptane-1 -carboxylic acid;

rac-(1 SR,5RS,6RS,7SR)-5-propyl-2-(6-(N-(6-(o-tolyl)-5-(trifluorome thyl)pyridin-2- yl)sulfamoyl)pyridin-2-yl)-2-azabicyclo[4.2.0]octane-7-carbo xylic acid;

(R)-1 -(6-(N-(6-(2-cyclopropylphenyl)pyridin-2-yl)sulfamoyl)pyridi n-2-yl)-3- methylpiperidine-3-carboxylic acid;

(R)-1 -(6-(N-(6-(2-cyclopropylphenyl)-5-methylpyridin-2-yl)sulfamo yl)pyridin-2-yl)-3- methylpiperidine-3-carboxylic acid;

(R)-1 -(6-(N-(5-cyclopropyl-6-(2-cyclopropylphenyl)pyridin-2-yl)su lfamoyl)pyridin-2-yl)-3- methylpiperidine-3-carboxylic acid;

(R)-3-methyl-1 -(6-(N-(5-methyl-6-(o-tolyl)pyridin-2-yl)sulfamoyl)pyridin-2 -yl)piperidi carboxylic acid;

R)-1 -(6-(N-(5-methoxy-6-(o-tolyl)pyridin-2-yl)sulfamoyl)pyridin- 2-yl)-3-methylpiperidi carboxylic acid;

R)-1 -(6-(N-(5-methoxy-6-(o-tolyl)pyridin-2-yl)sulfamoyl)pyridin- 2-yl)-3-methylpipen^ carboxylic acid;

(R)-3-methyl-1 -(6-(N-(6-(o-tolyl)pyridin-2-yl)sulfamoyl)pyridin-2-yl)piper idine-3-carb^ acid;

(R)-1 -(6-(N-(6-(2-cyclopropylphenyl)-5-(trifluoromethyl)pyridin-2 -yl)sulfamoyl)pyridin 3-methylpiperidine-3-carboxylic acid;

1 -(6-(N-(6-(2-chloro-5-methoxyphenyl)-5-(trifluoromethyl)pyri din-2-yl)sulfamoyl)pyn^ yl)-3-methylpiperidine-3-carboxylic acid;

(3R)-3-methyl-1 -(6-{[6-(2-methylphenyl)-5-(trifluoromethyl)pyridin-2-yl]sul famoyl}p yl)piperidine-3-carboxylic acid; (3R)-1 -(6-{[6-(5-fluoro-2-methylphenyl)-5-(trifluoromethyl)pyridin -2-yl]sulfamoyl^ yl)-3-methylpiperidine-3-carboxylic acid;

(3R)-1 -(6-{[6-(3-fluoro-2-methylphenyl)-5-(trifluoromethyl)pyridin -2-yl]sulfamoyl}pyri^ yl)-3-methylpiperidine-3-carboxylic acid;

(1 S,3S)-3-((6-(N-(6-(2-isopropylphenyl)-5-(trifluoromethyl)pyr idin-2-yl)sulfamoyl)pyridin-2- yl)amino)cyclohexanecarboxylic acid;

5-(6-(N-(6-(o-tolyl)-5-(trifluoromethyl)pyridin-2-yl)sulfamo yl)pyridin-2-yl)-5- azaspiro[2.4]heptane-1 -carboxylic acid;

5-(6-(N-(6-(2-cyclopropylphenyl)-5-(trifluoromethyl)pyridin- 2-yl)sulfamoyl)pyridin-2-yl)-5- azaspiro[2.4]heptane-1 -carboxylic acid;

(R)-1 -(6-(N-(6-(2-chlorophenyl)-5-(trifluoromethyl)pyridin-2-yl)s ulfamoyl)pyridin-2-yl)-3^ methylpiperidine-3-carboxylic acid;

(R)-1 -(6-(N-(5-chloro-6-(2-isobutoxyphenyl)pyridin-2-yl)sulfamoyl )pyridin-2-yl)-3- methylpiperidine-3-carboxylic acid;

(R)-3-methyl-1 -(6-(N-(6-(2^ropylphenyl)-5-(trifluoromethyl)pyridin-2-yl)su lfamoyl)pyridin 2-yl)piperidine-3-carboxylic acid;

(R)-1 -(6-(N-(6-(2-chloro-5-methoxyphenyl)-5-(trifluoromethyl)pyri din-2- yl)sulfamoyl)pyridin-2-yl)-3-methylpiperidine-3-carboxylic acid;

(S)-3-methyl-1 -(6-(N-(6-(2^ropylphenyl)-5-(trifluoromethyl)pyridin-2-yl)su lfamoyl)pyridin 2-yl)piperidine-3-carboxylic acid;

1 -(6-(N-(6-(5-chloro-2-methoxyphenyl)-5-(trifluoro

yl)-4-methylpiperidine-4-carboxylic acid;

1 -(6-(N-(6-(5-chloro-2-isopropoxyphenyl)-5-(trifluoromethyl)p yridin-2-yl)sulfamoyl)pyridin-

2- yl)-4-methylpiperidine-4-carboxylic acid;

(3S)-3-methyl-1 -(6-{[6-(2-methylphenyl)-5-(trifluoromethyl)pyridin-2-yl]sul famoyl}pyridi^ yl)piperidine-3-carboxylic acid;

(S)-1 -(6-(N-(6-(2-cyclopropylphenyl)-5-(trifluoromethyl)pyridin-2 -yl)sulfamoyl)pyridin-2-yl)^

3- methylpiperidine-3-carboxylic acid;

1 -(6-(N-(5-chloro-6-(2-cyclopropylphenyl)pyridin-2-yl)sulfamo yl)pyridin-2-yl)-4- methylpiperidine-4-carboxylic acid;

1 -(6-(N-(5-chloro-6-(2-cyclopropylphenyl)pyridin-2-yl)sulfamo yl)pyridin-2-yl)-3- methylpiperidine-3-carboxylic acid;

1 -(6-(N-(6-(5-chloro-2-methoxyphenyl)-5-(trifluoro

yl)-3-methylpiperidine-3-carboxylic acid;

1 -(6-(N-(6-(5-chloro-2-isopropoxyphenyl)-5-(trifluoromethyl)p yridin-2-yl)sulfamoyl)pyridin 2-yl)-3-methylpiperidine-3-carboxylic acid; rac-(1 SR,5RS,6RS,7SR)-2-(6-(N-(3-chloro-2'-isopropyl-[2,3'-bipyrid in]-6- yl)sulfamoyl)pyridin-2-yl)-5-propyl-2-azabicyclo[4.2.0]octan e-7-carboxylic acid;

(3S)-1 -(6-{[6-(5-fluoro-2-methylphenyl)-5-(trifluoromethyl)pyridin -2-yl]sulfamoyl}pyridin yl)-3-methylpiperidine-3-carboxylic acid;

(3S)-1 -(6-{[6-(3-fluoro-2-methylphenyl)-5-(trifluoromethyl)pyridin -2-yl]sulfamoyl}pyridin^ yl)-3-methylpiperidine-3-carboxylic acid;

(R)-1 -(6-(N-(5-chloro-6-(2-cyclopropylphenyl)pyridin-2-yl)sulfamo yl)pyridin-2-yl)-3- methylpiperidine-3-carboxylic acid;

rac-(1 RS,3RS,4SR)-3-((6-(N-(6-(2-cyclopropylphenyl)-5-(trifluorome thyl)pyridin-2- yl)sulfamoyl)pyridin-2-yl)amino)-7-oxabicyclo[2.2.1 ]heptane-1 -carboxylic acid;

5-(6-(N-(6-(5-fluoro-2-methylphenyl)-5-(trifluoromethyl)pyri din-2-yl)sulfamoyl)pyridin-2-^ 5-azaspiro[2.5]octane-1 -carboxylic acid;

5-(6-(N-(6-(3-fluoro-2-methylphenyl)-5-(trifluoromethyl)pyri din-2-yl)sulfamoyl)pyridin-2-y 5-azaspiro[2.5]octane-1 -carboxylic acid;

5-(6-(N-(6-(o-tolyl)-5-(trifluoromethyl)pyridin-2-yl)sulfamo yl)pyridin-2-yl)-5- azaspiro[2.5]octane-1 -carboxylic acid;

rac-(1 SR,6RS,7SR)-2-(6-(N-(6-(2-isopropylphenyl)-5-(trifluoromethy l)pyridin-2- yl)sulfamoyl)pyridin-2-yl)-2-azabicyclo[4.2.0]octane-7-carbo xylic acid;

rac-(1 SR,6RSJSR)-2-(6-(N-(6-(o-tolyl)-5-(trifluoromethyl)pyridin-2 -yl)sulfamoyl)pyridin-2- yl)-2-azabicyclo[4.2.0]octane-7-carboxylic acid;

1 -(6-(N-(6-(2-(hydroxymethyl)phenyl)-5-(trifluoromethyl)pyrid in-2-yl)sulfamoyl)pyridin-2- yl)-3-methylpiperidine-3-carboxylic acid;

1 -(6-(N-(6-(2-(2-hydroxyethyl)phenyl)-5-(trifluoromethyl)pyri din-2-yl)sulfamoyl)pyridin-2- yl)-3-methylpiperidine-3-carboxylic acid;

7-(6-(N-(6-(o-tolyl)-5-(trifluoromethyl)pyridin-2-yl)sulfamo yl)pyridin-2-yl)-7- azaspiro[3.5]nonane-2-carboxylic acid;

(R)-1 -(6-(N-(5-chloro-6-(o-tolyl)pyridin-2-yl)sulfamoyl)pyridin-2 -yl)-3-methylpiperidine-^ carboxylic acid;

(R)-1 -(6-(N-(5-chloro-6-(2,6-dimethylphenyl)pyridin-2-yl)sulfamoy l)pyridin-2-yl)-3- methylpiperidine-3-carboxylic acid;

(R)-1 -(6-(N-(6-(2-chloro-5-methoxyphenyl)-5-(trifluoromethyl)pyri din-2- yl)sulfamoyl)pyridin-2-yl)piperidine-3-carboxylic acid;

(R)-1 -(6-(N-(6-(5-chloro-2-methylphenyl)-5-(trifluoromethyl)pyrid in-2-yl)sulfamoyl)pyridi 2-yl)-3-methylpiperidine-3-carboxylic acid;

1 -(6-(N-(6-(5-chloro-2-methylphenyl)-5-(trifluoromethyl)pyrid in-2-yl)sulfamoyl)pyridin-2- yl)-4-methylpiperidine-4-carboxylic acid; 1 -(6-(N-(5-chloro-6-(o-tolyl)pyridin-2-yl)sulfamoyl)pyridin-2 -yl)-3-ethylpiperi^ carboxylic acid;

1 -(6-(N-(5-chloro-6-(2,6-dimethylphenyl)pyridin-2-yl)sulfamoy l)pyridin-2-yl)-3- ethylpiperidine-3-carboxylic acid;

3-ethyl-1 -(6-(N-(6-(o-tolyl)-5-(trifl^^

3-carboxylic acid;

(R)-1 -(6-(N-(6-(5-chloro-2-methoxyphenyl)-5-(trifluoromethyl)pyri din-2- yl)sulfamoyl)pyridin-2-yl)-3-methylpiperidine-3-carboxylic acid;

1 -(6-(N-(5-chloro-6-(o-tolyl)pyridin-2-yl)sulfamoyl)pyridin-2 -yl)-3-propylpiperidine-3- carboxylic acid;

1 -(6-(N-(5-chloro-6-(2,6-dimethylphenyl)pyridin-2-yl)sulfamoy l)pyridin-2-yl)-3- propylpiperidine-3-carboxylic acid;

3^ropyl-1 -(6-(N-(6-(o-tolyl)-5-(trifluoromethyl)pyridin-2-yl)sulfamoy l)pyridin-2- yl)piperidine-3-carboxylic acid;

3-((6-(N-(6-(o-tolyl)-5-(trifluoromethyl)pyridin-2-yl)sulfam oyl)pyridin-2- yl)amino)cyclopentanecarboxylic acid;

3-((6-(N-(6-(o-tolyl)-5-(trifluoromethyl)pyridin-2-yl)sulfam oyl)pyridin-2- yl)amino)cyclohexanecarboxylic acid;

(1 ,3-c/ ^' s)-3-((6-(N-(6-(o-tolyl)-5-(trifluoromethyl)pyridin-2- yl)sulfamoyl)pyridin^ yl)amino)cyclohexanecarboxylic acid;

(1 S,2S,4R)-7-(6-(N-(6-(o-tolyl)-5-(trifluoromethy

azabicyclo[2.2.1 ]heptane-2-carboxylic acid;

(1 ,3-frans)-3-((6-(N-(6-(o-tolyl)-5-(trifluoromethyl)pyridin-2 -yl)sulfamoyl)pyridin-2- yl)amino)cyclohexanecarboxylic acid;

(3R,6S)-6-methyl-1 -(6-(N-(6-(o-tolyl)-5-(trifluoromethyl)pyridin-2-yl)sulfamoy l)pyridi yl)piperidine-3-carboxylic acid; and

(R)-1 -(6-(N-(6-(2,6-dimethylphenyl)-5-(trifluoromethyl)pyridin-2- yl)sulfamoyl)pyridin-^ 3-methylpiperidine-3-carboxylic acid;

or a pharmaceutically acceptable salt thereof.

A thirtieth embodiment of the invention is a pharmaceutical composition comprising a compound according to any one of the first through twenty-ninth embodiments, or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable carriers, or diluents. A thirty-first embodiment of the invention is a pharmaceutical composition comprising a compound according embodiment thirty, or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable carriers, or diluents. A thirty-second embodiment of the invention is a pharmaceutical composition comprising a compound according embodiment thirty-one, wherein the additional pharmaceutical agent(s) is selected from a mucolytic agent, nebulized hypertonic saline, bronchodilator, an antibiotic, an anti-infective agent, a CFTR modulator, and an anti-inflammatory agent or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable carriers, or diluents.

A thirty-third embodiment of the invention is a pharmaceutical composition comprising a compound according embodiment thirty-one, wherein the additional pharmaceutical agent(s) is selected from a CFTR modulator, or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable carriers, or diluents.

A thirty-fourth embodiment of the invention is a pharmaceutical composition comprising a compound according embodiment thirty-one, wherein the additional pharmaceutical agent(s) is selected from a CFTR corrector, or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable carriers, or diluents.

A thirty-fifth embodiment of the invention is a pharmaceutical composition comprising a compound according embodiment thirty-one, wherein the additional pharmaceutical agent(s) is selected from a CFTR potentiator, or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable carriers, or diluents.

A thirty-sixth embodiment of the invention is a pharmaceutical composition comprising a compound according embodiment thirty-one, wherein the additional pharmaceutical agents are a CFTR modulator, and a CFTR potentiator, or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable carriers, or diluents.

A thirty-seventh embodiment of the invention is a method of treating a CFTR mediated disease in a subject comprising administering to the subject a compound a pharmaceutically acceptable salt thereof of any one of embodiments 1 to 29 or the pharmaceutical composition of any one of embodiments 30 to 36. A thirty-eighth embodiment of the invention comprising a method of treatment according to embodiment thirty-seven, wherein the CFTR mediated disease is selected from cystic fibrosis, asthma, COPD and chronic bronchitis. A thirty-ninth embodiment of the invention comprising a method of treatment according to embodiment thirty-seven or thirty-eight, wherein the CFTR mediated disease is selected from cystic fibrosis, COPD and emphysema.

A fortieth embodiment of the invention comprising a method of treatment according to embodiment thirty-seven or thirty-eight, wherein the CFTR mediated disease is cystic fibrosis.

A forty-first embodiment of the invention comprising a method of treatment according to embodiment thirty-seven, further comprising administering to the subject one or more additional pharmaceutical agent(s) prior to, concurrent with, or subsequent to the compound of any one of embodiments 1 to 29 or the pharmaceutical composition of any one of embodiments 30 to 36.

A forty-second embodiment of the invention comprising a method of treatment according to embodiment forty-one, wherein the additional pharmaceutical agent(s) is selected from a mucolytic agent, nebulized hypertonic saline, bronchodilator, an antibiotic, an anti-infective agent, a CFTR modulator, and an anti-inflammatory agent.

A forty-third embodiment of the invention comprising a method of treatment according to embodiment forty-one, wherein the additional pharmaceutical agent(s) is selected from a CFTR modulator.

A forty-fourth embodiment of the invention comprising a method of treatment according to embodiment forty-one, wherein the additional pharmaceutical agent(s) is selected from a CFTR potentiator.

A forty-fifth embodiment of the invention comprising a method of treatment according to embodiment forty-one, wherein the additional pharmaceutical agent(s) is selected from a CFTR modulator and a CFTR potentiator. A forty-sixth embodiment of the invention comprising the use of a compound of formula (I) in the manufacture of a medicament for treating a disease in an animal in which CFTR modulation contributes to the pathology and/or symptomology of a disease. A forty-seventh embodiment of the invention comprising a compound according to any one of the first through twenty-ninth embodiments, or a pharmaceutically acceptable salt thereof, for use in the treatment of a CFTR mediated disease which is selected from cystic fibrosis, asthma, COPD and chronic bronchitis. A forty-eighth embodiment of the invention comprising a compound according to any one of the first through twenty-ninth embodiments, or a pharmaceutically acceptable salt thereof, for use in the treatment of a CFTR mediated disease which is selected from cystic fibrosis, COPD and emphysema. A forty-ninth embodiment of the invention comprising a compound according to any one of the first through twenty-ninth embodiments, or a pharmaceutically acceptable salt thereof, for use in the treatment of a CFTR mediated disease which is cystic fibrosis.

In certain embodiments, the present invention relates to the aforementioned methods, wherein said compound is administered parenterally.

In certain embodiments, the present invention relates to the aforementioned methods, wherein said compound is administered intramuscularly, intravenously, subcutaneously, orally, pulmonary, intrathecally, topically or intranasally.

In certain embodiments, the present invention relates to the aforementioned methods, wherein said compound is administered systemically.

In certain embodiments, the present invention relates to the aforementioned methods, wherein said subject is a mammal.

In certain embodiments, the present invention relates to the aforementioned methods, wherein said subject is a primate.

In certain embodiments, the present invention relates to the aforementioned methods, wherein said subject is a human.

The compounds and intermediates described herein may be isolated and used as the compound per se. Alternatively, when a moiety is present that is capable of forming a salt, the compound or intermediate may be isolated and used as its corresponding salt. As used herein, the terms "salt" or "salts" refers to an acid addition or base addition salt of a compound of the invention. "Salts" include in particular "pharmaceutical acceptable salts". The term "pharmaceutically acceptable salts" refers to salts that retain the biological effectiveness and properties of the compounds of this invention and, which typically are not biologically or otherwise undesirable. In many cases, the compounds of the present invention are capable of forming acid and/or base salts by virtue of the presence of amino and/or carboxyl groups or groups similar thereto.

Pharmaceutically acceptable acid addition salts can be formed with inorganic acids and organic acids, e.g., acetate, aspartate, benzoate, besylate, bromide/hydrobromide, bicarbonate/carbonate, bisulfate/sulfate, camphorsulfornate, chloride/hydrochloride, chlortheophyllonate, citrate, ethandisulfonate, fumarate, gluceptate, gluconate, glucuronate, hippurate, hydroiodide/iodide, isethionate, lactate, lactobionate, laurylsulfate, malate, maleate, malonate, mandelate, mesylate, methylsulphate, naphthoate, napsylate, nicotinate, nitrate, octadecanoate, oleate, oxalate, palmitate, pamoate, phosphate/hydrogen phosphate/dihydrogen phosphate, polygalacturonate, propionate, stearate, succinate, sulfate, subsalicylate, tartrate, tosylate and trifluoroacetate salts.

Inorganic acids from which salts can be derived include, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like.

Organic acids from which salts can be derived include, for example, acetic acid, propionic acid, glycolic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, toluenesulfonic acid, sulfosalicylic acid, and the like. Pharmaceutically acceptable base addition salts can be formed with inorganic and organic bases.

Inorganic bases from which salts can be derived include, for example, ammonium salts and metals from columns I to XII of the periodic table. In certain embodiments, the salts are derived from sodium, potassium, ammonium, calcium, magnesium, iron, silver, zinc, and copper; particularly suitable salts include ammonium, potassium, sodium, calcium and magnesium salts.

Organic bases from which salts can be derived include, for example, primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines, basic ion exchange resins, and the like. Certain organic amines include isopropylamine, benzathine, cholinate, diethanolamine, diethylamine, lysine, meglumine, piperazine and tromethamine.

The salts can be synthesized by conventional chemical methods from a compound containing a basic or acidic moiety. Generally, such salts can be prepared by reacting free acid forms of these compounds with a stoichiometric amount of the appropriate base (such as Na, Ca, Mg, or K hydroxide, carbonate, bicarbonate or the like), or by reacting free base forms of these compounds with a stoichiometric amount of the appropriate acid. Such reactions are typically carried out in water or in an organic solvent, or in a mixture of the two. Generally, use of non-aqueous media like ether, ethyl acetate, ethanol, isopropanol, or acetonitrile is desirable, where practicable. Lists of additional suitable salts can be found, e.g., in "Remington's Pharmaceutical Sciences", 20th ed., Mack Publishing Company, Easton, Pa., (1985); and in "Handbook of Pharmaceutical Salts: Properties, Selection, and Use" by Stahl and Wermuth (Wiley-VCH, Weinheim, Germany, 2002).

Isotopically-labeled compounds of formula (I) can generally be prepared by conventional techniques known to those skilled in the art or by processes analogous to those described in the accompanying Examples and Preparations using an appropriate isotopically-labeled reagents in place of the non-labeled reagent previously employed. For example, the compound of the present invention can exist in a deuterated form as shown below:

Pharmaceutically acceptable solvates in accordance with the invention include those wherein the solvent of crystallization may be isotopically substituted, e.g. D ₂ 0, d ₆ -acetone, d ₆ -DMSO.

It will be recognized by those skilled in the art that the compounds of the present invention may contain chiral centers and as such may exist in different stereoisomeric forms. As used herein, the term "an optical isomer" or "a stereoisomer" refers to any of the various stereo isomeric configurations which may exist for a given compound of the present invention. It is understood that a substituent may be attached at a chiral center of a carbon atom. Therefore, the invention includes enantiomers, diastereomers or racemates of the compound.

"Enantiomers" are a pair of stereoisomers that are non- superimposable mirror images of each other. A 1 :1 mixture of a pair of enantiomers is a "racemic" mixture. The term is used to designate a racemic mixture where appropriate. When designating the stereochemistry for the compounds of the present invention, a single stereoisomer with known relative and absolute configuration of the two chiral centers is designated using the conventional RS system (e.g., (1 S.2S)); a single stereoisomer with known relative configuration but unknown absolute configuration is designated with stars (e.g., (1 R*,2R*)); and a racemate with two letters (e.g, (1 RS.2RS) as a racemic mixture of (1 R.2R) and (1 S.2S); (1 RS.2SR) as a racemic mixture of (1 R.2S) and (1 S.2R)). "Diastereoisomers" are stereoisomers that have at least two asymmetric atoms, but which are not mirror-images of each other. The absolute stereochemistry is specified according to the Cahn- Ingold- Prelog R-S system. When a compound is a pure enantiomer the stereochemistry at each chiral carbon may be specified by either R or S. Resolved compounds whose absolute configuration is unknown can be designated (+) or (-) depending on the direction (dextro- or levorotatory) which they rotate plane polarized light at the wavelength of the sodium D line. Alternatively, the resolved compounds can be defined by the respective retention times for the corresponding enantiomers/diastereomers via chiral HPLC.

Certain of the compounds described herein contain one or more asymmetric centers or axes and may thus give rise to enantiomers, diastereomers, and other stereoisomeric forms that may be defined, in terms of absolute stereochemistry, as (R)- or (S)-.

Unless specified otherwise, the compounds of the present invention are meant to include all such possible stereoisomers, including racemic mixtures, optically pure forms and intermediate mixtures. Optically active (R)- and (S)- stereoisomers may be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques (e.g., separated on chiral SFC or HPLC chromatography columns, such as CHIRALPAK® and CHIRALCEL® available from DAICEL Corp. using the appropriate solvent or mixture of solvents to achieve good separation). If the compound contains a double bond, the substituent may be E or Z configuration. If the compound contains a disubstituted cycloalkyl, the cycloalkyl substituent may have a cis- or trans-configuration. All tautomeric forms are also intended to be included.

PHARMACOLOGY AND UTILITY

Compounds of the present invention have been found to modulate CFTR activity and may be beneficial for the treatment of cystic fibrosis and additional diseases not directly caused by mutations in CFTR, such as secretory diseases and other protein folding diseases mediated by CFTR. These include, but are not limited to, chronic obstructive pulmonary disease (COPD), dry eye disease, and Sjogren's Syndrome.

COPD is characterized by airflow limitation that is progressive and not fully reversible. The airflow limitation is due to mucus hypersecretion, emphysema, and bronchiolitis.

Activators of mutant or wild-type CFTR offer a potential treatment of mucus hypersecretion and impaired mucociliary clearance that is common in COPD. Specifically, increasing anion secretion across CFTR may facilitate fluid transport into the airway surface liquid to hydrate the mucus and optimized periciliary fluid viscosity. This would lead to enhanced mucociliary clearance and a reduction in the symptoms associated with COPD. Dry eye disease is characterized by a decrease in tear aqueous production and abnormal tear film lipid, protein and mucin profiles. There are many causes of dry eye, some of which include age, Lasik eye surgery, arthritis, medications, chemical/thermal burns, allergies, and diseases, such as cystic fibrosis and Sjogrens's syndrome. Increasing anion secretion via CFTR would enhance fluid transport from the corneal endothelial cells and secretory glands surrounding the eye to increase corneal hydration. This would help to alleviate the symptoms associated with dry eye disease.

Sjogrens's syndrome is an autoimmune disease in which the immune system attacks moisture-producing glands throughout the body, including the eye, mouth, skin, respiratory tissue, liver, vagina, and gut. Symptoms, include, dry eye, mouth, and vagina, as well as lung disease. The disease is also associated with rheumatoid arthritis, systemic lupus, systemic sclerosis, and polymypositis/dermatomyositis. Defective protein trafficking is believed to cause the disease, for which treatment options are limited. Augmenters or inducers of CFTR activity may hydrate the various organs afflicted by the disease and help to elevate the associated symptoms.

Another aspect of the invention provides a method for treating or lessening the severity of a disease, disorder, or condition associated with the modulation of CFTR in a subject, which comprises administering to the subject a compound of formula (I) or a pharmaceutically acceptable salt thereof.

In certain embodiments, the present invention provides a method of treating a condition, disease, or disorder implicated by a deficiency of the CFTR activity, the method comprising administering a composition comprising a compound of formula (I) to a subject, preferably a mammal, in need of treatment thereof.

In certain embodiments, the present invention provides a method of treating diseases associated with reduced CFTR function due to mutations in the gene encoding CFTR or environmental factors (e.g., smoke). These diseases include, cystic fibrosis, chronic bronchitis, recurrent bronchitis, acute bronchitis, male infertility caused by congenital bilateral absence of the vas deferens (CBAVD), female infertility caused by congenital absence of the uterus and vagina (CAUV), idiopathic chronic pancreatitis (ICP), idiopathic recurrent pancreatitis, idiopathic acute pancreatitis, chronic rhinosinusitis, primary sclerosing cholangitis, allergic bronchopulmonary aspergillosis, diabetes, dry eye, constipation, allergic bronchopulmonary aspergillosis (ABPA), bone diseases (e.g., osteoporosis), and asthma.

In certain embodiments, the present invention provides a method for treating diseases associated with normal CFTR function. These diseases include, chronic obstructive pulmonary disease (COPD), chronic bronchitis or dyspnea associated therewith, recurrent bronchitis, acute bronchitis, rhinosinusitis, constipation, pancreatitis including chronic pancreatitis, recurrent pancreatitis, and acute pancreatitis, pancreatic insufficiency, male infertility caused by congenital bilateral absence of the vas deferens (CBAVD), mild pulmonary disease, idiopathic pancreatitis, liver disease, emphysema, hereditary

emphysema, gallstones, gastro-esophageal reflux disease, gastrointestinal malignancies, inflammatory bowel disease, constipation, diabetes, arthritis, osteoporosis, and osteopenia.

According to an alternative preferred embodiment, the present invention provides a method of treating cystic fibrosis comprising the step of administering to a mammal a composition comprising the step of administering to said mammal a composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof.

According to the invention an "effective dose" or an "effective amount" of the compound or pharmaceutical composition is that amount effective for treating or lessening the severity of one or more of the diseases, disorders or conditions as recited above.

The compounds and compositions, according to the methods of the present invention, may be administered using any amount and any route of administration effective for treating or lessening the severity of one or more of the diseases, disorders or conditions recited above.

The compounds of the present invention are typically used as a pharmaceutical composition (e.g., a compound of the present invention and at least one pharmaceutically acceptable carrier). As used herein, the term "pharmaceutically acceptable carrier" includes generally recognized as safe (GRAS) solvents, dispersion media, surfactants, antioxidants, preservatives (e.g., antibacterial agents, antifungal agents), isotonic agents, salts, preservatives, drug stabilizers, buffering agents (e.g., maleic acid, tartaric acid, lactic acid, citric acid, acetic acid, sodium bicarbonate, sodium phosphate, and the like), and the like and combinations thereof, as would be known to those skilled in the art (see, for example, Remington's Pharmaceutical Sciences, 18th Ed. Mack Printing Company, 1990, pp. 1289- 1329). Except insofar as any conventional carrier is incompatible with the active ingredient, its use in the therapeutic or pharmaceutical compositions is contemplated. For purposes of this invention, solvates and hydrates are considered pharmaceutical compositions comprising a compound of the present invention and a solvent (i.e., solvate) or water (i.e., hydrate).

The formulations may be prepared using conventional dissolution and mixing procedures. For example, the bulk drug substance (i.e., compound of the present invention or stabilized form of the compound (e.g., complex with a cyclodextrin derivative or other known complexation agent)) is dissolved in a suitable solvent in the presence of one or more of the excipients described above. The compound of the present invention is typically formulated into pharmaceutical dosage forms to provide an easily controllable dosage of the drug and to give the patient an elegant and easily handleable product. The pharmaceutical composition (or formulation) for application may be packaged in a variety of ways depending upon the method used for administering the drug. Generally, an article for distribution includes a container having deposited therein the pharmaceutical formulation in an appropriate form. Suitable containers are well-known to those skilled in the art and include materials such as bottles (plastic and glass), sachets, ampoules, plastic bags, metal cylinders, and the like. The container may also include a tamper-proof assemblage to prevent indiscreet access to the contents of the package. In addition, the container has deposited thereon a label that describes the contents of the container. The label may also include appropriate warnings.

The pharmaceutical composition comprising a compound of the present invention is generally formulated for use as a parenteral or oral administration.

For example, the pharmaceutical oral compositions of the present invention can be made up in a solid form (including without limitation capsules, tablets, pills, granules, powders or suppositories), or in a liquid form (including without limitation solutions, suspensions or emulsions). The pharmaceutical compositions can be subjected to conventional

pharmaceutical operations such as sterilization and/or can contain conventional inert diluents, lubricating agents, or buffering agents, as well as adjuvants, such as preservatives, stabilizers, wetting agents, emulsifers and buffers, etc.

Typically, the pharmaceutical compositions are tablets or gelatin capsules comprising the active ingredient together with

a) diluents, e.g. , lactose, dextrose, sucrose, mannitol, sorbitol, cellulose and/or glycine;

b) lubricants, e.g. , silica, talcum, stearic acid, its magnesium or calcium salt and/or polyethyleneglycol; for tablets also

c) binders, e.g. , magnesium aluminum silicate, starch paste, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose and/or polyvinylpyrrolidone; if desired

d) disintegrants, e.g. , starches, agar, alginic acid or its sodium salt, or effervescent mixtures; and/or

e) absorbents, colorants, flavors and sweeteners.

Tablets may be either film coated or enteric coated according to methods known in the art.

Suitable compositions for oral administration include a compound of the invention in the form of tablets, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsion, hard or soft capsules, or syrups or elixirs. Compositions intended for oral use are prepared according to any method known in the art for the manufacture of pharmaceutical compositions and such compositions can contain one or more agents selected from the group consisting of sweetening agents, flavoring agents, coloring agents and preserving agents in order to provide pharmaceutically elegant and palatable preparations. Tablets may contain the active ingredient in admixture with nontoxic pharmaceutically acceptable excipients which are suitable for the manufacture of tablets. These excipients are, for example, inert diluents, such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; granulating and disintegrating agents, for example, corn starch, or alginic acid; binding agents, for example, starch, gelatin or acacia; and lubricating agents, for example magnesium stearate, stearic acid or talc. The tablets are uncoated or coated by known techniques to delay disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action over a longer period. For example, a time delay material such as glyceryl monostearate or glyceryl distearate can be employed.

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

The parenteral compositions (e.g, intravenous (IV) formulation) are aqueous isotonic solutions or suspensions. The parenteral compositions may be sterilized and/or contain adjuvants, such as preserving, stabilizing, wetting or emulsifying agents, solution promoters, salts for regulating the osmotic pressure and/or buffers. In addition, they may also contain other therapeutically valuable substances. The compositions are generally prepared according to conventional mixing, granulating or coating methods, respectively, and contain about 0.1 -75%, or contain about 1 -50%, of the active ingredient.

The compound of the present invention or pharmaceutical composition thereof for use in a subject (e.g., human) is typically administered orally or parenterally at a therapeutic dose of less than or equal to about 100 mg/kg, 75 mg/kg, 50 mg/kg, 25 mg/kg, 10 mg/kg, 7.5 mg/kg, 5.0 mg/kg, 3.0 mg/kg, 1 .0 mg/kg, 0.5 mg/kg, 0.05 mg/kg or 0.01 mg/kg, but preferably not less than about 0.0001 mg/kg. When administered intravenously via infusion, the dosage may depend upon the infusion rate at which an iv formulation is administered. In general, the therapeutically effective dosage of a compound, the pharmaceutical composition, or the combinations thereof, is dependent on the species of the subject, the body weight, age and individual condition, the disorder or disease or the severity thereof being treated. A physician, pharmacist, clinician or veterinarian of ordinary skill can readily determine the effective amount of each of the active ingredients necessary to prevent, treat or inhibit the progress of the disorder or disease.

The above-cited dosage properties are demonstrable in vitro and in vivo tests using advantageously mammals, e.g., mice, rats, dogs, monkeys or isolated organs, tissues and preparations thereof. The compounds of the present invention can be applied in vitro in the form of solutions, e.g. , aqueous solutions, and in vivo either enterally, parenterally, advantageously intravenously, e.g. , as a suspension or in aqueous solution. The dosage in vitro may range between about 10 ³ molar and 10 ^~9 molar concentrations.

COMBINATION THERAPY

In certain instances, it may be advantageous to administer the compound of the present invention in combination with, or before or after, one or more other therapeutic agent. The compound of the present invention may be administered separately, by the same or different route of administration, or together in the same pharmaceutical composition as the other agents. A therapeutic agent is, for example, a chemical compound, peptide, antibody, antibody fragment or nucleic acid, which is therapeutically active or enhances the therapeutic activity when administered to a patient in combination with a compound of the invention.

In one embodiment, the invention provides a product comprising a compound of formula (I) and at least one other therapeutic agent as a combined preparation for simultaneous, separate or sequential use in therapy. In one embodiment, the therapy is the treatment of a disease or condition mediated by CFTR. Products provided as a combined preparation include a composition comprising the compound of formula (I) and the other therapeutic agent(s) together in the same pharmaceutical composition, or the compound of formula (I) and the other therapeutic agent(s) in separate form, e.g. in the form of a kit.

In one embodiment, the invention provides a pharmaceutical composition comprising a compound of formula (I) and another therapeutic agent(s). Optionally, the pharmaceutical composition may comprise a pharmaceutically acceptable carrier, as described above.

In one embodiment, the invention provides a kit comprising two or more separate pharmaceutical compositions, at least one of which contains a compound of formula (I). In one embodiment, the kit comprises means for separately retaining said compositions, such as a container, divided bottle, or divided foil packet. An example of such a kit is a blister pack, as typically used for the packaging of tablets, capsules and the like.

The kit of the invention may be used for administering different dosage forms, for example, oral and parenteral, for administering the separate compositions at different dosage intervals, or for titrating the separate compositions against one another. To assist compliance, the kit of the invention typically comprises directions for administration.

In the combination therapies of the invention, the compound of the invention and the other therapeutic agent may be manufactured and/or formulated by the same or different manufacturers. Moreover, the compound of the invention and the other therapeutic may be brought together into a combination therapy: (i) prior to release of the combination product to physicians (e.g. in the case of a kit comprising the compound of the invention and the other therapeutic agent); (ii) by the physician themselves (or under the guidance of the physician) shortly before administration; (iii) in the patient themselves, e.g. during sequential administration of the compound of the invention and the other therapeutic agent.

Accordingly, the invention provides the use of a compound of formula (I) for treating a disease or condition mediated by CFTR, wherein the medicament is prepared for administration with another therapeutic agent. The invention also provides the use of another therapeutic agent for treating a disease or condition mediated by CFTR, wherein the medicament is administered with a compound of formula (I).

The invention also provides a compound of formula (I) for use in a method of treating a disease or condition mediated by CFTR, wherein the compound of formula (I) is prepared for administration with another therapeutic agent. The invention also provides another therapeutic agent for use in a method of treating a disease or condition mediated by CFTR, wherein the other therapeutic agent is prepared for administration with a compound of formula (I). The invention also provides a compound of formula (I) for use in a method of treating a disease or condition mediated by CFTR, wherein the compound of formula (I) is administered with another therapeutic agent. The invention also provides another therapeutic agent for use in a method of treating a disease or condition mediated by CFTR, wherein the other therapeutic agent is administered with a compound of formula (I).

The invention also provides the use of a compound of formula (I) for treating a disease or condition mediated by CFTR, wherein the patient has previously (e.g. within 24 hours) been treated with another therapeutic agent. The invention also provides the use of another therapeutic agent for treating a disease or condition mediated by CFTR, wherein the patient has previously (e.g. within 24 hours) been treated with a compound of formula (I).

In one embodiment, the other therapeutic agent is selected from osmotic agents, ion channel modulating agents, mucolytic agents, bronchodilators, antihistamines, antibiotics, anti-inflammatory agents and CFTR modulators.

In another embodiment the other therapeutic agent is an osmotic agent, for example, nebulized hypertonic saline, dextran, mannitol or Xylitol.

In another embodiment the other therapeutic agent is a mucolytic agent, for example, Pulmozyme™.

In another embodiment, the other therapeutic agent is a bronchodilator, for example, albuterol, metaprotenerol sulfate, pirbuterol acetate, salmeterol, indacaterol or tetrabuline sulfate; suitable bronchodilatory agents also include anticholinergic and antimuscarinic agents, in particular, ipratropium bromide, oxitropium bromide, glycopyrronium saltsor tiotropium salts.

In another embodiment, the other therapeutic agent is an antihistamine, for example, cetirizine hydrochloride, clemastine fumarate, promethazine, loratidine, desloratidine, diphenhydramine fexofenadine hydrochloride, activastine, astemizole, azelastine, ebastine, epinastine, mizolastine or tefenadine

In another embodiment the other therapeutic agent is an antibiotic, for example tobramycin, including tobramycin inhaled powder, azithromycin, cayston, aztreonam, including the aerosolized for of aztreonam, amikacin, including liposomal formulations thereof, ciprofloxacin, including formulations thereof suitable of administration by inhalation, levofloxacin, including aerosolized formulations thereof and combinations of two antibiotics, for example, fosfomycin and tobramycin.

In another embodiment the other therapeutic agent is an anti-inflammatory agent, for example ibuprofen, docosahexanoic acid, sildenafil, inhaled glutathione, pioglitazone, hydroxychloroquine or simavastatin; a steroid, for example, glucocorticosteroids, such as budesonide, beclamethasone dipropionate, fluticasone propionate, ciclesonide or mometasone furoate; an LTD4 antagonist, such as montelukast or zafirlukast; a PDE4 inhibitor, such as Enprofylline, Theophylline, Roflumilaste, Ariflo (Cilomilaste), Tofimilaste, Pumafentrine, Lirimilaste, Apremilaste, Arofylline, Atizorame, Oglemilasturn, or Tetomilaste.

In another embodiment the other therapeutic agent is a CFTR modulator. In another embodiment the other therapeutic agent is a CFTR potentiator. In another embodiment the other therapeutic agent is a CFTR corrector. Exemplary CFTR modulators include N-(2-(5- chloro-2-methoxy-phenylamino)-4'-methyl-[4, 5']bithiazolyl-2'-yl)-benzamide (Corr-4a), N- (2,4-di-tert-butyl-5-hydroxyphenyl)-1 ,4-dihydro-4-oxoquinoline-3-carboxamide (Ivacaftor), N- [2-(1 ,1 -Dimeihyleihy )-4-[1 ,1 ii(meihyl-d ₃ )ethyl-2,2,2-a'3]-5-hydiOxyphenyl]-1 ,4-dihydro4-oxo- 3-quinoiinecarboxamide (CTP-656), (((3-((3-carbamoyl-5,5,7,7-tetramethyl-4,7-dihydro-5H- thieno[2,3-c]pyran-2-yl)carbamoyl)-1 H-pyrazol-1 -yl)methoxy)methyl)phosphonic acid (GLPG1833), 3-[6-({[1 -(2,2-difluoro-1 ,3-benzodioxol-5-yl)cyclopropyl]carbonyl}amino)-3- methylpyridin-2-yl]benzoic acid (Lumacaftor), N-(3-carbamoyl-5,5,7,7-tetramethyl-4,7- dihydro-5H-thieno[2,3-c]pyran-2-yl)-1 H-pyrazole-3-carboxamide, 1 -(2,2-difluoro-1 ,3- benzodioxol-5-yl)-N-[1 -[(2R)-2,3-dihydroxypropyl]-6-fluoro-2-(2-hydroxy-1 ,1 -dimethylethyl)- 1 H-indol-5-yl]-cyclopropanecarboxamide (VX-661), 4-((2R,4R)-4-(1 -(2,2- difluorobenzo[d][1 ,3]dioxol-5-yl)cyclopropane-1 -carboxamido)-7-(difluoromethoxy)chroman- 2-yl)benzoic acid (GLPG2222), 4-(3-(1 -(2,2-difluorobenzo[d][1 ,3]dioxol-5-yl)cyclopropane-1 - carboxamido)isoquinolin-1 -yl)benzoic acid, N-(4-(7-azabicyclo[2.2.1 ]heptan-7-yl)-2- (trifluoromethyl)phenyl)-4-oxo-5-(trifluromethyl)-1 ,4-dihydroquinoline-3-carboxamide, 3-[5-(2- fluorophenyl)-1 ,2,4-oxadiazol-3-yl]benzoic acid (Ataluren), 5,7-Dihydroxy-3-(4- hydroxyphenyl)chromen-4-one (Genistein), N-(2-(fe/?-butyl)-5-hydroxy-4-(2-(methyl- cf ₃ )propan-2-yl-1 ,1 ,1 ,3,3,3-c/ ₆ )phenyl)-4-oxo-1 ,4-dihydroquinoline-3-carboxamide (CTP-656), N-(3-carbamoyl-5,5,7,7-tetramethyl-4,7-dihydro-5H-thieno[2,3 -c]pyran-2-yl)-1 H-pyrazole-5- carboxamide (GLPG1837), 3-Chloro-4-(6-hydroxyquinolin-2-yl)benzoic acid (N-91 1 15) and (S)-3-amino-6-methoxy-N-(3,3,3-trifluoro-2-hydroxy-2-methylp ropyl)-5- (trifluoromethyl)picolinamide.

In one embodiment of the invention, there is provided a product comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof and a CFTR modulator as a combined preparation for simultaneous, separate or sequential use in therapy. In another embodiment, there is provided a product comprising a compound of formula (I) and a CFTR potentiator as a combined preparation for simultaneous, separate or sequential use in therapy. In another embodiment there is provided a product comprising a compound of formula (I), a CFTR potentiator and a CFTR corrector as a combined preparation for simultaneous, separate or sequential use in therapy.

In another embodiment there is provided a product comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof and (S)-3-amino-6-methoxy-N-(3,3,3-trifluoro-2- hydroxy-2-methylpropyl)-5-(trifluoromethyl)picolinamide or a pharmaceutically acceptable salt thereof as a combined preparation for simultaneous, separate or sequential use in therapy.

In another embodiment there is provided a product comprising 6-(4-cyclopropylpiperazin-

1 -yl)-N-(6-(3-fluoro-2-methylphenyl)-5-(trifluoromethyl)pyrid in-2-yl)pyridine-2-sulfonamide or a pharmaceutically acceptable salt thereof and (S)-3-amino-6-methoxy-N-(3,3,3-trifluoro-2- hydroxy-2-methylpropyl)-5-(trifluoromethyl)picolinamide or a pharmaceutically acceptable salt thereof as a combined preparation for simultaneous, separate or sequential use in therapy.

In another embodiment there is provided a product comprising N-(5-chloro-6-(5-fluoro-2- methylphenyl)pyridin-2-yl)-6-(((3R,4R)-4-hydroxytetrahydro-2 H-pyran-3-yl)amino)pyridine-2- sulfonamide or a pharmaceutically acceptable salt thereof and (S)-3-amino-6-methoxy-N- (3,3,3-trifluoro-2-hydroxy-2-methylpropyl)-5-(trifluoromethy l)picolinamide as a combined preparation for simultaneous, separate or sequential use in therapy.

In another embodiment there is provided a product comprising 6-(((1 s,3s)-3- hydroxycyclobutyl)amino)-N-(6-(o-tolyl)-5-(trifluoromethyl)p yridin-2-yl)pyridine-2-sulfonamide or a pharmaceutically acceptable salt thereof and (S)-3-amino-6-methoxy-N-(3,3,3-trifluoro-2- hydroxy-2-methylpropyl)-5-(trifluoromethyl)picolinamide or a pharmaceutically acceptable salt thereof as a combined preparation for simultaneous, separate or sequential use in therapy.

In another embodiment there is provided a product comprising (1 s,4s)-4-((6-(N-(5-chloro- 6-(2,6-dimethylphenyl)pyridin-2-yl)sulfamoyl)pyridin-2-yl)ox y)cyclohexane-1 -carboxylic acid or a pharmaceutically acceptable salt thereof and (S)-3-amino-6-methoxy-N-(3,3,3-trifluoro-2- hydroxy-2-methylpropyl)-5-(trifluoromethyl)picolinamide or a pharmaceutically acceptable salt thereof as a combined preparation for simultaneous, separate or sequential use in therapy.

In another embodiment there is provided a product comprising N-(5-chloro-6-(2,6- dimethylphenyl)pyridin-2-yl)-6-(3-cyclopropyl-3-hydroxyazeti din-1 -yl)pyridine-2-sulfonamide or a pharmaceutically acceptable salt thereof and (S)-3-amino-6-methoxy-N-(3,3,3-trifluoro-2- hydroxy-2-methylpropyl)-5-(trifluoromethyl)picolinamide or a pharmaceutically acceptable salt thereof as a combined preparation for simultaneous, separate or sequential use in therapy.

In another embodiment there is provided a product comprising (R)-6-(piperidin-3- ylamino)-N-(6-(o-tolyl)-5-(trifluoromethyl)pyridin-2-yl)pyri dine-2-sulfonamide or a pharmaceutically acceptable salt thereof and (S)-3-amino-6-methoxy-N-(3,3,3-trifluoro-2- hydroxy-2-methylpropyl)-5-(trifluoromethyl)picolinamide or a pharmaceutically acceptable salt thereof as a combined preparation for simultaneous, separate or sequential use in therapy.

In another embodiment there is provided a product comprising 6-amino-N-(5-chloro-6- (2,6-dimethylphenyl)pyridin-2-yl)pyridine-2-sulfonamide or a pharmaceutically acceptable salt thereof and (S)-3-amino-6-methoxy-N-(3,3,3-trifluoro-2-hydroxy-2-methylp ropyl)-5- (trifluoromethyl)picolinamide or a pharmaceutically acceptable salt thereof as a combined preparation for simultaneous, separate or sequential use in therapy.

In another embodiment there is provided a product comprising 6-(piperazin-1 -yl)-N-(6-(o- tolyl)-5-(trifluoromethyl)pyridin-2-yl)pyridine-2-sulfonamid e or a pharmaceutically acceptable salt thereof and (S)-3-amino-6-methoxy-N-(3,3,3-trifluoro-2-hydroxy-2-methylp ropyl)-5- (trifluoromethyl)picolinamide or a pharmaceutically acceptable salt thereof as a combined preparation for simultaneous, separate or sequential use in therapy.

In another embodiment there is provided a product comprising N-(5-chloro-6-(5-fluoro-2- methylphenyl)pyridin-2-yl)-6-(3-hydroxyazetidin-1 -yl)pyridine-2-sulfonamide or a pharmaceutically acceptable salt thereof and (S)-3-amino-6-methoxy-N-(3,3,3-trifluoro-2- hydroxy-2-methylpropyl)-5-(trifluoromethyl)picolinamide or a pharmaceutically acceptable salt thereof as a combined preparation for simultaneous, separate or sequential use in therapy.

In another embodiment there is provided a product comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof and /V-(2,4-di-tert-butyl-5-hydroxyphenyl)-1 ,4- dihydro-4-oxoquinoline-3-carboxamide or a pharmaceutically acceptable salt thereof as a combined preparation for simultaneous, separate or sequential use in therapy.

In another embodiment there is provided a product comprising 6-(4-cyclopropylpiperazin- 1 -yl)-N-(6-(3-fluoro-2-methylphenyl)-5-(trifluoromethyl)pyrid in-2-yl)pyridine-2-sulfonamide or a pharmaceutically acceptable salt thereof and /V-(2,4-di-tert-butyl-5-hydroxyphenyl)-1 ,4- dihydro-4-oxoquinoline-3-carboxamide or a pharmaceutically acceptable salt thereof as a combined preparation for simultaneous, separate or sequential use in therapy.

In another embodiment there is provided a product comprising N-(5-chloro-6-(5-fluoro-2- methylphenyl)pyridin-2-yl)-6-(((3R,4R)-4-hydroxytetrahydro-2 H-pyran-3-yl)amino)pyridine-2- sulfonamide or a pharmaceutically acceptable salt thereof and /V-(2,4-di-tert-butyl-5- hydroxyphenyl)-1 ,4-dihydro-4-oxoquinoline-3-carboxamide as a combined preparation for simultaneous, separate or sequential use in therapy. In another embodiment there is provided a product comprising 6-(((1 s,3s)-3- hydroxycyclobutyl)amino)-N-(6-(o-tolyl)-5-(trifluoromethyl)p yridin-2-yl)pyridine-2-sulfonami^ or a pharmaceutically acceptable salt thereof and /V-(2,4-di-tert-butyl-5-hydroxyphenyl)-1 ,4- dihydro-4-oxoquinoline-3-carboxamide or a pharmaceutically acceptable salt thereof as a combined preparation for simultaneous, separate or sequential use in therapy.

In another embodiment there is provided a product comprising (1 s,4s)-4-((6-(N-(5-chloro- 6-(2,6-dimethylphenyl)pyridin-2-yl)sulfamoyl)pyridin-2-yl)ox y)cyclohexane-1 -carboxylic acid or a pharmaceutically acceptable salt thereof and /V-(2,4-di-tert-butyl-5-hydroxyphenyl)-1 ,4- dihydro-4-oxoquinoline-3-carboxamide or a pharmaceutically acceptable salt thereof as a combined preparation for simultaneous, separate or sequential use in therapy.

In another embodiment there is provided a product comprising N-(5-chloro-6-(2,6- dimethylphenyl)pyridin-2-yl)-6-(3-cyclopropyl-3-hydroxyazeti din-1 -yl)pyridine-2-sulfonamide or a pharmaceutically acceptable salt thereof and /V-(2,4-di-tert-butyl-5-hydroxyphenyl)-1 ,4- dihydro-4-oxoquinoline-3-carboxamide or a pharmaceutically acceptable salt thereof as a combined preparation for simultaneous, separate or sequential use in therapy.

In another embodiment there is provided a product comprising (R)-6-(piperidin-3- ylamino)-N-(6-(o-tolyl)-5-(trifluoromethyl)pyridin-2-yl)pyri dine-2-sulfonamide or a pharmaceutically acceptable salt thereof and /V-(2,4-di-tert-butyl-5-hydroxyphenyl)-1 ,4- dihydro-4-oxoquinoline-3-carboxamide or a pharmaceutically acceptable salt thereof as a combined preparation for simultaneous, separate or sequential use in therapy.

In another embodiment there is provided a product comprising 6-amino-N-(5-chloro-6- (2,6-dimethylphenyl)pyridin-2-yl)pyridine-2-sulfonamide or a pharmaceutically acceptable salt thereof and /V-(2,4-di-tert-butyl-5-hydroxyphenyl)-1 ,4-dihydro-4-oxoquinoline-3-carboxamide or a pharmaceutically acceptable salt thereof as a combined preparation for simultaneous, separate or sequential use in therapy.

In another embodiment there is provided a product comprising 6-(piperazin-1 -yl)-N-(6-(o- tolyl)-5-(trifluoromethyl)pyridin-2-yl)pyridine-2-sulfonamid e or a pharmaceutically acceptable salt thereof and /V-(2,4-di-tert-butyl-5-hydroxyphenyl)-1 ,4-dihydro-4-oxoquinoline-3- carboxamide or a pharmaceutically acceptable salt thereof as a combined preparation for simultaneous, separate or sequential use in therapy.

In another embodiment there is provided a product comprising N-(5-chloro-6-(5-fluoro-2- methylphenyl)pyridin-2-yl)-6-(3-hydroxyazetidin-1 -yl)pyridine-2-sulfonamide or a pharmaceutically acceptable salt thereof and /V-(2,4-di-tert-butyl-5-hydroxyphenyl)-1 ,4- dihydro-4-oxoquinoline-3-carboxamide or a pharmaceutically acceptable salt thereof as a combined preparation for simultaneous, separate or sequential use in therapy.

In another embodiment there is provided a product comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof, /V-(2,4-di-tert-butyl-5-hydroxyphenyl)-1 ,4- dihydro-4-oxoquinoline-3-carboxamide or a pharmaceutically acceptable salt thereof and 3- [6-({[1 -(2,2-difluoro-1 ,3-benzodioxol-5-yl)cyclopropyl]carbonyl}amino)-3-methylpyri din-2- yl]benzoic acid or a pharmaceutically acceptable salt thereof as a combined preparation for simultaneous, separate or sequential use in therapy.

In another embodiment there is provided a product comprising 6-(4-cyclopropylpiperazin-

1 -yl)-N-(6-(3-fluoro-2-methylphenyl)-5-(trifluoromethyl)pyrid in-2-yl)pyridine-2-sulfonamide or a pharmaceutically acceptable salt thereof, /V-(2,4-di-tert-butyl-5-hydroxyphenyl)-1 ,4-dihydro- 4-oxoquinoline-3-carboxamide or a pharmaceutically acceptable salt thereof and 3-[6-({[1 - (2,2-difluoro-1 ,3-benzodioxol-5-yl)cyclopropyl]carbonyl}amino)-3-methylpyri din-2-yl]benzoic acid or a pharmaceutically acceptable salt thereof as a combined preparation for simultaneous, separate or sequential use in therapy.

In another embodiment there is provided a product comprising N-(5-chloro-6-(5-fluoro-2- methylphenyl)pyridin-2-yl)-6-(((3R,4R)-4-hydroxytetrahydro-2 H-pyran-3-yl)amino)pyridine-2- sulfonamide or a pharmaceutically acceptable salt thereof, /V-(2,4-di-tert-butyl-5- hydroxyphenyl)-1 ,4-dihydro-4-oxoquinoline-3-carboxamide or a pharmaceutically acceptable salt thereof and 3-[6-({[1 -(2,2-difluoro-1 ,3-benzodioxol-5-yl)cyclopropyl]carbonyl}amino)-3- methylpyridin-2-yl]benzoic acid or a pharmaceutically acceptable salt thereof as a combined preparation for simultaneous, separate or sequential use in therapy.

In another embodiment there is provided a product comprising 6-(((1 S,3S)-3- hydroxycyclobutyl)amino)-N-(6-(o-tolyl)-5-(trifluoromethyl)p yridin-2-yl)pyridine-2-sulfonamide or a pharmaceutically acceptable salt thereof, /V-(2,4-di-tert-butyl-5-hydroxyphenyl)-1 ,4- dihydro-4-oxoquinoline-3-carboxamide or a pharmaceutically acceptable salt thereof and 3- [6-({[1 -(2,2-difluoro-1 ,3-benzodioxol-5-yl)cyclopropyl]carbonyl}amino)-3-methylpyri din-2- yl]benzoic acid or a pharmaceutically acceptable salt thereof as a combined preparation for simultaneous, separate or sequential use in therapy.

In another embodiment there is provided a product comprising (1 S,4S)-4-((6-(N-(5- chloro-6-(2,6-dimethylphenyl)pyridin-2-yl)sulfamoyl)pyridin- 2-yl)oxy)cyclohexane-1 -carboxylic acid or a pharmaceutically acceptable salt thereof, /V-(2,4-di-tert-butyl-5-hydroxyphenyl)-1 ,4- dihydro-4-oxoquinoline-3-carboxamide or a pharmaceutically acceptable salt thereof and 3- [6-({[1 -(2,2-difluoro-1 ,3-benzodioxol-5-yl)cyclopropyl]carbonyl}amino)-3-methylpyri din-2- yl]benzoic acid or a pharmaceutically acceptable salt thereof as a combined preparation for simultaneous, separate or sequential use in therapy.

In another embodiment there is provided a product comprising N-(5-chloro-6-(2,6- dimethylphenyl)pyridin-2-yl)-6-(3-cyclopropyl-3-hydroxyazeti din-1 -yl)pyridine-2-sulfonamide or a pharmaceutically acceptable salt thereof, /V-(2,4-di-tert-butyl-5-hydroxyphenyl)-1 ,4- dihydro-4-oxoquinoline-3-carboxamide or a pharmaceutically acceptable salt thereof and 3- [6-({[1 -(2,2-difluoro-1 ,3-benzodioxol-5-yl)cyclopropyl]carbonyl}amino)-3-methylpyri din-2- yl]benzoic acid or a pharmaceutically acceptable salt thereof as a combined preparation for simultaneous, separate or sequential use in therapy.

In another embodiment there is provided a product comprising (R)-6-(piperidin-3- ylamino)-N-(6-(o-tolyl)-5-(trifluoromethyl)pyridin-2-yl)pyri dine-2-sulfonamide or a

pharmaceutically acceptable salt thereof, /V-(2,4-di-tert-butyl-5-hydroxyphenyl)-1 ,4-dihydro-4- oxoquinoline-3-carboxamide or a pharmaceutically acceptable salt thereof and 3-[6-({[1 -(2,2- difluoro-1 ,3-benzodioxol-5-yl)cyclopropyl]carbonyl}amino)-3-methylpyri din-2-yl]benzoic acid or a pharmaceutically acceptable salt thereof as a combined preparation for simultaneous, separate or sequential use in therapy.

In another embodiment there is provided a product comprising 6-amino-N-(5-chloro-6- (2,6-dimethylphenyl)pyridin-2-yl)pyridine-2-sulfonamide or a pharmaceutically acceptable salt thereof, /V-(2,4-di-tert-butyl-5-hydroxyphenyl)-1 ,4-dihydro-4-oxoquinoline-3-carboxamide or a pharmaceutically acceptable salt thereof and 3-[6-({[1 -(2,2-difluoro-1 ,3-benzodioxol-5- yl)cyclopropyl]carbonyl}amino)-3-methylpyridin-2-yl]benzoic acid or a pharmaceutically acceptable salt thereof as a combined preparation for simultaneous, separate or sequential use in therapy.

In another embodiment there is provided a product comprising 6-(piperazin-1 -yl)-N-(6-(o- tolyl)-5-(trifluoromethyl)pyridin-2-yl)pyridine-2-sulfonamid e or a pharmaceutically acceptable salt thereof, /V-(2,4-di-tert-butyl-5-hydroxyphenyl)-1 ,4-dihydro-4-oxoquinoline-3-carboxamide or a pharmaceutically acceptable salt thereof and 3-[6-({[1 -(2,2-difluoro-1 ,3-benzodioxol-5- yl)cyclopropyl]carbonyl}amino)-3-methylpyridin-2-yl]benzoic acid or a pharmaceutically acceptable salt thereof as a combined preparation for simultaneous, separate or sequential use in therapy.

In another embodiment there is provided a product comprising N-(5-chloro-6-(5-fluoro-2- methylphenyl)pyridin-2-yl)-6-(3-hydroxyazetidin-1 -yl)pyridine-2-sulfonamide or a

pharmaceutically acceptable salt thereof, /V-(2,4-di-tert-butyl-5-hydroxyphenyl)-1 ,4-dihydro-4- oxoquinoline-3-carboxamide or a pharmaceutically acceptable salt thereof and 3-[6-({[1 -(2,2- difluoro-1 ,3-benzodioxol-5-yl)cyclopropyl]carbonyl}amino)-3-methylpyri din-2-yl]benzoic acid or a pharmaceutically acceptable salt thereof as a combined preparation for simultaneous, separate or sequential use in therapy.

In another embodiment there is provided a product comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof, /V-(2,4-di-tert-butyl-5-hydroxyphenyl)-1 ,4- dihydro-4-oxoquinoline-3-carboxamide or a pharmaceutically acceptable salt thereof and 1 - (2,2-difluoro-1 ,3-benzodioxol-5-yl)-N-[1 -[(2R)-2,3-dihydroxypropyl]-6-fluoro-2-(2-hydroxy-1 ,1 - dimethylethyl)-1 H-indol-5-yl]-cyclopropanecarboxamide or a pharmaceutically acceptable salt thereof as a combined preparation for simultaneous, separate or sequential use in therapy. In another embodiment there is provided a product comprising 6-(4-cyclopropylpiperazin- 1 -yl)-N-(6-(3-fluoro-2-methylphenyl)-5-(trifluoromethyl)pyrid in-2-yl)pyridine-2-sulfonamide or a pharmaceutically acceptable salt thereof, /V-(2,4-di-tert-butyl-5-hydroxyphenyl)-1 ,4-dihydro- 4-oxoquinoline-3-carboxamide or a pharmaceutically acceptable salt thereof and 1 -(2,2- difluoro-1 ,3-benzodioxol-5-yl)-N-[1 -[(2R)-2,3-dihydroxypropyl]-6-fluoro-2-(2-hydroxy-1 ,1 - dimethylethyl)-1 H-indol-5-yl]-cyclopropanecarboxamide or a pharmaceutically acceptable salt thereof as a combined preparation for simultaneous, separate or sequential use in therapy.

In another embodiment there is provided a product comprising N-(5-chloro-6-(5-fluoro-2- methylphenyl)pyridin-2-yl)-6-(((3R,4R)-4-hydroxytetrahydro-2 H-pyran-3-yl)amino)pyridine-2- sulfonamide or a pharmaceutically acceptable salt thereof, /V-(2,4-di-tert-butyl-5- hydroxyphenyl)-1 ,4-dihydro-4-oxoquinoline-3-carboxamide or a pharmaceutically acceptable salt thereof and 1 -(2,2-difluoro-1 ,3-benzodioxol-5-yl)-N-[1 -[(2R)-2,3-dihydroxypropyl]-6- fluoro-2-(2-hydroxy-1 ,1 -dimethylethyl)-1 H-indol-5-yl]-cyclopropanecarboxamide or a pharmaceutically acceptable salt thereof as a combined preparation for simultaneous, separate or sequential use in therapy.

In another embodiment there is provided a product comprising 6-(((1 S,3S)-3- hydroxycyclobutyl)amino)-N-(6-(o-tolyl)-5-(trifluoromethyl)p yridin-2-yl)pyridine-2-sulfonamide or a pharmaceutically acceptable salt thereof, /V-(2,4-di-tert-butyl-5-hydroxyphenyl)-1 ,4- dihydro-4-oxoquinoline-3-carboxamide or a pharmaceutically acceptable salt thereof and 1 - (2,2-difluoro-1 ,3-benzodioxol-5-yl)-N-[1 -[(2R)-2,3-dihydroxypropyl]-6-fluoro-2-(2-hydroxy-1 ,1 - dimethylethyl)-1 H-indol-5-yl]-cyclopropanecarboxamide or a pharmaceutically acceptable salt thereof as a combined preparation for simultaneous, separate or sequential use in therapy.

In another embodiment there is provided a product comprising (1 S,4S)-4-((6-(N-(5- chloro-6-(2,6-dimethylphenyl)pyridin-2-yl)sulfamoyl)pyridin- 2-yl)oxy)cyclohexane-1 -carboxylic acid or a pharmaceutically acceptable salt thereof, /V-(2,4-di-tert-butyl-5-hydroxyphenyl)-1 ,4- dihydro-4-oxoquinoline-3-carboxamide or a pharmaceutically acceptable salt thereof and 1 - (2,2-difluoro-1 ,3-benzodioxol-5-yl)-N-[1 -[(2R)-2,3-dihydroxypropyl]-6-fluoro-2-(2-hydroxy-1 ,1 - dimethylethyl)-1 H-indol-5-yl]-cyclopropanecarboxamide or a pharmaceutically acceptable salt thereof as a combined preparation for simultaneous, separate or sequential use in therapy.

In another embodiment there is provided a product comprising N-(5-chloro-6-(2,6- dimethylphenyl)pyridin-2-yl)-6-(3-cyclopropyl-3-hydroxyazeti din-1 -yl)pyridine-2-sulfonamide or a pharmaceutically acceptable salt thereof, /V-(2,4-di-tert-butyl-5-hydroxyphenyl)-1 ,4- dihydro-4-oxoquinoline-3-carboxamide or a pharmaceutically acceptable salt thereof and 1 - (2,2-difluoro-1 ,3-benzodioxol-5-yl)-N-[1 -[(2R)-2,3-dihydroxypropyl]-6-fluoro-2-(2-hydroxy-1 ,1 - dimethylethyl)-1 H-indol-5-yl]-cyclopropanecarboxamide or a pharmaceutically acceptable salt thereof as a combined preparation for simultaneous, separate or sequential use in therapy. In another embodiment there is provided a product comprising (R)-6-(piperidin-3- ylamino)-N-(6-(o-tolyl)-5-(trifluoromethyl)pyridin-2-yl)pyri dine-2-sulfonamide or a

pharmaceutically acceptable salt thereof, /V-(2,4-di-tert-butyl-5-hydroxyphenyl)-1 ,4-dihydro-4- oxoquinoline-3-carboxamide or a pharmaceutically acceptable salt thereof and 1 -(2,2- difluoro-1 ,3-benzodioxol-5-yl)-N-[1 -[(2R)-2,3-dihydroxypropyl]-6-fluoro-2-(2-hydroxy-1 ,1 - dimethylethyl)-1 H-indol-5-yl]-cyclopropanecarboxamide or a pharmaceutically acceptable salt thereof as a combined preparation for simultaneous, separate or sequential use in therapy.

In another embodiment there is provided a product comprising 6-amino-N-(5-chloro-6- (2,6-dimethylphenyl)pyridin-2-yl)pyridine-2-sulfonamide or a pharmaceutically acceptable salt thereof, /V-(2,4-di-tert-butyl-5-hydroxyphenyl)-1 ,4-dihydro-4-oxoquinoline-3-carboxamide or a pharmaceutically acceptable salt thereof and 1 -(2,2-difluoro-1 ,3-benzodioxol-5-yl)-N-[1 -[(2R)- 2,3-dihydroxypropyl]-6-fluoro-2-(2-hydroxy-1 ,1 -dimethylethyl)-1 H-indol-5-yl]- cyclopropanecarboxamide or a pharmaceutically acceptable salt thereof as a combined preparation for simultaneous, separate or sequential use in therapy.

In another embodiment there is provided a product comprising 6-(piperazin-1 -yl)-N-(6-(o- tolyl)-5-(trifluoromethyl)pyridin-2-yl)pyridine-2-sulfonamid e or a pharmaceutically acceptable salt thereof, /V-(2,4-di-tert-butyl-5-hydroxyphenyl)-1 ,4-dihydro-4-oxoquinoline-3-carboxamide or a pharmaceutically acceptable salt thereof and 1 -(2,2-difluoro-1 ,3-benzodioxol-5-yl)-N-[1 - [(2R)-2,3-dihydroxypropyl]-6-fluoro-2-(2-hydroxy-1 ,1 -dimethylethyl)-1 H-indol-5-yl]- cyclopropanecarboxamide or a pharmaceutically acceptable salt thereof as a combined preparation for simultaneous, separate or sequential use in therapy.

In another embodiment there is provided a product comprising N-(5-chloro-6-(5-fluoro-2- methylphenyl)pyridin-2-yl)-6-(3-hydroxyazetidin-1 -yl)pyridine-2-sulfonamide or a

pharmaceutically acceptable salt thereof, /V-(2,4-di-tert-butyl-5-hydroxyphenyl)-1 ,4-dihydro-4- oxoquinoline-3-carboxamide or a pharmaceutically acceptable salt thereof and 1 -(2,2- difluoro-1 ,3-benzodioxol-5-yl)-N-[1 -[(2R)-2,3-dihydroxypropyl]-6-fluoro-2-(2-hydroxy-1 ,1 - dimethylethyl)-1 H-indol-5-yl]-cyclopropanecarboxamide or a pharmaceutically acceptable salt thereof as a combined preparation for simultaneous, separate or sequential use in therapy.

In another embodiment, there is provided a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof, a CFTR modulator and a pharmaceutically acceptable carrier.

In another embodiment there is provided a pharmaceutical composition comprising a compound of formula (I), a CFTR potentiator and a pharmaceutically acceptable carrier. In yet another embodiment there is provided a pharmaceutical composition comprising a compound of formula (I) a CFTR corrector and a pharmaceutically acceptable carrier.

In another embodiment, there is provided a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof, (S)-3-amino-6- methoxy-N-(3,3,3-trifluoro-2-hydroxy-2-methylpropyl)-5-(trif luoromethyl)picolin or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.

In another embodiment, there is provided a pharmaceutical composition comprising 6-(4- cyclopropylpiperazin-1 -yl)-N-(6-(3-fluoro-2-methylphenyl)-5-(trifluoromethyl)pyrid in-2- yl)pyridine-2-sulfonamide or a pharmaceutically acceptable salt thereof, (S)-3-amino-6- methoxy-N-(3,3,3-trifluoro-2-hydroxy-2-methylpropyl)-5-(trif luoromethyl)picolinamide or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.

In another embodiment, there is provided a pharmaceutical composition comprising N-(5- chloro-6-(5-fluoro-2-methylphenyl)pyridin-2-yl)-6-(((3R,4R)- 4-hydroxytetrahydro-2H-pyran-3- yl)amino)pyridine-2-sulfonamide or a pharmaceutically acceptable salt thereof, (S)-3-amino- 6-methoxy-N-(3,3,3-trifluoro-2-hydroxy-2-methylpropyl)-5-(tr ifluoromethyl)picolinamide or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.

In another embodiment, there is provided a pharmaceutical composition comprising 6- (((1 S,3S)-3-hydroxycyclobutyl)amino)-N-(6-(o-tolyl)-5-(trifluoro methyl)pyridin-2-yl)pyridine-2- sulfonamide or a pharmaceutically acceptable salt thereof, (S)-3-amino-6-methoxy-N-(3,3,3- trifluoro-2-hydroxy-2-methylpropyl)-5-(trifluoromethyl)picol inamide or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.

In another embodiment, there is provided a pharmaceutical composition comprising (1 S,4S)-4-((6-(N-(5-chloro-6-(2,6-dimethylphenyl)pyridin-2-yl) sulfamoyl)pyridin-2- yl)oxy)cyclohexane-1 -carboxylic acid or a pharmaceutically acceptable salt thereof, (S)-3- amino-6-methoxy-N-(3,3,3-trifluoro-2-hydroxy-2-methylpropyl) -5-(trifluoromethyl)picolinamide or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.

In another embodiment, there is provided a pharmaceutical composition comprising N-(5- chloro-6-(2,6-dimethylphenyl)pyridin-2-yl)-6-(3-cyclopropyl- 3-hydroxyazetidin-1 -yl)pyridine-2- sulfonamide or a pharmaceutically acceptable salt thereof, (S)-3-amino-6-methoxy-N-(3,3,3- trifluoro-2-hydroxy-2-methylpropyl)-5-(trifluoromethyl)picol inamide or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.

In another embodiment, there is provided a pharmaceutical composition comprising (R)- 6-(piperidin-3-ylamino)-N-(6-(o-tolyl)-5-(trifluoromethyl)py ridin-2-yl)pyridine-2-sulfonamide or a pharmaceutically acceptable salt thereof, (S)-3-amino-6-methoxy-N-(3,3,3-trifluoro-2- hydroxy-2-methylpropyl)-5-(trifluoromethyl)picolinamide or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.

In another embodiment, there is provided a pharmaceutical composition comprising 6- amino-N-(5-chloro-6-(2,6-dimethylphenyl)pyridin-2-yl)pyridin e-2-sulfonamide or a

pharmaceutically acceptable salt thereof, (S)-3-amino-6-methoxy-N-(3,3,3-trifluoro-2- hydroxy-2-methylpropyl)-5-(trifluoromethyl)picolinamide or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier. In another embodiment, there is provided a pharmaceutical composition comprising 6- (piperazin-1 -yl)-N-(6-(o-tolyl)-5-(trifluoromethyl)pyridin-2-yl)pyridine -2-sulfonamide or a pharmaceutically acceptable salt thereof, (S)-3-amino-6-methoxy-N-(3,3,3-trifluoro-2- hydroxy-2-methylpropyl)-5-(trifluoromethyl)picolinamide or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.

In another embodiment, there is provided a pharmaceutical composition comprising N-(5- chloro-6-(5-fluoro-2-methylphenyl)pyridin-2-yl)-6-(3-hydroxy azetidin-1 -yl)pyridine-2- sulfonamide or a pharmaceutically acceptable salt thereof, (S)-3-amino-6-methoxy-N-(3,3,3- trifluoro-2-hydroxy-2-methylpropyl)-5-(trifluoromethyl)picol inamide or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.

In another embodiment, there is provided a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof, /V-(2,4-di-tert-butyl-5- hydroxyphenyl)-1 ,4-dihydro-4-oxoquinoline-3-carboxamide or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.

In another embodiment, there is provided a pharmaceutical composition comprising 6-(4- cyclopropylpiperazin-1 -yl)-N-(6-(3-fluoro-2-methylphenyl)-5-(trifluoromethyl)pyrid in-2- yl)pyridine-2-sulfonamide or a pharmaceutically acceptable salt thereof, /V-(2,4-di-tert-butyl-5- hydroxyphenyl)-1 ,4-dihydro-4-oxoquinoline-3-carboxamide or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.

In another embodiment, there is provided a pharmaceutical composition comprising N-(5- chloro-6-(5-fluoro-2-methylphenyl)pyridin-2-yl)-6-(((3R,4R)- 4-hydroxytetrahydro-2H-pyran-3- yl)amino)pyridine-2-sulfonamide or a pharmaceutically acceptable salt thereof, /V-(2,4-di-tert- butyl-5-hydroxyphenyl)-1 ,4-dihydro-4-oxoquinoline-3-carboxamide or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.

In another embodiment, there is provided a pharmaceutical composition comprising 6-

(((1 S,3S)-3-hydroxycyclobutyl)amino)-N-(6-(o-tolyl)-5-(trifluoro methyl)pyridin-2-yl)pyridine-2- sulfonamide or a pharmaceutically acceptable salt thereof, /V-(2,4-di-tert-butyl-5- hydroxyphenyl)-1 ,4-dihydro-4-oxoquinoline-3-carboxamide or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.

In another embodiment, there is provided a pharmaceutical composition comprising (1 S,4S)-4-((6-(N-(5-chloro-6-(2,6-dimethylphenyl)pyridin-2-yl) sulfamoyl)pyridin-2- yl)oxy)cyclohexane-1 -carboxylic acid or a pharmaceutically acceptable salt thereof, /V-(2,4-di- tert-butyl-5-hydroxyphenyl)-1 ,4-dihydro-4-oxoquinoline-3-carboxamide or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.

In another embodiment, there is provided a pharmaceutical composition comprising N-(5- chloro-6-(2,6-dimethylphenyl)pyridin-2-yl)-6-(3-cyclopropyl- 3-hydroxyazetidin-1 -yl)pyridine-2- sulfonamide or a pharmaceutically acceptable salt thereof, /V-(2,4-di-tert-butyl-5- hydroxyphenyl)-1 ,4-dihydro-4-oxoquinoline-3-carboxamide or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.

In another embodiment, there is provided a pharmaceutical composition comprising (R)- 6-(piperidin-3-ylamino)-N-(6-(o-tolyl)-5-(trifluoromethyl)py ridin-2-yl)pyridine-2-sulfonamide or a pharmaceutically acceptable salt thereof, /V-(2,4-di-tert-butyl-5-hydroxyphenyl)-1 ,4-dihydro- 4-oxoquinoline-3-carboxamide or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.

In another embodiment, there is provided a pharmaceutical composition comprising 6- amino-N-(5-chloro-6-(2,6-dimethylphenyl)pyridin-2-yl)pyridin e-2-sulfonamide or a pharmaceutically acceptable salt thereof, /V-(2,4-di-tert-butyl-5-hydroxyphenyl)-1 ,4-dihydro-4- oxoquinoline-3-carboxamide or a pharmaceutically acceptable salt thereof and a

pharmaceutically acceptable carrier.

In another embodiment, there is provided a pharmaceutical composition comprising 6- (piperazin-1 -yl)-N-(6-(o-tolyl)-5-(trifluoromethyl)pyridin-2-yl)pyridine -2-sulfonamide or a pharmaceutically acceptable salt thereof, /V-(2,4-di-tert-butyl-5-hydroxyphenyl)-1 ,4-dihydro-4- oxoquinoline-3-carboxamide or a pharmaceutically acceptable salt thereof and a

pharmaceutically acceptable carrier.

In another embodiment, there is provided a pharmaceutical composition comprising N-(5- chloro-6-(5-fluoro-2-methylphenyl)pyridin-2-yl)-6-(3-hydroxy azetidin-1 -yl)pyridine-2- sulfonamide or a pharmaceutically acceptable salt thereof, /V-(2,4-di-tert-butyl-5- hydroxyphenyl)-1 ,4-dihydro-4-oxoquinoline-3-carboxamide or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.

In another embodiment, there is provided a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof, /V-(2,4-di-tert-butyl-5- hydroxyphenyl)-1 ,4-dihydro-4-oxoquinoline-3-carboxamide or a pharmaceutically acceptable salt thereof, 3-[6-({[1 -(2,2-difluoro-1 ,3-benzodioxol-5-yl)cyclopropyl]carbonyl}amino)-3- methylpyridin-2-yl]benzoic acid or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.

In another embodiment, there is provided a pharmaceutical composition comprising 6-(4- cyclopropylpiperazin-1 -yl)-N-(6-(3-fluoro-2-methylphenyl)-5-(trifluoromethyl)pyrid in-2- yl)pyridine-2-sulfonamide or a pharmaceutically acceptable salt thereof, /V-(2,4-di-tert-butyl-5- hydroxyphenyl)-1 ,4-dihydro-4-oxoquinoline-3-carboxamide or a pharmaceutically acceptable salt thereof, 3-[6-({[1 -(2,2-difluoro-1 ,3-benzodioxol-5-yl)cyclopropyl]carbonyl}amino)-3- methylpyridin-2-yl]benzoic acid or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.

In another embodiment, there is provided a pharmaceutical composition comprising N-(5- chloro-6-(5-fluoro-2-methylphenyl)pyridin-2-yl)-6-(((3R,4R)- 4-hydroxytetrahydro-2H-pyran-3- yl)amino)pyridine-2-sulfonamide or a pharmaceutically acceptable salt thereof, /V-(2,4-di-tert- butyl-5-hydroxyphenyl)-1 ,4-dihydro-4-oxoquinoline-3-carboxamide or a pharmaceutically acceptable salt thereof, 3-[6-({[1 -(2,2-difluoro-1 ,3-benzodioxol-5- yl)cyclopropyl]carbonyl}amino)-3-methylpyridin-2-yl]benzoic acid or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.

In another embodiment, there is provided a pharmaceutical composition comprising 6- (((1 S,3S)-3-hydroxycyclobutyl)amino)-N-(6-(o-tolyl)-5-(trifluoro methyl)pyridin-2-yl)pyridine-2- sulfonamide or a pharmaceutically acceptable salt thereof, /V-(2,4-di-tert-butyl-5- hydroxyphenyl)-1 ,4-dihydro-4-oxoquinoline-3-carboxamide or a pharmaceutically acceptable salt thereof, 3-[6-({[1 -(2,2-difluoro-1 ,3-benzodioxol-5-yl)cyclopropyl]carbonyl}amino)-3- methylpyridin-2-yl]benzoic acid or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.

In another embodiment, there is provided a pharmaceutical composition comprising (1 S,4S)-4-((6-(N-(5-chloro-6-(2,6-dimethylphenyl)pyridin-2-yl) sulfamoyl)pyridin-2- yl)oxy)cyclohexane-1 -carboxylic acid or a pharmaceutically acceptable salt thereof, /V-(2,4-di- tert-butyl-5-hydroxyphenyl)-1 ,4-dihydro-4-oxoquinoline-3-carboxamide or a pharmaceutically acceptable salt thereof, 3-[6-({[1 -(2,2-difluoro-1 ,3-benzodioxol-5- yl)cyclopropyl]carbonyl}amino)-3-methylpyridin-2-yl]benzoic acid or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.

In another embodiment, there is provided a pharmaceutical composition comprising N-(5- chloro-6-(2,6-dimethylphenyl)pyridin-2-yl)-6-(3-cyclopropyl- 3-hydroxyazetidin-1 -yl)pyridine-2- sulfonamide or a pharmaceutically acceptable salt thereof, /V-(2,4-di-tert-butyl-5- hydroxyphenyl)-1 ,4-dihydro-4-oxoquinoline-3-carboxamide or a pharmaceutically acceptable salt thereof, 3-[6-({[1 -(2,2-difluoro-1 ,3-benzodioxol-5-yl)cyclopropyl]carbonyl}amino)-3- methylpyridin-2-yl]benzoic acid or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.

In another embodiment, there is provided a pharmaceutical composition comprising (R)- 6-(piperidin-3-ylamino)-N-(6-(o-tolyl)-5-(trifluoromethyl)py ridin-2-yl)pyridine-2-sulfonamide or a pharmaceutically acceptable salt thereof, /V-(2,4-di-tert-butyl-5-hydroxyphenyl)-1 ,4-dihydro- 4-oxoquinoline-3-carboxamide or a pharmaceutically acceptable salt thereof, 3-[6-({[1 -(2,2- difluoro-1 ,3-benzodioxol-5-yl)cyclopropyl]carbonyl}amino)-3-methylpyri din-2-yl]benzoic acid or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.

In another embodiment, there is provided a pharmaceutical composition comprising 6- amino-N-(5-chloro-6-(2,6-dimethylphenyl)pyridin-2-yl)pyridin e-2-sulfonamide or a pharmaceutically acceptable salt thereof, /V-(2,4-di-tert-butyl-5-hydroxyphenyl)-1 ,4-dihydro-4- oxoquinoline-3-carboxamide or a pharmaceutically acceptable salt thereof, 3-[6-({[1 -(2,2- difluoro-1 ,3-benzodioxol-5-yl)cyclopropyl]carbonyl}amino)-3-methylpyri din-2-yl]benzoic acid or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.

In another embodiment, there is provided a pharmaceutical composition comprising 6- (piperazin-1 -yl)-N-(6-(o-tolyl)-5-(trifluoromethyl)pyridin-2-yl)pyridine -2-sulfonamide or a pharmaceutically acceptable salt thereof, /V-(2,4-di-tert-butyl-5-hydroxyphenyl)-1 ,4-dihydro-4- oxoquinoline-3-carboxamide or a pharmaceutically acceptable salt thereof, 3-[6-({[1 -(2,2- difluoro-1 ,3-benzodioxol-5-yl)cyclopropyl]carbonyl}amino)-3-methylpyri din-2-yl]benzoic acid or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.

In another embodiment, there is provided a pharmaceutical composition comprising N-(5- chloro-6-(5-fluoro-2-methylphenyl)pyridin-2-yl)-6-(3-hydroxy azetidin-1 -yl)pyridine-2- sulfonamide or a pharmaceutically acceptable salt thereof, /V-(2,4-di-tert-butyl-5- hydroxyphenyl)-1 ,4-dihydro-4-oxoquinoline-3-carboxamide or a pharmaceutically acceptable salt thereof, 3-[6-({[1 -(2,2-difluoro-1 ,3-benzodioxol-5-yl)cyclopropyl]carbonyl}amino)-3- methylpyridin-2-yl]benzoic acid or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.

In another aspect of the present invention, kits that include one or more compound of the present invention and a combination partner as disclosed herein are provided.

Representative kits include (a) a compound of the present invention or a pharmaceutically acceptable salt thereof, (b) at least one combination partner, e.g., as indicated above, whereby such kit may comprise a package insert or other labeling including directions for administration.

In the combination therapies of the invention, the compound of the present invention and the other therapeutic agent may be manufactured and/or formulated by the same or different manufacturers. Moreover, the compound of the present invention and the other therapeutic (or pharmaceutical agent) may be brought together into a combination therapy: (i) prior to release of the combination product to physicians (e.g. in the case of a kit comprising the compound of the invention and the other therapeutic agent); (ii) by the physician themselves (or under the guidance of the physician) shortly before administration; (iii) in the patient themselves, e.g. during sequential administration of the compound of the invention and the other therapeutic agent.

Embodiments of the present invention are illustrated by the following Examples. It is to be understood, however, that the embodiments of the invention are not limited to the specific details of these Examples, as other variations thereof will be known, or apparent in light of the instant disclosure, to one of ordinary skill in the art.

Definitions:

As used herein, "CFTR" stands for cystic fibrosis transmembrane conductance regulator. As used herein, "mutations" can refer to mutations in the CFTR gene or the CFTR protein. A "CFTR mutation" refers to a mutation in the CFTR gene, and a "CFTR mutation" refers to a mutation in the CFTR protein. A genetic defect or mutation, or a change in the nucleotides in a gene in general results in a mutation in the CFTR protein translated from that gene.

As used herein, a "F508del mutation" or "F508del" is a specific mutation within the CFTR protein. The mutation is a deletion of the three nucleotides that comprise the codon for amino acid phenylalanine at position 508, resulting in CFTR protein that lacks this phenylalanine residue.

The term "CFTR gating mutation" as used herein means a CFTR mutation that results in the production of a CFTR protein for which the predominant defect is a low channel open probability compared to normal CFTR (Van Goor, F., Hadida S. and Grootenhuis P., "Pharmacological Rescue of Mutant CFTR function for the Treatment of Cystic Fibrosis", Top. Med. Chem. 3: 91 -120 (2008)). Gating mutations include, but are not limited to, G551 D, G178R, S549N, S549R, G551 S, G970R, G1244E, S1251 N, S1255P, and G1349D.

As used herein, a patient who is ""homozygous" for a particular mutation, e.g. F508del, has the same mutation on each allele.

As used herein, a patient who is "heterozygous" for a particular mutation, e.g. F508del, has this mutation on one allele, and a different mutation on the other allele.

As used herein, the term "modulator" refers to a compound that increases the activity of a biological compound such as a protein. For example, a CFTR modulator is a compound that increases the activity of CFTR. The increase in activity resulting from a CFTR modulator may be through a corrector mechanism or a potentiator mechanism as described below.

As used herein, the term "CFTR corrector" refers to a compound that increases the amount of functional CFTR protein at the cell surface, resulting in enhanced ion transport.

As used herein, the term "CFTR potentiator" refers to a compound that increases the channel activity of CFTR protein located at the cell surface, resulting in enhanced ion transport.

As used herein, the term "modulating" as used herein means increasing or decreasing by a measurable amount.

As used herein, the term "inducing," as in inducing CFTR activity, refers to increasing CFTR activity, whether by the corrector, potentiator, or other mechanism.

As used herein "Asthma" includes both intrinsic (non-allergic) asthma and extrinsic (allergic) asthma, mild asthma, moderate asthma, severe asthma, bronchitic asthma, exercise-induced asthma, occupational asthma and asthma induced following bacterial infection. Treatment of asthma is also to be understood as embracing treatment of subjects, e.g., of less than 4 or 5 years of age, exhibiting wheezing symptoms and diagnosed or diagnosable as "wheezy infants", an established patient category of major medical concern and now often identified as incipient or early-phase asthmatics. (For convenience this particular asthmatic condition is referred to as "wheezy-infant syndrome".) Prophylactic efficacy in the treatment of asthma will be evidenced by reduced frequency or severity of symptomatic attack, e.g., of acute asthmatic or bronchoconstrictor attack, improvement in lung function or improved airways hyperreactivity. It may further be evidenced by reduced requirement for other, symptomatic therapy, i.e., therapy for or intended to restrict or abort symptomatic attack when it occurs, e.g., anti-inflammatory (e.g., cortico-steroid) or bronchodilatory. Prophylactic benefit in asthma may, in particular, be apparent in subjects prone to "morning dipping". "Morning dipping" is a recognized asthmatic syndrome, common to a substantial percentage of asthmatics and characterized by asthma attack, e.g., between the hours of about 4-6 am, i.e., at a time normally substantially distant from any previously administered symptomatic asthma therapy.

A "patient," "subject" or "individual" are used interchangeably and refer to either a human or non-human animal. The term includes mammals such as humans. Typically the animal is a mammal. A subject also refers to for example, primates (e.g. , humans, male or female), cows, sheep, goats, horses, dogs, cats, rabbits, rats, mice, fish, birds and the like. In certain embodiments, the subject is a primate. Preferably, the subject is a human.

As used herein, the term "inhibit", "inhibition" or "inhibiting" refers to the reduction or suppression of a given condition, symptom, or disorder, or disease, or a significant decrease in the baseline activity of a biological activity or process.

As used herein, the term "treat", "treating" or "treatment" of any disease or disorder, refers to the management and care of a patient for the purpose of combating the disease, condition, or disorder and includes the administration of a compound of the present invention to prevent the onset of the symptoms or complications, alleviating the symptoms or complications, or eliminating the disease, condition or disorder.

As used herein, the terms "treatment," "treating," and the like generally mean the improvement of CF or its symptoms or lessening the severity of CF or its symptoms in a subject. "Treatment," as used herein, includes, but is not limited to, the following: (i) to ameliorating the disease or disorder (i.e., slowing or arresting or reducing the development of the disease or at least one of the clinical symptoms thereof); (ii) to alleviating or ameliorating at least one physical parameter including those which may not be discernible by the patient; or (iii) to preventing or delaying the onset or development or progression of the disease or disorder, (iiii) increased growth of the subject, increased weight gain, reduction of mucus in the lungs, improved pancreatic and/or liver function, reduced cases of chest infections, and/or reduced instances of coughing or shortness of breath. Improvements in or lessening the severity of any of these conditions can be readily assessed according to standard methods and techniques known in the art.

As used herein, a subject is "in need of a treatment if such subject would benefit biologically, medically or in quality of life from such treatment (preferably, a human).

As used herein the term "co-administer" refers to the presence of two active agents in the blood of an individual. Active agents that are co-administered can be concurrently or sequentially delivered.

The term "combination therapy" or "in combination with" or "pharmaceutical combination" refers to the administration of two or more therapeutic agents to treat a therapeutic condition or disorder described in the present disclosure. Such administration encompasses coadministration of these therapeutic agents in a substantially simultaneous manner, such as in a single capsule having a fixed ratio of active ingredients. Alternatively, such administration encompasses co-administration in multiple, or in separate containers (e.g., capsules, powders, and liquids) for each active ingredient. Powders and/or liquids may be

reconstituted or diluted to a desired dose prior to administration. In addition, such administration also encompasses use of each type of therapeutic agent being administered prior to, concurrent with, or sequentially to each other with no specific time limits. In each case, the treatment regimen will provide beneficial effects of the drug combination in treating the conditions or disorders described herein.

As used herein, the phrase "optionally substituted" is used interchangeably with the phrase "substituted or unsubstituted." In general the term "optionally substituted" refers to the replacement of hydrogen radicals in a given structure with the radical of a specified substituent. Specific substituents are described in the definitions and in the description of compounds and examples thereof. Unless otherwise indicated, an optionally substituted group can have a substituent at each substitutable position of the group, and when more than one position in any given structure can be substituted with more than one substituent selected from a specified group, the substituent can be either the same or different at every position.

As used herein, the term "C^alkyl" refers to a fully saturated branched or unbranched hydrocarbon moiety having 1 to 6 carbon atoms. The terms "C^alkyl", "C ₁ _ ₄ alkyl" and "C^ ₂ alkyl" are to be construed accordingly. Representative examples of Chalky! include, but are not limited to, methyl, ethyl, n-propyl, / ^' so-propyl, n-butyl, sec-butyl, / ^' so-butyl, fe/ -butyl, n- pentyl, isopentyl, neopentyl and n-hexyl. Similarly, the alkyl portion (i.e., alkyl moiety) of an alkoxy have the same definition as above. When indicated as being "optionally substituted", the alkane radical or alkyl moiety may be unsubstituted or substituted with one or more substituents (generally, one to three substituents except in the case of halogen substituents such as perchloro or perfluoroalkyls). "Halo-substituted alkyl" refers to an alkyl group having at least one halogen substitution.

As used herein, the term "C _1-4 alkoxy" refers to an alkyl moiety attached through an oxygen bridge (i.e. a -0-C ₁ alkyl group wherein C ₁ alkyl is as defined herein).

Representative examples of alkoxy include, but are not limited to, methoxy, ethoxy, propoxy, 2-propoxy, butoxy, fe/ -butoxy and the like. Preferably, alkoxy groups have about 1 -4 carbons, more preferably about 1 -2 carbons.

As used herein, the term "C _1-4 alkoxy" refers to a fully saturated branched or unbranched hydrocarbon moiety having 1 to 4 carbon atoms. The term "C _1-2 alkoxy" is to be construed accordingly.

"Halogen" or "halo" may be fluorine, chlorine, bromine or iodine (preferred halogens as substituents are fluorine and chlorine).

As used herein, the term "halo-substituted-C^alkyl" or "halo-C^alkyl" refers to a C _1-4 alkyl group as defined herein, wherein at least one of the hydrogen atoms is replaced by a halo atom. The halo-C^alkyl group can be monohalo-C^alkyl, dihalo-C ₁ _ ₄ alkyl or polyhalo-C^ ₄ alkyl including perhalo-C _1-4 alkyl. A monohalo-C^alkyl can have one iodo, bromo, chloro or fluoro within the alkyl group. Dihalo-C^alkyl and polyhalo-C^alkyl groups can have two or more of the same halo atoms or a combination of different halo groups within the alkyl.

Typically the polyhalo-C^alkyl group contains up to 9, or 8, or 7, or 6, or 5, or 4, or 3, or 2 halo groups. Non-limiting examples of halo-C^alkyl include fluoromethyl, difluoromethyl, trifluoromethyl, chloromethyl, dichloromethyl, trichloromethyl, pentafluoroethyl,

heptafluoropropyl, difluorochloromethyl, dichlorofluoromethyl, difluoroethyl, difluoropropyl, dichloroethyl and dichloropropyl. A perhalo-C^alkyl group refers to a C ₁ _ ₄ alkyl group having all hydrogen atoms replaced with halo atoms.

As used herein, the term "halo-substituted-C^alkoxy" or "halo-C^alkoxy" refers to C _1-4 alkoxy group as defined herein above wherein at least one of the hydrogen atoms is replaced by a halo atom. Non-limiting examples of halo-substituted-C^alkoxy include fluoromethoxy, difluoromethoxy, trifluoromethoxy, chloromethoxy, dichloromethoxy, trichloromethoxy, difluorochloromethoxy, dichlorofluoromethoxy, difluoroethoxy, difluoropropoxy,

dichloroethoxy and dichloropropoxy and the like.

As used herein, the term "hydroxy-substituted-C^alkyl" refers to a C _1-4 alkyl group as defined herein, wherein at least one of the hydrogen atoms is replaced by a hydroxyl group. The hydroxy-substituted-C^alkyl group can be monohydroxy-C^alkyl, dihydroxy-C^alkyl or polyhydroxy-C^alkyl including perhydroxy-C^alkyl. A monohydroxy-C^alkyl can have one hydroxyl group within the alkyl group. Dihydroxy-C^alkyl and polyhydroxy-C^alkyl groups can have two or more of the same hydroxyl groups or a combination of different hydroxyl groups within the alkyl. Typically the polyhydroxy-C^alkyl group contains up to 9, or 8, or 7, or 6, or 5, or 4, or 3, or 2 hydroxy groups. Non-limiting examples of hydroxy substituted -C^ ₄ alkyl include hydroxy-methyl, dihydroxy-methyl, pentahydroxy-ethyl, dihydroxyethyl, and dihydroxypropyl. A perhydroxy-C^alkyl group refers to a C^alkyl group having all hydrogen atoms replaced with hydroxy atoms.

The term "oxo" (=0) refers to an oxygen atom connected to a carbon or sulfur atom by a double bond. Examples include carbonyl, sulfinyl, or sulfonyl groups (-C(O)-, -S(O)- or - S(0) ₂ -) such as, a ketone, aldehyde, or part of an acid, ester, amide, lactone, or lactam group and the like.

The term "aryl or C ₆ . ₁₀ aryl" refers to 6- to 10-membered aromatic carbocyclic moieties having a single (e.g., phenyl) or a fused ring system (e.g., naphthalene.). A typical aryl group is phenyl group.

The term "C ₃ . ₆ cycloalkyl" refers to a carbocyclic ring which is fully saturated (e.g., cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl).

The term "C ₄ . ₆ heterocycle" refers to a monocyclic ring which is fully saturated which has 4 to 6 ring atoms which contains 1 to 2 heteroatoms, independently selected from sulfur, oxygen and/or nitrogen. A typical "C ₄ . ₆ heterocycle" group includes oxtanyl,

tetrahydrofuranyl, dihydrofuranyl, 1 ,4-dioxanyl, morpholinyl, 1 ,4-dithianyl, piperazinyl, piperidinyl, 1 ,3-dioxolanyl, pyrrolinyl, pyrrolidinyl, tetrahydropyranyl, oxathiolanyl, dithiolanyl, 1 ,3-dioxanyl, 1 ,3-dithianyl, oxathianyl, thiomorpholinyl, thiomorpholinyl 1 ,1 dioxide, tetrahydro-thiopyranl ,1 -dioxide, 1 ,4-diazepanyl.

The term "fully or partially saturated heterocycle" refers to a nonaromatic ring that is either partially or fully saturated and may exist as a single ring, bicyclic ring (including fused heterocyclic rings) or a spiral ring. Unless specified otherwise, the heterocyclic ring is generally a 4- to 10-membered ring containing 1 to 4 heteroatoms (preferably 1 , 2 or 3 heteroatoms) independently selected from sulfur, oxygen and/or nitrogen. A partially saturated heterocyclic ring also includes groups wherein the heterocyclic ring is fused to an aryl or heteroaryl ring (e.g., 2,3-dihydrobenzofuranyl, indolinyl (or 2,3-dihydroindolyl), 2,3- dihydrobenzothiophenyl, 2,3-dihydrobenzothiazolyl, 1 ,2,3,4-tetrahydroquinolinyl, 1 ,2,3,4- tetrahydroisoquinolinyl, 5,6,7,8-tetrahydropyrido[3,4-b]pyrazinyl). As used herein the term "spiral" or "spiro" means a two ring system wherein both rings share one common atom.

Examples of spiral rings include 2,6-diazaspiro[3.3]heptanyl, -oxa-6-azaspiro[3.3]heptane, 2 2,6-diazaspiro[3.3]heptane, 3-azaspiro[5.5]undecanyl, 3,9-diazaspiro[5.5]undecanyl, 7- azaspiro[3.5]nonane, 2,6-diazaspiro[3.4]octane, 8-azaspiro[4.5]decane, 1 ,6- diazaspiro[3.3]heptane, 5-azaspiro[2.5]octane, 4,7-diazaspiro[2.5]octane, 5-oxa-2- azaspiro[3.4]octane, 6-oxa-1 -azaspiro[3.3]heptane, 3-azaspiro[5.5]undecanyl, 3,9- diazaspiro[5.5]undecanyl, and the like. Partially saturated or fully saturated heterocyclic rings include groups such as epoxy, aziridinyl, azetidinyl, tetrahydrofuranyl, dihydrofuranyl, dihydropyridinyl, pyrrolidinyl, imidazolidinyl, imidazolinyl, 1 H-dihydroimidazolyl, hexahydropyrimidinyl, piperidinyl, piperazinyl, pyrazolidinyl, 2H-pyranyl, 4H-pyranyl, oxazinyl, morpholino, thiomorpholino, tetrahydrothienyl, tetrahydrothienyl 1 ,1 -dioxide, oxazolidinyl, thiazolidinyl, 7- oxabicyclo[2.2.1 ]heptane, and the like.

The term "Fused heterocycle or 8 to 10 membered fused heterocycle" rings include fully or partially saturated groups such as 4,5,6,7-tetrahydro-3H-imidazo[4,5-c]pyridine, 8- azabicyclo[3.2.1 ]octan-3-ol, octahydropyrrolo[1 ,2-a]pyrazine, 5,6,7,8-tetrahydroimidazo[1 ,2- a]pyrazine, 3,8 diazabicyclo[3.2.1 ]octane, 8-oxa-3-azabicyclo[3.2.1 ]octane, 7- oxabicyclo[2.2.1 ]heptane, 1 H-pyrazole, 2,5-diazabicyclo[2.2.1 ]heptane, 5,6,7,8-tetrahydro- [1 ,2,4]triazolo[4,3-a]pyrazine or 3-azabicyclo[3.1 .0]hexane. A partially saturated heterocyclic ring also includes groups wherein the heterocyclic ring is fused to an aryl or heteroaryl ring (e.g., 2,3-dihydrobenzofuranyl, indolinyl (or 2,3-dihydroindolyl), 2,3-dihydrobenzothiophenyl, 2,3-dihydrobenzothiazolyl, 1 ,2,3,4-tetrahydroquinolinyl, 1 ,2,3,4-tetrahydroisoquinolinyl, 5,6,7,8-tetrahydropyrido[3,4-b]pyrazinyl, and the like).

The term "heteroaryl" refers to aromatic moieties containing at least one heteroatom (e.g., oxygen, sulfur, nitrogen or combinations thereof) within a 5- to 6-membered aromatic ring system (e.g., pyrrolyl, pyridyl, pyrazolyl, indolyl, indazolyl, thienyl, furanyl, benzofuranyl, oxazolyl, imidazolyl, tetrazolyl, triazinyl, pyrimidyl, pyrazinyl, thiazolyl, and the like.)

The phrase "pharmaceutically acceptable" indicates that the substance, composition or dosage form must be compatible chemically and/or toxicologically, with the other ingredients comprising a formulation, and/or the mammal being treated therewith.

Unless specified otherwise, the term "compounds of the present invention" refers to compounds of formula (I), as well as all stereoisomers (including diastereoisomers and enantiomers), rotamers, tautomers, isotopically labeled compounds (including deuterium substitutions), and inherently formed moieties (e.g., polymorphs, solvates and/or hydrates). When a moiety is present that is capable of forming a salt, then salts are included as well, in particular pharmaceutically acceptable salts.

As used herein, the term "a," "an," "the" and similar terms used in the context of the present invention (especially in the context of the claims) are to be construed to cover both the singular and plural unless otherwise indicated herein or clearly contradicted by the context. The use of any and all examples, or exemplary language (e.g. "such as") provided herein is intended merely to better illuminate the invention and does not pose a limitation on the scope of the invention otherwise claimed. In one Embodiment, there is provided a compound of the Examples as an isolated stereoisomer wherein the compound has one stereocenter and the stereoisomer is in the R configuration.

In one Embodiment, there is provided a compound of the Examples as an isolated stereoisomer wherein the compound has one stereocenter and the stereoisomer is in the S configuration.

In one Embodiment, there is provided a compound of the Examples as an isolated stereoisomer wherein the compound has two stereocenters and the stereoisomer is in the R R configuration.

In one Embodiment, there is provided a compound of the Examples as an isolated stereoisomer wherein the compound has two stereocenters and the stereoisomer is in the R S configuration.

In one Embodiment, there is provided a compound of the Examples as an isolated stereoisomer wherein the compound has two stereocenters and the stereoisomer is in the S R configuration.

In one Embodiment, there is provided a compound of the Examples as an isolated stereoisomer wherein the compound has two stereocenters and the stereoisomer is in the S S configuration.

In one Embodiment, there is provided a compound of the Examples, wherein the compound has one or two stereocenters, as a racemic mixture.

It is also possible that the intermediates and compounds of the present invention may exist in different tautomeric forms, and all such forms are embraced within the scope of the invention. The term "tautomer" or "tautomeric form" refers to structural isomers of different energies which are interconvertible via a low energy barrier. For example, proton tautomers (also known as prototropic tautomers) include interconversions via migration of a proton, such as keto-enol and imine-enamine isomerizations. A specific example of a proton tautomer is the imidazole moiety where the proton may migrate between the two ring nitrogens. Valence tautomers include interconversions by reorganization of some of the bonding electrons.

In one Embodiment, the invention relates to a compound of the formula (I) as defined herein, in free form. In another Embodiment, the invention relates to a compound of the formula (I) as defined herein, in salt form. In another Embodiment, the invention relates to a compound of the formula (I) as defined herein, in acid addition salt form. In a further Embodiment, the invention relates to a compound of the formula (I) as defined herein, in pharmaceutically acceptable salt form. In yet a further Embodiment, the invention relates to a compound of the formula (I) as defined herein, in pharmaceutically acceptable acid addition salt form. In yet a further Embodiment, the invention relates to any one of the compounds of the Examples in free form. In yet a further Embodiment, the invention relates to any one of the compounds of the Examples in salt form. In yet a further Embodiment, the invention relates to any one of the compounds of the Examples in acid addition salt form. In yet a further Embodiment, the invention relates to any one of the compounds of the Examples in pharmaceutically acceptable salt form. In still another Embodiment, the invention relates to any one of the compounds of the Examples in pharmaceutically acceptable acid addition salt form.

Furthermore, the compounds of the present invention, including their salts, may also be obtained in the form of their hydrates, or include other solvents used for their crystallization. The compounds of the present invention may inherently or by design form solvates with pharmaceutically acceptable solvents (including water); therefore, it is intended that the invention embrace both solvated and unsolvated forms. The term "solvate" refers to a molecular complex of a compound of the present invention (including pharmaceutically acceptable salts thereof) with one or more solvent molecules. Such solvent molecules are those commonly used in the pharmaceutical art, which are known to be innocuous to the recipient, e.g., water, ethanol, and the like. The term "hydrate" refers to the complex where the solvent molecule is water.

Compounds of the invention, i.e. compounds of formula (I) that contain groups capable of acting as donors and/or acceptors for hydrogen bonds may be capable of forming co-crystals with suitable co-crystal formers. These co-crystals may be prepared from compounds of formula (I) by known co-crystal forming procedures. Such procedures include grinding, heating, co-subliming, co-melting, or contacting in solution compounds of formula (I) with the co-crystal former under crystallization conditions and isolating co-crystals thereby formed. Suitable co-crystal formers include those described in WO 2004/078163. Hence the invention further provides co-crystals comprising a compound of formula (I).

The compounds of the present invention, including salts, hydrates and solvates thereof, may inherently or by design form polymorphs.

Compounds of the present invention may be synthesized by synthetic routes that include processes analogous to those well-known in the chemical arts, particularly in light of the description contained herein. The starting materials are generally available from commercial sources such as Sigma-Aldrich or are readily prepared using methods well known to those skilled in the art (e.g., prepared by methods generally described in Louis F. Fieser and Mary Fieser, Reagents for Organic Synthesis, v. 1 -19, Wiley, New York (1967-1999 ed.), or Beilsteins Handbuch der organischen Chemie, 4, Aufl. ed. Springer- Verlag, Berlin, including supplements (also available via the Beilstein online database)).

The further optional reduction, oxidation or other functionalization of compounds of formula (I) may be carried out according to methods well known to those skilled in the art. Within the scope of this text, only a readily removable group that is not a constituent of the particular desired end product of the compounds of the present invention is designated a "protecting group", unless the context indicates otherwise. The protection of functional groups by such protecting groups, the protecting groups themselves, and their cleavage reactions are described for example in standard reference works, such as J. F. W. McOmie, "Protective Groups in Organic Chemistry", Plenum Press, London and New York 1973, in T. W. Greene and P. G. M. Wuts, "Protective Groups in Organic Synthesis", Third edition, Wiley, New York 1999, in "The Peptides"; Volume 3 (editors: E. Gross and J. Meienhofer), Academic Press, London and New York 1981 , in "Methoden der organischen Chemie" (Methods of Organic Chemistry), Houben Weyl, 4th edition, Volume 15/1, Georg Thieme Verlag, Stuttgart 1974, and in H.-D. Jakubke and H. Jeschkeit, "Aminosauren, Peptide, Proteine" (Amino acids, Peptides, Proteins), Verlag Chemie, Weinheim, Deerfield Beach, and Basel 1982. A characteristic of protecting groups is that they can be removed readily (i.e. without the occurrence of undesired secondary reactions) for example by solvolysis, reduction, photolysis or alternatively under physiological conditions (e.g. by enzymatic cleavage).

Salts of compounds of the present invention having at least one salt-forming group may be prepared in a manner known to those skilled in the art. For example, acid addition salts of compounds of the present invention are obtained in customary manner, e.g. by treating the compounds with an acid or a suitable anion exchange reagent. Salts can be converted into the free compounds in accordance with methods known to those skilled in the art. Acid addition salts can be converted, for example, by treatment with a suitable basic agent.

Any resulting mixtures of isomers can be separated on the basis of the physicochemical differences of the constituents, into the pure or substantially pure geometric or optical isomers, diastereomers, racemates, for example, by chromatography and/or fractional crystallization.

For those compounds containing an asymmetric carbon atom, the compounds exist in individual optically active isomeric forms or as mixtures thereof, e.g. as racemic or diastereomeric mixtures. Diastereomeric mixtures can be separated into their individual diastereoisomers on the basis of their physical chemical differences by methods well known to those skilled in the art, such as by chromatography and/or fractional crystallization.

Enantiomers can be separated by converting the enantiomeric mixture into a diastereomeric mixture by reaction with an appropriate optically active compound (e.g., chiral auxiliary such as a chiral alcohol or Mosher's acid chloride), separating the diastereoisomers and converting (e.g., hydrolyzing) the individual diastereoisomers to the corresponding pure enantiomers. Enantiomers can also be separated by use of a commercially available chiral HPLC column. The invention further includes any variant of the present processes, in which the reaction components are used in the form of their salts or optically pure material. Compounds of the invention and intermediates can also be converted into each other according to methods generally known to those skilled in the art.

For illustrative purposes, the reaction schemes depicted below provide potential routes for synthesizing the compounds of the present invention as well as key intermediates. For a more detailed description of the individual reaction steps, see the Examples section below. Although specific starting materials and reagents are depicted in the schemes and discussed below, other starting materials and reagents can be easily substituted to provide a variety of derivatives and/or reaction conditions. In addition, many of the compounds prepared by the methods described below can be further modified in light of this disclosure using

conventional chemistry well known to those skilled in the art.

GENERAL SYNTHETIC METHODS

The following examples of compounds of the present invention illustrate the invention. Methods for preparing such compounds are described hereinafter.

Abbreviations:

Abbreviations used are those conventional in the art or the following:

Ac: Acetyl Min(s): minute(s)

AcOH, HOAc: acetic acid Me: methyl

aq.: aqueous m/z: mass to charge ratio

app. q: apparent quartet Alloc: allyloxycarbonyl protecting group

Ar: aromatic M and mM: molar and millimolar

ADME: absorption, distribution, metabolism

mg: milligram

and excretion

EDCI: 1 -ethyl-3-(3-

BPR: backpressure regulator

dimethylaminopropyl)carbodiimide

BOP: (Benzotriazol-1 - br: broad yloxy)tris(dimethylamino)phosphonium

hexaflurorophosphate

DCC: dicyclohexylcarbodiimide μΙ_, mL and L: microliter, milliliter and liter

PyBOP: (Benzotriazol-1 - yloxy)tripyrrolidinophosphonium N: equivalent per liter

hexaflurorophosphate

calc: calculated π-BuLi: n-butyilitium

d: doublet; dd: doublet of doublets NMR: nuclear magnetic resonance

DCM: dichloromethane o/n: over night

Diox: Dioxane PFA: perfluoroalkoxy (fluoropolymer)

DMF: Λ/,/V-dimethylformamide ppm: parts per million

DMSO: dimethylsulfoxide Ph: phenyl

DIPEA: Λ/,/V-diisopropylethylamine q: quartet

dppp: 1 ,3-bis(diphenylphosphino)propane rt: room temperature ESI-MS: electrospray ionization mass

rpm: revolutions per minute

spectrometry

Et and EtOAc: ethyl and ethyl acetate s: singlet

HATU: 0-(7-azobenzotriazol-1 -yl)-1 ,1 ,3,3-

SFC: supercritical fluid chromatography tetramethyluroniumhexafluorophosphate

HOAt: 1 -hydroxy-7-azaberizotriazoIe t: triplet

HPLC: high pressure liquid chromatography TEA: triethylamine

h, hr: hour(s) THF: tetrahydrofuran

HRMS: high resolution mass spectrometry 2-MeTHF: 2-methyltetrahydrofuran

LC and LCMS: liquid chromatography and

TFA: trifluoroacetic acid

liquid chromatography-mass spectrometry

HEK293: Human Embryonic Kidney 293

NMU: /V-nitroso-/V-methylurea

cells

DMEM: Dulbecco's modified eagle

MeOH: methanol

medium

HEPES: 4-(2-hydroxyethyl)-1 - wt: weight

piperazineethanesulfonic acid

EGTA: ethylene glycol tetraacetic acid TBME: fe/ -butyl methy ether

PBS: Phosphate Buffered Saline, pH7.4 TFAA: Trifluoroacetic acid

MS: mass UHP: urea-hydrogen peroxide

m: multiplet

ANALYTICAL METHODS

ESI-MS data (also reported herein as simply MS) were recorded using Waters System (Acquity UPLC and a Micromass ZQ mass spectrometer); all masses reported are the m/z of the protonated parent ions unless recorded otherwise.

LC/MS:

The sample is dissolved in suitable solvent such as MeCN, DMSO or MeOH and is injected directly into the column using an automated sample handler. The analysis is performed using one of the following methods:

HPLC Conditions:

Condition 1 :

Waters Acquity UPLC system:

-Acquity Binary Gradient Manager with Degasser

-Acquity Diode Array Detector

Leap Technologies HTS Pal Autosampler

Waters Waters SQD Mass Spectrometer

HPLC Column: Waters Acquity C18 1 .7um 2.1 x 30 mm

Mobile Phase: (A)H20 + 0.05%TFA and (B)Acetonitrile + 0.05%TFA Gradient: 1 mL/minute, initial 5% B for 0.1 minutes, ramp to 95% B over 1 .5 minutes, hold until 1 .6 minutes then to 100%B at 1 .7 and return to 5% B to at 1 .9 minutes until end of run at 2.25.

MS Scan: 180 to 800amu in 0.4 seconds

Diode Array Detector: 214nm - 400nm

Condition 2:

Waters Acquity UPLC system:

-Acquity Binary Gradient Manager with Degasser

-Acquity Column Compartment set at 50°C

-Acquity Diode Array Detector

Leap Technologies HTS Pal Autosampler

Antek Chemiluminescent Nitrogen Detector (CLND)

Waters ZQ2000 Mass Spectrometer

HPLC Column: Thermo Syncronis C18 30x2.1 mm

Mobile Phase: (A)95% H20/5% MeOH/IPA (75/25, v/v) + 0.05% formic acid, (B) MeOH/IPA

(75/25, v/v) + 0.035% formic acid

Gradient: 0.4mL/minute, initial 2% B for 1 .0 minutes, ramp to 95% B over 2.5 minutes, until 4.0 minutes, return to 2% B to at 4.25 minutes until end of run at 5.0.

MS Scan: 150 to 10OOamu in 1 second

Diode Array Detector: 190nm - 400nm

Condition 3:

Waters Acquity UPLC system

Waters Acquity UPLC BEH C18 1 .7um, 2.1x30mm (Part#: 186002349)

Flow rate: 1 mL/min

Temperature: 55°C (column temp)

Mobile phase compositions:

A: 0.05% formic acid in water.

B: 0.04% formic acid in methanol.

Gradient:

Time (min) Flow (mL/min) %A %B

0 1 .000 95.0 5.0

0.10 1 .000 95.0 5.0

0.50 1 .000 20.0 80.0

0.60 1 .000 5.0 95.0

0.80 1 .000 5.0 95.0 0.90 1 .000 95.0 5.0

1 .15 1 .000 95.0 5.0

Condition 4: (SQ4)

Waters Acquity UPLC system:

-Acquity Binary Gradient Manager with Degasser

-Acquity Diode Array Detector

Waters Sample Manager

Waters SQD Mass Spectrometer

HPLC Column: Waters ACQUITY UPLC BEH C18, 130A, 1 .7 μηι, 2.1 mm X 50 mm - 50°C Mobile Phase: (A)H20 + 0.1 Formic Acid and (B)Acetonitrile + 0.1 Formic Acid

Diode Array Detector: 214nm - 400nm

Gradient:

Condition 5: (LCT02)

Waters Acquity UPLC system:

-Acquity Binary Gradient Manager with Degasser

-Acquity Diode Array Detector

Waters Sample Manager

Waters LCT Premier Time of Flight Mass Spectrometer

HPLC Column: ACQUITY UPLC BEH C18, 130A, 1 .7 um, 2.1 mm X 50 mm - 50°C Mobile Phase: (A)H20 + 0.1 Formic Acid and (B)Acetonitrile + 0.1 Formic Acid

MS Scan: 180 to 800amu in 0.4 seconds

Diode Array Detector: 214nm - 400nm

Gradient:

Time (min) Flow (mL/min) %A %B

0 1 .000 98.0 2.0

7.50 1 .000 2.0 98.0

7.90 1 .000 2.0 98.0

8.05 1 .000 98.0 2.0 Condition 6: (SQ4 RxnMon Basic)

Waters Acquity UPLC system:

-Acquity Binary Gradient Manager with Degasser

-Acquity Diode Array Detector

Waters Sample Manager

Waters SQD Mass Spectrometer

HPLC Column: Waters ACQUITY UPLC BEH C18, 130A, 1 .7 μηι, 2.1 mm X 50 mm - 50°C Mobile Phase: (A)H20 + 5mM ammonium hydroxide and (B)Acetonitrile + 5 mM ammonium hydroxide

Diode Array Detector: 214nm - 400nm

Gradient:

Condition 7:

Agilent 1200 Series HPLC system:

-Agilent Binary Gradient Manager with Degasser

-Agilent Diode Array Detector

-Agilent 6140 Quadrupole LC/MS

-SoftA ELS Detector

HPLC column: Waters Acquity HSS T3 C18 1 .8um, 2.1x50mm

Flow rate: 0.9 mL/min

Temperature: 60 °C (column temp)

Mobile phase compositions:

A: 0.05% trifluoroacetic acid in water.

B: 0.035% trifluoroacetic acid in acetonitrile.

Gradient:

Time (min) Flow (mL/min) %A %B

0 0.9 10 90

0.15 0.9 10 90

1 .50 0.9 0 100

1 .95 0.9 0 100

2 0.9 10 90

2.25 0.9 10 90 NMR: Proton spectra are recorded on one of the following instruments: Bruker AVANCE II 400 MHz with 5 mm QNP Cryoprobe; Bruker AVANCE III 500 MHz with 5 mm QNP probe; or Bruker Avance 600 MHz with TCI cryoprobe. Chemical shifts are reported in ppm relative to dimethyl sulfoxide-d ₅ (δ 2.50), chloroform (δ 7.26), methanol-d ₂ (δ 3.34), dichloromethane-d (δ 5.32) or tetramethylsilane (δ 0.0).

Fluorine spectra are recorded on one of the following instruments: at 376.5 MHz on a Bruker AVANCE II 400 MHz with 5 mm QNP Cryoprobe or at 470.6 MHz on a Bruker AVANCE III 500 MHz with 5 mm QNP probe. The spectra are run with ¹ H-decoupling using appropriate composite pulse decoupling, unless specified. Chemical shifts are reported in ppm relative to an external CFCI ₃ standard (δ 0.0).

Spectra were acquired using a small amount of the dry sample (2-5 mg) dissolved in an appropriate deuterated solvent (1 ml_). HPLC PURIFICATION METHODS:

Condition 1 :

Waters Prep HPLC:

-Waters 2767 Autosampler

-Waters 2545 Binary Gradient Module

-Waters Diode Array Detector

-Waters Mass Spectrometer

-Waters 515 HPLC Pump

HPLC Column: Waters XBridge C18 5um 30 x 50 mm

Mobile Phase: Water/Acetonitrile with 10mM NH40H 75mL/min 1 .5mL injection

Water/Acetonitrile with 0.1 %Formic Acid 75mL/min 1 .5mL injection

PDA: 200 nm to 600 nm

Mass Range: 100 - 1250

Gradient: Method 1 : 5% to 20 % ACN 3.5 min gradient

Method 2: 10% to 30% ACN 3.5 min gradient

Method 3: 15% to 40% ACN 3.5 min gradient

Method 4: 25% to 50% ACN 3.5 min gradient

Method 5: 35% to 60% ACN 3.5 min gradient

Method 6: 45% to 70% ACN 3.5 min gradient

Method 7: 55% to 80% ACN 3.5 min gradient

Method 8: 65% to 95% ACN 3.5 min gradient Condition 2:

Agilent technologies 1200 series systems for prep HPLC

-Binary Gradient with Degasser

-Photo Diode Array Detector

Agilent 1200 Auto sampler with 1290-lnfinity 8 valve Auto collection.

Shimadzu LC2020 Single Quad Mass Spectrometer, and API 2000 and API 3000 Triple

Quad Mass Spectrometers.

HPLC Column: Phenomenox Gemini NX 5μ C18 1 1 OA AXIA 21 .2 mm x 150 mm

Mobile Phase 1 : 0.05% Formic Acid in Water (A) and Acetonitrile (B)

Mobile Phase 2: 0.1 % Formic Acid in Water (A) and Acetonitrile (B)

Gradient Time: 2 mL/minute Initial 30% B 0.5min 30% 2.5min 95% and 3.0min 30% ( 3.0 min run time)

MS Scan: 100 to 1000 0.4 Seconds

Diode Array Detector: 214nm - 400nm

Condition 3:

Agilent technologies 1200 series systems for prep HPLC

-Binary Gradient with Degasser

-Photo Diode Array Detector

Agilent 1200 Auto sampler with 1290-lnfinity 8 valve Auto collection.

Shimadzu LC2020 Single Quad Mass Spectrometer, and API 2000 and API 3000 Triple

Quad Mass Spectrometers.

HPLC Column: Agilent Eclipse Zorbax XDB C18 150x4.6 mm 5 urn

Mobile Phase 1 : 0.05% Formic Acid in Water (A) and Acetonitrile (B)

Mobile Phase 2: 0.2% ammonium acetate in Water (A) and Acetonitrile (B)

Gradient Time: 2 mL/minute Initial 30% B 0.5min 30% 2.5min 95% and 3.0min 30% ( 3.0 min run time)

MS Scan: 100 to 1000 0.4 Seconds

Diode Array Detector: 214nm - 400nm

Condition 4:

Agilent technologies 1200 series systems for prep HPLC

-Binary Gradient with Degasser

-Photo Diode Array Detector

Agilent 1200 Auto sampler with 1290-lnfinity 8 valve Auto collection. Shimadzu LC2020 Single Quad Mass Spectrometer, and API 2000 and API 3000 Triple Quad Mass Spectrometers.

HPLC Column: Phenominex Luna C18 250x4.6 mm 5um

Mobile Phase: 0.05% Formic Acid in Water (A) and Acetonitrile (B)

Gradient Time: 2 mL/minute Initial 30% B 0.5min 30% 2.5min 95% and 3.0min 30% ( 3.0 min run time)

MS Scan: 100 to 1000 0.4 Seconds

Diode Array Detector: 214nm - 400nm Condition 5:

Agilent technologies 1200 series systems for prep HPLC

-Binary Gradient with Degasser

-Photo Diode Array Detector

Agilent 1200 Auto sampler with 1290-lnfinity 8 valve Auto collection.

Shimadzu LC2020 Single Quad Mass Spectrometer, and API 2000 and API 3000 Triple Quad Mass Spectrometers.

HPLC Column : Kinetex Evo C18 150x 4.6mm 5 urn

Mobile Phase : 0.1 % Formic Acid in Water (A) and Acetonitrile (B)

Gradient Time : 2 mL/minute Initial 30% B 0.5min 30% 2.5min 95% and 3.0min 30% ( 3.0 min run time)

MS Scan: 100 to 1000 0.4 Seconds

Diode Array Detector: 214nm - 400nm

SCHEMES

Scheme I and II provide potential routes for making compounds of formula (I).

Scheme I:

100°C, 15

02

KN0 ₃ , S0 ₂ Ci5

ACM, -10°C, S inin

pyridine

H,N X . HCI in dioxane

Exampies 1 -96 _E

The starting materials for the above reaction scheme are commercially available or can be prepared according to methods known to one skilled in the art or by methods disclosed herein. In general, compounds 1 -96 of the invention are prepared in the above reaction Scheme I as follows: Suzuki cross-coupling of building block A with building block B provides intermediate C. Separately, building block D1 is converted into intermediate D2 which is subsequently converted into building block D. Intermediate C and building block D are combined to form intermediate E. Intermediate E is then converted in to the target compound following removal of the protecting group, typically the tert-butylcarbamate. In summary the combination of various building blocks and intermediates can then be applied to yield compounds 1 -96 of formula (I).

PREPARATION OF INTERMEDIATES

Intermediate (D): Procedure 1 , Scheme 1 -

100°C, 15 h

D1 D2 Step 1 : A 250 mL round bottom flask was charged with tert-butyl (6-bromopyridin-2- yl)carbamate (D1) (9.83 g, 36 mmol)), PdCI ₂ (dppf).CH ₂ Cl2 adduct (1 .47 g, 1 .8 mmol), Cs ₂ C0 ₃ (15.25 g, 46.8 mmol), triisopropylsilanethiol (10.05 mL, 46.8 mmol), and toluene (150 mL). The reaction mixture was filled with nitrogen and stirred at 100 °C for 15 h. The reaction mixture was filtered through Celite, washed with DCM and concentrated. The product was purified by silicagel chromatography (330 g silica gel column, 0-60% EA-hex) to give tert-butyl (6-thioxo-1 ,6-dihydropyridin-2-yl)carbamate (D2) (5.89 g, 72 % yield), yellow crystals. The product was partially oxidized into di-tert-butyl (6,6'-disulfanediylbis(pyridine- 6,2-diyl))dicarbamate. LCMS: m/z 227.1 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 12.63 (s, 1 H), 10.48 (s, 1 H), 7.38 (m, 1 H), 6.87 (d, J = 8.4 Hz, 1 H), 6.51 (d, J = 7.8 Hz, 1 H), 1 .50 (s, 9H).

Step 2: To a solution of tert-butyl (6-thioxo-1 ,6-dihydropyridin-2-yl)carbamate (D2) (1 .70 g, 7.51 mmol) in acetonitrile (60 mL) was added KN0 ₃ (1 .90 g, 18.8 mmol). The flask was cooled to -10 °C in ice water salt bath and S0 ₂ CI ₂ (1 .53 mL, 18.8 mmol) was added dropwise at the same temperature and stirred for 5 min. The mixture was diluted with ice-water and extracted with DCM (x3). The organic layer was dried over Na ₂ S0 ₄ , filtered, concentrated at RT in vacuo and dried to give tert-butyl (6-(chlorosulfonyl)pyridin-2-yl)carbamate (D) (2.0 g, 5.47 mmol, 91 % yield) as white solid. LCMS m/z 315.0 [M+Na] ^{+ 1} H NMR (400 MHz, DMSO- d ₆ ) δ 10.61 (s, 1 H), 7.96 (dd, J = 8.4, 7.6 Hz, 1 H), 7.66 (dd, J = 8.5, 0.8 Hz, 1 H), 7.46 (dd, J = 7.5, 0.9 Hz, 1 H), 1 .48 (s, 9H).

Intermediate (D): Procedure 2, Scheme 1

(D)

Step 1. To dry DMF (300 mL) taken in a sealed tube, was added NaOfBu (74.8 g, 777.85 mmol) followed by phenylmethanethiol (91 .1 mL, 777.85 mmol) at rt and stirred for 30 min. Then 6-chloropyridin-2-amine (50.0 g, 388.92 mmol) was added in portions for 15 min at rt, followed by KF (45.2 g, 777.85 mmol). The reaction was sealed and heated at 80-90°C for 36 h. Then the reaction was quenched with water (1 .5 L) and extracted with Et ₂ 0 thrice. The combined organic portion was washed with brine solution, dried over Na ₂ S0 ₄ , and concentrated in vacuo to yield the crude compound, which was purified by column chromatography on silica gel (60-120 mesh size) (15-20% EtOAc in Hexane) to afford 6- (benzylthio)pyridin-2-amine as yellowish oil (67.5 g, 80.2%). LC/MS, ESI-MS( ⁺ ): 2 1 7 . 4 . ¹ H NMR (300 MHz, CDCI ₃ ) δ ppm 7.42 - 7.39 (m, 2H), 7.33 - 7.23 (m, 4H), 7.55 (d, J= 7.8 Hz, 1 H), 7.21 (d, J= 8.1 Hz, 1 H), 4.44 (brs, 2H), 4.36 (s, 2H).

Step 2. To the stirred solution of 6-(benzylthio)pyridin-2-amine (135 g, 624.13 mmol), DMAP (7.61 g, 62.38 mmol), and R3 DIPEA (128 ml_, 748.95 mmol) in DCM (5.5 L), Boc anhydride dissolved in DCM (1 .5 L) was added dropwise by addition funnel over 6 h at 0°C . The reaction mixture was stirred at rt for 16 h. The reaction mixture was diluted with water and extracted with DCM twice. The combined organic portion was washed with brine solution, dried over Na ₂ S0 ₄ and concentrated in vacuo to yield the crude compound. The crude was purified by column chromatography on silica gel (60-120 mesh size) (5-10% EtOAc in Hexane) to afford ferf-butyl (6-(benzylthio)pyridin-2-yl)carbamate as a white solid (1 10 g, 55.7%). LC/MS, ESI-MS( ⁺ ) 317.0. ¹ H NMR (300 MHz, CDCI ₃ ) δ ppm 7.62 (d, J= 8.1 Hz, 1 H), 7.46 (t, J= 8.1 Hz, 1 H), 7.40 - 7.37 (m, 2H), 7.34 - 7.22 (m, 3H), 7.16 (brs, 1 H), 6.84 (dd, J= 7.8, 0.9 Hz, 1 H), 4.36 (s, 2H), 1 .54 (s, 9H).

Step 3. To a two-necked round bottom flask containing ferf-butyl (6- (benzylthio)pyridin-2-yl)carbamate (84 g, 265.47 mmol) was added DCM (800 mL) and water (200 mL) at room temperature. The content was then cool to 0 °C with an ice bath. Chlorine gas (generated from KMn0 ₄ -con HCI) was purged for 30 min and reaction mixture stirred for additional 30 min at 0°C . After completion of the reaction, N ₂ was purged for 20 min, reaction mixture was diluted with water (1000 mL). The organ ic portion was extracted with DCM thrice. The combined organic portion was washed with brine solution, dried over anhydrous Na ₂ S0 ₄ and concentrated in vacuo (at 40°C) to afford a brown oily residue. The residue was purified by Si-gel (60-120 mesh size) column chromatography (1 -30% EtOAc in Hexane) to afford ierf-butyl (6-(chlorosulfonyl)pyridin-2-yl)carbamate (D): as a white solid (63 g, 81 %). ¹ H NMR (300 MHz, CDCI ₃ ) δ ppm 8.36 (dd, J= 8.4, 0.8 Hz, 1 H), 7.96 (t, J= 8.1 Hz, 1 H), 7.72 (dd, J= 7.5, 0.8 Hz, 1 H), 7.55 (brs, 1 H), 1 .54 (s, 9H). Intermediate (D): Scheme 1 Step 1. To dry DMSO (100 mL) taken in a sealed tube, was added phenylmethanethiol (18.2 mL, 155.56 mmol) followed by K ₂ C0 ₃ (21 .49 g, 155.56 mmol) at rt and stirred for 15 min. Then 2-chloropyridin-4-amine (10.0 g, 77.78 mmol) was added at rt and the reaction mass was heated at 120 °C for 36 h. Then the reaction was quenched with water (1 L) and extracted with EtOAc thrice. The combined organic portion was washed with brine solution, dried over Na ₂ S0 ₄ , and concentrated in vacuo to yield the crude compound, which was purified by column chromatography on silica gel (60-120 mesh size) (20-25% EtOAc in Hexane) to afford 2-(benzylthio)pyridin-4-amine as a yellowish solid (8.0 g, 47.6%). LC/MS, ESI-MS ): 2 1 7 . 1 5 . ¹ H NMR (300 MHz, DMSO-d6) δ ppm 7.88 (d, J= 5.7 Hz, 1 H), 7.38 - 7.35 (m, 2H), 7.31 - 3.21 (m, 3H), 6.35 - 6.34 (m, 1 H), 6.26 (dd, J= 5.4, 1 .8 Hz, 1 H), 6.04 (brs, 2H), 4.31 (s, 2H).

Step 2. To the stirred solution of 2-(benzylthio)pyridin-4-amine (6.0 g, 27.73 mmol), DMAP (0.34 g, 2.77 mmol) and DIPEA (5.81 mL, 33.28 mmol) in DCM (300 mL), Boc anhydride (6.69 mL, 29.12 mmol) dissolved in DCM (100 mL) was added dropwise by addition funnel at 0°C . The reaction mixture was stirred at rt for 16 h. The reaction mixture was diluted with water and extracted with DCM twice. The combined organic portion was washed with brine solution, dried over Na ₂ S0 ₄ and concentrated in vacuo to yield the crude compound. The crude was purified by column chromatography on silica gel (60-120 mesh size) (0-10% EtOAc in Hexane) to afford fert-butyl (2-(benzylthio)pyridin-4-yl)carbamate as a white solid (4.0 g, 52.8%). LC/MS, ESI-MS( ⁺ ) 317.15. ¹ H NMR (300 MHz, CDCI ₃ ) δ ppm 8.28 (d, J= 6.0 Hz, 1 H), 7.42 - 7.39 (m, 2H), 7.32 - 7.23 (m, 4H), 6.97 (dd, J= 5.7, 2.1 Hz, 1 H), 6.54 (brs, 1 H), 4.42 (s, 2H), 1 .52 (s, 9H).

Step 3. A mixture of fe/ -butyl (2-(benzylthio)pyridin-4-yl)carbamate (2.0 g, 6.32 mmol) in CCI ₄ (80 mL) and water (20 mL) was cooled to 0°C with an ice-water bath. Chlorine gas (generated from KMn0 ₄ -conc HCI) was purged into the reaction mixture at 0°C for 30 min. After reaction completion, N ₂ was purged into the reaction mixture for 20 min. The reaction mixture was then diluted with water (40 mL). The organic portion was extracted with DCM thrice. The combined organic portion was washed with brine solution, dried over anhydrous Na ₂ S0 ₄ and concentrated in vacuo at 40°C to afford a crude oil. The crude was purified by combi flash using 12 g SiliCycle column (15-20% EtOAc in Hexane) to afford fert-butyl (2- (chlorosulfonyl)pyridin-4-yl)carbamate as a white solid (1 .38 g, 74.5%). ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 1 1 .17 (s, 1 H), 8.44 (d, J= 6.8 Hz, 1 H), 8.17 (s, 1 H), 7.84 - 7.83 (m, 1 H), 1 .52 (s, 9H).

Intermediate (D): Scheme 1

B

Step 1. To dry DMF (300 ml_) taken in a sealed tube, was added phenylmethanethiol (73.0 ml_, 622.27 mmol) followed by NaOfBu (65.78 g, 684.50 mmol) at rt and stirred for 30 min. Then 4-chloropyridin-2-amine (40.0 g, 31 1 .13 mmol) was added in portions at rt, followed by KF (36.14 g, 622.27 mmol). The reaction was sealed and heated at 90°C for 16 h. Then the reaction was poured into ice cold water and stirred for 30 min. The solid precipitated was filtered, washed with water and dried in vacuo. The isolated solid was stirred in hexane for 30 min, solid was collected by filtration and dried in vacuo to afford 4-(benzylthio)pyridin-2- amine as a white solid (36.0 g, 53.4%). LC/MS, ESI-MS( ⁺ ): 2 1 7 . 1 5 . ¹ H NMR (400 MHz, DMSO-d6) δ ppm 7.71 (d, J= 5.2 Hz, 1 H), 7.41 (d, J= 7.2 Hz, 1 H), 7.32 (t, J= 7.4 Hz, 2H), 7.26 (d, J= 7.2 Hz, 2H), 6.40 (dd, J= 5.2, 1 .6 Hz, 1 H), 6.33 (d, J= 1 .2 Hz, 1 H), 5.89 (brs, 2H), 4.22 (s, 2H).

Step 2. To the stirred solution of 4-(benzylthio)pyridin-2-amine (36 g, 166.43 mmol), DMAP (2.03 g, 16.64 mmol) and DIPEA (34.88 ml_, 199.72 mmol) in DCM (1 .2 L), Boc anhydride (49.7 ml_, 216.36 mmol) dissolved in DCM (0.6 L) was added dropwise by addition funnel at over 2 h 0°C. The reaction mixture was stirred at rt for 16 h. The reaction mixture was diluted with water and extracted with DCM twice. The combined organic portion was washed with brine solution, dried over Na ₂ S0 ₄ and concentrated in vacuo to yield the crude compound. To the crude compound Et ₂ 0 was added and stirred for 30 min. The solid separated was collected by filtration and dried in vacuo to afford fert-butyl (4-(benzylthio)pyridin-2- yl)carbamate as a pale yellow solid (42.0 g, 79.8%). LC/MS, ESI-MS( ⁺ ) 317.1 . ¹ H NMR (300 MHz, DMSO-d6) δ ppm 9.77 (s, 1 H), 8.02 (d, J= 5.4 Hz, 1 H), 7.73 (d, J= 1 .5 Hz, 1 H), 7.44 (d, J= 7.2 Hz, 2H), 7.33 - 7.22 (m, 3H), 6.94 (dd, J= 7.2, 1 .5 Hz, 1 H), 4.31 (s, 2H), 1 .45 (s, 9H). Step 3. A mixture of fe/ -butyl (4-(benzylthio)pyridin-2-yl)carbamate (22.0 g, 69.52 mmol) in DCM (600 ml_) and water (200 ml_) was cooled to 0°C with an ice-water bath. Chlorine gas (generated from KMn0 ₄ -conc HCI) was purged into the reaction mixture at 0°C for 1 h. After reaction completion, N ₂ was purged into the reaction mixture for 20 min. The reaction mixture was then diluted with water (100 ml_). The organic portion was extracted with DCM thrice. The combined organic portion was washed with brine solution, dried over anhydrous Na ₂ S0 ₄ and concentrated in vacuo at 40°C to afford a crude compound. To the crude compound DCM (50 ml_) was added and stirred at 0°C for 30 min. The solid separated was filtered, washed with cold DCM and dried in vacuo to afford ferf-butyl (4- (chlorosulfonyl)pyridin-2-yl)carbamate as a white solid (13.0 g, 63.8%). ¹ H NMR (400 MHz, DMSO-d6) δ ppm 1 1 .72 (s, 1 H), 8.32 (d, J= 6.4 Hz, 1 H), 7.70 (d, J= 1 .2 Hz, 1 H), 7.49 (dd, J= 6.0, 1 .6 Hz, 1 H), 1 .53 (s, 9H).

Intermediate (D): Scheme 1

Step 1. The stirred solution of 3-bromopyridin-2-amine (5.0 g, 28.90 mmol), phenylmethanethiol (5.08 ml_, 43.35 mmol), Pd ₂ (dba) ₃ (1 .32 g, 1 .45 mmol), Xanthophos (1 .67 g, 2.89 mmol) and DIPEA (10.0 ml_, 57.80 mmol) in 1 ,4-dioxane (100 mL) was degassed with argon for 15 min. The resulting reaction mixture was heated at reflux for 16 h under argon atmosphere. The reaction mixture was cooled to rt, filtered through celite bed. The celite bed was washed with EtOAc and the combined filtrate was concentrated to dryness under reduced pressure. The crude residue was purified by column chromatography on silica gel (60-120 mesh size) (30-40% EtOAc in Hexane) to afford 3-(benzylthio)pyridin-2-amine as a yellow solid (5.0 g, 80%). LC/MS, ESI-MS(+): 217.0. ¹ H NMR (300 MHz, CDCI ₃ ) δ ppm 7.99 (dd, J= 4.8, 1 .5 Hz, 1 H), 7.33 (dd, J= 7.5, 1 .8 Hz, 1 H), 7.26 - 7.21 (m, 3H), 7.13 - 7.1 1 (m, 2H), 6.53 - 6.49 (m, 1 H), 5.06 (brs, 2H), 3.91 (s, 2H).

Step 2. To the stirred solution of 3-(benzylthio)pyridin-2-amine (5.0 g, 23.1 1 mmol), DMAP (0.28 g, 2.31 mmol) and DIPEA (4.74 mL, 27.73 mmol) in DCM (120 mL), Boc anhydride (6.9 mL, 30.05 mmol) dissolved in DCM (80 mL) was added dropwise by addition funnel at 0°C. The reaction mixture was stirred at rt for 16 h. The reaction mixture was diluted with water and extracted with DCM twice. The combined organic portion was washed with brine solution, dried over Na ₂ S0 ₄ and concentrated in vacuo to yield the crude compound. The crude was purified by column chromatography on silica gel (60-120 mesh size) (25-30% EtOAc in Hexane) to afford (3-(benzylthio)pyridin-2-yl) bis(tert-butyl carbamate) as a pale yellow solid (5.5 g, 57.1 %). LC/MS, ESI-MS(+) 417.0. ¹ H NMR (400 MHz, CDCI ₃ ) δ ppm 8.33 (dd, J= 4.8, 1 .6 Hz, 1 H), 7.51 (dd, J= 8.0, 2.0 Hz, 1 H), 7.31 - 7.25 (m, 5H), 7.14 (dd, J= 7.6, 4.4 Hz, 1 H), 4.10 (s, 2H), 1 .42 (s, 18H).

Step 3: A mixture of (3-(benzylthio)pyridin-2-yl) bis(tert-butyl carbamate) (5.5 g, 13.20 mmol) in DCM (240 mL) and water (60 mL) was cool to 0°C with an ice-water bath. Chlorine gas (generated from KMn0 ₄ -conc HCI) was purged into the reaction mixture for 1 h at 0°C. After reaction completion, N ₂ was purged into the reaction mixture for 20 min. The reaction mixture was diluted with water (100 ml_) and the organic portion was extracted with DCM thrice. The combined organic portion was washed with brine solution, dried over anhydrous Na ₂ S0 ₄ and concentrated in vacuo at 40°C to afford a crude oil. The crude residue was purified by combi flash using 24 g SiliCycle column (10-15% EtOAc in Hexane) to provide (3- (chlorosulfonyl)pyridin-2-yl) bis(tert-butyl carbamate) as pale yellow oil (4.4 g, 84.9%). ¹ H NMR (400 MHz, CDCI ₃ ) δ ppm 8.90 - 8.88 (m, 1 H), 8.50 (dd, J= 7.6, 1 .2 Hz, 1 H), 7.61 (dd, J= 8.0, 4.8 Hz, 1 H), 1 .44 (s, 18H).

Intermediate (D): Scheme 1

Step 1 : The stirred solution of 5-bromopyridin-2-amine (50.0 g, 289.00 mmol), phenylmethanethiol (50.88 ml_, 433.50 mmol), Pd ₂ (dba) ₃ (13.23 g, 14.45 mmol), Xanthophos (16.72 g, 28.90 mmol) and DIPEA (100.9 ml_, 578.00 mmol) in 1 ,4-dioxane (750 mL) was degassed with argon for 15 min. The resulting reaction mixture was heated at reflux for 16 h under argon atmosphere. The reaction mixture was cooled to rt, filtered through celite bed. The celite bed was washed with EtOAc and the combined filtrate was concentrated to dryness under reduced pressure. The crude residue was purified by column chromatography on silica gel (60-120 mesh size) (35-50% EtOAc in Hexane) to afford 5-(benzylthio)pyridin- 2-amine as a yellow solid (60.5 g, 96.7%). LC/MS, ESI-MS(+): 216.95. ¹ H NMR (400 MHz, CDCI ₃ ) δ ppm 7.99 - 7.98 (m, 1 H), 7.31 - 7.21 (m, 4H), 7.15 - 7.13 (m, 2H), 6.36 (dd, J= 8.4, 0.8 Hz, 1 H), 4.51 (brs, 2H), 3.88 (s, 2H).

Step 2. To the stirred solution of 5-(benzylthio)pyridin-2-amine (59.0 g, 272.76 mmol), DMAP (3.33 g, 27.27 mmol) and DIPEA (55.96 mL, 327.32 mmol) in DCM (1 .5 L), Boc anhydride (75.19 mL, 327.32 mmol) dissolved in DCM (500 mL) was added dropwise by addition funnel over 2 h at 0°C. The reaction mixture was stirred at rt for 16 h. The reaction mixture was diluted with water and extracted with DCM twice. The combined organic portion was washed with brine solution, dried over Na ₂ S0 ₄ and concentrated in vacuo to yield the crude compound. The crude was stirred with Et ₂ 0 (180 mL) for 30 min. The solid separated was filtered and dried in vacuo to afford fert-butyl (5-(benzylthio)pyridin-2-yl)carbamate as a pale yellow solid (60.0 g, 69.5%) . LC/MS, ESI-MS(+) 317.0. ¹ H NMR (300 MHz, CDCI3) δ ppm 8.81 (brs, 1 H), 8.23 (d, J= 1 .8 Hz, 1 H), 7.89 (d, J= 9.0 Hz, 1 H), 7.55 (dd, J= 9.0, 2.4 Hz, 1 H), 7.28 - 7.22 (m, 3H), 7.16 - 7.13 (m, 2H), 3.95 (s, 2H), 1 .53 (s, 9H). Step 3: A mixture of fe/f-butyl (5-(benzylthio)pyridin-2-yl)carbamate (60.0 g, 189.62 mmol) in DCM (1 .6 L) and water (0.4 L) was cool to 0°C with an ice-water bath. Chlorine gas (generated from KMn0 ₄ -conc HCI) was purged into the reaction mixture for 1 h and 30 min at 0°C. After reaction completion, N ₂ was purged into the reaction mixture for 20 min. The reaction mixture was diluted with water (500 mL). The organic portion was extracted with DCM thrice. The combined organic portion was washed with brine solution, dried over anhydrous Na ₂ S0 ₄ and concentrated in vacuo at 40°C to afford a crude product. To the crude compound, DCM (120 mL) was added and stirred at 0°C for 30 min. The solid separated was filtered, washed with cold DCM and dried in vacuo to afford ferf-butyl (5- (chlorosulfonyl)pyridin-2-yl)carbamate as a white solid (48.0 g, 86.4%). ¹ H NMR (400 MHz, DMSO-d6) δ ppm 1 1 .48 (s, 1 H), 8.40 (d, J= 1 .5 Hz, 1 H), 8.28 (dd, J= 9.2, 2.0 Hz, 1 H), 7.51 (d, J= 8.8 Hz, 1 H), 1 .52 (s, 9H).

Building Block (C): 5-Chloro-6-(o-tolyl)pyridin-2-amine

Step 1. Reaction flask was charged with o-tolylboronic acid (B) (1 .357 g, 9.98 mmol), 6- bromo-5-chloropyridin-2-amine (A) (2.070 g, 9.98 mmol) in dioxane (60 mL), and 2 M Na ₂ C0 ₃ (15 mL). It was degassed and filled with nitrogen, then Pd(PPh ₃ ) ₄ (557 mg, 0.499 mmol) was added, and degassed again. The reaction mixture was heated at 100 °C for 12 h and cooled down to room temperature. DCM (100 mL) was added and the mixture was washed with brine, dried over sodium sulfate, filtered, and concentrated. The crude material was purified on silica gel (80 g silicagel chromatography column, EtOAc:Hexanes gradient 0- 35%) to give the desired product (C) (1 .96 g, 85%). LCMS m/z 219.2 [M+H] ^{+ 1} H NMR (400 MHz, Methylene Chloride-d ₂ ) δ 7.49 (d, J=8.7 Hz, 1 H), 7.36 - 7.13 (m, 4H), 6.48 (d, J=8.7 Hz, 1 H), 4.59 (s, 2H), 2.16 (s, 3H).

(2-(Methyl-c ₃ )phenyl)boronic acid: Intermediate (B) used in Ex. 20 and 26

Step 1 :

(2-Bromophenyl)methan-c ₂ -ol (J. Am. Chem. Soc. 1981 ,103, 6308-6313)

To a slurry of lithium aluminumdeuteride (1 .278 g, 30.5 mmol) in anhydrous THF (100 mL) was slowly added dropwise within 1 h a solution of methyl 2-bromobenzoate (10.75 g, 50 mmol) in anhydrous THF (100 mL) and stirred at rt for 1 h under nitrogen atmosphere. The reaction mixture was quenched by the slow addition of sat. Na2SC>4 (8.5 mL) followed by stirring for 1 h. The resulting mixture was filtered through celite, washed with THF (100 mL), dried over Na2SC>4, and the solvent was removed in vacuo. The crude product was recrystallized under hexanes to give the desired compound (6.50 g, 34.4 mmol, 68.8 % yield) as white crystals. LCMS: m/z 171 .1 [M-OH] ⁺ . ¹ H NMR (400 MHz, CDCI ₃ ) δ 7.55 (dd, J = 8.0, 1 .2 Hz, 1 H), 7.48 (dd, J = 7.6, 1 .7 Hz, 1 H), 7.34 (td, J = 7.5, 1 .2 Hz, 1 H), 7.17 (td, J = 7.7, 1 .7 Hz, 1 H).

Step 2:

1 -Bromo-2-(bromomethyl-c 2)benzene

(J. Am. Chem. Soc. 1981 ,103, 6308-6313)

To a solution of (2-bromophenyl)methan-cf ₂ -ol (6.50 g, 34.4 mmol) in anhydrous ether (60 mL) PBr ₃ (1 .946 mL, 20.6 mmol) was added slowly. The reaction mixture was refluxed for 2 h, cooled to rt, washed with water, saturated NaHCC>3 and dried over Na2SC>4. Evaporation gave the desired compound (8.20 g, 32.5 mmol, 95 % yield) as crystals. LCMS: no mass detected. ¹ H NMR (400 MHz, CDCI3) δ 7.58 (dd, J = 8.0, 1 .2 Hz, 1 H), 7.46 (dd, J = 7.6, 1 .7

Hz, 1 H), 7.30 (td, J = 7.5, 1 .3 Hz, 1 H), 7.17 (m, 1 H).

Step 3:

1 -Bromo-2-(methyl-c 3)benzene

(J. Am. Chem. Soc. 1981 ,103, 6308-6313)

To a slurry of LAD (1 .120 g, 26.7 mmol) in anhydrous THF (80 mL) was added dropwise a solution of 1 -bromo-2-(bromomethyl-cf ₂ )benzene (8.20 g, 32.5 mmol) in anhydrous THF (80 mL) over period of 1 h with stirring under nitrogen atmosphere. The reaction was refluxed for 3 h, cooled and then carefully quenched by the slow addition of saturated Na ₂ S0 ₄ (2.5 mL) followed by stirring for 1 h. Filtered through celite, washed with THF and dried over Na ₂ S0 ₄ , and the solvent was removed in vacuo to yield the desired product (7.33 g, 31 .6 mmol, 97 % yield) as transparent liquid. LCMS: m/z 171 .1 [M-OH] ⁺ . ¹ H NMR (400 MHz, CDCI3) δ 7.52 (dd, J = 7.9, 1 .1 Hz, 1 H), 7.21 (m, 2H), 7.04 (ddd, J = 7.9, 6.9, 2.2 Hz, 1 H). D content 97% (by ¹ H NMR, 2.37 (p, J = 2.2 Hz, 0.03 H). Step 4:

2-(Methyl-c ₃ )phenyl)boronic acid was obtained following the procedure for 2- methylphenylboronic acid (Sleveland, Dagfinn and Bjoersvik, Hans-Rene. Organic Process Research & Development, 16(5), 1 121 -1 130; 2012)

To a cooled mixture of 1 -bromo-2-(methyl-cf ₃ )benzene (7.33 g, 31 .6 mmol) in dry THF (105 mL) at -78 °C was added rj-BuLi (16.42 mL, 41 .1 mmol). The reaction mixture was stirred at - 78 °C for 30 minutes prior to the addition of B(OMe) ₃ (5.99 mL, 53.7 mmol). The reaction mixture was stirred at-78 °C for 30 min. After the solution reached rt, it was stirred at rt for 1 .5 h. 120 rnL of saturated NH Ci solution was added and THF was evaporated. The aqueous phase was acidified with 3 HCi until the pH < 4. The reaction mixture was extracted with DCM (x3). and the combined organic layers were washed with brine, dried over a2S04, filtered and concentrated. The crude solid was triturated under hexanes, and white crystals were filtered, yield 1 ,13 g (26%), LCMS: Rt no mass detected. ¹ H NMR (400 MHz, CDCI ₃ ) δ 8.22 (dd, J = 7.4, 1 .2 Hz, 1 H), 7.46 (td, J = 7.5, 1 .6 Hz, 1 H), 7.30 (m, 2H). D content 97% (by ¹ H NMR, 2.79 (p, J = Hz, 0.03 H).

PREPARATION OF EXAMPLES

Example 14: 6-Amino-N-(5-chloro-6-(o-tolyl)pyridin-2-yl)pyridine-2-sulfo namide

Ex.14

Step 1. To a solution of 5-chloro-6-(o-tolyl)pyridin-2-amine (C) (1 .006 g, 4.60 mmol) in pyridine (20 mL) was added tert-butyl (6-(chlorosulfonyl)pyridin-2-yl)carbamate (D) (2.02 g, 6.90 mmol) and stirred at RT o/n. Water was added and stirred for 30 min. Brine was added, the mixture was extracted with DCM (x3), and dried over sodium sulfate. The solution was filtered, concentrated and evaporated with toluene twice to remove pyridine. Purification on silicagel chromatography, 80 g column, 0-40% EA-hex afforded tert-Butyl (6-(N-(5-chloro-6- (o-tolyl)pyridin-2-yl)sulfamoyl)pyridin-2-yl)carbamate (2.18 g, 100%). LCMS m/z 475.2

[M+H] ⁺ . ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 1 1 .36 (s, 1 H), 10.18 (s, 1 H), 7.98 (m, 1 H), 7.92 (m, 2H), 7.54 (dd, J = 7.4, 0.8 Hz, 1 H), 7.25 (m, 4H), 6.98 (d, J = 7.3 Hz, 1 H), 1 .88 (s, 3H), 1 .47 (s, 9H). Step 2. tert-Butyl (6-(N-(5-chloro-6-(o-tolyl)pyridin-2-yl)sulfamoyl)pyridin-2- yl)carbamate (2.18 g, 4.59 mmol) was dissolved in 4 M HCI in dioxane (33 ml_, 132 mmol) and stirred at RT o/n. A precipitate resulted. Ether (33 ml_) was added, stirred for 30 min, filtered, and washed with ether. The white crystals were partitioned between DCM and sat. NaHC0 ₃ and extracted with DCM (x3). The combined extracts were washed with brine and dried over Na ₂ S0 ₄ . The solution was filtered, evaporated and dried in high vac. at 60°C o/n to afford 6- Amino-N-(5-chloro-6-(o-tolyl)pyridin-2-yl)pyridine-2-sulfona mide (Ex. 14) (1 .54 g, 89%) as white crystals. Condition 2, LCMS: m/z 375.1 [M+H] ⁺ , ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 1 1 .16 (s, 1 H), 7.89 (d, J = 8.8 Hz, 1 H), 7.51 (dd, J = 8.3, 7.4 Hz, 1 H), 7.31 (td, J = 7.4, 1 .4 Hz, 1 H), 7.23 (m, 3H), 7.02 (m, 2H), 6.62 (dd, J = 8.4, 0.6 Hz, 1 H), 6.45 (s, 2H), 1 .91 (s, 3H).

The following examples were prepared using a combination of various building blocks and intermediates as indicated within the general synthetic methods.

Example 1 : 6-amino-N-(6-(5-fluoro-2-methylphenyl)-5-(trifluoromethyl)py ridin-2- yl)pyridine-2-sulfonamide; Condition 2, LCMS: m/z 427.1 [M+H] ⁺ , 13.04 min. ¹ H NMR (500 MHz, DMSO-d ₆ ) δ 1 1 .61 (s, 1 H),8.16 (d, J = 8.9 Hz, 1 H), 7.49 (dd, J = 8.4, 7.3 Hz, 1 H), 7.37 (d, J = 8.7 Hz, 1 H), 7.28 (dd, J = 8.5, 5.8 Hz, 1 H), 7.17 (td, J = 8.6, 2.8 Hz, 1 H), 7.02 (dd, J = 7.3, 0.7 Hz, 1 H), 6.96 (d, J = 6.9 Hz, 1 H), 6.63 (dd, J = 8.4, 0.7 Hz, 1 H), 6.45 (s, 2H), 5.76 (s, 1 H), 1 .76 (s, 3H).

Example 2: 6-amino-N-(6-(2,6-dimethylphenyl)-5-(trifluoromethyl)pyridin -2-yl)pyridine- 2-sulfonamide; Condition 2, LCMS: m/z 423.1 [M+H] ⁺ 3.05 min. ¹ H NMR (400 MHz, Methanol-d ₄ ) δ 8.07 (d, J = 8.9 Hz, 1 H), 7.51 - 7.37 (m, 1 H), 7.20 (d, J = 7.6 Hz, 1 H), 7.15 (dd, J = 7.4, 0.7 Hz, 1 H), 7.06 (d, J = 7.6 Hz, 2H), 6.66 (d, J = 8.4 Hz, 1 H), 1 .85 (s, 6H).

Example 3: 6-amino-N-(5-bromo-6-(2,6-dimethylphenyl)pyridin-2-yl)pyridi ne-2- sulfonamide; Condition 2, LCMS: m/z 433.1 [M+H] ⁺ , 3.04 min. ¹ H NMR 400 MHz (DMSO-d ₆ ) 0 1 1 .1 1 (s, 1 H), 8.04 (d, J = 8.8 Hz, 1 H), 7.47 (dd, J = 8.3, 7.4, 1 H), 7.22-7.13 (m, 2H), 7.07 (d, J = 7.6, 2H), 6.98 (dd, J = 7.3, 0.6 Hz, 1 H), 6.61 (dd, J = 8.4, 0.7 Hz, 1 H), 6.41 (s, 2H), 1 .78 (s, 6H).

Example 4: 2-amino-N-(5-chloro-6-(2,6-dimethylphenyl)pyridin-2-yl)pyrid ine-4- sulfonamide; Condition 2, LCMS: m/z 389.1 [M+H] ⁺ , 2.80 min. ¹ H NMR (400 MHz,

Methanol-d ₄ ) δ 7.83 (d, J=5.5 Hz, 1 H), 7.70 (d, J=8.7 Hz, 1 H), 7.1 1 - 7.04 (m, 2H), 6.96 (d, J=7.6 Hz, 2H), 6.82 (d, J=1 .5 Hz, 1 H), 6.78 (dd, J=1 .6, 5.5 Hz, 1 H), 1 .74 (s, 6H). Example 5: 6-amino-N-(6-(2,6-dimethylphenyl)-4-(trifluoromethyl)pyridin -2-yl)pyridine- 2-sulfonamide; Condition 2, LCMS: m/z 423.1 [M+H] ⁺ , 3.21 min. ¹ H NMR (400 MHz, Methanol-d ₄ ) δ 7.60 - 7.44 (m, 2H), 7.18 (d, J = 7.4 Hz, 2H), 7.14 - 7.02 (m, 3H), 6.66 (d, J = 8.4 Hz, 1 H), 1 .93 (s, 6H).

Example 6: 6-amino-N-(5-chloro-6-(5-fluoro-2-methylphenyl)pyridin-2-yl) pyridine-2- sulfonamide; Condition 2, LCMS: m/z 393.1 [M+H] ⁺ , 3.01 min. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 1 1 .21 (s, 1 H), 7.92 (d, J = 8.8 Hz, 1 H), 7.50 (t, J = 7.8 Hz, 1 H), 7.30 (dd, J = 8.3, 5.9 Hz, 1 H), 7.22 (d, J = 8.8 Hz, 1 H), 7.16 (td, J = 8.7, 2.6 Hz, 1 H), 7.02 (d, J = 7.3 Hz, 1 H), 6.90 (dd, J = 9.3, 2.4 Hz, 1 H), 6.62 (d, J = 8.4 Hz, 1 H), 6.46 (s, 2H), 1 .88 (s, 3H). ¹⁹ F NMR (376 MHz, DMSO-d ₆ ) δ -1 17.93(s).

Example 7: 6-amino-N-(6-(3-fluoro-2-methylphenyl)-5-(trifluoromethyl)py ridin-2- yl)pyridine-2-sulfonamide; Condition 2, LCMS: m/z 427.1 [M+H] ⁺ , 3.07 min. ¹ H NMR (400 MHz, Methylene Chloride-d ₂ ) δ 7.99 (d, J=8.9 Hz, 1 H), 7.63 - 7.55 (m, 1 H), 7.53 (d, J=4.3 Hz, 1 H), 7.34 (d, J=7.3 Hz, 1 H), 7.23 (q, J=7.3 Hz, 1 H), 7.13 (t, J=8.7 Hz, 1 H), 6.97 (d, J=5.9 Hz,1 H), 6.66 (d, J=8.4 Hz, 1 H), 4.74 (d, J=47.8 Hz, 2H), 1 .92 (s, 3H). 19F NMR (376 MHz, Methylene Chloride-d2) δ -58.93 (s, 3F), -1 17.28 (d, J=74.2 Hz, 1 F). Example 8: 6-amino-N-(5-chloro-6-(2,6-dimethylphenyl)-4-(trifluoromethy l)pyridin-2- yl)pyridine-2-sulfonamide; Condition 2, LCMS: m/z 457.1 [M+H] ⁺ , 3.32 min. ¹ H NMR (500 MHz, Methanol-d ₄ ) δ 7.65 (s, 1 H), 7.50 (dd, J = 8.4, 7.3 Hz, 2H), 7.29 - 7.13 (m, 1 H), 7.1 1 - 7.03 (m,1 H), 6.69 (dd, J = 8.4, 0.6 Hz, 2H), 1 .85 (s, 6H). Example 9: 6-amino-N-(6-(2,6-dimethylphenyl)-5-fluoropyridin-2-yl)pyrid ine-2- sulfonamide; Condition 2, LCMS: m/z 373.1 [M+H] ⁺ , 2.89 min. ¹ H NMR (400 MHz, Methanol-d ₄ ) δ 7.58 (d, J = 8.6 Hz, 1 H), 7.48 (dd, J = 8.4, 7.3 Hz, 1 H), 7.37 (dd, J = 8.9, 3.2 Hz, 1 H), 7.22 - 7.1 1 (m, 2H), 7.06 (d, J = 7.6 Hz, 2H), 6.65 (d, J = 8.4 Hz, 1 H), 1 .91 (s, 6H). Example 10: 6-amino-N-(4-chloro-6-(2,6-dimethylphenyl)pyridin-2-yl)pyrid ine-2- sulfonamide; Condition 2, LCMS: m/z 389.1 [M+H] ⁺ , 3.02 min. ¹ H NMR (400 MHz, Methanol-d ₄ ) δ 7.54 (t, J = 7.9 Hz, 1 H), 7.37 (s, 1 H), 7.20 (dd, J = 13.1 , 7.4 Hz, 2H), 7.1 1 (d, J = 7.7 Hz, 2H), 6.92 (d, J = 1 .9 Hz, 1 H), 6.66 (d, J = 8.4 Hz, 1 H), 2.04 (d, J = 18.7 Hz, 6H). Example 11 : 6-amino-N-(5-chloro-6-(2,6-dimethylphenyl)pyridin-2-yl)pyrid ine-2- sulfonamide; Condition 2, LCMS: m/z 389.1 [M+H] ⁺ . 3.01 min. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 1 1 .12 (s, 1 H), 7.92 (d, J = 8.8 Hz, 1 H), 7.47 (dd, J = 8.3, 7.4 Hz, 1 H), 7.20 (m, 2H), 7.07 (d, J = 7.6 Hz, 2H), 6.97 (dd, J = 7.3, 0.6 Hz, 1 H), 6.59 (dd, J = 8.4, 0.7 Hz, 1 H), 6.43 (s, 2H), 1 .77 (s, 6H).

Example 12: 6-amino-N-(5-chloro-6-(3-fluoro-2-methylphenyl)pyridin-2-yl) pyridine-2- sulfonamide; Condition 2.LCMS: m/z 393.1 [M+H] ⁺ , 3.02 min. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 1 1 .22 (s, 1 H), 7.93 (d, J=8.8 Hz, 1 H), 7.52 (dd, J=7.4, 8.3 Hz, 1 H), 7.33 - 7.18 (m, 3H), 7.02 (dd, J=0.6, 7.3 Hz, 1 H), 6.92 (dd, J=1 .1 , 7.4 Hz, 1 H), 6.65 - 6.60 (m, 1 H), 6.46 (s, 2H), 1 .81 (d, J=2.1 Hz, 3H). Example 13: 6-amino-N-(5-chloro-6-(2-chloro-6-methylphenyl)pyridin-2-yl) pyridine-2- sulfonamide; Condition 2, LCMS: m/z 409.0 [M+H] ⁺ , 3.26 min. ¹ H NMR (400 MHz,

Methanol-d ₄ ) δ 7.82 (d, J = 8.7 Hz, 1 H), 7.49 (t, J = 7.8 Hz, 1 H), 7.36 (d, J = 8.8 Hz, 1 H), 7.28 (d, J = 4.4 Hz, 2H), 7.20 (t, J = 4.5 Hz, 1 H), 7.15 (d, J = 7.3 Hz, 1 H), 6.66 (d, J = 8.4 Hz, 1 H), 1 .90 (s, 3H).

Example 15: 6-amino-N-(6-(o-tolyl)-5-(trifluoromethyl)pyridin-2-yl)pyrid ine-2- sulfonamide; Condition 2, LCMS: m/z 409.1 [M+H] ⁺ , 2.98 min. ¹ H NMR (400 MHz,

Methanol-d ₄ ) δ 8.05 (d, J = 8.8 Hz, 1 H), 7.49 (dd, J = 8.4, 7.3 Hz, 1 H), 7.42 (d, J = 8.9 Hz, 1 H), 7.32 (d, J = 7.5 Hz, 1 H), 7.27 - 7.19 (m, 2H), 7.17 (d, J = 7.6 Hz, 1 H), 7.08 (d, J = 7.6 Hz, 1 H), 6.66 (d, J = 8.4 Hz, 1 H), 1 .94 (s, 3H).

Example 16: 6-amino-N-(5-chloro-6-(5-chloro-2-cyclopropylphenyl)pyridin- 2- yl)pyridine-2-sulfonamide; Condition 2, LCMS: m/z 409.1 [M+H] ⁺ , 2.98 min. ¹ H NMR (400 MHz, DMSO-d ₆ ) 1 1 .20 (s, 1 H), 7.92 (d, J = 8.7 Hz, 1 H), 7.51 (dd, J = 8.3, 7.4 Hz, 1 H), 7.36 (dd, J = 8.4, 2.3 Hz, 1 H), 7.23 (d, J = 8.8 Hz, 1 H), 7.05 - 7.01 (m, 2H), 6.98 (d, J = 8.5 Hz, 1 H), 6.62 (d, J = 8.3 Hz, 1 H), 6.45 (s, 2H), 1 .41 - 1 .33 (m, 1 H), 0.70 - 0.62 (m, 2H), 0.51 (brs, 2H).

Example 17: 6-amino-N-(6-(2-chlorophenyl)-5-(trifluoromethyl)pyridin-2-y l)pyridine-2- sulfonamide; Condition 2, LCMS: m/z 429.1 [M+H] ⁺ , 2.96 min. ¹ H NMR (400 MHz,

Methylene Chloride-d ₂ ) δ 7.99 (d, J=8.9 Hz, 1 H), 7.58 (dt, J=6.8, 8.2 Hz, 2H), 7.47 (dd, J=1 .2, 8.0 Hz, 1 H), 7.43 (dt, J=1 .9, 6.8 Hz, 1 H), 7.39 (dd, J=1 .6, 12.2 Hz, 1 H), 7.34 (dd, J=1 .7, 7.3 Hz, 2H), 7.27 (d, J=7.3 Hz, 1 H), 4.85 (s, 2H). Example 18: 6-amino-N-(5-(trifluoromethyl)-6-(2-(trifluoromethyl)phenyl) pyridin-2- yl)pyridine-2-sulfonamide; Condition 2, LCMS: m/z 463.1 [M+H] ⁺ , 3.00 min. ¹ H NMR (400 MHz, Methylene Chloride-d ₂ ) δ 7.98 (d, J=8.8 Hz, 1 H), 7.74 (dq, J=3.1 , 3.7, 6.4 Hz, 1 H), 7.66 - 7.52 (m, 4H), 7.31 (dd, J=6.3, 12.1 Hz, 2H), 6.73 - 6.60 (m, 1 H), 4.80 (s, 2H); ¹⁹ F NMR (376 MHz, Methylene Chloride-d ₂ ) δ -58.42 (s, 3F).

Example 19: 6-amino-N-(5-chloro-6-(2-cyclopropylphenyl)pyridin-2-yl)pyri dine-2- sulfonamide; Condition 2, LCMS: m/z 401 .1 [M+H] ⁺ , 3.04 min. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 1 1 .14 (s, 1 H), 7.90 (d, J = 8.8 Hz, 1 H), 7.51 (dd, J = 8.3, 7.4 Hz, 1 H), 7.35 - 7.28 (m, 1 H), 7.24 (d, J = 8.8 Hz, 1 H), 7.22 - 7.15 (m, 1 H), 7.05 - 6.98 (m, 2H), 6.97 (d, J = 7.7 Hz, 1 H), 6.64 - 6.58 (m, 1 H), 6.45 (s, 2H), 1 .46 - 1 .36 (m, 1 H), 0.68 - 0.58 (m, 2H), 0.49 (s, 2H). Example 20: 6-amino-N-(5-chloro-6-(2-(methyl-d3)phenyl)pyridin-2-yl)pyri dine-2- sulfonamide; Condition 2, LCMS: m/z 378.1 [M+H] ⁺ , 2.94 min. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 1 1 .16 (s, 1 H), 7.89 (d, J = 8.8 Hz, 1 H), 7.51 (dd, J = 8.3, 7.4 Hz, 1 H), 7.31 (td, J = 7.4,

1 .4 Hz, 1 H), 7.23 (m, 3H), 7.03 (m, 2H), 6.62 (d, J = 8.1 Hz, 1 H), 6.45 (s, 2H). Example 21 : 6-amino-N-(5-chloro-6-(2-cyclopropyl-5-fluorophenyl)pyridin- 2-yl)pyridine- 2-sulfonamide; Condition 2, LCMS: m/z 419.1 [M+H] ⁺ , 3.13 min. ¹ H NMR (400 MHz, DMSO- d ₆ ) 6 d ₆ ) 1 1 .19 (s, 1 H), 7.92 (d, J=8.8 Hz, 1 H), 7.50 (dd, J=7.3, 8.4 Hz, 1 H), 7.25 (d, J=8.8 Hz, 1 H), 7.15 (td, J=2.8, 8.7 Hz, 1 H), 7.05 - 6.98 (m, 2H), 6.88 (dd, J=2.8, 9.3 Hz, 1 H), 6.61 (dd, J=0.6, 8.4 Hz, 1 H), 6.45 (s, 2H), 1 .37 (ddd, J=5.5, 8.5, 13.7 Hz, 1 H), 0.59 (d, J=8.4 Hz, 2H), 0.45 (s, 2H).

Example 22: 6-amino-N-(5-chloro-6-(o-tolyl)-4-(trifluoromethyl)pyridin-2 -yl)pyridine-2- sulfonamide; Condition 2, LCMS: m/z 443.1 [M+H] ⁺ , 3.26 min. ¹ H NMR (500 MHz,

Chloroform-d) δ 7.86 (s, 1 H), 7.51 (dd, J = 8.3, 7.4 Hz, 1 H), 7.29 (dd, J = 1 1 .3, 7.5 Hz, 2H), 7.22-7.16 (m, 3H), 7.09 (d, J = 7.3 Hz, 1 H), 6.57 (d, J = 8.3 Hz, 1 H), 4.5 (s, 2H) 2.02 (s, 3H).

Example 23: 6-amino-N-(5-bromo-6-(o-tolyl)pyridin-2-yl)pyridine-2 -sulfonamide;

Condition 2, LCMS: m/z 419.1 [M+H] ⁺ , 2.95 min. ¹ H NMR (500 MHz, DMSO-d ₆ ) δ 1 1 .21 (s, 1 H), 7.84 (d, J = 8.8 Hz, 1 H), 7.44 - 7.37 (m, 1 H), 7.25 - 7.1 1 (m, 3H), 7.01 (d, J = 8.8 Hz, 1 H), 6.97-6.90 (m, 2H), 6.51 (d, J = 8.4 Hz, 1 H), 6.28 (s, 2H),1 .84 (s, 3H).

Example 24: 6-amino-N-(5-chloro-6-(2-chlorophenyl)pyridin-2-yl)pyridine- 2- sulfonamide; Condition 2, LCMS: m/z 395.0 [M+H] ⁺ , 2.92 min. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 1 1 .25 (s, 1 H), 7.92 (d, J=8.8 Hz, 1 H), 7.57 - 7.52 (m, 2H), 7.50 -7.45 (m, 1 H), 7.44 - 7.39 (m, 1 H), 7.30 (d, J=8.8 Hz, 1 H), 7.21 (dd, J=1 .7, 7.5 Hz, 1 H),

7.05 (dd, J=0.6, 7.3 Hz, 1 H), 6.64 (dd, J=0.7, 8.4 Hz, 1 H), 6.48 (s, 2H). Example 25: 2-amino-N-(6-(2,6-dimethylphenyl)-5-(trifluoromethyl)pyridin -2-yl)pyridine- 4-sulfonamide; Condition 2, LCMS: m/z 423.1 [M+H] ⁺ , 2.90 min. ¹ H NMR (400 MHz, Methanol-d ₄ ) δ 8.09 (d, J = 8.8 Hz, 1 H), 7.94 (d, J = 5.5 Hz, 1 H), 7.23 (s, 2 H), 7.08 (d, J = 7.6 Hz, 2H), 7.00 - 6.77 (m, 2H), 3.67 (s, 2H), 1 .82 (s, 6 H).

Example 26: 2-amino-N-(5-chloro-6-(2-(methyl-d3)phenyl)pyridin-2-yl)pyri dine-4- sulfonamide; Condition 2, LCMS: m/z 378.1 [M+H] ⁺ , 2.67 min. ¹ H NMR (400 MHz, DMSO- d _e ) δ 1 1 .45 (s, 1 H), 8.02 (m, 1 H), 7.97 (d, J = 8.7 Hz, 1 H), 7.32 (m, 1 H), 7.25 (m, 2H), 7.13 (d, J = 8.8 Hz, 1 H), 7.07 (dd, J = 7.5, 1 .1 Hz, 1 H), 6.79 (dd, J = 1 .6, 0.6 Hz, 1 H), 6.72 (dd, J = 5.3, 1 .6 Hz, 1 H), 6.50 (s, 2H).

Example 27: 6-amino-N-(5-chloro-6-(2-cyclopropyl-4-fluorophenyl)pyridin- 2-yl)pyridine- 2-sulfonamide; Condition 2, LCMS: m/z 419.1 [M+H] ⁺ , 3.13 min. ¹ H NMR (400 MHz, DMSO- d _e ) δ 1 1 .17 (s, 1 H), 7.91 (d, J = 8.8 Hz, 1 H), 7.52 (dd, J = 8.3, 7.4 Hz, 1 H), 7.25 (d, J = 8.8 Hz, 1 H), 7.08 - 6.97 (m, 3H), 6.77 (dd, J = 10.8, 2.3 Hz, 1 H), 6.61 (d, J = 8.3 Hz, 1 H), 6.45 (s, 2H), 1 .40 (ddd, J = 13.0, 8.0, 5.6 Hz, 1 H), 0.71 - 0.65 (m, 2H), 0.57 (brs, 2H).

Example 28: 6-amino-N-(6-(2-cyclopropyl-4-fluorophenyl)-5-(trifluorometh yl)pyridin-2- yl)pyridine-2-sulfonamide; Condition 2, LCMS: m/z 435.1 [M+H] ⁺ , 3.13 min. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 1 1 .45 (s, 1 H), 8.02 (m, 1 H), 7.97 (d, J = 8.7 Hz, 1 H), 7.32 (m, 1 H), 7.25 (m, 2H), 7.13 (d, J = 8.8 Hz, 1 H), 7.07 (dd, J = 7.5, 1 .1 Hz, 1 H), 6.79 (dd, J = 1 .6, 0.6 Hz, 1 H), 6.72 (dd, J = 5.3, 1 .6 Hz, 1 H), 6.50 (s, 2H).

Example 29: 6-amino-N-(5-chloro-6-(2-ethylphenyl)pyridin-2-yl)pyridine-2 -sulfonamide; Condition 2, LCMS: m/z 389.1 [M+H] ⁺ , 3.03 min ⁺ . ¹ H NMR (400 MHz, DMSO-d ₆ ) G 1 1 .15 (s, 1 H), 7.90 (d, J = 8.8 Hz, 1 H), 7.50 (dd, J = 8.3, 7.4 Hz, 1 H), 7.38 - 7.32 (m, 1 H), 7.31 - 7.26 (m, 1 H), 7.26 - 7.19 (m, 2H), 7.05 (dd, J = 7.6, 1 .1 Hz, 1 H), 7.01 (dd, J = 7.3, 0.6 Hz, 1 H), 6.62 (dd, J = 8.4, 0.6 Hz, 1 H), 6.46 (s, 2H), 2.21 (brs, 2H), 0.86 (t, J = 7.6 Hz, 3H). Example 30: 6-amino-N-(5-chloro-6-(4-fluoro-2,6-dimethylphenyl)pyridin-2 -yl)pyridine- 2-sulfonamide; Condition 2, LCMS: m/z 407.2 [M+H] ⁺ , 3.09 min. ¹ H NMR (500 MHz, Acetonitrile-ds) δ 8.39 (s, 1 H), 7.81 (d, J=8.8 Hz, 1 H), 7.52 (dd, J=7.4, 8.4 Hz, 1 H), 7.36 (d, J=8.8 Hz, 1 H), 7.15 (d, J=7.3 Hz, 1 H), 6.87 (d, J=9.8 Hz, 2H), 6.66 (d, J=8.4 Hz, 1 H), 5.20 (s, 2H), 1 .85 (s, 6H).

Example 31 : 6-amino-N-(5-chloro-6-(2-fluoro-6-methylphenyl)pyridin-2-yl) pyridine-2- sulfonamide; LCMS: m/z 393.1 Example 32: 6-amino-N-(5-chloro-6-mesitylpyridin-2-yl)pyridine-2 -sulfonamide;

Condition 2, LCMS: m/z 403.1 [M+H] ⁺ , 3.13 min. ¹ H NMR (400 MHz, Methanol-d ₄ ) δ 7.81 (d, J = 8.8 Hz, 1 H), 7.52 - 7.43 (m, 1 H), 7.32 (d, J = 8.8 Hz, 1 H), 7.15 (d, J = 7.3 Hz, 1 H), 6.89 (s, 2H), 6.65 (d, J = 8.4 Hz, 1 H), 3.74 (d, J = 5.8 Hz, OH), 3.67 (d, J = 5.5 Hz, 1 H), 3.59 (d, J = 5.2 Hz, OH), 2.30 (s, 3H), 1 .84 (s, 6H).

Example 33: 6-amino-N-(5-chloro-6-(o-tolyl)pyridin-2-yl)-3-fluoropyridin e-2- sulfonamide; Condition 2, LCMS: m/z 393.1 [M+H] ⁺ , 2.90 min. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 1 1 .45 (s, 1 H), 7.92 (d, J = 8.8 Hz, 1 H), 7.47 (t, J = 9.3 Hz, 1 H), 7.31 (td, J = 7.5, 1 .3 Hz, 1 H), 7.22 (m, 2H), 7.10 (d, J = 8.7 Hz, 1 H), 7.01 (d, J = 7.4 Hz, 1 H), 6.67 (dd, J = 9.0, 2.8 Hz, 1 H), 6.32 (s, 2H), 1 .90 (s, 3H). ¹⁹ F NMR (376 MHz, DMSO-d ₆ ) δ -135.96 (s).

Example 34: 6-amino-N-(5-chloro-6-(2-methyl-3-(trifluoromethyl)phenyl)py ridin-2- yl)pyridine-2-sulfonamide; Condition 2, LCMS: m/z 443.1 [M+H] ⁺ , 3.16 min. ¹ H NMR (400 MHz, Methylene Chloride-d ₂ ) δ 7.76 (d, J=8.8 Hz, 1 H), 7.71 (d, J=7.2 Hz, 1 H), 7.57 (dd, J=7.4, 8.3 Hz, 1 H), 7.47 (d, J=8.8 Hz, 1 H), 7.42 - 7.28 (m, 3H), 6.66 (d, J=8.4 Hz, 1 H), 4.78 (s, 2H), 2.22 - 2.04 (m, 3H); ¹⁹ F NMR (376 MHz, Methylene Chloride-d ₂ ) δ -61 .26 (s, 3F). Example 35: 6-amino-N-(5-fluoro-6-(2-isopropylphenyl)pyridin-2-yl)pyridi ne-2- sulfonamide; Condition 2, LCMS: m/z 387.1 [M+H] ⁺ , 3.03 min. ¹ H NMR (400 MHz,

Methanol-d ₄ ) δ 7.61 - 7.47 (m, 2H), 7.41 - 7.34 (m, 3H), 7.24 - 7.14 (m, 2H), 7.08 (d, J = 7.6 Hz, 1 H), 6.66 (dd, J = 8.5, 0.7 Hz, 1 H), 3.67 (d, J = 5.6 Hz, 3H), 1 .08 (d, J = 6.8 Hz, 7H). Example 36: 6-amino-5-methyl-N-(6-(o-tolyl)-5-(trifluoromethyl)pyridin-2 -yl)pyridine-2- sulfonamide; Condition 2, LCMS: m/z 423.2 [M+H] ⁺ , 3.12 min. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 1 1 .47 (s, 1 H), 8.08 (d, J = 8.9 Hz, 1 H), 7.37 - 7.24 (m, 3H), 7.23 - 7.12 (m, 2H), 7.01 (d, J = 7.4 Hz, 1 H), 6.96 (d, J = 7.4 Hz, 1 H), 6.23 (s, 2H), 2.02 (s, 3H), 1 .74 (s, 3H). Example 37: 6-amino-N-(5-chloro-6-(4-fluoro-2-methylphenyl)pyridin-2-yl) pyridine-2- sulfonamide; Condition 2, LCMS: m/z 393.1 [M+H] ⁺ , 3.00 min. ¹ H NMR (400 MHz,

Methanol-d ₄ ) δ 7.79 (dd, J = 8.8, 1 .3 Hz, 1 H), 7.50 (dd, J = 8.5, 7.3 Hz, 1 H), 7.30 (dd, J = 8.8, 1 .3 Hz, 1 H), 7.17 (dd, J = 7.3, 1 .4 Hz, 1 H), 7.10 (dd, J = 8.3, 6.1 Hz, 1 H), 7.03 - 6.89 (m, 2H), 6.67 (dd, J = 8.5, 1 .4 Hz, 1 H), 3.79 - 3.71 (m, 1 H), 3.71 - 3.63 (m, 2H), 3.59 (dd, J = 5.2, 1 .3 Hz, 1 H), 2.02 (s, 3H). Example 38: 6-amino-N-(5-chloro-6-(6-chloro-2-fluoro-3-methylphenyl)pyri din-2- yl)pyridine-2-sulfonamide; Condition 2, LCMS: m/z 427.0 [M+H] ⁺ , 3.01 min. ¹ H NMR (400 MHz, Methanol-d ₄ ) δ 7.83 (d, J = 8.8 Hz, 1 H), 7.53 (dd, J = 8.5, 7.3 Hz, 1 H), 7.38 (d, J = 8.8 Hz, 1 H), 7.31 (s, 1 H), 7.23 - 7.1 1 (m, 2H), 6.70 (d, J = 8.5 Hz, 1 H), 2.27 (d, J = 2.2 Hz, 4H).

Example 39: 6-amino-N-(5-chloro-6-(2-chloro-6-fluorophenyl)pyridin-2-yl) pyridine-2- sulfonamide; Condition 2, LCMS: m/z 413.0 [M+H] ⁺ , 2.88 min. ¹ H NMR (400 MHz,

Methanol-d ₄ ) δ 7.83 (d, J = 8.8 Hz, 1 H), 7.51 (dd, J = 8.4, 7.3 Hz, 1 H), 7.46 - 7.37 (m, 2H), 7.32 (d, J = 8.1 Hz, 1 H), 7.21 - 7.12 (m, 2H), 6.67 (d, J = 8.4 Hz, 1 H).

Example 40: 6-amino-N-(5-chloro-6-(o-tolyl)pyridin-2-yl)pyridine-3-sulfo namide;

Condition 2, LCMS: m/z 375.1 [M+H] ⁺ , 2.82 min. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 1 1 .02 (s, 1 H), 8.28 (m, 1 H), 7.91 (d, J = 8.7 Hz, 1 H), 7.64 (dd, J = 8.9, 2.6 Hz, 1 H), 7.34 (td, J = 7.4, 1 .4 Hz, 1 H), 7.27 (m, 2H), 7.10 (dd, J = 7.5, 1 .1 Hz, 1 H), 7.05 (d, J = 8.7 Hz, 1 H), 6.95 (s, 2H), 6.37 (dd, J = 8.9, 0.5 Hz, 1 H), 1 .95 (s, 3H).

Example 41 : 6-amino-N-(6-(2-chloro-4-fluorophenyl)-5-(trifluoromethyl)py ridin-2- yl)pyridine-2-sulfonamide; Condition 2, LCMS: m/z 447.2 [M+H] ⁺ , 3.06 min. ¹ H NMR (400 MHz, Methylene Chloride-d ₂ ) δ 8.00 (d, J=8.8 Hz, 1 H), 7.66 - 7.56 (m, 2H), 7.35 (d, J=7.4 Hz, 1 H), 7.30 - 7.20 (m, 2H), 7.08 (td, J=2.5, 8.4 Hz, 1 H), 6.67 (d, J=8.4 Hz, 1 H), 4.81 (s, 2H); ¹⁹ F NMR (376 MHz, Methylene Chloride-d ₂ ) δ -59.27 (s, 3F), -1 10.80 (s, 1 F).

Example 42: 2-amino-N-(6-(5-fluoro-2-methylphenyl)-5-(trifluoromethyl)py ridin-2- yl)pyridine-4-sulfonamide; Condition 2, LCMS: m/z 427.1 [M+H] ⁺ , 2.87 mi. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.25 (d, J = 8.9 Hz, 1 H), 8.03 (d, J = 6.3 Hz, 2H), 7.35-7.25 (m, 2H), 7.22 (td, J = 8.6, 2.8 Hz, 2H). 7.09 - 6.95 (m, 1 H), 6.92 (dd, J = 6.3, 1 .7 Hz, 1 H), 1 .78 (s, 3H).

Example 43: 6-amino-N-(5-chloro-6-(2-chloro-5-(trifluoromethyl)phenyl)py ridin-2- yl)pyridine-2-sulfonamide; Condition 2, LCMS: m/z 463.0 [M+H] ⁺ , 3.18 min. ¹ H NMR (400 MHz, Methylene Chloride-d ₂ ) δ 7.77 (d, J=8.8 Hz, 1 H), 7.66 (dd, J=1 .7, 8.5 Hz, 1 H), 7.62 (d, J=8.5 Hz, 1 H), 7.60 - 7.54 (m, 1 H), 7.51 (d, J=8.9 Hz, 2H), 7.32 (d, J=7.3 Hz, 1 H), 6.68 (d,J=8.4 Hz, 1 H), 4.88 (s, 2H); ¹⁹ F NMR (376 MHz, Methylene Chloride-d ₂ ) δ -62.83 (s, 3F).

Example 44: 6-amino-N-(5-chloro-6-(5-fluoro-2-methylphenyl)pyridin-2-yl) pyridine-3- sulfonamide; Condition 2, LCMS: m/z 393.1 [M+H] ⁺ , 2.89 min. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 1 1 .07 (s, 1 H), 8.27 (d, J = 2.5 Hz, 1 H), 7.90 (d, J = 8.8 Hz, 1 H), 7.64 (dd, J = 8.9, 2.6 Hz, 1 H), 7.33 (dd, J = 8.5, 5.8 Hz, 1 H), 7.19 (td, J = 8.6, 2.8 Hz, 1 H), 7.04 (d, J = 8.8 Hz, 1 H), 6.99 (dd, J = 9.3, 2.8 Hz, 1 H), 6.92 (s, 2H), 6.36 (m, 1 H), 1 .92 (s, 3H).

1 ⁹ F NMR (376 MHz, DMSO-d ₆ ) δ -1 17.72(s).

Example 45: 6-amino-N-(5-chloro-6-(2-isopropylphenyl)pyridin-2-yl)pyridi ne-3- sulfonamide; Condition 2, LCMS: m/z 403.2 [M+H] ⁺ , 3.04 min. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 10.99 (s, 1 H), 8.26 (d, J = 2.4 Hz, 1 H), 7.93 (d, J = 8.7 Hz, 1 H), 7.62 (dd, J = 8.9, 2.6 Hz, 1 H), 7.41 (d, J = 3.7 Hz, 2H), 7.28-7.21 (m, 1 H), 7.13 (d, J = 8.8 Hz, 1 H), 7.04 (d, J = 7.5 Hz, 1 H), 6.94 (s, 2H), 6.36 (d, J = 8.9 Hz, 1 H), 2.49-2.46 (m, 1 H), 1 .1 1 -0.92 (m, 6H). Example 46: 2-amino-N-(5-chloro-6-(5-fluoro-2-methylphenyl)pyridin-2-yl) pyridine-4- sulfonamide; Condition 2, LCMS: m/z 393.1 [M+H] ⁺ , 2.80 min. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 1 1 .48 (s, 1 H), 8.02 (dd, J = 5.3, 0.5 Hz, 1 H), 7.99 (d, J = 8.8 Hz, 1 H), 7.31 (dd, J = 8.5, 5.8 Hz, 1 H), 7.17 (m, 2H), 6.97 (dd, J = 9.3, 2.8 Hz, 1 H), 6.79 (dd, J = 1 .6, 0.6 Hz, 1 H), 6.72 (dd, J = 5.3, 1 .6 Hz, 1 H), 6.51 (s, 2H), 1 .84 (s, 3H).

Example 47: 6-amino-N-(5-chloro-6-(2,6-dimethylphenyl)pyridin-2-yl)pyrid ine-3- sulfonamide; Condition 2, LCMS: m/z 389.1 [M+H] ⁺ , 2.92 min. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 10.98 (s, 1 H), 8.23 (m, 1 H), 7.94 (d, J = 8.7 Hz, 1 H), 7.60 (dd, J = 8.9, 2.6 Hz, 1 H), 7.21 (m, 1 H), 7.09 (m, 3H), 6.93 (s, 2H), 6.34 (dd, J = 8.9, 0.5 Hz, 1 H), 1 .78 (s, 6H).

Example 48: 6-amino-N-(5-chloro-6-(2-(1 ,1 -difluoroethyl)phenyl)pyridin-2-yl)pyridine-2- sulfonamide; Condition 2, LCMS: m/z 425.1 [M+H] ⁺ , 2.93 min. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 1 1 .15 (s, 1 H), 7.88 (d, J = 8.8 Hz, 1 H), 7.51 (m, 4H), 7.25 (d, J = 8.8 Hz, 1 H), 7.16 (m, 1 H), 6.99 (dd, J = 7.3, 0.6 Hz, 1 H), 6.60 (m, 1 H), 6.46 (s, 2H), 1 .78 (t, J = 19.1 Hz, 3H). ¹⁹ F NMR (376 MHz, DMSO-d ₆ ) δ -82.35 (d, J = 240.6 Hz), -85.68 (d, J = 240.8 Hz).

Example 49: 2-amino-N-(5-chloro-6-(2-methyl-5-(trifluoromethyl)phenyl)py ridin-2- yl)pyridine-4-sulfonamide; Condition 2, LCMS: m/z 443.1 [M+H] ⁺ , 3.07 min. ¹ H NMR (400 MHz, Methylene Chloride-d ₂ ) δ 8.17 (s, 1 H), 7.79 (d, J=8.8 Hz, 1 H), 7.64 - 7.56 (m, 1 H), 7.43 - 7.39 (m, 2H), 7.36 (d, J=8.8 Hz, 1 H), 6.94 - 6.85 (m, 2H), 5.12 (s, 2H), 2.10 (s, 3H).

Example 50: 6-amino-N-(5-chloro-6-(2-isopropylphenyl)pyridin-2-yl)pyridi ne-2- sulfonamide; Condition 2, LCMS: m/z 403.1 [M+H] ⁺ , 3.15 min. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 1 1 .15 (s, 1 H), 7.90 (d, J = 8.8 Hz, 1 H), 7.50 (dd, J = 8.4, 7.3 Hz, 1 H), 7.39 (dd, J = 4.8, 1 .3 Hz, 2H), 7.26 (d, J = 8.8 Hz, 1 H), 7.22 (ddd, J = 7.7, 5.1 , 3.5 Hz, 1 H), 7.02 - 6.98 (m, 2H), 6.61 (dd, J = 8.4, 0.6 Hz, 1 H), 6.47 (s, 2H), 1 .04 (s, 3H), 0.96 (s, 3H). Example 51 : 6-amino-N-(5-chloro-6-(2-methyl-5-(trifluoromethyl)phenyl)py ridin-2- yl)pyridine-2-sulfonamide; Condition 2, LCMS: m/z 443.1 [M+H] ⁺ , 3.17 min. ¹ H NMR (400 MHz, Methanol-d ₄ ) δ 7.83 (d, J=8.8 Hz, 1 H), 7.60 (dd, J=2.0, 8.2 Hz, 1 H), 7.52 - 7.43 (m, 2H), 7.36 - 7.34 (m, 1 H), 7.32 (d, J=8.8 Hz, 1 H), 7.16 (d, J=7.3 Hz, 1 H), 6.69 - 6.64 (m, 1 H), 2.10 (s, 3H).

Example 52: 6-amino-N-(5-chloro-6-(2-chloro-6-(trifluoromethyl)phenyl)py ridin-2- yl)pyridine-2-sulfonamide; Condition 2, LCMS: m/z 462.9 [M+H] ⁺ , 3.00 min. ¹ H NMR (400 MHz, Methanol-d ₄ ) δ 7.82 (d, J = 8.8 Hz, 1 H), 7.75 (t, J = 7.3 Hz, 2H), 7.63 (d, J = 8.0 Hz, 1 H), 7.51 - 7.40 (m, 2H), 7.13 (d, J = 7.3 Hz, 1 H), 6.66 (d, J = 8.4 Hz, 1 H).

Example 53: 6-amino-N-(5-chloro-6-(2-methyl-6-(trifluoromethyl)phenyl)py ridin-2- yl)pyridine-2-sulfonamide; Condition 2, LCMS: m/z 443.1 [M+H] ⁺ , 3.03 min. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 1 1 .17 (s, 1 H), 7.93 (d, J = 8.8 Hz, 1 H), 7.60 (m, 3H), 7.43 (dd, J = 7.4, 8.3 Hz, 1 H), 7.27 (d, J = 8.8 Hz, 1 H), 6.94 (dd, J = 0.7, 7.3 Hz, 1 H), 6.59 (dd, J = 0.6, 8.4 Hz, 1 H), 6.43 (s, 2H), 1 .79 (s, 3H). ¹⁹ F NMR (376 MHz, DMSO-d ₆ ) δ -57.96 (s).

Example 54: 6-amino-N-(5-chloro-6-(2-cyclopropylphenyl)pyridin-2-yl)pyri dine-3- sulfonamide; Condition 2, LCMS: m/z 401 .1 [M+H] ⁺ , 2.97 min. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 10.99 (s, 1 H), 8.28 (d, J = 2.3 Hz, 1 H), 7.92 (d, J = 8.7 Hz, 1 H), 7.65 (dd, J = 8.9, 2.6 Hz, 1 H), 7.37 - 7.30 (m, 1 H), 7.26 - 7.19 (m, 1 H), 7.1 1 (d, J = 8.7 Hz, 1 H), 7.08 (dd, J = 7.6, 1 .3 Hz, 1 H), 7.00 (d, J = 7.7 Hz, 1 H), 6.95 (s, 2H), 6.36 (d, J = 9.0 Hz, 1 H), 1 .50 - 1 .37 (m, 1 H), 0.70 - 0.57 (m, 2H), 0.51 (brs, 2H). Example 55: 6-amino-N-(5-chloro-6-(2-(trifluoromethyl)phenyl)pyridin-2-y l)pyridine-2- sulfonamide; Condition 2, LCMS: m/z 429.1 [M+H] ⁺ , 2.96 min. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 1 1 .20 (s, 1 H), 7.92 (d, J=8.8 Hz, 1 H), 7.83 (d, J=7.5 Hz, 1 H), 7.75 (t, J=7.2 Hz, 1 H), 7.68 (t, J=7.5 Hz, 1 H), 7.49 (dd, J=7.4, 8.3 Hz, 1 H), 7.35 - 7.32 (m, 2H), 7.02

- 6.98 (m, 1 H), 6.62 (d, J=8.4 Hz, 1 H), 6.47 (s, 2H).

Example 56: 6-amino-N-(5-chloro-6-(2-chloro-4-fluorophenyl)pyridin-2-yl) pyridine-2- sulfonamide; Condition 2, LCMS: m/z 413.2 [M+H] ⁺ , 3.02 min. ¹ H NMR (500 MHz, DMSO- d ₆ ) δ 1 1 .24 (s, 1 H), 7.92 (d, J=8.8 Hz, 1 H), 7.56 (dd, J=3.2, 5.7 Hz, 1 H), 7.53 (d, J=8.4 Hz, 1 H), 7.36 - 7.24 (m, 3H), 7.05 (d, J=7.3 Hz, 1 H), 6.64 (d, J=8.4 Hz, 1 H), 6.45 (s, 2H); ¹⁹ F NMR (471 MHz, DMSO-d ₆ ) δ -1 10.57 (s, 1 F). Example 57: 2-amino-N-(5-chloro-6-(o-tolyl)pyridin-2-yl)pyridine-4-sulfo namide;

Condition 2, LCMS: m/z 374.9 [M+H] ⁺ , 2.69 min. ¹ H NMR (400 MHz, Methylene Chloride-d ₂ ) δ 8.12 (d, J=5.4 Hz, 1 H), 7.78 (d, J=8.8 Hz, 1 H), 7.35 (td, J=1 .5, 7.5 Hz, 1 H), 7.31 - 7.19 (m, 3H), 7.14 (dd, J=1 .4, 7.6 Hz, 1 H), 6.93 (dd, J=1 .6, 5.4 Hz, 1 H), 6.91 - 6.89 (m, 1 H), 2.04 (s, 3H).

Example 58: 6-amino-N-(5-chloro-6-(2-chloro-6-fluoro-3-methylphenyl)pyri din-2- yl)pyridine-2-sulfonamide; Condition 2, LCMS: m/z 427.0 [M+H] ⁺ , 3.00 min. ¹ H NMR (400 MHz, Methanol-d ₄ ) δ 7.84 (d, J = 8.9 Hz, 1 H), 7.57 (dd, J = 8.5, 7.3 Hz, 1 H), 7.36 (d, J = 8.8 Hz, 1 H), 7.20 (d, J = 7.2 Hz, 1 H), 7.07 (s, 1 H), 6.74 (d, J = 8.4 Hz, 1 H), 2.37 (s, 3H).

Example 59: 6-amino-N-(5-chloro-6-(2-(trifluoromethoxy)phenyl)pyridin-2- yl)pyridine-2- sulfonamide; Condition 2, LCMS: m/z 445.0 [M+H] ⁺ , 3.02 min. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 1 1 .25 (s, 1 H), 7.92 (d, J = 8.8 Hz, 1 H), 7.63 - 7.57 (m, 1 H), 7.54 - 7.43 (m, 3H), 7.29- 7.24 (m, 2H), 7.04 (dd, J = 7.3, 0.6 Hz, 1 H), 6.65 - 6.61 (m, 1 H), 6.47 (s, 2H).

Example 60: 6-amino-N-(5-chloro-6-(2-fluoro-6-methylphenyl)pyridin-2-yl) pyridine-3- sulfonamide; Condition 2, LCMS: m/z 393.1 [M+H] ⁺ , 2.79 min. ¹ H NMR (400 MHz, Methanol-d ₄ ) δ 8.33 (d, J = 2.5 Hz, 1 H), 7.82 (d, J = 8.7 Hz, 1 H), 7.75 (dd, J = 9.0, 2.5 Hz, 1 H), 7.33 (d, J = 5.8 Hz, 1 H), 7.1 1 (dd, J = 10.3, 8.2 Hz, 2H), 6.99 (s, 1 H), 6.44 (d, J = 8.9 Hz, 1 H), 1 .94 (s, 3H).

Example 61 : 2-amino-N-(5-chloro-6-(2-(trifluoromethyl)phenyl)pyridin-2-y l)pyridine-4- sulfonamide; Condition 2, LCMS: m/z 429.0 [M+H] ⁺ , 2.72 min. ¹ H NMR (400 MHz, Methanol-d ₄ ) δ 7.97 (d, J = 4.7 Hz, 1 H), 7.83 (d, J = 8.8 Hz, 1 H), 7.77 (d, J = 7.4 Hz, 1 H), 7.66 (dt, J = 15.4, 7.5 Hz, 3H), 7.31 - 7.24 (m, 2H), 6.94 (s, 1 H), 6.88 (dd, J = 5.5, 1 .6 Hz, 1 H).

Example 62: 6-amino-N-(5-chloro-6-(5-fluoro-2-methoxyphenyl)pyridin-2-yl )pyridine-2- sulfonamide; Condition 2, LCMS: m/z 409.1 [M+H] ⁺ , 2.84 min. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 1 1 .21 (s, 1 H), 7.84 (d, J = 8.8 Hz, 1 H), 7.55 (dd, J = 8.3, 7.4 Hz, 1 H), 7.30 - 7.22 (m, 1 H), 7.20 (d, J = 8.8 Hz, 1 H), 7.10 (dd, J = 9.2, 4.4 Hz, 1 H), 7.07 (dd, J = 7.3, 0.6 Hz, 1 H), 6.75 (dd, J = 8.6, 3.1 Hz, 1 H), 6.69 - 6.62 (m, 1 H), 6.49 (s, 2H), 3.70 (s, 3H). Example 63: 6-amino-N-(6-(2,6-dimethylphenyl)-4-methylpyridin-2-yl)pyrid ine-2- sulfonamide; Condition 2, LCMS: m/z 369.2 [M+H] ⁺ , 2.64 min. ¹ H NMR (400 MHz, Methanol-d ₄ ) δ 7.59 (dd, J = 8.4, 7.3 Hz, 1 H), 7.33 (dd, J = 8.2, 7.0 Hz, 1 H), 7.24 - 7.17 (m, 3H), 7.13 (s, 1 H), 6.74 (d, J = 1 .5 Hz, 1 H), 6.64 (d, J = 8.4 Hz, 1 H), 2.43 (s, 3H), 2.15 (s, 6H).

Example 64: 2-amino-N-(6-(5-cyano-2-methylphenyl)-5-(trifluoromethyl)pyr idin-2- yl)pyridine-4-sulfonamide; Condition 2, LCMS: m/z 434.1 [M+H] ⁺ , 2.86 min. ¹ H NMR (400 MHz, Chloroform-d) δ 7.95 (m, 1 H), 7.68 (m, 1 H), 7.62 (m, 1 H), 7.54 - 7.48 (m, 1 H), 7.42 (m, 1 H), 7.37 (m, 1 H), 7.32 (m, 1 H), 6.74 (m, 1 H), 2.15 (s, 3H).

Example 65: 6-amino-N-(5-chloro-6-(2-(difluoromethyl)phenyl)pyridin-2-yl )pyridine-2- sulfonamide; Condition 2, LCMS: m/z 41 1 .0 [M+H] ⁺ , 2.91 min. ¹ H NMR (400 MHz,

Acetonitrile-ds) δ 7.86 (d, J = 8.8 Hz, 1 H), 7.79 - 7.73 (m, 1 H), 7.64 - 7.59 (m, 2H), 7.55 (dd, J = 8.4, 7.3 Hz, 1 H), 7.41 (d, J = 8.8 Hz, 2H), 7.21 (dd, J = 7.4, 0.7 Hz, 1 H), 6.70 - 6.68 (m, 1 H), 5.29 (s, 2H). Example 66: 6-amino-N-(5-cyclopropyl-6-(o-tolyl)pyridin-2-yl)pyridine-2- sulfonamide;

Condition 2, LCMS: m/z 381 .1 [M+H] ⁺ , 2.73 min. ¹ H NMR (500 MHz, DMSO-d ₆ ) δ 10.81 (s, 1 H), 7.41 (dd, J = 8.3, 7.3 Hz, 1 H), 7.25 - 7.1 1 (m, 3H), 7.02 (dd, J = 14.7, 8.0 Hz, 2H), 6.94 (dd, J = 7.3, 0.7 Hz, 2H), 6.50 (dd, J = 8.3, 0.6 Hz, 1 H), 6.23 (s, 2H), 1 .90 (s, 3H), 1 .30 (ddd, J = 13.6, 8.4, 5.2 Hz, 1 H), 0.68 - 0.57 (m, 2H), 0.48 (dt, J = 6.3, 3.1 Hz, 2H).

Example 67: 6-amino-N-(5-chloro-6-(3-cyano-2-methylphenyl)pyridin-2-yl)p yridine-2- sulfonamide; Condition 2, LCMS: m/z 400.0 [M+H] ⁺ , 2.80 min. ¹ H NMR (400 MHz, Methanol-d ₄ ) δ 7.84 (m, 1 H), 7.78 - 7.66 (m, 1 H), 7.59 - 7.24 (m, 4H), 7.16 (m, 1 H), 6.69 (m, 1 H), 5.50 (s, 1 H), 2.17 (s, 3H).

Example 68: 6-amino-N-(6-(2,6-dimethylphenyl)pyridin-2-yl)pyridine-2 -sulfonamide;

Condition 2, LCMS: m/z 400.0 [M+H] ⁺ , 2.57 min. ¹ H NMR (400 MHz, Methanol-d ₄ ) δ 7.89 (t, J = 8.0 Hz, 1 H), 7.56 (t, J = 7.9 Hz, 1 H), 7.25 (dd, J = 46.7, 8.0 Hz, 4H), 6.85 (d, J = 7.2 Hz, 1 H), 6.63 (d, J = 8.4 Hz, 1 H), 2.1 1 (s, 6H).

Example 69: 6-amino-N-(5-chloro-6-(2-fluorophenyl)pyridin-2-yl)pyridine- 2- sulfonamide; Condition 2, LCMS: m/z 379.0 [M+H] ⁺ , 2.83 min. ¹ H NMR (400 MHz, Methanol-d ₄ ) δ 7.78 (d, J = 8.8 Hz, 1 H), 7.54 (dd, J = 8.4, 7.3 Hz, 1 H), 7.49 - 7.41 (m, 1 H), 7.31 (d, J = 8.8 Hz, 1 H), 7.26 - 7.19 (m, 3H), 7.18 - 7.1 1 (m, 1 H), 6.71 - 6.64 (m, 1 H), 3.67 (s, 3H). Example 70: 6-amino-N-(5-fluoro-6-(o-tolyl)pyridin-2-yl)pyridine-2 -sulfonamide;

Condition 2, LCMS: m/z 359.1 [M+Hf 2.82 min. ¹ H NMR (400 MHz, Methanol-d ₄ ) δ 7.61 - 7.48 (m, 2H), 7.36 - 7.12 (m, 6H), 6.67 (dd, J = 8.4, 0.8 Hz, 1 H), 2.12 (s, 3H). Example 71 : 6-amino-N-(5-chloro-6-(4-fluoro-2-methylphenyl)pyridin-2-yl) pyridine-3- sulfonamide; Condition 2, LCMS: m/z 393.0 [M+H] ⁺ , 2.92 min. ¹ H NMR (400 MHz,

Methanol-d ₄ ) δ 8.33 (d, J = 2.4 Hz, 1 H), 7.84 - 7.66 (m, 2H), 7.1 1 (d, J = 5.9 Hz, 1 H), 7.06 (d, J = 8.7 Hz, 1 H), 7.03 - 6.92 (m, 2H), 6.44 (d, J = 8.9 Hz, 1 H), 2.02 (s, 3H). Example 72: 6-amino-N-(6-(2,6-dimethylphenyl)-5-methoxypyridin-2-yl)pyri dine-2- sulfonamide hydrochloride; Condition 2, LCMS: m/z 385.1 [M+H] ⁺ , 2.63 min. ¹ H NMR (500 MHz, Methanol-d ₄ ) δ 8.04 (d, J = 9.3 Hz, 1 H), 7.90 (dd, J = 8.9, 7.2 Hz, 1 H), 7.52 (d, J = 9.2 Hz, 1 H), 7.38 - 7.29 (m, 2H), 7.24 - 7.19 (m, 2H), 7.03 (dd, J = 8.9, 0.9 Hz, 1 H), 3.89 (s,3H), 2.05 (s, 6H).

Example 73: 6-amino-N-(5-chloro-6-(3-(trifluoromethyl)phenyl)pyridin-2-y l)pyridine-2- sulfonamide; Condition 2, LCMS: m/z 429.0 [M+H] ⁺ 3.18 min. ¹ H NMR (400 MHz, Methylene Chloride-d ₂ ) δ 7.90 (m, 2H), 7.78 - 7.63 (m, 2H), 7.56 (m, 2H), 7.36 (m, 3H), 6.63 (m, 1 H), 4.78 (m, 2H).

Example 74: 2-amino-N-(5-chloro-6-(2,6-dimethylphenyl)pyridin-2-yl)pyrid ine-3- sulfonamide; Condition 2, LCMS: m/z 389.2 [M+H] ⁺ , 3.14 min. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 8.20 (dd, J = 5.3, 1 .8 Hz, 1 H), 8.03 (d, J = 7.4 Hz, 1 H), 7.98 (d, J = 8.8 Hz, 1 H), 7.58 - 7.31 (m, 2H), 7.28 - 7.19 (m, 2H), 7.1 1 (d, J = 7.4 Hz, 3H), 6.66 (dd, J = 7.6, 5.4 Hz, 1 H), 1 .77 (s, 6H).

Example 75: 6-amino-N-(5-methyl-6-(o-tolyl)pyridin-2-yl)pyridine-2 -sulfonamide;

Condition 2, LCMS: m/z 355.1 [M+H] ⁺ , 2.52 min. ¹ H NMR (400 MHz, Methanol-d ₄ ) δ 7.83 - 7.70 (m, 1 H), 7.56 (dd, J = 8.4, 7.3 Hz, 1 H), 7.50 - 7.28 (m, 4H), 7.25 (d, J = 8.9 Hz, 1 H), 7.18 (d, J = 7.2 Hz, 1 H), 6.62 (d, J = 8.4 Hz, 1 H), 2.13 (d, J = 27.4 Hz, 3H), 2.02 (s, 3H).

Example 76: 6-amino-N-(5-chloro-6-(2-methoxyphenyl)pyridin-2-yl)pyridine -2- sulfonamide; Condition 2, LCMS: m/z 391 .1 [M+H] ⁺ , 2.75 min. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 1 1 .16 (s, 1 H), 7.81 (d, J = 8.8 Hz, 1 H), 7.57 (dd, J = 8.3, 7.4 Hz, 1 H), 7.42 (ddd, J = 8.4, 7.4, 1 .9 Hz, 1 H), 7.18 (d, J = 8.7 Hz, 1 H), 7.13 - 7.04 (m, 2H), 7.02 - 6.95 (m, 1 H), 6.92 (d, J = 6.8 Hz, 1 H), 6.66 (d, J = 8.0 Hz, 1 H), 6.48 (s, 2H), 3.71 (s, 3H). Example 77: 6-amino-N-(6-(2-chlorophenyl)-5-methylpyridin-2-yl)pyridine- 2- sulfonamide hydrochloride; Condition 2, LCMS: m/z 375.1 [M+H] ⁺ , 2.66 min. ¹ H NMR (500 MHz, Methanol-d ₄ ) δ 8.14 - 8.08 (m, 2H), 7.64 - 7.57 (m, 1 H), 7.52 (t, J = 7.7 Hz, 2H), 7.30 - 7.22 (m, 2H), 7.12 (d, J = 7.6 Hz, 2H), 1 .90 (s, 6H).

Example 78: 6-amino-N-(5-chloro-6-(2,3,6-trifluorophenyl)pyridin-2-yl)py ridine-2- sulfonamide; Condition 2, LCMS: m/z 415.2 [M+H] ⁺ , 2.87 min. ¹ H NMR (500 MHz,

Acetonitrile-ds) δ 8.49 (s, 1 H), 7.79 (d, J=9.0 Hz, 1 H), 7.47 (dd, J=7.3, 8.4 Hz, 1 H), 7.40 (d, J=8.9 Hz, 1 H), 7.34 (qd, J=4.9, 9.3 Hz, 1 H), 7.13 (d, J=7.3 Hz, 1 H), 7.00 (tdd, J=2.2, 3.8, 8.9 Hz, 1 H), 6.61 (d, J=8.4 Hz, 1 H), 5.15 (s, 2H); ¹⁹ F NMR (471 MHz, Acetonitrile-d ₃ ) δ -1 19.26 (d, J=15.3 Hz, 1 F), -137.72 (d, J=20.8 Hz, 1 F), -143.81 (dd, J=15.2, 21 .0 Hz, 1 F).

Example 79: 6-amino-N-(5-(trifluoromethyl)-6-(3-(trifluoromethyl)phenyl) pyridin-2- yl)pyridine-2-sulfonamide; Condition 2, LCMS: m/z 463.1 [M+H] ⁺ , 3.20 min. ¹ H NMR (400 MHz, Methylene Chloride-d ₂ ) δ 8.00 (m, 1 H), 7.73 (m, 1 H), 7.70 - 7.63 (m, 2H), 7.63 - 7.54 (m, 2H), 7.52 (m, 1 H), 7.43 - 7.31 (m, 1 H), 6.72 - 6.62 (m, 1 H).

Example 80: 6-amino-N-(5-chloro-6-(2,6-difluorophenyl)pyridin-2-yl)pyrid ine-2- sulfonamide; Condition 2, LCMS: m/z 397.1 [M+H] ⁺ , 2.81 min. ¹ H NMR (500 MHz,

Acetonitrile-d ₃ ) δ 8.54 (s, 1 H), 7.85 (d, J=8.9 Hz, 1 H), 7.60 - 7.49 (m, 2H), 7.46 (d, J=8.8 Hz, 1 H), 7.24 - 7.19 (m, 1 H), 7.13 - 7.05 (m, 2H), 6.69 (d, J=8.4 Hz, 1 H), 5.23 (s, 2H); ¹⁹ F NMR (471 MHz, Acetonitrile-ds) δ -1 14.53 (s, 2F).

Example 81 : 6-amino-5-bromo-N-(5-chloro-6-(2,6-dimethylphenyl)pyridin-2- yl)pyridine- 2-sulfonamide; Condition 2, LCMS: m/z 467.0 [M+H] ⁺ , 3.30 min. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 1 1 .26 (s, 1 H), 7.93 (d, J = 8.8 Hz, 1 H), 7.81 (d, J = 7.9 Hz, 1 H), 7.19 (m, 2H), 7.07 (d, J = 7.6 Hz, 2H), 6.89 (d, J = 7.9 Hz, 1 H), 6.75 (s, 2H), 1 .74 (s, 6H).

Example 82: 6-amino-N-(6-(2-methyl-5-(trifluoromethoxy)phenyl)-5- (trifluoromethyl)pyridin-2-yl)pyridine-2-sulfonamide; Condition 2, LCMS: m/z 493.2

[M+H] ⁺ , 3.30 min. ¹ H NMR (400 MHz, Methylene Chloride-d ₂ ) δ 7.99 (d, J=8.9 Hz, 1 H), 7.57 (dd, J=7.4, 8.3 Hz, 1 H), 7.50 (d, J=8.4 Hz, 1 H), 7.39 - 7.30 (m, 1 H), 7.19 (d, J=8.3 Hz, 1 H), 7.15 (s, 1 H), 7.1 1 (d, J=8.3 Hz, 1 H), 6.65 (d, J=8.3 Hz, 1 H), 4.72 (s, 2H), 2.03 (s, 3H); ¹⁹ F NMR (376 MHz, Methylene Chloride-d ₂ ) δ -58.06 (s, 1 F), -58.90 (s, 1 F).

Example 83: 6-amino-N-(6-(5-cyano-2-methylphenyl)-5-(trifluoromethyl)pyr idin-2- yl)pyridine-2-sulfonamide; Condition 2, LCMS: m/z 434.1 [M+H] ⁺ , 2.68 min. ¹ H NMR (400 MHz, Methanol-d ₄ ) δ 8.00 (m, 1 H), 7.85 (m, 1 H), 7.60 (dd, J = 7.9, 1 .8 Hz, 1 H), 7.39 - 7.30 (m, 2H), 7.15 - 7.08 (m, 1 H), 6.83 (m, 1 H), 6.80 - 6.74 (m, 1 H), 1 .84 (s, 3H).

Example 84: 6-amino-N-(5-chloro-6-(5-cyano-2-methylphenyl)pyridin-2-yl)p yridine-2- sulfonamide; Condition 2, LCMS: m/z 400.1 [M+H] ⁺ , 2.80 min. ¹ H NMR (400 MHz,

Methanol-d ₄ ) δ 7.88 - 7.83 (m, 1 H), 7.68 (dd, J = 8.0, 1 .8 Hz, 1 H), 7.59 (dd, J = 8.5, 7.3 Hz, 1 H), 7.46 (d, J = 8.0 Hz, 1 H), 7.39 (d, J = 1 .7 Hz, 1 H), 7.30 - 7.24 (m, 1 H), 7.19 (dd, J = 7.3, 0.7 Hz, 1 H), 6.76 (dd, J = 8.5, 0.7 Hz, 1 H), 2.10 (s, 3H). Example 85: 2-amino-N-(5-chloro-6-(5-cyano-2-methylphenyl)pyridin-2-yl)p yridine-4- sulfonamide; Condition 2, LCMS: m/z 400.1 [M+H] ⁺ , 2.58 min. ¹ H NMR (400 MHz,

Chloroform-d) δ 8.18 (m, 1 H), 7.77 (m, 1 H), 7.61 (m, 1 H), 7.45 (m, 1 H), 7.39 (m, 2H), 7.32 - 7.25 (m, 1 H), 6.94 - 6.85 (m, 2H), 5.52 (s, 2H), 2.12 (s, 3H). Example 86: 6-amino-N-(5-chloro-6-(2,4,6-trifluorophenyl)pyridin-2-yl)py ridine-2- sulfonamide; Condition 2, LCMS: m/z 415.2 [M+H] ⁺ , 2.93 min. ¹ H NMR (500 MHz,

Acetonitrile-ds) δ 8.56 (s, 1 H), 7.85 (d, J=8.9 Hz, 1 H), 7.55 (dd, J=7.3, 8.4 Hz, 1 H), 7.46 (d, J=8.8 Hz, 1 H), 7.21 (dd, J=0.7, 7.3 Hz, 1 H), 7.02 - 6.88 (m, 2H), 6.69 (dd, J=0.8, 8.4 Hz,1 H), 5.45 (s, 1 H), 5.22 (s, 2H); ¹⁹ F NMR (471 MHz, Acetonitrile-d ₃ ) δ -107.52 (t, J=6.9 Hz, 1 F), - 1 1 1 .29 (d, J=7.2 Hz, 2F).

Example 87: 2-amino-N-(5-chloro-6-(3-cyano-2-methylphenyl)pyridin-2-yl)p yridine-4- sulfonamide; Condition 2, LCMS: m/z 400.1 [M+H] ⁺ , 2.58 min. ¹ H NMR (400 MHz,

Methanol-d ₄ ) δ 7.99 (dd, J = 5.5, 0.6 Hz, 1 H), 7.91 - 7.81 (m, 1 H), 7.75 (dd, J = 7.5, 1 .7 Hz, 1 H), 7.51 - 7.33 (m, 2H), 7.19 (d, J = 8.8 Hz, 1 H), 6.93 (m, 1 H), 6.90 - 6.86 (m, 1 H), 2.15 (s, 3H).

Example 88: 2-amino-N-(5-chloro-6-(o-tolyl)pyridin-2-yl)pyridine-3-sulfo namide;

Condition 2, LCMS: m/z 375.1 . ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 1 1 .44 (s, 1 H), 8.17 (dd, J = 4.7, 1 .8 Hz, 1 H), 7.92 (d, J = 8.7 Hz, 1 H), 7.88 (dd, J = 7.8, 1 .8 Hz, 1 H), 7.38 - 7.22 (m, 3H), 7.07 (d, J = 7.6 Hz, 1 H), 7.04 (d, J = 8.8 Hz, 1 H), 6.67 (s, 2H), 6.57 (dd, J = 7.8, 4.8 Hz, 1 H), 1 .94 (s, 3H).

Example 89: 6-amino-N-(5-chloro-6-(2-methyl-5-(trifluoromethoxy)phenyl)p yridin-2- yl)pyridine-2-sulfonamide; Condition 2, LCMS: m/z 459.2 [M+H] ⁺ , 3.25 min. ¹ H NMR (400 MHz, Methylene Chloride-d ₂ ) a 8.75 - 7.80 (m, 1 H), 7.72 (d, J=8.8 Hz, 1 H), 7.58 - 7.47 (m, 1 H), 7.39 (d, J=8.8 Hz, 1 H), 7.29 (d, J=7.3 Hz, 1 H), 7.20 (d, J=8.3 Hz, 1 H), 7.16 - 7.04 (m, 2H), 6.63 (d, J=8.3 Hz, 1 H), 4.84 (s, 2H), 2.07 (s, 3H); ¹⁹ F NMR (376 MHz, Methylene Chloride-d ₂ ) δ -58.02 (s, 3F).

Example 90: 6-amino-N-(5-chloro-6-(2-cyanophenyl)pyridin-2-yl)pyridine-2 - sulfonamide; Condition 2, LCMS: m/z 386.0 [M+H] ⁺ . ¹ H NMR (400 MHz, Chloroform-d) δ 7.85-7.75 (m, 1 H), 7.75 - 7.70 (m, 1 H), 7.69 - 7.62 (m, 1 H), 7.60 - 7.48 (m, 4H), 7.35 (m, 1 H), 6.68 (m, 1 H), 4.78 (brs, 2H).

Example 91 : 6-amino-N-(5-chloro-6-(4-cyano-2-methylphenyl)pyridin-2-yl)p yridine-2- sulfonamide; Condition 2, LCMS: m/z 400.1 [M+H] ⁺ , 2.85 min. ¹ H NMR (400 MHz,

Chloroform-d) δ 7.83 (d, J = 8.8 Hz, 1 H), 7.67 - 7.62 (m, 1 H), 7.62 - 7.57 (m, 1 H), 7.50 (dd, J = 8.4, 7.3 Hz, 1 H), 7.35 - 7.29 (m, 1 H), 7.27 (m, 1 H), 7.16 (dd, J = 7.3, 0.7 Hz, 1 H), 6.70 - 6.63 (m, 1 H), 2.06 (s, 3H) Example 92: 2-amino-N-(5-chloro-6-(4-cyano-2-methylphenyl)pyridin-2-yl)p yridine-4- sulfonamide; Condition 2, 400.1 , 2.62 min. ¹ H NMR (400 MHz, Chloroform-d) δ 8.10 (m, 1 H), 7.71 (m, 1 H), 7.48 (m, 3H), 7.31 (m, 1 H), 7.17 (s, 1 H), 6.89 - 6.78 (m, 2H), 4.87 (m, 2H), 2.06 (s, 3H). Example 93: 6-amino-N-(6-(2,6-dimethylphenyl)-3-fluoropyridin-2-yl)pyrid ine-2- sulfonamide; Condition 2, 373.6, 2.63 min.

Example 94: 6-amino-N-(5-chloro-6-(4-(trifluoromethyl)phenyl)pyridin-2-y l)pyridine-2- sulfonamide Condition 2, LCMS: m/z 429.0 [M+H] ⁺ , 3.25 min. ¹ H NMR (400 MHz, Methylene Chloride-d ₂ ) δ 7.74 (m, 4H), 7.63 - 7.52 (m, 1 H), 7.45 - 7.30 (m, 2H), 6.66 (m, 1 H), 4.78 (m, 2H).

Example 95: 6-amino-N-(5-chloro-6-(2,6-dimethylphenyl)-3-fluoropyridin-2 -yl)pyridine- 2-sulfonamide; Condition 2, LCMS: m/z 407.1 [M+H] ⁺ , 3.02 min. ¹ H NMR (400 MHz, Methanol-d ₄ ) δ 7.79 (d, J = 9.5 Hz, 1 H), 7.34 (t, J = 7.8 Hz, 1 H), 7.20 - 7.12 (m, 1 H), 7.03 (dd, J = 7.4, 2.0 Hz, 3H), 6.62 (d, J = 8.3 Hz, 1 H), 1 .77 (s, 6H).

Example 96: 6-amino-N-(3-chloro-6-(2,6-dimethylphenyl)pyridin-2-yl)pyrid ine-2- sulfonamide; Condition 2, LCMS: m/z 389.1 [M+H] ⁺ , 2.74 min. ¹ H NMR (400 MHz,

Methanol-d ₄ ) δ 8.00 (s, 1 H), 7.62 - 7.00 (m, 4H), 6.90 (d, J = 7.9 Hz, 1 H), 6.60 (d, J = 8.4 Hz, 1 H), 2.06 (s, 6H). 106

107

109

110

Scheme II:

G! ₂ (9), DCM- H ₂ O0°C, 1 h pyrsdsrse

The starting materials for the above reaction scheme are commercially available or can be prepared according to methods known to one skilled in the art or by methods disclosed herein. In general, the compounds of the invention are prepared in the above reaction Scheme II as follows: Suzuki cross-coupling of building block A with building block B provides intermediate C. Separately, building block D1 is converted into intermediate D2 which is subsequently converted into building block D. Intermediate C and building block D are combined to form intermediate E. Intermediate E can then be converted into F with an appropriate building block amine of the subtype NHR ⁶ R ⁷ to give target compound F.

Alternatively, intermediate E can be combined with the appropriate building block alcohol R ⁸ OH in the presence of a strong base to yield target compound G. The combination of various building blocks and intermediates can then be applied to yield compounds 102-327 of formula (I). Intermediate (2) :

(3)

Step 1. Synthesis of 4-(benzylthio)-2-fluoropyridine

The stirred solution of 4-bromo-2-fluoropyridine (10.0 g, 56.82 mmol), phenylmethanethiol (7.3 ml_, 62.50 mmol), Pd ₂ (dba) ₃ (2.60 g, 2.84 mmol), Xanthophos (3.28 g, 5.68 mmol) and DIPEA (1 9.4 ml_, 1 13.64 mmol) in dioxane (1 50 ml_) was degassed with argon for 15 min. The resulting reaction mixture was heated to reflux for 16 h under argon atmosphere. The reaction mixture was cooled to rt, filtered through celite bed, the celite bed was washed with EtOAc and the combined filtrate was concentrated to dryness under reduced pressure. The crude was purified by flash column chromatography (40 g SiliCycle column , 2-3% EtOAc in Hexane elution) to provide the title compound as yellow oil (12.0 g , 96.3%). LC/MS, ESI- MS( ⁺ ): 219.5. ¹ H NMR (400 MHz, CDCI ₃ ) δ ppm 7.99 (d , J= 5.2 Hz, 1 H), 7.43 - 7.30 (m, 5H), 7.00 - 6.98 (m, 1 H), 6.74 - 6.73 (m, 1 H).

Step 2. Synthesis of 2-fluoropyridine-4-sulfonyl chloride

To a two-necked round bottom flask containing 4-(benzylthio)-2-fluoropyridine (7.0 g, 31 .92 mmol) was added DCM (160 ml_) and water (40 ml_) at rt. The content was then cool to 0 ° C with an ice bath. Chlorine gas (generated from KMn0 ₄ -con HCI) was purged for 15 min and the reaction mixture was stirred at 0°C for additional 15 min. After completion of the reaction, N ₂ was purged for 20 min , reaction mixture was diluted with water (50 ml_). The organ ic portion was extracted with DCM thrice. The combined organic portion was washed with brine solution , dried over anhydrous Na ₂ S0 ₄ and concentrated in vacuo (at 40°C) to yield a crude oil. The crude was purified by flash column chromatography (40 g SiliCycle column, 2-1 0% EtOAc in Hexane elution) to afforded Intermediate (3): as as pale yellow oil (5.0 g , 80%). ¹ H NMR (300 MHz, CDCI ₃ ) δ ppm 8.62 (d, J= 5.4 Hz, 1 H), 7.80 (dt, J= 5.1 , 1 .5 Hz, 1 H), 7.56 - 7.54 (m, 1 H). Intermediate (6):

Route 1 :

(6)

Step 1. Synthesis of 2-chloro-3-(trifluoromethyl)pyridine 1 -oxide

The title compound was prepared analogous to the literature procedure (US2008/0275057). To a stirred solution of 2-chloro-3-(trifluoromethyl)pyridine (75.0 g, 413.13 mmol) in DCM (750 mL) was added UHP (79.7 g, 846.92 mmol). The solution was cooled to 0 °C with ice-bath and TFAA (1 14.0 mL, 913.02 mmol) was added dropwise. After completion of addition, reaction mixture was stirred at rt for 16 h. Then the reaction mixture was diluted with ice-water and neutralized with Na ₂ C0 ₃ , organic portion was separated and the aqueous portion was extracted with DCM twice. The combined organic portion was washed with brine solution, dried over anhydrous Na ₂ S0 ₄ and concentrated. The crude mass was triturated with 5% DCM in hexane, solid separated was collected by filtration and dried under vacuum to afford the product as a white solid (76.3 g, 93.5%). LC/MS, ESI-MS( ⁺ ): 197.9. ¹ H NMR (400 MHz, CDCI ₃ ) δ ppm 8.72 (dd, J= 6.8, 1 .2 Hz, 1 H), 7.80 (d, J= 8.4 Hz, 1 H), 7.60 (t, J= 7.2 Hz, 1 H). Step 2. Synthesis of 2-(o-tolyl)-3-(trifluoromethyl)pyridine 1 -oxide

The title compound was prepared analogous to the literature procedure (US2008/0275057). A solution of 2-chloro-3-(trifluoromethyl)pyridine 1 -oxide (30.0 g, 151 .87 mmol) in toluene (450 mL) and water (300 mL) was added o-tolylboronic acid (20.7 g, 151 .87 mmol), Na ₂ C0 ₃ (62.8 g, 597.61 mmol) and stirred under N ₂ for 10 min. Then Pd(PPh ₃ ) ₄ (8.8 g, 7.61 mmol) was added and the reaction mixture was stirred under reflux in a N ₂ atmosphere for 16 h. Reaction mixture was cooled to rt, diluted with EtOAc-water, organic portion was separated and the aqueous portion was extracted with EtOAc twice. Combined organic portion was washed with brine solution, dried over an hydrous Na ₂ S0 ₄ and concentrated. The crude mass was crystallized from EtOAc-Hexane to afford 27 g (70%) product as an off white solid. LC/MS, ESI-MS( ⁺ ): 254.05..

Step 3. Synthesis of 6-chloro-2-(o-tolyl)-3-(trifluoromethyl)pyridine A solution of 2-(o-tolyl)-3-(trifluoromethyl)pyridine 1 -oxide (8.25 g, 41 .76 mmol) in POCI ₃ (70 ml_) was heated at 100°C for 16 h. Then the reaction mixture was cooled, and concentrated under reduced pressure. The residue was poured into ice-water and extracted with EtOAc thrice. The combined organic portion was washed with sat. NaHC0 ₃ , dried over Na ₂ S0 ₄ and concentrated to afford a crude oil. The crude mass was purified by flash column chromatography (40 g RediSep Column, Hexane elution) to afford the title compound as colorless oil (4.9 g, 62%). LC/MS, ESI-MS( ⁺ ): 272.2. ¹ H NMR (400 MHz, CDCI ₃ ) δ ppm 8.04 (d, J= 8.4 Hz, 1 H), 7.47 (d, J= 8.0 Hz, 1 H), 7.34 (td, J= 8.0, 1 .6 Hz, 1 H), 7.28 - 7.22 (m, 2H), 7.16 (d, J= 7.6 Hz, 1 H). Step 4. Synthesis of 6-(o-tolyl)-5-(trifluoromethyl)pyridin-2-amine

To a solution of 6-chloro-2-(o-tolyl)-3-(trifluoromethyl)pyridine (4.9 g, 18.04 mmol) in DMSO (10 ml_) was added NH ₄ OAc (7.0 g, 90.2 mmol), the reaction vessel was closed and heated at 130°C for 18 h. After completion, cooled reaction mixture was partitioned between ice-water and EtOAc. Separated organic portion was washed with brine solution, dried over Na ₂ S0 ₄ and concentrated under reduced pressure to give crude residue. The crude mass was purified by flash column chromatography (12 g RediSep Column, 20% EtOAc in Hexane elution) to afford the product as a white solid (3.3 g, 72%). LC/MS, ESI-MS( ⁺ ): 253.2. ¹ H NMR (300 MHz, CDCI ₃ ) δ ppm 7.75 (d, J= 8.4 Hz, 1 H), 7.33 - 7.16 (m, 4H), 6.48 (d, J= 9.0 Hz, 1 H).

Step 5. Synthesis of 6-fluoro-N-(6-(o-tolyl)-5-(trifluoromethyl)pyridin-2-yl)pyri dine-2- sulfonamide

The solution of 6-(o-tolyl)-5-(trifluoromethyl)pyridin-2-amine (5.3 g, 21 .01 mmol) in pyridine (15 ml_) was cooled to 0°C and 6-fluoropyridine-2-sulfonyl chloride (5.75 g, 29.42 mmol) was added dropwise. Reaction mixture was stirred at rt. After 2 h, reaction was quenched with water and extracted with EtOAc thrice. The combined organic portion was washed with brine, dried over Na ₂ S0 ₄ and concentrated to afford an oily residue, which was purified by combi flash using 40 g RediSep column (30-35% EtOAc in Hexane) to yield Intermediate (6): as a white solid (6.9 g, 79%). LC/MS, ESI-MS( ⁺ ): 41 1 .9. ¹ H NMR (300 MHz, CD ₃ OD) δ ppm 8.08 (d, J= 8.7 Hz, 1 H), 8.01 - 7.94 (m, 1 H), 7.86 (dd, J= 7.2, 1 .5 Hz, 1 H), 7.35 - 7.30 (m, 2H), 7.27 - 7.17 (m, 4H), 7.01 (d, J= 7.2 Hz, 1 H), 1 .89 (s, 3H). Intermediate (6):

Route 2:

Route 2; Step 1. Synthesis of 6-fluoropyridine-2-sulfonamide

To a solution of 6-fluoropyridine-2-sulfonyl chloride (2.0875 g, 10.67 mmol) was dissolved in MeCN (50 mL) cooled to 0°C, concentrated aqueous ammonium hydroxide (70 mL, 539 mmol) was added dropwise. The resulting reaction mixture was stirred at 0°C for 30 minutes, then warmed to room temperature and allowed to stir at room temperature for 2 hours. The solution was concentrated by vacuum to remove some of the acetonitrile and dried by lyophilization to yield the desired product as a dark gray solid (95% yield). LC/MS, ESI-MS ): 177.0. ¹ H NMR (400 MHz, DMSO-d6) δ 8.26 (q, J = 7.9 Hz, 1H), 7.88 (ddd, J = 7.5, 2.3, 0.6 Hz, 1H), 7.63 (s, 2H), 7.48 (ddd, J = 8.3, 2.4, 0.6 Hz, 1H).

Synthesis of 6-fluoropyridine-2-sulfonamide Alternate route:

Step 1. Synthesis of 2-(benzylthio)-6-fluoropyridine

To a two-necked round bottom flask containing anhydrous tetrahydrofuran (500 ml) cooled at 0°C was added sodium hydride (60% suspension in oil) (19.2 g, 477.93 mmol) in portions. A solution of phenylmethanethiol (51.0 mL, 434.48 mmol) in tetrahydrofuran (100 mL) was added dropwise via an additional funnel and stirred at 0°C. After 30 min, 2,6-difluoropyridine (50 g, 434.48 mmol) in tetrahydrofuran (100 mL) was added dropwise via additional funnel maintaining the reaction temperature at 0°C. The reaction mixture was stirred at rt for 16h. Then cooled to 0°C, quenched with ice-water and extracted with EtOAc thrice. The combined organic portion was washed with brine solution, dried over anhydrous Na ₂ S0 ₄ and concentrated to afford a crude oil. The crude residue was purified by column chromatography on silica gel (60-120 mesh size) (0- 3% EtOAc in Hexane) to yield the title compound as ye llowish viscous oil (88 g, 92%). LC/MS, ESI-MSQ: 2 1 8 . 0 . ¹ H NMR (400 MHz, CDCI ₃ ) d ppm 7.61 - 7.55 (m, 1 H), 7.45 - 7.43 (m, 2H), 7.35 - 7.31 (m, 2H), 7.29 - 7.25 (m, 1 H), 7.24 (dt, J= 7.6, 1 .2 Hz, 1 H), 7.62 (dt, J= 8.0, 1 .2 Hz, 1 H), 4.43 (s, 2H).

Step 2. Synthesis of 6-fluoropyridine-2-sulfonyl chloride

A mixture of 2-(benzylthio)-6-fluoropyridine (60 g, 273.62 mmol) in DCM (2000 mL) and water (400 mL) was cooled to 0°C with an ice-water bath. Chlorine gas (generated from KMnCvconc HCI) was purged into the reaction mixture for 1 h and 15 min at 0°C . After reaction completion, N ₂ was purged into the reaction mixture for 20 min. The reaction mixture was then diluted with water (1000 mL). The organic portion was extracted with DCM thrice. The combined organic portion was washed with brine solution, dried over anhydrous Na ₂ S0 ₄ and concentrated in vacuo at 40°C to afford a crude oil. The crude was purified by Si-gel (60-120 mesh size) colum chromatography (10-15% EtOAc in Hexane) to afford the desired product as yellowish viscous oil (51 g, 95%). ¹ H NMR (400 MHz, CDCI ₃ ) d ppm 8.23 - 8.15 (m, 1 H), 8.04 - 8.01 (m, 1 H), 7.39 - 7.36 (m, 1 H). Step 3. Synthesis of 6-fluoropyridine-2-sulfonamide

A solution of 6-fluoropyridine-2-sulfonyl chloride (3g, 15.34 mmol) in DCM (50 mL) was cooled to 0 °C with an ice-water bath. Ammonia gas was purged into the reaction mixture for 10 min and then the reaction mixture was stirred at rt for 1 h. The reaction mixture was filtered through a pad of Celite to remove the solid, and the filtrate was concentrated in vacuo to yield the crude product, which was triturated with hexane, filtered and dried in vacuo to obtain the product as an off white solid (2.6 g, 87%). LCMS: m/z 174.90 [M+H] ⁺ . ¹ H NMR (300 MHz, DMSO-d6) d ppm 8.30 - 8.22 (m, 1 H), 7.88 (dd, J= 7.5, 2.1 Hz, 1 H), 7.67 (brs, 2H), 7.48 (dd, J= 8.1 , 2.1 Hz, 1 H).

Route 2. Step 2: Synthesis of 6-fluoro-N-(6-(o-tolyl)-5-(trifluoromethyl)pyridin-2- yl)pyridine-2-sulfonamide

To a suspension of 6-chloro-2-(o-tolyl)-3-(trifluoromethyl)pyridine (800 mg, 2.94 mmol), 6- fluoropyridine-2-sulfonamide (778 mg, 4.42 mmol), and cesium carbonate (1439 mg, 4.42 mmol) in Dioxane (30 mL), fBuXPhos palladacycle G3 (234 mg, 0.294 mmol) was added. The reaction mixture was purged with nitrogen and then was stirred at 80°C for 3h. The reaction was diluted with DCM, then was washed twice with saturated aqueous ammonium chloride solution followed by brine, dried over magnesium sulfate, concentrated in vacuo. The crude product was purified by an ISCO silica gel chromatography [40g RediSep column, eluted with 100% heptane to 50% EtOAc/heptane to 100% EtOAc] to yield Intermediate (6): as a creamy pale yellow solid (828 mg, 68%). LCMS: m/z 412.0 [M+H] ⁺ . Intermediate (7):

Step 1. Synthesis of 2-(5-fluoro-2-methylphenyl)-3-(trifluoromethyl)pyridine 1 -oxide

The title compound was prepared analogous to the literature procedure (US2008/0275057). A solution of 2-chloro-3-(trifluoromethyl)pyridine 1 -oxide (15.0 g, 75.93 mmol) in toluene (210 ml_) and water (114 ml_) was added (5-fluoro-2-methylphenyl)boronic acid (1 1 .7 g, 75.93 mmol), Na ₂ C0 ₃ (24.2 g, 227.80 mmol) and stirred under N ₂ for 10 min. Then Pd(PPh ₃ ) ₄ (4.4 g, 3.80 mmol) was added and the reaction mixture was stirred under reflux in a N ₂ atmosphere for 16 h. Reaction mixture was cooled to rt, diluted with EtOAc-water, organic portion was separated and the aqueous portion was extracted with EtOAc twice. Combined organic portion was washed with brine solution, dried over anhydrous Na ₂ S0 ₄ and concentrated. The crude mass was purified by flash column chromatography (40 g SiliCycle column, 60-70% EtOAc in Hexane elution) to afford 19.51 g (94%) of product as a white solid. LC/MS, ESI-MS( ⁺ ): 272.2.

Step 2. Synthesis of 6-chloro-2-(5-fluoro-2-methylphenyl)-3-(trifluoromethyl)pyri dine A solution of 2-(5-fluoro-2-methylphenyl)-3-(trifluoromethyl)pyridine 1 -oxide (19.5 g, 71.90 mmol) in POCI ₃ (130 ml_) was heated at 90°C for 18 h. Then the reaction mixture was cooled, and concentrated under reduced pressure. The residue was poured into ice-water and extracted with EtOAc thrice. The combined organic portion was washed with sat. NaHC0 ₃ , dried over Na ₂ S0 ₄ and concentrated to afford a crude oil. The crude mass was purified by flash chromatography (40 g RediSep column, Hexane elution) to afford the title compound as colorless oil (1 1 .0 g, 52.8%). LC/MS, ESI-MS( ⁺ ): 289.95. ¹ H NMR (400 MHz, CDCI ₃ ) δ ppm 8.05 (d, J= 8.4 Hz, 1 H), 7.50 (d, J= 8.4 Hz, 1 H), 7.42 - 7.21 (m, 1 H), 7.07 - 7.01 (m, 1 H), 6.91 (dd, J= 8.4, 2.0 Hz, 1 H).

Step 3. Synthesis of 6-(5-fluoro-2-methylphenyl)-5-(trifluoromethyl)pyridin-2-ami ne To a stirred solution of 6-chloro-2-(5-fluoro-2-methylphenyl)-3-(trifluoromethyl)pyri dine (9.0 g, 31 .07 mmol) in dioxane (100 ml_) was added aq. NH ₃ (150 ml_, 30%), the reaction vessel was closed and heated at 100°C for 16 h. Reaction mixture was cooled to rt and extracted with EtOAc thrice. The combined organic portion was dried over Na ₂ S0 ₄ and concentrated under reduced pressure to give crude residue. The residue was purified by flash column chromatography (40 g SiliCycle column, 30-35% EtOAc in Hexane elution) to yield 2.0 g (66%, based on starting material conversion; 6.0 g starting material recovered) product as a white solid. LC/MS, ESI-MS( ⁺ ): 271 .0.

Step 4. Synthesis of 6-fluoro-N-(6-(5-fluoro-2-methylphenyl)-5-(trifluoromethyl)p yridin- 2-yl)pyridine-2 -sulfonamide

The solution of 6-(5-fluoro-2-methylphenyl)-5-(trifluoromethyl)pyridin-2-ami ne (2.0 g, 7.40 mmol) in pyridine (5 ml_) was cooled to 0°C and 6-fluoropyridine-2-sulfonyl chloride (2.03 g, 10.36 mmol) was added dropwise. Reaction mixture was allowed to stir at rt for 2 h. Then the reaction was quenched with water and extracted with EtOAc thrice. The combined organic portion was washed with brine, dried over Na ₂ S0 ₄ and concentrated to afford an oily residue, which was purified by flash column chromatography (24 g SiliCycle column, 30-35% EtOAc in Hexane elution) to provide Intermediate (7): as an off white solid (1 .95 g, 61 %). LC/MS, ESI- MS( ⁺ ): 429.0. ¹ H NMR (300 MHz, CD ₃ OD) δ ppm 8.08 (d, J= 8.7 Hz, 1 H), 8.04 - 7.96 (m, 1 H), 7.86 (dd, J= 7.5, 2.1 Hz, 1 H), 7.29 - 7.20 (m, 3H), 7.08 - 7.02 (m, 1 H), 7.75 (d, J= 8.7 Hz, 1 H), 1 .82 (s, 3H). Intermediate (8):

(8) Step 1. Synthesis of 2-(3-fluoro-2-methylphenyl)-4,4,5,5-tetramethyl-1 ,3,2- dioxaborolane

A solution of 1 -bromo-3-fluoro-2-methylbenzene (24.0 g, 126.96 mmol) and bis(pinacolato)diboron (38.68 g, 152.35 mmol) and KOAc (37.38 g, 380.89 mmol) in dioxane was stirred under N ₂ for 10 min. Then Pd(dppf)CI ₂ .DCM (5.18 g, 6.35 mmol) and 1 ,1 '- bis(diphenylphosphino)ferrocene (2.1 1 g, 3.808 mmol) were added and the reaction mixture was stirred at 90°C for 16 h. After cooling to rt, the reaction mixture was diluted with water and extracted with EtOAc thrice. The combined organic portion was washed with water followed by brine solution, then dried over Na ₂ S0 ₄ and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (60-120 mesh size) (1 -5% EtOAc in Hexane) to afford the title compound as a colorless oil (28 g, 93%). ¹ H NMR (300 MHz, CD ₃ OD) δ ppm 7.52 (dd, J= 6.9, 1 .2 Hz, 1 H), 7.17 - 7.03 (m, 2H), 1 .35 (s, 12 H).

Step 2. Synthesis of 2-(3-fluoro-2-methylphenyl)-3-(trifluoromethyl)pyridine

A solution of 2-bromo-3-(trifluoromethyl)pyridine (16.0 g, 70.79 mmol), 2-(3-fluoro-2- methylphenyl)-4,4,5,5-tetramethyl-1 ,3,2-dioxaborolane (20.0 g, 84.95 mmol) and K ₃ P0 ₄ (30.0 g, 141 .59 mmol) in dioxane-water (240 mL : 60 mL) stirred under argon for 15 min. Then Pd(PPh ₃ ) ₄ (8.18 g, 7.08 mmol) was added, degassed and stirred at 100°C for 16 h. Then the reaction mixture was cooled to rt, diluted with water and extracted with EtOAc twice. Combined organic portion was washed with brine solution, dried over anhydrous Na ₂ S0 ₄ and concentrated. The residue was purified by flash column chromatography (40 g SiliCycle column, 5-7% EtOAc in Hexane elution) to yield the title compound as a pale yellow oil (14.5 g, 80%). LC/MS, ESI-MS( ⁺ ): 256.05.

Step 3. Synthesis of 2-(3-fluoro-2-methylphenyl)-3-(trifluoromethyl)pyridine 1 -oxide

To a stirred solution of 2-(3-fluoro-2-methylphenyl)-3-(trifluoromethyl)pyridine (14.5 g, 56.81 mmol) in DCM (150 mL) was added UHP (10.95 g, 1 16.40 mmol). The solution was cooled to 0°C with ice-bath and TFAA (15.7 mL, 125.76 mmol) was added dropwise. After completion of addition, reaction mixture was stirred at rt for 24 h. Then the reaction mixture was diluted with ice-water and neutralized with Na ₂ C0 ₃ , organic layer was separated and the aqueous portion was extracted with DCM twice. The combined organic portion was washed with brine solution, dried over anhydrous Na ₂ S0 ₄ and concentrated. The crude mass was stirred with hexane for 15 min, the solid separated was collected by filtration and dried in vacuo to afford the product as a pale yellow solid (13.2 g, 85.7%). LC/MS, ESI-MS( ⁺ ): 272.05. ¹ H NMR (300 MHz, CDCI ₃ ) δ ppm 8.49 (d, J= 6.6 Hz, 1 H), 7.64 (d, J= 8.4 Hz, 1 H), 7.45 (t, J= 7.2 Hz, 1 H), 7.32 - 7.25 (m, 1 H), 7.17 (d, J= 8.4 Hz, 1 H), 6.95 (d, J= 7.5 Hz, 1 H), 2.03 (s, 3H). Step 4. Synthesis of 6-chloro-2-(3-fluoro-2-methylphenyl)-3-(trifluoromethyl)pyri dine

A solution of 2-(3-fluoro-2-methylphenyl)-3-(trifluoromethyl)pyridine 1 -oxide (14.0 g, 51.62 mmol) in POCI ₃ (100 ml_) was heated at 100°C for 16 h. Then the reaction mixture was cooled, and concentrated under reduced pressure. The residue was poured into ice-water and extracted with EtOAc thrice. The combined organic portion was washed with sat. NaHC0 ₃ , dried over Na ₂ S0 ₄ and concentrated to afford a crude oil. The crude mass was purified by flash column chromatography (40 g RediSep column, Hexane elution) to provide the title compound as colorless oil (10.5 g, 70%). LC/MS, ESI-MS( ⁺ ): 290.0. ¹ H NMR (400 MHz, CDCI ₃ ) δ ppm 8.05 (d, J= 8.4 Hz, 1 H), 7.50 (d, J= 8.4, 1 H), 7.24 - 7.20 (m, 1 H), 7.1 1 (t, J= 8.8 Hz, 1 H), 6.97 (d, J= 8.0 Hz, 1 H), 1 .99 (s, 3H).

Step 5. Synthesis of 6-(3-fluoro-2-methylphenyl)-5-(trifluoromethyl)pyridin-2-ami ne

To a stirred solution of 6-chloro-2-(3-fluoro-2-methylphenyl)-3-(trifluoromethyl)pyri dine (4.3 g, 14.84 mmol) in dioxane (200 ml_) was added aq. NH ₃ (200 ml_, 30%), the reaction vessel was closed and heated at 100°C for 16 h. Reaction mixture was cooled to rt and extracted with EtOAc thrice. The combined organic portion dried over Na ₂ S0 ₄ and concentrated under reduced pressure to give crude residue. The residue was purified by flash column chromatography (40 g RediSep column, 10-50% EtOAC in Hexane elution) to afford 1 .85 g (94%, based on starting material conversion; 2.2 g starting material recovered) product as a pale yellow solid. LC/MS, ESI-MS( ⁺ ): 271 .2. Step 6. Synthesis of 6-fluoro-N-(6-(3-fluoro-2-methylphenyl)-5-(trifluoromethyl)p yridin- 2-yl)pyridine-2 -sulfonamide

The solution of 6-(3-fluoro-2-methylphenyl)-5-(trifluoromethyl)pyridin-2-ami ne (1 .9 g, 7.03 mmol) in pyridine (15 ml_) was cooled to 0°C and 6-fluoropyridine-2-sulfonyl chloride (1 .92 g, 9.84 mmol) was added dropwise. Reaction mixture was allowed to stir at rt for 16 h. Then the reaction was quenched with water and extracted with DCM thrice. The combined organic portion was washed with brine, dried over Na ₂ S0 ₄ and concentrated to afford an oily residue, which was purified by flash column chromatography (24 g SiliCycle, 25-30% EtOAc in Hexane elution) to afford Intermediate (8): as an off white solid (1 .99 g, 65.9%). LC/MS, ESI-MS( ⁺ ): 430.2. ¹ H NMR (400 MHz, CDCI ₃ ) δ ppm 8.03 - 7.49 (m, 3H), 7.44 (d, J= 8.8 Hz, 1 H), 7.24 - 7.21 (m, 1 H), 7.16 - 7.12 (m, 1 H), 6.99 (d, J= 7.6 Hz, 1 H), 2.00 (s, 3H).

Intermediate (9):

(9)

Step 1. Synthesis of 6-bromo-5-chloropyridin-2-amine

The title compound was prepared analogous to the literature procedure (WO2015/97122). A solution of 6-bromopyridin-2-amine (20.0 g, 1 15.60 mmol) and N-chlorosuccinimide (15.43 g, 115.60 mmol) in acetonitrile (250 mL) was heated at 80°C for 16 h. Reaction mixture was cooled, concentrated under reduced pressure. The residue was diluted with sat. NaHC0 ₃ solution (100 mL) and extracted with EtOAc thrice. The combined organic portion was washed with brine, dried over anhydrous Na ₂ S0 ₄ , and concentrated under reduce pressure. The crude product mass was stirred with hexane, the solid separated was collected by filtration and dried in vacuo to yield the title compound as an off white solid (16.0 g, 61 %). LC/MS, ESI-MS( ⁺ ): 210.9.

Step 2. Synthesis of 5-chloro-6-(5-fluoro-2-methylphenyl)pyridin-2-amine

To a stirred solution of 6-bromo-5-chloropyridin-2-amine (7.5 g, 36.15 mmol) in dioxane (120 mL) were added (5-fluoro-2-methylphenyl)boronic acid (6.7 g, 43.38 mmol) and 2M K ₃ P0 ₄ solution (55 mL) under N ₂ . Then Pd(PPh ₃ ) ₄ (4.2 g, 3.62 mmol) was added, degassed and the reaction mixture was stirred at 100°C for 16 h. The reaction mixture was cooled to rt, filtered through a celite bed, which was thoroughly washed with EtOAc. The organic portion was separated and washed with 10% HCI solution thrice. The combined (acidic) aqueous portion was basified with saturated NaHC0 ₃ solution and extracted with EtOAC thrice. The combined EtOAc extract was washed with brine solution, dried over anhydrous Na ₂ S0 ₄ and

concentrated. The residue was stirred with hexane, filtered and solid collected was dried in vacuo to yield 7.2 g (84%) product as an off white solid. LC/MS, ESI-MSf): 237.0. ¹ H NMR (300 MHz, CDCI ₃ ) δ ppm 7.50 (d, J= 8.7 Hz, 1 H), 7.24 - 7.19 (m, 1 H), 7.03 - 6.94 (m, 2H), 6.49 (d, J= 8.7 Hz, 1 H), 4.55 (brs, 2H), 2.15 (s, 3H). Step 3. Synthesis of N-(5-chloro-6-(5-fluoro-2-methylphenyl)pyridin-2-yl)-6- fluoropyridine-2 -sulfonamide

The solution of 5-chloro-6-(5-fluoro-2-methylphenyl)pyridin-2-amine (5.0 g, 21.12 mmol) in pyridine (10 ml_) was cooled to 0°C and 6-fluoropyridine-2-sulfonyl chloride (4.95 g, 25.35 mmol) was added dropwise. Reaction mixture was allowed to stir at rt for 16 h. The reaction was quenched with ice and stirred for 2 h. the solid separated was filtered, washed with water and hexane. And then dried in vacuo to yield Intermediate (9): as a pale brown solid (5.5 g, 65.8%). LC/MS, ESI-MS( ⁺ ): 396.0. ¹ H NMR (400 MHz, CD ₃ OD) δ ppm 8.06 - 8.00 (m, 1 H), 7.89 (dd, J= 7.6, 2.4 Hz, 1 H), 7.82 (d, J= 8.8 Hz, 1 H), 7.28 - 7.20 (m, 3H), 7.03 (td, J= 8.8, 3.2 Hz, 1 H), 6.72 (dd, J= 9.2, 2.8 Hz, 1 H), 1 .92 (s, 3H).

Intermediate (10):

To a stirred solution of 6-bromo-5-chloropyridin-2-amine (5.0 g, 24.10 mmol) in dioxane (60 ml_) were added (2,6-dimethylphenyl)boronic acid (5.42 g, 36.15 mmol) and 2M K ₃ P0 ₄ solution (36.3 ml_) under N ₂ . Then Pd(PPh ₃ ) ₄ (2.8 g, 2.41 mmol) was added, degassed and the reaction mixture was stirred at 100°C for 16 h. Then the reaction mixture was cooled to rt, diluted with water and extracted with EtOAc twice. Combined organic portion was washed with brine solution, dried over anhydrous Na ₂ S0 ₄ and concentrated. The residue was purified by flash column chromatography (12 g SiliCycle column, 14% EtOAc in Hexane elution) to afford Intermediate (10): as an off white solid. LC/MS, ESI-MS ( ⁺ ): 233.2. ¹ H NMR (300 MHz, CDCI ₃ ) δ ppm 7.52 (d, J= 8.4 Hz, 1 H), 7.21 - 7.17 (m, 1 H), 7.10 - 7.08 (m, 2H), 6.47 (d, J= 8.7 Hz, 1 H), 4.54 (brs, 2H), 2.06 (s, 3H)

Intermediate (11 ): 6-fluoro-N-(6-(2-isopropylphenyl)-5-(trifluoromethyl)pyridin -2- yl)pyridine-2-sulfonamide

Step 1. Synthesis of 6-(2-isopropylphenyl)-5-(trifluoromethyl)pyridin-2-amine

In a vial, 6-chloro-5-(trifluoromethyl)pyridin-2-amine (2.0 g, 10.18 mmol), (2- isopropylphenyl)boronic acid (2.003 g, 12.21 mmol), sodium carbonate (3.24 g, 30.5 mmol), and Pd(Ph ₃ P) ₄ (1 .176 g, 1 .018 mmol) were taken up in dioxane (Volume: 20 mL, Ratio: 6.67) and water (Volume: 3 mL, Ratio: 1 .000), the mixture was sparged with argon, then the reaction was heated to 120 °C for 3 d. The crude reaction material was evaporated on silica gel and purified by flash column chromatography (ISCO, 80 g silica gel column, 0-6% MeOH/DCM, dry loading) to give the product 6-(2-isopropylphenyl)-5-(trifluoromethyl)pyridin- 2-amine (2.6102 g, 9.31 mmol, 92% yield) as a light yellow solid.

Step 2. Synthesis of 6-fluoro-N-(6-(2-isopropylphenyl)-5-(trifluoromethyl)pyridin -2- yl)pyridine-2-sulfonamide

In a flask, 6-(2-isopropylphenyl)-5-(trifluoromethyl)pyridin-2-amine (2.61 g, 9.31 mmol) was taken up in THF (Volume: 100 mL) and the solution was cooled to 0 °C. To the solution was added 1 .0 M LHMDS in THF (18.62 mL, 18.62 mmol), then a solution of 6-fluoropyridine-2- sulfonyl chloride (3.64 g, 18.62 mmol) that had been dissolved in THF (5 mL). After stirring overnight the reaction was quenched with 1 M HCI and extracted into EtOAc (25 mL x 3). The organics were then washed with water and brine, dried over MgS0 ₄ , and concentrated in vacuo. The crude material was purified by flash column chromatography (ISCO, 220 g silica gel column, 0-80% EtOAc/heptanes) to give the title product Intermediate (11 ): 6-fluoro-N- (6-(2-isopropylphenyl)-5-(trifluoromethyl)pyridin-2-yl)pyrid ine-2-sulfonamide (3.3088 g, 7.53 mmol, 81 % yield) as a light tan solid. LC/MS, ESI-MS( ⁺ ): 440.1 , RT: 1 .84 min. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 12.12 (s, 1 H), 8.19 (d, J = 8.9 Hz, 1 H), 8.10 (q, J = 7.8 Hz, 1 H), 7.83 (dd, J = 7.4, 2.1 Hz, 1 H), 7.48 (ddd, J = 8.3, 2.4, 0.7 Hz, 1 H), 7.43 - 7.34 (m, 2H), 7.29 (s, 1 H), 7.17 (ddd, J = 7.6, 6.7, 1 .8 Hz, 1 H), 6.89 (d, J = 7.6 Hz, 1 H), 2.34 - 2.27 (m, 1 H), 1 .01 (d, J = 6.8 Hz, 3H), 0.91 (d, J = 6.8 Hz, 3H).

Intermediate (12): rac-ethyl (1SR,3SR,4RS)-3-(((benzyloxy)carbonyl)amino)-7- oxabicyclo[2.2.1]heptane-1 -carboxylate

(12)

Step 1. Synthesis of rac-3-(tert-butyl) 1 -ethyl (1 RS,3SR,4RS)-7-oxabicyclo[2.2.1]hept-5- ene-1 ,3-dicarboxylate

A solution of ethyl 2-furoate (12 g, 86 mmol), tert-butyl acrylate (62.1 ml_, 428 mmol) and 4,4'-dimethoxybenzophenone (2.075 g, 8.56 mmol) in acetonitrile (428 ml_) was passed through a flow photoreactor (reactor volume 0.9 ml_; PFA tubing 0.04" ID, 0.0625" ID;

irradiated area 20 cm ² ; 365 nm LED; 1 1 W radiant flux) equipped with 8-bar back pressure regulator at a rate of 0.4 ml_ per minute (Vapourtec R-Series pump). The solvent was then removed and the material was purified by flash column chromatography (ISCO, 220 g silica gel column, 0-60% EtOAc/hexanes) to afford rac-3-(tert-butyl) 1 -ethyl (1 RS,3SR,4RS)-7- oxabicyclo[2.2.1 ]hept-5-ene-1 ,3-dicarboxylate (7.05 g, 21 .02 mmol, 25 % yield),

contaminated with a small amount of sensitizer. LC/MS, ESI-MS(M+Na ⁺ ): 291 .2 observed. ¹ H NMR (400 MHz, Chloroform-d) δ 6.48 (d, J = 5.6 Hz, 1 H), 6.45 (dd, J = 5.7, 1 .7 Hz, 1 H), 5.23 (d, J = 1 .7 Hz, 1 H), 4.33 (q, J = 7.3 Hz, 2H), 2.47 (dd, J = 8.5, 4.0 Hz, 1 H), 2.29 (dd, J = 1 1 .5, 4.0 Hz, 1 H), 1 .88 (dd, J = 1 1 .5, 8.5 Hz, 1 H), 1 .47 (s, 9H), 1 .35 (t, J = 7.1 Hz, 3H). ¹³ C NMR (101 MHz, CDCI3) δ 171 .5, 169.5, 136.6, 135.6, 87.0, 82.1 , 81 .2, 61 .7, 45.5, 32.8, 28.1 , 14.2.

Step 2. Synthesis of rac-3-(tert-butyl) 1 -ethyl (1SR,3SR,4RS)-7- oxabicyclo[2.2.1]heptane-1 ,3-dicarboxylate

A solution of rac-3-(tert-butyl) 1 -ethyl (1 RS,3SR,4RS)-7-oxabicyclo[2.2.1 ]hept-5-ene-1 ,3- dicarboxylate (7.05 g, 26.3 mmol) in methanol (10 ml_) was added to a vial containing palladium on carbon, 10% (0.125 g, 0.1 18 mmol). The atmosphere in the vial was exchanged for hydrogen and the reaction was stirred under hydrogen overnight. The atmosphere was then exchanged for nitrogen and the catalyst was removed by filtration. The solvent was removed, and the residue was purified by flash column chromatography to afford rac-3-(tert- butyl) 1 -ethyl (1 SR,3SR,4RS)-7-oxabicyclo[2.2.1 ]heptane-1 ,3-dicarboxylate (5.84 g, 20.52 mmol, 78% yield). Step 3. Synthesis of rac-(1 RS,2SR,4SR)-4-(ethoxycarbonyl)-7- oxabicyclo[2.2.1]heptane-2-carboxylic acid

A sample of rac-3-(tert-butyl) 1 -ethyl (1 SR,3SR,4RS)-7-oxabicyclo[2.2.1 ]heptane-1 ,3- dicarboxylate (2.82 g, 8.35 mmol) was treated with trifluoroacetic acid (10 mL, 130 mmol) and aged for 2 hours. The solvent was then removed and the residue was co-evaporated with toluene 3 times to afford rac-(1 RS,2SR,4SR)-4-(ethoxycarbonyl)-7- oxabicyclo[2.2.1 ]heptane-2-carboxylic acid (2.1 g, 9.80 mmol, quantitative yield). LC/MS, ESI- MS( ⁺ ): 215.1 observed. ¹ H NMR (400 MHz, Chloroform-d) δ 5.01 (d, J = 4.9 Hz, 1 H), 4.31 (qd, J = 7.2, 3.1 Hz, 2H), 2.84 (dd, J = 9.1 , 4.9 Hz, 1 H), 2.42 - 2.34 (m, 2H), 2.18 (dd, J = 12.6, 9.1 Hz, 1 H), 2.09 - 1 .89 (m, 3H), 1 .77 - 1 .66 (m, 1 H), 1 .35 (t, J = 7.1 Hz, 3H).

Step 4. Synthesis of rac-ethyl (1SR,3SR,4RS)-3-(((benzyloxy)carbonyl)amino)-7- oxabicyclo[2.2.1]heptane-1 -carboxylate

A solution of rac-(1 RS,2SR,4SR)-4-(ethoxycarbonyl)-7-oxabicyclo[2.2.1 ]heptane-2-carboxylic acid (1 .789 g, 8.35 mmol), DPPA (3.45 g, 12.53 mmol) and triethylamine (3.49 mL, 25.05 mmol) in toluene (15 mL) was heated to 85 °C for 1 hour. The reaction was then treated with the benzyl alcohol (1 .736 mL, 16.70 mmol) and stirred at 85 °C for 4 hours. The reaction was then cooled to room temperature, diluted with ethyl acetate, washed with 1 M aqueous NaOH twice, 1 M aqueous HCI twice, and water once, dried over MgS0 ₄ , filtered, evaporated, and purified by flash column chromatography (ISCO, 80 g silica gel column, 0-60% EtOAc/hexanes) to afford the title compound Intermediate (12): rac-ethyl (1 SR,3SR,4RS)-3- (((benzyloxy)carbonyl)amino)-7-oxabicyclo[2.2.1 ]heptane-1 -carboxylate (1 .67 g, 4.97 mmol, 60 % yield) as a colorless oil that solidified upon standing. LC/MS, ESI-MS( ⁺ ): 320.2 observed. ¹ H NMR (400 MHz, Chloroform-d) δ 7.39 - 7.28 (m, 5H), 5.08 (s, 2H), 4.47 (d, J = 5.0 Hz, 1 H), 4.27 (qd, J = 7.1 , 1 .0 Hz, 2H), 3.99 (td, J = 8.3, 3.1 Hz, 1 H), 2.38 (dd, J = 13.3, 8.0 Hz, 1 H), 1 .85 (dddd, J = 17.9, 8.9, 7.7, 3.8 Hz, 3H), 1 .71 - 1 .58 (m, 3H), 1 .31 (t, J = 7.1 Hz, 3H). ¹³ C NMR (101 MHz, CDCI3) δ 170.87, 155.76, 136.47, 128.66, 128.62, 128.27, 128.13, 128.09, 84.18, 82.75, 66.86, 61 .61 , 55.37, 43.49, 32.94, 26.68, 14.30. Intermediate (13): rac-tert-butyl (1SR,6RS,7SR)-3-oxo-2-azabicyclo[4.2.0]oct-4-ene-7- carboxylate and Intermediate (14): rac-tert-butyl (1SR,5RS,6RS,7SR)-5-allyl-2- azabicyclo[4.2.0]octane-7 -carboxylate T

Step 1. Synthesis of rac-tert-butyl (1SR,6RS,7SR)-3-oxo-2-azabicyclo[4.2.0]oct-4-ene-7- carboxylate

A solution of fe/ -butyl acrylate (51 .3 mL, 350 mmol), 4,4'-dimethoxybenzophenone (0.848 g, 3.50 mmol) and pyridin-2(1 H)-one (3.328 g, 35.0 mmol) in acetonitrile (350 mL) was passed through the flow photoreactor (reactor volume 0.9 mL; PFA tubing 0.04" ID, 0.0625" ID; irradiated area 20 cm ² ; 365 nm LED; 1 1 W radiant flux) equipped with 8-bar back pressure regulator at a rate of 0.50 mL per minute (Vapourtec R-Series pump). The solvent was removed and the resulting residue was purified by flash column chromatography (ISCO, 220 g silica gel column, 0-100% EtOAc/hexanes) to afford Intermediate (13): rac-tert-butyl (1 SR,6RS,7SR)-3-oxo-2-azabicyclo[4.2.0]oct-4-ene-7-carboxylate (2.87 g, 12.21 mmol, 35 % yield). LC/MS, ESI-MS( ⁺ ): 224.2 observed. ¹ NMR (400 MHz, Chloroform-d) δ 6.55 (ddd, J = 10.0, 4.1 , 0.8 Hz, 1 H), 5.91 (dt, J = 10.1 , 1 .4 Hz, 1 H), 4.28 (tt, J = 7.3, 3.8 Hz, 1 H), 3.42 - 3.34 (m, 1 H), 2.94 (dtd, J = 9.5, 5.0, 1 .2 Hz, 1 H), 2.59 - 2.43 (m, 2H), 1 .46 (s, 9H). ¹³ NMR (101 MHz, CDCI ₃ ) δ 173.23, 164.18, 141 .25, 123.35, 81 .39, 46.37, 43.49, 37.25, 34.71 , 28.22, 28.19, 28.15, 28.12.

Step 2. Synthesis of rac-di-tert-butyl (1 SR,6RS,7SR)-3-oxo-2-azabicyclo[4.2.0]oct-4- ene-2,7-dicarboxylate

A solution of Intermediate (13): rac-tert-butyl (1 SR,6RS,7SR)-3-oxo-2-azabicyclo[4.2.0]oct- 4-ene-7-carboxylate (2.00 g, 8.96 mmol), BOC-anhydride (4.16 mL, 17.92 mmol), DMAP (1 .642 g, 13.44 mmol) and TEA (2.497 mL, 17.92 mmol) in dichloromethane (Volume: 10 mL) was stirred at room temperature for 2.5 hours. The reaction was diluted with ethyl acetate and washed with water followed by saturated sodium bicarbonate and brine. The organics were dried over MgS0 ₄ , filtered, evaporated and purified by flash column chromatography (ISCO, 80 g silica gel column, 0-50% EtOAc/toluene) to afford rac-di-tert- butyl (1 SR,6RS,7SR)-3-oxo-2-azabicyclo[4.2.0]oct-4-ene-2,7-dicarboxy late (2.675 g, 8.19 mmol, 91 % yield) as a colorless oil that solidified upon standing under vacuum overnight. LC/MS, ESI-MS(M-tBu+H ⁺ ): 268.0 observed. ¹ H NMR (400 MHz, Chloroform-d) δ 6.60 (ddd, J = 9.9, 3.8, 0.9 Hz, 1 H), 5.96 (dd, J = 9.9, 1 .8 Hz, 1 H), 4.91 (tdd, J = 9.1 , 7.6, 1 .0 Hz, 1 H), 3.48 (dddt, J = 7.5, 3.7, 1 .9, 1 .0 Hz, 1 H), 2.83 (dtd, J = 10.3, 3.8, 1 .1 Hz, 1 H), 2.62 (dddd, J = 1 1 .8, 8.0, 3.7, 2.7 Hz, 1 H), 2.53 (dddd, J = 12.3, 10.3, 8.2, 1 .0 Hz, 1 H), 1 .52 (s, 9H), 1 .48 (s, 9H). ¹³ C NMR (101 MHz, CDCI ₃ ) δ 172.92, 162.18, 151 .66, 141 .67, 125.00, 83.23, 81 .52, 49.34, 41 .96, 38.62, 33.62, 28.15.

Step 3. Synthesis of rac-di-tert-butyl (1 SR,5RS,6RS,7SR)-5-allyl-3-oxo-2- azabicyclo[4.2.0]octane-2,7-dicarboxylate

A suspension of copper(l) bromide-dimethyl sulfide complex (8.50 g, 41 .4 mmol) in THF (75 mL) was cooled in a dry ice/acetone bath and treated with allylmagnesium bromide (41 .4 mL, 41 .4 mmol). The resulting mixture was stirred at -78 °C for 1 hour. A solution of rac-di-tert- butyl (1 SR,6RS,7SR)-3-oxo-2-azabicyclo[4.2.0]oct-4-ene-2,7-dicarboxy late (2.675 g, 8.27 mmol) in THF (120 mL) was cooled in a dry ice / acetone bath and treated with TMS-CI (2.1 15 mL, 16.54 mmol). The solution of enone was then transferred by cannula to the stirring cuprate solution and the resulting mixture was stirred at -78 °C for 1 hour. The reaction was quenched by addition of saturated ammonium chloride solution and allowed to warm to room temperature. The reaction was diluted with ethyl acetate and water. The organics were isolated and washed once with water, dried over MgS04, filtered, evaporated and purified by flash column chromatography (ISCO, 80 g silica gel column, 0-50%

EtOAc/heptane) to afford rac-di-tert-butyl (1 SR,5RS,6RS,7SR)-5-allyl-3-oxo-2- azabicyclo[4.2.0]octane-2,7-dicarboxylate (2.708 g, 7.04 mmol, 85 % yield). LC/MS, ESI- MS(M-tBu+H ⁺ ): 310.2 observed. ¹ H NMR (400 MHz, Chloroform-d) δ 5.78 - 5.65 (m, 1 H), 5.09 (s, 1 H), 5.08 - 5.04 (m, 1 H), 4.52 - 4.44 (m, 1 H), 2.77 - 2.65 (m, 2H), 2.65 - 2.58 (m, 1 H), 2.52 (tt, J = 9.1 , 2.8 Hz, 1 H), 2.31 - 2.21 (m, 2H), 2.1 1 - 1 .95 (m, 3H), 1 .50 (s, 9H), 1 .47 (s, 9H). ¹³ C NMR (101 MHz, CDCI3) δ 173.79, 171 .13, 150.97, 134.40, 1 18.15, 83.15, 81 .00,

50.28, 42.1 1 , 39.19, 39.06, 37.45, 35.14, 32.73, 28.18, 28.15.

Step 4. Synthesis of rac-di-tert-butyl (1 SR,5RS,6RS,7SR)-5-allyl-2- azabicyclo[4.2.0]octane-2,7-dicarboxylate

A solution of rac-di-tert-butyl (1 SR,5RS,6RS,7SR)-5-allyl-3-oxo-2-azabicyclo[4.2.0]octane- 2,7-dicarboxylate (2.40 g, 6.57 mmol) in THF (20 mL) was cooled to -20 °C in an ice/salt bath and treated with LiBH ₄ (0.5 M in ether) (13.13 mL, 6.57 mmol). After stirring for 1 .5 hours, the reaction was quenched by addition of saturated ammonium chloride solution. The reaction was then diluted with ethyl acetate and water. The organics were separated, washed with water, dried over MgS04, filtered, and concentrated. The resulting oil was treated with triethylsilane (2.291 g, 19.70 mmol) and dissolved in DCM (20.00 mL), cooled in a dry ice/acetone bath and treated with BF ₃ -OEt ₂ (2.497 mL, 19.70 mmol). After stirring for 1 .5 hours, the reaction was quenched by addition of saturated sodium bicarbonate solution. The organics were separated and the aqueous layer was extracted with dichloromethane twice. The combined organics were dried over MgS0 ₄ , filtered, evaporated, and purified by flash column chromatography (ISCO, 80 g Gold silica column, 5-50% EtOAc/heptane) to afford rac-di-tert-butyl (1 SR,5RS,6RS,7SR)-5-allyl-2-azabicyclo[4.2.0]octane-2,7-dicarb oxylate (1 .935 g, 5.51 mmol, 84% yield). LC/MS, ESI-MS(M-tBu+H ⁺ ): 296.2 observed. ¹ H NMR (400 MHz, Chloroform-d) δ 5.78 (dddd, J = 16.9, 10.2, 7.8, 6.6 Hz, 1 H), 5.07 - 5.03 (m, 1 H), 5.03 - 5.00 (m, 1 H), 4.68 - 4.46 (m, 1 H), 3.79 (d, J = 1 1 .7 Hz, 1 H), 2.98 (t, J = 1 1 .6 Hz, 1 H), 2.60 - 2.51 (m, 1 H), 2.49 - 2.24 (m, 3H), 2.19 (dt, J = 12.6, 6.1 Hz, 1 H), 1 .99 (dt, J = 14.1 , 7.7 Hz, 1 H), 1 .82 - 1 .69 (m, 1 H), 1 .64 - 1 .53 (m, 2H), 1 .46 (s, 9H), 1 .44 (s, 9H), 1 .08 (dtd, J = 13.5, 1 1 .7, 4.0 Hz, 1 H). ¹³ C NMR (101 MHz, CDCI3) δ 136.16, 1 16.90, 80.38, 79.56, 46.60, 43.77, 40.99, 40.60, 39.1 1 , 37.81 , 30.10, 28.60, 28.20.

Step 5. Synthesis of rac-tert-butyl (1 SR,5RS,6RS,7SR)-5-allyl-2- azabicyclo[4.2.0]octane-7-carboxylate

A solution of rac-di-tert-butyl (1 SR,5RS,6RS,7SR)-5-allyl-2-azabicyclo[4.2.0]octane-2,7- dicarboxylate (1 .83 g, 5.21 mmol) in HCI (2M in diethyl ether) (2 mL, 4.00 mmol) was aged for 6.5 hours. The solvent was removed and the reaction was partitioned between ethyl acetate and 1 M NaOH. The aqueous phase was isolated and extracted once with ethyl acetate. The combined organics were dried over MgS0 ₄ , filtered and evaporated to afford the title compound Intermediate (14): rac-tert-butyl (1 SR,5RS,6RS,7SR)-5-allyl-2- azabicyclo[4.2.0]octane-7-carboxylate (840 mg, 3.27 mmol, 62.9 % yield) as an oil.

Intermediate (15): N-iS-chloro^'-isopropyl-^.S'-bipyridinl-e-y -e-fluoropyridine^ sulfonamide

Step 1. Synthesis of 2',3-dichloro-[2,3'-bipyridin]-6-amine In a microwave vial, 6-bromo-5-chloropyridin-2-ylamine (2.2 g, 10.60 mmol), 2- chloropyridine-3-boronic acid (2.003 g, 12.73 mmol), sodium carbonate (3.37 g, 31 .8 mmol), and Pd(Ph ₃ P) ₄ (1 .225 g, 1 .060 mmol) were taken up in dioxane (Volume: 12 mL, Ratio: 6.00) and water (Volume: 2 mL, Ratio: 1 .000), the solution was sparged with argon, then the reaction was heated in the microwave to 120 °C for 1 h. The crude reaction material was evaporated on silica gel and purified by flash column chromatography (ISCO, 80 g silica gel column, 0-6% MeOH/DCM, dry loading) to give the product 2',3-dichloro-[2,3'-bipyridin]-6- amine (2.1941 g, 9.14 mmol, 86% yield) as a light orange solid. Step 2. Synthesis of 3-chloro-2 prop-1 -en-2-yl)-[2,3'4jipyridin]-6-amine

In a microwave vial, 2',3-dichloro-[2,3'-bipyridin]-6-amine (1 .19 g, 4.96 mmol), 2- isopropenylboronic acid, pinacol ester (1 .1 18 mL, 5.95 mmol), sodium carbonate (1 .576 g, 14.87 mmol), and Pd(Ph ₃ P) ₄ (0.573 g, 0.496 mmol) were taken up in dioxane (Volume: 12 mL, Ratio: 6.00) and water (Volume: 2 mL, Ratio: 1 .000), the solution was sparged with Ar, then the reaction was heated in the microwave to 120 °C for 1 h. The crude reaction material was evaporated on silica gel and purified by flash column chromatography (ISCO, 80 g silica gel column, 0-8% MeOH/DCM, dry loading) to give the product 3-chloro-2'-(prop-1 -en-2-yl)- [2,3'-bipyridin]-6-amine (489 mg, 1 .99 mmol, 40% yield) as a yellow solid. Step 3. Synthesis of S-chloro^'-isopropyl-^.S'-bipyridinl-e-amine

In a vial, 3-chloro-2'-(prop-1 -en-2-yl)-[2,3'-bipyridin]-6-amine (489 mg, 1 .990 mmol) was taken up in EtOAc (Volume: 5 mL) and platinum(IV) oxide (48.8 mg, 0.199 mmol) was added, then the suspension was sparged with hydrogen and allowed to stir for 2 d. The reaction was filtered and the resulting solution was concentrated in vacuo to give the product 3-chloro-2'- isopropyl-[2,3'-bipyridin]-6-amine (579.3 mg) that was taken on directly to the next reaction with no purification. LC/MS, ESI-MS( ⁺ ): 248.1 , RT: 1 .01 min. ¹ H NMR (400 MHz, Methanol- d ₄ ) δ 8.55 (dd, J = 4.9, 1 .8 Hz, 1 H), 7.60 (dd, J = 7.7, 1 .8 Hz, 1 H), 7.56 (d, J = 8.9 Hz, 1 H), 7.33 (dd, J = 7.7, 4.9 Hz, 1 H), 6.62 (d, J = 8.9 Hz, 1 H), 2.92 (hept, J = 6.8 Hz, 1 H), 1 .24 - 1 .1 1 (m, 6H). Step 4. Synthesis of N-iS-chloro^'-isopropyl-^.S'-bipyridinl-e-ylJ-e-fluoropyridi ne^- sulfonamide

In a vial, 3-chloro-2'-isopropyl-[2,3'-bipyridin]-6-amine (579.3 mg, 2.338 mmol) was taken up in THF (Volume: 20 mL) and the solution was cooled to 0 °C. To the solution was added 1 .0 M LHMDS in THF (4.68 mL, 4.68 mmol), then a solution of 6-fluoropyridine-2-sulfonyl chloride (915 mg, 4.68 mmol) that had been dissolved in THF (2 mL). After stirring overnight the reaction was quenched with sat. aq. NH ₄ CI and extracted into EtOAc (10 mL x 3). The organics were then washed with water and brine, dried over MgS0 ₄ , and concentrated in vacuo. The crude material was purified by flash column chromatography (ISCO, 12 g silica gel column, 0-5% MeOH/DCM) to give the title product Intermediate (15): N-(3-chloro-2'- isopropyl-[2,3'-bipyridin]-6-yl)-6-fluoropyridine-2-sulfonam ide (716.1 mg, 1 .760 mmol, 75 % yield) as a yellow solid. LC/MS, ESI-MS( ⁺ ): 407.0, RT: 1 .21 min. ¹ H NMR (400 MHz, Methanol-d ₄ ) δ 8.53 (dd, J = 4.9, 1 .8 Hz, 1 H), 8.04 (dt, J = 8.3, 7.5 Hz, 1 H), 7.89 (ddd, J = 7.3, 2.1 , 0.7 Hz, 1 H), 7.86 (d, J = 8.8 Hz, 1 H), 7.43 (dd, J = 7.7, 1 .8 Hz, 1 H), 7.32 - 7.24 (m, 3H), 2.72 (hept, J = 6.8 Hz, 1 H), 1 .08 (d, J = 44.1 Hz, 6H).

Intermediate (16): rac-tert-butyl (1 SR,6RS,7SR)-2-azabicyclo[4.2.0]octane-7 carboxylate

{13}

(16)

Step 1. Synthesis of rac-tert-butyl (1 SR,6RS,7SR)-3-oxo-2-azabicyclo[4.2.0]octane-7- carboxylate

In a vial, Intermediate (13): rac-tert-butyl (1 SR,6RS,7SR)-3-oxo-2-azabicyclo[4.2.0]oct-4- ene-7-carboxylate (500 mg, 2.239 mmol) was taken up in MeOH (Volume: 10 mL), then 20% Pd(OH) ₂ on carbon (629 mg, 0.896 mmol) was added and the reaction mixture was sparged with hydrogen. After stirring for 16 h, the reaction was filtered and the solution was concentrated in vacuo to give the crude product rac-tert-butyl (1 SR,6RS,7SR)-3-oxo-2- azabicyclo[4.2.0]octane-7-carboxylate (476.2 mg, 2.1 14 mmol, 94 % yield) as a white solid that was taken on directly to the next reaction.

Step 2. Synthesis of rac-tert-butyl (1SR,6RS,7SR)-2-azabicyclo[4.2.0]octane-7- carboxylate

In a vial, crude rac-tert-butyl (1 SR,6RS,7SR)-3-oxo-2-azabicyclo[4.2.0]octane-7-carboxylate (476.2 mg, 2.1 14 mmol) was taken up in THF (Volume: 10 mL), the solution was cooled to 0 °C, then BH ₃ -THF (2.54 mL, 2.54 mmol) was added and the reaction was allowed to warm to RT for 16 h. No anticipated product was observed by LMCS, likely due to poor quality BH ₃ - THF. The reaction was cooled to 0 °C, and additional BH ₃ -THF (2.54 mL, 2.54 mmol) was added from a new bottle, and the reaction was allowed to warm to RT. After stirring for 3 d, reaction was again cooled to 0 °C and a third portion of BH ₃ -THF (2.54 mL, 2.54 mmol) was added. After stirring for 16 h, the reaction was cooled to 0 °C, quenched with AcOH, and concentrated. The resulting residue was dissolved in EtOAc and the organics were washed with sat. aq. NaHC0 ₃ and brine, dried over MgS0 ₄ , and concentrated in vacuo to give the crude title product Intermediate (16): rac-tert-butyl (1 SR,6RS,7SR)-2- azabicyclo[4.2.0]octane-7-carboxylate that was used directly without purification. Intermediate (17): 6-fluoro-N-(6-(2-(hydroxymethyl)phenyl)-5-(trifluoromethyl)p yridin- 2-yl)pyridine-2 -sulfonamide

(17) Step 1. Synthesis of N-(6-chloro-5-(trifluoromethyl)pyridin-2-yl)-6-fluoropyridin e-2- sulfonamide

6-chloro-5-(trifluoromethyl)pyridin-2-amine (100 mg, 1 .02 mmol) was suspended in pyridine (1 ml_) and 6-fluoropyridine-2-sulfonyl chloride (219 mg, 1 .12 mmol) was added. The reaction mixture was stirred at RT for 16 h. Pyridine was removed in vacuo and the resulting residue was dissolved in ethyl acetate. The organics were then washed with brine and water, dried over Na ₂ S0 ₄ , filtered, and concentrated. The crude material was then subjected to flash column chromatography (ISCO, 24 g silica gel column, 0-60% EtOAc/heptane) to give the product N-(6-chloro-5-(trifluoromethyl)pyridin-2-yl)-6-fluoropyridin e-2-sulfonamide (312 mg, 0.834 mmol, 82% yield) as light yellow solid. LC/MS, ESI-MS( ⁺ ): 356.0, RT: 1 .69 min. ¹ H NMR (600 MHz, DMSO-c/ ₆ ) δ 12.34 (s, 1 H), 8.36 (dt, J = 8.3, 7.6 Hz, 1 H), 8.19 - 8.10 (m, 2H), 7.53 (ddd, J = 8.3, 2.3, 0.7 Hz, 1 H), 7.21 - 7.12 (m, 1 H).

Step 2. Synthesis of 6-fluoro-N-(6-(2-(hydroxymethyl)phenyl)-5- (trifluoromethyl)pyridin-2-yl)pyridine-2 -sulfonamide

In a microwave vial, N-(6-chloro-5-(trifluoromethyl)pyridin-2-yl)-6-fluoropyridin e-2- sulfonamide (100 mg, 0.28 mmol), (2-(trifluoro-l4-boranyl)phenyl)methanol, potassium salt (47 mg, 0.225 mmol), potassium carbonate (78 mg, 0.56 mmol), Pd(OAc) ₂ (6 mg, 0.028 mmol) and 2-dicyclohexylphosphino-2',6'-dimethoxy-1 ,1 '-biphenyl (Sphos) (23 mg, 0.056 mmol) were taken up in dioxane (Volume: 4 ml_, Ratio: 4.00) and water (Volume: 1 ml_, Ratio: 1 .000), the solution was sparged with N ₂ , then the reaction was heated in the microwave to 120 °C for 1 h. The crude reaction material was evaporated on silica gel and purified by flash column chromatography (ISCO, 12 g silica gel column, 0-8% MeOH/DCM, dry loading) to give the product Intermediate (17): 6-fluoro-N-(6-(2-(hydroxymethyl)phenyl)- 5-(trifluoromethyl)pyridin-2-yl)pyridine-2-sulfonamide (78 mg, 0.183 mmol, 65% yield) as a yellow solid. LC/MS, ESI-MSf): 428.1 , RT: 1 .54 min. ¹ H NMR (400 MHz, Methanol-d4) δ 8.09 (d, J = 8.8 Hz, 1 H), 7.96 (dtd, J = 9.1 , 7.5, 1 .6 Hz, 1 H), 7.89 - 7.82 (m, 1 H), 7.61 - 7.39 (m, 2H), 7.37 - 7.16 (m, 3H), 7.03 (d, J = 7.6 Hz, 1 H), 4.26 (d, J = 1 1 .8 Hz, 2H). PREPARATION OF EXAMPLES

Example 129: (1 s,4s)-4-((6-(N-(5-chloro-6-(2,6-dimethylphenyl)pyridin-2- yl)sulfamoyl)pyridin-2-yl)oxy)cyclohexane-1 -carboxylic acid

Ex. 129

Step 1. To a solution of cis-4-hydroxycyclohexanecarboxylic acid (33.1 mg, 0.23 mmol) in N- methylpyrrolidone (0.8 mL) was added sodium hydride (18 mg, 0.77 mmol). The mixture was stirred at rt for 30 min. Solid N-(5-chloro-6-(2,6-dimethylphenyl)pyridin-2-yl)-6-fluoropyri dine- 2-sulfonamide (30 mg, 0.077 mmol) was added and stirred at rt o/n. Quenched with water, acidified with 1 N HCI to pH 3-4, taken into ethyl acetate, washed twice with water, four washes with brine, dried over sodium sulfate, filtered, and concentrated. Purification by flash silica gel chromatography using 0-70% hexanes/ethyl acetate gradient afforded (1 s,4s)-4- ((6-(N-(5-chloro-6-(2,6-dimethylphenyl)pyridin-2-yl)sulfamoy l)pyridin-2-yl)oxy)cyclohexane-1 - carboxylic acid (35.9 mg, 86 % yield) as white solid: LCMS: Rt 1 .56 min; m/z 516.2 [M+H] ⁺ .

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 12.14 (s, 1 H), 1 1 .37 (s, 1 H), 7.99 (d, J = 8.8 Hz, 1 H), 7.86

(dd, J = 7.4, 8.3 Hz, 1 H), 7.48 (dd, J = 0.6, 7.3 Hz, 1 H), 7.31 (d, J = 8.2 Hz, 1 H), 7.17 (m, 1 H), 7.04 (m, 3H), 4.89 (m, 1 H), 2.35 (m, 1 H), 1 .62 (m, 14H).

Example 249: 1 -(6-(N-(5-chloro-6-(2,6-dimethylphenyl)pyridin-2-yl)sulfamoy l)pyridin-2- yl)-4-methylpiperidine-4-carboxylic acid

Ex. 249 Step 1. The mixture of methyl 4-hydroxypiperidine-4-carboxylate (172 mg, 0.829 mmol), N- (5-chloro-6-(2,6-dimethylphenyl)pyridin-2-yl)-6-fluoropyridi ne-2-sulfonamide (65 mg, 0.166 mmol) and Huenig's Base (0.290 mL, 1 .659 mmol) in NMP (Volume: 1 .5 mL) was microwaved at 200°C for 30 min. LC-MS indicated that the reaction was complete. Aqueous work-up followed by ISCO purification (solid loading, 0-100% EtOAc in hexane) to yield the product ethyl 1 -(6-(N-(5-chloro-6-(2,6-dimethylphenyl)pyridin-2-yl)sulfamoy l)pyridin-2-yl)-4- methylpiperidine-4-carboxylate(86 mg, 0.150 mmol, 91 % yield) as a white solid. LC/MS, m/z 543.2 (M+H+), RT 1 .82 min. ¹ H NMR (400 MHz, DMSO-d6) δ 1 1 .15 (s, 1 H), 7.96 (d, J = 8.8 Hz, 1 H), 7.67 (dd, J = 8.7, 7.3 Hz, 1 H), 7.33 (d, J = 8.8 Hz, 1 H), 7.21 - 7.14 (m, 1 H), 7.10 - 7.01 (m, 4H), 4.09 (q, J = 7.1 Hz, 2H), 3.85 - 3.76 (m, 2H), 3.05 - 2.94 (m, 2H), 1 .91 - 1 .81 (m, 2H), 1 .27 - 1 .20 (m, 2H), 1 .17 (t, J = 7.1 Hz, 3H), 1 .10 (s, 3H).

Example 250: 1 -(6-(N-(5-chloro-6-(2,6-dimethylphenyl)pyridin-2-yl)sulfamoy l)pyridin-2- yl)-4-methylpiperidine-4-carboxylic acid

Step 1. To the solution of Example 249: ethyl 1 -(6-(N-(5-chloro-6-(2,6- dimethylphenyl)pyridin-2-yl)sulfamoyl)pyridin-2-yl)-4-methyl piperidine-4-carboxylate (70 mg, 0.129 mmol) in Dioxane (Volume: 3 mL, Ratio: 1 .000) was added a solution of LiOH (61 .7 mg, 2.58 mmol) in Water (Volume: 3.00 mL, Ratio: 1 .000). The resulting mixture was stirred at room temperature for overnight, LC-MS indicated that the reaction was complete. The reaction then was neutralized with 1 N HCI at room temperature. The resulting mixture was then extracted with EtOAc. The combined organic phases were dried over Na2S04, evaporated to yield Example 250: 1 -(6-(N-(5-chloro-6-(2,6-dimethylphenyl)pyridin-2- yl)sulfamoyl)pyridin-2-yl)-4-methylpiperidine-4-carboxylic acid (69 mg, 0.127 mmol, 99 % yield) as a white solid. LC/MS, m/z 515.2 (M+H+), RT 1 .62 min.

¹ H NMR (400 MHz, DMSO-d6) δ 7.93 (d, J = 8.8 Hz, 1 H), 7.66 (dd, J = 8.6, 7.3 Hz, 1 H), 7.33 (d, J = 8.8 Hz, 1 H), 7.20 - 7.13 (m, 1 H), 7.09 - 6.98 (m, 4H), 3.87 - 3.74 (m, 2H), 3.07 - 2.95 (m, 2H), 1 .85 (d, J = 13.7 Hz, 2H), 1 .75 (s, 6H), 1 .21 - 1 .1 1 (m, 2H), 1 .09 (s, 3H). Example 160: tert-butyl 4-(6-(N-(6-(o-tolyl)-5-(trifluoromethyl)pyridin-2- yl)sulfamoyl)pyridin-2-yl)piperazine-1 -carboxylate

( ⁶ ) Ex. 160

The mixture of Intermediate (6) 6-fluoro-N-(6-(o-tolyl)-5-(trifluoromethyl)pyridin-2-yl)pyri dine- 2-sulfonamide (2000mg, 4.86 mmol), tert-butyl piperazine-1 -carboxylate (4528 mg, 24.31 mmol) and Acetonitrile (Volume: 60 mL) was stirred at 120°C in a pressure tube for overnight. LC-MS indicated that the reaction was complete. Aqueous work-up followed by ISCO purification ( 0-100% EtOAc/hexane) to yield Example 160: tert-butyl 4-(6-(N-(6-(o- tolyl)-5-(trifluoromethyl)pyridin-2-yl)sulfamoyl)pyridin-2-y l)piperazine-1 -carboxylate (2779 mg, 4.81 mmol, 98 % yield) as a white solid. LC/MS, m/z 578.3 (M+H+), RT 1 .77 min. Example 161 : 6-(piperazin-1 -yl)-N-(6-(o olyl)^-(trifluoromethyl)pyridin-2-yl)pyridine-2- sulfonamide HCI salt)

Ex. 160

Ex. 161

To Example 160: Tert-butyl 4-(6-(N-(6-(o-tolyl)-5-(trifluoromethyl)pyridin-2- yl)sulfamoyl)pyridin-2-yl)piperazine-1 -carboxylate (2479 mg, 4.29 mmol) was added DCM (Volume: 20 mL) and 6 N HCI in IPA (20 mL, 120 mmol). The resulting solution was stirred at room temperature for 4hrs 30min. LC-MS indicated that the reaction was complete.

Evaporation to remove the solvents, the residue was dried under vacuum for overnight. Then diethyl ether was added, filtration to yield Example 161 : 6-(piperazin-1 -yl)-N-(6-(o-tolyl)-5- (trifluoromethyl)pyridin-2-yl)pyridine-2-sulfonamide (HCI salt) (2.14 g, 3.96 mmol, 92 % yield) as a white solid. LC/MS, m/z 478.2 3 (M+H+), RT 1 .34 min. ¹ H NMR (400 MHz, Methanol-d4) δ 8.09 (d, J = 8.9 Hz, 1 H), 7.74 (dd, J = 8.6, 7.4 Hz, 1 H), 7.53 (d, J = 8.8 Hz, 1 H), 7.37 (d, J = 7.3 Hz, 1 H), 7.32 (td, J = 7.5, 1 .3 Hz, 1 H), 7.27 - 7.16 (m, 2H), 7.10 (d, J = 8.6 Hz, 1 H), 7.05 (d, J = 7.5 Hz, 1 H), 3.82 - 3.73 (m, 4H), 3.27 - 3.20 (m, 4H), 1 .93 (s, 3H). Example 161 : 6-(piperazin-1 -yl)-N-(6-(o-tolyl)-5-(trifluoromethyl)pyridin-2-yl)pyridine -2- sulfonamide

To Example 160: To a solution of fe/ -butyl 4-(6-(N-(6-(o-tolyl)-5-(trifluoromethyl)pyridin-2- yl)sulfamoyl)pyridin-2-yl)piperazine-1 -carboxylate (1 .1323 g, 1 .960 mmol) in dioxane (2.5 ml_), 4N HCI in dioxane (12.25 ml_, 49.0 mmol) was added, and the reaction mixture was stirred at rt for 18h. The reaction mixture was concentrated in vacuo, then excess HCI was azeotroped twice with DCM and diethyl ether. The resulting yellow salt was triturated twice with diethyl ether, then was suspended in THF. The resulting solution was basified with a 7N ammonia in MeOH solution. The mixture was concentrated in vacuo, then was triturated twice with diethyl ether and DCM, followed by trituration with Dl water The resulting white solid was dried over high vacuum at rt for 78h, then at 50°C for 18h to yield 6-(piperazin-1 - yl)-N-(6-(o-tolyl)-5-(trifluoromethyl)pyridin-2-yl)pyridine- 2-sulfonamide as a white solid (784 mg, 84% yield). Condition 4, LCMS: R _t 1 .64 min; m/z 477.8 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO-d6) δ 7.79 (d, J = 8.9 Hz, 1 H), 7.69 (dd, J = 8.6, 7.3 Hz, 1 H), 7.28 - 7.22 (m, 2H), 7.17 (d, J = 8.8 Hz, 1 H), 7.13 - 7.04 (m, 2H), 6.92 (d, J = 7.3 Hz, 1 H), 6.84 (d, J = 8.6 Hz, 1 H), 5.75 (s, 1 H), 3.44 (s, 4H), 2.94 (d, J = 3.7 Hz, 4H), 1 .64 (s, 3H).

Example 291 : rac-6-{[(3RS,4SR)-4-hydroxyoxolan-3-yl]oxy}-N-[6-(2-methylph enyl)-5- (trifluoromethyl)pyridin-2-yl]pyridine-2 -sulfonamide

Step 1. To a solution of (3R,4S)-tetrahydrofuran-3,4-diol (260 mg, 2.5 mmol) and 6-fluoro-N- (6-(o-tolyl)-5-(trifluoromethyl)pyridin-2-yl)pyridine-2-sulf onamide (206 mg, 0.5 mmol) in DMF (Volume: 20 ml_) was added NaH (240 mg, 10 mmol) under nitrogen atmosphere. The mixture stirred at rt for 5 h and quenched with aq. citric acid, ethyl acetate added, washed with 10% citric acid, water, aq. NaHCC>3, brine (x3), and dried (Na2SC>4). The crude material was purified by flash silica gel chromathotography (hexanes/ethyl acetate 0-100% gradient) to afford rac-6-{[(3RS,4SR)-4-hydroxyoxolan-3-yl]oxy}-N-[6-(2-methylph enyl)-5- (trifluoromethyl)pyridin-2-yl]pyridine-2-sulfonamide (180 mg, 71 % yield) as white crystals. LCMS: Rt 1.47 min; m/z 496.2 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO-c/ ₆ ) 011.81 (s, 1 H), 8.21 (d, J = 8.9 Hz, 1H), 7.91 (m, 1H), 7.56 (dd, J = 0.6, 7.3 Hz, 1H), 7.47 (s, 1H), 7.32 (t, J = 7.3 Hz, 1H), 7.22 (m, 2H), 7.11 (d, J = 8.3 Hz, 1H), 7.05 (m, 1H), 5.07 (dd, J = 5.2, 14.7 Hz, 1H), 4.95 (m, 1H), 4.21 (m, 1H), 3.82 (m, 2H), 3.54 (m, 2H), 1.79 (m, 3H).

1 ⁹ F NMR (376 MHz, DMSO-c/ ₆ ) δ -57.17 (s).

Example 293: rac-6-{[(3RR,4SR)-4-hydroxy-4-methyloxolan-3-yl]oxy}-N-[6-(2 methylphenyl)-5-(trifluoromethyl)pyri To a solution of Example 292: 6-((4-oxotetrahydrofuran-3-yl)oxy)-N-(6-(o-tolyl)-5-

(trifluoromethyl)pyridin-2-yl)pyridine-2-sulfonamide (49.3 mg, 0.1 mmol) in DCM (Volume: 2 ml) was added at -78 °C 3 M MeMgBr in ether (0.167 ml, 0.500 mmol) under nitrogen atmosphere. The mixture was stirred at -78 °C for 2 h. Complete. Reaction mixture was quenched with 1N HCI, and EtOAcwas added. Organic layer was washed with 10% citric acid, water, aq. NaHC0 ₃ , brine (x3), and dried over Na ₂ S0 ₄ . The crude material was purified by silica gel column, (EtOAc/Hexanes 0-70%) to afford rac-6-{[(3RR,4SR)-4-hydroxy-4- methyloxolan-3-yl]oxy}-N-[6-(2-methylphenyl)-5-(trifluoromet hyl)pyridin-2-yl]pyridine-2- sulfonamide. Condition 2, LCMS: m/z 510.2 [M+H] ⁺ , 3.07 min. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 11.83 (s, 1 H), 8.22 (d, J = 8.9 Hz, 1 H), 7.91 (dd, J = 7.4, 8.3 Hz, 1 H), 7.55 (d, J = 7.3 Hz, 1 H), 7.45 (m, 1 H), 7.32 (t, J = 7.4 Hz, 1 H), 7.21 (m, 2H), 7.11 (d, J = 8.3 Hz, 1 H), 7.02 (m, 1 H), 4.97 (m, 1 H), 4.73 (m, 1 H), 3.93 (dd, J = 5.7, 9.5 Hz, 1 H), 3.60 (d, J = 8.5 Hz, 1 H), 3.49 (d, J = 8.5 Hz, 1H), 3.42 (m, 1H), 1.76 (m, 3H), 1.17 (m, 3H). ¹⁹ F NMR (376 MHz, DMSO-d ₆ ) δ -57.15 (m). The following examples were prepared using the specified intermediates and general procedures as indicated within the general synthetic methods section.

Example 102: (R)-6-(3-aminopiperidin-1 -yl)-N-(6-(o-tolyl)-5-(trifluoromethyl)pyridin-2- yl)pyridine-2-sulfonamide hydrochloride; Condition 2, LCMS: m/z 492.2 [M+H] ⁺ 2.53 min. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 11.61 (s, 1H), 8.21 (d, J = 8.9 Hz, 1H), 8.13 (s, 3H), 7.78- 7.71 (m, 1H), 7.55 (s, 1H), 7.38-7.29 (m, 1H), 7.28-7.19 (m, 2H), 7.18 (d, J = 7.3 Hz, 1H), 7.11 -7.02 (m, 2H), 4.17-4.03 (m, 1H), 3.79 (d, J = 12.4 Hz, 1H), 3.21 -3.06 (m, 2H), 3.00 (q, J = 11.7 Hz, 1H), 1.95 (s, 1H), 1.81 (d, J = 18.6 Hz, 3H), 1.72-1.52 (m, 2H), 1.41 - 1.23 (m, 1H). Example 103: (S)-6-(3-aminopiperidin-1 -yl)-N-(6-(o-tolyl)-5-(trifluoromethyl)pyridin-2- yl)pyridine-2-sulfonamide hydrochloride; Condition 2, LCMS: m/z 492.2 [M+H] ⁺ , 2.52 min. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 1 1 .61 (s, 1 H), 8.21 (d, J = 8.9 Hz, 1 H), 8.10 (s, 3H), 7.79 - 7.71 (m, 1 H), 7.55 (s, 1 H), 7.38 - 7.29 (m, 1 H), 7.29 - 7.19 (m, 2H), 7.18 (d, J = 7.3 Hz, 1 H),

7.07 (d, J = 8.7 Hz, 2H), 4.16 - 4.03 (m, 1 H), 3.79 (d, J = 12.4 Hz, 1 H), 3.21 - 3.07 (m, 2H),

3.08 - 2.93 (m, 1 H), 1 .95 (s, 1 H), 1 .81 (d, J = 19.1 Hz, 3H), 1 .73 - 1 .52 (m, 2H), 1 .34 (s, 1 H).

Example 104: (R)-6-(piperidin-3-ylamino)-N-(6-(o-tolyl)-5-(trifluoromethy l)pyridin-2- yl)pyridine-2-sulfonamide hydrochloride; Condition 2, LCMS: m/z 492.2 [M+H] ⁺ , 2.44 min. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 1 1 .56 (s, 1 H), 8.83 (s, 2H), 8.22 (d, J = 8.9 Hz, 1 H), 7.59 (t, J = 7.9 Hz, 1 H), 7.53 (d, J = 6.6 Hz, 1 H), 7.33 (dd, J = 13.1 , 6.0 Hz, 2H), 7.28 - 7.17 (m, 2H), 7.10 (d, J = 7.2 Hz, 1 H), 7.03 (s, 1 H), 6.73 (d, J = 8.5 Hz, 1 H), 3.89 (s, 1 H), 3.21 (s, 1 H), 3.12 (s, 1 H), 2.97 - 2.77 (m, 2H), 1 .88 - 1 .54 (m, 6H), 1 .51 - 1 .30 (m, 1 H).

Example 105: (S)-6-(piperidin-3-ylamino)-N-(6-(o-tolyl)-5-(trifluoromethy l)pyridin-2- yl)pyridine-2-sulfonamide hydrochloride; Condition 2, LCMS: m/z 492.2 [M+H] ⁺ , 2.45 min. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 1 1 .56 (s, 1 H), 8.68 (s, 2H), 8.25 - 8.17 (m, 1 H), 7.59 (t, J =

7.9 Hz, 1 H), 7.51 (d, J = 7.2 Hz, 1 H), 7.37 - 7.15 (m, 4H), 7.09 (dd, J = 15.2, 7.8 Hz, 2H), 6.73 (d, J = 8.3 Hz, 1 H), 3.86 (s, 1 H), 3.22 (d, J = 7.0 Hz, 1 H), 3.13 (s, 1 H), 2.97 - 2.81 (m,

2H), 1 .87 - 1 .55 (m, 6H), 1 .38 (s, 1 H).

Example 106: 6-(((3R,4S)-4-methoxypiperidin-3-yl)amino)-N-(6-(o-tolyl)-5- (trifluoromethyl)pyridin-2-yl)pyridine-2-sulfonamide hydrochloride; Condition 2, LCMS: m/z 522.2 [M+H] ⁺ , 2.44 min. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 1 1 .59 (s, 1 H), 8.88 (s, 1 H), 8.66 (s, 1 H), 8.21 (d, J = 8.8 Hz, 1 H), 7.59 (d, J = 7.8 Hz, 1 H), 7.45 (s, 1 H), 7.32 (t, J = 7.5 Hz, 1 H), 7.22 (d, J = 7.1 Hz, 3H), 7.13 - 6.91 (m, 2H), 6.85 (d, J = 8.0 Hz, 1 H), 4.13 (s, 1 H), 3.17 - 2.91 (m, 8H), 2.02 (s, 1 H), 1 .89 - 1 .60 (m, 4H). Example 107: 6-(6-amino-3-azabicyclo[3.1.0]hexan-3-yl)-N-(6-(o-tolyl)-5-

(trifluoromethyl)pyridin-2-yl)pyridine-2-sulfonamide hydrochloride; Condition 2, LCMS: m/z 490.2 [M+H] ⁺ , 2.57 min. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 1 1 .57 (s, 1 H), 8.29 - 8.19 (m, 4H), 7.68 (dd, J = 8.5, 7.4 Hz, 1 H), 7.58 (d, J = 6.8 Hz, 1 H), 7.38 - 7.30 (m, 1 H), 7.24 (dd, J = 13.5, 7.1 Hz, 2H), 7.15 (d, J = 7.3 Hz, 1 H), 7.08 (d, J = 7.2 Hz, 1 H), 6.73 (d, J = 8.5 Hz, 1 H), 3.61 - 3.52 (m, 2H), 3.28 (d, J = 10.2 Hz, 2H), 2.43 - 2.35 (m, 1 H), 2.06 (s, 2H), 1 .83 (s, 3H). Example 108: 6-(4-aminopiperidin-1 -yl)-N-(6-(o-tolyl)-5-(trifluoromethyl)pyridin-2- yl)pyridine-2-sulfonamide hydrochloride; Condition 2, LCMS: m/z 492.3 [M+H] ⁺ , 2.48 min. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 1 1 .59 (s, 1 H), 8.22 (d, J = 9.0 Hz, 1 H), 8.02 - 7.87 (m, 3H), 7.73 (dd, J = 8.7, 7.3 Hz, 1 H), 7.57 (d, J = 7.5 Hz, 1 H), 7.38 - 7.30 (m, 1 H), 7.24 (dd, J = 15.8, 7.6 Hz, 2H), 7.16 (d, J = 7.2 Hz, 1 H), 7.12 (d, J = 8.7 Hz, 1 H), 7.09 (d, J = 7.4 Hz, 1 H), 4.13 (d, J = 12.6 Hz, 2H), 3.34 - 3.20 (m, 1 H), 2.84 (t, J = 12.4 Hz, 2H), 1 .85 (s, 5H), 1 .34 (d, J = 1 1 .8 Hz, 2H).

Example 109: 6-(4-(methylamino)piperidin-1 -yl)-N-(6-(o-tolyl)-5-(trifluoromethyl)pyridin- 2-yl)pyridine-2-sulfonamide hydrochloride; Condition 2, LCMS: m/z 506.3 [M+H] ⁺ , 2.41 min. ¹ H NMR (400 MHz, DMSO-d ₆ ) 0 1 1 .61 (s, 1 H), 8.96 - 8.78 (m, 2H), 8.22 (d, J = 8.9 Hz, 1 H), 7.73 (dd, J = 8.6, 7.3 Hz, 1 H), 7.55 (d, J = 8.4 Hz, 1 H), 7.38 - 7.29 (m, 1 H), 7.24 (dd, J = 14.3, 7.3 Hz, 2H), 7.15 (dd, J = 9.8, 8.0 Hz, 2H), 7.09 (d, J = 7.5 Hz, 1 H), 4.20 (d, J = 13.2 Hz, 2H), 3.57 (s, 3H), 3.27 - 3.13 (m, 1 H), 2.79 (t, J = 1 1 .0 Hz, 2H), 1 .97 (d, J = 10.4 Hz, 2H), 1 .83 (s, 3H), 1 .44 - 1 .28 (m, 2H).

Example 110: 6-(4-amino-4-methylpiperidin-1 -yl)-N-(6-(o-tolyl)-5- (trifluoromethyl)pyridin-2-yl)pyridine-2-sulfonamide hydrochloride; Condition 2, LCMS: m/z 506.2 [M+H] ⁺ , 2.51 min. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 1 1 .59 (s, 1 H), 8.22 (d, J = 9.0 Hz, 1 H), 8.09 (s, 3H), 7.73 (dd, J = 8.7, 7.3 Hz, 1 H), 7.56 (d, J = 7.6 Hz, 1 H), 7.37 - 7.31 (m, 1 H), 7.24 (dd, J = 15.4, 7.5 Hz, 2H), 7.15 (dd, J = 15.7, 8.0 Hz, 2H), 7.08 (d, J = 7.2 Hz, 1 H), 3.81 (d, J = 12.4 Hz, 2H), 3.22 (ddd, J = 13.1 , 9.1 , 3.2 Hz, 2H), 1 .84 (s, 3H), 1 .68 - 1 .51 (m, 4H), 1 .31 (s, 3H). Example 111 : 6-((3S,4R)-4-amino-3-fluoropiperidin-1 -yl)-N-(6-(o-tolyl)-5-

(trifluoromethyl)pyridin-2-yl)pyridine-2-sulfonamide hydrochloride; Condition 2, LCMS: m/z 510.2 [M+H] ⁺ , 2.47 min. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 1 1 .62 (s, 1 H), 8.35 - 8.24 (m, 3H), 8.22 (d, J = 9.0 Hz, 1 H), 7.73 (dd, J = 8.6, 7.4 Hz, 1 H), 7.57 (d, J = 7.0 Hz, 1 H), 7.34 - 7.29 (m, 1 H), 7.24 (dd, J = 16.1 , 7.8 Hz, 2H), 7.16 (dd, J = 8.0, 5.7 Hz, 2H), 7.13 - 7.05 (m, 1 H), 4.95 (d, J = 49.2 Hz, 1 H), 4.57 (t, J = 13.1 Hz, 1 H), 4.23 (d, J = 12.4 Hz, 1 H), 3.66 - 3.50 (m, 1 H), 3.26 - 3.06 (m, 1 H), 2.88 (t, J = 12.4 Hz, 1 H), 1 .84 (s, 3H), 1 .76 (d, J = 10.1 Hz, 1 H), 1 .71 - 1 .56 (m, 1 H).

Example 112: 6-(piperidin-4-ylamino)-N-(6-(o-tolyl)-5-(trifluoromethyl)py ridin-2- yl)pyridine-2-sulfonamide hydrochloride; Condition 2, LCMS: m/z 492.3 [M+H] ⁺ , 2.41 min. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 1 1 .52 (s, 1 H), 8.81 (s, 2H), 8.21 (d, J = 8.9 Hz, 1 H), 7.56 (dd, J = 8.5, 7.3 Hz, 1 H), 7.49 (d, J = 8.6 Hz, 1 H), 7.36 (brs, 1 H), 7.40 - 7.28 (m, 2H), 7.25 - 7.18 (m, 2H), 7.05 (t, J = 7.9 Hz, 2H), 6.74 - 6.69 (m, 1 H), 3.28 - 3.09 (m, 2H), 2.87 (s, 2H), 1 .93 - 1 .76 (m, 2H), 1 .75 (s, 3H), 1 .63 - 1 .41 (m, 2H).

Example 113: 6-(((3S,4R)-3-hydroxypiperidin-4-yl)amino)-N-(6-(o-tolyl)-5- (trifluoromethyl)pyridin-2-yl)pyridine-2-sulfonamide hydrochloride; Condition 2, LCMS: m/z 508.2 [M+H] ⁺ , 2.43 min. mixture of cis isomer: ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 1 1 .52 (s, 1 H), 8.81 (s, 2H), 8.21 (d, J = 8.9 Hz, 1 H), 7.56 (dd, J = 8.5, 7.3 Hz, 1 H), 7.49 (d, J = 8.6 Hz, 1 H), 7.36 (brs, 1 H), 7.40 - 7.28 (m, 2H), 7.25 - 7.18 (m, 2H), 7.05 (t, J = 7.9 Hz, 2H), 6.74 - 6.69 (m, 1 H), 3.28 - 3.09 (m, 2H), 2.87 (s, 2H), 1 .93 - 1 .76 (m, 2H), 1 .75 (s, 3H), 1 .63 - 1 .41 (m, 2H).

Example 114: 6-(((3R,4R)-3-hydroxypiperidin-4-yl)amino)-N-(6-(o-tolyl)-5- (trifluoromethyl)pyridin-2-yl)pyridine-2-sulfonamide hydrochloride; Condition 2, LCMS: m/z 508.2 [M+H] ⁺ , 2.42 min. mixture of trans isomer: ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 1 1 .49 (s, 1 H), 8.91 (s, 1 H), 8.65 (s, 1 H), 8.19 (d, J = 8.9 Hz, 1 H), 7.62 - 7.47 (m, 2H), 7.34 (dd, J = 16.4, 7.8 Hz, 2H), 7.28 - 7.17 (m, 2H), 7.13 - 7.00 (m, 2H), 6.78 (d, J = 8.5 Hz, 1 H), 5.61 (s, 1 H), 3.74 (dd, J = 7.0, 3.2 Hz, 2H), 3.26 (s, 1 H), 3.07 (s, 1 H), 2.87 (s, 1 H), 2.77 (dt, J = 10.9, 6.0 Hz, 1 H), 1 .96 (s, 1 H), 1 .86 - 1 .69 (m, 3H), 1 .51 - 1 .29 (m, 1 H). Example 115: 6-(((3S,4R)-3-methoxypiperidin-4-yl)amino)-N-(6-(o-tolyl)-5-

(trifluoromethyl)pyridin-2-yl)pyridine-2-sulfonamide hydrochloride; Condition 2, LCMS: m/z 522.2 [M+H] ⁺ , 2.55 min. mixture of cis isomer: ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 1 1 .54 (s, 1 H), 9.08 (s, 1 H), 8.31 (d, J = 8.1 Hz, 1 H), 8.21 (d, J = 8.8 Hz, 1 H), 7.62 - 7.49 (m, 1 H), 7.39 (d, J = 15.7 Hz, 1 H), 7.34 - 7.29 (m, 1 H), 7.29 - 7.14 (m, 3H), 7.10 - 6.90 (m, 2H), 6.80 (t, J = 8.2 Hz, 1 H), 3.94 (s, 1 H), 3.38 - 3.33 (m, 1 H), 3.23 - 2.82 (m, 6H), 1 .88 - 1 .53 (m, 5H).

Example 116: 6-(((3R,4R)-3-methoxypiperidin-4-yl)amino)-N-(6-(o-tolyl)-5- (trifluoromethyl)pyridin-2-yl)pyridine-2-sulfonamide hydrochloride; Condition 2, LCMS: m/z 522.2 [M+H] ⁺ , 2.42 min. mixture of trans isomer: ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 1 1 .52 (s, 1 H), 8.92 (s, 1 H), 8.52 (s, 1 H), 8.18 (d, J = 8.9 Hz, 1 H), 7.58 (t, J = 7.8 Hz, 1 H), 7.51 (s, 1 H), 7.43 (d, J = 7.2 Hz, 1 H), 7.33 (t, J = 7.5 Hz, 1 H), 7.22 (dd, J = 14.3, 7.2 Hz, 2H), 7.1 1 - 6.99 (m, 2H), 6.78 (d, J = 8.4 Hz, 1 H), 3.84 (s, 1 H), 3.34 - 3.23 (m, 4H), 3.17 - 2.86 (m, 3H), 1 .99 - 1 .71 (m, 4H), 1 .63 - 1 .42 (m, 1 H).

Example 117: 6-(((3S,4R)-3-fluoropiperidin-4-yl)amino)-N-(6-(o-tolyl)-5- (trifluoromethyl)pyridin-2-yl)pyridine-2-sulfonamide hydrochloride; Condition 2, LCMS: m/z 510.2 [M+H] ⁺ , 2.54 min. mixture of cis isomer: ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 1 1 .52 (s, 1H), 9.19 (d, J = 7.4 Hz, 1H), 8.65 (q, J = 9.3, 8.6 Hz, 1H), 8.21 (d, J = 8.9 Hz, 1H), 7.60 (t, J = 7.8 Hz, 1H), 7.51 -7.37 (m, 2H), 7.37-7.28 (m, 1H), 7.27-7.18 (m, 2H), 7.12 (d, J = 7.2 Hz, 1 H), 7.03 (d, J = 6.5 Hz, 1 H), 6.80 (d, J = 8.4 Hz, 1 H), 4.99 - 4.62 (m, 1 H), 3.99 (d, J = 31.0 Hz, 1H), 3.53-3.30 (m, 1H), 3.32-3.13 (m, 2H), 3.04-2.91 (m, 1H), 1.88- 1.63 (m, 5H).

Example 118: 6-((3 ^, S,4'S)-4 ^, -hydroxy-[1 ,3'-bipyrrolidin]-1 '-yl)-N-(6-(o-tolyl)-5- (trifluoromethyl)pyridin-2-yl)pyridine-2-sulfonamide; Condition 2, LCMS: m/z 548.2

[M+H] ⁺ , 2.39 min. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 11.27 (s, 1 H), 7.97 (d, J = 8.7 Hz, 1 H), 7.44 (dd, J = 8.5, 7.4 Hz,2H), 7.11 (t, J = 7.4 Hz, 1H), 7.01 (dd, J = 16.5, 7.9 Hz, 2H), 6.93 - 6.83 (m, 2H), 6.46 (d, J = 8.6 Hz, 1H), 5.00 (s, 1H), 4.02 (s, 1H), 3.22 (s, 2H), 3.18 (s,2H), 3.05 (m, 1H),2.87(d, J = 9.8 Hz, 1H),2.29 (m,, 5H), 1.62 (d, J = 14.2 Hz, 3H), 1.43 (s,3H).

Example 119: (R)-6-(3-aminopyrrolidin-1 -yl)-N-(6-(o-tolyl)-5-(trifluoromethyl)pyridin-2- yl)pyridine-2-sulfonamide hydrochloride; Condition 2, LCMS: m/z 478.2 [M+H] ⁺ , 2.46 min. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 11.65 (s, 1H), 8.22 (d, J = 9.0 Hz, 1H), 8.19 (s, 3H), 7.70 (dd, J = 8.5, 7.4 Hz, 1H), 7.58 (s, 1H), 7.37-7.31 (m, 1H), 7.29-7.19 (m, 2H), 7.16 (d, J = 7.2 Hz, 1 H), 7.07 (d, J = 7.3 Hz, 1 H), 6.76 (d, J = 8.5 Hz, 1 H), 3.92 (s, 1 H), 3.62 - 3.54 (m, 1 H), 3.50 - 3.30 (m, 3H), 2.32 - 2.21 (m, 1 H), 2.11 - 2.01 (m, 1 H), 1.85 (s, 3H).

Example 120: (S)-6-(3-aminopyrrolidin-1 -yl)-N-(6-(o-tolyl)-5-(trifluoromethyl)pyridin-2- yl)pyridine-2-sulfonamide hydrochloride; Condition 2, LCMS: m/z 478.2 [M+H] ⁺ , 2.50 min. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 11.65 (s, 1 H), 8.30 - 8.16 (m, 4H), 7.70 (dd, J = 8.5, 7.4 Hz, 1 H), 7.59 (s, 1 H), 7.37 - 7.31 (m, 1 H), 7.29 - 7.19 (m, 2H), 7.15 (d, J = 7.2 Hz, 1 H), 7.07 (d, J = 7.4 Hz, 1 H), 6.75 (d, J = 8.5 Hz, 1 H), 3.96 - 3.86 (m, 1 H), 3.63 - 3.53 (m, 1 H), 3.49-3.30 (m, 3H), 2.27 (m, 1H), 2.07 (m, 1H), 1.85 (s, 3H).

Example 121 : (R)-6-(3-(methylamino)pyrrolidin-1 -yl)-N-(6-(o-tolyl)-5- (trifluoromethyl)pyridin-2-yl)pyridine-2-sulfonamide hydrochloride; Condition 2, LCMS: m/z 492.2 [M+H] ⁺ , 2.45 min. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 11.64 (s, 1H), 9.12-8.90 (m, 2H), 8.24 (d, J = 9.0 Hz, 1 H), 7.72 (dd, J = 8.5, 7.4 Hz, 1 H), 7.61 (d, J = 6.1 Hz, 1 H), 7.38 - 7.30 (m, 1 H), 7.29 - 7.19 (m, 2H), 7.17 (d, J = 7.2 Hz, 1 H), 7.08 (d, J = 7.2 Hz, 1 H), 6.77 (d, J = 8.5 Hz, 1 H), 3.88 - 3.80 (m, 1 H), 3.67 - 3.57 (m, 1 H), 3.35 - 3.27 (m, 1 H), 2.60 (t, J = 5.3 Hz, 3H), 2.33-2.26 (m, 1H), 2.20-2.10 (m, 1H), 1.86 (s, 3H).

Example 122: (S)-6-(3-(methylamino)pyrrolidin-1 -yl)-N-(6-(o-tolyl)-5- (trifluoromethyl)pyridin-2-yl)pyridine-2-sulfonamide hydrochloride; Condition 2, LCMS: m/z 492.2 [M+H] ⁺ , 2.47 min. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 11.65 (s, 1 H), 9.28 - 9.03 (m, 2H), 8.24 (d, J = 9.0 Hz, 1 H), 7.71 (dd, J = 8.5, 7.4 Hz, 1 H), 7.61 (d, J = 7.5 Hz, 1 H), 7.37 - 7.31 (m, 1H), 7.29-7.20 (m, 2H), 7.16 (d, J = 7.2 Hz, 1H), 7.08 (d, J = 7.3 Hz, 1H), 6.77 (d, J = 8.5 Hz, 1 H), 3.89 - 3.79 (m, 1 H), 3.65 - 3.60 (m, 1 H), 3.55 - 3.50 (m, 1 H), 3.49 - 3.43 (m, 1H), 3.35-3.25 (m, 1H), 2.59 (t, J = 5.3 Hz, 3H), 2.32-2.25 (m, 1H), 2.22-2.12 (m, 1H), 1.86 (s, 3H).

Example 123: (R)-6-(pyrrolidin-3-ylamino)-N-(6-(o olyl)-5-(trifluoromethyl)pyridin-2- yl)pyridine-2-sulfonamide hydrochloride; Condition 2, LCMS: m/z 478.2 [M+H] ⁺ , 2.47 min. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 11.64 (s, 1 H), 9.09 (s, 1 H), 9.01 (s, 1 H), 8.22 (d, J = 8.9 Hz, 1 H), 7.60 (dd, J = 8.4, 7.3 Hz, 1 H), 7.56 (s, 1 H), 7.48 (d, J = 8.2 Hz, 1 H), 7.36 - 7.30 (m, 1 H), 7.27-7.19 (m, 2H), 7.14 (d, J = 7.2 Hz, 1H), 7.06 (d, J = 6.7 Hz, 1H), 6.74 (d, J = 8.2 Hz, 1H), 4.15 (s, 1H), 3.38-3.23 (m, 2H), 3.18 (s, 1H), 3.04-2.87 (m, 1H), 2.15-1.99 (m, 1H), 1.80 (s, 4H).

Example 124: (S)-6-(pyrrolidin-3-ylamino)-N-(6-(o-tolyl)-5-(trifluorometh yl)pyridin-2- yl)pyridine-2-sulfonamide hydrochloride; Condition 2, LCMS: m/z 478.2 [M+H] ⁺ , 2.43 min. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 11.63 (s, 1H), 9.10 (s, 1H), 9.02 (s, 1H), 8.22 (d, J = 8.9 Hz, 1 H), 7.60 (dd, J = 8.4, 7.3 Hz, 1 H), 7.56 (s, 1 H), 7.48 (d, J = 8.7 Hz, 1 H), 7.38 - 7.29 (m, 1 H), 7.28-7.18 (m, 2H), 7.17-7.10 (m, 1H), 7.06 (d, J = 6.6 Hz, 1H), 6.74 (d, J = 8.1 Hz, 1H), 4.14 (s, 1H), 3.37-3.24 (m, 2H), 3.18 (s, 1H), 3.04-2.86 (m, 1H), 2.16-1.98 (m, 1H), 1.80 (s, 4H).

Example 125: N-(5-chloro-6-(2-(trifluoromethyl)phenyl)pyridin-2-yl)-6-((( 3S,4R)-4- hydroxytetrahydrofuran-3-yl)amino)pyridine-2-sulfonamide; Condition 2, LCMS: m/z 515.1 [M+H] ⁺ , 2.97 min. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 11.14 (s, 1H), 7.93 (d, J = 8.9 Hz, 1 H), 7.82 (d, J = 7.3 Hz, 1 H), 7.77 - 7.65 (m 2H), 7.54 (dd, J = 8.4, 7.3 Hz, 1 H), 7.45 (d, J = 8.9 Hz, 1 H), 7.40 - 7.27 (m, 2H), 7.06 (d, J = 7.2 Hz, 1 H), 6.71 (d, J = 8.4 Hz, 1 H), 5.21 - 5.09 (m, 1 H), 4.06 (s, 1 H), 3.94 - 3.80 (m, 3H), 3.48 (d, J = 9.6 Hz, 1 H), 3.43 - 3.36 (m, 1 H).

Example 126: N-(5-chloro-6-(2-(trifluoromethyl)phenyl)pyridin-2-yl)-6-((( 3R,4S)-4- hydroxytetrahydrofuran-3-yl)amino)pyridine-2-sulfonamide; Condition 2, LCMS: m/z 515.1 [M+H] ⁺ , 2.97 min. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 11.15 (s, 1H), 7.93 (d, J = 8.9 Hz, 1 H), 7.82 (d, J = 7.5 Hz, 1 H), 7.79 - 7.70 (m, 1 H), 7.68 (t, J = 7.5 Hz, 1 H), 7.54 (dd, J = 8.4, 7.3 Hz, 1 H), 7.45 (d, J = 8.9 Hz, 1 H), 7.41 - 7.27 (m, 2H), 7.06 (d, J = 7.1 Hz, 1 H), 6.71 (d, J = 8.5 Hz, 1 H), 5.21 - 5.11 (m, 1 H), 4.06 (s, 1 H), 3.90 (s, 1 H), 3.87 - 3.80 (m, 2H), 3.49 (d, J = 9.5 Hz, 1 H), 3.43 - 3.36 (m, 1 H). Example 127: N-(5-chloro-6-(5-fluoro-2-methylphenyl)pyridin-2-yl)-6-(((3R ,4S)-4- hydroxytetrahydrofuran-3-yl)amino)pyridine-2-sulfonamide; Condition 2, LCMS: m/z 479.2 [M+H] ⁺ , 3.04 min. ¹ H NMR (400 MHz, DMSO-d ₆ ) 611.16 (s, 1H), 7.93 (d, J = 8.8 Hz, 1H), 7.55 (dd, J = 7.3, 8.4 Hz, 1H), 7.34 (m, 2H), 7.29 (dd, J = 5.9, 8.5 Hz, 1H), 7.16 (td, J = 2.8, 8.6 Hz, 1H), 7.07 (m, 1H), 6.90 (dd, J = 2.4, 9.3 Hz, 1H), 6.70 (m, 1H), 5.15 (d, J = 3.6 Hz, 1 H), 4.04 (m, 1 H), 3.84 (m, 3H), 3.47 (dd, J = 2.3, 9.4 Hz, 1 H), 3.31 (m, 1 H), 1.86 (s, 3H). ¹⁹ F NMR (376 MHz, DMSO-d ₆ ) δ -117.86 (s). Example 128: N-(5-chloro-6-(5-fluoro-2-methylphenyl)pyridin-2-yl)-6-(((1S ,2R,3R,4R)-3- (hydroxymethyl)-7-oxabicyclo[2.2.1]heptan-2-yl)amino)pyridin e-2 -sulfonamide;

Condition 2, LCMS: m/z 519.2 [M+H] ⁺ , 3.11 min. ¹ H NMR (400 MHz, DMSO-d ₆ ) 611.10 (s, 1H), 7.99 (d, J = 8.9 Hz, 1H), 7.50 (m, 2H), 7.30 (dd, J = 5.8, 8.5 Hz, 1H), 7.16 (td, J = 2.8, 8.6 Hz, 1H), 7.10 (d, J = 8.6 Hz, 1H), 6.98 (m, 2H), 6.71 (d, J = 8.4 Hz, 1H), 4.44 (d, J = 4.0 Hz, 1H), 4.41 (t, J = 4.7 Hz, 1H), 4.10 (d, J = 4.3 Hz, 1H), 3.88 (t, J = 8.2 Hz, 1H), 3.17 (td, J = 5.3, 10.8 Hz, 1 H), 2.85 (m, 1 H), 1.91 (s, 3H), 1.78 (m, 1 H), 1.53 (m, 2H), 1.37 (m, 2H). ¹⁹ F NMR (376 MHz, DMSO-d ₆ ) δ -117.87 (s).

Example 129: (1 s,4s)-4-((6-(N-(5-chloro-6-(2,6-dimethylphenyl)pyridin-2- yl)sulfamoyl)pyridin-2-yl)oxy)cyclohexane-1-carboxylic acid; Condition 2, LCMS: m/z 516.2 [M+H] ⁺ ,3.23 min. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 12.14 (s, 1H), 11.37 (s, 1H), 7.99 (d, J = 8.8 Hz, 1H), 7.86 (dd, J = 7.4, 8.3 Hz, 1H), 7.48 (dd, J = 0.6, 7.3 Hz, 1H), 7.31 (d, J = 8.2 Hz, 1H), 7.17 (m, 1H), 7.04 (m, 3H), 4.89 (m, 1H), 2.35 (m, 1H), 1.62 (m, 14H). Example 130: (1r,4r)-4-((6-(N-(5-chloro-6-(2,6-dimethylphenyl)pyridin-2- yl)sulfamoyl)pyridin-2-yl)oxy)cyclohexane-1-carboxylic acid; Condition 2, LCMS: m/z 516.2 [M+H] ⁺ , 3.32 min. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 12.14 (s, 1H), 11.38 (s, 1H), 7.96 (d, J = 8.8 Hz, 1H), 7.86 (dd, J = 7.4, 8.3 Hz, 1H), 7.47 (m, 1H), 7.27 (d, J = 7.9 Hz, 1H), 7.17 (m, 1H), 7.04 (d, J = 7.6 Hz, 2H), 6.98 (d, J = 8.3 Hz, 1H), 4.69 (tt, J = 3.9, 10.2 Hz, 1H), 2.22 (tt, J = 3.3, 11.7 Hz, 1 H), 1.83 (m, 4H), 1.67 (s, 6H), 1.42 (m, 2H), 1.27 (m, 2H).

Example 131 : N-(5-chloro-6-(2,6-dimethylphenyl)pyridin-2-yl)-6-(3-oxopipe razin-1 - yl)pyridine-2-sulfonamide; Condition 2, LCMS: m/z 472.2 [M+H] ⁺ , 3.00 min. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 11.31 (s, 1H), 8.18 (s, 1H), 8.01 (d, J = 8.8 Hz, 1H), 7.78 (dd, J = 8.6, 7.3 Hz,1 H), 7.38 (d, J = 8.9 Hz,1 H), 7.29 - 7.21 (m, 2H), 7.13 (d, J = 7.6 Hz, 2H), 7.09 (d, J = 8.6 Hz, 1 H), 3.98 (s, 2H), 3.72 - 3.61 (m, 2H), 3.25 (t, J = 6.5 Hz, 2H), 1.81 (s,6H). Example 132: tert-butyl 4-(6-(N-(6-(2,6-dimethylphenyl)-4-(trifluoromethyl)pyridin-2 - yl)sulfamoyl)pyridin-2-yl)piperazine-1 -carboxylate; Condition 2, LCMS: m/z 592.3 [M+H] ⁺ , 3.58 min. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 1 1 .49 brs, 1 H), 7.76 (dd, J = 8.7, 7.3 Hz, 1 H), 7.69 (brs, 1 H), 7.34 (s, 1 H), 7.20 (dd, J = 7.3, 3.2 Hz, 2H), 7.09 (d, J = 8.3 Hz, 3H), 3.34 (brs, 4H), 3.25 (dd, J = 6.4, 3.3 Hz, 4H), 1 .84 (s, 6H), 1 .40 (s, 9H).

Example 133: N-(6-(2,6-dimethylphenyl)-4-(trifluoromethyl)pyridin-2-yl)-6 -(piperazin-1 - yl)pyridine-2-sulfonamide hydrochloride; Condition 2, LCMS: m/z 492.2 [M+H] ⁺ , 2.65 min. ¹ H NMR (600 MHz, DMSO-d ₆ ) δ 1 1 .59 (s, 1 H), 8.94 (s, 2 H), 7.81 (dd, J = 8.7, 7.4 Hz, 1 H), 7.59 (s, 1 H), 7.34 (s, 1 H), 7.28 (d, J = 7.2 Hz, 1 H), 7.24 - 7.18 (m, 1 H), 7.17 (d, J = 8.6 Hz, 1 H), 7.10 (d, J = 7.6 Hz, 2 H), 3.63 - 3.59 (m, 4H), 3.08 (s, 4H), 1 .84 (s, 6H).

Example 134: N-(5-chloro-6-(5-fluoro-2-methylphenyl)pyridin-2-yl)-6-((7S, 8aR)-7- fluorohexahydropyrrolo[1 ,2-a]pyrazin-2(1 H)-yl)pyridine-2 -sulfonamide; Condition 2, LCMS: m/z 520.1 [M+H] ⁺ , 2.58 min. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 1 1 .19 (s, 1 H), 7.98 (d, J = 8.8 Hz, 1 H), 7.72 (dd, J = 8.7, 7.3 Hz,1 H), 7.41 (d, J = 8.8 Hz,1 H), 7.30 (dd, J = 8.5, 5.8 Hz,1 H), 7.20 - 7.13 (m, 2H), 7.09 (d, J = 8.7 Hz, 1 H), 6.89 (dd, J = 9.3, 2.8 Hz, 1 H), 5.40 - 5.09 (m, 1 H), 4.23 (d, J = 1 1 .0 Hz, 1 H), 4.07 (d, J = 1 1 .6 Hz, 1 H), 3.52 (ddd, J = 16.6, 10.5, 6.3 Hz, 1 H), 2.92 (d, J = 1 1 .1 Hz, 1 H), 2.78 (td, J = 12.5, 3.1 Hz, 1 H), 2.42 - 2.34 (m, 1 H), 2.28 - 2.09 (m, 3H), 1 .99 - 1 .89 (m, 1 H), 1 .87 (s, 3H).

Example 135: N-(5-chloro-6-(5-fluoro-2-methylphenyl)pyridin-2-yl)-6-((1S, 7S)-7-fluoro-1 - methylhexahydropyrrolo[1 ,2-a]pyrazin-2(1 H)-yl)pyridine-2-sulfonamide; Condition 2, LCMS: m/z 534.1 [M+H] ⁺ , 2.64 min. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 1 1 .16 (d, J = 2.3 Hz, 1 H), 7.99 (d, J = 8.8 Hz, 1 H), 7.72 (dd, J = 8.7, 7.3 Hz, 1 H), 7.43 (d, J = 8.8 Hz, 1 H), 7.30 (dd, J = 8.5, 5.8 Hz, 1 H), 7.18 (dd, J = 8.6, 2.8 Hz,1 H), 7.14 (d, J = 7.2 Hz,1 H), 7.04 (d, J = 8.7 Hz,1 H), 6.87 (dd, J = 9.3, 2.6 Hz, 1 H), 5.47 - 5.17 (m,1 H), 4.37 (s,1 H), 4.06 (d, J = 10.4 Hz, 1 H), 3.53 (ddd, J = 15.8, 10.4, 6.4 Hz,1 H), 2.84 (d, J = 10.6 Hz, 1 H), 2.35 - 2.26 (m,1 H), 2.17 - 2.08 (m, 1 H), 1 .87 (s, 3H), 1 .68 - 1 .57 (m, 1 H), 1 .48 - 1 .35 (m, 1 H), 0.98 (d, J = 6.4 Hz, 3H).

Example 136: (S)-6-(7,7-difluorohexahydropyrrolo[1 ,2-a]pyrazin-2(1 H)-yl)-N-(6-(o-tolyl)- 5-(trifluoromethyl)pyridin-2-yl)pyridine-2-sulfonamide; Condition 2, LCMS: m/z 554.2 [M+H] ⁺ , 3.30 min. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 1 1 .70 (s, 1 H), 8.21 (d, J = 8.9 Hz, 1 H), 7.72 (dd, J = 8.6, 7.4 Hz, 1 H), 7.52 (s, 1 H), 7.36 - 7.28 (m, 1 H), 7.22 (dd, J = 13.5, 7.0 Hz, 2H), 7.16 (d, J = 7.2 Hz, 1 H), 7.10 (d, J = 8.7 Hz, 1 H), 7.06 (s, 1 H), 4.26 (t, J = 13.3 Hz,1 H), 4.15-4.05 (m, 1H), 3.41 (td, J = 12.3, 10.9, 2.8 Hz, 1H), 2.90 (t, J = 10.7 Hz, 1H), 2.35-2.13 (m, 2H), 2.13-2.03 (m, 1H), 1.91 (dd, J = 20.6, 14.0 Hz, 1H), 1.87- 1.69 (m, 4H).

Example 137: 6-((7S,8aS)-7-fluorohexahydropyrrolo[1 ,2-a]pyrazin-2(1 H)-yl)-N-(6-(o- tolyl)-5-(trifluoromethyl)pyridin-2-yl)pyridine-2-sulfonamid e; Condition 2, LCMS: m/z 536.3 [M+H] ⁺ , 2.60 min. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 11.62 (s, 1 H), 8.22 (d, J = 8.9 Hz, 1 H), 7.71 (dd, J = 8.7, 7.3 Hz, 1 H), 7.53 (d, J = 8.7 Hz, 1 H), 7.32 (td, J = 7.5, 1.3 Hz, 1 H), 7.22 (dd, J = 13.2, 7.0 Hz, 2H), 7.14 (d, J = 7.2 Hz, 1H), 7.09 (d, J = 8.7 Hz, 1H), 7.05 (d, J = 7.5 Hz, 1H), 5.17 (d, J = 55.8 Hz, 1H), 4.23 (s, 1H), 4.08 (d, J = 12.7 Hz, 1H), 3.16 (dd, J = 21.9, 11.4 Hz, 1 H), 2.96 (d, J = 10.5 Hz, 1 H), 2.84 (t, J = 12.1 Hz, 1 H), 2.40 - 2.26 (m, 1H), 2.16 (ddd, J = 34.9, 11.3, 4.8 Hz, 1H), 1.92 (d, J = 5.7 Hz, 1H), 1.78 (brs, 4H), 1.57- 1.35 (m, 1H).

Example 138: 6-((7S,8aR)-7-fluorohexahydropyrrolo[1 ,2-a]pyrazin-2(1 H)-yl)-N-(6-(o- tolyl)-5-(trifluoromethyl)pyridin-2-yl)pyridine-2-sulfonamid e; Condition 2, LCMS: m/z 536.3 [M+H] ⁺ , 2.58 min. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 11.65 (s, 1 H), 8.20 (d, J = 8.9 Hz,1H), 7.71 (dd, J = 8.7, 7.3 Hz, 1H), 7.53 (d, J = 8.6 Hz, 1H), 7.32 (td, J = 7.5, 1.3 Hz, 1H), 7.22 (dd, J = 13.2, 7.1 Hz, 2H), 7.14 (d, J = 7.2 Hz, 1H), 7.09 (d, J = 8.7 Hz,1H), 7.05 (d, J = 7.4 Hz, 1H), 5.36 - 5.11 (m, 1H), 4.26 (t, J = 10.8 Hz, 1H), 4.06 (brs, 1H), 3.52 (ddd, J = 16.7, 10.5, 6.3 Hz, 1 H), 2.89 (d, J = 10.4 Hz, 1 H), 2.78 (t, J = 11.9 Hz, 1 H), 2.39 (t, J = 11.3 Hz, 1 H), 2.29 - 2.03 (m, 3H), 1.96 - 1.81 (m, 1 H), 1.78 (d, J = 6.9 Hz, 3H).

Example 139: N-(6-(2,6-dimethylphenyl)-4-methoxypyridin-2-yl)-6-(piperazi n-1 - yl)pyridine-2-sulfonamide; Condition 2, LCMS: m/z 454.3 [M+H] ⁺ , 2.14 min. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.00 (s, 1 H), 7.78 (dd, J = 8.6, 7.4 Hz, 1 H), 7.24 (t, J = 6.3 Hz, 2H), 7.11 (dd, J = 13.0, 8.0 Hz, 4H), 6.44 (s, 1H), 3.84 (s, 3H), 3.73 - 3.68 (m, 2H), 3.54 - 3.45 (m, 2H), 3.13 (s, 4H), 2.02 (s, 6H).

Example 140: 6-(4-(tert-butyl)piperazin-1 -yl)-N-(5-chloro-6-(3-fluoro-2- methylphenyl)pyridin-2-yl)pyridine-2 -sulfonamide; Condition 2, LCMS: m/z 518.2 [M+H] ⁺ , 2.52 min. ¹ H NMR (400 MHz, Methylene Chloride-d ₂ ) δ 7.72 (m, 1H), 7.63 - 7.52 (m, 2H), 7.28-7.12 (m, 2H), 7.14-7.03 (m, 1H), 6.96 (dd, J = 7.6, 1.2 Hz, 1H), 6.75 (m, 1H), 3.40 (m, 4H), 2.57 (m, 4H), 1.97 (d, J = 2.3 Hz, 3H), 1.06 (s, 9H). Example 141: N-(5-chloro-6-(3-fluoro-2-methylphenyl)pyridin-2-yl)-6-(4- cyclopropylpiperazin-1-yl)pyridine-2 -sulfonamide; Condition 2, LCMS: m/z 502.2 [M+H] ⁺ , 2.62 min. ¹ H NMR (400 MHz, Methylene Chloride-d ₂ ) δ 7.74 (m, 1H), 7.63 - 7.54 (m, 2H), 7.22 (q, J = 7.2 Hz, 2H), 7.09 (t, J = 8.9 Hz, 1 H), 6.97 (m, 1 H), 6.78 (m, 1 H), 3.38 (m, 4H), 2.57 (m, 4H), 1 .96 (m, 3H), 1 .56 (m, 1 H), 0.45 (m, 4H).

Example 142: 6-(4-(tert-butyl)piperazin-1 -yl)-N-(6-(3-fluoro-2-methylphenyl)-5- (trifluoromethyl)pyridin-2-yl)pyridine-2-sulfonamide; Condition 2, LCMS: m/z 552.3

[M+H] ⁺ , 2.55 min. ¹ H NMR (400 MHz, Methylene Chloride-d ₂ ) δ 12.70 (m, 1 H), 7.89 (m, 1 H), 7.60 (dd, J=7.3, 8.6 Hz, 2H), 7.30 (m, 1 H), 7.21 (td, J=5.5, 7.9 Hz, 1 H), 7.10 (m, 1 H), 6.92 (m, 1 H), 6.68 (m, 1 H), 3.52 (m, 4H), 2.73 (m, 4H), 1 .90 (m, 3H), 1 .17 (s, 9H). Example 143: 6-(4-(tert-butyl)piperazin-1 -yl)-N-(6-(5-fluoro-2-methylphenyl)-5-

(trifluoromethyl)pyridin-2-yl)pyridine-2-sulfonamide; Condition 2, LCMS: m/z 552.3

[M+H] ⁺ , 2.59 min. ¹ H NMR (400 MHz, Methylene Chloride-d ₂ ) δ 7.81 (d, J=8.9 Hz, 1 H), 7.59 (dd, J=7.3, 8.6 Hz, 1 H), 7.50 (d, J=8.9 Hz, 1 H), 7.33 (d, J=7.2 Hz, 1 H), 7.23 (dd, J=5.6, 8.5 Hz, 1 H), 7.04 (td, J=2.8, 8.5 Hz, 1 H), 6.82 (dd, J=2.8, 9.1 Hz, 1 H), 6.64 (d, J=8.6 Hz, 1 H), 3.74 - 3.50 (m, 4H), 2.83 (t, J=5.2 Hz, 4H), 1 .95 (s, 3H), 1 .22 (s, 9H).

Example 144: 6-(4-cyclopropylpiperazin-1 -yl)-N-(6-(3-fluoro-2-methylphenyl)-5- (trifluoromethyl)pyridin-2-yl)pyridine-2-sulfonamide; Condition 2, LCMS: m/z 536.3

[M+H] ⁺ , 2.71 min. ¹ H NMR (400 MHz, Methylene Chloride-d ₂ ) δ 8.10 (m, 1 H), 7.66 (dd, J = 8.7, 7.3 Hz, 1 H), 7.60 (m, 1 H), 7.25 - 7.17 (m, 2H), 7.1 1 (t, J = 9.0 Hz, 1 H), 6.97 (m, 1 H),

6.90 (m, 1 H), 3.52 - 3.39 (m, 4H), 2.65 - 2.54 (m, 4H), 1 .81 (d, J = 2.1 Hz, 3H), 1 .65 (m, 1 H), 0.59 - 0.39 (m, 4H).

Example 145: 6-(4-cyclopropylpiperazin-1 -yl)-N-(6-(5-fluoro-2-methylphenyl)-5- (trifluoromethyl)pyridin-2-yl)pyridine-2-sulfonamide; Condition 2, LCMS: m/z 536.2

[M+H] ⁺ , 2.69 min. ¹ H NMR (400 MHz, Methylene Chloride-d ₂ ) δ 7.99 (m, 1 H), 7.69 (m, 1 H), 7.60 (dd, J = 8.7, 7.2 Hz, 1 H), 7.29 - 7.17 (m, 2H), 7.04 (td, J = 8.5, 2.8 Hz, 1 H), 6.89 - 6.75 (m, 2H), 3.41 - 3.33 (m, 4H), 2.60 - 2.52 (m, 4H), 1 .94 (s, 3H), 1 .65 - 1 .55 (m, 1 H), 0.51 - 0.37 (m, 4H).

Example 146: N-(5-chloro-6-(3-fluoro-2-methylphenyl)pyridin-2-yl)-6-(5,6- dihydro- [1 ,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)pyridine-2-sulfonamide; Condition 2, LCMS: m/z 500.1 [M+H] ⁺ , 2.92 min. ¹ H NMR (400 MHz, Methylene Chloride-d ₂ ) δ 12.67 (m, 1 H), 8.68 (m, 1 H), 7.77 - 7.66 (m, 2H), 7.45 (m, 1 H), 7.37 (m, 1 H), 7.17 (m, 1 H), 7.05 (t, J=8.8 Hz, 1 H), 6.98 (m, 1 H), 6.83 (m, 1 H), 4.25 (m, 2H), 4.07 (m, 2H), 1 .86 (m, 2H), 1 .26 (s, 3H). Example 147: tert-butyl 4-(6-(N-(6-(2-cyclopropylphenyl)-5-(trifluoromethyl)pyridin- 2- yl)sulfamoyl)pyridin-2-yl)piperazine-1 -carboxylate; Condition 1 , LCMS: m/z 604.2 [M+H] ⁺ ,

1 .37 min. ¹ H NMR (400 MHz, Methylene Chloride-d ₂ ) δ 8.02 (m, 1 H), 7.72 - 7.61 (m, 2H),

7.38 - 7.27 (m, 2H), 7.20 (td, J = 7.5, 1 .2 Hz, 1 H), 7.09 (m, 1 H), 6.97 (m, 1 H), 6.81 (m, 1 H), 3.41 (m, 8H), 1 .45 (s, 9H), 1 .42 - 1 .36 (m, 1 H), 0.70 - 0.47 (m, 4H).

Example 148: N-(6-(2-cyclopropylphenyl)-5-(trifluoromethyl)pyridin-2-yl)- 6-(piperazin-1 - yl)pyridine-2-sulfonamide; Condition 2, LCMS: m/z 504.2 [M+H] ⁺ , 2.54 min. ¹ H NMR (400 MHz, Methylene Chloride-d ₂ ) δ 7.89 (m, 1 H), 7.65 (dd, J = 8.6, 7.4 Hz, 1 H), 7.48 - 7.38 (m, 2H), 7.32 (td, J = 7.7, 1 .3 Hz, 1 H), 7.16 (td, J = 7.5, 1 .0 Hz, 1 H), 7.07 (m, 1 H), 6.88 (m, 1 H), 6.72 (m, 1 H), 3.64 (m, 4H), 3.12 (m, 4H), 1 .42 - 1 .29 (m, 1 H), 0.67 - 0.42 (m, 4H).

Example 149: 6-(4-(tert-butyl)piperazin-1 -yl)-N-(6-(5-fluoro-2-methoxyphenyl)-5- (trifluoromethyl)pyridin-2-yl)pyridine-2-sulfonamide; Condition 2, LCMS: m/z 568.3

[M+H] ⁺ , 2.38 min. ¹ H NMR (400 MHz, Methylene Chloride-d ₂ ) δ 7.95 (m, 1 H), 7.74 (m, 1 H), 7.58 (t, J = 7.9 Hz, 1 H), 7.49 (m, 1 H), 7.29 (m, 1 H), 7.10 (td, J = 8.6, 3.1 Hz, 1 H), 6.88 (m, 2H), 6.65 (m, 1 H), 3.70 (s, 3H), 3.50 - 3.44 (m, 2H), 3.37 - 3.30 (m, 2H), 2.75 (m, 2H), 2.54 (m, 2H), 1 .06 (s, 9H). Example 150: N-(6-(2-chlorophenyl)-5-(trifluoromethyl)pyridin-2-yl)-6-(pi perazin-1 - yl)pyridine-2-sulfonamide hydrochloride; Condition 2, LCMS: m/z 498.1 [M+H] ⁺ , 2.38 min. ¹ H NMR (400 MHz, Acetonitrile-d ₃ ) δ 9.37 (s, 2H), 8.1 1 (d, J=9.0 Hz, 1 H), 7.73 (dd, J=7.3, 8.7 Hz, 1 H), 7.64 (d, J=8.9 Hz, 1 H), 7.54 - 7.41 (m, 2H), 7.41 (td, J=1 .8, 7.3 Hz, 1 H), 7.34 - 7.25 (m, 2H), 6.99 (d, J=8.7 Hz, 1 H), 3.80 (t, J=4.7 Hz, 4H), 3.15 (s, 4H); ¹⁹ F NMR (376 MHz, Acetonitrile-ds) δ -59.30 (s, 3F).

Example 151 : N-(6-(3-fluoro-2-methylphenyl)-5-(trifluoromethyl)pyridin-2- yl)-6- (piperazin-1 -yl)pyridine-2-sulfonamide hydrochloride; Condition 2, LCMS: m/z 496.1 [M+H] ⁺ , 2.53 min. ¹ H NMR (400 MHz, Acetonitrile-d ₃ ) δ 9.1 1 (s, 2H), 8.30 (d, J=9.1 Hz, 1 H), 7.86 (d, J=9.0 Hz, 1 H), 7.81 - 7.69 (m, 1 H), 7.36 (d, J=7.3 Hz, 1 H), 7.37 - 7.28 (m, 2H), 7.23 (t, J=9.0 Hz, 1 H), 7.08 (s, 1 H), 7.05 (d, J=8.9 Hz, 1 H), 3.85 (d, J=4.7 Hz, 4H), 3.19 (s, 4H), 1 .90 (d, J=1 .6 Hz, 3H); ¹⁹ F NMR (376 MHz, Acetonitrile-d ₃ ) δ -59.12 (s, 3F), -1 17.47 (s, 1 F).

Example 152: N-(6-(5-fluoro-2-methylphenyl)-5-(trifluoromethyl)pyridin-2- yl)-6- (piperazin-1 -yl)pyridine-2-sulfonamide hydrochloride; Condition 2, LCMS: m/z 496.1 [M+H] ⁺ , 2..48 min. ¹ H NMR (400 MHz, Acetonitrile-d ₃ ) δ 8.85 (s, 2H), 8.37 (s, 1 H), 7.95 (s, 1 H), 7.79 (dd, J=7.3, 8.7 Hz, 1 H), 7.43 - 7.32 (m, 2H), 7.21 (td, J=2.8, 8.7 Hz, 1 H), 7.12 - 7.01 (m, 2H), 3.86 (t, J=5.0 Hz, 4H), 3.21 (q, J=4.7 Hz, 4H), 2.01 (d, J=2.2 Hz, 3H); ¹⁹ F NMR (376 MHz, Acetonitrile-ds) δ -59.25 (s, 3F), -1 18.89 (s, 1 F).

Example 153: N-(6-(2-chloro-4-fluorophenyl)-5-(trifluoromethyl)pyridin-2- yl)-6- (piperazin-1 -yl)pyridine-2-sulfonamide hydrochloride; Condition 2, LCMS: m/z 516.1 [M+H] ⁺ , 2.41 min. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 1 1 .78 (s, 1 H), 8.77 (s, 2H), 8.26 (d, J=8.9 Hz, 1 H), 7.81 (dd, J=7.4, 8.6 Hz, 1 H), 7.61 (d, J=8.6 Hz, 1 H), 7.56 (dd, J=2.5, 8.9 Hz, 1 H), 7.45 - 7.36 (m, 1 H), 7.31 (td, J=2.5,8.5 Hz, 1 H), 7.27 (d, J=7.3 Hz, 1 H), 7.17 (d, J=8.7 Hz, 1 H), 3.62 (s, 4H), 3.10 (s, 4H); ¹⁹ F NMR (376 MHz, DMSO-d ₆ ) δ - 57.49 (s, 3F), - 1 10.30 ( s, 1 F).

Example 154: N-(6-(2-chloro-5-methoxyphenyl)-5-(trifluoromethyl)pyridin-2 -yl)-6- (piperazin-1 -yl)pyridine-2-sulfonamide hydrochloride; Condition 2, LCMS: m/z 528.1 [M+H] ⁺ , 2.41 min. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 1 1 .75 (s, 1 H), 9.26 (s, 2H), 8.25 (d, J=8.9 Hz, 1 H), 7.81 (t, J=8.0 Hz, 1 H), 7.62 (d, J=8.7 Hz, 1 H), 7.42 (d, J=8.9 Hz, 1 H), 7.28 (d, J=7.3 Hz, 1 H), 7.18 (d, J=8.7 Hz, 1 H), 7.06 (dd, J=3.0, 8.9 Hz, 1 H), 6.89 (d, J=2.6 Hz, 1 H), 3.76 (s, 3H), 3.70 - 3.62 (m, 4H), 3.09 (s, 4H); ¹⁹ F NMR (376 MHz, DMSO-d ₆ ) δ -57.39 (s, 1 F).

Example 155: N-(6-(2-chloro-3-fluorophenyl)-5-(trifluoromethyl)pyridin-2- yl)-6- (piperazin-1 -yl)pyridine-2-sulfonamide hydrochloride; Condition 2, LCMS: m/z 516.1

[M+H] ⁺ , 2.44 min. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 1 1 .80 (s, 1 H), 9.18 (s, 2H), 8.29 (d, J=9.0 Hz, 1 H), 7.81 (t, J=8.0 Hz, 1 H), 7.62 (d, J=8.8 Hz, 1 H), 7.58 - 7.51 (m, 1 H), 7.48 (td, J=5.4, 8.0 Hz, 1 H), 7.26 (d, J=7.3 Hz, 1 H), 7.22 (s, 1 H), 7.19 (d, J=8.8 Hz, 1 H), 3.65 (s, 6H), 3.09 (s, 4H); ¹⁹ F NMR (376 MHz, DMSO-d ₆ ) δ - 57.47 (s, 3F), - 1 15.40 (dd, J=5.5, 9.0 Hz, 1 F).

Example 156: N-(5-chloro-6-(2-chlorophenyl)pyridin-2-yl)-6-(piperazin-1 -yl)pyridine-2- sulfonamide; Condition 2, LCMS: m/z 464.1 [M+H] ⁺ , 2.32 min. ¹ H NMR (400 MHz, DMSO- de) δ 7.75 (d, J=8.9 Hz, 1 H), 7.69 (dd, J=7.3, 8.6 Hz, 1 H), 7.50 (dd, J=1 .2, 8.0 Hz, 1 H), 7.43 (td, J=1 .7, 7.7 Hz, 1 H), 7.37 - 7.28 (m, 2H), 7.21 - 7.14 (m, 2H), 6.94 (d, J=8.7 Hz, 1 H), 3.46 - 3.40 (m, 4H), 2.90 - 2.80 (m, 4H).

Example 157: N-(5-chloro-6-(2-chloro-4-fluorophenyl)pyridin-2-yl)-6-(pipe razin-1 - yl)pyridine-2-sulfonamide; Condition 2, LCMS: m/z 482.1 [M+H] ⁺ , 2.42 min. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 7.74 (d, J=8.9 Hz, 1 H), 7.72 - 7.67 (m, 1 H), 7.49 (d, J=8.6 Hz, 1 H), 7.30 (d, J=8.9 Hz, 1 H), 7.20 (dd, J=3.2, 6.9 Hz, 3H), 6.94 (d, J=8.6 Hz, 1 H), 3.45 (d, J=4.8 Hz, 4H), 2.90 (s, 4H); ¹⁹ F NMR (376 MHz, DMSO-d ₆ ) δ -1 1 1 .03 (s, 1 F). Example 158: N-(5-chloro-6-(2-chloro-5-methoxyphenyl)pyridin-2-yl)-6-(pip erazin-1 - yl)pyridine-2-sulfonamide hydrochloride; Condition 2, LCMS: m/z 494.1 [M+H] ⁺ , 2.38 min. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 1 1 .33 (s, 1 H), 8.85 (s, 2H), 7.99 (d, J=8.8 Hz, 1 H), 7.82 (t, J=8.0 Hz, 1 H), 7.45 (dd, J=6.2, 8.8 Hz, 2H), 7.28 (d, J=7.3 Hz, 1 H), 7.18 (d, J=8.7 Hz, 1 H), 7.05 (dd, J=3.0, 8.9 Hz, 1 H), 6.80 (d, J=2.9 Hz, 1 H), 3.76 (s, 4H), 3.65 (s, 6H), 3.1 1 (s, 4H).

Example 159: N-(5-chloro-6-(2-chloro-3-fluorophenyl)pyridin-2-yl)-6-(pipe razin-1 - yl)pyridine-2-sulfonamide hydrochloride; Condition 1 , LCMS: m/z 482.1 [M+H] ⁺ , 0.71 min. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 1 1 .37 (s, 1 H), 8.85 (s, 2H), 8.03 (d, J=8.9 Hz, 1 H), 7.87 - 7.77 (m, 1 H), 7.58 - 7.43 (m, 3H), 7.27 (d, J=7.3 Hz, 1 H), 7.18 (d, J=8.7 Hz, 1 H), 7.14 (d, J=7.2 Hz, 1 H), 3.64 (s, 6H), 3.12 (s, 5H); ¹⁹ F NMR (376 MHz, DMSO-d ₆ ) δ -1 14.95 (dd, J=5.6, 9.0 Hz, 1 F).

Example 160: tert-butyl 4-(6-(N-(6-(o-tolyl)-5-(trifluoromethyl)pyridin-2- yl)sulfamoyl)pyridin-2-yl)piperazine-1 -carboxylate; Condition 2, LCMS: m/z 577.6 [M+H] ⁺ , 3.41 min.

Example 161 : 6-(piperazin-1 -yl)-N-(6-(o-tolyl)-5-(trifluoromethyl)pyridin-2-yl)pyridine -2- sulfonamide hydrochloride; Condition 2, LCMS: m/z 478.2 [M+H] ⁺ , 2.47 min. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 1 1 .68 (s, 1 H), 9.05 (s, 2H), 8.23 (d, J = 8.9 Hz, 1 H), 7.79 (dd, J = 8.6, 7.4 Hz, 1 H), 7.51 (d, J = 6.6 Hz, 1 H), 7.38 - 7.29 (m, 1 H), 7.28 - 7.19 (m, 3H), 7.17 (d, J = 8.7 Hz, 1 H), 7.08 (d, J = 7.4 Hz, 1 H), 3.68 - 3.62 (m, 4H), 3.10 (s, 4H), 1 .81 (s, 3H).

Example 162: tert-butyl 4-(6-(N-(5-chloro-6-(2,6-dimethylphenyl)pyridin-2- yl)sulfamoyl)pyridin-2-yl)piperazine-1 -carboxylate; Condition 1 , LCMS: m/z 558.3 [M+H] ⁺ , 1 .34 min.

Example 163: N-(5-chloro-6-(2,6-dimethylphenyl)pyridin-2-yl)-6-(piperazin -1 -yl)pyridine- 2-sulfonamide hydrochloride; Condition 2, LCMS: m/z 458.2 [M+H] ⁺ , 2.48 min. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 1 1 .27 (s, 1 H), 8.93 (s, 2H), 7.98 (d, J = 8.8 Hz, 1 H), 7.78 (dd, J = 8.6, 7.4 Hz, 1 H), 7.33 (d, J = 8.7 Hz, 1 H), 7.24 - 7.17 (m, 2H), 7.15 (d, J = 8.6 Hz, 1 H), 7.08 (d, J = 7.6 Hz, 2H), 3.67 - 3.62 (m, 4H), 3.1 1 (s, 4H), 1 .76 (s, 6H).

Example 164: tert-butyl (R)-2-(hydroxymethyl)-4-(6-(N-(6-(o-tolyl)-5- (trifluoromethyl)pyridin-2-yl)sulfamoyl)pyridin-2-yl)piperaz ine-1 -carboxylate; Condition 1 , LCMS: m/z 608.3 [M+H] ⁺ , 1 .22 min. Example 165: (R)-6-(3-(hydroxymethyl)piperazin-1 -yl)-N-(6-(o-tolyl)-5- (trifluoromethyl)pyridin-2-yl)pyridine-2-sulfonamide hydrochloride; Condition 2, LCMS: m/z 508.2 [M+H] ⁺ , 2.48 min. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 1 1 .67 (s, 1 H), 9.16 (s, 1 H), 8.86 (s, 1 H), 8.22 (d, J = 8.9 Hz, 1 H), 7.80 (dd, J = 8.6, 7.4 Hz, 1 H), 7.53 (s, 1 H), 7.34 (t, J = 7.5 Hz, 1 H), 7.28 - 7.16 (m, 4H), 7.08 (d, J = 6.9 Hz, 1 H), 5.55 (t, J = 4.7 Hz, 1 H), 4.21 (t, J = 13.4 Hz, 2H), 3.69 - 3.62 (m, 1 H), 3.55 - 3.50 (m, 1 H), 3.29 - 3.15 (m, 2H), 3.09 (t, J = 1 1 .7 Hz, 1 H), 3.04 - 2.89 (m, 2H), 1 .80 (s, 3H).

Example 166: tert-butyl (R)-2-methyl-4-(6-(N-(6-(o-tolyl)-5-(trifluoromethyl)pyridin -2- yl)sulfamoyl)pyridin-2-yl)piperazine-1 -carboxylate; Condition 1 , LCMS: m/z 592.3 [M+H] ⁺ , 1 .35 min.

Example 167: (R)-6-(3-methylpiperazin-1 -yl)-N-(6-(o-tolyl)-5-(trifluoromethyl)pyridin-2- yl)pyridine-2-sulfonamide hydrochloride; Condition 2, LCMS: m/z 492.3 [M+H] ⁺ , 2.51 min. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 1 1 .65 (s, 1 H), 9.08 (d, J = 6.3 Hz, 1 H), 8.83 (d, J = 9.0 Hz, 1 H), 8.23 (d, J = 8.9 Hz, 1 H), 7.80 (dd, J = 8.6, 7.4 Hz, 1 H), 7.55 (d, J = 6.9 Hz, 1 H), 7.34 (t, J = 7.5 Hz, 1 H), 7.28 - 7.17 (m, 4H), 7.08 (d, J = 7.0 Hz, 1 H), 4.19 (d, J = 13.5 Hz, 2H), 3.20 (s, 1 H), 3.12 - 3.02 (m, 1 H), 3.01 - 2.89 (m, 1 H), 2.88 - 2.76 (m, 1 H), 1 .81 (s, 3H), 1 .20 (d, J = 6.5 Hz, 3H).

Example 168: tert-butyl 4-(6-(N-(5-chloro-6-(2-methyl-5-(trifluoromethyl)phenyl)pyri din- 2-yl)sulfamoyl)pyridin-2-yl)piperazine-1 -carboxylate; Condition 1 , LCMS: m/z 612.2

[M+H] ⁺ , 1 .38 min. Example 169: N-(5-chloro-6-(2-methyl-5-(trifluoromethyl)phenyl)pyridin-2- yl)-6-

(piperazin-1 -yl)pyridine-2-sulfonamide hydrochloride; Condition 2, LCMS: m/z 512.2 [M+H] ⁺ , 2.64 min. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 1 1 .35 (s, 1 H), 9.00 (s, 2H), 8.02 (d, J = 8.8 Hz, 1 H), 7.78 (dd, J = 8.6, 7.4 Hz, 1 H), 7.75 - 7.67 (m, 1 H), 7.54 (d, J = 8.1 Hz, 1 H), 7.41 - 7.34 (m, 2H), 7.25 (d, J = 7.3 Hz, 1 H), 7.17 (d, J = 8.7 Hz, 1 H), 3.69 - 3.63 (m, 4H), 3.1 1 (s, 4H), 2.01 (s, 3H).

Example 170: (S)-6-(2-methylpiperazin-1 -yl)-N-(6-(o-tolyl)-5-(trifluoromethyl)pyridin-2- yl)pyridine-2-sulfonamide hydrochloride; Condition 2, LCMS: m/z 492.2 [M+H] ⁺ , 2.52 min. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 1 1 .66 (s, 1 H), 9.23 (s, 1 H), 8.75 (s, 1 H), 8.23 (d, J = 8.9 Hz, 1 H), 7.79 (dd, J = 8.5, 7.5 Hz, 1 H), 7.52 (s, 1 H), 7.33 (t, J = 7.5 Hz, 1 H), 7.23 (q, J = 9.6, 7.8 Hz, 3H), 7.1 1 (d, J = 8.7 Hz, 1 H), 7.09 - 6.97 (m, 1 H), 4.60 (s, 1 H), 4.15 - 4.04 (m, 1 H), 3.30 - 3.20 (m, 2H), 3.18 - 2.85 (m, 3H), 1 .79 (d, J = 17.2 Hz, 3H), 1 .07 - 0.95 (m, 3H). Example 171 : (R)-6-(2-methylpiperazin-1 -yl)-N-(6-(o-tolyl)-5-(trifluoromethyl)pyridin-2- yl)pyridine-2-sulfonamide hydrochloride; Condition 2, LCMS: m/z 492.2 [M+H] ⁺ , 2.55 min. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 11.66 (s, 1H), 9.18 (s, 1H), 8.70 (s, 1H), 8.23 (d, J = 8.9 Hz, 1H), 7.79 (dd, J = 8.5, 7.5 Hz, 1H), 7.52 (s, 1H), 7.38-7.29 (m, 1H), 7.28-7.18 (m, 3H), 7.11 (d, J = 8.7 Hz, 1H), 7.08-6.91 (m, 1H), 4.59 (s, 1H), 4.16-4.03 (m, 1H), 3.30-3.21 (m, 2H), 3.18-2.87 (m, 3H), 1.79 (d, J = 16.3 Hz, 3H), 1.08-0.93 (m, 3H).

Example 172: (R)-N-(6-(2,6-dimethylphenyl)-5-(trifluoromethyl)pyridin-2-y l)-6-(3- (hydroxymethyl)piperazin-1-yl)pyridine-2 -sulfonamide hydrochloride; Condition 2,

LCMS: m/z 522.2 [M+H] ⁺ , 2.58 min. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 11.69 (s, 1H), 9.14 (d, J = 10.3 Hz, 1 H), 8.82 (q, J = 9.6, 8.8 Hz, 1 H), 8.23 (d, J = 8.9 Hz, 1 H), 7.78 (dd, J = 8.6, 7.4 Hz, 1 H), 7.49 (s, 1 H), 7.25 - 7.15 (m, 3H), 7.07 (d, J = 7.6 Hz, 2H), 5.55 (s, 1 H), 4.22 (t, J = 10.7 Hz, 2H), 3.69-3.62 (m, 1H), 3.57-3.51 (m, 1H), 3.28 (d, J = 11.8 Hz, 1H), 3.17 (s, 1H), 3.12-2.98 (m, 1H), 2.99-2.87 (m, 2H), 1.73 (s, 6H).

Example 173: (S)-N-(6-(2,6-dimethylphenyl)-5-(trifluoromethyl)pyridin-2-y l)-6-(3- (hydroxymethyl)piperazin-1-yl)pyridine-2 -sulfonamide hydrochloride; Condition 2, LCMS: m/z 522.2 [M+H] ⁺ , 2.58 min. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 11.69 (s, 1H), 9.13 (s, 1 H), 8.82 (d, J = 9.7 Hz, 1 H), 8.23 (d, J = 8.9 Hz, 1 H), 7.78 (dd, J = 8.6, 7.4 Hz, 1 H), 7.48 (s, 1 H), 7.26 - 7.14 (m, 3H), 7.07 (d, J = 7.6 Hz, 2H), 5.55 (s, 1 H), 4.22 (t, J = 10.8 Hz, 2H), 3.71 -3.61 (m, 1H), 3.59-3.52 (m, 1H), 3.32-3.24 (m, 1H), 3.18 (s, 1H), 3.06 (t, J = 11.7 Hz, 1 H), 3.01 - 2.88 (m, 2H), 1.73 (s, 6H). Example 174: (R)-N-(6-(5-fluoro-2-methylphenyl)-5-(trifluoromethyl)pyridi n-2-yl)-6-(3- (hydroxymethyl)piperazin-1-yl)pyridine-2 -sulfonamide hydrochloride; Condition 2, LCMS: m/z 526.2 [M+H] ⁺ , 2.54 min. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 11.74 (s, 1 H), 9.21 (d, J = 9.2 Hz, 1H), 8.90 (q, J = 9.2 Hz, 1H), 8.24 (d, J = 8.9 Hz, 1H), 7.80 (dd, J = 8.6, 7.4 Hz, 1 H), 7.54 (d, J = 8.4 Hz, 1 H), 7.29 (dd, J = 8.5, 5.8 Hz, 1 H), 7.26 (d, J = 7.3 Hz, 1 H), 7.22 - 7.16 (m, 2H), 6.98 (d, J = 8.3 Hz, 1H), 5.55 (s, 1H), 4.22 (t, J = 12.5 Hz, 2H), 3.69-3.62 (m, 1H), 3.59-3.53 (m, 1H), 3.26 (d, J = 12.3 Hz, 1H), 3.19 (s, 1H), 3.14-3.04 (m, 1H), 3.03- 2.90 (m, 2H), 1.76 (s, 3H).

Example 175: (S)-N-(6-(5-fluoro-2-methylphenyl)-5-(trifluoromethyl)pyridi n-2-yl)-6-(3- (hydroxymethyl)piperazin-1-yl)pyridine-2 -sulfonamide hydrochloride; Condition 2,

LCMS: m/z 526.2 [M+H] ⁺ , 2.55 min. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 11.74 (s, 1H), 9.19 (s, 1H), 8.89 (s, 1H), 8.24 (d, J = 8.9 Hz, 1H), 7.80 (dd, J = 8.6, 7.4 Hz, 1H), 7.54 (d, J = 8.2 Hz, 1H), 7.29 (dd, J = 8.5, 5.8 Hz, 1H), 7.26 (d, J = 7.3 Hz, 1H), 7.23-7.15 (m, 2H), 6.98 (d, J =

8.2 Hz, 1H), 5.55 (t, J = 4.6 Hz, 1H), 4.21 (t, J = 12.6 Hz, 2H), 3.69 - 3.62 (m, 1H), 3.59 - 3.51 (m, 1H), 3.26 (d, J = 12.4 Hz, 1H), 3.19 (s, 1H), 3.15-3.03 (m, 1H), 3.03-2.90 (m, 2H), 1.76 (s, 3H).

Example 176: (R)-N-(6-(5-fluoro-2-methylphenyl)-5-(trifluoromethyl)pyridi n-2-yl)-6-(3- methylpiperazin-1-yl)pyridine-2 -sulfonamide hydrochloride; Condition 2, LCMS: m/z 510.3 [M+H] ⁺ , 2.56 min. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 11.72 (s, 1H), 9.16 (d, J = 8.5 Hz, 1 H), 9.02 - 8.85 (m, 1 H), 8.25 (d, J = 8.9 Hz, 1 H), 7.80 (dd, J = 8.6, 7.4 Hz, 1 H), 7.55 (d, J = 8.2 Hz, 1H), 7.30 (dd, J = 8.5, 5.8 Hz, 1H), 7.26 (d, J = 7.3 Hz, 1H), 7.23-7.16 (m, 2H), 6.97 (d, J = 8.5 Hz, 1H), 4.19 (d, J = 13.6 Hz, 2H), 3.20 (s, 1H), 3.15-3.03 (m, 1H), 3.02-2.88 (m, 1 H), 2.89 - 2.76 (m, 1 H), 1.76 (s, 3H), 1.21 (d, J = 6.5 Hz, 3H).

Example 177: (S)-N-(6-(5-fluoro-2-methylphenyl)-5-(trifluoromethyl)pyridi n-2-yl)-6-(3- methylpiperazin-1-yl)pyridine-2 -sulfonamide hydrochloride; Condition 2, LCMS: m/z 510.3 [M+H] ⁺ , 2.56 min. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 11.72 (s, 1H), 9.22 (d, J = 9.3 Hz, 1H), 9.00 (q, J = 7.5 Hz, 1H), 8.25 (d, J = 8.9 Hz, 1H), 7.79 (dd, J = 8.6, 7.4 Hz, 1H), 7.55 (d, J = 8.8 Hz, 1H), 7.30 (dd, J = 8.5, 5.7 Hz, 1H), 7.25 (d, J = 7.3 Hz, 1H), 7.22-7.16 (m, 2H), 6.97 (d, J = 7.5 Hz, 1H), 4.19 (d, J = 13.1 Hz, 2H), 3.31 (d, J = 12.4 Hz, 1H), 3.19 (s, 1H), 3.14-3.04 (m, 1H), 3.01 -2.77 (m, 2H), 1.76 (s, 3H), 1.21 (d, J = 6.5 Hz, 3H).

Example 178: 6-((3S,5R)-3,5-dimethylpiperazin-1 -yl)-N-(6-(5-fluoro-2-methylphenyl)-5- (trifluoromethyl)pyridin-2-yl)pyridine-2-sulfonamide hydrochloride; Condition 2, LCMS: m/z 524.3 [M+H] ⁺ , 2.56 min. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 11.69 (s, 1 H), 9.21 - 9.08 (m, 1H), 8.68 (q, J = 10.5 Hz, 1H), 8.26 (d, J = 8.9 Hz, 1H), 7.81 (dd, J = 8.6, 7.4 Hz, 1H), 7.59 (d, J = 8.0 Hz, 1H), 7.30 (dd, J = 8.5, 5.8 Hz, 1H), 7.26 (d, J = 7.3 Hz, 1H), 7.27-7.15 (m, 2H), 6.97 (d, J = 8.0 Hz, 1H), 4.28 (d, J = 13.9 Hz, 2H), 3.19 (s, 2H), 2.74-2.60 (m, 2H), 1.77 (s, 3H), 1.22 (d, J = 6.5 Hz, 6H). Example 179: N-(6-(5-fluoro-2-methylphenyl)-5-(trifluoromethyl)pyridin-2- yl)-6-(4- methylpiperazin-1-yl)pyridine-2 -sulfonamide; Condition 2, LCMS: m/z 510.2 [M+H] ⁺ , 2.55 min. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 11.53 (s, 1H), 8.21 -8.13 (m, 1H), 7.69 (dd, J = 8.7,

7.3 Hz, 1H), 7.48 (d, J = 8.8 Hz, 1H), 7.27 (dd, J = 8.5, 5.8 Hz, 1H), 7.21 -7.13 (m, 2H), 7.05 (d, J = 8.6 Hz, 1 H), 6.93 (dd, J = 9.2, 2.4 Hz, 1 H), 3.46 - 3.37 (m, 4H), 2.33 - 2.22 (m, 4H), 2.20 (s, 3H), 1.75 (s, 3H). Example 180: 6-(4-acetylpiperazin-1 -yl)-N-(6-(5-fluoro-2-methylphenyl)-5- (trifluoromethyl)pyridin-2-yl)pyridine-2-sulfonamide; Condition 2, LCMS: m/z 538.3

[M+H] ⁺ , 3.10 min. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 11.67 (s, 1H), 8.25 (d, J = 8.9 Hz, 1H), 7.73 (dd, J = 8.6, 7.3 Hz, 1H), 7.52 (d, J = 8.4 Hz, 1H), 7.28 (dd, J = 8.5, 5.8 Hz, 1H), 7.21 - 7.14 (m, 2H), 7.10 (d, J = 8.7 Hz, 1H), 6.96 (d, J = 7.9 Hz, 1H), 3.50-3.44 (m, 2H), 3.44- 3.36 (m, 6H), 2.02 (s, 3H), 1.75 (s, 3H).

Example 181: 6-(3,8-diazabicyclo[3.2.1]octan-3-yl)-N-(6-(o-tolyl)-5- (trifluoromethyl)pyridin-2-yl)pyridine-2-sulfonamide hydrochloride; Condition 2, LCMS: m/z 504.3 [M+H] ⁺ , 2.51 min. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 11.67 (s, 1H), 9.17 (d, J = 10.0 Hz, 1 H), 9.08 (d, J = 10.7 Hz, 1 H), 8.23 (d, J = 8.9 Hz, 1 H), 7.78 (dd, J = 8.6, 7.4 Hz, 1 H), 7.52 (s, 1H), 7.38-7.29 (m, 1H), 7.27-7.19 (m, 3H), 7.10-7.02 (m, 2H), 4.10 (s, 2H), 4.00 (d, J = 12.9 Hz, 2H), 3.13 (d, J = 13.0 Hz, 2H), 1.96- 1.83 (m, 2H), 1.76 (s, 3H), 1.61 (d, J = 7.7 Hz, 2H).

Example 182: 6-(4-(2-hydroxyethyl)piperazin-1 -yl)-N-(6-(o-tolyl)-5- (trifluoromethyl)pyridin-2-yl)pyridine-2-sulfonamide hydrochloride; Condition 2, LCMS: m/z 522.3 [M+H] ⁺ , 2.51 min. ¹ H NMR (600 MHz, DMSO-d ₆ ) δ 11.69 (s, 1H), 10.08 (s, 1H), 8.22 (d, J = 9.0 Hz, 1H), 7.80 (dd, J = 8.6, 7.4 Hz, 1H), 7.49 (s, 1H), 7.33 (t, J = 7.4 Hz, 1H), 7.31 -7.17 (m, 4H), 7.08 (s, 1H), 5.40 (brs, 1H), 4.26 (d, J = 13.6 Hz, 2H), 3.80-3.74 (m, 2H), 3.52 (d, J = 11.4 Hz, 2H), 3.27-3.17 (m, 4H), 3.08-2.99 (m, 2H), 1.81 (s, 3H).

Example 183: 2-(4-(6-(N-(6-(o-tolyl)-5-(trifluoromethyl)pyridin-2-yl)sulf amoyl)pyridin-2- yl)piperazin-1-yl)acetamide; Condition 2, LCMS: m/z 535.3 [M+H] ⁺ , 2.58 min. ¹ H NMR (600 MHz, DMSO-d ₆ ) δ 11.55 (s, 1 H), 8.20 (d, J = 8.6 Hz, 1 H), 7.70 (dd, J = 8.5, 7.5 Hz, 1 H), 7.50 (s, 1H), 7.35-7.29 (m, 1H), 7.26-7.19 (m, 3H), 7.16 (s, 1H), 7.13 (d, J = 7.3 Hz, 1H), 7.05 (d, J = 8.5 Hz, 2H), 3.42 (s, 4H), 2.85 (s, 2H), 2.37 (s, 4H), 1.79 (s, 3H).

Example 184: 4-(6-(N-(6-(o-tolyl)-5-(trifluoromethyl)pyridin-2-yl)sulfamo yl)pyridin-2- yl)piperazine-1-carboxamide; Condition 2, LCMS: m/z 521.2 [M+H] ⁺ , 3.01 min. ¹ H NMR

(600 MHz, DMSO-d ₆ ) δ 11.59 (s, 1H), 8.18 (s, 1H), 7.70 (t, J = 7.9 Hz, 1H), 7.44 (s, 1H), 7.31 (t, J = 7.4 Hz, 1H), 7.25-7.18 (m, 2H), 7.15 (d, J = 7.3 Hz, 1H), 7.10-7.02 (m, 2H), 6.06 (s, 2H), 3.39 - 3.36 (m, 4H), 3.29 - 3.25 (m, 4H), 1.78 (s, 3H). Example 185: 6-(4-(2,2-difluoroethyl)piperazin-1-yl)-N-(6-(o-tolyl)-5-

(trifluoromethyl)pyridin-2-yl)pyridine-2-sulfonamide; Condition 2, LCMS: m/z 542.3

[M+H] ⁺ , 3.20 min. ¹ H NMR (500 MHz, DMSO-d ₆ ) δ 11.55 (s, 1 H), 8.20 (d, J = 8.9 Hz, 1 H), 7.71 (dd, J = 8.7, 7.3 Hz, 1H), 7.50 (d, J = 9.1 Hz, 1H), 7.35-7.29 (m, 1H), 7.27-7.18 (m, 2H), 7.15 (d, J = 7.2 Hz, 1 H), 7.09 - 7.02 (m, 2H), 6.27 - 6.00 (m, 1 H), 3.42 - 3.35 (m, 4H), 2.78 - 2.67 (m, 2H), 2.50 - 2.44 (m, 4H), 1.80 (s, 3H).11.55 (s, 1 H), 8.20 (d, J = 8.9 Hz, 1 H),

7.71 (dd, J = 8.7, 7.3 Hz, 1 H), 7.50 (d, J = 9.1 Hz, 1 H), 7.35 - 7.29 (m, 1 H), 7.23 (dd, J = 17.5, 7.4 Hz, 2H), 7.15 (d, J = 7.2 Hz, 1H), 7.06 (t, J = 7.7 Hz, 2H), 6.14 (tt, J = 55.8, 4.3 Hz, 1 H), 3.42 - 3.35 (m, 4H), 2.78 - 2.67 (m, 2H), 2.50 - 2.44 (m, 4H), 1.80 (s, 3H).

Example 186: N-(6-(o-tolyl)-5-(trifluoromethyl)pyridin-2-yl)-6-(4-(2,2,2- trifluoroethyl)piperazin-1-yl)pyridine-2-sulfonamide; Condition 2, LCMS: m/z 560.2

[M+H] ⁺ , 3.40 min. ¹ H NMR (500 MHz, DMSO-d ₆ ) δ 11.53 (s, 1 H), 8.21 (d, J = 8.9 Hz, 1 H),

7.72 (dd, J = 8.6, 7.3 Hz, 1H), 7.52 (d, J = 6.5 Hz, 1H), 7.36 - 7.29 (m, 1H), 7.28 - 7.18 (m, 2H), 7.16 (d, J = 7.2 Hz, 1H), 7.10-7.03 (m, 2H), 3.43-3.36 (m, 4H), 3.24-3.12 (m, 2H), 2.58-2.53 (m, 4H), 1.81 (s, 3H). Example 187: 6-(4-(oxetan-3-yl)piperazin-1-yl)-N-(6-(o-tolyl)-5-(trifluor omethyl)pyridin- 2-yl)pyridine-2-sulfonamide; Condition 2, LCMS: m/z 534.3 [M+H] ⁺ , 2.77 min. ¹ H NMR (500 MHz, DMSO-d ₆ ) δ 11.59 (s, 1H), 8.18 (d, J = 8.7 Hz, 1H), 7.70 (dd, J = 8.6, 7.4 Hz, 1H), 7.50 (d, J = 8.8 Hz, 1H), 7.35-7.30 (m, 1H), 7.27-7.19 (m, 2H), 7.14 (d, J = 7.2 Hz, 1H), 7.08- 7.02 (m, 2H), 4.53 (t, J = 6.5 Hz, 2H), 4.43 (t, J = 6.1 Hz, 2H), 3.44 - 3.39 (m, 4H), 3.38 - 3.32 (m, 1H), 2.18 (t, J = 4.7 Hz, 4H), 1.80 (s, 3H).

Example 188: tert-butyl 4-(6-(N-(5-chloro-6-(2,6-dimethylphenyl)pyridin-2- yl)sulfamoyl)pyridin-2-yl)-3-oxopiperazine-1-carboxylate; Condition 2, LCMS: m/z 572.3 [M+H] ⁺ , 3.38 min. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 11.47 (s, 1H), 8.15 (d, J = 8.2 Hz, 1H), 8.05-7.97 (m, 2H), 7.73 (d, J = 7.5 Hz, 1H), 7.31 (s, 1H), 7.22-7.14 (m, 1H), 7.07 (d, J = 7.6 Hz, 2H), 4.15 (s, 2H), 3.81 -3.72 (m, 2H), 3.57-3.51 (m, 2H), 1.72 (s, 6H), 1.43 (s, 9H).

Example 189: 6-(4-methylpiperazin-1 -yl)-N-(6-(o-tolyl)-5-(trifluoromethyl)pyridin-2- yl)pyridine-2-sulfonamide; Condition 2, LCMS: m/z 492.3 [M+H] ⁺ , 2.50 min. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 11.56 (s, 1H), 8.17 (d, J = 8.9 Hz, 1H), 7.70 (dd, J = 8.7, 7.3 Hz, 1H), 7.49 (d, J = 8.8 Hz, 1H), 7.35-7.29 (m, 1H), 7.26-7.18 (m, 2H), 7.14 (d, J = 7.2 Hz, 1H), 7.07- 7.02 (m, 2H), 3.42-3.37 (m, 4H), 2.31 -2.23 (m, 4H), 2.19 (s, 3H), 1.79 (s, 3H).

Example 190: 6-(3-oxopiperazin-1 -yl)-N-(6-(o-tolyl)-5-(trifluoromethyl)pyridin-2- yl)pyridine-2-sulfonamide; Condition 2, LCMS: m/z 492.2 [M+H] ⁺ , 2.98 min. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 11.65 (s, 1H), 8.19 (d, J = 8.7 Hz, 1H), 8.12 (s, 1H), 7.73 (dd, J = 8.6, 7.4 Hz, 1H), 7.56-7.41 (m, 1H), 7.32 (t, J = 7.5 Hz, 1H), 7.27-7.20 (m, 2H), 7.19 (d, J = 7.2 Hz, 1 H), 7.08 (d, J = 7.2 Hz, 1 H), 7.04 (d, J = 8.7 Hz, 1 H), 3.91 (s, 2H), 3.63 - 3.55 (m, 2H), 3.22 - 3.14 (m, 2H), 1 .80 (s, 3H).

Example 191 : 6-(4-glycylpiperazin-1 -yl)-N-(6-(o-tolyl)-5-(trifluoromethyl)pyridin-2- yl)pyridine-2-sulfonamide hydrochloride; Condition 2, LCMS: m/z 535.3 [M+H] ⁺ , 2.52 min. ¹ H NMR (500 MHz, DMSO-d ₆ ) δ 1 1 .62 (s, 1 H), 8.23 (d, J = 9.0 Hz, 1 H), 8.06 (t, J = 4.7 Hz, 3H), 7.75 (dd, J = 8.7, 7.3 Hz, 1 H), 7.53 (s, 1 H), 7.37 - 7.30 (m, 1 H), 7.24 (dd, J = 10.2, 8.0 Hz, 2H), 7.20 (d, J = 7.2 Hz, 1 H), 7.12 (d, J = 8.7 Hz, 1 H), 7.07 (d, J = 7.3 Hz, 1 H), 3.91 (q, J = 5.5 Hz, 2H), 3.56 - 3.47 (m, 4H), 1 .81 (s, 3H).

Example 192: N-(5-chloro-6-(2,6-dimethylphenyl)pyridin-2-yl)-6-(2-oxopipe razin-1 - yl)pyridine-2-sulfonamide hydrochloride; Condition 2, LCMS: m/z 472.2 [M+H] ⁺ , 2.41 min. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 1 1 .59 (s, 1 H), 9.42 (s, 2H), 8.12 (dd, J = 8.4, 0.8 Hz, 1 H), 8.07 - 7.94 (m, 2H), 7.76 (dd, J = 7.5, 0.7 Hz, 1 H), 7.26 - 7.16 (m, 2H), 7.08 (d, J = 7.6 Hz, 2H), 3.99 (s, 2H), 3.96 - 3.90 (m, 2H), 3.53 - 3.45 (m, 2H), 1 .70 (s, 6H).

Example 193: N-(5-chloro-6-(5-fluoro-2-methylphenyl)pyridin-2-yl)-6-(pipe razin-1 - yl)pyridine-2-sulfonamide hydrochloride; Condition 2, LCMS: m/z 462.2 [M+H] ⁺ , 2.43 min. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 1 1 .32 (s, 1 H), 8.92 (s, 2H), 7.99 (d, J = 8.8 Hz, 1 H), 7.80 (dd, J = 8.6, 7.4 Hz, 1 H), 7.38 (d, J = 8.8 Hz, 1 H), 7.32 (dd, J = 8.5, 5.8 Hz, 1 H), 7.26 (d, J = 7.3 Hz, 1 H), 7.21 - 7.14 (m, 2H), 6.92 (dd, J = 9.3, 2.7 Hz, 1 H), 3.69 - 3.61 (m, 4H), 3.1 1 (s, 4H), 1 .88 (s, 3H).

Example 194: N-[5-chloro-6-(3-fluoro-2-methylphenyl)pyridin-2-yl]-6-(pipe razin-1 - yl)pyridine-2-sulfonamide hydrochloride; Condition 2, LCMS: m/z 462.2 [M+H] ⁺ , 2.42 min. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 1 1 .32 (s, 1 H), 9.02 (s, 2H), 8.00 (d, J = 8.8 Hz, 1 H), 7.81 (dd, J = 8.6, 7.4 Hz, 1 H), 7.38 (d, J = 8.8 Hz, 1 H), 7.34 - 7.20 (m, 3H), 7.17 (d, J = 8.6 Hz, 1 H), 6.94 (d, J = 6.6 Hz, 1 H), 3.69 - 3.63 (m, 4H), 3.1 1 (s, 4H), 1 .81 (d, J = 2.0 Hz, 3H). Example 195: N-(5-chloro-6-(o-tolyl)pyridin-2-yl)-6-(piperazin-1 -yl)pyridine-2- sulfonamide hydrochloride; Condition 2, LCMS: m/z 444.2 [M+H] ⁺ , 2.29 min. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 1 1 .26 (s, 1 H), 9.01 (s, 2H), 7.98 (d, J = 8.8 Hz, 1 H), 7.80 (dd, J = 8.6, 7.4 Hz, 1 H), 7.40 - 7.30 (m, 2H), 7.30 - 7.21 (m, 3H), 7.17 (d, J = 8.6 Hz, 1 H), 7.07 (d, J = 7.5 Hz, 1 H), 3.68 - 3.62 (m, 4H), 3.1 1 (s, 4H), 1 .92 (s, 3H).

Example 196: 6-(4-methyl-3-oxopiperazin-1 -yl)-N-(6-(o-tolyl)-5-(trifluoromethyl)pyridin- 2-yl)pyridine-2-sulfonamide; Condition 2, LCMS: m/z 506.2 [M+H] ⁺ , 3.06 min. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 1 1 .67 (s, 1 H), 8.19 (d, J = 8.9 Hz, 1 H), 7.74 (dd, J = 8.6, 7.3 Hz, 1 H), 7.45 (d, J = 6.3 Hz, 1 H), 7.32 (t, J = 7.5 Hz, 1 H), 7.26 - 7.17 (m, 3H), 7.1 1 - 7.04 (m, 2H), 3.98 (s, 2H), 3.71 (t, J = 5.4 Hz, 2H), 3.32 - 3.27 (m, 2H), 2.85 (s, 3H), 1 .76 (s, 3H). Example 197: N-(5-chloro-6-(2,6-dimethylphenyl)pyridin-2-yl)-6-(4-methyl- 2- oxopiperazin-1 -yl)pyridine-2-sulfonamide; Condition 2, LCMS: m/z 486.2 [M+H] ⁺ , 2.67 min. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 1 1 .49 (s, 1 H), 8.17 - 8.12 (m, 1 H), 8.02 - 7.96 (m, 2H), 7.72 (dd, J = 7.5, 0.6 Hz, 1 H), 7.31 (d, J = 8.8 Hz, 1 H), 7.22 - 7.16 (m, 1 H), 7.07 (d, J = 7.6 Hz, 2H), 3.62 - 3.55 (m, 2H), 3.19 (s, 2H), 2.69 - 2.62 (m, 2H), 2.27 (s, 3H), 1 .72 (s, 6H).

Example 198: N-(5-chloro-6-(2,6-dimethylphenyl)pyridin-2-yl)-6-(5,6- dihydroimidazo[1 ,2-a]pyrazin-7(8H)-yl)pyridine-2 -sulfonamide; Condition 2, LCMS: m/z 495.0 [M+H] ⁺ , 2.49 min. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 1 1 .34 (s, 1 H), 7.96 (d, J = 8.8 Hz, 1 H), 7.76 (dd, J = 8.6, 7.3 Hz, 1 H), 7.31 (d, J = 8.8 Hz, 1 H), 7.24 - 7.18 (m, 2H), 7.18 - 7.13 (m, 1 H), 7.06 (d, J = 1 .2 Hz, 1 H), 7.03 (d, J = 7.7 Hz, 2H), 6.88 (d, J = 1 .2 Hz, 1 H), 4.64 (s, 2H), 3.95 (s, 4H), 1 .68 (s, 6H).

Example 199: N-(5-chloro-6-(2,6-dimethylphenyl)pyridin-2-yl)-6-(2-(triflu oromethyl)-5,6- dihydroimidazo[1 ,2-a]pyrazin-7(8H)-yl)pyridine-2 -sulfonamide; Condition 2, LCMS: m/z 563.0 [M+H] ⁺ 3.36 min. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 1 1 .31 (s, 1 H), 7.95 (d, J = 8.8 Hz,

1 H), 7.78 (dd, J = 8.6, 7.3 Hz, 1 H), 7.75 (d, J = 1 .3 Hz, 1 H), 7.29 (d, J = 8.7 Hz, 1 H), 7.24 (d, J = 8.6 Hz, 1 H), 7.21 (d, J = 7.3 Hz, 1 H), 7.19 - 7.1 1 (m, 1 H), 7.02 (d, J = 7.6 Hz, 2H), 4.72 (s, 2H), 4.01 (dd, J = 12.2, 4.4 Hz, 4H), 1 .66 (s, 6H). Example 200: 6-((1 S,4S)-2,5-diazabicyclo[2.2.2]octan-2-yl)-N-(6-(5-fluoro-2- methylphenyl)-5-(trifluoromethyl)pyridin-2-yl)pyridine-2 -sulfonamide hydrochloride;

Condition 2, LCMS: m/z 522.1 [M+H] ⁺ , 2.58 min. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 1 1 .70 (s, 1 H), 8.85 (s, 2H), 8.25 (d, J = 9.0 Hz, 1 H), 7.81 - 7.73 (m, 1 H), 7.60 (d, J = 8.0 Hz, 1 H), 7.33 - 7.27 (m, 1 H), 7.23 - 7.16 (m, 2H), 6.96 (d, J = 8.3 Hz, 1 H), 6.88 (d, J = 8.0 Hz, 1 H), 4.54 (s, 1 H), 3.84 (s, 1 H), 3.66 (d, J = 1 1 .7 Hz, 1 H), 3.48 - 3.41 (m, 1 H), 3.29 - 3.13 (m, 2H), 2.02 (s, 1 H), 1 .83 - 1 .65 (m, 6H).

Example 201 : 6-(2,5-diazabicyclo[2.2.2]octan-2-yl)-N-(6-(5-fluoro-2-methy lphenyl)-5- (trifluoromethyl)pyridin-2-yl)pyridine-2-sulfonamide hydrochloride; Condition 2, LCMS: m/z 522.3 [M+H] ⁺ , 2.58 min. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 1 1 .70 (s, 1 H), 9.14 (s, 2H), 8.25 (d, J = 8.9 Hz, 1 H), 7.80 - 7.71 (m, 1 H), 7.59 (d, J = 7.9 Hz, 1 H), 7.30 (dd, J = 8.5, 5.9 Hz, 1 H), 7.23 - 7.15 (m, 2H), 6.96 (d, J = 8.0 Hz, 1 H), 6.87 (d, J = 8.0 Hz, 1 H), 4.55 (s, 1 H), 3.83 (s, 1 H), 3.68 (s, 1 H), 3.44 (d, J = 1 1 .7 Hz, 1 H), 3.29 - 3.13 (m, 2H), 2.06 (s, 1 H), 1 .85 - 1 .62 (m, 6H).

Example 202: 6-((5S)-1 ,4-diazabicyclo[3.2.1]octan-4-yl)-N-(6-(5-fluoro-2-methylphe nyl)- 5-(trifluoromethyl)pyridin-2-yl)pyridine-2-sulfonamide; Condition 2, LCMS: m/z 522.2 [M+H] ⁺ , 2.50 min. ¹ H NMR (400 MHz, Methylene Chloride-d ₂ ) δ 7.92 (d, J=8.9 Hz, 1 H), 7.67 - 7.54 (m, 2H), 7.34 (d, J=7.2 Hz, 1 H), 7.20 (s, 2H), 7.03 (td, J=2.7, 8.5 Hz, 1 H), 6.81 (d, J=7.0 Hz, 1 H), 6.71 (d, J=8.6 Hz, 1 H), 4.92 (s, OH), 3.59 (d, J=1 1 .2 Hz, 1 H), 3.23 (s, 1 H), 3.13 - 3.02 (m, 1 H), 2.92 (d, J=10.9 Hz, 3H), 2.76 (s, 1 H); ¹⁹ F NMR (376 MHz, Methylene Chloride- d ₂ ) δ -58.78 (s, 3F), -1 18.63 (s, 1 F).

Example 203: 6-((1 S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl)-N-(6-(o-tolyl)-5- (trifluoromethyl)pyridin-2-yl)pyridine-2-sulfonamide hydrochloride; Condition 2, LCMS: m/z 490.2 [M+H] ⁺ , 2.50 min. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 1 1 .67 (s, 1 H), 9.24 (s, 1 H), 8.67 (s, 1 H), 8.24 (d, J = 8.9 Hz, 1 H), 7.75 (t, J = 7.9 Hz, 1 H), 7.59 (s, 1 H), 7.34 (t, J = 7.5 Hz, 1 H), 7.30 - 7.17 (m, 3H), 7.08 (s, 1 H), 6.86 (d, J = 8.5 Hz, 1 H), 4.71 (d, J = 1 1 .7 Hz, 1 H), 4.47 (s, 1 H), 3.50 (s, 2H), 3.19 - 3.07 (m, 1 H), 2.98 (s, 1 H), 2.08 (d, J = 10.9 Hz, 1 H), 1 .94 - 1 .77 (m, 4H). Example 204: 6-(3-hydroxy-3-(trifluoromethyl)azetidin-1 -yl)-N-(6-(o-tolyl)-5-

(trifluoromethyl)pyridin-2-yl)pyridine-2-sulfonamide; Condition 2, LCMS: m/z 533 [M+H] ⁺ , 3.28 min. ¹ H NMR (400 MHz, Methanol-d ₄ ) δ 8.07 (d, J = 8.9 Hz, 1 H), 7.66 (dd, J = 8.4, 7.4 Hz, 1 H), 7.57 (s, 1 H), 7.31 (d, J = 7.4 Hz, 2H), 7.26 - 7.13 (m, 2H), 7.07 (d, J = 7.5 Hz, 1 H), 6.70 - 6.57 (m, 1 H), 4.16 (d, J = 9.8 Hz, 2H), 3.89 (d, J = 9.7 Hz, 2H), 1 .93 (d, J = 6.8 Hz, 3H).

Example 205: N-(6-(2,6-dimethylphenyl)-4-(trifluoromethyl)pyridin-2-yl)-6 -(3- hydroxyazetidin-1 -yl)pyridine-2-sulfonamide; Condition 2, LCMS: m/z 479.2 [M+H] ⁺ , 3.25 min. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 1 1 .49 (s, 1 H), 7.69 (dd, J = 8.4, 7.4 Hz, 1 H), 7.33 (s, 1 H), 7.18 (dd, J = 15.7, 7.3 Hz, 2H), 7.10 (d, J = 7.6 Hz, 2H), 6.60 (d, J = 8.3 Hz, 1 H), 5.68 (d, J = 6.4 Hz, 1 H), 4.59 - 4.37 (m, 1 H), 4.02 (dd, J = 10.3, 5.3 Hz, 2H), 3.55 (dt, J = 9.1 , 4.1 Hz, 2H), 1 .87 (s, 6H).

Example 206: N-(6-(2,6-dimethylphenyl)-4-methoxypyridin-2-yl)-6-(3-hydrox y-3- methylazetidin-1 -yl)pyridine-2-sulfonamide; Condition 2, LCMS: m/z 455.2 [M+H] ⁺ , 2.83 min. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 12.65 (s, 1 H), 7.65 (dd, J = 8.3, 7.4 Hz, 1 H), 7.27 (d, J = 7.2 Hz, 1H), 7.14 (d, J = 6.9 Hz, 4H), 6.51 (d, J = 8.1 Hz, 1H), 6.38 (s, 1H), 5.58 (s, 1H), 3.86 (s, 2H), 3.69 (s, 5H), 2.10 (s, 6H), 1.38 (s, 3H).

Example 207: N-(5-bromo-6-(o-tolyl)pyridin-2-yl)-6-(3-hydroxy-3-methylaze tidin-1 - yl)pyridine-2-sulfonamide; Condition 2, LCMS: m/z 489.1 [M+H] ⁺ , 3.06 min. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 11.18 (s, 1H), 8.09 (d, J = 8.8 Hz, 1H), 7.66 (dd, J = 8.4, 7.4 Hz, 1H), 7.36 - 7.29 (m, 2H), 7.24 (dd, J = 14.9, 7.3 Hz, 2H), 7.14 (d, J = 6.9 Hz, 1 H), 7.04 (d, J = 7.5 Hz, 1H), 6.60 (d, J = 8.2 Hz, 1H), 5.62 (s, 1H), 3.72 (q, J = 8.6 Hz, 4H), 1.92 (s, 3H), 1.38 (s,3H). Example 208: N-(6-(2-cyclopropylphenyl)-5-(trifluoromethyl)pyridin-2-yl)- 6-(3- hydroxyazetidin-1-yl)pyridine-2-sulfonamide; Condition 2, LCMS: m/z 491.2 [M+H] ⁺ , 3.18 min. ¹ H NMR (400 MHz, Methylene Chloride-d ₂ ) δ 7.99 (m, 1H), 7.66 (m, 1H), 7.55 (dd, J = 8.5, 7.3 Hz, 1H), 7.34 (td, J = 7.6, 1.5 Hz, 1H), 7.26 (dd, J = 7.3, 0.7 Hz, 1H), 7.18 (td, J = 7.5, 1.2 Hz, 1 H), 7.15 - 7.07 (m, 1 H), 6.96 (dd, J = 8.0, 1.2 Hz, 1 H), 6.41 (dd, J = 8.4, 0.7 Hz, 1H), 4.67 (m, 1H), 4.17-4.02 (m, 2H), 3.75-3.66 (m, 2H), 1.44 (m, 1H), 0.67 (m, 3H), 0.58 -0.47 (m, 1H).

Example 209: N-(6-(5-fluoro-2-methoxyphenyl)-5-(trifluoromethyl)pyridin-2 -yl)-6-(3- hydroxyazetidin-1-yl)pyridine-2 -sulfonamide; Condition 2, LCMS: m/z 499.2 [M+H] ⁺ , 2.95 min. ¹ H NMR (400 MHz, Methylene Chloride-d ₂ ) δ 7.95 (m, 1 H), 7.70 (m, 1 H), 7.59 (dd,

J=7.3, 8.5 Hz, 1H), 7.27 (dd, J=0.8, 7.3 Hz, 1H), 7.12 (m, 1H), 6.91 (dt, J=3.9, 7.9 Hz, 2H), 6.45 (dd, J=0.7, 8.5 Hz, 1H), 4.72 (m, 1H), 4.16 (m, 2H), 3.74 (m, 2H), 3.69 (s, 3H), 3.42 (s, 1H). Example 210: N-(5-chloro-6-(2,6-dimethylphenyl)pyridin-2-yl)-6-(3-hydroxy -3- methylazetidin-1-yl)pyridine-2-sulfonamide; Condition 2, LCMS: m/z 459.0 [M+H] ⁺ , 3.13 min. ¹ H NMR (400 MHz, Methylene Chloride-d ₂ ) δ 7.75 (d, J=8.8 Hz, 1 H), 7.61 - 7.48 (m, 2H), 7.28-7.16 (m, 2H), 7.08 (d, J=7.6 Hz, 2H), 6.41 (d, J=8.4 Hz, 1H), 3.85 (d, J=9.0 Hz, 2H), 3.80 (d, J=8.8 Hz,2H), 1.90 (s, 6H), 1.51 (s, 3H).

Example 211 : N-(5-chloro-6-(2,6-dimethylphenyl)pyridin-2-yl)-6-(3-cyclopr opyl-3- hydroxyazetidin-1-yl)pyridine-2-sulfonamide; Condition 2, LCMS: m/z 485.0 [M+H] ⁺ , 3.23 min. ¹ H NMR (400 MHz, Acetonitrile-d ₃ ) δ 8.46 (s, 1 H), 7.82 (d, J=8.8 Hz, 1 H), 7.59 (dd, J=7.4, 8.4 Hz, 1H), 7.47 (d, J=8.8 Hz, 1H), 7.26-7.17 (m, 1H), 7.15 (d, J=7.3 Hz, 1H), 7.09 (d, J=7.6 Hz, 2H), 6.50 (d, J=8.4 Hz, 1H), 3.73 (d, J=9.1 Hz, 2H), 3.66 (d, J=9.2 Hz, 2H), 3.53 (s, 1 H), 1.83 (s, 6H), 0.88 (t, J=6.8 Hz, 1 H), 0.51 - 0.41 (m, 2H), 0.30 (q, J=5.2 Hz, 2H). Example 212: N-(5-chloro-6-(2-methyl-5-(trifluoromethyl)phenyl)pyridin-2- yl)-6-(3- hydroxy-3-methylazetidin-1 -yl)pyridine-2-sulfonamide; Condition 2, LCMS: m/z 513.0 [M+H] ⁺ , 3.29 min. ¹ H NMR (400 MHz, Methylene Chloride-d ₂ ) δ 7.78 (d, J=8.8 Hz, 1 H), 7.62 (d, J=8.8 Hz, 1 H), 7.58 (dd, J=7.3, 8.4 Hz, 2H), 7.42 (d, J=7.1 Hz, 2H), 7.26 (d, J=7.3 Hz, 1 H), 6.46 (d, J=8.4 Hz, 1 H), 3.88 (d, J=9.0 Hz, 2H), 3.84 (d, J=8.9 Hz, 2H), 2.17 (s, 3H), 1 .54 (s, 4H); ¹⁹ F NMR (376 MHz, Methylene Chloride-d ₂ ) δ -62.53 (s, 3F).

Example 213: N-(5-chloro-6-(2-chloro-4-fluorophenyl)pyridin-2-yl)-6-(3-hy droxy-3- methylazetidin-1 -yl)pyridine-2-sulfonamide; Condition 2, LCMS: m/z 483.0 [M+H] ⁺ , 3.15 min. ¹ H NMR (400 MHz, Methylene Chloride-d ₂ ) δ 7.77 (d, J=8.8 Hz, 1 H), 7.65 (d, J=8.8 Hz, 1 H), 7.59 (dd, J=7.3, 8.4 Hz, 1 H), 7.29 (dd, J=6.0, 8.6 Hz, 1 H), 7.27 - 7.21 (m, 2H), 7.1 1 (td, J=2.5, 8.3 Hz, 1 H), 6.46 (d, J=8.4 Hz, 1 H), 3.91 (d, J=9.0 Hz, 2H), 3.86 (d, J=8.9 Hz, 2H), 1 .55 (s, 3H); ¹⁹ F NMR (376 MHz, Methylene Chloride-d ₂ ) δ -1 10.81 - -1 10.92 (m, 1 F). Example 214: N-(5-chloro-6-(2-chloro-4-fluorophenyl)pyridin-2-yl)-6-(3-hy droxyazetidin- 1 -yl)pyridine-2 -sulfonamide; Condition 2, LCMS: m/z 469.0 [M+H] ⁺ , 3.10 min. ¹ H NMR (400 MHz, Methylene Chloride-d ₂ ) δ 7.75 (d, J=8.8 Hz, 1 H), 7.65 (d, J=8.8 Hz, 1 H), 7.58 (dd, J=7.3, 8.4 Hz, 1 H), 7.29 (dd, J=6.0, 8.6 Hz, 1 H), 7.26 - 7.20 (m, 2H), 7.10 (td, J=2.5, 8.3 Hz, 1 H), 6.44 (d, J=8.4 Hz, 1 H), 4.73 (tt, J=4.3, 6.5 Hz, 1 H), 4.25 - 4.14 (m, 2H), 3.83 - 3.70 (m, 2H); ¹⁹ F NMR (376 MHz, Methylene Chloride-d ₂ ) δ -1 1 1 .01 (q, J=8.1 Hz, 1 F).

Example 215: N-(6-(3-fluoro-2-methylphenyl)-5-(trifluoromethyl)pyridin-2- yl)-6-(3- hydroxy-3-methylazetidin-1 -yl)pyridine-2-sulfonamide; Condition 2, LCMS: m/z 497.0 [M+H] ⁺ , 3.17 min. ¹ H NMR (400 MHz, Methylene Chloride-d ₂ ) δ 8.00 (d, J=8.8 Hz, 1 H), 7.71 (d, J=8.1 Hz, 1 H), 7.59 (dd, J=7.3, 8.4 Hz, 1 H), 7.28 (d, J=7.3 Hz, 1 H), 7.16 - 7.07 (m, 1 H), 6.99 (dd, J=2.4, 9.8 Hz, 1 H), 6.93 (td, J=2.6, 8.5 Hz, 1 H), 6.46 (d, J=8.4 Hz, 1 H), 3.85 (d, J=8.7 Hz, 2H), 3.81 (d, J=8.7 Hz, 2H), 2.01 (s, 3H), 1 .54 (s, 3H); ¹⁹ F NMR (376 MHz, Methylene Chloride-d ₂ ) δ -58.90 (s, 3F), -1 14.17 (s, 1 F). Example 216: N-(6-(3-fluoro-2-methylphenyl)-5-(trifluoromethyl)pyridin-2- yl)-6-(3- hydroxyazetidin-1 -yl)pyridine-2-sulfonamide; Condition 2, LCMS: m/z 483.0 [M+H] ⁺ , 3.13 min. ¹ H NMR (400 MHz, Methylene Chloride-d ₂ ) δ 8.02 (d, J=8.9 Hz, 1 H), 7.74 (d, J=8.8 Hz, 1 H), 7.59 (dd, J=7.3, 8.5 Hz, 1 H), 7.28 (d, J=7.3 Hz, 1 H), 7.25 - 7.17 (m, 1 H), 7.1 1 (t, J=8.9 Hz, 1 H), 6.95 (d, J=7.6 Hz, 1 H), 6.47 (d, J=8.4 Hz, 1 H), 4.75 (ddd, J=4.3, 6.5, 10.8 Hz, 1 H), 4.28 - 4.16 (m, 1 H), 3.87 (q, J=8.7 Hz, 1 H), 3.79 (dd, J=4.0, 9.2 Hz, 1 H), 1 .91 (d, J=2.1 Hz, 4H); ¹⁹ F NMR (376 MHz, Methylene Chloride-d ₂ ) δ -58.91 (d, J=3.9 Hz, 3F), -1 17.04 (s, 1 F). Example 217: N-(6-(4-fluoro-2-methylphenyl)-5-(trifluoromethyl)pyridin-2- yl)-6-(3- hydroxy-3-methylazetidin-1 -yl)pyridine-2-sulfonamide; Condition 2, LCMS: m/z 497.0 [M+H] ⁺ , 3.19 min. ¹ H NMR (400 MHz, Methylene Chloride-d ₂ ) δ 8.02 (d, J=8.9 Hz, 1 H), 7.74 (d, J=8.8 Hz, 1 H), 7.59 (dd, J=7.3, 8.4 Hz, 1 H), 7.28 (d, J=7.2 Hz, 1 H), 7.21 (td, J=5.6, 7.9 Hz, 1 H), 7.16 - 7.04 (m, 1 H), 6.95 (d, J=7.5 Hz, 1 H), 6.47 (d, J=8.3 Hz, 1 H), 3.87 (d, J=8.6 Hz, 2H), 3.83 (d, J=8.7 Hz, 2H), 1 .90 (d, J=2.1 Hz, 3H), 1 .55 (s, 3H); ¹⁹ F NMR (376 MHz, Methylene Chloride-d ₂ ) δ -58.90 (s, 3F), -1 17.06 (s, 1 F).

Example 218: N-(6-(4-fluoro-2-methylphenyl)-5-(trifluoromethyl)pyridin-2- yl)-6-(3- hydroxyazetidin-1 -yl)pyridine-2 -sulfonamide; Condition 2, LCMS: m/z 483.0 [M+H] ⁺ , 3.13 min. ¹ H NMR (400 MHz, Methylene Chloride-d ₂ ) δ 8.00 (d, J=8.9 Hz, 1 H), 7.71 (d, J=8.8 Hz, 1 H), 7.59 (dd, J=7.3, 8.4 Hz, 1 H), 7.28 (d, J=7.3 Hz, 1 H), 7.17 - 7.07 (m, 1 H), 6.99 (dd, J=2.5, 9.8 Hz, 1 H), 6.93 (td, J=2.6, 8.5 Hz, 1 H), 6.46 (d, J=8.4 Hz, 1 H), 4.74 (tt, J=4.3, 6.5 Hz, 1 H), 4.25 - 4.13 (m, 2H), 3.76 (dd, J=4.2, 9.8 Hz, 2H), 2.01 (s, 4H); ¹⁹ F NMR (376 MHz, Methylene Chloride-d ₂ ) δ -58.91 (s, 3F), -1 13.92 (s, 1 F)

Example 219: N-(6-(5-fluoro-2-methylphenyl)-5-(trifluoromethyl)pyridin-2- yl)-6-(3- hydroxy-3-methylazetidin-1 -yl)pyridine-2-sulfonamide; Condition 2, LCMS: m/z 497.0 [M+H] ⁺ , 3.16 min. ¹ H NMR (400 MHz, Methylene Chloride-d ₂ ) δ 8.03 (d, J=8.8 Hz, 1 H), 7.73 (d, J=8.8 Hz, 1 H), 7.60 (dd, J=7.4, 8.4 Hz, 1 H), 7.28 (d, J=7.3 Hz, 1 H), 7.24 (dd, J=5.7, 8.5 Hz, 1 H), 7.06 (td, J=2.7, 8.5 Hz, 1 H), 6.87 (dd, J=2.5, 9.0 Hz, 1 H), 6.48 (d, J=8.5 Hz, 1 H), 3.90 (d, J=8.8 Hz, 2H), 3.85 (d, J=8.9 Hz, 2H), 1 .97 (s, 4H), 1 .55 (s, 4H); ¹⁹ F NMR (376 MHz, Methylene Chloride-d ₂ ) δ -58.95 (s, 3F), -1 18.76 (s, 1 F). Example 220: N-(6-(5-fluoro-2-methylphenyl)-5-(trifluoromethyl)pyridin-2- yl)-6-(3- hydroxyazetidin-1 -yl)pyridine-2-sulfonamide; Condition 2, LCMS: m/z 483.0 [M+H] ⁺ , 3.09 min. ¹ H NMR (400 MHz, Methylene Chloride-d ₂ ) δ 8.02 (d, J=8.8 Hz, 1 H), 7.74 (d, J=8.8 Hz, 1 H), 7.59 (dd, J=7.4, 8.4 Hz, 1 H), 7.28 (d, J=7.3 Hz, 1 H), 7.24 (dd, J=5.7, 8.5 Hz, 1 H), 7.06 (td, J=2.7, 8.5 Hz, 1 H), 6.87 (dd, J=2.6, 9.0 Hz, 1 H), 6.47 (d, J=8.5 Hz, 1 H), 4.75 (ddd, J=4.3, 6.5, 10.8 Hz, 1 H), 4.21 (dd, J=6.6, 9.2 Hz, 2H), 3.78 (dd, J=4.1 , 9.3 Hz, 2H), 1 .96 (s, 3H); ¹⁹ F NMR (376 MHz, Methylene Chloride-d ₂ ) δ -58.97 (s, 3F), -1 18.81 (s, 1 F).

Example 221 : N-(6-(2-chlorophenyl)-5-(trifluoromethyl)pyridin-2-yl)-6-(3- hydroxy-3- methylazetidin-1 -yl)pyridine-2-sulfonamide; Condition 2, LCMS: m/z 499.0 [M+H] ⁺ , 3.12 min. ¹ H NMR (400 MHz, Methylene Chloride-d ₂ ) δ 8.02 (d, J=8.8 Hz, 1 H), 7.76 (d, J=8.8 Hz, 1 H), 7.59 (dd, J=7.3, 8.5 Hz, 1 H), 7.46 (dd, J=1 .4, 8.0 Hz, 1 H), 7.41 (td, J=1 .7, 7.6 Hz, 1 H), 7.35 (td, J=1 .5, 7.4 Hz, 1 H), 7.27 (dd, J=2.6, 7.3 Hz, 2H), 6.47 (d, J=8.5 Hz, 1 H), 3.96 - 3.78 (m, 4H), 1 .54 (s, 3H); ¹⁹ F NMR (376 MHz, Methylene Chloride-d ₂ ) a -59.18 (s, 3F).

Example 222: N-(6-(2-chlorophenyl)-5-(trifluoromethyl)pyridin-2-yl)-6-(3- hydroxyazetidin-1 -yl)pyridine-2 -sulfonamide; Condition 2, LCMS: m/z 485.0 [M+H] ⁺ , 3.05 min. ¹ H NMR (400 MHz, Methylene Chloride-d ₂ ) δ 8.01 (d, J=8.8 Hz, 1 H), 7.78 (d, J=8.8 Hz, 1 H), 7.59 (dd, J=7.4, 8.4 Hz, 1 H), 7.46 (dd, J=1 .4, 8.0 Hz, 1 H), 7.41 (td, J=1 .7, 7.6 Hz, 1 H), 7.35 (td, J=1 .4, 7.4 Hz, 1 H), 7.27 (dd, J=2.4, 7.2 Hz, 2H), 6.45 (d, J=8.4 Hz, 1 H), 4.72 (tt, J=4.3, 6.5 Hz, 1 H), 4.20 (d, J=8.8 Hz, 1 H), 4.16 (d, J=8.7 Hz, 1 H), 3.80 - 3.73 (m, 2H); ¹⁹ F NMR (376 MHz, Methylene Chloride-d ₂ ) δ -59.18 (s, 3F).

Example 223: N-(5-chloro-6-(2-methyl-5-(trifluoromethyl)phenyl)pyridin-2- yl)-6-(3- hydroxyazetidin-1 -yl)pyridine-2-sulfonamide; Condition 2, LCMS: m/z 499.0 [M+H] ⁺ , 3.23 min. ¹ H NMR (400 MHz, Methylene Chloride-d ₂ ) δ 7.76 (d, J=8.8 Hz, 1 H), 7.62 (d, J=8.8 Hz, 1 H), 7.60 - 7.52 (m, 2H), 7.41 (d, J=8.1 Hz, 2H), 7.24 (d, J=7.2 Hz, 1 H), 6.44 (d, J=8.4 Hz, 1 H), 4.72 (tt, J=4.3, 6.5 Hz, 1 H), 4.18 (ddd, J=0.9, 6.5, 9.1 Hz, 2H), 3.76 (ddd, J=0.9, 4.3, 9.3 Hz, 2H), 2.16 (s, 3H); ¹⁹ F NMR (376 MHz, Methylene Chloride-d ₂ ) δ -62.54 (s, 3F).

Example 224: 6-(3-hydroxyazetidin-1 -yl)-N-(5-(trifluoromethyl)-6-(2- (trifluoromethyl)phenyl)pyridin-2-yl)pyridine-2-sulfonamide; Condition 2, LCMS: m/z 519.0 [M+H] ⁺ , 3.06 min. ¹ H NMR (400 MHz, Acetonitrile-d ₃ ) δ 8.82 (d, J=43.4 Hz, 1 H), 8.09 (d, J=8.9 Hz, 1 H), 7.84 - 7.77 (m, 1 H), 7.75 (d, J=8.9 Hz, 1 H), 7.70 - 7.63 (m, 2H), 7.61 (dd, J=7.4, 8.4 Hz, 1 H), 7.39 - 7.30 (m, 1 H), 7.18 (d, J=7.3 Hz, 1 H), 6.52 (d, J=8.5 Hz, 1 H), 4.70 - 4.52 (m, 1 H), 4.21 - 4.02 (m, 2H), 3.65 (dt, J=4.7, 9.2 Hz, 2H); ¹⁹ F NMR (376 MHz, Acetonitrile-ds) δ -58.50 (d, J=2.2 Hz, 3F), -58.55 - -58.66 (m, 3F).

Example 225: N-(6-(2-chloro-4-fluorophenyl)-5-(trifluoromethyl)pyridin-2- yl)-6-(3- hydroxyazetidin-1 -yl)pyridine-2-sulfonamide; Condition 2, LCMS: m/z 503.1 [M+H] ⁺ , 3.13 min. ¹ H NMR (400 MHz, Chloroform-d) δ 8.00 (d, J=8.8 Hz, 1 H), 7.84 (d, J=8.8 Hz, 1 H), 7.58 (dd, J=7.4, 8.3 Hz, 1 H), 7.31 (d, J=7.3 Hz, 1 H), 7.28 - 7.24 (m, 1 H), 7.21 (dd, J=2.5, 8.5 Hz, 1 H), 7.06 (td, J=2.5, 8.3 Hz, 1 H), 6.44 (d, J=8.4 Hz, 1 H), 4.76 (tt, J=4.3, 6.5 Hz, 1 H), 4.20 (dd, J=8.8, 16.6 Hz, 2H), 3.79 (d, J=8.6 Hz, 2H); ¹⁹ F NMR (376 MHz, Chloroform-d) δ -58.88 (s, 3F), -109.92 (s, 1 F). Example 226: N-(6-(2-chloro-5-methoxyphenyl)-5-(trifluoromethyl)pyridin-2 -yl)-6-(3- hydroxyazetidin-1 -yl)pyridine-2 -sulfonamide; Condition 2, LCMS: m/z 515.1 [M+H] ⁺ , 3.01 min. ¹ H NMR (400 MHz, Chloroform-d) δ 8.00 (d, J=8.9 Hz, 1 H), 7.81 (d, J=8.8 Hz, 1 H), 7.57 (dd, J=7.4, 8.4 Hz, 1 H), 7.34 (d, J=8.9 Hz, 1 H), 7.31 (d, J=7.3 Hz, 1 H), 6.94 (dd, J=3.0, 8.9 Hz, 1 H), 6.82 (d, J=2.9 Hz, 1 H), 6.42 (d, J=8.4 Hz, 1 H), 4.74 (tt, J=4.3, 6.5 Hz, 1 H), 4.27 - 4.15 (m, 2H), 3.81 (s, 3H), 3.80 - 3.75 (m, 2H); ¹⁹ F NMR (376 MHz, Chloroform-d) δ -58.85 (s, 3F).

Example 227: N-(5-chloro-6-(2-chlorophenyl)pyridin-2-yl)-6-(3-hydroxyazet idin-1 - yl)pyridine-2-sulfonamide; Condition 2, LCMS: m/z 451 .0 [M+H] ⁺ , 2.96 min. ¹ H NMR (400 MHz, Chloroform-d) δ 7.74 (d, J=8.8 Hz, 1 H), 7.70 (d, J=8.8 Hz, 1 H), 7.56 (dd, J=7.4, 8.3 Hz, 1 H), 7.50 - 7.46 (m, 1 H), 7.43 - 7.39 (m, 1 H), 7.38 - 7.34 (m, 1 H), 7.33 - 7.30 (m, 1 H), 7.30 - 7.26 (m, 2H), 6.41 (d, J=8.4 Hz, 1 H), 4.79 - 4.67 (m, 1 H), 4.20 (dd, J=6.8, 9.4 Hz, 2H), 3.79 (dd, J=4.3, 9.8 Hz, 2H), 2.29 (s, 1 H).

Example 228: N-(5-chloro-6-(2-chloro-5-methoxyphenyl)pyridin-2-yl)-6-(3- hydroxyazetidin-1 -yl)pyridine-2-sulfonamide; Condition 2, LCMS: m/z 481 .0 [M+H] ⁺ , 2.98 min.. ¹ H NMR (400 MHz, Chloroform-d) δ 7.70 (s, 1 H), 7.69 (s, 1 H), 7.54 (dd, J=7.4, 8.4 Hz, 1 H), 7.48 (dd, J=2.7, 7.2 Hz, 1 H), 7.35 (d, J=8.8 Hz, 1 H), 7.26 (d, J=2.3 Hz, 1 H), 6.92 (dd, J=3.0, 8.9 Hz, 1 H), 6.82 (d, J=3.0 Hz, 1 H), 6.39 (d, J=8.4 Hz, 1 H), 4.72 (s, 1 H), 4.19 (dd, J=6.9, 9.4 Hz, 2H), 3.81 (s, 3H), 3.77 (dd, J=4.6, 9.7 Hz, 2H), 2.22 (d, J=1 1 .7 Hz, 1 H). Example 229: N-(5-chloro-6-(2-chloro-3-fluorophenyl)pyridin-2-yl)-6-(3-hy droxyazetidin- 1 -yl)pyridine-2-sulfonamide; Condition 2, LCMS: m/z 469.0 [M+H] ⁺ , 2.99 min. ¹ H NMR (400 MHz, Chloroform-d) δ 7.75 (s, 1 H), 7.74 (s, 1 H), 7.57 (dd, J=7.4, 8.4 Hz, 1 H), 7.53 (s, 1 H), 7.35 (td, J=5.1 , 8.0 Hz, 1 H), 7.29 (d, J=4.6 Hz, 2H), 7.25 (td, J=1 .5, 8.6 Hz, 1 H), 7.13 (dt, J=1 .2, 7.6 Hz, 1 H), 6.43 (d, J=8.4 Hz, 1 H), 4.75 (s, 1 H), 4.26 - 4.17 (m, 2H), 3.85 - 3.77 (m, 2H), 2.22 (d, J=5.8 Hz, 1 H); ¹⁹ F NMR (376 MHz, Chloroform-d) δ -1 13.69 (dd, J=5.2, 8.6 Hz, 1 F).

Example 230: N-(6-(2-chloro-3-fluorophenyl)-5-(trifluoromethyl)pyridin-2- yl)-6-(3- hydroxyazetidin-1 -yl)pyridine-2-sulfonamide; Condition 2, LCMS: m/z 503.1 [M+H] ⁺ , 3.04 min. ¹ H NMR (400 MHz, Chloroform-d) δ 8.02 (d, J=8.8 Hz, 1 H), 7.87 (d, J=8.8 Hz, 1 H), 7.69 (s, 1 H), 7.59 (dd, J=7.4, 8.4 Hz, 1 H), 7.33 (td, J=4.5, 7.1 , 7.7 Hz, 2H), 7.25 (dd, J=1 .5, 8.5 Hz, 1 H), 7.1 1 (d, J=7.5 Hz, 1 H), 6.45 (d, J=8.4 Hz, 1 H), 4.77 (d, J=4.1 Hz, 1 H), 4.28 - 4.18 (m, 2H), 3.81 (dd, J=4.1 , 9.6 Hz, 2H); ¹⁹ F NMR (376 MHz, Chloroform-d) δ -58.86 (s, 3F), - 1 13.97 (s, 1 F).

Example 231 : N-(5-chloro-6-(2,6-dimethylphenyl)pyridin-2-yl)-6-(3-hydroxy azetidin-1 - yl)pyridine-2-sulfonamide; Condition 2, LCMS: m/z 445.2 [M+H] ⁺ , 3.08 min. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 1 1 .19 (s, 1 H), 7.97 (d, J=8.8 Hz, 1 H), 7.64 (dd, J=7.4, 8.4 Hz, 1 H), 7.37 (d, J=8.8 Hz, 1 H), 7.23 - 7.15 (m, 1 H), 7.1 1 - 7.07 (m, 3H), 6.58 (d, J=8.3 Hz, 1 H), 5.68 (d, J=6.4 Hz, 1 H), 4.57 - 4.48 (m, 1 H), 4.10 - 4.03 (m, 2H), 3.58 (dd, J=4.7, 9.4 Hz, 2H), 1 .79 (s, 6H).

Example 232: N-(5-chloro-6-(3-fluoro-2-methylphenyl)pyridin-2-yl)-6-(3- hydroxyazetidin-1 -yl)pyridine-2-sulfonamide; Condition 2, LCMS: m/z 449.1 [M+H] ⁺ , 3.06 min. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 1 1 .26 (s, 1 H), 7.98 (d, J = 8.8 Hz, 1 H), 7.67 (dd, J = 8.4, 7.4 Hz, 1 H), 7.41 (d, J = 8.8 Hz, 1 H), 7.33 - 7.20 (m, 2H), 7.14 (d, J = 6.9 Hz, 1 H), 6.94 (d, J = 7.5 Hz, 1 H), 6.60 (d, J = 8.4 Hz, 1 H), 5.69 (d, J = 6.5 Hz, 1 H), 4.59 - 4.48 (m, 1 H), 4.07 (dd, J = 9.0, 6.8 Hz, 2H), 3.59 (dd, J = 9.3, 4.6 Hz, 2H), 1 .83 (d, J = 2.0 Hz, 3H).

Example 233: 6-(3-hydroxyazetidin-1 -yl)-N-(6-(o-tolyl)-5-(trifluoromethyl)pyridin-2- yl)pyridine-2-sulfonamide; Condition 2, LCMS: m/z 465.2 [M+H] ⁺ , 3.04 min. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 1 1 .60 (s, 1 H), 8.21 (d, J = 8.9 Hz, 1 H), 7.65 (dd, J = 8.4, 7.4 Hz, 1 H), 7.52 (s, 1 H), 7.37 - 7.28 (m, 1 H), 7.28 - 7.19 (m, 2H), 7.13 (d, J = 7.0 Hz, 1 H), 7.08 (d, J = 7.3 Hz, 1 H), 6.60 (d, J = 8.3 Hz, 1 H), 5.69 (d, J = 6.5 Hz, 1 H), 4.59 - 4.47 (m, 1 H), 4.06 (t, J = 7.6 Hz, 2H), 3.58 (dd, J = 9.1 , 4.7 Hz, 2H), 1 .82 (s, 3H). Example 234: N-(5-chloro-6-(5-fluoro-2-methylphenyl)pyridin-2-yl)-6-(3- hydroxyazetidin-1 -yl)pyridine-2-sulfonamide; Condition 2, LCMS: m/z 449.1 [M+H] ⁺ , 3.05 min. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 1 1 .25 (s, 1 H), 7.98 (d, J = 8.8 Hz, 1 H), 7.66 (dd, J = 8.4, 7.4 Hz, 1 H), 7.41 (d, J = 8.8 Hz, 1 H), 7.31 (dd, J = 8.5, 5.8 Hz, 1 H), 7.20 - 7.12 (m, 2H), 6.93 (dd, J = 9.3, 2.7 Hz, 1 H), 6.60 (dd, J = 8.4, 0.5 Hz, 1 H), 5.70 (d, J = 6.5 Hz, 1 H), 4.58 - 4.47 (m, 1 H), 4.08 (dd, J = 9.0, 6.8 Hz, 2H), 3.59 (dd, J = 9.3, 4.6 Hz, 2H), 1 .90 (s, 3H).

Example 235: N-(5-chloro-6-(5-fluoro-2-methylphenyl)pyridin-2-yl)-6-(3-hy droxy-3- (hydroxymethyl)azetidin-1 -yl)pyridine-2-sulfonamide; Condition 2, LCMS: m/z 479.2 [M+H] ⁺ , 2.99 min. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 1 1 .18 (s, 1 H), 7.90 (d, J = 7.9 Hz, 1 H), 7.52 (dd, J = 7.3, 8.4 Hz, 1 H), 7.41 (d, J = 8.6 Hz, 1 H), 7.29 (dd, J = 5.9, 8.5 Hz, 1 H), 7.15 (m, 2H), 7.03 (d, J = 7.2 Hz, 1 H), 6.91 (dd, J = 2.6, 9.4 Hz, 1 H), 6.79 (d, J = 8.5 Hz, 1 H), 5.89 (s, 1 H), 4.33 (d, J = 6.6 Hz, 2H), 4.26 (d, J = 6.6 Hz, 2H), 3.39 (d, J = 5.7 Hz, 2H), 1 .90 (s, 3H). ¹⁹ F NMR (376 MHz, DMSO-d ₆ ) δ -1 17.92 (s). Example 236: methyl 1 -(6-(N-(6-(2-cyclopropylphenyl)-5-(trifluoromethyl)pyridin-2 - yl)sulfamoyl)pyridin-2-yl)-4-methylpiperidine-4-carboxylate; Condition 2, LCMS: m/z 575.2 [M+H] ⁺ , 3.50 min. ¹ H NMR (400 MHz, Methylene Chloride-d ₂ ) δ 8.01 (m, 1 H), 7.69 (m, 1H), 7.59 (dd, J=7.3, 8.7 Hz, 1H), 7.35 (td, J=1.4, 7.6 Hz, 1H), 7.28-7.15 (m, 2H), 7.10 (m, 1 H), 6.96 (dd, J=1.2, 7.8 Hz, 1 H), 6.80 (dd, J=0.6, 8.8 Hz, 1 H), 3.83 - 3.73 (m, 1 H), 3.68 (s, 3H), 3.42 (s, 1 H), 3.02 (m, 2H), 2.11 - 1.99 (m, 2H), 1.53 - 1.20 (m, 4H), 1.18 (s, 3H), 0.71 - 0.57 (m, 3H).

Example 237: 1 -(6-(N-(6-(2-cyclopropylphenyl)-5-(trifluoromethyl)pyridin-2 - yl)sulfamoyl)pyridin-2-yl)-4-methylpiperidine-4-carboxylic acid; Condition 1, LCMS: m/z 561.2 [M+H] ⁺ , 1.19 min. ¹ H NMR (400 MHz, Methylene Chloride-d ₂ ) δ 7.99 (m, 1H), 7.67- 7.51 (m, 2H), 7.36-7.23 (m, 2H), 7.14 (t, J=7.4 Hz, 1H), 7.05 (m, 1H), 6.91 (m, 1H), 6.73 (m, 1H), 3.86 (m, 2H), 3.42 (m, 1H), 2.82 (m, 2H), 1.95 (m, 2H), 1.41 -1.19 (m, 5H), 0.67- 0.43 (m, 4H).

Example 238: 1 -(6-(N-(6-(2-chlorophenyl)-5-(trifluoromethyl)pyridin-2- yl)sulfamoyl)pyridin-2-yl)-4-methylpiperidine-4-carboxylic acid; Condition 2, LCMS: m/z 555.1 [M+H] ⁺ , 3.19 min. ¹ H NMR (400 MHz, Methylene Chloride-d ₂ ) δ 8.07 (d, J=9.0 Hz, 1H), 7.87 - 7.80 (m, 1 H), 7.66 - 7.59 (m, 1 H), 7.49 - 7.40 (m, 2H), 7.35 (ddd, J=2.1 , 5.4, 8.7 Hz, 1H), 7.27 (dd, J=7.4, 10.3 Hz, 2H), 6.83 (d, J=8.7 Hz, 1H), 3.85 (dd, J=5.0, 13.4 Hz, 2H), 3.02 (t, J=12.2 Hz, 2H), 2.02 (d, J=9.4 Hz, 3H), 1.37 (ddd, J=3.8, 9.1, 14.4 Hz, 2H), 1.22 (s, 3H); ¹⁹ F NMR (376 MHz, DMSO-d ₆ ) δ -56.10 (s, 3F).

Example 239: 1 -(6-(N-(5-chloro-6-(2-chlorophenyl)pyridin-2-yl)sulfamoyl)py ridin-2-yl)-4- methylpiperidine-4-carboxylic acid; Condition 2, LCMS: m/z 521.1 [M+H] ⁺ , 3.16 min. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 12.39 (s, 1H), 11.19 (s, 1H), 7.99 (d, J=8.9 Hz, 1H), 7.70 (dd, J=7.3, 8.6 Hz, 1 H), 7.54 (dd, J=1.2, 8.0 Hz, 1 H), 7.50 - 7.43 (m, 2H), 7.41 (td, J=1.3, 7.4 Hz, 1 H), 7.17 (dd, J=1.7, 7.5 Hz, 1 H), 7.11 (d, J=7.2 Hz, 1 H), 7.07 (d, J=8.7 Hz, 1 H), 3.87 - 3.73 (m, 2H), 3.35 (s, 1H), 3.09-2.93 (m, 2H), 1.85 (d, J=13.6 Hz, 2H), 1.21 -1.11 (m, 3H), 1.08 (s, 3H).

Example 240: 1 -(6-(N-(6-(2-chloro-4-fluorophenyl)-5-(trifluoromethyl)pyrid in-2- yl)sulfamoyl)pyridin-2-yl)-4-methylpiperidine-4-carboxylic acid; Condition 2, LCMS: m/z 573.1 [M+H] ⁺ , 3.29 min. ¹ H NMR (400 MHz, Chloroform-d) δ 7.92 (d, J=8.9 Hz, 1 H), 7.68 (d, J=8.8 Hz, 1H), 7.52 (dd, J=7.3, 8.6 Hz, 1H), 7.23 (d, J=7.2 Hz, 1H), 7.15 (dd, J=6.0, 8.5 Hz, 1 H), 7.10 (dd, J=2.4, 8.4 Hz, 1 H), 6.96 (td, J=2.5, 8.3 Hz, 1 H), 6.71 (d, J=8.7 Hz, 1 H), 3.89 - 3.75 (m, 2H), 2.89 (t, J=12.4 Hz, 2H), 2.01 -1.89 (m, 2H), 1.35-1.21 (m, 2H), 1.15 (s, 3H); ¹⁹ F NMR (376 MHz, Chloroform-d) δ -58.92 (s, 3F), -109.61 (d, J=6.1 Hz, 1F). Example 241 : 1 -(6-(N-(6-(2-chloro-5-methoxyphenyl)-5-(trifluoromethyl)pyri din-2- yl)sulfamoyl)pyridin-2-yl)-4-methylpiperidine-4-carboxylic acid; Condition 2, LCMS: m/z 585.2 [M+H] ⁺ , 3.19 min. ¹ H NMR (400 MHz, Chloroform-d) δ 7.91 (d, J=8.9 Hz, 1 H), 7.66 (d, J=8.8 Hz, 1 H), 7.51 (dd, J=7.3, 8.7 Hz, 1 H), 7.23 (d, J=2.6 Hz, 1 H), 7.21 (d, J=4.3 Hz, 1 H), 6.84 (dd, J=3.0, 8.9 Hz, 1 H), 6.74 - 6.66 (m, 2H), 3.88 - 3.75 (m, 2H), 3.68 (s, 3H), 2.89 (t, J=12.5 Hz, 2H), 1 .97 (d, J=7.9 Hz, 3H), 1 .28 (t, J=12.6 Hz, 2H), 1 .15 (s, 3H); ¹⁹ F NMR (376 MHz, Chloroform-d) δ -58.88 (s, 3F).

Example 242: 1 -(6-(N-(6-(2-chloro-3-fluorophenyl)-5-(trifluoromethyl)pyrid in-2- yl)sulfamoyl)pyridin-2-yl)-4-methylpiperidine-4-carboxylic acid; Condition 2, LCMS: m/z 573.2 [M+H] ⁺ , 3.20 min. ¹ H NMR (400 MHz, Chloroform-d) δ 7.94 (d, J=8.9 Hz, 1 H), 7.69 (d, J=8.9 Hz, 1 H), 7.52 (dd, J=7.3, 8.7 Hz, 1 H), 7.23 (td, J=2.4, 5.0 Hz, 2H), 7.18 - 7.1 1 (m, 1 H), 6.99 (d, J=7.5 Hz, 1 H), 6.72 (d, J=8.7 Hz, 1 H), 3.93 - 3.73 (m, 2H), 2.90 (dt, J=9.7, 18.4 Hz, 2H), 2.01 - 1 .89 (m, 2H), 1 .39 - 1 .22 (m, 2H), 1 .14 (s, 3H); ¹⁹ F NMR (376 MHz, Chloroform- d) δ -58.89 (s, 3F), -1 14.06 (dd, J=5.2, 8.5 Hz, 1 F).

Example 243: 1 -(6-(N-(5-chloro-6-(2-chloro-4-fluorophenyl)pyridin-2- yl)sulfamoyl)pyridin-2-yl)-4-methylpiperidine-4-carboxylic acid; Condition 2, LCMS: m/z 539.1 [M+H] ⁺ , 3.25 min. ¹ H NMR (400 MHz, Chloroform-d) δ 7.67 (d, J=8.9 Hz, 1 H), 7.59 (d, J=8.9 Hz, 1 H), 7.50 (dd, J=7.4, 8.6 Hz, 1 H), 7.22 - 7.14 (m, 2H), 7.12 (dd, J=2.5, 8.5 Hz,

1 H), 6.98 (td, J=2.5, 8.3 Hz, 1 H), 6.70 (d, J=8.7 Hz, 1 H), 3.80 (dt, J=3.5, 13.3 Hz, 2H), 3.03 - 2.84 (m, 2H), 1 .99 (d, J=10.3 Hz, 2H), 1 .37 - 1 .24 (m, 2H), 1 .16 (s, 3H); ¹⁹ F NMR (376 MHz, Chloroform-d) δ -109.71 (s, 1 F). Example 244: 1 -(6-(N-(5-chloro-6-(2-chloro-5-methoxyphenyl)pyridin-2- yl)sulfamoyl)pyridin-2-yl)-4-methylpiperidine-4-carboxylic acid; Condition 2, LCMS: m/z 551 .1 [M+H] ⁺ , 3.18 min. ¹ H NMR (400 MHz, Chloroform-d) δ 7.68 (d, J=8.9 Hz, 1 H), 7.59 (d, J=8.9 Hz, 1 H), 7.50 (dd, J=7.3, 8.6 Hz, 1 H), 7.25 (d, J=8.9 Hz, 1 H), 7.21 (d, J=7.4 Hz, 1 H), 6.84 (dd, J=3.0, 8.9 Hz, 1 H), 6.75 - 6.67 (m, 2H), 3.84 - 3.75 (m, 2H), 3.71 (s, 3H), 3.02 - 2.89 (m, 2H), 1 .99 (d, J=13.0 Hz, 2H), 1 .37 - 1 .25 (m, 2H), 1 .15 (s, 3H).

Example 245: 1 -(6-(N-(5-chloro-6-(2-chloro-3-fluorophenyl)pyridin-2- yl)sulfamoyl)pyridin-2-yl)-4-methylpiperidine-4-carboxylic acid; Condition 2, LCMS: m/z 539.1 [M+H] ⁺ , 3.18 min. ¹ H NMR (400 MHz, Chloroform-d) a 7.67 (d, J=8.9 Hz, 1 H), 7.59 (d, J=8.9 Hz, 1 H), 7.50 (dd, J=7.3, 8.7 Hz, 1 H), 7.24 (td, J=5.1 , 8.0 Hz, 1 H), 7.19 (d, J=7.1 Hz, 1 H), 7.15 (td, J=1 .5, 8.6 Hz, 1 H), 7.00 (d, J=7.6 Hz, 1 H), 6.70 (d, J=8.7 Hz, 1 H), 3.89 - 3.74 (m, 2H), 3.04 - 2.84 (m, 2H), 2.02 - 1 .93 (m, 2H), 1 .38 - 1 .24 (m, 2H), 1 .15 (s, 3H); ¹⁹ F NMR (376 MHz, Chloroform-d) δ -1 13.68 (dd, J=5.2, 8.6 Hz, 1 F).

Example 246: methyl 1 -(6-(N-(5-chloro-6-(2,6-dimethylphenyl)pyridin-2- yl)sulfamoyl)pyridin-2-yl)piperidine-4-carboxylate; Condition 2, LCMS: m/z 515.2 [M+H] ⁺ , 3.31 min. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 1 1 .16 (s, 1 H), 7.95 (d, J = 8.8 Hz, 1 H), 7.67 (dd, J = 7.3, 8.7 Hz, 1 H), 7.33 (d, J = 8.8 Hz, 1 H), 7.18 (m, 1 H), 7.06 (m, 4H), 4.07 (m, 2H), 3.58 (s, 3H), 2.89 (m, 2H), 2.61 (tt, J = 3.8, 1 1 .1 Hz, 1 H), 1 .73 (s, 8H), 1 .31 (m, 2H). Example 247: 1 -(6-(N-(5-chloro-6-(2,6-dimethylphenyl)pyridin-2-yl)sulfamoy l)pyridin-2- yl)piperidine-4-carboxylic acid; Condition 2, LCMS: m/z 501 .2 [M+H] ⁺ , 3.16 min. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 12.23 (s, 1 H), 1 1 .16 (s, 1 H), 7.95 (d, J = 8.8 Hz, 1 H), 7.67 (dd, J = 7.3, 8.7 Hz, 1 H), 7.35 (d, J = 8.7 Hz, 1 H), 7.18 (m, 1 H), 7.06 (m, 4H), 4.05 (m, 2H), 2.88 (m, 2H), 2.46 (m, 1 H), 1 .75 (m, 8H), 1 .31 (m, 2H)

Example 248: 1 -(6-(N-(5-chloro-6-(2,6-dimethylphenyl)pyridin-2-yl)sulfamoy l)pyridin-2- yl)-4-ethylpiperidine-4-carboxylic acid; Condition 2, LCMS: m/z 529.2 [M+H] ⁺ , 3.35 min. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 12.48 (s, 1 H), 1 1 .14 (s, 1 H), 7.97 (d, J = 8.8 Hz, 1 H), 7.66 (dd, J = 7.3, 8.6 Hz, 1 H), 7.33 (d, J = 8.8 Hz, 1 H), 7.18 (m, 1 H), 7.06 (m, 3H), 7.02 (d, J = 8.7 Hz, 1 H), 3.95 (m, 2H), 2.87 (m, 2H), 1 .89 (m, 2H), 1 .73 (s, 6H), 1 .40 (q, J = 7.5 Hz, 2H), 1 .08 (m, 2H), 0.75 (t, J = 7.5 Hz, 3H).

Example 249: ethyl 1 -(6-(N-(5-chloro-6-(2,6-dimethylphenyl)pyridin-2- yl)sulfamoyl)pyridin-2-yl)-4-methylpiperidine-4-carboxylate; Condition 2, LCMS: m/z 543.2 [M+H] ⁺ , 3.51 min. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 1 1 .15 (s, 1 H), 7.96 (d, J = 8.8 Hz, 1 H), 7.67 (dd, J = 8.7, 7.3 Hz, 1 H), 7.33 (d, J = 8.8 Hz, 1 H), 7.21 - 7.14 (m, 1 H), 7.10 - 7.01 (m, 4H), 4.09 (q, J = 7.1 Hz, 2H), 3.85 - 3.76 (m, 2H), 3.05 - 2.94 (m, 2H), 1 .91 - 1 .81 (m, 2H), 1 .27 - 1 .20 (m, 2H), 1 .17 (t, J = 7.1 Hz, 3H), 1 .10 (s, 3H). Example 250: 1 -(6-(N-(5-chloro-6-(2,6-dimethylphenyl)pyridin-2-yl)sulfamoy l)pyridin-2- yl)-4-methylpiperidine-4-carboxylic acid; Condition 2, LCMS: m/z 515.2 [M+H] ⁺ , 3.28 min. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 7.93 (d, J = 8.8 Hz, 1 H), 7.66 (dd, J = 8.6, 7.3 Hz, 1 H), 7.33 (d, J = 8.8 Hz, 1 H), 7.20 - 7.13 (m, 1 H), 7.09 - 6.98 (m, 4H), 3.87 - 3.74 (m, 2H), 3.07 - 2.95 (m, 2H), 1 .85 (d, J = 13.7 Hz, 2H), 1 .75 (s, 6H), 1 .21 - 1 .1 1 (m, 2H), 1 .09 (s, 3H).

Example 251 : ethyl 1 -(6-(N-(6-(5-fluoro-2-methylphenyl)-5-(trifluoromethyl)pyrid in-2- yl)sulfamoyl)pyridin-2-yl)-4-methylpiperidine-4-carboxylate; Condition 2, LCMS: m/z 581.2 [M+H] ⁺ , 3.53 min. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 11.58 (s, 1 H), 8.23 (d, J = 8.9 Hz, 1H), 7.69 (dd, J = 8.7, 7.3 Hz, 1H), 7.51 (d, J = 8.5 Hz, 1H), 7.27 (dd, J = 8.5, 5.8 Hz, 1H), 7.17 (td, J = 8.6, 2.8 Hz, 1H), 7.11 (d, J = 7.2 Hz, 1H), 7.07 (d, J = 8.7 Hz, 1H), 6.92 (d, J = 9.0 Hz, 1 H), 4.08 (q, J = 7.1 Hz, 2H), 3.84 - 3.67 (m, 2H), 3.03 - 2.91 (m, 2H), 1.88 - 1.76 (m, 2H), 1.70 (s, 3H), 1.25 - 1.13 (m, 5H), 1.08 (s, 3H).

Example 252: ethyl 1-(6-(N-(5-chloro-6-(3-fluoro-2-methylphenyl)pyridin-2- yl)sulfamoyl)pyridin-2-yl)-4-methylpiperidine-4-carboxylate; Condition 2, LCMS: m/z 547.1 [M+H] ⁺ , 3.53 min. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 11.19 (s, 1 H), 7.98 (d, J = 8.8 Hz, 1H), 7.70 (dd, J = 8.7, 7.3 Hz, 1H), 7.36 (d, J = 8.8 Hz, 1H), 7.31 - 7.18 (m, 2H), 7.10 (d, J = 7.2 Hz, 1 H), 7.06 (d, J = 8.7 Hz, 1 H), 6.87 (d, J = 6.5 Hz, 1 H), 4.09 (q, J = 7.1 Hz, 2H), 3.83 - 3.71 (m, 2H), 3.04-2.93 (m, 2H), 1.89- 1.80 (m, 2H), 1.77 (d, J = 1.9 Hz, 3H), 1.26- 1.18 (m, 2H), 1.16 (t, J = 7.1 Hz, 3H), 1.09 (s,3H). Example 253: 1-(6-(N-(5-chloro-6-(3-fluoro-2-methylphenyl)pyridin-2- yl)sulfamoyl)pyridin-2-yl)-4-methylpiperidine-4-carboxylic acid; Condition 2, LCMS: m/z 519.1 [M+H] ⁺ , 3.24 min. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 12.41 (s, 1H), 11.18 (s, 1H), 7.98 (d, J = 8.8 Hz, 1 H), 7.69 (dd, J = 8.7, 7.3 Hz, 1 H), 7.38 (d, J = 8.8 Hz, 1 H), 7.31 - 7.18 (m, 2H), 7.10 (d, J = 7.2 Hz, 1 H), 7.06 (d, J = 8.7 Hz, 1 H), 6.91 - 6.84 (m, 1 H), 3.83 - 3.72 (m, 2H), 3.06 - 2.94 (m, 2H), 1.88 - 1.80 (m, 2H), 1.78 (d, J = 2.0 Hz, 3H), 1.18 - 1.09 (m, 2H), 1.07 (s, 3H).

Example 254: ethyl 1-(6-(N-(5-chloro-6-(o-tolyl)pyridin-2-yl)sulfamoyl)pyridin- 2-yl)-4- methylpiperidine-4-carboxylate; Condition 2, LCMS: m/z 529.1 [M+H] ⁺ , 3.51 min. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 11.13 (s, 1H), 7.95 (d, J = 8.8 Hz, 1H), 7.69 (dd, J = 8.7, 7.3 Hz, 1H), 7.35 (d, J = 8.8 Hz, 1H), 7.31 (td, J = 7.5, 1.3 Hz, 1H), 7.27 - 7.17 (m, 2H), 7.10 (d, J = 7.2 Hz, 1 H), 7.06 (d, J = 8.7 Hz, 1 H), 7.00 (d, J = 7.4 Hz, 1 H), 4.09 (q, J = 7.1 Hz, 2H), 3.83 - 3.71 (m, 2H), 3.05-2.92 (m, 2H), 1.94- 1.79 (m, 5H), 1.26- 1.19 (m, 2H), 1.17 (d, J = 7.1 Hz, 3H), 1.09 (s, 3H).

Example 255: 1 -(6-(N-(5-chloro-6-(o-tolyl)pyridin-2-yl)sulfamoyl)pyridin-2 -yl)-4- methylpiperidine-4-carboxylic acid; Condition 2, LCMS: m/z 501.1 [M+H] ⁺ , 3.20 min. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 12.41 (s, 1H), 11.12 (s, 1H), 7.95 (d, J = 8.8 Hz, 1H), 7.69 (dd, J = 8.7, 7.3 Hz, 1 H), 7.36 (d, J = 8.8 Hz, 1 H), 7.30 (dd, J = 7.3, 1.3 Hz, 1 H), 7.27 - 7.18 (m, 2H), 7.09 (d, J = 7.2 Hz, 1 H), 7.05 (d, J = 8.7 Hz, 1 H), 7.01 (d, J = 7.5 Hz, 1 H), 3.85 - 3.70 (m, 2H), 3.07-2.93 (m, 2H), 1.89 (s, 3H), 1.87- 1.79 (m, 2H), 1.18- 1.10 (m, 2H), 1.08 (s, 3H). Example 256: ethyl 1 -(6-(N-(5-chloro-6-(5-fluoro-2-methylphenyl)pyridin-2- yl)sulfamoyl)pyridin-2-yl)-4-methylpiperidine-4-carboxylate; Condition 2, LCMS: m/z

547.1 M+H] ⁺ , 3.52 min. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 1 1 .18 (s, 1 H), 7.97 (d, J = 8.8 Hz, 1 H), 7.69 (dd, J = 8.7, 7.3 Hz, 1 H), 7.36 (d, J = 8.8 Hz, 1 H), 7.29 (dd, J = 8.5, 5.8 Hz, 1 H),

7.16 (td, J = 8.6, 2.8 Hz, 1 H), 7.1 1 (d, J = 7.2 Hz, 1 H), 7.06 (d, J = 8.7 Hz, 1 H), 6.83 (dd, J = 9.3, 2.7 Hz, 1 H), 4.09 (q, J = 7.1 Hz, 2H), 3.82 - 3.72 (m, 2H), 3.04 - 2.95 (m, 2H), 1 .89 - 1 .80 (m, 5H), 1 .24 - 1 .13 (m, 5H), 1 .09 (s, 3H). Example 257: 1 -(6-{[5-chloro-6-(5-fluoro-2-methylphenyl)pyridin-2-yl]sulfa moyl}pyridin- 2-yl)-4-methylpiperidine-4-carboxylic acid; Condition 2, LCMS: m/z 519.2 [M+H] ⁺ , 3.28 min. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 12.39 (s, 1 H), 1 1 .18 (s, 1 H), 7.97 (d, J = 8.8 Hz, 1 H), 7.68 (dd, J = 8.7, 7.3 Hz, 1 H), 7.36 (d, J = 8.8 Hz, 1 H), 7.29 (dd, J = 8.6, 5.9 Hz, 1 H), 7.16 (td, J = 8.6, 2.8 Hz, 1 H), 7.10 (d, J = 7.2 Hz, 1 H), 7.06 (d, J = 8.7 Hz, 1 H), 6.84 (dd, J = 9.3, 2.7 Hz, 1 H), 3.84 - 3.73 (m, 2H), 3.06 - 2.95 (m, 2H), 1 .88 - 1 .77 (m, 5H), 1 .18 - 1 .1 1 (m, 2H), 1 .07 (s, 3H).

Example 258: ethyl 1 -(6-{[6-(3-fluoro-2-methylphenyl)-5-(trifluoromethyl)pyridin -2- yl]sulfamoyl}pyridin-2-yl)-4-methylpiperidine-4-carboxylate; Condition 2, LCMS: m/z 581 .2 [M+H] ⁺ , 3.53 min. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 1 1 .59 (s, 1 H), 8.23 (d, J = 8.9 Hz, 1 H), 7.69 (dd, J = 8.7, 7.3 Hz, 1 H), 7.51 (d, J = 8.6 Hz, 1 H), 7.30 - 7.19 (m, 2H), 7.10 (d, J = 7.2 Hz, 1 H), 7.07 (d, J = 8.7 Hz, 1 H), 6.92 (d, J = 6.9 Hz, 1 H), 4.09 (q, J = 7.1 Hz, 2H), 3.82 - 3.68 (m, 2H), 3.04 - 2.90 (m, 2H), 1 .88 - 1 .76 (m, 2H), 1 .63 (s, 3H), 1 .25 - 1 .1 1 (m, 5H), 1 .08 (s, 3H).

Example 259: ethyl 4-methyl-1 -(6-{[6-(2-methylphenyl)-5-(trifluoromethyl)pyridin-2- yl]sulfamoyl}pyridin-2-yl)piperidine-4-carboxylate; Condition 2, LCMS: m/z 563.2 [M+H] ⁺ , 3.51 min. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 1 1 .52 (s, 1 H), 8.21 (d, J = 8.9 Hz, 1 H), 7.69 (dd, J = 8.7, 7.3 Hz, 1 H), 7.50 (d, J = 8.2 Hz, 1 H), 7.31 (t, J = 7.5 Hz, 1 H), 7.21 (dd, J = 14.0, 7.2 Hz, 2H), 7.10 (d, J = 7.2 Hz, 1 H), 7.05 (t, J = 8.4 Hz, 2H), 4.09 (q, J = 7.1 Hz, 2H), 3.84 - 3.68 (m, 2H), 3.03 - 2.90 (m, 2H), 1 .89 - 1 .78 (m, 2H), 1 .75 (s, 3H), 1 .25 - 1 .1 1 (m, 5H), 1 .08 (s, 3H).

Example 260: methyl 1 -(6-{[5-chloro-6-(2,6-dimethylphenyl)pyridin-2- yl]sulfamoyl}pyridin-2-yl)-4-hydroxypiperidine-4-carboxylate ; Condition 2, LCMS: m/z

531 .2 [M+H] ⁺ , 3.28 min. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.03 (d, J = 8.9 Hz, 1 H), 7.72 - 7.64 (m, 2H), 7.22 - 7.16 (m, 1H), 7.11 - 7.03 (m, 4H), 3.90 - 3.71 (m, 2H), 3.33 (s, 3H), 3.19 -

3.05 (m, 2H), 1.79 (s, 6H), 1.74 - 1.65 (m, 2H), 1.59 - 1.50 (m, 2H).

Example 261 : 1 -(6-{[5-chloro-6-(2,6-dimethylphenyl)pyridin-2-yl]sulfamoyl} pyridin-2-yl)- 4-hydroxypiperidine-4-carboxylic acid; Condition 2, LCMS: m/z 517.2 [M+H] ⁺ , 3.06 min. ¹ H NMR (400 MHz, DMSO-d ₆ ) 011.17 (s, 1 H), 7.94 (dd, J = 8.8, 0.9 Hz, 1 H), 7.70 - 7.62 (m, 1H), 7.38- 7.29 (m, 1H), 7.20-7.14 (m, 1H), 7.09- 7.03 (m, 4H), 4.06- 3.85 (m, 2H), 3.19-

3.07 (m, 2H), 1.75 (s, 6H), 1.66 - 1.46 (m, 2H), 1.46 - 1.29 (m, 2H). Example 262: 1-(6-{[6-(5-fluoro-2-methylphenyl)-5-(trifluoromethyl)pyridi n-2- yl]sulfamoyl}pyridin-2-yl)-4-methylpiperidine-4-carboxylic acid; Condition 2, LCMS: m/z 553.1 [M+H] ⁺ , 3.25 min. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 12.41 (s, 1H), 11.58 (s, 1H), 8.22 (d, J = 8.9 Hz, 1H), 7.68 (dd, J = 8.7, 7.3 Hz, 1H), 7.50 (d, J = 8.7 Hz, 1H), 7.27 (dd, J = 8.5,

5.8 Hz, 1H), 7.17 (td, J = 8.6, 2.8 Hz, 1H), 7.10 (d, J = 7.2 Hz, 1H), 7.06 (d, J = 8.7 Hz, 1H), 6.92 (d, J = 7.6 Hz, 1 H), 3.86 - 3.68 (m, 2H), 3.06 - 2.93 (m, 2H), 1.86 - 1.75 (m, 2H), 1.70 (s,

3H), 1.16 - 1.07 (m, 2H), 1.06 (s, 3H).

Example 263: 1 -(6-(N-(6-(3-fluoro-2-methylphenyl)-5-(trifluoromethyl)pyrid in-2- yl)sulfamoyl)pyridin-2-yl)-4-methylpiperidine-4-carboxylic acid; Condition 2, LCMS: m/z 553.2 [M+H] ⁺ , 3.27 min. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 12.41 (s, 1H), 11.58 (s, 1H), 8.23 (d, J = 8.8 Hz, 1 H), 7.69 (dd, J = 8.6, 7.3 Hz, 1 H), 7.51 (d, J = 8.7 Hz, 1 H), 7.30 - 7.19 (m, 2H), 7.10 (d, J = 7.2 Hz, 1H), 7.06 (d, J = 8.7 Hz, 1H), 6.92 (d, J = 7.1 Hz, 1H), 3.77 (t, J = 13.4 Hz, 2H), 3.06-2.93 (m, 2H), 1.81 (d, J = 11.2 Hz, 2H), 1.63 (s, 3H), 1.18-1.08 (m, 2H),

1.06 (s, 3H).

Example 264: 4-methyl-1 -(6-(N-(6-(o-tolyl)-5-(trifluoromethyl)pyridin-2- yl)sulfamoyl)pyridin-2-yl)piperidine-4-carboxylic acid; LCMS: m/z 535.2 [M+H] ⁺ , 3.22 min. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 12.41 (s, 1H), 11.52 (s, 1H), 8.20 (d, J = 8.8 Hz, 1H), 7.68 (dd, J = 8.7, 7.3 Hz, 1H), 7.50 (d, J = 8.1 Hz, 1H), 7.34 - 7.27 (m, 1H), 7.21 (dd, J = 13.0, 7.0 Hz, 2H), 7.09 (d, J = 7.2 Hz, 1H), 7.07 - 7.00 (m, 2H), 3.84 - 3.69 (m, 2H), 3.06 - 2.92 (m, 2H), 1.81 (d, J = 12.7 Hz, 2H), 1.75 (s, 3H), 1.18-1.08 (m, 2H), 1.06 (s, 3H).

Example 265: 1 -(6-{[6-(2,6-dimethylphenyl)-5-(trifluoromethyl)pyridin-2- yl]sulfamoyl}pyridin-2-yl)-4-methylpiperidine-4-carboxylic acid; Condition 2, LCMS: m/z 549.2 [M+H] ⁺ , 3.32 min. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 12.43 (s, 1H), 11.56 (s, 1H), 8.21 (d, J = 8.9 Hz, 1H), 7.67 (dd, J = 8.7, 7.3 Hz, 1H), 7.48 (s, 1H), 7.19 (t, J = 7.6 Hz, 1H), 7.07 (d, J = 7.2 Hz, 1 H), 7.06 - 7.01 (m, 3H), 3.86 - 3.74 (m, 2H), 3.06 - 2.93 (m, 2H), 1 .87 - 1 .76 (m, 2H), 1 .71 (s, 6H), 1 .15 - 1 .07 (m, 2H), 1 .06 (s, 3H).

Example 266: ethyl 1 -(6-{[6-(2,6-dimethylphenyl)-5-(trifluoromethyl)pyridin-2- yl]sulfamoyl}pyridin-2-yl)-4-methylpiperidine-4-carboxylate; Condition 2, LCMS: m/z 577.2 [M+H] ⁺ , 3.54 min. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 1 1 .56 (s, 1 H), 8.21 (d, J = 8.9 Hz, 1 H), 7.67 (dd, J = 8.6, 7.3 Hz, 1 H), 7.54 - 7.40 (m, 1 H), 7.19 (t, J = 7.6 Hz, 1 H), 7.10 - 7.00 (m, 4H), 4.08 (q, J = 7.1 Hz, 2H), 3.84 - 3.73 (m, 2H), 3.03 - 2.90 (m, 2H), 1 .89 - 1 .78 (m, 2H), 1 .70 (s, 6H), 1 .21 - 1 .13 (m, 5H), 1 .08 (s, 3H).

Example 267: methyl 4-{[(tert-butoxy)carbonyl]amino}-1 -(6-{[5-chloro-6-(2,6- dimethylphenyl)pyridin-2-yl]sulfamoyl}pyridin-2-yl)piperidin e-4-carboxylate; Condition 2, LCMS: m/z 630.2 [M+H] ⁺ , 3.35 min. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 1 1 .16 (s, 1 H), 7.92 (d, J = 8.8 Hz, 1 H), 7.68 (dd, J = 8.6, 7.3 Hz, 1 H), 7.42 (s, 1 H), 7.35 - 7.25 (m, 1 H), 7.21 - 7.14 (m, 1 H), 7.09 (d, J = 7.2 Hz, 1 H), 7.08 - 7.01 (m, 3H), 3.95 - 3.78 (m, 2H), 3.56 (s, 3H),

3.13 - 2.98 (m, 2H), 1 .93 - 1 .80 (m, 2H), 1 .73 (s, 6H), 1 .65 - 1 .54 (m, 2H), 1 .37 (s, 9H).

Example 268: 4-{[(tert-butoxy)carbonyl]amino}-1 -(6-{[5-chloro-6-(2,6- dimethylphenyl)pyridin-2-yl]sulfamoyl}pyridin-2-yl)piperidin e-4-carboxylic acid;

Condition 2, LCMS: m/z 616.2 [M+H] ⁺ , 3.26 min, ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 12.37 (s, 1 H), 1 1 .16 (s, 1 H), 7.92 (d, J = 8.8 Hz, 1 H), 7.67 (dd, J = 8.6, 7.3 Hz, 1 H), 7.43 - 7.21 (m, 2H), 7.20 - 7.15 (m, 1 H), 7.09 (d, J = 7.2 Hz, 1 H), 7.07 - 7.02 (m, 3H), 3.94 - 3.77 (m, 2H),

3.14 - 2.96 (m, 2H), 1 .95 - 1 .84 (m, 2H), 1 .75 (s, 6H), 1 .68 - 1 .58 (m, 2H), 1 .38 (s, 9H). Example 269: 4-amino-1 -(6-{[5-chloro-6-(2,6-dimethylphenyl)pyridin-2- yl]sulfamoyl}pyridin-2-yl)piperidine-4-carboxylic acid hydrochloride; Condition 2, LCMS: m/z 516.2 [M+H] ⁺ , 2.80 min. ¹ H NMR (400 MHz, Methanol-d ₄ ) δ 7.83 (d, J = 8.8 Hz, 1 H), 7.69 (dd, J = 8.6, 7.4 Hz, 1 H), 7.45 (d, J = 8.8 Hz, 1 H), 7.26 (d, J = 7.3 Hz, 1 H), 7.21 - 7.13 (m, 1 H), 7.05 (dd, J = 8.3, 2.3 Hz, 3H), 3.88 - 3.77 (m, 2H), 3.74 - 3.63 (m, 2H), 2.25 - 2.15 (m, 2H), 1 .86 (s, 6H), 1 .81 (dt, J = 8.6, 4.5 Hz, 2H).

Example 270: methyl 4-amino-1 -(6-{[5-chloro-6-(2,6-dimethylphenyl)pyridin-2- yl]sulfamoyl}pyridin-2-yl)piperidine-4-carboxylate; Condition 2, LCMS: m/z 530.1

[M+H] ⁺ , 2.54 min. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 7.92 (d, J = 8.8 Hz, 1 H), 7.66 (dd, J = 8.7, 7.3 Hz, 1 H), 7.32 (d, J = 8.8 Hz, 1 H), 7.18 (dd, J = 8.0, 7.1 Hz, 1 H), 7.10 - 7.00 (m, 4H), 3.73 - 3.64 (m, 2H), 3.58 (s, 3H), 3.44 - 3.36 (m, 2H), 1 .74 (s, 6H), 1 .67 - 1 .55 (m, 2H), 1 .43 - 1 .38 (m, 2H). Example 271 : N-[5-chloro-6-(2,6-dimethylphenyl)pyridin-2-yl]-6-[(oxan-4- yl)amino]pyridine-2-sulfonamide; Condition 2, LCMS: m/z 473.2 [M+H] ⁺ , 3.17 min. ¹ H NMR (400 MHz, Methylene Chloride-d ₂ ) δ 7.76 (d, J=8.8 Hz, 1 H), 7.59 - 7.41 (m, 2H), 7.26 - 7.15 (m, 2H), 7.09 (d, J=7.6 Hz, 2H), 6.54 (d, J=8.5 Hz, 1 H), 3.88 - 3.66 (m, 3H), 3.39 (td, J=2.2, 1 1 .6 Hz, 2H), 1 .98 - 1 .80 (m, 7H), 1 .54 (s, 2H), 1 .47 - 1 .31 (m, 2H).

Example 272: N-[5-chloro-6-(5-fluoro-2-methylphenyl)pyridin-2-yl]-6-{[(3R ,4R)-3- hydroxyoxan-4-yl]amino}pyridine-2-sulfonamide; Condition 2, LCMS: m/z 493.2 [M+H] ⁺ , 3.04 min. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 1 1 .08 (s, 1 H), 8.00 (d, J = 8.8 Hz, 1 H), 7.52 (dd, J = 7.2, 8.5 Hz, 1 H), 7.42 (d, J = 8.8 Hz, 1 H), 7.29 (dd, J = 5.8, 8.5 Hz, 1 H), 7.16 (td, J = 2.8, 8.6 Hz, 1 H), 7.01 (m, 1 H), 6.87 (m, 2H), 6.82 (d, J = 8.5 Hz, 1 H), 4.84 (d, J = 5.0 Hz, 1 H), 3.68 (m, 3H), 3.47 (d, J = 0.7 Hz, 1 H), 3.33 (m, 1 H), 3.27 (m, 1 H), 1 .87 (s, 3H), 1 .67 (m, 1 H), 1 .28 (m, 1 H). ¹⁹ F NMR (376 MHz, DMSO-d ₆ ) δ -1 17.85(s).

Example 273: N-[5-chloro-6-(5-fluoro-2-methylphenyl)pyridin-2-yl]-6-{[(3S ,4R)-3- hydroxyoxan-4-yl]amino}pyridine-2-sulfonamide; Condition 2, LCMS: m/z 493.2 [M+H] ⁺ , 3.08 min. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 1 1 .1 1 (s, 1 H), 7.97 (d, J = 8.8 Hz, 1 H), 7.52 (dd, J = 7.2, 8.5 Hz, 1 H), 7.41 (d, J = 8.8 Hz, 1 H), 7.29 (dd, J = 5.8, 8.5 Hz, 1 H), 7.16 (td, J = 2.8, 8.6 Hz, 1 H), 7.07 (d, J = 7.0 Hz, 1 H), 7.01 (m, 1 H), 6.89 (d, J = 7.9 Hz, 1 H), 6.70 (d, J = 8.3 Hz, 1 H), 4.92 (d, J = 5.0 Hz, 1 H), 3.79 (dd, J = 4.7, 1 1 .0 Hz, 1 H), 3.63 (m, 1 H), 3.48 (m, 1 H), 3.35 (m, 1 H), 3.20 (m, 1 H), 2.98 (dd, J = 9.7, 10.9 Hz, 1 H), 1 .88 (s, 3H), 1 .66 (m, 1 H), 1 .13 (m, 1 H). ¹⁹ F NMR (376 MHz, DMSO-d ₆ ) δ -1 17.89(s, 1 F). Example 274: 6-(((3S,4R)-3-hydroxytetrahydro-2H-pyran-4-yl)amino)-N-(6-(o -tolyl)-5- (trifluoromethyl)pyridin-2-yl)pyridine-2-sulfonamide; Condition 2, LCMS: m/z 509.2

[M+H] ⁺ , 3.06 min. 1 H NMR (400 MHz, DMSO-d6) δ 1 1 .48 (s, 1 H), 8.19 (d, J = 8.9 Hz, 1 H), 7.52 (m, 2H), 7.31 (t, J = 7.3 Hz, 1 H), 7.20 (m, 2H), 7.05 (m, 3H), 6.70 (d, J = 8.3 Hz, 1 H), 4.91 (d, J = 13.7 Hz, 1 H), 3.79 (m, 1 H), 3.54 (m, 2H), 3.34 (m, 2H), 3.16 (m, 1 H), 2.96 (m, 1 H), 1 .80 (m, 3H), 1 .55 (m, 1 H). ¹⁹ F NMR (376 MHz, DMSO-d6) δ -57.06(s).

Example 275: rac-6-{[(3RS,4RS)-3-hydroxyoxan-4-yl]amino}-N-[6-(2-methylph enyl)-5- (trifluoromethyl)pyridin-2-yl]pyridine-2-sulfonamide; Condition 2, LCMS: m/z 509.2

[M+H] ⁺ , 3.10 min 1 H NMR (400 MHz, DMSO-d6) δ 1 1 .45 (s, 1 H), 8.22 (m, 1 H), 7.51 (m, 2H), 7.31 (t, J = 7.5 Hz, 1 H), 7.22 (m, 2H), 7.03 (m, 2H), 6.84 (m, 2H), 4.86 (m, 1 H), 3.68 (m, 3H), 3.49 (m, 1 H), 3.27 (m, 2H), 1 .73 (m, 4H), 1 .29 (m, 1 H).

1 ⁹ F NMR (376 MHz, DMSO-d6) δ -57.06 (s). Example 276: 6-(((3R,4R)-3-hydroxytetrahydro-2H-pyran-4-yl)amino)-N-(6-(o -tolyl)-5- (trifluoromethyl)pyridin-2-yl)pyridine-2-sulfonamide; Example 275 was subjected to chiral HPLC under the following conditions: 80g/min, 82/18 C02/MeOH, 100bar, 30°C, column: 21 x250mm OD-H, run time: 3.4 min stacked injections, 8.5 minute elution time. Enantiomer A cis, (-) rotation at 245 nm, Analytical method: solvents : A: C02 (80%), B: MeOH (20%), flow rate: 2 mL/min, temp: 30°C, phase: 5um 4.6x50mm OD, Retention time 2.14 min. Condition 2, LCMS: m/z 509.2 [M+H] ⁺ , 2.98 min. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 1 1 .45 (s, 1 H), 8.22 (m, 1 H), 7.51 (m, 2H), 7.31 (t, J = 7.5 Hz, 1 H), 7.22 (m, 2H), 7.03 (m, 2H), 6.84 (m, 2H), 4.86 (m, 1 H), 3.68 (m, 3H), 3.49 (m, 1 H), 3.27 (m, 2H), 1 .73 (m, 4H), 1 .29 (m, 1 H). ¹⁹ F NMR (376 MHz, DMSO-d ₆ ) δ -57.06 (s).

Example 277: 6-(((3S,4S)-3-hydroxytetrahydro-2H-pyran-4-yl)amino)-N-(6-(o -tolyl)-5- (trifluoromethyl)pyridin-2-yl)pyridine-2-sulfonamide; Example 275 was subjected to chiral HPLC under the following conditions: 80g/min, 82/18 C02/MeOH, 100bar, 30°C, column: 21 x250mm OD-H, run time: 3.4 min stacked injections, 8.5 minute elution time. Enantiomer B (cis), (+) rotation at 245 nm, Analytical method: solvents : A: C02 (80%), B: MeOH (20%), flow rate: 2 mL/min, temp: 30°C, phase: 5um 4.6x50mm OD, Retention time 2.67 min. Condition 2, LCMS: m/z 509.2 [M+H] ⁺ , 3.01 min. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 1 1 .44 (s, 1 H), 8.21 (m, 1 H), 7.51 (m, 2H), 7.31 (t, J = 7.4 Hz, 1 H), 7.21 (m, 2H), 7.03 (m, 2H), 6.84 (m, 2H), 4.85 (m, 1 H), 3.69 (m, 3H), 3.47 (m, 1 H), 3.27 (m, 2H), 1 .73 (m, 4H), 1 .30 (m, 1 H). ¹⁹ F NMR (376 MHz, DMSO-d ₆ ) δ -57.06 (s).

Example 278: N-[5-chloro-6-(5-fluoro-2-methylphenyl)pyridin-2-yl]-6-{[(3R ,4R)-4- hydroxyoxan-3-yl]amino}pyridine-2-sulfonamide; Condition 2, LCMS: m/z 493.2 [M+H] ⁺ , 3.06 min. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 1 1 .17 (s, 1 H), 7.89 (d, J = 8.9 Hz, 1 H), 7.51 (dd, J = 7.2, 8.5 Hz, 1 H), 7.43 (d, J = 8.8 Hz, 1 H), 7.29 (dd, J = 5.8, 8.5 Hz, 1 H), 7.15 (td, J = 2.8, 8.6 Hz, 1 H), 7.02 (m, 2H), 6.96 (m, 1 H), 6.73 (d, J = 8.1 Hz, 1 H), 4.88 (d, J = 4.6 Hz, 1 H), 3.78 (dt, J = 3.9, 1 1 .5 Hz, 1 H), 3.65 (dd, J = 4.2, 10.9 Hz, 1 H), 3.45 (m, 2H), 3.31 (m, 1 H), 2.81 (dd, J = 8.7, 10.7 Hz, 1 H), 1 .89 (m, 4H), 1 .43 (m, 1 H).

1 ⁹ F NMR (376 MHz, DMSO-d ₆ ) δ -1 17.94 (s).

Example 279: 6-{[(3R,4R)-4-hydroxyoxan-3-yl]amino}-N-[6-(2-methylphenyl)- 5- (trifluoromethyl)pyridin-2-yl]pyridine-2-sulfonamide; Condition 2, LCMS: m/z 509.2

[M+H] ⁺ , 2.99 min. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 1 1 .49 (s, 1 H), 8.17 (d, J = 8.9 Hz, 1 H), 7.58 (m, 1 H), 7.51 (dd, J = 7.3, 8.5 Hz, 1 H), 7.31 (t, J = 7.3 Hz, 1 H), 7.22 (m, 2H), 7.08 (d, J = 7.1 Hz, 1 H), 7.02 (d, J = 6.9 Hz, 1 H), 6.86 (d, J = 8.5 Hz, 1 H), 6.80 (d, J = 6.4 Hz, 1 H), 4.94 (m, 1 H), 3.76 (m, 2H), 3.62 (m, 1 H), 3.45 (m, 1 H), 3.27 (m, 2H), 1 .83 (m, 3H), 1 .63 (m, 2H). ¹⁹ F NMR (376 MHz, DMSO-d ₆ ) δ -57.17 (s).

Example 280: rac-6-{[(3RS,4SR)-4-hydroxyoxan-3-yl]amino}-N-[6-(2-methylph enyl)-5- (trifluoromethyl)pyridin-2-yl]pyridine-2-sulfonamide; Condition 2, LCMS: m/z 509.2

[M+H] ⁺ , 2.98 min. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 1 1 .49 (s, 1 H), 8.17 (d, J = 8.9 Hz, 1 H), 7.58 (m, 1 H), 7.51 (dd, J = 7.3, 8.5 Hz, 1 H), 7.31 (t, J = 7.3 Hz, 1 H), 7.22 (m, 2H), 7.08 (d, J = 7.1 Hz, 1 H), 7.02 (d, J = 6.9 Hz, 1 H), 6.86 (d, J = 8.5 Hz, 1 H), 6.80 (d, J = 6.4 Hz, 1 H), 4.94 (m, 1 H), 3.76 (m, 2H), 3.62 (m, 1 H), 3.45 (m, 1 H), 3.27 (m, 2H), 1 .83 (m, 3H), 1 .63 (m, 2H). ¹⁹ F NMR (376 MHz, DMSO-d6) δ -57.17 (s).

Example 281 : 6-{[(3R,4S)-4-hydroxyoxan-3-yl]amino}-N-[6-(2-methylphenyl)- 5- (trifluoromethyl)pyridin-2-yl]pyridine-2-sulfonamide; Example 280 was subjected to chiral HPLC under the following conditions: 80g/min, 85/15 C02/MeOH, 100 bar, 30°C, column: 21 x250mm OD-H, run time: 3.3 min stacked injections, 8.5 min elution time

Enantiomer A (cis), (-) rotation at 245 nm, Analytical method: solvents : A: C02 (85%), B: MeOH (15%), flow rate: 2 mL/min, temp: 30°C, phase: 5um 4.6x50mm OD, Retention time 2.49 min. Condition 2, LCMS: m/z 509.2 [M+H] ⁺ , 2.98 min. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 1 1 .49 (s, 1 H), 8.16 (m, 1 H), 7.52 (m, 2H), 7.31 (t, J = 7.3 Hz, 1 H), 7.21 (m, 2H), 7.08 (d, J = 6.7 Hz, 1 H), 7.01 (d, J = 7.1 Hz, 1 H), 6.83 (m, 2H), 4.93 (m, 1 H), 3.76 (m, 2H), 3.62 (m, 1 H), 3.45 (m, 1 H), 3.28 (m, 2H), 1 .84 (m, 3H), 1 .63 (m, 2H).

1 ⁹ F NMR (376 MHz, DMSO-d6) δ -57.17 (s).

Example 282: 6-{[(3S,4R)-4-hydroxyoxan-3-yl]amino}-N-[6-(2-methylphenyl)- 5- (trifluoromethyl)pyridin-2-yl]pyridine-2-sulfonamide; Example 280 was subjected to chiral HPLC under the following conditions: 80g/min, 85/15 C02/MeOH, 100 bar, 30°C, column: 21 x250mm OD-H, run time: 3.3 min stacked injections, 8.5 min elution time.

Enantiomer B (cis), (+) rotation at 245 nm, Analytical method: solvents : A: C02 (85%), B: MeOH (15%), flow rate: 2 mL/min, temp: 30°C, phase: 5um 4.6x50mm OD, Retention time 3.04 min. Condition 2, LCMS: m/z 509.2 [M+H] ⁺ , 1 H NMR (400 MHz, DMSO-d6) δ 1 1 .49 (s, 1 H), 8.16 (s, 1 H), 7.53 (m, 2H), 7.31 (t, J = 7.2 Hz, 1 H), 7.21 (m, 2H), 7.08 (d, J = 6.7 Hz, 1 H), 7.01 (d, J = 7.2 Hz, 1 H), 6.83 (m, 2H), 4.93 (m, 1 H), 3.77 (m, 2H), 3.62 (m, 1 H), 3.46 (m, 1 H), 3.28 (m, 2H), 1 .84 (m, 3H), 1 .63 (m, 2H). ¹⁹ F NMR (376 MHz, DMSO-d6) δ -57.17 (s). Example 283: N-[6-(2-methylphenyl)-5-(trifluoromethyl)pyridin-2-yl]-6-{[( 1s,3s)-3- hydroxycyclobutyl]amino}pyridine-2-sulfonamide; Condition 2, LCMS: m/z 479.1 [M+H] ⁺ , 3.00 min. ¹ H NMR (400 MHz, Methanol-d ₄ ) δ 8.08 (d, J = 8.9 Hz, 1 H), 7.67 - 7.59 (m, 1 H), 7.47 (dd, J = 8.5, 7.3 Hz, 1 H), 7.31 (t, J = 7.5 Hz, 1 H), 7.21 (dd, J = 16.7, 8.0 Hz, 2H), 7.12 (dd, J = 7.2, 0.6 Hz, 1 H), 7.08 (d, J = 7.3 Hz, 1 H), 6.59 (dd, J = 8.5, 0.6 Hz, 1 H), 3.98 - 3.79 (m, 1 H), 3.70 - 3.55 (m, 1 H), 3.35 (s, 2H), 2.66 - 2.50 (m, 2H), 1 .95 (s, 3H), 1 .70 (s, 2H). Example 284: N-[6-(2-methylphenyl)-5-(trifluoromethyl)pyridin-2-yl]-6-{[( 1 r,3r)-3- hydroxycyclobutyl]amino}pyridine-2-sulfonamide; Condition 2, LCMS: m/z 479.1

[M+H] ⁺ , 3.05 min. ¹ H NMR (400 MHz, Methanol-d ₄ ) δ 8.08 (d, J = 8.9 Hz, 1 H), 7.59 (s, 1 H), 7.47 (dd, J = 8.5, 7.3 Hz, 1 H), 7.29 (d, J = 7.5 Hz, 1 H), 7.20 (dd, J = 16.3, 7.7 Hz, 2H), 7.16 - 7.1 1 (m, 1 H), 7.08 (d, J = 7.6 Hz, 1 H), 6.59 (d, J = 8.4 Hz, 1 H), 4.38 (t, J = 6.1 Hz, 1 H), 4.18 (dt, J = 7.7, 3.3 Hz, 1 H), 2.17 (d, J = 31 .2 Hz, 4H), 1 .92 (s, 3H).

Example 285: N-[5-chloro-6-(2,6-dimethylphenyl)pyridin-2-yl]-6-{[(1 r,3s)-3-hydroxy-3- methylcyclobutyl]amino}pyridine-2-sulfonamide; Condition 2, LCMS: m/z 473.2 [M+H] ⁺ , 3.10 min. ¹ H NMR (400 MHz, Methylene Chloride-d ₂ ) δ 7.75 (d, J=8.9 Hz, 1 H), 7.54 (t, J=7.9 Hz, 1 H), 7.48 (d, J=8.7 Hz, 1 H), 7.22 (dd, J=2.3, 7.3 Hz, 2H), 7.10 (d, J=7.6 Hz, 2H), 6.49 (d, J=8.5 Hz, 1 H), 5.10 (s,1 H), 3.76 - 3.58 (m, 1 H), 2.47 (ddd, J=2.7, 7.5, 9.9 Hz, 2H), 2.05 - 1 .96 (m, 3H), 1 .92 (s, 6H), 1 .33 (s, 3H).

Example 286: N-[5-chloro-6-(2,6-dimethylphenyl)pyridin-2-yl]-6-{[(1s,3s)- 3- hydroxycyclobutyl]amino}pyridine-2-sulfonamide; Condition 2, LCMS: m/z 459.2 [M+H] ⁺ , 3.05 min. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 1 1 .06 (s, 1 H), 7.98 (d, J=8.8 Hz, 1 H), 7.50 (dd, J=7.3, 8.4 Hz, 1 H), 7.43 (d, J=8.8 Hz, 1 H), 7.29 (d, J=7.0 Hz, 1 H), 7.23 - 7.15 (m, 1 H), 7.08 (d, J=7.6 Hz, 2H), 7.01 - 6.95 (m, 1 H), 6.59 (d, J=8.2 Hz, 1 H), 5.05 (d, J=6.1 Hz, 1 H), 3.80 - 3.67 (m, 1 H), 3.52 - 3.38 (m, 1 H), 2.43 (ddt, J=3.1 , 6.9, 9.5 Hz, 2H), 1 .80 (s, 6H), 1 .58 (qd, J=2.8, 8.7 Hz, 2H).

Example 287: N-[5-chloro-6-(2,6-dimethylphenyl)pyridin-2-yl]-6-{[(1 r,3r)-3- hydroxycyclobutyl]amino}pyridine-2-sulfonamide; Condition 2, LCMS: m/z 459.2 [M+H] ⁺ , 3.05 min. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 1 1 .1 1 (s, 1 H), 7.95 (d, J = 8.8 Hz, 1 H), 7.49 (dd, J = 8.4, 7.3 Hz, 1 H), 7.38 - 7.33 (m, 2H), 7.21 - 7.14 (m, 1 H), 7.07 (d, J = 7.6 Hz, 2H), 6.99 (d, J = 6.9 Hz, 1 H), 6.58 (d, J = 8.4 Hz, 1 H), 5.00 (d, J = 5.1 Hz, 1 H), 4.27 - 4.20 (m, 1 H), 4.13- 4.00 (m, 1 H), 2.1 1 -2.02 (m, 2H), 2.02-1 .94 (m, 2H), 1 .78 (s, 6H).

Example 288: N-[5-chloro-6-(2,6-dimethylphenyl)pyridin-2-yl]-6-{[(3S,5S)- 5- (hydroxymethyl)oxolan-3-yl]oxy}pyridine-2-sulfonamide; Condition 2, LCMS: m/z 490.2 [M+H] ⁺ , 3.10 min. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 1 1 .41 (s, 1 H), 7.86 (m, 2H), 7.50 (d, J = 7.3 Hz, 1 H), 7.25 (d, J = 8.5 Hz, 1 H), 7.17 (t, J = 7.5 Hz, 1 H), 7.04 (m, 3H), 5.20 (m, 1 H), 4.72 (t, J = 5.1 Hz, 1 H), 3.82 (m, 1 H), 3.74 (dd, J = 4.9, 10.4 Hz, 1 H), 3.63 (m, 1 H), 3.39 (m, 2H), 2.26 (dt, J = 7.3, 14.1 Hz, 1 H), 1 .74 (s, 3H), 1 .70 (s, 3H), 1 .59 (ddd, J = 3.3, 7.1 , 13.5 Hz, 1 H). Example 289: N-(5-chloro-6-(5-fluoro-2-methylphenyl)pyridin-2-yl)-6-(((3R ,4S)-4- hydroxytetrahydrofuran-3-yl)oxy)pyridine-2-sulfonamide; chiral HPLC under the following conditions: 80g/min, 75/25 C02/MeOH, 100 bar, 30°C, column: 21x250mm

Princeton DEAP, run time: 2 min stacked injections, 4.75 min elution time Analytical method: solvents : A: C02 (80%), B: MeOH (20%), flow rate: 2 mL/min, temp: 50°C, 125 bar, phase: 3um 2.1x100mm Princeton DEAP, tR 1 .02 min. Condition 2, LCMS: m/z 480.2 [M+H] ⁺ , 3.05 min. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 1 1 .44 (s, 1 H), 7.98 (d, J = 8.8 Hz, 1 H), 7.92 (dd, J = 7.4, 8.4 Hz, 1 H), 7.57 (dd, J = 0.6, 7.3 Hz, 1 H), 7.34 (d, J = 8.8 Hz, 1 H), 7.30 (dd, J = 5.9, 8.5 Hz, 1 H), 7.16 (td, J = 2.8, 8.6 Hz, 1 H), 7.12 (dd, J = 0.6, 8.4 Hz, 1 H), 6.88 (dd, J = 2.4, 9.3 Hz, 1 H), 5.06 (d, J = 5.6 Hz, 1 H), 4.97 (q, J = 5.8 Hz, 1 H), 4.22 (p, J = 5.2 Hz, 1 H), 3.89 (dd, J = 6.1 , 9.2 Hz, 1 H), 3.82 (dd, J = 5.3, 9.0 Hz, 1 H), 3.56 (dd, J = 4.6, 9.0 Hz, 1 H), 3.50 (dd, J = 5.7, 9.2 Hz, 1 H), 1 .85 (s, 3H). ¹⁹ F NMR (376 MHz, DMSO-d ₆ ) δ -1 17.82(s, 1 F).

Example 290: rac-N-[5-chloro-6-(2,6-dimethylphenyl)pyridin-2-yl]-6-{[(3R, 4S)-4- hydroxyoxolan-3-yl]oxy}pyridine-2-sulfonamide; Condition 2, LCMS: m/z 476.2 [M+H] ⁺ , 3.07 min. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 1 1 .41 (s, 1 H), 7.98 (d, J = 8.8 Hz, 1 H), 7.90 (dd, J = 7.4, 8.4 Hz, 1 H), 7.54 (dd, J = 0.6, 7.3 Hz, 1 H), 7.31 (d, J = 8.7 Hz, 1 H), 7.19 (t, J = 7.5 Hz, 1 H), 7.09 (m, 3H), 5.07 (d, J = 5.5 Hz, 1 H), 4.97 (q, J = 5.7 Hz, 1 H), 4.26 (p, J = 5.1 Hz, 1 H), 3.92 (dd, J = 6.1 , 9.2 Hz, 1 H), 3.83 (dd, J = 5.3, 9.0 Hz, 1 H), 3.56 (dd, J = 4.6, 9.0 Hz, 1 H), 3.49 (dd, J = 5.7, 9.2 Hz, 1 H), 1 .78 (s, 3H), 1 .70 (s, 3H).

Example 291 : rac-6-{[(3RS,4SR)-4-hydroxyoxolan-3-yl]oxy}-N-[6-(2-methylph enyl)-5- (trifluoromethyl)pyridin-2-yl]pyridine-2-sulfonamide; Condition 2, LCMS: m/z 496.2

[M+H] ⁺ , 3.04 min. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 1 1 .81 (s, 1 H), 8.21 (d, J = 8.9 Hz, 1 H), 7.91 (m, 1 H), 7.56 (dd, J = 0.6, 7.3 Hz, 1 H), 7.47 (s, 1 H), 7.32 (t, J = 7.3 Hz, 1 H), 7.22 (m, 2H), 7.1 1 (d, J = 8.3 Hz, 1 H), 7.05 (m, 1 H), 5.07 (m, 1 H), 4.95 (m, 1 H), 4.21 (m, 1 H), 3.82 (m, 2H), 3.54 (m, 2H), 1 .79 (m, 3H). ¹⁹ F NMR (376 MHz, DMSO-d ₆ ) δ -57.17 (s).

Example 292: rac-N-[6-(2-methylphenyl)-5-(trifluoromethyl)pyridin-2-yl]-6 -[(4- oxooxolan-3-yl)oxy]pyridine-2-sulfonamide; Condition 2, LCMS: m/z 494.2 [M+H] ⁺ , 3.08 min. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 1 1 .44 (s, 1 H), 7.98 (d, J = 8.8 Hz, 1 H), 7.92 (dd, J =

7.4, 8.4 Hz, 1 H), 7.57 (dd, J = 0.6, 7.3 Hz, 1 H), 7.34 (d, J = 8.8 Hz, 1 H), 7.30 (dd, J = 5.9, 8.5 Hz, 1 H), 7.16 (td, J = 2.8, 8.6 Hz, 1 H), 7.12 (dd, J = 0.6, 8.4 Hz, 1 H), 6.88 (dd, J = 2.4, 9.3 Hz, 1 H), 5.06 (d, J = 5.6 Hz, 1 H), 4.97 (q, J = 5.8 Hz, 1 H), 4.22 (p, J = 5.2 Hz, 1 H), 3.89 (dd, J = 6.1 , 9.2 Hz, 1 H), 3.82 (dd, J = 5.3, 9.0 Hz, 1 H), 3.56 (dd, J = 4.6, 9.0 Hz, 1 H), 3.50 (dd, J = 5.7, 9.2 Hz, 1 H), 1 .85 (s, 3H). Example 293: rac-6-{[(3RR,4SR)-4-hydroxy-4-methyloxolan-3-yl]oxy}-N-[6-(2 - methylphenyl)-5-(trifluoromethyl)pyridin-2-yl]pyridine-2 -sulfonamide; Condition 2, LCMS: m/z 510.2 [M+H] ⁺ , 3.07 min. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 1 1 .83 (s, 1 H), 8.22 (d, J = 8.9 Hz, 1 H), 7.91 (dd, J = 7.4, 8.3 Hz, 1 H), 7.55 (d, J = 7.3 Hz, 1 H), 7.45 (m, 1 H), 7.32 (t, J = 7.4 Hz, 1 H), 7.21 (m, 2H), 7.1 1 (d, J = 8.3 Hz, 1 H), 7.02 (m, 1 H), 4.97 (m, 1 H), 4.73 (m, 1 H), 3.93 (dd, J = 5.7, 9.5 Hz, 1 H), 3.60 (d, J = 8.5 Hz, 1 H), 3.49 (d, J = 8.5 Hz, 1 H), 3.42 (m, 1 H), 1 .76 (m, 3H), 1 .17 (m, 3H). ¹⁹ F NMR (376 MHz, DMSO-d ₆ ) δ -57.15 (m).

Example 294: 6-{[(3R,4S)-4-hydroxy-4-methyloxolan-3-yl]oxy}-N-[6-(2-methy lphenyl)-5- (trifluoromethyl)pyridin-2-yl]pyridine-2-sulfonamide; Example 293 was subjected to chiral HPLC under the following conditions: 80g/min, 90/10 C02/MeOH, 100 bar, 35°C, column: 21 x250mm IF, run time: 13 min. Enantiomer A, (-) rotation at 275 nm, Analytical method: solvents : A: C02, B: MeOH, 5-40% in 5 min, flow rate: 2 mL/min, temp: 30°C, phase: 3um 4.6x50mm IF, Retention time 3.20 min. Condition 2, LCMS: m/z 510.1 [M+H] ⁺ , Example 295: 6-{[(3R,4R)-4-hydroxy-4-methyloxolan-3-yl]oxy}-N-[6-(2-methy lphenyl)-5- (trifluoromethyl)pyridin-2-yl]pyridine-2-sulfonamide; Example 293 was subjected to chiral HPLC under the following conditions: 80g/min, 90/10 C02/MeOH, 100 bar, 35°C, column: 21 x250mm IF, run time: 13 min. Enantiomer B, (+) rotation at 275 nm, Analytical method: solvents : A: C02, B: MeOH, 5-40% in 5 min, flow rate: 2 mL/min, temp: 30°C, phase: 3um 4.6x50mm IF, Retention time 3.45 min. Condition 2, LCMS: m/z 510.1 [M+H] ⁺ ,

Example 296: 6-{[(3R,4S)-4-hydroxyoxolan-3-yl]oxy}-N-[6-(2-methylphenyl)- 5- (trifluoromethyl)pyridin-2-yl]pyridine-2-sulfonamide; Example 291 was subjected to chiral HPLC under the following conditions: 80g/min, 78/22 C02/MeOH, 100 bar, 30°C, column: 21 x250mm Cellulose-2, run time: 2.8 min stacked injections, 6.75 min elution time. Enantiomer A (cis), (+) rotation at 275 nm, Analytical method: solvents : A: C02 (80%), B: MeOH (20%), flow rate: 2 mL/min, temp: 30°C, phase: 3um 4.6x50mm Cellulose-2,

Retention time 2.17 min. Condition 2, LCMS: m/z 496.2 [M+H] ⁺ , 3.01 min. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 1 1 .81 (s, 1 H), 8.19 (m, 1 H), 7.90 (t, J = 7.2 Hz, 1 H), 7.55 (d, J = 7.3 Hz, 1 H), 7.45 (s, 1 H), 7.32 (t, J = 7.3 Hz, 1 H), 7.21 (m, 2H), 7.08 (m, 2H), 5.06 (m, 1 H), 4.96 (m, 1 H), 4.20 (m, 1 H), 3.83 (m, 2H), 3.50 (m, 2H), 1 .79 (m, 3H). ¹⁹ F NMR (376 MHz, DMSO-d ₆ ) δ - 57.14 (s). Example 297: ethyl 1 -(4-(6-(N-(6-(5-fluoro-2-methylphenyl)-5-(trifluoromethyl)py ridin-2- yl)sulfamoyl)pyridin-2-yl)piperazin-1 -yl)cyclopropane-1 -carboxylate; Purified by ISCO reverse-phase C18 chromatography [30g Redisep GOLD C18 column, eluted with 10-100% acetonitrile/water], Condition 3, LCMS: R _t 0.70 min; m/z 608.3 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO-d6) 5 1 1 .57 (s, 1 H), 8.22 (d, J = 8.9 Hz, 1 H), 7.69 (dd, J = 8.7, 7.3 Hz, 1 H), 7.55 (d, J = 8.7 Hz, 1 H), 7.28 (dd, J = 8.5, 5.8 Hz, 1 H), 7.21 - 7.14 (m, 1 H), 7.13 (d, J = 7.2 Hz, 1 H),

7.05 (d, J = 8.7 Hz, 1 H), 6.94 (d, J = 7.1 Hz, 1 H), 3.99 (q, J = 7.1 Hz, 2H), 3.31 (s, 4H), 2.81 (s, 4H), 1 .77 (s, 3H), 1 .19 (q, J = 3.8 Hz, 2H), 1 .09 (t, J = 7.1 Hz, 3H), 0.94 (q, J = 3.5 Hz, 2H).

Example 298: tert-butyl 4-(6-(N-(5-chloro-6-(5-fluoro-2-methylphenyl)pyridin-2- yl)sulfamoyl)pyridin-2-yl)piperazine-1 -carboxylate; Condition 3, LCMS: R _t 0.69 min; m/z 562.2 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO-d6) δ 1 1 .18 (s, 1 H), 7.99 (d, J = 8.7 Hz, 1 H), 7.77 - 7.69 (m, 1 H), 7.42 (d, J = 8.6 Hz, 1 H), 7.34 - 7.27 (m, 1 H), 7.22 - 7.1 1 (m, 2H), 7.06 (d, J =

8.6 Hz, 1 H), 6.94 - 6.86 (m, 1 H), 3.46 - 3.34 (m, 4H), 3.30 - 3.25 (m, 4H), 1 .89 (s, 3H), 1 .40 (s, 9H).

Example 299: W-(6-(5-cyano-2-methylphenyl)-5-(trifluoromethyl)pyridin-2-y l)-6-(3- hydroxy-3-methylazetidin-1 -yl)pyridine-2-sulfonamide; Purified by Condition 2, Mobile Phase 2. LCMS: m/z 504.1 [M+H] ⁺ , 0.66 min. ¹ H NMR (300 MHz, CD ₃ OD) δ ppm 8.1 1 (d, J= 9.0 Hz, 1 H), 7.67 (dd, J= 8.1 , 1 .8 Hz, 1 H), 7.58 (t, J= 8.1 , 3.6 Hz, 2H), 7.48 - 7.40 (m, 2H), 7.19 (d, J= 7.2 Hz, 1 H), 6.55 (d, J= 8.4 Hz, 1 H), 3.83 - 3.75 (m, 4H), 1 .99 (s, 3H), 1 .47 (s, 3H).

Example 300: 1 -(6-(N-(6-(5-fluoro-2-methylphenyl)-5-(trifluoromethyl) pyridin-2-yl) sulfamoyl) pyridin-2-yl) pyrrolidine-3-carboxylic acid; Purified by Condition 2, Mobile Phase 1 . Condition 3, LCMS: m/z 525.2 [M+H] ⁺ , 0.65 min. ¹ H NMR (400 MHz, DMSO-d6) δ ppm 8.14 (brs, 1 H), 7.64 (t, J= 8.0 Hz, 1 H), 7.57 (brs, 1 H), 7.27 (dd, J= 8.4, 5.6 Hz, 1 H), 7.16 (dt, J= 8.8, 2.8 Hz, 1 H), 7.08 (d, J= 7.2 Hz, 1 H), 6.97 - 6.95 (m, 1 H), 6.68 (d, J= 8.4, 1 H), 3.45 - 3.39 (m, 2H), 3.28 - 3.24 (m, 2H), 3.16 - 3.1 1 (m, 1 H), 2.18 - 2.12 (m, 1 H), 2.1 1 - 2.04 (m, 1 H), 1 .78 (s, 3H).

Example 301 : tert-butyl 1 -(6-(N-(6-(o-tolyl)-5-(trifluoromethyl)pyridin-2- yl)sulfamoyl)pyridin-2-yl)-1 ,6-diazaspiro[3.3]heptane-6-carboxylate; Condition 6, LCMS: R _t 0.92 min; m/z 590.4 [M+H] ⁺ . ¹ H NMR (400 MHz, Methanol-d4) δ 8.10 (d, J = 8.9 Hz, 1 H), 7.68 - 7.52 (m, 2H), 7.35 - 7.12 (m, 4H), 7.03 (d, J = 7.2 Hz, 1 H), 6.53 (d, J = 8.4 Hz, 1 H), 4.62 (s, 2H), 3.93 (d, J = 9.6 Hz, 2H), 3.82 (t, J = 7.1 Hz, 2H), 2.58 (t, J = 7.1 Hz, 2H), 1 .90 (s, 3H), 1 .49 (s, 9H).

Example 302: 6-(4,7-diazaspiro[2.5]octan-7-yl)-N-(6-(o-tolyl)-5-(trifluor omethyl)pyridin- 2-yl)pyridine-2-sulfonamide; Purified by ISCO reverse-phase C18 chromatography [30g Redisep GOLD C18 column, eluted with 10-100% acetonitrile/water]. Condition 4, LCMS: R _t 1 .64 min; m/z 504.1 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO-d6) δ 8.15 (d, J = 8.9 Hz, 1 H), 7.66 (dd, J = 8.7, 7.3 Hz, 1 H), 7.51 (d, J = 8.8 Hz, 1 H), 7.31 (dd, J = 7.4, 1 .3 Hz, 1 H), 7.27 - 7.17 (m, 2H), 7.09 (d, J = 7.2 Hz, 1 H), 7.06 (d, J = 7.5 Hz, 1 H), 7.00 (d, J = 8.7 Hz, 1 H), 3.43 - 3.35 (m, 2H), 3.29 (s, 2H), 2.78 - 2.70 (m, 2H), 1 .82 (s, 3H), 0.42 (s, 2H), 0.31 (d, J = 8.2 Hz, 2H).

Example 303: 6-(8-amino-5-oxa-2-azaspiro[3.4]octan-2-yl)-N-(6-(o-tolyl)-5 - (trifluoromethyl)pyridin-2-yl)pyridine-2-sulfonamide; Condition 4, LCMS: R _t 1 .64 min; m/z 520.4 [M+H] ⁺ . ¹ H NMR (400 MHz, Methanol-d4) δ 8.03 (d, J = 8.9 Hz, 1 H), 7.65 - 7.52 (m, 2H), 7.35 - 7.09 (m, 5H), 7.06 (d, J = 7.6 Hz, 1 H), 6.57 (d, J = 8.4 Hz, 1 H), 4.27 (d, J = 9.8 Hz, 1 H), 4.00 (q, J = 7.8 Hz, 1 H), 3.87 (h, J = 5.2 Hz, 3H), 3.80 - 3.72 (m, 1 H), 3.61 (dd, J = 6.6, 3.7 Hz, 1 H), 2.35 - 2.21 (m, 1 H), 1 .94 (s, 4H). Example 304: (R)-6-(1 -amino-8-azaspiro[4.5]decan-8-yl)-N-(6-(o-tolyl)-5-

(trifluoromethyl)pyridin-2-yl)pyridine-2-sulfonamide; Condition 5, LCMS: R _t 3.25 min; m/z 546.2 [M+H] ⁺ . ¹ H NMR (400 MHz, Methanol-d4) δ 7.79 (dd, J = 8.9, 1 .4 Hz, 1 H), 7.54 (ddd, J = 8.3, 7.4, 0.7 Hz, 1 H), 7.38 (dq, J = 9.0, 1 .0 Hz, 1 H), 7.30 - 7.09 (m, 4H), 7.03 (d, J = 7.6 Hz, 1 H), 6.84 (d, J = 8.5 Hz, 1 H), 4.13 - 3.99 (m, 2H), 3.08 - 2.89 (m, 3H), 2.10 (dd, J = 13.6, 6.5 Hz, 1 H), 1 .94 (d, J = 2.2 Hz, 3H), 1 .84 - 1 .45 (m, 6H), 1 .44 - 1 .25 (m, 4H).

Example 305: W-(5-chloro-6-(5-cyano-2-methylphenyl)pyridin-2-yl)-6-(3-hyd roxy-3- methylazetidin-1 -yl)pyridine-2-sulfonamide; Purified by Condition 2, Mobile Phase 1 . Condition 3, LCMS: m/z 470.3 [M+H] ⁺ , 0.61 min. ¹ H NMR (300 MHz, CD ₃ OD) δ ppm 7.84 (d, J= 8.7 Hz, 1 H), 7.67 - 7.58 (m, 2H), 7.45 - 7.42 (m, 2H), 7.37 (d, J= 1 .8 Hz, 1 H), 7.22 - 7.19 (m, 1 H), 6.56 (dd, J= 8.4, 0.6 Hz, 1 H), 3.85 - 3.76 (m, 4H), 2.1 1 (s, 3H), 1 .48 (s, 3H).

Example 306: (S)-6-(1 -amino-7-azaspiro[3.5]nonan-7-yl)-N-(6-(o-tolyl)-5- (trifluoromethyl)pyridin-2-yl)pyridine-2 -sulfonamide; Condition 5, LCMS: R _t 3.14 min; m/z 532.2 [M+H] ⁺ . ¹ H NMR (400 MHz, Methanol-d4) δ 7.84 (d, J = 8.9 Hz, 1 H), 7.54 (dd, J = 8.6, 7.3 Hz, 1 H), 7.47 - 7.39 (m, 1 H), 7.31 - 7.10 (m, 4H), 7.08 - 7.01 (m, 1 H), 6.82 (dd, J = 15.2, 8.6 Hz, 1 H), 4.17 - 3.90 (m, 2H), 3.17 (s, 1 H), 2.99 - 2.69 (m, 2H), 2.29 - 2.18 (m, 1 H), 1 .97 - 1 .83 (m, 5H), 1 .72 - 1 .41 (m, 5H).

Example 307: 6-((1 R)-1 -amino-2-(hydroxymethyl)-8-azaspiro[4.5]decan-8-yl)-N-(6-(o- tolyl)-5-(trifluoromethyl)pyridin-2-yl)pyridine-2 -sulfonamide; Condition 5, LCMS: R _t 3.14 min; m/z 576.2 [M+H] ⁺ . ¹ H NMR (400 MHz, Methanol-d4) δ 7.79 (d, J = 8.9 Hz, 1 H), 7.54 (dd, J = 8.6, 7.3 Hz, 1 H), 7.45 - 7.35 (m, 1 H), 7.31 - 7.09 (m, 4H), 7.03 (d, J = 7.9 Hz, 1 H), 6.82 (dd, J = 8.6, 2.7 Hz, 1 H), 4.21 - 3.81 (m, 2H), 3.73 - 3.51 (m, 2H), 3.10 - 2.80 (m, 2H), 2.74 (d, J = 9.1 Hz, 1 H), 2.12 - 1 .97 (m, 1 H), 1 .97 - 1 .77 (m, 5H), 1 .76 - 1 .20 (m, 9H).

Example 308: W-(6-(3-cyano-2-methylphenyl)-5-(trifluoromethyl)pyridin-2-y l)-6-(3- hydroxy-3-methylazetidin-1 -yl)pyridine-2-sulfonamide; Purified by Condition 2, Mobile Phase 1 . Condition 3, LCMS: R _t 0.63 min; m/z 504.3 [M+H] ⁺ . ¹ H NMR (400 MHz, CD ₃ OD) δ ppm 8.1 1 (d, J= 9.2 Hz, 1 H), 7.74 - 7.72 (m, 1 H), 7.60 - 7.56 (m, 2H), 7.39 - 7.37 (m, 2H), 7.20 (d, J= 7.2 Hz, 1 H), 6.55 (d, J= 8.4 Hz, 1 H), 3.84 - 3.75 (m, 4H), 2.06 (s, 3H), 1 .47 (s, 3H).

Example 309: N-(5-chloro-6-(3-cyano-2-methylphenyl)pyridin-2-yl)-6-(3-hyd roxy-3- methylazetidin-1 -yl)pyridine-2-sulfonamide; Purified by Condition 3, Mobile Phase 2. Condition 3, LCMS: R _t 0.62 min; m/z 470.3 [M+H] ⁺ . ¹ H NMR (400 MHz, CD ₃ OD) δ ppm 7.85 (d, J= 9.2 Hz, 1 H), 7.73 - 7.71 (m, 1 H), 7.60 (dd, J= 8.4, 7.6 Hz, 1 H), 7.47 (d, J= 8.8 Hz, 1 H), 7.41 - 7.39 (m, 2H), 7.21 (d, J= 7.6 Hz, 1 H), 6.55 (d, J= 8.8 Hz, 1 H), 3.84 - 3.76 (m, 4H), 2.18 (s, 3H), 1 .48 (s, 3H). Example 310: N-(5-chloro-6-(5-fluoro-2-methylphenyl)pyridin-2-yl)-6-(1 ,6- diazaspiro[3.3]heptan-1 -yl)pyridine-2-sulfonamide; Condition 3, LCMS: R _t 0.54 min; m/z 474.3 [M+H] ⁺ . ¹ H NMR (400 MHz, Methanol-d4) δ 7.69 (dd, J = 8.2, 7.5 Hz, 1 H), 7.46 (d, J = 8.8 Hz, 1 H), 7.23 - 7.17 (m, 2H), 7.01 (td, J = 8.6, 2.8 Hz, 1 H), 6.76 (d, J = 8.8 Hz, 1 H), 6.53 - 6.46 (m, 2H), 4.08 (d, J = 1 1 .4 Hz, 2H), 4.00 (s, 2H), 3.87 (t, J = 6.9 Hz, 2H), 2.46 (t, J = 6.9 Hz, 2H), 1 .88 (s, 3H).

Example 311 : W-(6-(5-cyano-2-methylphenyl)-5-(trifluoromethyl)pyridin-2-y l)-6- (piperazin-1 -yl)pyridine-2-sulfonamide; Purified by Condition 5. Condition 3, LCMS: m/z 503.2 [M+H] ⁺ , 0.54 min. ¹ H NMR (300 MHz, CD ₃ OD) δ ppm 8.34 (brs, 1 H), 8.07 (d, J= 8.7 Hz, 1 H), 7.73 - 7.68 (m, 2H), 7.43 (dd, J= 8.4, 3.6 Hz, 2H), 7.34 - 7.32 (m, 2H), 7.06 (d, J= 8.4 Hz, 1 H), 3.77 - 3.74 (m, 4H), 3.24 - 3.20 (m, 4H), 1 .97 (s, 3H). Example 312: W-(5-chloro-6-(5-cyano-2-methylphenyl)pyridin-2-yl)-6-(piper azin-1 - yl)pyridine-2-sulfonamide; Purified by Condition 3, Mobile Phase 2. Condition 3, LCMS: R _t 0.50 min; m/z 469.2 [M+H] ⁺ . ¹ H NMR (300 MHz, CD ₃ OD) δ ppm 7.76 (dd, J= 7.8, 1 .8 Hz, 1 H), 7.66 (t, J= 7.5 Hz, 2H), 7.46 (d, J= 1 .8 Hz, 1 H), 7.37 (d, J= 8.1 Hz, 1 H), 7.22 (d, J= 7.2 Hz, 1 H), 7.15 (d, J= 9.0 Hz, 1 H), 7.86 (d, J= 8.7 Hz, 1 H), 3.46 (brs, 4H), 2.93 (brs, 4H), 1 .86 (s, 3H).

Example 313: 6-(1 ,6-diazaspiro[3.3]heptan-1 -yl)-N-(6-(o-tolyl)-5-(trifluoromethyl)pyridin- 2-yl)pyridine-2-sulfonamide; Condition 6, LCMS: R _t 0.90 min; m/z 488.4 [M+H] ⁺ . ¹ H NMR (400 MHz, Methanol-d4) δ 7.71 - 7.63 (m, 2H), 7.31 - 7.24 (m, 1 H), 7.20 - 7.12 (m, 3H), 6.91 (d, J = 7.6 Hz, 1 H), 6.77 (d, J = 8.7 Hz, 1 H), 6.48 (d, J = 7.9 Hz, 1 H), 4.12 (d, J = 1 1 .4 Hz, 1 H), 3.99 (dd, J = 1 1 .4, 3.9 Hz, 1 H), 3.91 - 3.77 (m, 3H), 3.70 (dd, J = 1 1 .5, 3.5 Hz, 1 H), 2.54 - 2.32 (m, 2H), 1 .65 (s, 3H) Example 314: 6-((2R,3S)-3-hydroxy-2-methylpyrrolidin-1 -yl)-N-(6-(o-tolyl)-5-

(trifluoromethyl)pyridin-2-yl)pyridine-2-sulfonamide; Condition 4, LCMS: R _t 2.50 min; m/z 493.4 [M+H] ⁺ . ¹ H NMR (400 MHz, Methanol-d4) δ 8.55 (brs, 1 H), 8.04 (d, J = 9.3 Hz, 1 H), 7.84 (d, J = 9.3 Hz, 1 H), 7.58 (dd, J = 9.5, 7.3 Hz, 1 H), 7.29 (m, 1 H), 7.24 - 7.19 (m, 1 H), 7.18-7.14 (m, 2H), 7.1 1 -7.02 (m, 1 H), 6.62 (d, J = 8.5 Hz, 1 H), 4.05 (d, J = 3.7 Hz, 1 H), 3.94- 3.88 (m, 1 H), 3.44-3.38 (m, 2H), 2.24-2.18 (m, 1 H), 1 .93 (s, 3H), 1 .99-1 .86 (m, 1 H), 1 .01 (brs, 3H).

Example 315: 1 -(6-(W-(6-(5-fluoro-2-methylphenyl)-5-(trifluoromethyl)pyrid in-2- yl)sulfamoyl)pyridin-2-yl)-3-hydroxypyrrolidine-2-carboxylic acid; Condition 3, LCMS: m/z 541 .3 [M+H] ⁺ , 0.63 min. ¹ H NMR (300 MHz, CD ₃ OD) δ ppm 8.10 (d, J= 8.7 Hz, 1 H), 7.67 - 7.60 (m, 2H), 7.24 - 7.19 (m, 2H), 7.03 (dt, J= 8.7, 3.0 Hz, 1 H), 6.81 (d, J= 7.8 Hz, 1 H), 6.53 (d, J= 8.1 Hz, 1 H), 4.63 - 4.58 (m, 1 H), 4.43 (brs, 1 H), 3.66 - 3.59 (m, 1 H), 3.47 - 3.39 (m, 1 H), 2.22 - 2.04 (m, 2H), 1 .86 (s, 3H). Example 316: 6-{[(3S,4R)-4-hydroxyoxolan-3-yl]oxy}-N-[6-(2-methylphenyl)- 5-

(trifluoromethyl)pyridin-2-yl]pyridine-2-sulfonamide; Example 291 was subjected to chiral HPLC under the following conditions: 80g/min, 78/22 C02/MeOH, 100 bar, 30°C, column: 21 x250mm Cellulose-2, run time: 2.8 min stacked injections, 6.75 min elution time. Enantiomer B, (-) rotation at 275 nm cis, Analytical method: solvents : A: C02 (80%), B: MeOH (20%), flow rate: 2 mL/min, temp: 30°C, phase: 3um 4.6x50mm Cellulose-2,

Retention time 2.70 min. Condition 2, LCMS: m/z 496.2 [M+H] ⁺ , 1 .45 min. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 1 1 .81 (s, 1 H), 8.19 (m, 1 H), 7.90 (t,J = 7.2Hz, 1 H), 7.55 (d,J = 7.3Hz, 1 H), 7.45 (s, 1H), 7.32 (t,J = 7.3Hz, 1H), 7.21 (m, 2H), 7.08 (m, 2H), 5.06 (m, 1H), 4.96 (m, 1H), 4.20 (m, 1H), 3.83 (m, 2H), 3.50 (m, 2H), 1.79 (m, 3H). ^IS F NMR (376 MHz., DMSG-ii6) δ -57.14 (s). Example 317: W-(6-(5-cyano-2-methylphenyl)-5-(trifluoromethyl)pyridin-2-y l)-2-(3- hydroxy-3-methylazetidin-1-yl)pyridine-4-sulfonamide; Condition 3, LCMS: m/z 504.3 [M+H] ⁺ , 0.62 min. ¹ H NMR (300 MHz, CD ₃ OD) δ ppm 8.13 - 8.08 (m, 2H), 7.73 (dd, J= 8.7 Hz, 1H), 7.67-7.60 (m, 2H), 7.24-7.19 (m, 2H), 7.03 (dt, J= 8.7, 3.0 Hz, 1H), 6.81 (d, J= 7.8, 1.8 Hz, 1H), 7.51 (d, J= 7.8 Hz, 1H), 7.45 (s, 1H), 7.17 (d, J= 9.0 Hz, 1H), 6.95 (dd, J= 5.4, 1.8 Hz, 1 H), 6.72 (s, 1 H), 3.81 - 3.70 (m, 4H), 1.97 (s, 3H), 1.53 (s, 3H).

Example 318: (R)-W-(5-chloro-6-(5-fluoro-2-methylphenyl)pyridin-2-yl)-2-( 3- methylmorpholino)pyridine-4-sulfonamide; Condition 3, LCMS: m/z 477.2 [M+H] ⁺ , 0.67 min. ¹ H NMR (300 MHz, CD ₃ OD) δ ppm 8.21 (d, J= 5.4 Hz, 1H), 7.83 (d, J= 8.4 Hz, 1H), 7.28 (dd, J= 8.4, 5.7 Hz, 1H), 7.12-7.05 (m, 3H), 6.98 (dd, J= 5.1, 1.2 Hz, 1H), 6.85 (dd, J= 9.3, 2.7 Hz, 1H), 4.18-4.12 (m, 1H), 3.90 (dd, J= 11.1, 3.6 Hz, 1H), 3.73-3.58 (m, 3H), 3.49 (dt, J= 11.7, 3.0 Hz, 1H), 2.98 (dt, J= 11.7, 3.9 Hz, 1H), 1.96 (s, 3H), 1.07 (d, J= 6.6 Hz, 3H).

Example 319: (R)-W-(5-chloro-6-(3-fluoro-2-methylphenyl)pyridin-2-yl)-2-( 3- methylmorpholino)pyridine-4-sulfonamide; Condition 3, LCMS: m/z 477.2 [M+H] ⁺ , 0.67 min. ¹ H NMR (300 MHz, CD ₃ OD) δ ppm 8.21 (d, J= 5.1 Hz, 1H), 7.83 (d, J= 9.0 Hz, 1H), 7.27 -7.22 (m, 1H), 7.16-7.09 (m, 3H), 6.98-6.93 (m, 2H), 4.11 -4.15 (m, 1H), 3.90 (dd, J= 11.4, 3.0 Hz, 1H), 3.73-3.58 (m, 3H), 3.53-3.44 (m, 1H), 2.98 (dt, J= 12.9, 3.9 Hz, 1H), 1.87 (s, 3H), 1.07 (d, J= 6.6 Hz, 3H).

Example 320: W-(6-(5-fluoro-2-methylphenyl)-5-(trifluoromethyl)pyridin-2- yl)-2-(3- hydroxy-3-methylazetidin-1-yl)pyridine-4-sulfonamide; Condition 3, LCMS: m/z 497.3 [M+H] ⁺ , 0.64 min. ¹ H NMR (300 MHz, CD ₃ OD) δ ppm 8.09 (s, 1H), 8.07 (d, J= 3.0 Hz, 1H), 7.30 (dd, J= 8.4, 5.4 Hz, 1 H), 7.17 - 7.08 (m, 2H), 6.97 (dd, J= 5.4, 1.5 Hz, 1 H), 6.86 - 6.82 (m, 1 H), 6.76 (d, J= 0.6 Hz, 1 H), 3.77 - 3.69 (m, 4H), 1.87 (s, 3H), 1.52 (s, 3H).

Example 321 : (R)-W-(6-(5-fluoro-2-methylphenyl)-5-(trifluoromethyl)pyridi n-2-yl)-2-(3- methylmorpholino)pyridine-4-sulfonamide; Condition 3, LCMS: m/z 511.3 [M+H] ⁺ , 0.67 min. ¹ H NMR (300 MHz, CD ₃ OD) δ ppm 8.20 (d, J= 5.1 Hz, 1H), 8.06 (d, J= 8.7 Hz, 1H), 7.29 - 7.23 (m, 1 H), 7.20 - 7.08 (m, 3H), 6.98 (d, J= 5.1 Hz, 1 H), 6.82 (d, J= 8.7 Hz, 1 H), 4.23 - 4.12 (m, 1H), 3.91 (dd, J= 11.4, 3.0 Hz, 1H), 3.74-3.46 (m, 4H), 1.86 (d, J= 18.9 Hz, 3H), 1.09 (t, J= 7.2 Hz, 3H). Example 322: W-(5-chloro-6-(5-fluoro-2-methylphenyl)pyridin-2-yl)-2-(3- hydroxyazetidin-1 -yl)pyridine-4-sulfonamide; Condition 3, LCMS: m/z 449.1 [M+H] ⁺ , 0.61 min. ¹ H NMR (400 MHz, CD ₃ OD) δ ppm 8.08 (d, J= 6.0 Hz, 1 H), 7.82 (d, J= 8.8 Hz, 1 H), 7.29 (dd, J= 8.4, 6.0 Hz, 1 H), 7.09 - 7.06 (m, 2H), 6.94 (dd, J= 5.2, 1 .6 Hz, 1 H), 6.84 (dd, J= 8.8, 2.4 Hz, 1 H), 6.74 (d, J= 0.8 Hz, 1 H), 4.64 - 4.61 (m, 1 H), 4.05 (t, J= 8.0 Hz, 2H), 3.67 (dd, J= 9.2, 4.4 Hz, 2H), 1 .93 (s, 3H).

Example 323: W-(5-chloro-6-(3-fluoro-2-methylphenyl)pyridin-2-yl)-2-(3- hydroxyazetidin-1 -yl)pyridine-4-sulfonamide; Condition 3, LCMS: m/z 449.1 [M+H] ⁺ , 0.62 min. ¹ H NMR (400 MHz, CD ₃ OD) δ ppm 8.09 (d, J= 6.0 Hz, 1 H), 7.82 (d, J= 8.8 Hz, 1 H), 7.29 - 7.24 (m, 1 H), 7.14 (d, J= 8.4 Hz, 1 H), 7.07 (d, J= 8.8 Hz, 1 H), 6.95 - 6.92 (m, 2H), 6.74 (s, 1 H), 4.63 - 4.60 (m, 1 H), 4.03 (t, J= 8.0 Hz, 2H), 3.67 (dd, J= 9.2, 4.4 Hz, 2H), 1 .86 (d, J= 2.4 Hz, 3H).

Example 324: W-(6-(5-fluoro-2-methylphenyl)-5-(trifluoromethyl)pyridin-2- yl)-2-(3- hydroxyazetidin-1 -yl)pyridine-4-sulfonamide; Condition 3, LCMS: m/z 483.2 [M+H] ⁺ , 0.62 min. ¹ H NMR (400 MHz, CD ₃ OD) δ ppm 8.08 (s, 1 H), 8.06 (d, J= 2.8 Hz, 1 H), 7.29 (dd, J= 8.0, 5.6 Hz, 1 H), 7.15 - 7.08 (m, 2H), 6.94 (dd, J= 5.6, 1 .6 Hz, 1 H), 6.83 (dd, J= 9.2, 2.4 Hz, 1 H), 6.72 (d, J= 1 .2 Hz, 1 H), 4.67 - 4.62 (m, 1 H), 4.08 - 4.00 (m, 2H), 3.70 - 3.64 (m, 2H), 1 .82 (s, 3H).

Example 325: 2-(3-hydroxyazetidin-1 -yl)-W-(5-(trifluoromethyl)-6-(2- (trifluoromethyl)phenyl)pyridin-2-yl)pyridine-4-sulfonamide; Condition 3, LCMS: m/z 519.2 [M+H] ⁺ , 0.61 min. ¹ H NMR (400 MHz, CD ₃ OD) δ ppm 8.06 (d, J= 2.4 Hz, 1 H), 8.05 (d, J= 5.6 Hz, 1 H), 7.78 (dd, J= 5.6, 3.6 Hz, 1 H), 7.67 - 7.65 (m, 2H), 7.28 - 7.24 (m, 2H), 6.93 (dd, J= 5.2, 1 .2 Hz, 1 H), 6.70 (s, 1 H), 4.66 - 4.61 (m, 1 H), 4.10 - 4.05 (m, 2H), 3.68 (dd, J= 9.2, 4.4 Hz, 2H). Example 326: W-(6-(5-fluoro-2-methylphenyl)-5-(trifluoromethyl)pyridin-2- yl)-2-

(piperazin-1 -yl)pyridine-4-sulfonamide; Condition 3, LCMS: m/z 496.2 [M+H] ⁺ , 0.54 min. ¹ H NMR (400 MHz, CD ₃ OD) δ ppm 8.35 (brs, 1 H), 8.22 (d, J= 5.2 Hz, 1 H), 7.99 (d, J= 8.8 Hz, 1 H), 7.28 - 7.24 (m, 2H), 7.1 1 - 7.07 (m, 3H), 6.81 (dd, J= 8.8, 2.4 Hz, 1 H), 3.65 (t, J= 5.2 Hz, 4H), 3.22 (t, J= 5.2 Hz, 4H), 1 .84 (s, 3H).

Example 327: W-(5-chloro-6-(5-fluoro-2-methylphenyl)pyridin-2-yl)-2-(pipe razin-1 - yl)pyridine-4-sulfonamide; Condition 3, LCMS: R _t 0.53 min; m/z 462.2 [M+H] ⁺ , 0.53 min. ¹ H NMR (400 MHz, CD ₃ OD) δ ppm 8.33 (brs, 1 H), 8.26 (d, J= 5.2 Hz, 1 H), 7.81 (d, J= 8.4 Hz, 1 H), 7.31 - 7.28 (m, 2H), 7.1 1 - 7.06 (m, 3H), 6.83 (dd, J= 9.2, 2.4 Hz, 1 H), 3.66 (t, J= 5.2 Hz, 4H), 3.22 (t, J= 5.6 Hz, 4H), 1 .96 (s, 3H). Example 328:

(R)-1 -(6-(N-(6-(2-ethoxyphenyl)-5-(trifluoromethyl)pyridin-2-yl)s ulfamoyl)pyridin-2-yl)-3- methylpiperidine-3-carboxylic acid LCMS conditions 7: 1 .70 min, MS for C26H28F3N4O5S [M+H] ⁺ m/z = 565.2, found m/z = 564.9. Rotomers/atropisomers are present in the NMR spectra. ¹ H NMR (400 MHz, Chloroform-d) δ 10.10 (br. s, 2H), 8.01 (d, J = 8.8 Hz, 1 H), 7.76 (d, J = 8.7 Hz, 1 H), 7.47 (dd, J = 7.2, 8.7 Hz, 1 H), 7.40 - 7.32 (m, 1 H), 7.05 (d, J = 7.2 Hz, 2H), 6.93 (t, J = 7.4 Hz, 1 H), 6.88 (d, J = 8.3 Hz, 1 H), 6.77 (d, J = 8.7 Hz, 1 H), 4.82 (d, J = 13.4 Hz, 1 H), 3.88 (d, J = 13.8 Hz, 3H), 2.96 (td, J = 2.9, 13.3 Hz, 1 H), 2.73 (d, J = 13.5 Hz, 1 H), 2.05 (d, J = 1 1 .7 Hz, 1 H), 1 .72 (m, 1 H), 1 .49 (m, 1 H), 1 .34 (td, J = 4.7, 13.1 Hz, 1 H), 1 .16 (s, 3H), 1 .08 (s, 3H). ¹⁹ F NMR (376 MHz, Chloroform-d) δ -59.27 (br. s, 1 F).

Example 329:

(R)-3-methyl-1 -(6-(N-(6-(2-propoxyphenyl)-5-(trifluoromethyl)pyridin-2- yl)sulfamoyl)pyridin-2-yl)piperidine-3-carboxylic acid LCMS conditions 7: 1 .80 min, MS for C27H30F3N4O5S [M+H] ⁺ m/z = 579.2, found m/z = 578.9. Rotomers/atropisomers are present in the NMR spectra. ¹ H NMR (400 MHz, Chloroform-d) δ 10.16 (br. s, 1 H) 8.01 (d, J = 8.8 Hz, 1 H), 7.77 (d, J = 8.8 Hz, 1 H), 7.46 (dd, J = 7.2, 8.7 Hz, 1 H), 7.41 - 7.32 (m, 1 H), 7.05 (m, 2H), 6.94 (t, J = 7.5 Hz, 1 H), 6.88 (d, J = 8.3 Hz, 1 H), 6.76 (d, J = 8.7 Hz, 1 H), 4.86 (d, J = 13.5 Hz, 1 H), 3.88 (d, J = 13.6 Hz, 1 H), 3.79 (t, J = 6.2 Hz, 2H), 2.98 (td, J = 2.8, 13.3 Hz, 1 H), 2.73 (d, J = 13.5 Hz, 1 H), 2.10 - 1 .98 (m, 1 H), 1 .74 (m, 1 H), 1 .50 (m, 3H), 1 .39 - 1 .28 (m, 2H), 1 .16 (s, 3H), 0.68 (s, 3H). ¹⁹ F NMR (376 MHz, Chloroform-d) δ -59.26 (s, 1 F).

Example 330:

1 -(6-(N-(6-(o-tolyl)-5-(trifluoromethyl)pyridin-2-yl)sulfamoy l)pyridin-2-yl)azetidine-3- carboxylic acid LCMS conditions 7: 1 .53 min, MS for C22H20F3N4O4S [M+H]+ m/z = 493.1 ; found m/z 493.1 . ¹ H NMR (400 MHz, chloroform-d) 8.69 (s, 1 H), 8.46 (d, J = 8.8 Hz, 1 H),

8.08 (d, J = 8.8 Hz, 1 H), 7.90 - 7.75 (m, 2H), 7.58 - 7.48 (m, 1 H), 7.48 - 7.36 (m, 2H), 7.33 - 7.25 (m, 1 H), 3.57 (t, J = 6.0 Hz, 2H), 3.42 (s, 2H), 2.04 (s, 3H), 1 .07 (m, 2H). ¹⁹ F NMR (376 MHz, chloroform-d) δ -58.91 (s, 1 F). Example 331 :

3-((6-(N-(6-(o-tolyl)-5-(trifluoromethyl)pyridin-2-yl)sulfam oyl)pyridin-2- yl)oxy)cyclobutanecarboxylic acid Mixture of cis/trans isomers. LCMS conditions 7: 1 .56 min, MS for C23H21 F3N3O5S [M+H] ⁺ m/z = 508.1 , found m/z 508.1 ; MS for Czsh oFsNsNaOsS, [M+Na] ⁺ m/z = 530.1 , found m/z = 530.1 . ¹ H NMR (400 MHz, Chloroform-d) δ 8.78 (br. S, 1 H), 8.02 (d,J = 8.9 Hz, 1 H), 7.78 (dd,J = 7.4, 8.3 Hz, 1 H), 7.69 (d,J = 7.3 Hz, 1 H), 7.61 (d,J = 8.9 Hz, 1 H), 7.41 - 7.33 (m, 1 H), 7.27 - 7.18 (m, 2H), 7.12 (d, J = 7.5 Hz, 1 H), 6.93 (d,J = 8.3 Hz, 1 H), 4.90 (p,J = 7.8 Hz, 1 H), 2.76 - 2.57 (m, 3H), 2.35 (s, 2H), 2.03 (s, 3H). ¹⁹ F NMR (376 MHz, Chloroform-d) δ -58.82 (s, 1 F).

Example 332:

(3R)-1 -(6-{[6-(2-methylphenyl)-5-(trifluoromethyl)pyridin-2-yl]sul famoyl}pyridin-2- yl)piperidine-3-carboxylic acid LCMS conditions 7: 1 .795 min; MS for C24H24F3N4O4S

[M+H] ⁺ m/z = 521 .15, found m/z = 521 .15. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 12.40 (s, 1 H), 1 1 .58 (s, 1 H), 8.14 (dd, J = 9.2, 3.2 Hz, 1 H), 7.67 (dd, J = 8.7, 7.3 Hz, 1 H), 7.49 (d, J = 8.9 Hz, 1 H), 7.31 (td, J = 7.4, 1 .4 Hz, 1 H), 7.25 - 7.15 (m, 2H), 7.13 - 7.07 (m, 2H), 7.05 (d, J = 7.6 Hz, 1 H), 4.25 - 4.08 (m, 1 H), 3.94 - 3.79 (m, 1 H), 3.08 - 2.95 (m, 1 H), 2.95 - 2.82 (m, 1 H), 2.32 - 2.16 (m, 1 H), 1 .98 - 1 .84 (m, 1 H), 1 .77 (s, 3H), 1 .59 - 1 .48 (m, 1 H), 1 .34 - 1 .14 (m, 2H).

Example 333:

(3S)-1 -(6-{[6-(2-methylphenyl)-5-(trifluoromethyl)pyridin-2-yl]sul famoyl}pyridin-2- yl)piperidine-3-carboxylic acid LCMS conditions 7: 1 .795 min; MS for C24H24F3N4O4S

[M+H] ⁺ m/z = 521 .15, found m/z = 521 .20. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 12.40 (s, 1 H), 1 1 .58 (s, 1 H), 8.14 (d, J = 8.8 Hz, 1 H), 7.67 (dd, J = 8.7, 7.3 Hz, 1 H), 7.49 (d, J = 8.7 Hz, 1 H), 7.31 (td, J = 7.5, 1 .4 Hz, 1 H), 7.26 - 7.16 (m, 2H), 7.13 - 7.07 (m, 2H), 7.04 (d, J = 7.6 Hz, 1 H), 4.27 - 4.09 (m, 1 H), 3.94 - 3.80 (m, 1 H), 3.08 - 2.96 (m, 1 H), 2.96 - 2.83 (m, 1 H), 2.32 - 2.16 (m, 1 H), 1 .97 - 1 .84 (m, 1 H), 1 .77 (s, 3H), 1 .59 - 1 .49 (m, 1 H), 1 .33 - 1 .15 (m, 2H).

Example 334:

(2S)-1 -[(tert-butoxy)carbonyl]-4-(6-{[6-(2-methylphenyl)-5-(triflu oromethyl)pyridin-2- yl]sulfamoyl}pyridin-2-yl)piperazine-2-carboxylic acid LCMS conditions 7: 1 .648 min; MS for C ₂ 8H3i F3N ₅ 0 ₆ S [M+H] ⁺ m/z = 622.19, found m/z = 622.30. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 1 1 .61 (s, 1 H), 8.31 - 8.10 (m, 1 H), 7.73 (dd, J = 8.7, 7.3 Hz, 1 H), 7.66 - 7.46 (m, 1 H), 7.36 - 7.28 (m, 1 H), 7.27 - 7.14 (m, 3H), 7.13 - 6.99 (m, 2H), 4.63 - 4.29 (m, 2H), 4.03 - 3.84 (m, 1 H), 3.76 - 3.59 (m, 1 H), 3.20 - 2.94 (m, 2H), 2.84 - 2.75 (m, 1 H), 1 .83 (s, 3H), 1 .39 (d, J = 15.2 Hz, 9H).

Example 335: (2S)-4-(6-{[6-(2-methylphenyl)-5-(trifluoromethyl)pyridin-2- yl]sulfamoyl}pyridin-2- yl)piperazine-2-carboxylic acid LCMS conditions 7: 1.278 min; MS for C23H23F3N5O4S [M+H] ⁺ m/z = 522.14, found m/z = 522.20. ¹ H NMR (400 MHz, Methanol-d ₄ ) δ 8.08 (d, J = 8.9 Hz, 1H), 7.76 (dd, J = 8.6, 7.4 Hz, 1H), 7.57 (d, J = 8.9 Hz, 1H), 7.40 (d, J = 7.3 Hz, 1H), 7.32 (td, J = 7.5, 1.4 Hz, 1 H), 7.27 - 7.13 (m, 3H), 7.05 (d, J = 7.5 Hz, 1 H), 4.67 - 4.55 (m, 1 H), 4.23 - 4.09 (m, 2H), 3.50 - 3.33 (m, 3H), 3.23 - 3.10 (m, 1 H), 1.92 (s, 3H).

Example 336:

3-methyl-1 -(6-{[6-(2-methylphenyl)-5-(trifluoromethyl)pyridin-2-yl]sul famoyl}pyridin-2- yl)pyrrolidine-3-carboxylic acid LCMS conditions 7: 1.808 min; MS for C24H24F3N4O4S [M+H] ⁺ m/z = 521.15, found m/z = 521.15. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 12.59 (s, 1H), 11.51 (s, 1H), 8.18 (d, J = 8.9 Hz, 1H), 7.66 (dd, J = 8.6, 7.3 Hz, 1H), 7.63- 7.52 (m, 1H), 7.32 (td, J = 7.4, 1.4 Hz, 1H), 7.27-7.16 (m, 2H), 7.12-7.04 (m, 2H), 6.68 (d, J = 8.5 Hz, 1 H), 3.69 - 3.53 (m, 1 H), 3.33 - 3.17 (m, 2H), 3.09 - 2.92 (m, 1 H), 2.36 - 2.21 (m, 1 H), 1.91 - 1.73 (m, 4H), 1.32 - 1.15 (m,3H).

Example 337:

3-methyl-1 -(6-{[6-(2-methylphenyl)-5-(trifluoromethyl)pyridin-2-yl]sul famoyl}pyridin-2- yl)piperidine-3-carboxylic acid LCMS conditions 7: 1.743 min; MS for C25H26F3N4O4S [M+H] ⁺ m/z = 535.16, found m/z = 535.20. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 12.33 (s, 1H), 11.53 (s, 1H), 8.17 (d, J = 8.9 Hz, 1H), 7.65 (dd, J = 8.7, 7.2 Hz, 1H), 7.59- 7.45 (m, 1H), 7.36-7.27 (m, 1H), 7.26-7.17 (m, 2H), 7.13-7.00 (m, 3H), 3.87 (d, J = 13.1 Hz, 1H), 3.72- 3.56 (m, 1H), 3.18 - 3.07 (m, 1H), 3.07 - 2.94 (m, 1H), 2.05 - 1.92 (m, 1H), 1.80 (d, J = 10.2 Hz, 3H), 1.51 - 1.31 (m, 3H), 1.03 - 0.97 (m, 3H).

Example 338:

(2R)-1 -[(tert-butoxy)carbonyl]-4-(6-{[6-(2-methylphenyl)-5-(triflu oromethyl)pyridin-2- yl]sulfamoyl}pyridin-2-yl)piperazine-2-carboxylic acid LCMS conditions 7: 1.660 min; MS for C ₂₈ H3iF3N ₅ 0 ₆ S [M+H] ⁺ m/z = 622.19, found m/z = 622.30. ¹ H NMR (400 MHz, DMSO-d ₆ ) 511.62 (s, 1 H), 8.30 - 8.10 (m, 1 H), 7.73 (dd, J = 8.7, 7.3 Hz, 1 H), 7.67 - 7.50 (m, 1 H), 7.36 - 7.28 (m, 1H), 7.27 - 7.14 (m, 3H), 7.13 - 7.00 (m, 2H), 4.62 - 4.30 (m, 2H), 4.06 - 3.84 (m, 1 H), 3.77 - 3.59 (m, 1 H), 3.21 - 2.93 (m, 2H), 2.88 - 2.64 (m, 1 H), 1.83 (s, 3H), 1.39 (d, J = 15.3 Hz, 9H). Example 339:

(2R)-4-(6-{[6-(2-methylphenyl)-5-(trifluoromethyl)pyridin-2- yl]sulfamoyl}pyridin-2- yl)morpholine-2-carboxylic acid LCMS conditions 7: 1.702 min; MS for C23H22F3N4O5S [M+H] ⁺ m/z = 523.13, found m/z = 523.10. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 11.67 (s, 1H), 8.13 (d, J = 8.9 Hz, 1H), 7.73 (dd, J = 8.7, 7.3 Hz, 1H), 7.47 (d, J = 8.8 Hz, 1H), 7.31 (td, J = 7.5, 1.4 Hz, 1H), 7.26-7.16 (m, 3H), 7.11 (d, J = 8.7 Hz, 1H), 7.05 (d, J = 7.6 Hz, 1H), 4.18- 4.06 (m, 1 H), 4.06 - 3.95 (m, 1 H), 3.93 - 3.84 (m, 1 H), 3.71 - 3.57 (m, 1 H), 3.57 - 3.46 (m, 1 H), 3.19 - 2.99 (m, 2H), 1.78 (s, 3H).

Example 340:

(1R,2S,5S)-3-(6-{[6-(2-methylphenyl)-5-(trifluoromethyl)pyri din-2-yl]sulfamoyl}pyridin- 2-yl)-3-azabicyclo[3.1.0]hexane-2-carboxylic acid LCMS conditions 7: 1.793 min; MS for C24H22F3N4O4S [M+H] ⁺ m/z = 519.13, found m/z = 519.10. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 12.57 (s, 1H), 11.48 (s, 1H), 8.17 (d, J = 8.3 Hz, 1H), 7.74-7.56 (m, 2H), 7.36- 7.28 (m, 1H), 7.27-7.13 (m, 4H), 7.09 (d, J = 7.5 Hz, 1H), 4.33-4.16 (m, 1H), 3.61 - 3.47 (m, 1H), 3.40- 3.35 (m, 1 H), 2.11 - 1.95 (m, 1 H), 1.85 (s, 3H), 1.81 -1.64 (m, 1 H), 0.78 - 0.65 (m, 1 H), 0.55 -0.41 (m, 1H).

Example 341 :

(2R)-4-(6-{[6-(2-methylphenyl)-5-(trifluoromethyl)pyridin-2- yl]sulfamoyl}pyridin-2- yl)piperazine-2-carboxylic acid LCMS conditions 7: 1.508 min; MS for C23H23F3N5O4S

[M+H] ⁺ m/z = 522.14, found m/z = 522.10. ¹ H NMR (400 MHz, Methanol-d ₄ ) δ 8.08 (d, J = 8.9 Hz, 1 H), 7.76 (dd, J = 8.7, 7.4 Hz, 1 H), 7.58 (d, J = 8.8 Hz, 1 H), 7.40 (d, J = 7.3 Hz, 1 H), 7.32 (td, J = 7.5, 1.4 Hz, 1H), 7.27 - 7.18 (m, 2H), 7.16 (d, J = 8.7 Hz, 1H), 7.05 (d, J = 7.5 Hz, 1 H), 4.66 - 4.54 (m, 1 H), 4.26 - 4.09 (m, 2H), 3.53 - 3.32 (m, 3H), 3.24 - 3.11 (m, 1 H), 1.93 (s, 3H). Example 342:

4-((6-(N-(6-(o-tolyl)-5-(trifluoromethyl)pyridin-2-yl)sulfam oyl)pyridin-2- yl)oxy)cyclohexanecarboxylic acid Mixture (~2:1) of diastereomers. LCMS conditions 7: 1.63 min, MS for C25H25F3N3O5S [M+H] ⁺ m/z = 536.1 , found 536.1. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 12.13 (s, 1H), 11.79 (s, 1H), 8.21 (t, J = 8.3Hz, 1H), 7.94-7.82 (m, 1H), 7.60- 7.52 (m, 1 H), 7.51 (dd,J = 2.2, 7.3Hz, 1 H), 7.45 (s, 1 H), 7.31 (t,J = 7.4Hz, 1 H), 7.21 (t, J = 7.8Hz, 1 H), 7.09 - 7.01 (m, 2H), 7.01 - 6.93 (m, 1 H), 6.30 - 6.26 (m, 1 H), 5.02 - 4.85 (m, 1H), 1.82- 1.58 (m, 5H), 1.52 (m, 2H), 1.27 (m, 3H). ¹⁹ F NMR (376 MHz, DMSO-d ₆ ) δ -57.13 (s, 2F), -57.18 (s, 1F). Example 343:

4-methyl-1 -(6-(N-(6-(2-morpholinophenyl)-5-(trifluoromethyl)pyridin-2- yl)sulfamoyl)pyridin-2-yl)piperidine-4-carboxylic acid LCMS conditions 7: 1.60 min, MS for CzeHsiFsNsOsS [M+H] ⁺ m/z = 606.2, found m/z = 606.2. ¹ H NMR (400 MHz, Chloroform-d) δ 7.96 (d, J = 9.0 Hz, 1 H), 7.59 (dd, J = 7.3, 8.7 Hz, 2H), 7.47 - 7.40 (m, 1 H), 7.32 (d, J = 7.2 Hz, 1 H), 7.20 - 7.09 (m, 3H), 6.76 (d, J = 8.7 Hz, 1 H), 3.93 (d, J = 13.5 Hz, 2H), 3.43 (s, 4H), 2.93-2.80 (m, 2H), 2.80-2.66 (m, 4H), 2.03 (d, J = 13.5 Hz, 3H), 1.36 (dd, J = 3.1, 12.6 Hz, 2H), 1.23 (s, 3H). ¹⁹ F NMR (376 MHz, Chloroform-d) δ -58.19 (s, 1F).

Example 344:

1-(6-{[6-(2-methylphenyl)-5-(trifluoromethyl)pyridin-2-yl]su lfamoyl}pyridin-2- yl)piperidine-4-carboxylic acid LCMS conditions 7: 1.764 min; MS for C24H24F3N4O4S

[M+H] ⁺ m/z = 521.15, found m/z = 521.10. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 12.22 (s, 1H), 11.53 (s, 1 H), 8.27 - 8.07 (m, 1 H), 7.67 (t, J = 8.0 Hz, 1 H), 7.60 - 7.40 (m, 1 H), 7.31 (td, J = 7.4, 1.4 Hz, 1H), 7.26-7.16 (m, 2H), 7.14-6.98 (m, 3H), 4.11 - 3.91 (m, 2H), 2.97-2.78 (m, 2H), 2.48 -2.41 (m, 1H), 1.78 (s, 3H), 1.74- 1.64 (m, 2H), 1.38 - 1.15 (m, 2H). Example 345:

9-(6-{[6-(2-methylphenyl)-5-(trifluoromethyl)pyridin-2-yl]su lfamoyl}pyridin-2-yl)-9- azabicyclo[3.3.1]nonane-3-carboxylic acid LCMS conditions 7: 1.843 min; MS for C27H28F3N4O4S [M+H] ⁺ m/z = 561.18, found m/z = 561.15. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 12.13 (s, 1H), 11.52 (s, 1H), 8.18 (d, J = 8.9 Hz, 1H), 7.68 (dd, J = 8.7, 7.2 Hz, 1H), 7.59- 7.45 (m, 1H), 7.31 (td, J = 7.4, 1.4 Hz, 1H), 7.25-7.15 (m, 2H), 7.09-6.97 (m, 3H), 4.67- 4.18 (m, 2H), 3.24 - 3.07 (m, 1 H), 2.05 - 1.87 (m, 1 H), 1.85 - 1.69 (m, 5H), 1.67 - 1.49 (m, 6H), 1.49- 1.37 (m, 1H).

Example 346:

8-(6-{[6-(2-methylphenyl)-5-(trifluoromethyl)pyridin-2-yl ]sulfamoyl}pyridin-2-yl)-8- azabicyclo[3.2.1]octane-3-carboxylic acid LCMS conditions 7: 1.805 min; MS for

C26H26F3N4O4S [M+H] ⁺ m/z = 547.16, found m/z = 547.20. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 12.10 (s, 1H), 11.53 (s, 1H), 8.19 (d, J = 9.0 Hz, 1H), 7.69 (dd, J = 8.6, 7.3 Hz, 1H), 7.65- 7.50 (m, 1H), 7.31 (td, J = 7.4, 1.4 Hz, 1H), 7.27-7.15 (m, 2H), 7.13-7.02 (m, 2H), 6.95 (d, J = 8.6 Hz, 1 H), 4.49 - 4.22 (m, 2H), 2.90 - 2.74 (m, 1 H), 2.02 - 1.84 (m, 2H), 1.84 - 1.65 (m, 5H), 1.58- 1.20 (m, 4H).

Example 347:

(2R)-4-[(tert-butoxy)carbonyl]-1 -(6-{[6-(2-methylphenyl)-5-(trifluoromethyl)pyridin-2- yl]sulfamoyl}pyridin-2-yl)piperazine-2-carboxylic acid LCMS conditions 7: 1.703 min; MS for C ₂₈ H ₃ iF ₃ N ₅ 0 ₆ S [M+H] ⁺ m/z = 622.19, found m/z = 622.25. Example 348:

(3S)-1 -(6-{[6-(2-methylphenyl)-5-(trifluoromethyl)pyridin-2-yl]sul famoyl}pyridin-2- yl)pyrrolidine-3-carboxylic acid LCMS conditions 7: 1 .759 min; MS for C23H22F3N4O4S [M+H] ⁺ m/z = 507.13, found m/z = 507.20. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 12.52 (s, 1 H), 1 1 .54 (s, 1 H), 8.15 (d, J = 8.5 Hz, 1 H), 7.65 (dd, J = 8.6, 7.3 Hz, 1 H), 7.62 - 7.47 (m, 1 H), 7.32 (td, J = 7.5, 1 .4 Hz, 1 H), 7.27 - 7.16 (m, 2H), 7.13 - 7.01 (m, 2H), 6.69 (d, J = 8.5 Hz, 1 H), 3.52 - 3.36 (m, 2H), 3.33 - 3.19 (m, 2H), 3.19 - 3.03 (m, 1 H), 2.23 - 2.00 (m, 2H), 1 .83 (s, 3H). Example 349:

(3R)-1 -(6-{[6-(2-methylphenyl)-5-(trifluoromethyl)pyridin-2-yl]sul famoyl}pyridin-2- yl)pyrrolidine-3-carboxylic acid LCMS conditions 7: 1 .759 min; MS for C23H22F3N4O4S [M+H] ⁺ m/z = 507.13, found m/z = 507.10. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 12.52 (s, 1 H), 1 1 .54 (s, 1 H), 8.15 (d, J = 8.5 Hz, 1 H), 7.65 (dd, J = 8.6, 7.3 Hz, 1 H), 7.62 - 7.47 (m, 1 H), 7.32 (td, J = 7.5, 1 .4 Hz, 1 H), 7.27 - 7.16 (m, 2H), 7.13 - 7.01 (m, 2H), 6.69 (d, J = 8.5 Hz, 1 H), 3.52 - 3.36 (m, 2H), 3.33 - 3.19 (m, 2H), 3.19 - 3.03 (m, 1 H), 2.23 - 2.00 (m, 2H), 1 .83 (s, 3H).

Example 350:

(2S)-4-[(tert-butoxy)carbonyl]-1 -(6-{[6-(2-methylphenyl)-5-(trifluoromethyl)pyridin-2- yl]sulfamoyl}pyridin-2-yl)piperazine-2-carboxylic acid LCMS conditions 7: 1 .666 min; MS for C ₂₈ H3i F3N ₅ 0 ₆ S [M+H] ⁺ m/z = 622.19, found m/z = 622.20.

Example 351 :

1 -(6-{[6-(2-ethylphenyl)-5-(trifluoromethyl)pyridin-2-yl]sulf amoyl}pyridin-2-yl)-4- propylpiperidine-4-carboxylic acid LCMS conditions 7: 1 .925 min; MS for C28H32F3N4O4S [M+H] ⁺ m/z = 577.21 , found m/z = 577.20. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 12.48 (s, 1 H), 1 1 .49 (s, 1 H), 8.31 - 8.02 (m, 1 H), 7.67 (t, J = 8.0 Hz, 1 H), 7.58 - 7.42 (m, 1 H), 7.36 (td, J = 7.5, 1 .4 Hz, 1 H), 7.29 - 7.24 (m, 1 H), 7.20 (td, J = 7.5, 1 .4 Hz, 1 H), 7.08 (d, J = 7.2 Hz, 1 H), 7.06 - 6.94 (m, 2H), 3.98 - 3.78 (m, 2H), 2.93 - 2.77 (m, 2H), 2.22 - 1 .92 (m, 2H), 1 .92 - 1 .78 (m, 2H), 1 .38 - 1 .27 (m, 2H), 1 .20 - 0.97 (m, 4H), 0.87 (t, J = 7.6 Hz, 3H), 0.80 (t, J = 7.2 Hz, 3H).

Example 352:

1 -(6-{[6-(2-ethylphenyl)-5-(trifluoromethyl)pyridin-2-yl]sulf amoyl}pyridin-2-yl)-3- propylpiperidine-3-carboxylic acid LCMS conditions 7: 1 .966 min; MS for C28H32F3N4O4S [M+H] ⁺ m/z = 577.21 , found m/z = 577.20. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 12.33 (s, 1 H), 11.52 (s, 1H), 8.17 (d, J = 8.9 Hz, 1H), 7.65 (dd, J = 8.6, 7.3 Hz, 1H), 7.61 - 7.47 (m, 1H), 7.36 (td, J = 7.5, 1.4 Hz, 1H), 7.28 (dd, J = 7.4, 3.1 Hz, 1H), 7.21 (td, J = 7.5, 1.2 Hz, 1H), 7.13-6.99 (m, 3H), 3.90 (dd, J = 26.3, 13.1 Hz, 1H), 3.69 (dd, J = 43.7, 12.7 Hz, 1H), 3.09 (dd, J = 39.9, 13.2 Hz, 1H), 3.01 -2.81 (m, 1H), 2.27-2.11 (m, 1H), 2.11 - 1.90 (m, 2H), 1.57 - 1.04 (m, 7H), 0.97 - 0.84 (m, 3H), 0.84 - 0.66 (m, 3H).

Example 353:

(2R)-1 -(6-{[6-(2-methylphenyl)-5-(trifluoromethyl)pyridin-2-yl]sul famoyl}pyridin-2- yl)piperazine-2-carboxylic acid LCMS conditions 7: 1.300 min; MS for C23H23F3N5O4S [M+H] ⁺ m/z = 522.14, found m/z = 522.20. ¹ H NMR (400 MHz, Methanol-d ₄ ) δ 8.07 (d, J = 8.9 Hz, 1H), 7.73 (dd, J = 8.7, 7.4 Hz, 1H), 7.58 - 7.45 (m, 1H), 7.39 - 7.27 (m, 2H), 7.27 - 7.16 (m, 2H), 7.13 - 7.01 (m, 2H), 5.41 - 5.26 (m, 1 H), 4.43 - 4.30 (m, 1 H), 3.97 - 3.84 (m, 1 H), 3.40 - 3.32 (m, 2H), 3.28 - 3.18 (m, 1H), 3.17 - 3.06 (m, 1H), 2.03 - 1.87 (m, 3H). Example 354:

(2S)-1 -(6-{[6-(2-methylphenyl)-5-(trifluoromethyl)pyridin-2-yl]sul famoyl}pyridin-2- yl)piperazine-2-carboxylic acid LCMS conditions 7: 1.294 min; MS for C23H23F3N5O4S [M+H] ⁺ m/z = 522.14, found m/z = 522.20. ¹ H NMR (400 MHz, Methanol-d ₄ ) δ 8.07 (d, J = 9.0 Hz, 1 H), 7.72 (dd, J = 8.7, 7.3 Hz, 1 H), 7.53 (d, J = 8.9 Hz, 1 H), 7.37 - 7.28 (m, 2H), 7.26 - 7.16 (m, 2H), 7.12 - 7.03 (m, 2H), 5.32 - 5.20 (m, 1H), 4.43 - 4.31 (m, 1H), 3.95 - 3.81 (m, 1 H), 3.40 - 3.32 (m, 2H), 3.28 - 3.17 (m, 1 H), 3.15 - 3.02 (m, 1 H), 2.02 - 1.89 (m, 3H).

Example 355:

(1r,3r)-3-((6-(N-(6-(o-tolyl)-5-(trifluoromethyl)pyridin-2-y l)sulfamoyl)pyridin-2- yl)amino)cyclobutanecarboxylic acid LCMS conditions 7: 1.4 min, MS for C23H22F3N4O4S [M+H] ⁺ m/z = 507.1, found m/z = 507.2. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 12.20 (s, 1H), 11.56 (s, 1H), 8.18 (d, J= 8.9 Hz, 1H), 7.57-7.44 (m, 3H), 7.36-7.27 (m, 1H), 7.24-7.18 (m, 2H), 7.06-7.03 (m, 2H), 6.63 (d, J= 8.4 Hz, 1H), 4.29-4.19 (m, 1H), 2.97-2.91 (m, 1H), 2.36 - 2.33 (m, 2H), 2.12-1.95 (m, 2H), 1.78 (s, 3H).

Example 356:

(1s,3s)-1 -methyl-3-((6-(N-(6-(o-tolyl)-5-(trifluoromethyl)pyridin-2-y l)sulfamoyl)pyridin-2- yl)amino)cyclobutanecarboxylic acid LCMS conditions 7: 1.6 min, MS for C24H24F3N4O4S [M+H] ⁺ m/z = 521.2, found m/z = 521.2. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 11.49 (s, 1 H), 8.27 (d, J = 8.9 Hz, 1H), 7.60 (d, J = 7.1 Hz, 1H), 7.55 (dd, J = 8.4, 7.3 Hz, 1H), 7.49 (d, J= 7.2 Hz, 1 H), 7.32 (t, J = 7.5 Hz, 1 H), 7.28 - 7.17 (m, 2H), 7.09 - 7.00 (m, 2H), 6.62 (d, J = 8.5 Hz, 1 H), 3.94 (h, J = 8.5 Hz, 1 H), 3.60 (s, 3H), 2.76 - 2.63 (m, 1 H), 2.33 - 2.20 (m, 2H), 1.99 -1.85 (m, 2H), 1.83 (s,3H).

Example 357:

(3R)-1-(6-{[6-(5-fluoro-2-methylphenyl)-5-(trifluoromethy l)pyridin-2- yl]sulfamoyl}pyridin-2-yl)piperidine-3-carboxylic acid LCMS conditions 7: 1.806 min; MS for C24H23F4N4O4S [M+H] ⁺ m/z = 539.14, found m/z = 539.10. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 12.40 (s, 1H), 11.64 (s, 1H), 8.20- 8.06 (m, 1H), 7.67 (dd, J = 8.7, 7.3 Hz, 1H), 7.49 (d, J = 8.8 Hz, 1 H), 7.26 (dd, J = 8.6, 5.7 Hz, 1 H), 7.17 (td, J = 8.6, 2.8 Hz, 1 H), 7.13 - 7.04 (m, 2H), 6.99-6.87 (m, 1H), 4.26-4.09 (m, 1H), 3.94- 3.79 (m, 1H), 3.10-2.83 (m, 2H), 2.31 -2.17 (m, 1H), 1.96- 1.85 (m, 1H), 1.72 (s, 3H), 1.65- 1.48 (m, 2H), 1.33- 1.15 (m, 1H).

Example 358:

(3R)-1 -(6-{[6-(3-fluoro-2-methylphenyl)-5-(trifluoromethyl)pyridin -2- yl]sulfamoyl}pyridin-2-yl)piperidine-3-carboxylic acid LCMS conditions 7: 1.810 min; MS for C24H23F4N4O4S [M+H] ⁺ m/z = 539.14, found m/z = 539.10. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 12.40 (s, 1H), 11.64 (s, 1H), 8.16 (dd, J = 8.9, 5.6 Hz, 1H), 7.68 (dd, J = 8.7, 7.3 Hz, 1H), 7.49 (d, J = 8.8 Hz, 1H), 7.31 - 7.17 (m, 2H), 7.14-7.05 (m, 2H), 6.92 (d, J = 7.0 Hz, 1H), 4.28-4.09 (m, 1H), 3.94- 3.78 (m, 1H), 3.10-2.82 (m, 2H), 2.35-2.14 (m, 1H), 1.97-1.83 (m, 1H), 1.75- 1.45 (m, 5H), 1.36- 1.15 (m, 1H).

Example 359:

(3S)-1 -(6-{[6-(5-fluoro-2-methylphenyl)-5-(trifluoromethyl)pyridin -2- yl]sulfamoyl}pyridin-2-yl)piperidine-3-carboxylic acid LCMS conditions 7: 1.804 min; MS for C24H23F4N4O4S [M+H] ⁺ m/z = 539.14, found m/z = 539.20. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 12.40 (s, 1H), 11.64 (s, 1H), 8.21 - 8.07 (m, 1H), 7.67 (dd, J = 8.7, 7.3 Hz, 1H), 7.49 (d, J = 8.8 Hz, 1H), 7.27 (dd, J = 8.6, 5.7 Hz, 1H), 7.17 (td, J = 8.7, 2.8 Hz, 1H), 7.12-7.07 (m, 2H), 6.99 - 6.88 (m, 1H), 4.27 - 4.07 (m, 1H), 3.96 - 3.78 (m, 1H), 3.09 - 2.81 (m, 2H), 2.30 - 2.17 (m, 1H), 1.96- 1.85 (m, 1H), 1.72 (s, 3H), 1.65- 1.48 (m, 2H), 1.35- 1.15 (m, 1H).

Example 360:

(3S)-1 -(6-{[6-(3-fluoro-2-methylphenyl)-5-(trifluoromethyl)pyridin -2- yl]sulfamoyl}pyridin-2-yl)piperidine-3-carboxylic acid LCMS conditions 7: 1.809 min; MS for C24H23F4N4O4S [M+H] ⁺ m/z = 539.14, found m/z = 539.15. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 12.40 (s, 1H), 11.64 (s, 1H), 8.16 (dd, J = 8.8, 5.6 Hz, 1H), 7.68 (dd, J = 8.7, 7.3 Hz, 1H), 7.49 (d, J = 8.8 Hz, 1H), 7.32 - 7.18 (m, 2H), 7.14 - 7.03 (m, 2H), 6.92 (d, J = 7.1 Hz, 1H), 4.29-4.09 (m, 1H), 3.95- 3.76 (m, 1H), 3.11 -2.82 (m, 2H), 2.34-2.14 (m, 1H), 1.99- 1.83 (m, 1H), 1.73- 1.46 (m, 5H), 1.34- 1.15 (m, 1H).

Example 361 :

1-(6-{[6-(5-fluoro-2-methylphenyl)-5-(trifluoromethyl)pyr idin-2-yl]sulfamoyl}pyridin-2- yl)-3-methylpiperidine-3-carboxylic acid LCMS conditions 7: 1.754 min; MS for

C25H25F4N4O4S [M+H] ⁺ m/z = 553.15, found m/z = 553.20. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 12.32 (s, 1H), 11.59 (s, 1H), 8.19 (d, J = 8.9 Hz, 1H), 7.64 (dd, J = 8.7, 7.2 Hz, 1H), 7.55 (d, J = 8.8 Hz, 1H), 7.31 -7.21 (m, 1H), 7.17 (td, J = 8.6, 2.8 Hz, 1H), 7.11 -7.02 (m, 2H), 7.00 - 6.88 (m, 1H), 3.87 (d, J = 13.1 Hz, 1H), 3.74- 3.56 (m, 1H), 3.12 (d, J = 13.1 Hz, 1H), 3.09- 2.94 (m, 1 H), 2.05 - 1.92 (m, 1 H), 1.75 (d, J = 9.8 Hz, 3H), 1.60 - 1.31 (m, 3H), 1.02 - 0.97 (m, 3H).

Example 362:

1-(6-{[6-(3-fluoro-2-methylphenyl)-5-(trifluoromethyl)pyr idin-2-yl]sulfamoyl}pyridin-2- yl)-3-methylpiperidine-3-carboxylic acid LCMS conditions 7: 1.757 min; MS for

C25H25F4N4O4S [M+H] ⁺ m/z = 553.15, found m/z = 553.20. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 12.32 (s, 1H), 11.59 (s, 1H), 8.19 (d, J = 8.9 Hz, 1H), 7.65 (dd, J = 8.8, 7.2 Hz, 1H), 7.59- 7.47 (m, 1H), 7.30-7.17 (m, 2H), 7.08 (dd, J = 8.0, 5.3 Hz, 2H), 6.98-6.87 (m, 1H), 3.86 (d, J = 13.1 Hz, 1H), 3.71 - 3.56 (m, 1H), 3.13 (dd, J = 13.1, 8.8 Hz, 1H), 3.08-2.94 (m, 1H), 2.03 - 1.89 (m, 1 H), 1.75 - 1.62 (m, 3H), 1.53 - 1.30 (m, 3H), 1.00 (d, J = 8.0 Hz, 3H).

Example 363:

1-(6-(N-(6-(2-cyclobutylphenyl)-5-(trifluoromethyl)pyridin-2 -yl)sulfamoyl)pyridin-2-yl)-4- methylpiperidine-4-carboxylic acid LCMS conditions 7: 1.80 min, MS for C28H30F3N4O4S [M+H] ⁺ m/z = 575.2, found m/z = 575.1. ¹ H NMR (400 MHz, DMSO-c/ ₆ ) δ 12.45 (s, 1H), 11.49 (s, 1H), 8.20 (d, J = 8.9 Hz, 1H), 7.70 (dd, J = 7.4, 8.6Hz, 1H), 7.54 (d, J = 8.2 Hz, 1H), 7.40 (t, J = 7.5 Hz, 1H), 7.34 (d, J = 7.5 Hz, 1H), 7.21 (t, J = 7.4 Hz, 1H), 7.13-7.06 (m, 2H), 7.03 (d, J = 7.4Hz, 1 H), 3.88 - 3.74 (m, 2H), 3.03 (m, 3H), 1.97 - 1.91 (m, 1 H), 1.90 - 1.83 (m, 2H), 1.76 (m, 2H), 1.65-1.51 (m, 2H), 1.43 (s, 1H), 1.22-1.15 (m, 2H), 1.11 (s, 3H). ¹⁹ F NMR (376 MHz, DMSO-c/ ₆ ) δ -56.19 (s, 1F).

Example 364:

(1r,4r)-4-((6-(N-(6-(o-tolyl)-5-(trifluoromethyl)pyridin-2-y l)sulfamoyl)pyridin-2- yl)amino)cyclohexanecarboxylic acid LCMS conditions 7: 1.616 min, MS

for C25H26F3N4O4S [M+H] ⁺ m/z = 535.2, found m/z = 535.2. ¹ H NMR (400 MHz, Methanol-d ₄ ) δ 8.07 (d, J = 8.9 Hz, 1H), 7.59 (dd, J = 13.2, 8.9 Hz, 1H), 7.44 (ddd, J = 8.5, 7.2, 1.1 Hz, 1H), 7.33- 7.25 (m, 1H), 7.24-7.15 (m, 2H), 7.12-7.00 (m, 2H), 6.61 -6.52 (m, 1H), 3.66- 3.51 (m, 1 H), 2.34 - 2.06 (m, 1 H), 2.00 - 1.78 (m, 7H), 1.45 (d, J = 12.3 Hz, 2H), 1.14 (t, J = 14.1 Hz, 2H). Example 365:

(1r,3s)-1 -methyl-3-[(6-{[6-(2-methylphenyl)-5-(trifluoromethyl)pyridi n-2- yl]sulfamoyl}pyridin-2-yl)amino]cyclobutane-1-carboxylic acid LCMS conditions 7: 1.594 min; MS for C24H24F3N4O4S [M+H] ⁺ m/z = 521.15, found m/z = 521.20. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 12.31 (s, 1H), 11.55 (s, 1H), 8.14 (d, J = 8.9 Hz, 1H), 7.59-7.44 (m, 2H), 7.41 (d, J = 6.8 Hz, 1 H), 7.30 (td, J = 7.5, 1.4 Hz, 1 H), 7.25 - 7.14 (m, 2H), 7.09 - 6.95 (m, 2H), 6.60 (d, J = 8.4 Hz, 1 H), 4.22 - 4.04 (m, 1 H), 2.72 - 2.55 (m, 2H), 1.84 - 1.58 (m, 5H),

I.28 (s, 3H).

Example 366:

(R)-1-(6-(N-(6-(2-cyclobutylphenyl)-5-(trifluoromethyl)py ridin-2-yl)sulfamoyl)pyridin-2- yl)piperidine-3-carboxylic acid LCMS conditions 7: 1.76 min, MS for C27H28F3N4O4S

[M+H] ⁺ m/z = 561.2, found m/z = 561.2. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 12.43 (s, 1H), 11.56 (s, 1H), 8.13 (dd, J = 3.1, 8.9 Hz, 1H), 7.69 (t, J = 8.0 Hz, 1H), 7.51 (d, J = 7.6 Hz, 1H), 7.40 (t, J = 7.5 Hz, 1H), 7.33 (d, J = 7.7 Hz, 1H), 7.21 (t, J = 7.4 Hz, 1H), 7.12 (d, J = 7.9 Hz, 2H), 7.02 (d, J = 7.4 Hz, 1H), 4.23 (t, J = 15.4 Hz, 1H), 3.93 (t, J = 12.4 Hz, 1H), 3.01 (ddd, J =

5.9, 10.9, 13.6 Hz, 2H), 2.96 - 2.80 (m, 1H),2.31 (ddt, J = 4.3, 10.2, 14.3 Hz, 1H), 1.94 (dt, J = 4.8, 9.8 Hz, 2H), 1.84 - 1.69 (m, 2H), 1.68 - 1.50 (m, 4H), 1.43 (s, 1 H), 1.33 - 1.28 (m, 1H). ¹⁹ F NMR (376 MHz, DMSO-d ₆ ) δ -56.21 (d, J = 6.8 Hz, 1F). Example 367:

(S)-1-(6-(N-(6-(2-cyclobutylphenyl)-5-(trifluoromethyl)pyrid in-2-yl)sulfamoyl)pyridin-2- yl)piperidine-3-carboxylic acid LCMS conditions 7: 1.77 min, MS for C27H28F3N4O4S

[M+H] ⁺ m/z = 561.2, found m/z = 561.2. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 12.43 (s, 1H), 11.56 (s, 1H), 8.13 (dd, J = 3.0, 8.8 Hz, 1H), 7.69 (t, J = 7.9 Hz, 1H), 7.51 (d, J = 7.7 Hz, 1H), 7.40 (t, J = 7.5 Hz, 1H), 7.33 (d, J = 7.7 Hz, 1H), 7.21 (t, J = 7.2 Hz, 1H), 7.12 (d, J = 7.8 Hz, 2H), 7.02 (d, J = 7.4 Hz, 1 H), 4.32 - 4.14 (m, 1 H), 3.93 (t, J = 12.4 Hz, 1H), 3.01 (ddd, J = 6.1,

I I .1 , 13.6 Hz, 2H), 2.96 - 2.79 (m, 1 H), 2.39 - 2.21 (m, 1 H), 1.98 - 1.85 (m, 2H), 1.84 - 1.68 (m, 2H), 1.67 - 1.49 (m, 4H), 1.43 (s, 1 H), 1.29 (m, 1 H). ¹⁹ F NMR (376 MHz, DMSO-d ₆ ) δ - 56.21 (d, J = 6.7 Hz, 1F). Example 368:

1-(6-(N-(6-(2-cyclobutylphenyl)-5-(trifluoromethyl)pyridin-2 -yl)sulfamoyl)pyridin-2-yl)-3- methylpiperidine-3-carboxylic acid LCMS conditions 7: 1.81 min, MS for C28H30F3N4O4S [M+H] ⁺ m/z = 575.2, found m/z = 575.2. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 12.35 (s, 1H), 11.52 (s, 1H), 8.15 (d, J = 8.9 Hz, 1H), 7.71 -7.60 (m, 1H), 7.55 (s, 1H), 7.38 (m, 2H), 7.22 (t, J = 7.4 Hz, 1H), 7.10 (m, 2H), 7.03 (t, J = 7.2 Hz, 1H), 3.89 (m, 1H), 3.79-3.50 (m, 1H), 3.27- 2.94 (m, 3H), 2.05 - 1.88 (m, 2H), 1.80 (d, J = 9.1 Hz, 2H), 1.60 (d, J = 7.8 Hz, 2H), 1.54 -

I .35 (m, 4H), 1.03 (d, J = 8.2Hz, 3H). ¹⁹ F NMR (376 MHz, DMSO-d ₆ ) δ -56.22 (d, J = 12.0 Hz, 1F).

Example 369:

(R)-1 -(6-(N-(6-(2-ethylphenyl)-5-(trifluoromethyl)pyridin-2-yl)su lfamoyl)pyridin-2- yl)piperidine-3-carboxylic acid LCMS conditions 7: 1.68 min, MS for C25H26F3N4O4S

[M+H] ⁺ m/z = 535.2, found m/z = 535.2. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 12.41 (s, 1H), 11.56 (s, 1H), 8.15 (dd, J = 3.3, 8.8 Hz, 1H), 7.73-7.62 (m, 1H), 7.52 (d, J = 8.1 Hz, 1H), 7.36 (t, J = 7.5 Hz, 1H), 7.28 (d, J = 7.6 Hz, 1H), 7.21 (t, J = 7.4 Hz, 1H), 7.10 (dd, J = 6.1, 7.9 Hz, 2H), 7.03 (d, J = 7.5 Hz, 1H), 4.18 (t, J = 11.9 Hz, 1H), 3.88 (d, J = 13.0 Hz, 1H), 3.01 (m, 1H), 2.89 (q, J = 10.8 Hz, 1H), 2.36-2.22 (m, 1H), 2.15 (m, 1H), 2.08- 1.97 (m, 1H), 1.96-1.85 (m, 1 H), 1.67 - 1.48 (m, 2H), 0.87 (m, 4H). ¹⁹ F NMR (376 MHz, DMSO-d ₆ ) δ -56.62 (s, 1 F).

Example 370:

(S)-1-(6-(N-(6-(2-ethylphenyl)-5-(trifluoromethyl)pyridin-2- yl)sulfamoyl)pyridin-2- yl)piperidine-3-carboxylic acid LCMS conditions 7: 1.68 min, MS for C25H26F3N4O4S

[M+H] ⁺ m/z = 535.2, found m/z = 535.2. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 12.42 (s, 1H), 11.56 (s, 1H), 8.15 (d, J = 6.0Hz, 1H), 7.68 (dd, J = 7.4, 8.6 Hz, 1H), 7.51 (d, J = 7.0 Hz, 1H), 7.36 (t, J = 7.5 Hz, 1H), 7.28 (d, J = 7.5 Hz, 1H), 7.21 (t, J = 7.4 Hz, 1H), 7.14-7.07 (m, 2H), 7.03 (d, J = 7.4 Hz, 1H), 4.18 (t, J = 11.9 Hz, 1H), 3.88 (d, J = 13.3 Hz, 1H), 3.10-2.95 (m, 1H), 2.89 (q, J = 10.9 Hz, 1H), 2.28 (d, J = 10.7 Hz, 1H), 2.15 (dd, J = 7.4, 14.4 Hz, 1H), 2.08- 2.01 (m, 1 H), 1.92 (m, 1 H), 1.70 - 1.48 (m, 2H), 0.87 (m, 4H). ¹⁹ F NMR (376 MHz, DMSO-d ₆ ) δ -56.62 (s, 1F).

Example 371:

1-(6-(N-(6-(2-ethylphenyl)-5-(trifluoromethyl)pyridin-2-yl)s ulfamoyl)pyridin-2-yl)-3- methylpiperidine-3-carboxylic acid LCMS conditions 7: 1.75 min, MS for C26H28F3N4O4S [M+H]+ m/z = 549.2, found m/z = 549.2. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 12.34 (s, 1H),

II.52 (s, 1H), 8.18 (d, J = 8.9 Hz, 1H), 7.71 -7.61 (m, 1H), 7.56 (s, 1H), 7.37 (t, J = 7.5 Hz, 1H), 7.28 (d, J = 7.6 Hz, 1H), 7.22 (td, J = 1.0, 7.5 Hz, 1H), 7.14-6.98 (m, 3H), 3.87 (t, J = 12.7 Hz, 1H), 3.63 (m, 1H), 3.14 (m, 1H), 2.98 (d, J = 8.7 Hz, 1H), 2.18 (m, 1H), 2.12-2.01 (m, 1H), 1.99 (d, J = 3.7 Hz, 1H), 1.43 (m, 3H), 1.01 (d, J = 12.7 Hz, 3H), 0.89 (dq, J = 3.5, 7.2 Hz, 3H). ¹⁹ F NMR (376 MHz, DMSO-d ₆ ) δ -56.61 (s, 1F). Example 372:

4-((6-(N-(6-(o olyl)-5-(trifluoromethyl)pyridin-2-yl)sulfamoyl)pyridin-2- yl)amino)cyclohexanecarboxylic acid LCMS conditions 7: 1.628 min, MS for

C25H26F3N4O4S [M+H] ⁺ m/z = 535.2, found m/z = 534.9. ¹ H NMR (400 MHz, Methanol-d ₄ ) δ

8.07 (d, J = 8.9 Hz, 1H), 7.61 (d, J = 8.9 Hz, 1H), 7.44 (dd, J = 8.5, 7.3 Hz, 1H), 7.30 (td, J = 7.5, 1.4 Hz, 1H), 7.25-7.11 (m, 2H), 7.12-6.97 (m, 2H), 6.64 (dt, J = 8.6, 1.0 Hz, 1H), 3.71

(dt, J = 6.9, 4.0 Hz, 1H), 2.45 (dtt, J = 15.4, 7.8, 3.9 Hz, 1H), 1.92 (d, J = 1.5 Hz, 5H), 1.59 (s, 6H).

Example 373:

(S)-1-(6-(N-(6-(2-cyclobutylphenyl)-5-(trifluoromethyl)py ridin-2-yl)sulfamoyl)pyridin-2- yl)-3-methylpiperidine-3-carboxylic acid LCMS conditions 7: 1.81 min, MS for

C ₂₈ H3oF3N40 ₄ S [M+H] ⁺ m/z = 575.2, found m/z = 575.2. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 12.35 (s, 1H), 11.52 (s, 1H), 8.15 (d, J = 8.9 Hz, 1H), 7.71 -7.60 (m, 1H), 7.55 (s, 1H), 7.38 (m, 2H), 7.22 (t, J = 7.4 Hz, 1H), 7.10 (m, 2H), 7.03 (t, J = 7.2 Hz, 1H), 3.89 (m, 1H), 3.79- 3.50 (m, 1 H), 3.27 - 2.94 (m, 3H), 2.05 - 1.88 (m, 2H), 1.80 (d, J = 9.1 Hz, 2H), 1.60 (d, J =

7.8 Hz, 2H), 1.54 - 1.35 (m, 4H), 1.03 (d, J = 8.2Hz, 3H). ¹⁹ F NMR (376 MHz, DMSO-d ₆ ) δ - 56.22 (d, J = 12.0 Hz, 1F). Chiral purification conditions: isocratic6 min run, SFC 80/20 C0 ₂ /IPA eluent at 80g/min flowrate, 35 °C column temperature, preparatory column DAICEL ChiralPak IC 21 x 250 mm. The (S) enantiomer has a retention time of 3.18 min.

Example 374:

1-(4-(N-(6-(2-ethylphenyl)-5-(trifluoromethyl)pyridin-2-yl)s ulfamoyl)pyridin-2-yl)-4- methylpiperidine-4-carboxylic acid LCMS conditions 7: 1.69 min, MS for C26H28F3N4O4S [M+H] ⁺ m/z = 549.2, found m/z = 549.2. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 12.47 (s, 1H), 11.86 (s, 1H), 8.22 (d, J = 5.1 Hz, 1H), 8.18 (d, J = 8.8 Hz, 1H), 7.39 (td, J = 1.4, 7.5 Hz, 1H), 7.29 (d, J = 7.6 Hz, 1H), 7.22 (td, J = 1.3, 7.4 Hz, 2H), 7.05 (d, J = 7.7 Hz, 1H), 7.02 (d, J = 1.3 Hz, 1H), 6.87 (dd, J = 1.3, 5.1 Hz, 1H), 3.81 -3.62 (m, 2H), 3.01 (m, 2H), 2.19 (m, 1H), 2.10 - 1.99 (m, 1 H), 1.93 (m, 2H), 1.31 (m, 2H), 1.16 (s, 3H), 0.86 - 0.82 (m, 3H). ¹⁹ F NMR (376 MHz, DMSO-d ₆ ) δ -56.69 (s, 1F). Example 375:

(R)-1 -(6-(N-(6-(2-isopropylphenyl)-5-(trifluoromethyl)pyridin-2-y l)sulfamoyl)pyridin-2- yl)piperidine-3-carboxylic acid LCMS conditions 7: 1.92 min, MS for C26H28F3N4O4S

[M+H] ⁺ m/z = 549.2, found m/z = 549.1. Rotomers/atropisomers are present in the NMR spectra. ¹ H NMR (400 MHz, Chloroform-d) δ 9.80 (br. s, 1 H), 8.08 (t, J = 9.0 Hz, 1 H), 7.87 - 7.73 (m, 1H), 7.53 (m, 1H), 7.48-7.31 (m, 2H), 7.24-7.16 (m, 1H), 7.15-6.96 (m, 2H), 6.79 (dd, J = 2.2, 8.7 Hz, 1 H), 4.45 (m, 1 H), 3.61 (m, 1 H), 3.55 - 3.31 (m, 2H), 2.55 (dt, J = 4.8, 9.3 Hz, 1H), 2.32 (m, 1H), 1.86- 1.73 (m, 3H), 1.43 (m, 1H), 1.16-1.02 (m, 5H), 0.79 (m, 2H). ¹⁹ F NMR (376 MHz, Chloroform-d) δ -58.53 (s, 1F), -58.75 (s, 0.8F).

Example 376:

(S)-1 -(6-(N-(6-(2-isopropylphenyl)-5-(trifluoromethyl)pyridin-2-y l)sulfamoyl)pyridin-2- yl)piperidine-3-carboxylic acid LCMS conditions 7: 1.90 min, MS for C26H28F3N4O4S

[M+H] ⁺ m/z = 549.2, found m/z = 549.2. Rotomers/atropisomers are present in the NMR spectra. ¹ H NMR (400 MHz, Chloroform-d) δ 8.07 (dd, J = 7.6, 8.8 Hz, 1H), 7.79 (t, J = 9.5 Hz, 1 H), 7.54 (m, 1 H), 7.45 - 7.31 (m, 2H), 7.24 - 7.11 (m, 2H), 7.09 - 6.98 (m, 1 H), 6.80 (dd, J = 1.7, 8.7 Hz, 1H), 4.53-4.14 (m, 1H), 3.73-3.33 (m, 3H), 2.54 (m, 1H), 2.34 (m, 1 H), 1.93 - 1.69 (m, 3H), 1.50 - 1.37 (m, 1 H), 1.16 - 1.03 (m, 5H), 0.82 (d, J = 6.8 Hz, 2H). ¹⁹ F NMR (376 MHz, Chloroform-d) δ -58.51 (s, 1F), -58.69 (s, 0.8F).

Example 377:

1-(6-(N-(6-(2-isopropylphenyl)-5-(trifluoromethyl)pyridin-2- yl)sulfamoyl)pyridin-2-yl)-3- methylpiperidine-3-carboxylic acid LCMS conditions 7: 1.96 min, MS for C27H30F3N4O4S [M+H] ⁺ m/z = 563.2, found m/z = 563.2. Rotomers/atropisomers are present in the NMR spectra. ¹ H NMR (400 MHz, Chloroform-d) δ 10.22 (br. s, 1H), 8.09 (m, 1H), 7.80 (m, 1H), 7.48 (m, 1 H), 7.44 - 7.30 (m, 2H), 7.18 m, 1 H), 7.11 - 6.93 (m, 2H), 6.78 (m, 1 H), 4.82 (m, 1 H), 3.88 (m, 1 H), 3.09 - 2.91 (m, 1 H), 2.78 (m, 1 H), 2.30 (m 1 H), 2.02 (m, 1 H), 1.83 - 1.67 (m, 1H), 1.47 (m, 1H), 1.43-1.32 (m, 2H), 1.17 (m, 3H), 1.14-1.03 (m, 5H), 0.69 (d, J = 6.8 Hz, 1H). ¹⁹ F NMR (376 MHz, Chloroform-d) δ -58.53 (s, 1F), -58.88 (s, 0.9F).

Example 378:

1-(4-(N-(6-(2-cyclobutylphenyl)-5-(trifluoromethyl)pyridin-2 -yl)sulfamoyl)pyridin-2-yl)-4- methylpiperidine-4-carboxylic acid LCMS conditions 7: 1.78 min, MS for C28H30F3N4O4S [M+H] ⁺ m/z = 575.2, found m/z = 575.2. ¹ H NMR (400 MHz, Chloroform-d) δ 10.54 (s, 1H), 8.28 (d, J = 5.1 Hz, 1 H), 8.05 (d, J = 9.0 Hz, 1 H), 7.65 (d, J = 8.9 Hz, 1 H), 7.50 - 7.38 (m,

2H), 7.22 (td, J = 1.5, 7.4 Hz, 1 H), 7.11 (d, J = 1.2 Hz, 1 H), 7.07 (d, J = 7.6 Hz, 1 H), 6.93 (dd, J = 1.3, 5.1 Hz, 1H), 4.12-3.92 (m, 2H), 3.15 (p, J = 8.5 Hz, 1H), 3.01 -2.84 (m, 2H), 2.01 (q, J = 9.8, 1 1 .6 Hz, 4H), 1 .80 - 1 .64 (m, 4H), 1 .43 - 1 .31 (m, 3H), 1 .21 (s, 3H). ¹⁹ F NMR (376 MHz, Chloroform-d) δ -58.30 (s, 1 F).

Example 379:

1 -(6-(N-(6-(2-cyclopentylphenyl)-5-(trifluoromethyl)pyridin-2 -yl)sulfamoyl)pyridin-2-yl) 4-methylpiperidine-4-carboxylic acid

Step 1 : Synthesis of N-(6-chloro-5-(trifluoromethyl)pyridin-2-yl)-6-fluoropyridin e-2- sulfonamide

6-Chloro-5-(trifluoromethyl)pyridin-2-amine (1 .2 g, 6.1 1 mmol) and sulfonyl chloride 6- fluoropyridine-2-sulfonyl chloride (1 .493 g, 7.63 mmol) were dissolved in pyridine (10 mL). The resulting red solution was stirred at 20 °C for 3 days. The reaction mixture was diluted with ethyl acetate, washed with water, sat. NH ₄ CI, 1 N HCI and brine, dried over Na ₂ S0 ₄ and concentrated. The crude product was purified by silica gel chromatography (0-40%

EtOAc/hexane) to yield N-(6-chloro-5-(trifluoromethyl)pyridin-2-yl)-6-fluoropyridin e-2- sulfonamide (1 .05 g, 2.92 mmol, 47.9 % yield). LCMS conditions 7: 1 .56 min, MS for

CH H7CIF4N3O2S [M+H] ⁺ m/z = 356.0, found m/z = 355.9. ¹ H NMR (500 MHz, Chloroform-d) δ 8.14 - 8.07 (m, 1 H), 8.07 - 8.04 (m, 1 H), 7.97 (d, J = 8.6 Hz, 1 H), 7.79 (br. s, 1 H), 7.56 (d, J = 8.5 Hz, 1 H), 7.23 (ddd, J = 0.9, 2.6, 8.1 Hz, 1 H). ¹⁹ F NMR (471 MHz, Chloroform-d) δ - 62.67 (s, 3F), -62.73 (br. s, 1 F).

Step 2: Synthesis of N-(6-chloro-5-(trifluoromethyl)pyridin-2-yl)-6-fluoro-N- (methoxymethyl)pyridine-2 -sulfonamide

N-(6-chloro-5-(trifluoromethyl)pyridin-2-yl)-6-fluoropyri dine-2-sulfonamide (1 .02 g, 2.87 mmol) was dissolved in ACN (30 mL). The mixture was treated with powdered potassium carbonate (0.396 g, 2.87 mmol) and MOM-CI (0.218 mL, 2.87 mmol). The mixture was stirred at 20 °C for 18 h. The reaction mixture was filtered and concentrated. The crude product was purified by silica gel chromatography (0-40% EtOAc/heptane) to yield the desired product N-(6- chloro-5-(trifluoromethyl)pyridin-2-yl)-6-fluoro-N-(methoxym ethyl)pyridine-2-sulfonamide (0.98 g, 2.427 mmol, 85 % yield). LCMS conditions 7: 1 .69 min, MS for C ₁₃ H ₁₁ CIF ₄ N ₃ 0 ₃ S [M+H] ⁺ m/z = 400.0, found m/z = 400.1 . ¹ H NMR (500 MHz, Chloroform-d) δ 8.16 (ddd, J = 0.9, 2.1 , 7.5 Hz, 1 H), 8.14 - 8.09 (m, 1 H), 7.97 (d, J = 8.5 Hz, 1 H), 7.53 (d, J = 8.4 Hz, 1 H), 7.19 (ddd, J = 0.9, 2.6, 7.9 Hz, 1 H), 5.54 (s, 2H), 3.56 (s, 3H). ¹⁹ F NMR (471 MHz,

Chloroform-d) δ -62.87 (s, 3F), -64.16 (s, 1 F). Step 3: Synthesis of 6-fluoro-N-(6-(2-hydroxyphenyl)-5-(trifluoromethyl)pyridin-2 -yl)-N- (methoxymethyl)pyridine-2 -sulfonamide

N-(6-chloro-5-(trifluoromethyl)pyridin-2-yl)-6-fluoro-N-(met hoxymethyl)pyridine-2-sulfonamide (0.2 g, 0.500 mmol) and 2-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)phenol (0.165 g, 0.750 mmol) were dissolved in dioxane (10 ml_) and water (1 .5 ml_) and treated with sodium carbonate (0.159 g, 1 .501 mmol). The mixture was degassed using argon. The catalyst tetrakis(triphenylphosphino)palladium(0) (0.058 g, 0.050 mmol) was added, the mixture was degassed again, and was stirred at 120 °C for 18 h. The mixture was cooled, the aqueous layer was discarded and enough ethyl acetate was added until all solids were dissolved. The mixture was dried over Na ₂ S0 ₄ , filtered and concentrated to yield a reddish oil. The crude product was purified by silica gel chromatography (0-30% EtOAc/heptane) to yield the desired product 6-fluoro-N-(6-(2-hydroxyphenyl)-5-(trifluoromethyl)pyridin-2 -yl)-N- (methoxymethyl)pyridine-2-sulfonamide (0.145 g, 0.301 mmol, 60.2 % yield). LCMS conditions 7: 1 .67 min, MS for [M+H] ⁺ m/z = 458.1 , found m/z = 458.1 . ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.39 (s, 1 H), 8.26 (d, J = 8.8 Hz, 1 H), 8.00 (q, J = 7.8 Hz, 1 H), 7.77 (dd, J = 1 .9, 7.5 Hz, 1 H), 7.53 (d, J = 8.7 Hz, 1 H), 7.45 (dd, J = 2.0, 8.2 Hz, 1 H), 7.25 - 7.17 (m, 1 H), 6.82 (d, J = 8.3 Hz, 1 H), 6.77 (t, J = 7.4 Hz, 1 H), 6.72 - 6.68 (m, 1 H), 5.45 (s, 2H), 3.39 (s, 3H). ¹⁹ F NMR (376 MHz, DMSO-d ₆ ) δ -58.03 (s, 3F), -66.28 (s, 1 F).

Step 4: Synthesis of 2-(6-(6-fluoro-N-(methoxymethyl)pyridine-2-sulfonamido)-3- (trifluoromethyl)pyridin-2-yl)phenyl trifluoromethanesulfonate

6-Fluoro-N-(6-(2-hydroxyphenyl)-5-(trifluoromethyl)pyridin-2 -yl)-N-(methoxymethyl)pyridine-2- sulfonamide (0.15 g, 0.328 mmol) was dissolved in pyridine (3 ml_), treated with triflic anhydride (0.078 ml_, 0.459 mmol), and the mixture was stirred at 20 °C for 18 h. The mixture was diluted with water and extracted with ethyl acetate (2x 25 ml_). The combined extracts were washed with water, sat. NH ₄ CI, and brine, then dried over Na ₂ S0 ₄ , filtered and concentrated to yield a reddish oil. The crude product was purified by silica gel

chromatography (0-40% EtOAc/heptane) to yield the desired product 2-(6-(6-fluoro-N- (methoxymethyl)pyridine-2-sulfonamido)-3-(trifluoromethyl)py ridin

trifluoromethanesulfonate (0.13 g, 0.218 mmol, 67% yield). LCMS conditions 7: 1 .83 min, MS for C ₂ oH ₁₅ F ₇ N ₃ 0 ₆ S ₂ [M+H] ⁺ m/z = 590.0, found m/z = 590.1 . ¹ H NMR (500 MHz, Chloroform- d) δ 8.08 (d, J = 8.7 Hz, 1 H), 7.78 - 7.73 (m, 2H), 7.73 - 7.65 (m, 1 H), 7.59 - 7.51 (m, 1 H), 7.47 (td, J = 1 .2, 7.5 Hz, 1 H), 7.39 (dd, J = 1 .8, 7.7 Hz, 1 H), 7.32 (dd, J = 1 .1 , 8.3 Hz, 1 H), 7.04 (ddd, J = 0.9, 2.6, 8.0 Hz, 1 H), 5.64 (s, 1 H), 5.51 (s, 1 H), 3.53 (s, 3H). ¹⁹ F NMR (471 MHz, Chloroform-d) δ -58.71 (s, 3F), -64.66 (s, 1 F), -74.58 (s, 3F).

Step 5: Synthesis of N-(6-(2-(cyclopent-1 -en-1 -yl)phenyl)-5-(trifluoromethyl)pyridin-2- yl)-6-fluoro-N-(methoxymethyl)pyridine-2 -sulfonamide

2-(6-(6-Fluoro-N-(methoxymethyl)pyridine-2-sulfonamido)-3-(t rifluoromethyl)pyridin-2- yl)phenyl trifluoromethanesulfonate (0.13 g, 0.221 mmol) and cyclopent-1 -en-1 -ylboronic acid (0.031 g, 0.276 mmol) were dissolved in dioxane (10 mL) and water (1 .5 mL) and treated with sodium carbonate (0.093 g, 0.882 mmol). The mixture was degassed using argon, tetrakis(triphenylphosphino)palladium(0) (0.025 g, 0.022 mmol) was added, the mixture was degassed again, and was stirred at 120 °C for 18 h. The mixture was cooled, the aqueous layer was discarded and the mixture was filtered. The solids were washed with more dioxane. The combined filtrate was dried over Na ₂ S0 ₄ , filtered and concentrated to yield a reddish oil. The crude product was purified by silica gel chromatography (0-40%

EtOAc/heptane) to yield the desired product N-(6-(2-(cyclopent-1 -en-1 -yl)phenyl)-5- (trifluoromethyl)pyridin-2-yl)-6-fluoro-N-(methoxymethyl)pyr idine-2-sulfonamide (25 mg, 0.049 mmol, 22.34 % yield). LCMS conditions 7: 1 .93 min, MS for C24H22F4N3O3S [M+H] ⁺ m/z = 508.1 , found m/z = 508.2. ¹ H NMR (500 MHz, Chloroform-d) δ 7.98 (d, J = 8.7 Hz, 1 H), 7.73 - 7.63 (m, 1 H), 7.57 - 7.46 (m, 2H), 7.41 - 7.31 (m, 2H), 7.19 (ddd, J = 2.2, 6.5, 7.7 Hz, 1 H), 6.94 (ddd, J = 0.7, 2.6, 8.2 Hz, 1 H), 6.90 (d, J = 7.6 Hz, 1 H), 5.57 (d, J = 1 1 .5 Hz, 1 H), 5.48 (d, J = 1 1 .4 Hz, 1 H), 5.00 (p, J = 2.4 Hz, 1 H), 3.58 (s, 3H), 2.36 (m, 1 H), 2.27 - 2.09 (m, 2H), 1 .87 - 1 .60 (m, 3H). ¹⁹ F NMR (471 MHz, Chloroform-d) δ -58.87 (s, 3F), -65.33 (s, 1 F).

Step 6: Synthesis of N-(6-(2-cyclopentylphenyl)-5-(trifluoromethyl)pyridin-2-yl)- 6- fluoro-N-(methoxymethyl)pyridine-2 -sulfonamide

N-(6-(2-(cyclopent-1 -en-1 -yl)phenyl)-5-(trifluoromethyl)pyridin-2-yl)-6-fluoro-N- (methoxymethyl)pyridine-2-sulfonamide (22 mg, 0.043 mmol) was dissolved in ethyl acetate (10 mL) and treated with palladium black on carbon (10%; 9 mg, 0.9 mmol). The mixture was degassed using argon, then hydrogen, and stirred at 20 °C for 18 h. The mixture was filtered and concentrated to yield the desired product N-(6-(2-cyclopentylphenyl)-5-

(trifluoromethyl)pyridin-2-yl)-6-fluoro-N-(methoxymethyl) pyridine-2-sulfonamide (18 mg, 0.034 mmol, 77 % yield). LCMS conditions 7: 2.04 min, MS for C24H24F4N3O3S [M+H] ⁺ m/z = 510.1 , found m/z = 510.2. ¹ H NMR (500 MHz, Chloroform-d) δ 7.94 (d, J = 8.7 Hz, 1 H), 7.56 (ddd, J = 0.7, 1 .9, 7.5 Hz, 1 H), 7.46 (dd, J = 0.8, 8.7 Hz, 1 H), 7.40 (dt, J = 7.5, 8.2 Hz, 1 H), 7.32 - 7.24 (m, 2H), 7.01 (ddd, J = 2.0, 6.6, 7.7 Hz, 1 H), 6.85 (ddd, J = 0.7, 2.6, 8.2 Hz, 1 H), 6.70 (d, J = 7.6 Hz, 1 H), 5.51 (d, J = 1 1 .5 Hz, 1 H), 5.38 (d, J = 1 1 .5 Hz, 1 H), 3.49 (s, 3H), 2.42 (p, J = 8.5 Hz, 1 H), 1 .84 - 1 .67 (m, 2H), 1 .57 - 1 .43 (m, 4H), 1 .40 - 1 .27 (m, 2H). ¹⁹ F NMR (471 MHz, Chloroform-d) δ -58.51 (s, 3F), -65.20 (s, 1 F).

Step 7: Synthesis of 1 -(6-(N-(6-(2-cyclopentylphenyl)-5-(trifluoromethyl)pyridin-2 - yl)sulfamoyl)pyridin-2-yl)-4-methylpiperidine-4-carboxylic acid

The intermediate N-(6-(2-cyclopentylphenyl)-5-(trifluoromethyl)pyridin-2-yl)- 6-fluoro-N-

(methoxymethyl)pyridine-2-sulfonamide (18 mg, 0.035 mmol), methyl 4-methylpiperidine-4- carboxylate (9.52 mg, 0.053 mmol) and potassium carbonate (14.65 mg, 0.106 mmol) were dissolved/suspended in dioxane (8 mL) and the resulting mixture was stirred at 120 °C for 18 hr. The mixture was diluted with water and pH adjusted to ~1 with 1 N aq. HCI and then extracted with EtOAc (2 x 30 mL). The combined extracts were washed with brine, dried over Na ₂ S0 ₄ , filtered and concentrated. The crude product was purified by silica gel

chromatography (0-50% EtOAc/EtOH (3:1 ) mixture/heptane) to yield the desired title product Example 379: 1 -(6-(N-(6-(2-cyclopentylphenyl)-5-(trifluoromethyl)pyridin-2 - yl)sulfamoyl)pyridin-2-yl)-4-methylpiperidine-4-carboxylic acid (4 mg, 6.12 μηιοΙ, 17.31 % yield). LCMS conditions 7: 1 .97 min, MS for C29H32F3N4O4S [M+H] ⁺ m/z = 589.2, found m/z =

589.2. ¹ H NMR (400 MHz, Chloroform-d) δ 7.99 (d, J = 9.0 Hz, 1 H), 7.68 (d, J = 8.9 Hz, 1 H), 7.60 (dd, J = 7.2, 8.7 Hz, 1 H), 7.45 - 7.34 (m, 2H), 7.31 (d, J = 7.2 Hz, 1 H), 7.16 (td, J = 1 .5, 7.3 Hz, 1 H), 7.04 (d, J = 7.6 Hz, 1 H), 6.76 (d, J = 8.7 Hz, 1 H), 3.95 (m, 2H), 2.85 (m, 2H), 2.44 (m, 1 H), 2.01 (t, J = 12.9 Hz, 2H), 1 .86 - 1 .74 (m, 3H), 1 .70 (s, 3H), 1 .49 - 1 .38 (m, 5H), 1 .21 (s, 3H). ¹⁹ F NMR (376 MHz, Chloroform-d) δ -58.29 (s, 1 F).

Example 380:

1 -(6-(6-(2-ethylphenyl)-5-(trifluoromethyl)pyridine-2-sulfona mido)pyridin-2-yl)-4- methylpiperidine-4-carboxylic acid LCMS conditions 7: 1 .84 min, MS for C26H28F3N4O4S [M+H] ⁺ m/z = 549.2, found m/z = 549.2. Rotomers/atropisomers are present in the NMR spectra. ¹ H NMR (400 MHz, Chloroform-d) δ 8.36 - 8.20 (m, 0.5H), 7.93 (m, 1 H), 7.75 - 7.65 (m, 1 H), 7.63 - 7.54 (m, 0.5H), 7.52 - 7.33 (m, 2.5H), 7.26 - 7.07 (m, 2H), 6.93 (br. s, 1 H), 6.36 - 6.08 (m, 1 H), 4.10 - 3.97 (m, 1 H), 3.55 (m, 0.5H), 3.23 (m, 0.5H), 2.90 (m, 0.5H), 2.51 (m, 0.5H), 2.40 (m, 0.5H), 2.18 (m, 1 H), 2.04 (m, 1 .5H), 1 .52 (m, 2.5H), 1 .32 - 1 .26 (m, 5H), 1 .10 (t, J = 7.6 Hz, 2H), 1 .00 - 0.79 (m, 3H). ¹⁹ F NMR (376 MHz, Chloroform-d) δ -58.38 (s, 1 F), -58.31 (s, 0.74F). Example 381 :

4-methyl-1 -(6-(N-(6-(2-(2,2,2-trifluoroethoxy)phenyl)-5-(trifluorometh yl)pyridin-2- yl)sulfamoyl)pyridin-2-yl)piperidine-4-carboxylic acid LCMS conditions 7: 1 .84 min, MS for C26H ₂ 5F ₆ N ₄ 0 ₅ S [M+H] ⁺ m/z = 619.2, found m/z = 619.2. Rotomers/atropisomers are present in the NMR spectra. ¹ H NMR (400 MHz, Chloroform-d) δ 7.98 (dd, J = 2.0, 8.9 Hz, 1 H), 7.73 (d, J = 8.8 Hz, 1 H), 7.63 - 7.50 (m, 1 H), 7.43 (td, J = 2.0, 8.0 Hz, 1 H), 7.31 (d, J = 2.0 Hz, 1 H), 7.20 (dd, J = 1 .7, 7.6 Hz, 1 H), 7.10 (td, J = 1 .8, 7.4 Hz, 1 H), 6.94 (d, J = 8.2 Hz, 1 H), 6.76 (dd, J = 2.1 , 8.7 Hz, 1 H), 4.26 (qd, J = 2.0, 8.1 Hz, 2H), 3.91 (s, 2H), 2.92 (ddd, J =

2.6, 1 1 .3, 14.0 Hz, 2H), 2.01 (d, J = 13.7 Hz, 2H), 1 .38 - 1 .30 (m, 2H), 1 .21 (d, J = 2.0 Hz, 3H). ¹⁹ F NMR (376 MHz, Chloroform-d) δ -59.12 (s, 3F), -74.04 (s, 3F).

Example 382:

1 -(6-(N-(6-(2-isobutoxyphenyl)-5-(trifluoromethyl)pyridin-2-y l)sulfamoyl)pyridin-2-yl)-4- methylpiperidine-4-carboxylic acid LCMS conditions 7: 1 .93 min, MS for C28H32F3N4O5S [M+H] ⁺ m/z = 593.2, found m/z = 593.2. Rotomers/atropisomers are present in the NMR spectra. ¹ H NMR (400 MHz, Chloroform-d) δ 7.95 (d, J = 9.0 Hz, 1 H), 7.64 (d, J = 9.0 Hz, 1 H), 7.59 (dd, J = 7.3, 8.7 Hz, 1 H), 7.40 (ddd, J = 1 .7, 7.6, 9.2 Hz, 1 H), 7.31 (d, J = 7.2 Hz, 1 H), 7.13 - 7.07 (m, 1 H), 6.95 (dd, J = 0.9, 7.4 Hz, 1 H), 6.91 (d, J = 8.1 Hz, 1 H), 6.74 (d, J = 8.7 Hz, 1 H), 3.97 (d, J = 13.5 Hz, 2H), 3.64 (d, J = 6.4 Hz, 2H), 2.91 - 2.77 (m, 2H), 2.01 (d, J = 13.6 Hz, 2H), 1 .84 (hept, J = 6.7 Hz, 1 H), 1 .37 - 1 .31 (m, 2H), 1 .21 (s, 3H), 0.76 (dd, J =

6.7, 1 1 .8 Hz, 6H). ¹⁹ F NMR (376 MHz, Chloroform-d) δ -58.88 (s, 1 F).

Example 383:

(R)-1 -(6-(N-(6-(2-cyclobutylphenyl)-5-(trifluoromethyl)pyridin-2- yl)sulfamoyl)pyridin-2- yl)-3-methylpiperidine-3-carboxylic acid LCMS conditions 7: 1 .81 min, MS for

C ₂₈ H3oF3N40 ₄ S [M+H] ⁺ m/z = 575.2, found m/z = 575.2. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 12.35 (s, 1 H), 1 1 .52 (s, 1 H), 8.15 (d, J = 8.9 Hz, 1 H), 7.71 - 7.60 (m, 1 H), 7.55 (s, 1 H), 7.38 (m, 2H), 7.22 (t, J = 7.4 Hz, 1 H), 7.10 (m, 2H), 7.03 (t, J = 7.2 Hz, 1 H), 3.89 (m, 1 H), 3.79 - 3.50 (m, 1 H), 3.27 - 2.94 (m, 3H), 2.05 - 1 .88 (m, 2H), 1 .80 (d, J = 9.1 Hz, 2H), 1 .60 (d, J = 7.8 Hz, 2H), 1 .54 - 1 .35 (m, 4H), 1 .03 (d, J = 8.2Hz, 3H). ¹⁹ F NMR (376 MHz, DMSO-d ₆ ) δ - 56.22. (d, J = 12.0 Hz, 1 F). Chiral purification conditions: isocratic 6 min run, SFC 80/20 C0 ₂ /IPA eluent at 80g/min flowrate, 35 °C column temperature, preparatory column DAICEL ChiralPak IC 21 x 250 mm. The (R) enantiomer has a retention time of 2.25 min. Example 384:

(R)-1 -(6-(N-(6-(2-isopropylphenyl)-5-(trifluoromethyl)pyridin-2-y l)sulfamoyl)pyridin-2- yl)-3-methylpiperidine-3-carboxylic acid LCMS conditions 7: 1 .96 min, MS for C27H30F3N4O4S [M+H] ⁺ m/z = 563.2, found m/z = 563.2. Rotomers/atropisomers are present in the NMR spectra. ¹ H NMR (400 MHz, Chloroform-d) δ 10.22 (br. s, 1 H), 8.09 (m, 1 H), 7.80 (m, 1H), 7.48 (m, 1H), 7.44-7.30 (m, 2H), 7.18 m, 1H), 7.11 -6.93 (m, 2H), 6.78 (m, 1 H), 4.82 (m, 1 H), 3.88 (m, 1 H), 3.09 - 2.91 (m, 1 H), 2.78 (m, 1 H), 2.30 (m 1 H), 2.02 (m, 1H), 1.83- 1.67 (m, 1H), 1.47 (m, 1H), 1.43-1.32 (m, 2H), 1.17 (m, 3H), 1.14-1.03 (m, 5H), 0.69 (d, J = 6.8 Hz, 1H). ¹⁹ F NMR (376 MHz, Chloroform-d) δ -58.53 (s, 1F), -58.88 (s, 0.9F). Chiral purification conditions: isocratic9 min run, HPLC 90/10 heptane/ethanol eluent at 1 mL/min flowrate, 20 °C column temperature, column 3 μηι Whelk 0-14.6 x 50 mm. The (R) enantiomer has a retention time of 6.57 min.

Example 385:

(S)-1 -(6-(N-(6-(2-isopropylphenyl)-5-(trifluoromethyl)pyridin-2-y l)sulfamoyl)pyridin-2- yl)-3-methylpiperidine-3-carboxylic acid LCMS conditions 7: 1.96 min, MS for

C27H30F3N4O4S [M+H] ⁺ m/z = 563.2, found m/z = 563.2. Rotomers/atropisomers are present in the NMR spectra. ¹ H NMR (400 MHz, Chloroform-d) δ 10.22 (br. s, 1 H), 8.09 (m, 1 H), 7.80 (m, 1H), 7.48 (m, 1H), 7.44-7.30 (m, 2H), 7.18 m, 1H), 7.11 -6.93 (m, 2H), 6.78 (m, 1 H), 4.82 (m, 1 H), 3.88 (m, 1 H), 3.09 - 2.91 (m, 1 H), 2.78 (m, 1 H), 2.30 (m 1 H), 2.02 (m, 1H), 1.83- 1.67 (m, 1H), 1.47 (m, 1H), 1.43-1.32 (m, 2H), 1.17 (m, 3H), 1.14-1.03 (m, 5H), 0.69 (d, J = 6.8 Hz, 1H). ¹⁹ F NMR (376 MHz, Chloroform-d) δ -58.53 (s, 1F), -58.88 (s, 0.9F). Chiral purification conditions: isocratic 9 min run, HPLC 90/10 heptane/ethanol eluent at 1 mL/min flowrate, 20 °C column temperature, column 3 μηι Whelk O-I 4.6 x 50 mm. The (S) enantiomer has a retention time of 5.70 min.

Example 386:

1-(6-(N-(6-(2-isobutoxyphenyl)-5-(trifluoromethyl)pyridin -2-yl)sulfamoyl)pyridin-2-yl)-3- methylpiperidine-3-carboxylic acid LCMS conditions 7: 1.87 min, MS for C28H32F3N4O5S [M+H] ⁺ m/z = 593.2, found m/z = 593.1. Rotomers/atropisomers are present in the NMR spectra. ¹ H NMR (400 MHz, Chloroform-d) δ 8.04 (d, J = 8.8 Hz, 1H), 7.80 (d, J = 8.9 Hz, 1H), 7.48 (dd, J = 7.2, 8.7 Hz, 1H), 7.38 (ddd, J = 1.7, 7.4, 8.3 Hz, 1H), 7.09 (d, J = 7.5 Hz, 1 H), 7.06 (d, J = 7.2 Hz, 1 H), 7.00 - 6.92 (m, 1 H), 6.89 (d, J = 8.4 Hz, 1 H), 6.77 (d, J = 8.7 Hz, 1 H), 4.93 (d, J = 13.5 Hz, 1 H), 3.89 (d, J = 13.6 Hz, 1 H), 3.63 (t, J = 7.4 Hz, 2H), 3.09 - 2.96 (m, 1H), 2.76 (d, J = 13.5 Hz, 1 H), 2.13 - 2.03 (m, 1H), 1.86-1.72 (m, 1H), 1.56-1.48 (m, 1H), 1.37 (ddd, J = 4.6, 12.4, 13.8 Hz, 2H), 1.19 (s, 3H), 0.69 (br. s, 6H). ¹⁹ F NMR (376 MHz, Chloroform-d) δ -59.31 (br. s, 1F). Example 387:

1-(6-(N-(5-chloro-6-(2-ethylphenyl)pyridin-2-yl)sulfamoyl)py ridin-2-yl)-3- methylpiperidine-3-carboxylic acid LCMS conditions 7: 1.609 min; MS for C25H28CIN4O4S m/z[M+H] ⁺ = 515.20. ¹ H NMR (400 MHz, DMSO) δ 12.35 (s, 1H), 11.13 (s, 1H), 7.92 (d, J = 8.8 Hz, 1 H), 7.65 (dd, J = 8.7, 7.3 Hz, 1 H), 7.41 (d, J = 8.8 Hz, 1 H), 7.35 (td, J = 7.5, 1.4 Hz, 1H), 7.31 -7.27 (m, 1H), 7.24 (td, J = 7.4, 1.4 Hz, 1H), 7.10-7.03 (m, 3H), 3.88 (d, J= 13.1 Hz, 1H), 3.67 (d, J= 10.3 Hz, 1H), 3.13 (d, J= 13.1 Hz, 1H), 3.09-2.98 (m, 1H), 2.28-2.14 (m, 2H), 2.04 - 1.95 (m, 1 H), 1.55 - 1.36 (m, 3H), 1.04 (s, 3H), 0.90 - 0.81 (m, 3H). Example 388:

1-(6-(N-(5-chloro-6-(2-isopropylphenyl)pyridin-2-yl)sulfamoy l)pyridin-2-yl)-3- methylpiperidine-3-carboxylic acid LCMS conditions 7: 1.645 min; MS for C26H30CIN4O4S m/z [M+H] ⁺ = 529.20. ¹ H NMR (400 MHz, DMSO) δ 12.35 (s, 1H), 11.13 (s, 1H), 7.92 (d, J = 8.8 Hz, 1 H), 7.65 (dd, J = 8.7, 7.3 Hz, 1 H), 7.45 (d, J = 8.8 Hz, 1 H), 7.41 - 7.37 (m, 2H), 7.26 -7.19 (m, 1H), 7.08 (dd, J= 8.0, 4.9 Hz, 2H), 7.00 (d, J = 7.5 Hz, 1H), 3.88 (d, J= 12.6 Hz, 1H), 3.74-3.59 (m, 1H), 3.19-2.96 (m, 2H), 2.05- 1.94 (m, 1H), 1.56-1.36 (m, 3H), 1.32 - 1.20 (m, 1 H), 1.04 (s, 6H), 0.95 (s, 3H).

Example 389:

1-(6-(N-(5-chloro-6-(2-cyclobutylphenyl)pyridin-2-yl)sulf amoyl)pyridin-2-yl)-3- methylpiperidine-3-carboxylic acid LCMS conditions 7: 1.674 min; MS for C27H30CIN4O4S m/z [M+H] ⁺ = 541.20. ¹ H NMR (400 MHz, DMSO) δ 12.36 (s, 1H), 11.13 (s, 1H), 7.89 (d, J = 8.8 Hz, 1 H), 7.66 (dd, J = 8.7, 7.3 Hz, 1 H), 7.41 - 7.33 (m, 2H), 7.31 (d, J = 7.6 Hz, 1 H), 7.23 (td, J = 7.4, 1.0 Hz, 1 H), 7.09 (t, 2H), 7.04 (d, J = 7.5 Hz, 1 H), 3.96 - 3.54 (m, 2H), 3.29 - 2.97 (m, 4H), 2.06 - 1.94 (m, 1 H), 1.93 - 1.36 (m, 8H), 1.05 (s, 3H).

Example 390:

1-(6-(N-(6-(2-(tert-butyl)phenyl)-5-chloropyridin-2-yl)sulfa moyl)pyridin-2-yl)-3- methylpiperidine-3-carboxylic acid LCMS conditions 7: 1.656 min; MS C27H32CIN4O4S m/z [M+H] ⁺ = 543.20. ¹ H NMR (400 MHz, DMSO) δ 12.35 (s, 1 H), 11.19 - 11.01 (m, 1 H), 7.88 (d, J = 8.8 Hz, 1 H), 7.66 - 7.60 (m, 1 H), 7.53 (d, J = 8.0 Hz, 1 H), 7.42 (dd, J = 8.8, 3.9 Hz, 1H), 7.37-7.32 (m, 1H), 7.24-7.19 (m, 1H), 7.09-7.04 (m, 2H), 6.85 (ddd, J= 7.6, 4.1, 1.4 Hz, 1H), 3.90 (dd, J= 13.0, 6.8 Hz, 1H), 3.80-3.65 (m, 1H), 3.19-2.97 (m, 2H), 2.07 - 1.96 (m, 1 H), 1.58 - 1.37 (m, 3H), 1.06 (d, J = 2.0 Hz, 3H), 1.02 (d, J = 1.7 Hz, 9H). Example 391:

(R)-1 -(6-(N-(5-chloro-6-(2-cyclobutylphenyl)pyridin-2-yl)sulfamoy l)pyridin-2-yl)-3- methylpiperidine-3-carboxylic acid LCMS conditions 7: 1.670 min; MS for C27H30CIN4O4S [M+H] ⁺ m/z= 541.06, found m/z= 541.10. ¹ H NMR (400 MHz, DMSO-c/ ₆ ) δ 12.36 (s, 1H), 11.13 (s, 1H), 7.89 (d, J = 8.8 Hz, 1H), 7.67 (dd, J = 8.7, 7.3 Hz, 1H), 7.41 -7.33 (m, 2H), 7.31 (d, J = 7.6 Hz, 1 H), 7.26 - 7.21 (m, 1 H), 7.09 (t, 2H), 7.04 (d, J = 7.5 Hz, 1 H), 3.97 - 3.55 (m, 2H), 3.28 - 2.96 (m, 3H), 2.06 - 1.93 (m, 1 H), 1.93 - 1.36 (m, 9H), 1.05 (s, 3H).

Example 392:

(R)-1-(6-(N-(5-chloro-6-(2-isopropylphenyl)pyridin-2-yl)s ulfamoyl)pyridin-2-yl)-3- methylpiperidine-3-carboxylic acid LCMS conditions 7: 1.638 min; MS for C26H30CIN4O4S [M+H] ⁺ m/z= 529.05, found m/z= 529.15. ¹ H NMR (400 MHz, DMSO-c/ ₆ ) δ 12.31 (s, 1H),

11.12 (s, 1H), 7.93 (d, J = 8.8 Hz, 1H), 7.65 (dd, J = 8.7, 7.3 Hz, 1H), 7.45 (d, J= 8.7 Hz,

1 H), 7.40 - 7.37 (m, 2H), 7.26 - 7.19 (m, 1 H), 7.08 (dd, J = 8.0, 5.1 Hz, 2H), 7.00 (d, J = 7.5 Hz, 1H), 3.88 (d, J= 12.7 Hz, 1H), 3.66 (s, 1H), 3.19-2.95 (m, 2H), 2.06-1.94 (m, 1H), 1.57- 1.35 (m, 3H), 1.32-1.19 (m, 1H), 1.04 (s, 6H), 0.95 (s, 3H).

Example 393:

(R)-1 -(6-(N-(5-chloro-6-(2-ethylphenyl)pyridin-2-yl)sulfamoyl)pyr idin-2-yl)-3- methylpiperidine-3-carboxylic acid LCMS conditions 7: 1.609 min; MS for C25H28CIN4O4S [M+H] ⁺ m/z= 515.02, found m/z= 515.20. ¹ H NMR (400 MHz, DMSO-c/ ₆ ) δ 12.31 (s, 1H),

11.13 (s, 1H), 7.93 (d, 1H), 7.68-7.62 (m, 1H), 7.41 (d, 1H), 7.38-7.32 (m, 1H), 7.31 - 7.20 (m, 2H), 7.11 -7.03 (m, 3H), 3.88 (d, J= 13.1 Hz, 1H), 3.68 (d, J= 11.5 Hz, 1H), 3.13 (d, J= 13.1 Hz, 1H), 3.04 (s, 1H), 2.20 (s, 2H), 2.00 (q, J = 6.4 Hz, 1H), 1.44 (dq, J = 28.0, 9.3 Hz, 3H), 1.04 (s, 3H), 0.91 - 0.80 (m, 3H).

Example 394:

(R)-1 -(6-(N-(6-(2-ethylphenyl)-5-(trifluoromethyl)pyridin-2-yl)su lfamoyl)pyridin-2-yl)-3- methylpiperidine-3-carboxylic acid LCMS conditions 7: 1.82 min, MS for C26H28F3N4O4S [M+H] ⁺ m/z = 549.2, found m/z = 549.1. Rotomers/atropisomers are present in the NMR spectra. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 12.34 (s, 1H), 11.52 (s, 1H), 8.18 (d, J = 8.9 Hz, 1 H), 7.65 (ddd, J = 1.9, 7.1 , 9.0 Hz, 1 H), 7.56 (s, 1 H), 7.37 (td, J = 1.4, 7.5 Hz, 1 H), 7.28 (d, J = 7.6 Hz, 1H), 7.22 (td, J = 1.3, 7.4 Hz, 1H), 7.13-6.98 (m, 3H), 3.87 (t, J = 12.7 Hz, 1H), 3.63 (m, 1H), 3.14 (m, 1H), 3.07-2.90 (m, 1H), 2.18 (m, 1H), 2.06 (m, 1H), 1.44-1.32 (m, 2H), 1.01 (m, 3H), 0.88 (m, 5H). ¹⁹ F NMR (376 MHz, DMSO-d ₆ ) δ -56.61 (s, 1 F). Example 395:

rac-(1RS,3RS,4SR)-3-((6-(N-(6-(o-tolyl)-5-(trifluoromethy l)pyridin-2- yl)sulfamoyl)pyridin-2-yl)amino)-7-oxabicyclo[2.2.1]heptane- 1 -carboxylic acid LCMS conditions 7: 1.64 min, MS for C25H24F3N4O5S [M+H] ⁺ m/z = 549.1 , found m/z = 549.1. ¹ H NMR (400 MHz, Methanol-d ₄ ) δ 8.07 (d, J = 8.9 Hz, 1 H), 7.57 - 7.42 (m, 2H), 7.32 - 7.28 (m, 1H), 7.25-7.13 (m, 3H), 7.06 (s, 1H), 6.68-6.59 (m, 1H), 4.24 (d, J = 34.0 Hz, 1H), 3.98 (s, 1H), 2.25 (dd, J = 12.9, 7.9 Hz, 1H), 1.97- 1.85 (m, 3H), 1.85- 1.67 (m, 3H), 1.61 (d, J = 9.0 Hz, 2H). Example 396:

(R)-1 -(6-(N-(6-(2-isobutoxyphenyl)-5-(trifluoromethyl)pyridin-2-y l)sulfamoyl)pyridin-2- yl)-3-methylpiperidine-3-carboxylic acid LCMS conditions 7: 1.89 min, MS for

C28H32F3N4O5S [M+H] ⁺ m/z = 593.2, found m/z = 593.1. Rotomers/atropisomers are present in the NMR spectra. ¹ H NMR (400 MHz, Chloroform-d) δ 10.44 (s, 1H), 8.03 (d, J = 8.9 Hz, 1 H), 7.81 (d, J = 8.8 Hz, 1 H), 7.48 (dd, J = 7.2, 8.7 Hz, 1 H), 7.42 - 7.33 (m, 1 H), 7.09 (dd, J = 4.3, 8.0 Hz, 2H), 6.96 (td, J = 0.9, 7.5 Hz, 1 H), 6.91 - 6.85 (m, 1 H), 6.78 (d, J = 8.7 Hz, 1H), 4.74 (d, J = 13.4 Hz, 1H), 3.87 (d, J = 13.5 Hz, 1H), 3.66-3.53 (m, 2H), 2.97 (t, J = 12.6 Hz, 1H), 2.77 (d, J = 13.5 Hz, 1H), 2.07 (q, J = 3.6, 5.7 Hz, 1H), 1.80-1.62 (m, 2H), 1.51 (dq, J = 3.6, 14.0 Hz, 1H), 1.40-1.31 (m, 2H), 1.17 (s, 3H), 0.80 (d, J = 6.7 Hz, 1H), 0.70 - 0.53 (br. m, 6H). ¹⁹ F NMR (376 MHz, Chloroform-d) δ -59.20 (s, 1 F).

Example 397:

1-(6-(N-(5-chloro-6-(2-isobutoxyphenyl)pyridin-2-yl)sulfamoy l)pyridin-2-yl)-4- methylpiperidine-4-carboxylic acid LCMS conditions 7: 1.84 min, MS for C27H32CIN4O5S [M+H] ⁺ m/z = 559.2, found m/z = 559.1. ¹ H NMR (400 MHz, Chloroform-d) δ 7.69 (d, J = 8.9 Hz, 1 H), 7.57 (dd, J = 7.3, 8.7 Hz, 1 H), 7.53 (d, J = 8.9 Hz, 1 H), 7.37 (td, J = 1.7, 8.1 Hz, 1 H), 7.29 (d, J = 7.0 Hz, 1H), 7.13 (dd, J = 1.7, 7.4 Hz, 1H), 6.94 (t, J = 7.5 Hz, 2H), 6.73 (d, J = 8.7 Hz, 1H), 3.97 (d, J = 13.6 Hz, 2H), 3.67 (d, J = 6.4 Hz, 2H), 2.88 (ddd, J = 2.3, 11.4, 13.6 Hz, 2H), 2.03 (d, J = 13.5 Hz, 2H), 1.90 (dh, J = 6.7, 13.2 Hz, 1H), 1.39- 1.28 (m, 3H), 1.20 (s, 3H), 0.81 (d, J = 6.7 Hz, 6H).

Example 398:

4-methyl-1 -(6-(N-(6-(2-propylphenyl)-5-(trifluoromethyl)pyridin-2-yl)s ulfamoyl)pyridin-2- yl)piperidine-4-carboxylic acid LCMS conditions 7: 1.83 min, MS for C27H30F3N4O4S

[M+H] ⁺ m/z = 563.2, found m/z = 563.1. Rotomers/atropisomers are present in the NMR spectra. ¹ H NMR (400 MHz, Chloroform-d) δ 10.34 (br. s, 1H), 7.90 (d, J = 9.0 Hz, 1H), 7.60 (d, J = 8.9 Hz, 1H), 7.51 (dd, J = 7.3, 8.7 Hz, 1H), 7.28 (ddd, J = 1.4, 6.2, 7.5 Hz, 1H), 7.22 (d, J = 7.2 Hz, 1 H), 7.12 - 7.06 (m, 2H), 6.98 (d, J = 7.6 Hz, 1 H), 6.67 (d, J = 8.7 Hz, 1 H), 6.62 (d, J = 8.8 Hz, 1 H), 3.99 - 3.62 (m, 2H), 2.89 - 2.69 (m, 2H), 2.31 - 2.03 (m, 2H), 2.01 - 1.81 (m, 3H), 1.35 (ddt, J = 4.2, 7.4, 11.7 Hz, 2H), 1.28 - 1.22 (m, 2H), 0.85 - 0.74 (m, 2H), 0.66 (t, J = 7.3 Hz, 3H). ¹⁹ F NMR (376 MHz, Chloroform-d) δ -58.29 (br. s, 1F).

Example 399:

1-(6-(N-(6-(2-chlorophenyl)-5-(trifluoromethyl)pyridin-2-yl) sulfamoyl)pyridin-2-yl)-3- methylpiperidine-3-carboxylic acid LCMS conditions 7: 1.78 min, MS for C24H23CIF3N4O4S [M+H] ⁺ m/z = 555.1 , found m/z = 555.1. Rotomers/atropisomers are present in the NMR spectra. ¹ H NMR (500 MHz, Chloroform-d) δ 10.42 (br. s, 1H), 8.10 (m, 1H), 7.90-7.82 (m, 1 H), 7.55 - 7.36 (m, 3H), 7.35 - 7.30 (m, 1 H), 7.23 (m, 1 H), 7.01 (m, 1 H), 6.80 (d, J = 8.7 Hz, 1H), 4.89 (m, 1H), 3.93 (m, 1H), 3.14-2.97 (m, 1H), 2.85-2.72 (m, 1H), 2.07 (s, 1H), 2.02 - 1.88 (m, 1 H), 1.82 - 1.68 (m, 1 H), 1.48 - 1.32 (m, 2H), 1.19 (d, J = 3.9 Hz, 3H). ¹⁹ F NMR (471 MHz, Chloroform-d) δ -59.08 (s, 0.53F), -59.27 (s, 1F).

Example 400:

1-(6-(N-(5-chloro-6-(2-isobutoxyphenyl)pyridin-2-yl)sulfamoy l)pyridin-2-yl)-3- methylpiperidine-3-carboxylic acid LCMS conditions 7: 1.87 min, MS for C27H32CIN4O5S [M+H] ⁺ m/z = 559.2, found m/z = 559.1. Rotomers/atropisomers are present in the NMR spectra. ¹ H NMR (500 MHz, Chloroform-d) δ 7.79 (d, J = 8.7 Hz, 1 H), 7.64 (d, J = 8.7 Hz, 1H), 7.45 (dd, J = 7.2, 8.7 Hz, 1H), 7.38 (ddd, J = 1.8, 7.4, 8.3 Hz, 1H), 7.02 (d, J = 6.9 Hz, 1H), 6.96 (t, J = 7.5 Hz, 2H), 6.92 (d, J = 8.2 Hz, 1H), 6.76 (d, J = 8.7 Hz, 1H), 5.04 (d, J = 13.5 Hz, 1H), 3.93 (d, J = 12.3 Hz, 1H), 3.71 -3.57 (m, 2H), 3.07 (td, J = 2.8, 13.3 Hz, 1H), 2.75 (d, J = 13.6 Hz, 1 H), 2.05 (d, J = 15.8 Hz, 1 H), 1.95 - 1.76 (m, 2H), 1.50 (ddt, J = 2.6, 4.7, 10.5 Hz, 1H), 1.39 (td, J = 4.8, 13.2 Hz, 1H), 1.32 (d, J = 6.3 Hz, 1H), 1.19 (s, 3H), 0.79 (dd, J = 6.7, 10.8 Hz, 6H).

Example 401:

3-methyl-1 -(6-(N-(6-(2-propylphenyl)-5-(trifluoromethyl)pyridin-2-yl)s ulfamoyl)pyridin-2- yl)piperidine-3-carboxylic acid LCMS conditions 7: 1.87 min, MS for C27H30F3N4O4S

[M+H] ⁺ m/z = 563.2, found m/z = 563.1. Rotomers/atropisomers are present in the NMR spectra. ¹ H NMR (500 MHz, Chloroform-d) δ 11.39 - 8.91 (br. s, 1 H), 8.09 (m, 1 H), 7.80 (t, J = 8.8 Hz, 1H), 7.54-7.44 (m, 1H), 7.36 (t, J = 7.5 Hz, 1H), 7.25-7.13 (m, 3H), 7.12-7.05 (m, 1 H), 7.01 (t, J = 6.7 Hz, 1 H), 6.79 (dd, J = 8.6, 4.8 Hz, 1 H), 4.90 - 4.76 (m, 1 H), 3.97 - 3.83 (m, 1H), 3.12-2.95 (m, 1H), 2.84-2.74 (m, 1H), 2.41 -2.14 (m, 1H), 2.07- 1.98 (m, 1H), 1.95 (t, J = 7.9 Hz, 1H), 1.77 (m, 2H), 1.47 (dt, J = 14.8, 6.6 Hz, 3H), 1.20- 1.13 (m, 3H), 0.74 (m, 3H). ¹⁹ F NMR (471 MHz, Chloroform-d) δ -58.56 (s, 1F), -58.50 (s, 1.13F). Example 402:

1-(6-(N-(6-(2-cyclopropylphenyl)-5-(trifluoromethyl)pyridin- 2-yl)sulfamoyl)pyridin-2-yl)- 3-methylpiperidine-3-carboxylic acid LCMS conditions 7: 1.84 min, MS for C27H28F3N4O4S [M+H] ⁺ m/z = 561.2, found m/z = 561.1. Rotomers/atropisomers are present in the NMR spectra. ¹ H NMR (500 MHz, Chloroform-d) δ 10.17 (s, 1H), 8.09 (m, 1H), 7.80 (d, J = 8.6 Hz, 1H), 7.54-7.39 (m, 1H), 7.37-7.31 (m, 1H), 7.18 (m, 1H), 7.13-7.02 (m, 2H), 6.97 (t, J = 7.9 Hz, 2H), 6.79 (dd, J = 8.7, 3.2 Hz, 1 H), 4.78 (m, 1 H), 3.90 (m, 1 H), 3.11 - 2.94 (m, 1 H), 2.79 (d, J = 13.5 Hz, 1H), 2.00 (d, J = 14.7 Hz, 1H), 1.89- 1.65 (m, 1H), 1.56-1.46 (m, 1H), 1.42- 1.35 (m, 1H), 1.17 (d, J = 2.2 Hz, 3H), 1.03 (m, 1H), 0.81 -0.56 (m, 2H), 0.49-0.31 (m, 2H). ¹⁹ F NMR (471 MHz, Chloroform-d) δ -58.41 (s, 1F), -58.70 (s, 1.24F).

Example 403:

rac-(1RS,3RS,4SR)-3-((6-(N-(6-(2-isopropylphenyl)-5-(trif luoromethyl)pyridin-2- yl)sulfamoyl)pyridin-2-yl)amino)-7-oxabicyclo[2.2.1]heptane- 1-carboxylic acid LCMS conditions 7: 1.67 min, MS for C27H28F3N4O5S [M+H] ⁺ m/z = 577.2, found m/z = 577.1. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 11.42 (s, 1 H), 8.23 (dd, J = 9.0, 1.2 Hz, 1 H), 7.62 - 7.47 (m, 2H), 7.42 - 7.30 (m, 3H), 7.23 - 7.10 (m, 1 H), 7.07 - 6.90 (m, 2H), 6.71 - 6.68 (m, 1 H), 4.13 - 4.00 (m, 1 H), 3.73 - 3.62 (m, 1 H), 2.39 - 2.23 (m, 1 H), 2.08 - 2.02 (m, 1 H), 1.71 - 1.41 (m, 4H), 1.30 - 1.22 (m, 1 H), 1.03 - 0.99 (m, 3H), 0.93 - 0.84 (m, 3H).

Example 404:

rac-(1SR,5RS,6RS,7SR)-5-propyl-2-(6-(N-(6-(o-tolyl)-5-(tr ifluoromethyl)pyridin-2- yl)sulfamoyl)pyridin-2-yl)-2-azabicyclo[4.2.0]octane-7-carbo xylic acid LCMS conditions 7: 1.85 min, MS for C29H32F3N4O4S [M+H] ⁺ m/z = 589.2, found m/z = 589.1. ¹ H NMR (400

MHz, DMSO-d ₆ ) δ 12.30 (s, 1 H), 11.53 (s, 1 H), 8.21 (d, J = 8.9 Hz, 1 H), 7.69 (dd, J = 8.7, 7.3 Hz, 1H), 7.58 (d, J = 8.8 Hz, 1H), 7.33 - 7.29 (m, 1H), 7.26 - 7.17 (m, 2H), 7.14 (d, J = 7.3 Hz, 1 H), 7.05 (d, J = 7.6 Hz, 1 H), 6.78 (d, J = 8.7 Hz, 1 H), 4.53 - 4.35 (m, 1 H), 3.62 - 3.58 (m, 1H), 2.84 (d, J = 13.7 Hz, 1H), 2.71 -2.59 (m, 1H), 2.39-2.33 (m, 2H), 2.14-2.01 (m, 1H), 1.78- 1.73 (m, 3H), 1.59 (s, 1H), 1.44- 1.26 (m, 3H), 1.24- 1.13 (m, 2H), 1.05-1.01 (m, 1H), 0.88- 0.80 (m, 3H).

Example 405:

(R)-1 -(6-(N-(6-(2-cyclopropylphenyl)pyridin-2-yl)sulfamoyl)pyridi n-2-yl)-3- methylpiperidine-3-carboxylic acid conditions 7: 1.491 min; MS for C26H29N4O4S [M+H] ⁺ m/z= 493.59, found m/z= 493.20. ¹ H NMR (400 MHz, DMSO-c/ ₆ ) δ 12.44 (s, 1H), 11.05 (s, 1H), 7.79-7.73 (m, 1H), 7.69-7.63 (m, 1H), 7.37-7.25 (m, 2H), 7.19 (t, J = 6.9 Hz, 1H), 7.16-7.07 (m, 3H), 7.05 (d, J= 8.7 Hz, 1H), 6.98 (d, J= 7.7 Hz, 1H), 3.85 (d, J= 13.1 Hz, 1H), 3.74-3.63 (m, 1H), 3.17 (d, J= 13.1 Hz, 1H), 3.13-3.02 (m, 1H), 2.02- 1.89 (m, 3H), 1.55 - 1.34 (m, 2H), 1.01 (s, 3H), 0.74 - 0.66 (m, 2H), 0.58 - 0.50 (m, 2H). Example 406:

(R)-1 -(6-(N-(6-(2-cyclopropylphenyl)-5-methylpyridin-2-yl)sulfamo yl)pyridin-2-yl)-3- methylpiperidine-3-carboxylic acid LCMS conditions 7: 1.514 min; MS for C27H ₃₁ N ₄ 0 ₄ S [M+H] ⁺ m/z= 507.62, found m/z= 507.20. ¹ H NMR (400 MHz, DMSO-c/ ₆ ) δ 7.68 - 7.60 (m, 2H), 7.52-7.38 (m, 1H), 7.30 (t, J = 7.3 Hz, 1H), 7.19 (t, J = 7.0 Hz, 1H), 7.07 (d, J = 7.2 Hz, 1 H), 7.06 - 6.97 (m, 2H), 6.92 (d, J = 7.7 Hz, 1 H), 3.85 (d, J = 13.1 Hz, 1 H), 3.72 - 3.63 (m, 1H), 3.15 (d, J= 13.1 Hz, 1H), 3.07 (d, J = 6.1 Hz, 1H), 1.99 (d, J = 4.6 Hz, 1H), 1.95 (s, 3H), 1.44 (dd, J = 31.5, 11.8 Hz, 4H), 1.02 (s, 3H), 0.73 - 0.43 (m, 4H).

Example 407:

(R)-1-(6-(N-(5-cyclopropyl-6-(2-cyclopropylphenyl)pyridin -2-yl)sulfamoyl)pyridin-2-yl)- 3-methylpiperidine-3-carboxylic acid LCMS conditions 7: 1.576 min; MS for C29H33N4O4S [M+H] ⁺ m/z= 533.65, found m/z= 533.20. ¹ H NMR (400 MHz, DMSO-c/ ₆ ) δ 7.64 (dd, J= 8.7, 7.3 Hz, 1H), 7.52-7.34 (m, 1H), 7.33-7.24 (m, 2H), 7.19 (t, J = 7.4 Hz, 1H), 7.12-6.98 (m, 3H), 6.92 (d, J = 7.9 Hz, 1H), 3.86 (d, J= 12.9 Hz, 1H), 3.70-3.59 (m, 1H), 3.13 (d, J = 12.9 Hz, 1H), 3.08-2.96 (m, 1 H), 2.03 - 1.92 (m, 1H), 1.53 - 1.33 (m, 5H), 1.02 (s,3H), 0.81 -0.44 (m, 8H).

Example 408:

(R)-1 -(6-(N-(6-(2-cyclopropylphenyl)-5-methoxypyridin-2-yl)sulfam oyl)pyridin-2-yl)-3- methylpiperidine-3-carboxylic acid LCMS conditions 7: 1.516 min; MS for C27H ₃₁ N ₄ 0 ₅ S [M+H] ⁺ m/z= 523.62, found m/z= 523.20. ¹ H NMR (400 MHz, DMSO-c/ ₆ ) δ 12.35 (s, 1H), 10.57 (s, 1 H), 7.64 (dd, J = 8.7, 7.3 Hz, 1 H), 7.52 (d, J = 9.0 Hz, 1 H), 7.37 (d, J = 8.9 Hz, 1H), 7.24 (td, J = 7.6, 1.4 Hz, 1H), 7.13 (td, J = 7.4, 1.2 Hz, 1 H), 7.08 - 7.02 (m, 2H), 6.98 (dd, J = 7.6, 1.3 Hz, 1 H), 6.88 (d, J = 7.7 Hz, 1 H), 3.89 - 3.81 (m, 1 H), 3.71 - 3.63 (m, 4H), 3.14 (d, J= 13.1 Hz, 1H), 3.08-3.00 (m, 1H), 2.02-1.92 (m, 1H), 1.54-1.34 (m, 4H), 1.03 (s, 3H), 0.63 - 0.54 (m, 2H), 0.50 - 0.41 (m, 2H).

Example 409:

(R)-3-methyl-1 -(6-(N-(5-methyl-6-(o-tolyl)pyridin-2-yl)sulfamoyl)pyridin-2 -yl)piperidine- 3-carboxylic acid LCMS conditions 7: 1.456 min; MS for C25H29N4O4S [M+H] ⁺ m/z= 481.58, found m/z= 481.20. ¹ H NMR (400 MHz, DMSO-c/ ₆ ) δ 7.67 - 7.59 (m, 2H), 7.40 (s, 1 H), 7.33 - 7.19 (m, 3H), 7.09-6.98 (m, 3H), 3.85 (d, J= 13.1 Hz, 1H), 3.72-3.62 (m, 1H), 3.15 (d, J = 13.1 Hz, 1H), 3.11 -3.01 (m, 1H), 2.02- 1.95 (m, 1H), 1.90 (s, 6H), 1.55- 1.34 (m, 3H), 1.02 (s, 3H).

Example 410:

(R)-1-(6-(N-(5-methoxy-6-(o-tolyl)pyridin-2-yl)sulfamoyl) pyridin-2-yl)-3- methylpiperidine-3-carboxylic acid LCMS conditions 7: 1.471 min; MS for C25H29N4O5S [M+H] ⁺ m/z= 497.58, found m/z= 497.20. ¹ H NMR (400 MHz, DMSO-c/ ₆ ) δ 12.35 (s, 1H), 10.56 (s, 1 H), 7.68 - 7.62 (m, 1 H), 7.53 (d, J = 9.0 Hz, 1H), 7.36 (d, J = 8.9 Hz, 1 H), 7.28 - 7.15 (m, 3H), 7.08-7.01 (m, 3H), 3.87 (d, J= 13.2 Hz, 1H), 3.73-3.65 (m, 4H), 3.14 (d, J = 13.1 Hz, 1H), 3.08-3.00 (m, 1 H), 2.04 - 1.90 (m, 4H), 1.55 - 1.35 (m, 3H), 1.04 (s,3H).

Example 411:

(R)-1 -(6-(N-(5-cyclopropyl-6-(o-tolyl)pyridin-2-yl)sulfamoyl)pyri din-2-yl)-3- methylpiperidine-3-carboxylic acid LCMS conditions 7: 1.526 min; MS for C ₂₇ H ₃₁ N ₄ 0 ₄ S [M+H] ⁺ m/z= 507.62, found m/z= 507.20. ¹ H NMR (400 MHz, DMSO-c/ ₆ ) δ 12.41 (s, 1H),

10.91 (s, 1H), 7.66-7.60 (m, 1H), 7.44-7.33 (m, 1H), 7.33-7.19 (m, 4H), 7.15-7.08 (m, 1H), 7.08-6.99 (m, 2H), 3.86 (d, J= 13.1 Hz, 1H), 3.71 -3.60 (m, 1H), 3.14 (d, J= 13.1 Hz, 1 H), 3.08 - 2.98 (m, 1 H), 2.05 - 1.89 (m, 4H), 1.54 - 1.32 (m, 4H), 1.02 (s, 3H), 0.78 - 0.69 (m, 2H), 0.61 -0.53 (m, 2H).

Example 412:

(R)-3-methyl-1 -(6-(N-(6-(o-tolyl)pyridin-2-yl)sulfamoyl)pyridin-2-yl)piper idine-3- carboxylic acid LCMS conditions 7: 1.447 min; MS for C24H27N4O4S [M+H] ⁺ m/z= 466.55, found m/z= 467.20. ¹ H NMR (400 MHz, DMSO-c/ ₆ ) δ 12.41 (s, 1H), 11.10 (s, 1H), 7.78-7.72 (m, 1 H), 7.66 (dd, J = 8.7, 7.3 Hz, 1 H), 7.35 - 7.15 (m, 5H), 7.11 (dd, J = 7.2, 3.2 Hz, 1 H),

7.08-6.99 (m, 2H), 3.85 (d, J= 13.1 Hz, 1H), 3.72-3.63 (m, 1H), 3.16 (d, J= 13.1 Hz, 1H), 3.11 -3.01 (m, 1H), 2.18-2.10 (m, 3H), 2.02-1.91 (m, 1H), 1.53- 1.33 (m, 3H), 1.00 (s, 3H). Example 413:

(R)-1 -(6-(N-(6-(2-cyclopropylphenyl)-5-(trifluoromethyl)pyridin-2 -yl)sulfamoyl)pyridin-2- yl)-3-methylpiperidine-3-carboxylic acid LCMS conditions 7: 1.77 min, MS for

C ₂₇ H ₂₈ F ₃ N ₄ 0 ₄ S [M+H] ⁺ m/z = 561.2, found m/z = 561.1. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 12.33 (s, 1H), 11.53 (s, 1H), 8.18 (d, J = 8.9 Hz, 1H), 7.66 (t, J = 8.1 Hz, 1H), 7.62 (d, J = 6.3 Hz, 1H), 7.32 (t, J = 7.7 Hz, 1H), 7.18 (t, J = 7.5 Hz, 1H), 7.12-7.07 (m, 2H), 7.03 (s, 1H), 6.93 (d, J = 7.9 Hz, 1H), 3.88 (d, J = 13.3 Hz, 1H), 3.75-3.56 (m, 1H), 3.17-3.06 (m, 1H), 3.06 - 2.91 (m, 1 H), 1.99 (d, J = 6.7 Hz, 1 H), 1.55 - 1.33 (m, 3H), 1.29 (d, J = 7.2 Hz, 1 H), 1.01 (d, J = 5.7 Hz, 3H), 0.75 - 0.50 (m, 3H), 0.38 (d, J = 17.7 Hz, 1 H). ¹⁹ F NMR (376 MHz, DMSO-d ₆ ) δ -56.78 (s, 1F).

Example 414:

1-(6-(N-(6-(2-chloro-5-methoxyphenyl)-5-(trifluoromethyl) pyridin-2-yl)sulfamoyl)pyridin- 2-yl)-3-methylpiperidine-3-carboxylic acid LCMS conditions 7: 1.73 min, MS for

C25H25CIF3N4O5S [M+H] ⁺ m/z = 585.1 , found m/z = 585.1. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 12.33 (s, 1H), 11.62 (s, 1H), 8.20 (dd, J = 1.7, 8.9 Hz, 1H), 7.73-7.62 (m, 2H), 7.42 (dd, J = 1.8, 8.9 Hz, 1 H), 7.11 (dd, J = 2.0, 7.3 Hz, 2H), 7.05 (dd, J = 3.0, 8.9 Hz, 2H), 6.85 (dd, J = 2.6, 6.4 Hz, 1H), 3.88 (d, J = 13.0 Hz, 1H), 3.64 (d, J = 12.9 Hz, 1H), 3.11 (dd, J = 9.1, 13.1 Hz, 1 H), 3.07 - 2.94 (m, 1 H), 1.99 (s, 2H), 1.56 - 1.33 (m, 3H), 1.27 (d, J = 8.5 Hz, 1 H), 1.01 (d, J = 5.1 Hz, 3H). ¹⁹ F NMR (376 MHz, DMSO-d ₆ ) δ -57.48 (s, 1F).

Example 415:

(3R)-3-methyl-1-(6-{[6-(2-methylphenyl)-5-(trifluoromethy l)pyridin-2- yl]sulfamoyl}pyridin-2-yl)piperidine-3-carboxylic acid LCMS conditions 7: 1.759 min; MS for C25H26F3N4O4S [M+H] ⁺ m/z = 535.16, found m/z = 535.20. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 12.33 (s, 1H), 11.53 (s, 1H), 8.17 (d, J = 8.9 Hz, 1H), 7.64 (dd, J = 8.7, 7.2 Hz, 1H), 7.60- 7.44 (m, 1H), 7.35 - 7.27 (m, 1H), 7.27 - 7.16 (m, 2H), 7.11 - 6.99 (m, 3H), 3.87 (d, J = 13.2 Hz, 1 H), 3.71 - 3.59 (m, 1 H), 3.18 - 3.08 (m, 1 H), 3.08 - 2.90 (m, 1 H), 1.99 (d, J = 11.0 Hz, 1 H), 1.80 (d, J = 10.1 Hz, 3H), 1.52 - 1.32 (m, 3H), 1.04 - 0.97 (m, 3H).

Example 416:

(3R)-1 -(6-{[6-(5-fluoro-2-methylphenyl)-5-(trifluoromethyl)pyridin -2- yl]sulfamoyl}pyridin-2-yl)-3-methylpiperidine-3-carboxylic acid LCMS conditions 7:

1.769 min; MS for C25H25F4N4O4S [M+H] ⁺ m/z = 553.15, found m/z = 553.20. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 12.32 (s, 1H), 11.59 (s, 1H), 8.19 (d, J = 8.9 Hz, 1H), 7.64 (dd, J = 8.8, 7.2 Hz, 1H), 7.59- 7.49 (m, 1H), 7.31 -7.22 (m, 1 H), 7.20 - 7.13 (m, 1H), 7.11 -7.02 (m, 2H), 7.00-6.89 (m, 1H), 3.87 (d, J = 13.1 Hz, 1H), 3.73- 3.58 (m, 1H), 3.18-3.09 (m, 1H), 3.09- 2.96 (m, 1 H), 2.05 - 1.92 (m, 1 H), 1.75 (d, J = 9.7 Hz, 3H), 1.51 - 1.31 (m, 3H), 1.00 (d, J = 5.1 Hz, 3H).

Example 417:

(3R)-1 -(6-{[6-(3-fluoro-2-methylphenyl)-5-(trifluoromethyl)pyridin -2- yl]sulfamoyl}pyridin-2-yl)-3-methylpiperidine-3-carboxylic acid LCMS conditions 7:

1.770 min; MS for C25H25F4N4O4S [M+H] ⁺ m/z = 553.15, found m/z = 553.20. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 12.29 (s, 1H), 11.59 (s, 1H), 8.19 (d, J = 8.9 Hz, 1H), 7.65 (dd, J = 8.7, 7.2 Hz, 1H), 7.60-7.46 (m, 1 H), 7.32 - 7.17 (m, 2H), 7.13 - 7.01 (m, 2H), 6.99 - 6.83 (m, 1H), 3.86 (d, J = 13.1 Hz, 1H), 3.72-3.57 (m, 1H), 3.19-3.08 (m, 1H), 3.08-2.94 (m, 1H), 2.05- 1.90 (m, 1 H), 1.74 - 1.61 (m, 3H), 1.52 - 1.32 (m, 3H), 1.00 (d, J = 8.0 Hz, 3H). Example 418:

(1S,3S)-3-((6-(N-(6-(2-isopropylphenyl)-5-(trifluoromethyl)p yridin-2- yl)sulfamoyl)pyridin-2-yl)amino)cyclohexanecarboxylic acid LCMS conditions 7: 1.76 min, MS for C27H30F3N4O4S [M+H] ⁺ m/z = 563.2, found m/z = 563.1. ¹ H NMR (400 MHz, Chloroform-d) δ 7.98 (d, J = 9.0 Hz, 1 H), 7.63 (s, 1 H), 7.58 - 7.48 (m, 1 H), 7.43 (dt, J = 7.2, 12.2 Hz, 2H), 7.33-7.29 (m, 1H), 7.25-7.17 (m, 1H), 7.08 (dd, J = 7.8, 11.5 Hz, 1H), 6.61 -6.48 (m, 1H), 4.56 (s, 1H), 3.85-3.67 (m, 1H), 2.77-2.17 (m, 3H), 1.89 (s, 2H), 1.78 (s, 3H), 1.41 (s, 3H), 1.17-1.06 (m, 6H). ¹⁹ F NMR (376 MHz, Chloroform-d) δ -58.34 (s, 1F).

Example 419:

5-(6-(N-(6-(o-tolyl)-5-(trifluoromethyl)pyridin-2-yl)sulf amoyl)pyridin-2-yl)-5- azaspiro[2.4]heptane-1-carboxylic acid LCMS conditions 7: 1.531 min; MS for

C25H24F3N4O4S [M+H] ⁺ m/z= 533.54, found m/z= 533.10. ¹ H NMR (400 MHz, DMSO-c/ ₆ ) δ 12.27 (s, 1H), 11.54 (s, 1H), 8.23-8.14 (m, 1H), 7.70-7.53 (m, 2H), 7.32 (t, J= 7.5 Hz, 1H), 7.27-7.17 (m, 2H), 7.12-7.03 (m, 2H), 6.69-6.62 (m, 1H), 3.42-3.34 (m, 2H), 2.06 - 1.97 (m, 1 H), 1.90 - 1.70 (m, 5H), 1.30 - 1.04 (m, 4H).

Example 420:

5-(6-(N-(6-(2-cyclopropylphenyl)-5-(trifluoromethyl)pyridin- 2-yl)sulfamoyl)pyridin-2-yl)- 5-azaspiro[2.4]heptane-1-carboxylic acid LCMS conditions 7: 1.571 min; MS for

C27H26F3N4O4S [M+H] ⁺ m/z= 559.57, found m/z= 559.20. ¹ H NMR (400 MHz, Chloroform-d) δ 10.81 (s, 1H), 8.06-7.91 (m, 1H), 7.85 - 7.29 (m, 3H), 7.26 - 6.91 (m, 4H), 6.51 -6.11 (m, 1H), 3.76-3.56 (m, 1H), 3.54-3.09 (m, 3H), 2.23- 1.53 (m, 3H), 1.53-1.14 (m, 3H), 0.94 -0.50 (m, 4H). Example 421:

(R)-1 -(6-(N-(6-(2-chlorophenyl)-5-(trifluoromethyl)pyridin-2-yl)s ulfamoyl)pyridin-2-yl)-3- methylpiperidine-3-carboxylic acid LCMS conditions 7: 1.70 min, MS for C24H23CIF3N4O4S [M+H] ⁺ m/z = 555.1 , found m/z = 555.0. Rotomers/atropisomers are present in the NMR spectra. ¹ H NMR (400 MHz, Chloroform-d) δ 9.80 (br. s, 1H), 8.10 (m, 1H), 7.87 (dd, J = 3.9, 8.7 Hz, 1 H), 7.58 - 7.30 (m, 4H), 7.26 - 7.04 (m, 1 H), 6.86 (dd, J = 7.9, 46.2 Hz, 2H), 4.89 (m, 1H), 3.93 (m, 1H), 3.03 (m, 1H), 2.77 (t, J = 12.8 Hz, 1H), 2.06 (d, J = 4.0 Hz, 1H), 2.02- 1 .88 (m, 1 H), 1 .44 - 1 .34 (m, 2H), 1 .18 (d, J = 3.4 Hz, 4H). ¹⁹ F NMR (376 MHz, Chloroform- d) δ -59.26 (s, 1 F), -59.07 (s, 1 .9F).

Example 422:

(R)-1 -(6-(N-(5-chloro-6-(2-isobutoxyphenyl)pyridin-2-yl)sulfamoyl )pyridin-2-yl)-3- methylpiperidine-3-carboxylic acid LCMS conditions 7: 1 .80 min, MS for C27H32CIN4O5S [M+H] ⁺ m/z = 559.2, found m/z = 559.1 . Rotomers/atropisomers are present in the NMR spectrum. ¹ H NMR (400 MHz, Chloroform-d) δ 7.80 (d, J = 8.7 Hz, 1 H), 7.64 (d, J = 8.7 Hz, 1 H), 7.45 (dd, J = 7.2, 8.7 Hz, 1 H), 7.38 (ddd, J = 1 .9, 7.4, 8.4 Hz, 1 H), 6.96 (m, 4H), 6.76 (d, J = 8.7 Hz, 1 H), 5.05 (m, 1 H), 3.93 (m, 1 H), 3.71 - 3.59 (m, 2H), 3.07 (m, 1 H), 2.74 (m, 1 H), 2.05 (m, 1 H), 1 .83 (m, 2H), 1 .54 - 1 .44 (m, 2H), 1 .43 - 1 .32 (m, 2H), 1 .21 (m, 1 H), 0.83 - 0.68 (m, 6H).

Example 423:

(R)-3-methyl-1 -(6-(N-(6-(2-propylphenyl)-5-(trifluoromethyl)pyridin-2- yl)sulfamoyl)pyridin-2-yl)piperidine-3-carboxylic acid LCMS conditions 7: 1 .80 min, MS for C27H30F3N4O4S [M+H] ⁺ m/z = 563.2, found m/z = 563.1 . Rotomers/atropisomers are present in the NMR spectra. ¹ H NMR (400 MHz, Chloroform-d) δ 10.2 (br. s, 1 H), 8.10 (m, 1 H), 7.99 - 7.76 (m, 1 H), 7.59 - 7.42 (m, 1 H), 7.36 (t, J = 7.6 Hz, 1 H), 7.24 - 7.12 (m, 2H), 7.08 (m, 1 H), 7.03 - 6.92 (m, 1 H), 6.83 - 6.69 (m, 1 H), 4.97 - 4.84 (m, 1 H), 4.00 - 3.80 (m, 1 H), 3.04 (m, 1 H), 2.86 - 2.71 (m, 1 H), 2.27 (m, 1 H), 2.09 - 1 .86 (m, 3H), 1 .80 (m, 2H), 1 .46 - 1 .31 (m, 3H), 1 .18 (d, J = 5.8 Hz, 3H), 0.74 (m, 3H). ¹⁹ F NMR (376 MHz, Chloroform-d) δ - 58.55 (s, 1 F), -58.60 (s, 1 F). Example 424:

(R)-1 -(6-(N-(6-(2-chloro-5-methoxyphenyl)-5-(trifluoromethyl)pyri din-2- yl)sulfamoyl)pyridin-2-yl)-3-methylpiperidine-3-carboxylic acid LCMS conditions 7: 1 .70 min, MS for C25H25CIF3N4O5S [M+H] ⁺ m/z = 585.1 , found m/z = 585.0.

Rotomers/atropisomers are present in the NMR spectra. ¹ H NMR (400 MHz, Chloroform-d) δ 9.8 (br. s, 1 H), 8.09 (m, 1 H), 7.87 (dd, J = 5.0, 8.7 Hz, 1 H), 7.58 - 7.37 (m, 1 H), 7.33 (d, J = 8.9 Hz, 1 H), 7.24 (d, J = 8.9 Hz, 1 H), 7.14 - 6.86 (m, 2H), 6.81 (dd, J = 4.6, 8.7 Hz, 1 H), 6.76 (d, J = 2.7 Hz, 1 H), 4.89 (m, 1 H), 3.94 (m, 1 H), 3.79 (d, J = 10.2 Hz, 3H), 3.15 - 2.92 (m, 1 H), 2.78 (t, J = 12.7 Hz, 1 H), 2.13 - 1 .89 (m, 2H), 1 .48 - 1 .33 (m, 2H), 1 .20 (d, J = 2.8 Hz, 3H). ¹⁹ F NMR (376 MHz, Chloroform-d) δ -59.07 (s, 1 F), -59.20 (s, 2F). Example 425:

(S)-3-methyl-1 -(6-(N-(6-(2-propylphenyl)-5-(trifluoromethyl)pyridin-2- yl)sulfamoyl)pyridin-2-yl)piperidine-3-carboxylic acid LCMS conditions 7: 1 .80 min, MS for C27H30F3N4O4S [M+H] ⁺ m/z = 563.2, found m/z = 563.1 . Rotomers/atropisomers are present in the NMR spectra. ¹ H NMR (400 MHz, Chloroform-d) δ 8.08 (m, 1 H), 7.88 - 7.76 (m, 1 H), 7.55 - 7.38 (m, 1 H), 7.39 - 7.31 (m, 1 H), 7.17 (m, 2H), 7.1 1 - 6.92 (m, 2H), 6.75 (m, 1 H), 4.82 (m, 1 H), 3.97 - 3.78 (m, 1 H), 3.13 - 2.89 (m, 1 H), 2.82 - 2.63 (m, 1 H), 2.42 - 2.10 (m, 1 H), 2.01 - 1 .86 (m, 2H), 1 .81 - 1 .61 (m, 1 H), 1 .54 - 1 .41 (m, 2H), 1 .38 - 1 .29 (m, 2H), 1 .15 (d, J = 5.2 Hz, 3H), 0.72 (m, 3H). ¹⁹ F NMR (376 MHz, Chloroform-d) δ -58.52 (s, 1 F), - 58.58 (s, 1 .1 F).

Example 426:

1 - (6-(N-(6-(5-chloro-2-methoxyphenyl)-5-(trifluoromethyl)pyrid in-2-yl)sulfamoyl)pyridin-

2- yl)-4-methylpiperidine-4-carboxylic acid LCMS conditions 7: 1 .69 min, MS for

C25H25CIF3N4O5S [M+H] ⁺ m/z = 585.1 , found m/z = 585.0. ¹ H NMR (400 MHz, Chloroform-d) δ 7.96 (d, J = 9.0 Hz, 1 H), 7.67 (d, J = 8.9 Hz, 1 H), 7.61 (dd, J = 7.3, 8.7 Hz, 1 H), 7.37 (dd, J = 2.6, 8.8 Hz, 1 H), 7.32 (d, J = 7.2 Hz, 1 H), 7.09 (d, J = 2.6 Hz, 1 H), 6.89 (d, J = 8.9 Hz, 1 H), 6.79 (d, J = 8.7 Hz, 1 H), 4.13 - 3.79 (m, 2H), 3.72 (s, 3H), 2.89 (q, J = 1 1 .1 , 1 1 .5 Hz, 2H), 2.03 (s, 2H), 1 .41 - 1 .31 (m, 3H), 1 .23 (s, 3H). ¹⁹ F NMR (376 MHz, Chloroform-d) δ -59.32 (s, 1 F).

Example 427:

1 -(6-(N-(6-(5-chloro-2-isopropoxyphenyl)-5-(trifluoromethyl)p yridin-2- yl)sulfamoyl)pyridin-2-yl)-4-methylpiperidine-4-carboxylic acid LCMS conditions 7: 1 .80 min, MS for C27H29CIF3N4O5S [M+H] ⁺ m/z = 613.1 , found m/z = 613.1 .

Rotomers/atropisomers are present in the NMR spectra. ¹ H NMR (400 MHz, Chloroform-d) δ 7.97 (d, J = 9.0 Hz, 1 H), 7.71 (d, J = 8.9 Hz, 1 H), 7.61 (dd, J = 7.3, 8.7 Hz, 1 H), 7.35 (dd, J = 2.6, 8.9 Hz, 1 H), 7.32 (d, J = 7.2 Hz, 1 H), 7.08 (d, J = 2.6 Hz, 1 H), 6.84 (dd, J = 8.8, 28.0 Hz, 2H), 4.47 (dp, J = 6.0, 12.1 Hz, 1 H), 4.09 - 3.85 (m, 1 H), 3.81 - 3.55 (m, 1 H), 3.03 - 2.79 (m, 2H), 2.06 (d, J = 1 1 .2 Hz, 2H), 1 .41 - 1 .33 (m, 3H), 1 .24 (s, 3H), 1 .20 (br. s, 6H). ¹⁹ F NMR (376 MHz, Chloroform-d) δ -58.96 (s, 1 F).

Example 428:

(3S)-3-methyl-1 -(6-{[6-(2-methylphenyl)-5-(trifluoromethyl)pyridin-2- yl]sulfamoyl}pyridin-2-yl)piperidine-3-carboxylic acid LCMS conditions 7: 1 .868 min; MS for C25H26F3N4O4S [M+H] ⁺ m/z = 535.16, found m/z = 535.20. ¹ H NMR of S-isomer: ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 12.31 (s, 1 H), 1 1 .53 (s, 1 H), 8.17 (d, J = 8.9 Hz, 1 H), 7.65 (dd, J = 8.8, 7.3 Hz, 1H), 7.59-7.46 (m, 1H), 7.36-7.27 (m, 1H), 7.27-7.15 (m, 2H), 7.12-7.00 (m, 3H), 3.87 (d, J = 13.1 Hz, 1H), 3.72-3.54 (m, 1H), 3.19-3.07 (m, 1H), 3.07-2.91 (m, 1H), 2.07-1.91 (m, 1H), 1.80 (d, J = 10.1 Hz, 3H), 1.54- 1.32 (m, 3H), 1.06- 0.93 (m, 3H). Example 429:

(S)-1-(6-(N-(6-(2-cyclopropylphenyl)-5-(trifluoromethyl)pyri din-2-yl)sulfamoyl)pyridin-2- yl)-3-methylpiperidine-3-carboxylic acid LCMS conditions 7: 1.74 min, MS for

C27H28F3N4O4S [M+H] ⁺ m/z = 563.2, found m/z = 561.1. Rotomers/atropisomers are present in the NMR spectra. ¹ H NMR (400 MHz, Chloroform-d) δ 8.07 (dd, J = 8.8, 14.9 Hz, 1H), 7.79 (dd, J = 4.3, 8.7 Hz, 1 H), 7.44 (m, 1 H), 7.35 - 7.27 (m, 1 H), 7.23 - 7.11 (m, 1 H), 7.07 (t, J = 7.6 Hz, 1H), 7.03-6.90 (m, 2H), 6.82-6.69 (m, 1H), 4.70 (t, J = 14.3 Hz, 1H), 3.99-3.80 (m, 1H), 3.11 -2.84 (m, 1H), 2.77 (dd, J = 2.1, 13.5 Hz, 1H), 1.99 (t, J = 13.5 Hz, 1H), 1.84- 1.56 (m, 1H), 1.54-1.28 (m, 3H), 1.14 (d, J = 2.1 Hz, 3H), 1.01 (ddd, J = 5.8, 8.0, 14.0 Hz, 1 H), 0.77 - 0.52 (m, 2H), 0.47 - 0.26 (m, 2H). ¹⁹ F NMR (376 MHz, Chloroform-d) δ -58.39 (s, 1F), -58.68 (s, 1.2F).

Example 430:

1-(6-(N-(5-chloro-6-(2-cyclopropylphenyl)pyridin-2-yl)sulfam oyl)pyridin-2-yl)-4- methylpiperidine-4-carboxylic acid LCMS conditions 7: 1.69 min, MS for C26H28CIN4O4S [M+H] ⁺ m/z = 527.1 , found m/z = 527.1. ¹ H NMR (400 MHz, Chloroform-d) δ 7.71 (d, J = 8.9 Hz, 1H), 7.58-7.51 (m, 2H), 7.31 -7.27 (m, 1H), 7.15 (td, J = 1.0, 7.5 Hz, 1H), 7.07 (dd, J = 1.4, 7.6 Hz, 1H), 6.95 (d, J = 7.8 Hz, 1H), 6.71 (d, J = 8.7 Hz, 1H), 3.93 (d, J = 13.5 Hz, 2H), 2.98 - 2.71 (m, 2H), 1.99 (d, J = 13.5 Hz, 2H), 1.52 (tt, J = 5.3, 8.5 Hz, 1 H), 1.36 - 1.28 (m, 2H), 1.17 (s, 3H), 0.66 - 0.57 (m, 2H), 0.53 - 0.45 (m, 2H).

Example 431:

1-(6-(N-(5-chloro-6-(2-cyclopropylphenyl)pyridin-2-yl)sulfam oyl)pyridin-2-yl)-3- methylpiperidine-3-carboxylic acid LCMS conditions 7: 1.73 min, MS for C27H30F3N4O4S [M+H] ⁺ m/z = 527.1, found m/z = 527.1. ¹ H NMR (400 MHz, Chloroform-d) δ 10.3 (br. s, 1H), 7.82 (d, J = 8.7 Hz, 1 H), 7.64 (d, J = 8.8 Hz, 1 H), 7.38 (s, 1 H), 7.31 (td, J = 1.3, 7.7 Hz, 1 H), 7.19 (s, 1H), 7.01 (s, 2H), 6.92 (s, 1H), 6.74 (d, J = 8.5 Hz, 1H), 4.87 (d, J = 13.5 Hz, 1H), 3.90 (d, J = 13.7 Hz, 1 H), 3.03 (td, J = 2.5, 13.4 Hz, 1 H), 2.74 (d, J = 13.6 Hz, 1 H), 2.02 - 1.89 (m, 1H), 1.79 (m, 1H), 1.45 (ddt, J = 2.7, 4.8, 10.6 Hz, 1H), 1.35 (m, 2H), 1.15 (s, 3H), 0.79 - 0.47 (m, 2H), 0.33 (br. s, 3H). Example 432:

1- (6-(N-(6-(5-chloro-2-methoxyphenyl)-5-(trifluoromethyl)pyrid in-2-yl)sulfamoyl)pyridin

2- yl)-3-methylpiperidine-3-carboxylic acid LCMS conditions 7: 1.72 min, MS for

C25H25CIF3N4O5S [M+H] ⁺ m/z = 585.1, found m/z = 585.0. Rotomers/atropisomers are present in the NMR spectra. ¹ H NMR (400 MHz, Chloroform-d) δ 10.05 (br. s, 1H), 7.99 (d, J = 8.9 Hz, 1 H), 7.82 (d, J = 8.8 Hz, 1 H), 7.51 (dd, J = 7.2, 8.7 Hz, 1 H), 7.34 (dd, J = 2.6, 8.8 Hz, 1H), 7.15-7.07 (m, 1H), 7.04 (s, 1H), 6.83 (dd, J = 5.2, 8.7 Hz, 2H), 4.54 (d, J = 12.2 Hz, 1 H), 3.96 - 3.78 (m, 1 H), 3.67 (br. s, 3H), 3.05 - 2.86 (m, 1 H), 2.81 (d, J = 13.4 Hz, 1 H), 2.09 (d, J = 13.6 Hz, 1 H), 1.65 (s, 1 H), 1.56 - 1.43 (m, 1 H), 1.45 - 1.32 (m, 1 H), 1.14 (s, 4H). ¹⁹ F NMR (376 MHz, Chloroform-d) δ -58.55 (s, 1 F), -59.44 (br. s, 1 F).

Example 433:

1-(6-(N-(6-(5-chloro-2-isopropoxyphenyl)-5-(trifluoromethyl) pyridin-2- yl)sulfamoyl)pyridin-2-yl)-3-methylpiperidine-3-carboxylic acid LCMS conditions 7: 1.80 min, MS for C27H29CIF3N4O5S [M+H] ⁺ m/z = 563.2, found m/z = 613.1.

Rotomers/atropisomers are present in the NMR spectra. ¹ H NMR (400 MHz, Chloroform-d) δ 10.05 (br. s, 1H), 8.02 (d, J = 8.8 Hz, 1H), 7.81 (d, J = 8.8 Hz, 1H), 7.51 (dd, J = 7.3, 8.6 Hz, 1 H), 7.32 (dd, J = 2.6, 8.9 Hz, 1 H), 7.08 (d, J = 7.1 Hz, 1 H), 7.05 - 6.92 (m, 1 H), 6.83 (dd, J = 3.4, 8.8 Hz, 2H), 4.63 (d, J = 12.8 Hz, 1H), 4.41 (s, 1H), 3.89 (d, J = 13.0 Hz, 1H), 3.05- 2.93 (m, 1H), 2.84 (d, J = 13.4 Hz, 1H), 2.11 (d, J = 13.6 Hz, 1H), 1.73 (s, 1H), 1.55 (dt, J = 3.6, 13.6 Hz, 1H), 1.47- 1.35 (m, 1H), 1.34-1.29 (m, 1H), 1.18(s,4H), 1.12 (d, J = 6.0 Hz, 5H). ¹⁹ F NMR (376 MHz, Chloroform-d) δ -59.11 (br. s, 1F).

Example 434:

rac-ilSR.SRS.eRS.ZS^^-ie-iN-iS-chloro^'-isopropyl-^.S'-bi pyridinl-e- yl)sulfamoyl)pyridin-2-yl)-5-propyl-2-azabicyclo[4.2.0]octan e-7-carboxylic acid LCMS conditions 7: 1.50 min, MS for C29H35CIN5O4S [M+H] ⁺ m/z = 584.2, found m/z = 584.1. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 12.29 (s, 1 H), 11.21 (s, 1 H), 8.60 (dd, J = 4.8, 1.7 Hz, 1 H), 8.00 (dd, J = 8.8, 1.3 Hz, 1 H), 7.71 - 7.66 (m, 1 H), 7.54 (d, J = 7.7 Hz, 1 H), 7.48 (d, J = 8.8 Hz, 1H), 7.33 (dd, J = 7.9, 4.8 Hz, 1H), 7.18 - 7.04 (m, 1H), 6.77 (d, J = 8.7 Hz, 1H), 4.43 (s, 1H), 3.67 (s, 1 H), 2.93 - 2.87 (m, 1 H), 2.70 - 2.54 (m, 3H), 2.39 - 2.35 (m, 2H), 2.21 - 2.07 (m, 1H), 1.81 - 1.57 (m, 2H), 1.49- 1.14 (m, 5H), 1.12-0.77 (m, 8H).

Example 435:

(3S)-1-(6-{[6-(5-fluoro-2-methylphenyl)-5-(trifluoromethy l)pyridin-2- yl]sulfamoyl}pyridin-2-yl)-3-methylpiperidine-3-carboxylic acid LCMS conditions 7: 1.770 min; MS for C25H25F4N4O4S [M+H] ⁺ m/z = 553.15, found m/z = 553.15. ¹ H NMR of S- isomer: ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 12.31 (s, 1H), 11.59 (s, 1H), 8.19 (d, J = 8.9 Hz, 1H), 7.65 (dd, J = 8.7, 7.2 Hz, 1H), 7.55 (d, J = 8.8 Hz, 1H), 7.31 - 7.22 (m, 1H), 7.17 (td, J = 8.6, 2.8 Hz, 1H), 7.11 -7.02 (m, 2H), 6.99-6.89 (m, 1H), 3.87 (d, J = 13.1 Hz, 1H), 3.74- 3.56 (m, 1 H), 3.12 (d, J = 13.1 Hz, 1 H), 3.08 - 2.95 (m, 1 H), 2.05 - 1.88 (m, 1 H), 1.75 (d, J = 9.7 Hz, 3H), 1.54 - 1.32 (m, 3H), 1.00 (d, J = 5.2 Hz, 3H).

Example 436:

(3S)-1 -(6-{[6-(3-fluoro-2-methylphenyl)-5-(trifluoromethyl)pyridin -2- yl]sulfamoyl}pyridin-2-yl)-3-methylpiperidine-3-carboxylic acid LCMS conditions 7: 1.805 min; MS for C25H25F4N4O4S [M+H] ⁺ m/z = 553.15, found m/z = 553.15. ¹ H NMR of S- isomer: ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 12.32 (s, 1H), 11.59 (s, 1H), 8.19 (d, J = 8.9 Hz, 1H), 7.65 (dd, J = 8.7, 7.2 Hz, 1H), 7.59 - 7.49 (m, 1H), 7.31 - 7.17 (m, 2H), 7.12 - 7.01 (m, 2H), 6.97-6.88 (m, 1H), 3.86 (d, J = 13.1 Hz, 1H), 3.70-3.55 (m, 1H), 3.13 (dd, J = 13.1, 8.8 Hz, 1H), 3.08-2.95 (m, 1H), 2.04- 1.89 (m, 1H), 1.67 (d, J = 16.0 Hz, 3H), 1.53- 1.31 (m, 3H), 1.00 (d, J = 8.0 Hz, 3H).

Example 437:

(R)-1 -(6-(N-(5-chloro-6-(2-cyclopropylphenyl)pyridin-2-yl)sulfamo yl)pyridin-2-yl)-3- methylpiperidine-3-carboxylic acid LCMS conditions 7: 1.80 min, MS for C26H28CIN4O4S [M+H] ⁺ m/z = 527.1 , found m/z = 527.1. Rotomers/atropisomers are present in the NMR spectra. ¹ H NMR (400 MHz, Chloroform-d) δ 10.75 - 8.87 (br. s, 1H), 7.86 (d, J = 8.7 Hz, 1 H), 7.66 (d, J = 8.7 Hz, 1 H), 7.37 (s, 1 H), 7.33 (td, J = 1.3, 7.6 Hz, 1 H), 7.23 (d, J = 7.5 Hz, 1H), 7.14-6.98 (m, 2H), 6.93 (m, 1H), 6.75 (d, J = 7.5 Hz, 1H), 5.01 (m, 1H), 3.93 (d, J = 13.8 Hz, 1H), 3.18-2.98 (m, 1H), 2.75 (d, J = 13.6 Hz, 1H), 2.00 (m, 1H), 1.86 (dtt, J = 4.4, 8.6, 17.0 Hz, 1 H), 1.47 (ddt, J = 2.4, 4.9, 10.5 Hz, 1 H), 1.43 - 1.32 (m, 2H), 1.18 (s, 4H), 0.75 (s, 1H), 0.59 (s, 1H), 0.33 (s, 1H), 0.28 (s, 1H).

Example 438:

rac-(1RS,3RS,4SR)-3-((6-(N-(6-(2-cyclopropylphenyl)-5-(tr ifluoromethyl)pyridin-2- yl)sulfamoyl)pyridin-2-yl)amino)-7-oxabicyclo[2.2.1]heptane- 1 -carboxylic acid LCMS conditions 7: 1.61 min, MS for C27H26F3N4O5S [M+H] ⁺ m/z = 575.2, found m/z = 575.1. ¹ H NMR (400 MHz, Methanol-d ₄ ) δ 8.08 (dd, J = 8.9, 2.9 Hz, 1 H), 7.57 - 7.53 (m, 1 H), 7.47 (ddd, J = 8.4, 7.2, 2.5 Hz, 1H), 7.33 - 7.28 (m, 1H), 7.20 - 7.12 (m, 2H), 7.05 (dd, J = 14.4, 7.5 Hz, 1 H), 6.97 (dd, J = 7.9, 4.2 Hz, 1 H), 6.63 (dd, J = 8.3, 1.5 Hz, 1 H), 4.23 (dd, J = 42.4, 4.0 Hz, 1 H), 4.04 - 3.87 (m, 1 H), 2.29 - 2.22 (m, 1 H), 1.89 - 1.49 (m, 5H), 1.44 - 1.31 (m, 1 H), 0.69 - 0.51 (m, 3H), 0.46 - 0.37 (m, 1 H). Example 439:

5-(6-(N-(6-(5-fluoro-2-met ylp enyl)-5-(trifluoromet yl)pyridin-2-yl)sulfamoyl)pyridin-2- yl)-5-azaspiro[2.5]octane-1-carboxylic acid LCMS conditions 7: 1.538 min; MS for C26H25F4N4O4S [M+H] ⁺ m/z= 565.55, found m/z= 565.20. ¹ H NMR (400 MHz, Chloroform-d) δ 9.93 (s, 2H), 7.91 (d, J = 8.9 Hz, 1 H), 7.60 (dd, J = 8.9, 0.9 Hz, 1 H), 7.51 (dd, J = 8.7, 7.2 Hz, 1H), 7.22 (d, J = 7.2 Hz, 1H), 7.14-7.08 (m, 1H), 6.95 (td, J = 8.5, 2.7 Hz, 1H), 6.76 (dd, J = 8.8, 2.8 Hz, 1H), 6.69 (d, J = 8.7 Hz, 1H), 3.49-3.16 (m, 4H), 1.74- 1.59 (m, 2H), 1.59- 1.44 (m, 4H), 1.27-1.13 (m, 2H), 0.95-0.85 (m, 2H). Example 440:

5-(6-(N-(6-(3-fluoro-2-methylphenyl)-5-(trifluoromethyl)pyri din-2-yl)sulfamoyl)pyridin-2- yl)-5-azaspiro[2.5]octane-1-carboxylic acid LCMS conditions 7: 1.540 min; MS for C26H25F4N4O4S [M+H] ⁺ m/z= 565.55, found m/z= 565.20. ¹ H NMR (400 MHz, Methanol-c/ ₄ ) δ 7.98 (d, J = 8.8 Hz, 1 H), 7.51 (dd, J = 8.7, 7.3 Hz, 1 H), 7.44 (dd, J = 8.9, 4.5 Hz, 1 H), 7.08 (t, J= 7.9 Hz, 2H), 7.00 (ddd, J= 9.7, 8.2, 1.2 Hz, 1H), 6.83 (dd, J= 14.4, 8.1 Hz, 2H), 3.60- 3.23 (m, 4H), 1.71 (tt, J = 7.7, 3.7 Hz, 5H), 1.56 - 1.33 (m, 3H), 0.77 (dtd, J = 25.5, 9.3, 8.0, 4.8 Hz, 2H).

Example 441:

5-(6-(N-(6-(o-tolyl)-5-(trifluoromethyl)pyridin-2-yl)sulf amoyl)pyridin-2-yl)-5- azaspiro[2.5]octane-1-carboxylic acid LCMS conditions 7: 1.521 min; MS for

C26H26F3N4O4S [M+H] ⁺ m/z= 547.56, found m/z= 547.20. ¹ H NMR (400 MHz, Chloroform-d) δ 10.47 (s, 2H), 7.99 (d, J = 9.0 Hz, 1H), 7.67 (d, J = 8.9 Hz, 1H), 7.62-7.56 (m, 1H), 7.36- 7.29 (m, 2H), 7.23 (dqdd, J= 7.5, 6.7, 1.4, 0.7 Hz, 2H), 7.13-7.08 (m, 1H), 6.77 (dd, J = 8.7, 0.6 Hz, 1 H), 3.58 - 3.24 (m, 4H), 2.02 (s, 3H), 1.79 - 1.65 (m, 2H), 1.65 - 1.53 (m, 2H), 1.37 - 1.23 (m, 1 H), 0.97 (d, J = 6.9 Hz, 2H).

Example 442:

rac-(1SR,6RS,7SR)-2-(6-(N-(6-(2-isopropylphenyl)-5-(trifl uoromethyl)pyridin-2- yl)sulfamoyl)pyridin-2-yl)-2-azabicyclo[4.2.0]octane-7-carbo xylic acid LCMS conditions 7: 1.78 min, MS for C28H30F3N4O4S [M+H] ⁺ m/z = 575.2, found m/z = 575.1. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 12.23 (s, 1 H), 11.47 (s, 1 H), 8.20 (d, J = 8.9 Hz, 1 H), 7.71 - 7.67 (m, 1 H), 7.60 (s, 1 H), 7.45 - 7.28 (m, 2H), 7.26 - 7.09 (m, 2H), 7.01 - 6.97 (m, 1 H), 6.71 (d, J = 8.7 Hz, 1H), 4.17-4.00 (m, 1H), 3.38-3.35 (m, 1H), 3.06-2.89 (m, 1H), 2.86-2.75 (m, 2H), 2.42 - 2.23 (m, 2H), 1.98 - 1.87 (m, 1 H), 1.74 (d, J = 9.7 Hz, 2H), 1.62 - 1.40 (m, 2H), 1.04 - 1.00 (m, 3H), 0.93 - 0.87 (m, 3H). Example 443:

rac-(1SR,6RS,7SR)-2-(6-(N-(6-(o olyl)^-(trifluoromethyl)pyridin-2-yl)sulfamoyl)pyridin- 2-yl)-2-azabicyclo[4.2.0]octane-7-carboxylic acid LCMS conditions 7: 1.70 min, MS for C26H26F3N4O4S [M+H] ⁺ m/z = 547.2, found m/z = 546.9. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 12.22 (s, 1H), 11.54 (s, 1H), 8.20 (d, J = 8.9 Hz, 1H), 7.70 (dd, J = 8.6, 7.3 Hz, 1H), 7.53 (s, 1H), 7.33 - 7.29 (m, 1 H), 7.25 - 7.18 (m, 2H), 7.16 (d, J = 7.2 Hz, 1 H), 7.05 (d, J = 7.7 Hz, 1 H), 6.71 (d, J = 8.6 Hz, 1 H), 4.18 - 4.01 (m, 2H), 3.40 (s, 1 H), 3.01 (s, 1 H), 2.89 - 2.73 (m, 2H), 2.37 (s, 1 H), 1.95 - 1.92 (m, 1 H), 1.79 - 1.75 (m, 4H), 1.60 - 1.42 (m, 2H). Example 444:

1- (6-(N-(6-(2-(hydroxymethyl)phenyl)-5-(trifluoromethyl)pyridi n-2-yl)sulfamoyl)pyridin-

2- yl)-3-methylpiperidine-3-carboxylic acid LCMS conditions 7: 1.62 min, MS for C25H26F3N4O5S [M+H] ⁺ m/z = 551.15, found m/z = 551.2, ¹ H NMR (600 MHz, DMSO-c/ ₆ ) δ 12.32 (s, 1H), 11.52 (s, 1H), 8.14 (s, 1H), 7.63 (dd, J = 8.7, 7.3 Hz, 1H), 7.59-7.49 (m, 2H), 7.43 (td, J = 7.6, 1.3 Hz, 1H), 7.27 (td, J= 7.5, 1.3 Hz, 1H), 7.14-7.00 (m, 3H), 4.96 (s, 1H), 4.25 - 3.96 (m, 2H), 3.88 (d, J = 13.2 Hz, 1 H), 3.60 (d, J = 33.2 Hz, 1 H), 3.21 - 2.92 (m, 2H), 1.95 - 1.84 (m, 1 H), 1.57 - 1.32 (m, 2H), 1.32 - 1.20 (m, 1 H), 1.01 (s, 3H).

Example 445:

1-(6-(N-(6-(2-(2-hydroxyethyl)phenyl)-5-(trifluoromethyl) pyridin-2-yl)sulfamoyl)pyridin- 2-yl)-3-methylpiperidine-3-carboxylic acid LCMS conditions 7: 1.63 min, MS for

C ₂ 6H2 ₈ F ₃ N ₄ 0 ₅ S [M+H] ⁺ m/z = 565.17, found m/z = 565.2. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 12.32 (s, 1H), 11.55 (s, 1H), 8.17 (dd, J = 8.5, 6.0 Hz, 1H), 7.77-7.53 (m, 2H), 7.41 -7.28 (m, 2H), 7.23 (ddd, J = 7.6, 6.6, 2.1 Hz, 1 H), 7.15 - 6.94 (m, 3H), 4.52 (s, 1 H), 3.97 - 3.83 (m, 1 H), 3.75 - 3.58 (m, 1 H), 3.48 - 3.35 (m, 3H), 3.23 - 2.90 (m, 2H), 2.43 (t, J = 7.4 Hz, 1H), 2.29 (dd, J = 14.2, 7.2 Hz, 1H), 1.61 -1.32 (m, 3H), 1.02 (d, J = 5.3 Hz, 3H).

Example 446:

7-(6-(N-(6-(o-tolyl)-5-(trifluoromethyl)pyridin-2-yl)sulfamo yl)pyridin-2-yl)-7- azaspiro[3.5]nonane-2-carboxylic acid LCMS conditions 7: 1.74 min, MS for

C27H28F3N4O4S [M+H] ⁺ m/z = 561.2, found m/z = 561.2. ¹ H NMR (500 MHz, DMSO-c/ ₆ ) δ 12.03 (s, 1H), 11.49 (s, 1H), 8.19 (d, J = 8.9 Hz, 1H), 7.66 (dd, J = 8.7, 7.2 Hz, 1H), 7.48 (d, J = 8.9 Hz, 1H), 7.31 (td, J = 7.5, 1.4 Hz, 1H), 7.21 (m, 2H), 7.05 (m, 3H), 3.33 (m, 4H), 3.01 (m, 1 H), 1.96 (m, 2H), 1.88 (m, 2H), 1.75 (s, 3H), 1.38 (s, 2H), 1.27 (s, 2H). ¹⁹ F NMR (471 MHz, DMSO-c/ ₆ ) δ -57.04 (s, 1 F). Example 447:

(R)-1 -(6-(N-(5-chloro-6-(o olyl)pyridin-2-yl)sulfamoyl)pyridin-2-yl)-3-methylpiperidine - 3-carboxylic acid LCMS conditions 7: 1 .69 min, MS for C24H26CIN4O4S [M+H] ⁺ m/z = 501 .1 , found m/z = 500.9. Rotomers/atropisomers are present in the NMR spectra. ¹ H NMR (500 MHz, Chloroform-d) δ 7.82 (d, J = 8.8 Hz, 1 H), 7.64 (d, J = 8.8 Hz, 1 H), 7.43 (dd, J = 7.3, 8.6 Hz, 1 H), 7.30 (td, J = 1 .4, 7.6 Hz, 1 H), 7.19 (dd, J = 4.2, 7.2 Hz, 2H), 7.02 (s, 1 H), 6.91 (d, J = 7.2 Hz, 1 H), 6.75 (d, J = 8.7 Hz, 1 H), 4.97 (d, J = 13.6 Hz, 1 H), 3.92 (d, J = 13.8 Hz, 1 H), 3.05 (td, J = 3.0, 13.5 Hz, 1 H), 2.73 (d, J = 13.6 Hz, 1 H), 1 .97 (d, J = 13.5 Hz, 1 H), 1 .84 (m, 4H), 1 .46 (ddt, J = 2.6, 4.9, 10.6 Hz, 2H), 1 .36 (td, J = 4.9, 12.6, 13.1 Hz, 1 H), 1 .16 (s, 3H).

Example 448:

(R)-1 -(6-(N-(5-chloro-6-(2,6-dimethylphenyl)pyridin-2-yl)sulfamoy l)pyridin-2-yl)-3- methylpiperidine-3-carboxylic acid LCMS conditions 7: 1 .73 min, MS for C25H28CIN4O4S [M+H] ⁺ m/z = 515.1 , found m/z = 514.9. Rotomers/atropisomers are present in the NMR spectra. ¹ H NMR (500 MHz, Chloroform-d) δ 9.50 (br. s, 1 H), 7.85 (d, J = 8.7 Hz, 1 H), 7.64 (d, J = 8.7 Hz, 1 H), 7.38 (dd, J = 7.2, 8.7 Hz, 1 H), 7.18 (t, J = 7.6 Hz, 1 H), 7.05 (d, J = 7.6 Hz, 1 H), 6.98 (d, J = 7.6 Hz, 1 H), 6.87 - 6.80 (m, 1 H), 6.73 (d, J = 8.7 Hz, 1 H), 5.02 (d, J = 13.7 Hz, 1 H), 3.93 (d, J = 15.9 Hz, 1 H), 3.07 (td, J = 2.9, 13.5 Hz, 1 H), 2.71 (d, J = 13.6 Hz, 1 H), 1 .94 (s, 3H), 1 .91 (d, J = 1 .8 Hz, 1 H), 1 .82 (dtt, J = 4.5, 8.8, 17.3 Hz, 1 H), 1 .49 (s, 3H), 1 .43 (ddd, J = 2.4, 5.0, 13.4 Hz, 1 H), 1 .36 (td, J = 5.0, 12.6, 13.1 Hz, 1 H), 1 .32 - 1 .27 (m, 1 H), 1 .16 (s, 3H).

Example 449:

(R)-1 -(6-(N-(6-(2-chloro-5-methoxyphenyl)-5-(trifluoromethyl)pyri din-2- yl)sulfamoyl)pyridin-2-yl)piperidine-3-carboxylic acid LCMS conditions 7: 1 .80 min, MS for C27H30F3N4O4S [M+H] ⁺ m/z = 563.2, found m/z = 563.1 . Rotomers/atropisomers are present in the NMR spectra. ¹ H NMR (500 MHz, Chloroform-d) δ 1 1 .22 - 8.54 (br. s, 1 H), 8.08 (m, 1 H), 7.86 (d, J = 8.8 Hz, 1 H), 7.62 - 7.45 (m, 1 H), 7.33 (d, J = 8.8 Hz, 1 H), 7.22 - 6.99 (m, 2H), 6.97 - 6.88 (m, 1 H), 6.87 - 6.72 (m, 2H), 4.42 (m, 1 H), 3.79 (m, 3H), 3.65 (d, J = 1 1 .3 Hz, 1 H), 3.59 - 3.36 (m, 2H), 2.63 - 2.50 (m, 1 H), 1 .98 - 1 .91 (m, 1 H), 1 .90 - 1 .78

(m, 2H), 1 .48 (d, J = 13.6 Hz, 1 H). ¹⁹ F NMR (471 MHz, Chloroform-d) δ -59.04 (s, 1 F), -59.15 (s, 1 .2F).

Example 450:

(R)-1 -(6-(N-(6-(5-chloro-2-methylphenyl)-5-(trifluoromethyl)pyrid in-2- yl)sulfamoyl)pyridin-2-yl)-3-methylpiperidine-3-carboxylic acid LCMS conditions 7: 1 .80 min, MS for C25H25CIF3N4O4S [M+H] ⁺ m/z = 569.1 , found m/z = 568.8. Rotomers/atropisomers are present in the NMR spectra. ¹ H NMR (400 MHz, Chloroform-d) δ 10.11 (br. s, 1H), 8.13-8.00 (m, 1H), 7.82 (d, J = 8.8 Hz, 1H), 7.54-7.37 (m, 1H), 7.28 (dd, J = 2.2, 8.2 Hz, 1H), 7.16 (m, 1H), 7.09 (s, 1H), 7.03 (t, J = 8.5 Hz, 1H), 6.95 (d, J = 7.4 Hz, 1H), 6.80 (t, J = 7.8 Hz, 1H), 4.75 (m, 1H), 3.90 (d, J = 13.1 Hz, 1H), 3.00 (m, 1H), 2.78 (d, J = 13.5 Hz, 1 H), 2.10 - 1.99 (m, 1 H), 1.96 (s, 1 H), 1.82 - 1.66 (m, 2H), 1.61 (s, 2H), 1.55 - 1.45 (m, 1H), 1.38 (t, J = 12.7 Hz, 1H), 1.16 (d, J = 4.1 Hz, 3H). ¹⁹ F NMR (376 MHz, Chloroform-d) δ -58.96 (s, 1F), -59.12 (s, 1.1F).

Example 451:

1-(6-(N-(6-(5-chloro-2-methylphenyl)-5-(trifluorom

yl)-4-methylpiperidine-4-carboxylic acid LCMS conditions 7: 1.78 min, MS for

C25H25CIF3N4O4S [M+H] ⁺ m/z = 569.1, found m/z = 568.9. Rotomers/atropisomers are present in the ¹ H NMR spectrum. ¹ H NMR (400 MHz, Chloroform-d) δ 10.47 (br. s, 1H), 7.98 (d, J = 8.9 Hz, 1 H), 7.65 (d, J = 8.8 Hz, 1 H), 7.58 (dd, J = 7.3, 8.7 Hz, 1 H), 7.32 - 7.25 (m, 3H), 7.17 (d, J = 8.3 Hz, 1H), 7.06 (d, J = 1.9 Hz, 1H), 6.76 (d, J = 8.7 Hz, 1H), 4.12 (m, 1H), 3.86 (d, J = 12.0 Hz, 1 H), 2.85 (q, J = 10.8 Hz, 2H), 2.01 (m, 5H), 1.37 - 1.28 (m, 2H), 1.20 (s, 3H). ¹⁹ F NMR (376 MHz, Chloroform-d) δ -58.84 (s, 1F).

Example 452:

1-(6-(N-(5-chloro-6-(o-tolyl)pyridin-2-yl)sulfamoyl)pyrid in-2-yl)-3-ethylpiperidine-3- carboxylic acid LCMS conditions 7: 1.80 min, MS for C25H28CIN4O4S [M+H] ⁺ m/z = 515.1, found m/z = 514.9. ¹ H NMR (400 MHz, Chloroform-d) δ 10.10 (br. s, 1H), 7.81 (d, J = 8.8 Hz, 1H), 7.64 (d, J = 8.8 Hz, 1H), 7.43 (dd, J = 7.3, 8.7 Hz, 1H), 7.30 (td, J = 1.4, 7.6 Hz, 1H), 7.19 (dt, J = 3.3, 7.1 Hz, 2H), 7.06 (d, J = 7.6 Hz, 1H), 6.94 (d, J = 7.1 Hz, 1H), 6.75 (d, J = 8.7 Hz, 1H), 4.87 (d, J = 13.6 Hz, 1H), 3.92 (d, J = 13.7 Hz, 1H), 3.01 (td, J = 2.9, 13.4 Hz,

1H), 2.75 (d, J = 13.6 Hz, 1H), 2.06 (d, J = 12.7 Hz, 2H), 1.91 (dq, J = 7.3, 14.6 Hz, 3H), 1.77 (tdd, J = 4.4, 8.8, 17.0 Hz, 2H), 1.49 (ddt, J = 2.8, 4.7, 10.6 Hz, 1H), 1.33- 1.27 (m, 1H), 1.23 - 1.11 (m, 1 H), 0.76 (t, J = 7.4 Hz, 3H). Example 453:

1-(6-(N-(5-chloro-6-(2,6-dimethylphenyl)pyridin-2-yl)sulfamo yl)pyridin-2-yl)-3- ethylpiperidine-3-carboxylic acid LCMS conditions 7: 1.80 min, MS for C26H30CIN4O4S [M+H] ⁺ m/z = 529.2, found m/z = 528.9. Rotomers/atropisomers are present in the NMR spectra. ¹ H NMR (400 MHz, Chloroform-d) δ 9.45 (br. s, 1H), 7.85 (d, J = 8.7 Hz, 1H), 7.64 (d, J = 8.7 Hz, 1H), 7.38 (dd, J = 7.2, 8.7 Hz, 1H), 7.18 (t, J = 7.6 Hz, 1H), 7.05 (d, J = 7.5

Hz, 1H), 6.98 (d, J = 7.6 Hz, 1H), 6.84 (d, J = 7.1 Hz, 1H), 6.73 (d, J = 8.7 Hz, 1H), 4.95 (d, J = 13.6 Hz, 1H), 3.93 (d, J = 13.8 Hz, 1H), 3.05 (td, J = 2.9, 13.4 Hz, 1H), 2.72 (d, J = 13.6 Hz, 1 H), 2.04 - 1.97 (m, 2H), 1.95 (s, 3H), 1.77 (qt, J = 4.4, 13.0 Hz, 1 H), 1.50 (s, 3H), 1.49 - 1.42 (m, 1H), 1.28 (m, 2H), 1.13 (dq, J = 7.4, 14.6 Hz, 1H), 0.77 (t, J = 7.4 Hz, 3H).

Example 454:

3-ethyl-1-(6-(N-(6-(o olyl)-5-(trifluoromethyl)pyridin-2-yl)sulfamoyl)pyridin-2- yl)piperidine-3-carboxylic acid LCMS conditions 7: 1.77 min, MS for C26H28F3N4O4S

[M+H] ⁺ m/z = 549.2, found m/z = 548.9. Rotomers/atropisomers are present in the NMR spectra. ¹ H NMR (400 MHz, Chloroform-d) δ 10.25 (br. s, 1H), 8.06 (t, J = 8.9 Hz, 1H), 7.78 (d, J = 8.8 Hz, 1H), 7.51 -7.39 (m, 1H), 7.30 (m, 2H), 7.17 (dt, J = 7.3, 16.3 Hz, 2H), 7.12- 6.89 (m, 2H), 6.77 (d, J = 8.7 Hz, 1H), 4.73 (d, J = 13.5 Hz, 1H), 3.91 (t, J = 12.5 Hz, 1H), 2.96 (m, 1 H), 2.77 (d, J = 13.5 Hz, 1 H), 2.03 (m, 3H), 1.80 (m, 3H), 1.51 (m, 1 H), 1.29 (m, 2H), 0.75 (t, J = 7.4 Hz, 3H). ¹⁹ F NMR (376 MHz, Chloroform-d) δ -58.79 (s, 1F), -59.13 (s, 1.2F). Example 455:

(R)-1 -(6-(N-(6-(5-chloro-2-methoxyphenyl)-5-(trifluoromethyl)pyri din-2- yl)sulfamoyl)pyridin-2-yl)-3-methylpiperidine-3-carboxylic acid LCMS conditions 7: 1.74 min, MS for C25H25CIF3N4O5S [M+H] ⁺ m/z = 585.1 , found m/z = 584.8.

Rotomers/atropisomers are present in the NMR spectra. ¹ H NMR (400 MHz, Chloroform-d) δ 9.80 (br. s, 1 H), 8.01 (d, J = 8.8 Hz, 1 H), 7.82 (d, J = 7.4 Hz, 1 H), 7.50 (dd, J = 7.2, 8.7 Hz, 1H), 7.34 (dd, J = 2.6, 8.8 Hz, 1H), 7.06 (d, J = 6.6 Hz, 2H), 6.82 (t, J = 8.9 Hz, 2H), 4.74 (d, J = 10.5 Hz, 1H), 3.87 (d, J = 11.5 Hz, 1H), 3.66 (br. s, 3H), 3.04-2.88 (m, 1H), 2.75 (d, J = 13.4 Hz, 1H), 2.09 (d, J = 13.6 Hz, 1H), 1.52 (d, J = 13.4 Hz, 1H), 1.36 (td, J = 4.6, 13.1 Hz, 1H), 1.29 (m, 2H), 1.16 (s, 3H). ¹⁹ F NMR (376 MHz, Chloroform-d) δ -59.43 (br. s, 1F), -59.58 (br. s, 1F).

Example 456:

1-(6-(N-(5-chloro-6-(o-tolyl)pyridin-2-yl)sulfamoyl)pyridin- 2-yl)-3-propylpiperidine-3- carboxylic acid LCMS conditions 7: 1.80 min, MS for C26H30CIN4O4S [M+H] ⁺ m/z = 529.2, found m/z = 528.9. ¹ H NMR (400 MHz, Chloroform-d) δ 11.29 (br. s), 9.45 (s, 1H), 7.85 (d, J = 8.8 Hz, 1 H), 7.66 (d, J = 8.8 Hz, 1 H), 7.45 (dd, J = 7.3, 8.6 Hz, 1 H), 7.32 (td, J = 1.3, 7.5 Hz, 1H), 7.25-7.16 (m, 2H), 7.06 (d, J = 7.1 Hz, 1H), 6.93 (d, J = 7.1 Hz, 1H), 6.77 (d, J = 8.7 Hz, 1H), 5.00 (d, J = 13.6 Hz, 1H), 3.95 (d, J = 13.7 Hz, 1H), 3.06 (td, J = 2.7, 13.4 Hz, 1 H), 2.75 (d, J = 13.6 Hz, 1 H), 2.06 (d, J = 6.0 Hz, 1 H), 1.97 - 1.74 (m, 5H), 1.50 (ddt, J = 2.4, 4.8, 10.5 Hz, 2H), 1.34 (dd, J = 5.0, 13.2 Hz, 1H), 1.10 (qd, J = 2.8, 9.3, 10.7 Hz, 2H), 0.91 (t, J = 6.4 Hz, 3H). Example 457:

1-(6-(N-(5-chloro-6-(2,6-dimethylphenyl)pyridin-2-yl)sulfamo yl)pyridin-2-yl)-3- propylpiperidine-3-carboxylic acid LCMS conditions 7: 1.82 min, MS for C27H30F3N4O4S [M+H] ⁺ m/z = 543.2, found m/z = 542.9. Rotomers/atropisomers are present in the NMR spectra. ¹ H NMR (400 MHz, Chloroform-d) δ 11.53 (s, 1H), 9.64 (s, 1H), 7.87 (d, J = 8.7 Hz, 1H), 7.66 (d, J = 8.7 Hz, 1H), 7.40 (dd, J = 7.2, 8.7 Hz, 1H), 7.20 (t, J = 7.6 Hz, 1H), 7.07 (d, J = 7.6 Hz, 1H), 7.00 (d, J = 7.6 Hz, 1H), 6.86 (d, J = 7.1 Hz, 1H), 6.75 (d, J = 8.7 Hz, 1H), 4.99 (d, J = 13.6 Hz, 1H), 3.95 (d, J = 13.7 Hz, 1H), 3.07 (td, J = 2.8, 13.5 Hz, 1H), 2.74 (d, J = 13.6 Hz, 1H), 2.02 (d, J = 13.9 Hz, 1H), 1.97 (s, 4H), 1.92 (dd, J = 3.0, 10.2 Hz, 1H), 1.79 (dddd, J = 4.4, 8.7, 13.0, 17.4 Hz, 1H), 1.51 (s, 3H), 1.50-1.44 (m, 1H), 1.34 (dd, J = 5.0, 13.5 Hz, 2H), 1.09 (tt, J = 4.6, 8.8 Hz, 2H), 0.93 - 0.89 (m, 3H).

Example 458:

3-propyl-1 -(6-(N-(6-(o-tolyl)-5-(trifluoromethyl)pyridin-2-yl)sulfamoy l)pyridin-2- yl)piperidine-3-carboxylic acid LCMS conditions 7: 1.80 min, MS for C27H30F3N4O4S

[M+H] ⁺ m/z = 563.2, found m/z = 562.9. Rotomers/atropisomers are present in the NMR spectra. ¹ H NMR (400 MHz, Chloroform-d) δ 10.27 (s, 1H), 8.09 (t, J = 9.7 Hz, 1H), 7.81 (d, J = 8.7 Hz, 1 H), 7.53 - 7.40 (m, 1 H), 7.33 (td, J = 1.1 , 7.5 Hz, 1 H), 7.20 (dq, J = 7.4, 18.1 Hz, 2H), 7.13-6.92 (m, 2H), 6.79 (d, J = 8.7 Hz, 1H), 4.79 (d, J = 13.2 Hz, 1H), 3.93 (t, J = 13.5 Hz, 1H), 2.98 (dt, J = 12.3, 26.4 Hz, 1H), 2.77 (d, J = 13.5 Hz, 1H), 2.17-1.97 (m, 3H), 1.81 (dd, J = 18.8, 29.7 Hz, 2H), 1.53 (s, 1 H), 1.33 (d, J = 6.7 Hz, 2H), 1.22 - 0.99 (m, 2H), 0.90 (t, J = 7.1 Hz, 2H), 0.87 (t, J = 7.1 Hz, 3H). ¹⁹ F NMR (376 MHz, Chloroform-d) δ -58.79 (s, 1F), -59.15 (s, 1.2F). Example 459:

3-((6-(N-(6-(o-tolyl)-5-(trifluoromethyl)pyridin-2-yl)sulfam oyl)pyridin-2- yl)amino)cyclopentanecarboxylic acid Mixture of diastereomers. LCMS conditions 7: 1.71 min, MS for C24H24F3N4O4S [M+H] ⁺ m/z = 521.2, found m/z = 521.2. ¹ H NMR (400 MHz, Chloroform-d) δ 7.96 (d, J = 8.9 Hz, 1H), 7.66 (d, J = 8.8 Hz, 1H), 7.49 (dd, J = 7.4, 8.4 Hz, 1 H), 7.32 (td, J = 1.3, 7.5 Hz, 1 H), 7.27 (d, J = 7.3 Hz, 1 H), 7.23 (d, J = 7.2 Hz, 1 H), 7.20 (d, J = 7.4 Hz, 1H), 7.09 (d, J = 7.5 Hz, 1H), 6.54 (d, J = 8.5 Hz, 1H), 5.39 (s, 1H), 4.02 (s, 1H), 2.91 -2.73 (m, 1H), 2.18-2.07 (m, 1H), 2.01 (s, 3H), 1.90 (q, J = 7.4 Hz, 2H), 1.76 (qd, J = 5.7, 10.4, 12.0 Hz, 2H), 1.59 (dq, J = 6.6, 12.4 Hz, 1H), 1.30 (dd, J = 5.0, 10.3 Hz, 1H). ¹⁹ F NMR (376 MHz, Chloroform-d) δ -58.70 (s, 1F). Example 460:

3-((6-(N-(6-(o olyl)-5-(trifluoromethyl)pyridin-2-yl)sulfamoyl)pyridin-2- yl)amino)cyclohexanecarboxylic acid Mixture of diastereomers. LCMS conditions 7: 1 .72 min, MS for C25H26F3N4O4S [M+H] ⁺ m/z = 535.1 , found m/z = 535.1 . Rotomers/atropisomers are present in the NMR spectra. ¹ H NMR (400 MHz, Chloroform-d) δ 9.45 (br. s, 1 H), 7.97 (d, J = 8.9 Hz, 1 H), 7.59 (d, J = 8.6 Hz, 1 H), 7.52 (dd, J = 7.3, 8.4 Hz, 1 H), 7.39 - 7.32 (m, 1 H), 7.31 - 7.27 (m, 2H), 7.23 (d, J = 7.6 Hz, 1 H), 7.13 (d, J = 7.5 Hz, 1 H), 6.49 (d, J = 8.4 Hz, 1 H), 4.52 (s, 1 H), 3.53 (d, J = 6.9 Hz, 1 H), 2.38 (td, J = 3.6, 1 1 .7 Hz, 1 H), 2.24 (d, J = 12.6 Hz, 1 H), 2.05 (s, 3H), 1 .96 (d, J = 12.5 Hz, 2H), 1 .83 (s, 1 H), 1 .41 - 1 .28 (m, 4H), 1 .15 - 0.99 (m, 1 H). ¹⁹ F NMR (376 MHz, Chloroform-d) δ -58.63 (s, 1 F).

Example 461 :

(1 ,3-c;s)-3-((6-(N-(6-(o-tolyl)-5-(trifluoromethyl)pyridin-2-y l)sulfamoyl)pyridin-2- yl)amino)cyclohexanecarboxylic acid LCMS conditions 7: 1 .72 min, MS for C25H26F3N4O4S [M+H] ⁺ m/z = 535.2, found m/z = 535.2. ¹ H NMR (400 MHz, Chloroform-d) δ 7.97 (d, J = 9.0 Hz, 1 H), 7.59 (d, J = 8.8 Hz, 1 H), 7.52 (dd, J = 7.3, 8.4 Hz, 1 H), 7.35 (td, J = 1 .2, 7.5 Hz, 1 H), 7.29 (d, J = 7.1 Hz, 1 H), 7.26 - 7.24 (m, 1 H), 7.22 (d, J = 7.0 Hz, 1 H), 7.13 (d, J = 7.5 Hz, 1 H), 6.49 (d, J = 8.4 Hz, 1 H), 4.57 (s, 1 H), 3.51 (s, 1 H), 2.37 (dt, J = 5.8, 1 1 .5 Hz, 1 H), 2.22 (d, J = 1 1 .8 Hz, 1 H), 2.04 (d, J = 2.5 Hz, 3H), 1 .96 (s, 2H), 1 .85 (d, J = 19.3 Hz, 1 H), 1 .42 - 1 .28 (m, 3H), 1 .05 (q, J = 9.9, 10.4 Hz, 1 H). ¹⁹ F NMR (376 MHz, Chloroform-d) δ -58.64 (s, 1 F).

Example 462:

(1 S,2S,4R)-7-(6-(N-(6-(o-tolyl)-5-(trifluoromethyl)pyridin-2-y l)sulfamoyl)pyridin-2-yl)-7- azabicyclo[2.2.1]heptane-2-carboxylic acid LCMS conditions 7: 1 .71 min, MS for

C25H24F3N4O4S [M+H] ⁺ m/z = 533.1 , found m/z = 533.1 . Rotomers/atropisomers are present in the NMR spectra. ¹ H NMR (400 MHz, Chloroform-d) δ 9.77 (br. s, 1 H), 8.00 (d, J = 8.9 Hz, 1 H), 7.71 (d, J = 8.8 Hz, 1 H), 7.65 - 7.57 (m, 1 H), 7.42 (d, J = 7.3 Hz, 1 H), 7.33 (td, J = 1 .3, 7.5 Hz, 1 H), 7.24 (d, J = 8.9 Hz, 1 H), 7.20 (d, J = 7.4 Hz, 1 H), 7.09 (d, J = 7.5 Hz, 1 H), 6.82 (d, J = 8.4 Hz, 1 H), 4.61 (br. s, 1 H), 4.23 (br. s, 1 H), 2.95 (q, J = 7.8 Hz, 1 H), 2.01 (s, 3H), 1 .81 (d, J = 7.4 Hz, 2H), 1 .73 - 1 .61 (m, 1 H), 1 .56 (d, J = 7.5 Hz, 2H), 1 .50 - 1 .40 (m, 1 H). ¹⁹ F NMR (376 MHz, Chloroform-d) δ -58.77 (s, 1 F).

Example 463:

(1 ,3-irans)-3-((6-(N-(6-(o-tolyl)-5-(trifluoromethyl)pyridin-2 -yl)sulfamoyl)pyridin-2- yl)amino)cyclohexanecarboxylic acid LCMS conditions 7: 1 .73 min, MS for

C25H26F3N4O4S [M+H] ⁺ m/z = 535.2, found m/z = 535.2. Rotomers/atropisomers are present in the NMR spectra. ¹ H NMR (400 MHz, Chloroform-d) δ 7.99 (d, J = 8.9 Hz, 1 H), 7.61 (d, J = 7.0 Hz, 1 H), 7.58 - 7.49 (m, 1 H), 7.37 (td, J = 1 .2, 7.6 Hz, 1 H), 7.31 (d, J = 7.2 Hz, 1 H), 7.23 (d, J = 7.5 Hz, 1 H), 7.14 (d, J = 7.3 Hz, 1 H), 6.56 (d, J = 8.2 Hz, 1 H), 4.56 (s, 1 H), 3.81 - 3.69 (m, 1 H), 2.58 (t, J = 8.9 Hz, 1 H), 2.48 - 2.29 (m, 2H), 2.05 (s, 3H), 1 .95 - 1 .84 (m, 2H), 1 .79 (d, J = 10.4 Hz, 2H), 1 .65 (s, 3H). ¹⁹ F NMR (376 MHz, Chloroform-d) δ -58.75 (br. s, 1 F).

Example 464:

(3R,6S)-6-methyl-1 -(6-(N-(6-(o-tolyl)-5-(trifluoromethyl)pyridin-2-yl)sulfamoy l)pyridin-2- yl)piperidine-3-carboxylic acid LCMS conditions 7: 1 .73 min, MS for C25H26F3N4O4S

[M+H] ⁺ m/z = 535.1 , found m/z = 534.9. Rotomers/atropisomers are present in the NMR spectra. ¹ H NMR (400 MHz, Chloroform-d) δ 9.31 (br. s, 1 H), 7.99 (d, J = 8.9 Hz, 1 H), 7.75 (d, J = 8.2 Hz, 1 H), 7.59 (dd, J = 7.3, 8.7 Hz, 1 H), 7.34 - 7.28 (m, 2H), 7.22 (dd, J = 7.3, 14.5 Hz, 2H), 7.08 (d, J = 7.5 Hz, 1 H), 6.78 (d, J = 8.8 Hz, 1 H), 4.35 (d, J = 13.4 Hz, 2H), 3.00 - 2.85 (m, 1 H), 2.41 (tt, J = 4.1 , 1 1 .7 Hz, 1 H), 1 .99 (s, 3H), 1 .97 - 1 .88 (m, 2H), 1 .80 (qd, J = 4.6, 12.1 Hz, 1 H), 1 .68 (dd, J = 3.8, 8.2 Hz, 1 H), 1 .65 - 1 .57 (m, 1 H), 1 .07 (d, J = 6.8 Hz, 3H). ¹⁹ F NMR (376 MHz, Chloroform-d) δ -58.69 (s, 1 F).

Example 465:

(R)-1 -(6-(N-(6-(2,6-dimethylphenyl)-5-(trifluoromethyl)pyridin-2- yl)sulfamoyl)pyridin-2- yl)-3-methylpiperidine-3-carboxylic acidLCMS conditions 7: 1 .76 min, MS for

C26H28F3N4O4S [M+H] ⁺ m/z = 549.2, found m/z = 548.9. Rotomers/atropisomers are present in the NMR spectra. ¹ H NMR (400 MHz, Chloroform-d) δ 9.92 (br. s, 1 H), 8.13 (d, J = 8.8 Hz, 1 H), 7.82 (d, J = 8.7 Hz, 1 H), 7.42 (dd, J = 7.2, 8.7 Hz, 1 H), 7.20 (t, J = 7.6 Hz, 1 H), 7.06 (d, J = 7.6 Hz, 1 H), 6.98 (d, J = 7.6 Hz, 1 H), 6.90 (d, J = 7.2 Hz, 1 H), 6.77 (d, J = 8.7 Hz, 1 H), 4.98 (d, J = 13.6 Hz, 1 H), 3.94 (d, J = 13.8 Hz, 1 H), 3.08 (td, J = 2.7, 13.5 Hz, 1 H), 2.74 (d, J = 13.6 Hz, 1 H), 1 .99 (m), 1 .92 (s, 4H), 1 .80 (m, 1 H), 1 .51 (s, 3H), 1 .46 (dd, J = 2.4, 4.9 Hz,

-58.56 (s, 1 F).

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BIOLOGICAL ASSAYS

Measurement of delF508-CFTR-HRP surface expression in CFBE41 o- cells This assay quantifies the cell surface expressions of the mutant CFTR channel using an extracellular HRP tag.

A cellular assay was developed to measure surface expression of horseradish peroxidase (HRP) tagged delF508-CFTR in the human bronchial epithelial immortalized CFBE410- cell line (Phuan, P.W., et al, (2014) Molecular Pharmacology 86:42-51). Specifically, the HRP sequence was inserted into the fourth extracellular loop of delF508- CFTR and stably expressed in CFBE41 o- cells. Cells were seeded in 384 well plate at a density of 5000 cells/well and incubated at 37°C for 12 to 24 hours in medium (Gibco MEM #1 1095, 10% FBS, 10mM HEPES, 200mM L-Glutamine, 200μg/mL G418, 3μg/mL Puromycin). The delF508-CFTR-HRP expression was induced with 500ng/ml_ doxycycline (Sigma D-9891 , dissolved in H ₂ 0 and sterile filtered) in medium and the cells were incubated at 37°C for 48h. Old medium was removed and fresh medium was added containing 500ng/ml_ doxycycline and unknown test compound at required test concentration in DMSO, not exceeding 0.5% final DMSO concentration. The highest concentration tested was 10 μΜ with a 10-point concentration response curve using a 3-fold dilution. After addition of compounds, the cells were incubated for 24h at 37°C. On the final day, cells were washed four times in PBS containing 1 mM MgCI ₂ and 0.1 mM CaCI ₂ . HRP-Substrate (SuperSignal ELISA Pico, Fisher #37069) 20μΙΛ/νβΙΙ was added and the luminescence signal was determined (Viewlux, Perkin Elmer). Light was emitted upon addition of exogenous HRP- Substrate only when delF508-CFTR-HRP reached the cell surface and the HRP tag was accessible to the HRP-Substrate (note: HRP-Substrate cannot cross the lipid bilayer to reach delF508-CFTR-HRP misfolded within the cell).

The median activity for the lowest concentration of the compounds on each assay plate was calculated and this value was used to normalize the signal for each well on the respective plate. Three replicates at each concentrations for every compound were run to determine one EC ₅₀ . The median value was determined and used to calculate compound activities as described below. Effective half maximal values (EC ₅₀ ) were calculated for each compound by performing logistic regression on measured dose-response data points using the equation: where Ύ" is the observed activity, "Bottom" is the lowest observed value, "Top" is the highest observed value, and the "Hill coefficient" gives the largest absolute value of the slope. The curve fitting is carried out by a curve fitting program implemented at GNF using Matlab (Mathworks).

The dose response curves also were used to calculate Fold Change (FC) using the equation:

Top— Bottom

Fold change =

Bottom

Compound efficacy relative to the reference compound 3-(6-(1 -(2,2- difluorobenzo[d][1 ,3]dioxol-5-yl)cyclopropane-1 -carboxamido)-3-methylpyridin-2-yl) benzoic acid was determined using the following formula:

FC of test compound

%Amax = * 100

FC of reference compound Measurement of delF508-CFTR functional activity in primary Human Bronchial Epithelial Cells (HBECs) using Multi-Transepithelial Clamp Circuit (MTECC-24) assay This assay measures the functional activity of the CFTR channel (Chloride ion transport) in patient derived primary human bronchial epithilial cells with forskolin activation and in the presence of the CFTR corrector/potentiator combo.

Primary human delF508-CFTR bronchial epithelial cells were purchased from Asterand and cultured according to previously established methods (Fulcher et al. (2005) Methods Mol Med 107: 183-206). Briefly, vendor supplied cells were rapidly defrosted and added to a T175 flask in 50ml_ growth media (Lonza BEBM media with Lonza BEGM singlequots). Media was replaced after 24h and then cells were fed every other day until cells were 80- 90% confluent, at which point cells were cryopreserved. These P1 vials were thawed at 37°C as needed and added to T175 flasks in 50ml_ growth media at 5x10 ⁵ cells/flask. Media was replaced after 24h, and then cells were fed every other day until 80-90% confluent. Cells were lifted with 5ml_ accutase at 37°C for 5 minutes, centrifuged at 1000 rpms for 5 min (300 g), and resuspended in differentiation media (50% BEBM in DMEM, BEGM singlequots, all trans retinoic acid (5x10 8M)). Cells were then counted and cell suspension was added to collagen coated inserts at 3x10 ⁴ cells/insert in 0.15ml_ with 0.5ml_ differentiation media on the basolateral side.

Apical and basolateral media were replaced on alternate days, and following day 7 (or when confluent plus 2 days), air liquid interface was established for approximately two weeks by removal of apical media. One day prior to use on the MTECC24 system (EP-Devices, EP Design, Belgium), 0.15 ml_ of warmed (37°C) PBS was added to the apical surface of the cultures and returned to humidifier (37°C, 5%C0 ₂ incubator) for 30 min before aspirating the apical surface to remove any mucus.

Compound treatments were then prepared. Compound dilutions, typically a 10 point concentration response with 1 in 3 dilution steps, were made in 100% DMSO before dilution 1 in 1000 into differentiation medium with a final DMSO concentration of 0.1 % or 0.2% for the study. Compound containing medium was then transferred into the wells of a 24 well plate at 0.5ml_ per well and warmed for 30 min in a 37°C incubator prior to transferring washed inserts into the compound containing plates. Cells were incubated in compound containing medium (basolateral only) for 24h prior to measurement in the MTECC24 system.

Following 24hr treatment, compound dilutions were prepared again, diluted 1 in 1000 into 37°C assay medium (F-12 Coon's modified, 20mM HEPES pH7.4 with TRIS Base, No FCS or bicarbonate). Cells which were treated for 24h with test compound were then transferred into plates containing 0.75ml_ compound treatment in assay medium (basolateral) and 0.25ml_ of the compound containing assay medium was added to the apical surface. The plates were then transferred to the heated plate compartments of the MTECC24 system for 45 min prior to measurements (this can also be done in a non-C0 ₂ 37°C humidified incubator). Basolateral temperature should not exceed 36.5°C and apical temperature should be approximately 35.5°C.

Modulators were added sequentially as follows while the MTECC24 instrument recorded the equivalent short circuit current (leq):

Prior to dilution into F-12 medium the stocks are as follows:

Amiloride stock is 10mM in H ₂ 0

Forskolin Stock is 10mM in 100% DMSO

(S)-3-amino-6-methoxy-N-(3,3,3-trifluoro-2-hydroxy-2-methylp ropyl)-5- (trifluoromethyl)picolinamide is 0.5mM stock in 100% DMSO

INH-172 (4-[[4-Oxo-2-thioxo-3-[3-trifluoromethyl)phenyl]-5-thiazolid inylidene]methyl]ben acid) stock is 30mM in 100% DMSO

The data was normalized using the median signal from wells treated with 0.1 % DMSO as a baseline. Curve fitting and EC ₅₀ calculations were performed using the following equation:

where Ύ" is the observed activity, "Bottom" is the lowest observed value, "Top" is the highest observed value, and the "Hill coefficient" gives the largest absolute value of the slope. The curve fitting is carried out by a curve fitting program implemented at GNF using Matlab (Mathworks).

At least two replicates for every compound were run and EC ₅₀ reported in the table are mean values.

The dose response curves also were used to calculate Fold Change (FC) using the equation:

Top— Bottom

Fold change =

Bottom

%Amax calculations were performed using the equation:

n . . FC of test compound .

%Amax = - * 100%

FC of reference compound where the test compound (added 24h before assay) was in the presence of the potentiator (S)-3-amino-6-methoxy-N-(3,3,3-trifluoro-2-hydroxy-2-methylp ropyl)-5- (trifluoromethyl)picolinamide at the time of assay. The reference compound was combination of 2μΜ 3-(6-(1 -(2,2-difluorobenzo[d][1 ,3]dioxol-5-yl)cyclopropane-1 -carboxamido)-3- methylpyridin-2-yl)benzoic acid added 24h prior to assay and 0.5 μΜ N-(2,4-di-tert-butyl-5- hydroxyphenyl)-4-oxo-1 ,4-dihydroquinoline-3-carboxamide added at the time of assay.

Activity Table

Example No. DelF508- DelF508- MTECC24 MTECC24

CFTR-HRP CFTR-HRP CFHBEC- CFHBEC-

ECso (μΜ) Amax % ECso (μΜ) Amax %

1 1 .781 867.1 0.004 78.9

2 0.967 724.1 0.008 75.5

3 1 .443 688.1 0.0019 60.3

4 0.912 632.0 0.0408 52.0

5 1 .149 628.6 0.003 97.56

6 1 .506 612.2 0.0131 61 .0

7 1 .628 609.9 0.0027 66.8

8 1 .36 607.8 NT NT

9 1 .516 596.6 NT NT

10 1 .533 591 .9 0.0058 87.0

1 1 1 .352 578.7 0.0136 94.3

12 1 .322 555.3 0.0097 85.2

13 1 .308 536.2 0.0240 100.1

14 1 .352 523.4 NT NT

15 2.299 520.5 NT NT

16 1 .012 519.4 NT NT

17 2.091 509.9 0.0051 69.5

18 1 .885 504.6 0.0079 65.5

19 1 .296 501 .1 NT NT

20 1 .76 499.4 NT NT

21 1 .357 492.8 NT NT

22 1 .616 489.5 NT NT Example No. DelF508- DelF508- MTECC24 MTECC24

CFTR-HRP CFTR-HRP CFHBEC- CFHBEC-

EC ₅₀ (μΜ) Amax % EC ₅₀ (μΜ) Amax %

23 1.879 486.1 NT NT

24 1.458 484.6 NT NT

25 1.061 481.8 0.0145 94.2

26 2.204 450.2 NT NT

27 1.716 430.0 NT NT

28 1.384 429.2 0.0016 77.1

29 1.077 429.1 NT NT

30 1.702 421.0 NT NT

31 1.316 418.1 NT NT

32 1.643 412.0 NT NT

33 2.196 404.0 NT NT

34 2.518 399.5 0.0116 58.2

35 2.113 397.7 NT NT

36 2.097 390.2 0.0259 67.6

37 2.285 385.5 NT NT

38 1.998 376.5 NT NT

39 1.899 374.3 NT NT

40 2.358 373.1 NT NT

41 2.34 367.9 0.0139 88.8

42 2.263 367.2 0.0399 72.4

43 2.118 361.2 0.0633 54.2

44 1.771 346.5 0.0460 61.6

45 1.235 345.4 NT NT

46 1.946 339.3 NT NT

47 1.396 335.2 NT NT

48 2.327 334.0 NT NT

49 3.048 332.9 NT NT

50 0.683 332.4 NT NT

51 1.982 332.2 NT NT

52 1.379 327.1 NT NT

53 1.844 324.7 NT NT

54 2.354 305.3 NT NT

55 1.7 305.2 0.0155 86.7

56 2.579 301.3 0.0283 63.9

57 1.075 284.6 0.1184 72.9

58 1.777 269.7 NT NT

59 1.102 258.0 NT NT

60 2.98 253.1 NT NT

61 2.62 251.1 0.1026 74.0

62 1.73 239.5 0.0512 46.1

63 2.687 225.6 NT NT

64 1.959 223.1 NT NT

65 1.536 220.1 NT NT

66 3.072 214.6 NT NT

67 1.844 214.1 0.1136 45.8

68 2.425 208.6 NT NT

69 3.3 198.7 NT NT

70 2.636 197.4 NT NT

71 3.55 196.4 NT NT

72 3.41 192.6 NT NT

73 4.24 162.9 0.1345 64.2 Example No. DelF508- DelF508- MTECC24 MTECC24

CFTR-HRP CFTR-HRP CFHBEC- CFHBEC-

EC ₅₀ (μΜ) Amax % EC ₅₀ (μΜ) Amax %

74 2.576 158.4 0.2834 67.3

75 2.838 158.2 NT NT

76 2.304 155.5 NT NT

77 2.552 151.7 NT NT

78 2.727 141.1 NT NT

79 2.297 140.9 NT NT

80 2.284 136.9 0.0960 50.7

81 1.982 126.6 NT NT

82 0.942 124.4 NT NT

83 4.11 115.4 NT NT

84 1.537 110.9 NT NT

85 3.68 110.3 NT NT

86 3.53 107.8 NT NT

87 4.1 93.8 NT NT

88 3.78 92.9 NT NT

89 3.86 91.5 0.0399 35.7

90 3.78 50.0 NT NT

91 2.202 41.7 NT NT

92 1.109 23.9 NT NT

93 3.55 23.5 NT NT

94 3.19 20.3 NT NT

95 3.75 19.0 NT NT

96 4.33 10.0 NT NT

102 3.28 576.9 0.1361 54.3

103 2.974 370.2 0.0948 67.8

104 2.135 999.0 0.0245 73.4

105 3.19 309.9 0.2220 58.1

106 2.576 911.5 0.0795 106.4

107 1.993 755.6 0.1107 72.2

108 4.07 336.0 0.0549 61.4

109 2.682 331.5 0.1696 84.9

110 2.797 372.2 0.0280 65.6

111 0.0318 59.5

112 4.05 172.5 0.4950 55.0

113 4.22 72.0 NT NT

114 3.63 66.2 NT NT

115 3.81 192.0 NT NT

116 3.16 370.5 0.1071 60.8

117 2.78 264.3 0.0331 74.7

118 2.601 491.7 0.0117 78.5

119 1.832 411.3 0.0553 70.2

120 2.817 269.6 0.0372 57.9

121 3.45 308.1 0.1644 79.6

122 2.689 384.6 0.0271 81.8

123 3.151 217.7 0.2384 85.2

124 4.61 147.6 NT NT

125 1.944 214.8 0.0475 67.5

126 2.175 235.2 NT NT

127 2.323 382.0 0.0157 45.4

128 2.24 729.6 0.0053 61.9

129 1.723 1030.4 0.0195 54.8 Example No. DelF508- DelF508- MTECC24 MTECC24

CFTR-HRP CFTR-HRP CFHBEC- CFHBEC-

EC ₅₀ (μΜ) Amax % EC ₅₀ (μΜ) Amax %

130 2.921 156.7 0.0841 37.9

131 2.136 728.7 0.0250 78.4

132 0.803 894.0 NT NT

133 2.033 570.2 0.0979 71 .2

134 1 .98 905.9 0.0190 1 12.7

135 3.44 804.5 0.0130 95.3

136 1 .108 861 .5 NT NT

137 1 .352 853.5 NT NT

138 0.681 635.7 0.0156 108.4

139 4.97 53.2 NT NT

140 3.48 395.4 0.0295 65.3

141 2.015 938.2 0.0086 88.7

142 2.631 418.4 0.0052 63.7

143 2.99 888.4 NT NT

144 1 .883 1088.9 0.0020 80.5

145 1 .271 1275.6 0.0050 90.9

146 4.28 59.1 NT NT

147 0.375 482.5 0.0042 92.8

148 2.458 362.7 0.0854 74.1

149 1 .746 289.0 0.0228 76.0

150 3.51 180.5 0.0973 64.4

151 3.69 186.8 0.0956 75.3

152 2.676 332.5 0.0578 62.5

153 3.8 158.9 NT NT

154 3.46 395.2 0.2387 69.5

155 4.4 196.1 NT NT

156 4.03 177.6 NT NT

157 4.28 179.5 NT NT

158 4.19 229.7 0.0935 76.6

159 4.42 129.6 NT NT

160 0.743 476.0 0.0233 88.2

161 2.905 221 .9 0.0916 88.2

162 0.666 662.1 0.0177 58.8

163 3.142 304.7 0.0590 64.8

164 1 .058 577.7 0.0495 74.3

165 2.902 401 .4 0.3420 50.8

166 0.744 1224.3 0.01 18 62.4

167 3.71 316.6 0.0855 67.6

168 0.626 271 .1 NT NT

169 4 182.0 0.1442 40.5

170 2.204 306.3 0.1743 63.3

171 2.732 504.9 0.1 176 66.2

172 2.51 1 683.6 0.3144 77.0

173 2.369 682.3 0.0769 61 .4

174 2.64 515.4 0.2074 57.1

175 3.27 530.1 0.2813 63.4

176 3.42 528.7 0.2239 69.8

177 2.809 447.1 0.2317 79.7

178 1 .146 231 .4 0.2087 66.3

179 2.081 1082.0 0.0316 91 .9

180 1 .503 626.9 0.0094 44.5 Example No. DelF508- DelF508- MTECC24 MTECC24

CFTR-HRP CFTR-HRP CFHBEC- CFHBEC-

EC ₅₀ (μΜ) Amax % EC ₅₀ (μΜ) Amax %

181 2.67 453.8 0.0398 101.5

182 3.22 485.4 0.0878 89.6

183 0.896 191.4 0.0749 67.8

184 0.835 149.2 0.0535 69.2

185 1.456 877.0 0.0046 105.5

186 1.187 1049.3 0.0026 81.5

187 2.562 633.7 0.0920 78.8

188 0.971 658.3 NT NT

189 2.834 414.2 0.0317 79.0

190 3.41 565.3 0.0132 64.5

191 3.86 205.5 0.1013 64.4

192 2.521 279.4 0.0161 42.3

193 3.92 385.1 0.1780 81.2

194 3.84 177.3 NT NT

195 3.38 213.2 0.4640 80.0

196 3.061 389.0 0.0096 82.4

197 3.65 499.8 0.0670 73.9

198 1.953 691.5 NT NT

199 2.224 700.3 0.0383 87.1

200 3.17 553.1 NT NT

201 2.619 570.5 0.1354 75.9

202 3.93 159.4 NT NT

203 2.979 297.9 0.0233 80.9

204 1.727 943.3 0.0057 90.6

205 1.287 592.4 0.0018 66.8

206 3.7 95.9 NT NT

207 2.267 503.4 0.0194 78.0

208 1.381 607.0 0.0052 88.1

209 2.7 231.2 0.1392 95.6

210 0.716 507.1 0.0022 68.7

211 1.755 1042.4 0.0086 71.6

212 1.816 377.7 0.0820 68.0

213 2.49 224.3 0.0478 78.0

214 2.034 255.9 0.0519 71.1

215 2.104 302.6 0.0047 66.4

216 1.71 446.1 0.0048 82.1

217 0.3079 157.1 0.0380 66.3

218 1.745 465.3 0.0230 59.5

219 1.599 711.4 0.0111 119.0

220 1.606 901.5 0.0032 58.6

221 1.323 552.0 0.0070 63.5

222 1.711 427.0 0.0106 61.1

223 1.918 426.8 0.0144 59.9

224 1.383 499.1 0.0049 63.9

225 2.74 360.8 0.0176 87.7

226 2.399 720.8 0.0129 83.5

227 2.67 402.9 0.0491 104.9

228 2.994 405.0 0.0381 87.0

229 4.29 341.3 0.0533 69.0

230 2.94 512.7 0.0211 60.6

231 1.157 465.1 0.0206 71.8 Example No. DelF508- DelF508- MTECC24 MTECC24

CFTR-HRP CFTR-HRP CFHBEC- CFHBEC-

EC ₅₀ (μΜ) Amax % EC ₅₀ (μΜ) Amax %

232 1.7 349.0 0.0319 72.3

233 1.527 586.5 0.0052 85.3

234 1.934 513.1 0.0113 84.0

235 1.975 202.8 0.1820 57.6

236 0.573 601.9 NT NT

237 1.459 544.2 0.0043 55.4

238 3.46 425.8 0.0196 59.0

239 4.51 279.6 NT NT

240 3.42 385.2 NT NT

241 2.89 509.5 0.0124 48.9

242 2.92 468.2 0.0203 63.2

243 2.60 151.7 NT NT

244 3.65 221.8 NT NT

245 3.44 246.3 0.0431 48.0

246 1.787 875.3 0.0510 56.3

247 3.088 492.9 0.1911 57.0

248 1.608 568.0 0.0066 68.2

249 1.525 1104.7 0.0067 79.6

250 1.829 744.2 0.0110 59.4

251 1.448 894.2 0.0032 61.2

252 2.469 601.6 NT NT

253 2.289 202.7 0.0278 67.1

254 2.586 620.5 0.0038 62.2

255 3.159 222.0 0.0104 55.1

256 2.775 661.9 0.0029 52.6

257 1.352 197.8 0.0218 63.0

258 1.39 827.8 NT NT

259 1.566 801.1 0.0019 66.7

260 3.8 59.8 NT NT

261 4.14 22.8 NT NT

262 2.294 627.7 0.0140 81.2

263 2.867 481.1 0.0083 54.4

264 2.602 447.7 0.0117 67.2

265 1.828 879.3 0.0134 53.1

266 1.283 1404.5 NT NT

267 1.256 887.3 NT NT

268 3.73 103.3 NT NT

269 4 104.6 NT NT

270 1.936 560.8 0.0950 69.5

271 1.084 837.2 0.0088 66.6

272 2.313 806.0 0.0105 66.4

273 1.382 1065.8 0.0064 70.9

274 1.87 778.6 0.0033 77.0

275 1.07 1173.7 0.0015 77.9

276 3.2 523.1 0.0185 84.7

277 2.008 817.4 0.0046 85.1

278 1.098 1274.2 0.0054 73.4

279 1.193 1505.3 0.0035 93.7

280 1.96 844.4 0.0025 96.3

281 2.01 679.5 0.0037 85.9

282 1.88 1003.2 0.0024 69.6 Example No. DelF508- DelF508- MTECC24 MTECC24

CFTR-HRP CFTR-HRP CFHBEC- CFHBEC-

EC ₅₀ (μΜ) Amax % EC ₅₀ (μΜ) Amax %

283 1 .589 1 102.6 0.0008 84.0

284 2.28 492.8 0.0009 85.2

285 1 .235 1328.1 0.0189 74.1

286 1 .491 847.0 0.0239 153.1

287 1 .407 383.6 0.0071 74.8

288 1 .712 495.1 0.0341 69.5

289 2.358 450.0 0.0121 50.5

290 1 .441 615.6 0.0466 71 .4

291 2.5 496.5 0.0133 73.6

292 2.971 224.6 NT NT

293 1 .957 589.8 0.0220 78.6

294 2.363 641 .4 0.01 10 81 .9

295 2.035 467.8 0.0261 68.7

296 3.22 254.8 0.0300 54.3

297

298 1 .49 676.9 NT NT

299 2.44 554.5 0.0094 61 .7

300 3.27 625.6 0.0128 43.5

301 0.67 545.6 NT NT

302 2.32 530.2 0.0183 74.4

303 3.17 491 .2 0.0717 65.5

304 3.92 421 .4 0.0085 63.4

305 2.63 312.2 0.0443 81 .3

306 3.05 417.9 0.0315 88.1

307 3.76 258.8 0.0458 61 .5

308 3.75 232.6 0.2066 60.7

309 3.79 194.5 0.2102 75.6

310 4.98 136.8 NT NT

31 1 3.27 179.0 0.2199 61 .7

312 3.97 166.6 0.4583 49.8

313 4.57 128.1 NT NT

314 1 .59 1634.22 0.0100 96.4

315 3.29 269.3 0.0520 60.9

316 NT NT NT NT

317 4.67 185.3 NT NT

318 3.17 318.5 0.0776 48.7

319 3.48 194.9 0.0250 67.1

320 2.22 544.8 0.1256 74.2

321 1 .72 413.2 0.0183 49.1

322 2.61 309.6 0.2219 52.6

323 2.77 252.5 0.1472 67.7

324 2.64 401 .8 0.0479 49.4

325 2.40 257.3 0.0154 60.1

326 3.81 102.6 0.2034 50.5

327 4.26 92.5 NT NT

328 1 .79 1224.3 NT NT

329 0.93 1869.6 NT NT

330 2.301 9.1 NT NT

331 1 .522 218.5 0.0649 67.4

332 1 .109 521 .4 0.00475 84.0

333 1 .954 427.7 0.0079 47.6 Example No. DelF508- DelF508- MTECC24 MTECC24

CFTR-HRP CFTR-HRP CFHBEC- CFHBEC-

EC ₅₀ (μΜ) Amax % EC ₅₀ (μΜ) Amax %

334 2.472 164.2 NT NT

335 3.136 71.3 NT NT

336 1.763 265.5 NT NT

337 2.25 1082.2 0.002723 51.5

338 2.806 542.2 NT NT

339 2.314 122.5 NT NT

340 2.449 277.6 NT NT

341 3.026 89.2 NT NT

342 1.898 265.7 0.0802 85.8

343 2.148 197.1 0.0861 65.3

344 2.808 132.1 0.02277 46.7

345 1.331 557.2 0.0415 90.4

346 1.753 296.6 NT NT

347 1.893 245.0 NT NT

348 2.834 144.7 NT NT

349 1.642 252.3 NT NT

350 1.897 232.4 NT NT

351 0.87 492.1 0.107 99.7

352 0.699 714.0 0.000808 82.2

353 2.799 118.0 NT NT

354 2.738 154.1 NT NT

355 3.69 139.9 NT NT

356 1.513 553.8 0.00749 70.1

357 2.063 1024.1 0.0385 70.6

358 2.317 868.6 0.00402 57.9

359 1.956 647.9 0.002039 86.7

360 2.109 546.4 0.0474 57.5

361 2.079 1087.2 0.01126 51.9

362 2.005 1074.6 0.000533 77.9

363 0.705 615.5 NT NT

364 1.593 230.7 NT NT

365 1.888 165.6 NT NT

366 1.342 1225.4 0.000797 66.9

367 0.928 808.8 0.001398 91.2

368 0.671 1232.3 0.000152 66.2

369 1.724 962.2 NT NT

370 1.465 601.0 0.00085 105.9

371 1.126 961.9 0.00197 254.3

372 2.254 554.3 NT NT

373 0.273 367.1 0.001168 93.1

374 2.78 233.4 0.1326 39.8

375 1.209 1030.2 0.000682 63.5

376 0.913 629.2 NT NT

377 0.738 1477.2 NT NT

378 1.355 271.8 NT NT

379 1.081 645.7 NT NT

380 2.656 42.3 NT NT

381 2.506 284.0 NT NT

382 0.711 503.5 NT NT

383 0.498 1247.1 NT NT

384 0.501 1041.9 NT NT Example No. DelF508- DelF508- MTECC24 MTECC24

CFTR-HRP CFTR-HRP CFHBEC- CFHBEC-

EC ₅₀ (μΜ) Amax % EC ₅₀ (μΜ) Amax %

385 0.81 668.0 NT NT

386 0.605 1028.5 NT NT

387 1.634 587.9 NT NT

388 1.017 927.8 NT NT

389 1.043 749.3 NT NT

390 0.761 889.1 NT NT

391 0.53 502.9 NT NT

392 0.527 459.5 NT NT

393 1.038 680.4 NT NT

394 1.053 1331.2 NT NT

395 3.65 64.3 NT NT

396 0.845 1255.6 NT NT

397 1.279 303.3 NT NT

398 0.615 711.2 NT NT

399 2.088 727.9 NT NT

400 1.096 672.3 NT NT

401 0.796 1956.7 NT NT

402 0.778 728.9 NT NT

403 2.362 155.3 NT NT

404 0.786 1026.4 NT NT

405 2.483 235.3 NT NT

406 1.52 334.4 NT NT

407 1.605 467.6 NT NT

408 1.985 271.2 NT NT

409 1.669 330.0 NT NT

410 1.922 209.8 NT NT

411 1.391 400.0 NT NT

412 1.89 221.2 NT NT

413 0.576 906.4 NT NT

414 1.891 683.7 NT NT

415 1.77 1593.6 NT NT

416 1.896 1421.9 NT NT

417 1.883 1384.8 NT NT

418 1.221 643.6 NT NT

419 2.395 643.9 NT NT

420 1.925 704.9 NT NT

421 2.044 1139.0 NT NT

422 1.38 904.6 NT NT

423 0.757 2390.0 NT NT

424 2.019 1277.6 NT NT

425 1.223 1088.4 NT NT

426 2.317 287.3 NT NT

427 0.638 281.8 NT NT

428 1.681 712.9 NT NT

429 0.838 541.2 NT NT

430 1.713 370.0 NT NT

431 1.734 762.8 NT NT

432 1.916 596.1 NT NT

433 0.436 570.8 NT NT

434 2.227 734.4 NT NT

435 2.296 714.3 NT NT Example No. DelF508- DelF508- MTECC24 MTECC24

CFTR-HRP CFTR-HRP CFHBEC- CFHBEC-

EC ₅₀ (μΜ) Amax % EC ₅₀ (μΜ) Amax %

436 1 .768 438.3 NT NT

437 1 .563 869.0 NT NT

438 1 .981 53.4 NT NT

439 2.223 264.0 NT NT

440 2.54 274.4 NT NT

441 2.31 299.0 NT NT

442 1 .244 1732.1 NT NT

443 1 .752 1 161 .6 NT NT

444 4.06 47.5 NT NT

445 2.664 94.1 NT NT

446 2.1 15 278.5 NT NT

447 2.407 1204.1 NT NT

448 1 .493 1634.9 NT NT

449 2.367 1083.5 NT NT

450 1 .099 1773.2 NT NT

451 2.675 846.8 NT NT

452 2.358 990.0 NT NT

453 1 .594 1430.2 NT NT

454 1 .701 1 136.1 NT NT

455 1 .769 899.2 NT NT

456 1 .358 464.6 NT NT

457 0.622 702.0 NT NT

458 1 .598 638.7 NT NT

459 2.365 331 .5 NT NT

460 1 .806 361 .5 NT NT

461 1 .947 391 .6 NT NT

462 2.933 107.7 NT NT

463 2.954 410.0 NT NT

464 2.433 815.9 NT NT

465 1 .726 1977.5 NT NT

As indicated by the test results described hereinbefore, compounds of the present invention may be useful for treating diseases, conditions and disorders through the modulation of CFTR function; consequently, the compounds of the present invention (including the compositions and processes used therein) may be used in the manufacture of a medicament for the therapeutic applications described herein. Hence, another

Embodiment of the present invention is a pharmaceutical composition comprising a compound of the present invention either alone or in combination with at least one additional therapeutic agent, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable diluent or carrier.