TRPML MODULATORS

Abstract

The present invention provides compounds, pharmaceutically acceptable compositions thereof, and methods of using the same.

Claims

1. A compound of formula I: ##STR00583## or a pharmaceutically acceptable salt thereof, wherein X is NR.sup.5, C(R.sup.5).sub.2, C(O), or O; each of Y.sup.1 and Y.sup.2 is independently selected from N and C; L is an optionally substituted group selected from C.sub.0-C.sub.6 alkylenyl-S(O).sub.2, S(O).sub.2C.sub.0-C.sub.6 alkylenyl, S(O)C.sub.0-C.sub.6 alkylenyl, C.sub.0-C.sub.6 alkylenyl-S(O), C(O)C.sub.0-C.sub.6 alkylenyl, C(O)OC.sub.0-C.sub.6 alkylenyl, C(O)N(R.sup.8)C.sub.0-C.sub.6 alkylenyl, C.sub.1-C.sub.6 alkylenyl, and C.sub.3-C.sub.6 cycloalkylenyl; A is C.sub.3-C.sub.12 cycloaliphatic or 3- to 12-membered heterocyclyl comprising 1 to 3 heteroatoms selected from N, O, and S, wherein A is substituted with (R.sup.2).sub.m; B is a fused optionally substituted C.sub.5-C.sub.6 aryl or optionally substituted 5- to 6-membered heteroaryl comprising 1 to 3 heteroatoms selected from N, O, and S; R.sup.1 is C.sub.5-C.sub.12 aryl substituted with (R.sup.3).sub.p, 5- to 12-membered heteroaryl comprising 1 to 3 heteroatoms selected from N, O, and S substituted with (R.sup.3).sub.p, or 3- to 12-membered heterocyclyl comprising 1 to 3 heteroatoms selected from N, O, and S substituted with (R.sup.3).sub.p; each R.sup.2 is independently halo, oxo, NR.sup.2aR.sup.2b, C(O)OR.sup.2a, OC(O)Ra, S(O).sub.2, S(O).sub.2R.sup.2a, C(O)NR.sup.2aR.sup.2b, N(R.sup.2a)C(O)R.sup.2b, C(O)R.sup.2a, ORa, OC(O)NR.sup.2aR.sup.2b, NHC(O)NR.sup.2aR.sup.2b, NHC(O)OR.sup.2a, NHS(O).sub.2R.sup.2a, C.sub.1-C.sub.6 alkylenyl-C(O)NR.sup.2aR.sup.2b or an optionally substituted group selected from C.sub.1-C.sub.6 aliphatic, C.sub.5-C.sub.12 aryl, and 3- to 12-membered heterocyclyl comprising 1 to 3 heteroatoms selected from N, O, and S; each R.sup.2a and each R.sup.2b are independently selected from H and an optionally substituted group selected from C.sub.1-C.sub.6 aliphatic, C.sub.3-C.sub.12 cycloaliphatic, C.sub.5-C.sub.14 aryl, 5- to 12-membered heteroaryl comprising 1 to 4 heteroatoms selected from N, O, and S, and 3- to 12-membered heterocyclyl comprising 1 to 4 heteroatoms selected from N, O, and S; each R.sup.3 is independently halo, S(O).sub.2NR.sup.3aR.sup.3b, S(O).sub.2R.sup.3b, S(NR.sup.3c)O)NR.sup.3aR.sup.3b, S(O)(NR.sup.3c)R.sup.3b, S(O)R.sup.3b, NR.sup.3aS(O).sub.2R.sup.3b, OR.sup.3a, C(O)Ra, C(O)NHR.sup.3a, oxo, or an optionally substituted group selected from C.sub.1-C.sub.6 aliphatic, C.sub.5-C.sub.12 aryl, C.sub.3-C.sub.12 cycloaliphatic, 5- to 12-membered heteroaryl comprising 1 to 3 heteroatoms selected from N, O, and S, and 3- to 12-membered heterocyclyl comprising 1 to 3 heteroatoms selected from N, O, and S; R.sup.3a and R.sup.3b are each independently selected from H and optionally substituted C.sub.1-C.sub.6 aliphatic, or R.sup.3a and R.sup.3b come together with the atoms to which they are attached to form optionally substituted C.sub.3-C.sub.12 cycloaliphatic or 3- to 12-membered heterocyclyl comprising 1 to 4 heteroatoms selected from N, O, and S; each R.sup.3c is independently selected from H, OH, and optionally substituted C.sub.1-C.sub.6 aliphatic; each R.sup.5 is independently selected from hydrogen, halo, CN, and optionally substituted C.sub.1-C.sub.6 aliphatic; R.sup.8 is selected from H and optionally substituted C.sub.1-C.sub.6 aliphatic; n is 0 or 1; m is 0 to 4; p is 0 to 4; and q is 1 or 2.

2. The compound of claim 1, wherein n is 0.

3. The compound of claim 1, wherein q is 1.

4. The compound of claim 1, wherein L is optionally substituted S(O).sub.2C.sub.0-C.sub.6 alkylenyl.

5-7. (canceled)

8. The compound of claim 1, wherein L is selected from S(O).sub.2, S(O).sub.2CH.sub.2, S(O).sub.2CH(CH.sub.3), CH(CH.sub.3)S(O).sub.2, CH.sub.2S(O).sub.2, ##STR00584##

9. The compound of claim 1, wherein A is 3- to 12-membered heterocyclyl comprising 1 to 3 heteroatoms selected from N, O, and S.

10-11. (canceled)

12. The compound of claim 1, wherein A is C.sub.3-C.sub.12 cycloaliphatic.

13-16. (canceled)

17. The compound of claim 1, wherein B is a fused optionally substituted C.sub.5-C.sub.6 aryl.

18. The compound of claim 1, wherein B is a fused optionally substituted 5- to 12-membered heteroaryl comprising 1 to 3 heteroatoms selected from N, O, and S.

19-21. (canceled)

22. The compound of claim 1, wherein R.sup.1 is phenyl substituted with (R.sup.3).sub.p.

23-28. (canceled)

29. The compound of claim 1, wherein m is 1 or 2.

30. The compound of claim 29, wherein each R.sup.2 is halo, C(O)OR.sup.2a or an optionally substituted group selected from C.sub.1-C.sub.6 aliphatic and C.sub.5-C.sub.12 aryl.

31-32. (canceled)

33. The compound of claim 1, wherein the compound is of formula II: ##STR00585## or a pharmaceutically acceptable salt thereof.

34. The compound of claim 1, wherein the compound is of formula IIa: ##STR00586## or a pharmaceutically acceptable salt thereof.

35. The compound of claim 1, wherein the compound is of formula IIb: ##STR00587## or a pharmaceutically acceptable salt thereof.

36-37. (canceled)

38. A compound selected from Table 1.

39. (canceled)

40. A pharmaceutical composition comprising a compound of claim 1, and a pharmaceutically acceptable carrier or excipient.

41. A method of modulating TRPML in a subject comprising administering to the subject a compound of claim 1, or a composition thereof.

42. A method of treating a disease, disorder, or condition in a subject comprising administering to the subject a compound of claim 1, or a composition thereof.

43. The method of claim 42, wherein the disease, disorder, or condition is associated with TPRML modulation.

44-54. (canceled)

Description

DETAILED DESCRIPTION

TRPML and Autophagy

[0090] Autophagy is a mechanism of the cell that degrades cytoplasmic material and organelles. There are multiple types of autophagy: (1) macroautophagy (generally referred to as autophagy); (2) microautophagy, and (3) chaperone-mediated autophagy. See Eskelinen & Saftig, Biochimica et Biophysica ActaMol. Cell Res., 1793(4):664-673 (2009). In macroautophagy, the autophagosome engulfs waste materials in the cytoplasm and fuses to the lysosome, where materials are delivered for degradation. The lysosome is as a subcellular organelle containing more than 50 soluble acid hydrolases useful for digesting cellular components. Fusion of the lysosome to the autophagosome is activated, in part, by release of ions through ion channels in the membrane of the lysome, including Ca.sup.2+. See Cao, et al., J. Bio. Chem., 292(20)8424-8435 (2017).

[0091] Transient Receptor Potential Mucolipin-1 (also known as TRPML1 or ML1) is a Ca.sup.2+ channel in the lysosome that regulates autophagy. See Wang, et al., PNAS, E1373-E1381 (Mar. 2, 2015). In particular, TRPML1 is an inwardly rectifying current channel that transports cations from the lumen of the lysosome to the cytosol. See Di Paolda, et al., Cell Calcium 69:112-121 (2018). Release of Ca.sup.2+ from the lysosome via TRPML1 modulates transcription factor EB activity via local calcineurin activation, which ultimately induces autophagy and lysosomal biogenesis. See Medina, et al., Nat. Cell. Biol., 17(3):288-299 (2015).

[0092] It has recently been discovered that upregulation of autophagy is beneficial to patients suffering from a number of diseases and disorders. For example, it has been reported that inducing autophagy promotes clearance of hepatotoxic alpha-1-anti-trypsin (ATZ) in the liver. See Pastore, et al., EMBO Mol. Med. 5(3): 397-412 (March 2013). Moreover, autophagy was recently found to be useful in the treatment of neurodegenerative disorders, cancer, and heart disease. See Pierzynowska, el al., Metab. Brain Dis., 33(4); 989-1008 (2018) (discussing neurodegenerative disorders); Nelson & Shacka, Curr. Pathobiol. Rep., 1(4): 239-245 (2013) (discussing cancer); Sciaretta, et al., Annual Review of Physiology, 80:1-26 (2018) (discussing heart disease); Maiuri & Kroemer, Cell Death & Differentiation, 26: 680-689 (2019)(discussing therapeutic applications of autophagy, generally). It is, therefore, desirable to identify methods and modes of promoting autophagy. Given TRPML's role in autophagy, described herein are TRPML1 modulators useful for promoting autophagy and/or treating certain diseases, disorders, or conditions.

[0093] The present disclosure provides the insight that TRMPL may represent a particularly desirable target that, among other things, may permit modulation (e.g., enhancement) of autophagy in certain contexts.

TRPML Modulators

Structure

[0094] In some embodiments, the present disclosure provides and/or utilizes TRMPL modulators (e.g., TRPML1, TPRML2, and/or TPRML3) that are small molecule compounds having a chemical structure as indicated below in Formula I:

##STR00012## [0095] or a pharmaceutically acceptable salt thereof, [0096] wherein [0097] X is NR.sup.5, C(R.sup.5).sub.2, C(O), or O; [0098] each of Y.sup.1 and Y.sup.2 is independently selected from N and C; [0099] L is an optionally substituted group selected from C.sub.0-C.sub.6 alkylenyl-S(O).sub.2, S(O).sub.2C.sub.1-C.sub.6 alkylenyl, S(O)C.sub.0-C.sub.6 alkylenyl, C.sub.0-C.sub.6 alkylenyl-S(O), C(O)C.sub.0-C.sub.6 alkylenyl, C(O)OC.sub.0-C.sub.6 alkylenyl, C(O)N(R.sup.8)C.sub.0-C.sub.6 alkylenyl, C.sub.1-C.sub.6 alkylenyl, and C.sub.3-C.sub.6 cycloalkylenyl; [0100] A is C.sub.3-C.sub.12 cycloaliphatic or 3- to 12-membered heterocyclyl comprising 1 to 3 heteroatoms selected from N, O, and S, wherein A is substituted with (R.sup.2).sub.m; [0101] B is a fused optionally substituted C.sub.5-C.sub.6 aryl or optionally substituted 5- to 6-membered heteroaryl comprising 1 to 3 heteroatoms selected from N, O, and S; [0102] R.sup.1 is selected from C.sub.1-C.sub.6 aliphatic, C.sub.3-C.sub.12 cycloaliphatic, C.sub.5-C.sub.12 aryl, 5- to 12-membered heteroaryl comprising 1 to 3 heteroatoms selected from N, O, and S, and 3- to 12-membered heterocyclyl comprising 1 to 3 heteroatoms selected from N, O, and S, wherein R.sup.1 is substituted with (R.sup.3).sub.p; [0103] each R.sup.2 is independently halo, oxo, NR.sup.2aR.sup.2b, C(O)OR.sup.2a, OC(O)R.sup.2a, S(O).sub.2, S(O).sub.2R.sup.2a, C(O)NR.sup.2aR.sup.2b, N(R.sup.2a)C(O)R.sup.2b, C(O)R.sup.2a, OR.sup.2a, OC(O)NR.sup.2R.sup.2b, NHC(O)NR.sup.2aR.sup.2b, NHC(O)OR.sup.2a, NHS(O).sub.2R.sup.2a, C.sub.1-C.sub.6 alkylenyl-C(O)NR.sup.2aR.sup.2b or an optionally substituted group selected from C.sub.1-C.sub.6 aliphatic, C.sub.5-C.sub.12 aryl, and 3- to 12-membered heterocyclyl comprising 1 to 3 heteroatoms selected from N, O, and S; [0104] each R.sup.2a and each R.sup.2b are independently selected from H and an optionally substituted group selected from C.sub.1-C.sub.6 aliphatic, C.sub.3-C.sub.1 cycloaliphatic, C.sub.5-C.sub.14 aryl, 5- to 12-membered heteroaryl comprising 1 to 4 heteroatoms selected from N, O, and S, and 3- to 12-membered heterocyclyl comprising 1 to 3 heteroatoms selected from N, O, and S; [0105] each R.sup.3 is independently halo, S(O).sub.2NR.sup.3aR.sup.3b, S(O).sub.2R.sup.3b, S(O)(NR)NR.sup.3aR.sup.3b, S(O)(NR.sup.3cC)R.sup.3b, S(O)R.sup.3b, NR.sup.3aS(O).sub.2R.sup.3b, OR.sup.3a, C(O)R.sup.3a, C(O)NHR.sup.3a, oxo, or an optionally substituted group selected from C.sub.1-C.sub.6 aliphatic, C.sub.5-C.sub.12 aryl, C.sub.3-C.sub.12 cycloaliphatic, 5- to 12-membered heteroaryl comprising 1 to 3 heteroatoms selected from N, O, and S, and 3- to 12-membered heterocyclyl comprising 1 to 3 heteroatoms selected from N, O, and S; [0106] R.sup.3a and R.sup.3b are each independently selected from H and optionally substituted C.sub.1-C.sub.6 aliphatic, or R.sup.3a and R.sup.3b come together with the atoms to which they are attached to form optionally substituted C.sub.3-C.sub.12 cycloaliphatic or 3- to 12-membered heterocyclyl comprising 1 to 4 heteroatoms selected from N, O, and S; [0107] each R.sup.3c is independently H, OH, and optionally substituted C.sub.1-C.sub.6 aliphatic; [0108] each R.sup.5 is independently selected from hydrogen, halo, CN, and optionally substituted C.sub.1-C.sub.6 aliphatic; Rx is selected from H and optionally substituted C.sub.1-C.sub.6 aliphatic; [0109] n is 0 or 1; [0110] m is 0 to 4; [0111] p is 0 to 4; and [0112] q is 1 or 2.

[0113] As defined generally above, and in any formula described herein, X is NR.sup.3, C(R.sup.5).sub.2, C(O), or O. In some embodiments, X is NR.sup.5. In some embodiments, X is NH. In some embodiments, X is C(R.sup.5).sub.2. In some embodiments, X is CH(R.sup.5). In some embodiments, X is CH.sub.2. In some embodiments, X is CH(CH.sub.3). In some embodiments, X is O. In some embodiments, X is C(O).

[0114] As defined generally above, Y.sup.1 and Y.sup.2 are each independently N or C. In some embodiments, Y.sup.1 and Y.sup.2 are each N. In some embodiments, Y.sup.1 and Y.sup.2 are each C. In some embodiments, Y.sup.1 is N and Y.sup.2 is C. In some embodiments, Y.sup.1 is C and Y.sup.2 is N.

[0115] As defined generally above, L is an optionally substituted group selected from C.sub.0-C.sub.6 alkylenyl-S(O).sub.2, S(O).sub.2C.sub.0-C.sub.6 alkylenyl, S(O)C.sub.0-C.sub.6 alkylenyl, C.sub.0-C.sub.6 alkylenyl-S(O), C(O)C.sub.0-C.sub.6 alkylenyl, C(O)OC.sub.0-C.sub.6 alkylenyl, C(O)N(R.sup.8)C.sub.0-C.sub.6 alkylenyl, C.sub.1-C.sub.6 alkylenyl, and C.sub.3-C.sub.6 cycloalkylenyl.

[0116] In some embodiments, L is optionally substituted C.sub.0-C.sub.6 alkylenyl-S(O).sub.2. In some embodiments, L is S(O).sub.2. In some embodiments, L is optionally substituted C.sub.1-C.sub.6 alkylenyl-S(O).sub.2. In some embodiments, L is-C.sub.1-C.sub.6 alkylenyl-S(O).sub.2 substituted with halogen, (CH.sub.2).sub.0-4R.sup., (CH.sub.2).sub.0-4OR.sup., or O(CH.sub.2).sub.0-4R.sup.. In some embodiments, L is optionally substituted C.sub.1-C.sub.3 alkylenyl-S(O).sub.2. In some embodiments, L is-C.sub.1-C.sub.3 alkylenyl-S(O).sub.2 substituted with halogen, (CH.sub.2).sub.0-4R.sup., (CH.sub.2).sub.0-4OR.sup., or O(CH.sub.2).sub.0-4R.sup.. In some embodiments, L is CH.sub.2S(O).sub.2. In some embodiments, L is CH(CH.sub.3)S(O).sub.2. In some embodiments, L is CH(R.sup.)S(O).sub.2.

[0117] In some embodiments, L is optionally substituted S(O).sub.2C.sub.1-C.sub.6 alkylenyl. In some embodiments, L is-S(O).sub.2C.sub.1-C.sub.6 alkylenyl substituted with halogen, (CH.sub.2).sub.0-4R.sup., (CH.sub.2).sub.0-4OR.sup., or O(CH.sub.2).sub.0-4R.sup.. In some embodiments, L is optionally substituted S(O).sub.2C.sub.1-C.sub.3 alkylenyl. In some embodiments, L is-S(O).sub.2C.sub.1-C.sub.3 alkylenyl substituted with halogen, (CH.sub.2).sub.0-4R.sup., (CH.sub.2).sub.0-4OR.sup., or O(CH.sub.2).sub.0-4R.sup.. In some embodiments, L is S(O).sub.2CH.sub.2. In some embodiments, L is S(O).sub.2CH(CH.sub.3). In some embodiments L is S(O).sub.2CH(R.sup.). In some embodiments, L is

##STR00013##

In some embodiments, L is

##STR00014##

[0118] In some embodiments, L is optionally substituted S(O)C.sub.1-C.sub.6 alkylenyl. In some embodiments, L is-S(O)C.sub.1-C.sub.6 alkylenyl substituted with halogen, (CH.sub.2).sub.0-4R.sup., (CH.sub.2).sub.0-4OR.sup., or O(CH.sub.2).sub.0-4R.sup.. In some embodiments, L is optionally substituted S(O)C.sub.1-C.sub.3 alkylenyl. In some embodiments, L is S(O)C.sub.1-C.sub.3 alkylenyl substituted with halogen, (CH.sub.2).sub.0-4R.sup., (CH.sub.2).sub.0-4 OR.sup., or O(CH.sub.2).sub.0-4R.sup.. In some embodiments, L is S(O)CH.sub.2. In some embodiments, L is S(O)CH(CH.sub.3).

[0119] In some embodiments, L is optionally substituted C.sub.0-C.sub.6 alkylenyl-S(O). In some embodiments, L is S(O). In some embodiments, L is optionally substituted C.sub.1-C.sub.6 alkylenyl-S(O). In some embodiments, L is-C.sub.1-C.sub.6 alkylenyl-S(O) substituted with halogen, (CH.sub.2).sub.0-4R.sup., (CH.sub.2).sub.0-4OR.sup., or O(CH.sub.2).sub.0-4R.sup.. In some embodiments, L is optionally substituted C.sub.1-C.sub.3 alkylenyl-S(O). In some embodiments, L is-C.sub.1-C.sub.3 alkylenyl-S(O) substituted with halogen, (CH.sub.2).sub.0-4R.sup., (CH.sub.2).sub.0-4OR.sup., or O(CH.sub.2)).sub.4R.sup.. In some embodiments, L is CH.sub.2S(O). In some embodiments, L is CH(CH.sub.3)S(O). In some embodiments, L is CH(R.sup.)S(O).

[0120] In some embodiments, L is optionally substituted C(O)C.sub.0-C.sub.6 alkylenyl. In some embodiments, L is C(O). In some embodiments, L is-C(O)C.sub.1-C.sub.6 alkylenyl substituted with halogen, (CH.sub.2).sub.0-4R.sup., (CH.sub.2).sub.0-4OR.sup., or O(CH.sub.2)R.sup.. In some embodiments, L is optionally substituted C(O)C.sub.1-C.sub.3 alkylenyl. In some embodiments, L is-C(O)C.sub.1-C.sub.3 alkylenyl substituted with halogen, (CH.sub.2).sub.0-4R.sup., (CH.sub.2).sub.0-4OR.sup., or O(CH.sub.2).sub.0-4R.sup.. In some embodiments, L is C(O)CH.sub.2. In some embodiments, L is C(O)CH(CH.sub.3).

[0121] In some embodiments, L is optionally substituted C(O)OC.sub.0-C.sub.6 alkylenyl. In some embodiments, L is C(O)O.

[0122] In some embodiments, L is optionally substituted C(O)N(R.sup.8)C.sub.0-C.sub.6 alkylenyl. In some embodiments, L is optionally substituted C(O)N(H)C.sub.0-C.sub.6 alkylenyl. In some embodiments, L is optionally substituted C(O)N(C.sub.1-C.sub.6 aliphatic)-C.sub.0-C.sub.6 alkylenyl. In some embodiments, L is optionally substituted C(O)N(R.sup.8). In some embodiments, L is C(O)NH. In some embodiments, L is C(O)N(CH.sub.3).

[0123] In some embodiments, L is optionally substituted C.sub.1-C.sub.6 alkylenyl. In some embodiments, L is optionally substituted C.sub.1-C.sub.3 alkylenyl. In some embodiments, L is C.sub.1-C.sub.6 alkylenyl. In some embodiments, L is C.sub.1-C.sub.6 alkylenyl substituted with halogen, (CH.sub.2).sub.0-4R.sup., (CH.sub.2).sub.0-4OR.sup., or O(CH.sub.2).sub.0-4R.sup.. In some embodiments, L is C.sub.1-C.sub.3 alkylenyl substituted with halogen, (CH.sub.2).sub.0-4R.sup., (CH.sub.2).sub.0-4OR.sup., or O(CH.sub.2).sub.0-4R.sup.. In some embodiments, L is CH.sub.2. In some embodiments, L is CH.sub.2CH.sub.2. In some embodiments, L is CH(CH.sub.3).

[0124] In some embodiments, L is optionally substituted C.sub.3-C.sub.6 cycloalkylenyl. In some embodiments, L is optionally substituted C.sub.3 cycloalkylenyl. In some embodiments, L is optionally substituted cyclopropylenyl. In some embodiments, L is optionally substituted C.sub.4 cycloalkylenyl. In some embodiments, L is optionally substituted cyclobutylenyl. In some embodiments, L is optionally substituted C.sub.5 cycloalkylenyl. In some embodiments, L is optionally substituted cyclopentylenyl. In some embodiments, L is optionally substituted C.sub.6 cycloalkylenyl. In some embodiments, L is optionally substituted cyclohexylenyl. In some embodiments, L is

##STR00015##

[0125] In some embodiments, L is selected from S(O).sub.2, S(O).sub.2CH.sub.2, S(O).sub.2CH(CH.sub.3), CH.sub.2S(O).sub.2,

##STR00016##

[0126] As defined generally above, A is C.sub.3-C.sub.12 cycloaliphatic or 3- to 12-membered heterocyclyl comprising 1 to 3 heteroatoms selected from N, O, and S, wherein A is substituted with (R.sup.2).sub.m. In some embodiments, A is C.sub.3-C.sub.12 cycloaliphatic. In some embodiments, A is C.sub.3-C.sub.10 cycloaliphatic. In some embodiments, A is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or cycloheptyl. In some embodiments, A is cyclopentyl or cyclohexyl. In some embodiments, A is:

##STR00017##

In some embodiments, A is

##STR00018##

[0127] In some embodiments, A is 3- to 12-membered heterocyclyl comprising 1 to 3 heteroatoms selected from N, O, and S. In some embodiments, A is 4- to 6-membered heterocyclyl comprising 1 to 3 heteroatoms selected from N, O, and S. In some embodiments, A is 4-membered heterocyclyl comprising 1 to 3 heteroatoms selected from N, O, and S. In some embodiments, A azetidinyl. In some embodiments, A is 5-membered heterocyclyl comprising 1 to 3 heteroatoms selected from N, O, and S. In some embodiments, A is pyrrolidinyl. In some embodiments, A is 6-membered heterocyclyl comprising 1 to 3 heteroatoms selected from N, O, and S. In some embodiments, A is piperidinyl or tetrahydropyranyl. In some embodiments, A is pyrrolidinyl, piperidinyl, tetrahydropyranyl, or tetrahyrothiopyranyl. In some embodiments, A is pyrrolidinyl or piperidinyl. In some embodiments, A is

##STR00019##

[0128] In some embodiments, A is

##STR00020##

[0129] In some embodiments, A is substituted with (R.sup.2).sub.m. In some embodiments, A is substituted with 0, 1, 2, 3, or 4 instances of R.sup.2. In some embodiments, A is substituted with 0 instances of R.sup.2 (i.e., A is unsubstituted). In some embodiments, A is substituted with 1 R.sup.2. In some embodiments, A is substituted with 2 R.sup.2. In some embodiments, A is substituted with 3 R.sup.2. In some embodiments, A is substituted with 4 R.sup.2.

[0130] As defined generally above, B is a fused optionally substituted C.sub.5-C.sub.6 aryl or optionally substituted 5- to 6-membered heteroaryl comprising 1 to 3 heteroatoms selected from N, O, and S. In some embodiments, B is a fused C.sub.5-C.sub.6 aryl or 5- to 6-membered heteroaryl comprising 1 to 3 heteroatoms selected from N, O, and S, substituted with one or more instances of halogen, CN, (CH.sub.2).sub.0-4R.sup., (CH.sub.2).sub.0-4OR.sup., or O(CH.sub.2).sub.0-4R.sup.. In some embodiments, B is a fused optionally substituted C.sub.5-C.sub.6 aryl. In some embodiments, B is a fused C.sub.5-C.sub.6 aryl. In some embodiments, B is a fused C.sub.5-C.sub.6 aryl substituted with one or more instances of halogen, CN, (CH.sub.2).sub.0-4R.sup., (CH.sub.2).sub.0-4OR.sup., or O(CH.sub.2).sub.0-4R.sup.. In some embodiments, B is a fused C.sub.5-C.sub.6 aryl substituted with one or more instances of halogen, CN, or OCH.sub.3. In some embodiments, B is a fused phenyl. In some embodiments, B is a fused phenyl substituted with one or more instances of halogen, CN, or OCH.sub.3.

[0131] In some embodiments, B is fused optionally substituted 5- to 6-membered heteroaryl comprising 1 to 3 heteroatoms selected from N, O, and S. In some embodiments, B is fused 5- to 6-membered heteroaryl comprising 1 to 3 heteroatoms selected from N, O, and S. In some embodiments, B is fused 5- to 6-membered heteroaryl comprising 1 to 3 heteroatoms selected from N, O, and S substituted with one or more instances of halogen, CN, (CH.sub.2).sub.0-4R.sup., (CH.sub.2).sub.0-4OR.sup., or O(CH.sub.2).sub.0-4R.sup.. In some embodiments, B is fused 5- to 6-membered heteroaryl comprising 1 to 3 heteroatoms selected from N, O, and S substituted with one or more instances of halogen, CN, or OCH.sub.3. In some embodiments, B is fused thienyl. In some embodiments, B is a fused thienyl substituted with one or more instances of halogen, CN, or OCH.sub.3. In some embodiments, B is fused pyridyl. In some embodiments, B is fused pyridyl substituted with one or more instances of, (CH.sub.2).sub.0-4R.sup.. In some embodiments, B is fused pyridyl substituted with C.sub.1-C.sub.6aliphatic. In some embodiments, B is fused pyridyl substituted with methyl. In some embodiments, B is fused pyrazolyl. In some embodiments, B is fused pyrazolyl substituted with one or more instances of, (CH.sub.2).sub.0-4R.sup.. In some embodiments, B is fused pyrazolyl substituted with C.sub.1-C.sub.6aliphatic. In some embodiments, B is fused pyrazolyl substituted with methyl.

[0132] As defined generally above, R.sup.1 is selected from C.sub.1-C.sub.6 aliphatic, C.sub.3-C.sub.12cycloaliphatic, C.sub.5-C.sub.12 aryl, 5- to 12-membered heteroaryl comprising 1 to 3 heteroatoms selected from N, O, and S, and 3- to 12-membered heterocyclyl comprising 1 to 3 heteroatoms selected from N, O, and S, wherein R.sup.1 is substituted with (R.sup.3).sub.p.

[0133] In some embodiments, R.sup.1 is C.sub.5-C.sub.12 aryl substituted with (R.sup.3).sub.p, 5- to 12-membered heteroaryl comprising 1 to 3 heteroatoms selected from N, O, and S substituted with (R.sup.3).sub.p, or 3- to 12-membered heterocyclyl comprising 1 to 3 heteroatoms selected from N, O, and S substituted with (R.sup.3).sub.p.

[0134] In some embodiments, R.sup.1 is C.sub.1-C.sub.6 aliphatic substituted with (R.sup.3).sub.p. In some embodiments, R.sup.1 is C.sub.1-C.sub.6 aliphatic, wherein p is 0. In some embodiments, R.sup.1 is C.sub.1-C.sub.6 alkyl substituted with (R.sup.3).sub.p. In some embodiments, R.sup.1 is C.sub.1-C.sub.3 alkyl substituted with (R.sup.3).sub.p. In some embodiments, R.sup.1 is methyl, ethyl, propyl (e.g., n-propyl and iso-propyl), butyl (e.g., n-butyl, iso-butyl, sec-butyl, and tert-butyl), pentyl, or hexyl, optionally substituted with (R.sup.3).sub.p.

[0135] In some embodiments, R.sup.1 is C.sub.3-C.sub.12 cycloaliphatic substituted with (R.sup.3).sub.p. In some embodiments, R.sup.1 is C.sub.3-C.sub.12 cycloalkyl substituted with (R.sup.3)P. In some embodiments, R.sup.1 is C.sub.3-C.sub.6 cycloalkyl substituted with (R.sup.3).sub.p. In some embodiments, R.sup.1 is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl substituted with (R.sup.3).sub.p.

[0136] In some embodiments, R.sup.1 is C.sub.5-C.sub.12 aryl substituted with (R.sup.3).sub.p. In some embodiments, R.sup.1 is C.sub.3-C.sub.6 aryl substituted with (R.sup.3).sub.p. In some embodiments, R.sup.1 is phenyl substituted with (R.sup.3).sub.p.

[0137] In some embodiments, R.sup.1 is monocyclic or bicyclic 3- to 12-membered heterocyclyl comprising 1 to 3 heteroatoms selected from N, O, and S substituted with (R.sup.3).sub.p. In some embodiments, R.sup.1 is monocyclic 3- to 7-membered heterocyclyl comprising 1 to 3 heteroatoms selected from N, O, and S substituted with (R.sup.3).sub.p. In some embodiments, R.sup.1 is 4- to 6-membered heterocyclyl comprising 1 to 3 heteroatoms selected from N, O, and S substituted with (R.sup.3).sub.p. In some embodiments, R.sup.1 is 4-membered heterocyclyl comprising 1 to 3 heteroatoms selected from N, O, and S substituted with (R.sup.3).sub.p. In some embodiments, R.sup.1 is 5-membered heterocyclyl comprising 1 to 3 heteroatoms selected from N, O, and S substituted with (R.sup.3).sub.p. In some embodiments, R.sup.1 is 6-membered heterocyclyl comprising 1 to 3 heteroatoms selected from N, O, and S substituted with (R.sup.3).sub.p.

[0138] In some embodiments, R.sup.1 is bicyclic 10- to 12-membered heterocyclyl comprising 1 to 3 heteroatoms selected from N, O, and S substituted with (R.sup.3).sub.p. In some embodiments, R.sup.1 is bicyclic 10- to 12-membered heterocyclyl comprising 1 to 3 heteroatoms selected from N, O, and S, substituted with (R.sup.3).sub.p, where one ring of said bicyclic heterocyclyl is a fused aryl ring. In some embodiments, R.sup.1 is bicyclic 10-membered heterocyclyl comprising 1 to 3 heteroatoms selected from N, O, and S substituted with (R.sup.3).sub.p. In some embodiments, R.sup.1 is bicyclic 11-membered heterocyclyl comprising 1 to 3 heteroatoms selected from N, O, and S substituted with (R.sup.3)P. In some embodiments, R.sup.1 is bicyclic 12-membered heterocyclyl comprising 1 to 3 heteroatoms selected from N, O, and S substituted with (R.sup.3).sub.p.

[0139] In some embodiments, R.sup.1 is 5- to 12-membered heteroaryl comprising 1 to 3 heteroatoms selected from N, O, and S substituted with (R.sup.3).sub.p. In some embodiments, R.sup.1 is 5- to 6-membered heteroaryl comprising 1 to 3 heteroatoms selected from N, O, and S substituted with (R.sup.3).sub.p. In some embodiments, R.sup.1 is 5-membered heteroaryl comprising 1 to 3 heteroatoms selected from N, O, and S substituted with (R.sup.3).sub.p. In some embodiments, R.sup.1 is 6-membered heteroaryl comprising 1 to 3 heteroatoms selected from N, O, and S substituted with (R.sup.3).sub.p. In some embodiments, R.sup.1 is pyrrolyl, imidazolyl, pyrrazolyl, thiophenyl, pyridinyl, or pyrazinyl substituted with (R.sup.3).sub.p. In some embodiments, R.sup.1 is pyrrazolyl or thiophenyl substituted with (R.sup.3).sub.p.

[0140] As defined generally above, R.sup.1 is substituted with p-instances of R.sup.3 (i.e., (R.sup.3).sub.p). In some embodiments, p is 0 to 4 (i.e., 0, 1, 2, 3, or 4). In some embodiments, p is 0 (i.e., R.sup.1 is unsubstituted). In some embodiments, p is 1. In some embodiments, p is 2. In some embodiments, p is 3. In some embodiments, p is 4.

[0141] As defined generally above, each R.sup.3 is independently halo, S(O).sub.2NR.sup.3aR.sup.3b, S(O).sub.2R.sup.3b, S(NR.sup.3c)(O)NR.sup.3aR.sup.3b, S(O)(NR.sup.3c)R.sup.3b, S(O)R.sup.3b, NR.sup.3aS(O).sub.2R.sup.3b, OR.sup.3a, C(O)R.sup.3a, C(O)NHR.sup.3a, oxo, or an optionally substituted group selected from C.sub.1-C.sub.6 aliphatic, C.sub.5-C.sub.12 aryl, C.sub.3-C.sub.12cycloaliphatic, 5- to 12-membered heteroaryl comprising 1 to 3 heteroatoms selected from N, O, and S, and 3- to 12-membered heterocyclyl comprising 1 to 3 heteroatoms selected from N, O, and S.

[0142] In some embodiments, each R.sup.3 is halo, oxo, S(O).sub.2NR.sup.3aR.sup.3b, or an optionally substituted group selected from C.sub.1-C.sub.6 aliphatic or C.sub.3-C.sub.12 cycloaliphatic.

[0143] In some embodiments, R.sup.3 is oxo.

[0144] In some embodiments, R.sup.3 is halo. In some embodiments, R.sup.3 is F, Cl, Br, or I. In some embodiments, R.sup.3 is F. In some embodiments, R.sup.3 is Cl. In some embodiments, R.sup.3 is Br. In some embodiments, R.sup.3 is I.

[0145] In some embodiments, R.sup.3 is S(O).sub.2NR.sup.3aR.sup.3b. In some embodiments, R.sup.3 is S(O).sub.2NH.sub.2. In some embodiments, R; is S(O).sub.2NH(C.sub.1-C.sub.6 aliphatic). In some embodiments, R.sup.3 is S(O).sub.2N(C.sub.1-C.sub.6 aliphatic).sub.2. In some embodiments, R.sup.3 is S(O).sub.2N(CH.sub.3).sub.2.

[0146] In some embodiments, R.sup.3 is S(O).sub.2R.sup.b3. In some embodiments, R.sup.3 is S(O).sub.2C.sub.1-C.sub.6 aliphatic. In some embodiments, R.sup.3 is S(O).sub.2CH.sub.3. In some embodiments, R.sup.3 is S(O).sub.2CHF.sub.2. In some embodiments, R.sup.3 is S(O).sub.2-(3- to 12-membered heterocyclyl comprising 1 to 4 heteroatoms selected from N, O, and S). In some embodiments, R.sup.3 is S(O).sub.2-(azetidinyl).

[0147] In some embodiments, R.sup.3 is S(NH)(O)NR.sup.3aR.sup.3b. In some embodiments, R.sup.3 is S(NH)(O)N(C.sub.1-6 aliphatic).sub.2. In some embodiments, R is S(NH)(O)N(CH.sub.3).sub.2. In some embodiments, R.sup.3 is S(NH)(O)NH(CH.sub.3).

[0148] In some embodiments, R.sup.3 is S(O)(NH)R.sup.3b. In some embodiments, R.sup.3 is S(O)(NH)C.sub.1-6 aliphatic. In some embodiments, R.sup.3 is S(O)(NH)CH.sub.3. In some embodiments, R.sup.3 is S(O)(NH)CHF.sub.2.

[0149] In some embodiments, R.sup.3 is S(O)R.sup.3b. In some embodiments, R.sup.3 is S(O)C.sub.1-6 aliphatic. In some embodiments, R.sup.3 is S(O)CH.sub.3.

[0150] In some embodiments, R.sup.3 is NR.sup.3aS(O).sub.2R.sup.3b. In some embodiments, R.sup.3 is NHS(O).sub.2C.sub.1-C.sub.6 aliphatic. In some embodiments, R.sup.3 is NHS(O).sub.2CH.sub.3. In some embodiments, R.sup.3 is N(C.sub.1-C.sub.6 aliphatic)-S(O).sub.2C.sub.1-C.sub.6 aliphatic. In some embodiments, R.sup.3 is N(CH.sub.3)S(O).sub.2CH.sub.3.

[0151] In some embodiments, R.sup.3 is OR.sup.3a. In some embodiments, R.sup.3 is OH. In some embodiments, R.sup.3 is OC.sub.1-C.sub.6 aliphatic, wherein C.sub.1-C.sub.6 aliphatic is optionally substituted with halo. In some embodiments, R.sup.3 is OC.sub.1-C.sub.6 alkyl, wherein C.sub.1-C.sub.6 alkyl is optionally substituted with halo. In some embodiments, R.sup.3 is OCH.sub.3. In some embodiments, R.sup.3 is OCH.sub.2F. In some embodiments, R.sup.3 is OCHF.sub.2. In some embodiments, R.sup.3 is 0-CF.sub.3.

[0152] In some embodiments, R.sup.3 is C(O)R.sup.3a. In some embodiments, R.sup.3 is C(O)C.sub.1-C.sub.6 aliphatic. In some embodiments, R.sup.3 is C(O)C.sub.1-C.sub.6 alkyl. In some embodiments, R.sup.3 is C(O)CH.sub.3.

[0153] In some embodiments, R.sup.3 is C(O)NHR.sup.3a. In some embodiments, R.sup.3 is C(O)NHC.sub.1-C.sub.6 aliphatic. In some embodiments, R.sup.3 is C(O)NHC.sub.1-C.sub.6 alkyl. In some embodiments, R.sup.3 is C(O)NHCH.sub.3.

[0154] In some embodiments, R.sup.3 is optionally substituted C.sub.1-C.sub.6 aliphatic. In some embodiments, R.sup.3 is C.sub.1-C.sub.6 aliphatic. In some embodiments, R.sup.3 is C.sub.1-C.sub.6 aliphatic substituted with substituted with one or more instances of halogen, (CH.sub.2).sub.0-4R.sup., (CH.sub.2).sub.0-4OR.sup., or O(CH.sub.2).sub.0-4R. In some embodiments, R.sup.3 is C.sub.1-C.sub.6 alkyl substituted with substituted with one or more instances of halogen, (CH.sub.2).sub.0-4R.sup., (CH.sub.2).sub.0-4OR.sup., or O(CH.sub.2).sub.0-4R.sup.. In some embodiments, R.sup.3 is C.sub.1-C.sub.6 aliphatic substituted with substituted with one or more instances of halogen, (CH.sub.2).sub.0-4R.sup., (CH.sub.2).sub.0-4OR.sup., or O(CH.sub.2).sub.0-4R.sup., wherein each R.sup. is independently, halo, C.sub.1-C.sub.6 aliphatic, C(O)C.sub.1-C.sub.6 aliphatic, C(O)OC.sub.1-C.sub.6 aliphatic or OH. In some embodiments, R.sup.3 methyl, ethyl, propyl, or butyl. In some embodiments, R.sup.3 is CH.sub.2F. In some embodiments, R.sup.3 is CHF.sub.2. In some embodiments, R.sup.3 is CF.sub.3. In some embodiments, R.sup.3 is C(CH.sub.3).sub.2OCH.sub.3. In some embodiments, R.sup.3 is C(CH.sub.3).sub.2OH. In some embodiments, R.sup.3 is C(CH.sub.3).sub.2C(O)CH.sub.3.

[0155] In some embodiments, R.sup.3 is optionally substituted C.sub.5-C.sub.12 aryl. In some embodiments, R.sup.3 is C.sub.5-C.sub.12 aryl. In some embodiments, R.sup.3 is C.sub.5-C.sub.12 aryl substituted with (CH.sub.2).sub.0-4R.sup., (CH.sub.2).sub.0-4 OR.sup., or O(CH.sub.2).sub.0-4R.sup.. In some embodiments, R.sup.3 is optionally substituted phenyl. In some embodiments, R.sup.3 is phenyl substituted with C.sub.1-C.sub.6 aliphatic. In some embodiments, R.sup.3 is phenyl substituted with CH.sub.3.

[0156] In some embodiments, R.sup.3 is optionally substituted C.sub.3-C.sub.12 cycloaliphatic. In some embodiments, R.sup.3 is C.sub.3-C.sub.12 cycloaliphatic optionally substituted with halogen or C.sub.1-C.sub.6 aliphatic. In some embodiments, R.sup.3 is C.sub.3-C.sub.6 cycloaliphatic optionally substituted with halogen or C.sub.1-C.sub.6 aliphatic. In some embodiments, R.sup.3 is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl optionally substituted with halogen or C.sub.1-C.sub.6 aliphatic. In some embodiments, R.sup.3 is cyclopropyl. In some embodiments, R.sup.3 is cyclopropyl substituted with halogen.

[0157] In some embodiments, R.sup.3 is optionally substituted 5- to 12-membered heteroaryl comprising 1 to 3 heteroatoms selected from N, O, and S. In some embodiments, R.sup.3 is optionally substituted 5- to 6-membered heteroaryl. In some embodiments, R.sup.3 is 5- to 6-membered heteroaryl. In some embodiments, R.sup.3 is 5- to 6-membered heteroaryl optionally substituted with (CH.sub.2).sub.0-4R.sup., (CH.sub.2).sub.0-4OR.sup., or O(CH.sub.2).sub.0-4R.sup.. In some embodiments, R.sup.3 is 5- to 6-membered heteroaryl optionally substituted with (CH.sub.2).sub.0-4R.sup., (CH.sub.2).sub.0-4OR.sup., or O(CH.sub.2).sub.0-4R.sup., wherein R.sup. is C.sub.1-6 aliphatic or a 3- to 6-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0158] In some embodiments, R.sup.3 is optionally substituted 3- to 12-membered heterocyclyl comprising 1 to 3 heteroatoms selected from N, O, and S. In some embodiments, R.sup.3 is optionally substituted monocyclic 3- to 7-membered heterocyclyl comprising 1 to 3 heteroatoms selected from N, O, and S. In some embodiments, R.sup.3 is monocyclic 3- to 7-membered heterocyclyl comprising 1 to 3 heteroatoms selected from N, O, and S optionally substituted with halogen, (CH.sub.2).sub.0-4R.sup., (CH.sub.2).sub.0-4OR.sup., or O(CH.sub.2).sub.0-4R.sup.. In some embodiments, R.sup.3 is monocyclic 3- to 7-membered heterocyclyl comprising 1 to 3 heteroatoms selected from N, O, and S optionally substituted with halogen, (CH.sub.2).sub.0-4R.sup., (CH.sub.2).sub.0-4OR.sup., or O(CH.sub.2).sub.0-4R.sup.. In some embodiments, R.sup.3 is monocyclic 3- to 7-membered heterocyclyl comprising 1 to 3 heteroatoms selected from N, O, and S substituted with halogen, (CH.sub.2).sub.0-4R.sup., (CH.sub.2).sub.0-4OR.sup., or O(CH.sub.2).sub.0-4R.sup., where R.sup. is C.sub.1-C.sub.6 aliphatic. In some embodiments, R.sup.3 is optionally substituted monocyclic 3-membered heterocyclyl comprising 1 to 3 heteroatoms selected from N, O, and S. In some embodiments, R.sup.3 is optionally substituted monocyclic 4-membered heterocyclyl comprising 1 to 3 heteroatoms selected from N, O, and S. In some embodiments, R.sup.3 is optionally substituted monocyclic 5-membered heterocyclyl comprising 1 to 3 heteroatoms selected from N, O, and S. In some embodiments, R.sup.3 is optionally substituted monocyclic 6-membered heterocyclyl comprising 1 to 3 heteroatoms selected from N, O, and S. In some embodiments, R.sup.3 is optionally substituted monocyclic 7-membered heterocyclyl comprising 1 to 3 heteroatoms selected from N, O, and S. In some embodiments, R.sup.3 is dioxolanyl.

[0159] In some embodiments, R.sup.3 is optionally substituted 10- to 12-membered bicyclic heterocyclyl comprising 1 to 3 heteroatoms selected from N, O, and S. In some embodiments, R.sup.3 is optionally substituted 10- to 12-membered bicyclic heterocyclyl comprising 1 to 3 heteroatoms selected from N, O, and S optionally substituted with halogen, oxo, (CH.sub.2).sub.0-4R.sup., (CH.sub.2).sub.0-4OR.sup., or O(CH.sub.2).sub.0-4R.sup.. In some embodiments, R.sup.3 is optionally substituted 10- to 12-membered bicyclic heterocyclyl comprising 1 to 3 heteroatoms selected from N, O, and S optionally substituted with halogen, oxo, (CH.sub.2).sub.0-4R.sup., (CH.sub.2).sub.0-4OR.sup., or O(CH.sub.2).sub.0-4R, where R.sup. is C.sub.1-C.sub.6 aliphatic. In some embodiments, R.sup.3 is optionally substituted 10-membered bicyclic heterocyclyl comprising 1 to 3 heteroatoms selected from N, O, and S optionally substituted with halogen, oxo, (CH.sub.2).sub.0-4R.sup., (CH.sub.2).sub.0-4OR.sup., or O(CH.sub.2).sub.0-4R.sup., where R.sup. is C.sub.1-C.sub.6 aliphatic. In some embodiments, R.sup.3 is optionally substituted 11-membered bicyclic heterocyclyl comprising 1 to 3 heteroatoms selected from N, O, and S optionally substituted with halogen, oxo, (CH.sub.2).sub.0-4R.sup., (CH.sub.2).sub.0-4OR.sup., or O(CH.sub.2).sub.0-4R.sup., where R.sup. is C.sub.1-C.sub.6 aliphatic. In some embodiments, R.sup.3 is optionally substituted 12-membered bicyclic heterocyclyl comprising 1 to 3 heteroatoms selected from N, O, and S optionally substituted with halogen, oxo, (CH.sub.2).sub.0-4R.sup., (CH.sub.2).sub.0-4OR.sup., or O(CH.sub.2).sub.0-4R.sup., where R.sup. is C.sub.1-C.sub.6 aliphatic.

[0160] As defined generally above, R.sup.3a and R.sup.3b are each independently selected from H and optionally substituted C.sub.1-C.sub.6 aliphatic, or R.sup.3a and R.sup.3b come together with the atoms to which they are attached to form optionally substituted C.sub.3-C.sub.12 cycloaliphatic or 3- to 12-membered heterocyclyl comprising 1 to 4 heteroatoms selected from N, O, and S. In some embodiments, R.sup.3a and R.sup.3b are each independently selected from H and optionally substituted C.sub.1-C.sub.6 aliphatic. In some embodiments, R.sup.3a and R.sup.3b come together with the atoms to which they are attached to form optionally substituted C.sub.3-C.sub.12 cycloaliphatic or 3- to 12-membered heterocyclyl comprising 1 to 4 heteroatoms selected from N, O, and S.

[0161] As defined generally above, each R.sup.c is independently selected from H, OH, and optionally substituted C.sub.1-C.sub.6 aliphatic. In some embodiments, R.sup.3c is H. In some embodiments, R.sup.3c is OH. In some embodiments, R.sup.3c is optionally substituted C.sub.1-C.sub.6 aliphatic. In some embodiments, R.sup.3c is CH.sub.3.

[0162] In some embodiments, R.sup.1 is selected from: CH(CH.sub.3).sub.2,

##STR00021## ##STR00022## ##STR00023## ##STR00024## ##STR00025## ##STR00026##

[0163] As defined generally above, each R.sup.2 is independently halo, oxo, NR.sup.2aR.sup.2b, C(O)OR.sup.2a, OC(O)R.sup.2a, S(O).sub.2, S(O).sub.2R.sup.2a, C(O)NR.sup.2aR.sup.2b, N(R.sup.2a)C(O)R.sup.2b, C(O)R.sup.2a, OR.sup.2a, OC(O)NR.sup.2aR.sup.2b, NHC(O)NR.sup.2aR.sup.2b, NHC(O)OR.sup.2a, NHS(O).sub.2R.sup.2a, C.sub.1-C.sub.6 alkylenyl-C(O)NR.sup.2aR.sup.2b or an optionally substituted group selected from C.sub.1-C.sub.6 aliphatic, C.sub.5-C.sub.12 aryl, and 3- to 12-membered heterocyclyl comprising 1 to 3 heteroatoms selected from N, O, and S.

[0164] In some embodiments, each R.sup.2 is independently halo, oxo, NR.sup.2aR.sup.2b, C(O)OR.sup.2a, C(O)NR.sup.2aR.sup.2b, N(R.sup.2a)C(O)R.sup.2b, C(O)R.sup.23, OR.sup.2a, or an optionally substituted group selected from C.sub.1-C.sub.6 aliphatic, C.sub.5-C.sub.12 aryl, and 3- to 12-membered heterocyclyl comprising 1 to 3 heteroatoms selected from N, O, and S.

[0165] In some embodiments, R.sup.2 is halo. In some embodiments, R.sup.2 is F, Br, Cl, or I. In some embodiments, R.sup.2 is F. In some embodiments, R.sup.2 is Br. In some embodiments, R.sup.2 is Cl.

[0166] In some embodiments, R.sup.2 is oxo.

[0167] In some embodiments, R.sup.2 is N(R.sup.2a)(R.sup.2b). In some embodiments, R.sup.2 is NH(R.sup.2b). In some embodiments, R.sup.2 is NH(R.sup.2a). In some embodiments, R.sup.2 is NH.sub.2.

[0168] In some embodiments, R.sup.2 is C(O)OR.sup.2a. In some embodiments, R.sup.2 is C(O)OH. In some embodiments, R.sup.2 is C(O)OC.sub.1-C.sub.6 aliphatic. In some embodiments, R.sup.2 is C(O)OC.sub.1-C.sub.6 aliphatic optionally substituted with (CH.sub.2).sub.0-4R.sup., (CH.sub.2).sub.0-4OR.sup., or O(CH.sub.2).sub.0-4R.sup.. In some embodiments, R.sup.2 is C(O)OC.sub.1-C.sub.6 aliphatic optionally substituted with (CH.sub.2).sub.0-4R.sup.. In some embodiments R.sup.2 is C(O)OC.sub.1-C.sub.6 aliphatic optionally substituted with (CH.sub.2).sub.0-4R.sup., where R.sup. is an optionally substituted C.sub.1-6 aliphatic or an optionally substituted 3- to 6-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. In some embodiments R.sup.2 is C(O)OC.sub.1-C.sub.6 aliphatic optionally substituted with (CH.sub.2).sub.0-4R.sup., where R.sup. is C.sub.1, aliphatic or a 3- to 6-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, where R.sup. is substituted with (CH.sub.2).sub.0-2R.sup., where R.sup. is C.sub.1-C.sub.6 aliphatic. In some embodiments, R.sup.2 is C(O)OC.sub.1-C.sub.6 aliphatic optionally substituted with phenyl. In some embodiments, R.sup.2 is C(O)OC.sub.1-C.sub.6 aliphatic optionally substituted with pyridyl. In some embodiments, R.sup.2 is C(O)OC.sub.1-C.sub.6 aliphatic optionally substituted with pyrazolyl. In some embodiments, R.sup.2 is C(O)OC.sub.1-C.sub.6 aliphatic optionally substituted with pyrazolyl substituted with (CH.sub.2).sub.0-2R.sup.. In some embodiments, R.sup.2 is C(O)OC.sub.1-C.sub.6 aliphatic optionally substituted with imidazolyl. In some embodiments, R.sup.2 is C(O)OC.sub.1-C.sub.6 aliphatic optionally substituted with imidazolyl substituted with (CH.sub.2).sub.0-2R.sup.. In some embodiments, R.sup.2 is C(O)OC.sub.1-C.sub.6 aliphatic optionally substituted with isoxazolyl. In some embodiments, R.sup.2 is C(O)OC.sub.1-C.sub.6 aliphatic optionally substituted with C.sub.3-C.sub.6 cycloalkyl. In some embodiments, R.sup.2 is C(O)OC.sub.1-C.sub.6 aliphatic optionally substituted with cyclopropyl. In some embodiments, R.sup.2 is C(O)OCH(CH.sub.3).sub.2. In some embodiments, R.sup.2 is C(O)OC(CH.sub.3).sub.3. In some embodiments, R.sup.2 is C(O)OR.sup.2a, where R.sup.2a is optionally substituted C.sub.5-C.sub.14 aryl. In some embodiments, R.sup.2 is C(O)O-phenyl.

[0169] In some embodiments, R.sup.2 is C(O)N(R.sup.2a)(R.sup.2b). In some embodiments, R.sup.2 is C(O)N(H)(R.sup.2b). In some embodiments, R.sup.2 is C(O)N(C.sub.1-C.sub.6 aliphatic)(R.sup.2b). In some embodiments, R.sup.2 is C(O)N(R.sup.2a)(R.sup.2b), where R.sup.2b is optionally substituted C.sub.1-C.sub.6 aliphatic. In some embodiments R.sup.2, is C(O)N(R.sup.2a)(R.sup.2b), where R.sup.2b is C.sub.1-C.sub.6 aliphatic optionally substituted with halogen, (CH.sub.2).sub.0-4R.sup., or (CH.sub.2).sub.0-4OR.sup.. In some embodiments R.sup.2 is C(O)N(R.sup.2a)(R.sup.2b), where R.sup.2b is C.sub.1-C.sub.6 aliphatic optionally substituted with (CH.sub.2).sub.0-4R.sup., where R.sup. is selected from hydrogen and 3- to 6-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. . In some embodiments R.sup.2 is C(O)N(R.sup.2)(R.sup.2b) where R.sup.b is C.sub.1-C.sub.6 aliphatic optionally substituted with a group selected from cyclopropyl, phenyl, tetrahydrofuranyl, pyrazolyl, isoxazolyl, tetrahydropyranyl, and pyridyl. In some embodiments R.sup.2 is C(O)N(R.sup.2a)(R.sup.2b), where R.sup.2b is C.sub.1-C.sub.6 aliphatic optionally substituted with (CH.sub.2).sub.0-4OR.sup., where R.sup. is C.sub.1-6 aliphatic. In some embodiments, R.sup.2 is C(O)N(H)(CH.sub.2CHF.sub.2). In some embodiments, R.sup.2 is C(O)N(H)(CH.sub.2CF.sub.3). In some embodiments, R.sup.2 is C(O)N(H)(CH.sub.2CH.sub.2CF.sub.3). In some embodiments, R.sup.2 is C(O)N(H)(CH(CH.sub.3).sub.2). In some embodiments R.sup.2 is C(O)N(R.sup.2a)(R.sup.2b), where R.sup.2b is optionally substituted C.sub.3-C.sub.12 cycloaliphatic. In some embodiments R.sup.2 is C(O)N(R.sup.2a)(R.sup.2b), where R.sup.2b is optionally substituted C.sub.3-C.sub.6 cycloaliphatic. In some embodiments of R.sup.2, R.sup.2b is optionally substituted cyclopropyl. In some embodiments R.sup.2 is C(O)N(R.sup.2a)(R.sup.2b), where R.sup.2b is optionally substituted cyclobutyl. In some embodiments R.sup.2 is C(O)N(R.sup.2a)(R.sup.2b), where R.sup.2b is optionally substituted cyclohexyl. In some embodiments R.sup.2 is C(O)N(R.sup.2a)(R.sup.2b), where R.sup.2b is optionally substituted C.sub.5-C.sub.14 aryl. In some embodiments R.sup.2 is C(O)N(R.sup.2a)(R.sup.2b), where R.sup.2b is phenyl optionally substituted with (CH.sub.2).sub.0-4R.sup. or (CH.sub.2).sub.0-4OR.sup.. In some embodiments R.sup.2 is C(O)N(R.sup.2a)(R.sup.2b), where R.sup.b is optionally substituted 5- to 12-membered heteroaryl comprising 1 to 4 heteroatoms selected from N, O, and S. In some embodiments R.sup.2 is C(O)N(R.sup.2a)(R.sup.2b), where R.sup.2b is optionally substituted 5- to 6-membered heteroaryl comprising 1 to 2 heteroatoms selected from N, O, and S In some embodiments R.sup.2 is C(O)N(R.sup.2a)(R.sup.2b), where R.sup.2b is selected from pyridinyl, pyrrolyl, pyrazolyl, imidazolyl, isothiazolyl, and isoxazolyl optionally substituted with halogen, (CH.sub.2).sub.0-4R.sup., or (CH.sub.2).sub.0-4OR.sup.. In some embodiments R.sup.2 is C(O)N(R.sup.2a)(R.sup.2b), where R.sup.2b is optionally substituted 3- to 12-membered heterocyclyl comprising 1 to 3 heteroatoms selected from N, O, and S. In some embodiments R.sup.2 is C(O)N(R.sup.2a)(R.sup.2b), where R.sup.2b is optionally substituted tetrahydrofuranyl or tetrahydropyranyl. In some embodiments R.sup.2 is C(O)N(R.sup.2a)(R.sup.2b), where R.sup.2b is an optionally substituted 9- to 10-membered bicyclic heterocyclyl comprising 1 to 3 heteroatoms selected from N, O, and S.

[0170] In some embodiments, R.sup.2 is N(R.sup.2a)C(O)R.sup.2b.

[0171] In some embodiments, R.sup.2 is OC(O)R.sup.2a.

[0172] In some embodiments, R.sup.2 is S(O).sub.2.

[0173] In some embodiments, R.sup.2 is S(O).sub.2R.sup.2a.

[0174] In some embodiments, R.sup.2 is OC(O)NR.sup.2aR.sup.2b.

[0175] In some embodiments, R.sup.2 is NHC(O)NR.sup.2aR.sup.2b.

[0176] In some embodiments, R.sup.2 is NHC(O)OR.sup.2a.

[0177] In some embodiments, R.sup.2 is C.sub.1-C.sub.6 alkylenyl-C(O)NR.sup.2aR.sup.2b.

[0178] In some embodiments, R.sup.2 is NHS(O).sub.2R.sup.2a.

[0179] In some embodiments, R.sup.2 is C(O)R.sup.2a. In some embodiments, R.sup.2 is C(O)C.sub.1-C.sub.6 aliphatic. In some embodiments, R.sup.2 is C(O)C.sub.1-C.sub.6 aliphatic optionally substituted with halogen, (CH.sub.2).sub.0-4R.sup., (CH.sub.2).sub.0-4OR.sup., or O(CH.sub.2).sub.0-4R.sup.. In some embodiments, R.sup.2 is C(O)C.sub.1-C.sub.6 aliphatic optionally substituted with (CH.sub.2).sub.0-4R.sup. or (CH.sub.2).sub.0-4OR.sup., where R.sup. is 3- to 6-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. In some embodiments, R.sup.2 is C(O)C(CH.sub.3).sub.3. In some embodiments, R.sup.2 is C(O) C.sub.3-C.sub.12 cycloaliphatic. In some embodiments, R.sup.2 is C(O) C.sub.3-C.sub.12 cyclopropyl. In some embodiments, R.sup.2 is C(O)C.sub.5-C.sub.14 aryl. In some embodiments, R.sup.2 is C(O)-phenyl. In some embodiments, R.sup.2 is C(O)R.sup.2a, where R.sup.2a is a 3- to 12-membered heterocyclyl comprising 1 to 3 heteroatoms selected from N, O, and S. In some embodiments, R.sup.2 is C(O)R.sup.2a, where R.sup.2 is selected from optionally substituted pyrrolidinyl, piperidinyl, and morpholinyl. In some embodiments, R.sup.2 is C(O)R.sup.2, where R.sup.2 is a 7- to 11-membered spirocyclic ring system spirocyclic ring system comprising 1 to 3 heteroatoms selected from N, O, and S.

[0180] In some embodiments, R.sup.2 is OR.sup.2a. In some embodiments, R.sup.2 is OH. In some embodiments, R.sup.2 is OC.sub.1-C.sub.6 aliphatic. In some embodiments, R.sup.2 is OC.sub.1-C.sub.6 aliphatic, optionally substituted with (CH.sub.2).sub.0-4R.sup., (CH.sub.2).sub.0-4OR.sup., or O(CH.sub.2).sub.0-4R.sup.. In some embodiments, R.sup.2 is OCH.sub.3.

[0181] In some embodiments, R.sup.2 is optionally substituted C.sub.1-C.sub.6 aliphatic. In some embodiments, R.sup.2 is optionally substituted C.sub.1-C.sub.6 alkyl. In some embodiments, R.sup.2 is C.sub.1-C.sub.6 aliphatic optionally substituted with halo, (CH.sub.2).sub.0-4R.sup., (CH.sub.2).sub.0-4OR.sup., O(CH.sub.2).sub.0-4R.sup., or (CH.sub.2).sub.0-4N(R.sup.).sub.2. In some embodiments, R.sup.2 is methyl, ethyl, propyl, or butyl. In some embodiments, R.sup.2 is CH.sub.3. In some embodiments, R.sup.2 is (CH.sub.2).sub.0-6CF.sub.3. In some embodiments, R.sup.2 is CH.sub.2CF.sub.3. In some embodiments, R.sup.2 is C.sub.1-C.sub.6 aliphatic substituted with OR.sup., where R.sup. is C.sub.1-C.sub.6 aliphatic or a 3- to 6-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. In some embodiments, R.sup.2 is CH.sub.2OCH.sub.3. In some embodiments, R.sup.2 is CH.sub.2OCH.sub.2CH.sub.3. In some embodiments, R.sup.2 is CH.sub.2CF.sub.2CH.sub.3. In some embodiments, R.sup.2 is C.sub.1-C.sub.6 aliphatic optionally substituted with (CH.sub.2).sub.0-4N(R.sup.).sub.2. In some embodiments, R.sup.2 is C.sub.1-C.sub.6 aliphatic optionally substituted with (CH.sub.2).sub.0-4N(R.sup.).sub.2, where R.sup. is hydrogen, C.sub.1-6 aliphatic or a 3- to 6-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. In some embodiments, R.sup.2 is C.sub.1-C.sub.6 aliphatic optionally substituted with R.sup., where R.sup. is C.sub.1-6 aliphatic or a 3- to 6-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. In some embodiments, R.sup.2 is C.sub.1-C.sub.6 aliphatic optionally substituted with R.sup., where R.sup. is 3- to 6-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. In some embodiments, R.sup.2 is C.sub.1-C.sub.6 aliphatic optionally substituted with R.sup., where R.sup. is phenyl.

[0182] In some embodiments, R.sup.2 is optionally substituted C.sub.5-C.sub.12 aryl. In some embodiments, R.sup.2 is optionally substituted C.sub.5-C.sub.6 aryl. In some embodiments, R.sup.2 is C.sub.5-C.sub.6 aryl optionally substituted with halo, (CH.sub.2).sub.0-4R.sup., (CH.sub.2).sub.0-4OR.sup., or O(CH.sub.2).sub.0-4R.sup.. In some embodiments, R.sup.2 is C.sub.5-C.sub.6 aryl substituted with halo. In some embodiments, R.sup.2 is phenyl. In some embodiments, R.sup.2 is phenyl substituted with halo.

[0183] In some embodiments, R.sup.2 is 3- to 12-membered heterocyclyl comprising 1 to 3 heteroatoms selected from N, O, and S. In some embodiments, R.sup.2 is optionally substituted 3- to 12-membered heterocyclyl comprising 1 to 3 heteroatoms selected from N, O, and S. In some embodiments, R.sup.2 is optionally substituted monocyclic 3- to 7-membered heterocyclyl comprising 1 to 3 heteroatoms selected from N, O, and S. In some embodiments, R.sup.2 is monocyclic 3- to 7-membered heterocyclyl comprising 1 to 3 heteroatoms selected from N, O, and S optionally substituted with halogen, (CH.sub.2).sub.0-4R.sup., (CH.sub.2).sub.0-4OR.sup., or O(CH.sub.2).sub.0-4R.sup.. In some embodiments, R.sup.2 is monocyclic 3- to 7-membered heterocyclyl comprising 1 to 3 heteroatoms selected from N, O, and S optionally substituted with halogen, (CH.sub.2).sub.0-4R.sup., (CH.sub.2).sub.0-4OR.sup., or O(CH.sub.2).sub.0-4R.sup.. In some embodiments, R.sup.2 is optionally substituted monocyclic 3-membered heterocyclyl comprising 1 to 3 heteroatoms selected from N, O, and S. In some embodiments, R.sup.2 is optionally substituted monocyclic 4-membered heterocyclyl comprising 1 to 3 heteroatoms selected from N, O, and S. In some embodiments, R.sup.2 is optionally substituted monocyclic 5-membered heterocyclyl comprising 1 to 3 heteroatoms selected from N, O, and S. In some embodiments, R.sup.2 is optionally substituted monocyclic 6-membered heterocyclyl comprising 1 to 3 heteroatoms selected from N, O, and S. In some embodiments, R.sup.2 is optionally substituted monocyclic 7-membered heterocyclyl comprising 1 to 3 heteroatoms selected from N, O, and S.

[0184] In some embodiments, each R.sup.2 is selected from F, Br, C.sub.1, CN, OCH.sub.3, CH.sub.2CF.sub.3, CF.sub.3, NH.sub.2, CH.sub.2OCH.sub.3, CH.sub.2OCH.sub.2CH.sub.3, CH.sub.2CF.sub.2CH.sub.3, CH.sub.3, OH, oxo,

##STR00027## ##STR00028## ##STR00029## ##STR00030## ##STR00031## ##STR00032##

[0185] As defined generally above, each R.sup.2a and each R.sup.2b are independently selected from H and an optionally substituted group selected from C.sub.1-C.sub.6 aliphatic, C.sub.3-C.sub.12 cycloaliphatic, C.sub.0-C.sub.14 aryl, 5- to 12-membered heteroaryl comprising 1 to 4 heteroatoms selected from N, O, and S, and 3- to 12-membered heterocyclyl comprising 1 to 3 heteroatoms selected from N, O, and S.

[0186] As defined generally above, each R.sup.5 is independently selected from hydrogen, halo, CN, and optionally substituted C.sub.1-C.sub.6 aliphatic. In some embodiments, R.sup.1 is hydrogen. In some embodiments, R.sup.5 is halo. In some embodiments, R.sup.5 is CN. In some embodiments, R.sup.5 is optionally substituted C.sub.1-C.sub.6 aliphatic. In some embodiments, R.sup.8 is C.sub.1-C.sub.6 aliphatic optionally substituted with halogen, (CH.sub.2).sub.0-4R.sup., (CH.sub.2).sub.0-4OR.sup., or O(CH.sub.2).sub.0-4R.sup.. In some embodiments, R.sup.5 is methyl, ethyl, propyl, or butyl. In some embodiments, R.sup.5 is methyl.

[0187] As defined generally above, R.sup.8 is selected from H and optionally substituted C.sub.1-C.sub.6 aliphatic. In some embodiments, R.sup.8 is H. In some embodiments, R.sup.8 is C.sub.1-C.sub.6 aliphatic. In some embodiments, R.sup.8 is methyl.

[0188] As defined generally above, n is 0 or 1. In some embodiments, n is 0. In some embodiments, n is 1.

[0189] As defined generally above, m is 0 to 4. In some embodiments, m is 0, 1, 2, 3, or 4. In some embodiments, m is 0. In some embodiments, m is 1. In some embodiments, m is 2. In some embodiments, m is 3. In some embodiments, m is 4.

[0190] As defined generally above, p is 0 to 4. In some embodiments, p is 0, 1, 2, 3, or 4. In some embodiments, p is 0. In some embodiments, p is 1. In some embodiments, p is 2. In some embodiments, p is 3. In some embodiments, p is 4.

[0191] As defined generally above, q is 1 or 2. In some embodiments, q is 1. In some embodiments, q is 2.

[0192] In some embodiments, q is 1 and n is 0 or 1. In some embodiments, q is 1 and n is 0, and a compound of formula I is:

##STR00033##

wherein R.sup.1, L, Y.sup.1, Y.sup.2, A, and B are as defined herein and above.

[0193] In some embodiments, q is 1 and n is 1, and a compound of formula I is:

##STR00034## [0194] wherein R.sup.1, L, Y.sup.1, Y.sup.2, X, A, and B are as defined herein and above.

[0195] In some embodiments, q is 2, and n is 0, and a compound of formula I is:

##STR00035##

wherein R.sup.1, L, Y.sup.1, Y.sup.2, A, and B are as defined herein and above.

[0196] As provided herein, the present disclosure provides and/or utilizes TRMPL1 modulators that are small molecule compounds having a chemical structure as indicated below in Formula Ia:

##STR00036## [0197] or a pharmaceutically acceptable salt thereof, wherein [0198] X, n, A, L, and R.sup.1 are as defined generally herein, and [0199] each of X.sup.a, X.sup.b, X.sup.c, and X.sup.d are independently selected from N and CR.sup.6; and [0200] each R.sup.6 is H, halo, CN, OC.sub.1-C.sub.6 aliphatic, or an optionally substituted C.sub.1-C.sub.6 aliphatic.

[0201] In some embodiments, the present disclosure provides and/or utilizes TRMPL1 modulators that are small molecule compounds having a chemical structure as indicated below in Formula Ia:

##STR00037##

or a pharmaceutically acceptable salt thereof, wherein [0202] X is NR.sup.5, C(R.sup.5).sub.2, C(O), or O; [0203] each of X.sup.a, X.sup.b, X.sup.c, and X.sup.d are independently selected from N and CR.sup.6; [0204] L is an optionally substituted group selected from C.sub.0-C.sub.6 alkylenyl-S(O).sub.2, S(O).sub.2C.sub.0-C.sub.6 alkylenyl, S(O)C.sub.0-C.sub.6 alkylenyl, C.sub.0-C.sub.6 alkylenyl-S(O), C(O)C.sub.0-C.sub.6 alkylenyl, C(O)OC.sub.0-C.sub.6 alkylenyl, C(O)N(R.sup.8)C.sub.0-C.sub.6 alkylenyl, C.sub.1-C.sub.6 alkylenyl, and C.sub.3-C.sub.6 cycloalkylenyl; [0205] A is C.sub.3-C.sub.12 cycloaliphatic or 3- to 12-membered heterocyclyl comprising 1 to 3 heteroatoms selected from N, O, and S, wherein A is substituted with (R.sup.2).sub.m; [0206] R.sup.1 is selected from C.sub.1-C.sub.6 aliphatic, C.sub.3-C.sub.12 cycloaliphatic, C.sub.5-C.sub.12 aryl, 5- to 12-membered heteroaryl comprising 1 to 3 heteroatoms selected from N, O, and S, and 3- to 12-membered heterocyclyl comprising 1 to 3 heteroatoms selected from N, O, and S, wherein R.sup.1 is substituted with (R.sup.3).sub.p: [0207] each R.sup.2 is independently halo, oxo, NR.sup.2aR.sup.2b, C(O)OR.sup.2a, OC(O)R.sup.2a, S(O).sub.2, S(O).sub.2R.sup.2a, C(O)NR.sup.2aR.sup.2b, N(R.sup.2a)C(O)R.sup.2b, C(O)R.sup.2a, OR.sup.2a, OC(O)NR.sup.2aR.sup.2b, NHC(O)NR.sup.2aR.sup.2b, NHC(O)OR.sup.2a, NHS(O).sub.2R.sup.2a, C.sub.1-C.sub.6 alkylenyl-C(O)NR.sup.2aR.sup.2b or an optionally substituted group selected from C.sub.1-C.sub.6 aliphatic, C.sub.5-C.sub.12 aryl, and 3- to 12-membered heterocyclyl comprising 1 to 3 heteroatoms selected from N, O, and S; [0208] each R.sup.2a and each R.sup.2b are independently selected from H and an optionally substituted group selected from C.sub.1-C.sub.6 aliphatic, C.sub.3-C.sub.12 cycloaliphatic, C.sub.5-C.sub.14 aryl, 5- to 12-membered heteroaryl comprising 1 to 4 heteroatoms selected from N, O, and S, and 3- to 12-membered heterocyclyl comprising 1 to 3 heteroatoms selected from N, O, and S; [0209] each R.sup.3 is independently halo, S(O).sub.2NR.sup.3aR.sup.3b, S(O).sub.2R.sup.3b, S(O)(NR.sup.3c)R.sup.3b, S(NR.sup.3cO)NR.sup.3aR.sup.3b, S(O)R.sup.3b, NR.sup.3aS(O).sub.2R.sup.3b, OR.sup.3a, C(O)R.sup.3a, C(O)NHR.sup.3a, oxo, or an optionally substituted group selected from C.sub.1-C.sub.6 aliphatic, C.sub.5-C.sub.12 aryl, C.sub.3-C.sub.12 cycloaliphatic, 5- to 12-membered heteroaryl comprising 1 to 3 heteroatoms selected from N, O, and S, and 3- to 12-membered heterocyclyl comprising 1 to 3 heteroatoms selected from N, O, and S; [0210] R.sup.3a and R.sup.3b are each independently selected from H and optionally substituted C.sub.1-C.sub.6 aliphatic, or R.sup.3a and R.sup.3b come together with the atoms to which they are attached to form optionally substituted C.sub.3-C.sub.12 cycloaliphatic or 3- to 12-membered heterocyclyl comprising 1 to 4 heteroatoms selected from N, O, and S; [0211] each R.sup.3c is independently selected from H, OH, and optionally substituted C.sub.1-C.sub.6 aliphatic; [0212] each R.sup.5 is independently selected from hydrogen, halo, CN, and optionally substituted C.sub.1-C.sub.6 aliphatic; [0213] R.sup.8 is selected from H and optionally substituted C.sub.1-C.sub.6 aliphatic; [0214] each R.sup.6 is H, halo, CN, OC.sub.1-C.sub.6 aliphatic, or an optionally substituted C.sub.1-C.sub.6 aliphatic; [0215] n is 0 or 1, [0216] m is 0 to 4; and [0217] p is 0 to 4.

[0218] As described generally above, in some embodiments, each of X.sup.a, X.sup.b, X.sup.c, and X.sup.d are independently selected from N and CR.sup.6. In some embodiments, X.sup.a, X.sup.b, X.sup.c, and X.sup.d are each CR.sup.6. In some embodiments, X.sup.a, X.sup.b, X.sup.c, and X.sup.d are each CH. In some embodiments, X.sup.a, X.sup.b, and X.sup.c are each CR.sup.6, and X.sup.d is N. In some embodiments, X.sup.a, X.sup.b, and X.sup.d are each CR.sup.6, and X.sup.c is N. In some embodiments, X.sup.a, X, and X.sup.d are each CR.sup.6, and X.sup.b is N. In some embodiments, X.sup.b, X.sup.c, and X.sup.d are each CR.sup.6, and X.sup.a is N. In some embodiments, X.sup.a and X.sup.b, are each CR.sup.6, and X.sup.c and X.sup.d are each N. In some embodiments, X.sup.a and X.sup.c, are each CR.sup.6, and X.sup.b and X.sup.d are each N. In some embodiments, X.sup.a and X.sup.d, are each CR.sup.6, and X.sup.b and X.sup.c are each N. In some embodiments, X.sup.b and X.sup.c, are each CR.sup.6, and X.sup.a and X.sup.d are each N. In some embodiments, X and X.sup.d, are each CR.sup.6, and X.sup.a and X.sup.b are each N.

[0219] As described generally above, in some embodiments, each R.sup.6 is H, halo, CN, OC.sub.1-C.sub.6 aliphatic, or an optionally substituted C.sub.1-C.sub.6 aliphatic. In some embodiments, R.sup.6 is H or halo. In some embodiments, R.sup.6 is H. In some embodiments, R.sup.6 is halo (e.g., fluoro, chloro, bromo, iodo). In some embodiments, R.sup.6 is CN. In some embodiments, R.sup.6 is OC.sub.1-C.sub.6 aliphatic. In some embodiments, R.sup.6 is OCH.sub.3. In some embodiments, R.sup.6 is optionally substituted C.sub.1-C.sub.6 aliphatic. In some embodiments, R.sup.6 is C.sub.1-C.sub.6 aliphatic optionally substituted with halo. In some embodiments, R.sup.6 is CH.sub.3 or CF.sub.3. In some embodiments, R.sup.6 is CH.sub.3. In some embodiments, R.sup.6 is CF.sub.3.

[0220] As provided herein, the present disclosure provides and/or utilizes TRMPL1 modulators that are small molecule compounds having a chemical structure as indicated below in Formula Ib:

##STR00038## [0221] or a pharmaceutically acceptable salt thereof, wherein [0222] X, n, A, L, R.sup.1, Y.sup.1, and Y.sup.2 are as defined generally herein, and [0223] each of X.sup.e, X.sup.f, and X.sup.g are independently selected from S, N, O, and CR.sup.7; and [0224] each R.sup.7 is H, halo, CN, OC.sub.1-C.sub.6 aliphatic, or an optionally substituted group selected from C.sub.1-C.sub.6 aliphatic and C.sub.3-C.sub.6 cycloaliphatic.

[0225] In some embodiments, the present disclosure provides and/or utilizes TRMPL1 modulators that are small molecule compounds having a chemical structure as indicated below in Formula Ib:

##STR00039##

or a pharmaceutically acceptable salt thereof, wherein [0226] X is NR.sup.5, C(R.sup.5).sub.2, C(O), or O; [0227] each of X.sup.e, X.sup.f, and X.sup.g are independently selected from S, N, O, and CR.sup.7; [0228] each of Y.sup.1 and Y.sup.2 is independently selected from N and C; [0229] L is an optionally substituted group selected from C.sub.0-C.sub.6 alkylenyl-S(O).sub.2, S(O).sub.2C.sub.0-C.sub.6 alkylenyl, S(O)C.sub.0-C.sub.6 alkylenyl, C.sub.0-C.sub.6 alkylenyl-S(O), C(O)C.sub.0-C.sub.6 alkylenyl, C(O)OC.sub.0-C.sub.6 alkylenyl, C(O)N(R.sup.8)C.sub.0-C.sub.6 alkylenyl, C.sub.1-C.sub.6 alkylenyl, and C.sub.3-C.sub.6 cycloalkylenyl; [0230] A is C.sub.3-C.sub.12 cycloaliphatic or 3- to 12-membered heterocyclyl comprising 1 to 3 heteroatoms selected from N, O, and S, wherein A is substituted with (R.sup.2).sub.m; [0231] R.sup.1 is selected from C.sub.1-C.sub.6 aliphatic, C.sub.3-C.sub.12 cycloaliphatic, C.sub.5-C.sub.12 aryl, 5- to 12-membered heteroaryl comprising 1 to 3 heteroatoms selected from N, O, and S, and 3- to 12-membered heterocyclyl comprising 1 to 3 heteroatoms selected from N, O, and S, wherein R.sup.1 is substituted with (R.sup.3).sub.p; [0232] each R.sup.2 is independently halo, oxo, NR.sup.2aR.sup.2b, C(O)OR.sup.2a, OC(O)R.sup.2a, S(O).sub.2, S(O).sub.2R.sup.2a, C(O)NR.sup.2aR.sup.2b, N(R.sup.2a)C(O)R.sup.2b, C(O)R.sup.2a, OR.sup.2a, OC(O)NR.sup.2R.sup.2b, NHC(O)NR.sup.2aR.sup.2b, NHC(O)OR.sup.2a, NHS(O).sub.2R.sup.2a, C.sub.1-C.sub.6 alkylenyl-C(O)NR.sup.2aR.sup.2b or an optionally substituted group selected from C.sub.1-C.sub.6 aliphatic, C.sub.5-C.sub.12 aryl, and 3- to 12-membered heterocyclyl comprising 1 to 3 heteroatoms selected from N, O, and S, each R.sup.2a and each R.sup.2b are independently selected from H and an optionally substituted group selected from C.sub.1-C.sub.6 aliphatic, C.sub.3-C.sub.12cycloaliphatic, C.sub.5-C.sub.14 aryl, 5- to 12-membered heteroaryl comprising 1 to 4 heteroatoms selected from N, O, and S, and 3- to 12-membered heterocyclyl comprising 1 to 3 heteroatoms selected from N, O, and S; [0233] each R.sup.3 is independently halo, S(O).sub.2NR.sup.3aR.sup.3b, S(O).sub.2R.sup.35, S(NR.sup.3c)(O)NR.sup.3aR.sup.3b, S(O)(NR.sup.3c)R.sup.3b, S(O)R.sup.3b, NR.sup.3a, S(O).sub.2R.sup.3b, OR.sup.3a, C(O)R.sup.3a, C(O)NHR.sup.3a, oxo, or an optionally substituted group selected from C.sub.1-C.sub.6 aliphatic, C.sub.5-C.sub.12 aryl, C.sub.3-C.sub.12 cycloaliphatic, 5- to 12-membered heteroaryl comprising 1 to 3 heteroatoms selected from N, O, and S, and 3- to 12-membered heterocyclyl comprising 1 to 3 heteroatoms selected from N, O, and S; [0234] R.sup.3a and R.sup.3b are each independently selected from H and optionally substituted C.sub.1-C.sub.6 aliphatic, or R.sup.3a and R.sup.3b come together with the atoms to which they are attached to form optionally substituted C.sub.3-C.sub.12 cycloaliphatic or 3- to 12-membered heterocyclyl comprising 1 to 4 heteroatoms selected from N, O, and S; [0235] each R.sup.3c is independently selected from H, OH, and optionally substituted C.sub.1-C.sub.6 aliphatic; [0236] each R.sup.5 is independently selected from hydrogen, halo, CN, and optionally substituted C.sub.1-C.sub.6 aliphatic, [0237] each R.sup.7 is H, halo, CN, OC.sub.1-C.sub.6 aliphatic, or an optionally substituted group selected from C.sub.1-C.sub.6 aliphatic and C.sub.3-C.sub.6 cycloaliphatic; [0238] R.sup.8 is selected from H and optionally substituted C.sub.1-C.sub.6 aliphatic; [0239] n is 0 or 1; [0240] m is 0 to 4; and p is 0 to 4.

[0241] As described generally above, in some embodiments, each of X.sup.e, X.sup.f, and X.sup.g are independently selected from S, N, O, and CR.sup.7. In some embodiments, each of X.sup.e, X.sup.f, and X.sup.g are CR.sup.7. In some embodiments, each of X.sup.e, X.sup.f, and X.sup.g are independently selected from S and CR.sup.7. In some embodiments, each of X.sup.e, X.sup.f, and X.sup.g are independently selected from N and CR.sup.7.

[0242] As described generally above, in some embodiments, each R.sup.7 is H, halo, CN, OC.sub.1-C.sub.6 aliphatic, or an optionally substituted C.sub.1-C.sub.6 aliphatic. In some embodiments, R.sup.1 is H or halo. In some embodiments, R.sup.7 is H. In some embodiments, R.sup.7 is halo (e.g., fluoro, chloro, bromo, iodo). In some embodiments, R.sup.7 is CN. In some embodiments, R.sup.7 is OC.sub.1-C.sub.6 aliphatic. In some embodiments, R.sup.1 is OCH.sub.3. In some embodiments, R.sup.7 is an optionally substituted group selected from C.sub.1-C.sub.6 aliphatic and C.sub.3-C.sub.6 cycloaliphatic. In some embodiments, R.sup.7 is optionally substituted C.sub.1-C.sub.6 aliphatic. In some embodiments, R.sup.1 is C.sub.1-C.sub.6 aliphatic optionally substituted with halo. In some embodiments, R.sup.7 is CH.sub.3 or CF.sub.3. In some embodiments, R.sup.7 is CH.sub.3. In some embodiments, R.sup.1 is CF.sub.3. In some embodiments, R.sup.7 is optionally substituted C.sub.3-C.sub.6 cycloaliphatic.

[0243] In some embodiments, the present disclosure provides compounds of Formula Ic:

##STR00040##

or a pharmaceutically acceptable salt thereof, wherein: [0244] each of X.sup.a, X.sup.b, X.sup.c, and X.sup.d are independently selected from N and CR.sup.6; L is an optionally substituted group selected from C.sub.0-C.sub.6 alkylenyl-S(O).sub.2, S(O).sub.2C.sub.0-C.sub.6 alkylenyl, S(O)C.sub.0-C.sub.6 alkylenyl, C.sub.0-C.sub.6 alkylenyl-S(O), C(O)C.sub.0-C.sub.6 alkylenyl, C(O)OC.sub.0-C.sub.6 alkylenyl, C(O)N(R.sup.5)C.sub.0-C.sub.6 alkylenyl, C.sub.1-C.sub.6 alkylenyl, and C.sub.3-C.sub.6 cycloalkylenyl; [0245] R.sup.1 is selected from C.sub.1-C.sub.6 aliphatic, C.sub.3-C.sub.12 cycloaliphatic, C.sub.5-C.sub.12 aryl, 5- to 12-membered heteroaryl comprising 1 to 3 heteroatoms selected from N, O, and S, and 3- to 12-membered heterocyclyl comprising 1 to 3 heteroatoms selected from N, O, and S, wherein R.sup.1 is substituted with (R.sup.3).sub.p; [0246] each R.sup.2 is independently halo, oxo, NR.sup.2aR.sup.2b, C(O)OR.sup.2a, OC(O)R.sup.2a, S(O).sub.2, S(O).sub.2R.sup.2a, C(O)NR.sup.2aR.sup.2b, N(R.sup.2a)C(O)R.sup.2b, C(O)R.sup.2a, OR.sup.2a, OC(O)NR.sup.2aR.sup.2b, NHC(O)NR.sup.2aR.sup.2b, NHC(O)OR.sup.2a, NHS(O).sub.2R.sup.2a, C.sub.1-C.sub.6 alkylenyl-C(O)NR.sup.2bR.sup.2b or an optionally substituted group selected from C.sub.1-C.sub.6 aliphatic, C.sub.5-C.sub.12 aryl, and 3- to 12-membered heterocyclyl comprising 1 to 3 heteroatoms selected from N, O, and S; [0247] each R.sup.2a and each R.sup.2b are independently selected from H and an optionally substituted group selected from C.sub.1-C.sub.6 aliphatic, C.sub.3-C.sub.12cycloaliphatic, C.sub.5-C.sub.14 aryl, 5- to 12-membered heteroaryl comprising 1 to 4 heteroatoms selected from N, O, and S, and 3- to 12-membered heterocyclyl comprising 1 to 3 heteroatoms selected from N, O, and S; [0248] each R.sup.3 is independently halo, S(O).sub.2NR.sup.3aR.sup.3b, S(O).sub.2R.sup.35, S(O)(NR.sup.3c)R.sup.3b, S(NR.sup.3)(O)NR.sup.3aR.sup.3b, S(O)R.sup.3b, NR.sup.3a, S(O).sub.2R.sup.3b, OR.sup.3a, C(O)R.sup.3a, C(O)NHR.sup.3, oxo, or an optionally substituted group selected from C.sub.1-C.sub.6 aliphatic, C.sub.5-C.sub.12 aryl, C.sub.3-C.sub.12 cycloaliphatic, 5- to 12-membered heteroaryl comprising 1 to 3 heteroatoms selected from N, O, and S, and 3- to 12-membered heterocyclyl comprising 1 to 3 heteroatoms selected from N, O, and S; [0249] R.sup.3a and R.sup.3b are each independently selected from H and optionally substituted C.sub.1-C.sub.6 aliphatic, or R.sup.3a and R.sup.3b come together with the atoms to which they are attached to form optionally substituted C.sub.3-C.sub.12 cycloaliphatic or 3- to 12-membered heterocyclyl comprising 1 to 4 heteroatoms selected from N, O, and S; [0250] each R.sup.3 is independently selected from H, OH, and optionally substituted C.sub.1-C.sub.6 aliphatic; R.sup.8 is selected from H and optionally substituted C.sub.1-C.sub.6 aliphatic; [0251] each R.sup.6 is H, halo, CN, OC.sub.1-C.sub.6 aliphatic, or an optionally substituted C.sub.1-C.sub.6 aliphatic; and [0252] p is 0 to 4.

[0253] In some embodiments, the present disclosure provides compounds of Formula II:

##STR00041##

or a pharmaceutically acceptable salt thereof, wherein L, R.sup.1, and A are as defined generally and herein.

[0254] In some embodiments, the present disclosure provides compounds of Formula IIa:

##STR00042##

or a pharmaceutically acceptable salt thereof, wherein L, R.sup.1, R.sup.2, and m are as defined generally and herein.

[0255] In some embodiments, the present disclosure provides compounds of Formula IIIa:

##STR00043## [0256] or a pharmaceutically acceptable salt thereof, wherein [0257] L is an optionally substituted group selected from C.sub.0-C.sub.6 alkylenyl-S(O).sub.2, S(O).sub.2C.sub.0-C.sub.6 alkylenyl, S(O)C.sub.0-C.sub.6 alkylenyl, C.sub.0-C.sub.6 alkylenyl-S(O), C(O)C.sub.0-C.sub.6 alkylenyl, C(O)OC.sub.0-C.sub.6 alkylenyl, C(O)N(R.sup.8)C.sub.0-C.sub.6 alkylenyl, C.sub.1-C.sub.6 alkylenyl, and C.sub.3-C.sub.6 cycloalkylenyl; [0258] R.sup.1 is selected from C.sub.3-C.sub.12 cycloaliphatic, 5- to 12-membered heteroaryl comprising 1 to 3 heteroatoms selected from N, O, and S, and 3- to 12-membered heterocyclyl comprising 1 to 3 heteroatoms selected from N, O, and S, wherein R.sup.1 is substituted with (R.sup.3).sub.p; [0259] each R.sup.2 is independently halo, oxo, NR.sup.2aR.sup.2b, C(O)OR.sup.2a, OC(O)R.sup.2a, S(O).sub.2, S(O).sub.2R.sup.2, C(O)NR.sup.2aR.sup.2b, N(R.sup.2a)C(O)R.sup.2b, C(O)R.sup.2a, OR.sup.2a, OC(O)NR.sup.2aR.sup.2b, NHC(O)NR.sup.2aR.sup.2b, NHC(O)OR.sup.2a, NHS(O).sub.2R.sup.2a, C.sub.1-C.sub.6 alkylenyl-C(O)NR.sup.2aR.sup.2b or an optionally substituted group selected from C.sub.1-C.sub.6 aliphatic, C.sub.5-C.sub.12 aryl, and 3- to 12-membered heterocyclyl comprising 1 to 3 heteroatoms selected from N, O, and S; [0260] each R.sup.2a and each R.sup.2b are independently selected from H and an optionally substituted group selected from C.sub.1-C.sub.6 aliphatic, C.sub.3-C.sub.12 cycloaliphatic, C.sub.5-C.sub.14 aryl, 5- to 12-membered heteroaryl comprising 1 to 4 heteroatoms selected from N, O, and S, and 3- to 12-membered heterocyclyl comprising 1 to 4 heteroatoms selected from N, O, and S; [0261] each R.sup.3 is independently halo, S(O).sub.2NR.sup.3aR.sup.3b, S(O).sub.2R.sup.3b, S(NR.sup.3a)(O)NR.sup.3aR.sup.3b, S(O)(NR.sup.3C)R.sup.3b, S(O)R.sup.3b, NR.sup.3aS(O).sub.2R.sup.3b, OR.sup.3a, C(O)R.sup.3a, C(O)NHR.sup.3a, oxo, or an optionally substituted group selected from C.sub.1-C.sub.6 aliphatic, C.sub.5-C.sub.12 aryl, C.sub.3-C.sub.12 cycloaliphatic, 5- to 12-membered heteroaryl comprising 1 to 3 heteroatoms selected from N, O, and S, and 3- to 12-membered heterocyclyl comprising 1 to 3 heteroatoms selected from N, O, and S; [0262] R.sup.3a and R.sup.3b are each independently selected from H and optionally substituted C.sub.1-C.sub.6 aliphatic, or R.sup.3a and R.sup.3b come together with the atoms to which they are attached to form optionally substituted C.sub.3-C.sub.12 cycloaliphatic or 3- to 12-membered heterocyclyl comprising 1 to 4 heteroatoms selected from N, O, and S; [0263] each R.sup.3c is independently selected from H, OH, and optionally substituted C.sub.1-C.sub.6 aliphatic; [0264] R.sup.8 is selected from H and optionally substituted C.sub.1-C.sub.6 aliphatic; [0265] m is 0 to 4; and [0266] p is 0 to 4.

[0267] In some embodiments, the present disclosure provides compounds of Formula IIIb:

##STR00044##

or a pharmaceutically acceptable salt thereof, wherein L, R.sup.1, R.sup.2, and m are as defined generally and herein.

[0268] In some embodiments, the present disclosure provides compounds of Formula IIIb:

##STR00045## [0269] or a pharmaceutically acceptable salt thereof, wherein [0270] L is an optionally substituted group selected from C.sub.0-C.sub.6 alkylenyl-S(O).sub.2, S(O).sub.2C.sub.0-C.sub.6 alkylenyl, S(O)C.sub.0-C.sub.6 alkylenyl, C.sub.0-C.sub.6 alkylenyl-S(O), C(O)C.sub.0-C.sub.6 alkylenyl, C(O)OC.sub.0-C.sub.6 alkylenyl, C(O)N(R.sup.8)C.sub.0-C.sub.6 alkylenyl, C.sub.1-C.sub.6 alkylenyl, and C.sub.3-C.sub.6 cycloalkylenyl; [0271] R.sup.1 is selected from C.sub.3-C.sub.12 cycloaliphatic, 5- to 12-membered heteroaryl comprising 1 to 3 heteroatoms selected from N, O, and S, and 3- to 12-membered heterocyclyl comprising 1 to 3 heteroatoms selected from N, O, and S, wherein R.sup.1 is substituted with (R.sup.3).sub.p; [0272] each R.sup.2 is independently halo, oxo, NR.sup.2aR.sup.2b, C(O)OR.sup.2a, OC(O)R.sup.2a, S(O).sub.2, S(O).sub.2R.sup.2a, C(O)NR.sup.2aR.sup.2b, N(R.sup.2a)C(O)R.sup.2b, C(O)R.sup.2a, OR.sup.2a, OC(O)NR.sup.2aR.sup.2b, NHC(O)NR.sup.2aR.sup.2b, NHC(O)OR.sup.2a, NHS(O).sub.2R.sup.2a, C.sub.1-C.sub.6 alkylenyl-C(O)NR.sup.2aR.sup.2b or an optionally substituted group selected from C.sub.1-C.sub.6 aliphatic, C.sub.5-C.sub.2 aryl, and 3- to 12-membered heterocyclyl comprising 1 to 3 heteroatoms selected from N, O, and S; [0273] each R.sup.2a and each R.sup.2b are independently selected from H and an optionally substituted group selected from C.sub.1-C.sub.6 aliphatic, C.sub.3-C.sub.12 cycloaliphatic, C.sub.5-C.sub.14 aryl, 5- to 12-membered heteroaryl comprising 1 to 4 heteroatoms selected from N, O, and S, and 3- to 12-membered heterocyclyl comprising 1 to 4 heteroatoms selected from N, O, and S; [0274] each R.sup.3 is independently halo, S(O).sub.2NR.sup.3aR.sup.3b, S(O).sub.2R.sup.3b, S(NR.sup.3c)(O)NR.sup.3aR.sup.3b, S(O)(NR.sup.3c)R.sup.3b, S(O)R.sup.3b, NR.sup.3a_S(O).sub.2R.sup.3b, OR.sup.3a, C(O)R.sup.3a, C(O)NHR.sup.3a, oxo, or an optionally substituted group selected from C.sub.1-C.sub.6 aliphatic, C.sub.5-C.sub.12 aryl, C.sub.3-C.sub.12 cycloaliphatic, 5- to 12-membered heteroaryl comprising 1 to 3 heteroatoms selected from N, O, and S, and 3- to 12-membered heterocyclyl comprising 1 to 3 heteroatoms selected from N, O, and S; R.sup.3a and R.sup.3b are each independently selected from H and optionally substituted C.sub.1-C.sub.6 aliphatic, or R.sup.3a and R.sup.3b come together with the atoms to which they are attached to form optionally substituted C.sub.3-C.sub.12 cycloaliphatic or 3- to 12-membered heterocyclyl comprising 1 to 4 heteroatoms selected from N, O, and S; [0275] each R.sup.3c is independently selected from H, OH, and optionally substituted C.sub.1-C.sub.6 aliphatic; [0276] R.sup.8 is selected from H and optionally substituted C.sub.1-C.sub.6 aliphatic; [0277] m is 0 to 4; and [0278] p is 0 to 4.

[0279] In some embodiments, the present disclosure provides compounds of Formula IVa:

##STR00046##

or a pharmaceutically acceptable salt thereof, wherein A, L, R.sup.3, and p are as defined generally and herein.

[0280] In some embodiments, the present disclosure provides compounds of Formula IVa:

##STR00047## [0281] or a pharmaceutically acceptable salt thereof, wherein [0282] L is an optionally substituted group selected from C.sub.0-C.sub.6 alkylenyl-S(O).sub.2, S(O).sub.2C.sub.0-C.sub.6 alkylenyl, S(O)C.sub.0-C.sub.6 alkylenyl, C.sub.0-C.sub.6 alkylenyl-S(O), C(O)C.sub.0-C.sub.6 alkylenyl, C(O)OC.sub.0-C.sub.6 alkylenyl, C(O)N(R.sup.8)C.sub.0-C.sub.6 alkylenyl, C.sub.1-C.sub.6 alkylenyl, and C.sub.3-C.sub.6 cycloalkylenyl; [0283] A is C.sub.3-C.sub.12 cycloaliphatic or 3- to 12-membered heterocyclyl comprising 1 to 3 heteroatoms selected from N, O, and S, wherein A is substituted with (R.sup.2).sub.m; [0284] each R.sup.2 is independently halo, oxo, NR.sup.2aR.sup.2b, C(O)OR.sup.23, OC(O)R.sup.2a, S(O).sub.2, S(O).sub.2R.sup.2a, C(O)NR.sup.2aR.sup.2b, N(R.sup.2a)C(O)R.sup.2b, C(O)R.sup.2a, OR.sup.2a, OC(O)NR.sup.2aR.sup.2b, NHC(O)NR.sup.2aR.sup.2b, NHC(O)OR.sup.2a, NHS(O).sub.2R.sup.2a, C.sub.1-C.sub.6 alkylenyl-C(O)NR.sup.2aR.sup.2b or an optionally substituted group selected from C.sub.1-C.sub.6 aliphatic, C.sub.5-C.sub.12 aryl, and 3- to 12-membered heterocyclyl comprising 1 to 3 heteroatoms selected from N, O, and S; [0285] each R.sup.2a and each R.sup.2b are independently selected from H and an optionally substituted group selected from C.sub.1-C.sub.6 aliphatic, C.sub.3-C.sub.12 cycloaliphatic, C.sub.5-C.sub.14 aryl, 5- to 12-membered heteroaryl comprising 1 to 4 heteroatoms selected from N, O, and S, and 3- to 12-membered heterocyclyl comprising 1 to 4 heteroatoms selected from N, O, and S; [0286] each R.sup.3 is independently halo, S(O).sub.2NR.sup.3aR.sup.3b, S(O).sub.2R.sup.3b, S(NR.sup.3c)(O)NR.sup.3aR.sup.3b, S(O)(NR.sup.3c)R.sup.3b, S(O)R.sup.3b, NR.sup.3aS(O).sub.2R.sup.3b, OR.sup.3a, C(O)R.sup.3a, C(O)NHR 3a, oxo, or an optionally substituted group selected from C.sub.1-C.sub.6 aliphatic, C.sub.5-C.sub.12 aryl, C.sub.3-C.sub.12 cycloaliphatic, 5- to 12-membered heteroaryl comprising 1 to 3 heteroatoms selected from N, O, and S, and 3- to 12-membered heterocyclyl comprising 1 to 3 heteroatoms selected from N, O, and S; [0287] R.sup.3a and R.sup.3b are each independently selected from H and optionally substituted C.sub.1-C.sub.6 aliphatic, or R.sup.3a and R.sup.3b come together with the atoms to which they are attached to form optionally substituted C.sub.3-C.sub.12 cycloaliphatic or 3- to 12-membered heterocyclyl comprising 1 to 4 heteroatoms selected from N, O, and S; [0288] R.sup.8 is selected from H and optionally substituted C.sub.1-C.sub.6 aliphatic; [0289] m is 0 to 4; and [0290] p is 0 to 4.

[0291] In some embodiments, the present disclosure provides compounds of Formula IVb:

##STR00048##

or a pharmaceutically acceptable salt thereof, wherein A, L, R.sup.3, and p are as defined generally and herein.

[0292] In some embodiments, the present disclosure provides compounds of Formula IVb:

##STR00049## [0293] or a pharmaceutically acceptable salt thereof, wherein [0294] L is an optionally substituted group selected from C.sub.0-C.sub.6 alkylenyl-S(O).sub.2, S(O).sub.2C.sub.0-C.sub.6 alkylenyl, S(O)C.sub.0-C.sub.6 alkylenyl, C.sub.0-C.sub.6 alkylenyl-S(O), C(O)C.sub.0-C.sub.6 alkylenyl, C(O)OC.sub.0-C.sub.6 alkylenyl, C(O)N(R.sup.8)C.sub.0-C.sub.6 alkylenyl, C.sub.1-C.sub.6 alkylenyl, and C.sub.3-C.sub.6 cycloalkylenyl, [0295] A is C.sub.3-C.sub.12 cycloaliphatic or 3- to 12-membered heterocyclyl comprising 1 to 3 heteroatoms selected from N, O, and S, wherein A is substituted with (R.sup.2).sub.m; [0296] each R.sup.2 is independently halo, oxo, NR.sup.2aR.sup.2b, C(O)OR.sup.2a, OC(O)R.sup.2a, S(O).sub.2, S(O).sub.2R.sup.2a, C(O)NR.sup.2aR.sup.2b, N(R.sup.2a)C(O)R.sup.2b, C(O)R.sup.2, OR.sup.2a, OC(O)NR.sup.2aR.sup.2b, NHC(O)NR.sup.2aR.sup.2b, NHC(O)OR.sup.2a, NHS(O).sub.2R.sup.2a, C.sub.1-C.sub.6 alkylenyl-C(O)NR.sup.2aR.sup.2b or an optionally substituted group selected from C.sub.1-C.sub.6 aliphatic, C.sub.5-C.sub.12 aryl, and 3- to 12-membered heterocyclyl comprising 1 to 3 heteroatoms selected from N, O, and S; [0297] each R.sup.2a and each R.sup.2b are independently selected from H and an optionally substituted group selected from C.sub.1-C.sub.6 aliphatic, C.sub.3-C.sub.12cycloaliphatic, C.sub.5-C.sub.14 aryl, 5- to 12-membered heteroaryl comprising 1 to 4 heteroatoms selected from N, O, and S, and 3- to 12-membered heterocyclyl comprising 1 to 4 heteroatoms selected from N, O, and S; [0298] each R.sup.3 is independently halo, S(O).sub.2NR.sup.3aR.sup.3b, S(O).sub.2R.sup.3b, S(NR.sup.3c(O)NR.sup.3aR.sup.3b, S(O)(NR.sup.3c)R.sup.3b, S(O)R.sup.3b, NR.sup.3aS(O).sub.2R.sup.3b, OR.sup.3a, C(O)R.sup.3a, C(O)NHR.sup.3a, oxo, or an optionally substituted group selected from C.sub.1-C.sub.6 aliphatic, C.sub.5-C.sub.12 aryl, C.sub.3-C.sub.12 cycloaliphatic, 5- to 12-membered heteroaryl comprising 1 to 3 heteroatoms selected from N, O, and S, and 3- to 12-membered heterocyclyl comprising 1 to 3 heteroatoms selected from N, O, and S; [0299] R.sup.3a and R.sup.3b are each independently selected from H and optionally substituted C.sub.1-C.sub.6 aliphatic, or R.sup.3a and R.sup.3b come together with the atoms to which they are attached to form optionally substituted C.sub.3-C.sub.12 cycloaliphatic or 3- to 12-membered heterocyclyl comprising 1 to 4 heteroatoms selected from N, O, and S; [0300] R.sup.8 is selected from H and optionally substituted C.sub.1-C.sub.6 aliphatic; and [0301] m is 0 to 4.

[0302] In some embodiments, the present disclosure provides a compound, or a pharmaceutically acceptable salt thereof, selected from Table 1:

TABLE-US-00001 TABLE 1 Compound No. Structure I-1 [00050] I-2 [00051] I-3 [00052] I-4 [00053] I-5 [00054] I-6 [00055] I-7 [00056] I-8 [00057] I-9 [00058] I-10 [00059] I-11 [00060] I-12 [00061] I-13 [00062] I-14 [00063] I-15 [00064] I-16 [00065] I-17 [00066] I-18 [00067] I-19 [00068] I-20 [00069] I-21 [00070] I-22 [00071] I-23 [00072] I-24 [00073] I-25 [00074] I-26 [00075] I-27 [00076] I-28 [00077] I-29 [00078] I-30 [00079] I-31 [00080] I-32 [00081] I-33 [00082] I-34 [00083] I-35 [00084] I-36 [00085] I-37 [00086] I-38 [00087] I-39 [00088] I-40 [00089] I-41 [00090] I-42 [00091] I-43 [00092] I-44 [00093] I-45 [00094] I-46 [00095] I-47 [00096] I-48 [00097] I-49 [00098] I-50 [00099] I-51 [00100] I-52 [00101] I-53 [00102] I-54 [00103] I-55 [00104] I-56 [00105] I-57 [00106] I-58 [00107] I-59 [00108] I-60 [00109] I-61 [00110] I-62 [00111] I-63 [00112] I-64 [00113] I-65 [00114] I-66 [00115] I-67 [00116] I-68 [00117] I-69 [00118] I-70 [00119] I-71 [00120] I-72 [00121] I-73 [00122] I-74 [00123] I-75 [00124] I-76 [00125] I-77 [00126] I-78 [00127] I-79 [00128] I-80 [00129] I-81 [00130] I-82 [00131] I-83 [00132] I-84 [00133] I-85 [00134] I-86 [00135] I-87 [00136] I-88 [00137] I-89 [00138] I-90 [00139] I-91 [00140] I-92 [00141] I-93 [00142] I-94 [00143] I-95 [00144] I-96 [00145] I-97 [00146] I-98 [00147] I-99 [00148] I-100 [00149] I-101 [00150] I-102 [00151] I-103 [00152] I-104 [00153] I-105 [00154] I-106 [00155] I-114 [00156] I-115 [00157] I-116 [00158] I-117 [00159] I-118 [00160] I-119 [00161] I-120 [00162] I-121 [00163] I-122 [00164] I-123 [00165] I-124 [00166] I-125 [00167] I-126 [00168] I-127 [00169] I-128 [00170] I-129 [00171] I-130 [00172] I-131 [00173] I-132 [00174] I-133 [00175] I-134 [00176] I-135 [00177] I-136 [00178] I-137 [00179] I-138 [00180] I-139 [00181] I-140 [00182] I-141 [00183] I-142 [00184] I-143 [00185] I-144 [00186] I-145 [00187] I-146 [00188] I-147 [00189] I-148 [00190] I-149 [00191] I-150 [00192] I-151 [00193] I-152 [00194] I-153 [00195] I-154 [00196] I-155 [00197] I-157 [00198] I-158 [00199] I-159 [00200] I-160 [00201] I-161 [00202] I-162 [00203] I-163 [00204] I-164 [00205] I-165 [00206] I-166 [00207] I-167 [00208] I-168 [00209] I-169 [00210] I-170 [00211] I-171 [00212] I-172 [00213] I-173 [00214] I-174 [00215] I-175 [00216] I-176 [00217] I-177 [00218] I-178 [00219] I-179 [00220] I-180 [00221] I-181 [00222] I-182 [00223] I-183 [00224] I-184 [00225] I-185 [00226] I-186 [00227] I-187 [00228] I-188 [00229] I-189 [00230] I-190 [00231] I-191 [00232] I-192 [00233] I-193 [00234] I-194 [00235] I-195 [00236] I-196 [00237] I-197 [00238] I-198 [00239] I-199 [00240] I-200 [00241] I-201 [00242] I-202 [00243] I-203 [00244] I-204 [00245] I-205 [00246] I-206 [00247] I-207 [00248] I-208 [00249] I-209 [00250] I-210 [00251] I-211 [00252] I-212 [00253] I-213 [00254] I-214 [00255] I-215 [00256] I-216 [00257] I-217 [00258] I-218 [00259] I-219 [00260] I-220 [00261] I-221 [00262] I-222 [00263] I-223 [00264] I-224 [00265] I-225 [00266] I-226 [00267] I-227 [00268] I-228 [00269] I-229 [00270] I-230 [00271] I-231 [00272] I-232 [00273] I-233 [00274] I-234 [00275] I-235 [00276] I-236 [00277] I-237 [00278] I-238 [00279] I-239 [00280] I-240 [00281] I-241 [00282] I-242 [00283] I-243 [00284] I-244 [00285] I-245 [00286] I-246 [00287] I-247 [00288] I-248 [00289] I-249 [00290] I-250 [00291] I-251 [00292] I-252 [00293] I-253 [00294] I-254 [00295] I-255 [00296] I-256 [00297] I-257 [00298] I-258 [00299] I-259 [00300] I-260 [00301] I-261 [00302] I-262 [00303] I-263 [00304] I-264 [00305] I-265 [00306] I-266 [00307] I-267 [00308] I-268 [00309]

[0303] In some embodiments, the present disclosure provides a compound, or a pharmaceutically acceptable salt thereof, selected from Table 2:

TABLE-US-00002 TABLE 2 Compound No. Name I-1 1-phenylmethanesulfonyl-1,2-dihydrospiro[cyclopentane-1,3-indole] I-2 1-[(2,2-dimethyl-2,3-dihydro-1-benzofuran-5-yl)sulfonyl]-1,2- dihydrospiro[cyclopentane-1,3-indole] I-3 1-[4-({1,2-dihydrospiro[cyclopentane-1,3-indol]-1-yl}sulfonyl)phenyl]-2- methylpropan-1-one I-4 1-[4-(propan-2-yl)benzenesulfonyl]-1,2-dihydrospiro[cyclopentane-1,3-indole] I-5 1-[(3,3-dimethyl-2,3-dihydro-1-benzofuran-5-yl)sulfonyl]-1,2- dihydrospiro[cyclopentane-1,3-indole] I-6 6-({1,2-dihydrospiro[cyclopentane-1,3-indol]-1-yl}sulfonyl)-3-methyl-3,4- dihydro-2H-1,3-benzoxazin-2-one I-7 1-[2-(4-fluorophenyl)-2-methoxyethanesulfonyl]-1,2-dihydrospiro[cyclopentane- 1,3-indole] I-8 1-[(2-methoxy-2,3-dihydro-1H-inden-5-yl)sulfonyl]-1,2- dihydrospiro[cyclopentane-1,3-indole] I-9 1-(4-methanesulfonylbenzenesulfonyl)-1,2-dihydrospiro[cyclopentane-1,3-indole] I-10 1-(3-fluoro-4-methanesulfonylbenzenesulfonyl)-1,2-dihydrospiro[cyclopentane- 1,3-indole] I-11 1-(4-fluoro-3-methylbenzenesulfonyl)-1,2-dihydrospiro[cyclopentane-1,3-indole] I-12 1-[(4-methylphenyl)methanesulfonyl]-1,2-dihydrospiro[cyclopentane-1,3-indole] I-13 1-(4-methylbenzenesulfonyl)-1,2-dihydrospiro[cyclopentane-1,3-indole] I-14 1-[(3,4-dimethylphenyl)methanesulfonyl]-1,2-dihydrospiro[cyclopentane-1,3- indole] I-15 1-(3-fluoro-4-methylbenzenesulfonyl)-1,2-dihydrospiro[cyclopentane-1,3-indole] I-16 1-[(3-methylphenyl)methanesulfonyl]-1,2-dihydrospiro[cyclopentane-1,3-indole] I-17 1-[(1-cyclobutyl-1H-pyrazol-4-yl)sulfonyl]-1,2-dihydrospiro[cyclopentane-1,3- indole] I-18 1-[(1-cyclohexyl-1H-pyrazol-4-y1)sulfonyl]-1,2-dihydrospiro[cyclopentane-1,3 indole] I-19 1-{[]-(oxan-4-yl)-1H-pyrazol-4-yl]sulfonyl}-1,2-dihydrospiro[cyclopentane-1,3- indole] I-20 1-{[S-(difluoromethyl)pyridin-3-yl]sulfonyl}-1,2-dihydrospiro[cyclopentane-1,3- indole] I-21 1-{[4-(1,3-dioxolan-2-yl)thiophen-2-yl]sulfonyl}-1,2-dihydrospiro[cyclopentane- 1,3-indole] I-22 1-[4-(1,3-dioxolan-2-yl)-2-fluorobenzenesulfonyl]-1,2-dihydrospiro[cyclopentane- 1,3-indole] I-23 1-[4-(difluoromethoxy)-3-fluorobenzenesulfonyl]-1,2-dihydrospiro[cyclopentane- 1,3-indole] I-24 1{[(1S,2R)-2-(3-fluorophenyl)cyclopropyl]sulfonyl}-1,2- dihydrospiro[cyclopentane-1,3-indole] I-25 1-[(3-fluorophenyl)methanesulfonyl]-1,2-dihydrospiro[cyclopentane-1,3-indole] I-26 1-(3-cyclopropylbenzenesulfonyl)-1,2-dihydrospiro[cyclopentane-1,3-indole] I-27 1-[3-(1,3-dioxolan-2-yl)benzenesulfonyl]-1,2-dihydrospiro[cyclopentane-1,3- indole] I-28 1-[4-(difluoromethyl)benzenesulfonyl]-1,2-dihydrospiro[cyclopentane-1,3-indole] I-29 1-(4-cyclopropylbenzenesulfonyl)-1,2-dihydrospiro[cyclopentane-1,3-indole] I-30 1-[(4-fluorophenyl)methanesulfonyl]-1,2-dihydrospiro[cyclopentane-1,3-indole] I-31 1-[4-(trifluoromethoxy)benzenesulfonyl]-1,2-dihydrospiro[cyclopentane-1,3- indole] I-32 1-(4-bromobenzenesulfonyl)-1,2-dihydrospiro[cyclopentane-1,3-indole] I-33 1-[(5-cyclopropylthiophen-2-yl)sulfonyl]-1,2-dihydrospiro[cyclopentane-1,3- indole] I-34 1-[(3,4-dihydro-1H-2-benzopyran-7-yl)methanesulfonyl]-1,2- dihydrospiro[cyclopentane-1,3-indole] I-35 1-{[2-(difluoromethyl)-3,4-dihydro-2H-1-benzopyran-6-yl]sulfonyl}-1,2- dihydrospiro[cyclopentane-1,3-indole] I-36 1-(1,3-dihydro-2-benzofuran-5-sulfonyl)-1,2-dihydrospiro[cyclopentane-1,3- indole] I-37 1-(3,4-dihydro-1H-2-benzopyran-7-sulfonyl)-1,2-dihydrospiro[cyclopentane-1,3- indolel I-38 1-(2-fluoro-2-phenylethanesulfonyl)-1,2-dihydrospiro[cyclopentane-1,3-indole] I-39 1-[(2-phenyl-1,3-oxazol-5-yl)sulfonyl]-1,2-dihydrospiro[cyclopentane-1,3-indole] I-40 1-(2,3-dihydro-1-benzoxepine-4-sulfonyl)-1,2-dihydrospiro[cyclopentane-1,3- indole] I-41 1-(2H-chromene-3-sulfonyl)-1,2-dihydrospiro[cyclopentane-1,3-indole] I-42 1-(3,4-dihydronaphthalene-2-sulfonyl)-1,2-dihydrospiro[cyclopentane-1,3-indole] I-43 1-{[1-(2,2-difluorocyclopropyl)-1H-pyrazol-3-yl]sulfonyl}-1,2- dihydrospiro[cyclopentane-1,3-indole] I-44 1-[(2-fluoro-4-methylphenyl)methanesulfonyl]-1,2-dihydrospiro[cyclopentane- 1,3-indole] I-45 1-{[4-(difluoromethyl)phenyl]methanesulfonyl}-1,2-dihydrospiro[cyclopentane- 1,3-indole] I-46 1-[(3-chlorophenyl)methanesulfonyl]-1,2-dihydrospiro[cyclopentane-1,3-indole] I-47 1-[(2-fluoro-5-methylphenyl)methanesulfonyl]-1,2-dihydrospiro[cyclopentane- 1,3-indole] I-48 1-[4-(2,2-difluorocyclopropyl)benzenesulfonyl]-1,2-dihydrospiro[cyclopentane- 1,3-indole] I-49 1-[3-(2,2-difluorocyclopropyl)benzenesulfonyl]-1,2-dihydrospiro[cyclopentane- 1,3-indole] I-50 2-[4-({1,2-dihydrospiro[cyclopentane-1,3-indol]-1-yl}sulfonyl)phenyl]propan-2-ol I-51 5-({1,2-dihydrospiro[cyclopentane-1,3-indol]-1-yl}sulfonyl)-2,2-dimethyl-2,3- dihydro-1H-inden-1-one I-52 N-[4-({1,2-dihydrospiro[cyclopentane-1,3-indol]-1-yl}sulfonyl)phenyl]-N- methylmethanesulfonamide I-53 methyl 2-[4-({1,2-dihydrospiro[cyclopentane-1,3-indol]-1-yl}sulfonyl)phenyl]-2- methylpropanoate I-54 2-[4-({1,2-dihydrospiro[cyclopentane-1,3-indol]-1-yl}sulfonyl)phenyl]-2- methylpropan-1-ol I-55 5-({1,2-dihydrospiro[cyclopentane-1,3-indol]-1-yl}sulfonyl)-2-methyl-2,3- dihydro-1H-isoindol-1-one I-56 1-[4-(2-methoxypropan-2-yl)benzenesulfonyl]-1,2-dihydrospiro[cyclopentane-1,3- indole] I-57 1-[(2,2-dimethyl-2H-1,3-benzodioxol-5-yl)sulfony1]-1,2- dihydrospiro[cyclopentane-1,3-indole] I-58 1-[(3,3-dimethyl-1,3-dihydro-2-benzofuran-5-yl)sulfonyl]-1,2- dihydrospiro[cyclopentane-1,3-indole] I-59 1-(3,4-dihydro-1H-2-benzopyran-6-sulfonyl)-1,2-dihydrospiro[cyclopentane-1,3- indole] I-60 1-[3-(2-methoxypropan-2-yl)benzenesulfonyl]-1,2-dihydrospiro[cyclopentane-1,3- indole] I-61 2-[3-({1,2-dihydrospiro[cyclopentane-1,3-indol]-1-yl}sulfonyl)phenyl]propan-2-ol I-62 methyl 4-[({1,2-dihydrospiro[cyclopentane-1,3-indol]-1- yl}sulfonyl)methyl]benzoate I-63 N-[4-({1,2-dihydrospiro[cyclopentane-1,3-indol]-1- yl}sulfonyl)phenyl]methanesulfonamide I-64 1-({spiro[1,3-benzodioxole-2,1-cyclobutan]-6-yl}sulfonyl)-1,2- dihydrospiro[cyclopentane-1,3-indole] I-65 1-(4-chloro-2-fluorophenyl)-1-(4-methanesulfonylbenzenesulfonyl)-1,2- dihydrospiro[indole-3,4-piperidine] I-66 1-[(1,1-dimethyl-1,3-dihydro-2-benzofuran-5-yl)sulfonyl]-1,2- dihydrospiro[cyclopentane-1,3-indole] I-67 1-(2,3-dihydro-1H-indene-5-sulfonyl)-1,2-dihydrospiro[cyclopentane-1,3-indole] I-68 4-({1,2-dihydrospiro[cyclopentane-1,3-indol]-1-yl}sulfonyl)-N,N- dimethylbenzene-1-sulfonamide I-69 4-({1,2-dihydrospiro[indole-3,4-oxan]-1-yl}sulfonyl)-N,N-dimethylbenzene-1- sulfonamide I-70 4-({1,2-dihydrospiro[cyclopentane-1,3-pyrrolo[3,2-c]pyridin]-1-yl}sulfonyl)-N,N- dimethylbenzene-1-sulfonamide I-71 4-({1,2-dihydrospiro[cyclopentane-1,3-pyrrolo[2,3-b]pyridin]-1-yl}sulfonyl)-N,N- dimethylbenzene-1-sulfonamide I-72 4-({4-hydroxy-1,2-dihydrospiro[cyclohexane-1,3-indol]-1-yl}sulfonyl)-N,N- dimethylbenzene-1-sulfonamide I-73 4-{[1-(2,2-dimethylpropanoyl)-1,2-dihydrospiro[indole-3,3-pyrrolidin]-1- yl]sulfonyl}-N,N-dimethylbenzene-1-sulfonamide I-74 1-(3-methylbenzenesulfonyl)-1,2-dihydrospiro[cyclopentane-1,3-indole] I-75 1-{[1-(3-methylphenyl)-1H-pyrazol-4-yl]sulfonyl}-1,2-dihydrospiro[cyclopentane- 1,3-indole] I-76 4-({1,2-dihydrospiro[indole-3,3-oxolan]-1-yl}sulfonyl)-N,N-dimethylbenzene-1- sulfonamide I-77 4-({1,2-dihydrospiro[indole-3,2-oxolan]-1-yl}sulfonyl)-N,N-dimethylbenzene-1- sulfonamide I-78 4-({1,2-dihydrospiro[cyclopentane-1,3-pyrrolo[3,2-b]pyridin]-1-yl}sulfonyl)-N,N- dimethylbenzene-1-sulfonamide I-79 N,N-dimethyl-4-({6-methyl-1,2-dihydrospiro[cyclopentane-1,3-indol]-1- yl}sulfonyl)benzene-1-sulfonamide I-80 benzyl 1-phenylmethanesulfonyl-1,2-dihydrospiro[indole-3,4-piperidine]-1- carboxylate I-81 benzyl 1-[4-(difluoromethyl)benzenesulfonyl]-1,2-dihydrospirofindole-3,4- piperidine]-1-carboxylate I-82 1-methyl-1-phenylmethanesulfonyl-1,2-dihydrospiro[indole-3,4-piperidine] I-83 1-[4-(difluoromethyl)benzenesulfonyl]-1-methyl-1,2-dihydrospirofindole-3,4- piperidine] I-84 N,N-dimethyl-4-({1-methyl-1,2-dihydrospiro[indole-3,4-piperidin]-1- yl}sulfonyl)benzene-1-sulfonamide I-85 1-phenylmethanesulfonyl-1-(2,2,2-trifluoroethyl)-1,2-dihydrospiro[indole-3,4- piperidine] I-86 1-[4-(difluoromethyl)benzenesulfonyl]-1-(2,2,2-trifluoroethyl)-1,2- dihydrospiro[indole-3,4-piperidine] I-87 N,N-dimethyl-4-{[1-(2,2,2-trifluoroethyl)-1,2-dihydrospiro[indole-3,4-piperidin]- 1-yl]sulfonyl}benzene-1-sulfonamide I-88 1-methyl-1-phenylmethanesulfonyl-1,2-dihydrospiro[indole-3,3-pyrrolidine] I-89 1-[4-(difluoromethyl)benzenesulfonyl]-1-methyl-1,2-dihydrospirofindole-3,3- pyrrolidine] I-90 N,N-dimethyl-4-({1-methyl-1,2-dihydrospiro[indole-3,3-pyrrolidin]-1- yl}sulfonyl)benzene-1-sulfonamide I-91 benzyl 1-[4-(difluoromethyl)benzenesulfonyl]-1,2-dihydrospirofindole-3,3- pyrrolidine]-1-carboxylate I-92 1-[4-(difluoromethyl)benzenesulfonyl]-1-(2,2,2-trifluoroethyl)-1,2- dihydrospiro[indole-3,3-pyrrolidine] I-93 N,N-dimethyl-4-{[1-(2,2,2-trifluoroethyl)-1,2-dihydrospiro[indole-3,3-pyrrolidin]- 1-yl]sulfonyl }benzene-1-sulfonamide I-94 1-[(3,3-dimethyl-2,3-dihydro-1-benzofuran-5-yl)sulfony1]-1,2- dihydrospiro[cyclohexane-1,3-indole] I-95 4-({4-fluoro-1,2-dihydrospiro[cyclopentane-1,3-indol]-1-yl}sulfonyl)-N,N- dimethylbenzene-1-sulfonamide I-96 N,N-dimethyl-4-({1-[(oxan-4-yl)methyl]-1,2-dihydrospiro[indole-3,3-pyrrolidin]- 1-yl}sulfonyl)benzene-1-sulfonamide I-97 4-{[1-(2,2-difluoropropyl)-1,2-dihydrospiro[indole-3,4-piperidin]-1-yl]sulfonyl}- N,N-dimethylbenzene-1-sulfonamide I-98 N,N-dimethyl-4-({1-[(oxan-4-yl)methyl]-1,2-dihydrospiro[indole-3,4-piperidin]-1- yl }sulfonyl)benzene-1-sulfonamide I-99 4-({1,2-dihydrospiro[cyclohexane-1,3-indol]-1-yl}sulfonyl)-N,N- dimethylbenzene-1-sulfonamide I-100 1-[(3,3-dimethyl-2,3-dihydro-1-benzofuran-5-yl)sulfonyl]-4-fluoro-1,2- dihydrospiro[cyclopentane-1,3-indole] I-101 N,N-dimethyl-4-({1-[(oxan-4-yl)methyl]-1,2-dihydrospiro[azetidine-3,3-indol]-1- yl}sulfonyl)benzene-1-sulfonamide I-102 4-({1-benzyl-1,2-dihydrospiro[azetidine-3,3-indol]-1-yl}sulfonyl)-N,N- dimethylbenzene-1-sulfonamide I-103 N,N-dimethyl-4-{[1-(oxolan-3-yl)-1,2-dihydrospiro[indole-3,4-piperidin]-1- yl]sulfonyl}benzene-1-sulfonamide I-104 benzyl 1-[4-(dimethylsulfamoyl)benzenesulfonyl]-1,2-dihydrospirofindole-3,4- piperidine]-1-carboxylate I-105 benzyl 1-[4-(dimethylsulfamoyl)benzenesulfonyl]-1,2-dihydrospiro[azetidine-3,3- indole]-1-carboxylate I-106 4-{[1-(4-chloro-2-fluorophenyl)-1,2-dihydrospiro[indole-3,4-piperidin]-1- yl]sulfonyl}-N,N-dimethylbenzene-1-sulfonamide I-114 methyl 2-[4-({1,2-dihydrospiro[cyclopentane-1,3-indol]-1-yl}sulfonyl)phenyl]-2- methylpropanoate I-115 benzyl 1-phenylmethanesulfonyl-1,2-dihydrospiro[indole-3,3-pyrrolidine]-1- carboxylate I-116 4-((3,4-dihydrospiro[1,4-benzoxazine-2,1-cyclopentan]-4-yl}sulfonyl)-N,N- dimethylbenzene-1-sulfonamide I-117 1-(2-phenylpropanesulfonyl)-1,2-dihydrospiro[cyclopentane-1,3-indole] I-118 4-{[1-(2,2-dimethylpropanoyl)-1,2-dihydrospiro[indole-3,4-piperidin]-1- yl]sulfonyl}-N,N-dimethylbenzene-1-sulfonamide I-119 4-({4-methoxy-1,2-dihydrospiro[cyclohexane-1,3-indol]-1-yl}sulfonyl)-N,N- dimethylbenzene-1-sulfonamide I-120 1-phenylmethanesulfonyl-1-(2,2,2-trifluoroethyl)-1,2-dihydrospiro[indole-3,3- pyrrolidinel I-121 1-(benzylsulfonyl)spiro[cyclohexane-1,3-indoline] I-122 1-((4-(difluoromethyl)phenyl)sulfonyl)-1-(2,2-difluoropropyl)spiro[indoline-3,4- piperidine] I-123 N,N-dimethyl-4-({6-methyl-1,2-dihydrospiro[cyclohexane-1,3-pyrazolo[1,5- alimidazol]-1-yl}sulfonyl)benzene-1-sulfonamide I-124 4-({1,2-dihydrospiro[cyclopentane-1,3-pyrazolo[1,5-a]imidazol]-1-yl}sulfonyl)- N,N-dimethylbenzene-1-sulfonamide I-125 4-({1,2-dihydrospiro[cyclohexane-1,3-pyrazolo[1,5-a]imidazol]-1-yl}sulfonyl)- N,N-dimethylbenzene-1-sulfonamide I-126 N,N-dimethyl-4-{[1-(2,2,2-trifluoroethyl)-2,3-dihydro-1H-spiro[piperidine-4,4- quinolin]-1-yl]sulfonyl}benzene-1-sulfonamide I-127 4-({1,2-dihydrospiro[cyclopentane-1,3-pyrrolo[2,3-c]pyridin]-1-yl}sulfonyl)-N,N- dimethylbenzene-1-sulfonamide I-128 4-({2,3-dihydro-1H-spiro[cyclohexane-1,4-quinolin]-1-yl}sulfonyl)-N,N- dimethylbenzene-1-sulfonamide I-129 4-({1,2-dihydrospiro[cyclohexane-1,3-indol]-1-yl}sulfonyl)-N,N- dimethylbenzene-1-sulfonoimidamide I-130 benzyl 1-((4-(difluoromethyl)phenyl)sulfonyl)-4-fluorospiro[indoline-3,4- piperidine]-1-carboxylate I-131 benzyl 1-((4-(difluoromethyl)phenyl)sulfonyl)-6-fluorospiro[indoline-3,4- piperidine]-1-carboxylate I-132 benzyl 1-((4-(difluoromethyl)phenyl)sulfonyl)-5-fluorospiro[indoline-3,4- piperidine]-1-carboxylate I-133 benzyl 1-((4-(difluoromethyl)phenyl)sulfonyl)-7-fluorospiro[indoline-3,4- piperidine]-1-carboxylate I-134 benzyl 1-((4-(difluoromethyl)phenyl)sulfony1)-1,2-dihydrospiro[piperidine-4,3- pyrrolo[3,2-b]pyridine]-1-carboxylate I-135 benzyl 1-((4-(difluoromethyl)phenyl)sulfonyl)-1,2-dihydrospiro[piperidine-4,3- pyrrolo[2,3-c]pyridine]-1-carboxylate I-136 (1-((4-(difluoromethyl)phenyl)sulfonyl)spiro[indoline-3,4-piperidin]-1- yl)(pyrrolidin-1-yl)methanone I-137 (1r,4r)-1-((4-(difluoromethyl)phenyl)sulfonyl)-4-(ethoxymethyl)-4- methylspiro[cyclohexane-1,3-indoline] I-138 1-((4-(difluoromethyl)phenyl)sulfonyl)-4,4-difluorospiro[cyclohexane-1,3- indoline I-139 benzyl 1-((4-(cyclopropyldifluoromethyl)phenyl)sulfonyl)spiro[indoline-3,4- piperidine]-1-carboxylate I-140 benzyl 6-cyclopropyl-1-((4-(difluoromethyl)phenyl)sulfonyl)-1,2- dihydrospiro[imidazo[1,2-b]pyrazole-3,4-piperidine]-1-carboxylate I-141 pyridin-2-ylmethyl 1-((4-(difluoromethyl)phenyl)sulfonyl)spiro[indoline-3,4- piperidine]-1-carboxylate I-142 N-cyclopropyl-1-((4-(difluoromethyl)phenyl)sulfonyl)spiro[indoline-3,4- piperidine]-1-carboxamide 1-143 N-benzyl-1-((4-(difluoromethyl)phenyl)sulfonyl)spiro[cyclohexane-1,3-indoline]- 4-carboxamide I-144 N,N-dimethyl-4-{[1-(2,2,2-trifluoroethyl)-1,2-dihydrospiro[piperidine-4,3- pyrazolo[1,5-a]imidazol]-1-yl]sulfonyl}benzene-1-sulfonamide I-145 cyclopropylmethyl 1-[4-(dimethylsulfamoyl)benzenesulfonyl]-1,2- dihydrospiro[piperidine-4,3-pyrazolo[1,5-a]imidazole]-1-carboxylate I-146 N,N-dimethyl-4-([6-methyl-1,2-dihydrospiro[cyclohexane-1,3-pyrazolo[1,5- alimidazol]-1-yl}sulfonyl)benzene-1-sulfonoimidamide I-147 1-[(3,3-dimethyl-2,3-dihydro-1-benzofuran-5-yl)sulfonyl]-6-methyl-1,2- dihydrospiro[cyclohexane-1,3-pyrazolo[1,5-a]imidazole] I-148 1-[4-(difluoromethyl)benzenesulfonyl]-6-methyl-1,2-dihydrospiro[cyclohexane- 1,3-pyrazolo[1,5-a]imidazole] I-149 N,N-dimethyl-4-({6-methyl-1,2-dihydrospiro[cyclohexane-1,3-indol]-1- yl}sulfonyl)benzene-1-sulfonoimidamide I-150 4-(1-{1,2-dihydrospiro[cyclohexane-1,3-indol]-1-yl}ethyl)-N,N-dimethylbenzene- 1-sulfonamide I-151 {cyclopropyl[4-({1,2-dihydrospiro[cyclohexane-1,3-indol]-1- yl}sulfonyl)phenyl]imino-.sup.6-sulfanyl}one I-152 1-((4-(difluoromethyl)phenyl)sulfonyl)-2,3,5,6-tetrahydrospiro[indoline-3,4- thiopyran] 1,1-dioxide I-153 N,N-dimethyl-4-{[6-(trifluoromethyl)-1,2-dihydrospiro[cyclohexane-1,3- pyrazolo[1,5-a]imidazol]-1-yl]sulfonyl}benzene-1-sulfonamide I-154 4-({6,7-dimethyl-1,2-dihydrospiro[cyclohexane-1,3-pyrazolo[1,5-a]imidazol]-1- yl}sulfonyl)-N,N-dimethylbenzene-1-sulfonamide I-155 4-((1-benzyl-4-fluorospiro[indoline-3,4-piperidin]-1-yl)sulfonyl)-N,N- dimethylbenzenesulfonamide I-157 N,N-dimethyl-4-({6-methyl-1,2-dihydrospiro[cyclohexane-1,3-pyrrolo[3,2- b]pyridin]-1-yl}sulfonyl)benzene-1-sulfonoimidamide I-158 (pyridin-3-yl)methyl 1-[4-(difluoromethyl)benzenesulfonyl]-1,2- dihydrospiro[indole-3,4-piperidine]-1-carboxylate I-159 pyridin-4-ylmethyl 1-((4-(difluoromethyl)phenyl)sulfonyl)spiro[indoline-3,4- piperidine]-1-carboxylate I-160 propan-2-yl 1-[4-(difluoromethyl)benzenesulfonyl]-1,2-dihydrospiro[indole-3,4- piperidine]-1-carboxylate I-161 1-benzoyl-1-[4-(difluoromethyl)benzenesulfonyl]-1,2-dihydrospiro[indole-3,4- piperidine] I-162 1-cyclopropanecarbonyl-1-[4-(difluoromethyl)benzenesulfonyl]-1,2- dihydrospiro[indole-3,4-piperidine] I-163 1-[4-(difluoromethyl)benzenesulfonyl]-1-[(pyrazin-2-yl)methyl]-1,2- dihydrospiro[indole-3,4-piperidine] I-164 1-[4-(difluoromethyl)benzenesulfonyl]-1-[(pyridin-2-yl)methyl]-1,2- dihydrospiro[indole-3,4-piperidine I-165 1-[4-(difluoromethyl)benzenesulfonyl]-1-[(pyridin-3-yl)methyl]-1,2- dihydrospiro[indole-3,4-piperidine] I-166 1-[4-(difluoromethyl)benzenesulfonyl]-1-[(pyridin-4-yl)methyl]-1,2- dihydrospiro[indole-3,4-piperidine] I-167 1-[4-(difluoromethyl)benzenesulfonyl]-1-[(pyrimidin-2-yl)methyl]-1,2- dihydrospiro[indole-3,4-piperidine] I-168 1-benzyl-1-[4-(difluoromethyl)benzenesulfonyl]-1,2-dihydrospiro[indole-3,4- piperidine] I-169 phenyl 1-((4-(difluoromethyl)phenyl)sulfonyl)spiro[indoline-3,4-piperidine]-1- carboxylate I-170 cyclopropylmethyl 1-((4-(difluoromethyl)phenyl)sulfonyl)spiro[indoline-3,4- piperidine]-1-carboxylate I-171 (1-ethyl-1H-pyrazol-4-yl)methyl 1-((4- (difluoromethyl)phenyl)sulfonyl)spirofindoline-3,4-piperidine]-1-carboxylate I-172 (1-methyl-1H-imidazol-4-yl)methyl 1-((4- (difluoromethyl)phenyl)sulfonyl)spiro[indoline-3,4-piperidine]-1-carboxylate I-173 isoxazol-4-ylmethyl 1-((4-(difluoromethyl)phenyl)sulfonyl)spiro[indoline-3,4- piperidine]-1-carboxylate I-174 1-(1-((4-(difluoromethyl)phenyl)sulfonyl)spiro[indoline-3,4-piperidin]-1-y1)-3- phenylpropan-1-one I-175 1-(1-((4-(difluoromethyl)phenyl)sulfonyl)spiro[indoline-3,4-piperidin]-1-yl)-2- phenylethan-1-one I-176 (1-methyl-1H-pyrazol-4-yl)methyl 1-((4- (difluoromethyl)phenyl)sulfonyl)spirofindoline-3,4-piperidine]-1-carboxylate I-177 (1-ethyl-1H-pyrazol-3-yl)methyl 1-((4- (difluoromethyl)phenyl)sulfonyl)spiro[indoline-3,4-piperidine]-1-carboxylate 1-178 N-benzyl-1-((4-(difluoromethyl)phenyl)sulfonyl)-N-methylspiro[indoline-3,4- piperidine]-1-carboxamide I-179 N-benzyl-1-((4-(difluoromethyl)phenyl)sulfonyl)spiro[indoline-3,4-piperidine]-1- carboxamide I-180 benzyl 1-(4-methanesulfonylbenzenesulfonyl)-1,2-dihydrospirofindole-3,4- piperidine]-1-carboxylate I-181 benzyl 1-[4-(propane-2-sulfonyl)benzenesulfonyl]-1,2-dihydrospiro[indole-3,4- piperidine]-1-carboxylate I-182 benzyl 1-((1,1-dioxido-2,3-dihydrobenzo[b]thiophen-5-yl)sulfonyl)spiro[indoline- 3,4-piperidine]-1-carboxylate I-183 benzyl 1-((1,3-dihydroisobenzofuran-5-yl)sulfonyl)spiro[indoline-3,4-piperidine]- 1-carboxylate I-184 benzyl 1-benzoyl-1,2-dihydrospiro[indole-3,4-piperidine]-1-carboxylate I-185 benzyl 1-(4-(difluoromethyl)benzoyl)spiro[indoline-3,4-piperidine]-1-carboxylate I-186 benzyl 1-((4-((difluoromethyl)sulfonyl)phenyl)sulfonyl)spiro[indoline-3,4- piperidine]-1-carboxylate I-187 benzyl 1-((6-(trifluoromethyl)pyridin-3-yl)sulfonyl)spiro[indoline-3,4-piperidine]- 1-carboxylate I-188 benzyl 1-((4-cyclopropylphenyl)sulfonyl)spiro[indoline-3,4-piperidine]-1- carboxylate 1-189 benzyl 1-((2,2-dimethyl-2,3-dihydrobenzofuran-5-yl)sulfonyl)spiro[indoline-3,4- piperidine]-1-carboxylate I-190 benzyl 1-(2-methylpropanoyl)-1,2-dihydrospiro[indole-3,4-piperidine]-1- carboxylate I-191 benzyl 1-(1-phenylcyclopropanecarbonyl)-1,2-dihydrospiro[indole-3,4-piperidine]- 1-carboxylate I-192 1-((4-(difluoromethyl)phenyl)sulfonyl)-N-isopropylspiro[indoline-3,4-piperidine]- 1-carboxamide I-193 N-(cyclopropylmethyl)-1-((4-(difluoromethyl)phenyl)sulfonyl)spiro[indoline-3,4- piperidine]-1-carboxamide I-194 N-(2,2-difluoroethyl)-1-((4-(difluoromethyl)phenyl)sulfonyl)spiro[indoline-3,4- piperidine]-1-carboxamide I-195 1-((4-(difluoromethyl)phenyl)sulfonyl)-N-(tetrahydrofuran-3-yl)spiro[indoline-3,4- piperidine]-1-carboxamide I-196 1-((4-(difluoromethyl)phenyl)sulfonyl)-N-(2-ethoxyethyl)spiro[indoline-3,4- piperidine]-1-carboxamide I-197 1-((4-(difluoromethyl)phenyl)sulfonyl)-N-phenylspiro[indoline-3,4-piperidine]-1- carboxamide I-198 1-((4-(difluoromethyl)phenyl)sulfonyl)-N-(pyridin-3-yl)spiro[indoline-3,4- piperidine]-1-carboxamide I-199 1-((4-(difluoromethyl)phenyl)sulfonyl)-N-(1-methyl-1H-pyrrol-2-yl)spiro[indoline- 3,4-piperidine]-1-carboxamide I-200 1-((4-(difluoromethyl)phenyl)sulfonyl)-N-(1-methyl-1H-pyrazol-4- yl)spiro[indoline-3,4-piperidine]-1-carboxamide I-201 1-((4-(difluoromethyl)phenyl)sulfonyl)-N-(2,2,2-trifluoroethyl)spiro[indoline-3,4- piperidine]-1-carboxamide I-202 1-((4-(difluoromethyl)phenyl)sulfonyl)-N-(isothiazol-4-yl)spiro[indoline-3,4- piperidine]-1-carboxamide I-203 1-((4-(difluoromethyl)phenyl)sulfonyl)-N-((tetrahydrofuran-2- yl)methyl)spiro[indoline-3,4-piperidine]-1-carboxamide I-204 1-((4-(difluoromethyl)phenyl)sulfonyl)-N-((tetrahydrofuran-3- yl)methyl)spirofindoline-3,4-piperidine]-1-carboxamide I-205 1-((4-(difluoromethyl)phenyl)sulfonyl)-N-(tetrahydro-2H-pyran-4-yl)spiro[indoline- 3,4-piperidine]-1-carboxamide I-206 N-(3,3-difluorocyclobutyl)-1-((4-(difluoromethyl)phenyl)sulfonyl)spiro[indoline- 3,4-piperidine]-1-carboxamide I-207 1-((4-(difluoromethyl)phenyl)sulfonyl)-N-(1-ethyl-1H-pyrazol-4-yl)spiro[indoline- 3,4-piperidine]-1-carboxamide I-208 N-(2-(1H-pyrazol-1-yl)ethyl)-1-((4-(difluoromethyl)phenyl)sulfonyl)spiro[indoline- 3,4-piperidine]-1-carboxamide I-209 1-((4-(difluoromethyl)phenyl)sulfonyl)-N-((1-methyl-1H-pyrazol-4- yl)methyl)spiro[indoline-3,4-piperidine]-1-carboxamide I-210 1-((4-(difluoromethyl)phenyl)sulfonyl)-N-(5-fluoropyridin-3-yl)spiro[indoline-3,4- piperidine]-1-carboxamide I-211 1-((4-(difluoromethyl)phenyl)sulfonyl)-N-((5-methylisoxazol-3- yl)methyl)spiro[indoline-3,4-piperidine]-1-carboxamide I-212 1-((4-(difluoromethyl)phenyl)sulfonyl)-N-((3-methylisoxazol-5- yl)methyl)spirofindoline-3,4-piperidine]-1-carboxamide I-213 1-((4-(difluoromethyl)phenyl)sulfonyl)-N-(3,5-dimethylisoxazol-4- yl)spiro[indoline-3,4-piperidine]-1-carboxamide I-214 1-((4-(difluoromethyl)phenyl)sulfonyl)-N-(3,3,3-trifluoropropyl)spiro[indoline-3,4- piperidine]-1-carboxamide I-215 1-((4-(difluoromethyl)phenyl)sulfonyl)-N-((tetrahydro-2H-pyran-4- yl)methyl)spiro[indoline-3,4-piperidine]-1-carboxamide I-216 1-((4-(difluoromethyl)phenyl)sulfonyl)-N-(6-methoxypyridin-3-yl)spiro[indoline- 3,4-piperidine]-1-carboxamide I-217 1-((4-(difluoromethyl)phenyl)sulfonyl)-N-(1,3,5-trimethyl-1H-pyrazol-4- yl)spiro[indoline-3,4-piperidine]-1-carboxamide 1-218 N-(4,4-difluorocyclohexyl)-1-((4-(difluoromethyl)phenyl)sulfonyl)spiro[indoline- 3,4-piperidine]-1-carboxamide I-219 1-((4-(difluoromethyl)phenyl)sulfonyl)-N-(2,3-dihydrobenzofuran-5- yl)spiro[indoline-3,4-piperidine]-1-carboxamide I-220 N-(benzo[d][1,3]dioxol-5-yl)-1-((4-(difluoromethyl)phenyl)sulfonyl)spiro[indoline- 3,4-piperidine]-1-carboxamide I-221 N-(3-(difluoromethyl)phenyl)-1-((4-(difluoromethyl)phenyl)sulfonyl)spiro[indoline- 3,4-piperidine]-1-carboxamide I-222 N-(chroman-3-yl)-1-((4-(difluoromethyl)phenyl)sulfonyl)spiro[indoline-3,4- piperidine]-1-carboxamide I-223 N-(chroman-4-yl)-1-((4-(difluoromethyl)phenyl)sulfonyl)spiro[indoline-3,4- piperidine]-1-carboxamide I-224 1-((4-(difluoromethyl)phenyl)sulfonyl)-N-(1,1-dioxidotetrahydro-2H-thiopyran-4- yl)spiro[indoline-3,4-piperidine]-1-carboxamide I-225 1-((4-(difluoromethyl)phenyl)sulfonyl)-N-(2,3-dihydrobenzo[b][1,4]dioxin-6- yl)spiro[indoline-3,4-piperidine]-1-carboxamide I-226 1-((4-(difluoromethyl)phenyl)sulfonyl)-N-(3,4-dimethoxyphenyl)spiro[indoline- 3,4-piperidine]-1-carboxamide I-227 1-((4-(difluoromethyl)phenyl)sulfonyl)-N-(2,4-dimethoxyphenyl)spiro[indoline- 3,4-piperidine]-1-carboxamide I-228 1-((4-(difluoromethyl)phenyl)sulfonyl)-N-(2,3-dimethoxyphenyl)spiro[indoline- 3,4-piperidine]-1-carboxamide I-229 1-((4-(difluoromethyl)phenyl)sulfonyl)-N-(1,3-dimethyl-2,4-dioxo-1,2,3,4- tetrahydropyrimidin-5-yl)spiro[indoline-3,4-piperidine]-1-carboxamide I-230 1-((4-(difluoromethyl)phenyl)sulfonyl)-N-phenylspiro[cyclohexane-1,3-indoline]- 4-carboxamide I-231 1-((4-(difluoromethyl)phenyl)sulfonyl)-N-(pyridin-2-ylmethyl)spiro[cyclohexane- 1,3-indoline]-4-carboxamide I-232 1-((4-(difluoromethyl)phenyl)sulfonyl)-N-(pyridin-3-ylmethyl)spiro[cyclohexane- 1,3-indoline]-4-carboxamide I-233 1-((4-(difluoromethyl)phenyl)sulfonyl)-N-(pyridin-4-ylmethyl)spiro[cyclohexane- 1,3-indoline]-4-carboxamide I-234 1-((4-(difluoromethyl)phenyl)sulfonyl)-N-methyl-N-phenylspiro[cyclohexane-1,3- indoline]-4-carboxamide I-235 N-benzyl-1-((4-(difluoromethyl)phenyl)sulfonyl)-N-methylspiro[cyclohexane-1,3- indoline]-4-carboxamide I-236 N-(cyclopropylmethyl)-1-((4-(difluoromethyl)phenyl)sulfonyl)spiro[cyclohexane- 1,3-indoline]-4-carboxamide I-237 (1-((4-(difluoromethyl)phenyl)sulfonyl)spiro[cyclohexane-1,3-indolin]-4- yl)(pyrrolidin-1-yl)methanone I-238 (1-((4-(difluoromethyl)phenyl)sulfonyl)spiro[cyclohexane-1,3-indolin]-4- yl)(morpholino)methanone I-239 (1-((4-(difluoromethyl)phenyl)sulfonyl)spiro[cyclohexane-1,3-indolin]-4-yl)(4,4- difluoropiperidin-1-yl)methanone I-240 (1-((4-(difluoromethyl)phenyl)sulfonyl)spiro[cyclohexane-1,3-indolin]-4-y1)(2- oxa-7-azaspiro[4.4]nonan-7-yl)methanone I-241 1-((4-(difluoromethyl)phenyl)sulfonyl)-N-((1-ethyl-1H-pyrazol-4- yl)methyl)spiro[cyclohexane-1,3-indoline]-4-carboxamide I-242 1-((4-(difluoromethyl)phenyl)sulfonyl)-N-(isoxazol-3-ylmethyl)-N- methylspiro[cyclohexane-1,3-indoline]-4-carboxamide I-243 1-((4-(difluoromethyl)phenyl)sulfonyl)-N-methyl-N-(1-methyl-1H-pyrazol-5- yl)spiro[cyclohexane-1,3-indoline]-4-carboxamide I-244 (1-((4-(difluoromethyl)phenyl)sulfonyl)spiro[cyclohexane-1,3-indolin]-4-yl)(2- oxa-6-azaspiro[3.4]octan-6-yl)methanone I-245 1-((4-(difluoromethyl)phenyl)sulfonyl)-N-methyl-N-(1-methyl-1H-imidazol-2- yl)spiro[cyclohexane-1,3-indoline]-4-carboxamide I-246 benzyl 1-(2-(4-(difluoromethyl)phenyl)acetyl)spiro[indoline-3,4-piperidine]-1- carboxylate I-247 benzyl 1-((4-(difluoromethyl)phenyl)carbamoyl)spiro[indoline-3,4-piperidine]-1- carboxylate I-248 benzyl 1-((4-(difluoromethyl)phenyl)(methyl)carbamoyl)spiro[indoline-3,4- piperidine]-1-carboxylate I-249 1-benzyl 1-(4-(difluoromethyl)phenyl) spiro[indoline-3,4-piperidine]-1,1- dicarboxylate I-250 benzyl 1-((4-(difluoromethyl)benzyl)sulfonyl)spiro[indoline-3,4-piperidine]-1- carboxylate I-251 1-(1-((4-(difluoromethyl)phenyl)sulfonyl)spiro[indoline-3,4-piperidin]-1-y1)-4,4,4- trifluorobutan-1-one I-252 1-(1-((4-(difluoromethyl)phenyl)sulfonyl)spiro[indoline-3,4-piperidin]-1-yl)-3- (tetrahydrofuran-2-yl)propan-1-one I-253 1-(1-((4-(difluoromethyl)phenyl)sulfonyl)spiro[indoline-3,4-piperidin]-1-y1)-3- (tetrahydrofuran-3-yl)propan-1-one I-254 1-(1-((4-(difluoromethyl)phenyl)sulfonyl)spiro[indoline-3,4-piperidin]-1-yl)-2- ((tetrahydrofuran-3-yl)oxy)ethan-1-one I-255 1-(1-((4-(difluoromethyl)phenyl)sulfonyl)spiro[indoline-3,4-piperidin]-1-yl)-2- (tetrahydrofuran-3-yl)ethan-1-one I-256 1-(1-((4-(difluoromethyl)phenyl)sulfonyl)spiro[indoline-3,4-piperidin]-1-y1)-2- (tetrahydrofuran-2-yl)ethan-1-one I-257 4-({6-cyclopropyl-1,2-dihydrospiro[cyclohexane-1,3-pyrazolo[1,5-a]imidazol]-1- yl}sulfony1)-N,N-dimethylbenzene-1-sulfonamide I-258 phenyl (1-((4-(difluoromethyl)phenyl)sulfonyl)spiro[cyclohexane-1,3-indolin]-4- yl)carbamate I-259 1-(1-((4-(difluoromethyl)phenyl)sulfonyl)spiro[cyclohexane-1,3-indolin]-4-yl)-3- phenylurea I-260 1-((4-(difluoromethyl)phenyl)sulfonyl)spiro[cyclohexane-1,3-indolin]-4-yl phenylcarbamate I-261 N-(1-((4-(difluoromethyl)phenyl)sulfonyl)spiro[cyclohexane-1,3-indolin]-4-y1)-2- phenylacetamide I-262 1-benzyl-3-(1-((4-(difluoromethyl)phenyl)sulfonyl)spiro[cyclohexane-1,3-indolin]- 4-yl)urea I-263 1-((4-(difluoromethyl)phenyl)sulfonyl)spiro[cyclohexane-1,3-indolin]-4-yl benzylcarbamate I-264 2-(1-((4-(difluoromethyl)phenyl)sulfonyl)spiro[cyclohexane-1,3-indolin]-4-yl)-N- (pyridin-4-yl)acetamide I-265 1-((4-(difluoromethyl)phenyl)sulfonyl)-1-(phenylsulfonyl)spiro[indoline-3,4- piperidine] I-266 N-(1-((4-(difluoromethyl)phenyl)sulfonyl)spiro[cyclohexane-1,3-indolin]-4- yl)benzenesulfonamide I-267 1-(benzylsulfonyl)-1-((4-(difluoromethyl)phenyl)sulfonyl)spiro[indoline-3,4- piperidine] I-268 N-(1-((4-(difluoromethyl)phenyl)sulfonyl)spiro[cyclohexane-1,3-indolin]-4-yl)-1- phenylmethanesulfonamide

Characteristics

[0304] Among other things, in some embodiments, the present disclosure describes one or more characteristics of certain TRPML (e.g., TRPML1, TRPML2, and/or TRPML3) modulators provided by and/or useful in the practice of the present disclosure.

[0305] In some embodiments, the present disclosure provides technologies for assessing one or more relevant characteristics and/or for identifying, selecting, prioritizing, and/or characterizing one or more useful TRPML (e.g., TRPML1, TRPML2, and/or TRPML3) modulators.

[0306] In some embodiments, the present disclosure provides certain biological and/or chemical assays (e.g., that facilitate and/or permit assessment of one or more feature(s) of TRMPL (e.g., TRPML1, TRPML2, and/or TRPML3) expression and/or activity, and/or of impact of TRPML (e.g., TRPML1, TRPML2, and/or TRPML3) modulator(s) on such expression and/or activity. Alternatively or additionally, the present disclosure provides technologies for identifying and/or characterizing one or more aspects of biological pathway(s) (e.g., autophagy pathway(s)) involving TRMPL (e.g., TRPML1, TRPML2, and/or TRPML3), and thus permits identification and/or characterization of additional useful targets within such pathway(s) and/or of modulator(s) that impact such pathway(s) (whether or not targeting TRPML (e.g., TRPML1, TRPML2, and/or TRPML3) itself).

Compositions

[0307] In some embodiments, the present disclosure provides and/or utilizes a composition that comprises and/or delivers a compound as described herein (e.g., together with one or more other components).

[0308] In some embodiments, the present disclosure provides compositions that comprise and/or deliver compounds reported herein (e.g., compounds of Formula I-IVb), or an intermediate, degradant, or an active metabolite thereof, e.g., when contacted with or otherwise administered to a system or environment e.g., which system or environment may include TRPML (e.g., TRPML1, TRPML2, and/or TRPML3) activity; in some embodiments, administration of such a composition to the system or environment achieves the regulation of autophagy and lysosomal biogenesis as described herein.

[0309] In some embodiments, a provided composition as described herein may be a pharmaceutical composition in that it comprises an active agent (e.g., compounds of Formula I-IVb) and one or more pharmaceutically acceptable excipients (e.g., one or more pharmaceutically acceptable adjuvants, carriers, excipients, and/or vehicles); in some such embodiments, a provided pharmaceutical composition comprises and/or delivers a compound described herein (e.g., compounds of Formula I-IVb), or an active metabolite thereof to a relevant system or environment (e.g., to a subject in need thereof) as described herein.

[0310] In some embodiments, a provided composition (e.g., a pharmaceutical composition) includes a compound (e.g., as described herein) in a salt form such as a pharmaceutically acceptable salt form.

[0311] Is some embodiments, a provided composition (e.g., a pharmaceutical composition) may be formulated for administration to a subject (e.g., a human) according to a particular route (e.g., orally, parenterally, by inhalation or nasal spray, topically (e.g., as by powders, ointments, or drops), rectally, buccally, intravaginally, intraperitoneally, intracisternally or via an implanted reservoir, etc).

[0312] In some embodiments, a provided composition (e.g., a pharmaceutical composition) comprises or delivers an amount of a compound as described herein (or an active metabolite thereof) that is effective to measurably modulate TRPML (e.g., TRPML1, TRPML2, and/or TRPML3) activity, and/or to induce autophagy and/or lysosomal biogenesis in a biological sample or in a subject, when administered in accordance with a therapeutic regimen.

[0313] In certain embodiments, a provided compound or composition is formulated for administration to a patient in need of such composition. In some embodiments, a compound or composition as described herein may be administered in a dose amount and/or by a route of administration effective for treating or lessening the severity of a disease or disorder described herein.

[0314] In some embodiments, a composition (e.g., a pharmaceutical composition) as described herein may be formulated in unit form (e.g., which may offer ease of administration and/or uniformity of dosage).

[0315] Those skilled in the art will appreciate that effective dose amounts may vary from subject to subject, for example depending on a variety of factors, including the disorder being treated and the severity of the disorder; the activity of the specific compound employed; the specific composition employed and its route of administration; the species, age, body weight, sex and diet of the patient; the general condition of the subject; the time of administration; the rate of excretion of the specific compound employed; the duration of the treatment; drugs used in combination or coincidental with the specific compound employed, and the like.

[0316] In some embodiments, an appropriate dosage level may be within a range of about 0.01 mg/kg to about 50 mg/kg, of subject body weight per day, one or more times a day, to obtain the desired therapeutic effect.

Applications and Uses

[0317] The present application provides a variety of uses and applications for compounds and/or compositions as described herein, for example in light of their activities and/or characteristics as described herein. In some embodiments, such uses may include therapeutic and/or diagnostic uses. Alternatively, in some embodiments such uses may include research, production, and/or other technological uses.

[0318] Among other things, in some embodiments, the present disclosure provides technologies for modulating TRPML activity (e.g., TRPML1, TRPML2, TRPML3, or combinations thereof). In some embodiments, the present application relates to a method of modulating TRPML activity (e.g., TRPML1, TRPML2, TRPML3, or combinations thereof) in a subject comprising administering to the subject a provided compound, or a composition as described herein. In some embodiments, the present application relates to a method of modulating TRPML1 activity in a subject comprising administering to the subject a provided compound, or a composition as described herein. In some embodiments, the present application relates to a method of modulating TRPML2 activity in a subject comprising administering to the subject a provided compound, or a composition as described herein. In some embodiments, the present application relates to a method of modulating TRPML3 activity in a subject comprising administering to the subject a provided compound, or a composition as described herein. In some embodiments, the present application relates to a method of modulating TRPML1, TRPML2, and/or TRPML3 activity in a subject comprising administering to the subject a provided compound, or a composition as described herein.

Diseases, Disorders, and Conditions

[0319] The present disclosure demonstrates that compounds and/or compositions as described herein may be useful in medicine (e.g., in the treatment of one or more diseases, disorders, or conditions).

[0320] Among other things, as described herein, the present disclosure provides an insight that targeting (e.g., agonizing) TRPML (e.g., TRPML1, TRPML2, TRPML3, or combinations thereof) may be a particularly effective strategy for modulating (e.g., enhancing) autophagy and/or lysosomal biogenesis.

[0321] In some embodiments, a disease, disorder or condition that may be treated as described herein may be or comprise a disease, disorder or condition associated with TRPML (e.g., TRPML1, TRPML2, TRPML3, or combinations thereof) deficiency. Furthermore, in some embodiments, the present disclosure identifies that TRMPL (e.g., TRPML1, TRPML2, TRPML3, or combinations thereof) deficiency is associated with particular diseases, disorders or conditions, some or all of which may be treated in accordance with the present disclosure.

[0322] In some embodiments, treatment provided herein involves administration of a TRMPL1 modulator as described herein in an amount effective to modulate TRMPL (e.g., TRPML1, TRPML2, TRPML3, or combinations thereof) activity in a lysosome and/or increase autophagy.

[0323] In some embodiments, a disease, disorder, or condition amenable to treatment as described herein is or comprises a liver disease, a neurodegenerative disorder, cancer, or a heart disease.

[0324] In some embodiments, a disease, disorder, or condition amenable to treatment as described herein is or comprises a lysosomal storage disease, such as Niemann-Pick C (NPC) disease, Gaucher disease, and Pompe disease.

[0325] In some embodiments, a disease, disorder, or condition amenable to treatment as described herein is an age-related common neurodegenerative disease, such as Alzheimer's Disease, Parkinson's Disease, and Huntington's Disease.

[0326] In some embodiments, a disease, disorder, or condition amenable to treatment as described herein is a type IV Mucolipidosis (ML4) neurodegenerative lysosomal storage disease caused by mutations in TRPML (e.g., TRPML1, TRPML2, TRPML3, or combinations thereof).

[0327] In some embodiments, a disease, disorder, or condition amenable to treatment as described herein is related to reactive oxygen species or oxidative stress.

[0328] In some embodiments, the present application relates to use of a compound and/or composition described herein for use in the manufacture of a medicament e.g., for modulation of TRPML (e.g., TRPML1, TRPML2, TRPML3, or combinations thereof) activity.

[0329] In some embodiments, the present application relates to use of a compound and/or composition described herein for use in the manufacture of a medicament for treating a disease, disorder or condition, e.g., through modulation of TRPML (e.g., TRPML1, TRPML2, TRPML3, or combinations thereof) activity; in some embodiments, the disease, disorder, or condition is a liver disease, a neurodegenerative disorder, cancer, or a heart disease.

[0330] In some embodiments, a disease, disorder, or condition is a muscular disease, a liver disease, a metabolic disease, an atherosclerotic disease, an inflammatory bowel disease, an atherosclerotic disease, a neurodegenerative disease, or an oncological disease. In some embodiments, a disease, disorder, or condition is a muscular disease. In some embodiments, a muscular disease is a muscular dystrophy. In some embodiments, a muscular dystrophy is Duchenne muscular dystrophy.

[0331] In some embodiments, a disease, disorder, or condition is an infectious disease. In some embodiments, an infectious disease is an infection of Helicobacter pylori or Mycobacterium tuberculosis.

[0332] In some embodiments, a disease, disorder, or condition is tuberculosis.

EXEMPLARY EMBODIMENTS

[0333] The following numbered embodiments, while non-limiting, are exemplary of certain aspects of the disclosure: [0334] Embodiment 1. A compound of formula I:

##STR00310## [0335] or a pharmaceutically acceptable salt thereof, [0336] wherein [0337] X is NR.sup.5, C(R.sup.5).sub.2, C(O), or O; [0338] each of Y.sup.1 and Y.sup.2 is independently selected from N and C; [0339] L is an optionally substituted group selected from C.sub.0-C.sub.6 alkylenyl-S(O).sub.2, S(O).sub.2C.sub.0-C.sub.6 alkylenyl, S(O)C.sub.0-C.sub.6 alkylenyl, C.sub.0-C.sub.6 alkylenyl-S(O), C(O)C.sub.0-C.sub.6 alkylenyl, C(O)OC.sub.0-C.sub.6 alkylenyl, C(O)N(R.sup.8)C.sub.0-C.sub.6 alkylenyl, C.sub.1-C.sub.6 alkylenyl, and C.sub.3-C.sub.6 cycloalkylenyl; [0340] A is C.sub.3-C.sub.12 cycloaliphatic or 3- to 12-membered heterocyclyl comprising 1 to 3 heteroatoms selected from N, O, and S, wherein A is substituted with (R.sup.2).sub.m; [0341] B is a fused optionally substituted C.sub.5-C.sub.6 aryl or optionally substituted 5- to 6-membered heteroaryl comprising 1 to 3 heteroatoms selected from N, O, and S; [0342] R.sup.1 is selected from C.sub.1-C.sub.6 aliphatic, C.sub.3-C.sub.12 cycloaliphatic, C.sub.5-C.sub.12 aryl, 5- to 12-membered heteroaryl comprising 1 to 3 heteroatoms selected from N, O, and S, and 3- to 12-membered heterocyclyl comprising 1 to 3 heteroatoms selected from N, O, and S, wherein R.sup.1 is substituted with (R.sup.3).sub.p; [0343] each R.sup.2 is independently halo, oxo, NR.sup.2aR.sup.2b, C(O)OR.sup.2a, OC(O)R.sup.2, S(O).sub.2, S(O).sub.2R.sup.2a, C(O)NR.sup.2aR.sup.2b, N(R.sup.2a)C(O)R.sup.2b, C(O)R.sup.2a, OR.sup.2b, OC(O)NR.sup.2aR.sup.2b, NHC(O)NR.sup.2R.sup.2b, NHC(O)OR.sup.2a, NHS(O).sub.2R.sup.2, C.sub.1-C.sub.6 alkylenyl-C(O)NR.sup.2aR.sup.2b or an optionally substituted group selected from C.sub.1-C.sub.6 aliphatic, C.sub.5-C.sub.12 aryl, and 3- to 12-membered heterocyclyl comprising 1 to 3 heteroatoms selected from N, O, and S; [0344] each R.sup.2 and each R.sup.2b are independently selected from H and an optionally substituted group selected from C.sub.1-C.sub.6 aliphatic, C.sub.3-C.sub.12 cycloaliphatic, C.sub.5-C.sub.14 aryl, 5- to 12-membered heteroaryl comprising 1 to 4 heteroatoms selected from N, O, and S, and 3- to 12-membered heterocyclyl comprising 1 to 4 heteroatoms selected from N, O, and S; [0345] each R.sup.3 is independently halo, S(O).sub.2NR.sup.3aR.sup.3b, S(O).sub.2R.sup.3b, S(NR.sup.3c)(O)NR.sup.3aR.sup.3b, S(O)(NR.sup.3c)R.sup.3b, S(O)R.sup.3b, NR.sup.3a_S(O).sub.2R.sup.3b, OR.sup.3a, C(O)R.sup.3a, C(O)NHR.sup.3a, oxo, or an optionally substituted group selected from C.sub.1-C.sub.6 aliphatic, C.sub.5-C.sub.12 aryl, C.sub.3-C.sub.12 cycloaliphatic, 5- to 12-membered heteroaryl comprising 1 to 3 heteroatoms selected from N, O, and S, and 3- to 12-membered heterocyclyl comprising 1 to 3 heteroatoms selected from N, O, and S; [0346] R.sup.3a and R.sup.3b are each independently selected from H and optionally substituted C.sub.1-C.sub.6 aliphatic, or R.sup.3a and R.sup.3b come together with the atoms to which they are attached to form optionally substituted C.sub.3-C.sub.12 cycloaliphatic or 3- to 12-membered heterocyclyl comprising 1 to 4 heteroatoms selected from N, O, and S; [0347] each R.sup.C is independently selected from H, OH, and optionally substituted C.sub.1-C.sub.6 aliphatic; [0348] each R.sup.5 is independently selected from hydrogen, halo, CN, and optionally substituted C.sub.1-C.sub.6 aliphatic; [0349] R.sup.8 is selected from H and optionally substituted C.sub.1-C.sub.6 aliphatic; [0350] n is 0 or 1; [0351] m is 0 to 4; [0352] p is 0 to 4; and [0353] q is 1 or 2. [0354] Embodiment 2. The compound of Embodiment 1, wherein n is 0. [0355] Embodiment 3. The compound of Embodiments 1 or 2, wherein q is 1. [0356] Embodiment 4. The compound of any one of Embodiments 1-3, wherein L is optionally substituted S(O).sub.2C.sub.0-C.sub.6 alkylenyl. [0357] Embodiment 5. The compound of Embodiment 4, wherein L is S(O).sub.2. [0358] Embodiment 6. The compound of Embodiment 4, wherein L is optionally substituted S(O).sub.2C.sub.1-C.sub.6 alkylenyl. [0359] Embodiment 7. The compound of Embodiment 6, wherein L is S(O).sub.2CH.sub.2. [0360] Embodiment 8. The compound of Embodiment 1, wherein L is selected from S(O).sub.2, S(O).sub.2CH.sub.2, S(O).sub.2CH(CH.sub.3), CH(CH.sub.3)S(O).sub.2, CH.sub.2S(O).sub.2,

##STR00311## [0361] Embodiment 9. The compound of any one of Embodiments 1-8, wherein A is 3- to 12-membered heterocyclyl comprising 1 to 3 heteroatoms selected from N, O, and S. [0362] Embodiment 10. The compound of any one of Embodiments 1-9, wherein A is 4- to 6-membered heterocyclyl comprising 1 to 3 heteroatoms selected from N, O, and S. [0363] Embodiment 11. The compound of any one of Embodiments 1-10, wherein A is pyrrolidinyl or piperidinyl. [0364] Embodiment 12. The compound of any one of Embodiments 1-8, wherein A is C.sub.3-C.sub.12 cycloaliphatic. [0365] Embodiment 13. The compound of any one of Embodiments 1-8 or 12, wherein A is C.sub.5-C.sub.10 cycloaliphatic. [0366] Embodiment 14. The compound of any one of Embodiments 1-8 or 12-13, wherein A is cyclopentyl or cyclohexyl. [0367] Embodiment 15. The compound of Embodiment 1, wherein A is selected from:

##STR00312## [0368] Embodiment 16. The compound of Embodiment 15, wherein A is selected from:

##STR00313## [0369] Embodiment 17. The compound of any one of Embodiments 1-16, wherein B is a fused optionally substituted C.sub.5-C.sub.6 aryl. [0370] Embodiment 18. The compound of any one of Embodiments 1-16, wherein B is a fused optionally substituted 5- to 12-membered heteroaryl comprising 1 to 3 heteroatoms selected from N, O, and S. [0371] Embodiment 19. The compound of Embodiment 18, wherein B is a fused optionally substituted 5- to 6-membered heteroaryl comprising 1 to 3 heteroatoms selected from N, O, and S. [0372] Embodiment 20. The compound of any one of Embodiments 1-19, wherein R.sup.1 is C.sub.5-C.sub.12 aryl substituted with (R.sup.3).sub.p, 5- to 12-membered heteroaryl comprising 1 to 3 heteroatoms selected from N, O, and S substituted with (R.sup.3).sub.p, or 3- to 12-membered heterocyclyl comprising 1 to 3 heteroatoms selected from N, O, and S substituted with (R.sup.3).sub.p. [0373] Embodiment 21. The compound of any one of Embodiments 1-20, wherein R.sup.1 is C.sub.5-C.sub.12 aryl substituted with (R.sup.3)P. [0374] Embodiment 22. The compound of Embodiment 21, wherein R.sup.1 is phenyl substituted with (R.sup.3).sub.p. [0375] Embodiment 23. The compound of any one of Embodiments 1-22, wherein R.sup.1 is 3- to 12-membered heterocyclyl comprising 1 to 3 heteroatoms selected from N, O, and S substituted with (R.sup.3).sub.p. [0376] Embodiment 24. The compound of Embodiment 23, wherein R.sup. is bicyclic 10- to 12-membered heterocyclyl comprising 1 to 3 heteroatoms selected from N, O, and S substituted with (R.sup.3).sub.p. [0377] Embodiment 25. The compound of any one of Embodiments 1-22, wherein R.sup.1 is 5- to 12-membered heteroaryl comprising 1 to 3 heteroatoms selected from N, O, and S substituted with (R.sup.3).sub.p. [0378] Embodiment 26. The compound of Embodiment 25, wherein R.sup.1 is 5- to 6-membered heteroaryl comprising 1 to 3 heteroatoms selected from N, O, and S substituted with (R.sup.3).sub.p. [0379] Embodiment 27. The compound of Embodiment 1, wherein R.sup.1 is selected from CH(CH.sub.3).sub.2,

##STR00314## ##STR00315## ##STR00316## ##STR00317## ##STR00318## ##STR00319## [0380] Embodiment 28. The compound of any one of Embodiments 1-27, wherein m is 0. [0381] Embodiment 29. The compound of any one of Embodiments 1-27, wherein m is 1 or 2. [0382] Embodiment 30. The compound of any one of Embodiments 1-27 or 29, wherein each R.sup.2 is halo, C(O)OR.sup.2 or an optionally substituted group selected from C.sub.1-C.sub.6 aliphatic and C.sub.5-C.sub.12 aryl. [0383] Embodiment 31. The compound of any one of Embodiments 1-27 or 29, wherein R.sup.2 is halo, C(O)OR.sup.2 or optionally substituted C.sub.1-C.sub.6 aliphatic. [0384] Embodiment 32. The compound of Embodiment 1, wherein R.sup.2 is selected from F, Br, C.sub.1, CN, OCH.sub.3, CH.sub.2CF.sub.3, CF.sub.3, NH.sub.2, CH.sub.2OCH.sub.3, CH.sub.2OCH.sub.2CH.sub.3, CH.sub.2CF.sub.2CH.sub.3, CH.sub.3, OH, oxo, S(O).sub.2,

##STR00320## ##STR00321## ##STR00322## ##STR00323## ##STR00324## ##STR00325## [0385] Embodiment 33. The compound of Embodiment 1, wherein the compound is of formula II:

##STR00326## [0386] or a pharmaceutically acceptable salt thereof. [0387] Embodiment 34. The compound of Embodiment 1, wherein the compound is of formula IIIa:

##STR00327## [0388] or a pharmaceutically acceptable salt thereof. [0389] Embodiment 35. The compound of Embodiment 1, wherein the compound is of formula IIIb:

##STR00328## [0390] or a pharmaceutically acceptable salt thereof. [0391] Embodiment 36. A compound of formula Ia:

##STR00329## [0392] or a pharmaceutically acceptable salt thereof, wherein [0393] X is NR.sup.5, C(R.sup.5).sub.2, C(O), or O; [0394] each of X.sup.a, X.sup.b, X, and X.sup.d are independently selected from N and CR.sup.6; [0395] L is an optionally substituted group selected from C.sub.0-C.sub.6 alkylenyl-S(O).sub.2, S(O).sub.2C.sub.0-C.sub.6 alkylenyl, S(O)C.sub.0-C.sub.6 alkylenyl, C.sub.0-C.sub.6 alkylenyl-S(O), C(O)C.sub.0-C.sub.6 alkylenyl, C(O)OC.sub.0-C.sub.6 alkylenyl, C(O)N(R.sup.8)C.sub.0-C.sub.6 alkylenyl, C.sub.1-C.sub.6 alkylenyl, and C.sub.3-C.sub.6 cycloalkylenyl; [0396] A is C.sub.3-C.sub.12 cycloaliphatic or 3- to 12-membered heterocyclyl comprising 1 to 3 heteroatoms selected from N, O, and S, wherein A is substituted with (R.sup.2).sub.m; R.sup.1 is selected from C.sub.1-C.sub.6 aliphatic, C.sub.3-C.sub.12 cycloaliphatic, C.sub.5-C.sub.12 aryl, 5- to 12-membered heteroaryl comprising 1 to 3 heteroatoms selected from N, O, and S, and 3- to 12-membered heterocyclyl comprising 1 to 3 heteroatoms selected from N, O, and S, wherein R.sup.1 is substituted with (R.sup.3).sub.p; [0397] each R.sup.2 is independently halo, oxo, NR.sup.2aR.sup.2b, C(O)OR.sup.2a, OC(O)R.sup.2a, S(O).sub.2, S(O).sub.2R.sup.2a, C(O)NR.sup.2aR.sup.2b, N(R.sup.2a)C(O)R.sup.2b, C(O)R.sup.2a, OR.sup.2a, OC(O)NR.sup.2aR.sup.2b, NHC(O)NR.sup.2aR.sup.2b, NHC(O)OR.sup.2a, NHS(O).sub.2R.sup.2a, C.sub.1-C.sub.6 alkylenyl-C(O)NR.sup.2aR.sup.2b or an optionally substituted group selected from C.sub.1-C.sub.6 aliphatic, C.sub.5-C.sub.12 aryl, and 3- to 12-membered heterocyclyl comprising 1 to 3 heteroatoms selected from N, O, and S; [0398] each R.sup.2a and each R.sup.2b are independently selected from H and an optionally substituted group selected from C.sub.1-C.sub.6 aliphatic, C.sub.3-C.sub.12cycloaliphatic, C.sub.5-C.sub.14 aryl, 5- to 12-membered heteroaryl comprising 1 to 4 heteroatoms selected from N, O, and S, and 3- to 12-membered heterocyclyl comprising 1 to 3 heteroatoms selected from N, O, and S; [0399] each R.sup.3 is independently halo, S(O).sub.2NR.sup.3aR.sup.3b, S(O).sub.2R.sup.3b, S(NR.sup.3c)(O)NR.sup.3aR.sup.3b_, S(O)(NR.sup.3c)R.sup.3b, S(O)R.sup.3b, NR.sup.3aS(O).sub.2R.sup.3b, OR.sup.3a, C(O)R.sup.3a, C(O)NHR.sup.3a, oxo, or an optionally substituted group selected from C.sub.1-C.sub.6 aliphatic, C.sub.5-C.sub.12 aryl, C.sub.3-C.sub.12 cycloaliphatic, 5- to 12-membered heteroaryl comprising 1 to 3 heteroatoms selected from N, O, and S, and 3- to 12-membered heterocyclyl comprising 1 to 3 heteroatoms selected from N, O, and S; [0400] R.sup.3a and R.sup.3b are each independently selected from H and optionally substituted C.sub.1-C.sub.6 aliphatic, or R.sup.3a and R.sup.3b come together with the atoms to which they are attached to form optionally substituted C.sub.3-C.sub.12 cycloaliphatic or 3- to 12-membered heterocyclyl comprising 1 to 4 heteroatoms selected from N, O, and S; [0401] each R.sup.3c is independently selected from H, OH, and optionally substituted C.sub.1-C.sub.6 aliphatic; [0402] each R.sup.5 is independently selected from hydrogen, halo, CN, and optionally substituted C.sub.1-C.sub.6 aliphatic; [0403] each R.sup.6 is H, halo, CN, OC.sub.1-C.sub.6 aliphatic, or an optionally substituted C.sub.1-C.sub.6 aliphatic; [0404] R.sup.8 is selected from H and optionally substituted C.sub.1-C.sub.6 aliphatic; [0405] n is 0 or 1, [0406] m is 0 to 4; and [0407] p is 0 to 4. [0408] Embodiment 37. A compound of formula Ib

##STR00330## [0409] or a pharmaceutically acceptable salt thereof, wherein [0410] X is NR.sup.5, C(R.sup.5).sub.2, C(O), or O; [0411] each of X.sup.e, X.sup.f, and X.sup.g is independently selected from S, N, O, and CR.sup.7; [0412] each of Y.sup.1 and Y.sup.2 is independently selected from N and C; [0413] L is an optionally substituted group selected from C.sub.0-C.sub.6 alkylenyl-S(O).sub.2, S(O).sub.2C.sub.0-C.sub.6 alkylenyl, S(O)C.sub.0-C.sub.6 alkylenyl, C.sub.0-C.sub.6 alkylenyl-S(O), C(O)C.sub.0-C.sub.6 alkylenyl, C(O)OC.sub.0-C.sub.6 alkylenyl, C(O)N(R.sup.8)C.sub.0-C.sub.6 alkylenyl, C.sub.1-C.sub.6 alkylenyl, and C.sub.3-C.sub.6 cycloalkylenyl; [0414] A is C.sub.3-C.sub.12 cycloaliphatic or 3- to 12-membered heterocyclyl comprising 1 to 3 heteroatoms selected from N, O, and S, wherein A is substituted with (R.sup.2).sub.m; [0415] R.sup.1 is selected from C.sub.1-C.sub.6 aliphatic, C.sub.3-C.sub.12 cycloaliphatic, C.sub.5-C.sub.12 aryl, 5- to 12-membered heteroaryl comprising 1 to 3 heteroatoms selected from N, O, and S, and 3- to 12-membered heterocyclyl comprising 1 to 3 heteroatoms selected from N, O, and S, wherein R.sup.1 is substituted with (R.sup.3).sub.p; [0416] each R.sup.2 is independently halo, oxo, NR.sup.2aR.sup.2b, C(O)OR.sup.2a, OC(O)R.sup.2a, S(O).sub.2, S(O).sub.2R.sup.2a, C(O)NR.sup.2aR.sup.2b, N(R.sup.2a)C(O)R.sup.2b, C(O)R.sup.2a, OR.sup.2a, OC(O)NR.sup.2aR.sup.2b, NHC(O)NR.sup.2aR.sup.2b, NHC(O)OR.sup.2a, NHS(O).sub.2R.sup.2a, C.sub.1-C.sub.6 alkylenyl-C(O)NR.sup.2aR.sup.2b or an optionally substituted group selected from C.sub.1-C.sub.6 aliphatic, C.sub.5-C.sub.12 aryl, and 3- to 12-membered heterocyclyl comprising 1 to 3 heteroatoms selected from N, O, and S; [0417] each R.sup.2a and each R.sup.2b are independently selected from H and an optionally substituted group selected from C.sub.1-C.sub.6 aliphatic, C.sub.3-C.sub.12 cycloaliphatic, C.sub.5-C.sub.14 aryl, 5- to 12-membered heteroaryl comprising 1 to 4 heteroatoms selected from N, O, and S, and 3- to 12-membered heterocyclyl comprising 1 to 3 heteroatoms selected from N, O, and S; [0418] each R.sup.3 is independently halo, S(O).sub.2NR.sup.3aR.sup.3b, S(O).sub.2R.sup.3b, S(NR.sup.3c)(O)NR.sup.3aR.sup.3b, S(O)(NR.sup.3c)R.sup.3b, S(O)R.sup.3b, NR.sup.3aS(O).sub.2R.sup.3b, OR.sup.3a, C(O)R.sup.3a, C(O)NHR.sup.3a, oxo, or an optionally substituted group selected from C.sub.1-C.sub.6 aliphatic, C.sub.5-C.sub.12 aryl, C.sub.3-C.sub.12 cycloaliphatic, 5- to 12-membered heteroaryl comprising 1 to 3 heteroatoms selected from N, O, and S, and 3- to 12-membered heterocyclyl comprising 1 to 3 heteroatoms selected from N, O, and S; [0419] R.sup.3a and R.sup.3b are each independently selected from H and optionally substituted C.sub.1-C.sub.6 aliphatic, or R.sup.3a and R.sup.3b come together with the atoms to which they are attached to form optionally substituted C.sub.3-C.sub.12 cycloaliphatic or 3- to 12-membered heterocyclyl comprising 1 to 4 heteroatoms selected from N, O, and S; [0420] each R.sup.3c is independently selected from H, OH, and optionally substituted C.sub.1-C.sub.6 aliphatic; [0421] each R.sup.5 is independently selected from hydrogen, halo, CN, and optionally substituted C.sub.1-C.sub.6 aliphatic; [0422] each R.sup.7 is H, halo, CN, OC.sub.1-C.sub.6 aliphatic, or an optionally substituted group selected from C.sub.1-C.sub.6 aliphatic and C.sub.3-C.sub.6 cycloaliphatic; [0423] R.sup.8 is selected from H and optionally substituted C.sub.1-C.sub.6 aliphatic; [0424] n is 0 or 1; [0425] m is 0 to 4; and [0426] p is 0 to 4. [0427] Embodiment 38. A compound selected from Table 1. [0428] Embodiment 39. A compound selected from Table 2. [0429] Embodiment 40. A pharmaceutical composition comprising a compound of any one of Embodiments 1-39 and a pharmaceutically acceptable carrier or excipient. [0430] Embodiment 41. A method of modulating a TRPML (e.g., TRPML1, TRPML2, TRPML3, or combinations thereof) comprising administering to a subject a compound of any one Embodiments 1-39, or a composition thereof. [0431] Embodiment 42. A method of treating a disease, disorder, or condition in a subject comprising administering a compound of any one Embodiments 1-39, or a composition thereof. [0432] Embodiment 43. The method of Embodiment 42, wherein the disease, disorder, or condition is associated with TPRML (e.g., TRPML1, TRPML2, TRPML3, or combinations thereof) modulation. [0433] Embodiment 44. The method of Embodiments 42 or 43, wherein the disease, disorder, or condition is a lysosomal storage disorder. [0434] Embodiment 45. The method of Embodiment 44, wherein the lysosomal storage disorder is selected from Niemann-Pick C disease, Gaucher disease, and Pompe disease. [0435] Embodiment 46. The method of Embodiments 42 or 43, wherein the disease, disorder, or condition is age-related common neurodegenerative disease. [0436] Embodiment 47. The method of Embodiment 46, wherein the disease, disorder, or condition is selected from Alzheimer's Disease, Parkinson's Disease, and Huntington's Disease. [0437] Embodiment 48. The method of Embodiment 43, wherein the disease, disorder, or condition is a type IV Mucolipidosis (ML4) neurodegenerative lysosomal storage disease caused by mutations in TRPML (e.g., TRPML1, TRPML2, and/or TRPML3). [0438] Embodiment 49. The method of Embodiment 42, wherein the disease, disorder, or condition is a muscular disease, a liver disease, a metabolic disease, an atherosclerotic disease, an inflammatory bowel disease, an atherosclerotic disease, a neurodegenerative disease, an oncological disease, or an infectious disease. [0439] Embodiment 50. The method of Embodiment 49, wherein the disease, disorder, or condition is a muscular disease. [0440] Embodiment 51. The method of Embodiment 50, wherein the muscular disease is a muscular dystrophy. [0441] Embodiment 52. The method of Embodiment 51, wherein the muscular dystrophy is Duchenne muscular dystrophy. [0442] Embodiment 53. The method of Embodiment 49, wherein the disease, disorder, or condition is an infectious disease. [0443] Embodiment 54. The method of Embodiment 53, wherein the infectious disease is an infection of Heliobaccer pylori or Mycobacterium tuberculosis.

EXEMPLIFICATION

[0444] The present teachings include descriptions provided in the Examples that are not intended to limit the scope of any claim. Unless specifically presented in the past tense, inclusion in the Examples is not intended to imply that the experiments were actually performed. The following non-limiting examples are provided to further illustrate the present teachings. Those of skill in the art, in light of the present application, will appreciate that many changes can be made in the specific embodiments that are provided herein and still obtain a like or similar result without departing from the spirit and scope of the present teachings.

TABLE-US-00003 Table of Abbreviations ACN Acetonitrile aq. aqueous Boc tert-Butyloxycarbonyl Brettphos 2-(Dicyclohexylphosphino)3,6-dimethoxy-2,4,6-triisopropyl- 1,1-biphenyl CDI 1,1-Carbonyldiimidazole DAST Diethylaminosulfur trifluoride DCM Dichloromethane DIBAL Diisobutylaluminum hydride DIPEA N,N-Diisopropylethylamine DMAP 4-dimethylaminopyridine DMSO Dimethylsulfoxide EDC 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide eq Equivalent h Hour or hours HOBT 1-Hydroxy-7-azabenzotriazole HPLC High pressure liquid chromatography LCMS Liquid chromatography mass spectrometry LDA Lithium diisopropylamide LiHMDS Lithium bis(trimethylsilyl)amide mCPBA meta-Chloroperoxybenzoic acid MOST Morpholinosulfur trifluoride MTBE Methyl tert-butyl ether MW Microwave NMP N-Methyl-2-pyrrolidone NMR Nuclear Magnetic Resonance Pd.sub.2(dba).sub.3 Tris(dibenzylideneacetone)dipalladium(0) Py Pyridine RT Room temperature TBAF Tetrabutylammonium fluoride TFA Trifluoroacetic acid THF Tetrahydrofuran TLC Thin layer chromatography

Analytical Instrumentation and Purification:

[0445] NMR Instrument Details: Varian 400 MHz, Probe-1: Auto XID Probe 2: ATB.

[0446] LCMS Instrument Details: Shimadzu LCMS-2010EV system coupled to SPD-M20A PDA and ELS detectors. Softa model 400.

LCMS Method 1Acidic Conditions

[0447] Column: X-Select C18 CSH (3.0*50) mm 2.5; Make: Waters [0448] Mobile Phase A: 0.05% formic acid in water: Acetonitrile (95:5); pH=3.5 [0449] Mobile Phase B: 0.05% formic acid in Acetonitrile [0450] Column oven temperature: 50 C [0451] Flow rate: 1.2 ml/minute [0452] PDA: 210 nm Maxplot [0453] Gradient program:

TABLE-US-00004 Time(min) A % B % 0.0 100 0 2.0 2 98 3.0 2 98 3.2 100 0 4.0 100 0 [0454] MS Parameters [0455] Mode: Dual (+/) [0456] Detector voltage: 1.5 KV [0457] Scan rang: 80-2000 amu [0458] Scan speed: 2000

LCMS Method 2Basic Conditions

[0459] Column: X-Select C18 CSH (3.0*50) mm 2.5 m; Make: Waters [0460] Mobile Phase A: 5 mM Ammonium Bicarb; pH=8.8 [0461] Mobile Phase B: Acetonitrile [0462] Column oven temperature: 50 C [0463] Flow rate: 1.2 ml/minute [0464] PDA: 210 nm Maxplot [0465] Gradient program:

TABLE-US-00005 Time(min) A % B % 0.0 100 0 2.0 2 98 3.0 2 98 3.2 100 0 4.0 100 0 [0466] MS Parameters [0467] Mode: Dual (+/) [0468] Detector voltage: 1.5 KV [0469] Scan rang: 80-2000 amu [0470] Scan speed: 2000

HPLC Method 1Acidic Conditions

[0471] Column: X-Select CSH C18 (4.6*150) mm; 5; Make: Waters [0472] Mobile Phase: A0.1% Formic acid in water: Acetonitrile (95:05); pH=3.5 [0473] BAcetonitrile [0474] Flow Rate: 1.0. mL/minute [0475] PDA: 210 nm maxplot [0476] Gradient program:

TABLE-US-00006 Time(min A % B % 0.0 95 5 1.0 95 5 8.0 0 100 12.0 0 100 14.0 95 5 18.0 95 5

HPLC Method 2Basic Conditions

[0477] Column: Xbridge C18 (4.6*150) mm, 5: Make: Waters [0478] Mobile Phase A0.1% NH3 in water; pH=9.5 [0479] BAcetonitrile [0480] Flow Rate: 1.2. mL/minute [0481] PDA: 210 nm maxplot [0482] Gradient program:

TABLE-US-00007 Time(min) A % B % 0.0 98 2 6.0 0 85 8.0 0 85 9.0 0 100 12.0 0 100 14.0 98 2 18.0 98 2

SYNTHETIC EXAMPLES

[0483] As depicted in the Examples below, in certain exemplary embodiments, compounds are prepared according to the following general procedures. It will be appreciated that, although the general methods depict the synthesis of certain compounds of the present invention, the following general methods, and other methods known to one of ordinary skill in the art, can be applied to all compounds and subclasses and species of each of these compounds, as described herein.

Synthesis of Certain Intermediates

Spiro[cyclopentane-1,3-indoline] (Compound 1.4)

[0484] ##STR00331##

Step-1: Procedure for Synthesis of spiro[cyclopentane-1,3-indolin]-2-one 3

[0485] To a solution of indolin-2-one (1.1, 20 g, 150 mmol) in THF (200 mL) cooled to 78 C., was added LiHMDS (1.0 M in THF, 300 mL, 300 mmol) dropwise. It was slowly warmed to 50 C. and stirred for 30 min, followed by cooling to 78 C. and 1,5-dibromobutane (1.2, 35.7 g, 165 mmol) was added. The reaction mixture was stirred at room temperature for 3 h. The progress of the reaction was monitored by thin layer chromatography (TLC). After completion of reaction as monitored by TLC, the reaction mixture was quenched with saturated solution of ammonium chloride and extracted with ethyl acetate. The combined organic layers were washed with water, brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure to dryness to afford spiro[cyclopentane-1,3-indolin]-2-one 3 (1.3, 16 g, crude). This compound was used in the next step without further purification. LCMS: 188.0 [M+H]+.

Step-2: Procedure for Synthesis of spiro[cyclopentane-1,3-indoline 4

[0486] To a solution of spiro[cyclopentane-1,3-indolin]-2-one 3 (1.3, 16 g, 85.5 mmol) in THF (200 mL) cooled at 0 C. was added LiAlH4 (1.0 M in THF, 111 mL, 111.2 mmol) dropwise. The reaction mixture was stirred at room temperature for 4 h and refluxed at 80 C. for 2 hours, following which it was cooled to room temperature and quenched with saturated aq. Na.sub.2SO.sub.4 solution. The resulting slurry was filtered through a pad of Celite, the filtrate was washed with ethyl acetate and evaporated under reduced pressure. The crude product was purified by silica gel column chromatography to afford spiro[cyclopentane-1,3-indoline 4 (1.3, 10 g, 71%) as a yellowish powder. LCMS: 174.10 [M+H]+.

Generic Synthesis of Certain Compounds

[0487] Method 1

[0488] In some embodiments, compounds described herein are prepared according to the following scheme:

##STR00332##

[0489] Spiro[cyclopentane-1,3-indoline] (1.3, 1 eq.) in dry acetonitrile (0.7 mL) and diisopropylethylamine (1.5 eq.) were placed in vial and sulfonyl chloride (1.1 eq.) was added. The reaction mixture was stirred for 16 hours at 50 C. After cooling to room temperature the mixture was evaporated. The residue was dissolved in DMSO, filtered, and the solution was subjected to HPLC purification (deionized water/HPLC-grade methanol (acetonitrile)).

[0490] Method 2

[0491] In some embodiments, compounds described herein are prepared according to the following scheme:

##STR00333##

[0492] To a stirred solution of spiro[cyclopentane-1,3-indoline 1.3 (100 mg, 0.57 mmol, 1 eq) in acetonitrile (10 mL) was added pyridine (0.09 mL, 1.1 mmol, 2 eq) at room temperature and stirred for 5 min, sulfonyl chloride (1 eq) was added and the reaction mixture was stirred at room temperature for 2 h. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was diluted with water and extracted with ethyl acetate. The combined organic layers were dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure. The crude product was purified by reverse phase preparative HPLC.

Example 1Compounds Prepared According to Method 1

[0493] The following compounds were prepared according to Method 1. A person of skill in the art would understand what sulfonyl chloride compounds having certain values for variable R would be used in the generic scheme to prepare the compounds provided below, using standard chemical manipulations and procedures similar to those used for the preparation of Method 1.

TABLE-US-00008 Compound No. Structure Analytical data I-1 [00334] Yield: 19.6 mg, 12.3%; Appearance: Beige solid; .sup.1H NMR (600 MHz, DMSO-d.sub.6) 7.28 (ddt, J = 15.5, 7.8, 2.8 Hz, 5H), 7.21 (d, J = 7.5 Hz, 1H), 7.11 (d, J = 3.9 Hz, 2H), 6.98 (dq, J = 8.0, 4.3 Hz, 1H), 4.57 (s, 2H), 3.57 (s, 2H), 1.87 - 1.68 (m, 6H), 1.68 1.48 (m, 2H); HPLC purity: 98.07%; LCMS Calculated for C.sub.19H.sub.21NO.sub.2S: 327.44; Observed: 327.2 [M + H].sup.+. I-2 [00335] Yield: 57.0 mg, 31.4%; Appearance: Yellow solid; .sup.1H NMR (400 MHz, DMSO-d.sub.6) 7.58 (d, J = 1.9 Hz, 1H), 7.53 (dd, J = 8.4, 2.0 Hz, 1H), 7.47 (d, J = 8.0 Hz, 1H), 7.15 (td, J = 7.8, 1.4 Hz, 1H), 7.05 (dd, J = 7.5, 1.4 Hz, 1H), 7.01 - 6.90 (m, 1H), 6.71 (d, J = 8.4 Hz, 1H), 3.60 (s, 2H), 3.03 (s, 2H), 1.86 - 1.52 (m, 8H), 1.44 (s, 6H); HPLC purity: 100%; LCMS Calculated for C.sub.22H.sub.25NO.sub.3S: 383.51; Observed: 384.2 [M + H].sup.+. I-3 [00336] Yield: 78.2 mg, 45.2%; Appearance: Beige solid; .sup.1H NMR (600 MHz, DMSO-d.sub.6) 8.11 - 8.02 (m, 2H), 7.96 - 7.87 (m, 2H), 7.47 (d, J = 8.1 Hz, 1H), 7.20 (ddd, J = 8.2, 7.5, 1.3 Hz, 1H), 7.14 (dd, J = 7.5, 1.3 Hz, 1H), 7.01 (td, J = 7.5, 1.1 Hz, 1H), 3.71 (s, 2H), 3.59 (p, J = 6.8 Hz, 1H), 1.68 (ddq, J = 9.8, 6.1, 2.9 Hz, 2H), 1.66 - 1.56 (m, 2H), 1.53 (dddd, J = 12.1, 7.5, 5.4, 2.8 Hz, 2H), 1.49 - 1.35 (m, 2H), 1.03 (dd, J = 69, 1.1 Hz, 6H); HPLC purity: 97.60%; LCMS Calculated for C.sub.22H.sub.25NO.sub.3S: 383.51; Observed: 383.51 [M + H].sup.+. I-4 [00337] Yield: 83.8 mg, 48.8%; Appearance: Grey solid; .sup.1H NMR (400 MHz, Chloroform-d) 7.75 (d, J = 8.1 Hz, 2H), 7.66 (d, J = 8.1 Hz, 1H), 7.30 (d, J = 8.0 Hz, 2H), 7.25 - 7.15 (m, 1H), 7.04 (dt, J = 14.7, 7.3 Hz, 2H), 3.69 (s, 2H), 2.94 (p, J = 6.9 Hz, 1H), 1.79 (s, 2H), 1.73 - 1.61 (m, 4H), 1.57 (s, 2H), 1.23 (d, J = 6.9 Hz, 6H); HPLC purity: 100%; LCMS Calculated for C.sub.21H.sub.25NO.sub.2S: 355.50; Observed: 356.2 [M + H].sup.+. I-5 [00338] Yield: 28.4 mg, 17.6%; Appearance: Yellow solid; .sup.1H NMR (600 MHz, DMSO-d.sub.6) 7.61 (d, J = 2.0 Hz, 1H), 7.54 - 7.48 (m, 1H), 7.48 - 7.43 (m, 1H), 7.18 (ddt, J = 8.4, 7.6, 1.3 Hz, 1H), 7.11 (dd, J = 7.4, 1.4 Hz, 1H), 6.99 (td, J = 7.5, 1.1 Hz, 1H), 6.85 (dd, J = 8.4, 1.4 Hz, 1H), 4.27 (d, J = 1.4 Hz, 2H), 3.66 (d, J = 1.4 Hz, 2H), 1.67 (ddq, J = 9.9, 6.2, 3.1 Hz, 2H), 1.65 - 1.57 (m, 2H), 1.54 - 1.43 (m, 2H), 1.41 - 1.31 (m, 2H), 1.21 (d, J = 1.5 Hz, 6H); HPLC purity: 100%; LCMS Calculated for C.sub.22H.sub.25NO.sub.3S: 383.51; Observed: 384.4 [M + H].sup.+. I-6 [00339] Yield: 62.8 mg, 36.1%; Appearance: Pink solid; .sup.1H NMR (400 MHz, DMSO-d.sub.6) 7.85 - 7.75 (m, 1H), 7.69 (dd, J = 8.4, 2.2 Hz, 1H), 7.46 (d, J = 8.1 Hz, 1H), 7.16 (t, J = 7.5 Hz, 1H), 7.12 - 7.02 (m, 2H), 6.97 (t, J = 7.4 Hz, 1H), 4.53 (s, 2H), 3.65 (s, 2H), 3.01 (s, 3H), 1.91 - 1.51 (m, 8H); HPLC purity: 100%; LCMS Calculated for C.sub.21H.sub.22N.sub.2O.sub.4S: 398.48; Observed: 399.2 [M + H].sup.+. I-7 [00340] Yield: 48.9 mg, 27.4%; Appearance: Pink oil; .sup.1H NMR (600 MHz, DMSO-d.sub.6) 7.39 - 7.30 (m, 2H), 7.26 (d, J = 8.0 Hz, 1H), 7.21 (dd, J = 7.5, 1.3 Hz, 1H), 7.18 - 7.11 (m, 3H), 6.98 (td, J = 7.4, 1.0 Hz, 1H), 4.64 (dd, J = 9.3, 3.0 Hz, 1H), 3.80 - 3.75 (m, 1H), 3.75 - 3.69 (m, 2H), 3.36 (dd, J = 14.8, 3.0 Hz, 1H), 2.84 (s, 3H), 2.00 - 1.54 (m, 8H); HPLC purity: 100%; LCMS Calculated for C.sub.21H.sub.24FNO.sub.3S: 389.49; Observed: 389.49 [M + H].sup.+. I-8 [00341] Yield: 14.4 mg, 9.25%; Appearance: Yellow oil; .sup.1H NMR (600 MHz, DMSO-d.sub.6) 7.66 (d, J = 1.7 Hz, 1H), 7.58 (dd, J = 7.9, 1.7 Hz, 1H), 7.42 (d, J = 8.1 Hz, 1H), 7.37 (d, J = 7.9 Hz, 1H), 7.16 (td, J = 7.8, 1.2 Hz, 1H), 7.12 (dd, J = 7.5, 1.2 Hz, 1H), 6.97 (t, J = 7.5 Hz, 1H), 4.15 (tt, J = 6.1, 3.1 Hz, 1H), 3.65 (s, 2H), 3.17 (s, 3H) , 3.09 (d, J = 6.1 Hz, 1H), 3.06 (d, J = 6.1 Hz, 1H), 2.90 (dd, J = 7.6, 3.1 Hz, 1H), 2.87 (dd, J = 8.0, 3.0 Hz, 1H), 1.69 (tt, J = 7.8, 4.0 Hz, 2H), 1.66 - 1.60 (m, 2H), 1.57 (dd, J = 12.8, 6.5 Hz, 2H), 1.51 (dq, J = 14.0, 8.4, 7.0 Hz, 2H); HPLC purity: 100%; LCMS Calculated for C.sub.22H.sub.25NO.sub.3S: 383.51; Observed: 384.2 [M + H].sup.+. I-9 [00342] Yield: 45.8 mg, 25.4%; Appearance: Beige solid; .sup.1H NMR (600 MHz, DMSO-d.sub.6) 8.09 (s, 4H), 7.46 (d, J = 8.1 Hz, 1H), 7.20 (t, J = 7.8 Hz, 1H), 7.16 (d, J = 7.4 Hz, 1H), 7.02 (t, J = 7.4 Hz, 1H), 3.74 (s, 2H), 3.25 (s, 3H), 1.69 (dq, J = 11.4, 4.4 Hz, 2H), 1.67 - 1.60 (m, 2H), 1.57 (dt, J = 14.1, 7.0 Hz, 2H), 1.54 - 1.40 (m, 2H); HPLC purity: 100%; LCMS Calculated for C.sub.19H.sub.21NO.sub.4S.sub.2: 391.50; Observed: 392.2 [M + H].sup.+. I-10 [00343] Yield: 6.7 mg, 4.15%; Appearance: Light brown solid; .sup.1H NMR (600 MHz, DMSO-d.sub.6) 8.12 - 7.99 (m, 2H), 7.91 (dd, J = 8.1, 1.7 Hz, 1H), 7.46 (d, J = 8.1 Hz, 1H), 7.26 - 7.13 (m, 2H), 7.04 (t, J = 7.5 Hz, 1H), 3.78 (s, 2H), 3.35 (s, 3H), 1.72 (p, J = 5.2, 4.3 Hz, 2H), 1.70 - 1.63 (m, 2H), 1.63 - 1.58 (m, 2H), 1.56 (dq, J = 13.4, 5.3 Hz, 2H); HPLC purity: 100%; LCMS Calculated for C.sub.19H.sub.20FNO.sub.4S.sub.2: 409.49; Observed: 406.0 [M 3H].sup.. I-11 [00344] Yield: 64.9 mg, 36.6%; Appearance: Yellow solid; .sup.1H NMR (400 MHz, DMSO-d.sub.6) 7.74 (dd, J = 7.2, 2.3 Hz, 1H), 7.65 (ddd, J = 8.1, 4.8, 2.5 Hz, 1H), 7.49 (d, J = 8.0 Hz, 1H), 7.18 (q, J = 8.4, 7.5 Hz, 2H), 7.06 (d, J = 8.0 Hz, 1H), 6.98 (t, J = 7.4 Hz, 1H), 3.64 (s, 2H), 2.30 (d, J = 2.1 Hz, 3H), 1.92 - 1.45 (m, 8H); HPLC purity: 100%; LCMS Calculated for C.sub.19H.sub.20FNO.sub.2S: 345.43; Observed: 347.0 [M + 2H].sup.+. I-12 [00345] Yield: 29.5 mg, 16.6%; Appearance: Pink solid; .sup.1H NMR (400 MHz, Chloroform-d) 7.38 - 7.25 (m, 2H), 7.20 (t, J = 7.6 Hz, 1H), 7.13 (s, 4H), 7.04 (t, J = 7.4 Hz, 1H), 4.37 (d, J = 2.9 Hz, 2H), 3.47 (s, 2H), 2.34 (d, J = 2.9 Hz, 3H), 1.76 (s, 4H), 1.73 - 1.46 (m, 4H); HPLC purity: 98.75%; LCMS Calculated for C.sub.20H.sub.23NO.sub.2S: 341.47; Observed: 341.47 [M + H].sup.+. I-13 [00346] Yield: 3.2 mg, 1.75%; Appearance: Yellow solid; .sup.1H NMR (600 MHz, DMSO-d.sub.6) 7.68 (d, J = 7.9 Hz, 2H), 7.44 (d, J = 8.1 Hz, 1H), 7.34 (d, J = 7.9 Hz, 2H), 7.17 (t, J = 7.8 Hz, 1H), 7.12 (d, J = 7.5 Hz, 1H), 6.98 (t, J = 7.5 Hz, 1H), 3.65 (d, J = 1.4 Hz, 2H), 2.31 (s, 3H), 1.69 (q, J = 7.0, 6.0 Hz, 2H), 1.67 - 1.58 (m, 2H), 1.55 (dt, J = 14.4, 7.0 Hz, 2H), 1.51 - 1.40 (m, 2H); HPLC purity: 100%; LCMS Calculated for C.sub.19H.sub.21NO.sub.2S: 327.44; Observed: 328.2 [M + H].sup.+. I-14 [00347] Yield: 21.0 mg, 11.7%; Appearance: Pink solid; .sup.1H NMR (600 MHz, DMSO-d.sub.6) 7.20 (dt, J = 7.4, 1.0 Hz, 1H), 7.14 - 7.09 (m, 2H), 7.05 (d, J = 7.7 Hz, 1H), 6.98 (dddd, J = 8.5, 5.7, 2.7, 1.3 Hz, 2H), 6.94 (d, J = 1.8 Hz, 1H), 4.46 (s, 2H), 3.56 (s, 2H), 2.15 (s, 3H), 2.08 (s, 3H), 1.84 - 1.56 (m, 8H); HPLC purity: 100%; LCMS Calculated for C.sub.21H.sub.25NO.sub.2S: 355.50; Observed: 355.50 [M H].sup.. I-15 [00348] Yield: 21.2 mg, 11.9%; Appearance: Brown solid; .sup.1H NMR (600 MHz, DMSO-d.sub.6) 7.60 - 7.53 (m, 2H), 7.48 (t, J = 7.7 Hz, 1H), 7.44 (d, J = 8.1 Hz, 1H), 7.24 - 7.17 (m, 1H), 7.14 (dd, J = 7.6, 1.3 Hz, 1H), 7.00 (td, J = 7.5, 1.1 Hz, 1H), 3.69 (s, 2H), 2.23 (d, J = 1.8 Hz, 3H), 1.70 (dtt, J = 11.3, 8.2, 4.9 Hz, 2H), 1.64 (dt, J = 12.4, 8.0 Hz, 2H), 1.57 (dt, J = 14.0, 7.0 Hz, 2H), 1.54 - 1.45 (m, 2H); HPLC purity: 98.74%; LCMS Calculated for C.sub.19H.sub.20FNO.sub.2S: 345.43; Observed: 345.43 [M + H].sup.+. I-16 [00349] Yield: 21.4 mg, 13.6%; Appearance: Beige solid; .sup.1H NMR (600 MHz, DMSO-d.sub.6) 7.21 (dd, J = 7.5, 1.0 Hz, 1H), 7.18 (t, J = 7.6 Hz, 1H), 7.14 - 7.10 (m, 3H), 7.07 (d, J = 7.6 Hz, 1H), 7.00 (s, 1H), 6.99 - 6.95 (m, 1H), 4.53 (s, 2H), 3.56 (s, 2H), 2.18 (s, 3H), 1.83 - 1.57 (m, 8H); HPLC purity: 95.85%; LCMS Calculated for C.sub.20H.sub.23NO.sub.2S: 341.47; Observed: 341.47 [M + H].sup.+. I-17 [00350] Yield: 48.7 mg, 27.0%; Appearance: Beige solid; .sup.1H NMR (600 MHz, DMSO-d.sub.6) 8.52 (s, 1H), 7.80 (d, J = 1.4 Hz, 1H), 7.38 (d, J = 8.0 Hz, 1H), 7.21 - 7.11 (m, 2H), 6.99 (t, J = 7.5 Hz, 1H), 4.81 (p, J = 8.4 Hz, 1H), 3.61 (d, J = 1.4 Hz, 2H), 2.36 (pd, J = 10.4, 9.8, 2.0 Hz, 2H), 2.32 - 2.24 (m, 2H), 1.81 - 1.43 (m, 10H); HPLC purity: 100%; LCMS Calculated for C.sub.19H.sub.23N.sub.3O.sub.2S: 357.47; Observed: 358.2 [M + H].sup.+. I-18 [00351] Yield: 76.8 mg, 42.8%; Appearance: Brown oil; .sup.1H NMR (400 MHz, DMSO-d.sub.6) 8.26 (s, 1H), 7.54 (s, 1H), 7.43 (d, J = 8.1 Hz, 1H), 7.22 - 7.12 (m, 1H), 7.07 (d, J = 7.5 Hz, 1H), 6.98 (t, J = 7.5 Hz, 1H), 4.20 - 3.99 (m, 1H), 3.59 (s, 2H), 1.98 (d, J = 11.9 Hz, 2H), 1.83 (d, J = 16.4 Hz, 5H), 1.77 - 1.54 (m, 8H), 1.39 (q, J = 13.2 Hz, 2H), 1.23 (q, J = 12.7, 12.2 Hz, 1H); HPLC purity: 97.87%; LCMS Calculated for C.sub.21H.sub.27N.sub.3O.sub.2S: 385.53; Observed: 386.2 [M + H].sup.+. I-19 [00352] Yield: 73.5 mg, 42.0%; Appearance: Yellow solid; .sup.1H NMR (400 MHz, DMSO-d.sub.6) 8.37 (s, 1H), 7.59 (s, 1H), 7.44 (d, J = 8.1 Hz, 1H), 7.23 - 7.12 (m, 1H), 7.08 (d, J = 8.0 Hz, 1H), 6.98 (t, J = 7.4 Hz, 1H), 4.39 (ddd, J = 15.5, 10.0, 5.9 Hz, 1H), 3.94 (dt, J = 11.8, 3.2 Hz, 2H), 3.60 (s, 2H), 3.43 (td, J = 11.4, 3.7 Hz, 2H), 1.95 (td, J = 9.7, 8.8, 3.7 Hz, 4H), 1.88 - 1.53 (m, 8H); HPLC purity: 100%; LCMS Calculated for C.sub.20H.sub.25N.sub.3O.sub.3S: 387.50; Observed: 388.2 [M + H].sup.+. I-20 [00353] Yield: 94.4 mg, 54.9%; Appearance: Beige solid; .sup.1H NMR (600 MHz, DMSO-d.sub.6) 9.14 (d, J = 2.2 Hz, 1H), 9.04 (q, J = 1.4 Hz, 1H), 8.38 (t, J = 1.6 Hz, 1H), 7.49 (d, J = 8.1 Hz, 1H), 7.22 (td, J = 7.8, 1.3 Hz, 1H), 7.20 - 7.09 (m, 2H), 7.04 (td, J = 7.5, 1.0 Hz, 1H), 3.79 (s, 2H), 1.69 (ddt, J = 9.3, 6.4, 3.7 Hz, 2H), 1.67 - 1.59 (m, 2H), 1.54 (tdd, J = 12.4, 5.5, 2.7 Hz, 2H), 1.51 - 1.41 (m, 2H); HPLC purity: 100%; LCMS Calculated for C.sub.18H.sub.18F.sub.2N.sub.2O.sub.2S: 364.41; Observed: 365.2 [M + H].sup.+. I-21 [00354] Yield: 60.8 mg, 40.8%; Appearance: Light brown solid; .sup.1H NMR (400 MHz, DMSO-d.sub.6) 7.80 (d, J = 1.6 Hz, 1H), 7.56 (d, J = 1.5 Hz, 1H), 7.46 (d, J = 8.0 Hz, 1H), 7.25 - 7.15 (m, 1H), 7.10 (d, J = 7.5 Hz, 1H), 7.03 (t, J = 7.5 Hz, 1H), 5.75 (s, 1H), 4.14 - 3.83 (m, 4H), 3.66 (s, 2H), 2.01 - 1.44 (m, 8H); HPLC purity: 96.10%; LCMS Calculated for C.sub.19H.sub.21NO.sub.4S.sub.2: 391.50; Observed: 390.3 [M + H].sup.+. I-22 [00355] Yield: 49.0 mg, 31.8%; Appearance: Light brown solid; .sup.1H NMR (600 MHz, DMSO-d.sub.6) 7.98 (ddd, J = 8.1, 6.9, 1.3 Hz, 1H), 7.49 - 7.37 (m, 2H), 7.26 (d, J = 8.1 Hz, 1H), 7.18 (dd, J = 7.5, 1.3 Hz, 1H), 7.13 (td, J = 7.8, 1.4 Hz, 1H), 7.00 (td, J = 7.5, 1.2 Hz, 1H), 5.78 (s, 1H), 4.06 - 3.96 (m, 2H), 3.96 - 3.89 (m, 2H), 3.81 (s, 2H), 1.72 (h, J = 4.7, 3.7 Hz, 2H), 1.64 (tq, J = 8.2, 5.1 Hz, 4H), 1.58 (dt, J = 8.1, 2.7 Hz, 2H); HPLC purity: 100%; LCMS Calculated for C.sub.21H.sub.22FNO.sub.4S: 403.47; Observed: 404.2 [M + H].sup.+. I-23 [00356] Yield: 14.2 mg, 9.4%; Appearance: Beige oil; .sup.1H NMR (400 MHz, DMSO-d.sub.6) 7.80 - 7.59 (m, 2H), 7.49 (d, J = 7.8 Hz, 2H), 7.26 - 7.13 (m, 2H), 7.09 (d, J = 7.5 Hz, 1H), 7.06 - 6.93 (m, 1H), 3.69 (s, 2H), 1.94 - 1.45 (m, 8H); HPLC purity: 98.15%; LCMS Calculated for C.sub.19H.sub.18F.sub.3NO.sub.3S: 397.41; Observed: 399.0 [M + 2H].sup.+. I-24 [00357] Yield: 18.2 mg, 12.2%; Appearance: Beige solid; .sup.1H NMR (600 MHz, DMSO-d.sub.6) 7.32 (d, J = 7.9 Hz, 1H), 7.25 - 7.19 (m, 2H), 7.17 (td, J = 7.8, 1.3 Hz, 1H), 7.01 (td, J = 7.5, 1.0 Hz, 1H), 6.96 (td, J = 8.6, 2.7 Hz, 1H), 6.88 (dt, J = 7.7, 1.2 Hz, 1H), 6.85 (dt, J = 10.4, 2.2 Hz, 1H), 3.84 - 3.75 (m, 2H), 3.18 (dt, J = 8.5, 5.1 Hz, 1H), 2.69 (ddd, J = 9.9, 6.5, 4.5 Hz, 1H), 1.75 - 1.69 (m, 5H), 1.65 (ddt, J = 17.7, 9.6, 5.8 Hz, 4H), 1.55 (dt, J = 8.4, 6.1 Hz, 1H); HPLC purity: 100%; LCMS Calculated for C.sub.21H.sub.22FNO.sub.2S: 371.47; Observed: 372.2 [M + H].sup.+. I-25 [00358] Yield: 13.4 mg, 9.0%; Appearance: Beige solid; .sup.1H NMR (400 MHz, DMSO-d.sub.6) 7.37 (td, J = 7.9, 6.0 Hz, 1H), 7.24 (d, J = 7.5 Hz, 1H), 7.22 - 7.13 (m, 3H), 7.13 - 7.08 (m, 2H), 7.00 (ddd, J = 8.0, 5.2, 3.1 Hz, 1H), 4.66 (d, J = 1.8 Hz, 2H), 3.66 (d, J = 1.9 Hz, 2H), 1.94 - 1.52 (m, 8H); HPLC purity: 96.60%, LCMS Calculated for C.sub.19H.sub.20FNO.sub.2S: 345.43; Observed: 344.2 [M H].sup.. I-26 [00359] Yield: 99.5 mg, 63.3%; Appearance: Yellow solid; .sup.1H NMR (600 MHz, DMSO-d.sub.6) 7.52 (dt, J = 7.7, 1.6 Hz, 1H), 7.46 (d, J = 8.1 Hz, 1H), 7.42 - 7.37 (m, 1H), 7.36 (dp, J = 4.4, 1.7 Hz, 2H), 7.20 (td, J = 7.8, 1.4 Hz, 1H), 7.13 (dd, J = 7.5, 1.4 Hz, 1H), 7.01 (td, J = 7.4, 1.1 Hz, 1H), 3.65 (d, J = 1.4 Hz, 2H), 1.96 (tt, J = 8.3, 5.0 Hz, 1H), 1.66 (dp, J = 9.3, 3.4, 2.9 Hz, 2H), 1.64 - 1.56 (m, 2H), 1.56 - 1.47 (m, 2H), 1.42 - 1.27 (m, 2H), 1.01 - 0.87 (m, 2H), 0.55 (qd, J = 5.3, 4.6, 1.4 Hz, 2H); HPLC purity: 99.00%; LCMS Calculated for C.sub.21H.sub.23NO.sub.2S: 353.48; Observed: 354.2 [M + H].sup.+. I-27 [00360] Yield: 95.1 mg, 60.8%; Appearance: Light brown oil; .sup.1H NMR (400 MHz, DMSO-d.sub.6) 7.80 (s, 1H), 7.78 - 7.71 (m, 1H), 7.67 (d, J = 7.6 Hz, 1H), 7.53 (t, J = 7.5 Hz, 2H), 7.18 (t, J = 8.0 Hz, 1H), 7.05 (d, J = 7.9 Hz, 1H), 6.99 (t, J = 7.4 Hz, 1H), 5.78 (s, 1H), 3.97 (d, J = 1.4 Hz, 4H), 3.65 (s, 2H), 1.75 (d, J = 6.6 Hz, 2H), 1.72 - 1.66 (m, 2H), 1.66 - 1.55 (m, 2H), 1.47 (d, J = 12.2 Hz, 2H); HPLC purity: 100%; LCMS Calculated for C.sub.21H.sub.23NO.sub.4S: 385.48; Observed: 386.2 [M + H].sup.+. I-28 [00361] Yield: 89.8 mg, 58.1%; Appearance: Beige solid; .sup.1H NMR (400 MHz, DMSO-d.sub.6) 7.99 (d, J = 8.1 Hz, 2H), 7.78 (d, J = 8.0 Hz, 2H), 7.49 (d, J = 8.1 Hz, 1H), 7.31 - 7.20 (m, 1H), 7.17 (d, J = 7.5 Hz, 1H), 7.08 - 6.88 (m, 2H), 3.74 (s, 2H), 1.82 - 1.51 (m, 6H), 1.51 - 1.33 (m, 2H); HPLC purity: 100%; LCMS Calculated for C.sub.19H.sub.19F.sub.2NO.sub.2S: 363.42; Observed: 363.42 [M + H].sup.+. I-29 [00362] Yield: 25.3 mg, 16.9%; Appearance: Beige solid; .sup.1H NMR (400 MHz, DMSO-d.sub.6) 7.71 - 7.55 (m, 2H), 7.49 (d, J = 8.0 Hz, 1H), 7.28 - 7.09 (m, 3H), 7.05 (d, J = 7.5 Hz, 1H), 6.96 (t, J = 7.4 Hz, 1H), 3.60 (s, 2H), 1.94 (d, J = 8.2 Hz, 1H), 1.87 - 1.59 (m, 6H), 1.56 (d, J = 6.0 Hz, 2H), 1.04 (d, J = 7.9 Hz, 2H), 0.81 - 0.60 (m, 2H); HPLC purity: 100%; LCMS Calculated for C.sub.21H.sub.23NO.sub.2S: 353.48; Observed: 354.1 [M + H].sup.+. I-30 [00363] Yield: 43.0 mg, 28.0%; Appearance: Pink solid; .sup.1H NMR (400 MHz, DMSO-d.sub.6) 7.41 - 7.30 (m, 2H), 7.23 (d, J = 7.4 Hz, 1H), 7.16 (t, J = 8.9 Hz, 2H), 7.10 (dd, J = 7.7, 1.6 Hz, 2H), 7.03 - 6.94 (m, 1H), 4.62 (s, 2H), 3.66 (s, 2H), 1.92 - 1.54 (m, 8H); HPLC purity: 100%; LCMS Calculated for C.sub.19H.sub.20FNO.sub.2S: 345.43; Observed: 345.43 [M + H].sup.+. I-31 [00364] Yield: 68.6 mg, 44.6%; Appearance: Beige solid; .sup.1H NMR (600 MHz, DMSO-d.sub.6) 7.96 - 7.89 (m, 2H), 7.60 - 7.50 (m, 2H), 7.46 (d, J = 8.1 Hz, 1H), 7.20 (ddd, J = 8.3, 7.4, 1.2 Hz, 1H), 7.16 (dd, J = 7.5, 1.2 Hz, 1H), 7.02 (td, J = 7.5, 1.0 Hz, 1H), 3.70 (s, 2H), 1.67 (ddt, J = 12.3, 6.0, 3.5 Hz, 2H), 1.61 (qd, J = 8.3, 7.6, 4.3 Hz, 2H), 1.54 (dtd, J = 12.3, 7.7, 6.8, 2.9 Hz, 2H), 1.42 (ddd, J = 11.6, 6.0, 2.3 Hz, 2H); HPLC purity: 100%; LCMS Calculated for C.sub.19H.sub.18F.sub.3NO.sub.2S: 397.41; Observed: 397.41 [M H].sup.. I-32 [00365] Yield: 24.3 mg, 16.4%; Appearance: Yellow solid; .sup.1H NMR (600 MHz, DMSO-d.sub.6) 7.82 - 7.75 (m, 2H), 7.75 - 7.69 (m, 2H), 7.43 (d, J = 8.0 Hz, 1H), 7.19 (td, J = 7.8, 1.3 Hz, 1H), 7.15 (dd, J = 7.6, 1.3 Hz, 1H), 7.01 (td, J = 7.5, 1.0 Hz, 1H), 3.68 (s, 2H), 1.69 (dp, J = 9.9, 3.0 Hz, 2H), 1.67 - 1.60 (m, 2H), 1.56 (dddd, J = 14.2, 8.0, 5.8, 3.4 Hz, 2H), 1.52 - 1.42 (m, 2H); HPLC purity: 100%; LCMS Calculated for C.sub.18H.sub.18BrNO.sub.2S: 392.31; Observed: 392.0 [M H].sup.. I-33 [00366] Yield: 47.1 mg, 30.3%; Appearance: Light brown solid; .sup.1H NMR (400 MHz, DMSO-d.sub.6) 7.47 - 7.32 (m, 2H), 7.17 (td, J = 7.8, 1.6 Hz, 1H), 7.13 - 7.04 (m, 1H), 7.01 (t, J = 7.4 Hz, 1H), 6.78 (d, J = 3.7 Hz, 1H), 3.63 (d, J = 2.1 Hz, 2H), 2.10 (tt, J = 8.0, 4.9 Hz, 1H), 1.90 - 1.53 (m, 8H), 1.20 - 0.94 (m, 2H), 0.88 - 0.63 (m, 2H); HPLC purity: 100%; LCMS Calculated for C.sub.19H.sub.21NO.sub.2S.sub.2: 359.50; Observed: 360.0 [M + H].sup.+. I-34 [00367] Yield: 9.8 mg, 6.4%; Appearance: Yellow solid; .sup.1H NMR (600 MHz, DMSO-d.sub.6) 7.21 (d, J = 7.4 Hz, 1H), 7.12 - 7.03 (m, 4H), 7.00 - 6.93 (m, 1H), 6.83 (s, 1H), 4.50 (d, J = 4.1 Hz, 4H), 3.80 (t, J = 5.7 Hz, 2H), 3.59 (s, 2H), 2.71 (t, J = 5.7 Hz, 2H), 1.84 - 1.53 (m, 8H); HPLC purity: 100%; LCMS Calculated for C.sub.22H.sub.25NO.sub.3S: 383.51; Observed: 383.51 [M + H].sup.+. I-35 [00368] Yield: 51.4 mg, 33.1%; Appearance: Yellow solid; .sup.1H NMR (600 MHz, DMSO-d.sub.6) 7.62 (d, J = 2.1 Hz, 1H), 7.51 (dd, J = 8.7, 2.3 Hz, 1H), 7.41 (d, J = 8.1 Hz, 1H), 7.16 (tt, J = 7.9, 1.4 Hz, 1H), 7.13 (dd, J = 7.5, 1.3 Hz, 1H), 6.98 (td, J = 7.5, 1.1 Hz, 1H), 6.94 (dd, J = 8.8, 1.4 Hz, 1H), 6.20 (td, J = 54.5, 3.4 Hz, 1H), 4.44 (dt, J = 10.8, 3.1 Hz, 1H), 3.65 (d, J = 1.5 Hz, 2H), 2.87 - 2.75 (m, 2H), 2.10 - 2.01 (m, 1H), 1.77 - 1.68 (m, 3H), 1.63 (ddt, J = 12.3, 8.3, 4.5 Hz, 2H), 1.61 - 1.55 (m, 2H), 1.56 - 1.43 (m, 2H); HPLC purity: 98.77%; LCMS Calculated for C.sub.22H.sub.23F.sub.2NO.sub.3S: 419.49; Observed: 420.0 [M + H].sup.+. I-36 [00369] Yield: 17.2 mg, 11.6%; Appearance: White solid; .sup.1H NMR (600 MHz, DMSO-d.sub.6) 7.80 (d, J = 1.6 Hz, 1H), 7.72 (dd, J = 7.9, 1.7 Hz, 1H), 7.47 (d, J = 8.0 Hz, 1H), 7.43 (d, J = 8.0 Hz, 1H), 7.17 (td, J = 7.8, 1.3 Hz, 1H), 7.13 (dd, J = 7.5, 1.3 Hz, 1H), 6.98 (td, J = 7.5, 1.0 Hz, 1H), 4.98 (s, 4H), 3.68 (s, 2H), 1.70 (qd, J = 8.5, 7.4, 3.5 Hz, 2H), 1.67 - 1.61 (m, 2H), 1.58 (ddd, J = 15.3, 8.5, 4.6 Hz, 2H), 1.51 (ddd, J = 11.7, 6.1, 2.7 Hz, 2H); HPLC purity: 100%; LCMS Calculated for C.sub.20H.sub.21NO.sub.3S: 355.45; Observed: 356.1 [M + H].sup.+. I-37 [00370] Yield: 17.3 mg, 11.4%; Appearance: Brown solid; .sup.1H NMR (600 MHz, DMSO-d.sub.6) 7.56 (d, J = 6.2 Hz, 2H), 7.41 (d, J = 8.0 Hz, 1H), 7.29 (d, J = 8.5 Hz, 1H), 7.16 (td, J = 7.8, 1.4 Hz, 1H), 7.13 (dd, J = 7.4, 1.3 Hz, 1H), 6.98 (t, J = 7.4 Hz, 1H), 4.67 (s, 2H), 3.81 (t, J = 5.7 Hz, 2H), 3.67 (s, 2H), 2.78 (t, J = 5.7 Hz, 2H), 1.76 - 1.67 (m, 2H), 1.67 - 1.61 (m, 2H), 1.58 (ddd, J = 14.4, 8.5, 4.3 Hz, 2H), 1.55 - 1.46 (m, 2H); HPLC purity: 100%; LCMS Calculated for C.sub.21H.sub.23NO.sub.3S: 369.48; Observed: 369.4 [M H].sup.. I-38 [00371] Yield: 17.0 mg, 10.9%; Appearance: Pink solid; .sup.1H NMR (400 MHz, DMSO-d.sub.6) 7.60 (dd, J = 6.4, 3.0 Hz, 2H), 7.52 (d, J = 15.5 Hz, 1H), 7.43 - 7.24 (m, 4H), 7.22 - 7.06 (m, 3H), 6.97 (t, J = 7.2 Hz, 1H), 3.74 (s, 2H), 1.83 (d, J = 16.5 Hz, 8H); HPLC purity: 100%; LCMS Calculated for C.sub.20H.sub.22FNO.sub.2S: 359.46; Observed: 359.46 [M H].sup.. I-39 [00372] Yield: 26.3 mg, 17.6%; Appearance: Light brown solid; .sup.1H NMR (600 MHz, DMSO-d.sub.6) 8.17 (s, 1H), 7.86 (d, J = 7.6 Hz, 2H), 7.58 (t, J = 7.4 Hz, 1H), 7.52 (t, J = 7.5 Hz, 2H), 7.44 (d, J = 8.0 Hz, 1H), 7.25 (t, J = 7.8 Hz, 1H), 7.21 (d, J = 7.5 Hz, 1H), 7.08 (t, J = 7.5 Hz, 1H), 3.86 (s, 2H), 1.84 - 1.51 (m, 8H); HPLC purity: 100%; LCMS Calculated for C.sub.21H.sub.20N.sub.2O.sub.3S: 380.46; Observed: 381.2 [M + H].sup.+. I-40 [00373] Yield: 18.7 mg, 15.2%; Appearance: Brown solid; .sup.1H NMR (400 MHz, DMSO-d.sub.6) 7.47 (d, J = 7.7 Hz, 1H), 7.43 (s, 1H), 7.33 (d, J = 8.1 Hz, 1H), 7.27 (d, J = 7.9 Hz, 1H), 7.19 - 7.09 (m, 2H), 7.06 (t, J = 7.6 Hz, 1H), 6.98 (t, J = 7.6 Hz, 1H), 6.92 (d, J = 8.3 Hz, 1H), 4.18 (d, J = 4.7 Hz, 2H), 3.69 (d, J = 2.6 Hz, 2H), 2.78 (d, J = 5.1 Hz, 2H), 1.77 (d, J = 32.2 Hz, 8H); HPLC purity: 100%; LCMS Calculated for C.sub.22H.sub.23NO.sub.3S: 381.49; Observed: 382.2 [M + H].sup.+. I-41 [00374] Yield: 14.0 mg, 9.4%; Appearance: Beige solid; .sup.1H NMR (600 MHz, DMSO-d.sub.6) 7.56 (s, 1H), 7.41 (dd, J = 7.6, 1.5 Hz, 1H), 7.33 - 7.25 (m, 2H), 7.24 (d, J = 7.5 Hz, 1H), 7.21 - 7.13 (m, 1H), 7.04 (ddd, J = 8.4, 7.0, 1.1 Hz, 1H), 6.98 (tt, J = 7.5, 1.0 Hz, 1H), 6.82 (d, J = 8.2 Hz, 1H), 4.73 (d, J = 1.1 Hz, 2H), 3.76 (d, J = 1.0 Hz, 2H), 1.91 - 1.48 (m, 8H), HPLC purity: 100%; LCMS Calculated for C.sub.21H.sub.21NO.sub.3S: 367.46; Observed: 368.2 [M + H].sup.+. I-42 [00375] Yield: 29.0 mg, 19.4%; Appearance: Beige solid; .sup.1H NMR (600 MHz, DMSO-d.sub.6) 7.48 (s, 1H), 7.41 (dd, J = 7.4, 1.4 Hz, 1H), 7.31 (d, J = 8.1 Hz, 1H), 7.27 (td, J = 7.4, 1.5 Hz, 1H), 7.25 - 7.18 (m, 2H), 7.15 (td, J = 7.8, 1.4 Hz, 2H), 6.99 (t, J = 7.4 Hz, 1H), 3.71 (s, 2H), 2.74 (t, J = 8.3 Hz, 2H), 2.40 - 2.30 (m, 2H), 1.81 - 1.58 (m, 8H); HPLC purity: 100%; LCMS Calculated for C.sub.22H.sub.23NO.sub.2S: 365.49; Observed: 366.1 [M + H].sup.+. I-43 [00376] Yield: 89.9 mg, 59.7%; Appearance: Yellow oil; .sup.1H NMR (400 MHz, DMSO-d.sub.6) 7.99 (d, J = 2.3 Hz, 1H), 7.40 (d, J = 8.1 Hz, 1H), 7.20 - 7.09 (m, 1H), 7.07 (d, J = 7.4 Hz, 1H), 6.96 (t, J = 7.4 Hz, 1H), 6.63 (d, J = 2.3 Hz, 1H), 4.56 (q, J = 8.5 Hz, 1H), 3.75 (s, 2H), 2.45 - 2.30 (m, 1H), 2.22 (dt, J = 17.5, 10.3 Hz, 1H), 1.95 - 1.45 (m, 8H); HPLC purity: 100%; LCMS Calculated for C.sub.18H.sub.19F.sub.2N.sub.3O.sub.2S: 379.43; Observed: 380.2 [M + H].sup.+. I-44 [00377] Yield: 31.9 mg, 20.9%; Appearance: Pink solid; .sup.1H NMR (600 MHz, DMSO-d.sub.6) 7.25 (t, J = 7.9 Hz, 1H), 7.21 (dd, J = 7.4, 1.2 Hz, 1H), 7.07 (ddd, J = 8.4, 7.2, 1.3 Hz, 1H), 7.03 (dd, J = 8.1, 1.2 Hz, 1H), 7.00 - 6.93 (m, 3H), 4.53 (s, 2H), 3.65 (s, 2H), 2.26 (s, 3H), 1.75 (qd, J = 7.1, 4.3, 3.2 Hz, 6H), 1.70 - 1.57 (m, 2H); HPLC purity: 100%; LCMS Calculated for C.sub.20H.sub.22FNO.sub.2S: 359.46; Observed: 359.46 [M H].sup.. I-45 [00378] Yield: 21.5 mg, 14.1%; Appearance: Beige solid; .sup.1H NMR (600 MHz, DMSO-d.sub.6) 7.50 (d, J = 7.9 Hz, 2H), 7.44 (d, J = 7.9 Hz, 2H), 7.21 (d, J = 7.5 Hz, 1H), 7.13 - 7.03 (m, 2H), 7.01 - 6.87 (m, 2H), 4.65 (s, 2H), 3.63 (s, 2H), 1.74 (ddd, J = 17.8, 7.4, 4.0 Hz, 6H), 1.69 - 1.54 (m, 2H); HPLC purity: 100%; LCMS Calculated for C.sub.20H.sub.21F.sub.2NO.sub.2S: 377.45; Observed: 376.2 [M H].sup.. I-46 [00379] Yield: 15.5 mg, 10.4%; Appearance: Beige solid; .sup.1H NMR (600 MHz, DMSO-d.sub.6) 7.37 (dt, J = 8.2, 1.6 Hz, 1H), 7.35 - 7.30 (m, 2H), 7.28 (dt, J = 7.5, 1.4 Hz, 1H), 7.21 (d, J = 7.5 Hz, 1H), 7.09 (d, J = 4.1 Hz, 2H), 7.01 - 6.94 (m, 1H), 4.63 (s, 2H), 3.64 (s, 2H), 1.88 - 1.70 (m, 6H), 1.65 (dd, J = 10.1, 6.5 Hz, 2H); HPLC purity: 100%; LCMS Calculated for C.sub.19H.sub.20ClNO.sub.2S: 361.88; Observed: 361.88 [M H].sup.. I-47 [00380] Yield: 25.5 mg, 16.4%; Appearance: Yellow oil; .sup.1H NMR (400 MHz, DMSO-d.sub.6) 7.12 (s, 3H), 7.06 (d, J = 6.1 Hz, 2H), 6.93 (dt, J = 16.9, 7.8 Hz, 2H), 4.44 (s, 2H), 3.65 (s, 2H), 2.27 (s, 3H), 1.78 (d, J = 35.8 Hz, 8H); HPLC purity: 100%; LCMS Calculated for C.sub.20H.sub.22FNO.sub.2S: 359.46; Observed: 359.46 [M H].sup.. I-48 [00381] Yield: 36.3 mg, 24.3%; Appearance: Beige solid; .sup.1H NMR (400 MHz, DMSO-d.sub.6) 7.82 - 7.62 (m, 2H), 7.51 (d, J = 8.1 Hz, 1H), 7.48 - 7.35 (m, 2H), 7.17 (t, J = 7.7 Hz, 1H), 7.06 (d, J = 7.5 Hz, 1H), 6.98 (t, J = 7.4 Hz, 1H), 3.59 (s, 2H), 2.94 (dd, J = 12.3, 8.5 Hz, 1H), 2.07 - 1.82 (m, 2H), 1.82 - 1.57 (m, 6H), 1.58 - 1.44 (m, 2H); HPLC purity: 100%; LCMS Calculated for C.sub.21H.sub.21F.sub.2NO.sub.2S: 389.46; Observed: 390.2 [M + H].sup.+. I-49 [00382] Yield: 63.6 mg, 42.4%; Appearance: Grey solid; .sup.1H NMR (500 MHz, DMSO-d.sub.6) 7.69 - 7.58 (m, 2H), 7.50 (dd, J = 8.1, 4.7 Hz, 2H), 7.45 (td, J = 7.7, 1.8 Hz, 1H), 7.16 (t, J = 7.8 Hz, 1H), 7.03 (d, J = 7.6 Hz, 1H), 6.97 (t, J = 7.4 Hz, 1H), 3.63 (s, 2H), 2.95 (dd, J = 12.7, 8.4 Hz, 1H), 1.98 - 1.85 (m, 1H), 1.74 (tdd, J = 13.5, 7.2, 3.2 Hz, 3H), 1.69 - 1.63 (m, 2H), 1.58 (dq, J = 15.3, 7.7 Hz, 2H), 1.46 (td, J = 12.5, 11.4, 6.0 Hz, 2H); HPLC purity: 95.83%; LCMS Calculated for C.sub.21H.sub.21F.sub.2NO.sub.2S: 389.46; Observed: 390.2 [M + H].sup.+.

Example 2Compounds Prepared According to Method 2

[0494] The following compounds were prepared according to Method 2. A person of skill in the art would understand what sulfonyl chloride compounds having certain values for variable R would be used in the generic scheme to prepare the compounds provided below, using standard chemical manipulations and procedures similar to those used for the preparation of Method 2.

TABLE-US-00009 Compound No. Structure Analytical data I-50 [00383] .sup.1H NMR (400 MHz, DMSO-d.sub.6) 1.36 (s, 6H) 1.42-1.75 (m, 8H) 3.67 (s, 2 H) 5.19 (br s, 1 H) 6.98-7.02 (m, 1 H) 7.12-7.20 (m, 2 H) 7.45 (d, J = 7.34 Hz, 1 H) 7.62 (d, J = 6.85 Hz, 2 H) 7.73 (d, J = 6.36 Hz, 2 H); HPLC purity: 99.81%; LCMS Calculated for C.sub.21H.sub.25NO.sub.3S: 371.16; Observed: 372.0 [M + H].sup.+. I-51 [00384] .sup.1H NMR (400 MHz, DMSO-d.sub.6) 1.11 (s, 6 H) 1.43-1.76 (m, 8H) 3.06 (s, 2 H) 3.77 (s, 2 H) 7.01-7.07 (m, 1 H) 7.18 (d, J = 7.34 Hz, 1 H) 7.23 (t, J = 7.58 Hz, 1 H) 7.49 (d, J = 7.83 Hz, 1 H) 7.77-7.84 (m, 2 H) 8.08 (s, 1 H); HPLC purity: 99.63%; LCMS Calculated for C.sub.23H.sub.25NO.sub.3S: 395.16; Observed: 396.0 [M + H].sup.+. I-52 [00385] .sup.1H NMR (400 MHz, DMSO-d.sub.6) 1.42-1.51 (m, 2 H) 1.53-1.76 (m, 6 H) 2.99 (s, 3 H) 3.25 (s, 3 H) 3.71 (s, 2 H) 7.01-7.06 (m, 1 H) 7.14- 7.25 (m, 2 H) 7.48 (d, J = 8.31 Hz, 1 H) 7.57 (d, J = 8.80 Hz, 2 H) 7.83 (d, J = 8.80 Hz, 2 H); HPLC purity: 99.85%; LCMS Calculated for C.sub.20H.sub.24N.sub.2O.sub.4S.sub.2: 420.12; Observed: 421.0 [M + H].sup.+. I-53 [00386] .sup.1H NMR (400 MHz, DMSO-d.sub.6) 1.48 (s, 6 H) 1.51-1.79 (m, 8H) 3.56 (s, 3 H) 3.69 (s, 2 H) 7.00-7.07 (m, 1 H) 7.16 (d, J = 7.34 Hz, 1 H) 7.21 (t, J = 7.83 Hz, 1 H) 7.45-7.53 (m, 3 H) 7.78 (d, J = 8.31 Hz, 2 H); HPLC purity: 99.67%; LCMS Calculated for C.sub.23H.sub.27NO.sub.4S: 413.17; Observed: 414.01 [M + H].sup.+. I-54 [00387] .sup.1H NMR (400 MHz, DMSO-d.sub.6) 1.18 (s, 6 H) 1.45-1.76 (m, 8H) 3.40 (d, J = 4.89 Hz, 2 H) 3.68 (s, 2 H) 4.73 (t, J = 5.38 Hz, 1 H) 7.02 (d, J = 7.34 Hz, 1 H) 7.15-7.23 (m, 2 H) 7.47 (d, J = 8.31 Hz, 1 H) 7.56 (d, J = 8.31 Hz, 2 H) 7.74 (d, J = 8.80 Hz, 2 H); HPLC purity: 99.81%; LCMS Calculated for C.sub.22H.sub.27NO.sub.3S: 385.17; Observed: 385.9 [M].sup.+. I-55 [00388] .sup.1H NMR (400 MHz, DMSO-d.sub.6) 1.41-1.74 (m, 8 H) 3.05 (s, 3 H) 3.74 (s, 2 H) 4.50 (s, 2 H) 6.99-7.05 (m, 1 H) 7.16 (d, J = 7.34 Hz, 1 H) 7.21 (t, J = 7.83 Hz, 1 H) 7.48 (d, J = 7.82 Hz, 1 H) 7.77-7.83 (m, 1 H) 7.90 (d, J = 7.83 Hz, 1 H) 8.13 (s, 1 H); HPLC purity: 99.33%; LCMS Calculated for C.sub.21H.sub.22N.sub.2O.sub.3S: 382.14; Observed: 383.30 [M + H].sup.+. I-56 [00389] .sup.1H NMR (400 MHz, DMSO-d.sub.6) 1.40 (s, 6 H) 1.48-1.74 (m, 8H) 2.94 (s, 3 H) 3.69 (s, 2 H) 7.01-7.07 (m, 1 H) 7.16 (d, J = 6.85 Hz, 1 H) 7.22 (t, J = 7.83 Hz, 1 H) 7.49 (d, J = 7.83 Hz, 1 H) 7.57 (d, J = 8.31 Hz, 2 H) 7.78 (d, J = 8.31 Hz, 2 H); HPLC purity: 96.89%; LCMS Calculated for C.sub.22H.sub.27NO.sub.3S: 385.17; Observed: 385.9 [M].sup.+. I-57 [00390] .sup.1H NMR (400 MHz, DMSO-d.sub.6) 1.50-1.54 (m, 2 H) 1.57-1.62 (m, 2 H) 1.64 (s, 6H) 1.66-1.76 (m, 4H) 3.68 (s, 2 H) 6.98-7.05 (m, 2 H) 7.16- 7.24 (m, 3 H) 7.36 (d, J = 8.31 Hz, 1 H) 7.45 (d, J = 8.31 Hz, 1 H); HPLC purity: 99.81%; LCMS Calculated for C.sub.21H.sub.23NO.sub.4S: 385.13; Observed: 386.04 [M + H].sup.+. I-58 [00391] .sup.1H NMR (400 MHz, DMSO-d.sub.6) 1.34-1.36 (m, 1 H) 1.38 (s, 6 H) 1.49-1.55 (m, 3H) 1.60-1.74 (m, 4 H) 3.74 (s, 2 H) 4.95 (s, 2 H) 6.98-7.06 (m, 1 H) 7.14 (d, J = 7.34 Hz, 1 H) 7.21 (t, J = 7.58 Hz, 1 H) 7.41 (d, J = 7.83 Hz, 1 H) 7.51 (d, J = 8.31 Hz, 1 H) 7.64 (d, J = 7.83 Hz, 1 H) 7.77 (s, 1 H); HPLC purity: 97.01%; LCMS Calculated for C.sub.22H.sub.25NO.sub.3S: 383.16; Observed: 383.95 [M].sup.+. I-59 [00392] .sup.1H NMR (400 MHz, DMSO-d.sub.6) 1.47-1.80 (m, 8H) 2.78-2.88 (m, 2 H) 3.70 (s, 2 H) 3.84 (t, J = 5.62 Hz, 2 H) 4.69 (s, 2 H) 6.97-7.05 (m, 1 H) 7.13-7.24 (m, 3 H) 7.45 (d, J = 7.82 Hz, 1 H) 7.58 (d, J = 7.82 Hz, 1 H) 7.65 (s, 1 H); HPLC purity: 99.33%; LCMS Calculated for C.sub.21H.sub.23NO.sub.3S: 369.14; Observed: 369.95 [M + H].sup.+. I-60 [00393] .sup.1H NMR (400 MHz, DMSO-d.sub.6) 1.25-1.31 (m, 2 H) 1.34 (s, 6H) 1.44-1.51 (m, 2 H) 1.56- 1.72 (m, 4 H) 2.81 (s, 3 H) 3.69 (s, 2 H) 7.03- 7.07 (m, 1 H) 7.14 (d, J = 7.83 Hz, 1 H) 7.25 (t, J = 7.58 Hz, 1 H) 7.51-7.59 (m, 2 H) 7.64-7.72 (m, 3 H); HPLC purity: 98.50%; LCMS Calculated for C.sub.22H.sub.23NO.sub.3S: 385.17; Observed: 386.05 [M + H].sup.+. I-61 [00394] .sup.1H NMR (400 MHz, DMSO-d.sub.6) 1.33 (s, 6 H) 1.34-1.37 (m, 1 H) 1.45-1.56 (m, 3H) 1.57- 1.73 (m, 4 H) 3.69 (s, 2 H) 5.27 (s, 1 H) 7.01- 7.06 (m, 1 H) 7.14 (d, J = 7.34 Hz, 1 H) 7.22 (t, J = 7.58 Hz, 1 H) 7.46-7.53 (m, 2 H) 7.59 (d, J = 7.83 Hz, 1 H) 7.73 (d, J = 7.83 Hz, 1 H) 7.84 (s, 1 H); HPLC purity: 99.85%; LCMS Calculated for C.sub.21H.sub.25NO.sub.3S: 371.16; Observed: 371.87 [M].sup.+. I-62 [00395] .sup.1H NMR (400 MHz, CDCl.sub.3) 1.65-1.74 (m, 4 H) 1.76-1.87 (m, 4 H) 3.53 (s, 2 H) 3.93 (s, 3 H) 4.43 (s, 2 H) 7.03-7.08 (m, 1 H) 7.14-7.22 (m, 2 H) 7.31 (d, J = 7.83 Hz, 1 H) 7.36 (d, J = 7.83 Hz, 2 H) 7.99 (d, J = 8.31 Hz, 2 H); HPLC purity: 99.75%; LCMS Calculated for C.sub.21H.sub.23NO.sub.4S: 385.13; Observed: 403.31 [M + 18].sup.+. I-63 [00396] .sup.1H NMR (400 MHz, DMSO-d.sub.6) 1.43-1.82 (m, 8 H) 3.09 (s, 3 H) 3.68 (s, 2 H) 6.97-7.08 (m, 1 H) 7.15-7.24 (m, 2 H) 7.29 (d, J = 8.31 Hz, 2 H) 7.45 (d, J = 7.83 Hz, 1 H) 7.78 (d, J = 8.31 Hz, 2 H) 10.44 (br s, 1 H); HPLC purity: 99.80%; LCMS Calculated for C.sub.19H.sub.22N.sub.2O.sub.4S.sub.2: 406.10; Observed: 407.0 [M + H].sup.+. I-64 [00397] .sup.1H NMR (400 MHz, DMSO-d.sub.6) 1.48-1.85 (m, 10H) 2.56-2.60 (m, 4 H) 3.67 (s, 2 H) 6.98- 7.08 (m, 2 H) 7.14-7.23 (m, 2 H) 7.28 (s, 1 H) 7.40 (d, J = 8.31 Hz, 1 H) 7.44 (d, J = 8.31 Hz, 1 H); HPLC purity: 98.95%; LCMS Calculated for C.sub.22H.sub.23NO.sub.4S: 397.13; Observed: 398.25 [M + H].sup.+.

Example 3Synthesis of 1-(4-chloro-2-fluorophenyl)-1-((4-(methylsulfonyl)phenyl)sulfonyl)spiro[indoline-3,4-piperidine](I-65)

[0495] ##STR00398##

Step-1: Procedure for Synthesis of tert-butyl(methylsulfonyl)phenyl)sulfonyl)spiro[indoline-3,4-piperidine]-1-carboxylate 3.3

[0496] To a stirred solution of tert-butyl spiro[indoline-3,4-piperidine]-1-carboxylate 3.1 (1 g, 3.46 mmol, 1 eq.) and 4-(methylsulfonyl)benzenesulfonyl chloride 3.2 (971 mg, 3.81 mmol, 1.1 eq.) in acetonitrile (10 mL), pyridine (0.83 mL, 10.4 mmol, 3 eq.) was added at room temperature and the reaction mixture was stirred for 2 h. The progress of the reaction was monitored by TLC. After completion of reaction, the reaction mixture was concentrated under reduced pressure. The residue was dissolved in ethyl acetate and washed with water. The organic layer was dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel to afford tert-butyl 1-((4-(methylsulfonyl)phenyl)sulfonyl)spiro[indoline-3,4-piperidine]-1-carboxylate 3.3 (850 mg, 50%). LCMS: 507.15 [M+H].sup.+.

Step-2: Procedure for Synthesis of 1-((4-(methylsulfonyl)phenyl)sulfonyl)spiro[indoline-3,4-piperidine] 3.4

[0497] To a stirred solution of tert-butyl 1-((4-(methylsulfonyl)phenyl)sulfonyl)spiro[indoline-3,4-piperidine]-1-carboxylate 3.3 (850 mg, 1.67 mmol, 1 eq.) in DCM (10 mL), trifluoroacetic acid (5 mL) was added at 0 C. The reaction mixture was warmed to room temperature and stirred for 1 h. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was concentrated under reduced pressure. The residue was dissolved in saturated aqueous NaHCO.sub.3 solution and extracted with ethyl acetate. The combined organic layers were dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure to dryness to afford 1-((4-(methylsulfonyl)phenyl)sulfonyl)spiro[indoline-3,4-piperidine] 3.4 (600 mg, crude). This compound was used in the next step without further purification. LCMS: 407.10 [M+H].sup.+.

Step-3: Procedure for Synthesis of 1-(4-chloro-2-fluorophenyl)-1-((4-(methylsulfonyl)phenyl)sulfonyl)spiro[indoline-3,4-piperidine]

[0498] A microwave tube was charged with a solution of 1-((4-(methylsulfonyl)phenyl)sulfonyl)spiro[indoline-3,4-piperidine] 3.4 (300 mg, 0.74 mmol, 1 eq), 1-bromo-4-chloro-2-fluorobenzene 3.5 (230 mg, 1.1 mmol, 1.5 eq) and sodium tert-butoxide (141 mg, 1.47 mmol, 2 eq) in 1,4-dioxane (10 mL). The tube was sealed with a septum and the reaction mixture was purged with argon for 10 min. Tris(dibenzylideneacetone)dipalladium(0) (47 mg, 0.052 mmol, 0.07 eq) and Brettphos (59 mg, 0.11 mmol, 0.15 eq) were added to the reaction mixture under an argon atmosphere. The tube was then sealed with an aluminium cap and the reaction mixture was irradiated in a microwave reactor at 140 C. for 3 h. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was cooled to room temperature, filtered through a pad of Celite and the Celite pad was washed with ethyl acetate. The filtrate was concentrated under reduced pressure and the crude product was purified by column chromatography on silica gel followed by reverse phase preparative HPLC to afford 1-(4-chloro-2-fluorophenyl)-1-((4-(methylsulfonyl)phenyl)sulfonyl)spiro[indoline-3,4-piperidine]1-65.

[0499] Yield: 43 mg, 10.9%; Appearance: White solid; .sup.1H NMR (400 MHz, DMSO-d.sub.6) 8.13 (s, 4H), 7.53 (d, J=8.0 Hz, 1H), 7.36-7.24 (m, 3H), 7.21 (d, J=8.4 Hz, 1H), 7.14-7.05 (m, 2H), 3.97 (s, 2H), 3.28 (s, 3H), 3.20 (d, J=12.0 Hz, 2H), 2.80 (t, J=11.6 Hz, 2H), 1.86 (t, J=11.2 Hz, 2H), 1.25 (d, J=12.8 Hz, 2H): HPLC purity: 96.55%; LCMS calculated for C.sub.25H.sub.24ClFN.sub.2O.sub.4S.sub.2: 534.09; Observed: 535.20 [M+H].sup.+.

Example 4(1)Synthesis of 1-((1,1-dimethyl-1,3-dihydroisobenzofuran-5-yl)sulfonyl)spiro[cyclopentane-1,3-indoline] (I-66)

[0500] ##STR00399##

Step-1: Procedure for Synthesis of spiro[cyclopentane-1,3-indolin]-2-one 1.3

[0501] To a solution of indolin-2-one 1.1 (20 g, 150 mmol) in THF (200 mL) cooled to 78 C., was added LiHMDS (1.0 M in THF, 300 mL, 300 mmol) dropwise. It was slowly warmed to 50 C. and stirred for 30 min, followed by cooling to 78 C. and 1,5-dibromobutane 1.2 (35.7 g, 165 mmol) was added. The reaction mixture was stirred at room temperature for 3 h. The progress of the reaction was monitored by TLC. After completion of reaction as monitored by TLC, the reaction mixture was quenched with saturated solution of ammonium chloride and extracted with ethyl acetate. The combined organic layers were washed with water, brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure to dryness to afford spiro[cyclopentane-1,3-indolin]-2-one 1.3 (16 g, crude). This compound was used in the next step without further purification. LCMS: 188.0 [M+H].

Step-2: Procedure for Synthesis of spiro[cyclopentane-1,3-indoline 1.4

[0502] To a solution of spiro[cyclopentane-1,3-indolin]-2-one 1.3 (16 g, 85.5 mmol) in THF (200 mL) cooled at 0 C. was added LiAlH4 (1.0 M in THF, 111 mL, 111.2 mmol) dropwise. The reaction mixture was stirred at room temperature for 4 h and refluxed at 80 C. for 2 h, following which it was cooled to rt and carefully quenched with saturated aq. Na.sub.2SO.sub.4 solution. The resulting slurry was filtered through a pad of celite, the filtrate was washed with ethyl acetate and evaporated under reduced pressure. The crude product was purified by silica gel column chromatography to afford spiro[cyclopentane-1,3-indoline 1.4 (10 g, 71%) as a yellowish powder. LCMS: 174.10 [M+H].sup.+.

Step-3; Procedure for synthesis of 1-((1,1-dimethyl-1,3-dihydroisobenzofuran-5-yl)sulfonyl)spiro[cyclopentane-1,3-indoline]

[0503] To a stirred solution of spiro[cyclopentane-1,3-indoline 1.4 (100 mg, 0.57 mmol, 1 eq) in acetonitrile (10 mL) was added pyridine (0.09 mL, 1.1 mmol, 2 eq) at room temperature and stirred for 5 min, 1,1-dimethyl-1,3-dihydroisobenzofuran-5-sulfonyl chloride 4.1 (142 mg, 0.57 mmol, 1 eq) was added and the reaction mixture was stirred at room temperature for 2 h. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was diluted with water and extracted with ethyl acetate. The combined organic layers were dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure. The crude product was purified by reverse phase preparative HPLC to afford 1-((1,1-dimethyl-1,3-dihydroisobenzofuran-5-yl)sulfonyl)spiro[cyclopentane-1,3-indoline] 1-66.

[0504] Yield: 25 mg, 11%; Appearance: Off-white solid; .sup.1H NMR (400 MHz, DMSO-d.sub.6) 1.38 (s, 6H) 1.45-1.76 (m, 8H) 3.71 (s, 2H) 4.96 (s, 2H) 7.03 (d, J=7.34 Hz, 1H) 7.15-7.24 (m, 2H) 7.46 (d, J=8.31 Hz, 2H) 7.73 (d, J=7.83 Hz, 1H) 7.78 (s, 1H); HPLC purity: 99.59%; LCMS calculated for C.sub.22H.sub.25NO.sub.3S: 383.16; Observed: 384.05 [M+H].sup.+. Example 4(2)Synthesis of 1-((2,3-dihydro-1H-inden-5-yl)sulfonyl)spiro[cyclopentane-1,3-indoline] (I-67)

##STR00400##

[0505] Sulfonyl chloride (1.1 eq.) was added to the vial containing aniline (1 eq.) in dry pyridine (1 mL). The reaction mixture was heated at 100 C. with stirring for 16 hours. After cooling to the room temperature, the mixture was evaporated. The residue was dissolved in DMSO (2 mL), filtered from non-soluble impurities if there were any. The resulting filtrate was subjected to HPLC purification (deionized water/HPLC-grade methanol (acetonitrile)).

[0506] Yield: 25.2 mg, 16.8%; Appearance: Pink solid; .sup.1H NMR (600 MHz, DMSO-d.sub.6) 7.65 (s, 1H), 7.56 (dd, J=8.0, 1.8 Hz, 1H), 7.42 (d, J=8.1 Hz, 1H), 7.36 (d, J=7.9 Hz, 1H), 7.21-7.14 (m, 1H), 7.12 (d, J=7.5 Hz, 1H), 7.01-6.93 (m, 1H), 3.65 (s, 2H), 2.85 (t, J=7.5 Hz, 4H), 1.97 (p, J=7.5 Hz, 2H), 1.75-1.67 (m, 2H), 1.64 (dt, J=8.9, 6.4 Hz, 2H), 1.57 (dt, J=14.3, 7.0 Hz, 2H), 1.53-1.44 (m, 2H); HPLC purity: 100%; LCMS Calculated for C.sub.21H.sub.23NO.sub.2S: 353.48; Observed: 354.2 [M+H].sup.+.

Example 5Synthesis of 4-({1,2-dihydrospiro[cyclopentane-1,3-indol]-1-yl}sulfonyl)-N,N-dimethylbenzene-1-sulfonamide (I-68)

[0507] ##STR00401##

[0508] 4-(dimethylsulfamoyl)benzene-1-sulfonyl chloride (0.429 g, 1.51 mmol) was added to an ice-cooled solution of 1,2-dihydrospiro[cyclopentane-1,3-indole] (0.25 g, 1.44 mmol) and triethylamine (0.29 g, 2.86 mmol) in DCM (10 mL). After, DMAP (0.08 g, 0.654 mmol) was added and the reaction mixture was allowed to warm to room temperature and stir until completion (overnight, NMR control). After the reaction mixture was diluted with water (10 mL), the organic layer was separated, dried over MgSO.sub.4 and concentrated in vacuo. The residue was subjected to HPLC purification (deionized water/HPLC-grade acetonitrile) that afforded 4-({1,2-dihydrospiro[cyclopentane-1,3-indol]-1-yl}sulfonyl)-N,N-dimethylbenzene-1-sulfonamide, I-68. Yield: 341.3 mg, 53.5%; Appearance: White solid; .sup.1H NMR (400 MHz, DMSO-d.sub.6) 8.04 (d, J=8.6 Hz, 2H), 7.97-7.88 (m, 2H), 7.51 (d, J=8.1 Hz, 1H), 7.33-7.21 (m, 1H), 7.18 (d, J=7.5 Hz, 1H), 7.07 (t, J=7.4 Hz, 1H), 3.75 (s, 2H), 2.58 (s, 6H), 1.67 (d, J=7.9 Hz, 2H), 1.60 (dd, J=10.0, 6.0 Hz, 2H), 1.51 (p, J=6.2 Hz, 2H), 1.35 (dd, J=11.7, 6.3 Hz, 2H); HPLC purity: 100%; LCMS Calculated for C.sub.20H.sub.24N.sub.2O.sub.4S.sub.2: 420.54; Observed: 421.2 [M+H].sup.+. Example 6Synthesis of 4-({1,2-dihydrospiro[indole-3,4-oxan]-1-yl}sulfonyl)-N,N-dimethylbenzene-1-sulfonamide (I-69)

##STR00402##

[0509] 4-(dimethylsulfamoyl)benzene-1-sulfonyl chloride (0.125 g, 0.44 mmol) was added at 0 C. to a stirred solution of 1,2-dihydrospiro[indole-3,4-oxane] hydrochloride (0.1 g, 0.44 mmol) and diisopropylethylamine (0.142 g, 1.1 mmol) in DCM (3 mL). The resulting mixture was stirred for 12 h at room temperature and poured into water (5 mL). The organic layer was separated, washed with 10% aq NaHSO.sub.4 solution (5 mL), saturated aq NaHCO.sub.3 solution (5 mL), brine (5 mL), dried over sodium sulfate, filtered and evaporated under reduced pressure. Crude residue was subjected to HPLC purification (deionized water/HPLC-acetonitrile, TFA) that afforded the 4-({1,2-dihydrospiro[indole-3,4-oxan]-1-yl}sulfonyl)-N,N-dimethylbenzene-1-sulfonamide, I-69. Yield: 110.1 mg, 53.8%; Appearance: Yellow solid; .sup.1H NMR (400 MHz, DMSO-d.sub.6) 8.07 (d, J=8.0 Hz, 2H), 7.91 (d, J=8.1 Hz, 2H), 7.52 (d, J=8.0 Hz, 1H), 7.34-7.19 (m, 2H), 7.08 (t, J=7.5 Hz, 1H), 3.97 (s, 2H), 3.79-3.62 (m, 2H), 3.41 (t, J=12.2 Hz, 2H), 2.58 (s, 6H), 1.71 (dt, J=14.2, 7.0 Hz, 2H), 0.97 (d, J=13.3 Hz, 2H); HPLC purity: 100%; LCMS Calculated for C.sub.20H.sub.24N.sub.2O.sub.5S.sub.2: 436.54, Observed: 437.0 [M+H].sup.+.

Example 7Synthesis of 4-({1,2-dihydrospiro[cyclopentane-1,3-pyrrolo[3,2-c]pyridin]-1-yl}sulfonyl)-N,N-dimethylbenzene-1-sulfonamide (I-70)

[0510] ##STR00403##

Step 1. Synthesis of 1-(4-chloropyridin-3-yl)cyclopentane-1-carbonitrile

[0511] 2-(4-chloropyridin-3-yl)acetonitrile (10 g, 65.5 mmol) was added to a slurry of sodium hydride (60% w/w; 7.83 g, 196 mmol) in anhydrous THF (300 mL) at room temperature over 30 min. The reaction mixture was stirred for 3 h and cooled to 0 C. 1,4-dibromobutane (14.1 g, 65.5 mmol) was added over 15 min. them the reaction mixture was allowed to warm up to room temperature and stir for 18 h. Then it was poured in water (300 mL) and extracted with ethyl acetate (200 mL3). The organic layer was washed with water (500 mL) and brine (500 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to afford 1-(4-chloropyridin-3-yl)cyclopentane-1-carbonitrile as beige oil (10.2 g, 49.3 mmol, 95% purity, 75.5% yield).

Step 2. Synthesis of 1,2-dihydrospiro[cyclopentane-1,3-pyrrolo[3,2-c]pyridine]

[0512] 1-(4-chloropyridin-3-yl)cyclopentane-1-carbonitrile (2 g, 9.67 mmol) was added to a slurry of lithium aluminium hydride (0.550 g, 14.5 mmol) in anhydrous THF (150 mL) at 0 C. over 30 min and the reaction mixture was allowed to warm up and stir at room temperature for 18 h. Then, it was cooled to 0 C. and quenched with water (2 mL) and diluted with ethyl acetate (100 mL). The organic layer was separated, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to afford 1,2-dihydrospiro[cyclopentane-1,3-pyrrolo[3,2-c]pyridine] (0.8 g, 4.59 mmol, 95% purity, 45.2% yield).

Step 3. Synthesis of 4-({1,2-dihydrospiro[cyclopentane-1,3-pyrrolo[3,2-c]pyridin]-1-yl}sulfonyl)-N,N-dimethylbenzene-1-sulfonamide

[0513] Pyridine (0.271 g, 3.43 mmol) and 4-(dimethylsulfamoyl)benzene-1-sulfonyl chloride (0.649 g, 2.29 mmol) were added to a solution of 1,2-dihydrospiro[cyclopentane-1,3-pyrrolo[3,2-c]pyridine] (0.4 g, 2.29 mmol) in acetonitrile (25 mL). The reaction mixture was stirred at room temperature for 18 h until completion (TLC control) and the solvent was removed under reduced pressure. The residue was subjected to HPLC purification (deionized water/HPLC-grade acetonitrile) that afforded the 4-({1,2-dihydrospiro[cyclopentane-1,3-pyrrolo[3,2-c]pyridin]-1-yl}sulfonyl)-N,N-dimethylbenzene-1-sulfonamide, 1-70. Yield: 85.9 mg, 8.45%; Appearance: Beige solid; .sup.1H NMR (400 MHz, DMSO-d.sub.6) 8.50-8.32 (m, 2H), 8.14 (d, J=8.0 Hz, 2H), 7.96 (d, J=8.2 Hz, 2H), 7.44 (d, J=5.5 Hz, 1H), 3.81 (s, 2H), 2.61 (s, 6H), 1.70 (d, J=32.7 Hz, 6H), 1.55 (s, 2H); HPLC purity: 96.07%; LCMS Calculated for C.sub.19H.sub.23N.sub.3O.sub.4S.sub.2: 421.53; Observed: 422.0 [M+H].sup.+.

Example 8Synthesis of 4-({1,2-dihydrospiro[cyclopentane-1,3-pyrrolo[2,3-b]pyridin]-1-yl}sulfonyl)-N,N-dimethylbenzene-1-sulfonamide (I-71)

[0514] ##STR00404##

Step 1. Synthesis of 1-(2-chloropyridin-3-yl)cyclopentane-1-carbonitrile

[0515] 2-(2-chloropyridin-3-yl)acetonitrile (2 g, 13.1 mmol) was added to a slurry of sodium hydride (60% w/w; 0.314 g, 13.1 mmol) in anhydrous THF (50 m L) at room temperature over 30 min. The reaction mixture was stirred for 3 h and cooled to 0 C. 1,4-dibromobutane (2.82 g, 13.1 mmol) was added over 15 min to it. Then the reaction mixture was allowed to warm up to room temperature and stir for 18 h. After it was poured in water (50 mL) and extracted with ethyl acetate (50 mL3). The organic layer was washed with water (50 mL) and brine (50 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to afford 1-(2-chloropyridin-3-yl)cyclopentane-1-carbonitrile (2.69 g, 13 mmol, 95% purity, 94.4% yield).

Step 2. Synthesis of 1,2-dihydrospiro[cyclopentane-1,3-pyrrolo[2,3-b]pyridine]

[0516] 1-(2-chloropyridin-3-yl)cyclopentane-1-carbonitrile (1 g, 4.83 mmol) was added to a slurry of lithium aluminium hydride (0.201 g, 5.31 mmol) in anhydrous THF (30 mL) at 0 C. over 30 min and the reaction mixture was allowed to warm up and stir at room temperature for 18 h. Then, it was cooled to 0 C. and quenched with water (5 mL) and diluted with ethyl acetate (50 mL). The organic layer was separated, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to afford 1,2-dihydrospiro[cyclopentane-1,3-pyrrolo[2,3-b]pyridine] (0.5 g, 2.86 mmol, 85% purity, 50.5% yield) that was used in next step without further purification.

Step 3. Synthesis of 4-({1,2-dihydrospiro[cyclopentane-1,3-pyrrolo[2,3-b]pyridin]-1-yl}sulfonyl)-N,N-dimethylbenzene-1-sulfonamide

[0517] Pyridine (2.26 g, 28.6 mmol) and 4-(dimethylsulfamoyl)benzene-1-sulfonyl chloride (0.89 g, 3.14 mmol) were added to a solution of 1,2-dihydrospiro[cyclopentane-1,3-pyrrolo[2,3-b]pyridine] (0.5 g, 2.86 mmol) in acetonitrile (5 mL). The solution was stirred overnight and evaporated. The residue was subjected to HPLC purification (deionized water/HPLC-grade acetonitrile) that afforded 4-({1,2-dihydrospiro[cyclopentane-1,3-pyrrolo[2,3-b]pyridin]-1-yl}sulfonyl)-N,N-dimethylbenzene-1-sulfonamide, I-71. Yield: 100.0 mg, 7.98%, Appearance: Yellow solid; .sup.1H NMR (400 MHz, DMSO-d.sub.6) 8.34-8.16 (m, 2H), 8.07 (dq, J=5.2, 1.7 Hz, 1H), 7.94 (dq, J=8.4, 1.6 Hz, 2H), 7.61 (dt, J=7.5, 1.7 Hz, 1H), 7.00 (tq, J=5.3, 1.6 Hz, 1H), 4.01-3.74 (m, 2H), 2.63 (q, J=1.6 Hz, 6H), 1.76 (d, J=12.8 Hz, 8H); H PLC purity: 100%; LCMS Calculated for C.sub.19H.sub.23N.sub.3O.sub.4S.sub.2: 421.53; Observed: 422.2 [M+H].sup.+.

Example 9Synthesis of 4-({4-hydroxy-1,2-dihydrospiro[cyclohexane-1,3-indol]-1-yl}sulfonyl)-N,N-dimethylbenzene-1-sulfonamide. (I-72)

[0518] ##STR00405##

Step 1. Synthesis of 1,2-dihydrospiro[cyclohexane-1,3-indol]-4-ol

[0519] A solution of 1,2-dihydrospiro[cyclohexane-1,3-indole]-2,4-dione (1 g, 4.64 mmol) in anhydrous THF (10 mL) was added to a solution of LiAlH4 (0.44 g, 11.57 mmol) in anhydrous THF (15 mL) at 0 C. dropwise for 1 hour. Then the reaction mixture was refluxed for 4 hours, cooled to room temperature and quenched with water (1.76 mL). The resulting mixture was filtered and the filter cake was washed with a mixture of DCM and MeOH (1/1 (v/v), 20 mL). The filtrate was concentrated in vacuum to give 1,2-dihydrospiro[cyclohexane-1,3-indol]-4-ol (0.6 g, 2.95 mmol, 90% purity, 57.2% yield).

Step 2. Synthesis of 4-({4-hydroxy-1,2-dihydrospiro[cyclohexane-1,3-indol]-1-yl}sulfonyl)-N,N-dimethylbenzene-1-sulfonamide

[0520] 4-(dimethylsulfamoyl)benzene-1-sulfonyl chloride (0.278 g, 0.983 mmol) was added to a solution of 1,2-dihydrospiro[cyclohexane-1,3-indol]-4-ol (0.2 g, 0.983 mmol) and pyridine (0.621 g, 7.86 mmol) in DCM (5 mL) and the reaction mixture was stirred for 6 h. After it was diluted with water (5 mL) and the product extracted with DCM (5 mL2). The combined organic layers were washed with brine (10 mL), dried over MgSO4, filtered and concentrated under reduced pressure. The residue was subjected to HPLC purification (deionized water/HPLC-grade acetonitrile) to give 4-({4-hydroxy-1,2-dihydrospiro[cyclohexane-1,3-indol]-1-yl}sulfonyl)-N,N-dimethylbenzene-1-sulfonamide, I-72. Yield: 65.3 mg, 14.16%; Appearance: White solid; .sup.1H NMR (500 MHz, DMSO-d.sub.6) 8.10-8.02 (m, 2H), 7.91 (dt, J=11.6, 3.5 Hz, 2H), 7.52 (d, J=7.9 Hz, 1H), 7.26 (t, J=8.0 Hz, 1H), 7.16 (d, J=7.7 Hz, 1H), 7.07 (q, J=7.8 Hz, 1H), 3.81 (s, 2H), 3.47-3.33 (m, 1H), 2.58 (d, J=1.8 Hz, 6H), 1.85-1.54 (m, 2H), 1.46 (d, J=14.0 Hz, 3H), 1.31-0.48 (m, 3H); HPLC purity: 75.86%; LCMS Calculated for C.sub.21H.sub.26N.sub.2O.sub.5S.sub.2:450.57; Observed: 451.2 [M+H].sup.+.

Example 10Synthesis of 4-{[1-(2,2-dimethylpropanoyl)-1,2-dihydrospiro[indole-3,3-pyrrolidin]-1-yl]sulfonyl}-N,N-dimethylbenzene-1-sulfonamide (I-73)

[0521] ##STR00406##

Step 1. Synthesis of 1-{1,2-dihydrospiro[indole-3,3-pyrrolidin]-1-yl}-2,2-dimethylpropan-1-one

[0522] 1,2-dihydrospiro[indole-3,3-pyrrolidine] dihydrochloride (0.5 g, 2.02 mmol) and triethylamine (0.714 g, 7.06 mmol) were dissolved in dichloromethane (5 mL), the mixture was cooled to 0 C. and 2,2-dimethylpropanoyl chloride (0.243 g, 2.02 mmol) was added to it dropwise. The mixture was stirred overnight at room temperature and then washed with water (5 mL), brine (5 mL). The organic layer was dried over Na.sub.2SO.sub.4, filtered and the filtrate was evaporated under reduced pressure to afford 1-{1,2-dihydrospiro[indole-3,3-pyrrolidin]-1-yl}-2,2-dimethylpropan-1-one (0.6 g, 2.32 mmol, 79.55% purity, 91.5% yield) that was used in next step without further purification.

Step 2. Synthesis of 4-{[1-(2,2-dimethylpropanoyl)-1,2-dihydrospiro[indole-3,3-pyrrolidin]-1-yl]sulfonyl}-N,N-dimethylbenzene-1-sulfonamide

[0523] 4-(dimethylsulfamoyl)benzene-1-sulfonyl chloride (0.65 g, 2.29 mmol) was added to the mixture of crude 1-{1,2-dihydrospiro[indole-3,3-pyrrolidin]-1-yl}-2,2-dimethylpropan-1-one (0.6 g, 1.84 mmol, 79.55% purity) and pyridine (0.25 g, 3.16 mmol) in dry THE (20 mL). The reaction mixture was refluxed for 4 h and evaporated under reduced pressure. The crude material was purified by HPLC (deionized water/HPLC-grade methanol) to give 4-{[1-(2,2-dimethylpropanoyl)-1,2-dihydrospiro[indole-3,3-pyrrolidin]-1-yl]sulfonyl}-N,N-dimethy-lbenzene-1-sulfonamide, 1-73. Yield: 25.0 mg, 2.54%; Appearance: Pink solid; .sup.1H NMR (600 MHz, DMSO-d.sub.6) 8.11-7.97 (m, 2H), 7.95-7.84 (m, 2H), 7.53 (d, J=8.2 Hz, 1H), 7.33-7.26 (m, 1H), 7.16 (s, 1H), 7.08 (td, J=7.6, 1.0 Hz, 1H), 3.90 (q, 0.1=11.3 Hz, 2H), 3.34 (s, 4H), 2.59 (s, 6H), 1.71 (d, J=66.5 Hz, 2H), 1.06 (s, 9H); HPLC purity: 100%; LCMS Calculated for C.sub.24H.sub.31N.sub.3O.sub.5S.sub.2: 505.65; Observed: 506.2 [M+H].sup.+.

Example 11Synthesis of 1-(3-methylbenzenesulfonyl)-1,2-dihydrospiro[cyclopentane-1,3-indole] (I-74)

[0524] ##STR00407##

[0525] 3-methylbenzene-1-sulfonyl chloride (0.5 g, 2.62 mmol) was added to the mixture of 1,2-dihydrospiro[cyclopentane-1,3-indole] (0.453 g, 2.62 mmol) and pyridine (0.310 g, 3.93 mmol) in dry THF (20 mL). The reaction mixture was stirred overnight and evaporated. The residue was subjected to HPLC purification (deionized water/HPLC-grade methanol, ammonia) that afforded 1-(3-methylbenzenesulfonyl)-1,2-dihydrospiro[cyclopentane-1,3-indole], 1-74. Yield: 92.5 mg, 10.2%; Appearance: Pink solid; .sup.1H NMR (600 MHz, DMSO-d.sub.6) 7.63 (s, 1H), 7.56 (d, J=7.8 Hz, 1H), 7.43 (dt, J=18.8, 7.9 Hz, 3H), 7.24-7.15 (m, 1H), 7.13 (dd, J=7.6, 1.2 Hz, 1H), 7.01-6.94 (m, 1H), 3.67 (s, 2H), 2.31 (s, 3H), 1.81-1.66 (m, 2H), 1.62 (dddd, J=19.2, 14.6, 9.9, 5.3 Hz, 2H), 1.58-1.51 (m, 2H), 1.50-1.33 (m, 2H); HPLC purity: 100%; LCMS Calculated for C.sub.19H.sub.21NO.sub.2S: 327.44; Observed: 328.0 [M+H].sup.+.

Example 12Synthesis of 1-{[1-(3-methylphenyl)-1H-pyrazol-4-yl]sulfonyl}-1,2-dihydrospiro[cyclopentane-1,3-indole] (I-75)

[0526] ##STR00408##

[0527] 1-(3-methylphenyl)-1H-pyrazole-4-sulfonyl chloride (0.5 g, 1.94 mmol) was added to the mixture of 1,2-dihydrospiro[cyclopentane-1,3-indole] (0.34 g, 1.96 mmol) and pyridine (0.23 g, 2.9 mmol) in dry THF (20 mL). The reaction mixture was stirred overnight at room temperature and evaporated. The residue was subjected to HPLC purification (deionized water/HPLC-grade methanol, ammonia) that afforded 1-{[1-(3-methylphenyl)-1H-pyrazol-4-yl]sulfonyl}-1,2-dihydrospiro[cyclopentane-1,3-indole], I-75. Yield: 64.0 mg, 8.0%; Appearance: Yellow solid; .sup.1H NMR (400 MHz, DMSO-d.sub.6) 9.23 (s, 1H), 8.13 (s, 1H), 7.72 (s, 1H), 7.65 (d, J=8.1 Hz, 1H), 7.49 (d, J=8.0 Hz, 1H), 7.39 (t, J=7.9 Hz, 1H), 7.20 (q, J=7.0 Hz, 3H), 7.02 (t, J=7.5 Hz, 1H), 3.73 (s, 2H), 2.36 (s, 3H), 1.89-1.56 (m, 8H); HPLC purity: 100%; LCMS Calculated for C.sub.22H.sub.23N.sub.3O.sub.2S: 393.51; Observed: 394.2 [M+H].sup.+.

Example 13Synthesis of 4-({1,2-dihydrospiro[indole-3,3-oxolan]-1-yl}sulfonyl)-N,N-dimethylbenzene-1-sulfonamide (I-76)

[0528] ##STR00409##

Step 1. Synthesis of 3-(2-bromophenyl)oxolane-3-carbonitrile

[0529] 2-(2-bromophenyl)acetonitrile (3 g, 15.3 mmol) was added portionwise to the suspension of sodium hydride (1.83 g, 45.9 mmol, 60 w %) in DMF (20 mL) at 0 C. The mixture was stirred 30 min at this temperature and 1-bromo-2-(chloromethoxy)ethane (2.65 g, 15.3 mmol)) was added portionwise at the same temperature. After the mixture was allowed to warm up to room temperature and stir overnight until completion. The solvent was evaporated under reduced pressure, the residue was treated with water/ethyl acetate mixture (30 mL/30 mL). The organic layer was separated, dried over sodium sulfate, filtered and evaporated under reduced pressure. The crude product was purified by flash chromatography (hexane/MTBE) to afford 3-(2-bromophenyl)oxolane-3-carbonitrile (1.6 g, 6.34 mmol, 95% purity, 39.4% yield).

Step 2. Synthesis of 1,2-dihydrospiro[indole-3,3-oxolan]-2-one

[0530] Potassium iodide (0.105 g, 0.634 mmol), copper iodide (0.120 g, 0.634 mmol), and N-acetylglycine (0.0742 g, 0.634 mmol) were added to a solution of 3-(2-bromophenyl)oxolane-3-carbonitrile (1.6 g, 6.34 mmol) and sodium hydroxide (0.76 g, 19 mmol) in tert-butanol (20 mL). The mixture was refluxed for 24 h, then cooled to room temperature, filtered through silica, and the filtrate was evaporated to dryness. The residue was treated with water/ethyl acetate mixture (50 mL/50 mL). The organic layer was separated, dried over sodium sulfate, filtered and evaporated under reduced pressure. The crude product was purified by flash chromatography (chloroform/MTBE) to afford 1,2-dihydrospiro[indole-3,3-oxolan]-2-one (0.4 g, 2.11 mmol, 95% purity, 31.9% yield).

Step 3. Synthesis of 1,2-dihydrospiro[indole-3,3-oxolane]

[0531] 10 M dimethylsulfide borane complex solution in THF (0.63 mL, 0.480 g, 6.32 mmol) was added to a solution of 1,2-dihydrospiro[indole-3,3-oxolan]-2-one (0.4 g, 2.11 mmol) in dry THF (20 mL), the mixture was refluxed for 2 h and cooled to room temperature. Then methanol (10 mL) was added dropwise, the mixture was refluxed for 2 h, cooled to room temperature and evaporated under reduced pressure. The residue was treated with water/ethyl acetate mixture (20 mL/20 mL). The organic layer was separated, dried over sodium sulfate, filtered and evaporated under reduced pressure to afford crude 1,2-dihydrospiro[indole-3,3-oxolane] (0.3 g, 1.71 mmol, 46.6% purity, 37.6% yield) that was used in the next step without further purification.

Step 4. Synthesis of 4-({1,2-dihydrospiro[indole-3,3-oxolan]-1-yl}sulfonyl)-N,N-dimethylbenzene-1-sulfonamide

[0532] 4-(dimethylsulfamoyl)benzene-1-sulfonyl chloride (0.485 g, 1.71 mmol) was added to the mixture of 1,2-dihydrospiro[indole-3,3-oxolane] (0.3 g, 1.71 mmol) and pyridine (0.202 g, 2.56 mmol) in dry THF (20 mL). The reaction mixture was stirred overnight and evaporated to dryness. The residue was subjected to HPLC purification (deionized water/HPLC-grade methanol) that afforded 4-({1,2-dihydrospiro[indole-3,3-oxolan]-1-yl}sulfonyl)-N,N-dimethylbenzene-1-sulfonamide, I-76. Yield: 133.7 mg, 17.5%; Appearance: Yellow solid; .sup.1H NMR (400 MHz, DMSO-d.sub.6) 8.04 (dd, J=8.4, 1.6 Hz, 2H), 7.93 (dd, J=8.4, 1.6 Hz, 2H), 7.54 (d, J=8.1 Hz, 1H), 7.31 (t, J=8.0 Hz, 1H), 7.26 (d, J=7.5 Hz, 1H), 7.11 (t, J=7.5 Hz, 1H), 3.93 (s, 2H), 3.88 (dd, J=8.5, 4.7 Hz, 1H), 3.80 (q, 1=7.8 Hz, 1H), 2.60 (d, J=1.6 Hz, 6H), 1.97-1.89 (m, 1H), 1.83 (dq, J=12.5, 6.6, 6.0 Hz, 1H); HPLC purity: 100%; LCMS Calculated for C.sub.9H.sub.22N.sub.2O.sub.5S.sub.2: 422.52; Observed: 423.0 [M+H].sup.+.

Example 14Synthesis of 4-({1,2-dihydrospiro[indole-3,2-oxolan]-1-yl}sulfonyl)-N,N-dimethylbenzene-1-sulfonamide (I-77)

[0533] ##STR00410## ##STR00411##

Step 1. Synthesis of 2-(2-bromophenyl)-1,3-dioxane

[0534] Propane-1,3-diol (2.26 g, 29.7 mmol) and p-TsOH (0.464 g, 2.7 mmol) were added to a solution of 2-bromobenzaldehyde (5 g, 27 mmol) in toluene (50 mL). The mixture was stirred at 120 C. with Dean-Stark apparatus until complete water removal from reaction mixture (overnight). After cooling to room temperature, the reaction mixture was washed with brine (50 mL) and dried over magnesium sulfate. The evaporation under reduced pressure afforded 2-(2-bromophenyl)-1,3-dioxane (6 g, 24.6 mmol, 100/6 purity, 91.4% yield).

Step 2. Synthesis of 2-(2-bromophenyl)-2-(3-hydroxypropoxy)acetonitrile

[0535] Zinc iodide (1.96 g, 6.15 mmol) was added to an ice-cold solution of 2-(2-bromophenyl)-1,3-dioxane (3 g, 12.3 mmol) in DCM (30 mL) followed by addition of trimethylsilyl cyanide (1.82 g, 18.4 mmol) over a period of 10 minutes keeping the temperature at 0 C. After cooling was removed and the reaction was stirred for 40 hours at room temperature until the completion (TLC control). The mixture was poured into water (60 mL) and extracted with DCM (60 mL3), the combined organic layers were washed with brine (80 mL), dried over magnesium sulfate and concentrated in vacuo. The purification of residue by column chromatography (chloroform/acetonitrile) afforded 2-(2-bromophenyl)-2-(3-hydroxypropoxy)acetonitrile (0.5 g, 1.85 mmol, 95% purity, 14.3% yield).

Step 3. Synthesis of 2-(2-bromophenyl)-2-(3-bromopropoxy)acetonitrile

[0536] A solution of 2-(2-bromophenyl)-2-(3-hydroxypropoxy)acetonitrile (0.5 g, 1.85 mmol) and tetrabromomethane (1.71 g, 5.18 mmol) in DCM (30 mL) was cooled to 0 C. and the solution of triphenylphosphine (1.35 g, 5.18 mmol) in DCM (10 mL) was added dropwise over a period of 5 minutes. The reaction was stirred for 2 hours at 0 C. and then allowed to warm to room temperature. Ether (50 mL) was added to the mixture and the cloudy solution was filtered through a plug of celite. The filtrate was concentrated in vacuo and purified by flash chromatography (MTBE/hexane) to yield 2-(2-bromophenyl)-2-(3-bromopropoxy)acetonitrile (0.55 g, 1.65 mmol, 95% purity, 84.7% yield).

Step 4. Synthesis of 2-(2-bromophenyl)oxolane-2-carbonitrile

[0537] A solution of 2-(2-bromophenyl)-2-(3-bromopropoxy)acetonitrile (0.55 g, 1.65 mmol) in THF (60 mL) was cooled to 78 C. followed by addition of lithium bis(trimethylsilyl)amide (0.441 g, 2.64 mmol) 1M solution in THF (2.7 mL) and the resulting mixture was stirred for 1 hour at 78 C. After sat. aq. NH.sub.4C.sub.1 solution (10 mL) was added and the mixture was allowed to warm to room temperature. The reaction mixture was diluted with water (10 mL) and the product was extracted with ethyl acetate (15 mL3). The combined organic layers were washed with brine (30 mL), dried over magnesium sulfate, filtered and concentrated in vacuo to give 2-(2-bromophenyl)oxolane-2-carbonitrile (0.3 g, 1.18 mmol, 95% purity, 72.2% yield).

Step 5. Synthesis of 1-[2-(2-bromophenyl)oxolan-2-yl]methanamine

[0538] A solution of 2-(2-bromophenyl)oxolane-2-carbonitrile (0.3 g, 1.22 mmol) in THF (20 mL) was cooled to 0 C. followed by addition of BH.sub.3 dimethyl sulfide complex (0.268 g, 3.54 mmol) solution in THF under argon atmosphere. The resulting mixture was stirred at room temperature for 5 h. Then the mixture was cooled to 0 C. and methanol (10 mL) was added to quench the reaction. The resulting mixture was stirred under reflux conditions for 0.5 h. Following concentration under reduced pressure afforded 1-[2-(2-bromophenyl)oxolan-2-yl]methanamine (0.04 g, 0.156 mmol, 95.78% purity, 12.8% yield).

Step 6. Synthesis of N4-{[2-(2-bromophenyl)oxolan-2-yl]methyl}-N1,N1-dimethylbenzene-1,4-disulfonamide

[0539] 4-(dimethylsulfamoyl)benzene-1-sulfonyl chloride (0.05 g, 0.176 mmol) was added to a solution of 1-[2-(2-bromophenyl)oxolan-2-yl]methanamine (0.04 g, 0.156 mmol) and pyridine (0.037 g, 0.468 mmol) in DCM (5 mL). The reaction mixture was stirred at room temperature for 24 h. Then NH.sub.4Cl sat. aq. solution (10 mL) was added to the reaction mixture and the product was extracted with DCM (10 mL2). Combined organic layers were dried over magnesium sulfate, filtered and concentrated in vacuum to give N4-{[2-(2-bromophenyl)oxolan-2-yl]methyl}-N1,N1-dimethylbenzene-1,4-disulfonamide (0.1 g, 0.168 mmol, 88% purity, 95.2% yield) that was used in next step without further purification.

Step 7. Synthesis of 4-{[(3R)-1,2-dihydrospiro[indole-3,2-oxolan]-1-yl]sulfonyl}-N,N-dimethylbenzene-1-sulfonamide

[0540] A mixture of CuI (0.0754 g, 0.396 mmol), CsOAc (0.264 g, 1.38 mmol) and N4-{[2-(2-bromophenyl)oxolan-2-yl]methyl}-N1,N1-dimethylbenzene-1,4-disulfonamide (0.100 g, 0.198 mmol) in a 10 mL round-bottom flask was dried under high-vacuum for 0.5 h. After the flask was purged with argon, anhydrous DMSO (2.0 mL) was added and the mixture was heated at 100 C. for 24 h under argon atmosphere. After the mixture was diluted with ethyl acetate (30 mL) and sequentially washed with NH.sub.4Cl sat. aq. solution (10 mL) and 1 M aq HCl solution (10 mL), brine (20 mL). The organic layer was dried over magnesium sulfate and concentrated to afford crude product which was subjected to HPLC purification (deionized water/HPLC-grade methanol) to afford 4-{[1,2-dihydrospiro[indole-3,2-oxolan]-1-yl]sulfonyl}-N,N-dimethylbenzene-1-sulfonamide, I-77. Yield: 32.8 mg, 39.2%; Appearance: Yellow solid; .sup.1H NMR (400 MHz, DMSO-d.sub.6) 8.07-7.98 (m, 2H), 7.90 (dd, J=8.6, 1.8 Hz, 2H), 7.56 (d, J=8.1 Hz, 1H), 7.45-7.23 (m, 2H), 7.13 (t, J=7.4 Hz, 1H), 3.96-3.80 (m, 2H), 3.72 (d, J=6.3 Hz, 2H), 2.60 (d, J=1.7 Hz, 6H), 2.12-1.82 (m, 4H). HPLC purity: 95.43%; LCMS Calculated for C.sub.19H.sub.22N.sub.2O.sub.5S.sub.2: 422.52, Observed: 423.0 [MH].sup.+.

Example 15Synthesis of N,N-dimethyl-4-(spiro[cyclopentane-1,3-pyrrolo[3,2-b]pyridin]-1(2H)-ylsulfonyl)benzenesulfonamide (I-78)

[0541] ##STR00412##

Step 1. Synthesis of 1-(3-bromopyridin-2-yl)cyclopentanecarbonitrile

[0542] 2-(3-bromopyridin-2-yl)acetonitrile (2 g, 10.1 mmol) was added dropwise to the suspension of sodium hydride (60 w %, 1.21 g, 30.3 mmol) in DMF (20 mL) at 0 C. The mixture was stirred for 30 min at this temperature and 1,4-dibromobutane (2.18 g, 10.1 mmol) was slowly added. The solution was allowed to warm up to room temperature and stir overnight. After, the solvent was evaporated under reduced pressure, the residue was treated with mixture water (30 mL)/ethyl acetate (30 mL). The organic layer was separated, the water layer was extracted with ethyl acetate (30 mL2). The combined organic layers were dried over sodium sulfate, filtered and evaporated under reduced pressure. The residue was purified by column chromatography (hexane/MTBE) to afford 1-(3-bromopyridin-2-yl)cyclopentanecarbonitrile (1.2 g, 4.77 mmol, 95% purity, 45.0% yield).

Step 2. Synthesis of 1,2-dihydrospiro[cyclopentane-1,3-pyrrolo[3,2-b]pyridin]-2-one

[0543] Potassium iodide (0.0791 g, 0.477 mmol), copper iodide (0.0908 g, 0.477 mmol), and 2-acetamidoacetic acid (0.0558 g, 0.477 mmol) were added to the solution of 1-(3-bromopyridin-2-yl)cyclopentane-1-carbonitrile (1.2 g, 4.77 mmol)) followed by NaOH (0.571 g, 14.3 mmol) solution in t-BuOH (20 mL). The mixture was refluxed for 24 h, then filtered through silica, evaporated under reduced pressure. Water (30 mL) was added to the residue, and the product was extracted with ethyl acetate (30 mL3). Combined organic layers were dried over sodium sulfate, filtered and evaporated to afford crude product that was purified by column chromatography (chloroform/ethyl acetate) to give 1,2-dihydrospiro[cyclopentane-1,3-pyrrolo[3,2-b]pyridin]-2-one (0.5 g, 2.65 mmol, 95% purity, 52.9% yield).

Step 3. Synthesis of 1,2-dihydrospiro[cyclopentane-1,3-pyrrolo[3,2-b]pyridine]

[0544] Dimethylsulfide borane complex (0.603 g, 7.95 mmol, 0.795 mL of 10 M in THF solution) was added to the solution of 1,2-dihydrospiro[cyclopentane-1,3-pyrrolo[3,2-b]pyridin]-2-one (0.5 g, 2.65 mmol) in dry THF (20 mL). The reaction mixture was refluxed until completion (TLC control, 2 h). Then methanol (10 mL) was added dropwise, the solvent was evaporated, water (20 mL) was added and the product was extracted with ethyl acetate (20 mL3). After flash chromatography (chloroform-ethyl acetate) 1,2-dihydrospiro[cyclopentane-1,3-pyrrolo[3,2-b]pyridine] (0.3 g, 1.72 mmol, 95% purity, 65% yield) was obtained.

Step 4. Synthesis of N,N-dimethyl-4-(spiro[cyclopentane-1,3-pyrrolo[3,2-b]pyridin]-1(2H)-ylsulfonyl)benzenesulfonamide

[0545] 4-(dimethylsulfamoyl)benzene-1-sulfonyl chloride (0.488 g, 1.72 mmol) was added to the mixture of 1,2-dihydrospiro[cyclopentane-1,3-pyrrolo[3,2-b]pyridine] (0.3 g, 1.72 mmol) and pyridine (0.203 g, 2.57 mmol) in dry THF (20 mL). The reaction mixture was stirred overnight and evaporated. The residue was subjected to HPLC purification (deionized water/HPLC-grade methanol) that afforded N,N-dimethyl-4-(spiro[cyclopentane-1,3-pyrrolo[3,2-b]pyridin]-1(2H)-ylsulfonyl)benzenesulfonamide, 1-78. Yield: 168.4 mg, 21.9%; Appearance: Beige solid; .sup.1H NMR (400 MHz, DMSO-d.sub.6) 8.21 (dd, 1=4.9, 1.4 Hz, 1H), 8.07 (d, J=8.3 Hz, 2H), 7.94 (d, J=8.3 Hz, 2H), 7.81 (dd, J=8.1, 1.4 Hz, 1H), 7.30-7.20 (m, 1H), 3.84 (s, 2H), 2.59 (d, J=1.8 Hz, 6H), 1.79-1.55 (m, 6H), 1.37 (s, 2H). HPLC purity: 100%; LCMS Calculated for C.sub.19H.sub.23N.sub.3O.sub.4S.sub.2: 421.53; Observed: 422.2 [MH].sup.+.

Example 16Synthesis of N,N-dimethyl-4-((6-methylspiro[cyclopentane-1,3-indolin]-1-yl)sulfonyl)benzenesulfonamide (I-79)

[0546] ##STR00413## ##STR00414##

Step 1. Synthesis of (2-bromo-4-methylphenyl)methanol

[0547] Sodium borohydride (0.283 g, 7.45 mmol) was added portionwise to a solution of 2-bromo-4-methylbenzaldehyde (3 g, 15 mmol) in methanol (30 mL). The reaction mixture was stirred overnight at room temperature and the solvent was evaporated under reduced pressure. The residue was partitioned between water/ethyl acetate (50 mL/50 mL). The organic layer was separated, dried over sodium sulfate, filtered and evaporated under reduced pressure to afford (2-bromo-4-methylphenyl)methanol (2.8 g, 13.9 mmol, 90% purity, 83.7% yield) that was used for the next step without further purification.

Step 2. Synthesis of 2-bromo-1-(chloromethyl)-4-methylbenzene

[0548] Thionyl chloride (1.97 g, 16.6 mmol) was added dropwise to a solution of (2-bromo-4-methylphenyl)methanol (2.8 g, 13.9 mmol) in dichloromethane (30 mL) and the mixture was stirred overnight at room temperature. After reaction completion (NMR control) the mixture was washed with water (30 mL3) and concentrated in vacuum to afford 2-bromo-1-(chloromethyl)-4-methylbenzene (2.3 g, 10.4 mmol, 85% purity, 63.9% yield) that was used in next step without further purification.

Step 3. Synthesis of 2-(2-bromo-4-methylphenyl)acetonitrile

[0549] Potassium cyanide (1.01 g, 15.6 mmol) was added to a solution of 2-bromo-1-(chloromethyl)-4-methylbenzene (2.3 g, 10.4 mmol) in DMSO (20 mL), the mixture was stirred overnight and diluted with water (40 mL). The product was extracted with ethyl acetate (50 mL2), combined organic layers were dried over sodium sulfate, filtered and evaporated under reduced pressure to afford 2-(2-bromo-4-methylphenyl)acetonitrile (1.7 g, 8.09 mmol, 90% purity, 70.1% yield) that was used in next step without further purification.

Step 4. Synthesis of 1-(2-bromo-4-methylphenyl)cyclopentane-1-carbonitrile

[0550] 2-(2-bromo-4-methylphenyl)acetonitrile (1.7 g, 8.09 mmol) was added portionwise to the suspension of sodium hydride (0.966 g, 24.2 mmol, 60 w %) in DMF (20 mL) at 0 C. The mixture was stirred 30 min at this temperature and 1,4-dibromobutane (1.74 g, 8.09 mmol) was added portionwise at the same temperature. After the mixture was allowed to warm up to room temperature and stir overnight until completion. The solvent was evaporated under reduced pressure, the residue was treated with water/ethyl acetate mixture (30 mL/30 mL). The organic layer was separated, dried over sodium sulfate, filtered and evaporated under reduced pressure. The crude product was purified by flash chromatography (hexane/MTBE) to afford 1-(2-bromo-4-methylphenyl)cyclopentane-1-carbonitrile (0.6 g, 2.27 mmol, 95% purity, 26.7% yield).

Step 5. Synthesis of 6-methyl-1,2-dihydrospiro[cyclopentane-1,3-indol]-2-one

[0551] Potassium iodide (0.038 g, 0.228 mmol), copper iodide (0.043 g, 0.225 mmol), and N-acetylglycine (0.027 g, 0.230 mmol) were added to a solution of 1-(2-bromo-4-methylphenyl)cyclopentane-1-carbonitrile (0.6 g, 2.27 mmol) and sodium hydroxide (0.272 g, 6.81 mmol) in tert-butanol (20 mL). The mixture was refluxed for 24 h, then cooled to room temperature, filtered through silica, and the filtrate was evaporated to dryness. The residue was treated with water/ethyl acetate mixture (50 mL/50 mL). The organic layer was separated, dried over sodium sulfate, filtered and evaporated under reduced pressure. The crude product was purified by flash chromatography (chloroform/MTBE) to afford 6-methyl-1,2-dihydrospiro[cyclopentane-1,3-indol]-2-one (0.3 g, 1.49 mmol, 90% purity, 59.2% yield) that was used in next step without further purification.

Step 6. Synthesis of 6-methyl-1,2-dihydrospiro[cyclopentane-1,3-indole]

[0552] 10 M dimethylsulfide borane complex solution in THF (0.45 mL, 0.339 g, 4.47 mmol) was added to a solution of 6-methyl-1,2-dihydrospiro[cyclopentane-1,3-indol]-2-one (0.3 g, 1.49 mmol) in dry THF (20 mL), the mixture was refluxed for 2 h and cooled to room temperature. Then methanol (10 mL) was added dropwise, the mixture was refluxed for 2 h, cooled to room temperature and evaporated under reduced pressure. The residue was treated with water/ethyl acetate mixture (20 mL/20 mL). The organic layer was separated, dried over sodium sulfate, filtered and evaporated under reduced pressure to afford crude 6-methyl-1,2-dihydrospiro[cyclopentane-1,3-indole] (0.25 g, 1.33 mmol, 75% purity, 67% yield) that was used in the next step without further purification.

Step 7. Synthesis of N,N-dimethyl-4-({6-methyl-1,2-dihydrospiro[cyclopentane-1,3-indol]-1-yl}sulfonyl)benzene-1-sulfonamide

[0553] 4-(dimethylsulfamoyl)benzene-1-sulfonyl chloride (0.377 g, 1.33 mmol) was added to the mixture of 6-methylspiro[cyclopentane-1,3-indoline] (0.25 g, 1.33 mmol) and pyridine (0.157 g, 1.99 mmol) in dry tetrahydrofuran (20 mL). The reaction mixture was stirred overnight and evaporated to dryness. The residue was subjected to HPLC purification (deionized water/HPLC-grade methanol) that afforded the product as pink solid (0.0596 g, 0.137 mmol, 95% purity, 9.8% yield). The analytical data provided for this compound provisionally supports the proposed structure for N,N-dimethyl-4-((6-methylspiro[cyclopentane-1,3-indolin]-1-yl)sulfonyl)benzenesulfonamide, I-79. Yield: 59.6 mg, 9.8%; Appearance Pink solid; .sup.1H NMR (400 MHz, DMSO-d.sub.6) 8.04 (d, J=8.5 Hz, 2H), 7.97-7.88 (m, 2H), 7.34 (s, 1H), 7.05 (d, J=7.7 Hz, 1H), 6.89 (d, J=7.8 Hz, 1H), 3.73 (s, 2H), 2.33 (s, 3H), 1.73-1.54 (m, 4H), 1.48 (dd, J=12.8, 6.1 Hz, 2H), 1.31 (dd, J=11.8, 6.5 Hz, 2H). HPLC purity: 100%; LCMS Calculated for C.sub.21H.sub.26N.sub.2O.sub.4S.sub.2: 434.57; Observed 435.2 [MH].sup.+.

Example 17Synthesis of benzyl 1-(benzylsulfonyl)spiro[indoline-3,4-piperidine]-1-carboxylate (I-80)

[0554] ##STR00415##

[0555] Phenylmethanesulfonyl chloride (0.066 g, 0.346 mmol) was added to the vial containing benzyl 1,2-dihydrospiro[indole-3,4-piperidine]-1-carboxylate (0.101 g, 0.313 mmol) in dry pyridine (1 mL). The reaction mixture was heated at 100 C. with stirring for 16 h. After cooling to the room temperature the mixture was evaporated. The residue was dissolved in DMSO (2 mL), filtered from non-soluble impurities. The resulting filtrate was subjected to HPLC purification (deionized water/HPLC-grade acetonitrile) that afforded benzyl 1-(benzylsulfonyl)spiro[indoline-3,4-piperidine]-1-carboxylate, I-80. Yield: 28.8 mg, 16.6%; Appearance: Pink solid; .sup.1H NMR (400 MHz, DMSO-d.sub.6) 7.42-7.23 (m, 10H), 7.13 (dd, 1=15.1, 7.6 Hz, 3H), 7.03-6.88 (m, 1H), 5.06 (s, 2H), 4.50 (s, 2H), 4.02 (d, J=13.7 Hz, 2H), 3.68 (s, 2H), 1.71 (td, J=13.0, 4.5 Hz, 2H), 1.54 (d, J=13.5 Hz, 2H); HPLC purity: 100%; LCMS Calculated for C.sub.27H.sub.28N.sub.2O.sub.4S.sub.2: 476.59; Observed: 475.0 [MH].sup..

Example 18

[0556] The following example compound was prepared using standard chemical manipulations and procedures similar to those used in Example 17.

TABLE-US-00010 Compound No. Structure Analytical data I-81 [00416] Yield: 54.3 mg, 31.2%; Appearance: Pink solid; .sup.1H NMR (600 MHz, DMSO-d.sub.6) 7.96 (d, J = 8.1 Hz, 2H), 7.74 (d, J = 8.0 Hz, 2H), 7.47 (d, J = 8.1 Hz, 1H), 7.37-7.29 (m, 4H), 7.23-6.97 (m, 4H), 5.05 (d, J = 7.7 Hz, 2H), 3.90 (s, 2H), 3.86 (d, J = 13.7 Hz, 2H), 2.92 (d, J = 50.7 Hz, 2H), 1.55 (td, J = 13.1, 4.5 Hz, 2H), 1.07 (d, J = 13.2 Hz, 2H); HPLC purity: 100%; LCMS Calculated for C.sub.27H.sub.26F.sub.2N.sub.2O.sub.4S: 512.57; Observed: 513.2 [M + H].sup.+.

Example 19Synthesis of 1-methyl-1-phenylmethanesulfonyl-1,2-dihydrospiro[indole-3,4-piperidine] (I-82)

[0557] ##STR00417##

Step 1. Synthesis of tert-butyl 1-methyl-1,2-dihydrospiro[indole-3,4-piperidine]-1-carboxylate

[0558] A mixture of tert-butyl 1,2-dihydrospiro[indole-3,4-piperidine]-1-carboxylate (5 g, 17.3 mmol) and formaldehyde 37% aq. solution (5.83 mL, 78.9 mmol) in 1,2-dichloroethane (50 mL) was stirred at room temperature for 20 min followed by addition of sodium triacetoxyborohydride (8.14 g, 38.5 mmol). The reaction mixture was stirred for 15 h at room temperature and diluted with 1M sodium hydroxide aq. solution (100 mL). The product was extracted with dichloromethane (100 mL2). The combined organic layers were dried over sodium sulfate, filtered and evaporated to dryness to afford tert-butyl 1-methyl-1,2-dihydrospiro[indole-3,4-piperidine]-1-carboxylate (6 g, 19.8 mmol, 80% purity, 91.7% yield) that was used in next step without further purification.

Step 2. Synthesis of 1-methyl-1,2-dihydrospiro[indole-3,4-piperidine] dihydrochloride

[0559] tert-butyl 1-methyl-1,2-dihydrospiro[indole-3,4-piperidine]-1-carboxylate (4 g, 13.2 mmol) was dissolved in 1M HCl solution in methanol (100 mL). The reaction mixture was stirred for 1 h at room temperature, evaporated to dryness. Obtained residue was treated with ether (100 mL), formed solid was filtered-off, washed with ether (100 mL) and dried on air to give 1-methyl-1,2-dihydrospiro[indole-3,4-piperidine] dihydrochloride as yellow solid (3.5 g, 12.7 mmol, 95% purity, 91.4% yield).

Step 3. Synthesis of 1-methyl-1-phenylmethanesulfonyl-1,2-dihydrospiro[indole-3,4-piperidine]

[0560] Phenylmethanesulfonyl chloride (0.434 g, 2.28 mmol) was added to a solution of 1-methyl-1,2-dihydrospiro[indole-3,4-piperidine] dihydrochloride (0.6 g, 2.18 mmol) and pyridine (0.517 g, 6.54 mmol) in dichloromethane (10 mL), the reaction mixture was stirred for 16 h at room temperature and diluted with water (10 mL). The organic layer was separated, dried over sodium sulfate, filtered and evaporated under reduced pressure. The residue was purified by HPLC purification (deionized water/HPLC-grade methanol, ammonia) to give 1-methyl-1-phenylmethanesulfonyl-1,2-dihydrospiro[indole-3,4-piperidine], I-82. Yield: 135.0 mg, 16.4%; Appearance: Beige solid; .sup.1H NMR (600 MHz, DMSO-d.sub.6) 7.29 (dq, J=7.3, 4.8, 3.7 Hz, 5H), 7.21 (d, J=7.5 Hz, 1H), 7.15-7.06 (m, 2H), 6.96 (ddd, J=7.9, 6.2, 2.2 Hz, 1H), 4.61 (s, 2H), 3.61 (s, 2H), 2.67 (d, J=10.8 Hz, 2H), 2.14 (s, 3H), 1.87-1.69 (m, 4H), 1.53-1.39 (m, 2H). HPLC purity: 100%; LCMS Calculated for CH.sub.24N.sub.2O.sub.2S: 356.48; Observed: 357.4 [MH].sup.+.

Example 20

[0561] The following compounds were prepared using standard chemical manipulations and procedures similar to those used for the preparation in Example 19.

TABLE-US-00011 Compound No. Structure Analytical data I-83 [00418] Yield: 305.7 mg, 33.9%; Appearance: Beige solid; .sup.1H NMR (600 MHz, DMSO-d.sub.6) 7.95 (d, J = 8.1 Hz, 2H), 7.74 (d, J = 8.0 Hz, 2H), 7.47 (d, J = 8.0 Hz, 1H), 7.23- 6.97 (m, 4H), 3.78 (s, 2H), 2.58 (dt, J = 12.3, 3.2 Hz, 2H), 2.14 (s, 3H), 1.92-1.83 (m, 2H), 1.64 (td, J = 13.0, 4.0 Hz, 2H), 1.05-0.95 (m, 2H); HPLC purity: 100%; LCMS Calculated for C.sub.20H.sub.22F.sub.2N.sub.2O.sub.2S: 392.46; Observed: 393.2 [M + H].sup.+. I-84 [00419] Yield: 250.9 mg, 24.2%; Appearance: Beige solid; .sup.1H NMR (400 MHz, DMSO-d.sub.6) 8.05 (dd, J = 8.5, 1.7 Hz, 2H), 7.94-7.87 (m, 2H), 7.53 (d, J = 8.1 Hz, 1H), 7.31- 7.23 (m, 1H), 7.22-7.17 (m, 1H), 7.08 (td, J = 7.5, 1.2 Hz, 1H), 3.82 (s, 2H), 2.58 (d, J = 1.4 Hz, 8H), 2.16 (d, J = 1.4 Hz, 3H), 1.89 (t, J = 12.0 Hz, 2H), 1.72-1.62 (m, 2H), 0.97 (d, J = 12.8 Hz, 2H); HPLC purity: 100%; LCMS Calculated for C.sub.21H.sub.27N.sub.3O.sub.4S.sub.2: 449.59; Observed: 450.2 [M + H].sup.+.

Example 21Synthesis of 1-phenylmethanesulfonyl-1-(2,2,2-trifluoroethyl)-1,2-dihydrospiro[indole-3,4-piperidine] (I-85)

[0562] ##STR00420##

Step 1. Synthesis of tert-butyl 1-(2,2,2-trifluoroethyl)-1,2-dihydrospiro[indole-3,4-piperidine]-1-carboxylate

[0563] 2,2,2-trifluoroethyl trifluoromethanesulfonate (1.71 g, 7.37 mmol) was added to the mixture of tert-butyl spiro[indoline-3,4-piperidine]-1-carboxylate hydrochloride (2 g, 6.15 mmol) and ethylbis(propan-2-yl)amine (2.37 g, 18.4 mmol) in dry acetonitrile (25 mL). The reaction mixture was refluxed overnight, cooled to room temperature, poured into NaHCO.sub.3 sat. aq. solution (15 mL) and extracted with ethyl acetate (50 mL2). Combined organic layers were dried over anhydrous sodium sulfate, filtered and evaporated under reduced pressure to afford tert-butyl 1-(2,2,2-trifluoroethyl)-1,2-dihydrospiro[indole-3,4-piperidine]-1-carboxylate (1.9 g, 5.12 mmol, 91% purity, 75.7% yield) that was used in the next step without further purification.

Step 2. Synthesis of 1-(2,2,2-trifluoroethyl)-1,2-dihydrospiro[indole-3,4-piperidine]

[0564] tert-butyl 1-(2,2,2-trifluoroethyl)spiro[indoline-3,4-piperidine]-1-carboxylate (1.9 g, 5.12 mmol) was added to a stirred 1.5 M HCl solution in MeOH (20 mL), the resulting mixture was stirred overnight and evaporated. Crude residue was treated with NaHCO.sub.3 sat aq. solution to reach pH=8 and the product was extracted with dichlorimethane (20 mL3). Organic layers were combined, dried over sodium sulfate, filtered and evaporated under reduced pressure to give 1-(2,2,2-trifluoroethyl)-1,2-dihydrospiro[indole-3,4-piperidine] (1.1 g, 4.06 mmol, 95% purity, 75.3% yield).

Step 3. Synthesis of 1-phenylmethanesulfonyl-1-(2,2,2-trifluoroethyl)-1,2-dihydrospiro[indole-3,4-piperidine]

[0565] Phenylmethanesulfonyl chloride (0.192 g, 1.01 mmol) was added to the mixture of 1-(2,2,2-trifluoroethyl)spiro[indoline-3,4-piperidine] (0.25 g, 0.924 mmol) and ethylbis(propan-2-yl)amine (0.178 g, 1.38 mmol) in dry dichloromethane (5 mL). The reaction mixture was stirred overnight, poured into NaHCO.sub.3 aq. solution (15 mL) and extracted with dichloromethane (20 mL). Combined organic layers were dried over anhydrous sodium sulfate, filtered and evaporated under reduced pressure. Resulting solid was purified by HPLC (deionized water/HPLC-grade acetonitrile) to afford 1-phenylmethanesulfonyl-1-(2,2,2-trifluoroethyl)-1,2-dihydrospiro[indole-3,4-piperidine], I-85. Yield: 137.2 mg, 33.1%; Appearance: White solid; .sup.1H NMR (400 MHz, DMSO-d.sub.6) 7.37-7.19 (m, 6H), 7.14-7.03 (m, 2H), 6.95 (ddt, J=7.7, 5.6, 2.6 Hz, 1H), 4.60 (d, J=2.3 Hz, 2H), 3.63 (s, 2H), 3.14 (q, J=10.4 Hz, 2H), 2.82 (d, J=11.7 Hz, 2H), 2.31 (t, J=12.1 Hz, 2H), 1.78 (td, J=12.9, 4.0 Hz, 2H), 1.46 (d, J=13.1 Hz, 2H). HPLC purity: 100%; LCMS Calculated for C.sub.21H.sub.23F.sub.3N.sub.2O.sub.2S: 424.48; Observed: 425.2 [M+H].sup.+.

Example 22

[0566] The following compounds were prepared using standard chemical manipulations and procedures similar to those used for the preparation of Example 21.

TABLE-US-00012 Compound No. Structure Analytical data I-86 [00421] Yield: 80.8 mg, 18.0%; Appearance: White solid; .sup.1H NMR (400 MHz, DMSO-d.sub.6) 7.94 (d, J = 8.1 Hz, 2H), 7.72 (d, J = 8.0 Hz, 2H), 7.48-7.41 (m, 1H), 7.21 (dq, J = 7.3, 4.6, 3.2 Hz, 2H), 7.13-6.87 (m, 2H), 3.80 (d, J = 2.5 Hz, 2H), 3.13 (q, J = 10.7, 10.3 Hz, 2H), 2.74 (d, J = 11.8 Hz, 2H), 2.37 (t, J = 12.1 Hz, 2H), 1.66 (t, J = 12.8 Hz, 2H), 1.04 (d, J = 13.1 Hz, 2H). HPLC purity: 100%; LCMS Calculated for C.sub.21H.sub.21F.sub.5N.sub.2O.sub.2S: 460.46; Observed: 461.2 [M + H].sup.+. I-87 [00422] Yield: 77.2 mg, 15.3%; Appearance: White solid; .sup.1H NMR (500 MHz, DMSO-d.sub.6) 8.04 (d, J = 8.2 Hz, 2H), 7.90 (d. J = 8.2 Hz, 2H), 7.51 (d, J = 8.2 Hz, 1H), 7.25 (d, J = 7.5 Hz, 2H), 7.06 (t, J = 7.5 Hz, 1H), 3.84 (s, 2H), 3.15 (q, J = 10.2 Hz, 2H), 2.74 (d, J = 11.9 Hz, 2H), 2.61 (s, 6H), 2.37 (t, J = 12.2 Hz, 2H), 1.67 (td, J = 13.0, 4.1 Hz, 2H), 1.00 (d, J = 13.0 Hz, 2H). HPLC purity: 100%; LCMS Calculated for C.sub.22H.sub.26F.sub.3N.sub.3O.sub.4S.sub.2: 517.58; Observed: 518.2 [M + H].sup.+.

Example 23Synthesis of 1-methyl-1-phenylmethanesulfonyl-1,2-dihydrospiro[indole-3,3-pyrrolidine] (I-88)

[0567] ##STR00423##

Step 1. Synthesis of 1-methyl-1,2-dihydrospiro[indole-3,3-pyrrolidine]

[0568] Lithium aluminum hydride (0.75 g, 19.7 mmol) was suspended in anhydrous THF (20 mL). The solution of benzyl 1,2-dihydrospiro[indole-3,3-pyrrolidine]-1-carboxylate (1.3 g, 4.21 mmol) in anhydrous THF (5 mL) was added dropwise to this suspension, and the reaction mixture was stirred at room temperature overnight. The reaction was quenched with 20% aqueous solution of sodium hydroxide (25 mL). Solids were removed by filtration and washed with ethyl acetate (20 mL2). The combined organic phase was washed with brine (20 mL), dried over sodium sulfate, filtered and evaporated under reduced pressure. The crude product was purified by HPLC (deionized water/HPLC-grade methanol, ammonia) to give 1-methyl-1,2-dihydrospiro[indole-3,3-pyrrolidine] (0.34 g, 1.8 mmol, 95% purity, 40.7% yield).

Step 2. Synthesis of for 1-methyl-1-phenylmethanesulfonyl-1,2-dihydrospiro[indole-3,3-pyrrolidine]

[0569] phenylmethanesulfonyl chloride (0.125 g, 0.655 mmol) was added to the mixture of 1-methyl-1,2-dihydrospiro[indole-3,3-pyrrolidine] (0.12 g, 0.637 mmol) and pyridine (0.1 g, 1.27 mmol) in dry THF (3 mL). The reaction mixture was refluxed for 4 h, cooled to room temperature and evaporated to dryness. The crude residue was purified by HPLC (deionized water/HPLC-grade acetonitrile, ammonia) to give 1-methyl-1-phenylmethanesulfonyl-1,2-dihydrospiro[indole-3,3-pyrrolidine], I-88. Yield: 56.8 mg, 24.78%; Appearance: Yellow oil; .sup.1H NMR (400 MHz, DMSO-d.sub.6) 7.35-7.27 (m, 6H), 7.14 (d, J=9.5 Hz, 2H), 7.02 (t, J=7.1 Hz, 1H), 4.61 (s, 2H), 3.83-3.63 (m, 2H), 2.70 (s, 1H), 2.58 (d, J=9.1 Hz, 2H), 2.38 (d, J=9.0 Hz, 1H), 2.26 (s, 3H), 2.08-1.87 (m, 2H); HPLC purity: 100/o; LCMS Calculated for C.sub.19H.sub.22N.sub.2O.sub.2S: 342.46; Observed: 343.2 [M+H].sup.+.

Example 24

[0570] The following compounds were prepared using standard chemical manipulations and procedures similar to those used for the preparation of Example 23.

TABLE-US-00013 Compound No. Structure Analytical data I-89 [00424] Yield: 141 mg, 55.1%; Appearance: Pink oil; .sup.1H NMR (400 MHz, DMSO-d.sub.6) 7.96 (d, J = 8.0 Hz, 2H), 7.78 (d, J = 8.1 Hz, 2H), 7.48 (d, J = 8.1 Hz, 1H), 7.25 (t, J = 6.8 Hz, 2H), 7.14-6.91 (m, 2H), 3.90 (d, J = 10.8 Hz, 1H), 3.79 (d, J = 11.0 Hz, 1H), 2.65 (d, J = 7.5 Hz, 1H), 2.45 (d, J = 7.0 Hz, 1H), 2.24 (d, J = 9.4 Hz, 1H), 2.18 (d, J = 1.7 Hz, 3H), 2.15-2.06 (m, 1H), 1.92-1.80 (m, 1H), 1.79 (t, J = 7.1 Hz, 1H); HPLC purity: 100%; LCMS Calculated for C.sub.19H.sub.20F.sub.2N.sub.2O.sub.2S: 378.44; Observed: 379.4 [M + H].sup.+. I-90 [00425] Yield: 37.2 mg, 12.5%; Appearance: Beige solid; .sup.1H NMR (600 MHz, DMSO-d.sub.6) 8.00 (d, J = 8.5 Hz, 2H), 7.90 (d, J = 8.3 Hz, 2H), 7.48 (d, J = 8.0 Hz, 1H), 7.25 (t, J = 7.9 Hz, 2H), 7.07 (t, J = 7.5 Hz, 1H), 3.89 (d, J = 11.1 Hz, 1H), 3.80 (d, J = 11.1 Hz, 1H), 2.57 (s, 7H), 2.42 (dt, J = 8.9, 4.4 Hz, 1H), 2.21- 2.10 (m, 5H), 1.78 (ddd, J = 14.1, 8.8, 5.6 Hz, 1H), 1.66 (ddd, J = 13.5, 8.2, 5.9 Hz, 1H); HPLC purity: 100%; LCMS Calculated for C.sub.20H.sub.25N.sub.3O.sub.4S.sub.2: 435.56; Observed: 436.2 [M + H].sup.+.

Example 25Synthesis of benzyl 1-[4-(difluoromethyl)benzenesulfonyl]-1,2-dihydrospiro[indole-3,3-pyrrolidine]-1-carboxylate (I-91)

[0571] ##STR00426##

Step 1. Synthesis of benzyl 1,2-dihydrospiro[indole-3,3-pyrrolidine]-1-carboxylate

[0572] 1,2-dihydrospiro[indole-3,3-pyrrolidine] dihydrochloride (1.5 g, 6.06 mmol) and triethylamine (2.14 g, 21.2 mmol) were dissolved in dichloromethane (50 mL), the mixture was stirred for 30 min, cooled to 0 C. and benzyl carbonochloridate (1.03 g, 6.06 mmol) was added dropwise to it. The mixture was warmed to room temperature and stirred overnight, then washed with water (50 mL) and brine (50 mL). The organic layer was dried over sodium sulfate, filtered and evaporated under reduced pressure to afford benzyl 1,2-dihydrospiro[indole-3,3-pyrrolidine]-1-carboxylate (1.8 g, 5.83 mmol, 85% purity, 82.2% yield) that was used in next step without further purification.

Step 2. Synthesis of benzyl 1-[4-(difluoromethyl)benzenesulfonyl]-1,2-dihydrospiro[indole-3,3-pyrrolidine]-1-carboxylate

[0573] 4-(difluoromethyl)benzene-1-sulfonyl chloride (0.22 g, 0.972 mmol) was added to the mixture of benzyl 1,2-dihydrospiro[indole-3,3-pyrrolidine]-1-carboxylate (0.3 g, 0.972 mmol) and pyridine (0.230 g, 2.91 mmol) in dry THF (10 mL). The reaction mixture was refluxed for 4 h, cooled to room temperature and evaporated to dryness. The crude residue was purified by HPLC (deionized water/HPLC-grade acetonitrile) to give benzyl 1-[4-(difluoromethyl)benzenesulfonyl]-1,2-dihydrospiro[indole-3,3-pyrrolidine]-1-carboxylate, 1-91. Yield: 88.5 mg, 17.3%; Appearance: Pink oil; .sup.1H NMR (400 MHz, DMSO-d.sub.6) 7.98 (d, J=7.8 Hz, 2H), 7.75 (s, 2H), 7.52 (d, J=8.2 Hz, 1H), 7.45-7.28 (m, 5H), 7.23 (d, J=7.4 Hz, 1H), 7.15-6.98 (m, 2H), 5.08 (d, J=9.5 Hz, 2H), 3.93 (s, 2H), 3.30-3.24 (m, 2H), 1.93 (d, J=11.7 Hz, 1H), 1.77 (s, 1H)); HPLC purity: 100%; LCMS Calculated for C.sub.29H.sub.25N.sub.3O.sub.4S.sub.2: 498.54; Observed: 499.2[M+H].sup.+.

Example 26Synthesis of 1-[4-(difluoromethyl)benzenesulfonyl]-1-(2,2,2-trifluoroethyl)-1,2-dihydrospiro[indole-3,3-pyrrolidine] (I-92)

[0574] ##STR00427##

Step 1. Synthesis of 1-(2,2,2-trifluoroethyl)-1,2-dihydrospiro[indole-3,3-pyrrolidine]

[0575] 2,2,2-trifluoroethyl trifluoromethanesulfonate (1.87 g, 8.09 mmol) was added dropwise to a mixture of 1,2-dihydrospiro[indole-3,3-pyrrolidine] dihydrochloride (2 g, 8.09 mmol) and triethylamine (3.26 g, 32.3 mmol) in THF (30 mL). The mixture was stirred at 60 C. overnight, cooled to room temperature and concentrated under the reduced pressure. The residue was dissolved in ethyl acetate (50 mL), the solution was washed with water (50 mL), brine (50 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure to give 1-(2,2,2-trifluoroethyl)-1,2-dihydrospiro[indole-3,3-pyrrolidine] (1.65 g, 6.43 mmol, 87% purity, 69% yield) that was used in next step without further purification.

Step 2. Synthesis of 1-[4-(difluoromethyl)benzenesulfonyl]-1-(2,2,2-trifluoroethyl)-1,2-dihydrospiro-[indole-3,3-pyrrolidine]

[0576] 4-(difluoromethyl)benzene-1-sulfonyl chloride (0.2 g, 0.882 mmol) was added to the mixture of 1-(2,2,2-trifluoroethyl)-1,2-dihydrospiro[indole-3,3-pyrrolidine] (0.22 g, 0.858 mmol) and pyridine (0.203 g, 2.57 mmol) in dry THF (3 mL). The reaction mixture was refluxed for 4 h, cooled to room temperature and evaporated to dryness. The crude residue was purified by HPLC (deionized water/HPLC-grade acetonitrile) to give 1-[4-(difluoromethyl)benzenesulfonyl]-1-(2,2,2-trifluoroethyl)-1,2-dihydrospiro[indole-3,3-pyrrolidine], 1-92. Yield: 172 mg, 42.5%; Appearance: Pink solid; .sup.1H NMR (600 MHz, DMSO-d.sub.6) 7.93 (d, J=8.1 Hz, 2H), 7.74 (d, J=8.1 Hz, 2H), 7.47 (d, J=8.0 Hz, 1H), 7.27-6.95 (m, 4H), 3.93-3.76 (m, 2H), 3.23 (qq, J=10.5, 5.0 Hz, 2H), 2.88 (td, J=8.5, 6.4 Hz, 1H), 2.78 (td, J=9.0, 5.3 Hz, 1H), 2.49 (s, 2H), 1.85 (ddd, J=13.1, 8.8, 6.4 Hz, 1H), 1.74 (ddd, J=13.2, 8.2, 5.4 Hz, 1H). HPLC purity: 100%; LCMS Calculated for C.sub.20H.sub.19F.sub.5N.sub.2O.sub.2S: 446.43; Observed: 447.2 [M+H].sup.+.

Example 27

[0577] The following compound was prepared using standard chemical manipulations and procedures similar to those used for the preparation of Example 26.

TABLE-US-00014 Compound No. Structure Analytical data I-93 [00428] Yield: 71.7 mg, 15.7%; Appearance: White solid; .sup.1H NMR (600 MHz, DMSO-d.sub.6) 8.02 (d, J = 8.4 Hz, 2H), 7.89 (d, J = 8.3 Hz, 2H), 7.49 (d, J = 8.0 Hz, 1H), 7.26 (t, J = 7.8 Hz, 2H), 7.08 (t, J = 7.5 Hz, 1H), 3.91-3.80 (m, 2H), 3.23 (ddt, J = 14.8, 10.8, 4.5 Hz, 2H), 2.91-2.83 (m, 1H), 2.78 (td, J = 9.0, 5.3 Hz, 1H), 2.57 (s, 6H), 2.57-2.52 (m, 2H), 1.77 (ddd, J = 13.0, 8.8, 6.4 Hz, 1H), 1.66 (ddd, J = 13.2, 8.1, 5.3 Hz, 1H); HPLC purity: 100%; LCMS Calculated for C.sub.21H.sub.24F.sub.3N.sub.3O.sub.4S.sub.2: 503.56; Observed: 504.2 [M + H].sup.+.

Example 28Synthesis of 1-[(3,3-dimethyl-2,3-dihydro-1-benzofuran-5-yl)sulfonyl]-1,2-dihydrospiro[cyclohexane-1,3-indole] (I-94)

[0578] ##STR00429##

Step-1: Procedure for Synthesis of 1-bromo-2-((2-methylallyl)oxy)benzene 28.2

[0579] To a stirred solution of 2-bromophenole 28.1 (5.0 g, 28.90 mmol, 1.0 eq.) in acetonitrile (50 mL) was added 3-bromo-2-methylprop (4.27 g, 31.70 mmol, 1.1 eq.) and potassium carbonate (9.97 g, 72.20 mmol, 2.5 eq.) at room temperature. The reaction mixture was heated to 85 C. and stirred for 16 h. The progress of the reaction was monitored by LCMS. The residue was filtered and concentrated under reduced pressure to get the crude. The crude product was purified by column chromatography (0-10%, EA in PE) on silica gel to afford 1-bromo-2-((2-methylallyl)oxy)benzene 28.2 (6.6 g, 100%) as colorless oil. LCMS: 227.1 [M+H].sup.+.

Step-2: Procedure for Synthesis of 3,3-dimethyl-2,3-dihydrobenzofuran 28.3

[0580] To a stirred solution of 1-bromo-2-((2-methylallyl)oxy)benzene 28.2 (3.0 g, 13.20 mmol, 1.0 eq) in N,N-Dimethylformamide (60 mL) was added Sodium Formate (1.07 g, 15.80 mmol, 1.2 eq.), sodium acetate (2.7 g, 33.0 mmol, 2.5 eq), Tetraethyl ammonium chloride (2.61 g, 15.80 mmol, 1.2 eq.) and palladium acetate (296 mg, 1.32 mmol, 0.1 eq.) at room temperature under N.sub.2. The reaction mixture was heated to 85 C. and stirred for 16 h under N.sub.2. The progress of the reaction was monitored by LCMS. After completion of reaction, the residue was added water and extracted with ethyl acetate. The organic layer was dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure. The crude product was purified by column chromatography (PE) on silica gel to afford 3,3-dimethyl-2,3-dihydrobenzofuran 28.3 (1.34 g, 68.7%) as a colourless oil. LCMS: 149.1 [M+H]+.

Step-3: Procedure for Synthesis of spiro[cyclopentane-1,3-indoline 28.4

[0581] To the mixture of 3,3-dimethyl-2,3-dihydro-1-benzofuran 28.3 (188 mg, 1.26 mmol, 1.0 eq.) in DCM (8 mL) was added sulfurochloridic acid (220 mg, 1.89 mmol, 1.5 eq.) drop-wise at 0 C. The resulting mixture was stirred for 20 min at this temperature. When TLC show the reaction was completely. The resulting mixture was poured into ice-water (100 mL) and extracted with DCM (100 mL3). The combined organic phase washed with brine, dried over Na.sub.2SO.sub.4 and concentrated in vacuum. The residue was purified by column chromatography (0-10/0 EA in PE) to give 3,3-dimethyl-2,3-dihydro-1-benzofuran-5-sulfonyl chloride 28.4 (69.3 mg, 281 mol) as an off-white solid. LCMS: 243.3 [M-Cl+MeOH].sup.+.

[0582] .sup.1H NMR (400 MHz, DMSO-d.sub.6) 7.39 (d, J=1.5 Hz, 1H), 7.36 (dd, J=8.2, 1.8 Hz, 1H), 6.66 (d, J=8.2 Hz, 1H), 1.28 (s, 6H).

Step-4. Procedure for synthesis of 1-[(3,3-dimethyl-2,3-dihydro-1-benzofuran-5-yl)sulfonyl]-1,2-dihydrospiro[cyclohexane-1,3-indole]

[0583] To the mixture of 1,2-dihydrospiro[cyclohexane-1,3-indole] (30 mg, 160 mol, 1.0 eq), TEA (32.3 mg, 320 mol, 2.0 eq.) in DCM (5 mL) was added 3,3-dimethyl-2,3-dihydro-1-benzofuran-5-sulfonyl chloride (39.4 mg, 160 mol, 1.0 eq.) portion-wise at 20 C. The resulting mixture was stirred for 16 h at this temperature. Then the solution was poured into water and extracted with DCM (50 mL3). The combined organic phase washed with brine, dried over Na.sub.2SO.sub.4 and concentrated in vacuum. The residue was purified by column chromatography (0-30% EA in PE) to give 1-[(3,3-dimethyl-2,3-dihydro-1-benzofuran-5-yl)sulfonyl]-1,2-dihydrospiro[cyclohexane-1,3-indole], I-94.

[0584] Yield: 26.5 mg, 41.1%; Appearance: Off-white solid; .sup.1H NMR (400 MHz, CDCl3) 7.65 (d, J=8.0 Hz, 1H), 7.57 (dd, J=8.4, 2.0 Hz, 1H), 7.49 (d, J=1.6 Hz, 1H), 7.17-7.22 (m, 1H), 6.99-7.01 (m, 2H), 6.73 (d, J=8.4 Hz, 1H), 4.27 (s, 2H) 3.75 (s, 2H), 1.59-1.70 (m, 3H) 1.35-1.40 (m, 2H), 1.17-1.32 (m, 11H); HPLC purity: 99.06%; LCMS calculated for C.sub.23H.sub.27NO.sub.3S: 397.17; Observed: 398.4 [M+H].sup.+.

Example 29Synthesis of 4-({4-fluoro-1,2-dihydrospiro[cyclopentane-1,3-indol]-1-yl}sulfonyl)-N,N-dimethylbenzene-1-sulfonamide (I-95)

[0585] ##STR00430##

Step-1: Procedure for Synthesis of 4-fluorospiro[cyclopentane-1,3-indole] 29.2

[0586] To a solution of 4-fluoro-1H-indole 29.1 (500 mg, 3.69 mmol, 1.0 eq.) in THF (10 mL) was added t-BuOK (910 mg, 8.11 mmol, 2.2 eq.), the reaction mixture was stirred at room temperature for 30 min under N.sub.2. BEt.sub.3 (7.38 mL, 7.38 mmol, 2.0 eq.) was added to the mixture, the mixture continue stirred 30 min, then 1,4-diiodobutane (1.25 g, 4.05 mmol, 1.1 eq.) was added to the mixture. The mixture was stirred at 70 C. for 16 h. The mixture was cooled to r.t, diluted with H.sub.2O (20 mL), extracted with EA (30 mL3). The organic layer was combined, dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated. The residue was purified with flash column chromatography (EA in PE, from 0/6 to 17%) to afford 4-fluorospiro[cyclopentane-1,3-indole]29.2 (300 mg, 43.0%) as a yellow solid. LCMS: 190.2 [M+H].sup.+.

Step-2: Procedure for Synthesis of 4-fluorospiro[cyclopentane-1,3-indoline] 29.3

[0587] To a solution of 4-fluorospiro[cyclopentane-1,3-indole] 29.2 (300 mg, 1.59 mmol, 1.0 eq.) in THF (5 mL) was slowly added LiAlH.sub.4 (120.8 mg, 3.18 mmol, 2.0 eq.) at 0 C. The reaction mixture was stirred 0 C. for 3 h. The mixture was quenched with NH.sub.4Cl (5 mL), extracted with EA (15 mL3). The organic layer was combined, dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated. The residue was purified with flash column chromatography (EA in PE, from 0% to 20%) to afford 4-fluorospiro[cyclopentane-1,3-indoline] 29.3 (100 mg, 33%) as a yellow oil. LCMS: 192.2 [M+H].sup.+.

Step-3: Procedure for Synthesis of 4-((4-fluorospiro[cyclopentane-1,3-indolin]-1-yl)sulfonyl)-N,N-dimethylbenzenesulfonamide

[0588] To a solution of 4-fluoro-1,2-dihydrospiro[cyclopentane-1,3-indole] (100 mg, 522 mol, 1.0 eq.) in DCM (2 mL) were added 4-(dimethylsulfamoyl)benzene-1-sulfonyl chloride (148 mg, 522 mol, 1.0 eq.) and TEA (157 mg, 1.56 mmol, 3.0 eq.). The reaction mixture was stirred at r.t for 4 h. Then the mixture was diluted with H.sub.2O (10 mL), extracted with DCM (15 mL3). The organic layer was combined, dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated. The residue was purified by prep-HPLC to afford 4-({4-fluoro-1,2-dihydrospiro[cyclopentane-1,3-indol]-1-yl}sulfonyl)-N,N-dimethylbenzene-1-sulfonamide (I-95)

[0589] Yield: 45.9 mg, 20.0%; Appearance: White solid; .sup.1H NMR (400 MHz, CDCl3) 7.98-7.95 (m, 2H), 7.88-7.55 (m, 2H), 7.44 (dd, J=8.0 Hz, 0.8 Hz, 1H), 7.21-7.16 (m, 1H), 6.75-6.70 (m, 1H), 3.69 (s, 2H), 2.72 (s, 6H), 2.02-1.94 (m, 2H), 1.84-1.75 (m, 2H), 1.63-1.60 (m, 2H), 1.45-1.40 (m, 2H); HPLC purity: 95.43%; LCMS calculated for C.sub.20H.sub.23FN.sub.2O.sub.4S.sub.2: 438.11; Observed: 439.1[M+H].sup.+.

Example 30Synthesis of N,N-dimethyl-4-({1-[(oxan-4-yl)methyl]-1,2-dihydrospiro[azetidine-3,3-indol-1-yl}sulfonyl)benzene-1-sulfonamide (I-96)

[0590] ##STR00431##

Step-1: Procedure for Synthesis of 1-(tetrahydro-2H-pyran-4-carbonyl)spiro[indoline-3,3-pyrrolidin]-2-one 30.2

[0591] A 50 mL round-bottomed flask was charged with spiro[indoline-3,3-pyrrolidin]-2-one 30.1 (100 mg, 531 mol, 1 eq.), oxane-4-carbonyl chloride (86.7 mg, 584 mol, 1.1 eq.), triethylamine (53.7 mg, 531 mol, 1 eq.) and DCM (20 mL) at 0 C. under N.sub.2. The reaction mixture was stirred for 2 h. LCMS indicated the SM was consumed, the reaction was clear. The reaction mixture was poured into water (20 mL). The aqueous layer was extracted with DCM (20 mL) 3 times. The combined organic layer was washed with brine and dried over Na.sub.2SO.sub.4. The product did not require further purification. The product 1-(tetrahydro-2H-pyran-4-carbonyl)spiro[indoline-3,3-pyrrolidin]-2-one 30.2 (230 mg, 719 mol) was obtained. LCMS: 301.1 [M+H].sup.+.

Step-2: Procedure for Synthesis of 1-((tetrahydro-2H-pyran-4-yl)methyl)spiro[indoline-3,3-pyrrolidine] 30.3

[0592] A 50 mL round-bottomed flask was charged with 1-(tetrahydro-2H-pyran-4-carbonyl)spiro[indoline-3,3-pyrrolidin]-2-one 30.2 200 mg, 665 mol, 1 eq.) and 1 M trifluoro(oxolan-1-ium-1-yl)boranuide (20 mL, 20.0 mmol, 30 eq.) under N.sub.2. The reaction mixture was stirred at 70 C. for 8 h. LCMS indicated the SM was consumed. The reaction was quenched with MeOH (1 mL). The reaction mixture was poured into water (20 mL). The pH was adjusted to 8-9 with solid NaHCO.sub.3. The aqueous layer was extracted with EA (20 mL) 3 times. The combined organic layer was washed with brine and dried over Na.sub.2SO.sub.4. The solvent was removed under vacuum. The residue was purified by flash column chromatography (MeOH in DCM from 2% to 10%) to afford 1-((tetrahydro-2H-pyran-4-yl)methyl)spiro[indoline-3,3-pyrrolidine] 30.3 (95.0 mg, 348 mol) of the product as a pale-yellow solid. LCMS: 273.0 [M+H].sup.+.

Step-3: Procedure for Synthesis of N,N-dimethyl-4-((1-((tetrahydro-2H-pyran-4-yl)methyl)spiro[indoline-3,3-pyrrolidin]-1-yl)sulfonyl)benzenesulfonamide

[0593] A 50 mL round-bottomed flask was charged with 1-((tetrahydro-2H-pyran-4-yl)methyl)spiro[indoline-3,3-pyrrolidine] 30.3 (80 mg, 293 mol, 1 eq.), 4-(dimethylsulfamoyl)benzene-1-sulfonyl chloride (83.1 mg, 293 mol, 1 eq.), triethylamine (59.2 mg, 586 mol, 2 eq.) and DCM (10 mL) at room temperature. The reaction mixture was stirred for 2 h when LCMS revealed the starting material completely consumed. The reaction mixture was poured into H.sub.2O (20 mL). The aqueous layer was extracted with DCM (25 mL) 3 times. The organic layers were combined and washed with brine and dried over Na.sub.2SO.sub.4. The crude product was purified by prep-HPLC to give N,N-dimethyl-4-({1-[(oxan-4-yl)methyl]-1,2-dihydrospiro[indole-3,3-pyrrolidin]-1-yl}sulfonyl)benzene-1-sulfonamide, I-96.

[0594] Yield: 31.4 mg, 20.5%; Appearance: White solid; .sup.1H NMR (400 MHz, CDCl3) 7.96 (d, J=8.3 Hz, 2H), 7.85 (d, J=8.4 Hz, 2H), 7.64 (d, J=8.1 Hz, 1H), 7.24 (d, J=7.8 Hz, 1H), 7.20 (d, J=7.0 Hz, 1H), 7.08 (d, J=7.4 Hz, 1H), 4.04-3.89 (m, 3H), 3.72 (d, J=10.6 Hz, 1H), 3.38 (q, J=10.2 Hz, 2H), 2.73 (s, 6H), 2.57 (s, 1H), 2.36 (s, 2H), 2.27 (s, 2H), 1.94 (s, 4H), 1.67 (m, 2H); HPLC purity: 100.00%; LCMS calculated for C.sub.25H.sub.33N.sub.3O.sub.5S.sub.2: 519.19; Observed: 520.2 [M+H].sup.+.

Example 31Synthesis of 4-{[1-(2,2-difluoropropyl)-1,2-dihydrospiro[indole-3,4-piperidin]-1-yl]sulfonyl}-N,N-dimethylbenzene-1-sulfonamide (I-97)

[0595] ##STR00432##

Step-1: Procedure for Synthesis of tert-butyl 1-(2-oxopropyl)spiro[indoline-3,4-piperidine]-1-carboxylate 31.2

[0596] To the mixture of tert-butyl 1,2-dihydrospiro[indole-3,4-piperidine]-1-carboxylate 31.1 (HCl salt, 650 mg, 1.85 mmol, 1.0 eq.), TEA (935 mg, 9.25 mmol, 5.0 eq.) in DCM (10 mL) was added 1-bromopropan-2-one (260 mg, 1.90 mmol, 1.0 eq.) drop-wise at 25 C. The resulting mixture was stirred at 70 C. for 1.5 h before poured into water (30 mL). The mixture was extracted with EA (50 mL3). The combined organic phase was dried over Na.sub.2SO.sub.4 and concentrated in vacuo to get crude product tert-butyl 1-(2-oxopropyl)-1,2-dihydrospiro[indole-3,4-piperidine]-1-carboxylate 31.2 (598 mg, 1.73 mmol, 91.4%) as a yellow sticky oil. LCMS: 345.4 [M+H].sup.+.

Step-2: Procedure for Synthesis of 1-(spiro[indoline-3,4-piperidin]-1-yl)propan-2-one 31.3

[0597] A mixture of tert-butyl 1-(2-oxopropyl)spiro[indoline-3,4-piperidine]-1-carboxylate 31.2 (598 mg, 1.73 mmol, 1.0 eq.), 2,2,2-trifluoroacetaldehyde (55.2 mg, 564 umol, 0.32 eq.) in DCM (10 mL) at room temperature for 2 h. The reaction solution was concentrated to get crude product 1-(spiro[indoline-3,4-piperidin]-1-yl)propan-2-one 31.3 (1.2 g, TFA salt, purity: 49.3%) as a brown oil. LCMS: 246.2 [M+H].sup.+.

Step-3: Procedure for Synthesis of N,N-dimethyl-4-((1-(2-oxopropyl)spiro[indoline-3,4-piperidin]-1-yl)sulfonyl)benzenesulfonamide 31.4

[0598] The mixture of 1-{1,2-dihydrospiro[indole-3,4-piperidin]-1-yl}propan-2-one 31.3 (406 mg, TFA salt, purity: 49.3%, 818 umol, 1.0 eq.), 4-(dimethylsulfamoyl)benzene-1-sulfonyl chloride (232 mg, 818 umol, 1.0 eq.) and TEA (247 mg, 2.45 mmol, 3.0 eq.) in DCM (10 mL) was stirred at 25 C. for 2 h. LCMS indicated that the reaction was completed. Then, the reaction was quenched with saturated sodium bicarbonate, extracted with DCM (310 mL). The combined organic layer was washed by saturated brine, dried over Na.sub.2SO.sub.4, filtered, concentrated to dryness. The resulting residue was purified by column chromatography on silica gel (PE/EA=2/1) to afford N,N-dimethyl-4-((1-(2-oxopropyl)spiro[indoline-3,4-piperidin]-1-yl)sulfonyl)benzenesulfonamide 31.4 (110 mg, purity: 90%, 223 mol) as a white solid. LCMS: 492.3 [M+H].sup.+.

Step-4: Procedure for Synthesis of 4-((1-(2,2-difluoropropyl)spiro[indoline-3,4-piperidin]-1-yl)sulfonyl)-N,N-dimethylbenzenesulfonamide

[0599] To the mixture of N,N-dimethyl-4-({[1-(2-oxopropyl)-1,2-dihydrospiro[indole-3,4-piperidin]-1-yl]sulfonyl}benzene-1-sulfonamide 31.4 (110 mg, 223 mol) in DCM (5 mL) add DAST (178 mg, 1.11 mmol, 5.0 eq.) at 50 C. for 20 h. Then, the reaction was added water (20 mL), extracted with DCM (330 mL), combined organic layers, washed by saturated brine, dried over Na.sub.2SO.sub.4, filtered, concentrated to dryness. The resulting residue was purified by Pre-HPLC to afford product 4-({[1-(2,2-difluoropropyl)-1,2-dihydrospiro[indole-3,4-piperidin]-1-yl]sulfonyl}-N,N-dimethylbenzene-1 sulfonamide, I-97.

[0600] Yield: 20.4 mg, 17.8%; Appearance: White solid; .sup.1H NMR (400 MHz, CDCl3) 7.98 (d, J=8.4 Hz, 2H), 7.85 (d, J=8.4 Hz, 2H), 7.65 (d, J=8.1 Hz, 1H), 7.26-7.19 (m, 1H), 7.14-7.02 (m, 2H), 3.77 (s, 2H), 2.88 (d, J=7.0 Hz, 2H), 2.69 (d, J=20.5 Hz, 8H), 2.32-2.16 (m, 2H), 1.83 (t, J=12.3 Hz, 2H), 1.66 (d, J=18.7 Hz, 3H), 1.24 (d, J=13.2 Hz, 2H); HPLC purity: 100%; LCMS calculated for C.sub.23H.sub.29F.sub.2N.sub.3O.sub.4S.sub.2: 513.16; Observed: 514.1 [M+H].sup.+.

Example 32Synthesis of N,N-dimethyl-4-({1-[(oxan-4-yl)methyl]-1,2-dihydrospiro[indole-3,4-piperidin]-1-yl}sulfonyl)benzene-1-sulfonamide (I-98)

[0601] ##STR00433##

Step-1: Procedure for Synthesis of tert-butyl 1-((tetrahydro-2H-pyran-4-yl)methyl)spiro[indoline-3,4-piperidine]-1-carboxylate 32.2

[0602] To a solution of tert-butyl 1,2-dihydrospiro[indole-3,4-piperidine]-1-carboxylate 32.1 (200 mg, 693 mol, 1 eq.) and oxane-4-carbaldehyde (157 mg, 1.38 mmol, 2 eq.) in ethyl alcohol (10 mL) was triethylamine (70.1 mg, 693 mol, 1 eq.). After the mixture was stirred at RT for 6 hours, boron (3.sup.+) sodium iminomethanide trihydride (217 mg, 3.46 mmol, 5 eq.) was added and the resulting mixture was stirred for 12 h. The mixture was poured into water (20 mL). The aqueous layer was extracted with EA (20 mL) 3 times. The combined organic layer was washed with brine and dried over Na.sub.2SO.sub.4. The solvent was removed in vacuo. The product tert-butyl 1-[(oxan-4-yl)methyl]-1,2-dihydrospiro[indole-3,4-piperidine]-1-carboxylate (338 mg, 875 mol) 32.2 was obtained without further purification. LCMS: 387.3 [M+H].sup.+.

Step-2: Procedure for Synthesis of 1-((tetrahydro-2H-pyran-4-yl)methyl)spiro[indoline-3,4-piperidine] 32.3

[0603] A 50 mL round-bottomed flask was charged with tert-butyl 1-[(oxan-4-yl)methyl]-1,2-dihydrospiro[indole-3,4-piperidine]-1-carboxylate 32.2 (268 mg, 693 mol, 1 eq.), trifluoroacetic acid (790 mg, 6.93 mmol, 10 eq.) and methylene chloride (15 mL). The reaction mixture was stirred at room temperature for 1 h. LCMS indicated the SM was completely consumed. The reaction mixture was concentrated to dryness. The pH of mixture was adjusted to 8-9 with aqueous NaHCO.sub.3. The aqueous layer was extracted with DCM (20 mL) 3 times. The combined organic layer was washed with brine and dried over Na.sub.2SO.sub.4. No further purification was required. The product 1-((tetrahydro-2H-pyran-4-yl)methyl)spiro[indoline-3,4-piperidine] 32.3 (149 mg, 520 mol) was obtained. LCMS: 287.2 [M+H].sup.+.

Step-3: Procedure for Synthesis of N,N-dimethyl-4-((1-((tetrahydro-2H-pyran-4-yl)methyl)spiro[indoline-3,4-piperidin]-1-yl)sulfonyl)benzenesulfonamide

[0604] A 50 mL round-bottomed flask was charged with 1-[(oxan-4-yl)methyl]-1,2-dihydrospiro[indole-3,4-piperidine] (181.9 mg, 631 mol), 4-(dimethylsulfamoyl)benzene-1-sulfonyl chloride 32.3 (196 mg, 694 mol, 1 eq.), triethylamine (127 mg, 1.26 mmol, 1.8 eq.) and methylene chloride (15 mL) at RT. The reaction mixture was stirred for 3 h. LCMS indicated the SM was consumed, the reaction was clear. The reaction mixture was poured into water (20 mL). The aqueous layer was extracted with DCM (20 mL) 3 times. The combined organic layer was washed with brine and dried over Na.sub.2SO.sub.4. The crude product was purified by prep-HPLC to give N,N-dimethyl-4-({1-[(oxan-4-yl)methyl]-1,2-dihydrospiro[indole-3,4-piperidin]-1-yl}sulfonyl)benzene-1-sulfonamide, I-98.

[0605] Yield: 39.3 mg, 11.6%; Appearance: white solid; .sup.1H NMR (400 MHz, DMSO-d.sub.6) 8.06 (d, J=8.6 Hz, 2H), 7.92 (d, J=8.6 Hz, 2H), 7.53 (d, J=8.0 Hz, 1H), 7.35-7.24 (m, 1H), 7.24-7.19 (m, 1H), 7.07 (td, J.sub.1=7.5 Hz, J.sub.2=0.8 Hz, 1H), 3.83 (s, 2H), 3.80 (d, J=2.6 Hz, 2H), 3.31-3.10 (m, 2H), 2.65 (d, J=12.1 Hz, 2H), 2.59 (s, 6H), 2.13 (d, J=7.3 Hz, 2H), 1.91 (t, J=11.5 Hz, 2H), 1.79-1.70 (m, 1H), 1.68-1.62 (m, 2H), 1.58 (d, J=13.1 Hz, 2H), 1.22-1.05 (m, 2H), 1.01 (d, J=12.7 Hz, 2H); HPLC purity: 99.28%; LCMS calculated for C.sub.26H.sub.35N.sub.3O.sub.5S.sub.2: 533.20; Observed: 534.3 [M+H].sup.+.

Example 33

[0606] The following compounds were prepared using standard chemical manipulations and procedures similar to those used for the preparation of Example 32.

TABLE-US-00015 Compound No. Structure Analytical data I-99 [00434] .sup.1H NMR (400 MHz, CDCl.sub.3) 7.97 (d, J = 8.7 Hz, 2H), 7.83 (d, J = 8.6 Hz, 2H), 7.65 (d, J = 8.1 Hz, 1H), 7.25-7.20 (m, 1H), 7.05 (d, J = 4.2 Hz, 2H), 3.78 (s, 2H), 2.70 (s, 6H), 1.62 (m, 3H), 1.48-1.37 (m, 3H), 1.19-1.28 (m, 5H); HPLC purity: 99.00%; LCMS calculated for C21H26N2O4S2: 434.13; Observed: 435.3 [M + H].sup.+. I-121 [00435] .sup.1H NMR (400 MHz, DMSO-d.sub.6) 7.30-7.35 (m, 5H), 7.23 (d, J = 7.4 Hz, 1H), 7.09-7.15 (m, 2H), 7.02-6.93 (m, 1H), 4.62 (s, 2H), 3.64 (s, 2H), 1.80-1.38 (m, 7H), 1.15-1.30 (m, 3H); HPLC purity: 99.39%; LCMS calculated for C20H23NO2S: 341.14; Observed: 342.2 [M + H].sup.+. I-100 [00436] .sup.1H NMR (400 MHz, CDCl.sub.3) 7.58 (dd, J = 8.4 Hz, 2.0 Hz, IH), 7.48 (d, J = 1.6 Hz, 1H), 7.44 (dd, J = 8.4 Hz, J = 0.8 Hz, 1H), 7.18-7.12 (m, 1H), 6.78 (d, J = 8.4 Hz, 1H), 6.69-6.64 (m, 1H), 4.29 (s, 2H), 3.65 (s, 2H), 1.98-1.91 (m, 2H), 1.81-1.73 (m, 2H), 1.62-1.59 (m, 2H), 1.44-1.37 (m, 2H), 1.28 (s, 6H); HPLC purity: 100%; LCMS Calculated for C22H24FNO3S: 401.15; Observed: 402.4 [M + H].sup.+. I-101 [00437] .sup.1H NMR (400 MHz, DMSO-d.sub.6) 7.96-7.88 (m, 4H), 7.53 (d, J = 6.7 Hz, 1H), 7.49 (d, J = 8.0 Hz, 1H), 7.32 (dd, J = 7.9 Hz, 1.2 Hz, 1H), 7.18 (dd, J = 7.5 Hz, 0.8 Hz, 1H), 4.11 (s, 2H), 3.79 (dd, J = 11.3 Hz, 2.8 Hz, 2H), 3.22 (m, 2H), 3.01 (d, J = 7.0 Hz, 2H), 2.92 (d, J = 7.0 Hz, 2H), 2.60 (s, 6H), 2.22 (d, J = 6.9 Hz, 2H), 1.52 (d, J = 12.8 Hz, 2H), 1.47-1.26 (m, 1H), 1.15-1.04 (m, 2H); HPLC purity: 99.17%; LCMS Calculated for C24H31N3O5S2: 505.17; Observed: 506.1 [M + H].sup.+. I-102 [00438] .sup.1H NMR (400 MHz, CDCl.sub.3) 7.96-7.86 (m, 2H), 7.84-7.77 (m, 2H), 7.64 (d, J = 8.1 Hz, 1H), 7.40-7.28 (m, 7H), 7.15 (d, J = 7.5 Hz, 0.7 Hz, 1H), 4.12 (s, 2H), 3.70 (s, 2H), 3.29 (s, 4H), 2.64 (s, 6H); HPLC purity: 99.45%; LCMS Calculated for C25H27N3O4S2: 497.14; Observed: 498.1 [M + H].sup.+. I-122 [00439] .sup.1H NMR (400 MHz, CDCl.sub.3) 7.92 (d, J = 8.3 Hz, 2H), 7.65 (d, J = 8.1 Hz, 1H), 7.60 (d, J = 8.2 Hz, 2H), 7.23 (d, J = 7.2 Hz, 1H), 7.06 (dd, J = 15.8, 8.4 Hz, 2H), 6.65 (t, J = 55.9 Hz, 1H), 3.76 (s, 2H), 2.86 (s, 2H), 2.68 (s, 2H), 2.24 (s, 2H), 1.81 (s, 2H), 1.67 (t, J = 18.4 Hz, 3H), 1.25 (d, J = 12.9 Hz, 2H); HPLC purity: 99.56 %; LCMS Calculated for C22H24F4N2O2S: 456.15; Observed: 457.1 [M + H].sup.+. I-103 [00440] .sup.1H NMR (400 MHz, DMSO-d.sub.6) 8.06 (d, J = 8.5 Hz, 2H), 7.92 (d, J = 8.5 Hz, 2H), 7.52 (d, J = 8.0 Hz, 1H), 7.34-7.15 (m, 2H), 7.07 (t, J = 8.0 Hz, 1H), 3.84 (s, 2H), 3.81-3.69 (m, 2H), 3.64 (q, J = 7.9 Hz, IH), 3.46 (dd, J = 8.4 Hz, 6.8 Hz, 1H), 2.97-2.85 (m, 1H), 2.72 (d, J = 11.2 Hz, 1H), 2.59 (s, 6H), 2.55 (s, 1H), 2.11-1.86 (m, 3H), 1.76-1.63 (m, 3H), 1.03 (d, J = 13.3 Hz, 2H); HPLC purity: 96.24%; LCMS calculated for C24H31N3O5S2: 505.17; Observed: 506.1 [M + H].sup.+. I-104 [00441] 1H NMR (400 MHz, CDCl3) 8.00-7.97 (m, 2H), 7.87-7.84 (m, 2H), 7.65 (d, J = 8.0 Hz, 1H), 7.37-7.32 (m, 5H), 7.28-7.24 (m, 1H), 7.09-7.02 (m, 2H), 5.14 (s, 2H), 4.20-4.07 (m, 2H), 3.81 (s, 2H) 2.88-2.80 (m, 2H), 2.70 (s, 6H), 1.77-1.64 (m, 2H), 1.35-1.27 (m, 2H); HPLC purity: 100%; LCMS Calculated for C28H31N3O6S2: 569.17; Observed: 570.1 [M + H]+. I-105 [00442] 1H NMR (400 MHz, DMSO-d6) 8.03-7.75 (m, 4H), 7.52 (t, J = 6.8 Hz, 2H), 7.43-7.29 (m, 6H), 7.22 (t, J = 7.5 Hz, 1H), 5.03 (s, 2H), 4.24 (s, 2H), 3.84 (s, 2H), 3.67 (s, 2H), 2.55 (s, 6H); HPLC purity: 100.00%; LCMS Calculated for C26H27N3O6S2: 541.13; Observed: 542.0 [M + H]+.

Example 34Synthesis of N,N-dimethyl-4-({6-methyl-1,2-dihydrospiro[cyclohexane-1,3-pyrazolo[1,5-a]imidazol]-1-yl}sulfonyl)benzene-1-sulfonamide (I-123)

[0607] ##STR00443##

Step 1. Synthesis of 6-methylspiro[cyclohexane-1,3-imidazo[1,2-b]pyrazol]-2(1H)-one

[0608] (2Z)-3-aminobut-2-enenitrile (0.35 g, 4.25 mmol) was added to a suspension of the methyl 1-hydrazinylcyclohexane-1-carboxylate dihydrochloride (1.04 g, 4.25 mmol) in a 3M HCl/H.sub.2O mixture (, 12 mL), and the resulting mixture was heated under reflux for 12 hours. Then it was cooled to room temperature and neutralized with 2.5M sodium hydroxide aq. solution. The suspension was extracted with dichloromethane (30 mL3). The combined organic layers were washed with brine (20 mL), dried over sodium sulfate and evaporated in vacuo to give 6-methylspiro[cyclohexane-1,3-imidazo[1,2-b]pyrazol]-2(1H)-one as a white solid (0.35 g, 1.70 mmol, 100% purity, 40% yield).

Step 2. Synthesis of 6-methyl-1,2-dihydrospiro[cyclohexane-1,3-pyrazolo[1,5-a]imidazole]

[0609] A solution of 6-methyl-1,2-dihydrospiro[cyclohexane-1,3-pyrazolo[1,5-a]imidazol]-2-one (0.35 g, 1.70 mmol) in tetrahydrofuran (25 mL) was added dropwise at 5 C. to a suspension of lithium aluminum hydride (0.079 g, 2.03 mmol) in tetrahydrofuran (5 mL). After addition, the solution was warmed to room temperature and stirred for 12 hours. The solution was quenched with a mixture of water/tetrahydrofuran (1/1, 5 mL). The resulting mixture was filtered and the filtrate evaporated under reduce pressure to give 6-methyl-1,2-dihydrospiro[cyclohexane-1,3-pyrazolo[1,5-a]imidazole] (0.11 g, 0.575 mmol, 100% purity, 33.8% yield).

Step 3. Synthesis of N,N-dimethyl-4-({6-methyl-1,2-dihydrospiro[cyclohexane-1,3-pyrazolo[1,5-a]imidazol]-1-yl}sulfonyl)benzene-1-sulfonamide

[0610] 4-(dimethylsulfamoyl)benzene-1-sulfonyl chloride (0.179 g, 0.630 mmol) was added to the mixture of 6-methyl-1,2-dihydrospiro[cyclohexane-1,3-pyrazolo[1,5-a]imidazole] (0.11 g, 0.575 mmol) and pyridine (0.454 g, 5.75 mmol) in dry acetonitrile (25 mL). The reaction mixture was stirred at room temperature overnight and evaporated. The residue was subjected to HPLC purification (deionized water/HPLC-grade acetonitrile) to afford N,N-dimethyl-4-((6-methyl-1,2-dihydrospiro[cyclohexane-1,3-pyrazolo[1,5-a]imidazol]-1-yl sulfonyl)benzene-1-sulfonamide, 1-123. Yield: 33.1 mg, 12.4%; Appearance: White solid; .sup.1H NMR (600 MHz, DMSO-d.sub.6) 8.09 (dd, J=8.6, 2.1 Hz, 2H), 8.01-7.94 (m, 2H), 5.77 (d, J=2.0 Hz, 1H), 4.11 (d, J=2.1 Hz, 2H), 2.60 (d, J=2.0 Hz, 6H), 2.11 (d, J=2.1 Hz, 3H), 1.60 (dt, J=13.8, 4.2 Hz, 2H), 1.51 (ddd, J=15.2, 11.6, 3.8 Hz, 2H), 1.44 (d, J=12.5 Hz, 1H), 1.30-1.21 (m, 2H), 1.16 (d, J=11.5 Hz, 1H), 1.11 (d, J=13.0 Hz, 2H); HPLC purity: 100%; LCMS Calculated for C.sub.19H.sub.26N.sub.4O.sub.4S.sub.2: 438.56; Observed: 439.2[M+H].sup.+.

Example 35Synthesis of 4-({1,2-dihydrospiro[cyclohexane-1,3-pyrazolo[1,5-a]imidazol]-1-yl}sulfonyl)-N,N-dimethylbenzene-1-sulfonamide (I-125)

[0611] ##STR00444##

Step 1. Synthesis of methyl 1-({[(tert-butoxy)carbonyl](([(tert-butoxy)carbonyl]amino))amino}-cyclohexane-1-carboxylate

[0612] 2.5M n-butyllithium (3.14 g, 49.1 mmol) solution in hexane (19.6 mL) was added dropwise at 10 C. to a stirred solution of bis(propan-2-yl)amine (5.32 g, 52.6 mmol) in dry tetrahydrofuran (500 mL) under argon atmosphere and the reaction mixture was stirred at 0 C. for 0.5 h. Then, the solution of methyl cyclohexanecarboxylate (5 g, 35.1 mmol) in dry tetrahydrofuran (50 mL) was added at 78 C., and the reaction mixture was stirred at 70 C. for 1.5 h. Then, the solution of (E)-N-{[(tert-butoxy)carbonyl]imino}(tert-butoxy)formamide (12.1 g, 52.6 mmol) in dry tetrahydrofuran (50 mL) was added at 78 C., after the reaction mixture was allowed to warm up and stir overnight at room temperature. Then, it was poured in water (500 mL) and extracted with ethyl acetate (250 mL3). The organic layer was washed with water (250 mL), brine (250 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Methyl 1-([(tert-butoxy)carbonyl]({[(tert-butoxy)carbonyl]amino)amino}cyclohexane-1-carboxylate was obtained as beige oil (10 g, 26.8 mmol, 80% purity, 61.5% yield) and used in the next step without further purification.

Step 2. Synthesis of methyl 1-hydrazinylcyclohexane-1-carboxylate dihydrochloride

[0613] Methyl 1-({[(tert-butoxy)carbonyl]({[(tert-butoxy)carbonyl]amino})amino}cyclohexane-1-carboxylate (10 g, 21.4 mmol) was added to a stirred HCl sat. solution in dry dioxane (200 mL). The reaction mixture was stirred at room temperature for 18 h. The formed solid was filtered and washed with MTBE (50 mL3) that afforded methyl 1-hydrazinylcyclohexane-1-carboxylate dihydrochloride as white solid (3 g, 12.2 mmol, 95% purity, 54.3% yield).

Step 3. Synthesis of 1,2-dihydrospiro[cyclohexane-1,3-pyrazolo[1,5-a]imidazol]-2-one

[0614] Methyl 1-hydrazinylcyclohexane-1-carboxylate dihydrochloride (1 g, 4.07 mmol) and (2E)-3-ethoxyprop-2-enenitrile (0.473 g, 4.07 mmol) were added to acetic acid (50 mL). The reaction mixture was stirred at 120 C. for 18 h, cooled to room temperature, concentrated under reduced pressure. The residue was poured in 10% aq. solution of potassium carbonate (100 mL) and extracted with ethyl acetate (100 mL3). The organic layer was washed with water (300 mL), brine (300 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was subjected to HPLC purification (deionized water/HPLC-grade acetonitrile) to afford 1,2-dihydrospiro[cyclohexane-1,3-pyrazolo[1,5-a]imidazol]-2-one as beige solid (0.2455 g, 1.28 mmol, 95% purity, 29.9% yield).

Step 4. Synthesis of 1,2-dihydrospiro[cyclohexane-1,3-pyrazolo[1,5-a]imidazole]

[0615] 1,2-dihydrospiro[cyclohexane-1,3-pyrazolo[1,5-a]imidazol]-2-one (0.2455 g, 1.28 mmol) was added to slurry of lithium aluminium hydride (0.0651 g, 0.754 mmol) in anhydrous THF (50 mL) at 0 C. and the reaction mixture was allowed to warm up and stir at room temperature for 16 h. Then, it was poured in 10% aq. solution of sodium hydroxide (100 mL) and extracted with ethyl acetate (100 mL3). The organic layer was washed with water (100 mL), brine (100 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to afford 1,2-dihydrospiro[cyclohexane-1,3-pyrazolo[1,5-a]imidazole] as an beige oil (0.18 g, 0.944 mmol, 100% purity, 79.6% yield).

Step 5. Synthesis of 4-({1,2-dihydrospiro[cyclohexane-1,3-pyrazolo[1,5-a]imidazol]-1-yl}sulfonyl)-N,N-dimethylbenzene-1-sulfonamide

[0616] Pyridine (0.149 g, 1.88 mmol) and 4-(dimethylsulfamoyl)benzene-1-sulfonyl chloride (0.149 g, 0.525 mmol) were added to a solution of 1,2-dihydrospiro[cyclohexane-1,3-pyrazolo[1,5-a]imidazole] (0.078 g, 0.440 mmol) in acetonitrile (10 mL). The reaction mixture was stirred at room temperature for 18 h. The solvent was removed under reduced pressure and the residue was subjected to HPLC purification (deionized water/HPLC-grade acetonitrile) to afford 4-({1,2-dihydrospiro[cyclohexane-1,3-pyrazolo[1,5-a]imidazol]-1-yl}sulfonyl)-N,N-dimethylbenzene-1-sulfonamide as a white solid (0.0401 g, 0.0944 mmol, 95% purity, 20.4% yield). The analytical data provided for this compound provisionally supports the proposed structure for 4-({1,2-dihydrospiro[cyclohexane-1,3-pyrazolo[1,5-a]imidazol]-1-yl}sulfonyl)-N,N-dimethylbenzene-1-sulfonamide, 1-125. Yield: 40.1 mg, 20.4%; Appearance: White solid; .sup.1H NMR (400 MHz, DMSO-d.sub.6) 8.12 (dd, J=8.5, 1.8 Hz, 2H), 8.02-7.92 (m, 2H), 7.41 (d, J=1.9 Hz, 1H), 5.98 (d, J=1.9 Hz, 1H), 4.21 (s, 2H), 2.60 (d, J=1.8 Hz, 6H), 1.54 (tt, J=24.6, 9.5 Hz, 5H), 1.40-1.05 (m, 5H); HPLC purity: 96.75%; LCMS Calculated for C.sub.18H.sub.24N.sub.4O.sub.4S.sub.2: 424.54; Observed: 425.2[M+H].sup.+.

[0617] The following example was prepared using standard chemical manipulations and procedures similar to those used for the preparation of the previous example as indicated in the table below:

TABLE-US-00016 Compound No. Structure Analytical Data I-124 [00445] Yield: 293.8 mg, 23.3%; Appearance: Orange solid; .sup.1H NMR (400 MHz, DMSO- d.sub.6) 8.08 (d, J = 8.0 Hz, 2H), 7.97 (d, J = 8.3 Hz, 2H), 7.42 (d, J = 1.8 Hz, 1H), 5.99 (d, J = 1.8 Hz, 1H), 4.32 (s, 2H), 2.60 (d, J = 1.6 Hz, 6H), 1.71 (s, 2H), 1.55 (d, J = 14.4 Hz, 6H); HPLC purity: 97.3%; LCMS Calculated for C.sub.17H.sub.22N.sub.4O.sub.4S.sub.2: 410.51; Observed: 411.2[M + H].sup.+.

Example 36Synthesis of N,N-dimethyl-4-((1-(2,2,2-trifluoroethyl)-2,3-dihydro-1H-spiro[piperidine-4,4-quinolin]-1-yl)sulfonyl)benzenesulfonamide (I-126)

[0618] ##STR00446##

Step 1. Synthesis of 2,3-dihydro-1H-spiro[piperidine-4,4-quinoline]

[0619] 10% Pd/C (0.2 g) was added to the solution of 1-benzyl-2,3-dihydro-1H-spiro[piperidine-4,4-quinoline] (0.8 g, 2.73 mmol) in methanol (50 mL) and the reaction mixture was hydrogenated at ambient pressure and room temperature until reaction completion (3 h). After the mixture was filtered, formed precipitate washed with methanol (50 mL). Combined filtrates were concentrated under reduced pressure to afford 2,3-dihydro-1H-spiro[piperidine-4,4-quinoline] as colorless oil (0.453 g, 2.3 mmol, 91% purity, 74.6% yield) that was used in next step without further purification.

Step 2. Synthesis of 1-(2,2,2-trifluoroethyl)-2,3-dihydro-1H-spiro[piperidine-4,4-quinoline]

[0620] 2,2,2-trifluoroethyl trifluoromethanesulfonate (0.568 g, 2.45 mmol) was added to a solution of 2,3-dihydro-1H-spiro[piperidine-4,4-quinoline] (0.453 g, 2.23 mmol) and triethylamine (0.337 g, 3.34 mmol) in acetotitrile (15 mL). The mixture was stirred at 80 C. for 18 h, cooled to room temperature, and filtered. The filtrate was evaporated under reduced pressure to give 1-(2,2,2-trifluoroethyl)-2,3-dihydro-1H-spiro[piperidine-4,4-quinoline] (0.58 g, 2.03 mmol, 91% purity, 83.1% yield). The analytical data provided for this compound provisionally supports the proposed structure for 1-(2,2,2-trifluoroethyl)-2,3-dihydro-1H-spiro[piperidine-4,4-quinoline].

Step 3. Synthesis of N,N-dimethyl-4-((1-(2,2,2-trifluoroethyl)-2,3-dihydro-1H-spiro[piperidine-4,4-quinolin]-1-yl)sulfonyl)benzenesulfonamide

[0621] Pyridine (192 mg, 2.43 mmol) and 4-(dimethylsulfamoyl)benzene-1-sulfonyl chloride (632 mg, 2.23 mmol) were added to a solution of 1-(2,2,2-trifluoroethyl)-2,3-dihydro-1H-spiro[piperidine-4,4-quinoline] (0.58 g, 2.03 mmol) in acetonitrile (25 mL). The reaction mixture was stirred at room temperature for 18 h until completion (TLC control) and the solvent was removed under reduced pressure. The residue was subjected to HPLC purification (deionized water/HPLC-grade acetonitrile) that afforded N,N-dimethyl-4-((1-(2,2,2-trifluoroethyl)-2,3-dihydro-1H-spiro[piperidine-4,4-quinolin]-1-yl)sulfonyl)benzenesulfonamide, I-126. Yield: 46.8 mg, 4.37%; Appearance: Yellow solid; .sup.1H NMR (400 MHz, DMSO-d.sub.6) 7.90 (d, J=8.3 Hz, 2H), 7.77 (d, J=8.2 Hz, 2H), 7.69-7.56 (m, 1H), 7.50-7.38 (m, 1H), 7.25 (hept, J=5.5 Hz, 2H), 3.77 (dd, J=7.6, 3.9 Hz, 2H), 3.14 (q, J=10.3 Hz, 2H), 2.56 (d, J=15.5 Hz, 8H), 2.38 (t, J=12.0 Hz, 2H), 1.81 (td, J=13.1, 4.4 Hz, 2H), 1.42 (t, J=5.8 Hz, 2H), 0.93 (d, J=13.2 Hz, 2H); HPLC purity: 100%: LCMS Calculated for C.sub.23H.sub.28F.sub.3N.sub.3O.sub.4S.sub.2: 431.61; Observed: 432.0[M+H].sup.+.

Example 37Synthesis of 4-({1,2-dihydrospiro[cyclopentane-1,3-pyrrolo[2,3-c]pyridin]-1-yl}sulfonyl)-N,N-dimethylbenzene-1-sulfonamide (I-127)

[0622] ##STR00447##

Step 1. Synthesis of (3-bromopyridin-4-yl)methanol

[0623] Sodium borohydride (2.53 g, 67 mmol) was added portionwise to a solution of 3-bromopyridine-4-carbaldehyde (25 g, 134 mmol) in methanol (200 mL). The reaction mixture was stirred overnight at room temperature and the solvent was evaporated under reduced pressure. The residue was partitioned between water/ethyl acetate (200 mL/200 mL). The organic layer was separated, dried over sodium sulfate, filtered and evaporated under reduced pressure to afford (3-bromopyridin-4-yl)methanol (17 g, 90.4 mmol, 95% purity, 64.1% yield).

Step 2. Synthesis of 3-bromo-4-(chloromethyl)pyridine

[0624] Thionyl chloride (12.8 g, 108 mmol) was added dropwise to a solution of (3-bromopyridin-4-yl)methanol (17 g, 90.4 mmol) in dichloromethane (30 mL) and the mixture was stirred overnight at room temperature. After reaction completion (NMR control) the mixture was washed with NaHCO.sub.3 aq. sat. solution, concentrated in vacuum to afford 3-bromo-4-(chloromethyl)pyridine (12 g, 58.1 mmol, 64.5% yield) that was used in the next step immediately without further purification.

Step 3. Synthesis of 2-(3-bromopyridin-4-yl)acetonitrile

[0625] Potassium cyanide (5.67 g, 87.1 mmol) was added to a solution of 3-bromo-4-(chloromethyl)pyridine (12 g, 58.1 mmol) in DMSO (50 mL), the mixture was stirred overnight and diluted with water (100 mL). The product was extracted with ethylacetate (50 mL2), combined organic layers were dried over sodium sulfate, filtered and evaporated under reduced pressure to afford crude product which was purified by flash chromatography (chloroform/MTBE) to give 2-(3-bromopyridin-4-yl)acetonitrile (8 g, 40.6 mmol, 95% purity, 66.6% yield).

Step 4. Synthesis of 1-(3-bromopyridin-4-yl)cyclopentane-1-carbonitrile

[0626] 2-(3-bromopyridin-4-yl)acetonitrile (8 g, 40.6 mmol) was added portionwise to the suspension of sodium hydride (1.62 g, 40.6 mmol, 60 w %) in DMF (20 mL) at 0 C. The mixture was stirred 30 min at this temperature and 1,4-dibromobutane (8.76 g, 40.6 mmol) was added portionwise at the same temperature. After the mixture was allowed to warm up to room temperature and stirred overnight until completion. The solvent was evaporated under reduced pressure, the residue was treated with water/ethyl acetate mixture (30 mL/30 mL). The organic layer was separated, dried over sodium sulfate, filtered and evaporated under reduced pressure. The crude product was purified by flash chromatography (hexane/MTBE) to afford 1-(3-bromopyridin-4-yl)cyclopentanecarbonitrile (4 g, 15.9 mmol, 95% purity, 37.6% yield).

Step 5. Synthesis of spiro[cyclopentane-1,3-pyrrolo[2,3-c]pyridin]-2(1H)-one

[0627] Potassium iodide (0.066 g, 0.398 mmol), copper iodide (0.076 g, 0.398 mmol), and N-acetylglycine (0.047 g, 0.398 mmol) were added to a solution of 1-(3-bromopyridin-4-yl)cyclopentanecarbonitrile (1 g, 3.98 mmol) and sodium hydroxide (0.475 g, 11.9 mmol) in tert-butanol (20 mL). The mixture was refluxed for 24 h, then cooled to room temperature, filtered through silica, and the filtrate was evaporated to dryness. The residue was treated with water/ethyl acetate mixture (50 mL/50 mL). The organic layer was separated, dried over sodium sulfate, filtered and evaporated under reduced pressure. The crude product was purified by flash chromatography (chloroform/MTBE) to afford spiro[cyclopentane-1,3-pyrrolo[2,3-c]pyridin]-2(1H)-one (0.4 g, 2.12 mmol, 95% purity, 50.7% yield).

Step 6. Synthesis of 1,2-dihydrospiro[cyclopentane-1,3-pyrrolo[2,3-c]pyridine

[0628] 10 M dimethylsulfide borane complex solution in THF (0.636 mL, 0.483 g, 6.36 mmol) was added to a solution of spiro[cyclopentane-1,3-pyrrolo[2,3-c]pyridin]-2(1H)-one (0.4 g, 2.12 mmol) in dry THF (20 mL), the mixture was refluxed for 2 h and cooled to room temperature. Then methanol (10 mL) was added dropwise, the mixture was refluxed for 2 h, cooled to room temperature and evaporated under reduced pressure. The residue was treated with water/ethyl acetate mixture (20 mL/20 mL). The organic layer was separated, dried over sodium sulfate, filtered and evaporated under reduced pressure to afford crude 1,2-dihydrospiro[cyclopentane-1,3-pyrrolo[2,3-c]pyridine] (0.2 g, 1.14 mmol, 50% purity, 27.1% yield) that was used in the next step without further purification.

Step 7. Synthesis of 4-({1,2-dihydrospiro[cyclopentane-1,3-pyrrolo[2,3-c]pyridin]-1-yl}sulfonyl)-N,N-dimethylbenzene-1-sulfonamide

[0629] 4-(N,N-dimethylsulfamoyl)benzene-1-sulfonyl chloride (0.323 g, 1.14 mmol) was added to the mixture of 1,2-dihydrospiro[cyclopentane-1,3-pyrrolo[2,3-c]pyridine] (0.2 g, 1.14 mmol) and pyridine (0.135 g, 1.71 mmol) in dry THF (20 mL). The reaction mixture was stirred overnight and evaporated. The residue was subjected to HPLC purification (deionized water/HPLC-grade acetonitrile) that afforded 4-({1,2-dihydrospiro[cyclopentane-1,3-pyrrolo[2,3-c]pyridin]-1-yl}sulfonyl)-N,N-dimethylbenzene-1-sulfonamide, 1-127. Yield: 21.5 mg, 4.24%; Appearance: Yellow solid; .sup.1H NMR (400 MHz, DMSO-d.sub.6) 8.70 (s, 1H), 8.30 (d, J=4.9 Hz, 1H), 8.09 (dd, J=8.5, 1.9 Hz, 2H), 7.98-7.89 (m, 2H), 7.30 (d, J=4.9 Hz, 1H), 3.80 (s, 2H), 2.59 (s, 6H), 1.81-1.58 (m, 4H), 1.54 (q, J=5.8, 5.0 Hz, 2H), 1.41 (dd, J=11.4, 6.2 Hz, 2H); HPLC purity: 100%; LCMS Calculated for C.sub.19H.sub.23N.sub.3O.sub.4S.sub.2: 421.53; Observed: 422.2[M+H].sup.+. 1%

Example 38Synthesis of 4-({2,3-dihydro-1H-spiro[cyclohexane-1,4-quinolin]-1-yl}sulfonyl)-N,N-dimethylbenzene-1-sulfonamide (I-128)

[0630] ##STR00448##

Step 1. Synthesis of 2-cyclohexylidene-N-phenylacetamide

[0631] Triethylamine (5.41 g, 53.5 mmol) was added dropwise at 5 C. to the suspension of 2-cyclohexylideneacetic acid (3 g, 21.4 mmol), aniline (1.99 g, 21.4 mmol), EDC hydrochloride (4.5 g, 23.5 mmol), 1H-1,2,3-benzotriazol-1-ol (3.17 g, 23.5 mmol) in dichloromethane (30 mL). The mixture was stirred overnight, then diluted with water (100 mL). The organic layer was separated, concentrated under reduced pressure. The residue was subjected to flash chromatography (hexane/ethyl acetate) to give 2-cyclohexylidene-N-phenylacetamide (2.1 g, 9.75 mmol, 95% purity, 43.2% yield).

Step 2. Synthesis of 2,3-dihydro-1H-spiro[cyclohexane-1,4-quinolin]-2-one

[0632] Trichloroalumane (3.89 g, 29.2 mmol) was added at room temperature to a solution of 2-cyclohexylidene-N-phenylacetamide (2.1 g, 9.75 mmol) in dichloromethane (20 mL), the mixture was stirred overnight. Then water (50 mL) was added to it, the organic layer was separated and concentrated under reduced pressure. Flash chromatography (chloroform/MTBE) of residue resulted in 2,3-dihydro-1H-spiro[cyclohexane-1,4-quinolin]-2-one (2.1 g, 9.75 mmol, 90% purity, 90.4% yield).

Step 3. Synthesis of 2,3-dihydro-1H-spiro[cyclohexane-1,4-quinoline]

[0633] 10 M dimethylsulfide borane complex solution in THF (5.1 mL, 3.86 g, 50.9 mmol) was added to a solution of 2,3-dihydro-1H-spiro[cyclohexane-1,4-quinolin]-2-one (1.1 g, 5.1 mmol) in dry THF (20 mL). The mixture was refluxed for 2 h and cooled to room temperature. Then methanol (20 mL) was added dropwise, the mixture was refluxed for 2 h, cooled to room temperature and evaporated under reduced pressure. The residue was treated with water/ethyl acetate mixture (20 mL/20 mL). The organic layer was separated, dried over sodium sulfate, filtered and evaporated under reduced pressure to afford crude 2,3-dihydro-1H-spiro[cyclohexane-1,4-quinoline] (0.8 g, 3.97 mmol, 90% purity, 70.5% yield) that was used in the next step without further purification.

Step 4. Synthesis of 4-({2,3-dihydro-1H-spiro[cyclohexane-1,4-quinolin]-1-yl}sulfonyl)-N,N-dimethylbenzene-1-sulfonamide

[0634] 4-(N,N-dimethylsulfamoyl)benzene-1-sulfonyl chloride (1.12 g, 3.97 mmol) was added to the mixture of 2,3-dihydro-1H-spiro[cyclohexane-1,4-quinoline] (0.8 g, 3.97 mmol) and pyridine (0.47 g, 5.95 mmol) in dry THF (20 m|L. The reaction mixture was stirred overnight and evaporated. The residue was subjected to HPLC purification (deionized water/HPLC-grade methanol) that afforded 4-({2,3-dihydro-1H-spiro[cyclohexane-1,4-quinolin]-1-yl}sulfonyl)-N,N-dimethylbenzene-1-sulfonamide, I-128. Yield: 110.8 mg, 5.89%; Appearance: Beige solid; .sup.1H NMR (400 MHz, DMSO-d.sub.6) 7.89 (d, J=8.0 Hz, 2H), 7.75 (d, J=8.0 Hz, 2H), 7.68-7.59 (m, 1H), 7.49-7.40 (m, 1H), 7.29-7.14 (m, 2H), 3.76 (t, J=5.5 Hz, 2H), 2.57 (d, J=1.5 Hz, 6H), 1.52 (dd, J=19.5, 7.9 Hz, 3H), 1.37 (t, J=5.7 Hz, 4H), 1.22 (q, J=11.3, 8.9 Hz, 3H), 0.95 (d, J=13.0 Hz, 2H); HPLC purity: 100%; LCMS Calculated for C.sub.22H.sub.28N.sub.2O.sub.4S.sub.2: 448.6; Observed: 449.0[M+H].sup.+.

Example 39Synthesis of N,N-dimethyl-4-(spiro[cyclohexane-1,3-indolin]-1-ylsulfonyl)benzenesulfonimidamide (I-129)

[0635] ##STR00449##

Step 1. Synthesis of 4-[(tert-butyldimethylsilyl)dimethyl-S-aminosulfonimidoyl]benzene-1-sulfonyl chloride

[0636] 2.5M n-butyllithium (0.382 g, 5.97 mmol) in hexane (2.38 mL) was added to a solution of 4-bromo-N-(tert-butyldimethylsilyl)-N,N-dimethylbenzenesulfonimidamide (1.88 g, 4.98 mmol) in anhydrous tetrahydrofuran (20 mL) at 78 C. under argon atmosphere and the mixture was stirred for 1 h at 78 C. After the solution of SO.sub.2 (0.954 g, 14.9 mmol) in tetrahydrofuran (20 mL) was added to the resulting mixture at the same temperature. Then the cooling bath was removed and the mixture was allowed to warm to room temperature and stir for 12 h. The solution was evaporated in vacuo, the residue was dissolved in dichloromethane (20 mL) and N-chlorosuccinimide (0.797 g, 5.97 mmol) was added maintaining the reaction mixture temperature at 0 C. The mixture was stirred for 30 minutes, diluted with ethyl acetate (20 mL) and water (20 mL). The organic layer was separated, dried over sodium sulfate, filtered and the filtrate was evaporated in vacuo to give 4-[(tert-butyldimethylsilyl)dimethyl-S-aminosulfonimidoyl]benzene-1-sulfonyl chloride as a dark resin (1.76 g, 4.43 mmol, 58.66% purity, 52.2% yield) that was used in the next step without further purification.

Step 2. Synthesis of spiro[cyclohexane-1,3-indoline]

[0637] Lithium aluminium hydride (0.751 g, 19.8 mmol) was added portionwise to a solution of spiro[cyclohexane-1,3-indolin]-2-one (2 g, 9.93 mmol) in dry tetrahydrofuran (20 mL). The reaction mixture was stirred at room temperature for 10 h. Then it was heated to 50 C. for 2 h, after cooled to room temperature and quenched with water (2 mL) and 6N NaOH aq. solution (2 mL). The aqueous layer was extracted with ethyl acetate (20 mL-3). The combined organic layers were washed with brine (50 mL), dried over sodium sulfate, filtered and evaporated under reduced pressure to afford spiro[cyclohexane-1,3-indoline] as white solid (1.8 g, 9.61 mmol, 100% purity, 97.2% yield).

Step 3. Synthesis of N-(tert-butyldimethylsilyl)-N,N-dimethyl-4-(spiro[cyclohexane-1,3-indolin]-1-ylsulfonyl)benzenesulfonimidamide

[0638] 4-[(tert-butyldimethylsilyl)dimethyl-S-aminosulfonimidoyl]benzene-1-sulfonyl chloride (1.69 g, 4.27 mmol) was added to the mixture of 1,2-dihydrospiro[cyclohexane-1,3-indole] (0.8 g, 4.27 mmol) and pyridine (0.982 g, 12.4 mmol) in dry acetonitrile (20 mL). The reaction mixture was stirred for 12 h and evaporated in vacuo to give N-(tert-butyldimethylsilyl)-N,N-dimethyl-4-(spiro[cyclohexane-1,3-indolin]-1-ylsulfonyl)benzenesulfonimidamide (1.8 g, approx. 20% purity by NMR, 0.657 mmol, 15.4% yield) as a dark resin, which was used in the next step without purification.

Step 4. Synthesis of N,N-dimethyl-4-(spiro[cyclohexane-1,3-indolin]-1-ylsulfonyl)benzenesulfonimidamide

[0639] 1M solution TBAF in THF (0.857 g, 3.28 mmol, 3.28 mL) was added to a solution of N-(tert-butyldimethylsilyl)-4-({1,2-dihydrospiro[cyclohexane-1,3-indol]-1-yl}sulfonyl)-N,N-dimethylbenzene-1-sulfonoimidamide (1.8 g, 3.28 mmol) in dry tetrahydrofuran (50 mL) under argon atmosphere. The reaction mixture was stirred for 12 h at room temperature and evaporated in vacuo. The residue was subjected to HPLC purification (deionized water/HPLC-grade acetonitrile) that afforded N,N-dimethyl-4-(spiro[cyclohexane-1,3-indolin]-1-ylsulfonyl)benzenesulfonimidamide, 1-129. Yield: 70.5 mg, 4.71%; Appearance: Orange solid; .sup.1H NMR (400 MHz, DMSO-d.sub.6) 8.00 (d, J=8.4 Hz, 2H), 7.91 (d, J=8.0 Hz, 2H), 7.52 (d, J=8.0 Hz, 1H), 7.25 (t, J=7.7 Hz, 1H), 7.17 (d, J=7.5 Hz, 1H), 7.06 (t, J=7.5 Hz, 1H), 4.70 (s, 1H), 3.81 (s, 2H), 2.50 (s, 6H), 1.35 (dddt, J=70.4, 45.3, 24.2, 12.0 Hz, 8H), 0.96 (t, J=12.4 Hz, 2H); HPLC purity: 100%; LCMS Calculated for C.sub.21H.sub.26N.sub.3O.sub.3S.sub.2: 433.59; Observed: 434.2[M+H].sup.+.

Example 40Synthesis of benzyl 1-[4-(difluoromethyl)benzenesulfonyl]-4-fluoro-1,2-dihydrospiro[indole-3,4-piperidine]-1-carboxylate (I-130)

[0640] ##STR00450##

[0641] Step-1. Synthesis of tert-butyl 4-cyano-4-(2,6-difluorophenyl)piperidine-1-carboxylate:

[0642] 2-(2,6-difluorophenyl)acetonitrile (15 g, 97.9 mmol) was added to a slurry of sodium hydride (60% w/w; 9.75 g, 244 mmol) in anhydrous tetrahydrofuran (500 mL) at room temperature over 30 min. The reaction mixture was stirred for 1 h, tert-butyl N,N-bis(2-chloroethyl)carbamate (25.9 g, 107 mmol) was added over 15 min, and the reaction mixture was stirred at room temperature for 18 h. Then, it was poured into water (1000 mL) and extracted with ethyl acetate (250 mL3). The organic layer was washed with water (300 mL) and brine (300 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was subjected to silica gel chromatography purification (hexane/MTBE) to afford tert-butyl 4-cyano-4-(2,6-difluorophenyl)piperidine-1-carboxylate as colorless oil (12 g, 37.2 mmol, 95% purity, 38% yield).

Step-2. Synthesis of 4-(2,6-difluorophenyl)piperidine-4-carbonitrile hydrochloride

[0643] tert-butyl 4-cyano-4-(2,6-difluorophenyl)piperidine-1-carboxylate (5.3 g, 14.6 mmol) was added to a stirred solution of sat. hydrogen chloride solution in dry dioxane (250 mL). The reaction mixture was stirred at room temperature for 18 h. The solid was filtered and washed repeatedly with MTBE, and then air-dried to afford 4-(2,6-difluorophenyl)piperidine-4-carbonitrile hydrochloride as white solid (3.8 g, 14.6 mmol, 100% purity, 89.6% yield).

Step-3. Synthesis of 4-(2,6-difluorophenyl)piperidine-4-carbonitrile

[0644] Potassium carbonate (2.1 g, 14.6 mmol) was added to a stirred solution of 4-(2,6-difluorophenyl)piperidine-4-carbonitrile hydrochloride (3.8 g, 14.6 mmol) in water (250 mL) at 15 C. The mixture was extracted with ethyl acetate (150 mL3). The organic layer was washed with water (200 mL) and brine (200 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give 4-(2,6-difluorophenyl)piperidine-4-carbonitrile as white solid (2.8 g, 12.5 mmol, 95% purity, 82% yield).

Step-4. Synthesis of 4-fluorospiro[indoline-3,4-piperidine]

[0645] 4-(2,6-difluorophenyl)piperidine-4-carbonitrile (1.8 g, 8.09 mmol) was added to a slurry of lithium aluminium hydride (0.820 g, 24.2 mmol) in anhydrous tetrahydrofuran (100 mL) at 0 C. portionwise, and the reaction mixture was warmed to 50 C. and stirred for 18 hours. Then, the reaction mixture was cooled to 0 C., quenched with water (40 mL), and diluted with ethyl acetate (100 mL). The organic layer was separated, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to afford 4-fluorospiro[indoline-3,4-piperidine] (0.8 g, 3.29 mmol, 85% purity, 40.9% yield) that was used in the next step without further purification.

Step-5. Synthesis of benzyl 4-fluoro-1,2-dihydrospiro[indole-3,4-piperidine]-1-carboxylate

[0646] Triethylamine (0.809 mL, 5.80 mmol) and benzyl carbonochloridate (0.725 g, 4.25 mmol) were added to a solution of 4-fluorospiro[indoline-3,4-piperidine] (0.8 g, 3.87 mmol) in dichloromethane (50 mL) at room temperature. The mixture was stirred at room temperature for 5 h until completion (TLC control). The reaction mixture was then evaporated under reduced pressure to give benzyl 4-fluoro-1,2-dihydrospiro[indole-3,4-piperidine]-1-carboxylate as colorless oil (1.2 g, 3.27 mmol, 93% purity, 84.7% yield) that was used in the next step without further purification.

Step-6. Synthesis of benzyl 1-[4-(difluoromethyl)benzenesulfonyl]-4-fluoro-1,2-dihydrospiro[indole-3,4-piperidine]-1-carboxylate

[0647] Pyridine (0.417 g, 5.28 mmol) and 4-(difluoromethyl)benzene-1-sulfonyl chloride (0.417 g, 3.52 mmol) were added to a solution of benzyl 4-fluoro-1,2-dihydrospiro[indole-3,4-piperidine]-1-carboxylate (1.2 g, 3.52 mmol) in acetonitrile (100 mL). The reaction mixture was stirred at room temperature for 18 h. The solvent was removed under reduced pressure and the residue was subjected to HPLC purification (deionized water/HPLC-grade acetonitrile) to afford benzyl 1-[4-(difluoromethyl)benzenesulfonyl]-4-fluoro-1,2-dihydrospiro[indole-3,4-piperidine]-1-carboxylate (I-130). Yield: 210 mg, 10.6%; Appearance: Beige solid; .sup.1H NMR (400 MHz, DMSO-d.sub.6) 8.02 (d, J=7.4 Hz, 2H), 7.92-7.71 (m, 2H), 7.50-7.13 (m, 8H), 6.93-6.82 (m, 1H), 5.08 (s, 2H), 4.02 (s, 2H), 3.94-3.82 (m, 2H), 3.06-2.82 (m, 2H), 1.89-1.71 (m, 2H), 1.36-1.08 (m, 2H); HPLC purity: 100%; LCMS Calculated for C.sub.27H.sub.25F.sub.3N.sub.2O.sub.4S: 530.56; Observed: 532.2[M+H].sup.+.

Example 41

[0648] The following compound was prepared using standard chemical manipulations and procedures similar to those used for the preparation of the previous example.

TABLE-US-00017 Compound No. Structure Analytical Data I-131 [00451] Yield: 19 mg, 4%; Appearance: White solid; .sup.1H NMR (600 MHz, DMSO-d.sub.6) 8.02 (d, J = 8.1 Hz, 2H), 7.78 (d, J = 8.0 Hz, 2H), 7.38-7.27 (m, 5H), 7.27-7.21 (m, 2H), 7.21-7.01 (m, 1H), 6.89-6.82 (m, 1H), 5.12-4.96 (m, 2H), 3.95 (s, 2H), 3.86 (d, J = 13.6 Hz, 2H), 3.04-2.82 (m, 2H), 1.61-1.51 (m, 2H), 1.08 (d, J = 13.2 Hz, 2H).; HPLC purity: 100%; LCMS Calculated for C.sub.27H.sub.25F.sub.3N.sub.2O.sub.4S: 530.56; Observed: 531.2[M + H].sup.+.

Example 42Synthesis of 1-[4-(difluoromethyl)benzenesulfonyl]-5-fluoro-1,2-dihydrospiro[indole-3,4-piperidine]-1-carboxylate (I-132)

[0649] ##STR00452##

Step-1. Synthesis of benzyl 5-fluoro-1,2-dihydrospiro[indole-3,4-piperidine]-1-carboxylate

[0650] A solution of (4-fluorophenyl)hydrazine (3 g, 23.7 mmol) and trifluoroacetic acid (6.0 mL) in a toluene/acetonitrile mixture (49/1, 100 mL) was heated to 35 C., followed by addition dropwise of solution of 4-formyl-piperidine-1-carboxylic acid benzyl ester (5.31 g, 21.5 mmol) in toluene/acetonitrile mixture (49/1, 40 mL). The mixture was stirred at 35 C. for 16 h, then cooled to 0 C. and diluted with cold methanol (10 mL). NaBH.sub.4 (1.22 g, 32.3 mmol) was added slowly to the mixture, and it was stirred for additional 45 min. After, the reaction mixture was washed with aqueous NH.sub.4OH (6%, 50 mL) and brine (100 mL), then dried over sodium sulfate, filtered, and evaporated to dryness. The crude residue was purified by column chromatography (silica gel, ethyl acetate/hexane) to give benzyl 5-fluoro-1,2-dihydrospiro[indole-3,4-piperidine]-1-carboxylate as yellow solid (1.75 g, 5.14 mmol, 95% purity, 23.9% yield).

Step-2. Synthesis of 1-[4-(difluoromethyl)benzenesulfonyl]-5-fluoro-1,2-dihydrospiro[indole-3,4-piperidine]-1-carboxylate

[0651] 4-(Difluoromethyl)benzene-1-sulfonyl chloride (0.0729 g, 322 mol) was added to a mixture of benzyl 5-fluoro-1,2-dihydrospiro[indole-3,4-piperidine]-1-carboxylate (0.1 g, 0.293 mmol) and pyridine (0.0463 g, 0.586 mmol) in dry dichloromethane (25 mL). The reaction mixture was stirred at room temperature overnight and evaporated. The residue was subjected to HPLC purification (deionized water/HPLC-grade acetonitrile) to afford 1-[4-(difluoromethyl)benzenesulfonyl]-5-fluoro-1,2-dihydrospiro[indole-3,4-piperidine]-1-carboxylate (I-132). Yield: 82.9 mg, 50.7%; Appearance: Yellow oil solid; .sup.1H NMR (400 MHz, DMSO-d.sub.6) 7.98-7.92 (m, 2H), 7.76 (d, J=8.1 Hz, 2H), 7.52-7.45 (m, 1H), 7.39-7.26 (m, 5H), 7.20-6.99 (m, 3H), 5.05 (d, J=11.4 Hz, 2H), 3.94 (s, 2H), 3.88-3.76 (m, 2H), 2.90 (d, J=53.0 Hz, 2H), 1.64-1.51 (m, 2H), 1.00 (d, J=13.3 Hz, 2H); H PLC purity: 100%; LCMS Calculated for C.sub.27H.sub.25F.sub.3N.sub.2O.sub.4S: 530.56; Observed: 531.0[M+H].sup.+.

Example 43

[0652] The following compound was prepared using standard chemical manipulations and procedures similar to those used for the preparation of the previous example.

TABLE-US-00018 Compound No. Structure Analytical Data I-133 [00453] Yield: 285.3 mg, 58%; Appearance: Brown oil; .sup.1H NMR (600 MHz, DMSO-d.sub.6) 8.01 (d, J = 8.1 Hz, 2H), 7.80 (d, J = 8.1 Hz, 2H), 7.41-7.27 (m, 5H), 7.24-7.02 (m, 4H), 5.07 (d, J = 7.2 Hz, 2H), 4.18 (s, 2H), 3.93 (d, J = 13.6 Hz, 2H), 3.07- 2.85 (m, 2H), 1.72-1.60 (m, 2H), 1.28 (d, J = 13.2 Hz, 2H).; HPLC purity: 100%; LCMS Calculated for C.sub.27H.sub.25F.sub.3N.sub.2O.sub.4S: 530.56; Observed: [M + H].sup.+.

Example 44Synthesis of benzyl 1-[4-(difluoromethyl)benzenesulfonyl]-1,2-dihydrospiro[piperidine-4,3-pyrrolo[3,2-b]pyridine]-1-carboxylate (I-134)

[0653] ##STR00454##

Step-1. Synthesis of benzyl 4-cyanopiperidine-1-carboxylate

[0654] A solution of 4-cyanopiperidine hydrochloride (7.00 g, 47.7 mmol) and triethylamine (6.63 g, 47.7 mmol) in dichloromethane (100 mL) was cooled to 0 C., and benzyl chloroformate (8.52 g, 50.0 mmol) was added dropwise to it. The resulting mixture was warmed to room temperature and stirred for 16 hours. After, the mixture was diluted with water (100 mL) and extracted with dichloromethane (150 mL2). The combined organic layers were washed with citric acid aq. sat. solution (150 mL) and sodium hydrogen carbonate aq. sat. solution (150 mL), ten dried over sodium sulfate, filtered, and evaporated under reduced pressure to give benzyl 4-cyanopiperidine-1-carboxylate (10 g, 38.8 mmol, 95% purity, 81.8% yield).

Step-2. Synthesis of benzyl 4-cyano-4-(3-fluoropyridin-2-yl)piperidine-1-carboxylate

[0655] Potassium hexamethyldisilazane (37.5 mL, 40.9 mmol, 1.05 M solution in toluene) was slowly added to a solution of 2,3-difluoropyridine (4.70 g, 40.9 mmol) and benzyl 4-cyanopiperidine-1-carboxylate (10 g, 40.9 mmol) in toluene (200 mL) at 0 C. under argon atmosphere. The mixture was stirred at 0 C. for 1 hour. After, the reaction mixture was quenched with 1N HCl aq. solution (100 mL). The mixture was extracted with ethyl acetate (200 mL2). The combined organic layers were washed with water (200 mL), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to give the crude product, which was used without purification.

Step-3. Synthesis of benzyl 4-(aminomethyl)-4-(3-fluoropyridin-2-yl)piperidine-1-carboxylate

[0656] 10 M Borane dimethyl sulfide complex solution in tetrahydrofuran (17.2 mL, 172 mmol) was added to a solution of benzyl 4-cyano-4-(3-fluoropyridin-2-yl)piperidine-1-carboxylate (8.4 g, 17.3 mmol) in tetrahydrofuran (100 mL), and the mixture was stirred at reflux for 24 hours. After, the reaction mixture was diluted with methanol (10 mL) and ethyl acetate (200 mL). The organic layer was separated, washed with citric acid aq. sat. solution (100 mL) and sodium bicarbonate aq. sat. solution (100 mL), then dried over sodium sulfate, filtered, and evaporated under reduced pressure to give crude benzyl 4-(aminomethyl)-4-(3-fluoropyridin-2-yl)piperidine-1-carboxylate (8.8 g, 8.84 mmol, 34.5% purity, 51% yield), which was used without further purification.

Step-4. Synthesis of benzyl 1,2-dihydrospiro[piperidine-4,3-pyrrolo[3,2-b]pyridine]-1-carboxylate

[0657] Benzyl 4-(aminomethyl)-4-(3-fluoropyridin-2-yl)piperidine-1-carboxylate (8.8 g, 8.82 mmol) was dissolved in NMP (150 mL). Dipotassium carbonate (12.1 g, 88.2 mmol) was added, and the mixture was heated at 150 C. overnight. After, the reaction mixture was cooled to room temperature. The reaction mixture was washed with citric acid sat. aq. solution (100 mL) and sodium bicarbonate sat. aq. solution (100 mL), then dried over sodium sulfate, filtered, and evaporated under reduced pressure to afford benzyl 1,2-dihydrospiro[piperidine-4,3-pyrrolo[3,2-b]pyridine]-1-carboxylate (9 g, 7.68 mmol, 25% purity, 78.9% yield). Flash chromatography (chloroform/acetonitrile) of this crude product afforded benzyl 1,2-dihydrospiro[piperidine-4,3-pyrrolo[3,2-b]pyridine]-1-carboxylate (3 g, 4.63 mmol, 50% purity, 52.6% yield), which was used in the next step without further purification.

Step-5. Synthesis of benzyl 1-[4-(difluoromethyl)benzenesulfonyl]-1,2-dihydrospiro[piperidine-4,3-pyrrolo[3,2-b]pyridine]-1-carboxylate

[0658] 4-(Difluoromethyl)benzene-1-sulfonyl chloride (0.768 g, 3.39 mmol) was added to a mixture of benzyl 1,2-dihydrospiro[piperidine-4,3-pyrrolo[3,2-b]pyridine]-1-carboxylate (2 g, 3.09 mmol, 50% purity) and pyridine (0.488 g, 6.18 mmol) in dry dichloromethane (25 mL). The reaction mixture was stirred at room temperature overnight and evaporated. The residue was subjected to HPLC purification (deionized water/HPLC-grade acetonitrile) to afford benzyl 1-[4-(difluoromethyl)benzenesulfonyl]-1,2-dihydrospiro[piperidine-4,3-pyrrolo[3,2-b]pyridine]-1-carboxylate (I-134). Yield: 251 mg, 15%; Appearance: Beige solid; .sup.1H NMR (400 MHz, DMSO-d.sub.6) 8.17 (dd, J=4.0, 2.5 Hz, 1H), 8.03 (d, J=8.1 Hz, 2H), 7.86-7.72 (m, 3H), 7.41-7.29 (m, 5H), 7.29-6.93 (m, 2H), 5.08 (s, 2H), 3.96 (d, J=1.7 Hz, 2H), 3.86 (d, J=13.6 Hz, 2H), 3.20-2.96 (m, 2H), 1.60 (t, J=12.0 Hz, 2H), 1.21 (d, J=13.5 Hz, 2H); HPLC purity: %; LCMS Calculated for C.sub.26H.sub.25F.sub.2N.sub.3O.sub.4S: 513.56; Observed: 514[M+H]+.

Example 45Synthesis of benzyl 1-[4-(difluoromethyl)benzenesulfonyl]-1,2-dihydrospiro[piperidine-4,3-pyrrolo[2,3-c]pyridine]-1-carboxylate (I-135)

[0659] ##STR00455##

Step-1. Synthesis of 1-benzyl 4-methyl piperidine-1,4-dicarboxylate

[0660] Triethylamine (1.74 mL, 12.6 mmol) and benzyl carbonochloridate (1.97 g, 11.6 mmol) were added to a solution of 4-(3-fluoropyridin-4-yl)piperidine-4-carbonitrile (2 g, 9.74 mmol) in dichloromethane (50 mL) at 0 C. The mixture was stirred at room temperature for 18 h until completion (TLC control). After, the reaction mixture was washed with water (50 mL) and brine (50 mL), dried over anhydrous sodium sulfate, and filtered through silica. The silica was washed with dichloromethane (250 mL), and the combined filtrates were evaporated under reduced pressure to give 1-benzyl 4-methyl piperidine-1,4-dicarboxylate as a colorless oil (2.7 g, 6.52 mmol, 82% purity, 66.9% yield) that was used in the next step without further purification.

Step-2. Synthesis of benzyl 4-(aminomethyl)-4-(3-fluoropyridin-4-yl)piperidine-1-carboxylate

[0661] 10 M (Methylsulfanyl)methane borane solution in tetrahydrofuran (3.23 mL, 32.4 mmol) was added to a solution of benzyl 4-cyano-4-(3-fluoropyridin-4-yl)piperidine-1-carboxylate (2.2 g, 5.30 mmol, 82% purity) in anhydrous tetrahydrofuran (150 mL) at room temperature. The reaction mixture was allowed to warm up and stir at 60 C. for 18 hours. Then, it was cooled to 15 C. and quenched with methanol (50 mL). The mixture was stirred for additional 1 h. After, it was concentrated under reduced pressure to afford benzyl 4-(aminomethyl)-4-(3-fluoropyridin-4-yl)piperidine-1-carboxylate as a colorless oil (2.5 g, 5.82 mmol, 80% purity, 90% yield) that was used in the next step without further purification.

Step-3. Synthesis of benzyl 1,2-dihydrospiro[piperidine-4,3-pyrrolo[2,3-c]pyridine]-1-carboxylate

[0662] Benzyl 4-(aminomethyl)-4-(3-fluoropyridin-4-yl)piperidine-1-carboxylate (2.5 g, 5.82 mmol, 80% purity) was added to a stirred solution of dipotassium carbonate (1.60 g, 11.6 mmol) in dry NMP (50 mL). The mixture was stirred at 140 C. for 6 hours. Then, it was cooled to room temperature, poured into water (100 mL), and extracted with ethyl acetate (50 mL3). The organic layer was washed with water (100 mL) and brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was subjected to HPLC purification (deionized water/HPLC-grade acetonitrile) to give benzyl 1,2-dihydrospiro[piperidine-4,3-pyrrolo[2,3-c]pyridine]-1-carboxylate as beige oil (0.0339 g, 89.1 mol, 85% purity, 1.53% yield) that was used in the next step without further purification.

Step-4. Synthesis of benzyl 1-[4-(difluoromethyl)benzenesulfonyl]-1,2-dihydrospiro[piperidine-4,3-pyrrolo[2,3-c]pyridine]-1-carboxylate

[0663] Pyridine (0.0123 g, 0.156 mmol) and 4-(difluoromethyl)benzene-1-sulfonyl chloride (0.0281 g, 0.124 mmol) were added to a solution of benzyl 1,2-dihydrospiro[piperidine-4,3-pyrrolo[2,3-c]pyridine]-1-carboxylate (0.0339 g, 0.104 mmol) in acetonitrile (10 mL). The reaction mixture was stirred at room temperature for 18 h. The solvent was removed under reduced pressure and the residue was subjected to HPLC purification (deionized water/HPLC-grade acetonitrile) to afford benzyl 1-[4-(difluoromethyl)benzenesulfonyl]-1,2-dihydrospiro[piperidine-4,3-pyrrolo[2,3-c]pyridine]-1-carboxylate, (difluoromethyl)benzenesulfonyl]-1,2-dihydrospiro[piperidine-4,3-pyrrolo[2,3-c]pyridine]-1-carboxylate (I-135). Yield: 19 mg, 4%; Appearance: Yellow solid; .sup.1H NMR (400 MHz, Chloroform-d) 8.93 (s, 1H), 8.35 (d, J=4.9 Hz, 1H), 7.97 (d, J=8.1 Hz, 2H), 7.66 (d, J=8.1 Hz, 2H), 7.42-7.31 (m, 5H), 7.01 (d, J=4.9 Hz, 1H), 6.83-6.49 (m, 1H), 5.16 (s, 2H), 4.27-4.00 (m, 2H), 3.82 (s, 2H), 2.98-2.79 (m, 2H), 1.79-1.58 (m, 3H), 1.36 (d, J=13.6 Hz, 2H); HPLC purity: 100%; LCMS Calculated for C.sub.26H.sub.25F.sub.2N.sub.3O.sub.4S: 513.56; Observed: 514.2[M+H].sup.+.

Example 46Synthesis of (1-((4-(difluoromethyl)phenyl)sulfonyl)spiro[indoline-3,4-piperidin]-1-yl)(pyrrolidin-1-yl)methanone (I-136)

[0664] ##STR00456##

Step-1. Synthesis of benzyl 1,2-dihydrospiro[indole-3,4-piperidine]-1-carboxylate

[0665] A solution of benzyl 4-formylpiperidine-1-carboxylate (27 g, 109 mmol) in toluene/acetonitrile (49/1, 100 mL) was added dropwise to a mixture of phenyl hydrazine (12.9 g, 102 mmol) and trifluoroacetic acid (30 mL) in a toluene/acetonitrile (49/1, 500 mL) at 35 C. The reaction mixture was stirred at 35 C. overnight. Then, the reaction mixture was cooled to 0 C. and diluted with methanol (50 mL). Sodium boranuide (6.19 g, 163 mmol) was added slowly to the reaction mixture. The mixture was stirred for 45 min, then washed with 6% NH.sub.4OH aq. solution (250 mL) and brine (300 mL), dried over sodium sulfate, filtered, and evaporated. The residue was purified by flash chromatography (chloroform/MTBE) to afford benzyl 1,2-dihydrospiro[indole-3,4-piperidine]-1-carboxylate as white solid (22 g, 64.8 mmol, 95% purity, 63.7% yield).

Step-2. Synthesis of benzyl 1-[4-(difluoromethyl)benzenesulfonyl]-1,2-dihydrospiro[indole-3,4-piperidine]-1-carboxylate

[0666] Pyridine (2.57 g, 32.5 mmol) and 4-(difluoromethyl)benzene-1-sulfonyl chloride (5.89 g, 26.0 mmol) were added to a solution of benzyl 1,2-dihydrospiro[indole-3,4-piperidine]-1-carboxylate (7 g, 21.7 mmol) in acetonitrile (200 mL). The reaction mixture was stirred at room temperature for 18 h. The solvent was evaporated under reduced pressure. Flash chromatography (hexane/chloroform/MTBE) purification of the residue afforded benzyl 1-[4-(difluoromethyl)benzenesulfonyl]-1,2-dihydrospiro[indole-3,4-piperidine]-1-carboxylate as beige solid (10.5 g, 20.4 mmol, 100% purity, 94.5% yield).

Step-3. Synthesis of 1-[4-(difluoromethyl)benzenesulfonyl]-1,2-dihydrospiro[indole-3,4-piperidine]

[0667] Benzyl 1-[4-(difluoromethyl)benzenesulfonyl]-1,2-dihydrospiro[indole-3,4 (7.5 g, 14.6 mmol) was dissolved in a MeOH/tetrahydrofuran mixture (1/1, 300 mL). Pd/C (20%, 3 g) was added to the solution, and then the black suspension was hydrogenated at ambient pressure and room temperature for 18 h. Then, the mixture was filtered, the precipitate was washed with tetrahydrofuran (200 mL), and the combined filtrates were concentrated under reduced pressure to afford 1-[4-(difluoromethyl)benzenesulfonyl]-1,2-dihydrospiro[indole-3,4-piperidine] as beige oil (3.65 g, 9.25 mmol, 96% purity, 63.4% yield).

Step-4. Synthesis of (1-((4-(difluoromethyl)phenyl)sulfonyl)spiro[indoline-3,4-piperidin]-1-yl)(pyrrolidin-1-yl)methanone]

[0668] Triethylamine (0.217 L, 1.57 mmol) and pyrrolidine-1-carbonyl chloride (0.168 g, 1.26 mmol) were added to a solution of 1-[4-(difluoromethyl)benzenesulfonyl]-1,2-dihydrospiro[indole-3,4 (0.4 g, 1.05 mmol) in dichloromethane (50 mL). The reaction mixture was stirred at room temperature for 18 h. The solvent was removed under reduced pressure, and the residue was subjected to HPLC purification (deionized water/HPLC-grade acetonitrile) to afford (1-((4-(difluoromethyl)phenyl)sulfonyl)spiro[indoline-3,4-piperidin]-1-yl)(pyrrolidin-1-yl)methanone] (I-136). Yield: 166 mg, 31.4%; Appearance: White solid; .sup.1H NMR (400 MHz, DMSO-d.sub.6) 8.00 (d, J=8.1 Hz, 2H), 7.78 (d, J=8.1 Hz, 2H), 7.51 (d, J=8.1 Hz, 1H), 7.28-6.95 (m, 4H), 3.92 (s, 2H), 3.52 (d, J=13.4 Hz, 2H), 3.25 (d, J=13.0 Hz, 4H), 2.78 (t, J=12.9 Hz, 2H), 1.79-1.68 (m, 4H), 1.61 (td, J=12.9, 4.0 Hz, 2H), 1.12-1.02 (m, 2H); HPLC purity: 100%; LCMS Calculated for C.sub.24H.sub.27F.sub.2N.sub.3O.sub.3S: 475.55; Observed: 476.2[M+H].sup.+.

Example 47Synthesis of (1r,4r)-1-[4-(difluoromethyl)benzenesulfonyl]-4-(ethoxymethyl)-4-methyl-1,2-dihydrospiro[cyclohexane-1,3-indole] (I-137)

[0669] ##STR00457## ##STR00458##

Step-1. Synthesis of methyl 4-(hydroxymethyl)cyclohexane-1-carboxylate

[0670] 1-(1H-imidazole-1-carbonyl)-1H-imidazole (5.20 g, 32.1 mmol) was added at 0 C. to a stirred solution of 4-(methoxycarbonyl)cyclohexane-1-carboxylic acid (5 g, 26.8 mmol) in tetrahydrofuran (50 mL). The reaction mixture was stirred for 1 h at 0 C., and then sodium borohydride (1.51 g, 40.1 mmol) was added. The reaction mixture was stirred at room temperature for 1 h. The progress of the reaction was monitored by TLC. After completion, the reaction mixture was diluted with water (50 mL) and extracted with ethyl acetate (50 mL2). The combined organic extracts were washed with citric acid (50 mL), sodium bicarbonate sat. aq. solution (50 mL), and brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to provide methyl 4-(hydroxymethyl)cyclohexane-1-carboxylate (3.5 g, 12.2 mmol, 90% purity, 68% yield) that was used in the next step without further purification.

Step-2. Synthesis of methyl 4-formylcyclohexane-1-carboxylate

[0671] Methyl 4-(hydroxymethyl)cyclohexane-1-carboxylate (3.3 g, 19.1 mmol) was dissolved in dichloromethane (30 mL). The solution was cooled to 0 C., and chlorochromiumoylol; pyridine (5.34 g, 24.8 mmol) was added. The reaction mixture was warmed to room temperature, stirred for 3 h until completion (TLC control), and filtered through a Celite pad. The filtrate was evaporated under reduced pressure. The crude residue was dissolved in diethyl ether (100 mL) and filtered through Celite. The filtrate was evaporated to provide methyl 4-formylcyclohexane-1-carboxylate (2.4 g, 12.6 mmol, 90/% purity, 66.4% yield) that was used in the next step without further purification.

Step-3. Synthesis of methyl 4-(1,3-dioxolan-2-yl)cyclohexane-1-carboxylate

[0672] A solution of 4-(methoxycarbonyl)-cyclohexanecarboxaldehyde (4 g, 23.5 mmol), 1,2-ethanediol (2.91 g, 47.0 mmol), and p-toluenesulfonic acid monohydrate (0.201 g, 1.17 mmol) in benzene (100 mL) was refluxed under a Dean-Stark trap overnight. The mixture was cooled to room temperature, diluted with ether (100 mL), and washed with water (100 mL3), followed by washing with NaHCO.sub.3 sat. aq. solution (100 mL). The organic phase was dried over magnesium sulfate, filtered, and concentrated to give methyl 4-(1,3-dioxolan-2-yl)cyclohexane-1-carboxylate (3.8 g, 14.1 mmol, 80% purity, 60.4% yield) that was used in the next step without further purification.

Step-4. Synthesis of methyl 4-(1,3-dioxolan-2-yl)-1-methylcyclohexane-1-carboxylate

[0673] A 2.5M n-BuLi solution in hexane (2.7 mL, 6.71 mmol) was added at 0 C. to a solution of bis(propan-2-yl)amine (1.02 mL, 7.28 mmol) in 20 mL of anhydrous tetrahydrofuran. The mixture was stirred at 0 C. for 20 min. A solution of 4-(1,3-dioxolan-2-yl)cyclohexane-1-carboxylate (1.2 g, 5.60 mmol) in tetrahydrofuran (10 mL) was added dropwise after. The mixture was then stirred at 0 C. for 1 h. Then, the mixture was cooled to 78 C., and iodomethane (1.58 g, 1.2 mmol) was added dropwise. After the addition was completed, the mixture was stirred at 78 C. for an additional 1 h, then warmed to 15 C. and stirred for 12 h. The resulting mixture was poured into saturated aq. NH.sub.4Cl solution (50 mL) and extracted with ethyl acetate (30 mL3). The combined organic layers were washed with brine (100 mL2), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to afford methyl 4-(1,3-dioxolan-2-yl)-1-methylcyclohexane-1-carboxylate (1.2 g, 4.20 mmol, 80% purity, 75.5% yield) that was used in the next step without further purification.

Step-5. Synthesis of [4-(1,3-dioxolan-2-yl)-1-methylcyclohexyl]methanol

[0674] Methyl 4-(1,3-dioxolan-2-yl)-1-methylcyclohexane-1-carboxylate (1.2 g, 5.25 mmol) solution in tetrahydrofuran (3 mL) was added to a solution of LiAlH.sub.4 (0.196 g, 5.8 mmol) in tetrahydrofuran (10 mL). The reaction mixture was stirred at room temperature for 4 h. Then, it was quenched with water (0.8 mL) and 6N NaOH aq. solution (0.2 mL). The mixture was filtered, and the filter cake was washed with tetrahydrofuran (10 mL2). The combined filtrates were evaporated under reduced pressure to afford [4-(1,3-dioxolan-2-yl)-1-methylcyclohexyl]methanol (1.05 g, 4.71 mmol, 90% purity, 90% yield) that was used in the next step without further purification.

Step-6. Synthesis of 2-[4-(ethoxymethyl)-4-methylcyclohexyl]-1,3-dioxolane

[0675] Sodium hydride (0.230 g, 5.76 mmol, 60 w % dispersion in mineral oil) was added to an ice-cooled solution of [4-(1,3-dioxolan-2-yl)-1-methylcyclohexyl]methanol (1.05 g, 5.24 mmol) in tetrahydrofuran (15 mL). The reaction mixture was warmed to room temperature. After 3 h, iodoethane (1.22 g, 7.86 mmol) was added, and the reaction mixture was stirred at room temperature for 12 h. The excess sodium hydride was quenched with methanol (5 mL), and the reaction mixture was concentrated under reduced pressure to give 2-[4-(ethoxymethyl)-4-methylcyclohexyl]-1,3-dioxolane (1.2 g, 4.20 mmol, 80% purity, 80.6% yield) that was used in the next step without further purification.

Step-7. Synthesis of 4-(ethoxymethyl)-4-methylcyclohexane-1-carbaldehyde

[0676] A solution of 2-[4-(ethoxymethyl)-4-methylcyclohexyl]-1,3-dioxolane (1.2 g, 4.2 mmol) and 1N aq. HCl (14 mL) in tetrahydrofuran (45 mL) was heated at 65 C. for 4 h. The reaction mixture was cooled to room temperature, diluted with water (40 mL), and extracted with ethyl acetate (80 mL2). The combined organic extracts were washed with water (30 mL) and brine (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to provide 4-(ethoxymethyl)-4-methylcyclohexane-1-carbaldehyde (0.8 g, 3.03 mmol, 70% purity, 57.9% yield) that was used in the next step without further purification.

Step-8. Synthesis of 4-(ethoxymethyl)-4-methyl-1,2-dihydrospiro[cyclohexane-1,3-indole]

[0677] A solution of 4-(ethoxymethyl)-4-methylcyclohexane-1-carbaldehyde (0.8 g, 4.34 mmol) in dichloromethane (5 mL) was added dropwise to a mixture of phenyl hydrazine (0.469 g, 4.34 mmol) and trifluoroacetic acid (4.94 g, 43.4 mmol) in dichloromethane (10 mL). The mixture was stirred at 35 C. overnight. The mixture was then cooled to 0 C., and sodium triacetoxyborohydride (2.75 g, 13.0 mmol) was added slowly, followed by stirring at room temperature for 4 hours. The mixture was then washed with 6% NH.sub.4OH aq. solution (25 mL) and brine (30 mL), dried over sodium sulfate, filtered, and evaporated to dryness. The crude residue was purified by flash chromatography (hexane/MTBE) to provide 4-(ethoxymethyl)-4-methyl-1,2-dihydrospiro[cyclohexane-1,3-indole] (0.17 g, 0.589 mmol, 90% purity, 13.6% yield).

Step-9. Synthesis of (1r,4r)-1-[4-(difluoromethyl)benzenesulfonyl]-4-(ethoxymethyl)-4-methyl-1,2-dihydrospiro[cyclohexane-1,3-indole]

[0678] 4-(Difluoromethyl)benzene-1-sulfonyl chloride (0.178 g, 0.786 mmol) was added to an ice-cooled solution of 4-(ethoxymethyl)-4-methyl-1,2-dihydrospiro[cyclohexane-1,3-indole](0.17 g, 0.655 mmol) and pyridine (0.258 g, 3.27 mmol) in dichloromethane (10 mL). The reaction mixture was allowed to warm to room temperature and stir until completion (overnight, NMR control). The reaction mixture was then diluted with water (10 mL), and the organic layer was separated, dried over magnesium sulfate, filtered, and concentrated in vacuo. The residue was subjected to HPLC purification (deionized water/HPLC-grade acetonitrile) to give (1r,4r)-1-[4-(difluoromethyl)benzenesulfonyl]-4-(ethoxymethyl)-4-methyl-1,2-dihydrospiro[cyclohexane-1,3-indole] (I-137). Yield: 95.6 mg, 30.8%; Appearance: Pink solid; .sup.1H NMR (600 MHz, DMSO-d.sub.6) 7.96 (d, J=8.1 Hz, 2H), 7.74 (d, J=8.1 Hz, 2H), 7.48 (d, J=8.0 Hz, 1H), 7.27-7.18 (m, 2H), 7.17-6.97 (m, 2H), 3.78 (s, 2H), 3.41 (q, J=7.0 Hz, 2H), 3.25 (s, 2H), 1.58-1.48 (m, 2H), 1.46-1.38 (m, 2H), 1.19-1.11 (m, 2H), 1.08 (t, J=7.0 Hz, 3H), 0.91 (d, J=13.5 Hz, 2H), 0.87 (s, 3H), HPLC purity: 97.86%; LCMS Calculated for C.sub.24H.sub.29F.sub.2NO.sub.3S: 449.55; Observed: 450.2[M+H].sup.+.

Example 48Synthesis of 1-[4-(difluoromethyl)benzenesulfonyl]-4,4-difluoro-1,2-dihydrospiro[cyclohexane-1,3-indole] (I-138)

[0679] ##STR00459##

Step-1. Synthesis of 4,4-difluoro-1,2-dihydrospiro[cyclohexane-1,3-indol]-2-one

[0680] Morpholinosulfur trifluoride (12.1 g, 69.6 mmol)) was added to a stirred solution of 1,2-dihydrospiro[cyclohexane-1,3-indole]-2,4-dione (5 g, 23.2 mmol) in dichloromethane (50 mL). The resulting mixture was stirred overnight and evaporated to dryness. The crude residue was treated with sat. sodium carbonate aq. Solution, and the mixture was extracted with dichloromethane (30 mL2). The organic layers were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude residue was purified by flash chromatography (hexane/ethyl acetate) to provide 4,4-difluoro-1,2-dihydrospiro[cyclohexane-1,3-indol]-2-one (0.92 g, 3.87 mmol, 95% purity, 15.8% yield).

Step-2. Synthesis of 4,4-difluoro-1,2-dihydrospiro[cyclohexane-1,3-indole]

[0681] A solution of 4,4-difluoro-1,2-dihydrospiro[cyclohexane-1,3-indol]-2-one (0.92 g, 3.87 mmol) in tetrahydrofuran (3 mL) was added to a solution of LiAlH.sub.4 (0.196 g, 5.8 mmol) in tetrahydrofuran (10 mL). The reaction mixture was stirred at room temperature for 4 h. It was then refluxed for 2 h, cooled to room temperature, and quenched with water (0.8 mL) and 6N NaOH aq. solution (0.2 mL). The mixture was filtered, and the filter cake was washed with tetrahydrofuran (10 mL2). The combined filtrates were evaporated under reduced pressure to afford 4,4-difluoro-1,2-dihydrospiro[cyclohexane-1,3-indole] (0.8 g, 3.58 mmol, 95% purity, 87.9% yield).

Step-3. Synthesis of 1-[4-(difluoromethyl)benzenesulfonyl]-4,4-difluoro-1,2-dihydrospiro[cyclohexane-1,3-indole]

[0682] 4-(difluoromethyl)benzene-1-sulfonyl chloride (0.222 g, 0.984 mmol) was added to an ice-cooled solution of 4,4-difluoro-1,2-dihydrospiro[cyclohexane-1,3-indole] (0.2 g, 0.895 mmol) and pyridine (0.353 g, 4.47 mmol) in dichloromethane (10 mL). The reaction mixture was allowed to warm to room temperature and stir until completion (overnight, NMR control). Afterwards, the reaction mixture was diluted with water (10 mL), and the organic layer was separated, dried over magnesium sulfate, filtered, and concentrated in vacuo. The residue was subjected to HPLC purification (deionized water/HPLC-grade methanol) to give 1-[4-(difluoromethyl)benzenesulfonyl]-4,4-difluoro-1,2-dihydrospiro[cyclohexane-1,3-indole] (I-138). Yield: 22.7 mg, 5.81%; Appearance: Pink solid; .sup.1H NMR (600 MHz, DMSO-d) S 8.00 (d, J=8.1 Hz, 2H), 7.75 (d, J=8.1 Hz, 2H), 7.50 (d, J=8.1 Hz, 1H), 7.28-7.22 (m, 1H), 7.18 (d, J=7.4 Hz, 1H), 7.04 (dd, J=31.4, 24.0 Hz, 2H), 3.94 (s, 2H), 2.00 (t, J=14.6 Hz, 1H), 1.96-1.83 (m, 3H), 1.66 (td, J=13.6, 4.0 Hz, 2H), 1.18 (d, J=13.6 Hz, 2H); HPLC purity. 100%; LCMS Calculated for C.sub.20H.sub.19F.sub.4NO.sub.2S: 413.3; Observed: 414.0[M+H].sup.+.

Example 49Synthesis of benzyl 1-((4-(cyclopropyldifluoromethyl)phenyl)sulfonyl)spiro[indoline-3,4-piperidine]-1-carboxylate (I-139)

[0683] ##STR00460##

Step-1. Synthesis of ethyl 2-(4-bromophenyl)-2,2-difluoroacetate

[0684] 1-bromo-4-iodobenzene (20 g, 70.6 mmol) and ethyl 2-bromo-2,2-difluoroacetate (15.7 g, 77.6 mmol) were added under argon atmosphere to a suspension of activated copper powder (11.6 g, 183 mmol) in DMSO (200 mL), and the mixture was stirred at 60 C. for 12 h. Afterwards, the mixture was poured into a mixture of ice (400 g) and NH.sub.4Cl sat. aq. solution (200 mL), and the product was extracted with MTBE (200 mL3). The combined MTBE layers were washed with NH.sub.4Cl saturated aq. solution (400 mL) and brine (400 mL), dried over sodium sulfate, filtered, and evaporated under reduced pressure. The residue was purified by column chromatography (hexane/chloroform) to afford ethyl 2-(4-bromophenyl)-2,2-difluoroacetate as a light-yellow oil (14.2 g, 48.3 mmol, 95% purity, 68% yield).

Step-2. Synthesis of 2-(4-bromophenyl)-1-ethoxy-2,2-difluoroethanol

[0685] A 1 M solution of DIBAL (8.66 g, 60.9 mmol) in cyclohexane (60.9 mL) was added dropwise at 78 C. under argon atmosphere to a solution of ethyl 2-(4-bromophenyl)-2,2-difluoroacetate (14.2 g, 50.8 mmol) in dry dichloromethane (150 mL). The reaction mixture was stirred at 78 C. for 15 min, then poured into 10% HCl aq. solution (150 mL). The mixture was extracted with dichloromethane (150 mL2). The combined organic layers were washed with brine (150 mL), dried over sodium sulfate, filtered, and evaporated under reduced pressure to obtain 2-(4-bromophenyl)-1-ethoxy-2,2-difluoroethanol as a white solid (11.9 g, 42.3 mmol, 97% purity, 80.9% yield).

Step-3. Synthesis of 1-bromo-4-(1,1-difluoroallyl)benzene

[0686] Methyltriphenylphosphoniumbromide (59.8 g, 148 mmol) was suspended in dry tetrahydrofuran (200 mL) under argon atmosphere, and (tert-butoxy)potassium (16.6 g, 148 mmol) was added at 0 C. over 30 min. The mixture was stirred at 0 C. for 1 h. Then, 2-(4-bromophenyl)-1-ethoxy-2,2-difluoroethanol (11.9 g, 42.3 mmol) was added, and the mixture was stirred at room temperature for 12 h. Afterwards, the reaction was diluted with water (200 mL). The product was extracted with MTBE (200 mL2). The combined organic layers were washed with brine (200 mL), dried over sodium sulfate, filtered, and evaporated in vacuo. The crude product was purified by flash chromatography (hexane/chloroform) to give 1-bromo-4-(1,1-difluoroallyl)benzene as a colorless oil (6.85 g, 27.9 mmol, 95% purity, 65.9% yield).

Step-4. Synthesis of 1-bromo-4-(cyclopropyldifluoromethyl)benzene

[0687] A 0.8 M solution of diazomethane (6.13 g, 146 mmol) in MTBE (182 mL) was added at 40 C. to a mixture of 1-bromo-4-(1,1-difluoroallyl)benzene (6.85 g, 29.3 mmol) and Pd(OAc).sub.2 (0.327 g, 1.46 mmol) in dry MTBE (200 mL). The mixture was stirred at 40 C. until the evolution of gas ceased (for 2 h). The mixture was then filtered, and the filtrate was concentrated in vacuo. The residue was purified by flash chromatography (hexane/MTBE) to give 1-bromo-4-(cyclopropyldifluoromethyl)benzene as a colorless oil (3.5 g, 13.6 mmol, 96.39% purity, 46.6% yield).

Step-5. Synthesis of -(cyclopropyldifluoromethyl)benzene-1-sulfonyl chloride

[0688] 2 M n-Butyllithium (384 mg, 6 mmol) in hexane (2.4 mL) was added to a solution of 1-bromo-4-(cyclopropyldifluoromethyl)benzene (1.23 g, 5 mmol) in anhydrous tetrahydrofuran (20 mL) at 78 C. under argon atmosphere, and the mixture was stirred for 1 h at this temperature. A solution of SO.sub.2 (0.96 g, 15 mmol) in tetrahydrofuran (10 mL) was added to the resulting mixture at 78 C. The mixture was allowed to warm to room temperature and stirred for 12 h. The solution was evaporated in vacuo. The residue was dissolved in dichloromethane (20 mL) and N-chlorosuccinimide (0.801 g, 6 mmol) was added portionwise, maintaining the mixture temperature at 0 C. The mixture was stirred for 30 minutes, diluted with water (50 mL), and extracted with ethyl acetate (50 mL2). The organic layer was dried over sodium sulfate and filtered, and the filtrate was evaporated in vacuo. The residue was purified by flash chromatography (hexane/CHCl.sub.3) to give 4-(cyclopropyldifluoromethyl)benzene-1-sulfonyl chloride as a colorless oil (0.18 g, 0.674 mmol, 91% purity, 12.2% yield).

Step-6. Synthesis of benzyl 1-((4-(cyclopropyldifluoromethyl)phenyl)sulfonyl)spiro[indoline-3,4-piperidine]-1-carboxylate

[0689] 4-(Cyclopropyldifluoromethyl)benzene-1-sulfonyl chloride (0.18 g, 0.674 mmol) was added to a mixture of benzyl spiro[indoline-3,4-piperidine]-1-carboxylate (0.217 g, 0.674 mmol) and pyridine (0.266 g, 3.37 mmol) in dry acetonitrile (20 mL). The reaction mixture was stirred for 12 h and evaporated in vacuo. The residue was subjected to HPLC purification (deionized water/HPLC-grade acetonitrile) to afford benzyl 1-((4-(cyclopropyldifluoromethyl)phenyl)sulfonyl)spiro[indoline-3,4-piperidine]-1-carboxylate (I-139). Yield: 45.1 mg, 11.5%; Appearance: Pink solid; .sup.1H NMR (400 MHz, DMSO-d) S 7.94 (d, J=8.1 Hz, 2H), 7.76 (d, J=8.1 Hz, 2H), 7.51 (d, J=8.1 Hz, 1H), 7.36 (s, 6H), 7.31-7.19 (m, 3H), 7.05 (t, J=7.3 Hz, 1H), 5.07 (s, 2H), 3.93 (s, 2H), 3.86 (d, J=14.3 Hz, 2H), 2.95 (s, 2H), 1.67 (s, 1H), 1.56 (s, 2H), 1.03 (s, 2H), 0.63 (d, J=11.6 Hz, 4H); HPLC purity: 100%; LCMS Calculated for C.sub.30H.sub.30F.sub.2N.sub.2OS: 552.64; Observed: 554.2 [M+H].sup.+.

Example 50Synthesis of benzyl 1-[4-(difluoromethyl)benzenesulfonyl]-1,2-dihydrospiro[piperidine-4,3-pyrrolo[3,2-b]pyridine]-1-carboxylate (I-140)

[0690] ##STR00461## ##STR00462##

Step-1. Synthesis of 1-benzyl 4-methyl piperidine-1,4-dicarboxylate

[0691] Triethylamine (15.7 g, 156 mmol) and benzyl carbonochloridate (23.0 g, 135 mmol) were added to a solution of methyl piperidine-4-carboxylate (15 g, 104 mmol) in dichloromethane (500 mL) at 0 C. The mixture was stirred at room temperature for 18 h until completion (TLC control). Afterwards, the reaction mixture was washed with water (500 mL) and brine (500 mL), dried over anhydrous sodium sulfate, and filtered through silica. The silica was washed with dichloromethane (250 mL), and the combined filtrates were evaporated under reduced pressure. The residue was purified by flash chromatography (hexane/MTBE) that afforded 1-benzyl 4-methyl piperidine-1,4-dicarboxylate as colorless oil (28.8 g, 103 mmol, 95% purity, 91.3% yield).

Step-2. Synthesis of 1-benzyl 4-methyl 4-{[(tert-butoxy)carbonyl]({[(tert-butoxy)carbonyl]-amino})amino}piperidine-1,4-dicarboxylate

[0692] A 1 M solution of lithium bis(trimethylsilyl)amide in tetrahydrofuran (21.6 mL, 21.6 mmol) was added dropwise at 30 C. to a stirred solution of 1-benzyl 4-methyl piperidine-1,4-dicarboxylate (5 g, 18.0 mmol) in dry tetrahydrofuran (100 mL) under argon atmosphere, and the reaction mixture was stirred at 20 C. for 2 h. Then, a solution of (E)-N-{[(tert-butoxy)carbonyl]imino}(tert-butoxy)formamide (5.38 g, 23.4 mmol) in dry tetrahydrofuran (50 mL) was added at 78 C. Afterward, the reaction mixture was allowed to warm up and stir overnight at room temperature. Then, it was poured in water (250 mL) and extracted with ethyl acetate (100 mL3). The organic layer was washed with water (100 mL) and brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give 1-benzyl 4-methyl 4-({[(tert-butoxy)carbonyl](([(tert-butoxy)carbonyl]amino))amino}piperidine-1,4-dicarboxylate as a beige oil (10.2 g, 13.6 mmol, 68% purity, 76.9% yield) that was used in the next step without further purification.

Step-3. Synthesis of 1-benzyl 4-methyl 4-hydrazinylpiperidine-1,4-dicarboxylate dihydrochloride

[0693] 1-Benzyl 4-methyl 4-{[(tert-butoxy)carbonyl](([(tert-butoxy)carbonyl]amino))amino}piperidine-1,4-dicarboxylate (10.2 g, 13.6 mmol, 68% purity) was added to a stirred HCl aq. sat. solution in dry dioxane (100 mL). The reaction mixture was stirred at room temperature for 18 h. The residue was concentrated under reduced pressure to afford 1-benzyl 4-methyl 4-hydrazinylpiperidine-1,4-dicarboxylate dihydrochloride as a beige oil (7.3 g, 5.75 mmol, 30% purity, 42.3% yield) that was used in the next step without further purification.

Step-4. Synthesis of (2Z)-3-amino-3-cyclopropylprop-2-enenitrile

[0694] (tert-Butoxy)potassium (25 g, 223 mmol) was added to a stirred solution of cyclopropanecarbonitrile (10 g, 149 mmol) and acetonitrile (9.15 g, 223 mmol) in dry toluene (300 mL). The mixture was stirred at room temperature for 18 h. Afterward, the reaction mixture was poured into water (500 mL) and extracted with ethyl acetate (250 mL3). The organic layer was washed with water (500 mL) and brine (500 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give (2Z)-3-amino-3-cyclopropylprop-2-enenitrile as white oil (4.5 g, 20.8 mmol, 50% purity, 13.9% yield) that was used in the next step without further purification.

Step-5. Synthesis of benzyl 6-cyclopropyl-2-oxo-1,2-dihydrospiro[piperidine-4,3-pyrazolo[1,5-a]imidazole]-1-carboxylate

[0695] 1-Benzyl 4-methyl 4-hydrazinylpiperidine-1,4-dicarboxylate dihydrochloride (7.3 g, 5.75 mmol. 30% purity) and (2Z)-3-amino-3-cyclopropylprop-2-enenitrile (1.86 g, 8.62 mmol, 30% purity) were added to a 10% HCl aq. solution (100 mL). The reaction mixture was stirred at 90 C. for 18 h, cooled to room temperature, and concentrated under reduced pressure. The residue was poured into a 10% aq. solution of potassium carbonate (200 mL) and extracted with ethyl acetate (100 mL3). The organic layer was washed with water (300 mL) and brine (300 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was subjected to flash chromatography (hexane/MTBE) purification to afford benzyl 6-cyclopropyl-2-oxo-1,2-dihydrospiro[piperidine-4,3-pyrazolo[1,5-a]imidazole]-1-carboxylate as beige solid (0.2 g, 316 mol, 53% purity, 5.04% yield) that was used in the next step without further purification.

Step-6. Synthesis of benzyl 6-cyclopropyl-1,2-dihydrospiro[piperidine-4,3-pyrazolo[1,5-a]imidazole]-1-carboxylate

[0696] 10 M Borane dimethyl sulfide complex in tetrahydrofuran (0.1 mL, 1.09 mmol) was added to a solution of benzyl 6-cyclopropyl-2-oxo-1,2-dihydrospiro[piperidine-4,3-pyrazolo[1,5-a]imidazole]-1-carboxylate (0.2 g, 0.289 mmol, 53% purity) in tetrahydrofuran (10 mL), and the mixture was refluxed for 24 h. Afterwards, it was diluted with methanol (10 mL) and extracted with ethyl acetate (50 mL2). The combined organic layers were washed with citric acid aq. sat. solution (50 mL), sodium hydrogen carbonate aq. sat. solution (50 mL), dried over sodium sulfate, filtered and evaporated under reduced pressure to give benzyl 6-cyclopropyl-1,2-dihydrospiro[piperidine-4,3-pyrazolo[1,5-a]imidazole]-1-carboxylate (0.13 g, 0.265 mmol, 72% purity, 92.6% yield) that was used in the next step without further purification.

Step-7. Synthesis of benzyl 1-[4-(difluoromethyl)benzenesulfonyl]-1,2-dihydrospiro[piperidine-4,3-pyrrolo[3,2-b]pyridine]-1-carboxylate

[0697] 4-(Difluoromethyl)benzene-1-sulfonyl chloride (0.06 g, 0.268 mmol) was added to a mixture of benzyl 6-cyclopropyl-1,2-dihydrospiro[piperidine-4,3-pyrazolo[1,5-a]imidazole]-1-carboxylate (0.13 g, 0.265 mmol, 72% purity) and pyridine (0.2 g, 2.68 mmol) in dry dichloromethane (25 mL). The reaction mixture was stirred at room temperature overnight and evaporated. The residue was subjected to HPLC purification (deionized water/HPLC-grade acetonitrile) to afford benzyl 6-cyclopropyl-1-[4-(difluoromethyl)benzenesulfonyl]-1,2-dihydrospiro[piperidine-4,3-pyrazolo[1,5-a]imidazole]-1-carboxylate (I-140). Yield: 31.8 mg, 20.8%; Appearance: White solid; .sup.1H NMR (400 MHz, DMSO-d.sub.6) 8.02 (d, J=8.1 Hz, 2H), 7.84 (d, J=8.1 Hz, 2H), 7.42-7.30 (m, 5H), 7.30-6.98 (m, 1H), 5.69 (s, 1H), 5.07 (s, 2H), 4.16 (s, 2H), 3.77-3.63 (m, 2H), 3.29-3.13 (m, 2H), 1.84-1.74 (m, 1H), 1.63-1.52 (m, 2H), 1.46-1.37 (m, 2H), 0.88-0.77 (m, 2H), 0.70-0.59 (m, 2H); HPLC purity: 100%; LCMS Calculated for C.sub.27H.sub.25F.sub.2N.sub.4O.sub.4S: 542.6; Observed: 543.0[M+H].sup.+.

Example 51Synthesis of pyridin-2-ylmethyl 1-((4-(difluoromethyl)phenyl)sulfonyl)spiro[indoline-3,4-piperidine]-1-carboxylate (I-141)

[0698] ##STR00463##

[0699] (Pyridin-2-yl)methanol (0.028 g, 1.1 eq.) and 1,1-carbonyldiimidazole (0.053 g, 1.4 eq.) were mixed in dry dimethylformamide (1 mL). The reaction mixture was sealed and heated for 8 hours at 60 C. Then, the mixture was cooled to the ambient temperature and 1-[4-(difluoromethyl)benzenesulfonyl]-1,2-dihydrospiro[indole-3,4-piperidine] (0.088 g, 1 eq.) was added in one portion. The reaction mixture was stirred for 16 hours at 60 C., and cooled to ambient temperature. The solvent was evaporated under reduced pressure and the residue was dissolved in DMSO (1 mL). The solution was filtered, and subjected to HPLC purification (deionized water/HPLC-grade acetonitrile) to give pyridin-2-ylmethyl 1-((4-(difluoromethyl)phenyl)sulfonyl)spiro[indoline-3,4-piperidine]-1-carboxylate (I-141). Yield: 42.9 mg, 34.2%; Appearance: Beige solid; .sup.1H NMR (400 MHz, DMSO-d.sub.6) 8.50 (d, J=4.8 Hz, 1H), 7.96 (d, J=8.0 Hz, 2H), 7.78-7.66 (m, 3H), 7.54 (d, J=8.1 Hz, 1H), 7.33 (d, J=7.8 Hz, 1H), 7.28-6.77 (m, 5H), 5.13 (s, 2H), 4.15-3.94 (m, 2H), 3.91 (s, 2H), 3.00-2.84 (m, 2H), 1.75-1.58 (m, 2H), 1.22 (d, J=13.4 Hz, 2H): HPLC purity: 100%; LCMS Calculated for C.sub.26H.sub.25F.sub.2N.sub.3O.sub.4S: 513.56; Observed: 514.2[M+H].sup.+.

Example 52Synthesis of N-cyclopropyl-1-[4-(difluoromethyl)benzenesulfonyl]-1,2-dihydrospiro[indole-3,4-piperidine]-1-carboxamide (I-142)

[0700] ##STR00464##

[0701] 1-[4-(difluoromethyl)benzenesulfonyl]-1,2-dihydrospiro[indole-3,4-piperidine] (0.098 g, 1 eq.), isocyanatocyclopropane (0.024 g, 1.1 eq.), and N,N-diisopropylethylamine (0.067 g, 2 eq.) were mixed in dry N,N-dimethylformamide (1 mL), and the mixture was heated for 16 hours at 80 C. Afterwards, it was cooled to ambient temperature, and the solvent was evaporated under reduced pressure. The residue was dissolved in the DMSO (1 mL), and the solution was filtered and subjected to HPLC purification (deionized water/HPLC-grade methanol) to give N-cyclopropyl-1-[4-(difluoromethyl)benzenesulfonyl]-1,2-dihydrospiro[indole-3,4-piperidine]-1-carboxamide (I-142). Yield: 56.6 mg, 45.1%, Appearance: Yellow solid; .sup.1H NMR (600 MHz, DMSO-d.sub.6) 7.98 (d, J=8.4 Hz, 2H), 7.75 (d, J=7.8 Hz, 2H), 7.48 (d, J=8.1 Hz, 1H), 7.26-7.20 (m, 1H), 7.20-6.98 (m, 3H), 6.55 (s, 1H), 3.82-3.77 (m, 2H), 2.73-2.66 (m, 2H), 1.53-1.42 (m, 2H), 1.07-0.99 (m, 2H), 0.53-0.47 (m, 2H), 0.36-0.30 (m, 2H); HPLC purity: 95.03%; LCMS Calculated for C.sub.23H.sub.25F.sub.2N.sub.3O.sub.3S: 461.53; Observed: 462.2[M+H].sup.+.

Example 53Synthesis of N-benzyl-1-((4-(difluoromethyl)phenyl)sulfonyl)spiro[cyclohexane-1,3-indoline]-4-carboxamide (I-143)

[0702] ##STR00465##

[0703] 1-Phenylmethanamine (0.02 g, 1.1 eq.), 1-((4-(difluoromethyl)phenyl)sulfonyl)spiro[cyclohexane-1,3-indoline]-4-carboxylic acid (0.072 g, 1 eq.), N,N-diisopropylethylamine (0.055 g, 2.5 eq.), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (0.029 g, 1.05 eq.), and 1-hydroxy-7-azabenzotriazole (0.024 g, 1.1 eq.) were mixed in dry DMF (1 mL). The reaction mixture was stirred at ambient temperature for 18 hours. Then, the solvent was evaporated under reduced pressure and the residue was dissolved in DMSO (1 mL). The solution was filtered, analyzed by LCMS, and subjected to HPLC purification (deionized water/HPLC-grade methanol) to give N-benzyl-1-((4-(difluoromethyl)phenyl)sulfonyl)spiro[cyclohexane-1,3-indoline]-4-carboxamide (I-143). Yield: 30.3 mg, 30.2%; Appearance: Yellow solid; .sup.1H NMR (400 MHz, DMSO-d.sub.6) 8.14-8.06 (m, 1H), 7.98-7.86 (m, 2H), 7.72 (d, J=8.0 Hz, 2H), 7.53 (d, J=8.2 Hz, 1H), 7.34-7.18 (m, 6H), 7.18-6.79 (m, 3H), 4.32-4.23 (m, 2H), 3.83-3.65 (m, 2H), 2.41-2.12 (m, 1H), 1.94-1.82 (m, 1H), 1.77-1.42 (m, 5H), 1.32-1.15 (m, 2H); HPLC purity: 100%; LCMS Calculated for C.sub.28H.sub.28F.sub.2N.sub.2O.sub.3S: 510.6; Observed: 511.2[M+H].sup.+.

Example 54Synthesis of N,N-dimethyl-4-{[1-(2,2,2-trifluoroethyl)-1,2-dihydrospiro[piperidine-4,3-pyrazolo[1,5-alimidazol]-1-yl]sulfonyl}benzene-1-sulfonamide (I-144)

[0704] ##STR00466## ##STR00467##

Step-1. Synthesis of methyl 1-(2,2,2-trifluoroethyl)piperidine-4-carboxylate

[0705] Carbonyldiimidazole (3.58 g, 22.1 mmol) was added to a solution of triethylamine (6.10 g, 60.3 mmol) and 1-(2,2,2-trifluoroethyl)piperidine-4-carboxylic acid hydrochloride (5 g, 20.1 mmol) in dry THF (100 mL). The mixture was refluxed for 2 hours. Afterwards, methanol (6.44 g, 201 mmol) was added to the boiling mixture and refluxing was continued for additional 6 hours. The mixture was then concentrated under reduced pressure. The residue was dissolved in ethyl acetate (150 mL) and filtered. The filtrate was washed with water (150 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to afford methyl 1-(2,2,2-trifluoroethyl)piperidine-4-carboxylate (4 g, 17.7 mmol, 99.98% purity, 88.2% yield).

Step-2. Synthesis of methyl 4-{[(tert-butoxy)carbonyl]({[(tert-butoxy)carbonyl]amino})amino}-1-(2,2,2-tri fluoroethyl)piperidine-4-carboxylate

[0706] 2.5 M n-BuLi solution in hexane (7.76 mL, 19.4 mmol) was added at 78 C. to a solution of diisopropylamine (1.96 g, 19.4 mmol) in dry THF (100 mL). The mixture was stirred for 10 min, and a solution of methyl 1-(2,2,2-trifluoroethyl) piperidine-4-carboxylate (4 g, 17.7 mmol) in dry THF (20 mL) was added dropwise to it at the same temperature. The mixture was stirred for 3 h at 78 C. Afterwards, a solution of di-tert-butyl azodicarboxylate (4.46 g, 19.4 mmol) in dry THF (50 mL) was added. The reaction mixture was warmed to room temperature, stirred overnight, and concentrated under reduced pressure. The residue was dissolved in ethyl acetate (150 mL) and filtered. The filtrate was washed with water (150 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to afford methyl 4-{[(tert-butoxy)carbonyl]({[(tert-butoxy)carbonyl]amino})amino}-1-(2,2,2-trifluoroethyl)piperidine-4-carboxylate (7 g, 15.3 mmol, 80% purity, 69.4% yield) that was used in the next step without further purification.

Step-3. Synthesis of methyl 4-hydrazinyl-1-(2,2,2-trifluoroethyl)piperidine-4-carboxylate trishydrochloride

[0707] A 4 M solution of HCl in dioxane (31 mL) was added to a solution of methyl 4-{[(tert-butoxy)carbonyl]({[(tert-butoxy)carbonyl]amino})amino}-1-(2,2,2-trifluoroethyl)piperidine-4-carboxylate (7 g, 12.2 mmol) in dioxane (50 mL), and the mixture was stirred for 24 h at room temperature. Afterwards, it was concentrated under reduced pressure to afford methyl 4-hydrazinyl-1-(2,2,2-trifluoroethyl)piperidine-4-carboxylate trishydrochloride (4 g, 10.9 mmol, 75% purity, 96.4% yield) that was used in the next step without further purification.

Step-4. Synthesis of 1-(2,2,2-trifluoroethyl)-1,2-dihydrospiro[piperidine-4,3-pyrazolo[1,5-a]imidazol]-2-one

[0708] (2E)-3-methoxyprop-2-enenitrile (0.972 g, 11.7 mmol) was added to a suspension of methyl 4-hydrazinyl-1-(2,2,2-trifluoroethyl)piperidine-4-carboxylate trishydrochloride (4 g, 11.7 mmol) in acetic acid (50 mL), and the resulting mixture was heated under reflux for 12 hours. Afterwards, the reaction mixture was cooled to room temperature and evaporated to dryness in vacuo. The crude product was purified by flash chromatography (chloroform/acetonitrile) to give 1-(2,2,2-trifluoroethyl)-1,2-dihydrospiro[piperidine-4,3-pyrazolo[1,5-a]imidazol]-2-one as a white solid (0.4 g, 1.45 mmol, 90,% purity, 11.2% yield).

Step-5. Synthesis of 1-(2,2,2-trifluoroethyl)-1,2-dihydrospiro[piperidine-4,3-pyrazolo[1,5-a]imidazole]

[0709] A solution of 1-(2,2,2-trifluoroethyl)-1,2-dihydrospiro[piperidine-4,3-pyrazolo[1,5-a]imidazol]-2-one (0.4 g, 1.31 mmol) in tetrahydrofuran (25 mL) was added dropwise at 5 C. to a suspension of lithium aluminum hydride (0.099 g, 2.62 mmol) in tetrahydrofuran (5 mL). After addition, the solution was warmed to room temperature and stirred for 12 hours. The solution was quenched with a mixture of water/tetrahydrofuran (1/1.5 mL). The resulting mixture was filtered, and the filtrate was evaporated under reduced pressure to give 1-(2,2,2-trifluoroethyl)-1,2-dihydrospiro[piperidine-4,3-pyrazolo[1,5-a]imidazole] (0.35 g, 1.34 mmol, 91.35% purity, 93.8% yield).

Step-6. Synthesis of N,N-dimethyl-4-([1-(2,2,2-trifluoroethyl)-1,2-dihydrospiro[piperidine-4,3-pyrazolo[1,5-a]imidazol]-1-yl]sulfonyl)benzene-1-sulfonamide

[0710] 4-(Dimethylsulfamoyl)benzene-1-sulfonyl chloride (0.417 g, 1.47 mmol) was added to a mixture of 1-(2,2,2-trifluoroethyl)-1,2-dihydrospiro[piperidine-4,3-pyrazolo[1,5-a]imidazole](0.35 g, 1.22 mmol) and pyridine (0.965 g, 12.2 mmol) in dry acetonitrile (50 mL). The reaction mixture was stirred at room temperature overnight and evaporated. The residue was subjected to HPLC purification (deionized water/HPLC-grade acetonitrile) to afford the product N,N-dimethyl-4-{[1-(2,2,2-trifluoroethyl)-1,2-dihydrospiro[piperidine-4,3-pyrazolo[1,5-a]imidazol]-1-yl]sulfonyl}benzene-1-sulfonamide (I-144). Yield: 40.6 mg, 6.21%; Appearance: Beige solid; .sup.1H NMR (600 MHz, DMSO-d.sub.6) 12.21 (s, 1H), 7.39-7.36 (m, 2H), 7.33 (d, J=3.2 Hz, 1H), 7.15-7.12 (m, 2H), 3.32 (s, 3H), 3.28 (d, J=6.7 Hz, 2H), 1.87 (t, J 6.8 Hz, 2H), 1.25 (s, 9H); HPLC purity: 100%; LCMS Calculated for C.sub.19H.sub.24F.sub.3N.sub.5O.sub.4S.sub.2: 507.55; Observed: 508.2[M+H].sup.+.

Example 55Synthesis of cyclopropylmethyl 1-[4-(dimethylsulfamoyl)benzenesulfonyl]-1,2-dihydrospiro[pipridine-4,3-pyrazolo[1,5-a]imidazole]-1-carboxylate (I-145)

[0711] ##STR00468## ##STR00469##

Step-1. Synthesis of 1-cyclopropylmethyl 4-methyl piperidine-1,4-dicarboxylate

[0712] Cyclopropylmethyl carbonochloridate (5.15 g, 38.3 mmol) was added to a solution of triethylamine (3.87 g, 38.3 mmol) and methyl piperidine-4-carboxylate (5 g, 34.9 mmol) in dry dichloromethane (100 mL). The mixture was stirred for 12 hours at room temperature. Afterwards, the mixture was concentrated under reduced pressure. The residue was dissolved in ethyl acetate (150 mL) and filtered, and the filtrate was washed with water (150 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to afford 1-cyclopropylmethyl 4-methyl piperidine-1,4-dicarboxylate (8 g, 33.1 mmol, 100% purity, 95.0% yield).

Step-2. Synthesis of 4-methyl 4-{[(tert-butoxy)carbonyl]({[(tert-butoxy)carbonyl]amino})amino}piperidine-1,4-dicarboxylate

[0713] A 2.5 M n-BuLi solution in hexane (14.5 mL, 36.4 mmol) was added at 78 C. to a solution of diisopropylamine (3.68 g, 36.4 mmol) in dry THF (100 mL). The mixture was stirred for 10 min, and a solution of 1-cyclopropylmethyl 4-methyl piperidine-1,4-dicarboxylate (8 g, 33.1 mmol) in dry THF (20 mL) was added dropwise to it at the same temperature. The mixture was stirred for 3 h at 78 C. Then, a solution of di-tert-butyl azodicarboxylate (7.99 g, 34.7 mmol) in dry THF (50 mL) was added. The reaction mixture was warmed to room temperature, stirred overnight, and concentrated under reduced pressure. The residue was dissolved in ethyl acetate (150 mL) and filtered, and the filtrate was washed with water (150 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to afford 1-cyclopropylmethyl 4-methyl 4-{[(tert-butoxy)carbonyl]({[(tert-butoxy)carbonyl]amino})amino}piperidine-1,4-dicarboxylate (12 g, 25.4 mmol, 90% purity, 69.2% yield) that was used in the next step without further purification.

Step-3. Synthesis of 4-methyl 4-hydrazinylpiperidine-1,4-dicarboxylate bishydrochloride

[0714] A 4 M solution of HCl in dioxane (50 mL) was added to a solution of 1-cyclopropylmethyl 4-methyl 4-{[(tert-butoxy)carbonyl]({[(tert-butoxy)carbonyl]amino})amino}piperidine-1,4-dicarboxylate (12 g, 22.9 mmol) in dioxane (100 mL), and the mixture was stirred for 24 h at room temperature. Then, it was concentrated under the reduced pressure to afford 1-cyclopropylmethyl 4-methyl 4-hydrazinylpiperidine-1,4-dicarboxylate bishydrochloride (7 g, 12.2 mmol, 60% purity, 53.3% yield) that was used in the next step without further purification.

Step-4. Synthesis of cyclopropylmethyl 2-oxo-1,2-dihydrospiro[piperidine-4,3-pyrazolo[1,5-a]imidazole]-1-carboxylate

[0715] (2E)-3-methoxyprop-2-enenitrile (1.27 g, 15.4 mmol) was added to a suspension of 1-cyclopropylmethyl 4-methyl 4-hydrazinylpiperidine-1,4-dicarboxylate (7 g, 15.4 mmol) in an acetic acid (100 mL), and the resulting mixture was heated under reflux for 12 hours. Then, it was cooled to room temperature and evaporated to dryness in vacuo. The crude product was purified by flash chromatography (chloroform/acetonitrile) to give cyclopropylmethyl 2-oxo-1,2-dihydrospiro[piperidine-4,3-pyrazolo[1,5-a]imidazole]-1-carboxylate as a white solid (0.8 g, 15.4 mmol, 95% purity, 17.0% yield).

Step-5. Synthesis of cyclopropylmethyl 1,2-dihydrospiro[piperidine-4,3-pyrazolo[1,5-a]imidazole]-1-carboxylate

[0716] A solution of cyclopropylmethyl 2-oxo-1,2-dihydrospiro[piperidine-4,3-pyrazolo[1,5-a]imidazole]-1-carboxylate (0.8 g, 2.61 mmol) in tetrahydrofuran (25 mL) was added dropwise at 5 C. to borane dimethyl sulfide complex (0.587 g, 7.83 mmol). After addition, the solution was warmed to room temperature and refluxed for 12 hours. The solution was cooled to room temperature, quenched with methanol (5 mL), and filtered, and the filtrate was evaporated under reduced pressure to give cyclopropylmethyl 1,2-dihydrospiro[piperidine-4,3-pyrazolo[1,5-a]imidazole]-1-carboxylate (0.3 g, 1.08 mmol, 100% purity, 41.6% yield).

Step-6. Synthesis of cyclopropylmethyl 1-[4-(dimethylsulfamoyl)benzenesulfonyl]-1,2-dihydrospiro[piperidine-4,3-pyrazolo[1,5-a]imidazole]-1-carboxylate

[0717] 4-(Dimethylsulfamoyl)benzene-1-sulfonyl chloride (0.169 g, 0.596 mmol) was added to the mixture of cyclopropylmethyl 1,2-dihydrospiro[piperidine-4,3-pyrazolo[1,5-a]imidazole]-1-carboxylate (0.15 g, 0.542 mmol) and pyridine (0.213 g, 2.7 mmol) in dry acetonitrile (50 mL). The reaction mixture was stirred at room temperature overnight and evaporated. The residue was subjected to HPLC purification (deionized water/HPLC-grade acetonitrile) to afford the product cyclopropylmethyl 1-[4-(dimethylsulfamoyl)benzenesulfonyl]-1,2-dihydrospiro[piperidine-4,3-pyrazolo[1,5-a]imidazole]-1-carboxylate (I-145). Yield: 21.6 mg, 7.24%; Appearance: Colorless oil, .sup.1H NMR (400 MHz, DMSO-d.sub.6) 8.11 (d, J=8.2 Hz, 2H), 7.99 (d, J=8.2 Hz, 2H), 7.45 (d, J=1.9 Hz, 1H), 6.01 (d, J=1.9 Hz, 1H), 4.29 (s, 2H), 3.83 (d, J=7.2 Hz, 2H), 3.67 (d, J=14.7 Hz, 2H), 3.30 (s, 2H), 2.63 (s, 6H), 1.54 (dd, J=9.0, 4.0 Hz, 2H), 1.43 (s, 2H), 1.06 (q, J=6.2, 5.0 Hz, 1H), 0.52-0.42 (m, 2H), 0.23 (dt, J=6.3, 3.1 Hz, 2H); HPLC purity: 100%; LCMS Calculated for C.sub.22H.sub.29N.sub.5O.sub.6S.sub.2: 523.63; Observed: 524.4 [M+H].sup.+.

Example 56Synthesis of N,N-dimethyl-4-({6-methyl-1,2-dihydrospiro[cyclohexane-1,3-pyrazolo[1,5-a]imidazol]-1-yl}sulfonyl)benzene-1-sulfonoimidamide (I-146)

[0718] ##STR00470## ##STR00471##

Step-1. Synthesis of 6-methylspiro[cyclohexane-1,3-imidazo[1,2-b]pyrazol]-2(1H)-one

[0719] (2Z)-3-aminobut-2-enenitrile (1.05 g, 12.75 mmol) was added to a suspension of methyl 1-hydrazinylcyclohexane-1-carboxylate dihydrochloride (3.12 g, 12.75 mmol) in a 3 M HCl/H.sub.2O mixture (, 36 mL), and the resulting mixture was heated under reflux for 12 hours. Then it was cooled to room temperature and neutralized with 2.5M sodium hydroxide aq. solution. The suspension was extracted with dichloromethane (30 mL3). The combined organic layers were washed with brine (20 mL), dried over sodium sulfate, and evaporated in vacuo to give 6-methylspiro[cyclohexane-1,3-imidazo[1,2-b]pyrazol]-2(1H)-one as a white solid (1.05 g, 5.10 mmol, 100% purity, 40% yield).

Step-2. Synthesis of 6-methyl-1,2-dihydrospiro[cyclohexane-1,3-pyrazolo[1,5-a]imidazole]

[0720] A solution of 6-methyl-1,2-dihydrospiro[cyclohexane-1,3-pyrazolo[1,5-a]imidazol]-2-one (1.05 g, 5.10 mmol) in tetrahydrofuran (75 mL) was added dropwise at 5 C. to a suspension of lithium aluminum hydride (0.237 g, 6.09 mmol) in tetrahydrofuran (15 mL). After addition, the solution was warmed to room temperature and stirred for 12 hours. The solution was quenched with a mixture of water/tetrahydrofuran (3/4.5 mL). The resulting mixture was filtered, and the filtrate was evaporated under reduced pressure to give 6-methyl-1,2-dihydrospiro[cyclohexane-1,3-pyrazolo[1,5-a]imidazole] (0.33 g, 1.725 mmol, 100% purity, 33.8% yield).

Step-3. Synthesis of 4-[(tert-butyldimethylsilyl)dimethyl-S-aminosulfonimidoyl]benzene-1-sulfonyl chloride

[0721] A 2.5 M solution of n-butyllithium (0.382 g, 5.97 mmol) in hexane (2.38 mL) was added to a solution of 4-bromo-N-(tert-butyldimethylsilyl)-N,N-dimethylbenzenesulfonimidamide (1.88 g, 4.98 mmol) in anhydrous tetrahydrofuran (20 mL) at 78 C. under argon atmosphere, and the mixture was stirred for 1 h at 78 C. Afterwards, a solution of SO.sub.2 (0.954 g, 14.9 mmol) in tetrahydrofuran (20 mL) was added to the resulting mixture at the same temperature. Then, the cooling bath was removed, and the mixture was allowed to warm to room temperature and stir for 12 h. The solution was then evaporated in vacuo. The residue was dissolved in dichloromethane (20 mL), and N-chlorosuccinimide (0.797 g, 5.97 mmol) was added, maintaining the reaction mixture temperature at 0 C. The mixture was stirred for 30 minutes, and then diluted with ethyl acetate (20 mL) and water (20 mL). The organic layer was separated, dried over sodium sulfate, and filtered, and the filtrate was evaporated in vacuo to give 4-[(tert-butyldimethylsilyl)dimethyl-S-aminosulfonimidoyl]benzene-1-sulfonyl chloride as a dark resin (1.76 g, 4.43 mmol, 58.66% purity, 52.2% yield) that was used in the next step without further purification.

Step-4. Synthesis of N-(tert-butyldimethylsilyl)-N,N-dimethyl-4-({6-methyl-1,2-dihydrospiro[cyclohexane-1,3-pyrazolo[1,5-a]imidazol]-1-yl}sulfonyl)benzene-1-sulfonoimidamide

[0722] 4-(Difluoromethyl)benzene-1-sulfonyl chloride (0.387 g, 1.71 mmol) was added to a mixture of 6-methyl-1,2-dihydrospiro[cyclohexane-1,3-pyrazolo[1,5-a]imidazole] (0.3 g, 1.56 mmol) and pyridine (0.6 g, 7.80 mmol) in dry acetonitrile (25 mL). The reaction mixture was stirred at room temperature overnight and evaporated. The residue was subjected to HPLC purification (deionized water/HPLC-grade acetonitrile) to afford 1-[4-(difluoromethyl)benzenesulfonyl]-6-methyl-1,2-dihydrospiro[cyclohexane-1,3-pyrazolo[1,5-a]imidazole] as white solid (0.2882 g, 0.755 mmol, 95% purity, 45.8% yield). The analytical data provided for this compound provisionally supports the proposed structure for 1-[4-(difluoromethyl)benzenesulfonyl]-6-methyl-1,2-dihydrospiro[cyclohexane-1,3-pyrazolo[1,5-a]imidazole].

Step-5. Synthesis of N,N-dimethyl-4-((6-methylspiro[cyclohexane-1,3-imidazo[1,2-b]pyrazol]-1(2H)-yl)sulfonyl)benzenesulfonimidamide

[0723] A 1 M solution of TBAF in THF (1.55 mL, 0.405 g, 1.55 mmol) was added to a solution of N-(tert-butyldimethylsilyl)-N,N-dimethyl-4-((6-methylspiro[cyclohexane-1,3-imidazo[1,2-b]pyrazol]-1(2H)-yl)sulfonyl)benzenesulfonimidamide (0.86 g, 1.55 mmol) in dry THF (20 mL) under argon atmosphere. The reaction mixture was stirred for 12 h and evaporated in vacuo. The residue was subjected to HPLC purification (deionized water/HPLC-grade acetonitrile) to afford N,N-dimethyl-4-({6-methyl-1,2-dihydrospiro[cyclohexane-1,3-pyrazolo[1,5-a]imidazol]-1-yl}sulfonyl)benzene-1-sulfonoimidamide (I-146). Yield: 81 mg, 11.3%; Appearance: Yellow solid; 1H NMR (400 MHz, DMSO-d.sub.6) 8.07 (d, J=8.2 Hz, 2H), 7.98 (d, J=8.3 Hz, 2H), 5.78 (s, 1H), 4.76 (s, 1H), 4.12 (s, 2H), 2.54 (s, 6H), 2.12 (s, 3H), 1.62 (d, J=11.5 Hz, 2H), 1.50 (q, J=18.7, 15.1 Hz, 3H), 1.20 (dq, J=54.3, 13.2, 12.4 Hz, 5H); HPLC purity: 100%; LCMS Calculated for C.sub.19H.sub.27N.sub.5O.sub.3S.sub.2: 437.58; Observed: 438.2 [M+H].sup.+.

Example 57

[0724] The following compounds were prepared using standard chemical manipulations and procedures similar to those used for the preparation of the previous example.

TABLE-US-00019 Compound No. Structure Analytical Data I-147 [00472] Yield: 108.6 mg, 16.4%; Appearance: Yellow solid; .sup.1H NMR (600 MHz, DMSO-d.sub.6) 7.72 (d, J = 2.1 Hz, 1H), 7.56 (dd, J = 8.5, 2.0 Hz, 1H), 6.93 (d, J = 8.5 Hz, 1H), 5.72 (s, 1H), 4.32 (s, 2H), 4.06 (s, 2H), 2.08 (s, 3H), 1.60 (dt, J = 13.5, 4.0 Hz, 2H), 1.50 (td, J = 12.4, 3.9 Hz, 2H), 1.46- 1.42 (m, 1H), 1.25 (s, 8H), 1.15 (t, J = 11.8 Hz, 1H), 1.07 (d, J = 12.9 Hz, 2H); HPLC purity: 100%; LCMS Calculated for C.sub.21H.sub.27N.sub.3O.sub.3S: 401.21; Observed: 402.2 [M + H].sup.+. I-148 [00473] Yield: 288.2 mg, 45.8%; Appearance: White solid; .sup.1H NMR (600 MHz, DMSO-d.sub.6) 8.01 (d, J = 8.1 Hz, 2H), 7.81 (d, J = 8.1 Hz, 2H), 7.13 (t, J = 55.3 Hz, 1H), 5.74 (s, 1H), 2.09 (s, 3H), 1.61 (dt, J = 13.9, 4.3 Hz, 2H), 1.52 (td, J = 12.3, 3.9 Hz, 2H), 1.47-1.42 (m, 1H), 1.31-1.21 (m, 2H), 1.15 (d, J = 13.4 Hz, 3H); HPLC purity: 100%; LCMS Calculated for C.sub.18H.sub.21F.sub.2N.sub.3O.sub.2S: 381.44; Observed: 382.2 [M + H].sup.+. I-149 [00474] Yield: 356.7 mg, 36.6%; Appearance: Yellow solid; .sup.1H NMR (400 MHz, DMSO-d.sub.6) 8.06- 7.86 (m, 4H), 7.35 (s, 1H), 7.04 (d, J = 7.7 Hz, 1H), 6.87 (d, J = 7.6 Hz, 1H), 4.69 (s, 1H), 3.78 (s, 2H), 2.50 (s, 6H), 2.33 (s, 3H), 1.59 (d, J = 12.2 Hz, 1H), 1.53-1.43 (m, 2H), 1.41-1.06 (m, 5H), 0.94 (t, J = 12.4 Hz, 2H); HPLC purity: 100%; LCMS Calculated for C.sub.22H.sub.29N.sub.3O.sub.3S.sub.2: 447.61; Observed: 448.2 [M + H].sup.+.

Example 58Synthesis of 4-(1-{1,2-dihydrospiro[cyclohexane-1,3-indol]-1-yl}ethyl)-N,N-dimethylbenzene-1-sulfonamide (I-150)

[0725] ##STR00475##

Step-1. Synthesis of 1-[4-(dimethylsulfamoyl)phenyl]ethyl methanesulfonate

[0726] Triethylamine (0.164 g, 1.63 mmol) was added to a solution of 4-(1-hydroxyethyl)-N,N-dimethylbenzenesulfonamide (0.250 g, 1.09 mmol) in dichloromethane (10 mL). The solution was cooled in an ice-water bath and methanesulfonyl chloride (0.148 g, 1.30 mmol) was added dropwise. The mixture was stirred for 1 h at 0 C. and poured into water (20 mL). The layers were separated and the aqueous phase was extracted with dichloromethane (10 mL). The combined organic extracts were washed successively with saturated NaHCO.sub.3 aq. solution (10 mL) and brine (10 mL), then dried over sodium sulfate, filtered, and evaporated under reduced pressure to afford 1-[4-(dimethylsulfamoyl)phenyl]ethyl methanesulfonate as light-yellow solid (0.325 g, 1.05 mmol, 95% purity, 91.9% yield).

Step-2. Synthesis of 1,2-dihydrospiro[cyclohexane-1,3-indole]

[0727] A solution of 1,2-dihydrospiro[cyclohexane-1,3-indol]-2-one (0.55 g, 2.73 mmol) in THF (1 mL) was added to a suspension of LiAlH.sub.4 (0.117 g, 3.09 mmol) in THF (10 mL). The reaction mixture was stirred at room temperature for 8 h, and then refluxed for 2 h. The mixture was cooled to room temperature and carefully quenched with H.sub.2O (0.12 mL), then with 6 N NaOH aq. solution (0.12 mL). The mixture was then diluted with water (5 mL). The resulting slurry was filtered; the filtrate was concentrated under reduced pressure and dissolved in ethyl acetate (20 mL). The organic layer was washed with brine (10 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure to afford 1,2-dihydrospiro[cyclohexane-1,3-indole] (0.51 g, 2.58 mmol, 95% purity, 94.7% yield).

Step-3. Synthesis of 4-[(3-cyclohexyl-4-fluoro-1H-indol-1-yl)sulfonyl]-N,N-dimethylbenzene-1-sulfonamide

[0728] Dipotassium carbonate (0.439 g, 3.18 mmol) was added to a solution of 1,2-dihydrospiro[cyclohexane-1,3-indole] (0.2 g, 1.06 mmol) and 1-[4-(dimethylsulfamoyl)phenyl]ethyl methanesulfonate (0.325 g, 1.06 mmol) in acetonitrile (10 mL). The reaction mixture was stirred at 80 C. for 16 h. After completion (TLC control), the reaction mixture was diluted with water (10 mL) and extracted with ethyl acetate (20 mL2). The combined organic extracts were washed with water (10 mL) and brine (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by HPLC (deionized water/HPLC-grade acetonitrile, ammonia) to provide 4-(1-{1,2-dihydrospiro[cyclohexane-1,3-indol]-1-yl}ethyl)-N,N-dimethylbenzene-1-sulfonamide (I-150). Yield: 67.6 mg, 15.2%; Appearance: Yellow solid; .sup.1H NMR (600 MHz, DMSO-d.sub.6) 7.70 (dd, J=9.1, 7.4 Hz, 2H), 7.62 (d, J=8.3 Hz, 2H), 6.96 (dd, J=7.3, 1.3 Hz, 1H), 6.88 (td, J=7.6, 1.3 Hz, 1H), 6.55-6.47 (m, 1H), 6.29 (d, J=7.8 Hz, 1H), 4.84 (q, J=6.9 Hz, 1H), 3.30-3.19 (m, 2H), 2.57 (s, 6H), 1.66-1.53 (m, 6H), 1.51 (d, J=6.9 Hz, 3H), 1.44 (tt, J=13.0, 6.3 Hz, 1H), 1.36-1.18 (m, 3H); HPLC purity: 100%; LCMS Calculated for C.sub.23H.sub.10N.sub.2O.sub.2S: 398.56; Observed: 399.4 [M+H].sup.+.

Example 59Synthesis of cyclopropyl(imino)(4-(spiro[cyclohexane-1,3-indolin]-1-ylsulfonyl)phenyl)-).SUP.6.-sulfanone (I-151)

[0729] ##STR00476## ##STR00477##

Step-1. Synthesis of benzyl 1-(4-bromobenzenesulfonyl)-1,2-dihydrospiro[cyclohexane-1,3-indole]

[0730] Pyridine (0.471 mL, 5.84 mmol) and 4-bromobenzene-1-sulfonyl chloride (1 g, 3.91 mmol) were added to a solution of benzyl 1,2-dihydrospiro[cyclohexane-1,3-indole] (0.805 g, 4.3 mmol) in tetrahydrofuran (50 mL). The reaction mixture was stirred at room temperature for 12 hours. The solvent was evaporated under reduced pressure. Flash chromatography purification (hexane/chloroform/MTBE) of the residue afforded benzyl 1-(4-bromobenzenesulfonyl)-1,2-dihydrospiro[cyclohexane-1,3-indole] (1.4 g, 3.1 mmol, 90% purity, 79.7% yield).

Step-2. Synthesis of 1-((4-(cyclopropylthio)phenyl)sulfonyl)spiro[cyclohexane-1,3-indoline]

[0731] A mixture of 1-(4-bromobenzenesulfonyl)-1,2-dihydrospiro[cyclohexane-1,3-indole](0.5 g, 1.23 mmol), cyclopropanethiol (0.136 g, 1.84 mmol), dicaesium (1+) carbonate (0.8 g, 2.46 mmol), and copper iodide (0.0584 g, 0.307 mmol) in DMSO (20 mL) was stirred at 110 C. overnight. The reaction mixture was then cooled to room temperature, diluted with water (40 mL), and extracted with ethyl acetate (50 mL2). Combined layers were dried over sodium sulfate, filtered, and evaporated under reduced pressure. The residue was subjected to HPLC purification (deionized water/HPLC-grade acetonitrile) that afforded 1-((4-(cyclopropylthio)phenyl)sulfonyl)spiro[cyclohexane-1,3-indoline] (0.2 g, 0.5 mmol, 100% purity, 26% yield).

Step-3. Synthesis of 1-[4-(cyclopropanesulfinyl)benzenesulfonyl]-1,2-dihydrospiro[cyclohexane-1,3-indole]

[0732] 3-Chlorobenzene-1-carboperoxoic acid (0.0862 g, 0.5 mmol) was added to a solution of 1-[4-(cyclopropylsulfanyl)benzenesulfonyl]-1,2-dihydrospiro[cyclohexane-1,3-indole] (0.2 g, 0.5 mmol) in dichloromethane (20 mL). The mixture was stirred overnight, then washed with sodium bicarbonate sat. aq. solution (20 mL) and evaporated to dryness. The residue was subjected to HPLC purification (deionized water/HPLC-grade acetonitrile) to afford 1-[4-(cyclopropanesulfinyl)benzenesulfonyl]-1,2-dihydrospiro[cyclohexane-1,3-indole] (0.074 g, 0.178 mmol, 100% purity, 35.8% yield).

Step-4. Synthesis of (cyclopropanesulfonimidoyl)phenyl)sulfonyl)spiro[cyclohexane-1,3-indoline]

[0733] 1-((4-(cyclopropylsulfinyl)phenyl)sulfonyl)spiro[cyclohexane-1,3-indoline] (0.0743 g, 0.178 mmol), trifluoroacetamide (0.0441 g, 0.391 mmol), iodobenzene diacetate (0.0943 g, 0.293 mmol), and magnesium oxide (0.0315 g, 0.783 mmol) were mixed in a methanol/dichloromethane mixture (1/1, 30 mL). The mixture was stirred for 5 minutes, treated with rhodium(II) acetate dimer (0.0039 g, 0.0089 mmol), and stirred at room temperature for 12 hours. The, the suspension was diluted with methanol (25 mL), treated with saturated solution of potassium carbonate (30 mL), and stirred at room temperature for 4 hours. Afterwards, the mixture was treated with water (50 mL), and the organic phase was separated and filtered through Celite. The aqueous phase was extracted with dichloromethane (30 mL3). The solvent was evaporated under reduced pressure and the residue was subjected to HPLC purification (deionized water/HPLC-grade acetonitrile) to afford 1-((4-(cyclopropanesulfonimidoyl)phenyl)sulfonyl)spiro[cyclohexane-1,3-indoline] (I-151). Yield: 6.7 mg, 8.3%; Appearance: Colorless oil; .sup.1H NMR (600 MHz, CDCl.sub.3) 8.08-7.96 (m, 4H), 7.64 (d, J=8.1 Hz, 1H), 7.22 (ddd, J=8.3, 6.4, 2.4 Hz, 1H), 7.08-7.03 (m, 2H), 3.77 (s, 2H), 2.55 (tt, J=7.9, 4.7 Hz, 1H), 1.70 (d, J=11.3 Hz, 1H), 1.68-1.62 (m, 2H), 1.49-1.38 (m, 3H), 1.32-1.22 (m, 5H), 1.20-1.14 (m, 1H), 1.13-1.07 (m, 1H), 0.95 (dtd, J=8.9, 7.5, 5.2 Hz, 1H); HPLC purity: 100%; LCMS Calculated for C.sub.22H.sub.26N.sub.2O.sub.3S.sub.2: 430.58; Observed: 431.2 [M+H].sup.+.

Example 60Synthesis of 1-((4-(difluoromethyl)phenyl)sulfonyl)-2,3,5,6-tetrahydrospiro[indoline-3,4-thiopyran] 1,1-dioxide (I-152)

[0734] ##STR00478##

Step-1. Synthesis of 1,2-dihydrospiro[indole-3,4-[1.SUP.6.]thiane]-1,1-dione

[0735] A solution of 1,1-dioxo-[1.sup.6-thiane-4-carbaldehyde] (1 g, 6.16 mmol) in dichloromethane (5 mL) was added dropwise to a mixture of phenyl hydrazine (0.9 g, 8.31 mmol) and trifluoroacetic acid (7 g, 61.6 mmol) in dichloromethane (20 mL). The mixture was stirred at 35 C. overnight. The reaction mixture was then cooled to 0 C., and sodium triacetoxyborohydride (3.89 g, 18.4 mmol) was added slowly to the solution, followed by stirring at RT for 4 hours. Afterwards, the mixture was washed with 6% NH.sub.4OH aq. solution (25 mL) and brine (30 mL), dried over sodium sulfate, filtered, and evaporated to dryness to give 1,2-dihydrospiro[indole-3,4-[1.sup.6]thiane]-1,1-dione (1.3 g, 5.47 mmol, 100% purity, 89% yield).

Step-2. Synthesis of 1-[4-(difluoromethyl)benzenesulfonyl]-1,2-dihydrospiro[indole-3,4-[1.SUP.6.]thiane]-1,1-dione

[0736] 4-(difluoromethyl)benzene-1-sulfonyl chloride (0.251 g, 1.11 mmol) was added to an ice-cooled solution of 1,2-dihydrospiro[indole-3,4-[1.sup.6]thiane]-1,1-dione (0.24 g, 1.01 mmol) and pyridine (0.399 g, 5.05 mmol) in dichloromethane (10 mL). The reaction mixture was allowed to warm to room temperature and stir until completion (overnight, NMR control). Afterwards, the reaction mixture was diluted with water (10 mL), and the organic layer was separated, dried over magnesium sulfate, filtered, and concentrated in vacuo. The residue was subjected to HPLC purification (deionized water/HPLC-grade acetonitrile) to give 1-[4-(difluoromethyl)benzenesulfonyl]-1,2-dihydrospiro[indole-3,4-[1.sup.6]thiane]-1,1-dione (I-152). Yield: 192.3 mg, 42.2%; Appearance: Pink solid; .sup.1H NMR (400 MHz, DMSO-d.sub.6) 8.02 (d, J=8.1 Hz, 2H), 7.77 (d, J=8.2 Hz, 2H), 7.52 (d, J=8.1 Hz, J H), 7.29 (t, J=7.8 Hz, 1H), 7.25-6.92 (m, 3H), 4.09 (s, 2H), 3.35 (t, J=13.3 Hz, 2H), 2.94 (d, J=14.1 Hz, 2H), 2.12 (t, J=13.5 Hz, 2H), 1.48 (d, J=14.2 Hz, 2H); HPLC purity: 100%; LCMS Calculated for C.sub.19H.sub.19F.sub.2NO.sub.4S.sub.2: 427.48; Observed: 428.0 [M+H].sup.+.

Example 61

[0737] The following compounds were prepared according to the methods provided in the examples above, using routine modifications known and understood to a person of skill in the art.

TABLE-US-00020 Compound No. Structure Analytical Data I-153 [00479] Yield: 673.2 mg, 64.8%; Appearance: Beige solid; .sup.1H NMR (400 MHz, DMSO-d.sub.6) 8.23- 8.15 (m, 2H), 8.05-7.94 (m, 2H), 6.45 (s, 1H), 4.29 (s, 2H), 2.62 (s, 6H), 1.69-1.55 (m, 4H), 1.47 (s, 1H), 1.31 (h, J = 12.4, 11.5 Hz, 5H); HPLC purity: 100%; LCMS Calculated for C.sub.19H.sub.23F.sub.3N.sub.4O.sub.4S.sub.2: 492.53; Observed: 493.0[M + H].sup.+. I-154 [00480] Yield: 702.7 mg, 73.7%; Appearance: Pink solid; .sup.1H NMR (400 MHz, DMSO-d.sub.6) 8.07- 7.94 (m, 4H), 4.18 (s, 2H), 2.60 (s, 6H), 2.14- 2.06 (m, 6H), 1.60-1.50 (m, 2H), 1.49-1.36 (m, 3H), 1.31-1.06 (m, 3H), 0.89 (d, J = 12.9 Hz, 2H).; HPLC purity: 100%; LCMS Calculated for C.sub.20H.sub.28N.sub.4O.sub.4S.sub.2: 452.59; Observed: 453.4[M + H].sup.+. I-155 [00481] Yield: 1170 mg, 53.4%; Appearance: Beige solid; .sup.1H NMR (600 MHz, DMSO-d.sub.6) 8.05 (d, J = 8.4 Hz, 2H), 7.91 (d, J = 8.4 Hz, 2H), 7.36 (d, J = 8.1 Hz, 1H), 7.34-7.24 (m, 5H), 7.24-7.20 (m, 1H), 6.91-6.83 (m, 1H), 3.88 (s, 2H), 3.44 (s, 2H), 2.65-2.61 (m, 2H), 1.98-1.86 (m, 4H), 1.12-1.02 (m, 2H).; HPLC purity: 100%; LCMS Calculated for C.sub.27H.sub.30FN.sub.3O.sub.4S.sub.2: 543.67; Observed: 544.2[M + H].sup.+. I-157 [00482] Yield: 157.2 mg, 22.6%; Appearance: Orange solid; .sup.1H NMR (400 MHz, DMSO-d.sub.6) 8.08- 7.98 (m, 3H), 7.94 (d, J = 8.2 Hz, 2H), 7.65 (d, J = 1.8 Hz, 1H), 4.72 (s, 1H), 3.82 (s, 2H), 2.50 (s, 6H), 2.32 (s, 3H), 1.62-1.49 (m, 3H), 1.49-1.40 (m, 2H), 1.34-1.10 (m, 3H), 0.96 (m, 2H).; HPLC purity: 100%; LCMS Calculated for C.sub.21H.sub.28N.sub.4O.sub.3S.sub.2: 448.6; Observed: 449.4[M + H].sup.+. I-158 [00483] Yield: 37.5 mg, 29.9%; Appearance: Beige solid; .sup.1H NMR (400 MHz, DMSO-d.sub.6) 8.54 (s, 1H), 8.51-8.40 (m, 1H), 7.95 (d, J = 8.0 Hz, 2H), 7.77-7.67 (m, 3H), 7.53 (d, J = 8.1 Hz, 1H), 7.33 (dd, J = 7.8, 4.8 Hz, 1H), 7.24-7.15 (m, 1H), 7.13-6.77 (m, 3H), 5.11 (s, 2H), 3.96 (d, J = 13.7 Hz, 2H), 3.89 (s, 2H), 3.00-2.78 (m, 2H), 1.71- 1.52 (m, 2H), 1.20 (d, J = 13.3 Hz, 2H).; HPLC purity: 100%; LCMS Calculated for C.sub.26H.sub.25F.sub.2N.sub.3O.sub.4S: 513.56; Observed: 514.2[M + H].sup.+. I-159 [00484] Yield: 38.9 mg, 31%; Appearance: White solid; .sup.1H NMR (400 MHz, DMSO-d.sub.6) 8.51 (d, J = 5.9 Hz, 2H), 7.96 (d, J = 7.9 Hz, 2H), 7.73 (d, J = 8.1 Hz, 2H), 7.53 (d, J = 8.0 Hz, 1H), 7.27 (d, ) = 4.4 Hz, 2H), 7.24-7.16 (m, 1H), 7.18-6.74 (m, 3H), 5.11 (s, 2H), 4.08-3.93 (m, 2H), 3.91 (s, 2H), 2.99-2.83 (m, 2H), 1.71-1.59 (m, 2H), 1.23 (d, J = 13.3 Hz, 2H).; HPLC purity: 100%; LCMS Calculated for C.sub.26H.sub.25F.sub.2N.sub.3O.sub.4S: 513.56; Observed: 514.0[M + H].sup.+. I-160 [00485] Yield: 38.7 mg, 30.8%; Appearance: White solid; .sup.1H NMR (600 MHz, DMSO-d.sub.6) 7.97 (d, J = 8.1 Hz, 2H), 7.76 (d, J = 8.0 Hz, 2H), 7.48 (d, J = 8.1 Hz, 1H), 7.25-7.07 (m, 3H), 7.07-6.96 (m, 1H), 4.77-4.67 (m, 1H), 3.90 (s, 2H), 3.87- 3.70 (m, 2H), 3.00-2.70 (m, 2H), 1.58-1.46 (m, 2H), 1.16 (d, J = 6.3 Hz, 6H), 1.07 (d, J = 13.2 Hz, 2H).; HPLC purity: 100%; LCMS Calculated C.sub.23H.sub.26F.sub.2N.sub.2O.sub.4S: 464.53; Observed: 465.2[M + H].sup.+. I-161 [00486] Yield: 32.8 mg, 26.1%; Appearance: Light brown solid; .sup.1H NMR (600 MHz, DMSO-d.sub.6) 7.98 (d, J = 8.2 Hz, 2H), 7.75 (d, J = 8.1 Hz, 2H), 7.48 (d, J = 8.1 Hz, 1H), 7.46-7.38 (m, 5H), 7.30 (d, J = 7.5 Hz, 1H), 7.26-7.22 (m, 1H), 7.17- 6.96 (m, 2H), 4.35 (s, 1H), 3.96 (d, J = 18.7 Hz, 2H), 3.43 (s, 1H), 3.22-3.11 (m, 1H), 2.88 (s, 1H), 1.72-1.61 (m, 2H), 1.21-1.08 (m, 2H).; HPLC purity: 97.44%; LCMS Calculated for C.sub.26H.sub.24F.sub.2N.sub.2O.sub.3S: 482.55; Observed: 483.2[M + H].sup.+. I-162 [00487] Yield: 33.3 mg, 26.7%; Appearance: Yellow solid; .sup.1H NMR (400 MHz, DMSO-d.sub.6) 7.97 (d, J = 8.0 Hz, 2H), 7.73 (d, J = 8.1 Hz, 2H), 7.53 (d, J = 8.1 Hz, 1H), 7.24-7.15 (m, 1H), 7.14-6.79 (m, 3H), 4.31 (s, 1H), 4.14 (s, 1H), 4.06-3.84 (m, 2H), 3.84-3.72 (m, 1H), 3.33-3.21 (m, 1H), 3.19 (d, J = 5.1 Hz, 2H), 2.67 (s, 1H), 1.86 (s, 1H), 1.73-1.46 (m, 2H), 1.37-1.09 (m, 2H), 0.79 (s, 2H), 0.74-0.63 (m, 2H).; HPLC purity: 100%; LCMS Calculated for C.sub.23H.sub.24F.sub.2N.sub.2O.sub.3S: 446.51; Observed: 447.2[M + H].sup.+. I-163 [00488] Yield: 28.6 mg, 22.7%; Appearance: Yellow oil; .sup.1H NMR (600 MHz, DMSO-d.sub.6) 8.67 (d, J = 1.5 Hz, 1H), 8.56 (dd, J = 2.6, 1.5 Hz, 1H), 8.52 (d, J = 2.6 Hz, 1H), 7.97 (d, J = 8.2 Hz, 2H), 7.74 (d, J = 8.2 Hz, 2H), 7.48 (d, J = 8.0 Hz, 1H), 7.27- 6.95 (m, 4H), 3.82 (s, 2H), 3.66 (s, 2H), 2.69 (d, J = 11.7 Hz, 2H), 2.18-2.08 (m, 2H), 1.74-1.64 (m, 2H), 1.09 (d, J = 12.5 Hz, 2H).; HPLC purity: 97.4%; LCMS Calculated for C.sub.24H.sub.24F.sub.2N.sub.4O.sub.2S: 470.54; Observed: 471.2[M + H].sup.+. I-164 [00489] Yield: 48.8 mg, 38.9%; Appearance: Light brown solid; .sup.1H NMR (600 MHz, DMSO-d.sub.6) 8.52-8.41 (m, 1H), 7.97 (d, J = 8.2 Hz, 2H), 7.77- 7.70 (m, 3H), 7.48 (d, J = 8.1 Hz, 1H), 7.42 (d, J = 7.8 Hz, 1H), 7.25-6.93 (m, 5H), 3.82 (s, 2H), 3.59 (s, 2H), 2.68 (d, J = 12.4 Hz, 2H), 2.09 (t, J = 12.3 Hz, 2H), 1.75-1.63 (m, 2H), 1.14-1.04 (m, 2H).; HPLC purity: 100%; LCMS Calculated for C.sub.25H.sub.25F.sub.2N.sub.3O.sub.2S: 469.55; Observed: 470.0[M + H].sup.+. I-165 [00490] Yield: 30.9 mg, 24.6%; Appearance: Yellow solid; .sup.1H NMR (600 MHz, DMSO-d.sub.6) 8.48 (d, J = 2.1 Hz, 1H), 8.45 (dd, J = 4.8, 1.6 Hz, 1H), 7.96 (d, J = 8.2 Hz, 2H), 7.74 (d, J = 8.1 Hz, 2H), 7.72-7.59 (m, 1H), 7.47 (d, J = 8.0 Hz, 1H), 7.34 (dd, J = 7.8, 4.8 Hz, 1H), 7.27-7.19 (m, 2H), 7.19-6.90 (m, 2H), 3.81 (s, 2H), 3.50 (s, 2H), 2.64 (d, J = 11.7 Hz, 2H), 2.08-1.96 (m, 2H), 1.72-1.59 (m, 2H), 1.10 (d, J = 13.0 Hz, 2H).; HPLC purity: 100%; LCMS Calculated for C.sub.25H.sub.25F.sub.2N.sub.3O.sub.2S: 469.55; Observed: 470.0[M + H].sup.+. I-166 [00491] Yield: 35.7 mg, 28.4%; Appearance: Yellow oil; .sup.1H NMR (600 MHz, DMSO-d.sub.6) 8.53-8.45 (m, 2H), 7.96 (d, J = 8.0 Hz, 2H), 7.74 (d, J = 8.0 Hz, 2H), 7.48 (d, J = 7.9 Hz, 1H), 7.33-7.29 (m, 2H), 7.25-7.18 (m, 2H), 7.17-6.95 (m, 2H), 3.81 (s, 2H), 3.51 (s, 2H), 2.64 (d, J = 11.8 Hz, 2H), 2.05 (t, J = 12.0 Hz, 2H), 1.75-1.63 (m, 2H), 1.10 (d, J = 12.9 Hz, 2H).; HPLC purity: 100%; LCMS Calculated for C.sub.25H.sub.25F.sub.2N.sub.3O.sub.2S: 469.55; Observed: 470.0[M + H].sup.+. I-167 [00492] Yield: mg, %; Appearance: Yellow solid; .sup.1H NMR (400 MHz, DMSO-d.sub.6) 8.78 (d, J = 4.9 Hz, 2H), 7.98 (d, J = 8.0 Hz, 2H), 7.76 (d, J = 8.0 Hz, 2H), 7.49 (d, J = 8.0 Hz, 1H), 7.43-7.35 (m, 1H), 7.26-6.92 (m, 4H), 3.82 (s, 2H), 3.71 (s, 2H), 2.78 (d, J = 11.8 Hz, 2H), 2.18 (t, J = 12.0 Hz, 2H), 1.75-1.61 (m, 2H), 1.09 (d, J = 12.9 Hz, 2H).; HPLC purity: 96.39%; LCMS Calculated for C.sub.24H.sub.24F.sub.2N.sub.4O.sub.2S: 470.54; Observed: 471.2[M + H].sup.+. I-168 [00493] Yield: 26.8 mg, 21.3%; Appearance: Yellow solid; .sup.1H NMR (600 MHz, DMSO-d.sub.6) 7.96 (d, J = 8.1 Hz, 2H), 7.74 (d, J = 8.1 Hz, 2H), 7.47 (d, J = 8.0 Hz, 1H), 7.33-7.27 (m, 4H), 7.25-7.19 (m, 3H), 7.16-6.96 (m, 2H), 3.80 (s, 2H), 3.46 (s, 2H), 2.65 (d, J = 12.4 Hz, 2H), 2.03-1.94 (m, 2H), 1.71-1.61 (m, 2H), 1.09 (d, J = 12.9 Hz, 2H).; HPLC purity: 100%; LCMS Calculated for C.sub.26H.sub.26F.sub.2N.sub.2O.sub.2S: 468.56; Observed: 469.0[M + H].sup.+. I-169 [00494] Yield: 156.2 mg, 75.1%; Appearance: Yellow solid; .sup.1H NMR (500 MHz, DMSO-d.sub.6) 7.99 (d, J = 8.0 Hz, 2H), 7.77 (d, J = 8.0 Hz, 2H), 7.50 (d, J = 8.1 Hz, 1H), 7.40-7.32 (m, 2H), 7.29-7.23 (m, 2H), 7.22-6.96 (m, 5H), 4.07-3.99 (m, 1H), 3.97 (s, 2H), 3.94-3.83 (m, 1H), 3.20-3.08 (m, 1H), 3.05-2.93 (m, 1H), 1.81-1.61 (m, 2H), 1.16 (d, J = 13.0 Hz, 2H).; HPLC purity: 98.27%; LCMS Calculated for C.sub.26H.sub.24F.sub.2N.sub.2O.sub.4S: 498.54; Observed: 499.2[M + H].sup.+. I-170 [00495] Yield: 58.9 mg, 46.9%; Appearance: White solid; .sup.1H NMR (400 MHz, DMSO-d.sub.6) 7.95 (d, J = 8.0 Hz, 2H), 7.73 (d, J = 8.0 Hz, 2H), 7.53 (d, J = 8.1 Hz, 1H), 7.27-7.13 (m, 1H), 7.12-6.79 (m, 3H), 3.95 (d, J = 13.7 Hz, 2H), 3.88 (s, 2H), 3.83 (d, J = 7.0 Hz, 2H), 2.98-2.78 (m, 2H), 1.68- 1.54 (m, 2H), 1.29-1.16 (m, 2H), 1.15-1.02 (m, 1H), 0.59-0.45 (m, 2H), 0.32-0.22 (m, 2H).; HPLC purity: 100%; LCMS Calculated for C.sub.24H.sub.26F.sub.2N.sub.2O.sub.4S: 476.54; Observed: 477.2[M + H].sup.+. I-171 [00496] Yield: 17.5 mg, 16.6%; Appearance: White solid; .sup.1H NMR (600 MHz, DMSO-d.sub.6) 7.96 (d, J = 8.1 Hz, 2H), 7.79-7.70 (m, 3H), 7.48 (d, J = 8.2 Hz, 1H), 7.42 (s, 1H), 7.27-7.21 (m, 1H), 7.20-6.94 (m, 3H), 4.90 (s, 2H), 4.08 (q, J = 7.3 Hz, 2H), 3.90 (s, 2H), 3.81 (d, J = 34.4 Hz, 2H), 2.98-2.74 (m, 2H), 1.57-1.46 (m, 2H), 1.33 (t, J = 7.3 Hz, 3H), 1.05 (d, J = 13.1 Hz, 2H).; HPLC purity: 100%; LCMS Calculated for C.sub.26H.sub.28F.sub.2N.sub.4O.sub.4S: 530.59; Observed: 531.2[M + H].sup.+. I-172 [00497] Yield: 72.6 mg, 62.6%; Appearance: Yellow solid; .sup.1H NMR (400 MHz, DMSO-d.sub.6) 7.98 (d, J = 8.1 Hz, 2H), 7.77 (d, J = 8.1 Hz, 2H), 7.53 (d, J = 1.3 Hz, 1H), 7.50 (d, J = 8.1 Hz, 1H), 7.32- 6.95 (m, 5H), 4.87 (s, 2H), 3.92 (s, 2H), 3.90- 3.72 (m, 2H), 3.00-2.78 (m, 2H), 1.62-1.49 (m, 2H), 1.07 (d, J = 13.2 Hz, 2H).; HPLC purity: 100%; LCMS Calculated for C.sub.25H.sub.26F.sub.2N.sub.4O.sub.4S: 516.56; Observed: 517.0[M + H].sup.+. I-173 [00498] Yield: 41.6 mg, 20.2%; Appearance: Yellow oil; .sup.1H NMR (400 MHz, DMSO-d.sub.6) 9.01 (s, 1H), 8.66 (s, 1H), 7.99 (d, J = 8.0 Hz, 2H), 7.77 (d, J = 8.0 Hz, 2H), 7.50 (d, J = 8.1 Hz, 1H), 7.31-6.94 (m, 4H), 4.98 (s, 2H), 3.92 (s, 2H), 3.89-3.76 (m, 2H), 3.06-2.76 (m, 2H), 1.65-1.51 (m, 2H), 1.08 (d, J = 13.3 Hz, 2H).; HPLC purity: 100%; LCMS Calculated for C.sub.24H.sub.23F.sub.2N.sub.3O.sub.5S: 504.52; Observed: 505.2[M + H].sup.+. I-174 [00499] Yield: 57.6 mg, 54.9%; Appearance: White solid; .sup.1H NMR (400 MHz, DMSO-d.sub.6) 7.95 (d, J = 8.1 Hz, 2H), 7.72 (d, J = 8.1 Hz, 2H), 7.52 (d, J = 8.1 Hz, 1H), 7.26-7.12 (m, 6H), 7.10-6.80 (m, 3H), 4.36 (d, J = 13.7 Hz, 1H), 3.93-3.78 (m, 2H), 3.73 (d, J = 13.9 Hz, 1H), 3.09 (t, J = 13.4 Hz, 1H), 2.85 (t, J = 7.6 Hz, 2H), 2.70-2.55 (m, 3H), 1.47 (q, J = 13.5 Hz, 2H), 1.17 (t, J = 11.8 Hz, 2H).; HPLC purity: 100%; LCMS Calculated for C.sub.28H.sub.28F.sub.2N.sub.2O.sub.3S: 510.6; Observed: 511.2[M + H].sup.+. I-175 [00500] Yield: 24.1 mg, 22.8%; Appearance: Yellow solid; .sup.1H NMR (600 MHz, DMSO-d.sub.6) 7.97 (d, J = 8.2 Hz, 2H), 7.75 (d, J = 8.0 Hz, 2H), 7.47 (d, J = 8.1 Hz, 1H), 7.29 (dd, J = 8.4, 6.9 Hz, 2H), 7.27-7.18 (m, 4H), 7.11-6.93 (m, 3H), 4.26 (d, J = 13.7 Hz, 1H), 3.95-3.86 (m, 2H), 3.82 (d, J = 14.2 Hz, 1H), 3.77-3.60 (m, 2H), 3.07 (t, J = 13.6 Hz, 1H), 2.66 (t, J = 13.1 Hz, 1H), 1.48- 1.34 (m, 2H), 1.12-0.95 (m, 2H).; HPLC purity: 100%; LCMS Calculated for C.sub.27H.sub.26F.sub.2N.sub.2O.sub.3S; 496.57; Observed: 497.0[M + H].sup.+. I-176 [00501] Yield: 16 mg, 15.2%; Appearance: Beige solid; .sup.1H NMR (600 MHz, DMSO-d.sub.6) 7.96 (d, J = 8.2 Hz, 2H), 7.75 (d, J = 8.1 Hz, 2H), 7.70 (s, 1H), 7.48 (d, J = 8.1 Hz, 1H), 7.41 (s, 1H), 7.28-7.20 (m, 1H), 7.20-6.99 (m, 3H), 4.89 (d, J = 9.1 Hz, 2H), 3.89 (s, 2H), 3.88-3.79 (m, 2H), 3.79 (s, 3H), 2.98-2.78 (m, 2H), 1.58-1.44 (m, 2H), 1.05 (d, J = 12.8 Hz, 2H).; HPLC purity: 100%; LCMS Calculated for C.sub.25H.sub.26F.sub.2N.sub.4O.sub.4S: 516.56; Observed: 517.0[M + H].sup.+. I-177 [00502] Yield: 92.4 mg, 41.1%; Appearance: Beige solid; .sup.1H NMR (400 MHz, DMSO-d.sub.6) 7.99 (d, J = 8.1 Hz, 2H), 7.77 (d, J = 8.0 Hz, 2H), 7.69 (d, J = 2.2 Hz, 1H), 7.50 (d, J = 8.1 Hz, 1H), 7.31- 6.92 (m, 4H), 6.22 (d, J = 2.2 Hz, 1H), 4.97 (s, 2H), 4.09 (q, J = 7.3 Hz, 2H), 3.92 (s, 2H), 3.89 (s, 0H), 3.83 (s, 2H), 1.63-1.51 (m, 2H), 1.35 (t, J = 7.3 Hz, 3H), 1.07 (d, J = 13.2 Hz, 2H)., HPLC purity: 97.29%; LCMS Calculated for C.sub.26H.sub.28F.sub.2N.sub.4O.sub.4S: 530.59; Observed: 531.2[M + H].sup.+. I-178 [00503] Yield: 8.5 mg, 6.16%; Appearance: Yellow solid; .sup.1H NMR (600 MHz, DMSO-d.sub.6) 7.98 (d, J = 8.5 Hz, 2H), 7.75 (d, J = 8.1 Hz, 2H), 7.48 (d, J = 8.1 Hz, 1H), 7.36-7.27 (m, 2H), 7.27 - 6.94 (m, 7H), 4.30 (s, 2H), 3.91 (s, 2H), 3.44 (d, J = 13.5 Hz, 2H), 3.15 (dd, J = 5.2, 2.1 Hz, 1H), 2.83 (t, J = 13.4 Hz, 2H), 2.66 (s, 3H), 1.72-1.55 (m, 2H), 1.08 (d, J = 13.0 Hz, 2H).; HPLC purity: 100%; LCMS Calculated for C.sub.28H.sub.29F.sub.2N.sub.3O.sub.3S: 525.61; Observed: 526.4[M + H].sup.+. I-179 [00504] Yield: 208.6 mg, 48.8%; Appearance: White solid; .sup.1H NMR (400 MHz, DMSO-d.sub.6) 8.00 (d, J = 8.1 Hz, 2H), 7.77 (d, J = 8.1 Hz, 2H), 7.51 (d, J = 8.0 Hz, 1H), 7.32-7.17 (m, 7H), 7.12-7.02 (m, 2H), 4.23 (d, J = 5.7 Hz, 2H), 3.94 (s, 2H), 3.89 (d, J = 13.7 Hz, 2H), 2.80 (t, J = 12.9 Hz, 2H), 1.53 (td, J = 13.0, 4.3 Hz, 2H), 1.07 (d, J = 13.0 Hz, 2H); HPLC purity: 100%; LCMS Calculated for C.sub.27H.sub.27F.sub.2N.sub.3O.sub.3S: 511.59; Observed: 512.2[M + H].sup.+. I-180 [00505] Yield: 50.1 mg, 31.6%; Appearance: Yellow solid; .sup.1H NMR (600 MHz, DMSO-d.sub.6) 8.11 (s, 4H), 7.49 (d, J = 8.0 Hz, 1H), 7.39-7.29 (m, 5H), 7.27-7.20 (m, 2H), 7.08-6.99 (m, 1H), 5.07 (s, 2H), 3.95 (s, 2H), 3.89 (d, J = 13.6 Hz, 2H), 3.26 (s, 3H), 3.07-2.79 (m, 2H), 2.05 (s, 2H), 1.64- 1.51 (m, 2H), 1.15 (d, J = 13.2 Hz, 2H).; HPLC purity: 98%; LCMS Calculated for C.sub.27H.sub.28N.sub.2O.sub.6S.sub.2: 540.65; Observed: 541.2[M + H].sup.+. I-181 [00506] Yield: 63.8 mg, 18.9%; Appearance: White solid; .sup.1H NMR (400 MHz, DMSO-d.sub.6) 8.07 (q, J = 8.3 Hz, 4H), 7.53 (d, J = 8.1 Hz, 1H), 7.42- 7.31 (m, 5H), 7.28 (t, J = 7.8 Hz, 1H), 7.23 (d, J = 7.5 Hz, 1H), 7.07 (t, J = 7.5 Hz, 1H), 5.06 (s, 2H), 3.96 (s, 2H), 3.85 (s, 2H), 3.51 (p, J = 6.6 Hz, 1H), 2.94 (s, 2H), 1.56 (s, 2H), 1.08 (d, J = 6.8 Hz, 6H), 1.04 (s, 2H); HPLC purity: 100%; LCMS Calculated for C.sub.29H.sub.32N.sub.2O.sub.6S.sub.2: 569.7; Observed: 570.0[M + H].sup.+. I-182 [00507] Yield: 332.3 mg, 30.5%; Appearance: White solid; .sup.1H NMR (600 MHz, DMSO-d.sub.6) 8.12 (s, 1H), 7.95-7.90 (m, 2H), 7.47 (d, J = 8.0 Hz, 1H), 7.36 (h, J = 5.9 Hz, 4H), 7.31 (td, J = 6.5, 6.0, 2.5 Hz, 1H), 7.25-7.20 (m, 2H), 7.02 (t, J = 7.5 Hz, 1H), 5.07 (s, 2H), 3.95 (s, 2H), 3.91 (d, J = 14.1 Hz, 2H), 3.64 (t, J = 6.9 Hz, 2H), 3.39 (t, J = 6.9 Hz, 2H), 2.97 (d, J = 42.7 Hz, 2H), 1.60 (td, J = 13.2, 4.5 Hz, 2H), 1.19 (d, J = 13.3 Hz, 2H); HPLC purity: 100%; LCMS Calculated for C.sub.28H.sub.28N.sub.2O.sub.6S.sub.2: 553.66; Observed: 554.0[M + H].sup.+. I-183 [00508] Yield: 89.1 mg, 56.7%; Appearance: Yellow solid; .sup.1H NMR (400 MHz, DMSO-d.sub.6) 7.79 (s, 1H), 7.72 (d, J = 7.9 Hz, 1H), 7.51 (d, J = 8.1 Hz, 1H), 7.47-7.39 (m, 1H), 7.38-7.31 (m, 4H), 7.31-7.23 (m, 1H), 7.25-7.14 (m, 1H), 7.08 (d, J = 7.4 Hz, 1H), 7.02-6.92 (m, 1H), 5.07 (s, 2H), 5.03 (s, 4H), 3.99 (d, J = 13.6 Hz, 2H), 3.87 (s, 2H), 3.01-2.80 (m, 2H), 1.72-1.54 (m, 2H), 1.25 (d, J = 13.2 Hz, 2H).; HPLC purity: 99%; LCMS Calculated for C.sub.28H.sub.28N.sub.2O.sub.5S: 504.6; Observed: 505.2[M + H].sup.+. I-184 [00509] Yield: 41.8 mg, 28.6%; Appearance: Beige solid; .sup.1H NMR (600 MHz, DMSO-d.sub.6) 7.61- 7.54 (m, 2H), 7.54-7.50 (m, 1H), 7.51-7.46 (m, 2H), 7.39-7.33 (m, 4H), 7.31 (d, J = 7.3 Hz, 2H), 7.24-6.94 (m, 2H), 5.07 (s, 2H), 3.96 (s, 4H), 3.01-2.72 (m, 2H), 1.79-1.69 (m, 2H), 1.65 (d, J = 13.3 Hz, 2H).; HPLC purity: 100%; LCMS Calculated for C.sub.27H.sub.26N.sub.2O.sub.3: 426.52; Observed: 427.2[M + H].sup.+. I-185 [00510] Yield: 72.3 mg, 46%; Appearance: Yellow solid; .sup.1H NMR (600 MHz, DMSO-d.sub.6) 7.73 (s, 2H), 7.68 (d, J = 7.7 Hz, 2H), 7.38-7.28 (m, 6H), 7.25-6.98 (m, 3H), 5.07 (s, 2H), 4.06-3.85 (m, 4H), 3.02-2.71 (m, 2H), 1.80-1.69 (m, 2H), 1.69-1.60 (m, 2H).; HPLC purity: 100%; LCMS Calculated for C.sub.28H.sub.26F.sub.2N.sub.2O.sub.3: 476.52; Observed: 477.2[M + H].sup.+. I-186 [00511] Yield: 87.3 mg, 55.6%; Appearance: Orange solid; .sup.1H NMR (600 MHz, DMSO-d.sub.6) 8.21- 8.13 (m, 4H), 7.51 (d, J = 8.1 Hz, 1H), 7.48-7.18 (m, 8H), 7.09-7.01 (m, 1H), 5.05 (s, 2H), 3.95 (s, 2H), 3.84 (d, J = 13.9 Hz, 2H), 3.01-2.79 (m, 2H), 1.60-1.50 (m, 2H), 0.98 (s, 2H).; HPLC purity: 100%; LCMS Calculated for C.sub.27H.sub.26F.sub.2N.sub.2O.sub.6S.sub.2: 577.63; Observed: 578.8[M + H].sup.+. I-187 [00512] Yield: 83.7 mg, 53.3%; Appearance: Orange solid; .sup.1H NMR (600 MHz, DMSO-d.sub.6) 9.24 (d, J = 2.1 Hz, 1H), 8.55 (dd, J = 8.3, 2.2 Hz, 1H), 8.13 (d, J = 8.3 Hz, 1H), 7.52 (d, J = 8.0 Hz, 1H), 7.40-7.33 (m, 4H), 7.32-7.28 (m, 1H), 7.27- 7.23 (m, 2H), 7.10-6.99 (m, 1H), 5.07 (s, 2H), 3.99 (s, 2H), 3.91 (d, J = 13.6 Hz, 2H), 3.10-2.82 (m, 2H), 1.70-1.55 (m, 2H), 1.24 (d, J = 13.2 Hz, 2H).; HPLC purity: 100%; LCMS Calculated for C.sub.26H.sub.24F.sub.3N.sub.3O.sub.4S: 531.55; Observed: 532.0[M + H].sup.+. I-188 [00513] Yield: 77.9 mg, 49.6%; Appearance: Orange solid; .sup.1H NMR (400 MHz, DMSO-d.sub.6) 7.65 (d, J = 8.0 Hz, 2H), 7.51 (d, J = 8.1 Hz, 1H), 7.40- 7.24 (m, 5H), 7.24-7.10 (m, 3H), 7.06 (d, J = 7.5 Hz, 1H), 7.01-6.91 (m, 1H), 5.07 (s, 2H), 3.97 (d, J = 13.6 Hz, 2H), 3.81 (s, 2H), 2.98-2.80 (m, 2H), 1.99-1.86 (m, 1H), 1.66-1.51 (m, 2H), 1.19 (d, J = 13.4 Hz, 2H), 1.12-0.97 (m, 2H), 0.80-0.65 (m, 2H).; HPLC purity: 99%; LCMS Calculated for C.sub.29H.sub.30N.sub.2O.sub.4S: 502.63; Observed: 503.2[M + H].sup.+. I-189 [00514] Yield: 90.4 mg, 57.5%; Appearance: Yellow solid; .sup.1H NMR (400 MHz, DMSO-d.sub.6) 7.67- 7.59 (m, 1H), 7.55-7.47 (m, 2H), 7.38-7.24 (m, 5H), 7.23-7.14 (m, 1H), 7.06 (d, J = 7.5 Hz, 1H), 7.01-6.88 (m, 1H), 6.70 (d, J = 8.6 Hz, 1H), 5.06 (s, 2H), 3.99 (d, J = 13.6 Hz, 2H), 3.81 (s, 2H), 2.98-2.85 (m, 2H), 1.71-1.53 (m, 2H), 1.44 (s, 6H), 1.22 (d, J = 13.4 Hz, 2H).; HPLC purity: 100%; LCMS Calculated for C.sub.30H.sub.32N.sub.2O.sub.5S: 532.66; Observed: 533.2[M + H].sup.+. I-190 [00515] Yield: 88.9 mg, 56.6%; Appearance: Light brown solid; .sup.1H NMR (600 MHz, DMSO-d.sub.6) 8.08 (d, J = 8.1 Hz, 1H), 7.40-7.35 (m, 4H), 7.35- 7.28 (m, 1H), 7.25 (d, J = 7.5 Hz, 1H), 7.18- 7.11 (m, 1H), 7.03-6.93 (m, 1H), 5.10 (s, 2H), 4.08 (s, 2H), 4.01 (d, J = 13.5 Hz, 2H), 3.13-2.97 (m, 2H), 2.97-2.87 (m, 1H), 1.78-1.67 (m, 2H), 1.61 (d, J = 13.3 Hz, 2H), 1.09 (d, J = 6.7 Hz, 6H).; HPLC purity: 100%; LCMS Calculated for C.sub.24H.sub.28N.sub.2O.sub.3: 392.5; Observed: 393.2[M + H].sup.+. I-191 [00516] Yield: 14.2 mg, 9.05%; Appearance: Yellow solid; .sup.1H NMR (600 MHz, DMSO-d.sub.6) 8.02 (s, 1H), 7.40-7.27 (m, 7H), 7.27-7.12 (m, 5H), 7.06-6.94 (m, 1H), 5.05 (s, 2H), 3.83 (d, J = 13.6 Hz, 2H), 3.78 (s, 2H), 2.64-2.50 (m, 2H), 1.67- 1.54 (m, 2H), 1.44 (s, 2H), 1.33 (d, J = 13.3 Hz, 2H), 1.26 (s, 2H).; HPLC purity: 100%, LCMS Calculated for C.sub.30H.sub.30N.sub.2O.sub.3: 466.58; Observed: 467.1[M + H].sup.+. I-192 [00517] Yield: 43.2 mg, 34.4%; Appearance: Yellow solid; .sup.1H NMR (400 MHz, DMSO-d.sub.6) 7.95 (d, J = 8.1 Hz, 2H), 7.73 (d, J = 8.0 Hz, 2H), 7.53 (d, J = 8.1 Hz, 1H), 7.24-7.17 (m, 1H), 7.12-6.81 (m, 3H), 5.95 (d, J = 7.7 Hz, 1H), 3.89 (d, J = 13.2 Hz, 2H), 3.85 (s, 2H), 3.81-3.71 (m, 1H), 2.72 (t, J = 13.3 Hz, 2H), 1.64-1.49 (m, 2H), 1.17 (d, J = 13.3 Hz, 2H), 1.12-0.99 (m, 6H); HPLC purity: 100%; LCMS Calculated for C.sub.23H.sub.27F.sub.2N.sub.3O.sub.3S: 463.54; Observed: 464.2[M + H].sup.+. I-193 [00518] Yield: 37.9 mg, 30.2%; Appearance: Yellow solid; .sup.1H NMR (600 MHz, DMSO-d.sub.6) 7.98 (d, J = 8.1 Hz, 2H), 7.76 (d, J = 8.1 Hz, 2H), 7.49 (d, J = 8.1 Hz, 1H), 7.25-7.21 (m, 1H), 7.19-6.97 (m, 3H), 6.54 (t, J = 5.6 Hz, 1H), 3.90 (s, 2H), 3.83 (d, J = 13.6 Hz, 2H), 2.87 (t, J = 6.1 Hz, 2H), 2.73 (t, J = 13.4, 12.9 Hz, 2H), 1.54-1.45 (m, 2H), 1.05 (d, J = 13.1 Hz, 2H), 0.93-0.84 (m, 1H), 0.39-0.30 (m, 2H), 0.15-0.06 (m, 2H).; HPLC purity: 100%; LCMS Calculated for C.sub.24H.sub.27F.sub.2N.sub.3O.sub.3S: 475.55; Observed: 476.2[M + H].sup.+. I-194 [00519] Yield: 33.1 mg, 26.3%; Appearance: Yellow solid; .sup.1H NMR (400 MHz, DMSO-d.sub.6) 7.95 (d, J = 8.1 Hz, 2H), 7.73 (d, J = 8.1 Hz, 2H), 7.53 (d, J = 8.1 Hz, 1H), 7.24-7.15 (m, 1H), 7.09 (d, J = 6.7 Hz, 1H), 7.04-6.78 (m, 3H), 6.03-5.67 (m, 1H), 3.91 (d, J = 13.4 Hz, 2H), 3.87 (s, 2H), 3.42- 3.30 (m, 2H), 2.81 (t, J = 13.0 Hz, 2H), 1.65- 1.54 (m, 2H), 1.18 (d, J = 13.2 Hz, 2H).; HPLC purity: 96.3%; LCMS Calculated for C.sub.22H.sub.23F.sub.4N.sub.3O.sub.3S: 485.5; Observed: 486.0[M + H].sup.+. I-195 [00520] Yield: 7.8 mg, 6.79%; Appearance: Beige solid; .sup.1H NMR (600 MHz, DMSO-d.sub.6) 7.98 (d, J = 8.2 Hz, 2H), 7.76 (d, J = 8.1 Hz, 2H), 7.49 (d, J = 8.1 Hz, 1H), 7.27-7.20 (m, 1H), 7.20-6.98 (m, 3H), 6.45 (d, J = 6.1 Hz, 1H), 4.16-4.07 (m, 1H), 3.90 (s, 2H), 3.86 (d, J = 12.5 Hz, 2H), 3.78-3.71 (m, 2H), 3.66-3.59 (m, 1H), 3.40 (dd, J = 8.7, 4.7 Hz, 1H), 2.73 (t, J = 13.1 Hz, 2H), 2.05-1.95 (m, 1H), 1.79-1.70 (m, 1H), 1.57-1.41 (m, 2H), 1.06 (d, J = 12.9 Hz, 2H).; HPLC purity: 100%; LCMS Calculated for C.sub.24H.sub.27F.sub.2N.sub.3O.sub.4S: 491.55; Observed: 492.2[M + H].sup.+. I-196 [00521] Yield: 59.1 mg, 47.1%; Appearance: Yellow solid; .sup.1H NMR (400 MHz, DMSO-d.sub.6) 7.95 (d, J = 8.1 Hz, 2H), 7.73 (d, J = 8.0 Hz, 2H), 7.53 (d, J = 8.0 Hz, 1H), 7.26-7.15 (m, 1H), 7.12-6.80 (m, 3H), 6.34 (t, J = 5.5 Hz, 1H), 3.94-3.88 (m, 1H), 3.88-3.82 (m, 3H), 3.45 (q, J = 7.0 Hz, 2H), 3.40-3.29 (m, 2H), 3.21-3.13 (m, 2H), 2.76 (t, J = 13.0 Hz, 2H), 1.65-1.52 (m, 2H), 1.22-1.12 (m, 5H).; HPLC purity: 100%; LCMS Calculated for C.sub.24H.sub.29F.sub.2N.sub.3O.sub.4S: 493.57; Observed: 494.2[M + H].sup.+. I-197 [00522] Yield: 12.4 mg, 9.83%; Appearance: Brown oil; .sup.1H NMR (600 MHz, DMSO-d.sub.6) 8.48 (s, 1H), 8.00 (d, J = 8.1 Hz, 2H), 7.77 (d, J = 8.1 Hz, 2H), 7.50 (d, J = 8.1 Hz, 1H), 7.47-7.41 (m, 2H), 7.29- 7.08 (m, 5H), 7.07-7.00 (m, 1H), 6.90 (dd, J = 8.0, 6.7 Hz, 1H), 4.02 (d, J = 13.8 Hz, 2H), 3.96 (s, 2H), 2.89 (t, J = 12.9 Hz, 2H), 1.68-1.55 (m, 2H), 1.14 (d, J = 13.0 Hz, 2H).; HPLC purity: 98.48%; LCMS Calculated for C.sub.26H.sub.25F.sub.2N.sub.3O.sub.3S: 497.56; Observed: 498.2[M + H].sup.+. I-198 [00523] Yield: 16.7 mg, 14.4%; Appearance: Yellow solid; .sup.1H NMR (600 MHz, DMSO-d.sub.6) 9.12 (s, 1H), 8.85 (d, J = 2.5 Hz, 1H), 8.31-8.23 (m, 1H), 8.19-8.14 (m, 1H), 8.00 (d, J = 8.2 Hz, 2H), 7.77 (d, J = 8.1 Hz, 2H), 7.56 (dd, J = 8.5, 5.1 Hz, 1H), 7.50 (d, J = 8.1 Hz, 1H), 7.28-6.98 (m, 4H), 4.09- 4.01 (m, 2H), 3.97 (s, 2H), 3.00-2.91 (m, 2H), 1.68-1.57 (m, 2H), 1.17 (d, J = 13.2 Hz, 2H).; HPLC purity: 100%; LCMS Calculated for C.sub.25H.sub.24F.sub.2N.sub.4O.sub.3S: 498.55; Observed: 499.0[M + H].sup.+. I-199 [00524] Yield: 23.5 mg, 10.9%; Appearance: Pink solid; .sup.1H NMR (600 MHz, DMSO-d.sub.6) 8.08 (s, 1H), 7.99 (d, J = 8.2 Hz, 2H), 7.76 (d, J = 8.2 Hz, 2H), 7.50 (d, J = 8.1 Hz, 1H), 7.24 (td, J = 7.8, 1.3 Hz, 1H), 7.22-6.98 (m, 3H), 6.53 (t, J = 2.4 Hz, 1H), 5.84 (t, J = 3.3 Hz, 1H), 5.66 (dd, J = 3.6, 1.9 Hz, 1H), 3.95 (s, 2H), 3.94-3.89 (m, 2H), 3.33 (s, 3H), 2.93-2.79 (m, 2H), 1.57 (td, J = 13.1, 4.3 Hz, 2H), 1.09 (d, J = 12.9 Hz, 2H); HPLC purity: 97.6%; LCMS Calculated for C.sub.25H.sub.26F.sub.2N.sub.4O.sub.3S: 500.56; Observed: 501.2[M + H].sup.+. I-200 [00525] Yield: 124.1 mg, 57.6%; Appearance: White solid; .sup.1H NMR (400 MHz, DMSO-d.sub.6) 8.50 (s, 1H), 8.01 (d, J = 8.1 Hz, 2H), 7.78 (d, J = 8.0 Hz, 2H), 7.65 (s, 1H), 7.51 (d, J = 8.1 Hz, 1H), 7.31 (s, 1H), 7.28-7.18 (m, 2H), 7.03 (t, J = 7.5 Hz, 1H), 3.96 (s, 4H), 3.74 (s, 3H), 2.87 (t, J = 13.0 Hz, 2H), 1.57 (t, J = 9.8 Hz, 2H), 1.13 (d, J = 13.1 Hz, 2H); HPLC purity: 100%; LCMS Calculated for C.sub.24H.sub.25F.sub.2N.sub.5O.sub.3S: 501.55; Observed: 502.0[M + H].sup.+. I-201 [00526] Yield: 99.1 mg, 46.1%; Appearance: White solid; .sup.1H NMR (400 MHz, DMSO-d.sub.6) 8.00 (d, J = 8.0 Hz, 2H), 7.78 (d, J = 8.0 Hz, 2H), 7.51 (d, J = 8.0 Hz, 1H), 7.29-6.94 (m, 5H), 3.94 (s, 2H), 3.92-3.74 (m, 4H), 2.84 (t, J = 13.2 Hz, 2H), 1.68-1.40 (m, 2H), 1.09 (d, J = 13.2 Hz, 2H); HPLC purity: 100%; LCMS Calculated for C.sub.22H.sub.22F.sub.5N.sub.3O.sub.3S: 503.49; Observed: 504.0[M + H].sup.+. I-202 [00527] Yield: 76.1 mg, 37.3%; Appearance: Beige solid; .sup.1H NMR (400 MHz, DMSO-d.sub.6) 9.22 (s, 1H), 8.59 (d, J = 7.0 Hz, 2H), 8.02 (d, J = 8.1 Hz, 2H), 7.79 (d, J = 8.0 Hz, 2H), 7.52 (d, J = 8.0 Hz, 1H), 7.30-7.20 (m, 2H), 7.04 (t, J = 7.4 Hz, 1H), 4.08-3.90 (m, 4H), 2.94 (t, J = 13.1 Hz, 2H), 1.69-1.53 (m, 2H), 1.17 (d, J = 13.2 Hz, 2H); HPLC purity: 100%; LCMS Calculated for C.sub.23H.sub.22F.sub.2N.sub.4O.sub.3S.sub.2: 504.57; Observed: 505.2[M + H].sup.+. I-203 [00528] Yield: 55.7 mg, 48.5%; Appearance: Yellow solid; .sup.1H NMR (600 MHz, DMSO-d.sub.6) 7.98 (d, J = 8.0 Hz, 2H), 7.76 (d, J = 8.0 Hz, 2H), 7.49 (d, J = 8.1 Hz, 1H), 7.27-7.21 (m, 1H), 7.21-6.97 (m, 3H), 6.51 (t, J = 5.7 Hz, 1H), 3.90 (d, J = 1.6 Hz, 2H), 3.87-3.77 (m, 3H), 3.71 (q, J = 6.8 Hz, 1H), 3.57 (q, J = 7.1 Hz, 1H), 3.03 (q, J = 5.8, 5.4 Hz, 2H), 2.74 (t, J = 13.0 Hz, 2H), 1.87-1.69 (m, 3H), 1.54-1.44 (m, 3H), 1.04 (d, J = 13.1 Hz, 2H).; HPLC purity: 100%; LCMS Calculated for C.sub.25H.sub.29F.sub.2N.sub.3O.sub.4S: 506.58; Observed: 506.2[M + H].sup.+. I-204 [00529] Yield: 64.1 mg, 51%; Appearance: Orange solid; .sup.1H NMR (400 MHz, DMSO-d.sub.6) 7.95 (d, J = 8.1 Hz, 2H), 7.73 (d, J = 8.1 Hz, 2H), 7.53 (d, J = 8.1 Hz, 1H), 7.25-7.14 (m, 1H), 7.12-6.79 (m, 3H), 6.54-6.38 (m, 1H), 3.95-3.82 (m, 4H), 3.78-3.67 (m, 1H), 3.67-3.55 (m, 2H), 3.45 (dd, J = 8.6, 5.0 Hz, 1H), 3.12-3.04 (m, 1H), 3.00- 2.87 (m, 1H), 2.75 (t, J = 13.1 Hz, 2H), 2.43- 2.33 (m, 1H), 1.97-1.85 (m, 1H), 1.67-1.50 (m, 3H), 1.17 (d, J = 13.3 Hz, 2H).; HPLC purity: 100%; LCMS Calculated for C.sub.25H.sub.29F.sub.2N.sub.3O.sub.4S: 506.58; Observed: 506.0[M + H].sup.+. I-205 [00530] Yield: 52.2 mg, 41.5%; Appearance: Light brown solid; .sup.1H NMR (600 MHz, DMSO-d.sub.6) 7.98 (d, J = 8.1 Hz, 2H), 7.76 (d, J = 8.1 Hz, 2H), 7.49 (d, J = 8.1 Hz, 1H), 7.27-7.20 (m, 1H), 7.20- 6.97 (m, 3H), 6.26 (d, J = 7.5 Hz, 1H), 3.90 (s, 2H), 3.83 (dd, J = 27.8, 12.2 Hz, 4H), 3.67-3.55 (m, 1H), 3.29-3.24 (m, 2H), 2.72 (t, J = 13.1 Hz, 2H), 1.68-1.57 (m, 2H), 1.55-1.45 (m, 2H), 1.45-1.36 (m, 2H), 1.06 (d, J = 13.1 Hz, 2H).; HPLC purity: 100%, LCMS Calculated for C.sub.25H.sub.29F.sub.2N.sub.3O.sub.4S: 506.58; Observed: 506.0[M + H].sup.+. I-206 [00531] Yield: 46.3 mg, 36.8%; Appearance: Yellow solid; .sup.1H NMR (600 MHz, DMSO-d.sub.6) 7.98 (d, J = 8.1 Hz, 2H), 7.76 (d, J = 8.1 Hz, 2H), 7.49 (d, J = 8.1 Hz, 1H), 7.26-7.20 (m, 1H), 7.20-6.98 (m, 3H), 6.82 (d, J = 6.6 Hz, 1H), 3.99-3.92 (m, 1H), 3.91 (s, 2H), 3.83 (d, J = 13.8 Hz, 2H), 2.83- 2.73 (m, 4H), 2.62-2.52 (m, 2H), 1.56-1.43 (m, 2H), 1.07 (d, J = 13.1 Hz, 2H); HPLC purity: 100%; LCMS Calculated for C.sub.24H.sub.25F.sub.4N.sub.3O.sub.3S: 511.54; Observed: 512.2[M + H].sup.+. I-207 [00532] Yield: 3.2 mg, 2.55%; Appearance: Yellow solid; .sup.1H NMR (600 MHz, DMSO-d.sub.6) 8.48 (s, 1H), 7.99 (d, J = 8.1 Hz, 2H), 7.77 (d, J = 8.1 Hz, 2H), 7.66 (s, 1H), 7.49 (d, J = 8.1 Hz, 1H), 7.31 (s, 1H), 7.27-7.22 (m, 1H), 7.21-7.00 (m, 3H), 4.01 (q, J = 7.3 Hz, 2H), 3.97-3.85 (m, 4H), 2.85 (t, J = 12.9 Hz, 2H), 1.61-1.50 (m, 2H), 1.29 (t, J = 7.3 Hz, 3H), 1.11 (d, J = 13.2 Hz, 2H).; HPLC purity: 100%; LCMS Calculated for C.sub.25H.sub.27F.sub.2N.sub.5O.sub.3S: 515.58; Observed: 516.4[M + H].sup.+. I-208 [00533] Yield: 40.4 mg, 32.1%; Appearance: Yellow solid; .sup.1H NMR (400 MHz, DMSO-d.sub.6) 7.99- 7.90 (m, 2H), 7.73 (d, J = 8.1 Hz, 2H), 7.53 (d, J = 7.4 Hz, 2H), 7.35 (s, 1H), 7.23-7.14 (m, 1H), 7.13-6.78 (m, 3H), 6.58-6.43 (m, 1H), 6.22- 6.09 (m, 1H), 4.22-4.12 (m, 2H), 3.89-3.79 (m, 4H), 3.40 (q, J = 6.0 Hz, 2H), 2.77 (t, J = 13.1 Hz, 2H), 1.64-1.51 (m, 2H), 1.15 (d, J = 13.2 Hz, 2H).; HPLC purity: 100%; LCMS Calculated for C.sub.25H.sub.27F.sub.2N.sub.5O.sub.3S: 515.58; Observed: 516.0[M + H].sup.+. I-209 [00534] Yield: 47.5 mg, 13.6%; Appearance: Yellow solid; .sup.1H NMR (600 MHz, DMSO-d.sub.6) 7.97 (d, J = 8.1 Hz, 2H), 7.75 (d, J = 8.1 Hz, 2H), 7.51- 7.45 (m, 2H), 7.27 (s, 1H), 7.25-7.21 (m, 1H), 7.19-7.09 (m, 2H), 7.04-6.98 (m, 1H), 4.01 (s, 2H), 3.90 (s, 2H), 3.87-3.80 (m, 2H), 3.75 (s, 3H, 2.77-2.69 (m, 2H), 1.53-1.42 (m, 2H), 1.04 (d, J = 13.5 Hz, 2H).; HPLC purity: 97.92%; LCMS Calculated for C.sub.25H.sub.27F.sub.2N.sub.5O.sub.3S: 515.58; Observed: 516.0[M + H].sup.+. I-210 [00535] Yield: 91.2 mg, 41.4%; Appearance: White solid; .sup.1H NMR (400 MHz, DMSO-d.sub.6) 8.00 (d, J = 8.0 Hz, 2H), 7.78 (d, J = 8.0 Hz, 2H), 7.51 (d, J = 8.0 Hz, 1H), 7.28-6.97 (m, 5H), 3.94 (d, J = 1.9 Hz, 2H), 3.92-3.75 (m, 4H), 2.84 (t, J = 13.2 Hz, 2H), 1.61-1.45 (m, 2H), 1.09 (d, J = 13.2 Hz, 2H); HPLC purity: 100%; LCMS Calculated for C.sub.25H.sub.23F.sub.3N.sub.4O.sub.3S: 516.54; Observed: 517.2[M + H].sup.+. I-211 [00536] Yield: 16.9 mg, 4.87%; Appearance: Yellow solid; .sup.1H NMR (600 MHz, DMSO-d.sub.6) 7.98 (d, J = 8.2 Hz, 2H), 7.75 (d, J = 8.1 Hz, 2H), 7.49 (d, J = 8.1 Hz, 1H), 7.25-7.19 (m, 1H), 7.20-6.97 (m, 4H), 6.06 (s, 1H), 4.17 (d, J = 5.7 Hz, 2H), 3.91 (s, 2H), 3.83 (d, J = 13.8 Hz, 2H), 2.83-2.73 (m, 2H), 2.34 (s, 3H), 1.57-1.44 (m, 2H), 1.05 (d, J = 13.3 Hz, 2H).; HPLC purity: 100%; LCMS Calculated for C.sub.25H.sub.26F.sub.2N.sub.4O.sub.4S: 516.56; Observed: 517.0[M + H].sup.+. I-212 [00537] Yield: 28.5 mg, 20.6%; Appearance: Yellow solid; .sup.1H NMR (600 MHz, DMSO-d.sub.6) 7.98 (d, J = 8.1 Hz, 2H), 7.76 (d, J = 8.1 Hz, 2H), 7.49 (d, J = 8.1 Hz, 1H), 7.26-7.20 (m, 1H), 7.19-6.99 (m, 4H), 6.08 (s, 1H), 4.26 (s, 2H), 3.92 (s, 2H), 3.84 (d, J = 13.8 Hz, 2H), 2.83-2.74 (m, 2H), 2.17 (s, 3H), 1.56-1.48 (m, 2H), 1.06 (d, J = 13.1 Hz, 2H).; HPLC purity: 100%; LCMS Calculated for C.sub.25H.sub.26F.sub.2N.sub.4O.sub.4S: 516.56; Observed: 517.2[M + H].sup.+. I-213 [00538] Yield: 5.8 mg, 4.51%; Appearance: Yellow solid; .sup.1H NMR (600 MHz, DMSO-d.sub.6) 7.99 (d, J = 8.2 Hz, 2H), 7.90 (s, 1H), 7.76 (d, J = 8.1 Hz, 2H), 7.50 (d, J = 8.1 Hz, 1H), 7.28-7.22 (m, 1H), 7.22-7.00 (m, 3H), 3.95 (s, 2H), 3.91 (d, J = 14.0 Hz, 2H), 2.90 (t, J = 13.1 Hz, 2H), 2.20 (s, 3H), 2.04 (s, 3H), 1.65-1.54 (m, 2H), 1.12 (d, J = 12.9 Hz, 2H).; HPLC purity: 95.14%; LCMS Calculated for C.sub.25H.sub.26F.sub.2N.sub.4O.sub.4S: 516.56; Observed: 517.0[M + H].sup.+. I-214 [00539] Yield: 50.5 mg, 39.2%; Appearance: Yellow solid; .sup.1H NMR (400 MHz, DMSO-d.sub.6) 7.95 (d, J = 8.1 Hz, 2H), 7.73 (d, J = 8.1 Hz, 2H), 7.53 (d, J = 8.1 Hz, 1H), 7.25-7.16 (m, 1H), 7.12-6.78 (m, 3H), 6.60 (t, J = 5.5 Hz, 1H), 3,93-3.80 (m, 2H), 3.25 (q, J = 6.7 Hz, 2H), 2.78 (t, J = 12.9 Hz, 2H), 2.43-2.29 (m, 2H), 1.66-1.51 (m, 2H), 1.18 (d, J = 13.3 Hz, 2H).; HPLC purity: 100%; LCMS Calculated for C.sub.23H.sub.24F.sub.5N.sub.3O.sub.3S: 517.52; Observed: 518.0[M + H].sup.+. I-215 [00540] Yield: 53.5 mg, 42.3%; Appearance: Light brown solid; .sup.1H NMR (400 MHz, DMSO-d.sub.6) 7.95 (d, J = 8.1 Hz, 2H), 7.73 (d, J = 8.1 Hz, 2H), 7.53 (d, J = 8.1 Hz, 1H), 7.23-7.14 (m, 1H), 7.13- 6.81 (m, 3H), 6.36 (t, J = 5.7 Hz, 1H), 3.93- 3.75 (m, 7H), 3.26 (t, J = 11.7 Hz, 2H), 3.19 (d, J = 5.3 Hz, 1H), 2.91 (t, J = 6.2 Hz, 2H), 2.74 (t, J = 12.9 Hz, 2H), 1.72-1.61 (m, 1H), 1.57 (d, J = 12.8 Hz, 4H), 1.22-1.07 (m, 4H).; HPLC purity: 100%; LCMS Calculated for C.sub.26H.sub.31F.sub.2N.sub.3O.sub.4S: 519.61; Observed: 520.0[M + H].sup.+. I-216 [00541] Yield: 33.5 mg, 28.6%; Appearance: Yellow solid; .sup.1H NMR (600 MHz, DMSO-d.sub.6) 8.48 (s, 1H), 8.15 (d, J = 2.7 Hz, 1H), 8.00 (d, J = 8.1 Hz, 2H), 7.77 (d, J = 8.1 Hz, 2H), 7.73 (dd, J = 8.9, 2.7 Hz, 1H), 7.50 (d, J = 8.1 Hz, 1H), 7.27-7.00 (m, 4H), 6.71 (d, J = 8.8 Hz, 1H), 4.00 (d, J = 13.8 Hz, 2H), 3.96 (s, 2H), 2.90 (t, J = 13.3 Hz, 2H), 1.65-1.54 (m, 2H), 1.14 (d, J = 13.1 Hz, 2H).; HPLC purity: 100%; LCMS Calculated for C.sub.26H.sub.26F.sub.2N.sub.4O.sub.4S: 528.57; Observed: 529.0[M + H].sup.+. I-217 [00542] Yield: 90 mg, 39.7%; Appearance: White solid; .sup.1H NMR (400 MHz, DMSO-d.sub.6) 8.01 (d, J = 8.1 Hz, 2H), 7.78 (d, J = 8.1 Hz, 2H), 7.62 (s, 1H), 7.52 (d, J = 8.0 Hz, 1H), 7.31-7.23 (m, 1H), 7.19 (d, J = 7.6, 1.4 Hz, 1H), 7.14-6.95 (m, 2H), 3,92 (s, 4H), 3.60 (s, 3H), 2.93-2.80 (m, 2H), 2.01 (s, 3H), 1.93 (s, 3H), 1.64-1.52 (m, 2H), 1.11 (d, J = 13.1 Hz, 2H); HPLC purity: 100%; LCMS Calculated for C.sub.26H.sub.29F.sub.2N.sub.5O.sub.3S: 529.61; Observed: 530.0[M + H].sup.+. I-218 [00543] Yield: 48 mg, 41%; Appearance: Yellow solid; .sup.1H NMR (600 MHz, DMSO-d.sub.6) 7.98 (d, J = 8.5 Hz, 2H), 7.76 (d, J = 8.1 Hz, 2H), 7.49 (d, J = 8.2 Hz, 1H), 7.26-6.96 (m, 4H), 6.25 (d, J = 7.7 Hz, 1H), 3.90 (s, 2H), 3.84 (d, J = 13.7 Hz, 2H), 3.66-3.51 (m, 1H), 2.72 (t, J = 13.4 Hz, 2H), 2.02-1.91 (m, 2H), 1.91-1.72 (m, 4H), 1.55- 1.41 (m, 4H), 1.06 (d, J = 13.1 Hz, 2H); HPLC purity: 100%; LCMS Calculated for C.sub.26H.sub.29F.sub.4N.sub.3O.sub.3S: 539.59; Observed: 540.0[M + H].sup.+. I-219 [00544] Yield: 38.3 mg, 14.2%; Appearance: Light brown solid; .sup.1H NMR (400 MHz, DMSO-d.sub.6) 8.14 (s, 1H), 7.97 (d, J = 8.1 Hz, 2H), 7.74 (d, J = 7.9 Hz, 2H), 7.54 (d, J = 8.1 Hz, 1H), 7.30 (s, 1H), 7.27-7.16 (m, 1H), 7.17-6.81 (m, 4H), 6.55 (d, J = 8.5 Hz, 1H), 4.48 (dd, J = 9.9, 7.3 Hz, 2H), 4.05 (d, J = 13.8 Hz, 2H), 3.90 (s, 2H), 3.22-3.11 (m, 2H), 2.87 (t, J = 13.1 Hz, 2H), 1.73-1.60 (m, 2H), 1.23 (d, J = 13.0 Hz, 2H).; HPLC purity: 97.98%; LCMS Calculated for C.sub.28H.sub.27F.sub.2N.sub.3O.sub.4S: 539.6; Observed: 540.2[M + H].sup.+. I-220 [00545] Yield: 29.3 mg, 27.2%; Appearance: Yellow solid; .sup.1H NMR (600 MHz, DMSO-d.sub.6) 8.37 (s, 1H), 7.99 (d, J = 8.2 Hz, 2H), 7.77 (d, J = 8.1 Hz, 2H), 7.50 (d, J = 8.1 Hz, 1H), 7.27-7.00 (m, 5H), 6.80 (dd, J = 8.4, 2.1 Hz, 1H), 6.75 (d, J = 8.4 Hz, 1H), 5.92 (s, 2H), 3.98 (d, J = 13.8 Hz, 2H), 3.95 (s, 2H), 2.87 (t, J = 12.8 Hz, 2H), 1.63-1.54 (m, 2H), 1.12 (d, J = 13.0 Hz, 2H).; HPLC purity: 98.07%; LCMS Calculated for C.sub.27H.sub.25F.sub.2N.sub.3O.sub.5S: 541.57; Observed: 542.0[M + H].sup.+. I-221 [00546] Yield: 8.8 mg, 8.78%; Appearance: Yellow solid; .sup.1H NMR (600 MHz, DMSO-d.sub.6) 8.71 (s, 1H), 8.00 (d, J = 8.1 Hz, 2H), 7.77 (d, J = 8.1 Hz, 2H), 7.73 (s, 1H), 7.59 (d, J = 8.3 Hz, 1H), 7.50 (d, J = 8.2 Hz, 1H), 7.37-7.32 (m, 1H), 7.26- 7.08 (m, 4H), 7.04-6.85 (m, 2H), 4.03 (d, J = 13.8 Hz, 2H), 3.96 (s, 2H), 2.91 (t, J = 13.1 Hz, 2H), 1.66-1.55 (m, 2H), 1.15 (d, J = 13.1 Hz, 2H).; HPLC purity: 96.42%; LCMS Calculated for C.sub.27H.sub.25F.sub.4N.sub.3O.sub.3S: 547.57; Observed: 548.2[M + H].sup.+. I-222 [00547] Yield: 32.2 mg, 28.7%; Appearance: Light brown solid; .sup.1H NMR (400 MHz, DMSO-d.sub.6) 7.96 (d, J = 8.0 Hz, 2H), 7.73 (d, J = 8.1 Hz, 2H), 7.53 (d, J = 8.1 Hz, 1H), 7.25-7.14 (m, 1H), 7.14- 6.93 (m, 5H), 6.89-6.74 (m, 1H), 6.74-6.67 (m, 1H), 6.27 (d, J = 7.1 Hz, 1H), 4.22-4.10 (m, 1H), 4.10-3.99 (m, 1H), 3.93 (d, J = 13.8 Hz, 2H), 3.87 (s, 2H), 3.82-3.66 (m, 2H), 3.20 (d, J = 5.2 Hz, 2H), 2.91 (dd, J = 16.3, 5.5 Hz, 1H), 2.85-2.70 (m, 3H), 1.70-1.51 (m, 2H), 1.19 (d, J = 13.3 Hz, 2H).; HPLC purity: 100%; LCMS Calculated for C.sub.29H.sub.29F.sub.2N.sub.3O.sub.4S: 53.62; Observed: 554.2[M + H].sup.+. I-223 [00548] Yield: 37.3 mg, 31%; Appearance: Light brown solid; .sup.1H NMR (400 MHz, DMSO-d.sub.6) 7.95 (d, J = 8.1 Hz, 2H), 7.73 (d, J = 8.1 Hz, 2H), 7.53 (d, J = 8.1 Hz, 1H), 7.25-7.16 (m, 2H), 7.14-6.79 (m, 5H), 6.76 (d, J = 8.2 Hz, 1H), 6.70 (d, J = 8.3 Hz, 1H), 4.93 (q, J = 6.7 Hz, 1H), 4.32-4.13 (m, 2H), 3.97 (d, J = 13.7 Hz, 2H), 2.79 (t, J = 13.0 Hz, 2H), 2.12-1.91 (m, 2H), 1.69-1.54 (m, 2H), 1.19 (d, J = 13.3 Hz, 2H).; HPLC purity: 100%; LCMS Calculated for C.sub.29H.sub.29F.sub.2N.sub.3O.sub.4S: 554.62; Observed: 554.0[M + H].sup.+. I-224 [00549] Yield: 32 mg, 27.8%; Appearance: Light brown solid; .sup.1H NMR (400 MHz, DMSO-d.sub.6) 7.95 (d, J = 8.1 Hz, 2H), 7.73 (d, J = 8.0 Hz, 2H), 7.53 (d, J = 8.0 Hz, 1H), 7.25-7.16 (m, 1H), 7.14-6.79 (m, 3H), 6.33 (d, J = 7.8 Hz, 1H), 3.92 (d, J = 14.4 Hz, 2H), 3.86 (s, 2H), 3.22-3.08 (m, 2H), 3.02- 2.97 (m, 2H), 2.75 (t, J = 13.0 Hz, 2H), 2.13- 1.95 (m, 4H), 1.63-1.50 (m, 2H), 1.18 (d, J = 13.2 Hz, 2H).; HPLC purity: 100%; LCMS Calculated for C.sub.25H.sub.29F.sub.2N.sub.3O.sub.5S.sub.2: 553.64; Observed: 554.0[M + H].sup.+. I-225 [00550] Yield: 0.0441 mg, 37.3%; Appearance: Light brown solid; .sup.1H NMR (400 MHz, DMSO-d.sub.6) 8.17 (s, 1H), 7.97 (d, J = 8.1 Hz, 2H), 7.74 (d, J = 8.1 Hz, 2H), 7.54 (d, J = 8.1 Hz, 1H), 7.24-7.17 (m, 1H), 7.16-6.79 (m, 5H), 6.62 (d, J = 8.7 Hz, 1H), 4.26-4.14 (m, 4H), 4.05 (d, J = 13.9 Hz, 2H), 3.90 (s, 2H), 2.87 (t, J = 13.0 Hz, 2H), 1.66 (t, J = 12.1 Hz, 2H), 1.23 (d, J = 13.3 Hz, 2H); HPLC purity: 96%; LCMS Calculated for C.sub.28H.sub.27F.sub.2N.sub.3O.sub.5S: 555.6; Observed: 556.2[M + H].sup.+. I-226 [00551] Yield: 44.5 mg, 39%; Appearance: Light brown solid; .sup.1H NMR (600 MHz, DMSO-d.sub.6) 8.31 (d, J = 15.6 Hz, 1H), 8.00 (d, J = 8.1 Hz, 2H), 7.77 (d, J = 8.1 Hz, 2H), 7.50 (d, J = 8.1 Hz, 1H), 7.29- 7.08 (m, 4H), 7.05-7.00 (m, 1H), 6.95 (dd, J = 8.7, 2.4 Hz, 1H), 6.79 (d, J = 8.7 Hz, 1H), 4.00 (d, J = 13.7 Hz, 2H), 3.95 (s, 2H), 3.68 (d, J = 6.5 Hz, 6H), 2.87 (t, J = 12.7 Hz, 2H), 1.65-1.53 (m, 2H), 1.13 (d, J = 13.1 Hz, 2H).; HPLC purity: 100%; LCMS Calculated for C.sub.28H.sub.29F.sub.2N.sub.3O.sub.5S: 557.61; Observed: 558.0[M + H].sup.+. I-227 [00552] Yield: 5.4 mg, 4.66%; Appearance: Yellow solid; .sup.1H NMR (600 MHz, DMSO-d.sub.6) 7.99 (d, J = 8.2 Hz, 2H), 7.77 (d, J = 8.1 Hz, 2H), 7.54 (s, 1H), 7.50 (d, J = 8.1 Hz, 1H), 7.29 (d, J = 8.6 Hz, 1H), 7.27-7.22 (m, 1H), 7.22-6.99 (m, 3H), 6.55 (d, J = 2.6 Hz, 1H), 6.43 (dd, J = 8.7, 2.7 Hz, 1H), 3.94 (s, 2H), 3.92 (d, J = 13.5 Hz, 2H), 3.75 (s, 3H), 3.72 (s, 3H), 2.87 (t, J = 13.0 Hz, 2H), 1.64-1.51 (m, 2H), 1.10 (d, J = 13.2 Hz, 2H); HPLC purity: 100%; LCMS Calculated for C.sub.28H.sub.29F.sub.2N.sub.3O.sub.5S: 557.61; Observed: 558.2[M + H].sup.+. I-228 [00553] Yield: 45.5 mg, 40.3%; Appearance: Beige solid: .sup.1H NMR (400 MHz, DMSO-d.sub.6) 7.97 (d, J = 8.1 Hz, 2H), 7.74 (d, J = 8.1 Hz, 2H), 7.59 (s, 1H), 7.54 (d, J = 8.1 Hz, 1H), 7.40 (d, J = 8.2 Hz, 1H), 7.26-7.19 (m, 1H), 7.15-6.82 (m, 4H), 6.61 (d, J = 8.5 Hz, 1H), 3.97 (d, J = 13.6 Hz, 2H), 3.91 (s, 2H), 3.83 (s, 3H), 3.78 (s, 3H), 2.96 (d, J = 13.0 Hz, 2H), 1.79-1.62 (m, 2H), 1.24 (d, J = 13.2 Hz, 2H).; HPLC purity: 100%; LCMS Calculated for C.sub.28H.sub.29F.sub.2N.sub.3O.sub.5S: 557.61; Observed: 558.2[M + H].sup.+. I-229 [00554] Yield: 1.9 mg, 1.85%; Appearance: White solid; .sup.1H NMR (600 MHz, DMSO-d.sub.6) 7.99 (d, J = 8.2 Hz, 2H), 7.87 (s, 1H), 7.76 (d, J = 8.2 Hz, 2H), 7.58 (s, 1H), 7.49 (d, J = 8.1 Hz, 1H), 7.26-7.21 (m, 1H), 7.20-6.99 (m, 3H), 3.94 (s, 2H), 3.92- 3.83 (m, 2H), 3.30 (s, 3H), 3.19 (s, 3H), 2.89 (t, J = 12.9 Hz, 2H), 1.63-1.51 (m, 2H), 1.12 (d, J = 13.0 Hz, 2H).; HPLC purity: 100%; LCMS Calculated for C.sub.26H.sub.27F.sub.2N.sub.5O.sub.5S: 559.59; Observed: 560.2[M + H].sup.+. I-230 [00555] Yield: 14.1 mg, 11.5%; Appearance: Brown oil; .sup.1H NMR (600 MHz, DMSO-d.sub.6) 9.81 (d, J = 6.9 Hz, 1H), 8.03-7.95 (m, 2H), 7.80-7.72 (m, 2H), 7.63-7.57 (m, 2H), 7.50 (d, J = 8.1 Hz, 1H), 7.30-7.23 (m, 3H), 7.18 (d, J = 7.0 Hz, 1H), 7.11- 6.97 (m, 3H), 3.88-3.73 (m, 2H), 2.44-2.27 (m, 1H), 1.89-1.62 (m, 3H), 1.58-1.43 (m, 3H), 1.28-1.10 (m, 2H).; HPLC purity: 100%; LCMS Calculated for C.sub.27H.sub.26F.sub.2N.sub.2O.sub.3S: 496.57; Observed: 497.0[M + H].sup.+. I-231 [00556] Yield: 19.1 mg, 15.2%; Appearance: Yellow solid; .sup.1H NMR (600 MHz, DMSO-d.sub.6) 8.47 (dd, J = 11.1, 4.6 Hz, 1H), 8.42-8.31 (m, 1H), 7.97 (dd, J = 8.3, 4.1 Hz, 2H), 7.80-7.69 (m, 3H), 7.49 (dd, J = 8.0, 2.3 Hz, 1H), 7.28-7.19 (m, 3H), 7.19-6.97 (m, 3H), 4.34 (d, J = 6.0 Hz, 2H), 3.85- 3.67 (m, 2H), 2.43-2.21 (m, 0H), 2.30-2.15 (m, 1H), 1.86-1.76 (m, 1H), 1.68-1.63 (m, 1H), 1.63-1.43 (m, 4H), 1.21-1.08 (m, 2H).; HPLC purity: 100%; LCMS Calculated for C.sub.27H.sub.27F.sub.2N.sub.3O.sub.3S: 511.59; Observed: 512.2[M + H].sup.+. I-232 [00557] Yield: 16.9 mg, 17.7%; Appearance: Beige solid; .sup.1H NMR (600 MHz, DMSO-d.sub.6) 8.47- 8.40 (m, 2H), 8.38-8.32 (m, 1H), 7.97 (dd, J = 8.3, 5.6 Hz, 2H), 7.75 (dd, J = 8.5, 3.3 Hz, 2H), 7.63-7.59 (m, 1H), 7.49 (dd, J = 8.1, 3.0 Hz, 1H), 7.36-7.30 (m, 1H), 7.24-7.19 (m, 1H), 7.18- 6.97 (m, 3H), 4.33-4.24 (m, 2H), 3.84-3.71 (m, 2H), 2.24-2.13 (m, 1H), 1.84-1.43 (m, 6H), 1.19-1.08 (m, 2H).; HPLC purity: 100%; LCMS Calculated for C.sub.27H.sub.27F.sub.2N.sub.3O.sub.3S: 511.59; Observed: 512.2[M + H].sup.+. I-233 [00558] Yield: 15 mg, 19.5%; Appearance: Yellow solid; .sup.1H NMR (600 MHz, DMSO-d.sub.6) 8.51- 8.44 (m, 2H), 8.42-8.36 (m, 1H), 7.97 (dd, J = 8.1, 5.4 Hz, 2H), 7.75 (dd, J = 8.3, 4.1 Hz, 2H), 7.49 (dd, J = 8.1, 3.0 Hz, 1H), 7.25-7.19 (m, 3H), 7.18-6.96 (m, 3H), 4.27 (t, J = 5.8 Hz, 2H), 3.86- 3.71 (m, 2H), 2.41-2.19 (m, 1H), 1.86-1.76 (m, 1H), 1.68-1.63 (m, 1H), 1.61-1.43 (m, 4H), 1.21-1.08 (m, 2H).; HPLC purity: 97.6%; LCMS Calculated for C.sub.27H.sub.27F.sub.2N.sub.3O.sub.3S: 511.59; Observed: 512.2[M + H].sup.+. I-234 [00559] Yield: 5.8 mg, 5.51%; Appearance: Yellow solid; .sup.1H NMR (600 MHz, DMSO-d.sub.6) 8.00- 7.88 (m, 2H), 7.73 (d, J = 7.7 Hz, 2H), 7.50-7.41 (m, 3H), 7.37 (s, 1H), 7.30 (d, J = 7.6 Hz, 2H), 7.26-6.89 (m, 4H), 3.83-3.55 (m, 2H), 3.12 (s, 3H), 2.35-2.10 (m, 1H), 1.73-1.32 (m, 5H), 1.23-1.08 (m, 2H), 1.07-0.96 (m, 2H).; HPLC purity: 100%; LCMS Calculated for C.sub.28H.sub.28F.sub.2N.sub.2O.sub.3S: 510.6; Observed: 511.2[M + H].sup.+. I-235 [00560] Yield: 43 mg, 39.6%; Appearance: Yellow solid; .sup.1H NMR (600 MHz, DMSO-d.sub.6) 8.02- 7.92 (m, 2H), 7.78-7.72 (m, 2H), 7.52-7.45 (m, 1H), 7.38-7.34 (m, 1H), 7.34-7.26 (m, 2H), 7.26-7.13 (m, 4H), 7.12-6.97 (m, 2H), 4.65- 4.47 (m, 2H), 3.86-3.64 (m, 2H), 3.15 (dd, J = 5.3, 2.3 Hz, 1H), 2.93 (d, J = 8.7 Hz, 2H), 2.86- 2.64 (m, 2H), 1.79-1.66 (m, 1H), 1.63-1.46 (m, 4H), 1.34-1.01 (m, 2H).; HPLC purity: 100%; LCMS Calculated for C.sub.29H.sub.30F.sub.2N.sub.2O.sub.3S: 524.63; Observed: 525.2[M + H].sup.+. I-236 [00561] Yield: 33.9 mg, 34.6%; Appearance: White solid; .sup.1H NMR (400 MHz, DMSO-d.sub.6) 7.96- 7.87 (m, 2H), 7.71 (d, J = 8.1 Hz, 2H), 7.60-7.47 (m, 2H), 7.26-6.87 (m, 4H), 3.84-3.64 (m, 2H), 2.95 (t, J = 6.1 Hz, 2H), 2.34-2.01 (m, 1H), 1.88- 1.40 (m, 6H), 1.27-1.16 (m, 2H), 0.97-0.83 (m, 1H), 0.45-0.32 (m, 2H), 0.17 (d, J = 5.2 Hz, 2H).; HPLC purity: 100%; LCMS Calculated for C.sub.25H.sub.28F.sub.2N.sub.2O.sub.3S: 474.57; Observed: 475.2[M + H].sup.+. I-237 [00562] Yield: 58 mg, 38%; Appearance: Yellow solid; .sup.1H NMR (400 MHz, DMSO-d.sub.6) 8.01-7.88 (m, 2H), 7.75-7.66 (m, 2H), 7.53 (d, J = 8.1 Hz, 1H), 7.34-6.80 (m, 4H), 3.82-3.62 (m, 3H), 3.46 (q, J = 6.5 Hz, 2H), 3.32 (t, J = 6.8 Hz, 2H), 3.20 (d, J = 5.3 Hz, 2H), 2.43-2.26 (m, 1H), 2.00-1.89 (m, 2H), 1.89-1.73 (m, 3H), 1.65-1.42 (m, 5H), 1.25 (d, J = 10.7 Hz, 2H).; HPLC purity: 100%; LCMS Calculated for C.sub.25H.sub.28F.sub.2N.sub.2O.sub.3S: 474.57; Observed: 475.0[M + H].sup.+. I-238 [00563] Yield: 42.3 mg, 46.1%; Appearance: Yellow solid; .sup.1H NMR (600 MHz, DMSO-d.sub.6) 8.02- 7.93 (m, 2H), 7.79-7.71 (m, 2H), 7.53-7.44 (m, 1H), 7.26-6.94 (m, 4H), 3.83-3.66 (m, 2H), 3.58-3.39 (m, 8H), 2.79-2.58 (m, 1H), 1.76- 1.36 (m, 6H), 1.28-1.06 (m, 2H); HPLC purity: 100%; LCMS Calculated for C.sub.25H.sub.28F.sub.2N.sub.2O.sub.4S: 490.57; Observed: 491.0[M + H].sup.+. I-239 [00564] Yield: 14.8 mg, 15%; Appearance: Yellow solid; .sup.1H NMR (600 MHz, DMSO-d.sub.6) 7.98 (dd, J = 8.0, 5.8 Hz, 2H), 7.79-7.71 (m, 2H), 7.49 (dd, J = 8.2, 3.2 Hz, 1H), 7.26-6.97 (m, 4H), 3.83-3.65 (m, 2H), 3.64-3.50 (m, 4H), 2.86- 2.63 (m, 1H), 1.93 (d, J = 54.4 Hz, 4H), 1.72- 1.36 (m, 6H), 1.31-1.03 (m, 2H).; HPLC purity: 100%; LCMS Calculated for C.sub.26H.sub.28F.sub.4N.sub.2O.sub.3S: 524.57; Observed: 525.2[M + H].sup.+. I-240 [00565] Yield: 47.3 mg, 49.2%; Appearance: Beige solid; .sup.1H NMR (400 MHz, DMSO-d.sub.6) 8.00- 7.89 (m, 2H), 7.71 (d, J = 8.1 Hz, 2H), 7.53 (d, J = 8.2 Hz, 1H), 7.35-7.14 (m, 1H), 7.10-6.75 (m, 3H), 3.84-3.74 (m, 4H), 3.68-3.22 (m, 7H), 2.38 (sm, 1H), 2.01-1.71 (m, 5H), 1.67-1.44 (m, 5H), 1.25 (d, J = 9.8 Hz, 2H).; HPLC purity: 100%; LCMS Calculated for C.sub.28H.sub.32F.sub.2N.sub.2O.sub.4S: 530.63; Observed: 531.2[M + H].sup.+. I-241 [00566] Yield: 49.7 mg, 47.2%; Appearance: Yellow oil; .sup.1H NMR (400 MHz, DMSO-d.sub.6) 7.98-7.88 (m, 2H), 7.84 (s, 1H), 7.71 (d, J = 8.1 Hz, 2H), 7.53 (d, J = 8.1 Hz, 1H), 7.44 (d, J = 5.1 Hz, 1H), 7.26- 6.95 (m, 4H), 4.15-4.05 (m, 4H), 3.83-3.65 (m, 3H), 3.20 (dd, J = 5.3, 1.3 Hz, 2H), 2.36- 2.06 (m, 1H), 1.76-1.36 (m, 8H), 1.29-1.15 (m, 2H).; HPLC purity: 100%; LCMS Calculated for C.sub.27H.sub.30F.sub.2N.sub.4O.sub.3S: 528.62; Observed: 529.2[M + H].sup.+. I-242 [00567] Yield: 50 mg, 45%; Appearance: Yellow solid; .sup.1H NMR (400 MHz, DMSO-d.sub.6) 8.77-8.54 (m, 1H), 7.99-7.87 (m, 2H), 7.71 (d, J = 8.1 Hz, 2H), 7.53 (d, J = 8.1 Hz, 1H), 7.36-6.76 (m, 4H), 6.52- 6.26 (m, 1H), 4.69-4.50 (m, 2H), 3.87-3.60 (m, 2H), 3.04 (d, J = 5.4 Hz, 2H), 2.88 (s, 1H), 2.82-2.59 (m, 1H), 1.88-1.44 (m, 6H), 1.39- 1.15 (m, 2H).; HPLC purity: 100%; LCMS Calculated for C.sub.26H.sub.27F.sub.2N.sub.3O.sub.4S: 515.58; Observed: 516.0[M + H].sup.+. I-243 [00568] Yield: 15.6 mg, 13.9%; Appearance: Yellow solid; .sup.1H NMR (600 MHz, DMSO-d.sub.6) 7.95 (dd, J = 31.2, 8.1 Hz, 2H), 7.74 (d, J = 8.1 Hz, 2H), 7.52-7.42 (m, 2H), 7.30-6.91 (m, 4H), 6.29 (s, 1H), 3.78 (s, 2H), 3.62 (d, J = 6.1 Hz, 3H), 3.05 (d, J = 7.3 Hz, 3H), 2.20-1.95 (m, 1H), 1.69- 1.20 (m, 6H), 1.07-0.97 (m, 2H).; HPLC purity: 100%; LCMS Calculated for C.sub.26H.sub.28F.sub.2N.sub.4O.sub.3S: 514.59; Observed: 515.0[M + H].sup.+. I-244 [00569] Yield: 6.7 mg, 6.65%; Appearance: Beige solid; .sup.1H NMR (600 MHz, DMSO-d.sub.6) 8.03-7.92 (m, 2H), 7.79-7.70 (m, 2H), 7.53-7.43 (m, 1H), 7.29-7.13 (m, 2H), 7.11-6.91 (m, 2H), 4.53- 4.46 (m, 2H), 4.46-4.38 (m, 2H), 3.79 (d, J = 3.3 Hz, 1H), 3.70 (dd, J = 11.0, 6.3 Hz, 2H), 3.49 (s, 1H), 3.45 (q, J = 7.2 Hz, 1H), 3.26 (t, J = 7.1 Hz, 1H), 2.19-2.10 (m, 1H), 2.04 (q, J = 6.6 Hz, 1H), 1.71-1.61 (m, 2H), 1.59-1.48 (m, 3H), 1.44- 1.34 (m, 1H), 1.28-1.21 (m, 1H), 1.16-1.05 (m, 1H).; HPLC purity: 100%; LCMS Calculated for C.sub.27H.sub.30F.sub.2N.sub.2O.sub.4S: 516.6; Observed: 517.2[M + H].sup.+. I-245 [00570] Yield: 29.5 mg, 27.7%; Appearance: Yellow solid; .sup.1H NMR (400 MHz, DMSO-d.sub.6) 8.06- 7.87 (m, 2H), 7.75 (d, J = 8.1 Hz, 2H), 7.53-7.38 (m, 1H), 7.22-6.81 (m, 5H), 3.83-3.62 (m, 2H), 3.49 (s, 3H), 3.03 (d, J = 3.9 Hz, 3H), 2.04-0.91 (m, 9H).; HPLC purity: 100%; LCMS Calculated for C.sub.26H.sub.28F.sub.2N.sub.4O.sub.3S: 514.59; Observed: 515.0[M + H].sup.+. I-246 [00571] Yield: 33.2 mg, 21.1%; Appearance: Beige solid; .sup.1H NMR (600 MHz, DMSO-d.sub.6) 8.02 (d, J = 8.1 Hz, 1H), 7.52 (d, J = 7.8 Hz, 2H), 7.43 (d, J = 7.8 Hz, 2H), 7.37 (d, J = 4.4 Hz, 4H), 7.34- 7.30 (m, 1H), 7.27 (d, J = 7.5 Hz, 1H), 7.18-7.13 (m, 1H), 7.11-6.88 (m, 2H), 5.10 (s, 2H), 4.13 (s, 2H), 4.02 (d, J = 13.4 Hz, 2H), 3.97 (s, 2H), 3.13-2.89 (m, 2H), 1.81-1.70 (m, 2H), 1.59 (d, J = 13.2 Hz, 2H).; HPLC purity: 100%; LCMS Calculated for C.sub.29H.sub.28F.sub.2N.sub.2O.sub.3: 490.55; Observed: 491.0[M + H].sup.+. I-247 [00572] Yield: 30.3 mg, 19.2%; Appearance: Yellow solid; .sup.1H NMR (600 MHz, DMSO-d.sub.6) 8.02 (d, J = 8.1 Hz, 1H), 7.52 (d, J = 7.8 Hz, 2H), 7.43 (d, J = 7.8 Hz, 2H), 7.37 (d, J = 4.4 Hz, 4H), 7.34- 7.30 (m, 1H), 7.27 (d, J = 7.5 Hz, 1H), 7.18-7.13 (m, 1H), 7.11-6.88 (m, 2H), 5.10 (s, 2H), 4.13 (s, 2H), 4.02 (d, J = 13.4 Hz, 2H), 3.97 (s, 2H), 3.13-2.89 (m, 2H), 1.81-1.70 (m, 2H), 1.59 (d, J = 13.2 Hz, 2H).; HPLC purity: 100%; LCMS Calculated for C.sub.28H.sub.27F.sub.2N.sub.3O.sub.3: 491.54; Observed: 492.2[M + H].sup.+. I-248 [00573] Yield: 159.3 mg, 92%; Appearance: Yellow oil; .sup.1H NMR (400 MHz, DMSO-d6) 7.54 (d, J = 8.2 Hz, 2H), 7.47-7.27 (m, 8H), 7.16 (d, J = 7.6 Hz, 1H), 7.14-6.84 (m, 3H), 5.07 (s, 2H), 3.89 (d, J = 13.5 Hz, 2H), 3.49 (s, 2H), 3.26 (s, 3H), 2.73-2.57 (m, 2H), 2.09-2.02 (m, 2H), 1.69- 1.52 (m, 2H), 1.40 (d, J = 13.1 Hz, 2H); HPLC purity: 100%; LCMS Calculated for C.sub.29H.sub.29F.sub.2N.sub.3O.sub.3: 505.57; Observed: 507.2[M + H].sup.+. I-249 [00574] Yield: mg, %; Appearance: Yellow solid; .sup.1H NMR (400 MHz, DMSO-d.sub.6) 7.75-7.69 (m, 1H), 7.66 (d, J = 8.1 Hz, 2H), 7.43 (d, J = 8.1 Hz, 2H), 7.39 (d, J = 4.4 Hz, 4H), 7.37-7.31 (m, 2H), 7.24 (dd, J = 13.8, 6.2 Hz, 1H), 7.10-6.91 (m, 2H), 5.11 (s, 2H), 4.19 (s, 2H), 4.05 (d, J = 13.8 Hz, 2H), 3.18-2.96 (m, 2H), 1.85-1.64 (m, 4H).; HPLC purity: 100%; LCMS Calculated for C.sub.28H.sub.26F.sub.2N.sub.2O.sub.4: 492.52; Observed: 493.0[M + H].sup.+. I-250 [00575] Yield: 24.3 mg, 15.4%; Appearance: Light brown solid; .sup.1H NMR (600 MHz, DMSO-d.sub.6) 7.52 (d, J = 7.9 Hz, 2H), 7.46 (d, J = 7.9 Hz, 2H), 7.39-7.35 (m, 4H), 7.34-7.28 (m, 1H), 7.26 (d, J = 7.5 Hz, 1H), 7.12 (d, J = 4.1 Hz, 2H), 7.11- 6.91 (m, 2H), 5.08 (s, 2H), 4.71 (s, 2H), 3.97 (d, J = 13.4 Hz, 2H), 3.80 (s, 2H), 3.06-2.78 (m, 2H), 1.76-1.65 (m, 2H), 1.54 (d, J = 13.1 Hz, 2H).; HPLC purity: 100%; LCMS Calculated for C.sub.28H.sub.28F.sub.2N.sub.2O.sub.4S: 526.6; Observed: 527.2[M + H].sup.+. I-251 [00576] Yield: 47.9 mg, 45.5%; Appearance: White solid; .sup.1H NMR (400 MHz, DMSO-d.sub.6) 7.96 (d, J = 8.1 Hz, 2H), 7.73 (d, J = 8.1 Hz, 2H), 7.53 (d, J = 8.1 Hz, 1H), 7.21 (t, J = 7.6 Hz, 1H), 7.12- 7.08 (m, 1H), 7.04-6.79 (m, 2H), 4.35 (d, J = 13.7 Hz, 1H), 3.98-3.84 (m, 2H), 3.77 (d, J = 14.1 Hz, 1H), 3.17 (t, J = 13.2 Hz, 1H), 2.69 (t, J = 13.1 Hz, 1H), 2.61-2.55 (m, 2H), 2.48-2.36 (m, 2H), 1.70 (t, J = 13.0 Hz, 1H), 1.62-1.46 (m, 1H), 1.24 (dd, J = 41.4, 13.5 Hz, 2H).; HPLC purity: 100%; LCMS Calculated for C.sub.23H.sub.23F.sub.5N.sub.2O.sub.3S: 502.5; Observed: 503.0[M + H].sup.+. I-252 [00577] Yield: 52.6 mg, 50.2%; Appearance: White solid; .sup.1H NMR (400 MHz, DMSO-d.sub.6) 7.96 (d, J = 8.0 Hz, 2H), 7.73 (d, J = 8.1 Hz, 2H), 7.53 (d, J = 8.1 Hz, 1H), 7.24-7.17 (m, 1H), 7.13-6.78 (m, 3H), 4.35 (d, J = 13.6 Hz, 1H), 3.98-3.85 (m, 2H), 3.84-3.66 (m, 3H), 3.60 (q, J = 7.4 Hz, 1H), 3.23-3.08 (m, 1H), 2.63 (t, J = 13.0 Hz, 1H), 2.43-2.25 (m, 2H), 2.02-1.89 (m, 1H), 1.85 (q, J = 6.6 Hz, 2H), 1.78-1.36 (m, 5H), 1.29 (d, J = 13.7 Hz, 1H), 1.18 (d, J = 13.4 Hz, 1H).; HPLC purity: 100%; LCMS Calculated for C.sub.26H.sub.30F.sub.2N.sub.2O.sub.4S: 504.59; Observed: 505.2[M + H].sup.+. I-253 [00578] Yield: 52.5 mg, 50.1%; Appearance: White solid; .sup.1H NMR (400 MHz, DMSO-d.sub.6) 7.96 (d, J = 8.0 Hz, 2H), 7.73 (d, J = 8.0 Hz, 2H), 7.53 (d, J = 8.1 Hz, 1H), 7.21 (t, J = 7.9 Hz, 1H), 7.13- 6.78 (m, 3H), 4.34 (d, J = 13.7 Hz, 1H), 4.00- 3.84 (m, 2H), 3.82-3.68 (m, 3H), 3.63 (q, J = 7.6 Hz, 1H), 3.25 (t, J = 7.6 Hz, 1H), 3.15 (t, J = 13.6 Hz, 1H), 2.63 (t, J = 13.3 Hz, 1H), 2.30 (t, J = 7.9 Hz, 2H), 2.22-2.08 (m, 1H), 2.08-1.95 (m, 1H), 1.69-1.42 (m, 5H), 1.29 (d, J = 13.6 Hz, 1H), 1.18 (d, J = 13.6 Hz, 1H).; HPLC purity: 99.17%; LCMS Calculated for C.sub.26H.sub.30F.sub.2N.sub.2O.sub.4S: 504.59; Observed: 505.2[M + H].sup.+. I-254 [00579] Yield: 52.6 mg, 48.9%; Appearance: White solid; .sup.1H NMR (400 MHz, DMSO-d.sub.6) 7.96 (d, J = 8.0 Hz, 2H), 7.73 (d, J = 8.1 Hz, 2H), 7.53 (d, J = 8.1 Hz, 1H), 7.21 (t, J = 7.7 Hz, 1H), 7.13- 6.78 (m, 3H), 4.28 (d, J = 13.5 Hz, 1H), 4.22 4.00 (m, 3H), 3.91 (s, 2H), 3.81-3.63 (m, 5H), 3.13 (t, J = 13.0 Hz, 1H), 2.69 (t, J = 13.0 Hz, 1H), 2.01-1.89 (m, 2H), 1.75-1.63 (m, 1H), 1.62- 1.48 (m, 1H), 1.22 (dd, J = 23.6, 13.1 Hz, 2H).; HPLC purity: 100%; LCMS Calculated for C.sub.25H.sub.28F.sub.2N.sub.2O.sub.5S: 506.56; Observed: 507.1[M + H].sup.+. I-255 [00580] Yield: 61.9 mg, 59%; Appearance: White solid; .sup.1H NMR (400 MHz, DMSO-d.sub.6) 7.96 (d, J = 8.0 Hz, 2H), 7.73 (d, J = 8.0 Hz, 2H), 7.53 (d, J = 8.0 Hz, 1H), 7.26-7.16 (m, 1H), 7.15-6.79 (m, 3H), 4.34 (d, J = 13.6 Hz, 1H), 3.99-3.86 (m, 2H), 3.86-3.69 (m, 3H), 3.63 (q, J = 7.7 Hz, 1H), 3.32-3.21 (m, 1H), 3.15 (t, J = 13.8 Hz, 1H), 2.73-2.57 (m, 1H), 2.46-2.28 (m, 2H), 2.12- 1.97 (m, 1H), 1.70-1.59 (m, 1H), 1.59-1.44 (m, 2H), 1.29 (d, J = 13.5 Hz, IH), 1.18 (d, J = 13.5 Hz, 1H).; HPLC purity: 100%; LCMS Calculated for C.sub.25H.sub.28F.sub.2N.sub.2O.sub.4S: 490.57; Observed: 491.2[M + H].sup.+. I-256 [00581] Yield: 52.8 mg, 50.3%; Appearance: White solid; .sup.1H NMR (400 MHz, DMSO-d.sub.6) 7.96 (d, J = 8.1 Hz, 2H), 7.73 (d, J = 8.1 Hz, 2H), 7.53 (d, J = 7.9 Hz, 1H), 7.27-7.18 (m, 1H), 7.12-6.77 (m, 3H), 4.35 (d, J = 13.6 Hz, 1H), 4.14-4.04 (m, 1H), 3.97-3.86 (m, 2H), 3.86-3.71 (m, 2H), 3.67-3.58 (m, 1H), 3.15 (t, J = 13.2 Hz, 1H), 2.70-2.57 (m, 2H), 2.41-2.29 (m, 1H), 2.12- 2.01 (m, 1H), 1.93-1.80 (m, 2H), 1.73-1.60 (m, 1H), 1.60-1.42 (m, 2H), 1.28 (t, J = 12.7 Hz, 1H), 1.18 (d, J = 13.6 Hz, 1H).; HPLC purity: 100%; LCMS Calculated for C.sub.25H.sub.28F.sub.2N.sub.2O.sub.4S: 490.57; Observed: 491.2[M + H].sup.+. I-257 [00582] Yield: 160.5 mg, 17.7%; Appearance: Yellow solid; .sup.1H NMR (400 MHz, DMSO-d.sub.6) 8.11 (d, J = 8.2 Hz, 2H), 7.98 (d, J = 8.2 Hz, 2H), 5.67 (s, 1H), 4.11 (s, 2H), 2.61 (s, 6H), 1.80 (tt, J = 8.5, 5.0 Hz, 1H), 1.61 (d, J = 11.9 Hz, 2H), 1.57-1.48 (m, 2H), 1.46 (d, J = 9.2 Hz, 1H), 1.36-1.16 (m, 3H), 1.12 (d, J = 13.1 Hz, 2H), 0.83 (dt, J = 8.4, 3.2 Hz, 2H), 0.65 (dt, J = 5.0, 3.0 Hz, 2H); HPLC purity: 100%; LCMS Calculated for C.sub.21H.sub.28N.sub.4O.sub.4S.sub.2: 464.6; Observed: 465.2 [M + H].sup.+.

Example 62Biological Activity

Example 62a

[0738] For the TFEB nuclear translocation assay, HeLa wt or HeLa TRPML1 KO cells were plated at 2700 cells/well into black-walled, 384-well Cell carrier Ultra tissue culture treated plates in complete media and incubated overnight. The next day, cells are treated for 2 hrs with compounds and incubated at 37 C. Cells were then fixed for 30 minutes at room temperature in 4% final PFA and washed five times with 90 L PBS. PBS is aspirated from the wells and the cells are blocked with 7.5 L blocking buffer (1.1 PBS/Odyssey block buffer containing 0.1% triton x-100 and 1% goat serum). After 30-60 minutes of block, 7.5 L of primary anti-TFEB (rabbit) antibody is added for a final dilution of 1:200 antibody in 15 L blocking buffer. Plates are incubated overnight at 4 C. The following day, plates are washed again into PBS, 90 L with 5 washes, all PBS is aspirated from the wells and the cells are incubated for 1 hr in 1:1000 goat-anti rabbit Alexa 488 secondary antibody, also containing 10 g/mL Hoechst 33342. After the 1 hr RT incubation, plates are washed a final time into PBS, sealed with foil and imaged with an automated epifluorescence microscopy (PerkinElmer Operetta CLS). Four different fields were imaged per well using 20 magnification for DAPI and FITC filter sets. Images were quantified using PerkinElmer Harmony software, briefly: apply flatfield correction (basic/advanced) for input images. Use the Find Nuclei building block with channel set at Hoechst to find the nuclei. Use the Find cytoplasm building block with channel set to Alexa 488 to find the cytoplasm. Use select cell region with Channel set at Alexa 488 and region of interest as Nuclei and define outer border at 0 m and inner at 45 m to cover complete nuclei. Use select cell region with Channel set at Alexa 488 and region of interest as ring region and define outer border at 5 m and inner at 0 m to define a ring around the nucleus. Use the find calculate intensity parameter to calculate intensity of the nuclear region and the ring region. Define results as Number of nuclei and ratio of A/B where A is Intensity of Nuclei and B is intensity of the ring region.

[0739] Table 3 shows the activity of selected compounds of this invention in TFEB assays. Compounds having an activity designated as ++++ provided an EC.sub.50 of 2.00 M; compounds having an activity designated as +++ provided an EC.sub.50 of 2.01-8.00 M; compounds having an activity designated as ++ provided an EC.sub.50 of 8.01-9.99 M; and compounds having an activity designated as + provided an EC.sub.50 of 10.00 M.

TABLE-US-00021 TABLE 3 Compound No. TFEB EC.sub.50 (M) I-1 ++ I-2 +++ I-3 +++ I-4 ++ I-5 ++++ I-6 + I-7 + I-8 + I-9 +++ I-10 +++ I-11 + I-12 + I-13 + I-14 +++ I-15 ++ I-16 + I-17 + I-18 +++ I-19 + I-20 + I-21 + I-22 + I-23 + I-24 + I-25 +++ I-26 +++ I-27 +++ I-28 + I-29 +++ I-30 + I-31 +++ I-32 + I-33 + I-34 +++ I-35 +++ I-36 + I-37 +++ I-38 + I-39 + I-40 +++ I-41 ++ I-42 +++ I-43 + I-44 +++ I-45 +++ I-46 +++ I-47 +++ I-48 +++ I-49 +++ I-50 + I-51 ++ I-52 + I-53 + I-54 + I-55 + I-56 + I-57 +++ I-58 +++ I-59 + I-60 ++ I-61 + I-62 + I-63 + I-64 +++ I-65 ++++ I-66 +++ I-67 +++ I-68 ++++ I-69 ++++ I-70 + I-71 + I-72 +++ I-73 +++ I-74 +++ I-75 ++ I-76 +++ I-77 ++++ I-78 +++ I-79 ++++ I-80 ++++ I-81 ++++ I-82 + I-83 + I-84 + I-85 + I-86 ++++ I-87 ++++ I-88 + I-89 + I-90 + I-91 +++ I-92 +++ I-93 ++++ I-94 ++++ I-95 ++++ I-96 +++ I-97 ++++ I-98 ++++ I-99 ++++ I-100 ++++ I-101 +++ I-102 +++ I-103 +++ I-104 ++++ I-105 ++++ I-106 ++++ I-115 +++ I-116 ++++ I-117 + I-118 ++++ I-119 ++++ I-120 +++ I-121 ++++ I-122 ++++ I-123 +++ I-124 + I-125 + I-126 ++++ I-127 +++ I-128 ++++ I-129 ++++ I-130 ++++ I-131 ++++ I-132 ++++ I-133 ++++ I-134 ++++ I-137 ++++ I-139 ++++ I-144 + I-145 + I-146 + I-147 + I-148 + I-149 ++++ I-150 + I-151 + I-153 ++++ I-154 + I-157 ++++ I-158 ++++ I-160 ++++ I-161 +++ I-162 + I-163 ++++ I-164 ++++ I-165 +++ I-166 ++++ I-167 ++ I-168 ++++ I-169 ++++ I-170 ++++ I-174 ++++ I-178 +++ I-180 ++++ I-181 ++++ I-182 ++++ I-184 + I-186 ++++ I-187 ++++ I-188 ++++ I-189 ++++ I-190 + I-191 +++ I-219 + I-220 +++ I-221 +++ I-222 ++++ I-223 ++++ I-225 + I-226 + I-227 +++ I-228 ++++ I-230 ++++ I-234 ++++ I-235 ++++ I-246 + I-247 + I-248 + I-249 + I-250 ++++ I-257 ++++

Example 62b

[0740] For the Lamp1 lysosomal exocytosis assay, a human monocytic suspension cell line (THP-1) was used. Cells in culture should be used between a density of 800e5/mL and 1.2e6/mL on the day of the assay. For each 96-well assay plate to be used, pellet 11e6 THP-1 cells at 330g for 5 min in a 50 mL conical tube, aspirate media and resuspend in 22 mLs of RPMI 1640/10% FBS media for a final cell concentration of 5e5/mL. Prior to addition of cells to the assay plate, perform a 7 pt dilution curve using a top dose of compound at 2 mM and use a 3-fold serial dilution, the 8.sup.th point is DMSO only. Final top dose of compound in the assay was 20 M. 2 L of each serial dilution was transferred to a new 96-well v-bottom assay plate. 198 L of cells (1e5 total cells/well) was prepared as above in each well of the assay plate and incubated at 37 C./5% CO.sub.2/95% RH for 55 min. After the 55 min incubation, cells were pelleted for 5 min at 4 C at 400g in a tabletop centrifuge. The media was separated from the cell pellets in the plate. The pellets were washed using 200 L ice cold buffer (PBS Ca.sup.++/Mg.sup.++ containing 2% final BSA and 80 M final Dynasore). Cells were pelleted again at 400g-5 min in a 4 C. tabletop centrifuge. Buffer was separated from cells. Each well was suspended in 75 uL Lamp1-PE antibody buffer (PBS Ca.sup.++/Mg.sup.++ containing 2% final BSA with 80 uM final Dynasore and 1:800 final dilution of Lamp 1-PE labeled antibody). After a 45 min antibody incubation on ice, 25 L of sytox green was added (I drop/mL buffer), and each well was mixed and incubated for an additional 15 min on ice. After the 15 min sytox green incubation, 100 L of ice-cold buffer (PBS Ca.sup.++/Mg.sup.++ containing 2% final BSA and 80 uM final Dynasore) was added and cells were pelleted for 5 min at 400g. The buffer was removed and each sample was resuspended in 100 uL of ice-cold buffer (PBS Ca.sup.++/Mg.sup.++ containing 2% final BSA and 80 M final Dynasore). FACs gating strategy: FACS analyze for sytox green (A488) and Lamp1-PE (DsRed). First gate against FSC-A/SSC-A to find non-fragmented or live THP-1 cells. Next gate against FITC-A/FSC-A to omit sytox green positive cells. Then gate for FSC-A/FSC-H to remove any doublet cells. The last gate was a histogram for PE. The statistics for count and geometric mean fluorescence intensity (gWFI) for PE were repoted on the last gate.

[0741] Table 4 shows the activity of selected compounds of this invention in exocytosis assays. Compounds having an activity designated as ++++ provided an exocytosis readout of 0.50 M; compounds having an activity designated as +++ provided an exocytosis readout of 0.51-1.00 M; compounds having an activity designated as ++ provided an exocytosis readout of 1.01-5.00 M; and compounds having an activity designated as + provided an exocytosis readout of 5.01 M

TABLE-US-00022 TABLE 4 Compound No. Exocytosis (M) I-2 + I-5 + I-31 + I-35 + I-48 + I-57 + I-67 + I-68 ++++ I-73 + I-74 + I-79 ++++ I-80 + I-81 ++++ I-83 + I-86 + I-87 +++ I-91 + I-92 + I-94 + I-95 ++++ I-97 +++ I-98 ++ I-99 ++++ I-100 + I-101 + I-103 + I-104 ++++ I-105 + I-107 + I-108 + I-109 + I-116 + I-118 ++ I-119 ++ I-122 + I-124 + I-126 + I-127 ++ I-129 +++ I-130 ++++ I-131 + I-132 + I-133 + I-134 ++++ I-135 ++++ I-136 + I-137 ++++ I-138 + I-139 ++++ I-141 ++ I-142 + I-143 + I-145 + I-148 + I-149 ++++ I-152 + I-154 + I-155 ++++ I-157 + I-158 +++ I-159 + I-160 ++++ I-161 ++ I-162 + I-163 + I-164 + I-165 + I-166 + I-167 + I-168 + I-169 + I-170 +++ I-171 +++ I-172 + I-173 ++ I-174 ++++ I-175 + I-176 ++ I-177 +++ I-178 +++ I-179 + I-180 ++++ I-181 ++++ I-182 + I-183 ++++ I-184 + I-185 + I-186 ++++ I-187 +++ I-188 + I-189 ++++ I-190 + I-191 + I-192 + I-193 + I-194 + I-195 + I-196 + I-197 + I-198 + I-199 + I-200 + I-201 + I-202 + I-203 + I-204 + I-205 + I-206 + I-207 + I-208 + I-209 + I-210 + I-211 + I-212 + I-213 + I-214 + I-215 + I-216 + I-217 + I-218 + I-219 + I-220 + I-221 + I-222 + I-223 +++ I-224 + I-225 + I-226 + I-227 + I-228 + I-229 + I-230 + I-231 + I-232 + I-233 + I-234 + I-235 + I-236 + I-237 + I-238 + I-239 + I-240 + I-241 + I-242 + I-243 + I-244 + I-245 + I-246 + I-247 + I-248 + I-249 + I-250 ++++ I-251 ++ I-252 + I-253 + I-254 + I-255 + I-256 +