KIF18A INHIBITORS

Abstract

Compounds of formula (I):

##STR00001##

as defined herein, and synthetic intermediates thereof, which are capable of modulating KIF18A protein thereby influencing the process of cell cycle and cell proliferation to treat cancer and cancer-related diseases. The invention also includes pharmaceutical compositions, including the compounds, and methods of treating disease states related to the activity of KIF18A.

Claims

1. A compound of formula I: ##STR00307## or any pharmaceutically-acceptable salt thereof, wherein: X.sup.1 is N or —CR.sup.6; R.sup.1 is —CN, or a group —Z—R.sup.12 wherein Z is —C.sub.0-4alk-, —NR.sup.11—, —NR.sup.11SO.sub.2—, —SO.sub.2NR.sup.11—, —NR.sup.11—S(═O)(═NH), —S(═O)(═NH)—, —S—, —S(═O)—, —SO.sub.2—, C.sub.0-4alk-O—, —(C═O)—, —(C═O)NR.sup.11—, —C═N(OH)—, or —NR.sup.11(C═O); or the group —Z—R.sup.12 is —N═S(═O)—(R.sup.12).sub.2, wherein the two R.sup.12 pair can alternatively combine with the sulfur atom attached to each of them to form a saturated or partially-saturated 3-, 4-, 5-, or 6-membered monocyclic ring containing 0, 1, 2 or 3 N atoms and 0, 1, or 2 atoms selected from O and S; R.sup.2 is halo or a group —Y—R.sup.13, wherein Y is —C.sub.0-4alk-, —N(C.sub.0-1alk)-C.sub.0-4alk-, —C(═O)NR.sup.aR.sup.a(C.sub.1-4alk), —O—C.sub.0-4alk-, S, S═O, S(═O).sub.2, —SO.sub.2NR.sup.13, or —S(═O)(═NH)—; R.sup.3 is H, C.sub.1-4alk, or C.sub.1-4haloalk; R.sup.4 is H, halo, R.sup.4a or R.sup.4b; R.sup.5 is H, halo, C.sub.1-8alk, or C.sub.1-4haloalk; R.sup.6 is H, halo, C.sub.1-8alk, C.sub.1-4haloalk, —O—C.sub.1-8alk, or —O—R.sup.6a; wherein R.sup.6a is a saturated or partially-saturated 3-, 4-, 5-, or 6-membered monocyclic ring containing 0, 1, 2 or 3 N atoms and 0, 1, or 2 atoms selected from O and S; R.sup.7 is H, halo, C.sub.1-8alk, or C.sub.1-4haloalk; R.sup.8 is H, halo, C.sub.1-8alk, C.sub.1-4haloalk, —OH, —O—R.sup.8a, or —O—R.sup.8b; R.sup.9 is H, halo, C.sub.1-8alk, or C.sub.1-4haloalk; R.sup.x is selected from the group consisting of ##STR00308## Each of R.sup.10a, R.sup.10b, R.sup.10c, R.sup.10d, R.sup.10e, R.sup.10f, R.sup.10g, R.sup.10h, R.sup.10i, and R.sup.10j is H, halo, R.sup.10k, or R.sup.10l; or alternatively, each of R.sup.10a and R.sup.10b pair, R.sup.10c and R.sup.10d pair, R.sup.10e and R.sup.10f pair, R.sup.10g and R.sup.10h pair, or R.sup.10i and R.sup.10j pair, independently, can combine with the carbon atom attached to each of them to form a saturated or partially-saturated 3-, 4-, 5-, 6-membered monocyclic ring spiro to the R.sup.x ring; wherein said 3-, 4-, 5-, 6-membered monocyclic ring contains 0, 1, 2 or 3 N atoms and 0, 1, or 2 atoms selected from O and S, and further wherein said 3-, 4-, 5-, 6-membered monocyclic ring is substituted by 0, 1, 2 or 3 group(s) selected from F, Cl, Br, C.sub.1-6alk, C.sub.1-4haloalk, —OR.sup.a, —OC.sub.1-4haloalk, CN, —NR.sup.aR.sup.a, or oxo; R.sup.11 is H, R.sup.11a, or R.sup.11b; R.sup.12 is H, R.sup.12a, or R.sup.12b; R.sup.13 is R.sup.13a or R.sup.13b; R.sup.4a, R.sup.8a, R.sup.10k, R.sup.11a, R.sup.12a, and R.sup.13a is independently, at each instance, selected from the group consisting of a saturated, partially-saturated or unsaturated 3-, 4-, 5-, 6-, or 7-membered monocyclic or 4-, 5-, 6-, 7-, 8-, 9-, 10-, 11-, or 12-membered bicyclic ring containing 0, 1, 2 or 3 N atoms and 0, 1, or 2 atoms selected from O and S, which is substituted by 0, 1, 2 or 3 group(s) selected from F, Cl, Br, C.sub.1-6alk, C.sub.1-4haloalk, —OR.sup.a, —OC.sub.1-4haloalk, CN, —C(═O)R.sup.b, —C(═O)OR.sup.a, —C(═O)NR.sup.aR.sup.a, —C(═NR.sup.a)NR.sup.aR.sup.a, —OC(═O)R.sup.b, —OC(═O)NR.sup.aR.sup.a, —OC.sub.2-6alkNR.sup.aR.sup.a, —OC.sub.2-6alkOR.sup.a, —SR.sup.a, —S(═O)R.sup.b, —S(═O).sub.2R.sup.b, —S(═O).sub.2NR.sup.aR.sup.a, —NR.sup.aR.sup.a, —N(R.sup.a)C(═O)R.sup.b, —N(R.sup.a)C(═O)OR.sup.b, —N(R.sup.a)C(═O)NR.sup.aR.sup.a, —N(R.sup.a) C(═NR.sup.a)NR.sup.aR.sup.a, —N(R.sup.a)S(═O).sub.2R.sup.b, —N(R.sup.a)S(═O).sub.2NR.sup.aR.sup.a, —NR.sup.aC.sub.2-6alkNR.sup.aR.sup.a, —NR.sup.aC.sub.2-6alkOR.sup.a, —C.sub.1-6alkNR.sup.aR.sup.a, —C.sub.1-6alkOR.sup.a, —C.sub.1-6alkN(R.sup.a)C(═O)R.sup.b, —C.sub.1-6alkOC(═O)R.sup.b, —C.sub.1-6alkC(═O)NR.sup.aR.sup.a, —C.sub.1-6alkC(═O)OR.sup.a, R.sup.14, and oxo; R.sup.4b, R.sup.8b, R.sup.10l, R.sup.11b, R.sup.12b, and R.sup.13b is independently, at each instance, selected from the group consisting of C.sub.1-6alk substituted by 0, 1, 2, 3, 4, or 5 group(s) selected from F, Cl, Br, —OR.sup.a, —OC.sub.1-4haloalk, or CN; R.sup.14 is independently, at each instance, selected from the group consisting of a saturated, partially-saturated or unsaturated 3-, 4-, 5-, 6-, or 7-membered monocyclic or 4-, 5-, 6-, 7-, 8-, 9-, 10-, 11-, or 12-membered bicyclic ring containing 0, 1, 2 or 3 N atoms and 0 or 1 atoms selected from O and S, which is substituted by 0, 1, 2 or 3 group(s) selected from F, Cl, Br, C.sub.1-6alk, C.sub.1-4haloalk, —OR.sup.a, —OC.sub.1-4haloalk, CN, —C(═O)R.sup.b, —C(═O)OR.sup.a, —C(═O)NR.sup.aR.sup.a, —C(═NR.sup.a)NR.sup.aR.sup.a, —OC(═O)R.sup.b, —OC(═O)NR.sup.aR.sup.a, —OC.sub.2-6alkNR.sup.aR.sup.a, —OC.sub.2-6alkOR.sup.a, —SR.sup.a, —S(═O)R.sup.b, —S(═O).sub.2R.sup.b, —S(═O).sub.2NR.sup.aR.sup.a, —NR.sup.aR.sup.a, —N(R.sup.a)C(═O)R.sup.b, —N(R.sup.a)C(═O)OR.sup.b, —N(R.sup.a)C(═O)NR.sup.aR.sup.a, —N(R.sup.a)C(═NR.sup.a)NR.sup.aR.sup.a, —N(R.sup.a)S(═O).sub.2R.sup.b, —N(R.sup.a)S(═O).sub.2NR.sup.aR.sup.a, —NR.sup.aC.sub.2-6alkNR.sup.aR.sup.a, —NR.sup.aC.sub.2-6alkOR.sup.a, —C.sub.1-6alkNR.sup.aR.sup.a, —C.sub.1-6alkOR.sup.a, —C.sub.1-6alkN(R.sup.a)C(═O)R.sup.b, —C.sub.1-6alkOC(═O)R.sup.b, —C.sub.1-6alkC(═O)NR.sup.aR.sup.a, —C.sub.1-6alkC(═O)OR.sup.a, and oxo; R.sup.a is independently, at each instance, H or R.sup.b; and R.sup.b is independently, at each instance, C.sub.1-6alk, phenyl, or benzyl, wherein the C.sub.1-6alk is being substituted by 0, 1, 2 or 3 substituents selected from halo, —OH, —OC.sub.1-4alk, —NH.sub.2, —NHC.sub.1-4alk, —OC(═O)C.sub.1-4alk, or —N(C.sub.1-4alk)C.sub.1-4alk; and the phenyl or benzyl is being substituted by 0, 1, 2 or 3 substituents selected from halo, C.sub.1-4alk, C.sub.1-3haloalk, —OH, —OC.sub.1-4alk, —NH.sub.2, —NHC.sub.1-4alk, —OC(═O)C.sub.1-4alk, or —N(C.sub.1-4alk)C.sub.1-4alk.

2. The compound of claim 1, or the pharmaceutically-acceptable salt thereof, wherein X.sup.1 is N; having the formula (Ia): ##STR00309##

3. The compound of claim 1, or the pharmaceutically-acceptable salt thereof, wherein X.sup.1 is —CR.sup.6; having the formula (Ib): ##STR00310##

4. The compound of claim 1, or the pharmaceutically-acceptable salt thereof, wherein R.sup.3 is H or methyl.

5. The compound of any one of claims 1 to 4, or the pharmaceutically-acceptable salt thereof, wherein each of R.sup.10c, R.sup.10d, R.sup.10e, R.sup.10f, R.sup.10g, R.sup.10h, R.sup.10i, and R.sup.10j is H, halo, C.sub.1-6alk, or C.sub.1-4haloalk; and each of R.sup.10a and R.sup.10b pair combine with the carbon atom attached to each of them form a saturated 3-, 4-, or 5-membered monocyclic ring spiro to the R.sup.x ring; wherein said ring contains 0, 1, 2 or 3 N atoms and 0, 1, or 2 atoms selected from O and S.

6. The compound of claim 1, or the pharmaceutically-acceptable salt thereof, wherein each of R.sup.10c, R.sup.10d, R.sup.10e, R.sup.10f, R.sup.10g, R.sup.10h, R.sup.10i, and R.sup.10j is H, methyl, or ethyl; and each of R.sup.10a and R.sup.10b pair combine with the carbon atom attached to each of them form a cyclopropyl, cyclobutyl, or cyclopentyl ring spiro to the R.sup.x ring.

7. The compound of claim 1, or the pharmaceutically-acceptable salt thereof, wherein the group ##STR00311## is selected from: ##STR00312##

8. The compound of claim 1, or the pharmaceutically-acceptable salt thereof, wherein the group ##STR00313##

9. The compound of claim 1, or the pharmaceutically-acceptable salt thereof, wherein R.sup.1 is —CN, or a group —Z—R.sup.12, wherein Z is a bond, —NH—, —NHSO.sub.2—, —SO.sub.2NH—, —S(═O)(═NH)—, —S—, —S(═O)—, —SO.sub.2—, —(C═O)—, —(C═O)NH—, or —NH(C═O)—; and R.sup.12 is selected from: (a) H; (b) cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxiranyl, oxetanyl, tetrahydrofuranyl, azetidinyl, imidazolyl, morpholinyl, pyrrolidinyl, piperazinyl, ##STR00314## wherein each said ring is substituted by 0, 1, 2 or 3 group(s) selected from wherein each ring is substituted by 0, 1, 2 or 3 OH, F, methyl, —CH.sub.2OH, —C(═O)OCH.sub.3, —C(═O)OC(CH.sub.3).sub.3, NH.sub.2, CN, and oxo; or (c) C.sub.1-6alk substituted by 0, 1, 2 or 3 OH, F, —C(═O)OCH.sub.3, —NH.sub.2, —NH(CH.sub.3), or —N(CH.sub.3).sub.2.

10. The compound of claim 1, or the pharmaceutically-acceptable salt thereof, wherein R.sup.1 is —CN, or a group —Z—R.sup.12, wherein Z is a bond, —NH—, —NHSO.sub.2—, —SO.sub.2NH—, —S(═O)(═NH)—, —S—, —S(═O)—, —SO.sub.2—, —(C═O)—, —(C═O)NH—, or —NH(C═O)—; and (a) R.sup.12 is H; (b) R.sup.12 is oxetanyl, cyclopropyl; or (c) R.sup.12 is C.sub.1-6alk substituted by 0, 1, 2 or 3 OH group(s).

11. The compound of claim 1, or the pharmaceutically-acceptable salt thereof, wherein the group —Z—R.sup.12 is —N═S(═O)—(R.sup.12).sub.2, wherein the two R.sup.12 pair can alternatively combine with the sulfur atom attached to each of them to form a saturated or partially-saturated 3-, 4-, 5-, or 6-membered monocyclic ring containing 0, 1, 2 or 3 N atoms and 0, 1, or 2 atoms selected from O and S; which is selected from: ##STR00315##

12. The compound of claim 1, or the pharmaceutically-acceptable salt thereof, wherein R.sup.1 is a group —Z—R.sup.12, wherein Z is —NHSO.sub.2— or —SO.sub.2NH—; and R.sup.12 is oxetanyl, cyclopropyl, or R.sup.12 is C.sub.1-6alk substituted by 0, 1, 2 or 3 OH group(s).

13. The compound of claim 1, or the pharmaceutically-acceptable salt thereof, wherein R.sup.1 is a group —Z—R.sup.12, wherein Z is —NHSO.sub.2— and R.sup.12 is —CH.sub.2—CH.sub.2—OH.

14. The compound of claim 1, or the pharmaceutically-acceptable salt thereof, wherein R.sup.2 is halo or a group —Y—R.sup.13, wherein Y is a bond, —NH—, —NH—(CH.sub.2).sub.0-4—, or —O—(CH.sub.2).sub.0-4; and R.sup.13 is a saturated, partially-saturated or unsaturated 3-, 4-, 5-, 6-, or 7-membered monocyclic or 4-, 5-, 6-, 7-, 8-, 9-, 10-, 11-, or 12-membered bicyclic ring containing 0, 1, 2 or 3 N atoms and 0 or 1 atoms selected from O and S, which is substituted by 0, 1, 2 or 3 group(s) selected from F, Cl, Br, C.sub.1-6alk, C.sub.1-4haloalk, —OH, —OC.sub.1-4haloalk, CN, R.sup.14, and oxo; or R.sup.13 is C.sub.1-6alk substituted by 0, 1, 2, 3, 4, or 5 group(s) selected from F, Cl, Br, —OH, —OC.sub.1-4haloalk, or CN.

15. The compound of claim 1, or the pharmaceutically-acceptable salt thereof, wherein R.sup.2 is a saturated 5- or 6-membered monocyclic ring wherein each said ring contains 0, 1, or 2 N atoms and 0 or 1 O atom, and wherein each said ring is substituted by 0, 1, 2 or 3 group(s) selected from F, Cl, Br, C.sub.1-6alk, C.sub.1-4haloalk, —OH, —OC.sub.1-4haloalk, CN, R.sup.14, and oxo.

16. The compound of claim 1, or the pharmaceutically-acceptable salt thereof, wherein R.sup.2 is (a) halo; (b) a group —Y—R.sup.13, wherein Y is a bond; and R.sup.13 is morpholinyl, piperidinyl, azetidinyl, pyrrolidinyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, piperazinyl, tetrahydrofuranyl, ##STR00316## ##STR00317## wherein each said ring is substituted by 0, 1, 2 or 3 group(s) selected from F, Cl, Br, methyl, CF.sub.3, —OH, —OCHF.sub.2, CN, and oxo; or (c) a group —Y—R.sup.13, wherein Y is NH, —O—, —O—(CH.sub.2)—, —O—(CH.sub.2)—(CH.sub.2)—, or —O—(CH.sub.2)—(CH.sub.2)—(CH.sub.2)—, and wherein R.sup.13 is ##STR00318## or R.sup.13 is C.sub.1-6alk substituted by 0, 1, 2, 3, 4, or 5 group(s) selected from F, Cl, Br, methyl, CF.sub.3J—OH, or CN.

17. The compound of claim 1, or the pharmaceutically-acceptable salt thereof, wherein R.sup.2 is morpholinyl or piperidinyl substituted by 0, 1, 2 or 3 group(s) selected from F, Cl, Br, methyl, CF.sub.3, —OH, —OCHF.sub.2, CN, or oxo.

18. The compound of claim 17, or the pharmaceutically-acceptable salt thereof, of any one of claims 1-4, or the pharmaceutically-acceptable salt thereof, wherein R.sup.2 is morpholinyl substituted by 1, 2 or 3 methyl group(s).

19. The compound of claim 17, or the pharmaceutically-acceptable salt thereof, wherein R.sup.2 is piperidinyl substituted by 1, 2 or 3 fluoro group(s).

20. The compound of claim 1, or the pharmaceutically-acceptable salt thereof, wherein R.sup.2 is ##STR00319##

21. The compound of claim 1, or the pharmaceutically-acceptable salt thereof, wherein Z is a bond, —NH—, —NHSO.sub.2—, —SO.sub.2NH—, —S(═O)(═NH)—, —S—, —S(═O)—, —SO.sub.2—, —(C═O)—, —(C═O)NH—, or —NH(C═O)—.

22. The compound of claim 1, or the pharmaceutically-acceptable salt thereof, wherein R.sup.12 is selected from (a) H; (b) C.sub.1-6alk substituted by 0, 1, 2 or 3 group(s) selected from F, Cl, Br, —OH, —OCH.sub.3, or cyclopropyl; or (c) a saturated, partially-saturated or unsaturated 3-, 4-, 5-, 6-, or 7-membered monocyclic ring containing 0, 1, 2 or 3 N atoms and 0 or 1 atoms selected from O and S, which is substituted by 0, 1, 2 or 3 group(s) selected from F, Cl, Br, C.sub.1-6alk, C.sub.1-4haloalk, —C.sub.1-6alkOH, —OH, —OCH.sub.3, —NH.sub.2, or oxo.

23. The compound of claim 22, or the pharmaceutically-acceptable salt thereof, wherein R.sup.12 is selected from cyclopropyl, cyclobutyl, cyclopentyl, oxetanyl, azetidinyl, tetrahydrofuranyl, or 1,3,4-oxathiazinanyl.

24. The compound of claim 1, or the pharmaceutically-acceptable salt thereof, wherein R.sup.4 is selected from (a) H; (b) C.sub.1-6alk substituted by 0, 1, 2 or 3 OH group(s); or (c) cyclopropyl.

25. The compound of claim 24, or the pharmaceutically-acceptable salt thereof, wherein R.sup.4 is H or methyl.

26. The compound of claim 1, or the pharmaceutically-acceptable salt thereof, wherein R.sup.5 is H.

27. The compound of claim 1, or the pharmaceutically-acceptable salt thereof, wherein R.sup.6 is H or F.

28. The compound of claim 1, or the pharmaceutically-acceptable salt thereof, wherein R.sup.7 is H or F.

29. The compound of claim 1, or the pharmaceutically-acceptable salt thereof, wherein R.sup.8 is H.

30. The compound of claim 1, or the pharmaceutically-acceptable salt thereof, wherein R.sup.9 is H.

31. A compound of claim 1, selected from the group consisting of: TABLE-US-00017 Ex. # Chemical Structure Name 1  N-(2-((1-Hydroxy-2- methylpropan-2-yl)amino)-6- methylpyrimidin-4-yl)-4- (methylsulfonyl)-2-(6- azaspiro[2.5]octan-6-yl)benzamide  1-7 N-(2-((1-hydroxy-2-methylpropan- 2-yl)amino)-6-methylpyrimidin-4- yl)-4-(N-(3-methyloxetan-3- yl)sulfamoyl)-2-(6- azaspiro[2.5]octan-6-yl)benzamide 2  N-(2-(2-Hydroxypropan-2- yl)pyrimidin-4-yl)-4-(N-(3- methyloxetan-3-yl)sulfamoyl)-2- (6-azaspiro[2,5]octan-6- yl)benzamide  2-4 N-(2-(4,4-Difluoropiperidin-1- yl)pyridin-4-yl)-4-(N-(3- methyloxetan-3-yl)sulfamoyl)-2- (6-azaspiro[2.5]octan-6- yl)benzamide  2-8 N-(2-(4,4-Difluoropiperidin-1-yl)- 6-methylpyrimidin-4-yl)-4-((1- methylcyclopropane)-1- sulfonamido)-2-(6- azaspiro[2.5]octan-6-yl)benzamide 3  (R)-4-((2- Hydroxyethyl)sulfonamido)-N-(6- methyl-2-(2- methylmorpholino)pyrimidin-4- yl)-2-(6-azaspiro[2.5]octan-6- yl)benzamide 4  N-(2-(4,4-Difluoropiperidin-1-yl)- 6-methylpyrimidin-4-yl)-4-((2- hydroxyethyl)sulfonamido)-2-(6- azaspiro[2.5]octan-6-yl)benzamide  5-1 (R)-N-(2-(4,4-Difluoropiperidin-1- yl)-6-methylpyrimidin-4-yl)-4-((2- hydroxy-1- methylethyl)sulfonamido)-2-(6- azaspiro[2.5]octan-6-yl)benzamide  5-2 (S)-N-(2-(4,4-Difluoropiperidin-1- yl)-6-methylpyrimidin-4-yl)-4-((2- hydroxy-1- methylethyl)sulfonamido)-2-(6- azaspiro[2.5]octan-6-yl)benzamide  6-7 N-(2-(4,4-Difluoropiperidin-1-yl)- 6-methylpyrimidin-4-yl)-4- (ethylsulfonamido)-2-(6- azaspiro[2.5]octan-6-yl)benzamide 7  N-(2-(3,3-Difluoroazetidin-1-yl)-6- methylpyrimidin-4-yl)-4-((2- hydroxyethyl)sulfonamido)-2-(6- azaspiro[2.5]octan-6-yl)benzamide  8-1 (R)-N-(2-(4,4-Difluoropiperidin-1- yl)-6-methylpyrimidin-4-yl)-5- fluoro-4-((2-hydroxy-1- methylethyl)sulfonamido)-2-(6- azaspiro[2.5]octan-6-yl)benzamide  8-2 (S)-N-(2-(4,4-Difluoropiperidin-1- yl)-6-methylpyrimidin-4-yl)-5- fluoro-4-((2-hydroxy-1- methylethyl)sulfonamido)-2-(6- azaspiro[2.5]octan-6-yl)bcnzamide 10-1 (R)-N-(2-(3,3-Difluoroazetidin-1- yl)-6-methylpyrimidin-4-yl)-4-((2- hydroxypropyl)sulfonamido)-2-(6- azaspiro[2.5]octan-6-yl)benzamide 10-2 (S)-N-(2-(3,3-Difluoroazetidin-1- yl)-6-methylpyrimidin-4-yl)-4-((2- hydroxypropyl)sulfonamido)-2-(6- azaspiro[2.5]octan-6-yl)benzamide 12  N-(2-(4,4-difluoropiperidin-1-yl)- 6-methylpyrimidin-4-yl)-4-((2- hydroxyethyl)sulfonyl)-2-(6- azaspiro[2.5]octan-6-yl)benzamide 13-1 (S)-N-(2-(4,4-Difluoropiperidin-1- yl)-6-methylpyrimidin-4-yl)-4-((1- hydroxypropan-2-yl)sulfonyl)-2- (6-azaspiro[2.5]octan-6- yl)benzamide 13-2 (R)-N-(2-(4,4-Difluoropiperidin-1- yl)-6-methylpyrimidin-4-yl)-4-((1- hydroxypropan-2-yl)sulfonyl)-2- (6-azaspiro[2.5]octan-6- yl)benzamide 14  N-(2-(4,4-Difluoropiperidin-1-yl)- 6-methylpyrimidin-4-yl)-4-((1- hydroxy-2-methylpropan-2- yl)sulfonyl)-2-(6- azaspiro[2.5]octan-6-yl)benzamide 15  N-(2-(4,4-Difluorocyclohexyl)-6- methylpyrimidin-4-yl)-4-((2- hydroxyethyl)sulfonamido)-2-(6- azaspiro[2.5]octan-6-yl)benzamide 16-1 (R)-N-(2-(4,4-Difluoropiperidin-1- yl)-6-methylpyrimidin-4-yl)-4-((2- fluoro-1- (hydroxymethyl)ethyl)sulfona- mido)-2-(6-azaspiro[2.5]octan-6- yl)benzamide 16-2 (S)-N-(2-(4,4-Difluoropiperidin-1- yl)-6-methylpyrimidin-4-yl)-4-((2- fluoro-1- (hydroxymethyl)ethyl)sulfona- mido)-2-(6-azaspiro[2.5]octan-6- yl)benzamide 17  N-(2-(4,4-Difluoropiperidin-1- yl)pyridin-4-yl)-4-(N-(2- hydroxyethyl)sulfamoyl)-2-(6- azaspiro[2.5]octan-6-yl)benzamide 18-1 2-(6-Azaspiro[2.5]octan-6-yl)-4- (R-cyclopropylsulfommidoyl)-N- (2-(4,4-difluoro-1-piperidinyl)-6- methyl-4-pyrimidinyl)benzamide 18-2 2-(6-Azaspiro[2.5]octan-6-yl)-4- (S-cyclopropylsulfonimidoyl)-N- (2-(4,4-difluoro-1-piperidinyl)-6- methyl-4-pyrimidinyl)benzamide 20  (N.sup.1-(2-(4,4-Difluoropiperidin-1- yl)-6-methylpyrimidin-4-yl)-2-(6- azaspiro[2.5]octan-6- yl)terephthalamide 21  4-(Azetidin-3-ylsulfonyl)-N-(2- (4,4-difluoropiperidin-1-yl)-6- methylpyrimidin-4-yl)-2-(6- azaspiro[2.5]octan-6-yl)benzamide 22  N-(2-(4,4-difluoropiperidin-1-yl)- 6-methylpyrimidin-4-yl)-4-((1- methylazetidin-3-yl)sulfonyl)-2- (6-azaspiro[2.5]octan-6- yl)benzamide; or any pharmaceutically-acceptable salt thereof.

32. A pharmaceutical composition comprising the compound according to claim 1, or the pharmaceutically acceptable salt thereof, and a pharmaceutically-acceptable diluent or carrier.

33. A method of treating a condition that may be treated with KIF18a inhibitors, the method comprising administering to a patient in need thereof a therapeutically effective amount of the compound in accordance with claim 1, or the composition according to claim 32.

34. The method of claim 33, wherein said condition is cancer selected from the group consisting of (a) a solid or hematologically derived tumor selected from cancer of the bladder, endometrial, lung squamous cell, breast, colon, kidney, liver, lung, small cell lung cancer, esophagus, gall-bladder, brain, head and neck, ovary, pancreas, stomach, cervix, thyroid, prostate and skin, (b) a hematopoietic tumor of lymphoid lineage selected from leukemia, acute lymphocitic leukemia, acute lymphoblastic leukemia, B-cell lymphoma, T-cell-lymphoma, Hodgkin's lymphoma, non-Hodgkin's lymphoma, hairy cell lymphoma and Burkett's lymphoma, (c) a hematopoietic tumor of myeloid lineage selected from acute and chronic myelogenous leukemias, myelodysplastic syndrome and promyelocytic leukemia (d) a tumor of mesenchymal origin selected from fibrosarcoma and rhabdomyosarcoma, (e) a tumor of the central and peripheral nervous system selected from astrocytoma, neuroblastoma, glioma and schwannoma, or (f) a melanoma, seminoma, teratocarcinoma, osteosarcoma, xeroderma pigmentosum, keratoactanthoma, thyroid follicular cancer or Kaposi's sarcoma.

35. A method of reducing the size of a solid tumor in a subject, the method comprising administering to the subject in need thereof a therapeutically effective amount of the compound in accordance with claim 1, or the pharmaceutically acceptable salt thereof, or the composition according to claim 32.

36. A method of treating a cell proliferation disorder in a subject, the method comprising administering to the subject in need thereof a therapeutically effective amount of the compound in accordance with claim 1, or the pharmaceutically acceptable salt thereof, or the composition according to claim 32.

37. A method of inhibiting KIF18A in a cell, comprising contacting the cell with a compound, or pharmaceutically acceptable salts thereof, in accordance with claim 1, or the pharmaceutically acceptable salt thereof, or the composition according to claim 32.

Description

EXAMPLES

Preparation of Synthetic Intermediates

Ring Ar.SUP.1 .Intermediates

Intermediate 1: (R)-2-(2-Methylmorpholino)pyrimidin-4-amine

[0237] ##STR00062##

[0238] A mixture of 2-chloropyrimidin-4-amine (60.0 g, 463 mmol, Combi-Blocks, San Diego, Calif.), (R)-2-methylmorpholine (65.6 g, 648 mmol, Wuxi Apptec) and DIPEA (243 mL, 1389 mmol) in NMP (600 mL) was taken in an autoclave and heated at 150° C. for 36 h. The reaction mixture was cooled to room temperature and quenched with water (1 L) and extracted with ethyl acetate (3×500 mL). The organic layer was washed with brine solution (500 mL), dried (Na.sub.2SO.sub.4), filtered and concentrated under reduced pressure to give the crude material as a tan oil. The crude material was adsorbed onto a plug of silica gel and purified by column chromatography over silica gel (60-120 mesh), eluting with a gradient of 50% to 100% ethyl acetate in hexanes to give a yellow solid. This solid was further triturated with hexanes (300 mL), filtered and dried under vacuum to give the title compound (70 g, 78% yield) as a pale yellow solid. .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ ppm 7.75 (d, J=5.6 Hz, 1H), 6.42 (s, 2H), 5.75 (d, J=5.6 Hz, 1H), 4.26-4.49 (m, 2H), 3.83 (ddd, J=11.4, 3.6, 1.4 Hz, 1H), 3.31-3.50 (m, 2H), 2.78 (ddd, J=13.2, 11.8, 3.5 Hz, 1H), 2.42-2.48 (m, 1H), 1.11 (d, J=6.2 Hz, 3H). m/z (ESI): 195.2 (M+H).sup.+.

Intermediate 2: (R)-6-Methyl-2-(2-methylmorpholino)pyrimidin-4-amine

[0239] ##STR00063##

[0240] A mixture of 2-chloro-6-methylpyrimidin-4-amine (30.0 g, 209 mmol, Combi-Blocks, San Diego, Calif.), (R)-2-methylmorpholine (40.3 g, 293 mmol, Wuxi Apptec, PR China), and DIPEA (109 mL, 627 mmol) was taken in an autoclave (600 mL) and heated at 150° C. for 12 h. The reaction mixture was quenched with water (500 mL) and extracted with ethyl acetate (2×1500 mL). The organic layer was washed with brine solution (500 mL), dried (Na.sub.2SO.sub.4), filtered and concentrated under reduced pressure. The crude residue was purified by column chromatography over silica gel (60-120 mesh) using 50% ethyl acetate in hexanes as an eluent to give the title compound (25.0 g, 57% yield) as a yellow solid. .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 6.28 (s, 2H), 5.62 (s, 1H), 4.45-4.31 (m, 2H), 3.83 (ddd, J=11.4, 3.5, 1.3 Hz, 1H), 3.42 (ddt, J=14.4, 9.7, 2.8 Hz, 2H), 2.78-2.70 (m, 1H), 2.43 (dd, J=13.0, 10.3 Hz, 1H), 2.05 (s, 3H), 1.11 (d, J=6.2 Hz, 3H). m/z (ESI): 209.2 (M+H).sup.+.

Intermediate 3: 2-(4,4-Difluoropiperidin-1-yl)pyrimidin-4-amine

[0241] ##STR00064##

[0242] A glass microwave reaction vessel was successively charged with 2-chloro-4-aminopyrimidine (1.0 g, 7.7 mmol, Combi-Blocks, San Diego, Calif.), 4,4-difluoropiperidine hydrochloride (1.82 g, 11.58 mmol, Combi-Blocks, San Diego, Calif.) and DIPEA (4.04 mL, 23.2 mmol) in NMP (12 mL). The reaction mixture was stirred and heated in a microwave at 200° C. for 1 h. Reaction mixture was diluted with water (50 mL), extracted with ethyl acetate (30×2 mL). The organic extract was washed with brine (30×mL), dried over Na.sub.2SO.sub.4, concentrated in vacuo to give the crude material as a brownish sticky liquid. The crude material was absorbed onto a plug of silica gel and purified by flash chromatography through a Redi-Sep pre-packed silica gel column (40 g), eluting with 0% to 100% ethyl acetate in heptane to provide the title compound as an off-white solid (6.02 g, 91%). .sup.1H NMR (300 MHz, DMSO-d.sub.6) δ ppm 7.21 (d, J=5.6 Hz, 1H), 6.46 (br s, 2H), 5.77 (d, J=5.6 Hz, 1H), 3.80 (t, J=5.6 Hz, 4H), 1.85-1.90 (m, 4H). m/z (ESI): 215.2 (M+H).sup.+.

Intermediate 4: 2-(4,4-Difluoropiperidin-1-yl)-6-methylpyrimidin-4-amine

[0243] ##STR00065##

[0244] A mixture of 2-chloro-6-methylpyrimidin-4-amine (46 g, 320 mmol, Combi-Blocks, San Diego, Calif.), 4,4-difluoropiperidine hydrochloride (76 g, 481 mmol, Combi-Blocks, San Diego, Calif.) and DIPEA (166 mL, 961 mmol) in NMP (460 mL, 10.00 mL/g) was taken in an autoclave (1 L) and heated at 180° C. for 30 h. The reaction mixture was cooled to room temperature and quenched with water (500 mL), extracted with ethyl acetate (2×1000 mL). The organic layer was washed with brine (500 mL), dried (Na.sub.2SO.sub.4), filtered and concentrated under reduced pressure. The crude material was adsorbed onto a plug of silica gel and purified by column chromatography over silica gel (60-120 mesh), eluting with 50% to 100% ethyl acetate in hexanes as an eluent to give the product. This was re-dissolved in ethyl acetate (500 mL), washed with water (2×500 mL). The organic layer was dried (Na.sub.2SO.sub.4), filtered and concentrated under reduced pressure. The yellow solid was once again suspended in hexanes (400 mL) and stirred for 30 min. The slurry was filtered, washed with hexanes (100 mL), dried under vacuum to provide the title compound (58 g, 79% yield) as a pale yellow solid. .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ ppm 6.33 (s, 2H), 5.63 (s, 1H), 3.80-3.78 (dd, J=6.8, 4.7 Hz, 4H), 2.06 (s, 3H), 1.95-1.85 (tt, J=14.2, 5.7 Hz, 4H). m/z (ESI): 229.2 (M+H).sup.+.

Intermediate 5: 2-(3,3-Difluoroazetidin-1-yl)pyrimidin-4-amine

[0245] ##STR00066##

[0246] A mixture of 2-chloro-4-aminopyrimidine (5.0 g, 38.6 mmol, Combi-Blocks, San Diego, Calif.), 3,3-difluoroazetidine hydrochloride (7.50 g, 57.9 mmol, Combi-Blocks, San Diego, Calif.) and potassium carbonate (5.33 g, 38.6 mmol) in dioxane (25 mL) was heated at 95° C. for 16 h. The reaction mixture was cooled to room temperature and the suspension was filtered. The crude material was absorbed onto a plug of silica gel and purified by flash chromatography through a Redi-Sep pre-packed silica gel column (40 g), eluting with 10% MeOH in DCM to provide the title compound as light brown solid (6.1 g, 85%). .sup.1H NMR (300 MHz, DMSO-d.sub.6) δ ppm 8.29-8.66 (m, 2H), 7.81 (d, J=7.05 Hz, 1H), 6.22 (d, J=7.26 Hz, 1H), 4.61 (t, J=12.23 Hz, 4H). m/z (ESI): 187.2 (M+H).sup.+.

Intermediate 6: 2-(4,4-Difluorocyclohexyl)-6-methylpyrimidin-4-amine

[0247] ##STR00067##

[0248] Step 1: To a solution of 2-chloro-6-methylpyrimidin-4-amine (70.0 g, 488 mmol, Combi-Blocks, San Diego, Calif.) in 1,4-dioxane (560 mL) and water (210 mL) were added 2-(4,4-difluorocyclohex-1-en-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (119 g, 488 mmol, Combi-Blocks, San Diego, Calif.) and potassium phosphate tribasic (310 g, 1463 mmol). The reaction mixture was degassed and purged with nitrogen for 5 min. PdCl.sub.2(dppf)-DCM adduct (39.8 g, 48.8 mmol) was added to the reaction mixture and stirred at 100° C. for 16 h. The dark heterogeneous mixture was filtered through a CELITE® bed and the filter cake was washed with ethyl acetate (2×1000 mL). The filtrate was washed with 1N NaOH solution (300 mL), followed by water (500 mL). The organic layer was dried (Na.sub.2SO.sub.4), filtered and concentrated under reduced pressure. The crude residue was adsorbed onto a plug of silica gel and purified by column chromatography over silica gel (60-120 mesh), eluting with a gradient of 50% to 60% ethyl acetate in hexanes, to give 2-(4,4-difluorocyclohex-1-en-1-yl)-6-methylpyrimidin-4-amine (70 g, 64% yield) as a pale yellow solid. .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ ppm 6.85 (br s, 1H), 6.59 (br s, 2H), 6.13 (s, 1H), 2.62-2.80 (m, 4H), 2.19 (s, 3H), 2.04-2.17 (m, 2H). m/z (ESI): 226.2 (M+H).sup.+.

[0249] Step 2: To a solution of 2-(4,4-difluorocyclohex-1-en-1-yl)-6-methylpyrimidin-4-amine (70.0 g, 311 mmol) in EtOH (700 mL) was added 10% Pd on carbon (33.1 g, 155 mmol) under nitrogen. The reaction mixture was stirred at room temperature under hydrogen pressure (1 atm) for 16 h. The reaction mixture was filtered through a CELITE® bed and washed with a mixture of ethyl acetate and ethanol (1:1, 500 mL). The filtrate was concentrated under reduced pressure. The crude product was purified by column chromatography over silica gel (60-120 mesh) using 50% ethyl acetate in hexanes to give the title compound (58.5 g, 83% yield) as an off white solid. .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ ppm 6.61 (s, 2H), 6.09 (s, 1H), 2.56-2.67 (m, 1H), 2.16 (s, 3H), 1.72-2.10 (m, 8H). m/z (ESI): 228.1 (M+H).sup.+.

Intermediate 7: 2-Methyl-6-(3,3,3-trifluoropropoxy)pyridin-4-amine

[0250] ##STR00068##

[0251] To a solution of 3,3,3-trifluoropropan-1-ol (1.99 g, 17.44 mmol, Combi-Blocks) in 30 mL of THF at 0° C. was added sodium hydride (60% wt. in mineral oil, 0.79 g, 19.82 mmol). The mixture was stirred at RT for 30 min then treated with 2-fluoro-6-methylpyridin-4-amine (1.00 g, 7.93 mmol, AstaTech Inc). The mixture was heated at 65° C. in an oil bath for 5 h. It was cooled to RT, quenched with water (10 mL) and extracted with EtOAc (2×50 mL). The organic solution was dried over Na.sub.2SO.sub.4, filtered and concentrated in vacuo to give the crude material as a yellow oil. The crude material was absorbed onto a plug of silica gel and purified on a silica gel column (15% to 30% EtOAc in heptane) to give 2-methyl-6-(3,3,3-trifluoropropoxy)pyridin-4-amine (0.47 g, 2.13 mmol, 27% yield) as a light-yellow oil. m/z (ESI): 221.1 (M+H).sup.+.

TABLE-US-00003 TABLE 1 The intermediate below was prepared following a similar procedure for Intermediate 7: LRMS: (ESI + ve Int. # Chemical Structure Name ion) m/z 7-1 [00069] 6-Methyl-2-(3,3,3- trifluoropropoxy)pyrimidin-4-amine 222.0

Intermediate 8: 2-(4,4-Difluoropiperidin-1-yl)pyridin-4-amine

[0252] ##STR00070##

[0253] A mixture of 2-chloropyridin-4-amine (2.00 g, 15.56 mmol, Combi Blocks), DIPEA (6.03 g, 46.70 mmol, Sigma-Aldrich) and 4,4-difluoropiperidin (2.45 g, 20.22 mmol, Enamine) in NMP (6 mL) was heated in a microwave at 200° C. for 6 h. The reaction mixture was diluted with water (20 mL) and extracted with EtOAc (2×50 mL). The organic extracts were concentrated. The residue was purified by silica gel chromatography (20% to 70% EtOAc in heptane) to provide 2-(4,4-difluoropiperidin-1-yl)pyridin-4-amine (2.91 g. 13.65 mmol. 88% yield) as a light yellow solid, m/z (ESI): (M+H).sup.+214.1.

TABLE-US-00004 TABLE 2 Intermediates below were prepared following a similar procedure as described for Intermediate 8 LRMS: (ESI + Int. # Chemical Structure Name ve ion) m/z 8-1 [00071] 2-(4,4-Difluoropiperidin-1-yl)-6- methylpyridin-4-amine 228.2 8-2 [00072] 2-(4,4-Difluoropiperidin-1-yl)-6- ethylpyrimidin-4-amine 243.1 8-3 [00073] 6-Cyclopropyl-2-(4,4-difluoropiperidin- 1-yl)pyrimidin-4-amine 255.1

Intermediate 9: 2-(4,4-Difluoropiperidin-1-yl)-3-fluoro-6-methylpiperidin-4-amine

[0254] ##STR00074##

[0255] Step 1: To a solution of diisopropylamine (5.85 mL, 41.0 mmol) in tetrahydrofuran (50 mL) was added n-butyllithium (2M solution in hexanes, 20.52 mL, 41.0 mmol) dropwise at −60° C. The reaction mixture was slowly warmed to 0° C. and was stirred at the same temperature for 45 minutes. In another round bottom flask, to a solution of 2-bromo-3-fluoro-6-methylpyridine (3.9 g, 20.52 mmol) in tetrahydrofuran (50 mL) was added the above prepared LDA solution dropwise at −78° C. The reaction resultant reaction mixture was stirred for 45 minutes at the same temperature and then iodine (10.42 g, 41.0 mmol) in THF (40 mL) was added dropwise. The reaction mixture was stirred at same temperature for 1 h. After completion of the reaction, it was quenched with a saturated solution of ammonium chloride and was extracted in ethyl acetate. The organic layer was washed with sodium thiosulfate solution, water, and brine, dried over Na.sub.2SO.sub.4, filtered and concentrated to afford 2-bromo-3-fluoro-4-iodo-6-methylpyridine (6 g, 18.99 mmol, 93% yield) as yellow solid. The product was taken for next step without further purification. .sup.1H NMR (400 MHz, Chloroform-d) δ ppm 7.53 (d, J=3.8 Hz, 1H), 2.52 (s, 3H). m/z (ESI): 315.8, 317.8 (M+H).sup.+.

[0256] Step 2: A mixture of 2-bromo-3-fluoro-4-iodo-6-methylpyridine (1.5 g, 4.75 mmol), (4-methoxyphenyl)methanamine (0.782 g, 5.70 mmol), cesium carbonate (4.64 g, 14.24 mmol), Xantphos (0.549 g, 0.950 mmol) and Pd.sub.2(dba).sub.3 (0.065 g, 0.071 mmol) in 1,4-dioxane (30 mL) was stirred at ambient temperature for 16 h. Then the reaction mixture was filtered through a plug of CELITE® and filtrate was diluted with EtOAc. The resulting solution was washed with water, brine, dried over Na.sub.2SO.sub.4, filtered and concentrated. The concentrate was purified by flash column chromatography using a gradient of 0-18% ethyl acetate in petroleum ether to afford 2-bromo-3-fluoro-N-(4-methoxybenzyl)-6-methylpyridin-4-amine (0.7 g, 2.15 mmol, 45% yield) as pale-yellow solid. .sup.1H NMR (300 MHz, DMSO-d.sub.6) δ ppm 7.38 (s, 1H), 7.21-7.31 (m, 2H), 6.84-6.95 (m, 2H), 6.52 (d, J=6.0 Hz, 1H), 4.32 (d, J=6.3 Hz, 2H), 3.72 (s, 3H), 2.20 (s, 3H). m/z (ESI): 325.0, 327.0 (M+H).sup.+.

[0257] Step 3: A mixture of 2-bromo-3-fluoro-N-(4-methoxybenzyl)-6-methylpyridin-4-amine (0.7 g, 2.153 mmol), 4,4-difluoropiperidine hydrochloride (0.407 g, 2.58 mmol), cesium carbonate (2.81 g, 8.61 mmol), Xantphos (0.249 g, 0.431 mmol) and Pd.sub.2(dba).sub.3 (0.030 g, 0.032 mmol) in 1,4-dioxane (15 mL) was stirred in a sealed tube at 100° C. for 16 h. Then the reaction mixture was filtered through a plug of CELITE® and filtrate was diluted with EtOAc. The resulting solution was washed with water, brine, dried over Na.sub.2SO.sub.4, filtered, and concentrated. The concentrate was purified by flash column chromatography using a gradient of 0-6% ethyl acetate in petroleum ether to afford 2-(4,4-difluoropiperidin-1-yl)-3-fluoro-N-(4-methoxybenzyl)-6-methylpyridin-4-amine (0.67 g, 1.83 mmol, 85% yield) as pale-yellow solid. .sup.1H NMR (300 MHz, DMSO-d.sub.6) δ ppm 7.19-7.29 (m, 2H), 6.83-6.93 (m, 2H), 6.75 (m, 1H), 6.13 (d, J=5.4 Hz, 1H), 4.26 (d, J=6.3 Hz, 2H), 3.72 (s, 3H), 3.40 (d, J=11.5 Hz, 4H), 1.92-2.14 (m, 7H). m/z (ESI): 366.1 (M+H).sup.+.

[0258] Step 4: To a solution of 2-(4,4-difluoropiperidin-1-yl)-3-fluoro-N-(4-methoxybenzyl)-6-methylpyridin-4-amine (0.3 g, 0.821 mmol) in dichloromethane (3 mL) were added anisole (0.179 mL, 1.642 mmol) and TFA (1.5 mL, 19.47 mmol) at ambient temperature and the reaction mixture was stirred at 50° C. for 2.5 h. Then the reaction mixture quenched with water and pH was adjusted to 8 with 10% sodium bicarbonate solution before it was extracted with ethyl acetate. The organic layer was washed with water and brine, dried over Na.sub.2SO.sub.4, filtered and concentrated. The concentrate was purified by flash column chromatography using a gradient of 20% ethyl acetate in petroleum ether to afford 2-(4,4-difluoropiperidin-1-yl)-3-fluoro-6-methylpyridin-4-amine (0.17 g, 0.69 mmol, 84% yield) as yellow oil. .sup.1HNMR (400 MHz, DMSO-d.sub.6) δ ppm 6.15 (d, J=5.5 Hz, 1H), 5.79 (s, 2H), 3.40 (t, J=5.6 Hz, 4H), 2.13 (s, 3H), 2.02 (tt, J=14.2, 5.6 Hz, 4H). m/z (ESI): 246.2 (M+H).sup.+.

Intermediate 10: 2-(6-Amino-2-(4,4-difluoropiperidin-1-yl)pyrimidin-4-yl)propan-2-ol

[0259] ##STR00075##

[0260] Step 1: To a solution of methyl 2,6-dichloropyrimidine-4-carboxylate (20.00 g, 97 mmol), in tetrahydrofuran (200 mL) were added (3,5-dimethoxyphenyl)methanamine (19.39 g, 116 mmol) and DIPEA (33.7 mL, 193 mmol) at 0° C. Then the reaction mixture was stirred at ambient temperature for 16 h before it was quenched with water and was extracted with EtOAc. The organic layer was washed with brine, and dried over Na.sub.2SO.sub.4, filtered and concentrated. The concentrate was triturated with DCM and hexane to afford methyl 2-chloro-6-((3,5-dimethoxybenzyl)amino)pyrimidine-4-carboxylate (19.5 g, 57.7 mmol, 59.8% yield) as off white solid. .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ ppm 8.52 (t, J=5.5 Hz, 1H), 7.16 (d, J=8.9 Hz, 2H), 6.59 (d, J=2.4 Hz, 1H), 6.50 (dd, J=8.4, 2.4 Hz, 1H), 4.40 (d, J=5.4 Hz, 2H), 3.82 (d, J=14.5 Hz, 6H), 3.75 (d, J=5.8 Hz, 3H). m/z (ESI): 338.1 (M+H).sup.+.

[0261] Step 2: A solution of methyl 2-chloro-6-((3,5-dimethoxybenzyl)amino)pyrimidine-4-carboxylate (3 g, 8.88 mmol), 4,4-difluoropiperidine hydrochloride (2.10 g, 13.32 mmol) and DIPEA (3.44 g, 26.6 mmol) in DMF (30 mL) was stirred in a sealed tube at 90° C. for 16 h. Then the reaction mixture was quenched with water and was extracted with ethyl acetate. The organic layer was washed with brine, dried over Na.sub.2SO.sub.4, filtered, and concentrated. The crude material was purified by flash column chromatography using a gradient of 50% to 60% ethyl acetate in petroleum ether to provide methyl 2-(4,4-difluoropiperidin-1-yl)-6-((3,5-dimethoxybenzyl)amino)pyrimidine-4-carboxylate (2.6 g, 6.15 mmol, 69.3% yield) as pale yellow solid. .sup.1H NMR (300 MHz, DMSO-d.sub.6) δ ppm 7.74 (s, 1H), 7.13 (d, J=8.3 Hz, 1H), 6.55 (d, J=2.4 Hz, 1H), 6.47 (dd, J=8.3, 2.4 Hz, 2H), 4.39 (s, 2H), 3.82 (s, 3H), 3.79 (s, 3H), 3.73 (s, 3H), 3.33 (m, 4H), 1.85-2.00 (m, 4H).

[0262] Step 3: To a solution of methyl 2-(4,4-difluoropiperidin-1-yl)-6-((3,5-dimethoxybenzyl)amino)pyrimidine-4-carboxylate (1 g, 2.367 mmol) in DCM (10 mL) was dropwise added sulfuric acid (0.126 mL, 2.37 mmol) at 0° C. Then the mixture was allowed to warm to RT and the progress of the reaction was monitored by TLC. Upon completion of starting material, the reaction mixture was quenched with ice-water and pH was adjusted to 9 by using 10% NaHCCf solution. Then, the reaction mixture was extracted with ethyl acetate and the organic layer was washed with brine, dried over Na.sub.2SO.sub.4, filtered and concentrated to provide methyl 6-amino-2-(4,4-difluoropiperidin-1-yl)pyrimidine-4-carboxylate (0.45 g, 1.653 mmol, 69.8% yield) as off-white solid. .sup.1HNMR (300 MHz, DMSO-d.sub.6) δ ppm 6.90 (br s, 2H), 6.39 (s, 1H), 3.85-3.83 (m, 4H), 3.79 (s, 3H), 1.99-1.35 (m, 4H). m/z (ESI): 273.1 (M+H).sup.+.

[0263] Step 4: To a solution of methyl 6-amino-2-(4,4-difluoropiperidin-1-yl)pyrimidine-4-carboxylate (0.45 g, 1.653 mmol) in tetrahydrofuran (5 mL) was added methyl magnesium bromide (2.0 M diethyl ether) (2.07 mL, 4.13 mmol) at 0° C. and was stirred at room temperature for 2 h. Upon consumption of starting material, the reaction mixture was quenched with ice water and was extracted with ethyl acetate. The organic layer was washed with brine, dried over Na.sub.2SO.sub.4, filtered and concentrated. The concentrate was purified by flash column chromatography using a gradient of 0%-90% ethyl acetate in petroleum ether to provide 2-(6-amino-2-(4,4-difluoropiperidin-1-yl)pyrimidin-4-yl)propan-2-ol (0.35 g, 1.28 mmol, 78% yield) as pale yellow solid. m/z (ESP: 273.1 (M+H).sup.+.

TABLE-US-00005 TABLE 3 The intermediate below was prepared following a similar procedure as described for intermediate 10 LRMS: (ESI + Int. # Chemical Structure Name ve ion) m/z 10-1 [00076] (R)-2-(6-Amino-2-(2- methylmorpholino)pyrimidin- 4-yl)propan-2-ol 252.2

Intermediate 11: 2-(4-Amino-6-methylpyrimidin-2-yl)propan-2-ol

[0264] ##STR00077##

[0265] Step 1: A mixture of 2,4-dichloro-6-methylpyrimidine (3.0 g, 18.40 mmol, Aldrich, St. Louis, Mo., USA), bis(4-methoxybenzyl)-amine (7.10 g, 27.6 mmol, Combi-Blocks Inc., San Diego, Calif., USA), and potassium carbonate (7.63 g, 55.2 mmol, Aldrich, St. Louis, Mo., USA) in tetrahydrofuran (100 mL) was stirred at room temperature for 72 h. Then, the mixture was diluted with water (50 mL) and was then extracted with EtOAc (2×100 mL). The combined organic extracts were then dried over MgSO.sub.4 and concentrated in vacuo. Chromatographic purification of the residue (silica gel, 0%-100% EtOAc/heptane) provided 2-chloro-N,N-bis(4-methoxybenzyl)-6-methylpyrimidin-4-amine (3.11 g, 8.10 mmol, 44.0% yield) as an off white solid. .sup.1H NMR (DMSO-d6) δ ppm 7.16 (br d, J=6.2 Hz, 4H), 6.89 (d, J=8.7 Hz, 4H), 6.60 (s, 1H), 4.39-4.84 (m, 4H), 3.73 (s, 6H), 2.20 (s, 3H). m/z (ESI): 384.2 (M+H)+.

[0266] Step 2: A mixture of 2-chloro-A/V-bis(4-methoxybenzyl)-6-methylpyrimidin-4-amine (1.0 g, 2.61 mmol), 1,3-bis(diphenylphosphino)propane (64.5 mg, 0.156 mmol, Aldrich, St. Louis, Mo., USA), diethyl oxalate (0.529 mL, 3.91 mmol, Aldrich, St. Louis, Mo., USA), trans-dichlorobis(triphenyl-phosphine)palladium (ii) (54.9 mg, 0.078 mmol, Strem Chemicals Inc., Newburyport, Mass., USA), and 4-(dimethylamino) pyridine (477 mg, 3.91 mmol, Aldrich, St. Louis, Mo., USA) in ethanol (0.5 mL) was subjected to a microwave irradiation at 140° C. for 20 min. Then, the mixture was diluted with water (50 mL) and was then extracted with EtOAc (2×50 mL). The combined organic extracts were then dried over MgSO4 and concentrated in vacuo. Chromatographic purification of the residue (silica gel, 0%-100% EtOAc/heptane) provided ethyl 4-(bis(4-methoxybenzyl)amino)-6-methylpyrimidine-2-carboxylate (274 mg, 0.650 mmol, 24.95% yield) as a light yellow solid. .sup.1H NMR (Methanol-d4) δ ppm 7.29 (br s, 4H), 6.97 (d, J=8.5 Hz, 4H), 6.68 (s, 1H), 4.78-4.93 (m, 4H), 4.54 (q, J=7.2 Hz, 2H), 3.88 (s, 6H), 2.43 (s, 3H), 1.53 (t, 7=7.0 Hz, 3H). m/z (ESI): 422.1 (M+H)+.

[0267] Step 3: To a solution of ethyl 4-(bis(4-methoxybenzyl)amino)-6-methylpyrimidine-2-carboxylate (396 mg, 0.940 mmol) in 2-methyltetrahydrofuran (7 mL) at 0° C. under N.sub.2 was added methylmagnesium bromide, 3.4M in 2-methyltetrahydrofuran (0.829 mL, 2.82 mmol, Aldrich, St. Louis, Mo., USA) dropwise. After addition, the mixture was then stirred at 0° C. for 3.5 hours. Then, the mixture was quenched with saturated NH.sub.4Cl (10 mL) and was then extracted with EtOAc (2×50 mL). The combined organic extracts were then dried over MgSO.sub.4 and concentrated in vacuo. Chromatographic purification of the residue (silica gel, 0%-100% EtOAc/heptane) provided 2-(4-(bis(4-methoxybenzyl)amino)-6-methylpyrimidin-2-yl)propan-2-ol (307 mg, 0.753 mmol, 80% yield) as a yellow solid, m/z (ESI): 408.2 (M+H)+.

[0268] Step 4: A solution of 2-(4-(bis(4-methoxybenzyl)amino)-6-methylpyrimidin-2-yl)propan-2-ol (300 mg, 0.736 mmol) in trifluoroacetic acid (10 mL, Aldrich, St. Louis, Mo., USA) was subjected to a microwave irradiation at 110° C. for 30 min. Then, the mixture was concentrated under reduced pressure. The crude was then dissolved in DCM (10 mL) and was then quenched with saturated Na2CO3 (15 mL). The mixture was then extracted with EtOAc (2×50 mL). The combined organic extracts were then dried over MgSO4 and concentrated in vacuo. Chromatographic purification of the residue (silica gel, 0%-100% EtOAc:EtOH (3:1)/heptane) provided 2-(4-amino-6-methylpyrimidin-2-yl)propan-2-ol (123 mg) as a light yellow solid, m/z (ESI): 168.2 (M+H)+.

Preparation of Ring Ar.SUP.2 .Intermediates

Intermediate 12: 4-Iodo-2-(6-azaspiro[2.5]octan-6-yl)benzoic acid

[0269] ##STR00078##

[0270] To a solution of 2-fluoro-4-iodobenzoic acid (300 g, 1.13 mol, Combi-Blocks, San Diego, Calif.) in DMSO (2.10 L) was added 6-azaspiro[2.5]octane hydrochloride (216 g, 1.47 mol, Wuxi AppTec) at 20° C. Then K.sub.2CO.sub.3 (468 g, 3.38 mol) was added and the reaction solution was stirred at 140° C. for 48 hours under N.sub.2. The reaction solution was slowly poured into ice water (4.20 L), then extracted with hexanes (2.00 L×3). The water phase was separated and adjusted to pH=6 with HCl (2.00 mol/L, aq). Solid was precipitated out and collected. The solid was washed with water (700 mL×3) and filtered. The moist solid was spread out on a large watch glass and dried in the air at 25° C. for 72 hours. 4-Iodo-2-(6-azaspiro[2.5]octan-6-yl)benzoic acid (280 g, 777 mmol, 68.9% yield) was obtained as a light yellow solid. 400 MHz DMSO-d.sub.6 δ ppm 8.07 (s, 1H), 7.76-7.66 (m, 2H), 3.10 (t, J=5.2 Hz, 4H), 1.55 (br s, 4H), 0.41 (s, 4H).

TABLE-US-00006 TABLE 4 Intermediates below were prepared following a similar procedure for Int. 12: LRMS: (ESI + ve Int. # Chemical Structure Name ion) m/z 12-1 [00079] 4-Bromo-2-(6-azaspiro[2.5]octan-6- yl)benzoic acid 310.2/312.2 12-2 [00080] Methyl 4-bromo-2-(6- azaspiro[2.5]octan-6-yl)benzoate 324.0/326.0 12-3 [00081] 4-Iodo-2-(7-azaspiro[3.5]nonan-7- yl)benzoic acid 372.0 12-4 [00082] 2-(4,4-Dimethylpiperidin-1-yl)-4- iodobenzoic acid 360.0

Intermediate 13: 4-(Methylsulfonyl)-2-(6-azaspiro[2.5]octan-6-yl)benzoic

[0271] ##STR00083##

[0272] Step 1: To a solution of 2-fluoro-4-(methylsulfonyl)benzoic acid (90.0 g, 412.1 mmol) in N,N-dimethylformamide (1.0 L) were added benzyl bromide (78.1 g, 454.0 mmol) and sodium carbonate (52.5 g, 495 mmol) at 0° C. The reaction mixture was stirred for 12 h at room temperature. The reaction mixture was quenched with water (1 L) and extracted with MTBE (3×1 L). The combined organic layer was washed with brine (1 L), dried over Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure. The crude residue was purified by column chromatography over silica gel using 0 to 30% ethyl acetate in hexanes as an eluent to give benzyl 2-fluoro-4-(methylsulfonyl)benzoate (100 g, 79% yield) as a white solid. .sup.1H NMR (300 MHz, DMSO-d.sub.6) 3 ppm 8.16 (dd, J=8.2, 6.9 Hz, 1H), 7.98-7.86 (m, 2H), 7.48-7.31 (m, 5H), 5.40 (s, 2H), 3.33 (s, 3H).

[0273] Step 2: To a solution of benzyl 2-fluoro-4-(methylsulfonyl)benzoate (55 g, 178 mmol) in dimethyl sulfoxide (550 mL) was added DIPEA (57.6 g, 446 mmol) followed by 6-azaspiro[2.5]octane (29.8 g, 268 mmol) and the reaction mixture was stirred at 100° C. for 24 h. The reaction mixture was quenched with water (1 L) and extracted with MTBE (3×1 L). The combined organic layer was washed with brine solution (1 L), dried over Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure. The crude product was purified by column chromatography over silica gel (230-400 mesh) using 0 to 10% ethyl acetate in hexanes as an eluent to give benzyl 4-(methylsulfonyl)-2-(6-azaspiro[2.5]octan-6-yl)benzoate (55 g, 77% yield) as a white solid. .sup.1H NMR (400 MHz, DMSO-d.sub.6) 3 ppm 7.76 (d, J=8.0 Hz, 1H), 7.52-7.45 (m, 4H), 7.43-7.35 (m, 3H), 5.35 (s, 2H), 3.25 (s, 3H), 3.05 (t, J=5.3 Hz, 4H), 1.36 (t, J=5.3 Hz, 4H), 0.30 (s, 4H). m/z (ESI): 400.1 (M+H).sup.+.

[0274] Step 3: To a solution of benzyl 4-(methylsulfonyl)-2-(6-azaspiro[2.5]octan-6-yl)benzoate (65 g, 163 mmol) in tetrahydrofuran (108 mL) and methanol (36 mL) was added 1N aqueous sodium hydroxide solution (407 mL, 407 mmol) and the reaction mixture was stirred for 12 h at 60° C. The reaction mixture was concentrated under reduced pressure to remove THF and methanol. The remaining aqueous solution was acidified to pH˜2 with 1.5 N HCl solution. The precipitated solid was filtered, washed with water (200 mL) followed by hexanes (200 mL), dried under vacuum for 12 h to give 4-(methylsulfonyl)-2-(6-azaspiro[2.5]octan-6-yl)benzoic acid (42 g, 83% yield) as an off white solid. .sup.1H NMR (400 MHz, DMSO-d.sub.6)S ppm 16.13 (s, 1H), 8.04 (d, J=8.0 Hz, 1H), 7.99 (s, 1H), 7.75 (d, J=8.0 Hz, 1H), 3.29 (s, 3H), 3.17 (b s, 4H), 1.55 (b s, 4H), 0.41 (s, 4H). m/z (ESI): 310.1 (M+H).sup.+.

Intermediate 14: 4-((1-Methylcyclopropane)-1-sulfonamido)-2-(6-azaspiro[2.5]octan-6-yl)benzoic acid

[0275] ##STR00084##

[0276] Step 1: To a solution of 4-bromo-2-fluorobenzoic acid (50.0 g, 228 mmol, F Chemicals, China) in DMF (500 mL) was added sodium carbonate (31.5 g, 297 mmol) followed by benzyl bromide (43.0 g, 251 mmol) at 0° C. and the reaction mixture was stirred for 24 h at room temperature. The reaction mixture was quenched with water (1000 mL) and extracted with ethyl acetate (3×2000 mL). The organic layer was dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude residue was purified by column chromatography over silica gel using 10% ethyl acetate in hexanes as an eluent to give benzyl 4-bromo-2-fluorobenzoate (65 g, 92% yield) as a colorless viscous oil. .sup.1H NMR (400 MHz, Chloroform-d) δ ppm 7.91 (t, J=8.4 Hz, 1H), 7.47 (dt, J=6.0, 1.5 Hz, 2H), 7.43 (dd, J=6.8, 1.8 Hz, 1H), 7.41 (q, J=1.5 Hz, 1H), 7.39-7.35 (m, 1H), 7.02 (dd, J=8.7, 2.1 Hz, 1H), 6.79 (s, 1H), 5.38 (s, 2H). m/z (ESI): 310.2 (MH).sup.+.

[0277] Step 2: To a solution of benzyl 4-bromo-2-fluorobenzoate (60.0 g, 194 mmol) in DMSO (200 mL) were added 6-azaspiro[2.5]octane (32.4, 291 mmol, Wuxi Appec) in DMSO (200 mL) and DIPEA (30 g, 291 mmol) and stirred at 100° C. for 12 h. The reaction mixture was quenched with water (2000 mL) and extracted with ethyl acetate (3×2000 mL). The organic layer was dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude residue was purified by column chromatography over silica gel using 10% ethyl acetate in hexanes to give benzyl 4-bromo-2-(6-azaspiro[2.5]octan-6-yl)benzoate (70 g, 90% yield) as a yellow oil. .sup.1H NMR (400 MHz, Chloroform-d) δ ppm 7.60 (dd, J=8.4, 1.9 Hz, 1H), 7.50-7.45 (m, 2H), 7.49-7.28 (m, 3H), 7.20 (d, J=1.9 Hz, 1H), 7.07 (dd, J=8.3, 1.9 Hz, 1H), 5.36 (s, 2H), 3.12-3.02 (m, 4H), 1.47 (t, J=5.3 Hz, 4H), 0.33 (d, J=1.8 Hz, 4H). m/z (ESI): 398.1, 400.1 (M+H).sup.+.

[0278] Step 3: To a 250-mL sealed tube were added benzyl 4-bromo-2-(6-azaspiro[2.5]octan-6-yl)benzoate (9 g, 22.48 mmol), 1-methylcyclopropane-1-sulfonamide (3.95 g, 29.2 mmol, Combi-Blocks, San Diego, Calif.) and K.sub.2CO.sub.3 (6.21 g, 45.0 mmol) in 1,4-dioxane (90 mL) and the reaction was degassed and purged with nitrogen for 5 min. To this reaction mixture was added Xantphos (1.301 g, 2.248 mmol) followed by Pd.sub.2(dba).sub.3 (1.03 g, 1.12 mmol) and the sealed tube was closed and stirred at 110° C. for 18 h. The reaction mixture was quenched with water (250 mL) and extracted with ethyl acetate (2×150 mL). The organic layer was washed with water (100 mL), dried over Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure. The crude residue was purified by column chromatography over silica gel eluting with a gradient of 0% to 15% EtOAc in hexanes to give benzyl 4-((l-methylcyclopropane)-1-sulfonamido)-2-(6-azaspiro[2.5]octan-6-yl)benzoate (6.1 g, 59% yield) as an orange oil. .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ ppm 10.06 (s, 1H), 7.62 (d, J=8.5 Hz, 1H), 7.48-7.31 (m, 5H), 6.98 (s, 1H), 6.81 (d, J=8.5 Hz, 1H), 5.27 (s, 2H), 2.92 (t, J=4.96 Hz, 4H), 1.40-1.30 (m, 7H), 1.16 (dd, J=6.4, 4.7 Hz, 2H), 0.81 (dd, J=6.4, 4.7 Hz, 2H), 0.28 (s, 4H). m/z (ESI): 455.2 (M+H).sup.+.

[0279] Step 4: To a solution of benzyl 4-((1-methylcyclopropane)-1-sulfonamido)-2-(6-azaspiro[2.5]octan-6-yl)benzoate (2.1 g, 4.62 mmol) in methanol (20 mL) and ethyl acetate (10 mL) was added 10% Pd—C(1.05 g, 50% wt/wt) under nitrogen atmosphere. The reaction mixture was degassed and stirring under hydrogen pressure (1 atm, balloon pressure) for 4 h. The reaction mixture was filtered through a CELITE® bed and washed with methanol (20 mL). The filtrate was concentrated under reduced pressure. The residue was triturated with Et.sub.2O (50 mL) to give 4-((1-methylcyclopropane)-1-sulfonamido)-2-(6-azaspiro[2.5]octan-6-yl)benzoic acid (1.2 g, 71% yield) as an off white solid. .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ ppm 13.20 (s, 1H), 10.33 (s, 1H), 7.95 (d, J=8.6 Hz, 1H), 7.41 (s, 1H), 7.20 (d, J=8.6 Hz, 1H), 2.99 (s, 4H), 1.56 (s, 4H), 1.39 (s, 3H), 1.18 (t, J=4.8 Hz, 2H), 0.83 (t, J=4.7 Hz, 2H), 0.42 (s, 4H). m/z (ESI): 363.2 (M−H).sup.+.

Intermediate 15: 4-(N-(3-Methyloctan-3-yl)sulfamoyl)-2-(6-azaspiro[2.5]octan-6-yl)benzoic acid

[0280] ##STR00085##

[0281] Step 1: To a solution of 3-methyl-3-oxetanamine hydrochloride (5.50 g, 44.5 mmol) and N,N-diisopropylethylamine (23.26 mL, 134 mmol) in DCM (200 mL) at 0° C., methyl 4-(chlorosulfonyl)-2-fluorobenzoate (12.37 g, 49.0 mmol) was added and the mixture stirred from 0° C. to room temperature for 1 h. The mixture was diluted with 1.0 N HCl (200 mL) and extracted with dichloromethane (150 mL×2). The combined organic layers were washed with brine, dried with anhydrous sodium sulfate, filtered and concentrated under reduced pressure to afford crude product. The crude product was purified with Biotage SNAP 100 g column eluting with 0-30% 3:1 EtOAc-EtOH in heptane to afford methyl 2-fluoro-4-(N-(3-methyloxetan-3-yl)sulfamoyl)benzoate (13.59 g, 44.8 mmol, 100% yield) as a white solid. .sup.1H NMR (500 MHz, DMSO-d.sub.6) δ ppm 8.67 (s, 1H), 8.11 (t, J=7.37 Hz, 1H), 7.76-7.82 (m, 1H), 7.69-7.76 (m, 1H), 4.56 (d, J=6.23 Hz, 2H), 4.18 (d, J=6.75 Hz, 2H), 3.90 (s, 3H), 1.42 (s, 3H).

[0282] Step 2: A mixture of N,N-diisopropylethylamine (16.23 mL, 93 mmol), 6-azaspiro[2.5]octane (6.22 g, 55.9 mmol), and methyl 2-fluoro-4-(A-(3-methyloxetan-3-yl)sulfamoyl)benzoate (14.13 g, 46.6 mmol) in anhydrous 1,4-dioxane was stirred at 100° C. for 20 h. The mixture was cooled down to room temperature, quenched with water and extracted with ethyl acetate. The combined organic phases were washed with brine, dried and evaporated to dryness under reduced pressure. The crude product was purified using the Biotage SNAP 340 g column eluting with 0-40% 3:1 EtOAc-EtOH in heptane to get methyl 4-(N-(3-methyloxetan-3-yl)sulfamoyl)-2-(6-azaspiro[2.5]octan-6-yl)benzoate (14.15 g, 35.9 mmol, 77% yield) as an off-white solid. .sup.1H NMR (500 MHz, DMSO-d.sub.6) δ ppm 8.42 (s, 1H), 7.72 (d, J=8.04 Hz, 1H), 7.47 (d, J=1.56 Hz, 1H), 7.36 (dd, J=1.82, 8.04 Hz, 1H), 4.55 (d, J=5.97 Hz, 2H), 4.14 (d, J=6.49 Hz, 2H), 3.85 (s, 3H), 3.02-3.09 (m, 4H), 1.44-1.50 (m, 4H), 1.42 (s, 3H), 0.35 (s, 4H).

[0283] Step 3: A mixture of methyl 4-(N-(3-methyloxetan-3-yl)sulfamoyl)-2-(6-azaspiro[2.5]octan-6-yl)benzoate (14.15 g, 35.9 mmol) and lithium hydroxide monohydrate (22.58 g, 538 mmol) in THF-water-MeOH (1:1:1, 300 mL) was stirred at room temperature overnight. The mixture was concentrated under reduced pressure to partially remove the organic solvent. The solution was acidified with 2N HCl to reach pH<3. The precipitated solid was filtered and dried in air to give 4-(N-(3-methyloxetan-3-yl)sulfamoyl)-2-(6-azaspiro[2.5]octan-6-yl)benzoic acid (9.94 g, 26.1 mmol, 72.8% yield) as a white solid. .sup.1H NMR (500 MHz, DMSO-J.sub.6) δ ppm 8.51 (s, 1H), 8.04 (d, J=8.04 Hz, 1H), 7.89 (d, J=1.30 Hz, 1H), 7.66 (dd, J=1.69, 8.17 Hz, 1H), 4.55 (d, J=6.23 Hz, 2H), 4.09-4.17 (m, 2H), 3.06-3.19 (m, 4H), 1.56 (t, J=5.19 Hz, 4H), 1.40 (s, 3H), 0.36-0.46 (s, 4H).

Intermediate 16: 4-((1-(tert-Butoxycarbonyl)azetidin-3-yl)sulfonyl)-2-(6-azaspiro[2.5]octan-6-yl)benzoic acid

[0284] ##STR00086##

[0285] Step 1: A mixture of methyl 4-bromo-2-(6-azaspiro[2.5]octan-6-yl)benzoate (10.50 g, 32.4 mmol, Int. 12-2), DIPEA (8.37 mL, 64.8 mmol), Xantphos (1.874 g, 3.24 mmol) and Pd.sub.2(dba).sub.3 (2.97 g, 3.24 mmol) in 1,4-dioxane was bubbled with argon flow, then was added tert-butyl 3-mercaptoazetidine-1-carboxylate (7.66 mL, 40.5 mmol). The mixture was stirred at 100° C. for 18 h. The mixture was cooled down to room temperature, concentrated and purified through a Biotage SNAP eluting with a gradient of 0% to 25% 3:1 EtOAc-EtOH in heptane to provide tert-butyl 3-((4-(methoxycarbonyl)-3-(6-azaspiro[2.5]octan-6-yl)phenyl)thio)azetidine-1-carboxylate (13.85 g, 32.0 mmol, 99% yield) as a light-yellow sticky solid. .sup.1H NMR (500 MHz, DMSO-d.sub.6) δ ppm 7.55 (d, J=8.04 Hz, 1H), 6.79 (s, 1H), 6.76 (d, J=8.14 Hz, 1H), 4.34-4.43 (m, 2H), 4.27-4.34 (m, 1H), 3.79 (s, 3H), 3.70 (dd, J=4.67, 8.56 Hz, 2H), 2.97-3.04 (m, 4H), 1.41-1.51 (m, 4H), 1.38 (s, 9H), 0.29-0.37 (m, 4H).

[0286] Step 2: To a solution of tert-butyl 3-((4-(methoxycarbonyl)-3-(6-azaspiro[2.5]octan-6-yl)phenyl)thio)azetidine-1-carboxylate (13.85 g, 32.0 mmol) in 1,4-dioxane (300 mL) was added Oxone monopersulfate (39.4 g, 64.0 mmol) in 150 mL water. The mixture was stirred at room temperature for 5 h and added 150 mL of ethyl acetate and 150 mL of water and the mixture was stirred for 10 minutes. The organic layer was separated, the aqueous layer was extracted with ethyl acetate. The combined organics were washed with brine, dried, filtered and concentrated. The crude material was purified through a Biotage SNAP 340 g column eluting with a gradient of 0% to 25% EtOAc-EtOH (3:1) in heptane to give tert-butyl 3-((4-(methoxycarbonyl)-3-(6-azaspiro[2.5]octan-6-yl)phenyl)sulfonyl)azetidine-1-carboxylate (12.77 g, 27.5 mmol, 86% yield) as an off-white solid. .sup.1H NMR (500 MHz, DMSO-d.sub.6) δ 7.75 (d, J=8.04 Hz, 1H), 7.44-7.50 (m, 2H), 4.48-4.55 (m, 1H), 4.09 (br s, 2H), 3.97-4.02 (m, 2H), 3.86 (s, 3H), 3.04-3.17 (m, 4H), 1.42-1.51 (m, 4H), 1.38 (s, 9H), 0.35 (s, 4H).

[0287] Step 3: A mixture of tert-butyl 3-((4-(methoxycarbonyl)-3-(6-azaspiro[2.5]octan-6-yl)phenyl)sulfonyl) azetidine-1-carboxylate (12.77 g, 27.5 mmol) and lithium hydroxide monohydrate (11.53 g, 275 mmol) in THF-water-MeOH (1:1:1, 230 mL) was stirred at room temperature for 15 h. The mixture was concentrated under reduced pressure to remove some organic solvent. The solution was acidified with 2N HCl to pH<3. The precipitated solid was filtered and dried to give 4-((1-(tert-butoxycarbonyl)azetidin-3-yl)sulfonyl)-2-(6-azaspiro[2.5]octan-6-yl)benzoic acid (10.6 g, 23.53 mmol, 86% yield) as an off-white solid. .sup.1HNMR (500 MHz, DMSO-d.sub.6) δ ppm 8.03 (d, J=8.30 Hz, 1H), 7.93 (d, J=1.82 Hz, 1H), 7.72 (dd, J=1.69, 8.17 Hz, 1H), 4.48-4.60 (m, 1H), 4.10 (br. s., 2H), 3.99-4.06 (m, 3H), 3.14-3.22 (m, 4H), 1.49-1.59 (m, 4H), 1.38 (s, 9H), 0.41 (s, 4H).

Intermediates Compounds Having Ar.SUP.1 .and Ar.SUP.2 .Rings

Intermediate 17: N-(2-Chloro-6-methylpyrimidin-4-yl)-4-iodo-2-(6-azaspiro[2.5]octan-6-yl)benzamide

[0288] ##STR00087##

[0289] 2,4,6-Tripropyl-1,3,5,2,4,6-trioxatriphosphinane 2,4,6-trioxide (50 wt % solution in EtOAc, 12.50 mL, 21.00 mmol) and triethylamine (2.93 mL, 21.00 mmol) were added to a suspension of 4-iodo-2-(6-azaspiro[2.5]octan-6-yl)benzoic acid (3.0 g, 8.40 mmol, Int. 12) and 2-chloro-6-methylpyrimidin-4-amine (1.45 g, 10.08 mmol, Aurum Pharmtech Inc.) in DCE (20 mL). The mixture was heated to 85° C. for 24 h, then cooled to room temperature. Water (10 mL) was added, the layers were separated, and the aqueous layer was extracted with DCM (1×10 mL). The combined organic extracts were dried over anhydrous MgSO.sub.4, filtered, and concentrated in vacuo to give a solid. The solid was suspended in 1:1 EtOAc/heptane and filtered to provide N-(2-chloro-6-methylpyrimidin-4-yl)-4-iodo-2-(6-azaspiro[2.5]octan-6-yl)benzamide (3.61 g, 7.48 mmol, 89% yield) as an off white solid. .sup.1H NMR (400 MHz, CHLOROFORM-d) δ ppm 13.53 (br s, 1H) 8.11 (s, 1H) 7.92 (d, J=8.29 Hz, 1H) 7.70 (s, 1H) 7.65-7.69 (m, 1H) 3.05 (t, J=5.39 Hz, 4H) 2.53 (s, 3H) 1.61-1.88 (m, 4H) 0.44 (s, 4H). m/z (ESI): 483.0 (M+H).sup.+.

Intermediate 18: (R)-4-Bromo-N-(6-methyl-2-(2-methylmorpholino)pyrimidin-4-yl)-2-(6-azaspiro[2.5]octan-6-yl)benzamide

[0290] ##STR00088##

[0291] Step 1: To a 100-mL round-bottomed flask was added 4-bromo-2-(6-azaspiro[2.5]octan-6-yl)benzoic acid (0.9 g, 2.90 mmol, Int. 12-1), pyridine (0.657 mL, 8.12 mmol) and perfluorophenyl 2,2,2-trifluoroacetate (0.717 g, 3.77 mmol) in DCM (8 mL). The resultant mixture was stirred at rt for 16 h and the solvent was removed under vacuum to get crude product which was used for the next step without purification, m/z (ESI): 476 and 478 (M+1).

[0292] Step 2: To a 50-mL round-bottomed flask was added (R)-6-methyl-2-(2-methylmorpholino)pyrimidin-4-amine (0.223 g, 1.15 mmol, Int. 2) dissolved in N,N-dimethylformamide (6 mL) followed by sodium hydride (0.084 g, 2.1 mmol) at rt under nitrogen atmosphere. The reaction mixture was stirred for 10 min and then it was treated with perfluorophenyl 4-bromo-2-(6-azaspiro[2.5]octan-6-yl)benzoate (0.5 g, 1.050 mmol) at RT under nitrogen atmosphere. The resultant reaction mixture was stirred at rt for additional 2 h. Reaction mixture was extracted with DCM (2×30 mL), separated, dried over anhydrous sodium sulphate and evaporated to dryness to get crude material. It was then absorbed onto a plug of silica gel and purified by silica gel flash column chromatography eluting with 30% to 50% EtOAc/hexanes, to provide the title compound (0.20 g, 0.40 mmol, 38% yield) as white solid. .sup.1H NMR (300 MHz, DMSO-d.sub.6) δ ppm 13.19 (bs, 1H), 7.99 (d, J=8.4 Hz, 1H), 7.69 (s, 1H), 7.55 (d, J=8.4 Hz, 1H), 7.36 (s, 1H), 4.45 (t, J=12 Hz, 2H), 3.88 (m, 1H), 3.52-3.48 (m, 2H) 3.10-2.90 (m, 6H), 2.30 (s, 3H), 1.71-1.62 (m, 4H), 1.14 (d, J=6 Hz, 3H), 0.36 (s, 4H). m/z (ESI): 500 and 502 (M+1).

Intermediate 19: N-(2-(4,4-Difluoropiperidin-1-yl)-6-methylpyrimidin-4-yl)-4-iodo-2-(6-azaspiro[2.5]octan-6-yl)benzamide

[0293] ##STR00089##

[0294] 4-Iodo-2-(6-azaspiro[2.5]octan-6-yl)benzoic acid (150.0 g, 420 mmol, Int. 12) was suspended in dichloromethane (1000 mL) under argon. Catalytic DMF (1.0 mL) was added followed by dropwise addition of a solution of thionyl chloride (54.6 g, 28 mL, 459 mmol, Sigma-Aldrich Corporation) in dichloromethane (500 mL) over 10 minutes. After stirring at ambient temperature for 30 minutes, the mixture was evaporated to dryness under reduced pressure. The crude was azeotroped with toluene (2×300 mL) and suspended in dichloromethane (300 mL) under argon. Tribasic potassium phosphate (267 g, 1.26 mol, Sigma-Aldrich Corporation) was added followed by a solution of 2-(4,4-difluoropiperidin-1-yl)-6-methylpyrimidin-4-amine (100 g, 438 mmol, Int. 4) and N,N-diisopropylethylamine (200 mL, 1.14 mol, Sigma-Aldrich Corporation) in DCM (300 mL, added over 5 minutes). The yellow mixture was stirred at ambient temperature for 3 hours then evaporated to dryness under reduced pressure. The crude solids were suspended in dichloromethane (1 L) and stirred for 10 minutes. The mixture was filtered through a frit and the solids washed with additional dichloromethane (2×100 mL). The solids were discarded, and the filtrate was evaporated to dryness under reduced pressure. The crude residue was suspended in acetonitrile (750 mL) and stirred at ambient temperature for 15 minutes. The suspension was filtered through a glass frit and the solids washed with additional acetonitrile (75 mL). The solids were dried under a stream of nitrogen to give N-(2-(4,4-difluoropiperidin-1-yl)-6-methylpyrimidin-4-yl)-4-iodo-2-(6-azaspiro[2.5]octan-6-yl)benzamide (186 g, 328 mmol, 78% yield). .sup.1H NMR (400 MHz, DMSO-d.sub.6) 5 ppm 13.38 (br s, 1H) 7.72-7.87 (m, 3H) 7.39 (s, 1H) 3.91 (br s, 4H) 2.99-3.06 (m, 4H) 2.32 (s, 3H) 1.92-2.07 (m, 4H) 1.62-1.85 (m, 4H) 0.38 (s, 4H). m/z (ESI): 568.0 (M−H).sup.+.

Intermediate 20: 4-Bromo-N-(2-(4,4-difluoropiperidin-1-yl)-6-methylpyrimidin-4-yl)-2-fluoro-6-(6-azaspiro[2.5]octan-6-yl)benzamide

[0295] ##STR00090##

[0296] Step 1: To a solution of 4-bromo-2,6-difluorobenzoic acid (3.0 g, 12.7 mmol, Apollo Scientific Ltd.) in THF (50 mL) was oxalyl chloride (1.7 mL, 19.0 mmol) followed by 1 drop of DMF. The mixture was stirred for 1 h then the solvent was removed in vacuo to give a solid that was taken directly to the next stage without further characterization. The solid was dissolved in DCM (50 mL) and anhydrous pyridine (4.31 mL, 50.6 mmol) followed by 2-(4,4-difluoropiperidin-1-yl)-6-methylpyrimidin-4-amine (2.89 g, 12.7 mmol, Int. 4) were added and the mixture was stirred for 16 h at room temperature. EtOAc (200 mL) was added and the mixture was washed with saturated NH.sub.4Cl (1×), water (1×), brine (1×), dried over anhydrous MgSO.sub.4, filtered and concentrated in vacuo to give an oil. The oil was purified by silica gel chromatography, eluting with 0 to 40% EtOAc/heptane, to provide 4-bromo-N-(2-(4,4-difluoropiperidin-1-yl)-6-methylpyrimidin-4-yl)-2,6-difluorobenzamide (1.36 g, 3.04 mmol, 24% yield) as a white solid. .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ ppm 11.24 (s, 1H) 7.64 (d, J=7.05 Hz, 2H) 7.19-7.37 (m, 1H) 3.86 (br s, 4H) 2.32 (s, 3H) 1.98 (br d, J=11.40 Hz, 4H). m/z (ESI): 447.0, 449.0 (M+H).sup.+.

[0297] Step 2: A mixture of 4-bromo-N-(2-(4,4-difluoropiperidin-1-yl)-6-methylpyrimidin-4-yl)-2,6-difluorobenzamide (0.65 g, 1.45 mmol), 6-azaspiro[2.5]octane (0.18 g, 1.60 mmol, Wuxi App Tech), and DIPEA (0.31 mL, 1.74 mmol) in DMSO (2.5 mL) was heated to 100° C. for 8 h then cooled to room temperature. Water was added, and the resulting suspension was filtered and the solid obtained was dried. This solid was purified by silica gel chromatography, eluting with 0 to 15% EtOAc/heptane, to provide 4-bromo-N-(2-(4,4-difluoropiperidin-1-yl)-6-methylpyrimidin-4-yl)-2-fluoro-6-(6-azaspiro[2.5]octan-6-yl)benzamide (0.23 g, 0.43 mmol, 28.2% yield) as a white solid. .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ ppm 10.86 (br s, 1H) 7.30 (br s, 1H) 7.21 (br d, J=9.12 Hz, 1H) 7.10 (br s, 1H) 3.88 (br s, 4H) 3.05 (br s, 4H) 2.32 (br s, 3H) 1.77-2.04 (m, 4H) 1.36 (br s, 4H) 0.27 (s, 4H). .sup.19F NMR (376 MHz, DMSO-d.sub.6) δ ppm −94.88 (s, 1F) −113.60 (s, 1F). m/z (ESI): 538.2, 540.2 (M+H).sup.+.

Intermediate 21: 4-Amino-N-(2-(4,4-difluoropiperidin-1-yl)-6-methylpyrimidin-4-yl)-5-fluoro-2-(6-azaspiro[2.5]octan-6-yl)benzamide

[0298] ##STR00091##

[0299] Step 1: Triethylamine (3.11 mL, 22.2 mmol) and 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane 2,4,6-trioxide (50 wt % in EtOAc, 13.2 mL, 22.2 mmol) were added to a solution of 2,5-difluoro-4-nitrobenzenecarboxylic acid (1.5 g, 7.39 mmol, Combi-Blocks Inc.) and 2-(4,4-difluoropiperidin-1-yl)-6-methylpyrimidin-4-amine (1.69 g, 7.39 mmol, Int. 4) in DCE (15 mL) and the mixture was heated to 85° C. for 2 h then cooled to room temperature. Water (15 mL) was added, the resulting biphasic mixture was separated, and the organic layer was dried over anhydrous MgSO.sub.4, filtered, and concentrated in vacuo to give a solid. The solid was suspended in DCM (15 mL), filtered, and dried to provide N-(2-(4,4-difluoropiperidin-1-yl)-6-methylpyrimidin-4-yl)-2,5-difluoro-4-nitrobenzamide (3.05 g, 4.55 mmol, 62% yield) as a yellow solid. .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ ppm 11.15 (s, 1H) 8.27 (dd, J=8.81, 5.91 Hz, 1H) 7.99 (dd, J=10.57, 5.39 Hz, 1H) 7.23 (br s, 1H) 3.85 (br s, 3H) 2.33 (s, 4H) 1.89-2.05 (m, 4H). .sup.19F NMR (376 MHz, DMSO-d.sub.6) δ ppm −95.11 (s, 1F) −123.35 (s, 1F) −123.40 (s, 1F). m/z (ESI): 414.2 (M+H).sup.+.

[0300] Step 2: A mixture of N-(2-(4,4-difluoropiperidin-1-yl)-6-methylpyrimidin-4-yl)-2,5-difluoro-4-nitrobenzamide (1.0 g, 2.42 mmol) and palladium (10 wt. % on activated carbon, 0.45 g, 0.42 mmol) was placed under argon atmosphere and then EtOH (15 mL) was added, followed by ammonium formate (0.76 g, 12.1 mmol). The mixture was stirred at 75° C. for 10 min, then cooled to room temperature. The palladium was filtered off using CELITE® and the filtrate was concentrated in vacuo. The resulting residue was dissolved in EtOAc (10 mL) and the solution was washed with water (2×10 mL), brine (1×10 mL), dried over anhydrous MgSO.sub.4, filtered, and concentrated in vacuo to provide 4-amino-N-(2-(4,4-difluoropiperidin-1-yl)-6-methylpyrimidin-4-yl)-2,5-difluorobenzamide (0.93 g, 2.19 mmol, 91% yield) as a white solid. .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ ppm 9.68-9.80 (m, 1H) 7.40 (dd, J=11.61, 6.84 Hz, 1H) 7.28 (s, 1H) 6.54 (dd, J=13.48, 7.26 Hz, 1H) 6.26 (s, 2H) 3.83-3.90 (m, 4H) 2.30 (s, 3H) 1.92-2.05 (m, 4H). .sup.19F NMR (376 MHz, DMSO-d.sub.6) δ ppm −95.07 (s, 1F) −116.10 (s, 1F) −140.24 (s, 1F). m/z (ESI): 384.2 (M+H).sup.+.

[0301] Step 3: A mixture of 4-amino-N-(2-(4,4-difluoropiperidin-1-yl)-6-methylpyrimidin-4-yl)-2,5-difluorobenzamide (0.80 g, 2.09 mmol), 6-azaspiro[2.5]octane (0.70 g, 6.26 mmol, Wuxi App Tech), and DIPEA (1.1 mL, 6.26 mmol) in NMP (4 mL) was heated to 200° C. in a microwave reactor for 4 h. Water (4 mL) was added and the resulting suspension was stirred for 30 min, filtered, and the collected solid was dried to give a white solid. This solid was dissolved in DCM, fused to silica gel and purified by silica gel chromatography, eluting with 0 to 50% EtOAc/heptane, to provide 4-amino-N-(2-(4,4-difluoropiperidin-1-yl)-6-methylpyrimidin-4-yl)-5-fluoro-2-(6-azaspiro[2.5]octan-6-yl)benzamide (702 mg, 1.48 mmol, 70.9% yield) as a white solid. .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ ppm 13.77 (s, 1H) 7.64 (d, J=12.85 Hz, 1H) 7.38 (s, 1H) 6.83 (d, J=8.09 Hz, 1H) 6.04 (s, 2H) 3.90 (br t, J=5.39 Hz, 4H) 2.91 (br s, 4H) 2.29 (s, 3H) 1.88-2.04 (m, 4H) 0.37 (s, 4H). (Note: 4 protons not observed). .sup.19F NMR (376 MHz, DMSO-d.sub.6) δ ppm −94.73 (s, 1F) −138.31 (s, 1F). m/z (ESI): 475.2 (M+H).sup.+.

TABLE-US-00007 TABLE 5 Intermediates 21-1 to 21-20 were prepared following similar procedures for Int. 17 to 21: LRMS: (ESI + ve Int. # Chemical Structure Name ion) m/z 21-1 [00092] (R)-4-Bromo-N-(2-(2- methylmorpholino)pyrimidin-4-yl)-2-(6- azaspiro[2.5]octan-6-yl)benzamide 486.1/488.1 21-2 [00093] (R)-4-Iodo-N-(6-methyl-2-(2- methylmorpholino)pyrimidin-4-yl)-2-(6- azaspiro[2.5]octan-6-yl)benzamide 548.2 21-3 [00094] 4-Bromo-N-(2-(4,4-difluoropiperidin-1- yl)-6-methylpyrimidin-4-yl)-2-(6- azaspiro[2.5]octan-6-yl)benzamide 520.1/522.1 21-4 [00095] 4-Bromo-N-(2-(4,4-difluoropiperidin-1- yl)-6-(2-hydroxypropan-2-yl)pyrimidin-4- yl)-2-(6-azaspiro[2.5]octan-6- yl)benzamide 564.1/566.1 21-5 [00096] 4-Bromo-N-(2-(4,4-difluoropiperidin-1- yl)-6-ethylpyrimidin-4-yl)-2-(6- azaspiro[2.5]octan-6-yl)benzamide 534.2/536.2 21-6 [00097] 4-Bromo-N-(6-cyclopropyl-2-(4,4- difluoropiperidin-1-yl)pyrimidin-4-yl)-2- (6-azaspiro[2.5]octan-6-yl)benzamide 546.1/548.1 21-7 [00098] 4-Bromo-5-chloro-N-(2-(4,4- difluoropiperidin-1-yl)-6-methylpyrimidin- 4-yl)-2-(6-azaspiro[2.5]octan-6- yl)benzamide 553.0/555.0 21-8 [00099] 4-Bromo-N-(2-(4,4-difluoropiperidin-1- yl)-6-methylpyrimidin-4-yl)-5-methyl-2- (6-azaspiro[2.5]octan-6-yl)benzamide 534.2/536.2 21-9 [00100] (R)-4-Amino-5-fluoro-N-(2-(2- methylmorpholino)pyrimidin-4-yl)-2-(6- azaspiro[2.5]octan-6-yl)benzamide 441.2 21-10 [00101] (R)-4-Amino-5-fluoro-N-(6-methyl-2-(2- methylmorpholino)pyrimidin-4-yl)-2-(6- azaspiro[2.5]octan-6-yl)benzamide 455.2 21-11 [00102] 4-Amino-N-(2-(4,4-difluoropiperidin-1- yl)-6-methylpyrimidin-4-yl)-5-methoxy-2- (6-azaspiro[2.5]octan-6-yl)benzamide 487.4 21-12 [00103] 4-Bromo-N-(2-(4,4-difluoropiperidin-1- yl)-3-fluoro-6-methylpyridin-4-yl)-2-(6- azaspiro[2.5]octan-6-yl)benzamide 537.1/539.1 21-13 [00104] 4-Bromo-N-(2-(4,4-difluorocyclohexyl)-6- methylpyrimidin-4-yl)-2-(6- azaspiro[2.5]octan-6-yl)benzamide 519.1/521.1 21-14 [00105] N-(2-(4,4-Difluoropiperidin-1-yl)pyridin- 4-yl)-4-iodo-2-(6-azaspiro[2.5]octan-6- yl)benzamide 553.1 21-15 [00106] 4-Bromo-N-(2-(4,4-difluoropiperidin-1- yl)-6-methylpyridin-4-yl)-2-(6- azaspiro[2.5]octan-6-yl)benzamide 519.1/521.1 21-16 [00107] 4-Iodo-N-(6-methyl-2-(3,3,3- trifluoropropoxy)pyrimidin-4-yl)-2-(6- azaspiro[2.5]octan-6-yl)benzamide 561.0 21-17 [00108] 4-Bromo-N-(2-chloro-6-methylpyrimidin- 4-yl)-2-(6-azaspiro[2.5]octan-6- yl)benzamide 435.0/437.0 21-18 [00109] N-(2-Chloro-6-methylpyrimidin-4-yl)-4- nitro-2-(6-azaspiro[2.5]octan-6- yl)benzamide 402.2 21-19 [00110] N-(2-Chloro-6-methylpyrimidin-4-yl)-4- (methylsulfonyl)-2-(6-azaspiro[2.5]octan- 6-yl)benzamide 434.4 21-20 [00111] N-(2-Chloro-6-methylpyrimidin-4-yl)-4- (N-(3-methyloxetan-3-yl)sulfamoyl)-2-(6- azaspiro[2.5]octan-6-yl)benzamide 506.1

Intermediate 22: Ethyl 2-sulfamoylpropanoate

[0302] ##STR00112##

[0303] Step 1: To a solution of N,N-bis(4-methoxybenzyl)ethanesulfonamide (200.0 g, 572.0 mmol) in tetrahydrofuran (4000 mL) was added nBuLi (1.6 M in hexane, 608.0 mL, 973.0 mmol) at −78° C. slowly and stirred for 30 min. Ethyl carbonochloridate (92.0 mL, 973.0 mmol) in THF (50 mL) was added to the reaction mixture and stirred at −78° C. for 1 h. The reaction mixture was quenched with HCl (1.5 N, 3000 mL) and extracted with EtOAc (2×3000 mL). The organic extract was dried over sodium sulphate, filtered and concentrated in reduced pressure to give the crude material of ethyl 2-(N,N-bis(4-methoxybenzyl)sulfamoyl)propanoate (250.0 g, 60% pure) as yellow oil. The .sup.1H-NMR showed desired peaks and proceeded to next step without any purification.

[0304] Step 2: To solution of ethyl 2-(N,N-bis(4-methoxybenzyl)sulfamoyl)propanoate (600.0 g, 1.4 mol) in trifluoroacetic acid (2.50 L, 32.45 mol) was added anisole (500.0 mL, 4.57 mol) and stirred at room temperature for 3 h. The reaction mixture was concentrated under reduced pressure, quenched with 10% cold aqueous NaHCO.sub.3 solution (3 L) and extracted with EtOAc (2×3 L). The organic layer was dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude residue was purified by column chromatography over silica gel using 25% ethyl acetate in hexanes to give a pale yellow solid (168 g) which was dissolved in DCM (1 L) and precipitated by the addition of hexanes (3000 mL). The solid was filtered, dried under vacuum to give the title compound (109.0 g, 42% yield) as a white solid. .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ ppm 7.14 (s, 2H), 4.15 (q, J=7.1 Hz, 2H), 3.98 (q, J=7.0 Hz, 1H), 1.45 (d, J=7.0 Hz, 3H), 1.21 (t, J=7.1 Hz, 3H). m/z (ESI): 180.1 (M−H).sup.+.

Intermediate 23: 2-Hydroxypropane-1-sulfonamide

[0305] ##STR00113##

[0306] Step 1: Methanesulfonyl chloride (1.73 mL, 22.3 mmol) was added dropwise over 5 min to a 0° C. solution of bis(4-methoxylbenzyl)amine (5.0 g, 19.4 mmol, Combi-Blocks Inc.) and triethylamine (8.12 mL, 58.3 mmol) in DCM (40 mL). The mixture was then stirred for 2 h at room temperature and then 1N HCl (50 mL) was added. The layers were separated, and the organic layer was washed with brine (1×50 mL), dried over anhydrous MgSO.sub.4, filtered, and then concentrated in vacuo to give a brown oil. The oil was dissolved in MeOH (50 mL) and partially concentrated in vacuo until a thick suspension formed. The suspension was stirred for 30 min, filtered, and the collected solid was dried in vacuo to provide N,N-bis(4-methoxybenzyl)methanesulfonamide (5.11 g, 15.2 mmol, 78% yield) as a white solid. .sup.1H NMR (400 MHz, DMSO-t4) δ ppm 7.19 (d, J=8.50 Hz, 4H) 6.90 (d, J=8.50 Hz, 4H) 4.19 (s, 4H) 3.75 (s, 6H) 2.89 (s, 3H).

[0307] Step 2: n-Butyllithium (4.10 mL, 6.56 mmol) was added dropwise to a solution of N,N-bis(4-methoxybenzyl)methanesulfonamide (2.0 g, 5.96 mmol) in THF (15 mL) at −78° C. The mixture was stirred for 10 min before acetaldehyde (0.37 mL, 6.56 mmol) was added dropwise. This mixture was stirred at −78° C. for 5 min, and then the −78° C. bath was replaced with a 0° C. bath. The mixture was stirred for 15 min and then the reaction was quenched with saturated NH.sub.4Cl. EtOAc was added, the resulting biphasic mixture was separated, and the organic layer was dried over anhydrous MgSO.sub.4, filtered, and concentrated in vacuo to give an oil. The oil was purified by silica gel chromatography, eluting with 0 to 70% EtOAc/heptane gradient, to provide 2-hydroxy-N,N-bis(4-methoxybenzyl)propane-1-sulfonamide (1.84 g, 4.85 mmol, 81% yield) as an oil. .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ ppm 7.16 (d, J=8.50 Hz, 4H) 6.80-6.92 (m, 4H) 4.99 (d, J=5.18 Hz, 1H) 4.15-4.28 (m, 4H) 4.01-4.13 (m, 1H) 3.74 (s, 6H) 3.16 (dd, J=13.99, 6.53 Hz, 1H) 3.04 (dd, J=13.89, 5.39 Hz, 1H) 1.12-1.27 (m, 3H). m/z (ESI): 402.2 (M+Na).sup.+.

[0308] Step 3: A mixture of 2-hydroxy-N,N-bis(4-methoxybenzyl)propane-1-sulfonamide (1.84 g, 4.85 mmol) and anisole (1.06 mL, 9.70 mmol) in TFA (10 mL) was stirred at room temperature for 2 h, then the volatiles were removed in vacuo. The resulting oil was purified by silica gel chromatography, eluting with 0 to 100% EtOAc/heptane gradient, to provide 2-hydroxypropane-1-sulfonamide (592 mg, 4.25 mmol, 88% yield) as a colorless oil. .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ ppm 6.70 (s, 2H) 4.02-4.13 (m, 1H) 3.50-3.25 (br s, 1H) 3.07-3.15 (m, 1H) 2.98-3.06 (m, 1H) 1.20 (d, J=6.22 Hz, 3H).

Example 1: N-(2-((1-Hydroxy-2-methylpropan-2-yl)amino)-6-methylpyrimidin-4-yl)-4-(methylsulfonyl)-2-(6-azaspiro[2.5]octan-6-yl)benzamide

[0309] ##STR00114##

[0310] A mixture of N-(2-chloro-6-methylpyrimidin-4-yl)-4-(methylsulfonyl)-2-(6-azaspiro[2.5]octan-6-yl)benzamide (200 mg, 0.46 mmol, Int. 21-19), 2-amino-2-methyl-1-propanol (180 uL, 1.80 mmol, Sigma-Aldrich, St Louis, Mo.), and DIPEA (200 uL, 1.14 mmol) in NMP (1 mL) was heated at 130° C. for 60 h. The reaction mixture was cooled to room temperature and quenched with water (10 mL), extracted with ethyl acetate (2×10 mL). The organic layer was washed with brine (500 mL), dried (Na.sub.2SO.sub.4), filtered and concentrated under reduced pressure. The crude material was adsorbed onto a plug of silica gel and purified by column chromatography over silica gel (60-120 mesh), eluting with 0% to 70% ethyl acetate in heptane to give the title compound (111 mg, 49%) as an off white solid. .sup.1H NMR (400 MHz, DMSO-Je) δ ppm 11.65-11.96 (m, 1H), 8.07-8.25 (m, 1H), 7.82-7.87 (m, 1H), 7.75-7.81 (m, 1H), 7.32-7.41 (m, 1H), 6.13-6.24 (m, 1H), 4.73-4.91 (m, 1H), 3.42-3.54 (m, 2H), 3.30-3.33 (m, 3H), 3.01-3.16 (m, 4H), 2.18-2.28 (m, 3H), 1.55-1.75 (m, 4H), 1.25-1.42 (m, 6H), 0.27-0.40 (m, 4H). m/z (ESI): 487.4 (M+H).sup.+.

TABLE-US-00008 TABLE 6 Examples 1-1 to 1-7 were prepared following a similar procedure as described for Example 1: LRMS: (ESI + Ex. # Chemical Structure Name ve ion) m/z 1-1 [00115] (R)-N-(2-((1-Hydroxypropan-2- yl)amino)-6-methylpyrimidin-4-yl)-4- (methylsulfonyl)-2-(6- azaspiro[2.5]octan-6-yl)benzamide 474.0 1-2 [00116] (S)-N-(2-((1-Hydroxypropan-2- yl)amino)-6-methylpyrimidin-4-yl)-4- (methylsulfonyl)-2-(6- azaspiro[2.5]octan-6-yl)benzamide 474.0 1-3 [00117] N-(2-((2-Hydroxyethyl)amino)-6- methylpyrimidin-4-yl)-4- (methylsulfonyl)-2-(6- azaspiro[2.5]octan-6-yl)benzamide 460.4 1-4 [00118] (R)-N-(2-((2-Hydroxypropyl)amino)-6- methylpyrimidin-4-yl)-4- (methylsulfonyl)-2-(6- azaspiro[2.5]octan-6-yl)benzamide 474.4 1-5 [00119] (S)-N-(2-((2-Hydroxypropyl)amino)-6- methylpyrimidin-4-yl)-4- (methylsulfonyl)-2-(6- azaspiro[2.5]octan-6-yl)benzamide 474.4 1-6 [00120] N-(6-Methyl-2-(3,3,3- trifluoropropoxy)pyrimidin-4-yl)-4-(N- (3-methyloxetan-3-yl)sulfamoyl)-2-(6- azaspiro[2.5]octan-6-yl)benzamide 584.2 1-7 [00121] N-(2-((1-Hydroxy-2-methylpropan-2- yl)amino)-6-methylpyrimidin-4-yl)-4- (N-(3-methyloxetan-3-yl)sulfamoyl)-2- (6-azaspiro[2.5]octan-6-yl)benzamide 559.4

Example 2: N-(2-(2-Hydroxypropan-2-yl)pyrimidin-4-yl)-4-(N-(3-methyloxetan-3-yl)sulfamoyl)-2-(6-azaspiro[2.5]octan-6-yl)benzamide

[0311] ##STR00122##

[0312] To a solution of 4-(N-(3-methyloxetan-3-yl)sulfamoyl)-2-(6-azaspiro[2.5]octan-6-yl)benzoic acid (150 mg, 0.394 mmol, Int. 15) and 2-(4-aminopyrimidin-2-yl)propan-2-ol (91 mg, 0.591 mmol, AstaTech, Bristol, Pa., USA) in dichloromethane (2.6 mL) at 0° C. was added 1-propanephosphonic anhydride (50% in ethyl acetate, 0.469 mL, 0.789 mmol, Aldrich) followed by DIPEA (0.207 mL, 1.18 mmol, Aldrich). The resulting mixture was then stirred at room temperature overnight. Then, the mixture was then diluted with saturated NaHCO.sub.3 (2 mL) followed by saturated NH.sub.4Cl (7 mL). The mixture was then extracted with EtOAc (2×15 mL). The combined organic extracts were then dried over MgSO.sub.4 and concentrated. Chromatographic purification of the residue (silica gel, 0%-100% EtOAc/heptane) provided N-(2-(2-hydroxypropan-2-yl)pyrimidin-4-yl)-4-(N-(3-methyloxetan-3-yl)sulfamoyl)-2-(6-azaspiro[2.5]octan-6-yl)benzamide (45 mg, 0.087 mmol) as a light yellow solid. .sup.1H NMR (DMSO-d.sub.6) δ ppm 13.52 (brs, 1H), 8.76 (d, J=5.6 Hz, 1H), 8.54 (br d, J=3.5 Hz, 1H), 8.24 (d, J=8.1 Hz, 1H), 8.08 (br d, J=5.4 Hz, 1H), 7.86 (d, J=1.0 Hz, 1H), 7.74 (dd, J=8.1, 1.5 Hz, 1H), 4.96 (s, 1H), 4.55 (d, J=6.0 Hz, 2H), 4.13 (d, J=6.4 Hz, 2H), 3.08 (br t, J=5.2 Hz, 4H), 1.70 (brs, 4H), 1.51 (s, 6H), 1.41 (s, 3H), 0.38 (s, 4H). m/z (ESI): 516.2 (M+H)+.

TABLE-US-00009 TABLE 7 Examples 2-1 to 2-8 were prepared following a similar procedure as described for example 2: LRMS: (ESI + Ex. # Chemical Structure Name ve ion) m/z 2-1 [00123] N-(2-(2-Hydroxypropan-2-yl)-6- methylpyrimidin-4-yl)-4-(N-(3- methyloxetan-3-yl)sulfamoyl)-2- (6-azaspiro[2.5]octan-6- yl)benzamide 530.2 2-2 [00124] (R)-N-(2-(2- Methylmorpholino)pyrimidin-4- yl)-4-(N-(3-methyloxetan-3- yl)sulfamoyl)-2-(6- azaspiro[2.5]octan-6-yl)benzamide 557.2 2-3 [00125] (R)-N-(6-Methyl-2-(2- methylmorpholino)pyrimidin-4- yl)-4-(N-(3-methyloxetan-3- yl)sulfamoyl)-2-(6- azaspiro[2.5]octan-6-yl)benzamide 571.2 2-4 [00126] N-(2-(4,4-Difluoropiperidin-1- yl)pyridin-4-yl)-4-(N-(3- methyloxetan-3-yl)sulfamoyl)-2- (6-azaspiro[2.5]octan-6- yl)benzamide 576.2 2-5 [00127] N-(2-(4,4-Difluoropiperidin-1-yl)- 6-methylpyrimidin-4-yl)-4-(N-(3- methyloxetan-3-yl)sulfamoyl)-2- (6-azaspiro[2.5]octan-6- yl)benzamide 591.2 2-6 [00128] N-(2-(4,4-Difluoropiperidin-1-yl)- 6-methylpyrimidin-4-yl)-4- (methylsulfonyl)-2-(6- azaspiro[2.5]octan-6-yl)benzamide 520.0 2-7 [00129] (R)-N-(2-(2- Methylmorpholino)pyrimidin-4- yl)-4-(methylsulfonyl)-2-(6- azaspiro[2.5]octan-6-yl)benzamide 486.1 2-8 [00130] N-(2-(4,4-Difluoropiperidin-1-yl)- 6-methylpyrimidin-4-yl)-4-((1- methylcyclopropane)-1- sulfonamido)-2-(6- azaspiro[2.5]octan-6-yl)benzamide 575.4

Example 3: (R)-4-((2-Hydroxyethyl)sulfonamido)-N-(6-methyl-2-(2-methylmorpholino)pyrimidin-4-yl)-2-(6-azaspiro[2.5]octan-6-yl)benzamide

[0313] ##STR00131##

[0314] Tribasic potassium phosphate (9.89 g, 46.6 mmol, Sigma-Aldrich), copper(I) iodide (0.710 g, 3.73 mmol, Sigma-Aldrich), 2-hydroxyethane-1-sulfonamide (1.166 g, 9.32 mmol, Wuxi Apptec, China), sarcosine (0.830 g, 9.32 mmol), and (R)-4-iodo-N-(6-methyl-2-(2-methylmorpholino)pyrimidin-4-yl)-2-(6-azaspiro[2.5]octan-6-yl)benzamide (5.1 g, 9.32 mmol, Int. 21-2) were combined in a three neck flask under argon. Dry, degassed DMF (20 mL) was added and the mixture heated to 110° C. with overhead stirring for 45 minutes. The reaction was cooled to ambient temperature and saturated ammonium chloride (75 mL), water (200 mL) and ethyl acetate (200 mL) were added. The phases were mixed and separated and the organic dried with brine (75 mL) before evaporating to dryness under reduced pressure. The crude solids were stirred in boiling ethanol (15 mL) for 10 minutes then cooled to ambient temperature and filtered through a sintered glass frit. The solids were dried on the frit then suspended in water (75 mL) and heated to 80° C. After 10 minutes, the mixture was cooled to ambient temperature and filtered through a sintered glass frit. The solids were dried under a stream of nitrogen to give the title compound (3.3 g, 6.06 mmol, 65.0% yield) as an off-white solid. .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ ppm 13.23 (bs, 1H), 10.26 (bs, 1H), 8.05 (m, 1H), 7.37 (s, 1H), 7.26 (s, 1H), 7.13 (s, 1H), 4.95 (bs, 1H), 4.50-4.42 (m, 2H), 3.84 (m, 1H), 3.76-3.74 (m, 2H), 3.51-3.45 (m, 2H), 3.00-2.82 (m, 6H), 2.61-2.58 (m, 2H), 2.31 (s, 3H), 1.91-1.65 (m, 4H), 1.17 (d, J=6.0 Hz, 3H), 0.39 (s, 4H). m/z (ESI): 545.2 (M+H)+.

Example 4: N-(2-(4,4-Difluoropiperidin-1-yl)-6-methylpyrimidin-4-yl)-4-((2-hydroxyethyl)sulfonamido)-2-(6-azaspiro[2.5]octan-6-yl)benzamide

[0315] ##STR00132##

[0316] A mixture of 2-hydroxyethane-1-sulfonamide (1.28 g, 10.3 mmol, Wuxi AppTec), copper(I) iodide (0.49 g, 2.56 mmol), potassium phosphate tribasic (5.44 g, 25.6 mmol), and Sarcosine (0.48 g, 5.13 mmol) in a 100 mL round bottom flask was placed under argon atmosphere. Anhydrous DMF (20 mL) was added and the mixture was warmed to 50° C. for 5 minutes. N-(2-(4,4-difluoropiperidin-1-yl)-6-methylpyrimidin-4-yl)-4-iodo-2-(6-azaspiro[2.5]octan-6-yl)benzamide (2.91 g, 5.13 mmol, Int. 19) was added as a solid and the mixture was heated to 100° C. and stirred for 2 h, then cooled to room temperature. EtOAc (20 mL) and water (20 mL) were added, the resulting biphasic mixture was separated, and the aqueous layer was extracted with EtOAc (3×). The combined organic extracts were then washed with water (2×), 9:1 NH.sub.4Cl/NH.sub.4OH (aq), brine, dried over anhydrous MgSO.sub.4, filtered, and concentrated in vacuo to give an oil. The oil was purified by silica gel chromatography, eluting with 0 to 50% EtOAc/heptane gradient, then 50% EtOAc/heptane isocratic elution, to provide an off-white solid. This solid was suspended in methanol, filtered, and dried to give a white solid. This solid was then suspended in water, stirred for 24 h, filtered, and dried in vacuo to provide N-(2-(4,4-difluoropiperidin-1-yl)-6-methylpyrimidin-4-yl)-4-((2-hydroxyethyl)sulfonamido)-2-(6-azaspiro[2.5]octan-6-yl)benzamide (1.55 g, 2.75 mmol, 54% yield) as a white solid. .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ ppm 13.37 (s, 1H) 10.03-10.52 (m, 1H) 8.06 (d, J=8.71 Hz, 1H) 7.41 (s, 1H) 7.28 (d, J=1.87 Hz, 1H) 7.15 (dd, J=8.71, 1.87 Hz, 1H) 4.73-5.14 (m, 1H) 3.92 (br t, J=5.39 Hz, 4H) 3.77 (t, J=6.43 Hz, 2H) 3.34-3.40 (m, 2H) 2.98 (br t, J=4.56 Hz, 4H) 2.32 (s, 3H) 1.93-2.07 (m, 4H) 1.58-1.85 (m, 4H) 0.40 (s, 4H). .sup.19F NMR (376 MHz, DMSO-d.sub.6) δ ppm −94.74 (s, 1F). m/z (ESI): 565.2 (M+H).sup.+.

Examples 5-1 and 5-2: (R)-N-(2-(4,4-difluoropiperidin-1-yl)-6-methylpyrimidin-4-yl)-4-((2-hydroxy-1-methylethyl)sulfonamido)-2-(6-azaspiro[2.5]octan-6-yl)benzamide and (S)-N-(2-(4,4-difluoropiperidin-1-yl)-6-methylpyrimidin-4-yl)-4-((2-hydroxy-1-methylethyl)sulfonamido)-2-(6-azaspiro[2.5]octan-6-yl)benzamide

[0317] ##STR00133##

[0318] Step 1: A mixture of ethyl 2-sulfamoylpropanoate (1.44 g, 7.93 mmol, Int. 22), copper(I) iodide (0.503 g, 2.64 mmol, Strem), sarcosine (0.47 g, 5.29 mmol, Sigma-Aldrich Corporation), and potassium phosphate (4.49 g, 21.2 mmol) in DMF (15 mL) was placed under argon atmosphere and warmed to 50° C. for 5 min. N-(2-(4,4-difluoropiperidin-1-yl)-6-methylpyrimidin-4-yl)-4-iodo-2-(6-azaspiro[2.5]octan-6-yl)benzamide (3.0 g, 5.29 mmol, Int. 19) was added and the mixture was heated to 100° C. for 3 h, then cooled to room temperature. EtOAc (50 mL), IPA (5 mL) and water (50 mL) were added and the mixture was stirred vigorously for 5 min. The resulting biphasic mixture was transferred to a separatory funnel and the layers were separated. The aqueous layer was extracted with EtOAc (2×20 mL) and the combined extracts were then washed with water (2×50 mL), 9:1 NH.sub.4Cl/NH.sub.4OH (1×50 mL), dried over anhydrous MgSO.sub.4, filtered, and concentrated in vacuo to give an oil. The crude oil was purified by silica gel chromatography using a Redi-Sep pre-packed silica gel column (80 g), eluting with 0 to 50% EtOAc/heptane gradient, to provide ethyl 2-(N-(4-((2-(4,4-difluoropiperidin-1-yl)-6-methylpyrimidin-4-yl)carbamoyl)-3-(6-azaspiro[2.5]octan-6-yl)phenyl)sulfamoyl)propanoate (2.76 g, 4.45 mmol, 84% yield) as a white solid. .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ ppm 13.35 (s, 1H) 10.69 (br s, 1H) 8.07 (d, J=8.71 Hz, 1H) 7.40 (s, 1H) 7.31 (d, J=1.87 Hz, 1H) 7.17 (dd, J=8.60, 1.97 Hz, 1H) 4.06 (qd, J=7.08, 4.87 Hz, 2H) 3.92 (br t, J=5.49 Hz, 4H) 2.98 (br t, J=4.77 Hz, 4H) 2.32 (s, 3H) 1.85-2.06 (m, 5H) 1.73 (br s, 4H) 1.48 (d, J=6.84 Hz, 3H) 1.14 (t, J=7.05 Hz, 3H) 0.39 (s, 4H). .sup.19F NMR (376 MHz, DMSO-d.sub.6) δ ppm −94.75 (s, 1F). m/z (ESI): 621.2 (M+H).sup.+.

[0319] Step 2: To a 250 mL round bottom flask was added ethyl 2-(N-(4-((2-(4,4-difluoropiperidin-1-yl)-6-methylpyrimidin-4-yl)carbamoyl)-3-(6-azaspiro[2.5]octan-6-yl)phenyl)sulfamoyl)propanoate (10.39 g, 16.74 mmol) and lithium borohydride solution, (2.0M in THF, 16.7 mL, 33.5 mmol, Sigma-Aldrich Corporation) in THF (100 mL). Methanol (4.29 mL, 134 mmol) was added slowly over 5 min and the resulting solution was stirred at room temperature for 30 min. 1 N HCl (20 mL) was slowly added followed by EtOAc (20 mL) and the resulting biphasic mixture was transferred to a separatory funnel and the phases were separated. The aqueous layer was extracted with EtOAc (1×25 mL) and the combined extracts were washed with saturated NaHCO.sub.3 (1×50 mL), brine (1×50 mL), dried over anhydrous MgSO.sub.4, filtered, and concentrated to give 8.9 g racemic mixture. This material was separated by preparative SFC using a Chiral Tech AD column (250×30 mm, 5 mm) with a mobile phase of 85% Liquid CO.sub.2 and 15% MeOH with 0.2% TEA using a flowrate of 150 mL/min to give:

[0320] Example 5-1: (R)-N-(2-(4,4-difluoropiperidin-1-yl)-6-methylpyrimidin-4-yl)-4-((2-hydroxy-1-methylethyl)sulfonamido)-2-(6-azaspiro[2.5]octan-6-yl)benzamide. First eluting peak (3.50 g, 6.05 mmol, 36.1% yield, >99% ee). .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ ppm 13.36 (s, 1H) 8.05 (d, J=8.50 Hz, 1H) 7.40 (s, 1H) 7.31 (d, J=1.87 Hz, 1H) 7.17 (dd, J=8.71, 2.07 Hz, 1H) 3.88-3.97 (m, 4H) 3.84 (dd, J=10.99, 4.35 Hz, 1H) 3.37-3.54 (m, 1H) 3.25-3.30 (m, 1H) 2.97 (brt, J=4.77 Hz, 4H) 2.32 (s, 3H) 1.84-2.06 (m, 4H) 1.57-1.84 (br s, 4H) 1.30 (d, J=6.84 Hz, 3H) 0.39 (s, 4H). 2 exchangeable protons not observed. .sup.19F NMR (376 MHz, DMSO-d.sub.6) δ ppm −94.74 (s, 1F). m/z (ESI): 579.2 (M+H).sup.+.

[0321] Example 5-2: (S)-N-(2-(4,4-difluoropiperidin-1-yl)-6-methylpyrimidin-4-yl)-4-((2-hydroxy-1-methylethyl)sulfonamido)-2-(6-azaspiro[2.5]octan-6-yl)benzamide. Second eluting peak (2.66 g, 4.60 mmol, 27.5% yield. 98.9% ee). .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ ppm 13.35 (s, 1H) 8.05 (d, J=8.50 Hz, 1H) 7.40 (s, 1H) 7.31 (d, J=2.07 Hz, 1H) 7.17 (dd, J=8.60, 1.97 Hz, 1H) 3.88-3.97 (m, 4H) 3.84 (dd, J=10.99, 4.35 Hz, 1H) 3.50 (dd, J=10.99, 7.46 Hz, 1H) 3.25-3.32 (m, 1H) 2.97 (br t, J=4.77 Hz, 4H) 2.31 (s, 3H) 1.83-2.06 (m, 4H) 1.73 (br s, 4H) 1.30 (d, J=6.84 Hz, 3H) 0.39 (s, 4H). 2 exchangeable protons not observed. .sup.19F NMR (376 MHz, DMSO-d.sub.6) δ ppm −94.75 (s, 1F). m/z (ESI): 579.2 (M+H).sup.+. The stereochemistry was arbitrarily assigned.

TABLE-US-00010 TABLE 8 Examples 6-1 to 6-40 were prepared following a similar procedure for Examples 3 to 5-2: LRMS: (ESI + Ex. # Chemical Structure Name ve ion) m/z 6-1 [00134] 4- ((Fluoromethyl)sulfonamido)- N-(2-(4-fluoropiperidin-1-yl)- 6-methylpyrimidin-4-yl)-2-(6- azaspiro[2.5]octan-6- yl)benzamide 535.3 6-2 [00135] N-(2-(4,4-Difluoropiperidin-1- yl)-6-methylpyrimidin-4-yl)-4- ((fluoromethyl)sulfonamido)- 2-(6-azaspiro[2.5]octan-6- yl)benzamide 553.3 6-3 [00136] (R)-4- ((Fluoromethyl)sulfonamido)- N-(6-methyl-2-(2- methylmorpholino)pyrimidin- 4-yl)-2-(6-azaspiro[2.5]octan- 6-yl)benzamide 533.2 6-4 [00137] (R)-4-((2- Hydroxyethyl)sulfonamido)- N-(2-(2- methylmorpholino)pyrimidin- 4-yl)-2-(6-azaspiro[2.5]octan- 6-yl)benzamide 531.2 6-5 [00138] (R)-N-(6-Methyl-2-(2- methylmorpholino)pyrimidin- 4-yl)-4-(methylsulfonamido)- 2-(6-azaspiro[2.5]octan-6- yl)benzamide 515.2 6-6 [00139] (R)-4-(Ethylsulfonamido)-N- (6-methyl-2-(2- methylmorpholino)pyrimidin- 4-yl)-2-(6-azaspiro[2.5]octan- 6-yl)benzamide 529.2 6-7 [00140] N-(2-(4,4-Difluoropiperidin-1- yl)-6-methylpyrimidin-4-yl)-4- (ethylsulfonamido)-2-(6- azaspiro[2.5]octan-6- yl)benzamide 549.2 6-8 [00141] (R)-4-((3- Hydroxypropyl)sulfonamido)- N-(6-methyl-2-(2- methylmorpholino)pyrimidin- 4-yl)-2-(6-azaspiro[2.5]octan- 6-yl)benzamide 559.2 6-9 [00142] N-(2-(4,4-Difluoropiperidin-1- yl)-6-methylpyrimidin-4-yl)-4- (3,3-dioxido-1,3,4- oxathiazinan-4-yl)-2-(6- azaspiro[2.5]octan-6- yl)benzamide 577.2 6-10 [00143] 4-(Cyclopentanesulfonamido)- N-(2-(4,4-difluoropiperidin-1- yl)-6-methylpyrimidin-4-yl)-2- (6-azaspiro[2.5]octan-6- yl)benzamide 589.3 6-11 [00144] 4-(Cyclobutanesulfonamido)- N-(2-(4,4-difluoropiperidin-1- yl)-6-methylpyrimidin-4-yl)-2- (6-azaspiro[2.5]octan-6- yl)benzamide 575.2 6-12 [00145] N-(2-(4,4-Difluoropiperidin-1- yl)-6-methylpyrimidin-4-yl)-4- (oxetane-3-sulfonamido)-2-(6- azaspiro[2.5]octan-6- yl)benzamide 577.2 6-13 [00146] 4-(Cyclobutanesulfonamido)- N-(2-(3,3-difluoroazetidin-1- yl)-6-methylpyrimidin-4-yl)-2- (6-azaspiro[2.5]octan-6- yl)benzamide 547.2 6-14 [00147] N-(2-(4,4-Difluoropiperidin-1- yl)-6-methylpyrimidin-4-yl)-4- ((1,1- dimethylethyl)sulfonamido)-2- (6-azaspiro[2.5]octan-6- yl)benzamide 577.3 6-15 [00148] N-(2-(4,4-Difluoropiperidin-1- yl)-6-methylpyrimidin-4-yl)-4- ((3- hydroxypropyl)sulfonamido)- 2-(6-azaspiro[2.5]octan-6- yl)benzamide 579.2 6-16 [00149] 4-(Cyclopropanesulfonamido)- N-(2-(4,4-difluoropiperidin-1- yl)-6-methylpyrimidin-4-yl)-2- (6-azaspiro[2.5]octan-6- yl)benzamide 561.2 6-17 [00150] N-(2-(4,4-Difluoropiperidin-1- yl)-6-methylpyrimidin-4-yl)-4- ((2- methoxyethyl)sulfonamido)-2- (6-azaspiro[2.5]octan-6- yl)benzamide 579.9 6-18 [00151] 4-((Cyclopropyl- methyl)sulfonamido)- N-(2-(4,4- difluoropiperidin-1-yl)-6- methylpyrimidin-4-yl)-2-(6- azaspiro[2.5]octan-6- yl)benzamide 575.2 6-19 [00152] N-(2-(4,4-Difluoropiperidin-1- yl)-6-methylpyrimidin-4-yl)-4- (((3-hydroxyoxetan-3- yl)methyl)sulfonamido)-2-(6- azaspiro[2.5]octan-6- yl)benzamide 607.2 6-20 [00153] N-(2-(4,4-Difluoropiperidin-1- yl)-6-methylpyrimidin-4-yl)-4- ((2-hydroxy-1,1- dimethylethyl)sulfonamido)-2- (6-azaspiro[2.5]octan-6- yl)benzamide 593.2 6-21 [00154] N-(2-(4,4-Difluoropiperidin-1- yl)-6-methylpyrimidin-4-yl)-4- (methylsulfonamido)-2-(6- azaspiro[2.5]octan-6- yl)benzamide 535.2 6-22 [00155] N-(2-(4,4-Difluoropiperidin-1- yl)-6-methylpyrimidin-4-yl)-4- ((1-methylethyl)sulfonamido)- 2-(6-azaspiro[2.5]octan-6- yl)benzamide 563.2 6-23-1 [00156] 4-(((S)-2-Hydroxy-1- methylethyl)sulfonamido)-N- (6-methyl-2-((R)-2- methylmorpholino)pyrimidin- 4-yl)-2-(6-azaspiro[2.5]octan- 6-yl)benzamide 559.2 6-23-2 [00157] 4-(((R)-2-Hydroxy-1- methylethyl)sulfonamido)-N- (6-methyl-2-((R)-2- methylmorpholino)pyrimidin- 4-yl)-2-(6-azaspiro[2.5]octan- 6-yl)benzamide 559.2 6-24-1 [00158] 4-(((S)-2-Hydroxy-1- methylethyl)sulfonamido)-N- (2-((R)-2- methylmorpholino)pyrimidin- 4-yl)-2-(6-azaspiro[2.5]octan- 6-yl)benzamide 545.2 6-24-2 [00159] 4-(((R)-2-hydroxy-1- methylethyl)sulfonamido)-N- (2-((R)-2- methylmorpholino)pyrimidin- 4-yl)-2-(6-azaspiro[2.5]octan- 6-yl)benzamide 545.2 6-25-1 [00160] (S)-N-(2-(4-fluoropiperidin-1- yl)-6-methylpyrimidin-4-yl)-4- ((2-hydroxy-1- methylethyl)sulfonamido)-2- (6-azaspiro[2.5]octan-6- yl)benzamide 561.2 6-25-2 [00161] (R)-N-(2-(4-Fluoropiperidin-1- yl)-6-methylpyrimidin-4-yl)-4- ((2-hydroxy-1- methylethyl)sulfonamido)-2- (6-azaspiro[2.5]octan-6- yl)benzamide 561.2 6-26-1 [00162] (S)-N-(2-(4,4- Difluoropiperidin-1- yl)pyrimidin-4-yl)-4-((2- hydroxy-1- methylethyl)sulfonamido)-2- (6-azaspiro[2.5]octan-6- yl)benzamide 565.2 6-26-2 [00163] (R)-N-(2-(4,4- Difluoropiperidin-1- yl)pyrimidin-4-yl)-4-((2- hydroxy-1- methylethyl)sulfonamido)-2- (6-azaspiro[2.5]octan-6- yl)benzamide 565.2 6-27-1 [00164] 4-(((R)-2- Hydroxypropyl)sulfonamido)- N-(6-methyl-2-((R)-2- methylmorpholino)pyrimidin- 4-yl)-2-(6-azaspiro[2.5]octan- 6-yl)benzamide 559.2 6-27-2 [00165] 4-(((S)-2- Hydroxypropyl)sulfonamido)- N-(6-methyl-2-((R)-2- methylmorpholino)pyrimidin- 4-yl)-2-(6-azaspiro[2.5]octan- 6-yl)benzamide 559.2 6-28-1 [00166] (R)-4-((2- Hydroxypropyl)sulfonamido)- N-(6-methyl-2-(3,3,3- trifluoropropoxy)pyrimidin-4- yl)-2-(6-azaspiro[2.5]octan-6- yl)benzamide 572.2 6-28-2 [00167] (S)-4-((2- Hydroxypropyl)sulfonamido)- N-(6-methyl-2-(3,3,3- trifluoropropoxy)pyrimidin-4- yl)-2-(6-azaspiro[2.5]octan-6- yl)benzamide 572.2 6-29 [00168] N-(2-(4,4-Difluoropiperidin-1- yl)pyridin-4-yl)-4-((2- hydroxyethyl)sulfonamido)-2- (6-azaspiro[2.5]octan-6- yl)benzamide 550.2 6-30 [00169] N-(2-(4,4-Difluoropiperidin-1- yl)-6-methylpyridin-4-yl)-4- ((2- hydroxyethyl)sulfonamido)-2- (6-azaspiro[2.5]octan-6- yl)benzamide 564.2 6-31-1 [00170] (R)-N-(2-(4,4- Difluoropiperidin-1-yl)-6- methylpyrimidin-4-yl)-4-((1- (1- hydroxyethyl)cyclopropane)- 1-sulfonamido)-2-(6- azaspiro[2.5]octan-6- yl)benzamide 605.2 6-31-2 [00171] (S)-N-(2-(4,4- Difluoropiperidin-1-yl)-6- methylpyrimidin-4-yl)-4-((1- (1- hydroxyethyl)cyclopropane)- 1-sulfonamido)-2-(6- azaspiro[2.5]octan-6- yl)benzamide 605.2 6-32-1 [00172] (R)-N-(2-(4,4- Difluoropiperidin-1-yl)-6- methylpyrimidin-4-yl)-4-((2- hydroxypropyl)sulfonamido)- 2-(6-azaspiro[2.5]octan-6- yl)benzamide 579.1 6-32-2 [00173] (S)-N-(2-(4,4- Difluoropiperidin-1-yl)-6- methylpyrimidin-4-yl)-4-((2- hydroxypropyl)sulfonamido)- 2-(6-azaspiro[2.5]octan-6- yl)benzamide 579.1 6-33-1 [00174] 4-(((S)-2- Hydroxypropyl)sulfonamido)- N-(2-((R)-2- methylmorpholino)pyrimidin- 4-yl)-2-(6-azaspiro[2.5]octan- 6-yl)benzamide 545.2 6-33-2 [00175] 4-(((R)-2- hydroxypropyl)sulfonamido)- N-(2-((R)-2- methylmorpholino)pyrimidin- 4-yl)-2-(6-azaspiro[2.5]octan- 6-yl)benzamide 545.2 6-34 [00176] 5-Chloro-N-(2-(4,4- difluoropiperidin-1-yl)-6- methylpyrimidin-4-yl)-4-((2- hydroxyethyl)sulfonamido)-2- (6-azaspiro[2.5]octan-6- yl)benzamide 599.2 6-35 [00177] N-(2-(4,4-Difluoropiperidin-1- yl)-6-methylpyrimidin-4-yl)-4- ((2- hydroxyethyl)sulfonamido)-5- methyl-2-(6- azaspiro[2.5]octan-6- yl)benzamide 579.2 6-36 [00178] N-(2-(4,4-Difluoropiperidin-1- yl)-6-methylpyrimidin-4-yl)-4- ((2- hydroxyethyl)sulfonamido)-5- methoxy-2-(6- azaspiro[2.5]octan-6- yl)benzamide 595.2 6-37 [00179] N-(2-(4,4-Difluoropiperidin-1- yl)-6-(2-hydroxypropan-2- yl)pyrimidin-4-yl)-4-((2- hydroxyethyl)sulfonamido)-2- (6-azaspiro[2.5]octan-6- yl)benzamide 609.1 6-38 [00180] N-(2-(4,4-Difluoropiperidin-1- yl)-6-ethylpyrimidin-4-yl)-4- ((2- hydroxyethyl)sulfonamido)-2- (6-azaspiro[2.5]octan-6- yl)benzamide 579.2 6-39 [00181] N-(6-Cyclopropyl-2-(4,4- difluoropiperidin-1- yl)pyrimidin-4-yl)-4-((2- hydroxyethyl)sulfonamido)-2- (6-azaspiro[2.5]octan-6- yl)benzamide 591.2 6-40 [00182] (R)-4-((2- Hydroxyethyl)sulfonamido)- N-(6-(2-hydroxypropan-2-yl)- 2-(2- methylmorpholino)pyrimidin- 4-yl)-2-(6-azaspiro[2.5]octan- 6-yl)benzamide 589.3

Example 7: N-(2-(3,3-Difluoroazetidin-1-yl)-6-methylpyrimidin-4-yl)-4-((2-hydroxyethyl)sulfonamido)-2-(6-azaspiro[2.5]octan-6-yl)benzamide

[0322] ##STR00183##

[0323] Step 1: A solution of N-(2-chloro-6-methylpyrimidin-4-yl)-4-nitro-2-(6-azaspiro[2.5]octan-6-yl)benzamide (0.3 g, 0.747 mmol, Int. 21-18), 3,3-difluoroazetidine hydrochloride (0.145 g, 1.120 mmol, Combi-Blocks) and DIPEA (0.261 mL, 1.49 mmol) in DMF (0.5 mL) and ethanol (1 mL) was heated at 80° C. for 4 h. Then the reaction mixture was quenched with water (50 mL) and extracted with ethyl acetate (3×50 mL). The combined organic layers were washed with brine (50 mL), dried over Na.sub.2SO.sub.4, filtered, and concentrated. The concentrate was purified by flash column chromatography eluting with 30% to 50% ethyl acetate in petroleum ether to provide N-(2-(3,3-difluoroazetidin-1-yl)-6-methylpyrimidin-4-yl)-4-nitro-2-(6-azaspiro[2.5]octan-6-yl)benzamide (180 mg, 0.393 mmol, 52.6% yield) as yellow solid .sup.1H NMR (400 MHz, Chloroform-d) δ ppm 8.47 (d, J=8.7 Hz, 1H), 8.25 (d, J=12 Hz, 1H), 8.17 (dd, J=8.7, 2.2 Hz, 1H), 7.68 (s, 1H), 3.79-3.66 (m, 4H), 3.17 (t, J=5.4 Hz, 4H), 2.60 (s, 3H), 1.28 (s, 4H), 0.50 (s, 4H). m/z (ESI): 459.2 (M+H).sup.+.

[0324] Step 2: To a solution of N-(2-(3,3-difluoroazetidin-1-yl)-6-methylpyrimidin-4-yl)-4-nitro-2-(6-azaspiro[2.5]octan-6-yl)benzamide (0.18 g, 0.39 mmol) in ethanol (8 mL) and water (8 mL) were added iron powder (0.066 g, 1.18 mmol) and ammonium chloride (0.063 g, 1.18 mmol). Then the mixture was heated at 90° C. for 3 h before it was filtered through a bed of CELITE® and was washed with ethyl acetate (3×100 mL). The filtrate was washed with brine, dried over Na.sub.2SO.sub.4, filtered, and concentrated to provide 4-amino-N-(2-(3,3-difluoroazetidin-1-yl)-6-methylpyrimidin-4-yl)-2-(6-azaspiro[2.5]octan-6-yl)benzamide (0.12 g, 0.280 mmol, 71.3% yield) as pale yellow solid. It was used directly for the next step without further purification, m/z (ESI): 429.2 (M+H).sup.+.

[0325] Step 3: To a solution of 4-amino-N-(2-(3,3-difluoroazetidin-1-yl)-6-methylpyrimidin-4-yl)-2-(6-azaspiro[2.5]octan-6-yl)benzamide (0.120 g, 0.280 mmol) in DCM (5 mL) were added Et.sub.3N (0.078 mL, 0.560 mmol) and methyl 2-(chlorosulfonyl)acetate (0.058 g, 0.336 mmol, Combi-blocks) at 0° C. The mixture was stirred at room temperature for 4 h before it was quenched with water (50 mL) and was extracted with DCM (3×50 mL). The combined organic layers were washed with brine (50 mL), dried over Na.sub.2SO.sub.4, filtered and concentrated to afford methyl 2-(N-(4-((2-(3,3-difluoroazetidin-1-yl)-6-methylpyrimidin-4-yl)carbamoyl)-3-(6-azaspiro[2.5]octan-6-yl)phenyl)sulfamoyl)acetate (140 mg, 0.25 mmol, 89% yield) as pale yellow solid. It was used for the next step without further purification. m/z (ESI): 565.2 (M+H).sup.+.

[0326] Step 4: A solution of methyl 2-(N-(4-((2-(3,3-difluoroazetidin-1-yl)-6-methylpyrimidin-4-yl)carbamoyl)-3-(6-azaspiro[2.5]octan-6-yl)phenyl)sulfamoyl)acetate (130 mg, 0.230 mmol) in THE (5 mL) was treated with LiBH.sub.4 (230 μl, 0.460 mmol) at −30° C. The reaction mixture was stirred for 30 min at 0° C. before it was quenched with a saturated aqueous solution of NH.sub.4Cl (50 mL) at 0° C. and was extracted with EtOAc (2×10 mL). The combined organic layers were washed with brine (5 mL), dried over Na.sub.2SO.sub.4, filtered and concentrated. The concentrate was purified by flash column chromatography eluting with a gradient of 20% to 100% EtOAc in hexanes to provide N-(2-(3,3-difluoroazetidin-1-yl)-6-methylpyrimidin-4-yl)-4-((2-hydroxyethyl)sulfonamido)-2-(6-azaspiro[2.5]octan-6-yl)benzamide (60 mg, 0.112 mmol, 48.6% yield) as white solid. .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ ppm 13.55 (s, 1H), 10.28 (s, 1H), 8.05 (d, J=8.7 Hz, 1H), 7.51 (s, 1H), 7.28 (d, J=2.2 Hz, 1H), 7.14 (dd, 7=8.6, 2.2 Hz, 1H), 4.95 (s, 1H), 4.45 (d, 7=12.3 Hz, 4H), 3.76 (t, 7=6.4 Hz, 2H), 3.64 (s, 1H), 3.57 (s, 1H), 2.97 (t, 7=5.4 Hz, 4H), 2.34 (s, 3H), 1.74 (br s, 4H), 0.40 (s, 4H). m/z (ESI): 537.2 (M+H).sup.+.

Examples 8-1 and 8-2: (R)-N-(2-(4,4-Difluoropiperidin-1-yl)-6-methylpyrimidin-4-yl)-5-fluoro-4-((2-hydroxy-1-methylethyl)sulfonamido)-2-(6-azaspiro[2.5]octan-6-yl)benzamide and (S)-N-(2-(4,4-Difluoropiperidin-1-yl)-6-methylpyrimidin-4-yl)-5-fluoro-4-((2-hydroxy-1-methylethyl)sulfonamido)-2-(6-azaspiro[2.5]octan-6-yl)benzamide

[0327] ##STR00184##

[0328] Step 1: Methyl 2-(chlorosulfonyl)propanoate (177 mg, 0.95 mmol, Enamine) was added to a solution of 4-amino-N-(2-(4,4-difluoropiperidin-1-yl)-6-methylpyrimidin-4-yl)-5-fluoro-2-(6-azaspiro[2.5]octan-6-yl)benzamide (0.41 g, 0.86 mmol, Int. 21) and triethylamine (0.18 mL, 1.30 mmol) in DCM (3 mL) at 0° C. The mixture was stirred for 1 h then the mixture was concentrated in vacuo and then purified by silica gel chromatography using a Redi-Sep pre-packed silica gel column (12 g), eluting with 25% EtOAc/heptane gradient, to provide methyl 2-(N-(4-((2-(4,4-difluoropiperidin-1-yl)-6-methylpyrimidin-4-yl)carbamoyl)-2-fluoro-5-(6-azaspiro[2.5]octan-6-yl)phenyl)sulfamoyl)propanoate (0.54 g, 0.48 mmol, 54.8% yield) as a white solid. .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ ppm 13.71 (s, 1H) 10.66 (brs, 1H) 7.88 (d, J=11.61 Hz, 1H) 7.60 (d, J=7.26 Hz, 1H) 7.39 (s, 1H) 4.38 (d, J=7.05 Hz, 1H) 3.88-3.96 (m, 4H) 3.57 (s, 3H) 2.98 (br t, J=4.56 Hz, 4H) 2.33 (s, 3H) 1.92-2.07 (m, 4H) 1.57-1.91 (m, 4H) 1.52 (d, J=6.84 Hz, 3H) 0.40 (s, 4H). .sup.19F NMR (376 MHz, DMSO-d.sub.6) δ ppm −94.77 (s, 1F) −126.39 (s, 1F). m/z (ESI): 625.2 (M+H).sup.+.

[0329] Step 2: Methanol (0.10 mL, 2.52 mmol) was added dropwise to a THF (2.5 mL) solution of methyl 2-(N-(4-((2-(4,4-difluoropiperidin-1-yl)-6-methylpyrimidin-4-yl)carbamoyl)-2-fluoro-5-(6-azaspiro[2.5]octan-6-yl)phenyl)sulfamoyl)propanoate (192 mg, 0.31 mmol) and lithium borohydride (2.0 M in THF, 0.35 mL, 0.69 mmol). The mixture was stirred for 30 minutes and then aqueous NH.sub.4Cl was added. The product was extracted into EtOAc (2×), and the combined extracts were dried over anhydrous MgSO.sub.4, filtered, and concentrated in vacuo to give racemic product as a solid. This material was separated by preparative SFC using a OD column (250×21 mm, 5 mm) and OD column (150×21 mm, 5 mm) with a mobile phase of 90% Liquid CO.sub.2 and 10% EtOH/0.2% triethylamine using a flowrate of 80 mL/min to give:

[0330] Example 8-1: (R)-N-(2-(4,4-Difluoropiperidin-1-yl)-6-methylpyrimidin-4-yl)-5-fluoro-4-((2-hydroxy-1-methylethyl)sulfonamido)-2-(6-azaspiro[2.5]octan-6-yl)benzamide. First eluting peak (94 mg, 0.16 mmol, 33.2% yield, >99% ee). .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ ppm 13.74 (s, 1H) 7.82 (d, J=11.82 Hz, 1H) 7.58 (d, J=7.26 Hz, 1H) 7.39 (s, 1H) 3.77-3.96 (m, 6H) 3.37-3.54 (m, 1H) 3.22-3.30 (m, 1H) 2.88-3.05 (m, 4H) 2.32 (s, 3H) 1.92-2.05 (m, 4H) 1.73 (brs, 4H) 1.31 (d, J=6.84 Hz, 3H) 0.40 (s, 4H). .sup.19F NMR (376 MHz, DMSO-d.sub.6) δ ppm −94.77 (s, 1F) −127.36 (s, 1F). m/z (ESI): 597.2 (M+H).sup.+.

[0331] Example 8-2: (S)-N-(2-(4,4-Difluoropiperidin-1-yl)-6-methylpyrimidin-4-yl)-5-fluoro-4-((2-hydroxy-1-methylethyl)sulfonamido)-2-(6-azaspiro[2.5]octan-6-yl)benzamide. Second eluting peak (102 mg, 0.17 mmol, 36.1% yield, 98.4% ee). .sup.1HNMR (400 MHz, DMSO-d.sub.6) δ ppm 13.74 (s, 1H) 7.82 (d, J=11.82 Hz, 1H) 7.58 (d, J=7.26 Hz, 1H) 7.39 (s, 1H) 3.77-3.96 (m, 6H) 3.37-3.54 (m, 1H) 3.22-3.30 (m, 1H) 2.88-3.05 (m, 4H) 2.32 (s, 3H) 1.92-2.05 (m, 4H) 1.73 (brs, 4H) 1.31 (d, 7=6.84 Hz, 3H) 0.40 (s, 4H). .sup.19F NMR (376 MHz, DMSO-d.sub.6) δ ppm −94.76 (s, 1F) −127.73 (s, 1F). m/z (ESI): 597.2 (M+H).sup.+. The stereochemistry was arbitrarily assigned.

TABLE-US-00011 TABLE 9 Examples 9-1 to 9-2 were prepared following similar procedure for Examples 8-1 and 8- 2: LRMS: (ESI + ve Ex. # Chemical Structure Name ion) m/z 9-1 [00185] (R)-5-Fluoro-4-((2- hydroxyethyl)sulfonamido)-N- (2-(2- methylmorpholino)pyrimidin-4- yl)-2-(6-azaspiro[2.5]octan-6- yl)benzamide 549.2 9-2 [00186] (R)-5-Fluoro-4-((2- hydroxyethyl)sulfonamido)-N- (6-methyl-2-(2- methylmorpholino)pyrimidin-4- yl)-2-(6-azaspiro[2.5]octan-6- yl)benzamide 563.2

Examples 10-1 and 10-2: (R)-N-(2-(3,3-Difluoroazetidin-1-yl)-6-methylpyrimidin-4-yl)-4-((2-hydroxypropyl)sulfonamido)-2-(6-azaspiro[2.5]octan-6-yl)benzamide and (S)-N-(2-(3,3-difluoroazetidin-1-yl)-6-methylpyrimidin-4-yl)-4-((2-hydroxypropyl)sulfonamido)-2-(6-azaspiro[2.5]octan-6-yl)benzamide

[0332] ##STR00187##

[0333] Step 1: A mixture of N-(2-chloro-6-methylpyrimidin-4-yl)-4-iodo-2-(6-azaspiro[2.5]octan-6-yl)benzamide (2.0 g, 4.14 mmol, Int. 17), 3,3-difluoroazetidine hydrochloride (1.07 g, 8.29 mmol, Combi-Blocks Inc.), and potassium carbonate (1.72 g, 12.4 mmol, Combi-Blocks, Inc.) in NMP (10 mL) was heated to 90° C. for 24 h. The mixture was cooled to room temperature, EtOAc (10 mL) was added, and then the mixture was washed with water (1×10 mL), 1N HCl (1×10 mL) and brine (1×10 mL). The mixture was then dried over anhydrous MgSO.sub.4, filtered, and concentrated in vacuo to give a solid. The solid was then suspended in MeOH and filtered, then dried in vacuo to provide N-(2-(3,3-difluoroazetidin-1-yl)-6-methylpyrimidin-4-yl)-4-iodo-2-(6-azaspiro[2.5]octan-6-yl)benzamide (1.16 g, 2.15 mmol, 51.9% yield) as a light brown solid. .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ ppm 13.53 (br s, 1H) 7.79-7.86 (m, 2H) 7.73-7.77 (m, 1H) 7.49 (s, 1H) 4.43 (t, J=12.44 Hz, 4H) 3.02 (br t, J=5.08 Hz, 4H) 2.31-2.38 (m, 3H) 1.65-1.82 (m, 4H) 0.39 (s, 4H). .sup.19F NMR (376 MHz, DMSO-d.sub.6) δ ppm −99.09 (s, 1F). m/z (ESI): 540.0 (M+H).sup.+.

[0334] Step 2: A mixture of 2-hydroxypropane-1-sulfonamide (206 mg, 1.48 mmol, Int. 23), copper(I) iodide (71 mg, 0.37 mmol), Sarcosine (66 mg, 0.74 mmol), and potassium phosphate (787 mg, 3.71 mmol) was placed under argon atmosphere, taken up in anhydrous DMF (3 mL), and warmed to 50° C. for 5 min. N-(2-(3,3-difluoroazetidin-1-yl)-6-methylpyrimidin-4-yl)-4-iodo-2-(6-azaspiro[2.5]octan-6-yl)benzamide (0.40 g, 0.74 mmol) was added in one portion and the mixture was heated to 100° C. for 2.5 h, then cooled to room temperature. Water was added, and the product was extracted into EtOAc (2×). The combined extracts were washed with water (2×), 9:1 saturated NH.sub.4Cl/NH.sub.4OH (1×), dried over anhydrous MgSO.sub.4, filtered, and concentrated in vacuo to give racemic product as an oil. This material was separated by preparative SFC using an IF column (250×301 mm, 5 mm) with a mobile phase of 75% Liquid CO.sub.2 and 25% MeOH using a flowrate of 130 mL/min to give:

[0335] Example 10-1: (R)-N-(2-(3,3-difluoroazetidin-1-yl)-6-methylpyrimidin-4-yl)-4-((2-hydroxypropyl)sulfonamido)-2-(6-azaspiro[2.5]octan-6-yl)benzamide. First eluting peak (88 mg, 0.16 mmol, 21.6% yield, >99% ee). .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ ppm 13.54 (s, 1H) 8.05 (d, J=8.71 Hz, 1H) 7.51 (s, 1H) 7.27 (d, J=1.87 Hz, 1H) 7.14 (dd, J=8.71, 1.87 Hz, 1H) 4.44 (t, J=12.44 Hz, 4H) 4.07-4.15 (m, 1H) 3.22-3.29 (m, 2H) 2.97 (br t, J=4.87 Hz, 4H) 2.34 (s, 3H) 1.74 (br s, 4H) 1.19 (d, J=6.22 Hz, 3H) 0.40 (s, 4H). 2 exchangeable protons not observed. .sup.19F NMR (376 MHz, DMSO-d.sub.6) 5 ppm −99.08 (s, 1F). m/z (ESI): 551 (M+H).sup.+.

[0336] Example 10-2: (S)-N-(2-(3,3-difluoroazetidin-1-yl)-6-methylpyrimidin-4-yl)-4-((2-hydroxypropyl)sulfonamido)-2-(6-azaspiro[2.5]octan-6-yl)benzamide. Second eluting peak (89 mg, 0.162 mmol, 21.8% yield, 99% ee). .sup.1HNMR (400 MHz, DMSO-d.sub.6) δ ppm 13.55 (s, 1H) 8.05 (d, J=8.71 Hz, 1H) 7.51 (s, 1H) 7.26 (d, J=1.87 Hz, 1H) 7.14 (dd, J=8.71, 1.87 Hz, 1H) 4.43 (t, J=12.44 Hz, 4H) 4.11 (d, J=6.01 Hz, 1H) 3.21-3.31 (m, 2H) 2.97 (br t, J=4.87 Hz, 4H) 2.34 (s, 3H) 1.53-2.01 (m, 4H) 1.19 (d, J=6.43 Hz, 3H) 0.40 (s, 4H). 2 exchangeable protons not observed. .sup.19F NMR (376 MHz, DMSO-d.sub.6) δ ppm −99.09 (s, 1F). m/z (ESI): 551 (M+H).sup.+. The stereochemistry was arbitrarily assigned.

TABLE-US-00012 TABLE 10 Examples 11-1 to 11-83 were prepared following similar procedures for Example 10: LRMS: (ESI + ve Ex. # Chemical Structure Name ion) m/z 11-1  [00188] (S)-4-((2- Hydroxyethyl)sulfonamido)-N- (2-(2- methylmorpholino)pyrimidin-4- yl)-2-(6-azaspiro[2.5]octan-6- yl)benzamide 531.2 11-2  [00189] 4-((2- Hydroxyethyl)sulfonamido)-N- (2-isopropyl-6- methylpyrimidin-4-yl)-2-(6- azaspiro[2.5]octan-6- yl)benzamide 488.2 11-3  [00190] N-(2-Cyclopropyl-6- methylpyrimidin-4-yl)-4-((2- hydroxyethyl)sulfonamido)-2- (6-azaspiro[2.5]octan-6- yl)benzamide 486.1 11-4  [00191] N-(2-Cyclobutoxy-6- methylpyrimidin-4-yl)-4-((2- hydroxyethyl)sulfonamido)-2- (6-azaspiro[2.5]octan-6- yl)benzamide 516.2 11-5  [00192] N-(2-(3-Fluoroazetidin-1-yl)-6- methylpyrimidin-4-yl)-4-((2- hvdroxyethyl)sulfonamido)-2- (6-azaspiro[2.5]octan-6- yl)benzamide 519.2 11-6  [00193] N-(2-(3-Fluoroazetidin-1- yl)pyrimidin-4-yl)-4-((2- hydroxyethyl)sulfonamido)-2- (6-azaspiro[2.5]octan-6- yl)benzamide 505.1 11-7  [00194] N-(2-(3,3-Difluoroazetidin-1- yl)pyrimidin-4-yl)-4-((2- hydroxyethyl)sulfonamido)-2- (6-azaspiro[2.5]octan-6- yl)benzamide 523.1 11-8  [00195] 4-((2- Hydroxyethyl)sulfonamido)-N- (6-methyl-2-(2-oxa-6- azaspiro[3.3]heptan-6- yl)pyrimidin-4-yl)-2-(6- azaspiro[2.5]octan-6- yl)benzamide 543.2 11-9  [00196] 4-((2- Hydroxyethyl)sulfonamido)-N- (6-methyl-2-(6-oxa-1- azaspiro[3,3]heptan-1- yl)pyrimidin-4-yl)-2-(6- azaspiro[2.5]octan-6- yl)benzamide 543.2 11-10 [00197] N-(2-(3- (Difluoromethoxy)azetidin-1- yl)-6-methylpyrimidin-4-yl)-4- ((2-hydroxyethyl)sulfonamido)- 2-(6-azaspiro[2.5]octan-6- yl)benzamide 567.2 11-11 [00198] N-(2-(1,1-Difluoro-5- azaspiro[2.3]hexan-5-yl)-6- methylpyrimidin-4-yl)-4-((2- hydroxyethyl)sulfonamido)-2- (6-azaspiro[2.5]octan-6- yl)benzamide 563.2 11-12 [00199] 4-((2- Hydroxyethyl)sulfonamido)-N- (6-methyl-2-(3- (trifluoromethyl)azetidin-1- yl)pyrimidin-4-yl)-2-(6- azaspiro[2.5]octan-6- yl)benzamide 569.2 11-13 [00200] N-(2-(3-Cyanoazetidin-1-yl)-6- methylpyrimidin-4-yl)-4-((2- hydroxyethyl)sulfonamido)-2- (6-azaspiro[2.5]octan-6- yl)benzamide 526.2 11-14 [00201] 4-((2- Hydroxyethyl)sulfonamido)-N- (2-(3-(2-hydroxypropan-2- yl)azetidin-1-yl)-6- methylpyrimidin-4-yl)-2-(6- azaspiro[2.5]octan-6- yl)benzamide 559.2 11-15 [00202] N-(2-(3-Hydroxy-3- methylazetidin-1-yl)-6- methylpyrimidin-4-yl)-4-((2- hydroxyethyl)sulfonamido)-2- (6-azaspiro[2.5]octan-6- yl)benzamide 531.2 11-16 [00203] N-(2-(3-Cyclopropyl-3- hydroxyazetidin-1-yl)-6- methylpyrimidin-4-yl)-4-((2- hydroxyethyl)sulfonamido)-2- (6-azaspiro[2.5]octan-6- yl)benzamide 557.2 11-17 [00204] 4-((2- Hydroxyethyl)sulfonamido)-N- (6-methyl-2-(5- azaspiro[2.3]hexan-5- yl)pyrimidin-4-yl)-2-(6- azaspiro[2.5]octan-6- yl)benzamide 527.2 11-18 [00205] N-(2-(3-Hydroxy-3- (trifluoromethyl)azetidin-1-yl)- 6-methylpyrimidin-4-yl)-4-((2- hydroxyethyl)sulfonamido)-2- (6-azaspiro[2.5]octan-6- yl)benzamide 585.2 11-19 [00206] N-(2-(Azetidin-1-yl)-6- methylpyrimidin-4-yl)-4-((2- hydroxyethyl)sulfonamido)-2- (6-azaspiro[2.5]octan-6- yl)benzamide 501.2 11-20 [00207] N-(2-(3-Hydroxyazetidin-1-yl)- 6-methylpyrimidin-4-yl)-4-((2- hydroxyethyl)sulfonamido)-2- (6-azaspiro[2.5]octan-6- yl)benzamide 517.2 11-21 [00208] (S)-N-(2-(3-(1- Hydroxyethyl)azetidin-1-yl)-6- methylpyrimidin-4-yl)-4-((2- hydroxyethyl)sulfonamido)-2- (6-azaspiro[2.5]octan-6- yl)benzamide 545.2 11-22 [00209] 4-(Cyclopropanesulfonamido)- N-(2-(3,3-difluoroazetidin-1- yl)-6-methylpyrimidin-4-yl)-2- (6-azaspiro[2.5]octan-6- yl)benzamide 533.2 11-23 [00210] N-(2-(3,3-Difluoroazetidin-1- yl)-6-methylpyrimidin-4-yl)-4- (oxetane-3-sulfonamido)-2-(6- azaspiro[2.5]octan-6- yl)benzamide 549.2 11-24 [00211] N-(2-(3,3-Difluoroazetidin-1- yl)-6-methylpyrimidin-4-yl)-4- (methylsulfonamido)-2-(6- azaspiro[2.5]octan-6- yl)benzamide 507.1 11-25 [00212] 4-((2- Hydroxyethyl)sulfonamido)-N- (6-methyl-2-(5- azaspiro[2.4]heptan-5- yl)pyrimidin-4-yl)-2-(6- azaspiro[2.5]octan-6- yl)benzamide 541.2 11-26 [00213] 4-((2- Hydroxyethyl)sulfonamido)-N- (6-methyl-2-(pyrrolidin-1- yl)pyrimidin-4-yl)-2-(6- azaspiro[2.5]octan-6- yl)benzamide 515.2 11-27 [00214] (R)-N-(2-(3-Fluoro-3- methylpyrrolidin-1-yl)-6- methylpyrimidin-4-yl)-4-((2- hydroxyethyl)sulfonamido)-2- (6-azaspiro[2.5]octan-6- yl)benzamide 547.3 11-28 [00215] N-(2-(2- Azabicyclo[3.1.0]hexan-2-yl)- 6-methylpyrimidin-4-yl)-4-((2- hydroxyethyl)sulfonamido)-2- (6-azaspiro[2.5]octan-6- yl)benzamide 527.2 11-29 [00216] N-(2-((1R,5S)-3- Azabicyclo[3.1.0]hexan-3-yl)- 6-methylpyrimidin-4-yl)-4-((2- hydroxyethyl)sulfonamido)-2- (6-azaspiro[2.5]octan-6- yl)benzamide 527.2 11-30 [00217] N-(2-(3,3-Difluoropyrrolidin-1- yl)-6-methylpyrimidin-4-yl)-4- ((2-hydroxyethyl)sulfonamido)- 2-(6-azaspiro[2.5]octan-6- yl)benzamide 551.2 11-31 [00218] 4-((2- Hydroxyethyl)sulfonamido)-N- (6-methyl-2-(6- azaspiro[2.5]octan-6- yl)pyrimidin-4-yl)-2-(6- azaspiro[2.5]octan-6- yl)benzamide 555.2 11-32 [00219] N-(2-((1R)-1-Hydroxy-3- azabicyclo[3.1.0]hexan-3-yl)-6- methylpyrimidin-4-yl)-4-((2- hydroxyethyl)sulfonamido)-2- (6-azaspiro[2.5]octan-6- yl)benzamide 543.2 11-33 [00220] N-(2-(4-Cyanopiperidin-1-yl)- 6-methylpyrimidin-4-yl)-4-((2- hydroxyethyl)sulfonamido)-2- (6-azaspiro[2.5]octan-6- yl)benzamide 554.2 11-34 [00221] (R)-N-(2-(3-Cyanopiperidin-1- yl)-6-methylpyrimidin-4-yl)-4- ((2-hydroxyethyl)sulfonamido)- 2-(6-azaspiro[2.5]octan-6- yl)benzamide 554.2 11-35 [00222] (S)-N-(2-(3-Cyanopiperidin-1- yl)-6-methylpyrimidin-4-yl)-4- ((2-hydroxyethyl)sulfonamido)- 2-(6-azaspiro[2.5]octan-6- yl)benzamide 554.2 11-36 [00223] 4-((2- Hydroxyethyl)sulfonamido)-N- (6-methyl-2-(piperidin-1- yl)pyrimidin-4-yl)-2-(6- azaspiro[2.5]octan-6- yl)benzamide 529.3 11-37 [00224] 4-((2- Hydroxyethyl)sulfonamido)-N- (2-(4-hydroxypiperidin-1-yl)-6- methylpyrimidin-4-yl)-2-(6- azaspiro[2.5]octaii-6- yl)benzamide 545.2 11-38 [00225] N-(2-(4-Hydroxy-4- methylpiperidin-1-yl)-6- methylpyrimidin-4-yl)-4-((2- hydroxyethyl)sulfonamido)-2- (6-azaspiro[2.5]octan-6- yl)benzamide 559.2 11-39 [00226] N-(2-(3,3-Difluoropiperidin-1- yl)-6-methylpyrimidin-4-yl)-4- ((2-hydroxyethyl)sulfonamido)- 2-(6-azaspiro[2.5]octan-6- yl)benzamide 565.2 11-40 [00227] N-(2-(4,4-Difluoropiperidin-1- yl)-6-methylpyrimidin-4-yl)-4- ((2-hydroxyethyl)sulfonamido)- 2-(7-azaspiro[3.5]nonan-7- yl)benzamide 579.2 11-41 [00228] N-(2-(4.4-Difluoropiperidin-1- yl)-6-methylpyrimidin-4-yl)-2- (4.4-dimethylpiperidin-1-yl)-4- ((2- hydroxyethyl)sulfonamido) benzamide 567.2 11-42 [00229] N-(2-((1R)-1-Hydroxy-3- azabicyclo[4.1.0]heptan-3-yl)- 6-methylpyrimidin-4-yl)-4-((2- hydroxyethyl)sulfonamido)-2- (6-azaspiro[2.5]octan-6- yl)benzamide 557.2 11-43 [00230] N-(2-((1R,6R)-3- Azabicyclo[4.1.0]heptan-3-yl)- 6-methylpyrimidin-4-yl)-4-((2- hydroxyethyl)sulfonamido)-2- (6-azaspiro[2.5]octan-6- yl)benzamide 541.2 11-44 [00231] N-(2-((1S,6R)-2- Azabicyclo[4.1.0]heptan-2-yl)- 6-methylpyrimidin-4-yl)-4-((2- hydroxyethyl)sulfonamido)-2- (6-azaspiro[2.5]octan-6- yl)benzamide 541.2 11-45 [00232] (S)-4-((2- Hydroxyethyl)sulfonamido)-N- (6-methyl-2-(2- methylmorpholino)pyrimidin-4- yl)-2-(6-azaspiro[2.5]octan-6- yl)benzamide 545.2 11-46 [00233] N-(2-(2,2- Dimethylmorpholino)-6- methylpyrimidin-4-yl)-4-((2- hydroxyethyl)sulfonamido)-2- (6-azaspiro[2.5]octan-6- yl)benzamide 559.3 11-47 [00234] 4-((2- Hydroxyethyl)sulfonamido)-N- (6-methyl-2-(4-oxa-7- azaspiro[2.5]octan-7- yl)pyrimidin-4-yl)-2-(6- azaspiro[2.5]octan-6- yl)benzamide 557.3 11-48 [00235] N-(2-((3S,5R)-3,5- Dimethylmorpholino)-6- methylpyrimidin-4-yl)-4-((2- hydroxyethyl)sulfonamido)-2- (6-azaspiro[2.5]octan-6- yl)benzaniide 559.3 11-49 [00236] N-(2-((3S,5S)-3,5- Dimethylmorpholino)-6- methylpyrimidin-4-yl)-4-((2- hydroxyethyl)sulfonamido)-2- (6-azaspiro[2.5]octan-6- yl)benzamide 559.3 11-50 [00237] N-(2-((3R,5R)-3,5- Dimethylmorpholino)-6- methylpyrimidin-4-yl)-4-((2- hydroxyethyl)sulfonamido)-2- (6-azaspiro[2.5]octan-6- yl)benzamide 559.3 11-51 [00238] N-(2-(4-Fluoropiperidin-1-yl)- 6-methylpyrimidin-4-yl)-4-((2- hydroxyethyl)sulfonamido)-2- (6-azaspiro[2.5]octan-6- yl)benzamide 547.2 11-52 [00239] N-(2-(4-Fluoro-4- methylpiperidin-1-yl)-6- methylpyrimidin-4-yl)-4-((2- hydroxyethyl)sulfonamido)-2- (6-azaspiro[2.5]octan-6- yl)benzamide 561.3 11-53 [00240] (S)-4-((2- Hydroxyethyl)sulfonamido)-N- (2-(3-hydroxypiperidin-1-yl)-6- methylpyrimidin-4-yl)-2-(6- azaspiro[2.5]octan-6- yl)benzamide 545.2 11-54 [00241] (R)-4-((2- Hydroxyethyl)sulfonamido)-N- (2-(3-hydroxypiperidin-1-yl)-6- methylpyrimidin-4-yl)-2-(6- azaspiro[2.5]octan-6- yl)benzamide 545.2 11-55 [00242] (R)-N-(2-(3-Fluoro-3- methylpiperidin-1-yl)-6- methylpyrimidin-4-yl)-4-((2- hydroxyethyl)sulfonamido)-2- (6-azaspiro[2.5]octan-6- yl)benzamide 561.2 11-56 [00243] N-(2-(4-Fluoropiperidin-1- yl)pyrimidin-4-yl)-4-((2- hydroxyethyl)sulfonamido)-2- (6-azaspiro[2.5]octan-6- yl)benzamide 533.2 11-57 [00244] N-(2-(4,4-Difluoropiperidin-1- yl)pyrimidin-4-yl)-4-((2- hydroxyethyl)sulfonamido)-2- (6-azaspiro[2.5]octan-6- yl)benzamide 551.2 11-58 [00245] N-(2-(4,4-Difluoropiperidin-1- yl)-6-methylpyrimidin-4-yl)-2- fluoro-4-((2- hydroxyethyl)sulfonamido)-6- (6-azaspiro[2.5]octan-6- yl)benzamide 583.2 11-59 [00246] 4-((2- Hydroxyethyl)sulfonamido)-2- (6-azaspiro[2.5]octan-6-yl)-N- (2-(3,3,3- trifluoropropoxy)pyridin-4- yl)benzamide 543.2 11-60 [00247] 4-((2- Hydroxyethyl)sulfonamido)-N- (2-methyl-6-(3,3,3- trifluoropropoxy)pyridin-4-yl)- 2-(6-azaspiro[2.5]octan-6- yl)benzamide 557.2 11-61 [00248] 4-((2- Hydroxyethyl)sulfonamido)-N- (6-methyl-2-(3,3,3- trifluoropropoxy)pyrimidin-4- yl)-2-(6-azaspiro[2.5]octan-6- yl)benzamide 558.2 11-62 [00249] N-(2-((1-Hydroxy-2- methylpropan-2-yl)amino)-6- methylpyrimidin-4-yl)-4-((2- hydroxyethyl)sulfonamido)-2- (6-azaspiro[2.5]octan-6- yl)benzamide 533.2 11-63 [00250] N-(2-(4.4-Difluoropiperidin-1- yl)-3-fluoropyridin-4-yl)-4-((2- hydroxyethyl)sulfonamido)-2- (6-azaspiro[2.5]octan-6- yl)benzamide 568.2 11-64 [00251] N-(2-(4,4-Difluoropiperidin-1- yl)-3-fluoro-6-methylpyridin-4- yl)-4-((2- hydroxyethyl)sulfonamido)-2- (6-azaspiro[2.5]octan-6- yl)benzamide 582.2 11-65 [00252] (R)-4-((2- Hydroxyethyl)sulfonamido)-N- (2-(2- methylmorpholino)pyridin-4- yl)-2-(6-azaspiro[2.5]octan-6- yl)benzamide 530.2 11-66 [00253] (R)-4-((2- Hydroxyethyl)sulfonamido)-N- (2-methyl-6-(2- methylmorpholino)pyridin-4- yl)-2-(6-azaspiro[2.5]octan-6- yl)benzamide 544.3 11-67 [00254] N-(2-(4,4-Difluoropiperidin-1- yl)-6-methylpyrimidin-4-yl)-5- fluoro-4-((2- hydroxyethyl)sulfonamido)-2- (6-azaspiro[2.5]octan-6- yl)benzamide 583.4 11-68 [00255] N-(2-(3,3-Difluoroazetidin-1- yl)-6-methylpyrimidin-4-yl)-4- ((1- (hydroxymethyl)cyclopropane)- 1-sulfonamido)-2-(6- azaspiro[2.5]octan-6- yl)benzamide 563.2 11-69 [00256] N-(2-(4,4-Difluoropiperidin-1- yl)-6-methylpyrimidin-4-yl)-4- ((1- (hydroxymethyl)cyclopropane)- 1-sulfonamido)-2-(6- azaspiro[2.5]octan-6- yl)benzamide 591.2 11-70 [00257] (S)-N-(2-(3,3-Difluoroazetidin- 1-yl)-6-methylpyrimidin-4-yl)- 2-(6-azaspiro[2.5]octan-6-yl)-4- ((tetrahydrofuran)-3- sulfonamido)benzamide 563.2 11-71 [00258] (R)-N-(2-(3,3-Difluoroazetidin- 1-yl)-6-methylpyrimidin-4-yl)- 2-(6-azaspiro[2.5]octan-6-yl)-4- ((tetrahydrofuran)-3- sulfonamido)benzamide 563.2 11-72 [00259] (S)-N-(2-(4,4- Difluoropipcridin-1-yl)-6- methylpyrimidin-4-yl)-2-(6- azaspiro[2.5]octan-6-yl)-4- ((tetrahydrofuran)-3- sulfonamido)benzamide 591.3 11-73 [00260] (R)-N-(2-(4,4- Difluoropiperidin-1-yl)-6- methylpyrimidin-4-yl)-2-(6- azaspiro[2.5]octan-6-yl)-4- ((tetrahydrofuran)-3- sulfonamido)benzamide 591.3 11-74 [00261] N-(2-(3,3-Difluoroazetidin-1- yl)-6-methylpyrimidin-4-yl)-4- ((1-methylcyclopropane)-1- sulfonamido)-2-(6- azaspiro[2.5]octan-6- yl)benzamide 547.2 11-75 [00262] N-(2-(3,3-Difluoroazetidin-1- yl)-6-methylpyrimidin-4-yl)-4- ((1-methylethyl)sulfonamido)- 2-(6-azaspiro[2.5]octan-6- yl)benzamide 535.2 11-76 [00263] (R)-N-(2-(3,3-Difluoroazetidin- 1-yl)-6-methylpyrimidin-4-yl)- 4-((2-hydroxy-1- methylethyl)sulfonamido)-2-(6- azaspiro[2.5]octan-6- yl)benzamide 551.2 11-77 [00264] (S)-N-(2-(3,3-Difluoroazetidin- 1-yl)-6-methylpyrimidin-4-yl)- 4-((2-hydroxy-1- methylethyl)sulfonamido)-2-(6- azaspiro[2.5]octan-6- yl)benzamide 551.2 11-78 [00265] 4- ((Cyclopropylmethyl)sulfona- mido)-N-(2-(3,3-difluoroazetidin- 1-yl)-6-methylpyrimidin-4-yl)- 2-(6-azaspiro[2.5]octan-6- yl)benzamide 547.2 11-79 [00266] 4-((2- Hydroxyethyl)sulfonarnido)-N- (2-isopropoxy-6- methylpyrimidin-4-yl)-2-(6- azaspiro[2.5]octan-6- yl)benzamide 504.2 11-80 [00267] (R)-4-((2- Hydroxyethyl)sulfonamido)-N- (6-methyl-2-((tetrahydrofuran- 3-yl)oxy)pyrimidin-4-yl)-2-(6- azaspiro[2.5]octan-6- yl)benzamide 532.2 11-81 [00268] N-(2-(4-Fluoropiperidin-1-yl)- 6-methylpyrimidin-4-yl)-4- (methylsulfonamido)-2-(6- azaspiro[2.5]octan-6- yl)benzamide 517.2 11-82 [00269] 4-(Ethylsulfonamido)-N-(2-(4- fluoropiperidin-1-yl)-6- methylpyrimidin-4-yl)-2-(6- azaspiro[2.5]octan-6- yl)benzamide 531.2 11-83 [00270] N-(2-(3,3-Difluoroazetidin-1- yl)-6-methylpyrimidin-4-yl)-4- ((1,1- dimethylethyl)sulfonamido)-2- (6-azaspiro[2.5]octan-6- yl)benzamide 549.2

Example 12: N-(2-(4,4-difluoropiperidin-1-yl)-6-methylpyrimidin-4-yl)-4-((2-hydroxyethyl)sulfonyl)-2-(6-azaspiro[2.5]octan-6-yl)benzamide

[0337] ##STR00271##

[0338] Step 1: A mixture of/V-(2-(4,4-difluoropiperidin-1-yl)-6-methylpyrimidin-4-yl)-4-iodo-2-(6-azaspiro[2.5]octan-6-yl)benzamide (500 mg, 0.881 mmol, Int. 19), triphenylphosphine (34.7 mg, 0.132 mmol, Aldrich St. Louis, Mo. USA), 1,10-phenanthroline (23.82 mg, 0.132 mmol, Aldrich St. Louis, Mo. USA), palladium(II) acetate (9.89 mg, 0.044 mmol, Strem Chemicals, Inc. Newburyport, Mass. USA), sodium formate (132 mg, 1.939 mmol, Thermo Fisher Scientific, Grand Island, N.Y. USA), and tetrabutylammonium bromide (426 mg, 1.322 mmol, Aldrich St. Louis, Mo. USA) in dimethyl sulfoxide (3 mL) under N2 was stirred at 70° C. for 45 min. Then, the mixture was cooled to room temperature and ethyl iodoacetate (0.157 mL, 1.322 mmol, Aldrich St. Louis, Mo. USA) was added. The mixture was then stirred at room temperature for 10 min. Then, the mixture was diluted with water (20 mL) and was then extracted with EtOAc (2×40 mL). The combined organic extracts were then dried over MgSO.sub.4 and concentrated. Chromatographic purification of the residue (silica gel, 0%-100% EtOAc/heptane) provided ethyl 2-((4-((2-(4,4-difluoropiperidin-1-yl)-6-methylpyrimidin-4-yl)carbamoyl)-3-(6-azaspiro[2.5]octan-6-yl)phenyl)sulfonyl)acetate (330 mg, 0.558 mmol) as a light yellow solid. .sup.1H NMR (DMSO-d.sub.6) δ 13.14 (brs, 1H), 8.27 (br d, J=8.1 Hz, 1H), 7.97 (s, 1H), 7.84 (br d, J=1.1 Hz, 1H), 7.40 (s, 1H), 4.80 (s, 2H), 4.05 (q, J=7.2 Hz, 2H), 3.92 (brs, 4H), 3.03-3.13 (m, 4H), 2.34 (s, 3H), 1.90-2.07 (m, 4H), 1.71 (brs, 4H), 1.07 (t, J=7.0 Hz, 3H), 0.39 (s, 4H). m/z (ESI): 592.3 (M+H)+.

[0339] Step 2: To a solution of ethyl 2-((4-((2-(4,4-difluoropiperidin-1-yl)-6-methylpyrimidin-4-yl)carbamoyl)-3-(6-azaspiro[2.5]octan-6-yl)phenyl)sulfonyl)acetate (320 mg, 0.541 mmol) in 2-methyltetrahydrofuran (3.5 mL) under N.sub.2 at 0° C. was added lithium borohydride solution (2.0M in tetrahydrofuran 0.541 mL, 1.082 mmol, Aldrich St. Louis, Mo. USA) dropwise. After addition, the mixture was stirred at room temperature overnight. Then, the mixture was quenched with saturated NH.sub.4Cl (18 mL) and was stirred at room temperature for 15 min. The mixture was then extracted with EtOAc (2×30 mL). The combined organic extracts were then dried over MgSO.sub.4 and concentrated. Chromatographic purification of the residue (silica gel, 0%-100% EtOAc/heptane) provided N-(2-(4,4-difluoropiperidin-1-yl)-6-methylpyrimidin-4-yl)-4-((2-hydroxyethyl)sulfonyl)-2-(6-azaspiro[2.5]octan-6-yl)benzamide (60 mg, 0.109 mmol, 20% yield) provided N-(2-(4,4-difluoropiperidin-1-yl)-6-methylpyrimidin-4-yl)-4-((2-hydroxyethyl)sulfonyl)-2-(6-azaspiro[2.5]octan-6-yl)benzamide (60 mg, 0.109 mmol) as a white solid. .sup.1H NMR (DMSO-d.sub.6) δ ppm 13.17 (brs, 1H), 8.25 (br d, J=8.3 Hz, 1H), 7.93 (brs, 1H), 7.82 (brd, J=8.3 Hz, 1H), 7.40 (brs, 1H), 4.91 (br t, J=5.0 Hz, 1H), 3.92 (brs, 4H), 3.68-3.77 (m, 2H), 3.52-3.60 (m, 2H), 3.09 (brs, 4H), 2.34 (s, 3H), 1.87-2.08 (m, 4H), 1.70 (br d, J=1.0 Hz, 4H), 0.39 (s, 4H). .sup.19F NMR (DMSO-d.sub.6) δ ppm −94.76 (s, 2F). m/z (ESI): 550.1 (M+H)+.

Examples 13-1 and 13-2: (S)-N-(2-(4,4-Difluoropiperidin-1-yl)-6-methylpyrimidin-4-yl)-4-((1-hydroxypropan-2-yl)sulfonyl)-2-(6-azaspiro[2.5]octan-6-yl)benzamide and (R)-N-(2-(4,4-difluoropiperidin-1-yl)-6-methylpyrimidin-4-yl)-4-((1-hydroxypropan-2-yl)sulfonyl)-2-(6-azaspiro[2.5]octan-6-yl)benzamide

[0340] ##STR00272##

[0341] Step 1: N-(2-(4,4-difluoropiperidin-1-yl)-6-methylpyrimidin-4-yl)-4-iodo-2-(6-azaspiro[2.5]octan-6-yl)benzamide (1.08 g, 1.90 mmol, Int. 19), 2-mercaptopropan-1-ol (0.48 g, 5.21 mmol, Enamine), and potassium carbonate (0.237 mL, 3.91 mmol) in 4 mL DMSO were heated at 90° C. in a sealed vial for 4 h. The mixture was cooled to RT, added 50 mL ethyl acetate and 10 mL brine. The organic layer was separated, washed with brine, dried, and evaporated. The resulting product was adsorbed onto a plug of silica gel and purified by silica gel chromatography (0-30% of EtOAc in heptane) to give N-(2-(4,4-difluoropiperidin-1-yl)-6-methylpyrimidin-4-yl)-4-((1-hydroxypropan-2-yl)thio)-2-(6-azaspiro[2.5]octan-6-yl)benzamide as a yellow solid. .sup.1H NMR (400 MHz, CHLOROFORM-d) δ ppm 0.39-0.44 (m, 4H) 1.37-1.43 (m, 3H) 1.55-1.60 (m, 4H) 1.96-2.04 (m, 4H) 2.35-2.41 (m, 3H) 3.01-3.11 (m, 4H) 3.46-3.78 (m, 3H) 3.96-4.05 (m, 4H) 7.28-7.36 (m, 2H) 7.48-7.53 (m, 1H) 8.12-8.32 (m, 1H) 13.01-13.37 (m, 1H). m/z (ESI): 531.4 (M+H).sup.+.

[0342] Step 2: To N-(2-(4,4-difluoropiperidin-1-yl)-6-methylpyrimidin-4-yl)-4-((1-hydroxypropan-2-yl)thio)-2-(6-azaspiro[2.5]octan-6-yl)benzamide (0.62 g, 1.17 mmol) in 15 mL THF was added oxone(r) monopersulfate compound (0.72 g, 1.17 mmol) in 5 mL water. After stirring for 1.5 h, LCMS showed a mixture of sulfone and sulfoxide formed. Additional 0.4 g of oxone in 3 mL water was added. After stirring for additional 2 h, EtOAc (50 mL) and brine (20 mL) were added to the reaction mixture and the organic layer was taken, washed with brine, dried, and evaporated. The crude product was purified via preparative SFC using an (S,S) Whelk-01 (250×21 mm, 5 mm) column with a mobile phase of 60% Liquid CO.sub.2 and 40% MeOH, flowrate of 80 mL/min. to give N-2-(4,4-difluoropiperidin-1-yl)-6-methylpyrimidin-4-yl)-4-((1-hydroxypropan-2-yl)sulfonyl)-2-(6-azaspiro[2.5]octan-6-yl)benzamide (337 mg, 0.58 mmol, 50% yield). .sup.1H NMR (400 MHz, CHLOROFORM-d) δ ppm 0.30-0.57 (m, 4H) 1.27-1.37 (m, 3H) 1.59-1.72 (m, 4H) 1.94-2.10 (m, 4H) 2.40-2.54 (m, 3H) 2.55-2.97 (m, 1H) 3.05-3.23 (m, 4H) 3.28-3.41 (m, 1H) 3.84-4.06 (m, 6H) 7.63-7.86 (m, 2H) 8.13-8.37 (m, 1H) 11.08-11.59 (m, 1H). m/z (ESI): 598.3 (M+H).sup.+. This racemic mixture was separated by preparative SFC using an OD (250×21 mm, 5 mm) with a mobile phase of 85% Liquid CO.sub.2 and 15% iPrOH and a flowrate of 90 mL/min to generate:

[0343] Example 13-1: (S)-N-(2-(4,4-difluoropiperidin-1-yl)-6-methylpyrimidin-4-yl)-4-((1-hvdroxypropan-2-yl)sulfonyl)-2-(6-azaspiro[2.5]octan-6-yl)benzamide. First eluting peak (85 mg, ee>99%). .sup.1H NMR (400 MHz, CHLOROFORM-d) δ ppm 12.74-13.01 (m, 1H), 8.36-8.54 (m, 1H), 7.69-8.03 (m, 2H), 7.41-7.58 (m, 1H), 3.83-4.06 (m, 6H), 3.25-3.43 (m, 1H), 3.03-3.17 (m, 4H), 2.50-2.81 (m, 1H), 2.31-2.42 (m, 3H), 1.93-2.10 (m, 4H), 1.61-1.90 (m, 4H), 1.28-1.36 (m, 3H), 0.35-0.50 (m, 4H). m/z (ESI): 563.2 (M+H).sup.+.

[0344] Example 13-2: (R)-N-(2-(4,4-difluoropiperidin-1-yl)-6-methylpyrimidin-4-yl)-4-((1-hvdroxypropan-2-yl)sulfonyl)-2-(6-azaspiro[2.5]octan-6-yl)benzamide. Second eluting peak (84 mg, ee 97%). .sup.1H NMR (400 MHz, CHLOROFORM-d) δ ppm 12.71-13.05 (m, 1H), 8.39-8.56 (m, 1H), 7.74-8.03 (m, 2H), 7.38-7.54 (m, 1H), 3.81-4.04 (m, 6H), 3.26-3.39 (m, 1H), 3.03-3.19 (m, 4H), 2.48-2.83 (m, 1H), 2.33-2.41 (m, 3H), 1.92-2.10 (m, 4H), 1.60-1.90 (m, 4H), 1.28-1.33 (m, 3H), 0.36-0.46 (m, 4H). m/z (ESI): 563.2 (M+H).sup.+. The stereochemistry was arbitrary assigned.

Example 14: N-(2-(4,4-difluoropiperidin-1-yl)-6-methylpyrimidin-4-yl)-4-((1-hydroxy-2-methylpropan-2-yl) sulfonyl)-2-(6-azaspiro[2.5]octan-6-yl)benzamide

[0345] ##STR00273##

[0346] Step 1: N-(2-(4,4-difluoropiperidin-1-yl)-6-methylpyrimidin-4-yl)-4-iodo-2-(6-azaspiro[2.5]octan-6-yl)benzamide (0.55 g, 0.967 mmol, Int. 19), 4,5-bis(diphenylphosphino)-9,9-dimethyl-xanthene (0.034 g, 0.058 mmol), tris(dibenzylideneacetone)dipalladium (0) chloroform adduct (0.035 g, 0.034 mmol), DIPEA (0.4 mL, 2.29 mmol), and 2-mercapto-2-methylpropan-1-ol (0.134 g, 1.29 mmol) in 3 mL dioxane were passed through N.sub.2 for 5 min in a sealed tube. The mixture was heated at 90° C. for 3 h and cooled to RT. The resulting crude product was adsorbed onto a plug of silica gel and purified by silica gel chromatography (0-7% EtOAc in DCM) to give N-(2-(4,4-difluoropiperidin-1-yl)-6-methylpyrimidin-4-yl)-4-((l-hydroxy-2-methylpropan-2-yl)thio)-2-(6-azaspiro[2.5]octan-6-yl)benzamide. .sup.1H NMR (400 MHz, CHLOROFORM-d) δ ppm 0.38-0.47 (m, 4H) 1.25-1.31 (m, 6H) 1.56-1.56 (m, 4H) 1.94-2.04 (m, 4H) 2.35-2.41 (m, 3H) 3.03-3.12 (m, 4H) 3.31-3.38 (m, 2H) 3.95-4.04 (m, 4H) 7.41-7.47 (m, 2H) 7.48-7.52 (m, 1H) 8.14-8.32 (m, 1H) 12.96-13.41 (m, 1H). 4H overlapped with water peak, m/z (ESI): 546.2 (M+H).sup.+.

[0347] Step 2: To N-(2-(4,4-difluoropiperidin-1-yl)-6-methylpyrimidin-4-yl)-4-((1-hydroxy-2-methylpropan-2-yl)thio)-2-(6-azaspiro[2.5]octan-6-yl)benzamide (0.36 g, 0.66 mmol) in THF (15 mL) cooled to 0° C. was added oxone(r) monopersulfate compound (0.52 g, 0.85 mmol) in water (5 mL). The mixture was stirred for 2.5 h from 0° C. to RT. Additional 0.35 g oxone was added. After 1 h lcms showed the sulfoxide was almost consumed. Ethyl acetate (40 mL) and brine (20 mL) were added and organic layer was separated, dried and evaporated. The crude mixture was purified via preparative SFC using an (S,S) Whelk-01 (250×21 mm, 5 mm) with a mobile phase of 60% Liquid CO.sub.2 and 40% MeOH using a flowrate of 80 mL/min to give N-(2-(4,4-difluoropiperidin-1-yl)-6-methylpyrimidin-4-yl)-4-((l-hydroxy-2-methylpropan-2-yl)sulfonyl)-2-(6-azaspiro[2.5]octan-6-yl)benzamide. .sup.1H NMR (400 MHz, CHLOROFORM-d) δ ppm 8.15-8.73 (m, 1H), 7.64-7.90 (m, 2H), 7.41-7.52 (m, 1H), 3.94-4.07 (m, 4H), 3.70-3.83 (m, 2H), 3.04-3.20 (m, 4H), 2.34-2.47 (m, 3H), 1.96-2.12 (m, 4H), 1.47-1.95 (m, 4H), 1.30-1.41 (m, 6H), 0.37-0.52 (m, 4H). .sup.19F NMR (376 MHz, CHLOROFORM-d) δ ppm −96.68 (br s, 1F). m/z (ESI): 578.2 (M+H).sup.+.

TABLE-US-00013 TABLE 11 Examples 14-1 to 14-9 were prepared following similar procedures for Examples 12 to 14: LRMS: (ESI + ve ion) Ex. # Chemical Structure Name m/z 14-1 [00274] N-(2-(4,4-Difluoropiperidin-1- yl)-6-methylpyrimidin-4-yl)-4- (oxetan-3-ylsulfonyl)-2-(6- azaspiro[2.5]octan-6- yl)benzamide 562.3 14-2 [00275] N-(2-(4,4-Difluoropiperidin-1- yl)-6-methylpyrimidin-4-yl)-4- (ethylsulfonyl)-2-(6- azaspiro[2.5]octan-6- yl)benzamide 534.2 14-3 [00276] N-(2-(4,4-Difluoropiperidin-1- yl)-6-methylpyrimidin-4-yl)-4- (isopropylsulfonyl)-2-(6- azaspiro[2.5]octan-6- yl)benzamide 548.2 14-4 [00277] N-(2-(4,4-Difluoropiperidin-1- yl)-6-methylpyrimidin-4-yl)-4- ((2-hydroxy-2- methylpropyl)sulfonyl)-2-(6- azaspiro[2.5]octan-6- yl)benzamide 578.2 14-5 [00278] 4-(Cyclopropylsulfonyl)-N-(2- (4,4-difluoropiperidin-1-yl)-6- methylpyrimidin-4-yl)-2-(6- azaspiro[2.5]octan-6- yl)benzamide 546.2 14-6 [00279] 4-(tert-Butylsulfonyl)-N-(2-(4,4- difluoropiperidin-1-yl)-6- methylpyrimidin-4-yl)-2-(6- azaspiro[2.5]octan-6- yl)benzamide 562.3 14-7 [00280] N-(2-(4,4-Difluoropiperidin-1- yl)-6-methylpyrimidin-4-yl)-4- (((3R,4R)-4- hydroxytetrahydrofuran-3- yl)sulfonyl)-2-(6- azaspiro[2.5]octan-6- yl)benzamide 592.2 14-8 [00281] N-(2-(4,4-Difluoropiperidin-1- yl)-6-methylpyrimidin-4-yl)-4- (((3S,4S)-4- hydroxytetrahydrofuran-3- yl)sulfonyl)-2-(6- azaspiro[2.5]octan-6- yl)benzamide 592.2 14-9 [00282] N-(2-(4,4-Difluoropiperidin-1- yl)-6-methylpyrimidin-4-yl)-4- (((1R,2R)-2- hydroxycyclopentyl)sulfonyl)-2- (6-azaspiro[2.5]octan-6- yl)benzamide 590.2

Example 15: N-(2-(4,4-Difluorocyclohexyl)-6-methylpyrimidin-4-yl)-4-((2-hydroxyethyl)sulfonamido)-2-(6-azaspiro[2.5]octan-6-yl)benzamide

[0348] ##STR00283##

[0349] A mixture of 4-bromo-N-(2-(4,4-difluorocyclohexyl)-6-methylpyrimidin-4-yl)-2-(6-azaspiro[2.5]octan-6-yl)benzamide (0.055 g, 0.106 mmol, Int. 21-13), 2-hydroxyethane-1-sulfonamide (0.020 g, 0.159 mmol, Wuxi), potassium phosphate tribasic (0.045 g, 0.212 mmol), copper(I) iodide (0.020 g, 0.106 mmol) and (1R,2R)-N,N′-dimethyl-1,2-cyclohexanediamine (7.53 mg, 0.053 mmol, Combi-Blocks) in DMF (1.5 mL) was heated at 90° C. for 16 h. Then the reaction mixture was filtered through a pad of CELITE® pad and filtrate was diluted with EtOAc. The resulting solution was washed with water and brine, dried over Na.sub.2SO.sub.4, filtered and concentrated. The residue was purified by reverse phase HPLC using a gradient of 60% ACN in water (0.1% TFA) to afford N-(2-(4,4-difluorocyclohexyl)-6-methylpyrimidin-4-yl)-4-((2-hydroxyethyl)sulfonamido)-2-(6-azaspiro[2.5]octan-6-yl)benzamide (0.025 g, 0.044 mmol, 42% yield) as white solid. .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ ppm 13.70 (s, 1H), 8.04 (d, 2=8.8 Hz, 1H), 7.92 (s, 1H), 7.25 (d, 2=2.2 Hz, 1H), 7.16-7.08 (m, 1H), 3.75 (t, 2=6.3 Hz, 2H), 3.03-2.85 (m, 6H), 2.44 (d, 2=4.5 Hz, 5H), 2.05 (s, 5H), 1.92 (d, 2=11.7 Hz, 4H), 1.72 (s, 4H), 0.38 (s, 4H). m/z (ESI): 564.1 (M+H).sup.+.

Example 16-1 and 16-2: (S)-N-(2-(4,4-Difluoropiperidin-1-yl)-6-methylpyrimidin-4-yl)-4-((2-fluoro-1-(hydroxymethyl)ethyl)sulfonamido)-2-(6-azaspiro[2.5]octan-6-yl)benzamide and (R)-N-(2-(4,4-Difluoropiperidin-1-yl)-6-methylpyrimidin-4-yl)-4-((2-fluoro-1-(hydroxymethyl)ethyl)sulfonamido)-2-(6-azaspiro[2.5]octan-6-yl)benzamide

[0350] ##STR00284##

[0351] Step 1: To a solution of 1-(benzyloxy)-3-((tert-butyldimethylsilyl)oxy)propane-2-sulfonamide (0.803 g, 2.23 mmol) in THF was added tetrabutylammonium fluoride solution (2.75 mL, 2.75 mmol, 1M in THF) at RT. The reaction was stirred for 1 hour and then concentrated under reduced pressure. The resulting material was used immediately in the next step.

[0352] Step 2: To a pressure relief vial charged with the sulfonamide from the previous step was added copper(I) iodide (0.196 g, 1.03 mmol), methyl glycine (0.128 g, 1.440 mmol), potassium phosphate, tribasic (0.934 g, 4.40 mmol), and N-(2-(4,4-difluoropiperidin-1-yl)-6-methylpyrimidin-4-yl)-4-iodo-2-(6-azaspiro[2.5]octan-6-yl)benzamide (0.975 g, 1.72 mmol, Int. 19). The vial was sealed and evacuated/backfilled with nitrogen and then DMF (7 mL) was added. The cap was replaced, and the reaction was stirred in a pre-heated 100° C. oil bath for 16 h. The reaction mixture was partitioned between satd. NH.sub.4Cl:NH.sub.4OH (9:1) and EtOAc. The organic phase was separated, washed with brine, and concentrated in vacuo. The material was purified by silica gel chromatography (20-100% EtOAc in heptane) to afford 4-((2-(benzyloxy)-1-(hydroxymethyl)ethyl)sulfonamido)-N-(2-(4,4-difluoropiperidin-1-yl)-6-methylpyrimidin-4-yl)-2-(6-azaspiro[2.5]octan-6-yl)benzamide (0.635 g, 0.927 mmol, 54.0% yield). .sup.1H NMR (400 MHz, CHLOROFORM-d) δ ppm 13.11 (br dd, J=4.66, 2.38 Hz, 1H) 8.14 (d, J=8.50 Hz, 1H) 7.49 (br s, 1H) 7.31-7.44 (m, 5H) 7.13 (d, J=1.87 Hz, 1H) 6.83 (dd, J=8.60, 2.18 Hz, 2H) 4.49-4.62 (m, 2H) 4.08 (dt, J=11.77, 5.83 Hz, 1H) 3.94-4.03 (m, 5H) 3.88-3.93 (m, 1H) 3.95 (br s, 1H) 3.45-3.55 (m, 1H) 2.96 (br t, J=4.98 Hz, 4H) 2.29-2.49 (m, 4H) 1.95-2.07 (m, 4H) 1.57 (brs, 4H) 1.18-1.35 (m, 2H) 0.85-0.91 (m, 1H) 0.40 (s, 4H). m/z (ESI, +ve ion): 683.8 (M+H).sup.+.

[0353] Step 3: To a solution of xtalfluor-m (0.351 g, 1.446 mmol) in DCM (6 mL) in a brine/ice bath was added triethylamine trihydrofluoride (0.262 mL, 1.61 mmol) followed by a solution of 4-((2-(benzyloxy)-1-(hydroxymethyl)ethyl)sulfonamido)-7V-(2-(4,4-difluoropiperidin-1-yl)-6-methylpyrimidin-4-yl)-2-(6-azaspiro[2.5]octan-6-yl)benzamide (0.55 g, 0.803 mmol) in DCM (10 mL) dropwise via addition funnel. The reaction was gradually warmed to RT and stirred for 16 h. The reaction was quenched with saturated sodium bicarbonate (aq) and diluted with water and DCM. The organic phase was separated, washed with brine, dried over magnesium sulfate, and concentrated in vacuo. The crude material was purified by silica gel chromatography (20-100% EtOAc in heptane) to afford a 1:0.8 mixture of rac-4-((2-(benzyloxy)-1-(fluoromethyl)ethyl)sulfonamido)-N-(2-(4,4-difluoropiperidin-1-yl)-6-methylpyrimidin-4-yl)-2-(6-azaspiro[2.5]octan-6-yl)benzamide and 4-((1-((benzyloxy)methyl)vinyl)sulfonamido)-N-(2-(4,4-difluoropiperidin-1-yl)-6-methylpyrimidin-4-yl)-2-(6-azaspiro[2.5]octan-6-yl)benzamide (265 mg). The mixture was carried forward without further purification.

[0354] Step 4: To a suspension of 265 mg of the product mixture from the previous step and palladium hydroxide on carbon (0.135 g, 0.193 mmol), in EtOH (20 mL) was added and AcOH (0.033 mL, 0.579 mmol). The reaction was hydrogenated under 55 psi hydrogen at room temperature for 24 hours. After flushing the reaction with Nitrogen, an additional portion of palladium hydroxide on carbon (0.135 mL, 0.193 mmol) was added followed by additional AcOH (0.033 mL, 0.579 mmol). The reaction vessel was flushed with N.sub.2 before replacing the atmosphere with 55 psi hydrogen. The reaction was continued at room temperature for an additional 48 hours. The reaction was flushed with nitrogen then filtered over CELITE® and the filtrate was concentrated in vacuo. The racemic mixture was purified by preparative SFC using an IE (250×21 mm, 5 mm) with a mobile phase of 80% Liquid CO.sup.2 and 20% MeOH (flowrate of 80 mL/min) to give:

[0355] Example 16-1: (S)-N-(2-(4,4-Difluoropiperidin-1-yl)-6-methylpyrimidin-4-yl)-4-((2-fluoro-1-(hydroxymethyl)ethyl)sulfonamido)-2-(6-azaspiro[2.5]octan-6-yl)benzamide. First eluting peak .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ ppm 13.35 (s, 1H), 10.21-10.84 (m, 1H), 8.06 (d, J=8.50 Hz, 1H) 7.40 (s, 1H), 7.29 (d, J=2.07 Hz, 1H), 7.16 (dd, J=8.50, 2.07 Hz, 1H), 5.12-5.38 (m, 1H), 4.88-4.97 (m, 1H) 4.71-4.84 (m, 1H), 3.85-4.01 (m, 5H), 3.74 (dd, J=11.30, 7.98 Hz, 1H), 3.51-3.63 (m, 1H) 2.98 (br t, J=4.77 Hz, 4H), 2.32 (s, 3H), 1.93-2.07 (m, 4H), 1.51-1.91 (m, 4H), 0.40 (s, 4H). m/z (ESI, +ve ion): 597.2 (M+H).sup.+.

[0356] Example 16-2: (R)-N-(2-(4,4-Difluoropiperidin-1-yl)-6-methylpyrimidin-4-yl)-4-((2-fluoro-1-(hydroxymethyl)ethyl)sulfonamido)-2-(6-azaspiro[2.5]octan-6-yl)benzamide. Second eluting peak. .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ ppm 13.35 (s, 1H) 10.32-10.70 (m, 1H) 8.05 (d, J=8.71 Hz, 1H) 7.40 (s, 1H) 7.29 (d, J=2.07 Hz, 1H) 7.16 (dd, J=8.71, 2.07 Hz, 1H) 5.14-5.40 (m, 1H) 4.85-4.97 (m, 1H) 4.73-4.84 (m, 1H) 3.87-3.98 (m, 5H), 3.74 (dd, J=11.09, 7.98 Hz, 1H) 3.48. m/z (ESI, +ve ion): 597.2 (M+H).sup.+. The stereochemistry was arbitrarily assigned

Example 17: N-(2-(4,4-Difluoropiperidin-1-yl)pyridin-4-yl)-4-(N-(2-hydroxyethyl)sulfamoyl)-2-(6-azaspiro[2.5]octan-6-yl)benzamide

[0357] ##STR00285##

[0358] A mixture of N-(2-(4,4-difluoropiperidin-1-yl)pyridin-4-yl)-4-iodo-2-(6-azaspiro[2.5]octan-6-yl)benzamide (212 mg, 0.384 mmol, Int. 21-14), 1,4-diazabicyclo[2.2.2]octane bis(sulfur dioxide) adduct (DABSO) (55 mg, 0.23 mmol, Sigma-Aldrich), diacetoxypalladium (13 mg, 0.06 mmol, Strem), rac-((3R,5R,7R)-adamantan-1-yl)((3S,5S,7S)-adamantan-1-yl)(butyl)phosphane (cataCXium® A) (28 mg, 0.08 mmol, Strem), and triethylamine (107 uL, 0.77 mmol) in IPA (3 mL) in a glass tube was degassed for 3 min. The tube was sealed then heated at 85° C. in an oil bath for 3 h. The heterogeneous mixture was cooled to RT and treated with 2-aminoethan-1-ol (47 mg, 0.77 mmol, Sigma-Aldrich) followed by sodium hypochlorite solution (10% wt., 571 mg, 0.77 mmol, Sigma-Aldrich) and stirred at RT for 18 h. The mixture was treated with 2-aminoethan-1-ol (23 mg) followed by sodium hypochlorite solution (10% wt., 275 mg) then stirred at RT for 5 h. EtOAc (20 mL) and water (5 mL) were added to the heterogeneous mixture and the insoluble solid was filtered off. The filter cake was washed with water (2×2 mL) followed by EtOAc (2×4 mL). The organic solution was taken and concentrated under vacuum. The residue was purified by silica gel chromatography (10% to 60% EtOAc in heptane) to give N-(2-(4,4-difluoropiperidin-1-yl)pyridin-4-yl)-4-(N-(2-hydroxyethyl)sulfamoyl)-2-(6-azaspiro[2.5]octan-6-yl)benzamide (100 mg, 0.18 mmol, 47% yield) as an off-white solid. .sup.1H NMR (400 MHz, METHANOL-d.sub.4) δ ppm 7.99-8.14 (m, 2H), 7.79 (s, 1H), 7.68 (d, J=7.88 Hz, 1H), 7.47 (s, 1H), 7.01 (d, J=4.77 Hz, 1H), 3.76 (t, J=5.29 Hz, 4H), 3.58 (t, J=5.91 Hz, 2H), 3.16 (t, J=5.08 Hz, 4H), 3.02 (t, J=5.80 Hz, 2H), 1.98-2.11 (m, 4H), 1.62 (s, 4H), 0.42 (s, 4H). m/z (ESI): (M+H).sup.+550.1.

TABLE-US-00014 TABLE 12 Examples 17-1 to 17-8 were prepared following similar procedures for Example 17: LRMS: (ESI + ve Ex. # Chemical Structure Name ion) m/z 17-1 [00286] 4-(N-(2- Hydroxyethyl)sulfamoyl)-2-(6- azaspiro[2.5]octan-6-yl)-N-(2- (3,3,3- trifluoropropoxy)pyrimidin-4- yl)benzamide 544.2 17-2 [00287] 4-(N-(2- Hydroxyethyl)sulfamoyl)-N-(6- methyl-2-(3,3,3- trifluoropropoxy)pyrimidin-4- yl)-2-(6-azaspiro[2.5]octan-6- yl)benzamide 558.2 17-3 [00288] N-(2-(4,4-Difluoropiperidin-1- yl)-6-methylpyrimidin-4-yl)-4- (N-(2-hydroxyethyl)sulfamoyl)- 2-(6-azaspiro[2.5]octan-6- yl)benzamide 565.2 17-4 [00289] N-(2-(4,4-Difluoropiperidin-1- yl)pyrimidin-4-yl)-4-(N-(2- hydroxyethyl)sulfamoyl)-2-(6- azaspiro[2.5]octan-6- yl)benzamide 551.2 17-5 [00290] N-(2-(3,3-Difluoroazetidin-1- yl)-6-methylpyrimidin-4-yl)-4- (N-(2-hydroxyethyl)sulfamoyl)- 2-(6-azaspiro[2.5]octan-6- yl)benzamide 537.2 17-6 [00291] (R)-N-(2-(4,4- Difluoropiperidin-1-yl)-6- methylpyrimidin-4-yl)-4-(N-(1- hydroxypropan-2- yl)sulfamoyl)-2-(6- azaspiro[2.5]octan-6- yl)benzamide 579.4 17-7 [00292] ((S)-N-(2-(4,4- Difluoropiperidin-1-yl)-6- methylpyrimidin-4-yl)-4-(N-(1- hydroxypropan-2- yl)sulfamoyl)-2-(6- azaspiro[2.5]octan-6- yl)benzamide 579.4 17-8 [00293] N-(2-(4,4-Difluoropiperidin-1- yl)-6-methylpyrimidin-4-yl)-4- (N-(2-hydroxy-2- methylpropyl)sulfamoyl)-2-(6- azaspiro[2.5]octan-6- yl)benzamide 593.4

Examples 18-1 and 18-2: 2-(6-Azaspiro[2.5]octan-6-yl)-4-(R-cyclopropylsulfonimidoyl)-N-(2-(4,4-difluoro-1-piperidinyl)-6-methyl-4-pyrimidinyl)benzamide and 2-(6-azaspiro[2.5]octan-6-yl)-4-(S-cyclopropylsulfonimidoyl)-N-(2-(4,4-difluoro-1-piperidinyl)-6-methyl-4-pyrimidinyl)benzamide

[0359] ##STR00294##

[0360] Step 1: Into a 20 mL microwave vessel were placed N-(2-(4,4-difluoropiperidin-1-yl)-6-methylpyrimidin-4-yl)-4-iodo-2-(6-azaspiro[2.5]octan-6-yl)benzamide (1.00 g, 1.762 mmol, Int. 19), tris (dibenzylideneacetone) dipalladium (0) (0.161 g, 0.176 mmol) and 4,5-bis(diphenylphos-phino)-9,9-dimethyl-xanthene (0.102 g, 0.176 mmol) followed by 1,4-dioxane (10 mL). The resulting mixture was stirred and purged with nitrogen for 5 min before 1,1′-dimethyltriethylamine (0.616 mL, 3.52 mmol) was added under nitrogen followed by cyclopropanethiol (0.142 mL, 1.939 mmol). The vessel was sealed and subjected to microwave condition (10 h, 90° C.). The crude mixture was directly loaded onto a silica gel precolumn and subjected to combi-flash column chromatography on a 40-g ISCO gold column eluting with MeOH/DCM (5 min at 0% and 25 min from 0 to 6%) twice to give 4-(cyclopropylthio)-N-(2-(4,4-difluoropiperidin-1-yl)-6-methylpyrimidin-4-yl)-2-(6-azaspiro[2.5]octan-6-yl)benzamide (0.92 g, 1.791 mmol, 102% yield) as an off-white solid. .sup.1H NMR (400 MHz, DICHLOROMETHANE-d.sub.2) δ ppm 13.33 (s, 1H), 8.15 (d, J=8.29 Hz, 1H), 7.48 (s, 1H), 7.22-7.35 (m, 2H), 3.91-4.09 (m, 4H), 3.06 (brt, J=5.18 Hz, 4H), 2.35 (s, 3H), 2.17-2.28 (m, 1H), 1.62-2.10 (m, 6H), 1.52 (s, 2H), 1.13-1.21 (m, 2H), 0.68-0.76 (m, 2H), 0.40 (s, 4H). m/z (ESI): 514.1 (M+H).sup.+.

[0361] Step 2: To a stirred solution of 4-(cyclopropylthio)-N-(2-(4,4-difluoropiperidin-1-yl)-6-methylpyrimidin-4-yl)-2-(6-azaspiro[2.5]octan-6-yl)benzamide (0.89 g, 1.733 mmol) and ammonium carbonate (0.250 g, 2.60 mmol) in MeOH (4.5 mL) and dichloromethane (9.0 mL) was added (acetyloxy)(phenyl)-iodanyl acetate (1.284 g, 3.99 mmol) in one portion as a solid. The resulting mixture was stirred in open air at rt for 18 h. The resulting mixture was directly loaded onto silica gel precolumn (25 g) and subjected to combi-flash column chromatography on a 40-g ISCO gold column eluting with MeOH/DCM (3 min at 0% and 25 min from 0 to 14%) to give a racemic mixture of 4-(cyclopropanesulfonimidoyl)-N-(2-(4,4-difluoropiperidin-1-yl)-6-methylpyrimidin-4-yl)-2-(6-azaspiro[2.5]octan-6-yl)benzamide (0.95 g, 1.744 mmol, 101% yield) as an off-white solid. The enantiomers were separated via preparative SFC using a Regis (S,S) Whelk-01 (250×21 mm, 5 mm) with a mobile phase of 50% Liquid CO.sub.2 and 50% MeOH using a flow rate of 60 mL/min to generate:

[0362] Example 18-1: 2-(6-Azaspiro[2.5]octan-6-yl)-4-(R-cyclopropylsulfonimidoyl)-N-(2-(4,4-difluoro-1-piperidinyl)-6-methyl-4-pyrimidinyl)benzamide. First eluting peak, .sup.1H NMR (400 MHz, CHLOROFORM-d) δ ppm 13.20 (br d, J=3.73 Hz, 1H), 8.44 (d, J=8.29 Hz, 1H), 7.96 (d, J=1.45 Hz, 1H), 7.87 (dd, J=1.66, 8.29 Hz, 1H), 7.52 (s, 1H), 4.03 (br s, 4H), 3.14 (t, J=5.29 Hz, 4H), 2.53-2.63 (m, 1H), 2.44 (br s, 3H), 1.95-2.10 (m, 4H), 1.53-1.89 (m, 5H), 1.45 (tdd, J=5.08, 6.92, 10.29 Hz, 1H), 1.20-1.30 (m, 1H), 1.07-1.17 (m, 1H), 0.93-1.03 (m, 1H), 0.44 (s, 4H). m/z (ESI): 545.2 (M+H).sup.+.

[0363] Example 18-2: 2-(6-Azaspiro[2.5]octan-6-yl)-4-(S-cyclopropylsulfonimidoyl)-N-(2-(4,4-difluoro-1-piperidinyl)-6-methyl-4-pyrimidinyl)benzamide. Second eluting peak. .sup.1H NMR (400 MHz, CHLOROFORM-d) δ ppm 13.20 (br d, J=3.73 Hz, 1H), 8.44 (d, J=8.29 Hz, 1H), 7.96 (d, J=1.45 Hz, 1H), 7.87 (dd, J=1.66, 8.29 Hz, 1H), 7.52 (s, 1H), 4.03 (br s, 4H), 3.14 (t, J=5.29 Hz, 4H), 2.53-2.63 (m, 1H), 2.44 (br s, 3H), 1.95-2.10 (m, 4H), 1.53-1.89 (m, 5H), 1.45 (tdd, J=5.08, 6.92, 10.29 Hz, 1H), 1.20-1.30 (m, 1H), 1.07-1.17 (m, 1H), 0.93-1.03 (m, 1H), 0.44 (s, 4H). m/z (ESI): 545.2 (M+H).sup.+. The stereochemistry assignments were arbitrary.

TABLE-US-00015 TABLE 13 Examples 19-1 to 19-9 were prepared following the procedure described for Examples 18-1 and 18-2: LRMS: (ESI + Ex. # Chemical Structure Name ve ion) m/z 19-1 [00295] N-(2-(4,4-Difluoropiperidin- 1-yl)-6-methylpyrimidin-4- yl)-4-(oxetane-3- sulfonimidoyl)-2-(6- azaspiro[2.5]octan-6- yl)benzamide 561.2 19-2 [00296] N-(2-(4,4-Difluoropiperidin- 1-yl)-6-methylpyrimidin-4- yl)-4-(methylsulfonimidoyl)- 2-(6-azaspiro[2.5]octan-6- yl)benzamide 519.2 19-3 [00297] 2-(6-Azaspiro[2.5]octan-6- yl)-N-(2-(4,4-difluoro-1- pieridinyl)-6-methyl-4- pyrimidinyl)-4-(S- ethylsulfonimidoyl)benzamide 533.2 19-4 [00298] 2-(6-Azaspiro[2.5]octan-6- yl)-N-(2-(4,4-difluoro-1- pieridinyl)-6-methyl-4- pyrimidinyl)-4-(R- ethylsulfonimidoyl)benzamide 533.2 19-5 [00299] N-(2-(4,4-Difluoropiperidin- 1-yl)-6-methylpyrimidin-4- yl)-4-(propan-2- ylsulfonimidoyl)-2-(6- azaspiro[2.5]octan-6- yl)benzamide 547.3 19-6 [00300] 4- (Cyclopropanesulfonimidoyl)- N-(2-(4,4-difluoropiperidin- 1-yl)pyridin-4-yl)-2-(6- azaspiro[2.5]octan-6- yl)benzamide 530.0 19-7 [00301] 2-(6-Azaspiro[2.5]octan-6- yl)-4-(S- cyclopropylsulfonimidoyl)-N- (6-methy-2-((2R)-2-methyl-4- moprpholinyl)-4- pyrimidinyl)benzamide 525.2 19-8 [00302] 2-(6-Azaspiro[2.5]octan-6- yl)-4-(R- cyclopropylsulfonimidoyl)-N- (6-methy-2-((2R)-2-methyl-4- moprpholinyl)-4- pyrimidinyl)benzamide 525.2 19-9 [00303] 4- (Cyclopropanesulfonimidoyl)- N-(2-(3,3-difluoroazetidin-1- yl)-6-methylpyrimidin-4-yl)- 2-(6-azaspiro[2.5]octan-6- yl)benzamide 517.3

Example 20: (N.SUP.1.-(2-(4,4-Difluoropiperidin-1-yl)-6-methylpyrimidin-4-yl)-2-(6-azaspiro[2.5]octan-6-yl)terephthalamide

[0364] ##STR00304##

[0365] Step 1: To a solution of 4-bromo-N-(2-(4,4-difluoropiperidin-1-yl)-6-methylpyrimidin-4-yl)-2-(6-azaspiro[2.5]octan-6-yl)benzamide (250 mg, 0.48 mmol, Int. 21-3) in DMF (2.5 mL) was added Pd(PPh.sub.3).sub.4 (6 mg, 4.8 μmol) and Zn(CN).sub.2 (113 mg, 0.961 mmol) and the reaction mixture was stirred at 100° C. for 16 h. Then the reaction mixture was diluted with EtOAc and filtered through a CELITE® bed. The filtrate was washed with water and brine, dried over Na.sub.2SO.sub.4, filtered, concentrated and purified by flash column chromatography using a gradient of 30% EtOAc in petroleum ether to provide 4-cyano-N-(2-(4,4-difluoropiperidin-1-yl)-6-methylpyrimidin-4-yl)-2-(6-azaspiro[2.5]octan-6-yl)benzamide (160 mg, 0.343 mmol, 71.4% yield) as an off white solid. .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ ppm 13.20 (s, 1H), 8.18 (d, J=8.1 Hz, 1H), 8.03 (s, 1H), 7.79 (d, J=8.1 Hz, 1H), 7.39 (s, 1H), 4.00-3.80 (m, 4H), 3.07 (t, J=5.2 Hz, 4H), 2.34 (s, 3H), 1.99 (tt, J=13.3, 5.7 Hz, 4H), 1.69 (s, 4H), 0.38 (s, 4H). m/z (ESI): 467.2 (M+H).sup.+.

[0366] Step 2: To a solution of 4-cyano-N-(2-(4,4-difluoropiperidin-1-yl)-6-methylpyrimidin-4-yl)-2-(6-azaspiro[2.5]octan-6-yl)benzamide (110 mg, 0.236 mmol) in dimethyl sulfoxide (2 mL) were added K.sub.2CO.sub.3 (6.52 mg, 0.047 mmol) and H.sub.2O.sub.2 (103 μL, 1.179 mmol) at 0° C. and the reaction mixture was stirred for 1 h before it was quenched with water and was extracted with EtOAc (2×20 mL). The combined organic layers were washed with brine, dried over Na.sub.2SO.sub.4, filtered, concentrated and purified by flash column chromatography using a gradient of 10% methanol in dichloromethane to provide N.sup.1-(2-(4,4-difluoropiperidin-1-yl)-6-methylpyrimidin-4-yl)-2-(6-azaspiro[2.5]octan-6-yl)terephthalamide (108 mg, 0.223 mmol, 95% yield) as off white solid. .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ ppm 13.75 (s, 1H), 8.26 (m, 1H), 8.17 (m, 1H), 8.00 (s, 1H), 7.89-7.78 (m, 1H), 7.61 (s, 1H), 7.42 (s, 1H), 3.94 (d, J=5.8 Hz, 4H), 3.06 (d, J=6.0 Hz, 4H), 2.34 (d, J=2.3 Hz, 3H), 2.01 (q, J=8.5, 8.1 Hz, 4H), 1.74 (s, 4H), 0.41 (d, J=2.3 Hz, 4H). m/z (ESI): 485.2 (M+H).sup.+.

Example 21: 4-(Azetidin-3-ylsulfonyl)-N-(2-(4,4-difluoropiperidin-1-yl)-6-methylpyrimidin-4-yl)-2-(6-azaspiro[2.5]octan-6-yl)benzamide

[0367] ##STR00305##

[0368] To a solution of 4-((1-(tert-butoxycarbonyl)azetidin-3-yl)sulfonyl)-2-(6-azaspiro[2.5]octan-6-yl)benzoic acid (2.54 g, 5.64 mmol, Int. 16) and HATU (3.22 g, 8.46 mmol, ChemPep) in DMF (35 mL), was added 2-(4,4-difluoropiperidin-1-yl)-6-methylpyrimidin-4-amine (1.93 g, 8.46 mmol, Int. 4) and DIPEA (2.46 mL, 14.09 mmol). The mixture was stirred at room temperature for 18 h. The mixture was diluted with saturated Na.sub.2CO.sub.3 and EtOAc. The organic was separated and washed with Na.sub.2CO.sub.3, water and brine, dried over Na.sub.2SO.sub.4 and concentrated in vacuo. The crude was purified by silica gel chromatography: 0-30%-60% EtOAc in heptane, m/z (ESI): 661.3 (M+H).sup.+. The residue was treated with DCM (8 mL) and TFA (4 mL) at room temperature for 30 min and concentrated in vacuo. The solid obtained was suspended in EtOAc and washed with 1N NaOH solution and the mixture was extracted with EtOAc. The organic extracts were washed with water and brine, dried over Na.sub.2SO.sub.4 and concentrated in vacuo. The crude was purified by silica gel chromatography: 0-20% MeOH in DCM with 2% NH4OH to give the title compound as a white solid. .sup.1H NMR (400 MHz, METHANOL-d.sub.4) δ ppm 8.35 (d, J=8.09 Hz, 1H), 7.90 (d, J=1.24 Hz, 1H), 7.81 (dd, J=1.66, 8.09 Hz, 1H), 7.46 (s, 1H), 4.46-4.60 (m, 1H), 3.97-4.06 (m, 6H), 3.76-3.86 (m, 2H), 3.10-3.21 (m, 4H), 2.37 (s, 3H), 1.93-2.01 (m, 4H), 1.73-1.88 (m, 4H), 0.45 (s, 4H). m/z (ESI): 561.2 (M+H).sup.+.

Example 22: 4-N-(2-(4,4-Difluoropiperidin-1-yl)-6-methylpyrimidin-4-yl)-4-((1-methylazetidin-3-yl)sulfonyl)-2-(6-azaspiro[2.5]octan-6-yl)benzamide

[0369] ##STR00306##

[0370] To a mixture of 4-(azetidin-3-ylsulfonyl)-N-(2-(4,4-difluoropiperidin-1-yl)-6-methylpyrimidin-4-yl)-2-(6-azaspiro[2.5]octan-6-yl)benzamide (0.045 g, 0.080 mmol, ex. 21), MeOH (1 mL), and formaldehyde with 10-15% MeOH (0.016 g, 0.482 mmol, Fisher) was added AcOH (0.037 mL, 0.642 mmol, Aldrich), followed by sodium triacetoxyborohydride (0.204 g, 0.963 mmol, Aldrich). The mixture was stirred at room temperature for 18 h and concentrated in vacuo. The acid was neutralized with 1N NaOH solution and the mixture was extracted with EtOAc. The organic phase was washed with water and brine, dried over Na.sub.2SO.sub.4 and concentrated in vacuo. Purification by silica gel chromatography: 0-100% EtOAc/EtOH (3/1) in heptane gave the title compound as a white solid. .sup.1H NMR (400 MHz, CHLOROFORM-d) δ ppm 12.82 (br s, 1H), 8.44 (d, J=8.29 Hz, 1H), 7.82 (d, J=1.66 Hz, 1H), 7.73 (dd, J=1.76, 8.19 Hz, 1H), 7.46 (s, 1H), 3.97-4.11 (m, 5H), 3.60-3.90 (m, 4H), 3.12 (t, J=5.29 Hz, 4H), 2.44-2.57 (m, 3H), 2.39 (s, 3H), 1.68-2.06 (m, 8H), 0.43 (s, 4H). m/z (ESI): 575.3 (M+H).sup.+.

BIOLOGICAL EXAMPLES

[0371] The following assays were used in testing the exemplary compounds of the invention. Data for those examples tested in accordance with the procedures described below are presented in Table A below.

[0372] KIF18A Enzyme Assay: Microtubule-stimulated ATPase activity assay is used to measure KIF18A enzyme activity after treatment with compound. Compounds were 2-fold serially diluted in DMSO (Sigma Inc) over 22-point concentration range. Recombinant human KIF18A (1-467 His-tagged) protein was expressed using a baculovirus system and purified by affinity chromatography by Amgen Inc. Concentrations of KIF18A protein, microtubules (MT), and ATP in the reaction were optimized for standardized homogenous enzyme assay using ADP-Glo™ Kinase/ATPase Assay Kit (Promega Inc). The assay measures ADP formed from the ATPase reaction. Prepare reaction buffer [(15 mM Tris, pH 7.5 (Teknova Inc), 10 mM MgCl2 (JT Baker Inc), 0.01% Pluronic F-68 (Life Technologies Inc), 1 μM Taxol (Cytoskeleton Inc), and 30 μg/mL pig microtubules (Cytoskeleton Inc)]. Add compound and KIF18A protein (30 nM) to prepared reaction buffer and incubated for 15 minutes at room temperature, next add ATP (at K.sub.m, 75 μM) to the reaction mixture and incubated for an additional 15 minutes at room temperature. Mix 5 μl of ADP-Glo™ Reagent and 2.5 μl of the reaction mixture and incubate for 40 minutes at room temperature. Add 10 μl ADP-Glo™ Detection Reagent and incubate for 40 minutes at room temperature. Read luminescence using EnVision microplate reader with ultra-luminescence module (Perkin Elmer Inc). Concentration-response curve-fitting and IC.sub.50 determination was performed using Genedata Screener Software (Standard 15.0.1, Genedata Inc) with a four-parameter logistic regression fit model.

[0373] Table A provides data for compounds exemplified in the present application and priority document thereof, as representative compounds of the present invention, as follows: compound name and biological data. (IC.sub.50 in uM, where available. Ex. # refers to Example No.)

TABLE-US-00016 TABLE A BIOLOGICAL DATA KIF18A ATPase Ex. # Compound Name IC.sub.50 (μM) 1 N-(2-((1-Hydroxy-2-methylpropan-2-yl)amino)-6-methylpyrimidin-4-yl)- 0.186 4-(methylsulfonyl)-2-(6-azaspiro[2.5]octan-6-yl)benzamide  1-1 (R)-N-(2-((1-Hydroxypropan-2-yl)amino)-6-methylpyrimidin-4-yl)-4- 0.216 (methylsulfonyl)-2-(6-azaspiro[2.5]octan-6-yl)benzamide  1-2 (S)-N-(2-((1-Hydroxypropan-2-yl)amino)-6-methylpyrimidin-4-yl)-4- 0.491 (methylsulfonyl)-2-(6-azaspiro[2.5]octan-6-yl)benzamide  1-3 N-(2-((2-Hydroxyethyl)amino)-6-methylpyrimidin-4-yl)-4- 0.849 (methylsulfonyl)-2-(6-azaspiro[2.5]octan-6-yl)benzamide  1-4 (R)-N-(2-((2-Hydroxypropyl)amino)-6-methylpyrimidin-4-yl)-4- 0.580 (methylsulfonyl)-2-(6-azaspiro[2.5]octan-6-yl)benzamide  1-5 (S)-N-(2-((2-Hydroxypropyl)amino)-6-methylpyrimidin-4-yl)-4- 0.451 (methylsulfonyl)-2-(6-azaspiro[2.5]octan-6-yl)benzamide  1-6 N-(6-Methyl-2-(3,3,3-trifluoropropoxy)pyrimidin-4-yl)-4-(N-(3- 0.032 methyloxetan-3-yl)sulfamoyl)-2-(6-azaspiro[2.5]octan-6-yl)benzamide  1-7 N-(2-((1-hydroxy-2-methylpropan-2-yl)amino)-6-methylpyrimidin-4-yl)- 0.168 4-(N-(3-methyloxetan-3-yl)sulfamoyl)-2-(6-azaspiro[2.5]octan-6- yl)benzamide 2 N-(2-(2-Hydroxypropan-2-yl)pyrimidin-4-yl)-4-(N-(3-methyloxetan-3- 0.143 yl)sulfamoyl)-2-(6-azaspiro[2.5]octan-6-yl)benzamide  2-1 N-(2-(2-Hydroxypropan-2-yl)-6-methylpyrimidin-4-yl)-4-(N-(3- 0.065 methyloxetan-3-yl)sulfamoyl)-2-(6-azaspiro[2.5]octan-6-yl)benzamide  2-2 (R)-N-(2-(2-methylmorpholino)pyrimidin-4-yl)-4-(N-(3-methyloxetan-3- 0.068 yl)sulfamoyl)-2-(6-azaspiro[2.5]octan-6-yl)benzamide  2-3 (R)-N-(6-Methyl-2-(2-methylmorpholino)pyrimidin-4-yl)-4-(N-(3- 0.115 methyloxetan-3-yl)sulfamoyl)-2-(6-azaspiro[2.5]octan-6-yl)benzamide  2-4 N-(2-(4,4-Difluoropiperidin-1-yl)pyridin-4-yl)-4-(N-(3-methyloxetan-3- 0.029 yl)sulfamoyl)-2-(6-azaspiro[2.5]octan-6-yl)benzamide  2-5 N-(2-(4,4-Difluoropiperidin-1-yl)-6-methylpyrimidin-4-yl)-4-(N-(3- 0.103 methyloxetan-3-yl)sulfamoyl)-2-(6-azaspiro[2.5]octan-6-yl)benzamide  2-6 N-(2-(4,4-Difluoropiperidin-1-yl)-6-methylpyrimidin-4-yl)-4- 0.260 (methylsulfonyl)-2-(6-azaspiro[2.5]octan-6-yl)benzamide  2-7 (R)-N-(2-(2-Methylmorpholino)pyrimidin-4-yl)-4-(methylsulfonyl)-2-(6- 0.240 azaspiro[2.5]octan-6-yl)benzamide  2-8 N-(2-(4,4-Difluoropiperidin-1-yl)-6-methylpyrimidin-4-yl)-4-((1- 0.713 methylcyclopropane)-1-sulfonamido)-2-(6-azaspiro[2.5]octan-6- yl)benzamide 3 (R)-4-((2-Hydroxyethyl)sulfonamido)-N-(6-methyl-2-(2- 0.057 methylmorpholino)pyrimidin-4-yl)-2-(6-azaspiro[2.5]octan-6- yl)benzamide 4 N-(2-(4,4-Difluoropiperidin-1-yl)-6-methylpyrimidin-4-yl)-4-((2- 0.071 hydroxyethyl)sulfonamido)-2-(6-azaspiro[2.5]octan-6-yl)benzamide  5-1 (R)-N-(2-(4,4-difluoropiperidin-1-yl)-6-methylpyrimidin-4-yl)-4-((2- 0.062 hydroxy-l-methylethyl)sulfonamido)-2-(6-azaspiro[2.5]octan-6- yl)benzamide  5-2 (S)-N-(2-(4,4-difluoropiperidin-1-yl)-6-methylpyrimidin-4-yl)-4-((2- 0.070 hydroxy-1-methylethyl)sulfonamido)-2-(6-azaspiro[2.5]octan-6- yl)benzamide  6-1 4-((Fluoromethyl)sulfonamido)-N-(2-(4-fluoropiperidin-1-yl)-6- 0.062 methylpyrimidin-4-yl)-2-(6-azaspiro[2.5]octan-6-yl)benzamide  6-2 N-(2-(4,4-Difluoropiperidin-1-yl)-6-methylpyrimidin-4-yl)-4- 0.042 ((fluoromethyl)sulfonamido)-2-(6-azaspiro[2.5]octan-6-yl)benzamide  6-3 (R)-4-((Fluoromethyl)sulfonamido)-N-(6-methyl-2-(2- 0.079 methylmorpholino)pyrimidin-4-yl)-2-(6-azaspiro[2.5]octan-6- yl)benzamide  6-4 (R)-4-((2-Hydroxyethyl)sulfonamido)-N-(2-(2- 0.032 methylmorpholino)pyrimidin-4-yl)-2-(6-azaspiro[2.5]octan-6- yl)benzamide  6-5 (R)-N-(6-Methyl-2-(2-methylmorpholino)pyrimidin-4-yl)-4- 0.120 (methylsulfonamido)-2-(6-azaspiro[2.5]octan-6-yl)benzamide  6-6 (R)-4-(Ethylsulfonamido)-N-(6-methyl-2-(2- 0.067 methylmorpholino)pyrimidin-4-yl)-2-(6-azaspiro[2.5]octan-6- yl)benzamide  6-7 N-(2-(4,4-Difluoropiperidin-1-yl)-6-methylpyrimidin-4-yl)-4- 0.122 (ethylsulfonamido)-2-(6-azaspiro[2.5]octan-6-yl)benzamide  6-8 (R)-4-((3-Hydroxypropyl)sulfonamido)-N-(6-methyl-2-(2- 0.107 methylmorpholino)pyrimidin-4-yl)-2-(6-azaspiro[2.5]octan-6- yl)benzamide  6-9 N-(2-(4,4-Difluoropiperidin-1-yl)-6-methylpyrimidin-4-yl)-4-(3,3- 0.246 dioxido-1,3,4-oxathiazinan-4-yl)-2-(6-azaspiro[2.5]octan-6-yl)benzamide  6-10 4-(Cyclopentanesulfonamido)-N-(2-(4,4-difluoropiperidin-1-yl)-6- 2.42 methylpyrimidin-4-yl)-2-(6-azaspiro[2.5]octan-6-yl)benzamide  6-11 4-(Cyclobutanesulfonamido)-N-(2-(4,4-difluoropiperidin-1-yl)-6- 0.127 methylpyrimidin-4-yl)-2-(6-azaspiro[2.5]octan-6-yl)benzamide  6-12 N-(2-(4,4-Difluoropiperidin-1-yl)-6-methylpyrimidin-4-yl)-4-(oxetane-3- 0.040 sulfonamido)-2-(6-azaspiro[2.5]octan-6-yl)benzamide  6-13 4-(Cyclobutanesulfonamido)-N-(2-(3,3-difluoroazetidin-1-yl)-6- 0.052 methylpyrimidin-4-yl)-2-(6-azaspiro[2.5]octan-6-yl)benzamide  6-14 N-(2-(4,4-Difluoropiperidin-1-yl)-6-methylpyrimidin-4-yl)-4-((1,1- 0.413 dimethylethyl)sulfonamido)-2-(6-azaspiro[2.5]octan-6-yl)benzamide  6-15 N-(2-(4,4-Difluoropiperidin-1-yl)-6-methylpyrimidin-4-yl)-4-((3- 0.086 hydroxypropyl)sulfonamido)-2-(6-azaspiro[2.5]octan-6-yl)benzamide  6-16 4-(Cyclopropanesulfonamido)-N-(2-(4,4-difluoropiperidin-1-yl)-6- 0.052 methylpyrimidin-4-yl)-2-(6-azaspiro[2.5]octan-6-yl)benzamide  6-17 N-(2-(4,4-Difluoropiperidin-1-yl)-6-methylpyrimidin-4-yl)-4-((2- 0.032 methoxyethyl)sulfonamido)-2-(6-azaspiro[2.5]octan-6-yl)benzamide  6-18 4-((Cyclopropylmethyl)sulfonamido)-N-(2-(4,4-difluoropiperidin-1-yl)-6- 0.085 methylpyrimidin-4-yl)-2-(6-azaspiro[2.5]octan-6-yl)benzamide  6-19 N-(2-(4,4-Difluoropiperidin-1-yl)-6-methylpyrimidin-4-yl)-4-(((3- 0.039 hydroxyoxetan-3-yl)methyl)sulfonamido)-2-(6-azaspiro[2.5]octan-6- yl)benzamide  6-20 N-(2-(4,4-Difluoropiperidin-1-yl)-6-methylpyrimidin-4-yl)-4-((2- 0.049 hydroxy-1,1-dimethylethyl)sulfonamido)-2-(6-azaspiro[2.5]octan-6- yl)benzamide  6-21 N-(2-(4,4-Difluoropiperidin-1-yl)-6-methylpyrimidin-4-yl)-4- 0.039 (methylsulfonamido)-2-(6-azaspiro[2.5]octan-6-yl)benzamide  6-22 N-(2-(4,4-Difluoropiperidin-1-yl)-6-methylpyrimidin-4-yl)-4-((1- 0.151 methylethyl)sulfonamido)-2-(6-azaspiro[2.5]octan-6-yl)benzamide  6-23-1 4-(((S)-2-Hydroxy-1-methylethyl)sulfonamido)-N-(6-methyl-2-((R)-2- 0.039 methylmorpholino)pyrimidin-4-yl)-2-(6-azaspiro[2.5]octan-6- yl)benzamide  6-23-2 4-(((R)-2-Hydroxy-1-methylethyl)sulfonamido)-N-(6-methyl-2-((R)-2- 0.0373 methylmorpholino)pyrimidin-4-yl)-2-(6-azaspiro[2.5]octan-6- yl)benzamide  6-24-1 4-(((S)-2-Hydroxy-1-methylethyl)sulfonamido)-N-(2-((R)-2- 0.0174 methylmorpholino)pyrimidin-4-yl)-2-(6-azaspiro[2.5]octan-6- yl)benzamide  6-24-2 4-(((R)-2-hydroxy-1-methylethyl)sulfonamido)-N-(2-((R)-2- 0.028 methylmorpholino)pyrimidin-4-yl)-2-(6-azaspiro[2.5]octan-6- yl)benzamide  6-25-1 (S)-N-(2-(4-fluoropiperidin-1-yl)-6-methylpyrimidin-4-yl)-4-((2-hydroxy- 0.047 1-methylethyl)sulfonamido)-2-(6-azaspiro[2.5]octan-6-yl)benzamide  6-25-2 (R)-N-(2-(4-Fluoropiperidin-1-yl)-6-methylpyrimidin-4-yl)-4-((2- 0.041 hydroxy-1-methylethyl)sulfonamido)-2-(6-azaspiro[2.5]octan-6- yl)benzamide  6-26-1 (S)-N-(2-(4,4-Difluoropiperidin-1-yl)pyrimidin-4-yl)-4-((2-hydroxy-1- 0.031 methylethyl)sulfonamido)-2-(6-azaspiro[2.5]octan-6-yl)benzamide  6-26-2 (R)-N-(2-(4,4-Difluoropiperidin-1-yl)pyrimidin-4-yl)-4-((2-hydroxy-1- 0.021 methylethyl)sulfonamido)-2-(6-azaspiro[2.5]octan-6-yl)benzamide  6-27-1 4-(((R)-2-Hydroxypropyl)sulfonamido)-N-(6-methyl-2-((R)-2- 0.162 methylmorpholino)pyrimidin-4-yl)-2-(6-azaspiro[2.5]octan-6- yl)benzamide  6-27-2 4-(((S)-2-Hydroxypropyl)sulfonamido)-N-(6-methyl-2((R)-2- 0.151 methylmorpholino)pyrimidin-4-yl)-2-(6-azaspiro[2.5]octan-6- yl)benzamide  6-28-1 (R)-4-((2-Hydroxypropyl)sulfonamido)-N-(6-methyl-2-(3,3,3- 0.068 trifluoropropoxy)pyrimidin-4-yl)-2-(6-azaspiro[2.5]octan-6-yl)benzamide  6-28-2 (S)-4-((2-Hydroxypropyl)sulfonamido)-N-(6-methyl-2-(3,3,3- 0.071 trifluoropropoxy)pyrimidin-4-yl)-2-(6-azaspiro[2.5]octan-6-yl)benzamide  6-29 N-(2-(4,4-Difluoropiperidin-1-yl)pyridin-4-yl)-4-((2- 0.017 hydroxyethyl)sulfonamido)-2-(6-azaspiro[2.5]octan-6-yl)benzamide  6-30 N-(2-(4,4-Difluoropiperidin-1-yl)-6-methylpyridin-4-yl)-4-((2- 0.0384 hydroxyethyl)sulfonamido)-2-(6-azaspiro[2.5]octan-6-yl)benzamide  6-31-1 (R)-N-(2-(4,4-Difluoropiperidin-1-yl)-6-methylpyrimidin-4-yl)-4-((1-(1- 0.324 hydroxyethyl)cyclopropane)-1-sulfonamido)-2-(6-azaspiro[2.5]octan-6- yl)benzamide  6-31-2 (S)-N-(2-(4,4-Difluoropiperidin-1-yl)-6-methylpyrimidin-4-yl)-4-((1-(1- 0.281 hydroxyethyl)cyclopropane)-1-sulfonamido)-2-(6-azaspiro[2.5]octan-6- yl)benzamide  6-32-1 (R)-N-(2-(4,4-Difluoropiperidin-1-yl)-6-methylpyrimidin-4-yl)-4-((2- 0.112 hydroxypropyl)sulfonamido)-2-(6-azaspiro[2.5]octan-6-yl)benzamide  6-32-2 (S)-N-(2-(4,4-Difluoropiperidin-1-yl)-6-methylpyrimidin-4-yl)-4-((2- 0.141 hydroxypropyl)sulfonamido)-2-(6-azaspiro[2.5]octan-6-yl)benzamide  6-33-1 4-(((S)-2-Hydroxypropyl)sulfonamido)-N-(2-((R)-2- 0.115 methylmorpholino)pyrimidin-4-yl)-2-(6-azaspiro[2.5]octan-6- yl)benzamide  6-33-2 4-(((R)-2-hydroxypropyl)sulfonamido)-N-(2-((R)-2- 0.086 methylmorpholino)pyrimidin-4-yl)-2-(6-azaspiro[2.5]octan-6- yl)benzamide  6-34 5-Chloro-N-(2-(4,4-difluoropiperidin-1-yl)-6-methylpyrimidin-4-yl)-4- 0.0922 ((2-hydroxyethyl)sulfonamido)-2-(6-azaspiro[2.5]octan-6-yl)benzamide  6-35 N-(2-(4,4-Difluoropiperidin-1-yl)-6-methylpyrimidin-4-yl)-4-((2- 0.144 hydroxyethyl)sulfonamido)-5-methyl-2-(6-azaspiro[2.5]octan-6- yl)benzamide  6-36 N-(2-(4,4-Difluoropiperidin-1-yl)-6-methylpyrimidin-4-yl)-4-((2- 0.114 hydroxyethyl)sulfonamido)-5-methoxy-2-(6-azaspiro[2.5]octan-6- yl)benzamide  6-37 N-(2-(4,4-Difluoropiperidin-1-yl)-6-(2-hydroxypropan-2-yl)pyrimidin-4- 0.125 yl)-4-((2-hydroxyethyl)sulfonamido)-2-(6-azaspiro[2.5]octan-6- yl)benzamide  6-38 N-(2-(4,4-Difluoropiperidin-1-yl)-6-ethylpyrimidin-4-yl)-4-((2- 0.060 hydroxyethyl)sulfonamido)-2-(6-azaspiro[2.5]octan-6-yl)benzamide  6-39 N-(6-Cyclopropyl-2-(4,4-difluoropiperidin-1-yl)pyrimidin-4-yl)-4-((2- 0.225 hydroxyethyl)sulfonamido)-2-(6-azaspiro[2.5]octan-6-yl)benzamide  6-40 (R)-4-((2-Hydroxyethyl)sulfonamido)-N-(6-(2-hydroxypropan-2-yl)-2-(2- 0.161 methylmorpholino)pyrimidin-4-yl)-2-(6-azaspiro[2.5]octan-6- yl)benzamide 7 N-(2-(3,3-Difluoroazetidin-1-yl)-6-methylpyrimidin-4-yl)-4-((2- 0.023 hydroxyethyl)sulfonamido)-2-(6-azaspiro[2.5]octan-6-yl)benzamide  8-1 (R)-N-(2-(4,4-Difluoropiperidin-1-yl)-6-methylpyrimidin-4-yl)-5-fluoro- 0.091 4-((2-hydroxy-1-methylethyl)sulfonamido)-2-(6-azaspiro[2.5]octan-6- yl)benzamide  8-2 (S)-N-(2-(4,4-Difluoropiperidin-1-yl)-6-methylpyrimidin-4-yl)-5-fluoro- 0.073 4-((2-hydroxy-1-methylethyl)sulfonamido)-2-(6-azaspiro[2.5]octan-6- yl)benzamide  9-1 (R)-5-Fluoro-4-((2-hydroxyethyl)sulfonamido)-N-(2-(2- 0.078 methylmorpholino)pyrimidin-4-yl)-2-(6-azaspiro[2.5]octan-6- yl)benzamide  9-2 (R)-5-Fluoro-4-((2-hydroxyethyl)sulfonamido)-N-(6-methyl-2-(2- 0.158 methylmorpholino)pyrimidin-4-yl)-2-(6-azaspiro[2.5]octan-6- yl)benzamide 10-1 (R)-N-(2-(3,3-Difluoroazetidin-1-yl)-6-methylpyrimidin-4-yl)-4-((2- 0.083 hydroxypropyl)sulfonamido)-2-(6-azaspiro[2.5]octan-6-yl)benzamide 10-2 (S)-N-(2-(3,3-Difluoroazetidin-1-yl)-6-methylpyrimidin-4-yl)-4-((2- 0.073 hydroxypropyl)sulfonamido)-2-(6-azaspiro[2.5]octan-6-yl)benzamide 11-1 (S)-4-((2-Hydroxyethyl)sulfonamido)-N-(2-(2- 0.037 methylmorpholino)pyrimidin-4-yl)-2-(6-azaspiro[2.5]octan-6- yl)benzamide 11-2 4-((2-Hydroxyethyl)sulfonamido)-N-(2-isopropyl-6-methylpyrimidin-4- 0.027 yl)-2-(6-azaspiro[2.5]octan-6-yl)benzamide 11-3 N-(2-Cyclopropyl-6-methylpyrimidin-4-yl)-4-((2- 0.049 hydroxyethyl)sulfonamido)-2-(6-azaspiro[2.5]octan-6-yl)benzamide 11-4 N-(2-Cyclobutoxy-6-methylpyrimidin-4-yl)-4-((2- 0.018 hydroxyethyl)sulfonamido)-2-(6-azaspiro[2.5]octan-6-yl)benzamide 11-5 N-(2-(3-Fluoroazetidin-1-yl)-6-methylpyrimidin-4-yl)-4-((2- 0.032 hydroxyethyl)sulfonamido)-2-(6-azaspiro[2.5]octan-6-yl)benzamide 11-6 N-(2-(3-Fluoroazetidin-1-yl)pyrimidin-4-yl)-4-((2- 0.068 hydroxyethyl)sulfonamido)-2-(6-azaspiro[2.5]octan-6-yl)benzamide 11-7 N-(2-(3,3-Difluoroazetidin-1-yl)pyrimidin-4-yl)-4-((2- 0.023 hydroxyethyl)sulfonamido)-2-(6-azaspiro[2.5]octan-6-yl)benzamide 11-8 4-((2-Hydroxyethyl)sulfonamido)-N-(6-methyl-2-(2-oxa-6- 0.640 azaspiro[3.3]heptan-6-yl)pyrimidin-4-yl)-2-(6-azaspiro[2.5]octan-6- yl)benzamide 11-9 4-((2-Hydroxyethyl)sulfonamido)-N-(6-methyl-2-(6-oxa-1- 0.128 azaspiro[3.3]heptan-1-yl)pyrimidin-4-yl)-2-(6-azaspiro[2.5]octan-6- yl)benzamide 11-10 N-(2-(3-(Difluoromethoxy)azetidin-1-yl)-6-methylpyrimidin-4-yl)-4-((2- 0.192 hydroxyethyl)sulfonamido)-2-(6-azaspiro[2.5]octan-6-yl)benzamide 11-12 N-(2-(1,1-Difluoro-5-azaspiro[2.3]hexan-5-yl)-6-methylpyrimidin-4-yl)- 0.093 4-((2-hydroxyethyl)sulfonamido)-2-(6-azaspiro[2.5]octan-6-yl)benzamide 11-13 4-((2-Hydroxyethyl)sulfonamido)-N-(6-methyl-2-(3- 0.067 (trifluoromethyl)azetidin-1-yl)pyrimidin-4-yl)-2-(6-azaspiro[2.5]octan-6- yl)benzamide 11-14 N-(2-(3-Cyanoazetidin-1-yl)-6-methylpyrimidin-4-yl)-4-((2- 0.172 hydroxyethyl)sulfonamido)-2-(6-azaspiro[2.5]octan-6-yl)benzamide 11-15 4-((2-Hydroxyethyl)sulfonamido)-N-(2-(3-(2-hydroxypropan-2- 0.935 yl)azetidin-1-yl)-6-methylpyrimidin-4-yl)-2-(6-azaspiro[2.5]octan-6- yl)benzamide 11-16 N-(2-(3-Hydroxy-3-methylazetidin-1-yl)-6-methylpyrimidin-4-yl)-4-((2- 1.01 hydroxyethyl)sulfonamido)-2-(6-azaspiro[2.5]octan-6-yl)benzamide 11-17 N-(2-(3-Cyclopropyl-3-hydroxyazetidin-1-yl)-6-methylpyrimidin-4-yl)-4- 1.09 ((2-hydroxyethyl)sulfonamido)-2-(6-azaspiro[2.5]octan-6-yl)benzamide 11-18 4-((2-Hydroxyethyl)sulfonamido)-N-(6-methyl-2-(5-azaspiro[2.3]hexan- 0.064 5-yl)pyrimidin-4-yl)-2-(6-azaspiro[2.5]octan-6-yl)benzamide 11-19 N-(2-(3-Hydroxy-3-(trifluoromethyl)azetidin-1-yl)-6-methylpyrimidin-4- 0.205 yl)-4-((2-hydroxyethyl)sulfonamido)-2-(6-azaspiro[2.5]octan-6- yl)benzamide 11-20 N-(2-(Azetidin-1-yl)-6-methylpyrimidin-4-yl)-4-((2- 0.0483 hydroxyethyl)sulfonamido)-2-(6-azaspiro[2.5]octan-6-yl)benzamide 11-21 (S)-N-(2-(3-(1-Hydroxyethyl)azetidin-1-yl)-6-methylpyrimidin-4-yl)-4- 0.704 ((2-hydroxyethyl)sulfonamido)-2-(6-azaspiro[2.5]octan-6-yl)benzamide 11-22 4-(Cyclopropanesulfonamido)-N-(2-(3,3-difluoroazetidin-1-yl)-6- 0.788 methylpyrimidin-4-yl)-2-(6-azaspiro[2.5]octan-6-yl)benzamide 11-23 N-(2-(3,3-Difluoroazetidin-1-yl)-6-methylpyrimidin-4-yl)-4-(oxetane-3- 0.0489 sulfonamido)-2-(6-azaspiro[2.5]octan-6-yl)benzamide 11-24 N-(2-(3,3-Difluoroazetidin-1-yl)-6-methylpyrimidin-4-yl)-4- 0.0551 (methylsulfonamido)-2-(6-azaspiro[2.5]octan-6-yl)benzamide 11-25 4-((2-Hydroxyethyl)sulfonamido)-N-(6-methyl-2-(5-azaspiro[2.4]heptan- 0.0176 5-yl)pyrimidin-4-yl)-2-(6-azaspiro[2.5]octan-6-yl)benzamide 11-26 4-((2-Hydroxyethyl)sulfonamido)-N-(6-methyl-2-(pyrrolidin-1- 0.0716 yl)pyrimidin-4-yl)-2-(6-azaspiro[2.5]octan-6-yl)benzamide 11-27 (R)-N-(2-(3-Fluoro-3-methylpyrrolidin-1-yl)-6-methylpyrimidin-4-yl)-4- 0.020 ((2-hydroxyethyl)sulfonamido)-2-(6-azaspiro[2.5]octan-6-yl)benzamide 11-28 N-(2-(2-Azabicyclo[3.1.0]hexan-2-yl)-6-methylpyrimidin-4-yl)-4-((2- 0.059 hydroxyethyl)sulfonamido)-2-(6-azaspiro[2.5]octan-6-yl)benzamide 11-29 N-(2-((1R,5S)-3-Azabicyclo[3.1.0]hexan-3-yl)-6-methylpyrimidin-4-yl)- 0.020 4-((2-hydroxyethyl)sulfonamido)-2-(6-azaspiro[2.5]octan-6-yl)benzamide 11-30 N-(2-(3,3-Difluoropyrrolidin-1-yl)-6-methylpyrimidin-4-yl)-4-((2- 0.033 hydroxyethyl)sulfonamido)-2-(6-azaspiro[2.5]octan-6-yl)benzamide 11-31 4-((2-Hydroxyethyl)sulfonamido)-N-(6-methyl-2-(6-azaspiro[2.5]octan- 0.146 6-yl)pyrimidin-4-yl)-2-(6-azaspiro[2.5]octan-6-yl)benzamide 11-32 N-(2-((1R)-1-Hydroxy-3-azabicyclo[3.1.0]hexan-3-yl)-6- 0.193 methylpyrimidin-4-yl)-4-((2-hydroxyethyl)sulfonamido)-2-(6- azaspiro[2.5]octan-6-yl)benzamide 11-33 N-(2-(4-Cyanopiperidin-1-yl)-6-methylpyrimidin-4-yl)-4-((2- 0.088 hydroxyethyl)sulfonamido)-2-(6-azaspiro[2.5]octan-6-yl)benzamide 11-34 (R)-N-(2-(3-Cyanopiperidin-1-yl)-6-methylpyrimidin-4-yl)-4-((2- 0.092 hydroxyethyl)sulfonamido)-2-(6-azaspiro[2.5]octan-6-yl)benzamide 11-35 (S)-N-(2-(3-Cyanopiperidin-1-yl)-6-methylpyrimidin-4-yl)-4-((2- 0.043 hydroxyethyl)sulfonamido)-2-(6-azaspiro[2.5]octan-6-yl)benzamide 11-36 4-((2-Hydroxyethyl)sulfonamido)-N-(6-methyl-2-(piperidin-1- 0.082 yl)pyrimidin-4-yl)-2-(6-azaspiro[2.5]octan-6-yl)benzamide 11-37 4-((2-Hydroxyethyl)sulfonamido)-N-(2-(4-hydroxypiperidin-1-yl)-6- 0.144 methylpyrimidin-4-yl)-2-(6-azaspiro[2.5]octan-6-yl)benzamide 11-38 N-(2-(4-Hydroxy-4-methylpiperidin-1-yl)-6-methylpyrimidin-4-yl)-4-((2- 0.065 hydroxyethyl)sulfonamido)-2-(6-azaspiro[2.5]octan-6-yl)benzamide 11-39 N-(2-(3,3-Difluoropiperidin-1-yl)-6-methylpyrimidin-4-yl)-4-((2- 0.045 hydroxyethyl)sulfonamido)-2-(6-azaspiro[2.5]octan-6-yl)benzamide 11-40 N-(2-(4,4-Difluoropiperidin-1-yl)-6-methylpyrimidin-4-yl)-4-((2- 0.109 hydroxyethyl)sulfonamido)-2-(7-azaspiro[3.5]nonan-7-yl)benzamide 11-41 N-(2-(4,4-Difluoropiperidin-1-yl)-6-methylpyrimidin-4-yl)-2-(4,4- 0.127 dimethylpiperidin-1-yl)-4-((2-hydroxyethyl)sulfonamido)benzamide 11-42 N-(2-((1R)-1-Hydroxy-3-azabicyclo[4.1.0]heptan-3-yl)-6- 0.034 methylpyrimidin-4-yl)-4-((2-hydroxyethyl)sulfonamido)-2-(6- azaspiro[2.5]octan-6-yl)benzamide 11-43 N-(2-((1R,6R)-3-Azabicyclo[4.1.0]heptan-3-yl)-6-methylpyrimidin-4-yl)- 0.035 4-((2-hydroxyethyl)sulfonamido)-2-(6-azaspiro[2.5]octan-6-yl)benzamide 11-44 N-(2-((1S,6R)-2-Azabicyclo[4.1.0]heptan-2-yl)-6-methylpyrimidin-4-yl)- 0.033 4-((2-hydroxyethyl)sulfonamido)-2-(6-azaspiro[2.5]octan-6-yl)benzamide 11-45 (S)-4-((2-Hydroxyethyl)sulfonamido)-N-(6-methyl-2-(2- 0.035 methylmorpholino)pyrimidin-4-yl)-2-(6-azaspiro[2.5]octan-6- yl)benzamide 11-46 N-(2-(2,2-Dimethylmorpholino)-6-methylpyrimidin-4-yl)-4-((2- 0.150 hydroxyethyl)sulfonamido)-2-(6-azaspiro[2.5]octan-6-yl)benzamide 11-47 4-((2-Hydroxyethyl)sulfonamido)-N-(6-methyl-2-(4-oxa-7- 0.095 azaspiro[2.5]octan-7-yl)pyrimidin-4-yl)-2-(6-azaspiro[2.5]octan-6- yl)benzamide 11-48 N-(2-((3S,5R)-3,5-Dimethylmorpholino)-6-methylpyrimidin-4-yl)-4-((2- 0.095 hydroxyethyl)sulfonamido)-2-(6-azaspiro[2.5]octan-6-yl)benzamide 11-49 N-(2-((3S,5S)-3,5-Dimethylmorpholino)-6-methylpyrimidin-4-yl)-4-((2- 0.245 hydroxyethyl)sulfonamido)-2-(6-azaspiro[2.5]octan-6-yl)benzamide 11-50 N-(2-((3R,5R)-3,5-Dimethylmorpholino)-6-methylpyrimidin-4-yl)-4-((2- 0.187 hydroxyethyl)sulfonamido)-2-(6-azaspiro[2.5]octan-6-yl)benzamide 11-51 N-(2-(4-Fluoropiperidin-1-yl)-6-methylpyrimidin-4-yl)-4-((2- 0.020 hydroxyethyl)sulfonamido)-2-(6-azaspiro[2.5]octan-6-yl)benzamide 11-52 N-(2-(4-Fluoro-4-methylpiperidin-1-yl)-6-methylpyrimidin-4-yl)-4-((2- 0.063 hydroxyethyl)sulfonamido)-2-(6-azaspiro[2.5]octan-6-yl)benzamide 11-53 (S)-4-((2-Hydroxyethyl)sulfonamido)-N-(2-(3-hydroxypiperidin-1-yl)-6- 0.105 methylpyrimidin-4-yl)-2-(6-azaspiro[2.5]octan-6-yl)benzamide 11-54 (R)-4-((2-Hydroxyethyl)sulfonamido)-N-(2-(3-hydroxypiperidin-1-yl)-6- 0.074 methylpyrimidin-4-yl)-2-(6-azaspiro[2.5]octan-6-yl)benzamide 11-55 (R)-N-(2-(3-Fluoro-3-methylpiperidin-1-yl)-6-methylpyrimidin-4-yl)-4- 0.041 ((2-hydroxyethyl)sulfonamido)-2-(6-azaspiro[2.5]octan-6-yl)benzamide 11-56 N-(2-(4-Fluoropiperidin-1-yl)pyrimidin-4-yl)-4-((2- 0.022 hydroxyethyl)sulfonamido)-2-(6-azaspiro[2.5]octan-6-yl)benzamide 11-57 N-(2-(4,4-Difluoropiperidin-1-yl)pyrimidin-4-yl)-4-((2- 0.022 hydroxyethyl)sulfonamido)-2-(6-azaspiro[2.5]octan-6-yl)benzamide 11-58 N-(2-(4,4-Difluoropiperidin-1-yl)-6-methylpyrimidin-4-yl)-2-fluoro-4- 0.071 ((2-hydroxyethyl)sulfonamido)-6-(6-azaspiro[2.5]octan-6-yl)benzamide 11-59 4-((2-Hydroxyethyl)sulfonamido)-2-(6-azaspiro[2.5]octan-6-yl)-N-(2- 0.058 (3,3,3-trifluoropropoxy)pyridin-4-yl)benzamide 11-60 4-((2-Hydroxyethyl)sulfonamido)-N-(2-methyl-6-(3,3,3- 0.084 trifluoropropoxy)pyridin-4-yl)-2-(6-azaspiro[2.5]octan-6-yl)benzamide 11-61 4-((2-Hydroxyethyl)sulfonamido)-N-(6-methyl-2-(3,3,3- 0.070 trifluoropropoxy)pyrimidin-4-yl)-2-(6-azaspiro[2.5]octan-6-yl)benzamide 11-62 N-(2-((1-Hydroxy-2-methylpropan-2-yl)amino)-6-methylpyrimidin-4-yl)- 0.018 4-((2-hydroxyethyl)sulfonamido)-2-(6-azaspiro[2.5]octan-6-yl)benzamide 11-63 N-(2-(4,4-Difluoropiperidin-1-yl)-3-fluoropyridin-4-yl)-4-((2- 0.022 hydroxyethyl)sulfonamido)-2-(6-azaspiro[2.5]octan-6-yl)benzamide 11-64 N-(2-(4,4-Difluoropiperidin-1-yl)-3-fluoro-6-methylpyridin-4-yl)-4-((2- 0.054 hydroxyethyl)sulfonamido)-2-(6-azaspiro[2.5]octan-6-yl)benzamide 11-65 (R)-4-((2-Hydroxyethyl)sulfonamido)-N-(2-(2- 0.151 methylmorpholino)pyridin-4-yl)-2-(6-azaspiro[2.5]octan-6-yl)benzamide 11-66 (R)-4-((2-Hydroxyethyl)sulfonamido)-N-(2-methyl-6-(2- 0.148 methylmorpholino)pyridin-4-yl)-2-(6-azaspiro[2.5]octan-6-yl)benzamide 11-67 N-(2-(4,4-Difluoropiperidin-1-yl)-6-methylpyrimidin-4-yl)-5-fluoro-4- 0.034 ((2-hydroxyethyl)sulfonamido)-2-(6-azaspiro[2.5]octan-6-yl)benzamide 11-68 N-(2-(3,3-Difluoroazetidin-1-yl)-6-methylpyrimidin-4-yl)-4-((1- 0.053 (hydroxymethyl)cyclopropane)-1-sulfonamido)-2-(6-azaspiro[2.5]octan- 6-yl)benzamide 11-69 N-(2-(4,4-Difluoropiperidin-1-yl)-6-methylpyrimidin-4-yl)-4-((1- 0.099 (hydroxymethyl)cyclopropane)-1-sulfonamido)-2-(6-azaspiro[2.5]octan- 6-yl)benzamide 11-70 (S)-N-(2-(3,3-Difluoroazetidin-1-yl)-6-methylpyrimidin-4-yl)-2-(6- 0.072 azaspiro[2.5]octan-6-yl)-4-((tetrahydrofuran)-3-sulfonamido)benzamide 11-71 (R)-N-(2-(3,3-Difluoroazetidin-1-yl)-6-methylpyrimidin-4-yl)-2-(6- 0.042 azaspiro[2.5]octan-6-yl)-4-((tetrahydrofuran)-3-sulfonamido)benzamide 11-72 (S)-N-(2-(4,4-Difluoropiperidin-1-yl)-6-methylpyrimidin-4-yl)-2-(6- 0.135 azaspiro[2.5]octan-6-yl)-4-((tetrahydrofuran)-3-sulfonamido)benzamide 11-73 (R)-N-(2-(4,4-Difluoropiperidin-1-yl)-6-methylpyrimidin-4-yl)-2-(6- 0.079 azaspiro[2.5]octan-6-yl)-4-((tetrahydrofuran)-3-sulfonamido)benzamide 11-74 N-(2-(3,3-Difluoroazetidin-1-yl)-6-methylpyrimidin-4-yl)-4-((1- 0.094 methylcyclopropane)-1-sulfonamido)-2-(6-azaspiro[2.5]octan-6- yl)benzamide 11-75 N-(2-(3,3-Difluoroazetidin-1-yl)-6-methylpyrimidin-4-yl)-4-((1- 0.056 methylethyl)sulfonamido)-2-(6-azaspiro[2.5]octan-6-yl)benzamide 11-76 (R)-N-(2-(3,3-Difluoroazetidin-1-yl)-6-methylpyrimidin-4-yl)-4-((2- 0.020 hydroxy-1-methylethyl)sulfonamido)-2-(6-azaspiro[2.5]octan-6- yl)benzamide 11-77 (S)-N-(2-(3,3-Difluoroazetidin-1-yl)-6-methylpyrimidin-4-yl)-4-((2- 0.034 hydroxy-1-methylethyl)sulfonamido)-2-(6-azaspiro[2.5]octan-6- yl)benzamide 11-78 4-((Cyclopropylmethyl)sulfonamido)-N-(2-(3,3-difluoroazetidin-1-yl)-6- 0.125 methylpyrimidin-4-yl)-2-(6-azaspiro[2.5]octan-6-yl)benzamide 11-79 4-((2-Hydroxyethyl)sulfonamido)-N-(2-isopropoxy-6-methylpyrimidin-4- 0.057 yl)-2-(6-azaspiro[2.5]octan-6-yl)benzamide 11-80 (R)-4-((2-Hydroxyethyl)sulfonamido)-N-(6-methyl-2-((tetrahydrofuran-3- 0.117 yl)oxy)pyrimidin-4-yl)-2-(6-azaspiro[2.5]octan-6-yl)benzamide 11-81 N-(2-(4-Fluoropiperidin-1-yl)-6-methylpyrimidin-4-yl)-4- 0.060 (methylsulfonamido)-2-(6-azaspiro[2.5]octan-6-yl)benzamide 11-82 4-(Ethylsulfonamido)-N-(2-(4-fluoropiperidin-1-yl)-6-methylpyrimidin- 0.051 4-yl)-2-(6-azaspiro[2.5]octan-6-yl)benzamide 11-83 N-(2-(3,3-Difluoroazetidin-1-yl)-6-methylpyrimidin-4-yl)-4-((1,1- 0.098 dimethylethyl)sulfonamido)-2-(6-azaspiro[2.5]octan-6-yl)benzamide 12 N-(2-(4,4-Difluoropiperidin-1-yl)-6-methylpyrimidin-4-yl)-4-((2- 0.076 hydroxyethyl)sulfonyl)-2-(6-azaspiro[2.5]octan-6-yl)benzamide 13-1 (S)-N-(2-(4,4-Difluoropiperidin-1-yl)-6-methylpyrimidin-4-yl)-4-((1- 0.057 hydroxypropan-2-yl)sulfonyl)-2-(6-azaspiro[2.5]octan-6-yl)benzamide 13-2 (R)-N-(2-(4,4-difluoropiperidin-1-yl)-6-methylpyrimidin-4-yl)-4-((1- 0.064 hydroxypropan-2-yl)sulfonyl)-2-(6-azaspiro[2.5]octan-6-yl)benzamide 14 N-(2-(4,4-Difluoropiperidin-1-yl)-6-methylpyrimidin-4-yl)-4-((1- 0.122 hydroxy-2-methylpropan-2-yl)sulfonyl)-2-(6-azaspiro[2.5]octan-6- yl)benzamide 14-1 N-(2-(4,4-Difluoropiperidin-1-yl)-6-methylpyrimidin-4-yl)-4-(oxetan-3- 0.182 ylsulfonyl)-2-(6-azaspiro[2.5]octan-6-yl)benzamide 14-2 N-(2-(4,4-Difluoropiperidin-1-yl)-6-methylpyrimidin-4-yl)-4- 0.108 (ethylsulfonyl)-2-(6-azaspiro[2.5]octan-6-yl)benzamide 14-3 N-(2-(4,4-Difluoropiperidin-1-yl)-6-methylpyrimidin-4-yl)-4- 0.128 (isopropylsulfonyl)-2-(6-azaspiro[2.5]octan-6-yl)benzamide 14-4 N-(2-(4,4-Difluoropiperidin-1-yl)-6-methylpyrimidin-4-yl)-4-((2- 0.806 hydroxy-2-methylpropyl)sulfonyl)-2-(6-azaspiro[2.5]octan-6- yl)benzamide 14-5 4-(Cyclopropylsulfonyl)-N-(2-(4,4-difluoropiperidin-1-yl)-6- 0.826 methylpyrimidin-4-yl)-2-(6-azaspiro[2.5]octan-6-yl)benzamide 14-6 4-(tert-Butylsulfonyl)-N-(2-(4,4-difluoropiperidin-1-yl)-6- 1.88 methylpyrimidin-4-yl)-2-(6-azaspiro[2.5]octan-6-yl)benzamide 14-7 N-(2-(4,4-Difluoropiperidin-1-yl)-6-methylpyrimidin-4-yl)-4-(((3R,4R)- 0.094 4-hydroxytetrahydrofuran-3-yl)sulfonyl)-2-(6-azaspiro[2.5]octan-6- yl)benzamide 14-8 N-(2-(4,4-Difluoropiperidin-1-yl)-6-methylpyrimidin-4-yl)-4-(((3S,4S)-4- 0.097 hydroxytetrahydrofuran-3-yl)sulfonyl)-2-(6-azaspiro[2.5]octan-6- yl)benzamide 14-9 N-(2-(4,4-Difluoropiperidin-1-yl)-6-methylpyrimidin-4-yl)-4-(((1R,2R)- 0.195 2-hydroxycyclopentyl)sulfonyl)-2-(6-azaspiro[2.5]octan-6-yl)bezamide 15 N-(2-(4,4-Difluorocyclohexyl)-6-methylpyrimidin-4-yl)-4-((2- 0.017 hydroxyethyl)sulfonamido)-2-(6-azaspiro[2.5]octan-6-yl)benzamide 16-1 (R)-N-(2-(4,4-Difluoropiperidin-1-yl)-6-methylpyrimidin-4-yl)-4-((2- 0.089 fluoro-1-(hydroxymethyl)ethyl)sulfonamido)-2-(6-azaspiro[2.5]octan-6- yl)benzamide 16-2 (S)-N-(2-(4,4-Difluoropiperidin-1-yl)-6-methylpyrimidin-4-yl)-4-((2- 0.096 fluoro-1-(hydroxymethyl)ethyl)sulfonamido)-2-(6-azaspiro[2.5]octan-6- yl)benzamide 17 N-(2-(4,4-Difluoropiperidin-1-yl)pyridin-4-yl)-4-(N-(2- 0.023 hydroxyethyl)sulfamoyl)-2-(6-azaspiro[2.5]octan-6-yl)benzamide 17-1 4-(N-(2-Hydroxyethyl)sulfamoyl)-2-(6-azaspiro[2.5]octan-6-yl)-N-(2- 0.027 (3,3,3-trifluoropropoxy)pyrimidin-4-yl)benzamide 17-2 4-(N-(2-Hydroxyethyl)sulfamoyl)-N-(6-methyl-2-(3,3,3- 0.042 trifluoropropoxy)pyrimidin-4-yl)-2-(6-azaspiro[2.5]octan-6-yl)benzamide 17-3 N-(2-(4,4-Difluoropiperidin-1-yl)-6-methylpyrimidin-4-yl)-4-(N-(2- 0.063 hydroxyethyl)sulfamoyl)-2-(6-azaspiro[2.5]octan-6-yl)benzamide 17-4 N-(2-(4,4-Difluoropiperidin-1-yl)pyrimidin-4-yl)-4-(N-(2- 0.023 hydroxyethyl)sulfamoyl)-2-(6-azaspiro[2.5]octan-6-yl)benzamide 17-5 N-(2-(3,3-Difluoroazetidin-1-yl)-6-methylpyrimidin-4-yl)-4-(N-(2- 0.133 hydroxyethyl)sulfamoyl)-2-(6-azaspiro[2.5]octan-6-yl)benzamide 17-6 (R)-N-(2-(4,4-Difluoropiperidin-1-yl)-6-methylpyrimidin-4-yl)-4-(N-(1- 0.127 hydroxypropan-2-yl)sulfamoyl)-2-(6-azaspiro[2.5]octan-6-yl)benzamide 17-7 (S)-N-(2-(4,4-Difluoropiperidin-1-yl)-6-methylpyrimidin-4-yl)-4-(N-(1- 0.147 hydroxypropan-2-yl)sulfamoyl)-2-(6-azaspiro[2.5]octan-6-yl)benzamide 17-8 N-(2-(4,4-Difluoropiperidin-1-yl)-6-methylpyrimidin-4-yl)-4-(N-(2- 0.286 hydroxy-2-methylpropyl)sulfamoyl)-2-(6-azaspiro[2.5]octan-6- yl)benzamide 18-1 2-(6-Azaspiro[2.5]octan-6-yl)-4-(R-cyclopropylsulfonimidoyl)-N-(2-(4,4- 0.064 difluoro-1-piperidinyl)-6-methyl-4-pyrimidinyl)benzamide 18-2 2-(6-azaspiro[2.5]octan-6-yl)-4-(S-cyclopropylsulfonimidoyl)-N-(2-(4,4- 0.057 difluoro-1-piperidinyl)-6-methyl-4-pyrimidinyl)benzamide 19-1 N-(2-(4,4-Difluoropiperidin-1-yl)-6-methylpyrimidin-4-yl)-4-(oxetane-3- 0.163 sulfonimidoyl)-2-(6-azaspiro[2.5]octan-6-yl)benzamide 19-2 N-(2-(4,4-Difluoropiperidin-1-yl)-6-methylpyrimidin-4-yl)-4-(S- 0.438 methylsulfonimidoyl)-2-(6-azaspiro[2.5]octan-6-yl)benzamide 19-3 2-(6-Azaspiro[2.5]octan-6-yl)-N-(2-(4,4-difluoro-1-pieridinyl)-6-methyl- 0.078 4-pyrimidinyl)-4-(S-ethylsulfonimidoyl)benzamide 19-4 2-(6-Azaspiro[2.5]octan-6-yl)-N-(2-(4,4-difluoro-1-pieridinyl)-6-methyl- 0.035 4-pyrimidinyl)-4-(R-ethylsulfonimidoyl)benzamide 19-5 N-(2-(4,4-Difluoropiperidin-1-yl)-6-methylpyrimidin-4-yl)-4-(propan-2- 0.175 ylsulfonimidoyl)-2-(6-azaspiro[2.5]octan-6-yl)benzamide 19-6 4-(Cyclopropanesulfonimidoyl)-N-(2-(4,4-difluoropiperidin-1-yl)pyridin- 0.042 4-yl)-2-(6-azaspiro[2.5]octan-6-yl)benzamide 19-7 2-(6-Azaspiro[2.5]octan-6-yl)-4-(S-cyclopropylsulfonimidoyl)-N-(6- 0.195 methy-2-((2R)-2-methyl-4-moprpholinyl)-4-pyrimidinyl)benzamide 19-8 2-(6-Azaspiro[2.5]octan-6-yl)-4-(R-cyclopropylsulfonimidoyl)-N-(6- 0.078 methy-2-((2R)-2-methyl-4-moprpholinyl)-4-pyrimidinyl)benzamide 19-9 4-(Cyclopropanesulfonimidoyl)-N-(2-(3,3-difluoroazetidin-1-yl)-6- 0.069 methylpyrimidin-4-yl)-2-(6-azaspiro[2.5]octan-6-yl)benzamide 20 (N.sup.1-(2-(4,4-Difluoropiperidin-1-yl)-6-methylpyrimidin-4-yl)-2-(6- 0.119 azaspiro[2.5]octan-6-yl)terephthalamide 21 4-(Azetidin-3-ylsulfonyl)-N-(2-(4,4-difluoropiperidin-1-yl)-6- 0.040 methylpyrimidin-4-yl)-2-(6-azaspiro[2.5]octan-6-yl)benzamide 22 4-N-(2-(4,4-Difluoropiperidin-1-yl)-6-methylpyrimidin-4-yl)-4-((1- 0.406 methylazetidin-3-yl)sulfonyl)-2-(6-azaspiro[2.5]octan-6-yl)benzamide

[0374] The foregoing invention has been described in some detail by way of illustration and example, for purposes of clarity and understanding. Those skilled in the art understand that changes and modifications may be practiced within the scope of the appended claims. Therefore, it is to be understood that the above description is intended to be illustrative and not restrictive. The scope of the invention should, therefore, be determined not with reference to the above description, but should instead be determined with reference to the following appended claims, along with the full scope of equivalents to which such claims are entitled.

[0375] All patents, patent applications and publications cited herein are hereby incorporated by reference in their entirety for all purposes to the same extent as if each individual patent, patent application or publication were so individually denoted.