Aza-indazole compounds for use in tendon and/or ligament injuries

Abstract

The present invention provides a compound of formula (I) in free form or in pharmaceutically acceptable salt form ##STR00001##
a method for manufacturing the compounds of the invention, and its therapeutic uses. The present invention further provides a combination of pharmacologically active agents and a pharmaceutical composition.

Claims

1. A method of treating a tendon injury in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein: ##STR00148## R.sub.1 is selected from C1-C3alkyl and halogen; R.sub.2 is —SO.sub.2NR.sub.5R.sub.6; R.sub.5 is selected from H and C.sub.1-C.sub.3alkyl; R.sub.6 is selected from a C.sub.3-C.sub.6cycloalkyl optionally substituted with R.sub.7; phenyl optionally substituted with halogen; C.sub.1-C.sub.6alkyl optionally substituted with hydroxyl; 4- to 6-membered heterocyclic non-aromatic ring comprising at least one heteroatom selected from N, O or S optionally substituted with oxo; and benzyl; and R.sub.7 is independently selected from hydroxyl, haloC.sub.1-C.sub.3alkyl, halogen, C.sub.1-C.sub.3alkyl, C(O)OH, and hydroxyC.sub.1-C.sub.3alkyl; or R.sub.5 and R.sub.6 together with the N atom to which they are attached form a 4-, 5- or 6-membered heterocyclic non-aromatic ring optionally comprising one additional heteroatom selected from N, O, or S, wherein the ring is optionally substituted with R.sub.8; or a 6- to 8-membered saturated bicyclic ring system; and R.sub.8 is independently selected from halogen, hydroxyC.sub.1-C.sub.3alkyl, C(O)NH.sub.2, hydroxyl, haloC.sub.1-C.sub.3alkyl optionally substituted with hydroxyl, phenoxy, and SO.sub.2C.sub.1-C.sub.3alkyl.

2. The method of claim 1, wherein: R.sub.1 is chloro or methyl; and R.sub.2 is SO.sub.2NR.sub.5R.sub.6.

3. The method of claim 1, wherein: R.sub.5 is H or methyl; R.sub.6 is C.sub.4-C.sub.6cycloalkyl optionally substituted once or more than once with R.sub.7; and R.sub.7 is independently selected from hydroxyl, haloC.sub.1-C.sub.3alkyl, halogen, C.sub.1-C.sub.3alkyl, and hydroxyC.sub.1-C.sub.3alkyl.

4. The method of claim 1, wherein the compound is 4-(3-amino-1H-pyrazolo[4,3-b]pyridin-5-yl)-3-chloro-N-((1s,3s)-3-hydroxy-3-(trifluoromethyl)cyclobutyl)benzenesulfonamide or a pharmaceutically acceptable salt thereof.

5. The method of claim 1, wherein the compound is 4-(3-amino-1H-pyrazolo[4,3-b]pyridin-5-yl)-N-(3,3-difluorocyclobutyl)-3-methylbenzenesulfonamide or a pharmaceutically acceptable salt thereof.

6. The method of claim 1, wherein the compound is 4-(3-amino-1H-pyrazolo[4,3-b]pyridin-5-yl)-N-((1s,3s)-3-hydroxy-3-(trifluoromethyl)cyclobutyl)-N,3-dimethylbenzenesulfonamide or a pharmaceutically acceptable salt thereof.

7. The method of claim 1, wherein the compound is 4-(3-amino-1H-pyrazolo[4,3-b]pyridin-5-yl)-3-chloro-N-(1,1-dioxidothietan-3-yl)benzenesulfonamide or a pharmaceutically acceptable salt thereof.

8. The method of claim 1, wherein the compound is 4-(3-amino-1H-pyrazolo[4,3-b]pyridin-5-yl)-3-chloro-N-phenylbenzenesulfonamide or a pharmaceutically acceptable salt thereof.

9. The method of claim 1, wherein the compound is 1-((4-(3-amino-1H-pyrazolo[4,3-b]pyridin-5-yl)-3-methylphenyl)sulfonyl)-3-(trifluoromethyl)azetidin-3-ol or a pharmaceutically acceptable salt thereof.

10. The method of claim 1, wherein the tendon injury is selected from a tendon partial rupture, a tendon full rupture, and tendon degeneration.

11. The method of claim 1, wherein the tendon is the Achilles tendon or a rotator cuff tendon.

12. A method of treating a ligament injury in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein: ##STR00149## R.sub.1 is selected from C.sub.1-C.sub.3alkyl and halogen; R.sub.2 is —SO.sub.2NR.sub.5R.sub.6; R.sub.5 is selected from H and C.sub.1-C.sub.3alkyl; R.sub.6 is selected from a C.sub.3-C.sub.6cycloalkyl optionally substituted with R.sub.7; phenyl optionally substituted with halogen; C.sub.1-C.sub.6alkyl optionally substituted with hydroxyl; 4- to 6-membered heterocyclic non-aromatic ring comprising at least one heteroatom selected from N, O or S optionally substituted with oxo; and benzyl; and R.sub.7 is independently selected from hydroxyl, haloC.sub.1-C.sub.3alkyl, halogen, C.sub.1-C.sub.3alkyl, C(O)OH, and hydroxyC.sub.1-C.sub.3alkyl; or R.sub.5 and R.sub.6 together with the N atom to which they are attached form a 4-, 5- or 6-membered heterocyclic non-aromatic ring optionally comprising one additional heteroatom selected from N, O, or S, wherein the ring is optionally substituted with R.sub.8; or a 6- to 8-membered saturated bicyclic ring system; and R.sub.8 is independently selected from halogen, hydroxyC.sub.1-C.sub.3alkyl, C(O)NH.sub.2, hydroxyl, haloC.sub.1-C.sub.3alkyl optionally substituted with hydroxyl, phenoxy, and SO.sub.2C.sub.1-C.sub.3alkyl.

13. The method of claim 12, wherein: R.sub.1 is chloro or methyl; and R.sub.2 is SO.sub.2NR.sub.5R.sub.6.

14. The method of claim 12, wherein: R.sub.5 is H or methyl; R.sub.6 is C.sub.4-C.sub.6cycloalkyl optionally substituted once or more than once with R.sub.7; and R.sub.7 is independently selected from hydroxyl, haloC.sub.1-C.sub.3alkyl, halogen, C.sub.1-C.sub.3alkyl, and hydroxyC.sub.1-C.sub.3alkyl.

15. The method of claim 12, wherein the compound is 4-(3-amino-1H-pyrazolo[4,3-b]pyridin-5-yl)-3-chloro-N-((1s,3s)-3-hydroxy-3-(trifluoromethyl)cyclobutyl)benzenesulfonamide or a pharmaceutically acceptable salt thereof.

16. The method of claim 12, wherein the compound is 4-(3-amino-1H-pyrazolo[4,3-b]pyridin-5-yl)-N-(3,3-difluorocyclobutyl)-3-methylbenzenesulfonamide or a pharmaceutically acceptable salt thereof.

17. The method of claim 12, wherein the compound is 4-(3-amino-1H-pyrazolo[4,3-b]pyridin-5-yl)-N-((1s,3s)-3-hydroxy-3-(trifluoromethyl)cyclobutyl)-N,3-dimethylbenzenesulfonamide or a pharmaceutically acceptable salt thereof.

18. The method of claim 12, wherein the compound is 4-(3-amino-1H-pyrazolo[4,3-b]pyridin-5-yl)-3-chloro-N-(1,1-dioxidothietan-3-yl)benzenesulfonamide or a pharmaceutically acceptable salt thereof.

19. The method of claim 12, wherein the compound is 4-(3-amino-1H-pyrazolo[4,3-b]pyridin-5-yl)-3-chloro-N-phenylbenzenesulfonamide or a pharmaceutically acceptable salt thereof.

20. The method of claim 12, wherein the compound is 1-((4-(3-amino-1H-pyrazolo[4,3-b]pyridin-5-yl)-3-methylphenyl)sulfonyl)-3-(trifluoromethyl)azetidin-3-ol or a pharmaceutically acceptable salt thereof.

21. The method of claim 12, wherein the ligament injury is selected from a ligament partial rupture, a ligament full rupture, and ligament degeneration.

Description

EXAMPLES

Abbreviations

(1) δ chemical shift ACN acetonitrile aq. aqueous API-MS atmospheric pressure ionization mass spectroscopy cDNA complimentary deoxyribonucleic acid Ct cycle threshold DCM methylene chloride DIPEA diisopropylethylamine DMSO-d.sub.6 dimethylsulfoxide-d6 EtOAc ethyl acetate EtOH ethanol ESI-MS electron-spray ionisation mass spectroscopy FIA-MS flow injection analysis mass spectroscopy h hour HBSS Hank's Balanced Salt Solution HPLC high performance liquid chromatography K.sub.2CO.sub.3 potassium carbonate KOAc potassium acetate L liter LiAlH.sub.4 lithium aluminium hydride LPM liters per minute M molar mg milligram mM millimolar MeOH methanol min minute mL milliliter MgSO.sub.4 magnesium sulfate MHz megahertz MSCGM Mesenchymal Stem Cell Growth Media MW microwave N normal Na.sub.2SO.sub.4 sodium sulfate NaHCO.sub.3 sodium bicarbonate NaOH sodium hydroxide NH.sub.4Cl ammonium chloride NH.sub.4OH ammonium hydroxide NMR nuclear magnetic resonance PCy.sub.3 tricyclohexylphosphine PdCl.sub.2(dppf) [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) ppm parts per million qPCR quantitative polymerase chain reaction RNA ribonucleic acid RT room temperature SAIB sucrose acetate isobutyrate sat. aq. saturated aqueous Scx scleraxis Scx-Luc scleraxis-luciferase SFC supercritical fluid chromatography TGFβ1 transforming growth factor-beta 1 THF tetrahydrofuran t.sub.R retention time UPLC-MS ultra high performance liquid chromatography mass spectroscopy

(2) UPLC-MS

(3) Column: Waters Acquity HSS T3, 1.8 μm, 2.1×50 mm, oven at 60° C. Flow: 1.0 mL/min. Gradient: 5% to 98% B in 1.40 min, then 98% B for 0.40 min, 98% to 5% B in 0.10 min, 5% B for 0.10 min; A=water+0.05% formic acid+3.75 mM ammonium acetate, B=acetonitrile+0.04% formic acid. Detection UV/VIS (DAD), ESI (+/−). Mass spectrometer range: 100-1200 Da.

(4) Preparative HPLC (Method 1)

(5) Gilson GX-281, pumps 331/332.

(6) Column: Waters Sunfire C18, 30×100 mm, 5 μm. Flowrate 30 mL/min.

(7) Mobile phase: Water+0.1% TFA and Acetonitrile.

(8) Reverse Phase Column Chromatography (Method 2):

(9) Teledyne ISCO CombiFlash

(10) Column Redisep Rf Gold C18 High Performance, 15.5 g or 50 g pre-packed columns, 20-40 μm, 100A

(11) Mobile phase: Water and Acetonitrile

(12) Preparative HPLC (Method 3)

(13) Gilson GX-281, pumps 331/332.

(14) Column: Dr Maisch Reprosil-Pur Basic C18 5 μm, 30×100 mm)

(15) Mobile phase: Water (+7.3 mM NH.sub.4OH) and Acetonitrile (+7.3 mM NH.sub.4OH)

(16) Preparative achiral SFC (Method 4)

(17) Waters THAR SFC 100

(18) Flowrate: 100 mL/min

(19) Mobile phase: MeOH

(20) NMR

(21) Measurements were performed on a Bruker Ultrashield Plus™ 400 (400 MHz) spectrometer using or not tetramethylsilane as an internal standard. Chemical shifts (d-values) are reported in ppm downfield from tetramethylsilane, spectra splitting pattern are designated as singlet (s), doublet (d), triplet (t), quartet (q), multiplet, unresolved or more overlapping signals (m), broad signal (br). Solvents are given in parentheses.

INTERMEDIATES

Intermediate 1a: 4-bromo-3-chloro-N-((1s,3s)-3-hydroxy-3-(trifluoromethyl)cyclobutyl)benzenesulfonamide

(22) A solution of 4-bromo-3-chlorobenzene-1-sulfonyl chloride (80 mg, 0.28 mmol) and (1s,3s)-3-amino-1-(trifluoromethyl)cyclobutan-1-ol hydrochloride (53 mg, 0.28 mmol) in DCM (2 mL) was stirred at 0° C. and DIPEA (0.15 mL, 0.83 mmol) was added. The reaction mixture was allowed to reach room temperature and stirred for 2 h, then partitioned between EtOAc and an sat. aq. NaHCO.sub.3 solution. The aq. layer was extracted twice with EtOAc. The combined organic layers were washed with brine, dried over anhydrous MgSO.sub.4, filtered and concentrated under reduced pressure. The crude material was purified by silica gel column chromatography (0 to 30% EtOAc in Cyclohexane) to give the title compound as a white solid. (UPLC-MS) t.sub.R 1.07 min; ESI-MS 408.0 [M−H].sup.+.

Intermediate 1b: 3-chloro-4-(6-cyano-5-fluoropyridin-2-yl)-N-((1s,3s)-3-hydroxy-3-(trifluoromethyl)cyclobutyl)benzenesulfonamide

(23) Step 1: A vial was charged with 6-bromo-3-fluoropicolinonitrile (48 mg, 0.24 mmol), bis(pinacolato)diboron (73 mg, 0.29 mmol), KOAc (47 mg, 0.48 mmol) and PdCl.sub.2(dppf) (8.7 mg, 0.012 mmol). The vial was sealed, dioxane (4 mL) was added via syringe, and the reaction mixture was stirred at 80° C. for 1 h, cooled down to room temperature, diluted with DCM/EtOAc and passed through a pad of Celite. The pad was washed several times with EtOAc and MeOH. The combined filtrates were concentrated under reduced pressure to give crude 3-fluoro-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)picolinonitrile.

(24) Step 2: The crude material was diluted with ACN (4 mL) and treated with 4-bromo-3-chloro-N-((1s,3s)-3-hydroxy-3-(trifluoromethyl)cyclobutyl)benzenesulfonamide (Intermediate 1a, 103 mg, 0.24 mmol), K.sub.2CO.sub.3 (99 mg, 0.72 mmol), and PdCl.sub.2(dppf) (8.7 mg, 0.012 mmol). The vial was sealed and irradiated in a microwave reactor at 120° C. for 30 min. The reaction was diluted with EtOAc and passed through a pad of Celite. The filtrate was washed with a sat. aq. NaHCO.sub.3 solution, and the aq. layer was extracted twice with EtOAc. The combined organic layers were washed with brine, dried over anhydrous MgSO.sub.4, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (0 to 50% EtOAc in Cyclohexane) to give the title compound as an off-white solid. (UPLC-MS) t.sub.R 1.06 min; ESI-MS 448.0 [M−H].sup.+.

Intermediate 2a: 4-bromo-N-((1s,3s)-3-hydroxy-3-(trifluoromethyl)cyclobutyl)-3-methylbenzenesulfonamide

(25) A solution of (1s,3s)-3-amino-1-(trifluoromethyl)cyclobutan-1-ol hydrochloride (ActivateScientific, CAS Nr. 1408075-93-3) (249 mg, 1.30 mmol) in pyridine (6.5 ml) was treated with 4-bromo-3-methylbenzenesulfonyl chloride (Sigma-Aldrich, CAS Nr. 72256-93-0) (350 mg, 1.30 mmol) and stirred at 50° C. for 3 h. The reaction mixture was concentrated under reduced pressure and the resulting product was purified by silica gel column chromatography (0 to 100% EtOAc in hexanes) to afford the title compound. (UPLC-MS) t.sub.R 1.60 min; API-MS 387.9 [M+H].sup.+.

Intermediate 2b: 4-(6-cyano-5-fluoropyridin-2-yl)-N-((1s,3s)-3-hydroxy-3-(trifluoromethyl)cyclo-butyl)-3-methyl benzenesulfonamide

(26) The title compound was prepared in an analogous manner to 3-chloro-4-(6-cyano-5-fluoropyridin-2-yl)-N-((1s,3s)-3-hydroxy-3-(trifluoromethyl)cyclobutyl)benzenesulfonamide (Intermediate 1 b) using 4-bromo-N-((1s,3s)-3-hydroxy-3-(trifluoromethyl)cyclobutyl)-3-methylbenzenesulfonamide (Intermediate 2a) to give the title compound. (UPLC-MS) t.sub.R 1.52 min; API-MS 430.2 [M+H].sup.+.

Intermediate 3a: 6-(4-amino-2-chlorophenyl)-3-fluoropicolinonitrile

(27) A MW vial was charged with 6-bromo-3-fluoropicolinonitrile (Enamine, CAS Nr. 1256788-71-2) (1 g, 4.98 mmol), 3-chloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (abcr, CAS Nr. 877160-63-9) (1.514 g, 5.97 mmol) and PdCl.sub.2(dppf) (0.182 g, 0.249 mmol). ACN (20 mL) and aq. K.sub.2CO.sub.3 2M (7.46 mL, 14.93 mmol) were added and the mixture was submitted to MW irradiations for 30 min at 120° C. The reaction was diluted with EtOAc and passed through a pad of Celite. The organic layer was washed with a sat. aq. NaHCO.sub.3 solution. The aq. layer was back-extracted twice with EtOAc. The combined organic layers were washed with brine, dried over anhydrous MgSO.sub.4, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (0% to 25% EtOAc in Cylohexane) to afford the title product as a beige solid. (UPLC-MS) t.sub.R 0.97 min; ESI-MS 248.1 [M+H].sup.+; ESI-MS 246.0 [M−H].sup.−.

Intermediate 3b: 4-chloro-N-(3-chloro-4-(6-cyano-5-fluoropyridin-2-yl)phenyl)benzenesulfonamide

(28) To a sealed vial containing a stirring solution of 4-chlorobenzene-1-sulfonyl chloride (54 mg, 0.256 mmol) in Pyridine (0.5 mL) cooled down to 0° C. was added dropwise a solution of 6-(4-amino-2-chlorophenyl)-3-fluoropicolinonitrile (Intermediate 3a, 57 mg, 0.230 mmol) in Pyridine (1 mL). The reaction was stirred at 0° C. for 3 h. The reaction was diluted with EtOAc and washed twice with an aq. 1N NH.sub.4Cl solution, water and brine. The organic layer was dried over anhydrous MgSO.sub.4, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (0% to 30% EtOAc in Cyclohexane) to afford the title product as an off white solid. (UPLC-MS) t.sub.R 1.18 min; ESI-MS 422.0/424.0 [M+H].sup.+; ESI-MS 420.0/422.0 [M−H].sup.−.

Intermediate 4a: 4-bromo-3-chloro-N-(3,3-difluorocyclobutyl)benzenesulfonamide

(29) The title compound was prepared in an analogous manner to 4-bromo-3-chloro-N-((1s,3s)-3-hydroxy-3-(trifluoromethyl)cyclobutyl)benzenesulfonamide (Intermediate 1a) using 3,3-difluorocyclobutanamine to give the title compound as a colorless solid. (UPLC-MS) t.sub.R 1.03 min; ESI-MS 356.0 [M+H].sup.+.

Intermediate 4b: 3-chloro-4-(6-cyano-5-fluoropyridin-2-yl)-N-(3,3-difluorocyclobutyl)benzenesulfonamide

(30) The title compound was prepared in an analogous manner to 3-chloro-4-(6-cyano-5-fluoropyridin-2-yl)-N-(3-hydroxy-3-(trifluoromethyl)cyclobutyl)benzenesulfonamide (Intermediate 1 b) using 4-bromo-3-chloro-N-(3,3-difluorocyclobutyl)benzenesulfonamide (Intermediate 4a) to give the title compound. (UPLC-MS) t.sub.R 1.09 min; ESI-MS 400.1 [M−H].sup.+.

Intermediate 5b: N-(3-chloro-4-(6-cyano-5-fluoropyridin-2-yl)phenyl)-4-methoxybenzenesulfonamide

(31) The title compound was prepared in an analogous manner to 4-chloro-N-(3-chloro-4-(6-cyano-5-fluoropyridin-2-yl)phenyl)benzenesulfonamide (Intermediate 3b) using 4-methoxybenzene-1-sulfonyl chloride and 6-(4-amino-2-chlorophenyl)-3-fluoropicolinonitrile (Intermediate 3a) at RT for 45 h without extracting workup to afford the title compound as a white solid. (UPLC-MS) t.sub.R 1.11 min; ESI-MS 418.1 [M+H].sup.+; ESI-MS 416.1 [M−H].sup.−.

Intermediate 6b: N-(3-chloro-4-(6-cyano-5-fluoropyridin-2-yl)phenyl)-4-fluorobenzenesulfonamide

(32) The title compound was prepared in an analogous manner to 4-chloro-N-(3-chloro-4-(6-cyano-5-fluoropyridin-2-yl)phenyl)benzenesulfonamide (Intermediate 3b) using 4-fluorobenzenesulfonyl chloride (Sigma-Aldrich, CAS Nr. 349-88-2) and 6-(4-amino-2-chlorophenyl)-3-fluoropicolinonitrile (Intermediate 3a) to afford the title compound as an off-white solid. (UPLC-MS) t.sub.R 1.12 min; ESI-MS 406.1 [M+H].sup.+; ESI-MS 404.1 [M−H].sup.−.

Intermediate 7a: 4-bromo-3-chloro-N-((1R,2S)-2-hydroxycyclopentyl)benzenesulfonamide

(33) The title compound was prepared in an analogous manner to 4-bromo-3-chloro-N-((1s,3s)-3-hydroxy-3-(trifluoromethyl)cyclobutyl)benzenesulfonamide (Intermediate 1a) using (1S,2R)-2-aminocyclopentan-1-ol to afford the title compound as a colorless solid. (UPLC-MS) t.sub.R 1.03 min; ESI-MS 356.0 [M+H].sup.+.

Intermediate 7b: 3-chloro-4-(6-cyano-5-fluoropyridin-2-yl)-N-((1R,2S)-2-hydroxycyclopentyl)benzenesulfonamide

(34) The title compound was prepared in an analogous manner to 3-chloro-4-(6-cyano-5-fluoropyridin-2-yl)-N-(3-hydroxy-3-(trifluoromethyl)cyclobutyl)benzenesulfonamide (Intermediate 1 b) using 4-bromo-3-chloro-N-((1R,2S)-2-hydroxycyclopentyl)benzenesulfonamide (Intermediate 7a) to give the title compound as an off-white solid. (UPLC-MS) t.sub.R 1.00 min; ESI-MS 396.2 [M+H].sup.+.

Intermediate 8a: 4-bromo-N-(3,3-difluorocyclobutyl)-3-methylbenzenesulfonamide

(35) The title compound was prepared in an analogous manner to 4-bromo-3-chloro-N-((1s,3s)-3-hydroxy-3-(trifluoromethyl)cyclobutyl)benzenesulfonamide (Intermediate 1a) using 4-bromo-3-methylbenzene-1-sulfonyl chloride and 3,3-difluorocyclobutanamine to give the title compound as a colorless solid. (UPLC-MS) t.sub.R 1.11 min; ESI-MS 340.0 [M−H].sup.+.

Intermediate 8b: 4-(6-cyano-5-fluoropyridin-2-yl)-N-(3,3-difluorocyclobutyl)-3-methylbenzenesulfonamide

(36) The title compound was prepared in an analogous manner to 3-chloro-4-(6-cyano-5-fluoropyridin-2-yl)-N-(3-hydroxy-3-(trifluoromethyl)cyclobutyl)benzenesulfonamide (Intermediate 1 b) using 4-bromo-N-(3,3-difluorocyclobutyl)-3-methyl benzenesulfonamide (Intermediate 8a) to give the title compound. (UPLC-MS) t.sub.R 1.06 min; ESI-MS 380.1 [M−H].sup.+.

Intermediate 9a: 4-bromo-N-((1s,3s)-3-hydroxy-3-(trifluoromethyl)cyclobutyl)-N,3-dimethylbenzenesulfonamide

(37) To a solution of 4-bromo-3-methylbenzene-1-sulfonyl chloride (1.32 g, 4.90 mmol) and (1s,3s)-3-(methylamino)-1-(trifluoromethyl)cyclobutanol (Intermediate 9c, 828 mg, 4.90 mmol) in DCM (20 mL) was added DIPEA (2.57 mL, 14.7 mmol). The reaction mixture was stirred for 40 min, then partitioned between EtOAc and an sat. aq. NaHCO.sub.3 solution. The aq. layer was extracted twice with EtOAc. The combined organic layers were washed with brine, dried over anhydrous MgSO.sub.4, filtered and concentrated under reduced pressure. The crude material was purified by silica gel column chromatography (0 to 100% EtOAc in Cyclohexane) to give the title compound as a colorless solid. (UPLC-MS) t.sub.R 1.13 min; ESI-MS 402.1/404.1 [M+H].sup.+.

Intermediate 9b: 4-(6-cyano-5-fluoropyridin-2-yl)-N-((1s,3s)-3-hydroxy-3-(trifluoromethyl)cyclobutyl)-N,3-dimethylbenzenesulfonamide

(38) Step 1: A vial was charged with 6-bromo-3-fluoropicolinonitrile (435 mg, 2.16 mmol), bis(pinacolato)diboron (659 mg, 2.60 mmol), KOAc (425 mg, 4.33 mmol) and PdCl.sub.2(dppf) (79 mg, 0.108 mmol). The vial was sealed, dioxane (3.75 mL) was added via syringe, and the reaction mixture was stirred at 80° C. for 1 h, cooled down to room temperature and filtered through Celite. The Celite pad was washed with MeOH. The combined filtrates were concentrated under reduced pressure to give crude 3-fluoro-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)picolinonitrile.

(39) Step 2: The crude material was diluted with ACN (15 mL) and treated with 4-bromo-N-((1s,3s)-3-hydroxy-3-(trifluoromethyl)cyclobutyl)-N,3-dimethylbenzenesulfonamide (Intermediate 9a, 871 mg, 2.16 mmol), K.sub.2CO.sub.3 (897 mg, 6.49 mmol), and PdCl.sub.2(dppf) (79 mg, 0.108 mmol). The vial was sealed and irradiated in a microwave reactor at 120° C. for 30 min. The reaction was treated with water and EtOAc. After phase separation the aq. layer was extracted twice with EtOAc. The combined organic layers were dried over anhydrous MgSO.sub.4, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (0 to 100% EtOAc in Cyclohexane) to give the title compound as an off-white solid. (UPLC-MS) t.sub.R 1.08 min; ESI-MS 461.1 [M+H.sub.2O+H].sup.+.

Intermediate 9c: (1s,3s)-3-(methylamino)-1-(trifluoromethyl)cyclobutan-1-ol

(40) To a solution of (1s,3s)-3-amino-1-(trifluoromethyl)cyclobutan-1-ol (324 mg, 1.69 mmol) and DIPEA (0.86 ml, 5.07 mmol) in THF (15 mL) was added methyl carbonochloridate (0.26 mL, 3.38 mmol). The reaction mixture was stirred at room temperature for 18 h and treated with LiAlH.sub.4 (1M in THF, 8.46 mL, 8.46 mmol) at 0° C. under an argon atmosphere, then stirred at 60° C. for 5 h. The reaction mixture was quenched with water and aq. 1N NaOH, extracted with EtOAc, dried over Na.sub.2SO.sub.4, filtered, and concentrated under reduced pressure to afford the title compound which was used without further purification. FIA-MS (ES) 170.1 [M+H].sup.+.

Intermediate 10b: N-(3-chloro-4-(6-cyano-5-fluoropyridin-2-yl)phenyl)-3,4-difluorobenzenesulfonamide

(41) The title compound was prepared in an analogous manner to 4-chloro-N-(3-chloro-4-(6-cyano-5-fluoropyridin-2-yl)phenyl)benzenesulfonamide (Intermediate 3b) using 3,4-difluorobenzene-1-sulfonyl chloride and 6-(4-amino-2-chlorophenyl)-3-fluoropicolinonitrile (Intermediate 3b) at 0° C. for 2 h without extracting workup to afford the title compound as a white solid. (UPLC-MS) t.sub.R 1.17 min; ESI-MS 424.2 [M+H].sup.+; ESI-MS 422.1 [M−H].sup.−.

Intermediate 11b: N-(3-chloro-4-(6-cyano-5-fluoropyridin-2-yl)phenyl)benzo[d][1,3]dioxole-5-sulfonamide

(42) The title compound was prepared in an analogous manner to 4-chloro-N-(3-chloro-4-(6-cyano-5-fluoropyridin-2-yl)phenyl)benzenesulfonamide (Intermediate 3b) using benzo[d][1,3]dioxole-5-sulfonyl chloride and 6-(4-amino-2-chlorophenyl)-3-fluoropicolinonitrile (Intermediate 3a) at 0° C. for 2.5 h to afford the title compound as white solid. (UPLC-MS) t.sub.R 1.09 min; ESI-MS 432.1 [M+H].sup.+; ESI-MS 430.1 [M−H].sup.−.

Intermediate 12a: 4-bromo-3-chloro-N-(2-hydroxycyclohexyl)benzenesulfonamide

(43) The title compound was prepared in an analogous manner to 4-bromo-3-chloro-N-((1s,3s)-3-hydroxy-3-(trifluoromethyl)cyclobutyl)benzenesulfonamide (Intermediate 1a) using 2-aminocyclohexanol to give the title compound as a colorless solid (UPLC-MS) t.sub.R 1.08 min; ESI-MS 366.0/368.0/370.0 [M−H].sup.−.

Intermediate 12b: 3-chloro-4-(6-cyano-5-fluoropyridin-2-yl)-N-(2-hydroxycyclohexyl)benzenesulfonamide

(44) The title compound was prepared in an analogous manner to 3-chloro-4-(6-cyano-5-fluoropyridin-2-yl)-N-(3-hydroxy-3-(trifluoromethyl)cyclobutyl)benzenesulfonamide (Intermediate 1 b) using 4-bromo-3-chloro-N-(2-hydroxycyclohexyl)benzenesulfonamide (Intermediate 12a) to give the title compound. (UPLC-MS) t.sub.R 1.05 min; ESI-MS 410.2 [M+H].sup.+.

Intermediate 13b: 4-chloro-N-(3-chloro-4-(6-cyano-5-fluoropyridin-2-yl)phenyl)-3-fluorobenzenesulfonamide

(45) The title compound was prepared in an analogous manner to 4-chloro-N-(3-chloro-4-(6-cyano-5-fluoropyridin-2-yl)phenyl)benzenesulfonamide (Intermediate 3b) using 4-chloro-3-fluorobenzene-1-sulfonyl chloride and 6-(4-amino-2-chlorophenyl)-3-fluoropicolinonitrile (Intermediate 3a) at 0° C. for 1.5 h to afford the title compound as an off-white solid. (UPLC-MS) t.sub.R 1.20 min; ESI-MS 440.0/442.0 [M+H].sup.+; ESI-MS 438./440.0 [M−H].sup.−.

Intermediate 15b: N-(3-chloro-4-(6-cyano-5-fluoropyridin-2-yl)phenyl)cyclohexanesulfonamide

(46) The title compound was prepared in an analogous manner to 4-chloro-N-(3-chloro-4-(6-cyano-5-fluoropyridin-2-yl)phenyl)benzenesulfonamide (Intermediate 3b) using an large excess of cyclohexanesulfonyl chloride (5 eq) and 6-(4-amino-2-chlorophenyl)-3-fluoropicolinonitrile (Intermediate 3a) at RT overnight to complete the reaction. Two purifications using silica gel column chromatography (0 to 30% EtOAc in Cyclohexane) afforded the title compound as a pale yellow solid. (UPLC-MS) t.sub.R 1.18 min; ESI-MS 394.1 [M+H].sup.+; ESI-MS 392.2 [M−H].sup.−.

Intermediate 16a: 4-bromo-3-methyl-N-phenylbenzenesulfonamide

(47) The title compound was prepared in an analogous manner to 4-bromo-3-chloro-N-((1s,3s)-3-hydroxy-3-(trifluoromethyl)cyclobutyl)benzenesulfonamide (Intermediate 1a) using 4-bromo-3-methylbenzene-1-sulfonyl chloride and aniline to give the title compound as a colorless solid. (UPLC-MS) t.sub.R 1.15 min; ESI-MS 328.0 [M+H].sup.+.

Intermediate 16b: 4-(6-cyano-5-fluoropyridin-2-yl)-3-methyl-N-phenylbenzenesulfonamide

(48) The title compound was prepared in an analogous manner to 3-chloro-4-(6-cyano-5-fluoropyridin-2-yl)-N-(3-hydroxy-3-(trifluoromethyl)cyclobutyl)benzenesulfonamide (Intermediate 1 b) using 4-bromo-3-methyl-N-phenylbenzenesulfonamide (Intermediate 16a) to give the title compound that was used as a crude material without purification. (UPLC-MS) t.sub.R 1.11 min; ESI-MS 366.2 [M−H].sup.−.

Intermediate 17b: N-(3-chloro-4-(6-cyano-5-fluoropyridin-2-yl)phenyl)-2-hydroxycyclohexane-1-sulfonamide

(49) The title compound was prepared in an analogous manner to 4-chloro-N-(3-chloro-4-(6-cyano-5-fluoropyridin-2-yl)phenyl)benzenesulfonamide (Intermediate 3b) using a large excess of 2-hydroxycyclohexane-1-sulfonyl chloride (3 eq) and 6-(4-amino-2-chlorophenyl)-3-fluoropicolinonitrile (Intermediate 3a) to afford the title compound as a white solid. (UPLC-MS) t.sub.R 1.07 min; ESI-MS 410.1 [M+H].sup.+; ESI-MS 408.1 [M−H].sup.−.

Intermediate 18a: (S)-(1-((4-bromo-3-chlorophenyl)sulfonyl)-4,4-difluoropyrrolidin-2-yl)methanol

(50) The title compound was prepared in an analogous manner to 4-bromo-N-(3-hydroxy-3-(trifluoromethyl)cyclobutyl)-3-methylbenzenesulfonamide (Intermediate 2a) using (S)-(4,4-difluoropyrrolidin-2-yl)methanol and 4-bromo-3-chlorobenzene-1-sulfonyl chloride to give the title compound. (UPLC-MS) t.sub.R 1.56 min; API-MS m/z: 390.0 [M+H].sup.+.

Intermediate 18b: (S)-6-(2-chloro-4-((4,4-difluoro-2-(hydroxymethyl)pyrrolidin-1-yl)sulfonyl)phenyl)-3-fluoropicolinonitrile

(51) The title compound was prepared in an analogous manner to 4-(6-cyano-5-fluoropyridin-2-yl)-N-(3-hydroxy-3-(trifluoromethyl)cyclobutyl)-3-methylbenzenesulfonamide (Intermediate 2b) using (S)-(1-((4-bromo-3-chlorophenyl)sulfonyl)-4,4-difluoropyrrolidin-2-yl)methanol (Intermediate 18a) to give the title compound. (UPLC-MS) t.sub.R 1.51 min; API-MS 432.1 [M+H].sup.+.

Intermediate 19a: 4-bromo-N-((1R,3S)-3-hydroxycyclopentyl)-3-methylbenzenesulfonamide

(52) The title compound was prepared in an analogous manner to 4-bromo-3-chloro-N-((1s,3s)-3-hydroxy-3-(trifluoromethyl)cyclobutyl)benzenesulfonamide (Intermediate 1a) using 4-bromo-3-methylbenzene-1-sulfonyl chloride and (1R,3S)-3-aminocyclopentanol to give the title compound as a colorless solid. (UPLC-MS) t.sub.R 0.90 min; ESI-MS 334.0 [M−H].sup.−.

Intermediate 19b: 4-(6-cyano-5-fluoropyridin-2-yl)-N-((1R,3S)-3-hydroxycyclopentyl)-3-methylbenzenesulfonamide

(53) The title compound was prepared in an analogous manner to 3-chloro-4-(6-cyano-5-fluoropyridin-2-yl)-N-(3-hydroxy-3-(trifluoromethyl)cyclobutyl)benzenesulfonamide (Intermediate 1 b) using 4 bromo-N-((1R,3S)-3-hydroxycyclopentyl)-3-methylbenzenesulfonamide (Intermediate 19a) to give the title compound. (UPLC-MS) t.sub.R 0.89 min; ESI-MS 374.2 [M−H].sup.−.

Intermediate 20a: 4-bromo-N-((1R,2S)-2-hydroxycyclopentyl)-3-methylbenzenesulfonamide

(54) The title compound was prepared in an analogous manner to 4-bromo-3-chloro-N-((1s,3s)-3-hydroxy-3-(trifluoromethyl)cyclobutyl)benzenesulfonamide (Intermediate 1a) using 4-bromo-3-methylbenzene-1-sulfonyl chloride and (1S,2R)-2-aminocyclopentanol to give the title compound as a colorless solid. (UPLC-MS) t.sub.R 1.01 min; ESI-MS 334.1/336.0 [M+H].sup.+.

Intermediate 20b: 4-(6-cyano-5-fluoropyridin-2-yl)-N-((1R,2S)-2-hydroxycyclopentyl)-3-methylbenzenesulfonamide

(55) The title compound was prepared in an analogous manner to 3-chloro-4-(6-cyano-5-fluoropyridin-2-yl)-N-(3-hydroxy-3-(trifluoromethyl)cyclobutyl)benzenesulfonamide (Intermediate 1 b) using 4-bromo-N-((1R,2S)-2-hydroxycyclopentyl)-3-methylbenzenesulfonamide (Intermediate 20a) to give the title compound. (UPLC-MS) t.sub.R 0.96 min; ESI-MS 376.1 [M+H].sup.+.

Intermediate 21a: 2-((4-bromo-3-methylphenyl)sulfonyl)octahydrocyclopenta[c]pyrrole

(56) The title compound was prepared in an analogous manner to 4-bromo-3-chloro-N-((1s,3s)-3-hydroxy-3-(trifluoromethyl)cyclobutyl)benzenesulfonamide (Intermediate 1a) using 4-bromo-3-methylbenzene-1-sulfonyl chloride and octahydrocyclopenta[c]pyrrole to give the title compound as a colorless solid. (UPLC-MS) t.sub.R 1.33 min; ESI-MS 344.1/346.2 [M+H].sup.+.

Intermediate 21b: 3-fluoro-6-(4-((hexahydrocyclopenta[c]pyrrol-2(1H)-yl)sulfonyl)-2-methylphenyl)picolinonitrile

(57) The title compound was prepared in an analogous manner to 3-chloro-4-(6-cyano-5-fluoropyridin-2-yl)-N-(3-hydroxy-3-(trifluoromethyl)cyclobutyl)benzenesulfonamide (Intermediate 1 b) using 2-((4-bromo-3-methylphenyl)sulfonyl)octahydrocyclopenta[c]pyrrole (Intermediate 21a) to give the title compound. (UPLC-MS) t.sub.R 1.24 min; ESI-MS 386.2 [M+H].sup.+.

Intermediate 22b: N-(3-chloro-4-(6-cyano-5-fluoropyridin-2-yl)phenyl)-3-cyanobenzenesulfonamide

(58) The title compound was prepared in an analogous manner to 4-chloro-N-(3-chloro-4-(6-cyano-5-fluoropyridin-2-yl)phenyl)benzenesulfonamide (Intermediate 3b) using 3-cyanobenzene-1-sulfonyl chloride and 6-(4-amino-2-chlorophenyl)-3-fluoropicolinonitrile (Intermediate 3a) at 0° C. for 2 h without extracting workup to afford the title compound as a white solid. (UPLC-MS) t.sub.R 1.08 min; ESI-MS 413.1 [M+H].sup.+; ESI-MS 411.1 [M−H].sup.−.

Intermediate 23a: 4-bromo-3-chloro-N-((1R,3S)-3-hydroxycyclopentyl)benzenesulfonamide

(59) The title compound was prepared in an analogous manner to 4-bromo-3-chloro-N-((1s,3s)-3-hydroxy-3-(trifluoromethyl)cyclobutyl)benzenesulfonamide (Intermediate 1a) using (1R,3S)-3-aminocyclopentanol to give the title compound as a colorless solid. (UPLC-MS) t.sub.R 0.92 min; ESI-MS 354.2 [M+H].sup.+.

Intermediate 23b: 3-chloro-4-(6-cyano-5-fluoropyridin-2-yl)-N-((1R,3S)-3-hydroxycyclopentyl)benzenesulfonamide

(60) The title compound was prepared in an analogous manner to 3-chloro-4-(6-cyano-5-fluoropyridin-2-yl)-N-(3-hydroxy-3-(trifluoromethyl)cyclobutyl)benzenesulfonamide (Intermediate 1 b) using 4-bromo-3-chloro-N-((1R,3S)-3-hydroxycyclopentyl)benzenesulfonamide (Intermediate 23a) to give the title compound. (UPLC-MS) t.sub.R 0.93 min; ESI-MS 394.1 [M+H].sup.+.

Intermediate 24a: 4-bromo-3-chloro-N-(4,4-dimethylcyclohexyl)benzenesulfonamide

(61) The title compound was prepared in an analogous manner to 4-bromo-3-chloro-N-((1s,3s)-3-hydroxy-3-(trifluoromethyl)cyclobutyl)benzenesulfonamide (Intermediate 1a) using 4,4-dimethylcyclohexanamine to give the title compound as a colorless solid. (UPLC-MS) t.sub.R 1.36 min; ESI-MS 380.0 [M−H].sup.−.

Intermediate 24b: 3-chloro-4-(6-cyano-5-fluoropyridin-2-yl)-N-(4,4-dimethylcyclohexyl)benzenesulfonamide

(62) The title compound was prepared in an analogous manner to 3-chloro-4-(6-cyano-5-fluoropyridin-2-yl)-N-(3-hydroxy-3-(trifluoromethyl)cyclobutyl)benzenesulfonamide (Intermediate 1 b) using 4-bromo-3-chloro-N-(4,4-dimethylcyclohexyl)benzenesulfonamide (Intermediate 24a) to give the title compound. (UPLC-MS) t.sub.R 1.15 min; ESI-MS 420.0 [M+H].sup.+.

Intermediate 25b: N-(3-chloro-4-(6-cyano-5-fluoropyridin-2-yl)phenyl)-4-methylbenzenesulfonamide

(63) The title compound was prepared in an analogous manner to 4-chloro-N-(3-chloro-4-(6-cyano-5-fluoropyridin-2-yl)phenyl)benzenesulfonamide (Intermediate 3b) using 4-methylbenzene-1-sulfonyl chloride and 6-(4-amino-2-chlorophenyl)-3-fluoropicolinonitrile (Intermediate 3a) at 0° C. for 2 h to afford the title compound as a white solid. (UPLC-MS) t.sub.R 1.15 min; ESI-MS 402.2 [M+H].sup.+; ESI-MS 400.1 [M−H].sup.−.

Intermediate 26a: 4-bromo-N-(1-(hydroxymethyl)cyclopentyl)-3-methylbenzenesulfonamide

(64) The title compound was prepared in an analogous manner to 4-bromo-3-chloro-N-((1s,3s)-3-hydroxy-3-(trifluoromethyl)cyclobutyl)benzenesulfonamide (Intermediate 1a) using 4-bromo-3-methylbenzene-1-sulfonyl chloride and (1-aminocyclopentyl)methanol to give the title compound as a colorless solid. (UPLC-MS) t.sub.R 1.02 min; ESI-MS 346.0/348.0 [M−H].sup.−.

Intermediate 26b: 4-(6-cyano-5-fluoropyridin-2-yl)-N-(1-(hydroxymethyl)cyclopentyl)-3-methylbenzenesulfonamide

(65) The title compound was prepared in an analogous manner to 3-chloro-4-(6-cyano-5-fluoropyridin-2-yl)-N-(3-hydroxy-3-(trifluoromethyl)cyclobutyl)benzenesulfonamide (Intermediate 1 b) using 4-bromo-N-(1-(hydroxymethyl)cyclopentyl)-3-methyl benzenesulfonamide (Intermediate 26a) to give the title compound. (UPLC-MS) t.sub.R 0.98 min; ESI-MS 388.2 [M−H].sup.−.

Intermediate 27b: 3-chloro-N-(3-chloro-4-(6-cyano-5-fluoropyridin-2-yl)phenyl)-4-fluorobenzenesulfonamide

(66) The title compound was prepared in an analogous manner to 4-chloro-N-(3-chloro-4-(6-cyano-5-fluoropyridin-2-yl)phenyl)benzenesulfonamide (Intermediate 3b) using 3-chloro-4-fluorobenzene-1-sulfonyl chloride and 6-(4-amino-2-chlorophenyl)-3-fluoropicolinonitrile (Intermediate 3a) at 0° C. for 2 h without extracting workup to afford the title compound as an off-white solid. (UPLC-MS) t.sub.R 1.22 min; ESI-MS 440.0/442.0 [M+H].sup.+; ESI-MS 438.0/440.1 [M−H].sup.−.

Intermediate 28b: 3-chloro-N-(3-chloro-4-(6-cyano-5-fluoropyridin-2-yl)phenyl)benzenesulfonamide

(67) The title compound was prepared in an analogous manner to 4-chloro-N-(3-chloro-4-(6-cyano-5-fluoropyridin-2-yl)phenyl)benzenesulfonamide (Intermediate 3b) using 3-chlorobenzene-1-sulfonyl chloride and 6-(4-amino-2-chlorophenyl)-3-fluoropicolinonitrile (Intermediate 3a) at 0° C. for 1 h then, RT for 30 min to afford the title compound as an off-white solid. (UPLC-MS) t.sub.R 1.20 min; ESI-MS 421.9/424.1 [M+H].sup.+; ESI-MS 420.1/422.0 [M−H].sup.−.

Intermediate 29a: 4-bromo-3-chloro-N-((1R,2R)-2-hydroxycyclopentyl)benzenesulfonamide

(68) The title compound was prepared in an analogous manner to 4-bromo-3-chloro-N-((1s,3s)-3-hydroxy-3-(trifluoromethyl)cyclobutyl)benzenesulfonamide (Intermediate 1a) using (1R,2R)-2-aminocyclopentanol to give the title compound as a colorless solid. (UPLC-MS) t.sub.R 0.94 min; ESI-MS 354.0 [M−H].sup.−.

Intermediate 29b: 3-chloro-4-(6-cyano-5-fluoropyridin-2-yl)-N-((1R,2R)-2-hydroxycyclopentyl)benzenesulfonamide

(69) The title compound was prepared in an analogous manner to 3-chloro-4-(6-cyano-5-fluoropyridin-2-yl)-N-(3-hydroxy-3-(trifluoromethyl)cyclobutyl)benzenesulfonamide (Intermediate 1 b) using 4-bromo-3-chloro-N-((1R,2R)-2-hydroxycyclopentyl)benzenesulfonamide (Intermediate 29a) to give the title compound as an off-white solid. (UPLC-MS) t.sub.R 0.94 min; ESI-MS 394.0 [M−H].sup.−.

Intermediate 30a: 4-bromo-3-chloro-N-(1-(hydroxymethyl)cyclopentyl)benzenesulfonamide

(70) The title compound was prepared in an analogous manner to 4-bromo-3-chloro-N-((1s,3s)-3-hydroxy-3-(trifluoromethyl)cyclobutyl)benzenesulfonamide (Intermediate 1a) using (1-aminocyclopentyl)methanol to give the title compound as a colorless solid. (UPLC-MS) t.sub.R 1.04 min; ESI-MS 366.1/368.1/370.1 [M−H].sup.−.

Intermediate 30b: 3-chloro-4-(6-cyano-5-fluoropyridin-2-yl)-N-(1-(hydroxymethyl)cyclopentyl)benzenesulfonamide

(71) The title compound was prepared in an analogous manner to 3-chloro-4-(6-cyano-5-fluoropyridin-2-yl)-N-(3-hydroxy-3-(trifluoromethyl)cyclobutyl)benzenesulfonamide (Intermediate 1 b) using 4-bromo-3-chloro-N-(1-(hydroxymethyl)cyclopentyl)benzenesulfonamide (Intermediate 30a) to give the title compound. (UPLC-MS) t.sub.R 1.02 min; ESI-MS 408.2 [M−H].sup.−.

Intermediate 31a: 4-bromo-3-chloro-N-(1,1-dioxidotetrahydrothiophen-3-yl)benzenesulfonamide

(72) The title compound was prepared in an analogous manner to 4-bromo-3-chloro-N-((1s,3s)-3-hydroxy-3-(trifluoromethyl)cyclobutyl)benzenesulfonamide (Intermediate 1a) using 3-aminotetrahydrothiophene 1,1-dioxide to give the title compound as a colorless solid. (UPLC-MS) t.sub.R 0.91 min; ESI-MS 388.0 [M−H].sup.−.

Intermediate 31 b: 3-chloro-4-(6-cyano-5-fluoropyridin-2-yl)-N-(1,1-dioxidotetrahydrothiophen-3-yl)benzenesulfonamide

(73) The title compound was prepared in an analogous manner to 3-chloro-4-(6-cyano-5-fluoropyridin-2-yl)-N-(3-hydroxy-3-(trifluoromethyl)cyclobutyl)benzenesulfonamide (Intermediate 1 b) using 4-bromo-3-chloro-N-(1,1-dioxidotetrahydrothiophen-3-yl)benzenesulfonamide (Intermediate 31a) to give the title compound as an off-white solid. (UPLC-MS) t.sub.R 0.90 min; ESI-MS 428.1 [M−H].sup.−.

Intermediate 32b: N-(3-chloro-4-(6-cyano-5-fluoropyridin-2-yl)phenyl)-2-hydroxy-5-methylbenzenesulfonamide

(74) The title compound was prepared in an analogous manner to 4-chloro-N-(3-chloro-4-(6-cyano-5-fluoropyridin-2-yl)phenyl)benzenesulfonamide (Intermediate 3b) using an excess of 2-hydroxy-5-methylbenzene-1-sulfonyl chloride (1.7 eq) and 6-(4-amino-2-chlorophenyl)-3-fluoropicolinonitrile (Intermediate 3a) at RT for 4 days to afford the title compound as a white foam. (UPLC-MS) t.sub.R 1.09 min; ESI-MS 418.0 [M+H].sup.+.

Intermediate 33a: N-(4-bromo-3-methylphenyl)-3-fluorobenzenesulfonamide

(75) The title compound was prepared in an analogous manner to 4-chloro-N-(3-chloro-4-(6-cyano-5-fluoropyridin-2-yl)phenyl)benzenesulfonamide (Intermediate 3b) using 3-fluorobenzene-1-sulfonyl chloride and 4-bromo-3-methylaniline at 0° C. for 2.5 hr. No workup done, the reaction was concentrated under reduced pressure and the crude material was purified using silica gel column chromatography (0 to 10% EtOAc in Cyclohexane) to afford the title compound as a white solid. (UPLC-MS) t.sub.R 1.15 min; ESI-MS 342.0/344.0 [M−H].sup.−.

Intermediate 33b: N-(4-(6-cyano-5-fluoropyridin-2-yl)-3-methylphenyl)-3-fluorobenzenesulfonamide

(76) Step 1: A vial was charged with 6-bromo-3-fluoropicolinonitrile (50 mg, 0.249 mmol), bis(pinacolato)diboron (76 mg, 0.299 mmol), KOAc (48.8 mg, 0.498 mmol) and PdCl.sub.2(dppf) (9.10 mg, 0.012 mmol). The vial was sealed, Dioxane (1 mL) was added, and the reaction mixture was stirred at 80° C. for 3 h, cooled down to RT, diluted with EtOAc and passed through a pad of Celite. The pad was washed several times with EtOAc. The combined filtrates were concentrated under reduced pressure to give crude 3-fluoro-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)picolinonitrile.

(77) Step 2: The crude material was diluted with ACN (2 mL) and treated with N-(4-bromo-3-methylphenyl)-3-fluorobenzenesulfonamide (Intermediate 33a, 94 mg, 0.274 mmol), K.sub.2CO.sub.3 aq. 2M (0.249 mL, 0.498 mmol), and PdCl.sub.2(dppf) (9.10 mg, 0.012 mmol). The vial was sealed and irradiated in a microwave reactor at 120° C. for 30 min. The reaction was diluted with EtOAc and passed through a pad of Celite. The filtrate was washed with a sat. aq. NaHCO.sub.3 solution, and the aqueous layer was extracted twice with EtOAc. The combined organic layers were washed with brine, dried over anhydrous MgSO.sub.4, filtered and concentrated under reduced pressure. The residue was purified by normal phase chromatography (0 to 20% EtOAc in Cyclohexane) to afford the title compound as a pale yellow solid. (UPLC-MS) t.sub.R 1.09 min; ESI-MS 386.1 [M+H].sup.+; ESI-MS 384.1 [M−H].sup.−.

Intermediate 34a: 1-((4-bromo-3-methylphenyl)sulfonyl)-4,4-difluoropyrrolidine-2-carboxamide

(78) The title compound was prepared in an analogous manner to 4-bromo-N-(3-hydroxy-3-(trifluoromethyl)cyclobutyl)-3-methylbenzenesulfonamide (Intermediate 2a) using 4,4-difluoropyrrolidine-2-carboxamide to give the title compound. (UPLC-MS) t.sub.R 1.66 min; API-MS m/z: 384.0/386.0 [M+H].sup.+.

Intermediate 34b: 1-((4-(6-cyano-5-fluoropyridin-2-yl)-3-methylphenyl)sulfonyl)-4,4-difluoropyrrolidine-2-carboxamide

(79) The title compound was prepared in an analogous manner to 3-chloro-4-(6-cyano-5-fluoropyridin-2-yl)-N-(3-hydroxy-3-(trifluoromethyl)cyclobutyl)benzenesulfonamide (Intermediate 1 b) using 1-((4-bromo-3-methylphenyl)sulfonyl)-4,4-difluoropyrrolidine-2-carboxamide (Intermediate 34a) to give the title compound. (UPLC-MS) t.sub.R 0.91 min; ESI-MS 425.2 [M+H].sup.+.

Intermediate 35a: 4-bromo-3-chloro-N-((1S,2R)-2-hydroxycyclopentyl)benzenesulfonamide

(80) The title compound was prepared in an analogous manner to 4-bromo-3-chloro-N-((1s,3s)-3-hydroxy-3-(trifluoromethyl)cyclobutyl)benzenesulfonamide (Intermediate 1a) using (1R,2S)-2-aminocyclopentanol to give the title compound as a colorless solid. (UPLC-MS) t.sub.R 1.00 min; ESI-MS 354.0 [M−H].sup.−.

Intermediate 35b: 3-chloro-4-(6-cyano-5-fluoropyridin-2-yl)-N-((1S,2R)-2-hydroxycyclopentyl)benzenesulfonamide

(81) The title compound was prepared in an analogous manner to 3-chloro-4-(6-cyano-5-fluoropyridin-2-yl)-N-(3-hydroxy-3-(trifluoromethyl)cyclobutyl)benzenesulfonamide (Intermediate 1 b) using 4-bromo-3-chloro-N-((1S,2R)-2-hydroxycyclopentyl)benzenesulfonamide (Intermediate 29a) to give the title compound as an off-white solid. (UPLC-MS) t.sub.R 0.98 min; ESI-MS 394.0 [M−H].sup.−.

Intermediate 36a: 4-bromo-3-chloro-N-(4-methylcyclohexyl)benzenesulfonamide

(82) The title compound was prepared in an analogous manner to 4-bromo-3-chloro-N-((1s,3s)-3-hydroxy-3-(trifluoromethyl)cyclobutyl)benzenesulfonamide (Intermediate 1a) using 4-methylcyclohexanamine to give the title compound as a colorless solid. (UPLC-MS) t.sub.R 1.33 min and 1.45 min (mixture of diastereomers); ESI-MS 368.0 [M+H].sup.+.

Intermediate 36b: 3-chloro-4-(6-cyano-5-fluoropyridin-2-yl)-N-(4-methylcyclohexyl)benzenesulfonamide

(83) The title compound was prepared in an analogous manner to 3-chloro-4-(6-cyano-5-fluoropyridin-2-yl)-N-(3-hydroxy-3-(trifluoromethyl)cyclobutyl)benzenesulfonamide (Intermediate 1 b) using 4-bromo-3-chloro-N-(4-methylcyclohexyl)benzenesulfonamide (Intermediate 36a) to give the title compound. (UPLC-MS) t.sub.R 1.28 min; ESI-MS 408.1 [M+H].sup.+.

Intermediate 37a: (S)-(1-((4-bromo-3-methylphenyl)sulfonyl)-4,4-difluoropyrrolidin-2-yl)methanol

(84) The title compound was prepared in an analogous manner to (S)-(1-((4-bromo-3-chlorophenyl)sulfonyl)-4,4-difluoropyrrolidin-2-yl)methanol (Intermediate 18a) using 4-bromo-3-methylbenzene-1-sulfonyl chloride to give the title compound. (UPLC-MS) t.sub.R 1.52 min; API-MS m/z: 370.1 [M+H].sup.+.

Intermediate 37b: (S)-6-(4-((4,4-difluoro-2-(hydroxymethyl)pyrrolidin-1-yl)sulfonyl)-2-methylphenyl)-3-fluoropicolinonitrile

(85) The title compound was prepared in an analogous manner to (S)-6-(2-chloro-4-((4,4-difluoro-2-(hydroxymethyl)pyrrolidin-1-yl)sulfonyl)phenyl)-3-fluoropicolinonitrile (Intermediate 18b) using (S)-(1-((4-bromo-3-methylphenyl)sulfonyl)-4,4-difluoropyrrolidin-2-yl)methanol (Intermediate 37a) to give the title compound. (UPLC-MS) t.sub.R 1.51 min; API-MS 412.2 [M+H].sup.+.

Intermediate 38a: 5-chloro-3-nitro-1H-pyrazolo[4,3-b]pyridine

(86) A solution of HNO.sub.3 (4.18 mL, 61 mmol) and H.sub.2SO.sub.4 (4.13 mL, 75 mmol) was added dropwise to solution of 5-chloro-1H-pyrazolo[4,3-b]pyridine (1.05 g, 6.84 mmol) in H.sub.2SO.sub.4 (6.84 mL) at 0° C. The mixture was stirred at 115° C. for 30 min and then poured onto ice water and adjusted to pH 8 with aq. NH.sub.4OH (33%). The light-yellow suspension was filtered, and the filter cake was washed several times with ice water to afford the title compound that was dried under high vacuum. (UPLC-MS) t.sub.R 0.60 min; ESI-MS 199.1 [M+H].sup.+.

Intermediate 38b: 5-chloro-1H-pyrazolo[4,3-b]pyridin-3-amine

(87) To a suspension of 5-chloro-3-nitro-1H-pyrazolo[4,3-b]pyridine (Intermediate 38a) (1.48 g, 7.45 mmol) in MeOH (100 mL) was added Pd—C (0.16 g, 0.15 mmol). The reaction mixture was put under a hydrogen atmosphere, stirred at room temperature for 5 h and filtered over Celite. The filter cake was washed with MeOH, and the combined solutions were concentrated under reduced pressure to give the title compound which was used without further purification. (UPLC-MS) t.sub.R 0.48 min; ESI-MS 169.0 [M+H].sup.+.

Intermediate 38c: 4-Bromo-3-chloro-N-phenylbenzenesulfonamide

(88) To a solution of 4-bromo-3-chlorobenzene-1-sulfonyl chloride (1.00 g, 3.45 mmol) in anhydrous pyridine (6.9 mL) was added dropwise aniline (0.32 mL, 3.52 mmol). The reaction was stirred at room temperature for 2.5 h and then concentrated under reduced pressure. The crude material was purified by silica gel column chromatography (0 to 100% EtOAc in Cyclohexane) to give the title compound. (UPLC-MS) t.sub.R 1.14 min; ESI-MS 346.6 [M+H].sup.+.

Intermediate 39a: 4-bromo-N-cyclohexyl-3-methylbenzenesulfonamide

(89) The title compound was prepared in an analogous manner to 4-bromo-3-chloro-N-((1s,3s)-3-hydroxy-3-(trifluoromethyl)cyclobutyl)benzenesulfonamide (Intermediate 1a) using 4-bromo-3-methylbenzene-1-sulfonyl chloride and cyclohexanamine to give the title compound as a colorless solid. (UPLC-MS) t.sub.R 1.26 min; ESI-MS 332.1/334.1 [M+H].sup.+.

Intermediate 39b: 4-(6-cyano-5-fluoropyridin-2-yl)-N-cyclohexyl-3-methylbenzenesulfonamide

(90) The title compound was prepared in an analogous manner to 3-chloro-4-(6-cyano-5-fluoropyridin-2-yl)-N-(3-hydroxy-3-(trifluoromethyl)cyclobutyl)benzenesulfonamide (Intermediate 1 b) using 4-bromo-N-cyclohexyl-3-methyl benzenesulfonamide (Intermediate 39a) to give the title compound. (UPLC-MS) t.sub.R 1.18 min; ESI-MS 374.2 [M+H].sup.+.

Intermediate 40a: 4-bromo-3-chloro-N-(3-fluorophenyl)benzenesulfonamide

(91) The title compound was prepared in an analogous manner to 4-bromo-N-(3-hydroxy-3-(trifluoromethyl)cyclobutyl)-3-methylbenzenesulfonamide (Intermediate 2a) using 4-bromo-3-chlorobenzene-1-sulfonyl chloride and 3-fluoroaniline. The reaction mixture was stirred at RT for 17 h to afford the title compound as a colorless solid. (UPLC-MS) t.sub.R 1.17 min; ESI-MS 362.0/364.0/366.0 [M+H].sup.+.

Intermediate 40b: 3-chloro-4-(6-cyano-5-fluoropyridin-2-yl)-N-(3-fluorophenyl)benzenesulfonamide

(92) The title compound was prepared in an analogous manner to 3-chloro-4-(6-cyano-5-fluoropyridin-2-yl)-N-(3-hydroxy-3-(trifluoromethyl)cyclobutyl)benzenesulfonamide (Intermediate 1 b) using 4-bromo-3-chloro-N-(3-fluorophenyl)benzenesulfonamide (Intermediate 40a) to give the title compound. (UPLC-MS) t.sub.R 1.16 min; ESI-MS 404.1/406.1 [M−H].sup.−.

Intermediate 41 b: N-(3-chloro-4-(6-cyano-5-fluoropyridin-2-yl)phenyl)-3-fluorobenzenesulfonamide

(93) The title compound was prepared in an analogous manner to 4-chloro-N-(3-chloro-4-(6-cyano-5-fluoropyridin-2-yl)phenyl)benzenesulfonamide (Intermediate 3b) using 3-fluorobenzene-1-sulfonyl chloride and 6-(4-amino-2-chlorophenyl)-3-fluoropicolinonitrile (Intermediate 3a) at 0° C. for 1 h then, RT, 30 min to afford the title compound as an off-white solid. (UPLC-MS) t.sub.R 1.15 min; ESI-MS 406.1 [M+H].sup.+; ESI-MS 404.1 [M−H].sup.−.

Intermediate 42a: N-(4-bromo-3-methylphenyl)-3-chlorobenzenesulfonamide

(94) The title compound was prepared in an analogous manner to 4-chloro-N-(3-chloro-4-(6-cyano-5-fluoropyridin-2-yl)phenyl)benzenesulfonamide (Intermediate 3b) using 3-chlorobenzene-1-sulfonyl chloride and 4-bromo-3-methylaniline at 0° C. for 4 h. No extracting workup done, the reaction was concentrated under reduced pressure and the crude material was purified by silica gel column chromatography (0 to 15% EtOAc in Cyclohexane) to afford the title compound as a white solid. (UPLC-MS) t.sub.R 1.22 min; ESI-MS 358.0/360.0 [M−H].sup.−.

Intermediate 42b: 3-chloro-N-(4-(6-cyano-5-fluoropyridin-2-yl)-3-methylphenyl)benzenesulfonamide

(95) The title compound was prepared in an analogous manner to N-(4-(6-cyano-5-fluoropyridin-2-yl)-3-methylphenyl)-3-fluorobenzenesulfonamide (Intermediate 33b) using N-(4-bromo-3-methylphenyl)-3-chlorobenzenesulfonamide (Intermediate 42a) at the second step to afford the title compound as pale yellow solid. (UPLC-MS) t.sub.R 1.14 min; ESI-MS 402.1 [M+H].sup.+; ESI-MS 400.1 [M−H].sup.−.

Intermediate 43b: 3,4-dichloro-N-(3-chloro-4-(6-cyano-5-fluoropyridin-2-yl)phenyl)benzenesulfonamide

(96) The title compound was prepared in an analogous manner to 4-chloro-N-(3-chloro-4-(6-cyano-5-fluoropyridin-2-yl)phenyl)benzenesulfonamide (Intermediate 3b) using 3,4-dichlorobenzene-1-sulfonyl chloride and 6-(4-amino-2-chlorophenyl)-3-fluoropicolinonitrile (Intermediate 3a) at 0° C. for 1.5 h to afford the title compound as an off-white solid. (UPLC-MS) t.sub.R 1.25 min; ESI-MS 456.0/458.0/459.9 [M+H].sup.+; ESI-MS 454.0/456.0/458.0 [M−H].sup.−.

Intermediate 44a: 4-bromo-3-chloro-N-(3-hydroxycyclohexyl)benzenesulfonamide

(97) The title compound was prepared in an analogous manner to 4-bromo-3-chloro-N-((1s,3s)-3-hydroxy-3-(trifluoromethyl)cyclobutyl)benzenesulfonamide (Intermediate 1a) using 3-aminocyclohexanol was to give the title compound as a colorless solid. (UPLC-MS) t.sub.R 0.94 min; ESI-MS 366.0/368.0/370.0 [M−H].sup.−.

Intermediate 44b: 3-chloro-4-(6-cyano-5-fluoropyridin-2-yl)-N-(3-hydroxycyclohexyl)benzenesulfonamide

(98) The title compound was prepared in an analogous manner to 3-chloro-4-(6-cyano-5-fluoropyridin-2-yl)-N-(3-hydroxy-3-(trifluoromethyl)cyclobutyl)benzenesulfonamide (Intermediate 1 b) using 4-bromo-3-chloro-N-(3-hydroxycyclohexyl)benzenesulfonamide (Intermediate 44a) to give the title compound. (UPLC-MS) t.sub.R 0.94 min; ESI-MS 410.2 [M+H].sup.+.

Intermediate 45a: 4-bromo-3-chloro-N-((1r,4r)-4-hydroxycyclohexyl)benzenesulfonamide

(99) The title compound was prepared in an analogous manner to 4-bromo-3-chloro-N-((1s,3s)-3-hydroxy-3-(trifluoromethyl)cyclobutyl)benzenesulfonamide (Intermediate 1a) using (1r,4r)-4-aminocyclohexanol to give the title compound as a colorless solid. (UPLC-MS) t.sub.R 0.89 min; ESI-MS 366.0/368.0/370.0 [M−H].sup.−.

Intermediate 45b: 3-chloro-4-(6-cyano-5-fluoropyridin-2-yl)-N-((1r,4r)-4-hydroxycyclohexyl)benzenesulfonamide

(100) The title compound was prepared in an analogous manner to 3-chloro-4-(6-cyano-5-fluoropyridin-2-yl)-N-(3-hydroxy-3-(trifluoromethyl)cyclobutyl)benzenesulfonamide (Intermediate 1 b) using 4-bromo-3-chloro-N-((1r,4r)-4-hydroxycyclohexyl)benzenesulfonamide (Intermediate 45a) to give the title compound. (UPLC-MS) t.sub.R 0.90 min; ESI-MS 408.2 [M−H].sup.−.

Intermediate 46a: N-(4-bromo-3-chlorophenyl)benzenesulfonamide

(101) The title compound was prepared in an analogous manner to 4-bromo-N-(3-hydroxy-3-(trifluoromethyl)cyclobutyl)-3-methylbenzenesulfonamide (Intermediate 2a) using 4-bromo-3,5-difluoroaniline and benzenesulfonyl chloride at RT for 2 hr. No extracting workup done, the reaction was concentrated under reduced pressure and the residue was purified by silica gel column chromatography (0 to 20% MeOH in DCM) to afford the title compound as a white solid. (UPLC-MS) t.sub.R 1.13 min; ESI-MS 343.9/345.9 [M−H].sup.−.

Intermediate 46b: N-(3-chloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)benzenesulfonamide

(102) To a solution of N-(4-bromo-3-chlorophenyl)benzenesulfonamide (Intermediate 46a, 219 mg, 0.632 mmol) in anhydrous dioxane (3 mL) was added bis(pinacolato)diboron (193 mg, 0.758 mmol), PCy.sub.3 (12.40 mg, 0.044 mmol), KOAc (93 mg, 0.948 mmol) and Pd.sub.2(dba).sub.3 (17.36 mg, 0.019 mmol). The reaction mixture was irradiated in a microwave reactor at 120° C. for 1 h. The reaction was quenched with water and extracted three times with EtOAc. The combined organic layers were dried over anhydrous MgSO.sub.4, filtered and concentrated under reduced pressure. The crude material was purified by silica gel column chromatography (0 to 100% EtOAc in cyclohexane) to give the title compound. (UPLC-MS) t.sub.R 1.19 min; ESI-MS 392.2 [M−H].sup.−.

Intermediate 47a: 4-bromo-N-((1s,3s)-3-(hydroxymethyl)cyclobutyl)-3-methylbenzenesulfonamide

(103) The title compound was prepared in an analogous manner to 4-bromo-3-chloro-N-((1s,3s)-3-hydroxy-3-(trifluoromethyl)cyclobutyl)benzenesulfonamide (Intermediate 1a) using 4-bromo-3-methylbenzene-1-sulfonyl chloride and ((1s,3s)-3-aminocyclobutyl)methanol to give the title compound as a colorless solid. (UPLC-MS) t.sub.R 0.89 min; ESI-MS 334.1/336.0 [M+H].sup.+.

Intermediate 47b: 4-(6-cyano-5-fluoropyridin-2-yl)-N-((1s,3s)-3-(hydroxymethyl)cyclobutyl)-3-methylbenzenesulfonamide

(104) The title compound was prepared in an analogous manner to 3-chloro-4-(6-cyano-5-fluoropyridin-2-yl)-N-(3-hydroxy-3-(trifluoromethyl)cyclobutyl)benzenesulfonamide (Intermediate 1 b) using 4-bromo-N-((1s,3s)-3-(hydroxymethyl)cyclobutyl)-3-methylbenzenesulfonamide (Intermediate 47a) to give the title compound. (UPLC-MS) t.sub.R 0.91 min; ESI-MS 376.1 [M−H].sup.−.

Intermediate 48a: 4-bromo-3-chloro-N-((1s,4s)-4-hydroxycyclohexyl)benzenesulfonamide

(105) The title compound was prepared in an analogous manner to 4-bromo-3-chloro-N-((1s,3s)-3-hydroxy-3-(trifluoromethyl)cyclobutyl)benzenesulfonamide (Intermediate 1a) using (1s,4s)-4-aminocyclohexanol to give the title compound as a colorless solid. (UPLC-MS) t.sub.R 0.97 min; ESI-MS 366.0/368.0/370.0 [M−H].sup.−.

Intermediate 48b: 3-chloro-4-(6-cyano-5-fluoropyridin-2-yl)-N-((1s,4s)-4-hydroxycyclohexyl)benzenesulfonamide

(106) The title compound was prepared in an analogous manner to 3-chloro-4-(6-cyano-5-fluoropyridin-2-yl)-N-(3-hydroxy-3-(trifluoromethyl)cyclobutyl)benzenesulfonamide (Intermediate 1 b) using 4-bromo-3-chloro-N-((1s,4s)-4-hydroxycyclohexyl)benzenesulfonamide (Intermediate 48a) to give the title compound. (UPLC-MS) t.sub.R 0.96 min; ESI-MS 410.1 [M+H].sup.+.

Intermediate 49a: 4-bromo-3-fluoro-N-phenylbenzenesulfonamide

(107) To a solution of aniline (0.033 mL, 0.366 mmol) in pyridine (2 mL) was added dropwise 4-bromo-3-fluorobenzene-1-sulfonyl chloride (0.054 mL, 0.366 mmol). The reaction mixture was stirred at RT for 35 min, then partitioned between water and EtOAc. The organic layer was separated and the aq. layer was extracted twice with EtOAc. The combined organic layers were dried over MgSO.sub.4, filtered and concentrated under reduced pressure. The resulting product was purified by silica gel column chromatography (4 to 20% MeOH in DCM) to afford the title compound. (UPLC-MS) t.sub.R 1.09 min; ESI-MS 328.0 [M−H].sup.−.

Intermediate 49b: 3-fluoro-N-phenyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzenesulfonamide

(108) The title compound was prepared in na analogous manner to N-(3-chloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)benzenesulfonamide (Intermediate 46b) using 4-bromo-3-fluoro-N-phenylbenzenesulfonamide (Intermediate 49a) in anhydrous dioxane. The reaction mixture was filtered through a pad of Celite which was washed with DCM. The combined solutions were concentrated under reduced pressure. The crude material was purified by silica gel column chromatography (0 to 100% EtOAc in cyclohexane) to give the title compound as a yellow solid. (UPLC-MS) t.sub.R 1.22 min; ESI-MS 376.0 [M−H].sup.−.

Intermediate 50a: 4-bromo-3-chloro-N-(1,1-dioxidotetrahydro-2H-thiopyran-4-yl)benzenesulfonamide

(109) The title compound was prepared in an analogous manner to 4-bromo-3-chloro-N-((1s,3s)-3-hydroxy-3-(trifluoromethyl)cyclobutyl)benzenesulfonamide (Intermediate 1a) using 4-aminotetrahydro-2H-thiopyran 1,1-dioxide to give the title compound as a colorless solid. (UPLC-MS) t.sub.R 0.88 min; ESI-MS 402.3 [M−H].sup.−.

Intermediate 50b: 3-chloro-4-(6-cyano-5-fluoropyridin-2-yl)-N-(1,1-dioxidotetrahydro-2H-thiopyran-4-yl)benzenesulfonamide

(110) The title compound was prepared in an analogous manner to 3-chloro-4-(6-cyano-5-fluoropyridin-2-yl)-N-(3-hydroxy-3-(trifluoromethyl)cyclobutyl)benzenesulfonamide (Intermediate 1 b) using 4-bromo-3-chloro-N-(1,1-dioxidotetrahydro-2H-thiopyran-4-yl)benzenesulfonamide (Intermediate 50a) to give the title compound. (UPLC-MS) t.sub.R 0.90 min; ESI-MS 442.2 [M−H].sup.−.

Intermediate 51a: 2-((4-bromo-3-chlorophenyl)sulfonyl)octahydrocyclopenta[c]pyrrole

(111) The title compound was prepared in an analogous manner to 4-bromo-3-chloro-N-((1s,3s)-3-hydroxy-3-(trifluoromethyl)cyclobutyl)benzenesulfonamide (Intermediate 1a) using octahydrocyclopenta[c]pyrrole to give the title compound as a colorless solid. (UPLC-MS) t.sub.R 1.33 min; ESI-MS 364.1/366.0/367.8 [M+H].sup.+.

Intermediate 51b: 6-(2-chloro-4-((hexahydrocyclopenta[c]pyrrol-2(1H)-yl)sulfonyl)phenyl)-3-fluoropicolinonitrile

(112) The title compound was prepared in an analogous manner to 3-chloro-4-(6-cyano-5-fluoropyridin-2-yl)-N-(3-hydroxy-3-(trifluoromethyl)cyclobutyl)benzenesulfonamide (Intermediate 1 b) using 2-((4-bromo-3-chlorophenyl)sulfonyl)octahydrocyclopenta[c]pyrrole (Intermediate 51a) to give the title compound. (UPLC-MS) t.sub.R 1.27 min; ESI-MS 406.2 [M+H].sup.+.

Intermediate 52a: 4-bromo-3-chloro-N-(3-chloro-2-fluorophenyl)benzenesulfonamide

(113) The title compound was prepared in an analogous manner to 4-bromo-N-(3-hydroxy-3-(trifluoromethyl)cyclobutyl)-3-methylbenzenesulfonamide (Intermediate 2a) using 4-bromo-3-chlorobenzene-1-sulfonyl chloride and 3-chloro-2-fluoroaniline. The reaction mixture was stirred at RT for 4.5 h. The title compound was obtained as a colorless solid. (UPLC-MS) t.sub.R 1.22 min; ESI-MS 395.9/397.9/399.9 [M−H].sup.−.

Intermediate 52b: 3-chloro-N-(3-chloro-2-fluorophenyl)-4-(6-cyano-5-fluoropyridin-2-yl)benzenesulfonamide

(114) The title compound was prepared in an analogous manner to 3-chloro-4-(6-cyano-5-fluoropyridin-2-yl)-N-(3-hydroxy-3-(trifluoromethyl)cyclobutyl)benzenesulfonamide (Intermediate 1 b) using 4-bromo-3-chloro-N-(3-chloro-2-fluorophenyl)benzenesulfonamide (Intermediate 52a) to give the title compound. (UPLC-MS) t.sub.R 1.20 min; ESI-MS 438.0/440.0 [M−H].sup.−.

Intermediate 53b: 4-acetyl-N-(3-chloro-4-(6-cyano-5-fluoropyridin-2-yl)phenyl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-sulfonamide

(115) The title compound was prepared in an analogous manner to 4-chloro-N-(3-chloro-4-(6-cyano-5-fluoropyridin-2-yl)phenyl)benzenesulfonamide (Intermediate 3b) using an excess of 4-acetyl-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-sulfonyl chloride (1.5 eq) and 6-(4-amino-2-chlorophenyl)-3-fluoropicolinonitrile (Intermediate 3a) at RT overnight to afford the title compound as an off-white solid. (UPLC-MS) t.sub.R 1.02 min; ESI-MS 487.2 [M+H].sup.+; ESI-MS 485.3 [M−H].sup.−.

Intermediate 54a: 4-bromo-N-((1R,4R)-4-hydroxycyclohexyl)-3-methylbenzenesulfonamide

(116) The title compound was prepared in an analogous manner to 4-bromo-3-chloro-N-((1s,3s)-3-hydroxy-3-(trifluoromethyl)cyclobutyl)benzenesulfonamide (Intermediate 1a) using 4-bromo-3-methylbenzene-1-sulfonyl chloride and (1r,4r)-4-aminocyclohexanol to give the title compound as a colorless solid. (UPLC-MS) t.sub.R 0.87 min; ESI-MS 348.0/350.0 [M+H].sup.+.

Intermediate 54b: 4-(6-cyano-5-fluoropyridin-2-yl)-N-((1R,4R)-4-hydroxycyclohexyl)-3-methylbenzenesulfonamide

(117) The title compound was prepared in an analogous manner to 3-chloro-4-(6-cyano-5-fluoropyridin-2-yl)-N-(3-hydroxy-3-(trifluoromethyl)cyclobutyl)benzenesulfonamide (Intermediate 1 b) using 4-bromo-N-((1R,4R)-4-hydroxycyclohexyl)-3-methylbenzenesulfonamide (Intermediate 54a) to give the title compound. (UPLC-MS) t.sub.R 0.88 min; ESI-MS 390.1 [M+H].sup.+.

Intermediate 55a: (2R,4R)-1-((4-bromo-3-chlorophenyl)sulfonyl)-4-fluoropyrrolidine-2-carboxamide

(118) The title compound was prepared in an analogous manner to 4-bromo-3-chloro-N-((1s,3s)-3-hydroxy-3-(trifluoromethyl)cyclobutyl)benzenesulfonamide (Intermediate 1a) using (2R,4R)-4-fluoropyrrolidine-2-carboxamide to give the title compound as a colorless solid. (UPLC-MS) t.sub.R 0.85 min; ESI-MS 387.2 [M+H].sup.+.

Intermediate 55b: (2R,4R)-1-((3-chloro-4-(6-cyano-5-fluoropyridin-2-yl)phenyl)sulfonyl)-4-fluoropyrrolidine-2-carboxamide

(119) The title compound was prepared in an analogous manner to 3-chloro-4-(6-cyano-5-fluoropyridin-2-yl)-N-(3-hydroxy-3-(trifluoromethyl)cyclobutyl)benzenesulfonamide (Intermediate 1 b) using (2R,4R)-1-((4-bromo-3-chlorophenyl)sulfonyl)-4-fluoropyrrolidine-2-carboxamide (Intermediate 55a) to give the title compound as an off-white solid. (UPLC-MS) t.sub.R 0.88 min; ESI-MS 427.1 [M−H].sup.−.

Intermediate 56a: 4-bromo-3-chloro-N-(2,3-dichlorophenyl)benzenesulfonamide

(120) The title compound was prepared in an analogous manner to 4-bromo-N-(3-hydroxy-3-(trifluoromethyl)cyclobutyl)-3-methylbenzenesulfonamide (Intermediate 2a) using 4-bromo-3-chlorobenzene-1-sulfonyl chloride and 2,3-dichloroaniline. The reaction mixture was stirred at RT for 5.5 h. The title compound was obtained as a colorless solid. (UPLC-MS) t.sub.R 1.30 min; ESI-MS 411.9/413.9/415.9/417.9 [M−H].sup.−.

Intermediate 56b: 3-chloro-4-(6-cyano-5-fluoropyridin-2-yl)-N-(2,3-dichlorophenyl)benzenesulfonamide

(121) The title compound was prepared in an analogous manner to 3-chloro-4-(6-cyano-5-fluoropyridin-2-yl)-N-(3-hydroxy-3-(trifluoromethyl)cyclobutyl)benzenesulfonamide (Intermediate 1 b) using 4-bromo-3-chloro-N-(2,3-dichlorophenyl)benzenesulfonamide (Intermediate 56a) to give the title compound. (UPLC-MS) t.sub.R 1.25 min; ESI-MS 454.0/456.0 [M−H].sup.−.

Intermediate 57a: (R)-1-((4-bromo-3-chlorophenyl)sulfonyl)pyrrolidin-3-ol

(122) The title compound was prepared in an analogous manner to 4-bromo-N-(3-hydroxy-3-(trifluoromethyl)cyclobutyl)-3-methylbenzenesulfonamide (Intermediate 2a) using 4-bromo-3-chlorobenzene-1-sulfonyl chloride and (R)-pyrrolidin-3-ol. The reaction mixture was stirred at 0° C. for 60 min. The title compound was obtained as a yellow solid. (UPLC-MS) t.sub.R 0.91 min; ESI-MS 340.0/342.1 [M+H].sup.+.

Intermediate 57b: (R)-6-(2-chloro-4-((3-hydroxypyrrolidin-1-yl)sulfonyl)phenyl)-3-fluoropicolinonitrile

(123) The title compound was prepared in an analogous manner to 3-chloro-4-(6-cyano-5-fluoropyridin-2-yl)-N-(3-hydroxy-3-(trifluoromethyl)cyclobutyl)benzenesulfonamide (Intermediate 1b) using (R)-1-((4-bromo-3-chlorophenyl)sulfonyl)pyrrolidin-3-ol (Intermediate 57a) to give the title compound. (UPLC-MS) t.sub.R 0.92 min; ESI-MS 382.1 [M+H].sup.+.

Intermediate 58a: 4-bromo-3-chloro-N-((1R,4R)-4-hydroxy-4-methylcyclohexyl)benzenesulfonamide

(124) The title compound was prepared in an analogous manner to 4-bromo-N-(3-hydroxy-3-(trifluoromethyl)cyclobutyl)-3-methylbenzenesulfonamide (Intermediate 2a) using 4-bromo-3-chlorobenzene-1-sulfonyl chloride and (1R,4R)-4-amino-1-methylcyclohexanol. The reaction mixture was stirred at 0° C. for 30 min and at RT for 6.5 h, then diluted with EtOAc. The organic layer was washed twice with a 1N aq. NH.sub.4Cl. The aq. layer was extracted twice with EtOAc. The combined organic layers were washed with brine, dried over anhydrous MgSO.sub.4, filtered and concentrated under reduced pressure. The crude material was purified by silica gel column chromatography (0 to 40% EtOAc in Cyclohexane) to give the title compound as a white solid. (UPLC-MS) t.sub.R 0.94 min; 380.0/382.1/384.0 [M−H].sup.−.

Intermediate 58b: 3-chloro-4-(6-cyano-5-fluoropyridin-2-yl)-N-((1R,4R)-4-hydroxy-4-methylcyclohexyl)benzenesulfonamide

(125) The title compound was prepared in an analogous manner to 3-chloro-4-(6-cyano-5-fluoropyridin-2-yl)-N-(3-hydroxy-3-(trifluoromethyl)cyclobutyl)benzenesulfonamide (Intermediate 1 b) 4-bromo-3-chloro-N-((1R,4R)-4-hydroxy-4-methylcyclohexyl)benzenesulfonamide (Intermediate 58a) to give the title compound. (UPLC-MS) t.sub.R 0.95 min; ESI-MS 422.1 [M−H].sup.−.

Intermediate 59b: N-(3-chloro-4-(6-cyano-5-fluoropyridin-2-yl)phenyl)-1-phenylmethanesulfonamide

(126) The title compound was prepared in an analogous manner to 4-chloro-N-(3-chloro-4-(6-cyano-5-fluoropyridin-2-yl)phenyl)benzenesulfonamide (Intermediate 3b) using phenylmethanesulfonyl chloride and 6-(4-amino-2-chlorophenyl)-3-fluoropicolinonitrile (Intermediate 3a) at 0° C. for 2 h without extracting workup to afford the title compound as a pale yellow solid. (UPLC-MS) t.sub.R 1.12 min; ESI-MS 402.1 [M+H].sup.+; ESI-MS 400.1 [M−H].sup.−.

Intermediate 61b: N-(5-(N-(3-chloro-4-(6-cyano-5-fluoropyridin-2-yl)phenyl)sulfamoyl)-2-methoxyphenyl)acetamide

(127) To a solution of 6-(4-amino-2-chlorophenyl)-3-fluoropicolinonitrile (56 mg, 0.226 mmol) in Pyridine (3 mL) cooled down to 0° C. was added 3-acetamido-4-methoxybenzene-1-sulfonyl chloride (59.6 mg, 0.226 mmol). The reaction was stirred at this temperature for 5 h. 0.6 eq of 3-acetamido-4-methoxybenzene-1-sulfonyl chloride was added and the reaction was stirred overnight at RT. The mixture was quenched with a sat. aq. NH.sub.4Cl solution and EtOAc was added. Both phases were separated and the aq. layer was extracted twice with EtOAc. The combined organic layers were dried over anhydrous MgSO.sub.4, filtered and evaporated to under reduced pressure. The residue was purified by silica gel column chromatography (0 to 100% EtOAc in Cyclohexane) to afford the title compound as a light yellow foam. (UPLC-MS) t.sub.R 1.01 min; ESI-MS 475.1 [M+H].sup.+; ESI-MS 473.1 [M−H].sup.−.

Intermediate 62b: N-(3-chloro-4-(6-cyano-5-fluoropyridin-2-yl)phenyl)-3-(trifluoromethyl)benzenesulfonamide

(128) The title compound was prepared in an analogous manner to 4-chloro-N-(3-chloro-4-(6-cyano-5-fluoropyridin-2-yl)phenyl)benzenesulfonamide (Intermediate 3b) using 3-(trifluoromethyl)benzene-1-sulfonyl chloride and 6-(4-amino-2-chlorophenyl)-3-fluoropicolinonitrile (Intermediate 3a) at 0° C. for 2 h to afford the title compound as a white solid. (UPLC-MS) t.sub.R 1.20 min; ESI-MS 456.1 [M+H].sup.+; ESI-MS 454.1 [M−H].sup.−.

Intermediate 63a: 3-((4-bromo-3-chlorophenyl)sulfonyl)-3-azabicyclo[3.1.0]hexane

(129) The title compound was prepared in an analogous manner to 4-bromo-3-chloro-N-((1s,3s)-3-hydroxy-3-(trifluoromethyl)cyclobutyl)benzenesulfonamide (Intermediate 1a) using 3-azabicyclo[3.1.0]hexane to give the title compound as a colorless solid. (UPLC-MS) t.sub.R 1.17 min; ESI-MS 338.0 [M+H].sup.+.

Intermediate 63b: 6-(4-(3-azabicyclo[3.1.0]hexan-3-ylsulfonyl)-2-chlorophenyl)-3-fluoropicolinonitrile

(130) The title compound was prepared in an analogous manner to 3-chloro-4-(6-cyano-5-fluoropyridin-2-yl)-N-(3-hydroxy-3-(trifluoromethyl)cyclobutyl)benzenesulfonamide (Intermediate 1 b) using 3-((4-bromo-3-chlorophenyl)sulfonyl)-3-azabicyclo[3.1.0]hexane (Intermediate 63a) to give the title compound. (UPLC-MS) t.sub.R 1.19 min; ESI-MS 378.2 [M+H].sup.+.

Intermediate 64a: 4-bromo-N-((1S,3S)-3-hydroxycyclobutyl)-3-methylbenzenesulfonamide

(131) The title compound was prepared in an analogous manner to 4-bromo-3-chloro-N-((1s,3s)-3-hydroxy-3-(trifluoromethyl)cyclobutyl)benzenesulfonamide (Intermediate 1a) using 4-bromo-3-methylbenzene-1-sulfonyl chloride and (1S,3S)-3-aminocyclobutanol to give the title compound as a colorless solid. (UPLC-MS) t.sub.R 0.82 min; ESI-MS 320.0 [M+H].sup.+.

Intermediate 64b: 4-(6-cyano-5-fluoropyridin-2-yl)-N-((1S,3S)-3-hydroxycyclobutyl)-3-methylbenzenesulfonamide

(132) The title compound was prepared in an analogous manner to 3-chloro-4-(6-cyano-5-fluoropyridin-2-yl)-N-(3-hydroxy-3-(trifluoromethyl)cyclobutyl)benzenesulfonamide (Intermediate 1 b) using 4-bromo-N-((1S,3S)-3-hydroxycyclobutyl)-3-methylbenzenesulfonamide (Intermediate 64a) to give the title compound. (UPLC-MS) t.sub.R 0.83 min; ESI-MS 362.0 [M+H].sup.+.

Intermediate 65a: 4-bromo-N-(3-hydroxycyclohexyl)-3-methylbenzenesulfonamide

(133) The title compound was prepared in an analogous manner to 4-bromo-3-chloro-N-((1s,3s)-3-hydroxy-3-(trifluoromethyl)cyclobutyl)benzenesulfonamide (Intermediate 1a) using 4-bromo-3-methylbenzene-1-sulfonyl chloride and 3-aminocyclohexanol to give the title compound as a colorless solid. (UPLC-MS) t.sub.R 0.91 min; ESI-MS 348.1/350.0 [M+H].sup.+.

Intermediate 65b: 4-(6-cyano-5-fluoropyridin-2-yl)-N-(3-hydroxycyclohexyl)-3-methylbenzenesulfonamide

(134) The title compound was prepared in an analogous manner to 3-chloro-4-(6-cyano-5-fluoropyridin-2-yl)-N-(3-hydroxy-3-(trifluoromethyl)cyclobutyl)benzenesulfonamide (Intermediate 1 b) using 4-bromo-N-(3-hydroxycyclohexyl)-3-methylbenzenesulfonamide (Intermediate 65a) to give the title compound. (UPLC-MS) t.sub.R 0.90 min; ESI-MS 390.2 [M+H].sup.+.

Intermediate 66a: 1-((4-bromo-3-methylphenyl)sulfonyl)-3-(trifluoromethyl)azetidin-3-ol

(135) The title compound was prepared in an analogous manner to 4-bromo-3-chloro-N-((1s,3s)-3-hydroxy-3-(trifluoromethyl)cyclobutyl)benzenesulfonamide (Intermediate 1a) using 4-bromo-3-methylbenzene-1-sulfonyl chloride and 3-(trifluoromethyl)azetidin-3-ol to give the title compound as a colorless solid. (UPLC-MS) t.sub.R 1.07 min; ESI-MS 372.2 [M−H].sup.−.

Intermediate 66b: 3-fluoro-6-(4-((3-hydroxy-3-(trifluoromethyl)azetidin-1-yl)sulfonyl)-2-methylphenyl)picolinonitrile

(136) The title compound was prepared in an analogous manner to 3-chloro-4-(6-cyano-5-fluoropyridin-2-yl)-N-(3-hydroxy-3-(trifluoromethyl)cyclobutyl)benzenesulfonamide (Intermediate 1 b) using 1-((4-bromo-3-methylphenyl)sulfonyl)-3-(trifluoromethyl)azetidin-3-ol (Intermediate 66a) to give the title compound. (UPLC-MS) t.sub.R 0.78 min; ESI-MS 428.1 [M+H].sup.+.

Intermediate 67b: N-(3-chloro-4-(6-cyano-5-fluoropyridin-2-yl)phenyl)-3-methoxybenzenesulfonamide

(137) The title compound was prepared in an analogous manner to 4-chloro-N-(3-chloro-4-(6-cyano-5-fluoropyridin-2-yl)phenyl)benzenesulfonamide (Intermediate 3b) using 3-methoxybenzene-1-sulfonyl chloride and 6-(4-amino-2-chlorophenyl)-3-fluoropicolinonitrile (Intermediate 3a) at 0° C. for 2 h to afford the title compound as white solid. (UPLC-MS) t.sub.R 1.12 min; ESI-MS 418.1 [M+H].sup.+; ESI-MS 416.1 [M−H].sup.−.

Intermediate 68a: 4-bromo-N-((1R,4R)-4-hydroxy-4-(trifluoromethyl)cyclohexyl)-3-methylbenzenesulfonamide

(138) The title compound was prepared in an analogous manner to 4-bromo-3-chloro-N-((1s,3s)-3-hydroxy-3-(trifluoromethyl)cyclobutyl)benzenesulfonamide (Intermediate 1a) using 4-bromo-3-methylbenzene-1-sulfonyl chloride and (1R,4R)-4-amino-1-(trifluoromethyl)cyclohexanol to give the title compound as a colorless solid. (UPLC-MS) t.sub.R 1.06 min; ESI-MS 414.1/416.1 [M−H].sup.−.

Intermediate 68b: 4-(6-cyano-5-fluoropyridin-2-yl)-N-((1r,4r)-4-hydroxy-4-(trifluoromethyl)cyclohexyl)-3-methylbenzenesulfonamide

(139) The title compound was prepared in an analogous manner to 3-chloro-4-(6-cyano-5-fluoropyridin-2-yl)-N-(3-hydroxy-3-(trifluoromethyl)cyclobutyl)benzenesulfonamide (Intermediate 1 b) using 4-bromo-N-((1r,4r)-4-hydroxy-4-(trifluoromethyl)cyclohexyl)-3-methylbenzenesulfonamide (Intermediate 68a) to give the title compound. (UPLC-MS) t.sub.R 1.03 min; ESI-MS 458.2 [M+H].sup.+. Intermediate 69a: 4-bromo-N-((1S,4S)-4-hydroxycyclohexyl)-3-methylbenzenesulfonamide. The title compound was prepared in an analogous manner to 4-bromo-3-chloro-N-((1s,3s)-3-hydroxy-3-(trifluoromethyl)cyclobutyl)benzenesulfonamide (Intermediate 1a) using 4-bromo-3-methylbenzene-1-sulfonyl chloride and (1S,4S)-4-aminocyclohexanol to give the title compound as a colorless solid. (UPLC-MS) t.sub.R 0.96 min; ESI-MS 348.0/350.0 [M+H].sup.+.

Intermediate 69b: 4-(6-cyano-5-fluoropyridin-2-yl)-N-((1S,4S)-4-hydroxycyclohexyl)-3-methylbenzenesulfonamide

(140) The title compound was prepared in an analogous manner to 3-chloro-4-(6-cyano-5-fluoropyridin-2-yl)-N-(3-hydroxy-3-(trifluoromethyl)cyclobutyl)benzenesulfonamide (Intermediate 1 b) using 4-bromo-N-((1S,4S)-4-hydroxycyclohexyl)-3-methylbenzenesulfonamide (Intermediate 69a) to give the title compound. (UPLC-MS) t.sub.R 0.92 min; ESI-MS 390.2 [M+H].sup.+.

Intermediate 70a: (S)-(1-((4-bromo-3-methylphenyl)sulfonyl)pyrrolidin-2-yl)methanol

(141) The title compound was prepared in an analogous manner to 4-bromo-3-chloro-N-((1s,3s)-3-hydroxy-3-(trifluoromethyl)cyclobutyl)benzenesulfonamide (Intermediate 1a) using 4-bromo-3-methylbenzene-1-sulfonyl chloride and (S)-pyrrolidin-2-ylmethanol to give the title compound as a colorless solid. (UPLC-MS) t.sub.R 0.98 min; ESI-MS 336.0 [M+H].sup.+.

Intermediate 70b: (S)-3-fluoro-6-(4-((2-(hydroxymethyl)pyrrolidin-1-yl)sulfonyl)-2-methylphenyl)picolinonitrile

(142) The title compound was prepared in an analogous manner to 3-chloro-4-(6-cyano-5-fluoropyridin-2-yl)-N-(3-hydroxy-3-(trifluoromethyl)cyclobutyl)benzenesulfonamide (Intermediate 1 b) using (S)-(1-((4-bromo-3-methylphenyl)sulfonyl)pyrrolidin-2-yl)methanol (Intermediate 70a) to give the title compound. (UPLC-MS) t.sub.R 0.98 min; ESI-MS 376.1 [M+H].sup.+.

Intermediate 71a: (S)-1-((4-bromo-3-chlorophenyl)sulfonyl)pyrrolidin-3-ol

(143) The title compound was prepared in an analogous manner to (S)-1-((4-bromo-3-chlorophenyl)sulfonyl)pyrrolidin-3-ol (Intermediate 57a) using (S)-pyrrolidin-3-ol and purification was preceded by an aqueous workup whereby the reaction mixture was diluted with EtOAc and washed subsequently with 1N aq. NH.sub.4Cl solution, 0.1M aq. LiBr solution, and brine. The organic layer was dried over anhydrous MgSO.sub.4, filtered, and concentrated under reduced pressure to afford the title compound. (UPLC-MS) t.sub.R 0.91 min; ESI-MS 340.0/342.0 [M+H].sup.+.

Intermediate 71b: (S)-6-(2-chloro-4-((3-hydroxypyrrolidin-1-yl)sulfonyl)phenyl)-3-fluoropicolinonitrile

(144) The title compound was prepared in an analogous manner to 3-chloro-4-(6-cyano-5-fluoropyridin-2-yl)-N-(3-hydroxy-3-(trifluoromethyl)cyclobutyl)benzenesulfonamide (Intermediate 1 b) using (S)-1-((4-bromo-3-chlorophenyl)sulfonyl)pyrrolidin-3-ol (Intermediate 71a) to give the title compound. (UPLC-MS) t.sub.R 0.95 min; ESI-MS 382.1 [M+H].sup.+.

Intermediate 72a: 4-bromo-3-chloro-N-(2-hydroxyethyl)benzenesulfonamide

(145) The title compound was prepared in an analogous manner to 4-bromo-3-chloro-N-((1s,3s)-3-hydroxy-3-(trifluoromethyl)cyclobutyl)benzenesulfonamide (Intermediate 1a) using 2-aminoethanol to give the title compound as a colorless solid. (UPLC-MS) t.sub.R 0.84 min; ESI-MS 311.9/313.9/315.9 [M−H].sup.−.

Intermediate 72b: 3-chloro-4-(6-cyano-5-fluoropyridin-2-yl)-N-(2-hydroxyethyl)benzenesulfonamide

(146) The title compound was prepared in an analogous manner to 3-chloro-4-(6-cyano-5-fluoropyridin-2-yl)-N-(3-hydroxy-3-(trifluoromethyl)cyclobutyl)benzenesulfonamide (Intermediate 1 b) using 4-bromo-3-chloro-N-(2-hydroxyethyl)benzenesulfonamide (Intermediate 72a) to give the title compound. (UPLC-MS) t.sub.R 0.89 min; ESI-MS 356.1 [M+H].sup.+.

Intermediate 73a: N-benzyl-4-bromo-3-chlorobenzenesulfonamide

(147) The title compound was prepared in an analogous manner to 4-bromo-N-(3-hydroxy-3-(trifluoromethyl)cyclobutyl)-3-methylbenzenesulfonamide (Intermediate 2a) using 4-bromo-3-chlorobenzene-1-sulfonyl chloride and benzylamine. The reaction mixture was stirred at 0° C. for 3.5 h. The title compound was obtained as a yellow solid. (UPLC-MS) t.sub.R 1.16 min; ESI-MS 357.9/359.9 [M+H].sup.+.

Intermediate 73b: N-benzyl-3-chloro-4-(6-cyano-5-fluoropyridin-2-yl)benzenesulfonamide

(148) The title compound was prepared in an analogous manner to 3-chloro-4-(6-cyano-5-fluoropyridin-2-yl)-N-(3-hydroxy-3-(trifluoromethyl)cyclobutyl)benzenesulfonamide (Intermediate 1 b) using N-benzyl-4-bromo-3-chlorobenzenesulfonamide (Intermediate 73a) to give the title compound. (UPLC-MS) t.sub.R 1.15 min; ESI-MS 402.1 [M+H].sup.+.

Intermediate 74a: 1-((4-bromo-3-chlorophenyl)sulfonyl)-3,3-difluoroazetidine

(149) The title compound was prepared in an analogous manner to 4-bromo-3-chloro-N-((1s,3s)-3-hydroxy-3-(trifluoromethyl)cyclobutyl)benzenesulfonamide (Intermediate 1a) using 3,3-difluoroazetidine to give the title compound as a colorless solid. (UPLC-MS) t.sub.R 1.12 min; no ESI-MS ionization of parent observed.

Intermediate 74b: 6-(2-chloro-4-((3,3-difluoroazetidin-1-yl)sulfonyl)phenyl)-3-fluoropicolinonitrile

(150) The title compound was prepared in an analogous manner to 3-chloro-4-(6-cyano-5-fluoropyridin-2-yl)-N-(3-hydroxy-3-(trifluoromethyl)cyclobutyl)benzenesulfonamide (Intermediate 1 b) using 1-((4-bromo-3-chlorophenyl)sulfonyl)-3,3-difluoroazetidine (Intermediate 74a) to give the title compound. (UPLC-MS) t.sub.R 1.10 min; ESI-MS 384.3 [M+H].sup.+.

Intermediate 75a: 4-bromo-N-(tert-butyl)-3-fluorobenzenesulfonamide

(151) The title compound was prepared in an analogous manner to 4-bromo-3-chloro-N-((1s,3s)-3-hydroxy-3-(trifluoromethyl)cyclobutyl)benzenesulfonamide (Intermediate 1a) using 4-bromo-3-fluorobenzene-1-sulfonyl chloride and tert-butylamine to give the title compound as a colorless solid. (UPLC-MS) t.sub.R 1.12 min; ESI-MS 308.0/309.9 [M−H].sup.−.

Intermediate 75b: 6-(2-chloro-4-((3,3-difluoroazetidin-1-yl)sulfonyl)phenyl)-3-fluoropicolinonitrile

(152) The title compound was prepared in an analogous manner to 3-chloro-4-(6-cyano-5-fluoropyridin-2-yl)-N-(3-hydroxy-3-(trifluoromethyl)cyclobutyl)benzenesulfonamide (Intermediate 1 b) using 4-bromo-N-(tert-butyl)-3-fluorobenzenesulfonamide (Intermediate 75a) to give the title compound. (UPLC-MS) t.sub.R 1.11 min; ESI-MS 350.1 [M−H].sup.−.

Intermediate 76b: N1-(3-chloro-4-(6-cyano-5-fluoropyridin-2-yl)phenyl)-N4-methyl benzene-1,4-disulfonamide

(153) The title compound was prepared in an analogous manner to 4-chloro-N-(3-chloro-4-(6-cyano-5-fluoropyridin-2-yl)phenyl)benzenesulfonamide (Intermediate 3b) using 4-(N-methylsulfamoyl)benzene-1-sulfonyl chloride and 6-(4-amino-2-chlorophenyl)-3-fluoropicolinonitrile (Intermediate 3a) at 0° C. for 2 h to afford the title compound as a pale yellow solid. (UPLC-MS) t.sub.R 1.03 min; ESI-MS 481.1 [M+H].sup.+; ESI-MS 479.0 [M−H].sup.−.

Intermediate 77a: 4-bromo-N-((1R,3R)-3-hydroxycyclobutyl)-3-methylbenzenesulfonamide

(154) The title compound was prepared in an analogous manner to 4-bromo-3-chloro-N-((1s,3s)-3-hydroxy-3-(trifluoromethyl)cyclobutyl)benzenesulfonamide (Intermediate 1a) using 4-bromo-3-methylbenzene-1-sulfonyl chloride was used in place of 4-bromo-3-chlorobenzene-1-sulfonyl chloride and (1R,3R)-3-aminocyclobutanol to give the title compound as a colorless solid. (UPLC-MS) t.sub.R 0.84 min; ESI-MS 320.0 [M+H].sup.+.

Intermediate 77b: 4-(6-cyano-5-fluoropyridin-2-yl)-N-((1R,3R)-3-hydroxycyclobutyl)-3-methylbenzenesulfonamide

(155) The title compound was prepared in an analogous manner to 3-chloro-4-(6-cyano-5-fluoropyridin-2-yl)-N-(3-hydroxy-3-(trifluoromethyl)cyclobutyl)benzenesulfonamide (Intermediate 1 b) using 4-bromo-N-((1R,3R)-3-hydroxycyclobutyl)-3-methylbenzenesulfonamide (Intermediate 77a) to give the title compound. (UPLC-MS) t.sub.R 0.79 min; ESI-MS 362.2 [M+H].sup.+.

Intermediate 78b: N-(3-chloro-4-(6-cyano-5-fluoropyridin-2-yl)phenyl)-4-(trifluoromethyl)benzenesulfonamide

(156) The title compound was prepared in an analogous manner to 4-chloro-N-(3-chloro-4-(6-cyano-5-fluoropyridin-2-yl)phenyl)benzenesulfonamide (Intermediate 3b) using 4-(trifluoromethyl)benzene-1-sulfonyl chloride and 6-(4-amino-2-chlorophenyl)-3-fluoropicolinonitrile (Intermediate 3a) at 0° C. for 1.5 h to afford the title compound as a yellow solid. (UPLC-MS) t.sub.R 1.23 min; ESI-MS 456.1 [M+H].sup.+; ESI-MS 454.1 [M−H].sup.−.

Intermediate 79b: N-(3-chloro-4-(6-cyano-5-fluoropyridin-2-yl)phenyl)-3,4-dimethoxybenzenesulfonamide

(157) The title compound was prepared in an analogous manner to 4-chloro-N-(3-chloro-4-(6-cyano-5-fluoropyridin-2-yl)phenyl)benzenesulfonamide (Intermediate 3b) using a large excess of 3,4-dimethoxybenzene-1-sulfonyl chloride and 6-(4-amino-2-chlorophenyl)-3-fluoropicolinonitrile (Intermediate 3a) at RT for 2 days to afford the title compound as an off-white solid. (UPLC-MS) t.sub.R 1.08 min; ESI-MS 448.1 [M+H].sup.+; ESI-MS 446.1 [M−H].sup.−.

Intermediate 80a: 4-bromo-N-((1R,4R)-4-hydroxy-4-methylcyclohexyl)-3-methylbenzenesulfonamide

(158) The title compound was prepared in an analogous manner to 4-bromo-3-chloro-N-((1s,3s)-3-hydroxy-3-(trifluoromethyl)cyclobutyl)benzenesulfonamide (Intermediate 1a) using 4-bromo-3-methylbenzene-1-sulfonyl chloride and (1R,4R)-4-amino-1-methylcyclohexanol to give the title compound as a colorless solid. (UPLC-MS) t.sub.R 0.92 min; 362.1/364.0 [M+H].sup.+.

Intermediate 80b: 4-(6-cyano-5-fluoropyridin-2-yl)-N-((1R,4R)-4-hydroxy-4-methylcyclohexyl)-3-methylbenzenesulfonamide

(159) The title compound was prepared in an analogous manner to 3-chloro-4-(6-cyano-5-fluoropyridin-2-yl)-N-(3-hydroxy-3-(trifluoromethyl)cyclobutyl)benzenesulfonamide (Intermediate 1 b) using 4 bromo-N-((1R,4R)-4-hydroxy-4-methylcyclohexyl)-3-methylbenzenesulfonamide (Intermediate 80a) to give the title compound. (UPLC-MS) t.sub.R 0.91 min; ESI-MS 404.2 [M−H].sup.−.

Intermediate 81a: 4-bromo-3-chloro-N-(2,3-difluorophenyl)benzenesulfonamide

(160) The title compound was prepared in an analogous manner to 4-bromo-N-(3-hydroxy-3-(trifluoromethyl)cyclobutyl)-3-methylbenzenesulfonamide (Intermediate 2a) using 2,3-difluoroaniline. The reaction mixture was stirred at RT for 5.5 h. The title compound was obtained as an off-white solid. (UPLC-MS) t.sub.R 1.19 min; ESI-MS 380.0/382.0/383.5/384.8 [M−H].sup.−.

Intermediate 81b: 3-chloro-4-(6-cyano-5-fluoropyridin-2-yl)-N-(2,3-difluorophenyl)benzenesulfonamide

(161) The title compound was prepared in an analogous manner to 3-chloro-4-(6-cyano-5-fluoropyridin-2-yl)-N-(3-hydroxy-3-(trifluoromethyl)cyclobutyl)benzenesulfonamide (Intermediate 1 b) using 4-bromo-3-chloro-N-(2,3-difluorophenyl)benzenesulfonamide (Intermediate 82a) to give the title compound. (UPLC-MS) t.sub.R 1.16 min; ESI-MS 424.0 [M+H].sup.+.

Intermediate 82b: N-(3-chloro-4-(6-cyano-5-fluoropyridin-2-yl)phenyl)naphthalene-2-sulfonamide

(162) The title compound was prepared in an analogous manner to 4-chloro-N-(3-chloro-4-(6-cyano-5-fluoropyridin-2-yl)phenyl)benzenesulfonamide (Intermediate 3b) using naphthalene-2-sulfonyl chloride and 6-(4-amino-2-chlorophenyl)-3-fluoropicolinonitrile (Intermediate 3a) at 0° C. for 2 h to afford the title compound as an off-white solid. (UPLC-MS) t.sub.R 1.21 min; ESI-MS 438.1 [M+H].sup.+; ESI-MS 436.1 [M−H].sup.−.

Intermediate 83a: 2-(1-((4-bromo-3-methylphenyl)sulfonyl)pyrrolidin-3-yl)ethanol

(163) The title compound was prepared in an analogous manner to 4-bromo-3-chloro-N-((1s,3s)-3-hydroxy-3-(trifluoromethyl)cyclobutyl)benzenesulfonamide (Intermediate 1a) using 4-bromo-3-methylbenzene-1-sulfonyl chloride and 2-(pyrrolidin-3-yl)ethanol to give the title compound as a colorless solid. (UPLC-MS) t.sub.R 0.96 min; 348.2/350.0 [M+H].sup.+.

Intermediate 83b: 3-fluoro-6-(4-((3-(2-hydroxyethyl)pyrrolidin-1-yl)sulfonyl)-2-methylphenyl)picolinonitrile

(164) The title compound was prepared in an analogous manner to 3-chloro-4-(6-cyano-5-fluoropyridin-2-yl)-N-(3-hydroxy-3-(trifluoromethyl)cyclobutyl)benzenesulfonamide (Intermediate 1 b) using 2-(1-((4-bromo-3-methylphenyl)sulfonyl)pyrrolidin-3-yl)ethanol (Intermediate 83a) to give the title compound. (UPLC-MS) t.sub.R 0.94 min; ESI-MS 390.2 [M+H].sup.+.

Intermediate 84b: N-(3-chloro-4-(6-cyano-5-fluoropyridin-2-yl)phenyl)-3-methylbenzenesulfonamide

(165) The title compound was prepared in an analogous manner to 4-chloro-N-(3-chloro-4-(6-cyano-5-fluoropyridin-2-yl)phenyl)benzenesulfonamide (Intermediate 3b) using 3-methylbenzene-1-sulfonyl chloride and 6-(4-amino-2-chlorophenyl)-3-fluoropicolinonitrile (Intermediate 3a) at 0° C. for 2 h to afford the title compound as a white solid. (UPLC-MS) t.sub.R 1.15 min; ESI-MS 402.1 [M+H].sup.+; ESI-MS 400.1 [M−H].sup.−.

Intermediate 85a: 4-bromo-3-chloro-N-((1S,3S)-3-(hydroxymethyl)cyclobutyl)benzenesulfonamide

(166) The title compound was prepared in an analogous manner to 4-bromo-3-chloro-N-((1s,3s)-3-hydroxy-3-(trifluoromethyl)cyclobutyl)benzenesulfonamide (Intermediate 1a) using ((1S,3S)-3-aminocyclobutyl)methanol to give the title compound as a colorless solid. (UPLC-MS) t.sub.R 0.88 min; ESI-MS 356.1 [M+H].sup.+.

Intermediate 85b: 3-chloro-4-(6-cyano-5-fluoropyridin-2-yl)-N-((1S,3S)-3-(hydroxymethyl)cyclobutyl)benzenesulfonamide

(167) The title compound was prepared in an analogous manner to 3-chloro-4-(6-cyano-5-fluoropyridin-2-yl)-N-(3-hydroxy-3-(trifluoromethyl)cyclobutyl)benzenesulfonamide (Intermediate 1 b) using 4-bromo-3-chloro-N-((1S,3S)-3-(hydroxymethyl)cyclobutyl)benzenesulfonamide (Intermediate 85a) to give the title compound. (UPLC-MS) t.sub.R 0.92 min; ESI-MS 396.1 [M−H].sup.−.

Intermediate 86b: 4-acetyl-N-(3-chloro-4-(6-cyano-5-fluoropyridin-2-yl)phenyl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-sulfonamide

(168) The title compound was prepared in an analogous manner to 4-chloro-N-(3-chloro-4-(6-cyano-5-fluoropyridin-2-yl)phenyl)benzenesulfonamide (Intermediate 3b) using an excess of 4-acetyl-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-sulfonyl chloride and 6-(4-amino-2-chlorophenyl)-3-fluoropicolinonitrile (Intermediate 3a) at 0° C. to RT for 8 h to afford the title compound. (UPLC-MS) t.sub.R 1.04 min; ESI-MS 487.1 [M+H].sup.+; ESI-MS 485.1 [M−H].sup.−.

Intermediate 87a: 1-((4-bromo-3-chlorophenyl)sulfonyl)-3-phenoxyazetidine

(169) The title compound was prepared in an analogous manner to 4-bromo-3-chloro-N-((1s,3s)-3-hydroxy-3-(trifluoromethyl)cyclobutyl)benzenesulfonamide (Intermediate 1a) using 3-phenoxyazetidine to give the title compound as a colorless solid. (UPLC-MS) t.sub.R 1.27 min; no ESI-MS ionization of parent observed.

Intermediate 87b: 6-(2-chloro-4-((3-phenoxyazetidin-1-yl)sulfonyl)phenyl)-3-fluoropicolinonitrile

(170) The title compound was prepared in an analogous manner to 3-chloro-4-(6-cyano-5-fluoropyridin-2-yl)-N-(3-hydroxy-3-(trifluoromethyl)cyclobutyl)benzenesulfonamide (Intermediate 1 b) using 1-((4-bromo-3-chlorophenyl)sulfonyl)-3-phenoxyazetidine (Intermediate 87a) to give the title compound. (UPLC-MS) t.sub.R 1.23 min; ESI-MS 444.2 [M+H].sup.+.

Intermediate 88b: N-(3-chloro-4-(6-cyano-5-fluoropyridin-2-yl)phenyl)-4-(trifluoromethoxy)benzenesulfonamide

(171) To a solution of 6-(4-amino-2-chlorophenyl)-3-fluoropicolinonitrile (60 mg, 0.242 mmol) in DCM (4 mL) cooled down to 0° C. were added 4-(trifluoromethoxy)benzene-1-sulfonyl chloride (0.042 mL, 0.254 mmol) and DIPEA (0.085 mL, 0.485 mmol). The reaction was warmed up to RT and stirred at this temperature for 24 h. The mixture was quenched with a sat. aq. NaHCO.sub.3 solution and EtOAc was added. Both phases were separated and the aq. layer was extracted twice with EtOAc. The combined organic layers were dried over anhydrous MgSO.sub.4, filtered and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (0 to 20% EtOAc in Cyclohexane) to afford the title compound. (UPLC-MS) t.sub.R 1.22 min; ESI-MS 472.0 [M+H].sup.+; ESI-MS 470.0 [M−H].sup.−.

Intermediate 89a: 2-(4-((4-bromo-3-chlorophenyl)sulfonyl)piperazin-2-yl)-1,1,1-trifluoropropan-2-ol

(172) The title compound was prepared in an analogous manner to 4-bromo-3-chloro-N-((1s,3s)-3-hydroxy-3-(trifluoromethyl)cyclobutyl)benzenesulfonamide (Intermediate 1a) using 1,1,1-trifluoro-2-(piperazin-2-yl)propan-2-ol to give the title compound as a colorless solid. (UPLC-MS) t.sub.R 0.96 min; ESI-MS 453.2 [M+H].sup.+.

Intermediate 89b: 6-(2-chloro-4-((3-(1,1,1-trifluoro-2-hydroxypropan-2-yl)piperazin-1-yl)sulfonyl)phenyl)-3-fluoropicolinonitrile

(173) The title compound was prepared in an analogous manner to 3-chloro-4-(6-cyano-5-fluoropyridin-2-yl)-N-(3-hydroxy-3-(trifluoromethyl)cyclobutyl)benzenesulfonamide (Intermediate 1 b) using 2-(4-((4-bromo-3-chlorophenyl)sulfonyl)piperazin-2-yl)-1,1,1-trifluoropropan-2-ol (Intermediate 89a) to give the title compound. (UPLC-MS) t.sub.R 0.96 min; ESI-MS 493.4 [M+H].sup.+.

Intermediate 90a: 4-bromo-3-chloro-N-(3-chlorophenyl)benzenesulfonamide

(174) The title compound was prepared in an analogous manner to 4-bromo-N-(3-hydroxy-3-(trifluoromethyl)cyclobutyl)-3-methylbenzenesulfonamide (Intermediate 2a) using 4-bromo-3-chlorobenzene-1-sulfonyl chloride and 3-chloroaniline I. The reaction mixture was stirred at RT for 4.5 h. The title compound was obtained as a colorless solid. (UPLC-MS) t.sub.R 1.23 min; ESI-MS 377.9/379.9/381.9 [M−H].sup.−.

Intermediate 90b: 3-chloro-N-(3-chlorophenyl)-4-(6-cyano-5-fluoropyridin-2-yl)benzenesulfonamide

(175) The title compound was prepared in an analogous manner to 3-chloro-4-(6-cyano-5-fluoropyridin-2-yl)-N-(3-hydroxy-3-(trifluoromethyl)cyclobutyl)benzenesulfonamide (Intermediate 1 b) using 4-bromo-3-chloro-N-(3-chlorophenyl)benzenesulfonamide (Intermediate 90a) to give the title compound. (UPLC-MS) t.sub.R 1.22 min; ESI-MS 422.1/242.0 [M+H].sup.+.

Intermediate 91a: 4-bromo-N-(2-hydroxycyclohexyl)-3-methylbenzenesulfonamide

(176) The title compound was prepared in an analogous manner to 4-bromo-3-chloro-N-((1s,3s)-3-hydroxy-3-(trifluoromethyl)cyclobutyl)benzenesulfonamide (Intermediate 1a) using 4-bromo-3-methylbenzene-1-sulfonyl chloride and 2-aminocyclohexanol to give the title compound as a yellow solid. (UPLC-MS) t.sub.R 1.04 min; ESI-MS 346.1/348.1 [M−H].sup.−.

Intermediate 91b: 4-(6-cyano-5-fluoropyridin-2-yl)-N-(2-hydroxycyclohexyl)-3-methylbenzenesulfonamide

(177) The title compound was prepared in an analogous manner to 3-chloro-4-(6-cyano-5-fluoropyridin-2-yl)-N-(3-hydroxy-3-(trifluoromethyl)cyclobutyl)benzenesulfonamide (Intermediate 1b) using 4-bromo-N-(2-hydroxycyclohexyl)-3-methylbenzenesulfonamide (Intermediate 91a) to give the title compound. (UPLC-MS) t.sub.R 1.01 min; ESI-MS 390.2 [M+H].sup.+.

Intermediate 92a: 4-bromo-3-chloro-N-(1,1-dioxidothietan-3-yl)benzenesulfonamide

(178) The title compound was prepared in an analogous manner to 4-bromo-3-chloro-N-((1s,3s)-3-hydroxy-3-(trifluoromethyl)cyclobutyl)benzenesulfonamide (Intermediate 1a) using 3-aminothietane 1,1-dioxide to give the title compound as a colorless oil. (UPLC-MS) t.sub.R 0.89 min; ESI-MS 373.9 [M−H].sup.−.

Intermediate 92b: 3-chloro-4-(6-cyano-5-fluoropyridin-2-yl)-N-(1,1-dioxidothietan-3-yl)benzenesulfonamide

(179) The title compound was prepared in an analogous manner to 3-chloro-4-(6-cyano-5-fluoropyridin-2-yl)-N-(3-hydroxy-3-(trifluoromethyl)cyclobutyl)benzenesulfonamide (Intermediate 1 b) using 4-bromo-3-chloro-N-(1,1-dioxidothietan-3-yl)benzenesulfonamide (Intermediate 92a) to give the title compound as a yellow solid. (UPLC-MS) t.sub.R 0.92 min; ESI-MS 414.0 [M−H].sup.−.

Intermediate 93a: 1-((4-bromo-3-chlorophenyl)sulfonyl)-3-(methylsulfonyl)azetidine

(180) The title compound was prepared in an analogous manner to 4-bromo-3-chloro-N-((1s,3s)-3-hydroxy-3-(trifluoromethyl)cyclobutyl)benzenesulfonamide (Intermediate 1a) using 3-(methylsulfonyl)azetidine to give the title compound as a colorless oil. (UPLC-MS) t.sub.R 0.93 min; no ESI ionization of parent observed.

Intermediate 93b: 6-(2-chloro-4-((3-(methylsulfonyl)azetidin-1-yl)sulfonyl)phenyl)-3-fluoropicolinonitrile

(181) The title compound was prepared in an analogous manner to 3-chloro-4-(6-cyano-5-fluoropyridin-2-yl)-N-(3-hydroxy-3-(trifluoromethyl)cyclobutyl)benzenesulfonamide (Intermediate 1 b) using 1-((4-bromo-3-chlorophenyl)sulfonyl)-3-(methylsulfonyl)azetidine (Intermediate 93a) to give the title compound. (UPLC-MS) t.sub.R 0.95 min; ESI-MS 432.0 [M+H].sup.+.

Intermediate 94a: 4-bromo-3-chloro-N-((1S,2S)-2-hydroxycyclopentyl)benzenesulfonamide

(182) The title compound was prepared in an analogous manner to 4-bromo-3-chloro-N-((1s,3s)-3-hydroxy-3-(trifluoromethyl)cyclobutyl)benzenesulfonamide (Intermediate 1a) using (1S,2S)-2-aminocyclopentanol to give the title compound as a colorless oil. (UPLC-MS) t.sub.R 0.93 min; ESI-MS 354.0 [M−H].sup.−.

Intermediate 94b: 3-chloro-4-(6-cyano-5-fluoropyridin-2-yl)-N-((1S,2S)-2-hydroxycyclopentyl)benzenesulfonamide

(183) The title compound was prepared in an analogous manner to 3-chloro-4-(6-cyano-5-fluoropyridin-2-yl)-N-(3-hydroxy-3-(trifluoromethyl)cyclobutyl)benzenesulfonamide (Intermediate 1 b) using 4-bromo-3-chloro-N-((1S,2S)-2-hydroxycyclopentyl)benzenesulfonamide (Intermediate 94a) to give the title compound. (UPLC-MS) t.sub.R 0.94 min; ESI-MS 394.1 [M−H].sup.+.

EXAMPLES

Example 1: 4-(3-amino-1H-pyrazolo[4,3-b]pyridin-5-yl)-3-chloro-N-((1s,3s)-3-hydroxy-3-(trifluoromethyl)cyclobutyl)benzenesulfonamide

(184) ##STR00054##

(185) In a vial, a solution of 3-chloro-4-(6-cyano-5-fluoropyridin-2-yl)-N-((1s,3s)-3-hydroxy-3-(trifluoromethyl)cyclobutyl)benzenesulfonamide (Intermediate 1b, 148 mg, 0.29 mmol) in EtOH (2 mL) was treated with aq. hydrazine hydrate (78%, 274 μL, 4.39 mmol). The vial was sealed and the reaction mixture stirred at 80° C. for 2 h. The reaction mixture was partitioned between a sat. aq. NaHCO.sub.3 solution and EtOAc. The aq. layer was extracted twice with EtOAc. The combined organic layers were dried over MgSO.sub.4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (0 to 20% MeOH in DCM) to give the title compound as a yellow solid. .sup.1H NMR (400 MHz, DMSO-d6) δ ppm 11.85 (s, 1H) 8.39 (d, 1H) 7.93 (m, 1H) 7.86-7.81 (m, 3H) 7.56 (d, 1H) 6.66 (s, 1H) 5.46 (s, 2H) 3.44 (q, 1H) 2.62-2.54 (m, 2H) 2.12-2.03 (m, 2H). (UPLC-MS) t.sub.R 0.79 min; ESI-MS 462.1 [M+H].sup.+.

Example 2: 4-(3-amino-1H-pyrazolo[4,3-b]pyridin-5-yl)-N-((1s,3s)-3-hydroxy-3-(trifluoromethyl)cyclobutyl)-3-methylbenzenesulfonamide

(186) ##STR00055##

(187) The title compound was prepared in an analogous manner to 4-(3-amino-1H-pyrazolo[4,3-b]pyridin-5-yl)-3-chloro-N-((1s,3s)-3-hydroxy-3-(trifluoromethyl)cyclobutyl)benzenesulfonamide (Example 1) using 4-(6-cyano-5-fluoropyridin-2-yl)-N-((1s,3s)-3-hydroxy-3-(trifluoromethyl)cyclobutyl)-3-methylbenzenesulfonamide (Intermediate 2b). The reaction mixture was concentrated under reduced pressure without extractive workup. The crude product was purified by silica gel column chromatography (0 to 15% MeOH in DCM) to give the title compound as a yellow solid. .sup.1H NMR (400 MHz, acetonitrile-d.sub.3) δ ppm 10.03 (s, 1H), 7.84 (d, 1H), 7.80 (d, 1H), 7.75 (dd, 1H), 7.65 (d, 1H), 7.47 (d, 1H), 6.14 (d, 1H), 4.67 (s, 2H), 4.39 (s, 1H), 3.64-3.52 (m, 1H), 2.77-2.68 (m, 2H), 2.49 (s, 3H), 2.14-2.09 (m, 2H). (UPLC-MS) t.sub.R 1.26 min; API-MS 442.2 [M+H].sup.+.

Example 3: N-(4-(3-amino-1H-pyrazolo[4,3-b]pyridin-5-yl)-3-chlorophenyl)-4-chlorobenzenesulfonamide

(188) ##STR00056##

(189) To a MW vial containing a solution of 4-chloro-N-(3-chloro-4-(6-cyano-5-fluoropyridin-2-yl)phenyl)benzenesulfonamide (Intermediate 3b, 94 mg, 0.211 mmol) in EtOH (3 mL) was added hydrazine hydrate 55% in water (0.187 mL, 2.115 mmol). The vial was sealed and the mixture was heated up and stirred at 80° C. for 6 h. The reaction was cooled down to RT and concentrated under reduced pressure without any extracting workup. The residue was purified by silica gel column chromatography (0 to 3% MeOH in DCM) to afford the title product as pale yellow solid. .sup.1H NMR (400 MHz, DMSO-d6) δ ppm 11.72 (s, 1H) 10.79 (br s, 1H) 7.84 (d, 2H) 7.74 (d, 1H) 7.69 (d, 2H) 7.48 (d, 1H) 7.41 (d, 1H) 7.24 (d, 1H) 7.18 (dd, 1H) 5.36 (s, 2H). (UPLC-MS) t.sub.R 0.92 min; ESI-MS 434.1/436.1 [M+H].sup.+; ESI-MS 432.1/434.1 [M−H].sup.−.

Example 4: 4-(3-amino-1H-pyrazolo[4,3-b]pyridin-5-yl)-3-chloro-N-(3,3-difluorocyclobutyl)benzenesulfonamide

(190) ##STR00057##

(191) The title compound was prepared in an analogous manner to 4-(3-amino-1H-pyrazolo[4,3-b]pyridin-5-yl)-3-chloro-N-((1s,3s)-3-hydroxy-3-(trifluoromethyl)cyclobutyl)benzenesulfonamide (Example 1) using 3-chloro-4-(6-cyano-5-fluoropyridin-2-yl)-N-(3,3-difluorocyclobutyl)benzenesulfonamide (Intermediate 4b). .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ ppm 11.85 (s, 1H) 8.41 (d, 1H) 7.95 (d, 1H) 7.89-7.81 (m, 3H) 7.57 (d, 1H) 5.45 (s, 2H) 3.61-3.72 (m, 1H) 2.89-2.75 (m, 2H) 2.54-2.38 (m, 2H). (UPLC-MS) t.sub.R 0.82 min; ESI-MS 414.2 [M+H].sup.+; ESI-MS 412.2 [M−H].sup.−.

Example 5: N-(4-(3-amino-1H-pyrazolo[4,3-b]pyridin-5-yl)-3-chlorophenyl)-4-methoxybenzenesulfonamide

(192) ##STR00058##

(193) The title compound was prepared in an analogous manner to N-(4-(3-amino-1H-pyrazolo[4,3-b]pyridin-5-yl)-3-chlorophenyl)-4-chlorobenzenesulfonamide (Example 3) using N-(3-chloro-4-(6-cyano-5-fluoropyridin-2-yl)phenyl)-4-methoxybenzenesulfonamide (Intermediate 5b) at 80° C. for 4.5 h. The residue was purified by reverse phase column chromatography (Method 2) (10% to 30% ACN in water). A second purification using silica gel column chromatography (0 to 3% MeOH in DCM) afforded the title compound as pale yellow solid. .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ ppm 11.71 (s, 1H) 10.57 (br s, 1H) 7.75-7.80 (m, 2H) 7.73 (d, 1H) 7.46 (d, 1H) 7.40 (d, 1H) 7.24 (d, 1H) 7.18 (dd, 1H) 7.12 (m, 2H) 5.35 (s, 2H) 3.82 (s, 3H). (UPLC-MS) t.sub.R 0.83 min; ESI-MS 430.2 [M+H].sup.+; ESI-MS 428.2 [M−H].sup.−.

Example 6: N-(4-(3-amino-1H-pyrazolo[4,3-b]pyridin-5-yl)-3-chlorophenyl)-4-fluorobenzenesulfonamide

(194) ##STR00059##

(195) The title compound was prepared in an analogous manner to N-(4-(3-amino-1H-pyrazolo[4,3-b]pyridin-5-yl)-3-chlorophenyl)-4-chlorobenzenesulfonamide (Example 3) using N-(3-chloro-4-(6-cyano-5-fluoropyridin-2-yl)phenyl)-4-fluorobenzenesulfonamide (Intermediate 6b) at 80° C. for 6 h. The residue was purified by silica gel column chromatography (0 to 3% MeOH in DCM) to afford the title compound as yellow solid. .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ ppm 11.72 (s, 1H) 10.73 (br s, 1H) 7.90 (m, 2H) 7.74 (d, 1H) 7.50-7.43 (m, 3H) 7.41 (d, 1H) 7.24 (d, 1H) 7.18 (dd, 1H) 5.35 (s, 2H). (UPLC-MS) t.sub.R 0.85 min; ESI-MS 418.1 [M+H].sup.+; ESI-MS 416.1 [M−H].sup.−.

Example 7: 4-(3-amino-1H-pyrazolo[4,3-b]pyridin-5-yl)-3-chloro-N-((1R,2S)-2-hydroxycyclopentyl)benzenesulfonamide

(196) ##STR00060##

(197) In a vial, a solution of 3-chloro-4-(6-cyano-5-fluoropyridin-2-yl)-N-((1R,2S)-2-hydroxycyclopentyl)benzenesulfonamide (Intermediate 7b, 55 mg, 0.14 mmol) in THF (2 mL) was treated with hydrazine anhydrous (1M solution in THF, 0.70 mL, 0.70 mmol). The vial was sealed and the reaction mixture stirred at 80° C. for 1 h. The reaction mixture was concentrated under reduced pressure and the residue was purified by silica gel column chromatography (0 to 4% MeOH in DCM) to afford the title compound as a yellow solid. .sup.1H NMR (400 MHz, DMSO-d6) b ppm 11.83 (br s, 1H) 8.02 (d, 1H) 7.90 (dd, 1H) 7.81 (dd, 2H) 7.60-7.54 (m, 2H) 5.45 (br s, 2H) 4.71 (d, 1H) 3.84-3.77 (m, 1H) 3.41-3.33 (m, 1H) 1.70-1.56 (m, 2H) 1.52-1.34 (m, 4H). (UPLC-MS) t.sub.R 0.70 min; ESI-MS 408.1 [M+H].sup.+; ESI-MS 414.2 [M+H].sup.+; ESI-MS 406.1 [M−H].sup.−.

Example 8: 4-(3-amino-1H-pyrazolo[4,3-b]pyridin-5-yl)-N-(3,3-difluorocyclobutyl)-3-methylbenzenesulfonamide

(198) ##STR00061##

(199) The title compound was prepared in an analogous manner to 4-(3-amino-1H-pyrazolo[4,3-b]pyridin-5-yl)-3-chloro-N-((1s,3s)-3-hydroxy-3-(trifluoromethyl)cyclobutyl)benzenesulfonamide (Example 1) using 4-(6-cyano-5-fluoropyridin-2-yl)-N-(3,3-difluorocyclobutyl)-3-methylbenzenesulfonamide (Intermediate 8b). .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ ppm 11.76 (br s, 1H) 8.18 (d, 1H) 7.81 (d, 1H) 7.74 (s, 1H) 7.71 (br d, 1H) 7.65-7.61 (m, 1H) 7.45 (d, 1H) 5.41 (s, 2H) 3.61 (quin, 1H) 2.85-2.71 (m, 2H) 2.44 (s, 3H) 2.48-2.38 (m, 2H). (UPLC-MS) t.sub.R 0.78 min; ESI-MS 394.2 [M+H].sup.+; ESI-MS 392.2 [M−H].sup.−.

Example 9: 4-(3-amino-1H-pyrazolo[4,3-b]pyridin-5-yl)-N-((1s,3s)-3-hydroxy-3-(trifluoromethyl)cyclobutyl)-N,3-dimethylbenzenesulfonamide

(200) ##STR00062##

(201) In a vial, a solution of 4-(6-cyano-5-fluoropyridin-2-yl)-N-((1s,3s)-3-hydroxy-3-(trifluoromethyl)cyclobutyl)-N,3-dimethylbenzenesulfonamide (Intermediate 9b, 1.50 g, 2.37 mmol) in EtOH (20 mL) was treated with aq. hydrazine hydrate (78%, 2.21 mL, 35.5 mmol). The vial was sealed and the reaction mixture stirred at 80° C. for 60 min. The reaction mixture was partitioned between a sat. aq. NaHCO.sub.3 solution and EtOAc. The aq. layer was extracted twice with EtOAc. The combined organic layers were dried over MgSO.sub.4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (0 to 20% MeOH in DCM) and by reverse phase column chromatography (Method 2) (5% to 50% ACN in water) to give the title compound as an off-white solid. The stereo-configuration of the title compound was determined by X-ray crystallography. .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ ppm 11.79 (5, 1H) 7.82 (d, 1H) 7.69 (d, 3H) 7.47 (d, 1H) 6.72 (s, 1H) 5.45 (br s, 2H) 3.75 (quin, 1H) 2.71 (s, 3H) 2.66-2.58 (m, 2H) 2.47 (s, 3H) 2.38-2.32 (m, 2H). (UPLC-MS) t.sub.R 0.81 min; ESI-MS 456.2 [M+H].sup.+ ESI-MS 454.2 [M−H].sup.−.

Example 10: N-(4-(3-amino-1H-pyrazolo[4,3-b]pyridin-5-yl)-3-chlorophenyl)-3,4-difluorobenzenesulfonamide

(202) ##STR00063##

(203) The title compound was prepared in an analogous manner to N-(4-(3-amino-1H-pyrazolo[4,3-b]pyridin-5-yl)-3-chlorophenyl)-4-chlorobenzenesulfonamide (Example 3) using N-(3-chloro-4-(6-cyano-5-fluoropyridin-2-yl)phenyl)-3,4-difluorobenzenesulfonamide (Intermediate 10b) at 80° C. for 1.5 h. The residue was purified twice by silica gel column chromatography (0 to 4% MeOH in DCM) to afford the title compound as yellow solid. .sup.1H NMR (600 MHz, DMSO-d6) δ ppm 11.75 (s, 1H) 10.84 (s, 1H) 7.93 (m, 1H) 7.75 (d, 1H) 7.70-7.73 (m, 2H) 7.50 (d, 1H) 7.42 (d, 1H) 7.26 (d, 1H) 7.21 (dd, 1H) 5.38 (br s, 2H). (UPLC-MS) t.sub.R 0.88 min; ESI-MS 436.1 [M+H].sup.+; ESI-MS 434.1 [M−H].sup.−.

Example 11: N-(4-(3-amino-1H-pyrazolo[4,3-b]pyridin-5-yl)-3-chlorophenyl)benzo[d][1,3]dioxole-5-sulfonamide

(204) ##STR00064##

(205) The title compound was prepared in an analogous manner to N-(4-(3-amino-1H-pyrazolo[4,3-b]pyridin-5-yl)-3-chlorophenyl)-4-chlorobenzenesulfonamide (Example 3) using N-(3-chloro-4-(6-cyano-5-fluoropyridin-2-yl)phenyl)benzo[d][1,3]dioxole-5-sulfonamide (Intermediate 11b) at 80° C. for 2 h. The residue was purified twice by normal phase column chromatography (0 to 3% MeOH in DCM) to afford the title compound as pale yellow solid. .sup.1H NMR (400 MHz, DMSO-d6) δ ppm 11.72 (s, 1H) 10.58 (s, 1H) 7.74 (d, 1H) 7.48 (d, 1H) 7.37-7.44 (m, 2H) 7.28 (d, 1H) 7.25 (d, 1H) 7.20 (dd, 1H) 7.08 (d, 1H) 6.16 (s, 2H) 5.36 (s, 2H). (UPLC-MS) t.sub.R 0.83 min; ESI-MS 444.1 [M+H].sup.+; ESI-MS 442.1 [M−H].sup.−.

Example 12: 4-(3-amino-1H-pyrazolo[4,3-b]pyridin-5-yl)-3-chloro-N-(2-hydroxycyclohexyl)benzenesulfonamide

(206) ##STR00065##

(207) The title compound was prepared in an analogous manner to 4-(3-amino-1H-pyrazolo[4,3-b]pyridin-5-yl)-3-chloro-N-((1R,2S)-2-hydroxycyclopentyl)benzenesulfonamide (Example 7) using 3-chloro-4-(6-cyano-5-fluoropyridin-2-yl)-N-(2-hydroxycyclohexyl)benzenesulfonamide (Intermediate 12b). .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ ppm 11.83 (s, 1H) 8.01 (d, 1H) 7.89 (dd, 1H) 7.81 (dd, 2H) 7.60 (d, 1H) 7.55 (d, 1H) 5.45 (br s, 2H) 4.60 (d, 1H) 3.66-3.59 (m, 1H) 3.20-3.10 (m, 1H) 1.66-1.32 (m, 5H) 1.26-1.09 (m, 3H). (UPLC-MS) t.sub.R 0.76 min; ESI-MS 422.1 [M+H].sup.+; ESI-MS 420.2 [M−H].sup.−.

Example 13: N-(4-(3-amino-1H-pyrazolo[4,3-b]pyridin-5-yl)-3-chlorophenyl)-4-chloro-3-fluorobenzenesulfonamide

(208) ##STR00066##

(209) The title compound was prepared in an analogous manner to N-(4-(3-amino-1H-pyrazolo[4,3-b]pyridin-5-yl)-3-chlorophenyl)-4-chlorobenzenesulfonamide (Example 3) using 4-chloro-N-(3-chloro-4-(6-cyano-5-fluoropyridin-2-yl)phenyl)-3-fluorobenzenesulfonamide (Intermediate 13b) at 80° C. for 2 h. The residue was purified by preparative HPLC (Method 3, 5% to 50% ACN (+7.3 mM NH.sub.4OH) in water (+7.3 mM NH.sub.4OH)). A second purification by silica gel column chromatography (0 to 2% MeOH in DCM) afforded the title compound as pale yellow solid. .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ ppm 11.73 (s, 1H) 10.87 (br s, 1H) 7.92-7.83 (m, 2H) 7.75 (d, 1H) 7.68 (dd, 1H) 7.51 (d, 1H) 7.42 (d, 1H) 7.26 (d, 1H) 7.21 (dd, 1H) 5.36 (s, 2H). (UPLC-MS) t.sub.R 0.95 min; ESI-MS 452.1 [M+H].sup.+; ESI-MS 450.0 [M−H].sup.−.

Example 14: (1S,2R)-N-(4-(3-amino-1H-pyrazolo[4,3-b]pyridin-5-yl)-3-chlorophenyl)-2-hydroxycyclohexane-1-sulfonamide

(210) ##STR00067##

(211) The title compound was obtained by chiral separation of N-(4-(3-amino-1H-pyrazolo[4,3-b]pyridin-5-yl)-3-chlorophenyl)-2-hydroxycyclohexane-1-sulfonamide (Example 17) using SEPIATEC ASAP HPLC System (column Chiralpak AD-H, 5□m, 250×20 mm; mobile phase: n-heptane:EtOH:MeOH 70:15:15 (v:v:v)+0.1% DEA; flowrate 10 mL/min; detection 270 nm) to afford the title compound. .sup.1H NMR (400 MHz, DMSO-d6) δ ppm 11.72 (s, 1H), 9.62 (s, 1H), 7.75 (d, 1H), 7.53 (d, 1H), 7.45 (d, 1H), 7.35 (d, 1H), 7.28 (dd, 1H), 5.34 (s, 2H), 5.05 (d, 1H), 3.77 (s, 1H), 3.01-2.91 (m, 1H), 2.05 (d, 1H), 1.88 (d, 1H), 1.65 (d, 2H), 1.47 (d, 1H), 1.33-1.12 (m, 4H). (UPLC-MS) t.sub.R 0.78 min; ESI-MS 422.1 [M+H].sup.+; ESI-MS 420.1 [M−H].sup.−.

Example 15: N-(4-(3-amino-1H-pyrazolo[4,3-b]pyridin-5-yl)-3-chlorophenyl)cyclohexanesulfonamide

(212) ##STR00068##

(213) The title compound was prepared in an analogous manner to N-(4-(3-amino-1H-pyrazolo[4,3-b]pyridin-5-yl)-3-chlorophenyl)-4-chlorobenzenesulfonamide (Example 3) using N-(3-chloro-4-(6-cyano-5-fluoropyridin-2-yl)phenyl)cyclohexanesulfonamide (Intermediate 15b) at 80° C. for 7 hr. The crude material was first purified by silica gel column chromatography (0% to 3% MeOH in DCM). A second purification by preparative HPLC (Method 1, 5% to 95% ACN in water (+0.1% TFA)) was performed. A third purification by silica gel column chromatography (0 to 4% MeOH in DCM) afforded the title compound as yellow solid. .sup.1H NMR (400 MHz, DMSO-d6) δ ppm 11.74 (s, 1H) 10.12 (s, 1H) 7.77 (d, 1H) 7.55 (d, 1H) 7.47 (d, 1H) 7.37 (d, 1H) 7.30 (dd, 1H) 5.35 (s, 2H) 3.11 (tt, 1H) 2.09-2.02 (m, 2H) 1.82-1.73 (m, 2H) 1.60 (dq, 1H) 1.51-1.38 (m, 2H) 1.32-1.19 (m, 2H) 1.19-1.07 (m, 1H). (UPLC-MS) t.sub.R 0.88 min; ESI-MS 406.1 [M+H].sup.+; ESI-MS 404.2 [M−H].sup.−.

Example 16: 4-(3-amino-1H-pyrazolo[4,3-b]pyridin-5-yl)-3-methyl-N-phenylbenzenesulfonamide

(214) ##STR00069##

(215) In a vial, a solution of 4-(6-cyano-5-fluoropyridin-2-yl)-3-methyl-N-phenylbenzenesulfonamide (Intermediate 16b, 30 mg, 0.039 mmol) in aq. hydrazine hydrate (64%, 0.10 mL, 3.15 mmol) was stirred at 100° C. for 80 min. The reaction mixture was partitioned between a sat. aq. NaHCO.sub.3 solution and EtOAc. The organic layer was washed three times with water and once with brine, then dried over MgSO.sub.4, filtered, and concentrated under reduced pressure. The residue was purified by reverse phase column chromatography (Method 2, 2 to 100% ACN in water) to afford the title compound as an off-white solid. .sup.1H NMR (400 MHz, DMSO-d6) δ ppm 11.73 (s, 1H) 10.31 (s, 1H) 7.77 (d, 1H) 7.73-7.69 (m, 1H) 7.66 (dd, 1H) 7.55 (d, 1H) 7.40 (d, 1H) 7.28-7.22 (m, 2H) 7.17-7.15 (m, 1H) 7.15-7.12 (m, 1H) 7.07-7.00 (m, 1H) 5.40 (br s, 2H) 2.35 (s, 3H). (UPLC-MS) t.sub.R 0.85 min; ESI-MS 380.1 [M+H].sup.+; ESI-MS 378.2 [M−H].sup.−.

Example 17: N-(4-(3-amino-1H-pyrazolo[4,3-b]pyridin-5-yl)-3-chlorophenyl)-2-hydroxycyclohexane-1-sulfonamide

(216) ##STR00070##

(217) The title compound was prepared in an analogous manner to N-(4-(3-amino-1H-pyrazolo[4,3-b]pyridin-5-yl)-3-chlorophenyl)-4-chlorobenzenesulfonamide (Example 3) using N-(3-chloro-4-(6-cyano-5-fluoropyridin-2-yl)phenyl)-2-hydroxycyclohexane-1-sulfonamide (Intermediate 17b) at 80° C. for 2 h. The reaction was quenched with a sat. aq. NaHCO.sub.3 solution and extracted twice with EtOAc. The combined organic layers were dried over MgSO.sub.4, filtered and evaporated under reduced pressure. The residue was purified first using silica gel column chromatography (0 to 20% MeOH in DCM). Second purification by reverse phase column chromatography (Method 2) (2 to 100% ACN in water). A third purification by normal phase column chromatography (0 to 4% MeOH in DCM) afforded the title compound as beige foam. .sup.1H NMR (400 MHz, DMSO-d6) δ ppm 11.73 (s, 1H) 9.64 (br s, 1H) 7.77 (d, 1H) 7.54 (d, 1H) 7.47 (d, 1H) 7.37 (d, 1H) 7.29 (dd, 1H) 5.35 (s, 2H) 5.07 (br s, 1H) 3.83-3.75 (m, 1H) 2.92-3.03 (m, 1H) 2.11-2.02 (m, 1H) 1.94-1.86 (m, 1H) 1.74-1.65 (m, 1H) 1.65-1.58 (m, 1H) 1.54-1.42 (m, 1H) 1.31-1.17 (m, 3H). (UPLC-MS) t.sub.R 0.79 min; ESI-MS 422.2 [M+H].sup.+; ESI-MS 420.1 [M−H].sup.−.

Example 18: (S)-(1-((4-(3-amino-1H-pyrazolo[4,3-b]pyridin-5-yl)-3-chlorophenyl)sulfonyl)-4,4-difluoropyrrolidin-2-yl)methanol

(218) ##STR00071##

(219) The title compound was prepared in an analogous manner to 4-(3-amino-1H-pyrazolo[4,3-b]pyridin-5-yl)-3-chloro-N-((1s,3s)-3-hydroxy-3-(trifluoromethyl)cyclobutyl)benzenesulfonamide (Example 1) using (S)-6-(2-chloro-4-((4,4-difluoro-2-(hydroxymethyl)pyrrolidin-1-yl)sulfonyl)phenyl)-3-fluoropicolinonitrile (Intermediate 18b). The reaction mixture was concentrated under reduced pressure without extractive workup. The crude product was purified by silica gel column chromatography (0 to 25% MeOH in DCM) to afford the title compound as a yellow solid. .sup.1H NMR (400 MHz, acetonitrile-d.sub.3) δ ppm 10.11 (s, 1H), 8.04 (d, 1H), 7.91 (dd, 1H), 7.88-7.84 (m, 2H), 7.64 (d, 1H), 4.68 (s, 2H), 3.99 (dtd, 1H), 3.89 (dddd, 1H), 3.77 (dq, 2H), 3.72-3.66 (m, 1H), 3.20 (t, 1H), 2.52-2.31 (m, 2H). (UPLC-MS) t.sub.R 1.23 min; API-MS 444.2 [M+H].sup.+.

Example 19: 4-(3-amino-1H-pyrazolo[4,3-b]pyridin-5-yl)-N-((1R,3S)-3-hydroxycyclopentyl)-3-methylbenzenesulfonamide

(220) ##STR00072##

(221) The title compound was prepared in an analogous manner to 4-(3-amino-1H-pyrazolo[4,3-b]pyridin-5-yl)-3-chloro-N-((1s,3s)-3-hydroxy-3-(trifluoromethyl)cyclobutyl)benzenesulfonamide (Example 1) using 4-(6-cyano-5-fluoropyridin-2-yl)-N-((1R,3S)-3-hydroxycyclopentyl)-3-methylbenzenesulfonamide (Intermediate 19b). .sup.1H NMR (400 MHz, DMSO-d6) δ ppm 11.75 (s, 1H) 7.80 (d, 1H) 7.74 (s, 1H) 7.73-7.69 (m, 1H) 7.67 (d, 1H) 7.60 (d, 1H) 7.44 (d, 1H) 5.42 (s, 2H) 4.57 (d, 1H) 3.97-3.88 (m, 1H) 3.44-3.37 (m, 1H) 2.43 (s, 3H) 1.98-1.89 (m, 1H) 1.66-1.39 (m, 4H) 1.29-1.20 (m, 1H). (UPLC-MS) t.sub.R 0.67 min; ESI-MS 388.3 [M+H].sup.+; ESI-MS 368.3 [M−H].sup.−.

Example 20: 4-(3-amino-1H-pyrazolo[4,3-b]pyridin-5-yl)-N-((1R,2S)-2-hydroxycyclopentyl)-3-methylbenzenesulfonamide

(222) ##STR00073##

(223) The title compound was prepared in an analogous manner to 4-(3-amino-1H-pyrazolo[4,3-b]pyridin-5-yl)-3-chloro-N-((1R,2S)-2-hydroxycyclopentyl)benzenesulfonamide (Example 7) using 4-(6-cyano-5-fluoropyridin-2-yl)-N-((1R,2S)-2-hydroxycyclopentyl)-3-methylbenzene sulfonamide (Intermediate 20b). .sup.1H NMR (400 MHz, DMSO-d6) δ ppm 11.74 (br s, 1H) 7.82-7.78 (m, 2H) 7.75 (dd, 1H) 7.58 (d, 1H) 7.44 (d, 1H) 7.27 (d, 1H) 5.41 (br s, 2H) 4.63 (d, 1H) 3.83-3.76 (m, 1H) 3.30-3.25 (m, 1H) 2.42 (s, 3H) 1.69-1.54 (m, 2H) 1.51-1.28 (m, 4H). (UPLC-MS) t.sub.R 0.70 min; ESI-MS 388.1 [M+H].sup.+; ESI-MS 386.1 [M−H].sup.−.

Example 21: 5-(4-((hexahydrocyclopenta[c]pyrrol-2(1H)-yl)sulfonyl)-2-methylphenyl)-1H-pyrazolo[4,3-b]pyridin-3-amine

(224) ##STR00074##

(225) The title compound was prepared in an analogous manner to 4-(3-amino-1H-pyrazolo[4,3-b]pyridin-5-yl)-3-chloro-N-((1R,2S)-2-hydroxycyclopentyl)benzenesulfonamide (Example 7) using 3-fluoro-6-(4-((hexahydrocyclopenta[c]pyrrol-2(1H)-yl)sulfonyl)-2-methylphenyl) picolinonitrile (Intermediate 21b). The product was further purified by preparative HPLC (Method 1, 5 to 95% ACN in water (+0.1% TFA)). Fractions containing pure product were combined and passed through a PL-HCO3 MP cartridge (Stratospheres, pre-conditioned with MeOH), following by wash-out with MeOH. The filtrate was concentrated under reduced pressure to afford the title compound as an off-white solid. .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ ppm 11.77 (br s, 1H) 7.81 (d, 1H) 7.70 (s, 1H) 7.66 (s, 2H) 7.46 (d, 1H) 5.42 (br s, 2H) 3.12 (m, 2H) 2.85 (dd, 2H) 2.58-2.52 (m, 2H) 2.45 (s, 3H) 1.75-1.64 (m, 2H) 1.58-1.37 (m, 2H) 1.36-1.27 (m, 2H). (UPLC-MS) t.sub.R 0.96 min; ESI-MS 398.3 [M+H].sup.+; ESI-MS 396.2 [M−H].sup.−.

Example 22: N-(4-(3-amino-1H-pyrazolo[4,3-b]pyridin-5-yl)-3-chlorophenyl)-3-cyanobenzenesulfonamide

(226) ##STR00075##

(227) The title compound was prepared in an analogous manner to N-(4-(3-amino-1H-pyrazolo[4,3-b]pyridin-5-yl)-3-chlorophenyl)-4-chlorobenzenesulfonamide (Example 3) using N-(3-chloro-4-(6-cyano-5-fluoropyridin-2-yl)phenyl)-3-cyanobenzenesulfonamide (Intermediate 22b) at 80° C. for 2.5 h. The residue was purified by reverse phase column chromatography (Method 2, 10% to 35% ACN in water). A second purification using silica gel column chromatography (0 to 3% MeOH in DCM) afforded the title product as pale yellow solid. .sup.1H NMR (400 MHz, DMSO-d6) δ ppm 11.73 (s, 1H) 10.89 (br s, 1H) 8.28 (s, 1H) 8.18-8.10 (m, 2H) 7.84 (t, 1H) 7.74 (d, 1H) 7.50 (d, 1H) 7.41 (d, 1H) 7.25 (d, 1H) 7.21 (dd, 1H) 5.36 (s, 2H). (UPLC-MS) t.sub.R 0.82 min; ESI-MS 425.1 [M+H].sup.+; ESI-MS 423.1 [M−H].sup.−.

Example 23: 4-(3-amino-1H-pyrazolo[4,3-b]pyridin-5-yl)-3-chloro-N-((1R,3S)-3-hydroxycyclopentyl)benzenesulfonamide

(228) ##STR00076##

(229) The title compound was prepared in an analogous manner to 4-(3-amino-1H-pyrazolo[4,3-b]pyridin-5-yl)-3-chloro-N-((1s,3s)-3-hydroxy-3-(trifluoromethyl)cyclobutyl)benzenesulfonamide (Example 1) using 3-chloro-4-(6-cyano-5-fluoropyridin-2-yl)-N-((1R,3S)-3-hydroxycyclopentyl)benzenesulfonamide (Intermediate 23b). .sup.1H NMR (400 MHz, DMSO-d6) b ppm 11.85 (s, 1H), 8.03-7.78 (m, 5H), 7.58 (d, 1H), 5.47 (s, 2H), 4.61 (d, 1H), 3.95 (s, 1H), 3.47 (q, 1H), 3.18 (d, 1H), 1.97 (dt, 1H), 1.79-1.39 (m, 4H), 1.38-1.19 (m, 2H). (UPLC-MS) t.sub.R 0.67 min; ESI-MS 408.2 [M+H].sup.+; ESI-MS 406.2 [M−H].sup.−.

Example 24: 4-(3-amino-1H-pyrazolo[4,3-b]pyridin-5-yl)-3-chloro-N-(4,4-dimethylcyclohexyl)benzenesulfonamide

(230) ##STR00077##

(231) The title compound was prepared in an analogous manner to 4-(3-amino-1H-pyrazolo[4,3-b]pyridin-5-yl)-3-chloro-N-((1s,3s)-3-hydroxy-3-(trifluoromethyl)cyclobutyl)benzenesulfonamide (Example 1) except 3-chloro-4-(6-cyano-5-fluoropyridin-2-yl)-N-(4,4-dimethylcyclohexyl)benzenesulfonamide (Intermediate 24b) was used in place of 3-chloro-4-(6-cyano-5-fluoropyridin-2-yl)-N-(3-hydroxy-3-(trifluoromethyl)cyclobutyl)benzenesulfonamide (Intermediate 1b). .sup.1H NMR (400 MHz, DMSO-d6) δ ppm 11.82 (s, 1H), 7.93 (d, 1H), 7.88-7.78 (m, 4H), 7.55 (d, 1H), 5.43 (s, 2H), 2.98 (s, 1H), 1.52-1.42 (m, 2H), 1.42-1.19 (m, 5H), 1.17-1.03 (m, 2H), 0.82 (d, 6H). (UPLC-MS) t.sub.R 1.04 min; ESI-MS 434.2 [M+H].sup.+.

Example 25: N-(4-(3-amino-1H-pyrazolo[4,3-b]pyridin-5-yl)-3-chlorophenyl)-4-methylbenzenesulfonamide

(232) ##STR00078##

(233) The title compound was prepared in an analogous manner to N-(4-(3-amino-1H-pyrazolo[4,3-b]pyridin-5-yl)-3-chlorophenyl)-4-chlorobenzenesulfonamide (Example 3) using N-(3-chloro-4-(6-cyano-5-fluoropyridin-2-yl)phenyl)-4-methylbenzenesulfonamide (Intermediate 25b) at 80° C. for 2 h. The residue was purified by silica gel column chromatography (0 to 4% MeOH in DCM). A second purification by preparative HPLC (Method 1, 5% to 95% ACN in water (+0.1% TFA)) afforded the title compound as pale yellow solid. .sup.1H NMR (400 MHz, DMSO-d6) δ ppm 11.71 (s, 1H) 10.64 (s, 1H) 7.76-7.70 (m, 3H) 7.46 (d, 1H) 7.40 (d, 3H) 7.24 (d, 1H) 7.18 (dd, 1H) 5.35 (s, 2H) 2.36 (s, 3H). (UPLC-MS) t.sub.R 0.89 min; ESI-MS 414.2 [M+H].sup.+; ESI-MS 412.1 [M−H].sup.−.

Example 26: 4-(3-amino-1H-pyrazolo[4,3-b]pyridin-5-yl)-N-(1-(hydroxymethyl)cyclopentyl)-3-methylbenzenesulfonamide

(234) ##STR00079##

(235) The title compound was prepared in an analogous manner to 4-(3-amino-1H-pyrazolo[4,3-b]pyridin-5-yl)-3-chloro-N-((1R,2S)-2-hydroxycyclopentyl)benzenesulfonamide (Example 7) using 4-(6-cyano-5-fluoropyridin-2-yl)-N-(1-(hydroxymethyl)cyclopentyl)-3-methylbenzenesulfonamide (Intermediate 26b). The product was further purified by preparative HPLC (Method 1, 5 to 95% ACN in water (+0.1% TFA)). Fractions containing pure product were combined and passed through a PL-HCO3 MP cartridge (Stratospheres, pre-conditioned with MeOH), following by wash-out with MeOH. The filtrate was concentrated under reduced pressure to afford the title compound as a yellow solid. .sup.1H NMR (400 MHz, DMSO-d6) δ ppm 11.74 (br s, 1H) 7.80 (d, 1H) 7.75 (br s, 1H) 7.74-7.70 (m, 1H) 7.58 (d, 1H) 7.45-7.41 (m, 2H) 5.42 (br s, 2H) 4.72 (t, 1H) 3.37 (d, 2H) 2.42 (s, 3H) 1.79-1.68 (m, 2H) 1.66-1.54 (m, 2H) 1.49-1.34 (m, 4H). (UPLC-MS) t.sub.R 0.70 min; ESI-MS 402.3 [M+H].sup.+; ESI-MS 400.2 [M−H].sup.−.

Example 27: N-(4-(3-amino-1H-pyrazolo[4,3-b]pyridin-5-yl)-3-chlorophenyl)-3-chloro-4-fluorobenzenesulfonamide

(236) ##STR00080##

(237) The title compound was prepared in an analogous manner to N-(4-(3-amino-1H-pyrazolo[4,3-b]pyridin-5-yl)-3-chlorophenyl)-4-chlorobenzenesulfonamide (Example 3) using 3-chloro-N-(3-chloro-4-(6-cyano-5-fluoropyridin-2-yl)phenyl)-4-fluorobenzenesulfonamide (Intermediate 27b) at 80° C. for 2 h. The residue was purified by reverse phase column chromatography (Method 2, 10% to 45% ACN in water). The product was purified by silica gel column chromatography (0 to 3% MeOH in DCM) to afford the title compound as pale yellow solid. .sup.1H NMR (600 MHz, DMSO-d6) δ ppm 11.75 (s, 1H) 10.84 (s, 1H) 8.06-8.03 (m, 1H) 7.83-7.87 (m, 1H) 7.75 (d, 1H) 7.68 (t, 1H) 7.51 (d, 1H) 7.42 (d, 1H) 7.26 (d, 1H) 7.21 (dd, 1H) 5.38 (br s, 2H). (UPLC-MS) t.sub.R 0.93 min; ESI-MS 452.1/454.0 [M+H].sup.+; ESI-MS 450.1/452.1 [M−H].sup.−.

Example 28: N-(4-(3-amino-1H-pyrazolo[4,3-b]pyridin-5-yl)-3-chlorophenyl)-3-chlorobenzenesulfonamide

(238) ##STR00081##

(239) The title compound was prepared in an analogous manner to N-(4-(3-amino-1H-pyrazolo[4,3-b]pyridin-5-yl)-3-chlorophenyl)-4-chlorobenzenesulfonamide (Example 3) using 3-chloro-N-(3-chloro-4-(6-cyano-5-fluoropyridin-2-yl)phenyl)benzenesulfonamide (Intermediate 28b) at 80° C. for 3.5 h. The crude material was purified by reverse phase column chromatography (Method 2, 5% to 45% ACN in water). The product was further purified by silica gel column chromatography (0 to 3% MeOH in DCM) to afford the title compound as yellow solid. .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ ppm 11.73 (s, 1H) 10.81 (s, 1H) 7.85 (t, 1H) 7.82-7.72 (m, 3H) 7.65 (t, 1H) 7.50 (d, 1H) 7.41 (d, 1H) 7.25 (d, 1H) 7.20 (dd, 1H) 5.36 (s, 2H). (UPLC-MS) t.sub.R 0.91 min; ESI-MS 434.1/436.1 [M+H].sup.+; ESI-MS 432.1/434.1 [M−H].sup.−.

Example 29: 4-(3-amino-1H-pyrazolo[4,3-b]pyridin-5-yl)-3-chloro-N-((1R,2R)-2-hydroxycyclopentyl)benzenesulfonamide

(240) ##STR00082##

(241) The title compound was prepared in an analogous manner to 4-(3-amino-1H-pyrazolo[4,3-b]pyridin-5-yl)-3-chloro-N-((1s,3s)-3-hydroxy-3-(trifluoromethyl)cyclobutyl)benzenesulfonamide (Example 1) using 3-chloro-4-(6-cyano-5-fluoropyridin-2-yl)-N-((1R,2R)-2-hydroxycyclopentyl)benzenesulfonamide (Intermediate 29b). .sup.1H NMR (400 MHz, DMSO-d6) δ ppm 11.84 (br s, 1H) 7.96 (d, 1H) 7.89-7.85 (m, 1H) 7.85-7.78 (m, 3H) 7.56 (d, 1H) 5.46 (br s, 2H) 4.74 (d, 1H) 3.84-3.77 (m, 1H) 3.24 (br s, 1H) 1.81-1.70 (m, 2H) 1.60-1.50 (m, 2H) 1.43-1.25 (m, 2H). (UPLC-MS) t.sub.R 0.67 min; ESI-MS 408.2 [M+H].sup.+; ESI-MS 406.1 [M−H].sup.−.

Example 30: 4-(3-amino-1H-pyrazolo[4,3-b]pyridin-5-yl)-3-chloro-N-(1-(hydroxymethyl)cyclopentyl)benzenesulfonamide

(242) ##STR00083##

(243) The title compound was prepared in an analogous manner to 4-(3-amino-1H-pyrazolo[4,3-b]pyridin-5-yl)-3-chloro-N-((1R,2S)-2-hydroxycyclopentyl)benzenesulfonamide (Example 7) using 3-chloro-4-(6-cyano-5-fluoropyridin-2-yl)-N-(1-(hydroxymethyl)cyclopentyl)benzene sulfonamide (Intermediate 30b). The product was further purified by preparative HPLC (Method 1, 5 to 95% ACN in water (+0.1% TFA)). Fractions containing pure product were combined, solid NaHCO.sub.3 was added, acetonitrile was evaporated under reduced pressure, and the resulting aqueous layer was extracted three times with DCM. The combined organic layers were washed with brine, dried over anhydrous MgSO.sub.4, filtered and concentrated under reduced pressure to afford the title compound as a yellow solid. .sup.1H NMR (400 MHz, DMSO-d6) δ ppm 11.83 (br s, 1H) 7.97 (d, 1H) 7.89-7.85 (m, 1H) 7.84-7.77 (m, 2H) 7.67 (s, 1H) 7.55 (d, 1H) 5.46 (br s, 2H) 4.78 (t, 1H) 3.36 (d, 2H) 1.78-1.70 (m, 2H) 1.67-1.57 (m, 2H) 1.51-1.37 (m, 4H). (UPLC-MS) t.sub.R 0.74 min; ESI-MS 422.2 [M+H].sup.+; ESI-MS 420.2 [M−H].sup.−.

Example 31: 4-(3-amino-1H-pyrazolo[4,3-b]pyridin-5-yl)-3-chloro-N-(1,1-dioxidotetrahydrothiophen-3-yl)benzenesulfonamide

(244) ##STR00084##

(245) The title compound was prepared in an analogous manner to 4-(3-amino-1H-pyrazolo[4,3-b]pyridin-5-yl)-3-chloro-N-((1s,3s)-3-hydroxy-3-(trifluoromethyl)cyclobutyl)benzenesulfonamide (Example 1) using 3-chloro-4-(6-cyano-5-fluoropyridin-2-yl)-N-(1,1-dioxidotetrahydrothiophen-3-yl)benzenesulfonamide (Intermediate 31b). .sup.1H NMR (400 MHz, DMSO-d6) δ ppm 11.85 (br s, 1H) 8.49 (d, 1H) 7.98 (d, 1H) 7.92-7.88 (m, 1H) 7.87-7.82 (m, 2H) 7.58 (d, 1H) 5.45 (br s, 2H) 4.12-4.00 (m, 1H) 3.30-3.20 (m, 2H) 3.16-3.07 (m, 1H) 2.88 (dd, 1H) 2.31-2.22 (m, 1H) 2.09-1.95 (m, 1H). (UPLC-MS) t.sub.R 0.65 min; ESI-MS 442.2 [M+H].sup.+; ESI-MS 440.1 [M−H].sup.−.

Example 32: N-(4-(3-amino-1H-pyrazolo[4,3-b]pyridin-5-yl)-3-chlorophenyl)-2-hydroxy-5-methylbenzenesulfonamide

(246) ##STR00085##

(247) The title compound was prepared in an analogous manner to N-(4-(3-amino-1H-pyrazolo[4,3-b]pyridin-5-yl)-3-chlorophenyl)-2-hydroxycyclohexane-1-sulfonamide (Example 17) using N-(3-chloro-4-(6-cyano-5-fluoropyridin-2-yl)phenyl)-2-hydroxy-5-methylbenzenesulfonamide (Intermediate 32b) at 80° C. for 1 hr. The product was purified twice using reverse phase column chromatography (Method 2, 2-100% ACN in water) to afford the title compound as white solid. .sup.1H NMR (400 MHz, DMSO-d6) δ ppm 11.69 (br s, 1H) 7.72 (d, 1H) 7.55 (s, 1H) 7.43-7.37 (m, 2H) 7.28-7.20 (m, 2H) 7.20-7.14 (m, 1H) 6.84 (d, J=8.19 Hz, 1H) 5.35 (br s, 1H) 2.23 (s, 3H). (UPLC-MS) t.sub.R 0.79 min; ESI-MS 430.2 [M+H].sup.+; ESI-MS 428.3 [M−H].sup.−.

Example 33: N-(4-(3-amino-1H-pyrazolo[4,3-b]pyridin-5-yl)-3-methylphenyl)-3-fluorobenzenesulfonamide

(248) ##STR00086##

(249) The title compound was prepared in an analogous manner to N-(4-(3-amino-1H-pyrazolo[4,3-b]pyridin-5-yl)-3-chlorophenyl)-4-chlorobenzenesulfonamide (Example 3) using N-(4-(6-cyano-5-fluoropyridin-2-yl)-3-methylphenyl)-3-fluorobenzenesulfonamide (Intermediate 33b) at 80° C. for 20 hr. The crude material was purified by reverse phase column chromatography (Method 2, 10 to 30% ACN in water). The product was further purified by silica gel column chromatography (0 to 3% MeOH in DCM) to afford the title product as pale yellow solid. .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ ppm 11.63 (s, 1H) 10.45 (s, 1H) 7.71 (d, 1H) 7.67-7.63 (m, 2H) 7.63-7.58 (m, 1H) 7.56-7.48 (m, 1H) 7.32-7.25 (m, 2H) 7.06-7.00 (m, 2H) 5.32 (br s, 2H) 2.24 (s, 3H). (UPLC-MS) t.sub.R 0.82 min; ESI-MS 398.2 [M+H].sup.+; ESI-MS 396.1 [M−H].sup.−.

Example 34: 1-((4-(3-amino-1H-pyrazolo[4,3-b]pyridin-5-yl)-3-methylphenyl)sulfonyl)-4,4-difluoropyrrolidine-2-carboxamide

(250) ##STR00087##

(251) The title compound was prepared in an analogous manner to 4-(3-amino-1H-pyrazolo[4,3-b]pyridin-5-yl)-3-chloro-N-((1s,3s)-3-hydroxy-3-(trifluoromethyl)cyclobutyl)benzenesulfonamide (Example 1) using 1-((4-(6-cyano-5-fluoropyridin-2-yl)-3-methyl phenyl)sulfonyl)-4,4-difluoropyrrolidine-2-carboxamide (Intermediate 34b). .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ ppm 11.78 (s, 1H), 7.87 (s, 1H), 7.83 (d, 2H), 7.69-7.63 (m, 2H), 7.47 (d, 1H), 7.39 (s, 1H), 5.45 (s, 2H), 4.32 (dd, 1H), 3.95-3.83 (m, 2H), 2.48 (s, 3H). (UPLC-MS) t.sub.R 0.65 min; ESI-MS 437.2 [M+H].sup.+; ESI-MS 435.2 [M−H].sup.−.

Example 35: 4-(3-amino-1H-pyrazolo[4,3-b]pyridin-5-yl)-3-chloro-N-((1S,2R)-2-hydroxycyclopentyl)benzenesulfonamide

(252) ##STR00088##

(253) The title compound was prepared in an analogous manner to 4-(3-amino-1H-pyrazolo[4,3-b]pyridin-5-yl)-3-chloro-N-((1s,3s)-3-hydroxy-3-(trifluoromethyl)cyclobutyl)benzenesulfonamide (Example 1) using 3-chloro-4-(6-cyano-5-fluoropyridin-2-yl)-N-((1S,2R)-2-hydroxycyclopentyl)benzene sulfonamide (Intermediate 35b). .sup.1H NMR (400 MHz, DMSO-d6) δ ppm 11.83 (s, 1H) 8.02 (d, 1H) 7.90 (dd, 1H) 7.81 (dd, 2H) 7.61-7.54 (m, 2H) 5.45 (s, 2H) 4.71 (d, 1H) 3.83-3.78 (m, 1H) 3.41-3.33 (m, 1H) 1.71-1.56 (m, 2H) 1.52-1.32 (m, 4H). (UPLC-MS) t.sub.R 0.72 min; ESI-MS 408.2 [M+H].sup.+; ESI-MS 406.2 [M−H].sup.−.

Example 36: 4-(3-amino-1H-pyrazolo[4,3-b]pyridin-5-yl)-3-chloro-N-(4-methylcyclohexyl)benzenesulfonamide

(254) ##STR00089##

(255) The title compound was prepared in an analogous manner to 4-(3-amino-1H-pyrazolo[4,3-b]pyridin-5-yl)-3-chloro-N-((1s,3s)-3-hydroxy-3-(trifluoromethyl)cyclobutyl)benzenesulfonamide (Example 1) using 3-chloro-4-(6-cyano-5-fluoropyridin-2-yl)-N-(4-methylcyclohexyl)benzenesulfonamide (Intermediate 36b). .sup.1H NMR (400 MHz, DMSO-d6) δ ppm 11.82 (s, 1H), 7.94 (dd, 1H), 7.89-7.75 (m, 4H), 7.55 (d, 1H), 5.43 (s, 2H), 3.26-2.89 (m, 1H), 1.68-0.87 (m, 9H), 0.86-0.76 (m, 3H). (UPLC-MS) t.sub.R 0.99 min; ESI-MS 420.2 [M+H].sup.+; ESI-MS 418.2 [M−H].sup.−.

Example 37: (S)-(1-((4-(3-amino-1H-pyrazolo[4,3-b]pyridin-5-yl)-3-methylphenyl)sulfonyl)-4,4-difluoropyrrolidin-2-yl)methanol

(256) ##STR00090##

(257) The title compound was prepared in an analogous manner to 4-(3-amino-1H-pyrazolo[4,3-b]pyridin-5-yl)-3-chloro-N-((1s,3s)-3-hydroxy-3-(trifluoromethyl)cyclobutyl)benzenesulfonamide (Example 1) using (S)-6-(4-((4,4-difluoro-2-(hydroxymethyl)pyrrolidin-1-yl)sulfonyl)-2-methylphenyl)-3-fluoropicolinonitrile (Intermediate 37b). The reaction mixture was concentrated under reduced pressure without extractive workup. The crude product was purified by normal phase chromatography (0 to 25% MeOH in DCM) to give the title compound as a yellow solid. .sup.1H NMR (400 MHz, acetonitrile-d3) δ ppm 10.07 (s, 1H), 7.86-7.81 (m, 2H), 7.79 (dd, 1H), 7.67 (d, 1H), 7.46 (d, 1H), 4.70 (s, 2H), 3.95 (ddt, 1H), 3.90-3.82 (m, 1H), 3.82-3.74 (m, 2H), 3.74-3.67 (m, 1H), 3.21 (t, 1H), 2.50 (s, 3H), 2.48-2.39 (m, 1H), 2.39-2.27 (m, 1H). (UPLC-MS) t.sub.R 1.19 min; API-MS 424.2 [M+H].sup.+.

Example 38: 4-(3-amino-1H-pyrazolo[4,3-b]pyridin-5-yl)-3-chloro-N-phenylbenzenesulfonamide

(258) ##STR00091##

(259) In a vial, a solution of 5-chloro-1H-pyrazolo[4,3-b]pyridin-3-amine (Intermediate 38b, 100 mg, 0.48 mmol) in anhydrous dioxane (2.5 mL) was treated with hexamethylditin (171 mg, 0.52 mmol) and Pd(PPh.sub.3).sub.4 (27.4 mg, 0.024 mmol) in an argon atmosphere and stirred at 110° C. for 24 h. 4-Bromo-3-chloro-N-phenylbenzenesulfonamide (Intermediate 38c) was added, and the reaction mixture was irradiated in a microwave reactor at 140° C. for 2 h. The reaction mixture was then partitioned between water and EtOAc. The aq. layer was extracted three times with EtOAc, and the combined organic layers were dried over MgSO.sub.4, filtered, and concentrated under reduced pressure. The product was purified by silica gel chromatography (0 to 4% MeOH in DCM) to give the title compound as a yellow solid. .sup.1H NMR (400 MHz, DMSO-d6) δ ppm 11.82 (s, 1H) 10.46 (s, 1H) 7.88 (d, 1H) 7.82-7.75 (m, 3H) 7.52 (d, 1H) 7.32-7.26 (m, 2H) 7.16 (d, 2H) 7.11-7.06 (m, 1H) 5.44 (br s, 2H). (UPLC-MS) t.sub.R 0.84 min; ESI-MS 400.1 [M+H].sup.+; ESI-MS 398.2 [M−H].sup.−.

Example 39: 4-(3-amino-1H-pyrazolo[4,3-b]pyridin-5-yl)-N-cyclohexyl-3-methylbenzenesulfonamide

(260) ##STR00092##

(261) The title compound was prepared in an analogous manner to 4-(3-amino-1H-pyrazolo[4,3-b]pyridin-5-yl)-3-chloro-N-((1R,2S)-2-hydroxycyclopentyl)benzenesulfonamide (Example 7) using 4-(6-cyano-5-fluoropyridin-2-yl)-N-cyclohexyl-3-methylbenzenesulfonamide (Intermediate 39b). .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ ppm 11.75 (br s, 1H) 7.80 (d, 1H) 7.75 (d, 1H) 7.71 (dd, 1H) 7.65 (d, 1H) 7.60 (d, 1H) 7.45 (d, 1H) 5.41 (br s, 2H) 2.98 (m, 1H) 2.42 (s, 3H) 1.68-1.54 (m, 4H) 1.50-1.40 (m, 1H) 1.27-0.99 (m, 5H). (UPLC-MS) t.sub.R 0.90 min; ESI-MS 386.2 [M+H].sup.+; ESI-MS 384.2 [M−H].sup.−.

Example 40: 4-(3-amino-1H-pyrazolo[4,3-b]pyridin-5-yl)-N-cyclohexyl-3-methylbenzenesulfonamide

(262) ##STR00093##

(263) The title compound was prepared in an analogous manner to 4-(3-amino-1H-pyrazolo[4,3-b]pyridin-5-yl)-3-methyl-N-phenylbenzenesulfonamide (Example 16) using 3-chloro-4-(6-cyano-5-fluoropyridin-2-yl)-N-(3-fluorophenyl)benzenesulfonamide (Intermediate 40b). .sup.1H NMR (400 MHz, DMSO-d6) δ ppm 11.83 (br s, 1H) 10.78 (s, 1H) 7.93 (d, 1H) 7.86-7.77 (m, 3H) 7.53 (d, 1H) 7.38-7.29 (m, 1H) 7.02-6.88 (m, 3H) 5.46 (br s, 2H). (UPLC-MS) t.sub.R 0.91 min; ESI-MS 418.1 [M+H].sup.+; ESI-MS 416.1 [M−H].sup.−.

Example 41: N-(4-(3-amino-1H-pyrazolo[4,3-b]pyridin-5-yl)-3-chlorophenyl)-3-fluorobenzenesulfonamide

(264) ##STR00094##

(265) The title compound was prepared in an analogous manner to N-(4-(3-amino-1H-pyrazolo[4,3-b]pyridin-5-yl)-3-chlorophenyl)-4-chlorobenzenesulfonamide (Example 3) using N-(3-chloro-4-(6-cyano-5-fluoropyridin-2-yl)phenyl)-3-fluorobenzenesulfonamide (Intermediate 41 b) at 80° C. for 3.5 h. The crude material was purified by reverse phase column chromatography (Method 2, 5% to 45% ACN in water). The residue was further purified by silica gel column chromatography (0% to 3% MeOH in DCM) to afford the product as yellow solid. .sup.1H NMR (400 MHz, DMSO-d6) δ ppm 11.72 (s, 1H) 10.81 (s, 1H) 7.74 (d, 1H) 7.68 (m, 2H) 7.64 (br d, 1H) 7.60-7.52 (m, 1H) 7.50 (d, 1H) 7.41 (d, 1H) 7.25 (d, 1H) 7.21 (dd, 1H) 5.36 (br s, 2H). (UPLC-MS) t.sub.R 0.85 min; ESI-MS 418.1 [M+H].sup.+; ESI-MS 416.1 [M−H].sup.−.

Example 42: N-(4-(3-amino-1H-pyrazolo[4,3-b]pyridin-5-yl)-3-methylphenyl)-3-chlorobenzenesulfonamide

(266) ##STR00095##

(267) The title compound was prepared in an analogous manner to N-(4-(3-amino-1H-pyrazolo[4,3-b]pyridin-5-yl)-3-chlorophenyl)-4-chlorobenzenesulfonamide (Example 3) using 3-chloro-N-(4-(6-cyano-5-fluoropyridin-2-yl)-3-methylphenyl)benzenesulfonamide (Intermediate 42b) at 80° C. for 2.5 h then, RT overnight. The residue was purified by reverse phase column chromatography (Method 2, 10% to 35% ACN in water). The residue was further purified by silica gel column chromatography (0 to 3% MeOH in DCM) to afford the title compound as pale yellow solid. .sup.1H NMR (400 MHz, DMSO-d6) δ ppm 11.63 (s, 1H) 10.46 (br s, 1H) 7.82 (d, 1H) 7.78-7.69 (m, 3H) 7.65-7.59 (dt, 1H) 7.29 (dt, 2H) 7.02 (m, 2H) 5.32 (br s, 2H) 2.24 (s, 3H). (UPLC-MS) t.sub.R 0.88 min; ESI-MS 414.1 [M+H].sup.+; ESI-MS 412.1 [M−H].sup.−.

Example 43: N-(4-(3-amino-1H-pyrazolo[4,3-b]pyridin-5-yl)-3-chlorophenyl)-3,4-dichlorobenzenesulfonamide

(268) ##STR00096##

(269) The title compound was prepared in an analogous manner to N-(4-(3-amino-1H-pyrazolo[4,3-b]pyridin-5-yl)-3-chlorophenyl)-4-chlorobenzenesulfonamide (Example 3) using 3,4-dichloro-N-(3-chloro-4-(6-cyano-5-fluoropyridin-2-yl)phenyl)benzenesulfonamide (Intermediate 43b) at 80° C. for 2 h. The residue was purified by preparative HPLC (Method 3, 20% to 70% ACN (+7.3 mM NH.sub.4OH) in water (+7.3 mM NH.sub.4OH)). The residue was further purified by silica gel column chromatography (0% to 3% MeOH in DCM) to afford the title compound as pale yellow solid. .sup.1H NMR (400 MHz, DMSO-d6) δ ppm 11.73 (s, 1H) 10.86 (br s, 1H) 8.04 (d, 1H) 7.91 (d, 1H) 7.79-7.76 (dd, 1H) 7.75 (d, 1H) 7.51 (d, 1H) 7.42 (d, 1H) 7.26 (d, 1H) 7.21 (dd, 1H) 5.36 (s, 2H). (UPLC-MS) t.sub.R 1.00 min; ESI-MS 468.1/470.1/472.1 [M+H].sup.+; ESI-MS 466.0/468.0/470.0 [M−H].sup.−.

Example 44: 4-(3-amino-1H-pyrazolo[4,3-b]pyridin-5-yl)-3-chloro-N-(3-hydroxycyclohexyl)benzenesulfonamide

(270) ##STR00097##

(271) The title compound was prepared in an analogous manner to 4-(3-amino-1H-pyrazolo[4,3-b]pyridin-5-yl)-3-chloro-N-((1R,2S)-2-hydroxycyclopentyl)benzenesulfonamide (Example 7) using 3-chloro-4-(6-cyano-5-fluoropyridin-2-yl)-N-(3-hydroxycyclohexyl)benzenesulfonamide (Intermediate 44b). The crude product was purified by preparative HPLC (Method 1, 5% to 95% ACN in water (+0.1% TFA)). Fractions containing purified product were combined and passed through a PL-HCO3 MP cartridge (Stratospheres, pre-conditioned with MeOH). After wash-out with MeOH, the filtrate was concentrated under reduced pressure. This product was further purified by silica gel column chromatography (0 to 10% MeOH in DCM) to afford the title compound as a yellow solid diastereoisomeric mixture. .sup.1H NMR (400 MHz, DMSO-d6) δ ppm 11.83 (s, 1H) 7.96-7.91 (m, 1H) 7.89-7.79 (m, 3H) 7.98-7.78 (m, 1H) 7.56 (d, 1H) 5.46 (br s, 2H) 4.65-4.41 (m, 1H) 3.87-3.36 (m, 1H) 3.31-2.98 (m, 1H) 1.86-1.65 (m, 1H) 1.63-1.30 (m, 4H) 1.27-0.82 (m, 3H) (UPLC-MS) t.sub.R 0.68 min; ESI-MS 422.2 [M+H].sup.+; ESI-MS 420.2 [M−H].sup.−.

Example 45: 4-(3-amino-1H-pyrazolo[4,3-b]pyridin-5-yl)-3-chloro-N-((1r,4r)-4-hydroxycyclohexyl)benzenesulfonamide

(272) ##STR00098##

(273) The title compound was prepared in an analogous manner to 4-(3-amino-1H-pyrazolo[4,3-b]pyridin-5-yl)-3-chloro-N-(3-hydroxycyclohexyl)benzenesulfonamide (Example 44) using 3-chloro-4-(6-cyano-5-fluoropyridin-2-yl)-N-((1r,4r)-4-hydroxycyclohexyl)benzenesulfonamide (Intermediate 45b). .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ ppm 11.84 (s, 1H) 7.94 (s, 1H) 7.89-7.79 (m, 4H) 7.57 (d, 1H) 5.45 (s, 2H) 4.50 (d, 1H) 3.05-2.94 (m, 1H) 1.77-1.69 (m, 2H) 1.68-1.60 (m, 2H) 1.28-1.04 (m, 5H). (UPLC-MS) t.sub.R 0.65 min; ESI-MS 422.2 [M+H].sup.+; ESI-MS 420.2 [M−H].sup.−.

Example 46: N-(4-(3-amino-1H-pyrazolo[4,3-b]pyridin-5-yl)-3-chlorophenyl)benzenesulfonamide

(274) ##STR00099##

(275) In a MW vial, a solution of 5-chloro-1H-pyrazolo[4,3-b]pyridin-3-amine (Intermediate 38b) (30 mg, 0.142 mmol) in ACN (0.75 mL) was treated with N-(3-chloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)benzenesulfonamide (Intermediate 46b, 119 mg, 0.184 mmol), Pd(PPh.sub.3).sub.2Cl.sub.2 (9.99 mg, 0.014 mmol) and a 2M aq. Na.sub.2CO.sub.3 solution (214 μL, 0.427 mmol) in an argon atmosphere and irradiated in a microwave reactor at 120° C. for 2 h. After removing the volatiles under reduced pressure, the crude product was purified by reverse phase column chromatography (Method 2, 2% to 100% ACN in water). Fractions containing the product were combined, concentrated under reduced pressure and the so obtained product was further purified by silica gel column chromatography (0 to 6% MeOH in DCM) to afford the title compound as a beige solid. .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ ppm 11.72 (br s, 1H) 10.73 (s, 1H) 7.88-7.82 (m, 2H) 7.73 (d, 1H) 7.69-7.58 (m, 3H) 7.47 (d, 1H) 7.40 (d, 1H) 7.24 (d, 1H) 7.19 (dd, 1H) 5.36 (br s, 2H). (UPLC-MS) t.sub.R 0.81 min; ESI-MS 400.1 [M+H].sup.+; ESI-MS 398.1 [M−H].sup.−.

Example 47: 4-(3-amino-1H-pyrazolo[4,3-b]pyridin-5-yl)-N-((1s,3s)-3-(hydroxymethyl)cyclobutyl)-3-methyl benzenesulfonamide

(276) ##STR00100##

(277) The title compound was prepared in an analogous manner to 4-(3-amino-1H-pyrazolo[4,3-b]pyridin-5-yl)-3-chloro-N-((1s,3s)-3-hydroxy-3-(trifluoromethyl)cyclobutyl)benzenesulfonamide (Example 1) using 3-chloro-4-(6-cyano-5-fluoropyridin-2-yl)-N-(4-methylcyclohexyl)benzenesulfonamide (Intermediate 36b). .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ ppm 11.75 (s, 1H) 7.85 (d, 1H) 7.80 (d, 1H) 7.71 (d, 1H) 7.69 (dd, 1H) 7.62-7.58 (m, 1H) 7.44 (d, 1H) 5.41 (s, 2H) 4.42 (t, 1H) 3.61-3.49 (m, 1H) 3.23 (t, 2H) 2.43 (s, 3H) 2.04-1.95 (m, 2H) 1.95-1.85 (m, 1H) 1.55-1.45 (m, 2H). (UPLC-MS) t.sub.R 0.59 min; ESI-MS 388.3 [M+H].sup.+; ESI-MS 386.3 [M−H].sup.−.

Example 48: 4-(3-amino-1H-pyrazolo[4,3-b]pyridin-5-yl)-3-chloro-N-((1s,4s)-4-hydroxycyclohexyl)benzenesulfonamide

(278) ##STR00101##

(279) The title compound was prepared in an analogous manner to 4-(3-amino-1H-pyrazolo[4,3-b]pyridin-5-yl)-3-chloro-N-(3-hydroxycyclohexyl)benzenesulfonamide (Example 44) using 3-chloro-4-(6-cyano-5-fluoropyridin-2-yl)-N-((1s,4s)-4-hydroxycyclohexyl)benzenesulfonamide (Intermediate 48b). .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ ppm 11.83 (s, 1H) 7.96 (d, 1H) 7.90-7.86 (m, 1H) 7.86-7.80 (m, 3H) 7.56 (d, 1H) 5.46 (s, 2H) 4.36 (d, 1H) 3.63-3.56 (m, 1H) 3.13-3.02 (m, 1H) 1.63-1.48 (m, 4H) 1.45-1.32 (m, 4H). (UPLC-MS) t.sub.R 0.69 min; ESI-MS 422.2 [M+H].sup.+; ESI-MS 420.2 [M−H].sup.−.

Example 49: 4-(3-amino-1H-pyrazolo[4,3-b]pyridin-5-yl)-3-fluoro-N-phenylbenzenesulfonamide

(280) ##STR00102##

(281) The title compound was prepared in an analogous manner to N-(4-(3-amino-1H-pyrazolo[4,3-b]pyridin-5-yl)-3-chlorophenyl)benzenesulfonamide (Example 46) using 3-fluoro-N-phenyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzenesulfonamide (Intermediate 49b). After removing the volatiles under reduced pressure, the crude product was purified twice by silica gel column chromatography (first 0 to 20% MeOH in DCM, then 0 to 100% EtOAc in cyclohexane). The so obtained product was further purified by reverse phase column chromatography (Method 2, 2% to 100% ACN in water) to afford the title compound as an off-white solid. .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ ppm 11.84 (s, 1H) 10.42 (s, 1H) 8.13 (t, 1H) 7.81 (d, 1H) 7.71-7.62 (m, 3H) 7.31-7.23 (m, 2H) 7.14 (d, 2H) 7.07 (t, 1H) 5.48 (s, 2H). (UPLC-MS) t.sub.R 0.81 min; ESI-MS 384.1 [M+H].sup.+; ESI-MS 382.1 [M−H].sup.−.

Example 50: 4-(3-amino-1H-pyrazolo[4,3-b]pyridin-5-yl)-3-chloro-N-(1,1-dioxidotetrahydro-2H-thiopyran-4-yl)benzenesulfonamide

(282) ##STR00103##

(283) The title compound was prepared in an analogous manner to 4-(3-amino-1H-pyrazolo[4,3-b]pyridin-5-yl)-3-chloro-N-((1s,3s)-3-hydroxy-3-(trifluoromethyl)cyclobutyl)benzenesulfonamide (Example 1) using 3-chloro-4-(6-cyano-5-fluoropyridin-2-yl)-N-(1,1-dioxidotetrahydro-2H-thiopyran-4-yl)benzenesulfonamide (Intermediate 50b). .sup.1H NMR (400 MHz, DMSO-d6) δ ppm 11.85 (s, 1H) 8.20 (br s, 1H) 7.96 (s, 1H) 7.80-7.92 (m, 3H) 7.57 (d, 1H) 5.44 (s, 2H) 3.55 (br s, 1H) 3.15-3.25 (m, 2H) 3.05 (br d, 2H) 2.03-1.82 (m, 4H). (UPLC-MS) t.sub.R 0.64 min; ESI-MS 456.2 [M+H].sup.+; ESI-MS 454.2 [M−H].sup.−.

Example 51: 5-(2-chloro-4-((hexahydrocyclopenta[c]pyrrol-2(1H)-yl)sulfonyl)phenyl)-1H-pyrazolo[4,3-b]pyridin-3-amine

(284) ##STR00104##

(285) The title compound was prepared in an analogous manner to 4-(3-amino-1H-pyrazolo[4,3-b]pyridin-5-yl)-3-chloro-N-(1-(hydroxymethyl)cyclopentyl)benzenesulfonamide (Example 30) using 6-(2-chloro-4-((hexahydrocyclopenta[c]pyrrol-2(1H)-yl)sulfonyl)phenyl)-3-fluoropicolinonitrile (Intermediate 51b). .sup.1H NMR (400 MHz, DMSO-d6) δ ppm 11.86 (s, 1H) 7.90-7.81 (m, 4H) 7.58 (d, 1H) 5.45 (br s, 2H) 3.18 (br dd, 2H) 2.89 (dd, 2H) 2.61-2.53 (m, 2H) 1.76-1.65 (m, 2H) 1.59-1.38 (m, 2H) 1.37-1.28 (m, 2H). (UPLC-MS) t.sub.R 1.00 min; ESI-MS 418.2 [M+H].sup.+; ESI-MS 416.1 [M−H].sup.−.

Example 52: 4-(3-amino-1H-pyrazolo[4,3-b]pyridin-5-yl)-3-chloro-N-(3-chloro-2-fluorophenyl)benzenesulfonamide

(286) ##STR00105##

(287) The title compound was prepared in an analogous manner to 4-(3-amino-1H-pyrazolo[4,3-b]pyridin-5-yl)-3-chloro-N-((1s,3s)-3-hydroxy-3-(trifluoromethyl)cyclobutyl)benzenesulfonamide (Example 1) using 3-chloro-N-(3-chloro-2-fluorophenyl)-4-(6-cyano-5-fluoropyridin-2-yl)benzenesulfonamide (Intermediate 52b). The reaction mixture was concentrated under reduced pressure to afford a yellow oil that underwent purification by reverse phase column chromatography (Method 2, 5% to 50% ACN in water) to afford the title compound as a yellow solid. .sup.1H NMR (400 MHz, DMSO-d6) δ ppm 11.85 (br s, 1H) 10.70 (br s, 1H) 7.89 (d, 1H) 7.85-7.77 (m, 3H) 7.55 (d, 1H) 7.47-7.41 (m, 1H) 7.33-7.26 (m, 1H) 7.25-7.18 (m, 1H) 5.47 (br s, 2H). (UPLC-MS) t.sub.R 0.92 min; ESI-MS 452.2/454.1 [M+H].sup.+; ESI-MS 450.2/452.2 [M−H].sup.−.

Example 53: N-(4-(3-amino-1H-pyrazolo[4,3-b]pyridin-5-yl)-3-chlorophenyl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-sulfonamide

(288) ##STR00106##

(289) A solution of 4-acetyl-N-(3-chloro-4-(6-cyano-5-fluoropyridin-2-yl)phenyl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-sulfonamide (Intermediate 53b) (82 mg, 0.168 mmol) in hydrazine hydrate 78% in water (600 μL, 9.63 mmol) was heated up and stirred at 100° C. for 1 h. The reaction was diluted with EtOAc and washed three times with water and brine, dried over anhydrous MgSO.sub.4, filtered and concentrated under reduced pressure. The residue was purified by reverse phase column chromatography (Method 2, 2% to 100% ACN in water) to afford the title compound as white solid. .sup.1H NMR (400 MHz, DMSO-d6) δ ppm 11.69 (s, 1H), 10.47 (s, 1H), 7.72 (d, 1H), 7.42 (dd, 2H), 7.22 (d, 1H), 7.15 (dd, 1H), 7.03 (d, 1H), 6.93 (dd, 1H), 6.76 (d, 1H), 6.34 (s, 1H), 5.34 (s, 2H), 4.20-4.09 (m, 2H), 3.27 (s, 2H). (UPLC-MS) t.sub.R 0.78 min; ESI-MS 457.2 [M+H].sup.+; ESI-MS 455.1 [M−H].sup.−.

Example 54: 4-(3-amino-1H-pyrazolo[4,3-b]pyridin-5-yl)-N-((1r,4r)-4-hydroxycyclohexyl)-3-methylbenzenesulfonamide

(290) ##STR00107##

(291) The title compound was prepared in an analogous manner to 4-(3-amino-1H-pyrazolo[4,3-b]pyridin-5-yl)-3-chloro-N-((1R,2S)-2-hydroxycyclopentyl)benzenesulfonamide (Example 7) using 4-(6-cyano-5-fluoropyridin-2-yl)-N-((1r,4r)-4-hydroxycyclohexyl)-3-methylbenzenesulfonamide (Intermediate 54b). .sup.1H NMR (400 MHz, DMSO-d6) δ ppm 11.75 (br s, 1H) 7.80 (d, 1H) 7.76-7.73 (m, 1H) 7.73-7.69 (m, 1H) 7.65-7.58 (m, 2H) 7.45 (d, 1H) 5.42 (br s, 2H) 4.48 (br s, 1H) 3.37-3.24 (m, 1H) 3.00-2.88 (m, 1H) 2.42 (s, 3H) 1.76-1.69 (m, 2H) 1.68-1.60 (m, 2H) 1.25-1.02 (m, 4H). (UPLC-MS) t.sub.R 0.60 min; ESI-MS 402.3 [M+H].sup.+; ESI-MS 400.3 [M−H].sup.−.

Example 55: (2R,4R)-1-((4-(3-amino-1H-pyrazolo[4,3-b]pyridin-5-yl)-3-chlorophenyl)sulfonyl)-4-fluoropyrrolidine-2-carboxamide

(292) ##STR00108##

(293) The title compound was prepared in an analogous manner to 4-(3-amino-1H-pyrazolo[4,3-b]pyridin-5-yl)-3-chloro-N-((1s,3s)-3-hydroxy-3-(trifluoromethyl)cyclobutyl)benzenesulfonamide (Example 1) using (2R,4R)-1-((3-chloro-4-(6-cyano-5-fluoropyridin-2-yl)phenyl)sulfonyl)-4-fluoropyrrolidine-2-carboxamide (Intermediate 55b). .sup.1H NMR (400 MHz, DMSO-d6) δ ppm 11.85 (s, 1H) 8.05 (d, 1H) 7.96 (dd, 1H) 7.88-7.81 (m, 2H) 7.58 (d, 1H) 7.30 (br d, 2H) 5.45 (s, 2 H) 5.32-5.12 (m, 1H) 4.32 (d, 1H) 3.77-3.64 (m, 1H) 3.63-3.46 (m, 1H) 2.31-2.18 (m, 1H) 2.11-1.89 (m, 1H). (UPLC-MS) t.sub.R 0.62 min; ESI-MS 439.2 [M+H].sup.+; ESI-MS 437.1 [M−H].sup.−.

Example 56: 4-(3-amino-1H-pyrazolo[4,3-b]pyridin-5-yl)-3-chloro-N-(2,3-dichlorophenyl)benzenesulfonamide

(294) ##STR00109##

(295) The title compound was prepared in an analogous manner to 4-(3-amino-1H-pyrazolo[4,3-b]pyridin-5-yl)-3-chloro-N-((1s,3s)-3-hydroxy-3-(trifluoromethyl)cyclobutyl)benzenesulfonamide (Example 1) using 3-chloro-4-(6-cyano-5-fluoropyridin-2-yl)-N-(2,3-dichlorophenyl)benzenesulfonamide (Intermediate 56b). The reaction mixture was concentrated under reduced pressure to afford a crude material that underwent purification by reverse phase column chromatography (Method 2, 5% to 50% ACN in water). Fractions containing pure title compound were combined and extracted three times with DCM. The combined organic layers were washed with brine, dried over anhydrous MgSO.sub.4, and concentrated under reduced pressure to afford the title compound as a yellow solid. .sup.1H NMR (400 MHz, DMSO-d6) δ ppm 11.85 (br s, 1H) 10.54 (br s, 1H) 7.89 (d, 1H) 7.85-7.77 (m, 3H) 7.57-7.51 (m, 2H) 7.40-7.33 (m, 1H) 7.32-7.27 (m, 1H) 5.47 (br s, 2H). (UPLC-MS) t.sub.R 0.99 min; ESI-MS 468.0/470.0/472.0 [M+H].sup.+; ESI-MS 466.0/468.0/470.0 [M−H].sup.−.

Example 57: (R)-1-((4-(3-amino-1H-pyrazolo[4,3-b]pyridin-5-yl)-3-chlorophenyl)sulfonyl) pyrrolidin-3-ol

(296) ##STR00110##

(297) The title compound was prepared in an analogous manner to 4-(3-amino-1H-pyrazolo[4,3-b]pyridin-5-yl)-3-chloro-N-((1s,3s)-3-hydroxy-3-(trifluoromethyl)cyclobutyl)benzenesulfonamide (Example 1) using (R)-6-(2-chloro-4-((3-hydroxypyrrolidin-1-yl)sulfonyl)phenyl)-3-fluoropicolinonitrile (Intermediate 57b). .sup.1H NMR (400 MHz, DMSO-d6) δ ppm 11.84 (s, 1H) 7.91 (s, 1H) 7.89-7.81 (m, 3H) 7.57 (d, 1H) 5.46 (s, 2H) 4.96 (d, 1H) 4.25-4.18 (m, 1H) 3.40-3.22 (m, 3H) 3.11 (br d, 1H) 1.88-1.77 (m, 1H) 1.75-1.65 (m, 1H). (UPLC-MS) t.sub.R 0.66 min; ESI-MS 394.1 [M+H].sup.+; ESI-MS 392.1 [M−H].sup.−.

Example 58: 4-(3-amino-1H-pyrazolo[4,3-b]pyridin-5-yl)-3-chloro-N-((1r,4r)-4-hydroxy-4-methylcyclohexyl)benzenesulfonamide

(298) ##STR00111##

(299) The title compound was prepared in an analogous manner to 4-(3-amino-1H-pyrazolo[4,3-b]pyridin-5-yl)-3-chloro-N-(1-(hydroxymethyl)cyclopentyl)benzenesulfonamide (Example 30) using 3-chloro-4-(6-cyano-5-fluoropyridin-2-yl)-N-((1r,4r)-4-hydroxy-4-methylcyclohexyl)benzenesulfonamide (Intermediate 58b). .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ ppm 11.83 (s, 1H) 7.95 (d, 1H) 7.89-7.85 (m, 1H) 7.84-7.79 (m, 3H) 7.56 (d, 1H) 5.45 (br s, 2H) 4.15 (s, 1H) 3.14 (br s, 1H) 1.69-1.59 (m, 2H) 1.55-1.46 (m, 2H) 1.35-1.22 (m, 4H) 1.07 (s, 3H). (UPLC-MS) t.sub.R 0.68 min; ESI-MS 436.1 [M+H].sup.+; ESI-MS 434.2 [M−H].sup.−.

Example 59: N-(4-(3-amino-1H-pyrazolo[4,3-b]pyridin-5-yl)-3-chlorophenyl)-1-phenylmethanesulfonamide

(300) ##STR00112##

(301) The title compound was prepared in an analogous manner to N-(4-(3-amino-1H-pyrazolo[4,3-b]pyridin-5-yl)-3-chlorophenyl)-4-chlorobenzenesulfonamide (Example 3) using N-(3-chloro-4-(6-cyano-5-fluoropyridin-2-yl)phenyl)-1-phenylmethanesulfonamide (Intermediate 59b) at 80° C. for 2.5 h. The residue was first purified by purification by reverse phase column chromatography (Method 2, 10% to 30% ACN in water). Fractions containing the product were combined and concentrated under reduced pressure and the so obtained product was further purified by silica gel column chromatography (0 to 3% MeOH in DCM) to afford the title compound as a pale yellow solid. .sup.1H NMR (400 MHz, DMSO-d6) δ ppm 11.74 (s, 1H) 10.19 (br s, 1H) 7.78 (d, 1H) 7.55 (d, 1H) 7.47 (d, 1H) 7.41-7.35 (m, 3H) 7.33-7.29 (m, 2H) 7.28-7.22 (m, 2H) 5.36 (s, 2H) 4.58 (s, 2H). (UPLC-MS) t.sub.R 0.83 min; ESI-MS 414.2 [M+H].sup.+; ESI-MS 412.1 [M−H].sup.−.

Example 60: (1R,2S)-N-(4-(3-amino-1H-pyrazolo[4,3-b]pyridin-5-yl)-3-chlorophenyl)-2-hydroxycyclohexane-1-sulfonamide

(302) ##STR00113##

(303) The title compound was obtained by chiral separation of N-(4-(3-amino-1H-pyrazolo[4,3-b]pyridin-5-yl)-3-chlorophenyl)-2-hydroxycyclohexane-1-sulfonamide (Example 17) using the same conditions described for (1S,2R)-N-(4-(3-amino-1H-pyrazolo[4,3-b]pyridin-5-yl)-3-chlorophenyl)-2-hydroxycyclohexane-1-sulfonamide (Example 14) to afford the title compound. .sup.1H NMR (400 MHz, DMSO-d6) δ ppm 11.72 (s, 1H) 9.62 (s, 1H) 7.75 (d, 1H) 7.53 (d, 1H) 7.46 (d, 1H) 7.35 (d, 1H) 7.28 (dd, 1H) 5.34 (s, 2H) 5.05 (d, 1H) 3.77 (d, 1H) 3.02-2.92 (m, 1H) 2.05 (d, 1H) 1.88 (d, 1H) 1.65 (d, 2H) 1.54-1.38 (m, 1H) 1.25 (dd, 4H). (UPLC-MS) t.sub.R 0.76 min; ESI-MS 422.1 [M+H].sup.+; ESI-MS 420.1 [M−H].sup.−.

Example 61: N-(5-(N-(4-(3-amino-1H-pyrazolo[4,3-b]pyridin-5-yl)-3-chlorophenyl)sulfamoyl)-2-methoxyphenyl)acetamide

(304) ##STR00114##

(305) The title compound was prepared in an analogous manner to N-(4-(3-amino-1H-pyrazolo[4,3-b]pyridin-5-yl)-3-chlorophenyl)-4-chlorobenzenesulfonamide (Example 3) using N-(5-(N-(3-chloro-4-(6-cyano-5-fluoropyridin-2-yl)phenyl)sulfamoyl)-2-methoxyphenyl)acetamide (Intermediate 61b) at 80° C. for 3.5 h. The residue was purified by reverse phase column chromatography (Method 2, 2% to 100% ACN in water) to afford the title compound. .sup.1H NMR (400 MHz, DMSO-d6) δ ppm 11.71 (s, 1H) 10.64 (br s, 1H) 9.37 (s, 1H) 8.63 (s, 1H) 7.73 (d, 1H) 7.55 (dd, 1H) 7.44 (d, 1H) 7.40 (d, 1H) 7.15-7.25 (m, 3H) 5.35 (s, 2H) 3.90 (s, 3H) 2.12 (s, 3H). (UPLC-MS) t.sub.R 0.72 min; ESI-MS 487.3 [M+H].sup.+; ESI-MS 485.3 [M−H].sup.−.

Example 62: N-(4-(3-amino-1H-pyrazolo[4,3-b]pyridin-5-yl)-3-chlorophenyl)-3-(trifluoromethyl)benzenesulfonamide

(306) ##STR00115##

(307) The title compound was prepared in an analogous manner to N-(4-(3-amino-1H-pyrazolo[4,3-b]pyridin-5-yl)-3-chlorophenyl)-4-chlorobenzenesulfonamide (Example 3) using N-(3-chloro-4-(6-cyano-5-fluoropyridin-2-yl)phenyl)-3-(trifluoromethyl)benzenesulfonamide (Intermediate 62B) at 80° C. for 2 h. The residue was purified by preparative HPLC (Method 1, 5% to 95% ACN in water (+0.1% TFA)). The residue was further purified by silica gel column chromatography (0 to 4% MeOH in DCM) to afford the title compound as yellow solid. .sup.1H NMR (400 MHz, DMSO-d6) b ppm 11.73 (s, 1H) 10.86 (s, 1H) 8.06-8.14 (m, 3H) 7.87 (t, 1H) 7.74 (d, 1H) 7.50 (d, 1H) 7.40 (d, 1H) 7.25 (d, 1H) 7.20 (dd, 1H) 5.35 (s, 2H). (UPLC-MS) t.sub.R 0.95 min; ESI-MS 468.1 [M+H].sup.+; ESI-MS 466.1 [M−H].sup.−.

Example 63: 5-(4-(3-azabicyclo[3.1.0]hexan-3-ylsulfonyl)-2-chlorophenyl)-1H-pyrazolo[4,3-b]pyridin-3-amine

(308) ##STR00116##

(309) The title compound was prepared in an analogous manner to 4-(3-amino-1H-pyrazolo[4,3-b]pyridin-5-yl)-3-chloro-N-((1s,3s)-3-hydroxy-3-(trifluoromethyl)cyclobutyl)benzenesulfonamide (Example 1) using 6-(4-(3-azabicyclo[3.1.0]hexan-3-ylsulfonyl)-2-chlorophenyl)-3-fluoropicolinonitrile (Intermediate 63b). .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ ppm 11.85 (s, 1H) 7.91-7.81 (m, 4H) 7.59 (d, 1H) 5.45 (br s, 2H) 3.45 (d, 2H) 3.17-3.11 (m, 2H) 1.57-1.51 (m, 2H) 0.64-0.56 (m, 1H) 0.11-0.06 (m, 1H). (UPLC-MS) t.sub.R 0.87 min; ESI-MS 390.0 [M+H].sup.+; ESI-MS 388.1 [M−H].sup.−.

Example 64: 4-(3-amino-1H-pyrazolo[4,3-b]pyridin-5-yl)-N-((1s,3s)-3-hydroxycyclobutyl)-3-methylbenzenesulfonamide

(310) ##STR00117##

(311) The title compound was prepared in an analogous manner to 4-(3-amino-1H-pyrazolo[4,3-b]pyridin-5-yl)-3-chloro-N-((1s,3s)-3-hydroxy-3-(trifluoromethyl)cyclobutyl)benzenesulfonamide (Example 1) using 4-(6-cyano-5-fluoropyridin-2-yl)-N-((1s,3s)-3-hydroxycyclobutyl)-3-methylbenzenesulfonamide (Intermediate 64b). .sup.1H NMR (400 MHz, DMSO-d6) δ ppm 11.75 (br s, 1H) 7.87 (d, 1H) 7.80 (d, 1H) 7.71 (s, 1H) 7.68 (d, 1H) 7.62-7.58 (m, 1H) 7.44 (d, 1H) 5.42 (br s, 2H) 5.01 (d, 1H) 3.71-3.60 (m, 1H) 3.19-3.11 (m, 1H) 2.43 (s, 3H) 2.31-2.23 (m, 2H) 1.65-1.55 (m, 2H). (UPLC-MS) t.sub.R 0.60 min; ESI-MS 374.1 [M+H].sup.+; ESI-MS 372.1 [M−H].sup.−.

Example 65: 4-(3-amino-1H-pyrazolo[4,3-b]pyridin-5-yl)-N-(3-hydroxycyclohexyl)-3-methylbenzenesulfonamide

(312) ##STR00118##

(313) The title compound was prepared in an analogous manner to 5-(4-((hexahydrocyclopenta[c]pyrrol-2(1H)-yl)sulfonyl)-2-methylphenyl)-1H-pyrazolo[4,3-b]pyridin-3-amine (Example 21) using 4-(6-cyano-5-fluoropyridin-2-yl)-N-(3-hydroxycyclohexyl)-3-methylbenzenesulfonamide (Intermediate 65b) to give a mixture of diastereomers that was not characterized by .sup.1H NMR. (UPLC-MS) t.sub.R 0.64 min; ESI-MS 402.3 [M+H].sup.+; ESI-MS 400.2 [M−H].sup.−.

Example 66: 1-((4-(3-amino-1H-pyrazolo[4,3-b]pyridin-5-yl)-3-methylphenyl)sulfonyl)-3-(trifluoromethyl)azetidin-3-ol

(314) ##STR00119##

(315) The title compound was prepared in an analogous manner to 4-(3-amino-1H-pyrazolo[4,3-b]pyridin-5-yl)-3-chloro-N-((1s,3s)-3-hydroxy-3-(trifluoromethyl)cyclobutyl)benzenesulfonamide (Example 1) using 3-fluoro-6-(4-((3-hydroxy-3-(trifluoromethyl)azetidin-1-yl)sulfonyl)-2-methylphenyl)picolinonitrile (Intermediate 66b). .sup.1H NMR (400 MHz, DMSO-d6) δ 11.77 (s, 1H), 7.82 (s, 2H), 7.77-7.68 (m, 2H), 7.46 (s, 2H), 5.42 (s, 2H), 4.05 (d, 2H), 3.75 (d, 2H), 2.51-2.45 (m, 3H). (UPLC-MS) t.sub.R 0.78 min; ESI-MS 428.1 [M+H].sup.+; ESI-MS 426.1 [M−H].sup.−.

Example 67: N-(4-(3-amino-1H-pyrazolo[4,3-b]pyridin-5-yl)-3-chlorophenyl)-3-methoxybenzenesulfonamide

(316) ##STR00120##

(317) The title compound was prepared in an analogous manner to N-(4-(3-amino-1H-pyrazolo[4,3-b]pyridin-5-yl)-3-chlorophenyl)-4-chlorobenzenesulfonamide (Example 3) using N-(3-chloro-4-(6-cyano-5-fluoropyridin-2-yl)phenyl)-3-methoxybenzenesulfonamide (Intermediate 67b) at 80° C. for 2.5 h. The residue was purified by reverse phase column chromatography (Method 2, 10% to 30% ACN in water). The residue was further purified by silica gel column chromatography (0 to 3% of MeOH in DCM) to afford the title compound as pale yellow solid. .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ ppm 11.72 (s, 1H) 10.68 (br s, 1H) 7.74 (d, 1H) 7.55-7.50 (m, 1H) 7.48 (d, 1H) 7.43-7.38 (m, 2H) 7.33 (t, 1H) 7.25 (d, 1H) 7.24-7.17 (m, 2H) 5.35 (s, 2H) 3.80 (s, 3H). (UPLC-MS) t.sub.R 0.85 min; ESI-MS 430.2 [M+H].sup.+; ESI-MS 428.1 [M−H].sup.−.

Example 68: 4-(3-amino-1H-pyrazolo[4,3-b]pyridin-5-yl)-N-((1r,4r)-4-hydroxy-4-(trifluoromethyl)cyclohexyl)-3-methylbenzenesulfonamide

(318) ##STR00121##

(319) The title compound was prepared in an analogous manner to 4-(3-amino-1H-pyrazolo[4,3-b]pyridin-5-yl)-3-chloro-N-((1R,2S)-2-hydroxycyclopentyl)benzenesulfonamide (Example 7) using 4-(6-cyano-5-fluoropyridin-2-yl)-N-((1r,4r)-4-hydroxy-4-(trifluoromethyl)cyclohexyl)-3-methylbenzenesulfonamide (Intermediate 68b). .sup.1H NMR (400 MHz, DMSO-d6) δ ppm 11.75 (s, 1H) 7.80 (d, 1H) 7.71-7.78 (m, 3H) 7.62 (d, 1H) 7.45 (d, 1H) 5.66 (s, 1H) 5.41 (br s, 2H) 3.25 (br s, 1H) 2.43 (s, 3H) 1.88-1.77 (m, 2H) 1.76-1.64 (br t, J=13.14 Hz, 2H) 1.57-1.42 (m, 4H). (UPLC-MS) t.sub.R 0.75 min; ESI-MS 470.2 [M+H].sup.+; ESI-MS 468.2 [M−H].sup.−.

Example 69: 4-(3-amino-1H-pyrazolo[4,3-b]pyridin-5-yl)-N-((1s,4s)-4-hydroxycyclohexyl)-3-methylbenzenesulfonamide

(320) ##STR00122##

(321) The title compound was prepared in an analogous manner to 5-(4-((hexahydrocyclopenta[c]pyrrol-2(1H)-yl)sulfonyl)-2-methylphenyl)-1H-pyrazolo[4,3-b]pyridin-3-amine (Example 21) using 4-(6-cyano-5-fluoropyridin-2-yl)-N-((1s,4s)-4-hydroxycyclohexyl)-3-methylbenzenesulfonamide (Intermediate 69b). .sup.1H NMR (400 MHz, DMSO-d6) δ ppm 11.75 (br s, 1H) 7.80 (d, 1H) 7.75 (s, 1H) 7.74-7.70 (m, 1H) 7.64-7.58 (m, 2H) 7.45 (d, 1H) 5.44 (br s, 2H) 4.34 (br s, 1H) 3.58 (br s, 1H) 3.09-2.93 (m, 1H) 2.42 (s, 3H) 1.64-1.46 (m, 4H) 1.44-1.29 (m, 4H). (UPLC-MS) t.sub.R 0.64 min; ESI-MS 402.3 [M+H].sup.+; ESI-MS 400.2 [M−H].sup.−.

Example 70: (S)-(1-((4-(3-amino-1H-pyrazolo[4,3-b]pyridin-5-yl)-3-methylphenyl)sulfonyl)pyrrolidin-2-yl)methanol

(322) ##STR00123##

(323) The title compound was prepared in an analogous manner to 4-(3-amino-1H-pyrazolo[4,3-b]pyridin-5-yl)-3-chloro-N-((1s,3s)-3-hydroxy-3-(trifluoromethyl)cyclobutyl)benzenesulfonamide (Example 1) using (S)-3-fluoro-6-(4-((2-(hydroxymethyl)pyrrolidin-1-yl)sulfonyl)-2-methylphenyl)picolinonitrile (Intermediate 70b). .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ ppm 11.76 (s, 1H) 7.81 (d, 1H) 7.76 (s, 1H) 7.74-7.70 (m, 1H) 7.68-7.63 (m, 1H) 7.46 (d, 1H) 5.42 (s, 2H) 4.84 (t, 1H) 3.64-3.55 (m, 2H) 3.38-3.32 (m, 2H) 3.16-3.07 (m, 1H) 2.46 (s, 3H) 1.86-1.74 (m, 2H) 1.56-1.39 (m, 2H). (UPLC-MS) t.sub.R 0.65 min; ESI-MS 388.2 [M+H].sup.+; ESI-MS 386.2 [M−H].sup.−.

Example 71: (S)-1-((4-(3-amino-1H-pyrazolo[4,3-b]pyridin-5-yl)-3-chlorophenyl)sulfonyl) pyrrolidin-3-ol

(324) ##STR00124##

(325) The title compound was prepared in an analogous manner to 4-(3-amino-1H-pyrazolo[4,3-b]pyridin-5-yl)-3-chloro-N-((1s,3s)-3-hydroxy-3-(trifluoromethyl)cyclobutyl)benzenesulfonamide (Example 1) using (S)-6-(2-chloro-4-((3-hydroxypyrrolidin-1-yl)sulfonyl)phenyl)-3-fluoropicolinonitrile (Intermediate 71b). .sup.1H NMR (400 MHz, DMSO-d6) δ ppm 11.84 (s, 1H) 7.92 (d, 1H) 7.89-7.81 (m, 3H) 7.57 (d, 1H) 5.46 (s, 2H) 4.96 (d, 1H) 4.21 (br d, 1H) 3.40-3.32 (m, 2H) 3.30-3.22 (m, 1H) 3.11 (d, 1H) 1.88-1.78 (m, 1H) 1.75-1.66 (m, 1H). (UPLC-MS) t.sub.R 0.64 min; ESI-MS 394.3 [M+H].sup.+; ESI-MS 392.3 [M−H].sup.−.

Example 72: 4-(3-amino-1H-pyrazolo[4,3-b]pyridin-5-yl)-3-chloro-N-(2-hydroxyethyl)benzenesulfonamide

(326) ##STR00125##

(327) The title compound was prepared in an analogous manner to 4-(3-amino-1H-pyrazolo[4,3-b]pyridin-5-yl)-3-chloro-N-((1R,2S)-2-hydroxycyclopentyl)benzenesulfonamide (Example 7) using 3-chloro-4-(6-cyano-5-fluoropyridin-2-yl)-N-(2-hydroxyethyl)benzenesulfonamide (Intermediate 72b). .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ ppm 11.83 (br s, 1H) 7.94 (s, 1H) 7.88-7.80 (m, 4H) 7.56 (d, 1H) 5.45 (s, 2H) 4.74 (t, 1H) 3.41 (q, 2H) 2.87 (q, 2H). (UPLC-MS) t.sub.R 0.61 min; ESI-MS 368.1 [M+H].sup.+; ESI-MS 366.0 [M−H].sup.−.

Example 73: 4-(3-amino-1H-pyrazolo[4,3-b]pyridin-5-yl)-N-benzyl-3-chlorobenzenesulfonamide

(328) ##STR00126##

(329) The title compound was prepared in an analogous manner to 4-(3-amino-1H-pyrazolo[4,3-b]pyridin-5-yl)-3-chloro-N-((1s,3s)-3-hydroxy-3-(trifluoromethyl)cyclobutyl)benzenesulfonamide (Example 1) using N-benzyl-3-chloro-4-(6-cyano-5-fluoropyridin-2-yl)benzenesulfonamide (Intermediate 73b). The reaction mixture was concentrated under reduced pressure without extractive workup. The crude product was purified by reverse phase HPLC (Method 3, 5% to 50% ACN (+7.3 mM NH.sub.4OH) in water (+7.3 mM NH.sub.4OH)). Fractions were combined, ACN was removed under reduced pressure, and the aq. layer was extracted three times with DCM. The combined organic layers were washed with brine, dried over anhydrous MgSO.sub.4, filtered and concentrated under reduced pressure to afford a yellow solid. This material was further purified by silica gel column chromatography (0 to 2% MeOH in DCM) to give the title compound as an off-white solid. .sup.1H NMR (400 MHz, DMSO-d6) δ ppm 11.84 (s, 1H) 8.38 (br s, 1H) 7.89-7.76 (m, 4H) 7.54 (d, 1H) 7.34-7.20 (m, 5H) 5.44 (s, 2H) 4.08 (s, 2H). (UPLC-MS) t.sub.R 0.89 min; ESI-MS 414.1 [M+H].sup.+; ESI-MS 412.1 [M−H].sup.−.

Example 74: 5-(2-chloro-4-((3,3-difluoroazetidin-1-yl)sulfonyl)phenyl)-1H-pyrazolo[4,3-b]pyridin-3-amine

(330) ##STR00127##

(331) The title compound was prepared in an analogous manner to 4-(3-amino-1H-pyrazolo[4,3-b]pyridin-5-yl)-3-chloro-N-((1s,3s)-3-hydroxy-3-(trifluoromethyl)cyclobutyl)benzenesulfonamide (Example 1) using 6-(2-chloro-4-((3,3-difluoroazetidin-1-yl)sulfonyl)phenyl)-3-fluoropicolinonitrile (Intermediate 74b). .sup.1H NMR (400 MHz, DMSO-d6) δ ppm 11.87 (s, 1H) 8.08 (d, 1H) 8.02-7.97 (m, 1H) 7.95-7.91 (m, 1H) 7.85 (d, 1H) 7.59 (d, 1H) 5.48 (s, 2H) 4.40 (t, 4H). (UPLC-MS) t.sub.R 0.85 min; ESI-MS 400.0 [M+H].sup.+; ESI-MS 398.0 [M−H].sup.−.

Example 75: 4-(3-amino-1H-pyrazolo[4,3-b]pyridin-5-yl)-N-tert-butyl-3-fluorobenzenesulfonamide

(332) ##STR00128##

(333) The title compound was prepared in an analogous manner to 4-(3-amino-1H-pyrazolo[4,3-b]pyridin-5-yl)-3-chloro-N-((1s,3s)-3-hydroxy-3-(trifluoromethyl)cyclobutyl)benzenesulfonamide (Example 1) using N-(tert-butyl)-4-(6-cyano-5-fluoropyridin-2-yl)-3-fluorobenzenesulfonamide (Intermediate 75b). The crude product was purified by preparative HPLC (Method 1, 5% to 95% ACN in water (+0.1% TFA)). Fractions containing pure product were combined, solid NaHCO.sub.3 was added, ACN was evaporated under reduced pressure, and the resulting aqueous layer was extracted three times with DCM. The combined organic layers were washed with brine, dried over anhydrous MgSO.sub.4, filtered and concentrated under reduced pressure to afford the title compound as a yellow solid. .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 11.84 (s, 1H) 8.18 (t, 1H), 7.84 (d, 1H), 7.78 (d, 1H), 7.69-7.76 (m, 3H), 5.50 (s, 2H), 1.15 (s, 9H). (UPLC-MS) t.sub.R 0.82 min; ESI-MS 364.2 [M+H].sup.+; ESI-MS 362.1 [M−H].sup.−.

Example 76: N1-(4-(3-amino-1H-pyrazolo[4,3-b]pyridin-5-yl)-3-chlorophenyl)-N4-methylbenzene-1,4-disulfonamide

(334) ##STR00129##

(335) The title compound was prepared in an analogous manner to N-(4-(3-amino-1H-pyrazolo[4,3-b]pyridin-5-yl)-3-chlorophenyl)-4-chlorobenzenesulfonamide (Example 3) using N1-(3-chloro-4-(6-cyano-5-fluoropyridin-2-yl)phenyl)-N4-methylbenzene-1,4-disulfonamide (Intermediate 76b) at 80° C. for 6 h. The residue was purified twice by silica gel column chromatography (0 to 3% MeOH in DCM) to afford the title compound as pale yellow solid. .sup.1H NMR (400 MHz, DMSO-d6) δ ppm 11.73 (s, 1H) 10.88 (s, 1H) 8.19 (s, 1H) 8.07 (d, 1H) 8.03 (d, 1H) 7.86 (t, 1H) 7.70-7.76 (m, 2H) 7.49 (d, 1H) 7.39 (d, 1H) 7.24 (s, 1H) 7.20 (dd, 1H) 5.35 (s, 2H) 2.37 (d, 3H). (UPLC-MS) t.sub.R 0.80 min; ESI-MS 493.2 [M+H].sup.+; ESI-MS 491.1 [M−H].sup.−.

Example 77: 4-(3-amino-1H-pyrazolo[4,3-b]pyridin-5-yl)-N-((1r,3r)-3-hydroxycyclobutyl)-3-methylbenzenesulfonamide

(336) ##STR00130##

(337) The title compound was prepared in an analogous manner to 4-(3-amino-1H-pyrazolo[4,3-b]pyridin-5-yl)-3-chloro-N-((1s,3s)-3-hydroxy-3-(trifluoromethyl)cyclobutyl)benzenesulfonamide (Example 1) using 4-(6-cyano-5-fluoropyridin-2-yl)-N-((1r,3r)-3-hydroxycyclobutyl)-3-methylbenzenesulfonamide (Intermediate 77b). .sup.1H NMR (400 MHz, DMSO-d6) δ ppm 11.75 (s, 1H) 7.90 (d, 1H) 7.80 (d, 1H) 7.71-7.69 (m, 1H) 7.69-7.64 (m, 1H) 7.63-7.59 (m, 1H) 7.44 (d, 1H) 5.41 (br s, 2H) 4.93 (d, 1H) 4.15 (br d, 1H) 3.81-3.71 (m, 1H) 2.43 (s, 3H) 2.05-1.96 (m, 2H) 1.96-1.87 (m, 2H). (UPLC-MS) t.sub.R 0.55 min; ESI-MS 374.1 [M+H].sup.+; ESI-MS 372.1 [M−H].sup.−.

Example 78: N-(4-(3-amino-1H-pyrazolo[4,3-b]pyridin-5-yl)-3-chlorophenyl)-4-(trifluoromethyl)benzenesulfonamide

(338) ##STR00131##

(339) The title compound was prepared in an analogous manner to N-(4-(3-amino-1H-pyrazolo[4,3-b]pyridin-5-yl)-3-chlorophenyl)-4-chlorobenzenesulfonamide (Example 3) using N-(3-chloro-4-(6-cyano-5-fluoropyridin-2-yl)phenyl)-4-(trifluoromethyl)benzenesulfonamide (Intermediate 78b) at 80° C. for 2.5 h. The residue was purified by silica gel column chromatography (0 to 3% MeOH in DCM) to afford the title compound as yellow solid. .sup.1H NMR (400 MHz, DMSO-d6) δ ppm 11.73 (s, 1H) 10.95 (br s, 1H) 7.99-8.09 (m, 4H) 7.74 (d, 1H) 7.50 (d, 1H) 7.41 (d, 1H) 7.27 (d, 1H) 7.21 (dd, 1H) 5.36 (s, 2H). (UPLC-MS) t.sub.R 0.95 min; ESI-MS 468.1 [M+H].sup.+; ESI-MS 466.1 [M−H].sup.−.

Example 79: N-(4-(3-amino-1H-pyrazolo[4,3-b]pyridin-5-yl)-3-chlorophenyl)-3,4-dimethoxybenzenesulfonamide

(340) ##STR00132##

(341) The title compound was prepared in an analogous manner to N-(4-(3-amino-1H-pyrazolo[4,3-b]pyridin-5-yl)-3-chlorophenyl)-4-chlorobenzenesulfonamide (Example 3) using N-(3-chloro-4-(6-cyano-5-fluoropyridin-2-yl)phenyl)-3,4-dimethoxybenzenesulfonamide (Intermediate 79b) at 80° C. for 3 h. The residue was purified by preparative HPLC (Method 3, 5% to 95% ACN (+7.3 mM NH.sub.4OH) in water (+7.3 mM NH.sub.4OH)). The residue was further purified by silica gel column chromatography (0 to 3% MeOH in DCM) to afford the title compound as pale yellow solid. .sup.1H NMR (400 MHz, DMSO-d6) δ ppm 11.72 (s, 1H) 10.51 (s, 1H) 7.74 (d, 1H) 7.47 (d, 1H) 7.43-7.41 (m, 1H) 7.41-7.38 (m, 1H) 7.34 (d, 1H) 7.26 (d, 1H) 7.19 (dd, Hz, 1H) 7.11 (d, 1H) 5.35 (s, 2H) 3.80 (d, 6H). (UPLC-MS) t.sub.R 0.81 min; ESI-MS 460.2 [M+H].sup.+; ESI-MS 458.1 [M−H].sup.−.

Example 80: 4-(3-amino-1H-pyrazolo[4,3-b]pyridin-5-yl)-N-((1r,4r)-4-hydroxy-4-methylcyclohexyl)-3-methylbenzenesulfonamide

(342) ##STR00133##

(343) The title compound was prepared in an analogous manner to 4-(3-amino-1H-pyrazolo[4,3-b]pyridin-5-yl)-3-chloro-N-(3-hydroxycyclohexyl)benzenesulfonamide (Example 44) using 4-(6-cyano-5-fluoropyridin-2-yl)-N-((1r,4r)-4-hydroxy-4-methylcyclohexyl)-3-methylbenzenesulfonamide (Intermediate 80b). .sup.1H NMR (400 MHz, DMSO-d6) δ ppm 11.75 (br s, 1H) 7.80 (d, 1H) 7.75 (s, 1H) 7.72 (d, 1H) 7.60 (dd, 2H) 7.45 (d, 1H) 5.42 (br s, 2H) 4.13 (br s, 1H) 3.12-3.03 (m, 1H) 2.42 (s, 3H) 1.67-1.56 (m, 2H) 1.55-1.47 (m, 2H) 1.34-1.22 (m, 4H) 1.06 (s, 3H). (UPLC-MS) t.sub.R 0.64 min; ESI-MS 416.3 [M+H].sup.+; ESI-MS 414.2 [M−H].sup.−.

Example 81: 4-(3-amino-1H-pyrazolo[4,3-b]pyridin-5-yl)-3-chloro-N-(2,3-difluorophenyl)benzenesulfonamide

(344) ##STR00134##

(345) The title compound was prepared in an analogous manner to 4-(3-amino-1H-pyrazolo[4,3-b]pyridin-5-yl)-3-chloro-N-(2,3-dichlorophenyl)benzenesulfonamide (Example 56) using 3-chloro-4-(6-cyano-5-fluoropyridin-2-yl)-N-(2,3-difluorophenyl)benzenesulfonamide (Intermediate 81 b). .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ ppm 11.85 (br s, 1H) 10.72 (br s, 1H) 7.90 (d, 1H) 7.85-7.77 (m, 3H) 7.55 (d, 1H) 7.34-7.26 (m, 1H) 7.23-7.15 (m, 1H) 7.15-7.09 (m, 1H) 5.47 (br s, 2H). (UPLC-MS) t.sub.R 0.87 min; ESI-MS 436.2 [M+H].sup.+; ESI-MS 434.2 [M−H].sup.−.

Example 82: N-(4-(3-amino-1H-pyrazolo[4,3-b]pyridin-5-yl)-3-chlorophenyl)naphthalene-2-sulfonamide

(346) ##STR00135##

(347) The title compound was prepared in an analogous manner to N-(4-(3-amino-1H-pyrazolo[4,3-b]pyridin-5-yl)-3-chlorophenyl)-4-chlorobenzenesulfonamide (Example 3) using N-(3-chloro-4-(6-cyano-5-fluoropyridin-2-yl)phenyl)naphthalene-2-sulfonamide (Intermediate 82b) at 80° C. for 4 h. The residue was purified by reverse phase column chromatography (Method 2, 5% to 40% ACN in water) to afford the title compound as yellow solid. .sup.1H NMR (600 MHz, DMSO-d6) δ ppm 11.70 (s, 1H) 10.85 (br s, 1H) 8.56 (s, 1H) 8.19 (d, 1H) 8.15 (d, 1H) 8.03 (d, 1H) 7.84 (dd, 1H) 7.66-7.75 (m, 3H) 7.43 (d, 1H) 7.36 (d, 1H) 7.29 (d, 1H) 7.23 (dd, 1H) 5.35 (s, 2H). (UPLC-MS) t.sub.R 0.94 min; ESI-MS 450.1 [M+H].sup.+; ESI-MS 448.1 [M−H].sup.−.

Example 83: 2-(1-((4-(3-amino-1H-pyrazolo[4,3-b]pyridin-5-yl)-3-methylphenyl)sulfonyl)pyrrolidin-3-yl)ethanol

(348) ##STR00136##

(349) The title compound was prepared in an analogous manner to 5-(4-((hexahydrocyclopenta[c]pyrrol-2(1H)-yl)sulfonyl)-2-methylphenyl)-1H-pyrazolo[4,3-b]pyridin-3-amine (Example 21) except 3-fluoro-6-(4-((3-(2-hydroxyethyl)pyrrolidin-1-yl)sulfonyl)-2-methylphenyl)picolinonitrile (Intermediate 83b) was used in place of 3-fluoro-6-(4-((hexahydrocyclopenta[c]pyrrol-2(1H)-yl)sulfonyl)-2-methylphenyl)picolinonitrile (Intermediate 21b). .sup.1H NMR (400 MHz, DMSO-d6) δ ppm 11.76 (s, 1H) 7.81 (d, 1H) 7.74 (s, 1H) 7.72-7.69 (m, 1H) 7.67-7.63 (m, 1H) 7.46 (d, 1H) 5.42 (br s, 2H) 4.42 (br t, 1H) 3.47-3.40 (m, 1H) 3.26-3.39 (m, 3H) 3.09-3.18 (m, 1H) 2.74-2.83 (m, 1H) 2.45 (s, 3H) 2.11-1.98 (m, 1H) 1.96-1.86 (m, 1H) 1.41-1.31 (m, 2H). (UPLC-MS) t.sub.R 0.68 min; ESI-MS 402.3 [M+H].sup.+; ESI-MS 400.3 [M−H].sup.−.

Example 84: N-(4-(3-amino-1H-pyrazolo[4,3-b]pyridin-5-yl)-3-chlorophenyl)-3-methylbenzenesulfonamide

(350) ##STR00137##

(351) The title compound was prepared in an analogous manner to N-(4-(3-amino-1H-pyrazolo[4,3-b]pyridin-5-yl)-3-chlorophenyl)-4-chlorobenzenesulfonamide (Example 3) using N-(3-chloro-4-(6-cyano-5-fluoropyridin-2-yl)phenyl)-3-methylbenzenesulfonamide (Intermediate 84b) at 80° C. for 2 h. The residue was purified by preparative HPLC (Method 1, 5 to 65% ACN in water (+0.1% TFA)). The residue was further purified by silica gel column chromatography (0 to 3% MeOH in DCM) to afford the title product as pale yellow solid. .sup.1H NMR (400 MHz, DMSO-d6) δ ppm 11.72 (s, 1H) 10.67 (s, 1H) 7.74 (d, 1H) 7.67 (s, 1H) 7.64 (br d, 1H) 7.52-7.45 (m, 3H) 7.40 (d, 1H) 7.24 (d, 1H) 7.19 (dd, 1H) 5.35 (br s, 2H) 2.38 (s, 3H). (UPLC-MS) t.sub.R 0.88 min; ESI-MS 414.2 [M+H].sup.+; ESI-MS 412.1 [M−H].sup.−.

Example 85: 4-(3-amino-1H-pyrazolo[4,3-b]pyridin-5-yl)-3-chloro-N-((1s,3s)-3-(hydroxymethyl)cyclobutyl)benzenesulfonamide

(352) ##STR00138##

(353) The title compound was prepared in an analogous manner to 4-(3-amino-1H-pyrazolo[4,3-b]pyridin-5-yl)-3-chloro-N-((1s,3s)-3-hydroxy-3-(trifluoromethyl)cyclobutyl)benzenesulfonamide (Example 1) using 3-chloro-4-(6-cyano-5-fluoropyridin-2-yl)-N-((1s,3s)-3-(hydroxymethyl)cyclobutyl)benzenesulfonamide (Intermediate 85b). .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ ppm 11.83 (s, 1H) 8.07 (d, 1H) 7.92 (d, 1H) 7.87-7.79 (m, 3H) 7.56 (d, 1H) 5.45 (s, 2H) 4.45 (t, 1H) 3.65-3.53 (m, 1H) 3.24 (t, 2H) 2.06-1.86 (m, 3H) 1.58-1.45 (m, 2H). (UPLC-MS) t.sub.R 0.66 min; ESI-MS 408.1 [M+H].sup.+; ESI-MS 406.1 [M−H].sup.−.

Example 86: 4-acetyl-N-(4-(3-amino-1H-pyrazolo[4,3-b]pyridin-5-yl)-3-chlorophenyl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-sulfonamide

(354) ##STR00139##

(355) The title compound was prepared in an analogous manner to N-(4-(3-amino-1H-pyrazolo[4,3-b]pyridin-5-yl)-3-chlorophenyl)-2-hydroxycyclohexane-1-sulfonamide (Example 17) using 4-acetyl-N-(3-chloro-4-(6-cyano-5-fluoropyridin-2-yl)phenyl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-sulfonamide (Intermediate 86b) at 80° C. for 1 h. The residue was purified three times using reverse phase column chromatography (Method 2, 2-100% ACN in water) to afford the title compound. .sup.1H NMR (400 MHz, DMSO-d6) δ ppm 11.72 (s, 1H) 10.64 (s, 1H) 7.74 (d, 1H) 7.52-7.44 (m, 2H) 7.40 (d, 1H) 7.25 (d, 1H) 7.20 (dd, 1H) 7.07 (d, 1H) 5.37-5.30 (m, 2H) 4.33 (t, 2H) 3.87 (t, 2H) 2.22 (br s, 3H). (UPLC-MS) t.sub.R 0.78 min; ESI-MS 499.2 [M+H].sup.+; ESI-MS 497.1 [M−H].sup.−.

Example 87: 5-(2-chloro-4-((3-phenoxyazetidin-1-yl)sulfonyl)phenyl)-1H-pyrazolo[4,3-b]pyridin-3-amine

(356) ##STR00140##

(357) The title compound was prepared in an analogous manner to 4-(3-amino-1H-pyrazolo[4,3-b]pyridin-5-yl)-3-chloro-N-((1s,3s)-3-hydroxy-3-(trifluoromethyl)cyclobutyl)benzenesulfonamide (Example 1) using 6-(2-chloro-4-((3-phenoxyazetidin-1-yl)sulfonyl)phenyl)-3-fluoropicolinonitrile (Intermediate 87b). .sup.1H NMR (400 MHz, DMSO-d6) δ 11.86 (s, 1H) 8.01-7.98 (m, 1H) 7.93 (d, 2H) 7.86 (d, 1H) 7.60 (d, 1H) 7.30-7.22 (m, 2H) 7.00-6.93 (m, 1H) 6.80-6.73 (m, 2H) 5.46 (br s, 2H) 4.97-4.88 (m, 1H) 4.34 (dd, 2H) 3.74 (dd, 2H). (UPLC-MS) t.sub.R 0.96 min; ESI-MS 456.2 [M+H].sup.+; ESI-MS 454.1 [M−H].sup.−.

Example 88: N-(4-(3-amino-1H-pyrazolo[4,3-b]pyridin-5-yl)-3-chlorophenyl)-4-(trifluoromethoxy)benzenesulfonamide

(358) ##STR00141##

(359) The title compound was prepared in an analogous manner to N-(4-(3-amino-1H-pyrazolo[4,3-b]pyridin-5-yl)-3-chlorophenyl)-2-hydroxycyclohexane-1-sulfonamide (Example 17) using N-(3-chloro-4-(6-cyano-5-fluoropyridin-2-yl)phenyl)-4-(trifluoromethoxy)benzenesulfonamide (Intermediate 88b) at 80° C. for 1 h. The residue was purified by silica gel column chromatography (0 to 20% MeOH in DCM) to afford the title compound as colorless oil. .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ ppm 11.73 (s, 1H) 10.85 (s, 1H) 7.97 (d, 2H) 7.74 (d, 1H) 7.62 (br d, 2H) 7.50 (d, 1H) 7.41 (d, 1H) 7.25 (s, 1H) 7.20 (br d, 1H) 5.36 (s, 2H). (UPLC-MS) t.sub.R 0.94 min; ESI-MS 484.2 [M+H].sup.+; ESI-MS 482.2 [M−H].sup.−.

Example 89: 2-(4-((4-(3-amino-1H-pyrazolo[4,3-b]pyridin-5-yl)-3-chlorophenyl)sulfonyl)piperazin-2-yl)-1,1,1-trifluoropropan-2-ol

(360) ##STR00142##

(361) The title compound was prepared in an analogous manner to 4-(3-amino-1H-pyrazolo[4,3-b]pyridin-5-yl)-3-chloro-N-((1s,3s)-3-hydroxy-3-(trifluoromethyl)cyclobutyl)benzenesulfonamide (Example 1) using 6-(2-chloro-4-((3-(1,1,1-trifluoro-2-hydroxypropan-2-yl)piperazin-1-yl)sulfonyl)phenyl)-3-fluoropicolinonitrile (Intermediate 89b). Purification by silica gel column chromatography was repeated twice to remove impurities from the title compound. .sup.1H NMR (400 MHz, DMSO-d6) δ ppm 11.88 (s, 1H), 7.92 (d, 1H), 7.88-7.80 (m, 3H), 7.60 (d, 1H), 6.18 (s, 1H), 5.47 (s, 2H), 3.76 (d, 1H), 3.55 (d, 1H), 3.02 (d, 1H), 2.20-2.10 (m, 4H), 1.26 (s, 3H), 1.10-1.25 (m, 1H). (UPLC-MS) t.sub.R 0.71 min; ESI-MS 505.2 [M+H].sup.+; ESI-MS 503.2 [M−H].sup.−.

Example 90: 4-(3-amino-1H-pyrazolo[4,3-b]pyridin-5-yl)-3-chloro-N-(3-chlorophenyl)benzenesulfonamide

(362) ##STR00143##

(363) The title compound was prepared in an analogous manner to 4-(3-amino-1H-pyrazolo[4,3-b]pyridin-5-yl)-3-chloro-N-(2,3-dichlorophenyl)benzenesulfonamide (Example 56) using 3-chloro-N-(3-chlorophenyl)-4-(6-cyano-5-fluoropyridin-2-yl)benzenesulfonamide (Intermediate 90b). After preparative HPLC (Method 1), fractions containing pure product were combined, solid NaHCO.sub.3 was added, ACN was evaporated under reduced pressure, and the resulting aq. layer was extracted three times with DCM. The combined organic layers were washed with brine, dried over anhydrous MgSO.sub.4, filtered and concentrated under reduced pressure to afford the title compound as an off-white solid. .sup.1H NMR (400 MHz, 400 MHz, DMSO-d6) δ ppm 11.85 (s, 1H), 10.79 (s, 1H), 7.93 (d, 1H), 7.87-7.79 (m, 3H), 7.55 (d, 1H), 7.35 (t, 1H), 7.20 (d, 1H), 7.16 (d, 2H), 5.48 (s, 2H). (UPLC-MS) t.sub.R 0.97 min; ESI-MS 434.1/436.1 [M+H].sup.+. ESI-MS 432.0/434.1 [M−H].sup.−.

Example 91: 4-(3-amino-1H-pyrazolo[4,3-b]pyridin-5-yl)-N-(2-hydroxycyclohexyl)-3-methylbenzenesulfonamide

(364) ##STR00144##

(365) The title compound was prepared in an analogous manner to 4-(3-amino-1H-pyrazolo[4,3-b]pyridin-5-yl)-3-chloro-N-((1R,2S)-2-hydroxycyclopentyl)benzenesulfonamide (Example 7) using 4-(6-cyano-5-fluoropyridin-2-yl)-N-(2-hydroxycyclohexyl)-3-methylbenzenesulfonamide (Intermediate 91b). The crude product was purified first by preparative HPLC (Method 1, 5% to 95% ACN in water (+0.1% TFA)). Fractions containing pure product were combined and passed through a PL-HCO3 MP cartridge (Stratospheres, pre-conditioned with MeOH), following by wash out with MeOH. The filtrate was concentrated under reduced pressure, and the residue was further purified by silica gel chromatography (0 to 11% MeOH in DCM) and by preparative achiral SFC (Column Waters VIRIDIS BEH 250×30 mm, 5 μm, 100A; 18% to 22% CO.sub.2 in MeOH) to afford the title compound as yellow solid. .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ ppm 11.74 (s, 1H) 7.82-7.77 (m, 2H) 7.74 (d, 1H) 7.58 (d, 1H) 7.44 (d, 1H) 7.31 (d, 1H) 5.41 (s, 2H) 4.53 (d, 1H) 3.62 (br s, 1H) 3.13-3.04 (m, 1H) 2.42 (s, 3H) 1.65-1.29 (m, 4H) 1.28-1.05 (m, 4H). (UPLC-MS) t.sub.R 0.73 min; ESI-MS 402.3 [M+H].sup.+; ESI-MS 400.2 [M−H].sup.−.

Example 92: 4-(3-amino-1H-pyrazolo[4,3-b]pyridin-5-yl)-3-chloro-N-(1,1-dioxidothietan-3-yl)benzenesulfonamide

(366) ##STR00145##

(367) The title compound was prepared in an analogous manner to 4-(3-amino-1H-pyrazolo[4,3-b]pyridin-5-yl)-3-chloro-N-((1s,3s)-3-hydroxy-3-(trifluoromethyl)cyclobutyl)benzenesulfonamide (Example 1) using 3-chloro-4-(6-cyano-5-fluoropyridin-2-yl)-N-(1,1-dioxidothietan-3-yl)benzenesulfonamide (Intermediate 92b). After extractive workup, the crude compound underwent purification by reverse phase column chromatography (5% to 95% ACN in water (+0.1% TFA)). Fractions containing pure product were combined, a sat. aq. NaHCO.sub.3 solution was added, and the resulting mixture was extracted three times with EtOAc. The combined organic layers were washed with brine, dried over anhydrous MgSO.sub.4, filtered and concentrated under reduced pressure to afford the title compound as a colorless solid. .sup.1H NMR (400 MHz, DMSO-d6) δ 11.86 (s, 1H), 7.95 (s, 1H), 7.85 (d, 3H), 7.59 (d, 1H), 5.45 (s, 2H), 4.49 (s, 2H), 4.04 (d, 3H). (UPLC-MS) t.sub.R 0.66 min; ESI-MS 428.1 [M+H].sup.+; ESI-MS 426.1 [M−H].sup.−.

Example 93: 5-(2-chloro-4-((3-(methylsulfonyl)azetidin-1-yl)sulfonyl)phenyl)-1H-pyrazolo[4,3-b]pyridin-3-amine

(368) ##STR00146##

(369) The title compound was prepared in an analogous manner to 4-(3-amino-1H-pyrazolo[4,3-b]pyridin-5-yl)-3-chloro-N-((1s,3s)-3-hydroxy-3-(trifluoromethyl)cyclobutyl)benzenesulfonamide (Example 1) using 6-(2-chloro-4-((3-(methylsulfonyl)azetidin-1-yl)sulfonyl)phenyl)-3-fluoropicolinonitrile (Intermediate 93b). Purification by silica gel column chromatography was repeated to remove impurities from the title compound. .sup.1H NMR (400 MHz, DMSO-d6) δ ppm 11.87 (s, 1H) 7.99 (s, 1H) 7.95-7.89 (m, 2H) 7.85 (d, 1H) 7.57 (d, 1H) 5.47 (s, 2H) 4.34-4.24 (m, 1H) 4.14 (t, 2H) 4.09-4.02 (m, 2H) 2.96 (s, 3H). (UPLC-MS) t.sub.R 0.68 min; ESI-MS 442.2 [M+H].sup.+; ESI-MS 440.2 [M−H].sup.−.

Example 94: 4-(3-amino-1H-pyrazolo[4,3-b]pyridin-5-yl)-3-chloro-N-((1S,2S)-2-hydroxycyclopentyl)benzenesulfonamide

(370) ##STR00147##

(371) The title compound was prepared in an analogous manner to 4-(3-amino-1H-pyrazolo[4,3-b]pyridin-5-yl)-3-chloro-N-((1s,3s)-3-hydroxy-3-(trifluoromethyl)cyclobutyl)benzenesulfonamide (Example 1) using 3-chloro-4-(6-cyano-5-fluoropyridin-2-yl)-N-((1S,2S)-2-hydroxycyclopentyl)benzenesulfonamide (Intermediate 94b). After extractive workup, the crude product was purified by preparative HPLC (Method 1, 5% to 95% ACN in water (+0.1% TFA)). Fractions containing pure product were combined, a sat. aq. NaHCO.sub.3 solution was added, and the resulting mixture was extracted three times with EtOAc. The combined organic layers were washed with brine, dried over anhydrous MgSO.sub.4, filtered and concentrated under reduced pressure to afford the title compound as a colorless solid. .sup.1H NMR (400 MHz, DMSO-d6) δ ppm 11.83 (br s, 1H) 7.96 (d, 1H) 7.89-7.85 (m, 1H) 7.85-7.77 (m, 3H) 7.56 (d, 1H) 5.45 (s, 2H) 4.73 (d, 1H) 3.84-3.78 (m, 1H) 3.28-3.21 (m, 1H) 1.82-1.69 (m, 2H) 1.59-1.50 (m, 2H) 1.43-1.22 (m, 2H). (UPLC-MS) t.sub.R 0.67 min; ESI-MS 408.2 [M+H].sup.+; ESI-MS 406.1 [M−H].sup.−.

Example 95—In Vitro, Ex Vivo and In Vivo Assays

(372) SCX-LUC In Vitro Assay

(373) Scleraxis (Scx) is a tendon cell specific transcription factor. Based on the literature Scx appears to act early in the tendon cell differentiation pathway. A 1.5 kb stretch of genomic sequence upstream of the Scx coding region was cloned into the pGreenFire1 lentiviral reporter construct. This construct was used to make a stable line in TT-D6 immortalized cells that expresses Luciferase upon Scx transcriptional activation.

(374) To determine transcriptional activation of Scleraxis (Scx) gene after treatment with the compounds of the invention, a mouse immortalized TT-D6 Scx-luciferase (ScxL) cell line was first seeded in a white, solid bottom 384 well plate (Greiner, cat #789163-G) in 50 ul media (Alpha MEM, 10% FBS, 1% pen-strep; Gibco, cat #12571048 and 15140122) supplemented with 1 ng/ml TGFβ1 (PeproTech, cat #100-21) at a density of 6,000 cells/well. Cells were then treated with a serial dilution (1:3) of the compounds of the invention or DMSO alone for four days at 37° C. After the incubation period, media was removed and 20 ul Bright-Glo Reagent (Promega, cat #E2620) was added to the wells. Immediately, luciferase luminescence was read on a SprectraMax M5E plate reader with 50 ms integration.

(375) The results are shown in the table below.

(376) Ex Vivo Assays

(377) Tenogenic differentiation was measured ex vivo looking at mRNA levels for both tenogenic and extracellular matrix genes. Both Scleraxis (Sex) and Tenomodulin (Tnmd) genes have been shown to be enriched in tendon cells and associated with tenogenesis while an increase in tendon collagen type I (Col1a2) is secondary to tenogenic differentiation and is necessary for proper healing.

(378) To determine ex vivo gene expression changes after stimulation with compounds of the invention, tendon fascicles were first removed from approximately 2-3 month old male Sprague Dawley rat tails. The tendon fascicles were washed in Hank's Balanced Salt Solution (HBSS, Hyclone, GE cat #SH30268.01) before being cut into 2.5 cm length pieces. Next, two tendon fascicle pieces were placed per well in a 48 well tissue culture plate containing 1 ml of Mesenchymal Stem Cell Growth Media (MSCGM, Lonza, cat #PT-3001) with serial dilutions (1:2) of compounds or DMSO alone. Tendon fascicles were then stimulated at 37° C. for four days in a cell culture incubator. RNA was isolated after the incubation period from the tendon fascicles using the RNeasy 96 Kit (Qiagen, cat #74181). cDNA was then synthesized from the RNA using Quanta's qScript Supermix (VWR, cat #101414-106) and thermocycler protocol: 25° C. for 5 minutes, 42° C. for 45 minutes, 85° C. for 5 minutes, hold at 4° C. Using SYBR green (Roche, cat #04707516001), qPCR reactions were carried out in a Roche Lightcycler 480 II (Software version: 1.5.0 SP3, Roche cat #05015243001) using the following cycling protocol: preincubation for 10 minutes at 95° C. followed by 45 amplification cycles of 10 seconds at 95° C., 10 seconds at 60° C. and 20 seconds at 72° C. Finally, gene expression data was calculated by using the delta-delta Ct method using the average of 3 housekeeping genes (Gadph, B-actin and 36b4).

(379) TABLE-US-00003 Primer sequences Gene name Forward primer Reverse primer Gadph ATC ACC ATC TTC CAG GAG CGA AGC CTT CTC CAT GGT GGT GAA (SEQ ID NO: 1) (SEQ ID NO: 7) 36b4 GAT GCC CAG GGA AGA CAG CAC AAT GAA GCA TTT TGG GTA G (SEQ ID NO: 2) (SEQ ID NO: 8) Beta-actin GCT CCT CCT GAG CGC AAG CAT CTG CTG GAA GGT GGA CA (SEQ ID NO: 3) (SEQ ID NO: 9) Scleraxis CCC AAA CAG ATC TGC ACC TT TCT GTC ACG GTC TTT GCT CA (SEQ ID NO: 4) (SEQ ID NO: 10) Tenomodulin TGG ATC AAT CCC ACT CTA ATA TCG CTG GTA GGA AAG TGA AGA GC (SEQ ID NO: 11) (SEQ ID NO: 5) Collagen type 1 CCT GGC TCT CGA GGT GAA C CAA TGC CCA GAG GAC CAG (col1a2) (SEQ ID NO: 6) (SEQ ID NO: 12)

(380) The results are shown in the table below and show that compounds of the invention

(381) For the Scx-Luc assay, EC.sub.50 values were obtained using luciferase luminescence read on a SprectraMax M5E plate reader.

(382) For the ex vivo assays, EC.sub.50 calculations were done using delta-delta Ct values for each gene calculated using the average of 3 housekeeping genes.

(383) TABLE-US-00004 Ex- Scx-Luc Ex vivo Ex vivo Ex vivo am- (EC.sub.50 Scx (EC.sub.50 Tnmd Col1a2 ple μM) μM) (EC.sub.50 μM) (EC.sub.50 μM) 1 0.183 2.108 0.804 1.586 2 0.376 n.d. n.d. n.d. 3 0.801 >10 1.153 3.079 4 0.444 n.d. n.d. n.d. 5 0.909 n.d. n.d. n.d. 6 0.580 n.d. n.d. n.d. 7 0.305 1.602 1.681 2.062 8 0.346 0.110 0.261 1.292 9 0.460 2.271 2.141 0.577 10 0.640 n.d. n.d. n.d. 11 0.801 3.048 0.841 2.458 12 0.765 5.793 5.387 4.623 13 1.343 n.d. n.d. n.d. 14 1.119 n.d. n.d. n.d. 15 0.874 n.d. n.d. n.d. 16 0.610 3.864 2.807 4.646 17 1.840 n.d. n.d. n.d. 18 0.764 1.767 0.750 1.827 19 1.698 n.d. n.d. n.d. 20 0.797 n.d. n.d. n.d. 21 0.598 4.927 3.508 3.709 22 0.035 n.d. n.d. n.d. 23 2.278 n.d. n.d. n.d. 24 1.592 n.d. n.d. n.d. 25 0.611 n.d. n.d. n.d. 26 0.811 n.d. n.d. n.d. 27 1.083 n.d. n.d. n.d. 28 2.500 n.d. n.d. n.d. 29 1.909 n.d. n.d. n.d. 30 2.067 n.d. n.d. n.d. 31 0.411 2.314 2.762 2.634 32 1.937 n.d. n.d. n.d. 33 1.025 n.d. n.d. n.d. 34 5.021 n.d. n.d. n.d. 35 2.729 n.d. n.d. n.d. 36 0.414 n.d. n.d. n.d. 37 0.593 n.d. n.d. n.d. 38 0.610 0.188 1.892 0.396 39 0.473 n.d. n.d. n.d. 40 0.416 n.d. n.d. n.d. 41 2.250 n.d. n.d. n.d. 42 2.001 n.d. n.d. n.d. 43 3.309 n.d. n.d. n.d. 44 4.122 n.d. n.d. n.d. 45 4.725 n.d. n.d. n.d. 46 0.010 n.d. n.d. n.d. 47 5.341 n.d. n.d. n.d. 48 2.025 n.d. n.d. n.d. 49 0.870 n.d. n.d. n.d. 50 >10 2.325 6.301 6.372 51 2.391 n.d. n.d. n.d. 52 1.104 n.d. n.d. n.d. 53 2.737 n.d. n.d. n.d. 54 1.127 n.d. n.d. n.d. 55 6.157 n.d. n.d. n.d. 56 1.638 n.d. n.d. n.d. 57 0.633 n.d. n.d. n.d. 58 1.514 n.d. n.d. n.d. 59 4.319 >10 4.614 5.706 60 3.040 n.d. n.d. n.d. 61 1.540 n.d. n.d. n.d. 62 1.300 n.d. n.d. n.d. 63 1.239 2.125 4.602 3.344 64 0.162 n.d. n.d. n.d. 65 0.122 n.d. n.d. n.d. 66 0.794 0.890 0.719 0.921 67 2.317 n.d. n.d. n.d. 68 0.354 n.d. n.d. n.d. 69 0.912 n.d. n.d. n.d. 70 0.762 n.d. n.d. n.d. 71 3.532 n.d. n.d. n.d. 72 4.091 3.937 3.421 3.283 73 3.533 n.d. n.d. n.d. 74 2.033 n.d. n.d. n.d. 75 1.523 n.d. n.d. n.d. 76 0.003 n.d. n.d. n.d. 77 0.777 n.d. n.d. n.d. 78 2.435 n.d. n.d. n.d. 79 0.061 n.d. n.d. n.d. 80 0.225 n.d. n.d. n.d. 81 0.203 n.d. n.d. n.d. 82 2.609 >10 4.874 7.274 83 5.328 n.d. n.d. n.d. 84 0.045 n.d. n.d. n.d. 85 1.754 n.d. n.d. n.d. 86 5.387 >10 4.864 >10 87 0.830 n.d. n.d. n.d. 88 2.430 n.d. n.d. n.d. 89 2.186 4.444 5.007 7.273 90 2.542 n.d. n.d. n.d. 91 1.815 n.d. n.d. n.d. 92 0.968 4.889 6.281 1.352 93 5.740 2.951 3.524 1.759 94 0.026 n.d. n.d. n.d.

(384) The compounds (S)-(1-((4-(3-amino-1H-pyrazolo[4,3-b]pyridin-5-yl)-3-chlorophenyl)sulfonyl)pyrrolidin-2-yl)methanol and 4-(3-amino-1H-pyrazolo[4,3-b]pyridin-5-yl)-3-chloro-N-((1R,4R)-4-hydroxy-4-(trifluoromethyl)cyclohexyl)benzenesulfonamide exhibit efficacy in the Scx-Luc assay described above with an EC.sub.50>10 μM.

(385) The data shown in the table above shows that the compounds of the invention have activity as inducers of scleraxis, tenomodulin and collagen type I suggesting that the compounds are useful in the treatment of tendon injuries.

(386) In Vivo Assay

(387) Animals are treated 3 days post-surgery with 1 mg of compound in 10 μl of vehicle delivered by injection under the skin in the peri-tendinous region. Tendons are harvested 25 days post treatment. Strong Alcian blue staining is used to detect endochondral tissue forming which further ossifies with time. A comparison between vehicle treated animals and animals treated with a compound of the invention can be made. Treatment with a compound of the invention is expected to be able to counter some of the improper healing caused by aberrant differentiation towards the chondrogenic and osteogenic lineages. Definiens Tissue Studio software can be used for quantitative image analysis of the Alcian blue positive area. Serial step sections encompassing 2 mm of the lesion are used for quantification.

Example 96: Ex Vivo Fascicle Assay

(388) Sample Preparation

(389) Tail from skeletal mature rat (Sprague Dawley, female, 30-50 weeks old) is removed and kept on ice. Approximately 40 mm long segment is cut from the mid-portion of the tail. Rat tail fascicles (n=12) were carefully extracted from the segment. Fascicles are then randomly selected into three groups, fresh (n=4), vehicle (n=4) and 4-(3-amino-1H-pyrazolo[4,3-b]pyridin-5-yl)-N-((1s,3s)-3-hydroxy-3-(trifluoromethyl)cyclobutyl)-3-methyl benzenesulfonamide (Test Compound A hereinafter) treated (n=4). Biomechanical properties are measure immediately after extraction for the fresh group. Samples of the vehicle and Test Compound A groups are placed into 6 well plates (2 fascicles/well) in 2 ml/well of serum free tissue culture medium consisting of DMEM/F12 (Gibco®, catalogue number: 31331093), N2 supplement (1× concentration, Gibco®, catalogue number: 17502048), ascorbic acid (300 ug/ml, Wako catalogue number: 013-10641) and Pen-strep (1%, Gibco®, catalogue number: 15140122). For the Test Compound group, 1 uM Test Compound A is added to the wells. Equal amount of DMSO is added to the vehicle group. Both groups were incubated at 37° C. for 4 weeks. Media are refreshed once per week.

(390) Mechanical Testing

(391) Samples are clamped for mechanical testing using a standard uniaxial material testing machine (ElectroPuls E3000, 50N load-cell, Instron, US) in a custom environmental testing chamber filled with PBS. Samples are preloaded to a position where crimp (macroscopic fascicle waviness) disappears and initial length (L0) based on grip-to-grip distance is recorded. Images of the fascicle are taken from orthogonal perspectives using two telecentric lenses (FABRIMEX T80 1.0L, Fabrimex AG, Switzerland) to characterize the ellipsoidal cross-sectional area of each specimen. Samples are ramped to failure at a constant strain rate of 0.025% L0/s. Sample lengths and corresponding forces are recorded to calculate engineering stress and strain. Young's moduli are calculated from the linear region of the stress-strain curves. Failure stress iss obtained at the point where maximum stress was reached.

(392) In unloaded condition, tendon degeneration can thus be observed in vitro shown by morphological changes in tendon structure and decrease in biomechanical properties (failure stress and young's modulus).

Example 97: Microparticle Formulation for Injection with 4-(3-amino-1H-pyrazolo[4,3-b]pyridin-5-yl)-N-((1s,3s)-3-hydroxy-3-(trifluoromethyl)cyclobutyl)-3-methylbenzenesulfonamide (Test Compound A)

(393) In the current invention, the microparticles formulation contains a copolymer of DL-lactide and glycolide in a 50:50 molar ratio with an ester end group plus Test Compound A is used. The total amount of Test Compound A incorporated into the microparticles ranges from 2% to 10% (w/w). The microparticles are formulated to mean mass range in size from 5 to 25 microns. The population of microparticles is formulated to be delivered through a 22 gauges or higher needles (see Table A below). Organic solvent was used for preparation of microparticles were dichloromethane (DCM) and ethyl acetate (EA) either alone or in combination with methanol (MeOH) and/or dimethyl sulfoxide (DMSO) e.g., ratio of MeOH/DMSO from 5-15% in DCM or EA as primary solvent. Additional excipients may be added such as, but not limited to, carboxymethylcellulose sodium, mannitol and ploxamer to achieve isotonicity and promote syringeability.

(394) Test Compound A incorporated into the microparticles provides an initial release (burst) of about 5-10% of drug over a period of 1 to 2 days, followed by a steady state release of drug over a period of 21 days (FIG. 1). In-vivo the microparticles could extend the release of Test Compound A over 4 weeks in a rat model.

(395) The detailed formulation is presented below (See also Table A):

(396) Materials and Methods:

(397) Formulation A: Using DCM as primary solvent:

(398) 1. Dissolve 180 mg of PLGA in 2 mL of methylene chloride (DCM) using a 4 mL vial. Prepare two vials.

(399) 2. Add 20 mg of Test Compound A to each vial. Label as vial 1 and vial 2.

(400) 3. In vial 1, add 300 uL of MeOH to obtain a clear/yellow solution.

(401) 4. In vial 2, add 120 uL of DMSO to obtain a clear/yellow solution.

(402) 5. Prepare two 250 mL beakers with 240 mL of 0.1% PVA solution and label as beaker 1 and 2. Add stir bar and allow to stir at room temperature with moderate agitation (˜250 rpm).

(403) 6. Prepare two 20 mL vials with 8 mL of 2% PVA solution. Label each vial as 1 and 2.

(404) 7. Slowly pipette vial 1 to the respective 2% PVA solution vial to form a drug-polymer solution using a homogenizer (speed approx. 5000 rpm).

(405) 8. After pipetting, allow homogenizer to continue emulsification of the binary system for approximately 10 seconds.

(406) 9. Transfer the binary system to the respective 250 mL beaker (as prepared in Step 5).

(407) 10. Repeat steps 7-9 for vial 2.

(408) 11. Allow mixtures to stir overnight.

(409) 12. Label four 50 mL capillary centrifuge tubes as “1”.

(410) 13. Transfer the contents of from Beaker 1 into the four (or more) 50 mL tubes and fill to 50 mL. qs with water if needed.

(411) 14. Repeat steps 12 and 13 for sample 2.

(412) 15. Ensure all tubes are of equal weight. Centrifuge all tubes 4000 rpm for 4 minutes.

(413) 16. Decant the supernatant from all vials, leave pellets undisturbed.

(414) 17. Consolidate all pellets from sample 1 tubes into one tube. Rinse each empty tube with water and collect. complete final tube to 50 mL. Vortex.

(415) 18. Repeat step 17 for sample 2.

(416) 19. Repeat steps 15 through 18 to centrifuge, decant, refill with water, and vortex for a total of 3 wash cycles.

(417) 20. Transfer the final product solutions into 4 mL glass vials (labeled 1 and 2, respectively)

(418) 21. Dip into liquid nitrogen for approximately 45 seconds.

(419) 22. Cover the vial tops with KimWipe (folded into a square, four layers thick), tape around vial to secure, and ensure tape is labeled 1 and 2 for the respective sample.

(420) 23. Store samples under vacuum for 24 hours

(421) 24. Create a calibration curve using Test Compound A in ACN:H2O 1:1, 1 mg/mL working solution, three standards [0.1 mg/mL], [0.01 mg/mL], [0.001 mg/mL]

(422) The dried particles are analyzed for encapsulation efficiency using UPLC as follows:

(423) 25. 0.97 mg of (1) PLGA particles are dissolved in 250 uL of acetonitrile. 750 uL of methanol is added to precipitate PLGA (Test Compound A is dissolved in methanol).

(424) 26. 1.01 mg of (2) PLGA particles are dissolved in 250 uL of acetonitrile. 750 uL of methanol is added to precipitate PLGA (Test Compound A is dissolved in methanol).

(425) 27. The suspension is vortexed and centrifuged at 15000 rpm using a 0.22 um filter eppendorf centrifuge tube

(426) 28. The clear solution in analyzed using UPLC for drug loading

(427) Formulation B: Using EA as Primary Solvent:

(428) The procedure used is exactly the same as for Formulation A. The only difference is that in step 3, the amount of MeOH added is 120 uL and in step 4 the amount of DMSO added is 50 uL.

(429) TABLE-US-00005 TABLE A Formulation of Test Compound A (“drug”) into PLGA microparticles with different drug loading and PLGA composition Mw (kDa) Drug ester loading Formulation PLGA 50:50 capped (w/w) % 1 Linear 7-17 2.15 2 Linear 7-17 2.09 3 Linear 7-17 9.12 4 Linear 7-17 8.52

(430) Test Compound A incorporated into the microparticles provides an initial release (burst) of about 5-10% of drug over a period of 1 to 2 days, followed by a steady state release of drug over a period of 21 days (FIG. 1). In-vivo the microparticles could extend the release of Test Compound A over 4 weeks in a rat model.

(431) Instead of Test Compound A, any other one of the exemplified compounds can be formulated using the same procedure as in the present example. The microparticles can also be produced using Ethyl acetate as a primary solvent to increase the drug loading and achieve a controlled release of the encapsulated material.