Sulfinylaminobenzamide and sulfonylaminobenzamide derivatives

Abstract

To provide a novel compound capable of uncoupling mitochondrial oxidative phosphorylation. [Solution] Formula (I): Compounds are provided in TIFF2026090413000275.tif2873, where the variable groups are as defined herein. This disclosure relates to novel compounds capable of uncoupling mitochondrial oxidative phosphorylation. This disclosure also relates to methods for preparing these compounds, pharmaceutical compositions containing such compounds, and methods for using these compounds or pharmaceutical compositions in therapeutic treatments. Surprisingly, the present invention produces remarkable effects that were not readily apparent to those skilled in the art from the prior art.

Description

[Technical Field]

[0001] field This disclosure relates to novel compounds capable of uncoupling mitochondrial oxidative phosphorylation. The disclosure also relates to methods for preparing these compounds, pharmaceutical compositions containing such compounds, and methods for using these compounds or pharmaceutical compositions in therapeutic procedures. [Background technology]

[0002] background Mitochondria are bimembrane organelles that provide an efficient pathway for eukaryotic cells to produce ATP from energy-rich molecules. Electrons from oxidative substrates are transferred to oxygen via a series of redox reactions to produce water. In this process, protons are pumped from their matrix across the inner mitochondrial membrane through respiratory complexes I, III, and IV. As the protons return to the mitochondrial matrix along their electrochemical gradient, ATP is synthesized by complex V (ATP synthase).

[0003] Mitochondrial dysfunction is linked, among other conditions, particularly to neurodegenerative diseases and cancer (de Moura et al., Environmental and Molecular Mutagenesis 51:391-405 (2010)), insulin resistance, type 2 diabetes, hypertension and dyslipidemia (Kim et al., Circ Res. 2008 February 29;102(4):401-414), alcoholic steatohepatitis, non-alcoholic fatty liver disease, and non-alcoholic steatohepatitis (NASH).

[0004] Non-alcoholic fatty liver disease (NAFLD), a major liver disorder, is estimated to affect more than 25 percent of the world's population and one in three Americans (Younosi et al., Hepatology, 2016;64:73-84; (Shulman, 2000, J. Clin. Invest. 106:171-176). If left untreated, NAFLD often progresses to non-alcoholic steatohepatitis (NASH) and can lead to fibrosis, cirrhosis, or hepatocellular carcinoma (HCC), or any one or all of these.

[0005] One proposed treatment for NAFLD, NASH, and other diseases mediated at least partially by mitochondrial dysfunction is the use of mitochondrial uncouplers. The use of protonophores (i.e., proton translocation agents) is one proposed method for "uncouple" the mitochondrial energy transport mechanism. This uncoupling leads to the processing (degradation) of energy-rich compounds, such as lipids and fatty acids. Furthermore, mitochondrial uncoupling is thought to reduce the generation of reactive oxygen species (ROS). ROS are responsible for DNA damage and protein alteration in vivo, and can therefore cause cellular dysfunction or programmed cell death (apoptosis). Several mitochondrial uncouplers have been proposed (see, e.g., L. Santos et al., Small Molecule Mitochondrial Uncouplers and Their Therapeutic Potential, J. Med. Chem. Nov. 2017, DOI: 10.1021 / acs.jmedchem.7b01182).

[0006] There is a need to provide uncoupling compounds that treat mitochondrial-mediated diseases or conditions without significantly increasing body temperature. [Prior art documents] [Non-patent literature]

[0007] [Non-Patent Document 1] de Moura et al.,Environmental and Molecular Mutagenesis 51:391-405(2010) [Non-Patent Document 2] Kim et al.,Circ Res.2008 February 29;102(4):401-414 [Non-Patent Document 3] Younosi et al.,Hepatology,2016;64:73-84 [Non-Patent Document 4] Shulman,2000,J.Clin.Invest.106:171-176 [Non-Patent Document 5] L. Santos et al.,Small Molecule Mitochondrial Uncouplers and Their Therapeutic Potential,J.Med.Chem.Nov.2017,DOI:10.1021 / acs.jmedchem.7b01182 [Overview of the project] [Means for solving the problem]

[0008] Summary of the Invention In one embodiment of this disclosure, Formula I: [ka] A compound of the same or a pharmaceutically acceptable salt thereof, stereoisomer, mixture of stereoisomers, tautomers, or deuterated analog is provided, in which formula I: Q is -S(O)2-, -S(O)-, -S(O)(NH)-, -S(O)(NR 8 Selected from the group consisting of )-. R 1 C 1~6 Alkyl, C 2~6 Alkenil, C 2~6 Alkinyl, -NR 13 R 13, 6- to 10-membered aryl, 5- to 10-membered heteroaryl, C 3~12 cycloalkyl, and 4- to 12-membered heterocyclyl, each independently selected from the group consisting thereof, wherein C 1~6 alkyl, C 2~6 alkenyl, C 2~6 alkynyl, 6- to 10-membered aryl, 5- to 10-membered heteroaryl, C 3~12 cycloalkyl, and 4- to 12-membered heterocyclyl may each be further substituted with one or more R 11 groups, if desired; R 11 is hydroxyl, oxo, halo, -CN, C 1~6 alkyl, C 2~6 alkenyl, C 2~6 alkynyl, C 1~6 alkoxy, C 1~6 hydroxyalkyl, C 1~6 heteroalkyl, 3- to 12-membered cycloalkyl, 4- to 12-membered heterocyclyl, 6- to 10-membered aryl, 5- to 10-membered heteroaryl, -P(O)R 14 R 14 , -S(O)(NH)R 14 , -S(O)(NR 8 )R 14 , -S(O)(NH)NR 13 R 13 , -S(O)(NR 8 )NR 13 R 13 , -SH, -S(O) 0~2 R 14 , -S(O) 1~2 NR 13 R 13 , -SF5, -NO2, -NR 13 R 13 , -NR 13 SO2R 14 , -OS(O)2R 14 , -C(O)OR 14 , -C(O)R 14 , -NR 13 C(O)OR 14 , -NR 13 C(O)NR 13 R 13 , -NR 13S(O)2NR 13 R 13 、 and -C(O)NR 13 R 13 selected from the group consisting of, where C 1~6 alkyl, C 2~6 alkenyl, C 2~6 alkynyl, C 1~6 alkoxy, C 1~6 hydroxyalkyl, C 1~6 heteroalkyl, 3 - to 12 - member cycloalkyl, 4 - to 12 - member heterocyclyl, 6 - to 10 - member aryl, and 5 - to 10 - member heteroaryl are each optionally substituted with one or more R 9 groups; Each R 9 is independently -H, oxo, -OH, -CN, halo, C 1~6 alkyl, C 1~6 alkoxy, C 1~6 hydroxyalkyl, C 1~6 heteroalkyl, 3 - to 12 - member cycloalkyl, 4 - to 12 - member heterocyclyl, 6 - to 10 - member aryl, 5 - to 10 - member heteroaryl, -NR 13 R 13 , -NR 13 C(O)OR 14 , -OS(O)2R 14 -C(O)OR 14 , -S(O)(NH)R 14 , -S(O)(NR 8 )R 14 , -S(O)(NH)NR 13 R 13 , -S(O)(NR 8 )NR 13 R 13 , -S(O) 0~2 R 14 , -S(O) 1~2 NR 13 R 13 , -C(O)NR 13 R 13 , -NR 13 SO2R 14 , -C(O)R 14 , -NR 13 C(O)NR 13 R 13 , -NR 13S(O)2NR 13 R 13 is selected from the group consisting of SF5 and -NO2, wherein C 1~6 alkyl, C 1~6 alkoxy, C 1~6 hydroxyalkyl, C 1~6 heteroalkyl, 3- to 12-member cycloalkyl, 4- to 12-member heterocyclyl, 6- to 10-member aryl, and 5- to 10-member heteroaryl are each optionally substituted with one or more R 16 groups; Each R 13 is independently -H, C 1~6 alkyl, C 1~6 hydroxyalkyl, C 1~6 heteroalkyl, C 3~6 cycloalkyl, 6- to 10-member aryl, 4- to 12-member heterocyclyl and 5- to 10-member heteroaryl are selected from the group consisting of, wherein this C 1~6 alkyl, C 1~6 hydroxyalkyl, C 1~6 heteroalkyl, 3- to 6-member cycloalkyl, 4- to 12-member heterocyclyl, 6- to 10-member aryl and 5- to 10-member heteroaryl are optionally substituted with one or more R 15 groups. Each R 14 is independently C 1~6 alkyl, C 1~6 hydroxyalkyl, C 1~6 heteroalkyl, C 3~6 cycloalkyl, 6- to 10-member aryl, 4- to 12-member heterocyclyl and 5- to 10-member heteroaryl are selected from the group consisting of, wherein this C 1~6 alkyl, C 1~6 hydroxyalkyl, C 1~6 heteroalkyl, 3- to 6-member cycloalkyl, 4- to 12-member heterocyclyl, 6- to 10-member aryl and 5- to 10-member heteroaryl are optionally substituted with one or more R 15 groups. Each R 15 is independently -H, halo, -CN, -OH, oxo, -NO2, -SF5, C1~6 Alkyl, C 1~6 Haloalkyl, C 1~6 Alkoxy, C 1~6 Haloalkoxy, C 1~6 Hydroxyalkyl, C 1~6 Heteroalkyl, 3- to 12-membered cycloalkyl, 4- to 12-membered heterocyclyl, 6- to 10-membered aryl, 5- to 10-membered heteroaryl, -S(O)(NH)R 16 -S(O)(NR 8 )R 16 -S(O)(NH)NR 16 R 16 -S(O)(NR 8 )NR 16 R 16 , -S(O) 0~2 R 16 , -S(O)2NH2, -NH2, -S(O)2NR 16 R 16 , C(O)R 16 -C(O)NR 16 R 16 and C(O)OR 16 Selected from, where 3- to 6-membered cycloalkyls, 4- to 12-membered heterocyclines, 6- to 10-membered aryls, and 5- to 10-membered heteroaryls, one or more R 16 It is replaced as needed in the base. Each R 16 These are independently: halo, -CN, -OH, -NH2, oxo, -NO2, -SF5, C 1~3 Alkyl, C 1~3 Haloalkyl, C 1~6 Alkoxy, C 1~6 Haloalkoxy, C 1~6 Selected from hydroxyalkyl, thiohaloalkyl, sulfonylalkyl, sulfonylhaloalkyl, sulfonylcycloalkyl, 3- to 6-membered cycloalkyl, -C(O)NH2, and -S(O)2NH2. R 2 -H, -CN, -F, -Cl, C 1~3 Alkyl, C 1~3 Haloalkyl, C 1~3 Heteroalkyl, C 1~3 Alkoxy and C 1~3A group consisting of haloalkoxys Selected; R 3 and R 4 Each of these is independently -H, halo, -OH, -CN, C 1~6 Alkyl, C 2~6 Alkenil, C 2~6 Alkinyl, C 1~6 Alkoxy, C 1~6 Hydroxyalkyl, C 1~6 Heteroalkyl, 3- to 12-membered cycloalkyl, 4- to 12-membered heterocyclyl, 6- to 10-membered aryl, 5- to 10-membered heteroaryl, -SF5, -S(O) 0~2 R 14 -S(O)(NH)R 14 -S(O)(NR 8 )R 14 -S(O)(NH)NR 13 R 13 -S(O)(NR 8 )NR 13 R 13 -SH, -NR 13 R 13 , -NR 13 SO2R 14 , -NR 13 S(O)2NR 13 R 13 , -NR 13 C(O)NR 13 R 13 , -NR 13 C(O)OR 14 , Tri-C 1~4 Alkylsilyl, -C(O)R 14 , -C(O)OR 14 -C(O)NR 13 R 13 Selected from the group consisting of , and -NO2, where C 1~6 Alkyl, C 2~6 Alkenil, C 2~6 Alkinyl, C 1~6 Alkoxy, C 1~6 Hydroxyalkyl, C 1~6 Heteroalkyls, 3- to 12-membered cycloalkyls, 4- to 12-membered heterocyclines, 6- to 10-membered aryls, and 5- to 10-membered heteroaryls have one or more R9 The base is further substituted as needed; R 5 -H, -CN, -F, -Cl, C 1~3 Alkyl, C 1~3 Haloalkyl, C 1~3 Heteroalkyl, C 1~3 Alkoxy and C 1~3 Selected from the group consisting of haloalkoxys; Here R 2 and R 3 , or R 3 and R 4 , or R 4 and R 5 These can, as needed, bond with the atom to which they are bonded to form a 5- to 6-membered cycloalkyl, 5- to 6-membered heterocyclyl, phenyl, or 5- to 6-membered heteroaryl, each such cyclic group being condensed with the phenyl to which it is bonded, and each having one or more R 9 Substituted as needed in the base; R 6 The ring is selected from the group consisting of 5- to 10-membered carbon bicyclic rings, 8- to 10-membered tricyclic rings, 6- to 12-membered heterobicyclic rings, and 8- to 12-membered polycyclic rings, where the 5- to 10-membered carbon bicyclic ring, the 8- to 10-membered tricyclic ring, the 8- to 12-membered polycyclic ring, or the 6- to 12-membered heterobicyclic ring may be fused, bridged, or spiro, and the 5- to 10-membered carbon bicyclic ring, the 8- to 10-membered tricyclic ring, the 6- to 12-membered heterobicyclic ring, and the 8- to 12-membered polycyclic ring may have one or more R 7 It has been replaced with; R 7 -H, halo, -CN, oxo, -OH, C 1~6 Alkyl, C 2~6 Alkenil, C 2~6 Alkinyl, Tri-C 1~4 Alkylsilyl, C 1~6 Alkoxy, C 1~6 Hydroxyalkyl, C 1~6 Heteroalkyl, 3-membered to 12-membered cycloalkyl, -S(O) 0~2 R 14 -S(O)(NH)R14 -S(O)(NR 8 )R 14 -S(O)(NH)NR 13 R 13 -S(O)(NR 8 )NR 13 R 13 -SH, -NR 13 R 13 ,-P(O)R 14 R 14 -C(O)OH, -C(O)OR 14 -C(O)NR 13 R 13 -S(O)2NR 13 R 13 , -C(O)R 14 Selected from the group consisting of 6- to 10-membered aryls, 5- to 10-membered heteroaryls, and 4- to 12-membered heterocyclines; here, these 4- to 12-membered heterocyclines, 6- to 10-membered aryls, 5- to 10-membered heteroaryls, C 1~6 Alkyl, C 2~6 Alkenil, C 2~6 Alkinyl, Tri-C 1~4 Alkylsilyl, C 1~6 Alkoxy, C 1~6 Hydroxyalkyl, C 1~6 Each of the heteroalkyl and 3- to 12-membered cycloalkyl groups has one or more R 15 It is replaced as needed; and n is 1, 2, or 3; R 8 C 1~6 Alkyl, -C(O)R 14 , 3-membered to 12-membered cycloalkyl, C 1~6 Heteroalkyl, 6- to 10-membered aryl, 5- to 10-membered heteroaryl, 4- to 12-membered heterocyclyl, -C(O)OR 14 -C(O)NR 13 R 13 and -SO2R 14 And here C 1~6 Alkyl, -C(O)R 14 , 3-membered to 12-membered cycloalkyl, C 1~6Each of the heteroalkyl, 6- to 10-membered aryl, 5- to 10-membered heteroaryl, and 4- to 12-membered heterocyclyl compounds is defined as halo, -CN, oxo, hydroxyl, or C. 1~6 Alkyl, C 1~6 Alkoxy, -S(O) 1~2 R 14 -S(O)2NR 13 R 13 , -NO 2, -SF5, C 1~6 Haloalkyl, C 1~6 Haloalkoxy, C 1~6 Hydroxyalkyl, -NR 13 R 13 , -C(O)OR 14 , C 1~6 Heteroalkyl, one or more R 16 3- to 6-membered cycloalkyl groups, one or more R groups, substituted as needed. 16 4- to 12-membered heterocyclines, substituted as needed, one or more R 16 6-membered to 10-membered aryls, one or more Rs, substituted as needed. 16 It is substituted as needed with 5-membered to 10-membered heteroaryls; however: R 6 C 8~12 It is a carbon bicyclic ring, and R 3 and R 7 If both are H, R 4 C 7~12 Cycloalkyl, C 2~6 Alkenil, C 2~6 Alkinyl, C 1~6 Hydroxyalkyl, C 1~6 Heteroalkyl, 4-membered heterocyclyl, 7-membered heterocyclyl, 7- to 12-membered monocyclic heterocyclyl, -SF5, -NR 13 R 13 , -NR 13 C(O)OR 14 , -NR 13 SO2R 14 , -NR 13 S(O)2NR 13 R 13, -NR 13 C(O)NR 13 R 13 , Tri-C 1~4 Alkylsilyl, -C(O)R 14 , -C(O)OR 14 -C(O)NR 13 R 13 , -S(O) 0~2 R 14 -S(O)(NH)R 14 -S(O)(NR 8 )R 14 -S(O)(NH)NR 13 R 13 -S(O)(NR 8 )NR 13 R 13 Selected from the group consisting of -SH and -NO2, where C 7~12 Cycloalkyl, C 2~6 Alkenil, C 2~6 Alkinyl, C 1~6 Hydroxyalkyl, C 1~6 Heteroalkyl, 4-membered heterocyclyl, 7-membered heterocyclyl, and 7- to 12-membered monocyclic heterocyclyls have one or more R 9 They are substituted as needed; 5-membered to 6-membered heterocyclines are R 17 They are substituted as needed; and 8- to 10-membered bicyclic heterocyclines have one or more R 18 It is replaced as needed; R 6 It is an 8- to 10-member complex biring ring, and R 3 H is H, and R 7 However, -H, halo, cyano, oxo, -OH, C 1~4 Alkoxy, C 1~4 Alkyl or C 1~4 If it is a haloalkyl, R 4 C 7~12 Cycloalkyl, C 2~6 Alkenil, C 2~6 Alkinyl, C 1~6 Hydroxyalkyl, C 1~6Heteroalkyl, 4-membered heterocyclyl, 7-membered heterocyclyl, 7- to 12-membered monocyclic heterocyclyl, -SF5, -NR 13 R 13 , -NR 13 C(O)OR 14 , -NR 13 SO2R 14 , -NR 13 S(O)2NR 13 R 13 , -NR 13 C(O)NR 13 R 13 , Tri-C 1~4 Alkylsilyl, -C(O)R 14 , -C(O)OR 14 -C(O)NR 13 R 13 , -S(O) 0~2 R 14 -S(O)(NH)R 14 -S(O)(NR 8 )R 14 -S(O)(NH)NR 13 R 13 -S(O)(NR 8 )NR 13 R 13 Selected from the group consisting of -SH and -NO2, where C 7~12 Cycloalkyl, C 2~6 Alkenil, C 2~6 Alkinyl, C 1~6 Hydroxyalkyl, C 1~6 Heteroalkyl, 4-membered heterocyclyl, 7-membered heterocyclyl, and 7- to 12-membered monocyclic heterocyclyls have one or more R 9 They are substituted as needed; 5-membered to 6-membered heterocyclines are R 17 They are substituted as needed, and 8- to 10-membered bicyclic heterocyclines have one or more R 18 It is replaced as needed; R 6 It is a C6-C7 carbon bicyclic ring, and R 7 If it is H or methyl, R 3 is, Haro, -CN, C 1~6 Alkyl, C 2~6Alkenil, C 2~6 Alkinyl, C 1~6 Alkoxy, C 1~6 Hydroxyalkyl, C 1~6 Heteroalkyl, 3- to 12-membered cycloalkyl, 4- to 12-membered heterocyclyl, 6- to 10-membered aryl, 5- to 10-membered heteroaryl, -SF5, -S(O) 0~2 R 14 -S(O)(NH)R 14 -S(O)(NR 8 )R 14 -S(O)(NH)NR 13 R 13 -S(O)(NR 8 )NR 13 R 13 -SH, -NR 13 R 13 , -NR 13 SO2R 14 , -NR 13 S(O)2NR 13 R 13 , -NR 13 C(O)NR 13 R 13 , -NR 13 C(O)OR 14 , Tri-C 1~4 Alkylsilyl, -C(O)R 14 , -C(O)OR 14 -C(O)NR 13 R 13 Selected from the group consisting of , and -NO2, where C 1~6 Alki Ru, C 2~6 Alkenil, C 2~6 Alkinyl, C 1~6 Alkoxy, C 1~6 Hydroxyalkyl, C 1~6 Heteroalkyls, 3- to 12-membered cycloalkyls, 4- to 12-membered heterocyclines, 6- to 10-membered aryls, and 5- to 10-membered heteroaryls have one or more R 9 The base is further substituted as needed; Here R 17 -OH, oxo, -CN, C 2~6 Alkenil, C 2~6 Alkinyl, C 1~6Hydroxyalkyl, C 1~6 Heteroalkyl, 3- to 12-membered cycloalkyl, 4- to 12-membered heterocyclyl, 6- to 10-membered aryl, 5- to 10-membered heteroaryl, -S(O) 0~2 R 14 , -NR 13 SO2R 14 , -NR 13 S(O)2NR 13 R 13 , -NR 13 C(O)NR 13 R 13 , -NR 13 C(O)OR 14 , -C(O)R 14 , -C(O)OR 14 and -C(O)NR 13 R 13 Selected from. And R 18 C 2~6 Alkenil, C 2~6 Alkinyl, C 1~6 Alkoxy, C 1~6 Haloalkoxy, C 1~6 Hydroxyalkyl, C 1~6 Heteroalkyl, 3- to 12-membered cycloalkyl, 4- to 12-membered heterocyclyl, 6- to 10-membered aryl, 5- to 10-membered heteroaryl, -S(O) 0~2 R 14 , -NR 13 R 13 , -NR 13 SO2R 14 , -NR 13 S(O)2NR 13 R 13 , -NR 13 C(O)NR 13 R 13 , -NR 13 C(O)OR 14 , -C(O)R 14 , -C(O)OR 14 and -C(O)NR 13 R 13 Selected from.

[0009] In another embodiment, R 6The ring is selected from the group consisting of 5- to 10-membered carbon bicyclic rings, 6- to 12-membered heterobicyclic rings, and 8- to 10-membered tricyclic rings, where the 5- to 10-membered carbon bicyclic ring, the 8- to 10-membered tricyclic ring, or the 6- to 12-membered heterobicyclic ring may be fused, bridged, or spiro, and the 5- to 10-membered carbon bicyclic ring, the 6- to 12-membered heterobicyclic ring, and the 8- to 10-membered tricyclic ring may have one or more R 7 It has been replaced with.

[0010] In another embodiment, R 6 The ring is selected from the group consisting of 5- to 10-membered carbon bicyclic rings, 8- to 10-membered tricyclic rings, and 6- to 12-membered heterobicyclic rings, where the 5- to 10-membered carbon bicyclic ring, the 8- to 10-membered tricyclic ring, or the 6- to 12-membered heterobicyclic ring is bridged, and the 5- to 10-membered carbon bicyclic ring, the 8- to 10-membered tricyclic ring, and the 6- to 12-membered heterobicyclic ring are connected by one or more R 7 It has been replaced with.

[0011] In another embodiment, R 6 The ring is selected from the group consisting of 5- to 10-membered carbon bicyclic rings and 6- to 12-membered heterobicyclic rings, where the 5- to 10-membered carbon bicyclic ring or the 6- to 12-membered heterobicyclic ring is bridged, and the 5- to 10-membered carbon bicyclic ring and the 6- to 12-membered heterobicyclic ring are connected by one R 7 It has been replaced with.

[0012] In some embodiments, Q is -S(O)2-, -S(O)-, and -S(O)(NR 8 Selected from the group consisting of )-.

[0013] In some embodiments, R 1 C 1~6 Alkyl, -NR 13 R 13 , 6-10 member aryl, 5-10 member heteroaryl, C 3~12 Selected from the group consisting of cycloalkyls and 4- to 12-membered heterocyclines, where C 1~6Alkyl, 6- to 10-membered aryl, 5- to 10-membered heteroaryl, C 3~12 Each of the cycloalkyl and 4- to 12-membered heterocyclyls has one or more R 11 It is further substituted with the base.

[0014] In some embodiments, R 2 The group is selected from the group consisting of -H, -CN, -F, methyl, methoxy, and C1 haloalkoxy.

[0015] In another embodiment, R 2 The group is selected from the group consisting of -H and -F.

[0016] In some embodiments, R 4 -H, halo, -OH, -CN, C 1~6 Alkyl, C 1~6 Alkoxy, C 1~6 Hydroxyalkyl, C 1~6 Heteroalkyl, -SF5, -S(O) 0~2 R 14 -S(O)(NH)R 14 -S(O)(NR 8 )R 14 -S(O)(NH)NR 13 R 13 -S(O)(NR 8 )NR 13 R 13 , -NR 13 R 13 , -NR 13 SO2R 14 , -NR 13 S(O)2NR 13 R 13 , -NR 13 C(O)NR 13 R 13 , -NR 13 C(O)OR 14 , -C(O)R 14 , -C(O)OR 14 -C(O)NR 13 R 13 Selected from the group consisting of , -NO2, where C 1~6 Alkyl, C 1~6Alkoxy, C 1~6 Hydroxyalkyl, and C 1~6 Heteroalkyl groups have one or more R 9 It is further substituted with the base.

[0017] In some embodiments, R 4 -H, -F, -Cl, -OH, -CN, -S(O) 0~2 R 14 , -C(O)R 14 -SF5, -NO2, C 1~6 Alkyl, and C 1~6 Selected from the group consisting of alkoxys, and here this C 1~6 Alkyl or C 1~6 The alkoxy is substituted as needed with one or more -F atoms, and R 14 C 1~6 Alkyl, C 3~6 Cycloalkyl, C 1~6 Hydroxyalkyl, C 1~6 Selected from the group consisting of heteroalkyl groups, where this C 1~6 Alkyl, C 3~6 Cycloalkyl, C 1~6 Hydroxyalkyl, and C 1~6 Heteroalkyl groups have one or more R 16 It is substituted as needed in the base, and R 16 These are independently selected from halo, -CN, and -OH.

[0018] In some embodiments, R 4 -H, -F, -Cl, -OH, -CN, -SR 14 , -SF5, C 1~6 Alkyl, and C 1~6 Selected from the group consisting of alkoxys, and here this C 1~6 Alkyl or C 1~6 The alkoxy is substituted as needed with one or more -F atoms, and R 14 C 1~3 Selected from the group consisting of haloalkyls.

[0019] In some embodiments, R 3 -H, halo, -OH, -CN, C 1~6 Alkyl, 6-10 membered aryl, 4-12 membered heterocyclyl, 5-10 membered heteroaryl, C 3~12 Cycloalkyl, C 1~6 Alkoxy, C 1~6 Hydroxyalkyl, C 1~6 Heteroalkyl, -S(O) 0~2 R 14 Selected from the group consisting of -NO2 and -SF5, where this C 1~6 Alkyl, 6-10 membered aryl, 4-12 membered heterocyclyl, 5-10 membered heteroaryl, C 3~12 Cycloalkyl, C 1~6 Alkoxy, C 1~6 Hydroxyalkyl, and C 1~6 Heteroalkyl groups have one or more R 9 The base is further substituted as needed.

[0020] In some embodiments, R 3 -H, -F, -Cl, -OH, -CN, C 1~6 Alkyl, 4- to 12-membered heterocyclyl, 5- to 10-membered heteroaryl, C 3~12 Cycloalkyl, C 1~6 Alkoxy, C 1~6 Hydroxyalkyl, C 1~6 Heteroalkyl, -SR 14 Selected from the group consisting of , and -SF5, where this C 1~6 Alkyl, C 1~6 Alkoxy, C 3~12 Cycloalkyls, 4- to 12-membered heterocyclines, and 5- to 10-membered heteroaryls have one or more R 16 It is replaced as needed, and R 14 is C 1~3 It is a haloalkyl group.

[0021] In some embodiments, R 5 The group is selected from the group consisting of -H, -F, and methyl.

[0022] In another embodiment of this disclosure, Formula II: [ka] Compounds of the same or pharmaceutically acceptable salts thereof, stereoisomers, mixtures of stereoisomers, tautomers, or deuterated analogs are provided, in formula II: x, y, and z are independently 1, 2, 3, or 4. Q is -S(O)2-, -S(O)-, -S(O)(NH)-, -S(O)(NR 28 Selected from the group consisting of )-; R 21 C 1~6 Alkyl, C 2~6 Alkenil, C 2~6 Alkinyl, -NR 33 R 33 , 6-10 member aryl, 5-10 member heteroaryl, C 3~12 Selected from the group consisting of cycloalkyls and 4- to 12-membered heterocyclines, where C 1~6 Alkyl, C 2~6 Alkenil, C 2~6 Alkinyl, 6- to 10-membered aryl, 5- to 10-membered heteroaryl, C 3~12 Each of the cycloalkyl and 4- to 12-membered heterocyclyls has one or more R 31 The base is further substituted as needed; R 31 is hydroxyl, oxo, halo, -CN, C 1~6 Alkyl, C 2~6 Alkenil, C 2~6 Alkinyl, C 1~6 Alkoxy, C 1~6 Hydroxyalkyl, C 1~6 Heteroalkyl, 3- to 12-membered cycloalkyl, 4- to 12-membered heterocyclyl, 6- to 10-membered aryl, 5- to 10-membered heteroaryl, -P(O)R 34 R 34 -S(O)(NH)R 34 -S(O)(NR 28 )R 34 -S(O)(NH)NR33 R 33 -S(O)(NR 28 )NR 33 R 33 -SH, -S(O) 0~2 R 34 , -S(O) 1~2 NR 33 R 33 -SF5, -NO2, -NR 33 R 33 , -NR 33 SO2R 34 -OS(O)2R 34 , -C(O)OR 34 , -C(O)R 34 , -NR 33 C(O)OR 34 , -NR 33 C(O)NR 33 R 33 , -NR 33 S(O)2NR 33 R 33 , and -C(O)NR 33 R 33 A group consisting of C is selected, where C 1~6 Alkyl, C 2~6 Alkenil, C 2~6 Alkinyl, C 1~6 Alkoxy, C 1~6 Hydroxyalkyl, C 1~6 Each of the heteroalkyl, 3- to 12-membered cycloalkyl, 4- to 12-membered heterocyclyl, 6- to 10-membered aryl, and 5- to 10-membered heteroaryl compounds contains one or more R 29 Substituted as needed in the base; Each R 29 These are independently -H, oxo, -OH, -CN, halo, and C. 1~6 Alkyl, C 1~6 Alkoxy, C 1~6 Hydroxyalkyl, C 1~6 Heteroalkyl, 3- to 12-membered cycloalkyl, 4- to 12-membered heterocyclyl, 6- to 10-membered aryl, 5- to 10-membered heteroaryl, -NR 33 R 33 , -NR 33 C(O)OR 34 -OS(O)2R 34 -C(O)OR 34 -S(O)(NH)R 34 -S(O)(NR 8 )R 34 -S(O)(NH)NR 33 R 33 -S(O)(NR 28 )NR 33 R 33 , -S(O) 0~2 R 34 , -S(O) 1~2 NR 33 R 33 -C(O)NR 33 R 33 , -NR 33 SO2R 34 , -C(O)R 34 , -NR 33 C(O)NR 33 R 33 , -NR 33 S(O)2NR 33 R 33 Selected from the group consisting of -SF5 and -NO2, where C 1~6 Alkyl, C 1~6 Alkoxy, C 1~6 Hydroxyalkyl, C 1~6 Each of the heteroalkyl, 3- to 12-membered cycloalkyl, 4- to 12-membered heterocyclyl, 6- to 10-membered aryl, and 5- to 10-membered heteroaryl compounds contains one or more R 36 Place as needed It has been replaced; Each R 33 These are independently -H, C 1~6 Alkyl, C 1~6 Hydroxyalkyl, C 1~6 Heteroalkyl, C 3~6 Selected from the group consisting of cycloalkyl, 6- to 10-membered aryl, 4- to 12-membered heterocyclyl, and 5- to 10-membered heteroaryl, where this C 1~6 Alkyl, C 1~6 Hydroxyalkyl, C 1~6 Heteroalkyl, 3- to 6-membered cycloalkyl, 4- to 12-membered heterocyclyl, 6- to 10-membered aryl, and 5- to 10-membered heteroaryl contain one or more R 35Substituted as needed in the base; Each R 34 C 1~6 Alkyl, C 1~6 Hydroxyalkyl, C 1~6 Heteroalkyl, C 3~6 Selected from the group consisting of cycloalkyl, 6- to 10-membered aryl, 4- to 12-membered heterocyclyl, and 5- to 10-membered heteroaryl, where this C 1~6 Alkyl, C 1~6 Hydroxyalkyl, C 1~6 Heteroalkyl, 3- to 6-membered cycloalkyl, 4- to 12-membered heterocyclyl, 6- to 10-membered aryl, and 5- to 10-membered heteroaryl contain one or more R 35 Substituted as needed in the base; Each R 35 These are independently -H, halo, -CN, -OH, oxo, -NO2, -SF5, C 1~6 Alkyl, C 1~6 Haloalkyl, C 1~6 Alkoxy, C 1~6 Haloalkoxy, C 1~6 Hydroxyalkyl, C 1~6 Heteroalkyl, 3- to 12-membered cycloalkyl, 4- to 12-membered heterocyclyl, 6- to 10-membered aryl, 5- to 10-membered heteroaryl, -S(O)(NH)R 36 -S(O)(NR 28 )R 36 -S(O)(NH)NR 36 R 36 -S(O)(NR 28 )NR 36 R 36 , -S(O) 0~2 R 36 , -S(O)2NH2, -NH2, -S(O)2NR 36 R 36 , C(O)R 36 -C(O)NR 36 R 36 and C(O)OR 36 Selected from, where 3- to 6-membered cycloalkyl, 4- to 12-membered heterocyclyl, 6- to 10-membered aryl, and 5- to 10-membered heteroaryl, one or more R 36Substituted as needed in the base; Each R 36 These are independently: halo, -CN, -OH, -NH2, oxo, -NO2, -SF5, C 1~3 Alkyl, C 1~3 Haloalkyl, C 1~6 Alkoxy, C 1~6 Haloalkoxy, C 1~6 Selected from hydroxyalkyl, thiohaloalkyl, sulfonylalkyl, sulfonylhaloalkyl, sulfonylcycloalkyl, 3-membered to 6-membered cycloalkyl, -C(O)NH2 and -S(O)2NH2; R 22 -H, -CN, -F, -Cl, C 1~3 Alkyl, C 1~3 Haloalkyl, C 1~3 Heteroalkyl, C 1~3 Alkoxy and C 1~3 Selected from the group consisting of haloalkoxys; R 23 and R 24 Each of these is independently -H, halo, -OH, -CN, C 1~6 Alkyl, C 2~6 Alkenil, C 2~6 Alkinyl, C 1~6 Alkoxy, C 1~6 Hydroxyalkyl, C 1~6 Heteroalkyl, 3- to 12-membered cycloalkyl, 4- to 12-membered heterocyclyl, 6- to 10-membered aryl, 5- to 10-membered heteroaryl, -SF5, -S(O) 0~2 R 34 -S(O)(NH)R 34 -S(O)(NR 28 )R 34 -S(O)(NH)NR 33 R 33 -S(O)(NR 28 )NR 33 R 33 -SH, -NR 33 R 33 , -NR 33 SO2R 34 , -NR 33 S(O)2NR 33 R 33 , -NR 33C(O)NR 33 R 33 , -NR 33 C(O)OR 34 , Tri-C 1~4 Alkylsilyl, -C(O)R 34 , -C(O)OR 34 -C(O)NR 33 R 33 Selected from the group consisting of , -NO2, where C 1~6 Alkyl, C 2~6 Alkenil, C 2~6 Alkinyl, C 1~6 Alkoxy, C 1~6 Hydroxyalkyl, C 1~6 Heteroalkyl, 3- to 12-membered cycloalkyl, 4- to 12-membered heterocyclyl, 6- to 10-membered aryl, and 5- to 10-membered heteroaryl contain one or more R 29 The base is further substituted as needed; Here R 22 and R 23 , or R 23 and R 24 These can, as needed, bond with the atom to which they are bonded to form a 5- to 6-membered cycloalkyl, 5- to 6-membered heterocyclyl, phenyl, or 5- to 6-membered heteroaryl, each such cyclic group being condensed with the phenyl to which it is bonded, and each having one or more R 29 Substituted as needed in the base; R 27 -H, halo, -CN, oxo, -OH, C 1~6 Alkyl, C 2~6 Alkenil, C 2~6 Alkinyl, Tri-C 1~4 Alkylsilyl, C 1~6 Alkoxy, C 1~6 Hydroxyalkyl, C 1~6 Heteroalkyl, 3-membered to 12-membered cycloalkyl, -S(O) 0~2 R 34 -S(O)(NH)R 34 -S(O)(NR 28 )R 34 -S(O)(NH)NR 33 R 33-S(O)(NR 28 )NR 33 R 33 , -NR 33 R 33 ,-P(O)R 34 R 34 -C(O)OH, -C(O)OR 34 -C(O)NR 33 R 33 -S(O)2NR 33 R 33 , -C(O)R 34 Selected from the group consisting of 6- to 10-membered aryls, 5- to 10-membered heteroaryls, and 4- to 12-membered heterocyclines; here, these 4- to 12-membered heterocyclines, 6- to 10-membered aryls, 5- to 10-membered heteroaryls, C 1~6 Alkyl, C 2~6 Alkenil, C 2~6 Alkinyl, Tri-C 1~4 Alkylsilyl, C 1~6 Alkoxy, C 1~6 Hydroxyalkyl, C 1~6 Each of the heteroalkyl and 3- to 12-membered cycloalkyl groups has one or more R 35 It is replaced as needed; R 28 C 1~6 Alkyl, -C(O)R 34 , 3-membered to 12-membered cycloalkyl, C 1~6 Heteroalkyl, 6- to 10-membered aryl, 5- to 10-membered heteroaryl, 4- to 12-membered heterocyclyl, -C(O)OR 34 -C(O)NR 33 R 33 , -SO2R 34 And here C 1~6 Alkyl, C 1~6 Alkylcarbonyl, 3-membered to 12-membered cycloalkyl, C 1~6 Each of the heteroalkyl, 6- to 10-membered aryl, 5- to 10-membered heteroaryl, and 4- to 12-membered heterocyclyl compounds is defined as halo, -CN, oxo, hydroxyl, or C. 1~6 Alkyl, C 1~6 Alkoxy, -S(O) 1~2 R 34 -S(O)2NR 33R 33 -NO2, -SF5, C 1~6 Haloalkyl, C 1~6 Haloalkoxy, C 1~6 Hydroxyalkyl, -NR 33 R 33 , -C(O)OR 34 , C 1~6 Heteroalkyl, one or more R 36 3- to 6-membered cycloalkyl groups, one or more R groups, substituted as needed. 36 4- to 12-membered heterocyclines, substituted as needed, one or more R 36 6-membered to 10-membered aryls, one or more Rs, substituted as needed. 36 It is substituted as needed with 5-membered to 10-membered heteroaryls; however: x+y+z is between 6 and 10, and R 23 and R 27 If both are H, then R 24 C 7~12 Cycloalkyl, C 2~6 Alkenil, C 2~6 Alkinyl, C 1~6 Hydroxyalkyl, C 1~6 Heteroalkyl, 4-membered heterocyclyl, 7-membered heterocyclyl, 7- to 12-membered monocyclic heterocyclyl, -SF5, -NR 33 R 33 , -NR 33 C(O)OR 34 , -NR 33 SO2R 34 , -NR 33 S(O)2NR 33 R 33 , -NR 33 C(O)NR 33 R 33 , Tri-C 1~4 Alkylsilyl, -C(O)R 34 , -C(O)OR 34 -C(O)NR 33 R 33 , -S(O) 0~2 R 34 -S(O)(NH)R 34-S(O)(NR 28 )R 34 -S(O)(NH)NR 33 R 33 -S(O)(NR 28 )NR 33 R 33 Selected from the group consisting of -SH and -NO2, where C 7~12 Cycloalkyl, C 2~6 Alkenil, C 2~6 Alkinyl, C 1~6 Hydroxyalkyl, C 1~6 Heteroalkyl, 4-membered heterocyclyl, 7-membered heterocyclyl, and 7- to 12-membered monocyclic heterocyclyls have one or more R 29 They are substituted as needed; 5-membered to 6-membered heterocyclines are R 37 They are substituted as needed; and 8- to 10-membered bicyclic heterocyclines have one or more R 38 It is replaced as needed; and x+y+z is 4 or 5, and R 27 If R is -H or methyl, 23 is, Haro, -CN, C 1~6 Alkyl, C 2~6 Alkenil, C 2~6 Alkinyl, C 1~6 Alkoxy, C 1~6 Hydroxyalkyl, C 1~6 Heteroalkyl, 3- to 12-membered cycloalkyl, 4- to 12-membered heterocyclyl, 6- to 10-membered aryl, 5- to 10-membered heteroaryl, -SF5, -S(O) 0~2 R 34 -S(O)(NH)R 34 -S(O)(NR 28 )R 34 -S(O)(NH)NR 33 R 33 -S(O)(NR 28 )NR 33 R 33 -SH, -NR 33 R 33 , -NR 33 SO2R 34 , -NR 33 S (O)2NR 33 R 33 、 -NR 33 C(O)NR 33 R 33 、 -NR 33 C(O)OR 34 、 tri - C 1~4 alkylsilyl, -C(O)R 34 、 -C(O)OR 34 、 -C(O)NR 33 R 33 、 -NO2, selected from the group consisting of, where C 1~6 alkyl, C 2~6 alkenyl, C 2~6 alkynyl, C 1~6 alkoxy, C 1~6 hydroxyalkyl, C 1~6 heteroalkyl, 3 - to 12 - member cycloalkyl, 4 - to 12 - member heterocyclyl, 6 - to 10 - member aryl, 5 - to 10 - member heteroaryl may be further substituted with one or more R 29 groups as necessary; where R 37 is -OH, oxo, -CN, C 2~6 alkenyl, C 2~6 alkynyl, C 1~6 hydroxyalkyl, C 1~6 heteroalkyl, 3 - to 12 - member cycloalkyl, 4 - to 12 - member heterocyclyl, 6 - to 10 - member aryl, 5 - to 10 - member heteroaryl, -S(O) 0~2 R 34 、 -NR 33 SO2R 34 、 -NR 33 S(O)2NR 33 R 33 、 -NR 33 C(O)NR 33 R 33 、 -NR 33 C(O)OR 34 、 -C(O)R 34 、 -C(O)OR 34 and -C(O)NR 33 R 33 selected from; and R 38 is C 2~6 alkenyl, C 2~6Alkinyl, C 1~6 Alkoxy, C 1~6 Haloalkoxy, C 1~6 Hydroxyalkyl, C 1~6 Heteroalkyl, 3- to 12-membered cycloalkyl, 4- to 12-membered heterocyclyl, 6- to 10-membered aryl, 5- to 10-membered heteroaryl, -S(O) 0~2 R 34 , -NR 33 R 33 , -NR 33 SO2R 34 , -NR 33 S(O)2NR 33 R 33 , -NR 33 C(O)NR 33 R 33 , -NR 33 C(O)OR 34 , -C(O)R 34 , -C(O)OR 34 and -C(O)NR 33 R 33 Selected from.

[0023] In some embodiments, Q is -S(O)2-, -S(O)-, and -S(O)(NR 28 Selected from the group consisting of )-.

[0024] In some embodiments, R 21 C 1~6 Alkyl, -NR 33 R 33 , 6-10 member aryl, 5-10 member heteroaryl, C 3~12 Selected from the group consisting of cycloalkyls and 4- to 12-membered heterocyclines, where C 1~6 Alkyl, 6- to 10-membered aryl, 5- to 10-membered heteroaryl, C 3~12 Each of the cycloalkyl and 4- to 12-membered heterocyclyls has one or more R 31 It is further substituted with the base.

[0025] In some embodiments, R 22 -H, -CN, -F, methyl, C1 haloalkyl, C1~3 It is selected from the group consisting of heteroalkyl, methoxy, and C1 haloalkoxy.

[0026] In some embodiments, R 22 is selected from the group consisting of -H, -CN, -F, - and methyl.

[0027] In some embodiments, R 24 is -H, halo, -OH, -CN, C 1~6 alkyl, C 1~6 alkoxy, C 1~6 hydroxyalkyl, C 1~6 heteroalkyl, -SF5, -S(O) 0~2 R 34 , -S(O)(NH)R 34 , -S(O)(NR 28 )R 34 , -S(O)(NH)NR 33 R 33 , -S(O)(NR 28 )NR 33 R 33 , -NR 33 R 33 , -NR 33 SO2R 34 , -NR 33 S(O)2NR 33 R 33 , -NR 33 C(O)NR 33 R 33 , -NR 33 C(O)OR 34 , -C(O)R 34 , -C(O)OR 34 , -C(O)NR 33 R 33 , -NO2, where C 1~6 alkyl, C 1~6 alkoxy, C 1~6 hydroxyalkyl, C 1~6 heteroalkyl is further substituted with one or more R 29 groups.

[0028] In some embodiments, R 24-H, -F, -Cl, -OH, -CN, S(O) 0~2 R 34 , -C(O)R 34 -NO2, -SF5, C 1~6 Alkyl, and C 1~6 Selected from the group consisting of alkoxys, and here this C 1~6 Alkyl or C 1~6 The alkoxy is substituted as needed with one or more -F atoms, and R 34 C 1~6 Alkyl, C 3~6 Cycloalkyl, C 1~6 Hydroxyalkyl, C 1~6 Selected from the group consisting of heteroalkyl groups, where this C 1~6 Alkyl, C 3~6 Cycloalkyl, C 1~6 Hydroxyalkyl, and C 1~6 Heteroalkyl groups have one or more R 36 It is substituted as needed in the base, and R 36 These are independently selected from halo, -CN, and -OH.

[0029] In some embodiments, R 24 -H, -F, -Cl, -OH, -CN, -SR 34 , -SF5, C 1~6 Alkyl, and C 1~6 Selected from the group consisting of alkoxys, and here this C 1~6 Alkyl or C 1~6 The alkoxy is substituted as needed with one or more -F atoms, and R 34 C 1~3 Selected from the group consisting of haloalkyls.

[0030] In some embodiments, R 23 -H, halo, -OH, -CN, C 1~6 Alkyl, C 1~6 Alkyl, 6-10 membered aryl, 5-10 membered heteroaryl, 4-12 membered heterocyclyl, 3-12 membered cycloalkyl, C1~6 Hydroxyalkyl, C 1~6 Heteroalkyl, -S(O) 0~2 R 34 Selected from the group consisting of -NO2 and -SF5, here this C 1~6 Alkyl, C 1~6 Alkoxy, C 1~6 Hydroxyalkyl, C 1~6 Heteroalkyls, 6- to 10-membered aryls, 5- to 10-membered heteroaryls, 4- to 12-membered heterocyclyls, and 3- to 12-membered cycloalkyls have one or more R 36 The base is further substituted as needed.

[0031] In some embodiments, R 23 -H, -F, -Cl, -OH, -CN, C 1~6 Alkyl, C 1~6 Alkoxy, C 1~6 Hydroxyalkyl, C 1~6 Heteroalkyl, -SR 34 Selected from the group consisting of , and -SF5, where this C 1~6 Alkyl, C 1~6 Alkoxy, C 1~6 Hydroxyalkyl, and C 1~6 Heteroalkyl groups have one or more R 36 It is further substituted with R 34 is C 1~3 It is a haloalkyl group.

[0032] In another embodiment of this disclosure, Formula III: [ka] Compounds of or pharmaceutically acceptable salts thereof, stereoisomers, mixtures of stereoisomers, tautomers, or deuterated analogs of the compound in formula III: Q is -S(O)2-, -S(O)-, -S(O)(NH)-, -S(O)(NR 48 Selected from the group consisting of )-. R 41 C 1~6 Alkyl, C2~6 Alkenil, C 2~6 Alkinyl, -NR 53 R 53 , 6-10 member aryl, 5-10 member heteroaryl, C 3~12 Selected from the group consisting of cycloalkyls and 4- to 12-membered heterocyclines, where C 1~6 Alkyl, C 2~6 Alkenil, C 2~6 Alkinyl, 6- to 10-membered aryl, 5- to 10-membered heteroaryl, C 3~12 Each of the cycloalkyl and 4- to 12-membered heterocyclyls has one or more R 51 The base is further substituted as needed; R 51 is hydroxyl, oxo, halo, -CN, C 1~6 Alkyl, C 2~6 Alkenil, C 2~6 Alkinyl, C 1~6 Alkoxy, C 1~6 Hydroxyalkyl, C 1~6 Heteroalkyl, 3- to 12-membered cycloalkyl, 4- to 12-membered heterocyclyl, 6- to 10-membered aryl, 5- to 10-membered heteroaryl, -P(O)R 54 R 54 -S(O)(NH)R 54 -S(O)(NR 48 )R 54 -S(O)(NH)NR 53 R 53 -S(O)(NR 48 )NR 53 R 53 , -S(O) 0~2 R 54 , -S(O) 1~2 NR 53 R 53 -SF5, -NO2, -NR 53 R 53 , -NR 53 SO2R 54 -OS(O)2R 54 , -C(O)OR 54 , -C(O)R 54 , -NR 53 C(O)OR 54 , -NR 53C(O)NR 53 R 53 , -NR 53 S(O)2NR 53 R 53 , and -C(O)NR 53 R 53 A group consisting of C is selected, where C 1~6 Alkyl, C 2~6 Alkenil, C 2~6 Alkinyl, C 1~6 Alkoxy, C 1~6 Hydroxyalkyl, C 1~6 Each of the heteroalkyl, 3- to 12-membered cycloalkyl, 4- to 12-membered heterocyclyl, 6- to 10-membered aryl, and 5- to 10-membered heteroaryl compounds contains one or more R 49 Substituted as needed in the base; Each R 49 These are independently -H, oxo, -OH, -CN, halo, and C. 1~6 Alkyl, C 1~6 Alkoxy, C 1~6 Hydroxyalkyl, C 1~6 Heteroalkyl, 3- to 12-membered cycloalkyl, 4- to 12-membered heterocyclyl, 6- to 10-membered aryl, 5- to 10-membered heteroaryl, -NR 53 R 53 , -NR 53 C(O)OR 54 -OS(O)2R 54 -C(O)OR 54 -S(O)(NH)R 54 -S(O)(NR 48 )R 54 -S(O)(NH)NR 53 R 53 -S(O)(NR 48 )NR 53 R 53 , -S(O) 0~2 R 54 , -S(O) 1~2 NR 53 R 53 -C(O)NR 53 R 53 , -NR 53 SO2R 54 , -C(O)R 54 , -NR53 C(O)NR 53 R 53 , -NR 53 S(O)2NR 53 R 53 Selected from the group consisting of -SF5 and -NO2, where C 1~6 Alkyl, C 1~6 Alkoxy, C 1~6 Hydroxyalkyl, C 1~6 Each of the heteroalkyl, 3- to 12-membered cycloalkyl, 4- to 12-membered heterocyclyl, 6- to 10-membered aryl, and 5- to 10-membered heteroaryl compounds is R 56 It is replaced as needed; Each R 53 These are independently -H, C 1~6 Alkyl, C 1~6 Hydroxyalkyl, C 1~6 Heteroalkyl, C 3~6 Selected from the group consisting of cycloalkyl, 6- to 10-membered aryl, 4- to 12-membered heterocyclyl, and 5- to 10-membered heteroaryl, where this C 1~6 Alkyl, C 1~6 Hydroxyalkyl, C 1~6 Heteroalkyl, 3- to 6-membered cycloalkyl, 4- to 12-membered heterocyclyl, 6- to 10-membered aryl, and 5- to 10-membered heteroaryl contain one or more R 55 Substituted as needed in the base; Each R 54 C 1~6 Alkyl, C 1~6 Hydroxyalkyl, C 1~6 Heteroalkyl, C 3~6 Selected from the group consisting of cycloalkyl, 6- to 10-membered aryl, 4- to 12-membered heterocyclyl, and 5- to 10-membered heteroaryl, where this C 1~6 Alkyl, C 1~6 Hydroxyalkyl, C 1~6 Heteroalkyl, 3- to 6-membered cycloalkyl, 4- to 12-membered heterocyclyl, 6- to 10-membered aryl, and 5- to 10-membered heteroaryl contain one or more R 55 Substituted as needed in the base; Each R 55These are independently -H, halo, -CN, -OH, oxo, -NO2, -SF5, C 1~6 Alkyl, C 1~6 Haloalkyl, C 1~6 Alkoxy, C 1~6 Haloalkoxy, C 1~6 Hydroxyalkyl, C 1~6 Heteroalkyl, 3- to 12-membered cycloalkyl, 4- to 12-membered heterocyclyl, 6- to 10-membered aryl, 5- to 10-membered heteroaryl, -S(O)(NH)R 56 -S(O)(NR 48 )R 56 -S(O)(NH)NR 56 R 56 -S(O)(NR 48 )NR 56 R 56 , -S(O) 0~2 R 56 , -S(O)2NH2, -NH2, -S(O)2NR 56 R 56 , C(O)R 56 -C(O)NR 56 R 56 and C(O)OR 56 Selected from, where 3- to 6-membered cycloalkyl, 4- to 12-membered heterocyclyl, 6- to 10-membered aryl, and 5- to 10-membered heteroaryl, one or more R 56 Substituted as needed in the base; Each R 56 These are independently: halo, -CN, -OH, -NH2, oxo, -NO2, -SF5, C 1~3 Alkyl, C 1~3 Haloalkyl, C 1~6 Alkoxy, C 1~6 Hello Arco Kishi, C 1~6 Selected from hydroxyalkyl, thiohaloalkyl, sulfonylalkyl, sulfonylhaloalkyl, sulfonylcycloalkyl, 3-membered to 6-membered cycloalkyl, -C(O)NH2 and -S(O)2NH2; R 42 -H, -CN, -F, -Cl, C 1~3 Alkyl, C 1~3 Haloalkyl, C 1~3Heteroalkyl, C 1~3 Alkoxy and C 1~3 Selected from the group consisting of haloalkoxys; R 43 and R 44 Each of these is independently -H, halo, -OH, -CN, C 1~6 Alkyl, C 2~6 Alkenil, C 2~6 Alkinyl, C 1~6 Alkoxy, C 1~6 Hydroxyalkyl, C 1~6 Heteroalkyl, 3- to 12-membered cycloalkyl, 4- to 12-membered heterocyclyl, 6- to 10-membered aryl, 5- to 10-membered heteroaryl, -SF5, -S(O) 0~2 R 54 -S(O)(NH)R 54 -S(O)(NR 48 )R 54 -S(O)(NH)NR 53 R 53 -S(O)(NR 48 )NR 53 R 53 -SH, -S(O) 1~2 NR 53 R 53 , -NR 53 R 53 , -NR 53 SO2R 54 , -NR 53 S(O)2NR 53 R 353 , -NR 53 C(O)NR 53 R 53 , -NR 53 C(O)OR 54 , Tri-C 1~4 Alkylsilyl, -C(O)R 54 , -C(O)OR 54 -C(O)NR 53 R 53 Selected from the group consisting of , -NO2, where C 1~6 Alkyl, C 2~6 Alkenil, C 2~6 Alkinyl, C 1~6 Alkoxy, C 1~6 Hydroxyalkyl, C 1~6Heteroalkyl, 3- to 12-membered cycloalkyl, 4- to 12-membered heterocyclyl, 6- to 10-membered aryl, and 5- to 10-membered heteroaryl contain one or more R 49 The base is further substituted as needed; Here R 42 and R 43 , or R 43 and R 44 These can, as needed, bond with the atom to which they are bonded to form a 5- to 6-membered cycloalkyl, 5- to 6-membered heterocyclyl, phenyl, or 5- to 6-membered heteroaryl, each such cyclic group being condensed with the phenyl to which it is bonded, and each having one or more R 49 Substituted as needed in the base; R 47 -H, Halo, -CN, -OH, C 1~6 Alkyl, C 2~6 Alkenil, C 2~6 Alkinyl, Tri-C 1~4 Alkylsilyl, C 1~6 Alkoxy, C 1~6 Hydroxyalkyl, C 1~6 Heteroalkyl, 3-membered to 12-membered cycloalkyl, -S(O) 0~2 R 54 -S(O)(NH)R 54 -S(O)(NR 48 )R 54 -S(O)(NH)NR 53 R 53 -S(O)(NR 48 )NR 53 R 53 -SH, -NR 53 R 53 ,-P(O)R 54 R 54 -C(O)OH, -C(O)OR 54 -C(O)NR 53 R 53 -S(O)2NR 53 R 53 , -C(O)R 54Selected from the group consisting of 6- to 10-membered aryls, 5- to 10-membered heteroaryls, and 4- to 12-membered heterocyclines; here, these 4- to 12-membered heterocyclines, 6- to 10-membered aryls, 5- to 10-membered heteroaryls, C 1~6 Alkyl, C 2~6 Alkenil, C 2~6 Alkinyl, Tri-C 1~4 Alkylsilyl, C 1~6 Alkoxy, C 1~6 Hydroxyalkyl, C 1~6 Each of the heteroalkyl and 3- to 12-membered cycloalkyl groups has one or more R 55 It is replaced as needed; R 48 C 1~6 Alkyl, -C(O)R 54 , 3-membered to 12-membered cycloalkyl, C 1~6 Heteroalkyl, 6-10 membered aryl, 5-10 membered heteroaryl, 4-12 membered heterocyclyl, C(O)OR 54 , C(O)NR 53 R 53 , and SO2R 54 And here C 1~6 Alkyl, C 1~6 Alkylcarbonyl, 3-membered to 12-membered cycloalkyl, C 1~6 Each of the heteroalkyl, 6- to 10-membered aryl, 5- to 10-membered heteroaryl, and 4- to 12-membered heterocyclyl is a halo, -CN, oxo, hydroxyl, C 1~6 Alkyl, C 1~6 Alkoxy, -S(O) 1~2 R 54 -S(O)2NR 53 R 53 -NO2, -SF5, C 1~6 Haloalkyl, C 1~6 Haloalkoxy, C 1~6 Hydroxyalkyl, -NR 53 R 53 , -C(O)OR 54 , C 1~6 Heteroalkyl, R 56 3- to 6-membered cycloalkyl groups, one or more R groups, substituted as needed. 564- to 12-membered heterocyclines, substituted as needed, one or more R 56 6- to 10-membered aryls as needed, and one or more Many R 56 It is substituted as needed with 5-membered to 10-membered heteroaryls; however: R 43 and R 47 If both are H, then R 44 C 7~12 Cycloalkyl, C 2~6 Alkenil, C 2~6 Alkinyl, C 1~6 Hydroxyalkyl, C 1~6 Heteroalkyl, 4-membered heterocyclyl, 7-membered heterocyclyl, 7- to 12-membered monocyclic heterocyclyl, -SF5, -NR 53 R 53 , -NR 53 C(O)OR 54 , -NR 53 SO2R 54 , -NR 53 S(O)2NR 53 R 53 , -NR 53 C(O)NR 53 R 53 , Tri-C 1~4 Alkylsilyl, -C(O)R 54 , -C(O)OR 54 -C(O)NR 53 R 53 , -S(O) 0~2 R 54 -S(O)(NH)R 54 -S(O)(NR 8 )R 54 -S(O)(NH)NR 53 R 53 -S(O)(NR 8 )NR 53 R 53 Selected from the group consisting of -SH and -NO2, where C 7~12 Cycloalkyl, C 2~6 Alkenil, C 2~6 Alkinyl, C 1~6 Hydroxyalkyl, C1~6 Heteroalkyl, 4-membered heterocyclyl, 7-membered heterocyclyl, and 7- to 12-membered monocyclic heterocyclyls have one or more R 49 They are substituted as needed; 5-membered to 6-membered heterocyclines are R 57 They are substituted as needed; and 8- to 10-membered bicyclic heterocyclines have one or more R 58 It is replaced as needed; Here R 57 -OH, oxo, -CN, C 2~6 Alkenil, C 2~6 Alkinyl, C 1~6 Hydroxyalkyl, C 1~6 Heteroalkyl, 3- to 12-membered cycloalkyl, 4- to 12-membered heterocyclyl, 6- to 10-membered aryl, 5- to 10-membered heteroaryl, -S(O) 0~2 R 54 , -NR 53 SO2R 54 , -NR 53 S(O)2NR 53 R 53 , -NR 53 C(O)NR 53 R 53 , -NR 53 C(O)OR 54 , -C(O)R 54 , -C(O)OR 54 and -C(O)NR 53 R 53 Selected from. And R 58 C 2~6 Alkenil, C 2~6 Alkinyl, C 1~6 Alkoxy, C 1~6 Haloalkoxy, C 1~6 Hydroxyalkyl, C 1~6 Heteroalkyl, 3- to 12-membered cycloalkyl, 4- to 12-membered heterocyclyl, 6- to 10-membered aryl, 5- to 10-membered heteroaryl, -S(O) 0~2 R 54 , -NR 53 R 53 , -NR 53 SO2R 54 , -NR53 S(O)2NR 53 R 53 , -NR 53 C(O)NR 53 R 53 , -NR 53 C(O)OR 54 , -C(O)R 54 , -C(O)OR 54 and -C(O)NR 53 R 53 Selected from.

[0033] In some embodiments, R 47 -H, Halo, -CN, -OH, C 1~6 Alkyl, C 2~6 Alkenil, C 2~6 Alkinyl, C 1~6 Alkoxy, C 1~6 Hydroxyalkyl, C 1~6 Heteroalkyl, 3-membered to 12-membered cycloalkyl, -S(O) 0~2 R 54 -S(O)(NH)R 54 -S(O)(NR 48 )R 54 -S(O)(NH)NR 53 R 53 -S(O)(NR 48 )NR 53 R 53 , -NR 53 R 53 -C(O)OH, -C(O)OR 54 -C(O)NR 53 R 53 -S(O)2NR 53 R 53 , -C(O)R 54 Selected from the group consisting of 6- to 10-membered aryls, 5- to 10-membered heteroaryls, and 4- to 12-membered heterocyclines; here, these 4- to 12-membered heterocyclines, 6- to 10-membered aryls, 5- to 10-membered heteroaryls, C 1~6 Alkyl, C 2~6 Alkenil, C 2~6 Alkinyl, C 1~6 Alkoxy, C 1~6 Hydroxyalkyl, C 1~6Each of the heteroalkyl and 3- to 12-membered cycloalkyl groups has one or more R 55 It is replaced as needed.

[0034] In some embodiments, R 47 -H, Halo, -CN, -OH, C 1~6 Alkyl, C 2~6 Alkinyl, C 1~6 Alkoxy, C 1~6 Hydroxyalkyl, C 1~6 Heteroalkyl, 3-membered to 6-membered cycloalkyl, -S(O) 0~2 R 54 -C(O)OH, -C(O)OR 54 -C(O)NR 53 R 53 -S(O)2NR 53 R 53 , -C(O)R 54 Selected from the group consisting of 6- to 10-membered aryls, 5- to 10-membered heteroaryls, and 4- to 12-membered heterocyclines; here, these 4- to 12-membered heterocyclines, 6- to 10-membered aryl, 5- to 10-membered heteroaryl, C 1~6 Alkyl, C 2~6 Alkinyl, C 1~6 Alkoxy, C 1~6 Hydroxyalkyl, C 1~6 Each of the heteroalkyl and 3- to 6-membered cycloalkyl groups has one or more R 56 It is replaced as needed.

[0035] In some embodiments, R 47 -H, Halo, -CN, -OH, C 1~3 Alkyl, C 1~3 Alkoxy, C 1~3 Hydroxyalkyl, C 1~6 Selected from the group consisting of heteroalkyls and 6- to 10-membered aryls, where these 6- to 10-membered aryls, C 1~3 Alkyl, C 1~3 Alkoxy, C 1~3 Hydroxyalkyl, and C 1~6Each heteroalkyl group contains one or more R 56 And it is replaced as needed, and here R 56 is Halo, -CN, -NO2, -SF5, C 1~3 Alkyl, C 1~3 Haloalkyl, C 1~6 Alkoxy, C 1~6 Selected from haloalkoxy, thiohaloalkyl, sulfonylalkyl, sulfonylhalalkyl, and sulfonylcycloalkyl; In some embodiments, Q is -S(O)2-, -S(O)-, and -S(O)(NR 48 Selected from the group consisting of )-.

[0036] In some embodiments, R 41 C 1~6 Alkyl, -NR 53 R 53 , 6-10 member aryl, 5-10 member heteroaryl, C 3~12 Selected from the group consisting of cycloalkyls and 4- to 12-membered heterocyclines, where C 1~6 Alkyl, 6- to 10-membered aryl, 5- to 10-membered heteroaryl, C 3~12 Each of the cycloalkyl and 4- to 12-membered heterocyclines may further contain one or more R 51 It is replaced as needed in the base.

[0037] In some embodiments, R 51 is hydroxyl, oxo, halo, -CN, C 1~6 Alkyl, C 1~6 Alkoxy, C 1~6 Hydroxyalkyl, C 1~6 Heteroalkyl, 3- to 6-membered cycloalkyl, 4- to 12-membered heterocyclyl, 6- to 10-membered aryl, 5- to 10-membered heteroaryl, -S(O)(NH)R 54 -S(O)(NR 48 )R 54 -S(O)(NH)NR 53 R 53 -S(O)(NR 48 )NR 53 R53 , -S(O) 0~2 R 54 , -S(O) 1~2 NR 53 R 53 -SF5, -NO2, -NR 53 R 53 , -NR 53 SO2R 54 , -C(O)OR 54 , -C(O)R 54 , -NR 53 C(O)OR 54 , and -C(O)NR 53 R 53 A group consisting of C is selected, where C 1~6 Alkyl, C 1~6 Alkoxy, C 1~6 Hydroxyalkyl, C 1~6 Each of the heteroalkyl, 3- to 6-membered cycloalkyl, 4- to 12-membered heterocyclyl, 6- to 10-membered aryl, and 5- to 10-membered heteroaryl compounds contains one or more R 49 It is replaced as needed in the base.

[0038] In some embodiments, each R 49 These are independently -H, oxo, -OH, -CN, halo, and C. 1~3 Alkyl, C 1~3 Alkoxy, C 1~6 Hydroxyalkyl, C 1~6 Heteroalkyl, 3-membered to 6-membered cycloalkyl, -NR 53 R 53 , -C(O)OR 54 , -S(O) 0~2 R 54 , -S(O) 1~2 NR 53 R 53 -C(O)NR 53 R 53 , -NR 53 SO2R 54 , -C(O)R 54 Selected from the group consisting of -SF5 and -NO2, where C 1~3 Alkyl, C 1~3Each alkoxy and 3- to 6-membered cycloalkyl group may have -CN, one or more halos, or C 1~6 Heteroalkyl substitutions are used as needed.

[0039] In some embodiments, R 42 -H, -CN, -F, methyl, C1 haloalkyl, C 1~3 Selected from the group consisting of heteroalkyl, methoxy, and C1-haloalkoxy.

[0040] In some embodiments, R 42 The group is selected from the group consisting of -H and -F.

[0041] In some embodiments, R 44 -H, halo, -OH, -CN, C 1~6 Alkyl, C 1~6 Alkoxy, C 1~6 Hydroxyalkyl, C 1~6 Heteroalkyl, -SF5, -S(O) 0~2 R 54 -S(O)(NH)R 54 -S(O)(NR 48 )R 54 -S(O)(NH)NR 53 R 53 -S(O)(NR 48 )NR 53 R 53 , -NR 53 R 53 , -NR 53 SO2R 54 , -NR 53 S(O)2NR 53 R 53 , -NR 53 C(O)NR 53 R 53 , -NR 53 C(O)OR 54 , -C(O)R 54 , -C(O)OR 54 -C(O)NR 53 R 53 Selected from the group consisting of , -NO2, where C 1~6 Alkyl, C 1~6Alkoxy, C 1~6 Hydroxyalkyl, C 1~6 Heteroalkyl groups have one or more R 49 It is further substituted with the base.

[0042] In some embodiments, R 44 -H, -F, -Cl, -OH, -CN, -S(O) 0~2 R 54 -NO2, -SF5, C 1~6 Alkyl, and C 1~6 Selected from the group consisting of alkoxys, and here this C 1~6 Alkyl or C 1~6 The alkoxy is substituted as needed with one or more -F atoms, and R 54 C 1~6 Alkyl, C 1~6 Hydroxyalkyl, C 1~6 Selected from the group consisting of heteroalkyl groups, where this C 1~6 Alkyl, C 1~6 Hydroxyalkyl, and C 1~6 Heteroalkyl groups have one or more R 55 It is substituted as needed in the base, and R 55 The ion is independently selected from halo, -CN, -OH, and oxo.

[0043] In some embodiments, R 44 -H, -F, -Cl, -OH, -CN, -SR 54 , -SF5, C 1~6 Alkyl, and C 1~6 Selected from the group consisting of alkoxys, and here this C 1~6 Alkyl or C 1~6 The alkoxy is substituted as needed with one or more -F atoms, and R 54 is C 1~3 It is a haloalkyl group.

[0044] In some embodiments, R 43 -H, halo, -OH, -CN, C 1~6 Alkyl, C1~6 Alkoxy, C 1~6 Hydroxyalkyl, C 1~6 Heteroalkyl, C 3~12 Cycloalkyl, 4- to 12-membered heterocyclyl, 6- to 10-membered aryl, 5- to 10-membered heteroaryl, -SF5, -S(O) 0~2 R 54 -S(O)(NH)R 54 -S(O)(NR 48 )R 54 -S(O)(NH)NR 53 R 53 -S(O)(NR 48 )NR 53 R 53 , -NR 53 R 53 , -NR 53 SO2R 54 , -NR 53 S(O)2NR 53 R 53 , -NR 53 C(O)NR 53 R 53 , -NR 53 C(O)OR 54 , -C(O)R 54 , -C(O)OR 54 -C(O)NR 53 R 53 Selected from the group consisting of , and -NO2, where C 1~6 Alkyl, C 1~6 Alkoxy, C 1~6 Hydroxyalkyl, C 1~6 Heteroalkyl, C 3~12 Cycloalkyls, 4- to 12-membered heterocyclines, 6- to 10-membered aryls, and 5- to 10-membered heteroaryls have one or more R 49 It is further substituted with the base.

[0045] In some embodiments, R 49 -H, oxo, -OH, -CN, halo, C 1~3 Alkyl, C 1~3 Alkoxy, C 1~6 Hydroxyalkyl, C 1~6 Heteroalkyl, 3-membered to 6-membered cycloalkyl, -NR53 R 53 , -C(O)OR 54 , -S(O) 0~2 R 54 , -S(O) 1~2 NR 53 R 53 -C(O)NR 53 R 53 , -C(O)R 54 A group consisting of C is selected, where C 1~3 Alkyl, C 1~3 Alkoxy, C 1~6 Hydroxyalkyl, C 1~6 Each of the heteroalkyl and 3- to 6-membered cycloalkyl groups is substituted as needed with -CN or one or more halos.

[0046] In some embodiments, R 43 -H, Halo, -CN, C 1~3 Alkyl, C 1~3 Alkoxy, C 1~3 Hydroxyalkyl, C 1~6 Heteroalkyl, C 3~6 Cycloalkyl, 4- to 6-membered heterocyclyl, 5- to 10-membered heteroaryl, -SF5, - S(O) 0~2 R 54 Selected from the group consisting of , and -NO2, where C 1~3 Alkyl, C 1~3 Alkoxy, C 1~3 Hydroxyalkyl, C 1~6 Heteroalkyl, C 3~6 Cycloalkyls, 4- to 6-membered heterocyclines, and 5- to 10-membered heteroaryls have one or more R 49 It is further substituted with the base.

[0047] In some embodiments, R 49 -H, oxo, -OH, -CN, halo, C 1~3 Alkyl, C 1~3 Alkoxy, C 1~3 Hydroxyalkyl, C 1~6 Heteroalkyl, 3-membered to 6-membered cycloalkyl, -C(O)OR54 , -S(O) 0~2 R 54 , -S(O) 1~2 NR 53 R 53 , -C(O)R 54 A group consisting of C is selected, where C 1~3 Alkyl, C 1~3 Alkoxy, C 1~3 Hydroxyalkyl, C 1~6 Each of the heteroalkyl and 3- to 6-membered cycloalkyl groups is substituted as needed with -CN or one or more halos.

[0048] In another embodiment of this disclosure, Formula IV: [ka] Compounds of the same or pharmaceutically acceptable salts thereof, stereoisomers, mixtures of stereoisomers, tautomers, or deuterated analogs are provided, in formula IV: Q is -S(O)2-, -S(O)-, -S(O)(NH)-, -S(O)(NR 68 Selected from the group consisting of )-; R 61 C 1~6 Alkyl, C 2~6 Alkenil, C 2~6 Alkinyl, -NR 73 R 73 , 6-10 member aryl, 5-10 member heteroaryl, C 3~12 Selected from the group consisting of cycloalkyls and 4- to 12-membered heterocyclines, where C 1~6 Alkyl, C 2~6 Alkenil, C 2~6 Alkinyl, 6- to 10-membered aryl, 5- to 10-membered heteroaryl, C 3~12 Each of the cycloalkyl and 4- to 12-membered heterocyclyls has one or more R 71 The base is further substituted as needed; R 71 is hydroxyl, oxo, halo, -CN, C 1~6 Alkyl, C 2~6 Alkenil, C2~6 Alkinyl, C 1~6 Alkoxy, C 1~6 Hydroxyalkyl, C 1~6 Heteroalkyl, 3- to 12-membered cycloalkyl, 4- to 12-membered heterocyclyl, 6- to 10-membered aryl, 5- to 10-membered heteroaryl, -P(O)R 74 R 74 -S(O)(NH)R 74 -S(O)(NR 68 )R 74 -S(O)(NH)NR 73 R 73 -S(O)(NR 68 )NR 73 R 73 -SH, -S(O) 0~2 R 74 , -S(O) 1~2 NR 73 R 73 -SF5, -NO2, -NR 73 R 73 , -NR 73 SO2R 74 -OS(O)2R 74 , -C(O)OR 74 , -C(O)R 74 , -NR 73 C(O)OR 74 , -NR 73 C(O)NR 73 R 73 , -NR 73 S(O)2NR 73 R 73 , and -C(O)NR 73 R 73 A group consisting of C is selected, where C 1~6 Alkyl, C 2~6 Alkenil, C 2~6 Alkinyl, C 1~6 Alkoxy, C 1~6 Hydroxyalkyl, C 1~6 Each of the heteroalkyl, 3- to 12-membered cycloalkyl, 4- to 12-membered heterocyclyl, 6- to 10-membered aryl, and 5- to 10-membered heteroaryl compounds contains one or more R 69 Substituted as needed in the base; Each R 69These are independently -H, oxo, -OH, -CN, halo, and C. 1~6 Alkyl, C 1~6 Alkoxy, C 1~6 Hydroxyalkyl, C 1~6 Heteroalkyl, 3- to 12-membered cycloalkyl, 4- to 12-membered heterocyclyl, 6- to 10-membered aryl, 5- to 10-membered heteroaryl, -NR 73 R 73 , -NR 73 C(O)OR 74 -OS(O)2R 74 -C(O)OR 74 -S(O)(NH)R 74 -S(O)(NR 68 )R 74 -S(O)(NH)NR 73 R 73 -S(O)(NR 68 )NR 73 R 73 -SH, -S(O) 0~2 R 74 , -S(O) 1~2 NR 73 R 73 -C(O)NR 73 R 73 , -NR 73 SO2R 74 , -C(O)R 74 , -NR 73 C(O)NR 73 R 73 , -NR 73 S(O)2NR 73 R 73 Selected from the group consisting of -SF5 and -NO2, where C 1~6 Alkyl, C 1~6 Alkoxy, C 1~6 Hydroxyalkyl, C 1~6 Each of the heteroalkyl, 3- to 12-membered cycloalkyl, 4- to 12-membered heterocyclyl, 6- to 10-membered aryl, and 5- to 10-membered heteroaryl compounds contains one or more R 76 Substituted as needed in the base; Each R 73 These are independently -H, C 1~6 Alkyl, C 1~6 Hydroxyalkyl, C1~6 Heteroalkyl, C 3~6 Selected from the group consisting of cycloalkyl, 6- to 10-membered aryl, 4- to 12-membered heterocyclyl, and 5- to 10-membered heteroaryl, where this C 1~6 Alkyl, C 1~6 Hydroxyalkyl, C 1~6 Heteroalkyl, 3- to 6-membered cycloalkyl, 4- to 12-membered heterocyclyl, 6- to 10-membered aryl, and 5- to 10-membered heteroaryl contain one or more R 75 Substituted as needed in the base; Each R 74 C 1~6 Alkyl, C 1~6 Hydroxyalkyl, C 1~6 Heteroalkyl, C 3~6 Selected from the group consisting of cycloalkyl, 6- to 10-membered aryl, 4- to 12-membered heterocyclyl, and 5- to 10-membered heteroaryl, where this C 1~6 Alkyl, C 1~6 Hydroxyalkyl, C 1~6 Heteroalkyl, 3- to 6-membered cycloalkyl, 4- to 12-membered heterocyclyl, 6- to 10-membered aryl, and 5- to 10-membered heteroaryl contain one or more R 75 Substituted as needed in the base; Each R 75 These are independently -H, halo, -CN, -OH, oxo, -NO2, -SF5, C 1~6 Alkyl, C 1~6 Haloalkyl, C 1~6 Alkoxy, C 1~6 Haloalkoxy, C 1~6 Hydroxyalkyl, C 1~6 Heteroalkyl, 3- to 12-membered cycloalkyl, 4- to 12-membered heterocyclyl, 6- to 10-membered aryl, 5- to 10-membered heteroaryl, -S(O)(NH)R 66 -S(O)(NR 68 )R 66 -S(O)(NH)NR 66 R 66 -S(O)(NR 68 )NR 66 R 66--SH, -S(O) 0~2 R 66 , -S(O)2NH2, -NH2, -S(O)2NR 66 R 66 , C(O)R 66 -C(O)NR6 66 R 66 and C(O)OR 66 Selected from, where 3- to 6-membered cycloalkyl, 4- to 12-membered heterocyclyl, 6- to 10-membered aryl, and 5- to 10-membered heteroaryl, one or more R 76 Substituted as needed in the base; Each R 76 These are independently: halo, -CN, -OH, -NH2, oxo, -NO2, -SF5, C 1~3 Alkyl, C 1~3 Haloalkyl, C 1~6 Alkoxy, C 1~6 Haloalkoxy, C 1~6 Selected from hydroxyalkyl, thioalkyl, thiohaloalkyl, thiocycloalkyl, sulfonylalkyl, sulfonylhaloalkyl, sulfonylcycloalkyl, 3-membered to 6-membered cycloalkyl, -C(O)NH2 and -S(O)2NH2; R 62 -H, -CN, -F, -Cl, C 1~3 Alkyl, C 1~3 Haloalkyl, C 1~3 Heteroalkyl, C 1~3 Alkoxy and C 1~3 Selected from the group consisting of haloalkoxys; R 63 and R 64 Each of these is independently -H, halo, -OH, -CN, C 1~6 Alkyl, C 2~6 Alkenil, C 2~6 Alkinyl, C 1~6 Alkoxy, C 1~6 Hydroxyalkyl, C 1~6 Heteroalkyl, 3- to 12-membered cycloalkyl, 4- to 12-membered heterocyclyl, 6- to 10-membered aryl, 5- to 10-membered heteroaryl, -SF5, -S(O) 0~2 R 74 -S(O)(NH)R74 -S(O)(NR 68 )R 74 -S(O)(NH)NR 73 R 73 -S(O)(NR 68 )NR 73 R 73 -SH, -NR 73 R 73 , -NR 73 SO2R 74 , -NR 73 S(O)2NR 73 R 73 , -NR 73 C(O)NR 73 R 73 , -NR 73 C(O)OR 74 , Tri-C 1~4 Alkylsilyl, -C(O)R 74 , -C(O)OR 74 -C(O)NR 73 R 73 A selection is made from the group consisting of and -NO2, where C 1~6 Alkyl, C 2~6 Alkenil, C 2~6 Alkinyl, C 1~6 Alkoxy, C 1~6 Hydroxyalkyl, C 1~6 Heteroalkyl, 3- to 12-membered cycloalkyl, 4- to 12-membered heterocyclyl, 6- to 10-membered aryl, and 5- to 10-membered heteroaryl contain one or more R 69 The base is further substituted as needed; Here R 62 and R 63 , or R 63 and R 64 These can, as needed, bond with the atom to which they are bonded to form a 5- to 6-membered cycloalkyl, 5- to 6-membered heterocyclyl, phenyl, or 5- to 6-membered heteroaryl, each such cyclic group being condensed with the phenyl to which it is bonded, and each having one or more R 69 Substituted as needed in the base; R 67 -H, Halo, -CN, -OH, C1~6 Alkyl, C 2~6 Alkenil, C 2~6 Alkinyl, Tri-C 1~4 Alkylsilyl, C 1~6 Alkoxy, C 1~6 Hydroxyalkyl, C 1~6 Heteroalkyl, 3-membered to 12-membered cycloalkyl, -S(O) 0~2 R 74 -S(O)(NH)R 74 -S(O)(NR 68 )R 74 -S(O)(NH)NR 73 R 73 -S(O)(NR 68 )NR 73 R 73 -SH, -NR 73 R 73 ,-P(O)R 74 R 74 -C(O)OH, -C(O)OR 74 -C(O)NR 73 R 73 -S(O)2NR 73 R 73 , -C(O)R 74 , selected from the group consisting of 6- to 10-membered aryls, 5- to 10-membered heteroaryls, and 4- to 12-membered heterocyclines; here, these 4- to 12-membered heterocyclines, 6- to 10-membered aryls, 5- to 10-membered heteroaryls, C 1~6 Alkyl, C 2~6 Alkenil, C 2~6 Alkinyl, Tri-C 1~4 Alkylsilyl, C 1~6 Alkoxy, C 1~6 Hydroxyalkyl, C 1~6 Each of the heteroalkyl and 3- to 12-membered cycloalkyl groups has one or more R 75 It is replaced as needed; R 68 C 1~6 Alkyl, -C(O)R 74 , 3-membered to 12-membered cycloalkyl, C 1~6 Heteroalkyl, 6- to 10-membered aryl, 5- to 10-membered heteroaryl, 4- to 12-membered heterocyclyl, -C(O)OR74 -C(O)NR 73 R 73 , -SO2R 74 And here C 1~6 Alkyl, C 1~6 Alkylcarbonyl, 3-membered to 12-membered cycloalkyl, C 1~6 Each of the heteroalkyl, 6- to 10-membered aryl, 5- to 10-membered heteroaryl, and 4- to 12-membered heterocyclyl is a halo, -CN, oxo, hydroxyl, C 1~6 Alkyl, C 1~6 Alkoxy, -S(O) 1~2 R 74 -S(O)2NR 73 R 73 -NO2, -SF5, C 1~6 Haloalkyl, C 1~6 Haloalkoxy, C 1~6 Hydroxyalkyl, NR 73 R 73 , -C(O)OR 74 , C 1~6 Heteroalkyl, R 76 3- to 6-membered cycloalkyl groups, one or more R groups, substituted as needed. 76 4- to 12-membered heterocyclines, substituted as needed, one or more R 76 6- to 10-membered aryls as needed, and one or more R 76 It is substituted as needed with 5-membered to 10-membered heteroaryls;

[0049] In some embodiments, Q is -S(O)2-, -S(O)-, and -S(O)(NR 68 Selected from the group consisting of )-.

[0050] In some embodiments, R 61 C 1~6 Alkyl, -NR 73 R 73 , 6-10 member aryl, 5-10 member heteroaryl, C 3~12 Selected from the group consisting of cycloalkyls and 4- to 12-membered heterocyclines, where C 1~6Alkyl, 6- to 10-membered aryl, 5- to 10-membered heteroaryl, C 3~12 Each of the cycloalkyl and 4- to 12-membered heterocyclyls has one or more R 71 It is further substituted with the base.

[0051] In some embodiments, R 62 -H, -CN, -F, methyl, C1 haloalkyl, C 1~3 Selected from the group consisting of heteroalkyl, methoxy, and C1-haloalkoxy.

[0052] In some embodiments, R 62 The is selected from the group consisting of -H and -F.

[0053] In some embodiments, R 64 -H, halo, -OH, -CN, C 1~6 Alkyl, C 1~6 Alkoxy, C 1~6 Hydroxyalkyl, C 1~6 Heteroalkyl, -SF5, -S(O) 0~2 R 74 -S(O)(NH)R 74 -S(O)(NR 68 )R 74 -S(O)(NH)NR 73 R 73 -S(O)(NR 68 )NR 73 R 73 , -NR 73 R 73 , -NR 73 SO2R 74 , -NR 73 S(O)2NR 73 R 73 , -NR 73 C(O)NR 73 R 73 , -NR 73 C(O)OR 74 , -C(O)R 74 , -C(O)OR 74 -C(O)NR 73 R 73 Selected from the group consisting of , -NO2, where C1~6 Alkyl, C 1~6 Alkoxy, C 1~6 Hydroxyalkyl, C 1~6 Heteroalkyl groups have one or more R 69 It is further substituted with the base.

[0054] In some embodiments, R 64 -H, -F, -Cl, -OH, -CN, -S(O) 0~2 R 74 -SF5, -NO2, C 1~6 Alkyl, and C 1~6 Selected from the group consisting of alkoxys, and here this C 1~6 Alkyl or C 1~6 The alkoxy is substituted with one or more -F as needed. And R 74 C 1~6 Alkyl, C 1~6 Hydroxyalkyl, C 1~6 Selected from the group consisting of heteroalkyl groups, where this C 1~6 Alkyl, C 1~6 Hydroxyalkyl, and C 1~6 Heteroalkyl groups have one or more R 75 It is substituted as needed in the base, and R 75 The ion is independently selected from halo, -CN, -OH, and oxo.

[0055] In some embodiments, R 64 -H, -F, -Cl, -OH, -CN, SR 74 , -SF5, C 1~6 Alkyl, and C 1~6 Selected from the group consisting of alkoxys, and here this C 1~6 Alkyl or C 1~6 The alkoxy is substituted as needed with one or more -F atoms, and R 74 is C 1~3 It is a haloalkyl group.

[0056] In some embodiments, R 63-H, halo, -OH, -CN, C 1~6 Alkyl, C 1~6 Alkoxy, C 1~6 Hydroxyalkyl, C 1~6 Heteroalkyl, C 3~12 Cycloalkyl, 4- to 12-membered heterocyclyl, 6- to 10-membered aryl, 5- to 10-membered heteroaryl, -SF5, -S(O) 0~2 R 74 -S(O)(NH)R 74 -S(O)(NR 68 )R 74 -S(O)(NH)NR 73 R 73 -S(O)(NR 48 )NR 73 R 73 , -NR 73 R 73 , -NR 73 SO2R 74 , -NR 73 S(O)2NR 73 R 73 , -NR 73 C(O)NR 73 R 73 , -NR 73 C(O)OR 74 , -C(O)R 74 , -C(O)OR 74 -C(O)NR 73 R 73 Selected from the group consisting of , and -NO2, where C 1~6 Alkyl, C 1~6 Alkoxy, C 1~6 Hydroxyalkyl, C 1~6 Heteroalkyl, C 3~12 Cycloalkyls, 4- to 12-membered heterocyclines, 6- to 10-membered aryls, and 5- to 10-membered heteroaryls have one or more R 69 It is further substituted with the base.

[0057] In some embodiments, R 69 -H, oxo, -OH, -CN, halo, C 1~3 Alkyl, C 1~3 Alkoxy, C 1~6 Hydroxyalkyl, C1~6 Heteroalkyl, 3-membered to 6-membered cycloalkyl, -NR 73 R 73 , -C(O)OR 74 , -S(O) 0~2 R 74 , -S(O) 1~2 NR 73 R 73 -C(O)NR 73 R 73 , -C(O)R 74 A group consisting of C is selected, where C 1~3 Alkyl, C 1~3 Alkyl, C1 ~6 Hydroxyalkyl, C 1~6 Each of the heteroalkyl and 3- to 6-membered cycloalkyl groups is substituted as needed with -CN or one or more halos.

[0058] In some embodiments, R 63 -H, Halo, -CN, C 1~3 Alkyl, C 1~3 Alkoxy, C 1~3 Hydroxyalkyl, C 1~6 Heteroalkyl, C 3~6 Cycloalkyl, 4- to 6-membered heterocyclyl, 5- to 10-membered heteroaryl, -SF5, -S(O) 0~2 R 74 Selected from the group consisting of , and -NO2, where C 1~3 Alkyl, C 1~3 Alkoxy, C 1~3 Hydroxyalkyl, C 1~6 Heteroalkyl, C 3~6 Cycloalkyls, 4- to 6-membered heterocyclines, and 5- to 10-membered heteroaryls have one or more R 69 It is further substituted with the base.

[0059] In some embodiments, R 69 -H, oxo, -OH, -CN, halo, C 1~3 Alkyl, C 1~3 Alkoxy, C 1~3 Hydroxyalkyl, C 1~6Heteroalkyl, 3-membered to 6-membered cycloalkyl, -C(O)OR 74 , -S(O) 0~2 R 74 , -S(O) 1~2 NR 73 R 73 , -C(O)R 74 A group consisting of C is selected, where C 1~3 Alkyl, C 1~3 Alkoxy, C 1~3 Hydroxyalkyl, C 1~6 Each of the heteroalkyl and 3- to 6-membered cycloalkyl groups is substituted as needed with -CN or one or more halos.

[0060] Pharmaceutical compositions are also provided that contain compounds of formulas I, II, III, and IV, or pharmaceutically acceptable salts, stereoisomers, mixtures of stereoisomers, tautomers, or deuterated analogs thereof, together with pharmaceutically acceptable excipients.

[0061] A method for treating NAFLD, NASH, ASH, or lipodystrophy is also provided, which comprises the step of administering to a patient in need an effective amount of a composition of formula I, formula II, formula III, formula IV, or a pharmaceutically acceptable salt thereof, stereoisomer, mixture of stereoisomers, tautomer, or deuterated analog thereof.

[0062] In another embodiment, R 7 However, -H, halo, -CN, -OH, C 1~6 Alkyl, C 2~6 Alkenil, C 2~6 Alkinyl, C 1~6 Alkoxy, C 1~6 Hydroxyalkyl, C 1~6 Heteroalkyl, 3-membered to 12-membered cycloalkyl, -S(O) 0~2 R 14 -S(O)(NH)R 14 -S(O)(NR 8 )R 14 -S(O)(NH)NR 13 R 13 -S(O)(NR 8 )NR13 R 13 , -NR 13 R 13 -C(O)OH, -C(O)OR 14 -C(O)NR 13 R 13 -S(O)2NR 13 R 13 , -C(O)R 14 Selected from the group consisting of 6- to 10-membered aryls, 5- to 10-membered heteroaryls, and 4- to 12-membered heterocyclines; here, these 4- to 12-membered heterocyclines, 6- to 10-membered aryls, 5- to 10-membered heteroaryls, C 1~6 Alkyl, C 2~6 Alkenil, C 2~6 Alkinyl, C 1~6 Alkoxy, C 1~6 Hydroxyalkyl, C 1~6 Each of the heteroalkyl and 3- to 12-membered cycloalkyl groups has one or more R 15 Compounds of formula I are provided, which are substituted as necessary.

[0063] In another embodiment, R 7 However, -H, halo, -CN, -OH, C 1~6 Alkyl, C 2~6 Alkinyl, C 1~6 Alkoxy, C 1~6 Hydroxyalkyl, C 1~6 Heteroalkyl, 3-membered to 6-membered cycloalkyl, -S(O) 0~2 R 14 -C(O)OH, -C(O)OR 14 -C(O)NR 13 R 13 -S(O)2NR 13 R 13 , -C(O)R 14 Selected from the group consisting of 6- to 10-membered aryls, 5- to 10-membered heteroaryls, and 4- to 12-membered heterocyclines; here, these 4- to 12-membered heterocyclines, 6- to 10-membered aryls, 5- to 10-membered heteroaryls, C 1~6 Alkyl, C 2~6 Alkinyl, C 1~6 Alkoxy, C 1~6Hydroxyalkyl, C 1~6 Each of the heteroalkyl and 3- to 6-membered cycloalkyl groups has one or more R 16 Replaced as needed A compound of formula I is provided.

[0064] In another embodiment, R 7 However, -H, halo, -CN, -OH, C 1~3 Alkyl, C 1~3 Alkoxy, C 1~3 Hydroxyalkyl, C 1~6 Selected from the group consisting of heteroalkyls and 6- to 10-membered aryls, where these 6- to 10-membered aryls, C 1~3 Alkyl, C 1~3 Alkoxy, C 1~3 Hydroxyalkyl, and C 1~6 Each heteroalkyl group contains one or more R 16 And it is replaced as needed, and here R 16 is Halo, -CN, -NO2, -SF5, C 1~3 Alkyl, C 1~3 Haloalkyl, C 1~6 Alkoxy, C 1~6 Compounds of formula I, selected from haloalkoxy, thiohaloalkyl, sulfonylalkyl, sulfonylhalalkyl, and sulfonylcycloalkyl, are provided;

[0065] In another embodiment, R 8 However, C 1~6 Alkyl, -C(O)R 14 , 3-membered to 12-membered cycloalkyl, C 1~6 Heteroalkyl, 6- to 10-membered aryl, 5- to 10-membered heteroaryl, 4- to 12-membered heterocyclyl, -C(O)OR 14 -C(O)NR 13 R 13 , and -SO2R 14 A group consisting of C is selected, where C 1~6 Alkyl, 3-membered to 12-membered cycloalkyl, C 1~6Each of the heteroalkyl, 6- to 10-membered aryl, 5- to 10-membered heteroaryl, and 4- to 12-membered heterocyclyl has one or more R 16 Compounds of formula I are provided, which are substituted as necessary.

[0066] In another embodiment, R 27 However, -H, halo, -CN, -OH, C 1~6 Alkyl, C 2~6 Alkenil, C 2~6 Alkinyl, C 1~6 Alkoxy, C 1~6 Hydroxyalkyl, C 1~6 Heteroalkyl, 3-membered to 12-membered cycloalkyl, -S(O) 0~2 R 34 -S(O)(NH)R 34 -S(O)(NR 28 )R 34 -S(O)(NH)NR 33 R 33 -S(O)(NR 28 )NR 33 R 33 , -NR 33 R 33 -C(O)OH, -C(O)OR 34 -C(O)NR 33 R 33 -S(O)2NR 33 R 33 , -C(O)R 34 Selected from the group consisting of 6- to 10-membered aryls, 5- to 10-membered heteroaryls, and 4- to 12-membered heterocyclines; here, these 4- to 12-membered heterocyclines, 6- to 10-membered aryls, 5- to 10-membered heteroaryls, C 1~6 Alkyl, C 2~6 Alkenil, C 2~6 Alkinyl, C 1~6 Alkoxy, C 1~6 Hydroxyalkyl, C 1~6 Each of the heteroalkyl and 3- to 12-membered cycloalkyl groups has one or more R 35 Compounds of formula II are provided, substituted as necessary;

[0067] In another embodiment, R 27 However, -H, halo, -CN, -OH, C 1~6 Alkyl, C 2~6 Alkinyl, C 1~6 Alkoxy, C 1~6 Hydroxyalkyl, C 1~6 Heteroalkyl, 3-membered to 6-membered cycloalkyl, -S(O) 0~2 R 34 -C(O)OH, -C(O)OR 34 -C(O)NR 33 R 33 -S(O)2NR 33 R 33 , -C(O)R 34 Selected from the group consisting of 6- to 10-membered aryls, 5- to 10-membered heteroaryls, and 4- to 12-membered heterocyclines; here, these 4- to 12-membered heterocyclines, 6- to 10-membered aryls, 5- to 10-membered heteroaryls, C 1~6 Alkyl, C 2~6 Alkinyl, C 1~6 Alkoxy, C 1~6 Hydroxyalkyl, C 1~6 Each of the heteroalkyl and 3- to 6-membered cycloalkyl groups has one or more R 36 Compounds of formula II are provided, which are substituted as necessary.

[0068] In another embodiment, R 27 However, -H, halo, -CN, -OH, C 1~3 Alkyl, C 1~3 Alkoxy, C 1~3 Hydroxyalkyl, C 1~6 Selected from the group consisting of heteroalkyls and 6- to 10-membered aryls, where 6- to 10-membered aryls, C 1~3 Alkyl, C 1~3 Alkoxy, C 1~3 Hydroxyalkyl, and C 1~6 Each heteroalkyl group contains one or more R 36 And it is replaced as needed, and here R 36 is Halo, -CN, -NO2, -SF5, C 1~3 Alkyl, C 1~3 Hello Walk Ru, C 1~6 Alkoxy, C 1~6 Compounds of formula II, selected from haloalkoxy, thiohaloalkyl, sulfonylalkyl, sulfonylhalalkyl, and sulfonylcycloalkyl, are provided;

[0069] In another embodiment, R 28 However, C 1~6 Alkyl, -C(O)R 34 , 3-membered to 12-membered cycloalkyl, C 1~6 Heteroalkyl, 6- to 10-membered aryl, 5- to 10-membered heteroaryl, 4- to 12-membered heterocyclyl, -C(O)OR 34 -C(O)NR 33 R 33 , and -SO2R 34 A group consisting of C is selected, where C 1~6 Alkyl, 3-membered to 12-membered cycloalkyl, C 1~6 Each of the heteroalkyl, 6- to 10-membered aryl, 5- to 10-membered heteroaryl, and 4- to 12-membered heterocyclyl has one or more R 36 Compounds of formula II are provided, substituted as necessary;

[0070] In another embodiment of the present invention, a method is provided for treating a patient who requires treatment of a disease or condition mediated at least partially by mitochondrial dysfunction, the method comprising administering to the patient an effective amount of a compound of a pharmaceutically acceptable composition of the present disclosure, comprising each of the individual compounds exemplified below.

[0071] In another embodiment of the present invention, a method is provided for treating a disease or condition that is treatable by mitochondrial uncoupling in a patient, the method comprising administering to the patient an effective amount of a compound of a pharmaceutical composition of the present disclosure, comprising each of the individual compounds exemplified below. [Modes for carrying out the invention]

[0072] Detailed description of the invention definition The following description outlines methods and parameters, etc. However, it should be recognized that such description is not intended to limit the scope of this disclosure and is provided as a description of exemplary embodiments.

[0073] A dash ("-") that is not between two letters or symbols is used to indicate the attachment point of a substituent. For example, -C(O)NH2 is attached via a carbon atom. Dashes before or after a chemical group are for convenience only. Chemical groups may be shown with or without one or more dashes without losing their usual meaning. A wavy line drawn across a line in a structure indicates the attachment point of a group. Direction is neither indicated nor implied by the order in which chemical groups are listed or designated, unless chemically or structurally required.

[0074] Prefix “C” u~v " indicates that the following group has u to v carbon atoms. For example, "C 1~6 The term "alkyl" indicates that the alkyl group has 1 to 6 carbon atoms.

[0075] In this specification, references to values ​​or parameters "about" include (and describe) embodiments relating to that value or parameter itself. In certain embodiments, the term "about" includes the indicated amount ± 10%. In other embodiments, the term "about" includes the indicated amount ± 5%. In certain other embodiments, the term "about" includes the indicated amount ± 1%. Also, the term "about X" includes a description of "X". Furthermore, the singular forms "a" and "the" include multiple reference objects unless the context clearly indicates otherwise. Thus, for example, a reference to "compound" includes multiple such compounds, and a reference to "assay" includes one or more assays and their equivalents known to those skilled in the art.

[0076] "Acyl" refers to the base -C(O)-.

[0077] "Alkylcarbonyl" refers to the group -C 1~6 This refers to C(O)-.

[0078] "Alkyl" refers to a straight or branched saturated hydrocarbon chain. As used herein, alkyl refers to a chain of 1 to 20 carbon atoms (i.e., C 1~20 Alkyl), 1 to 8 carbon atoms (i.e., C 1~8 Alkyl), 1 to 6 carbon atoms (i.e., C 1~6 Alkyl) or 1 to 4 carbon atoms (i.e., C 1~4 Alkyl compounds include methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, pentyl, 2-pentyl, isopentyl, neopentyl, hexyl, 2-hexyl, 3-hexyl, and 3-methylpentyl. When an alkyl residue having a specified number of carbon atoms is named by its chemical name or identified by its molecular formula, all positional isomers having that number of carbon atoms may be included. For example, "butyl" includes n-butyl (i.e., -(CH2)3CH3), sec-butyl (i.e., -CH(CH3)CH2CH3), isobutyl (i.e., -CH2CH(CH3)2), and tert-butyl (i.e., -C(CH3)3), and "propyl" includes n-propyl (i.e., -(CH2)2CH3) and isopropyl (i.e., -CH(CH3)2).

[0079] An "alkenyl" is defined as a molecule containing at least one carbon-carbon double bond and 2 to 20 carbon atoms (i.e., C 2~20 Alkenyl), 2 to 8 carbon atoms (i.e., C 2~8 Alkenyl), 2 to 6 carbon atoms (i.e., C 2~6 Alkenyls), or 2 to 4 carbon atoms (i.e., C 2~4 This refers to an alkyl group having an alkenyl group. Examples of alkenyl groups include ethenyl, propenyl, and butadienyl (including 1,2-butadienyl and 1,3-butadienyl).

[0080] "Alkynyl" refers to a compound that contains at least one carbon-carbon triple bond and 2 to 20 carbon atoms (i.e., C 2~20 Alkynyl), 2 to 8 carbon atoms (i.e., C 2~8 Alkynyl), 2 to 6 carbon atoms (i.e., C 2~6 Alkynyl) or 2 to 4 carbon atoms (i.e., C 2~4 This refers to an alkyl group having an alkynyl bond. The term "alkynyl" also includes groups having one triple bond and one double bond.

[0081] "Alkoxy" refers to the group "alkyl-O-". Examples of alkoxy groups include methoxy, ethoxy, n-propoxy, iso-propoxy, n-butoxy, tert-butoxy, sec-butoxy, n-pentoxy, n-hexoxy, and 1,2-dimethylbutoxy. As used herein, alkoxy includes cyclic hydrocarbons bonded via non-ring member oxygen. Examples include cyclopropoxy and cyclobutoxy.

[0082] It should be understood that when alkyl, alkenyl, or alkynyl groups are substituted as required, the resulting divalent (or greater than divalent) group may be named alkylene, alkenylene, or alkynylene. In this specification, for simplicity, the names "alkyl, alkenyl, and alkynyl" are presented regardless of whether the part is monovalent, divalent, or polyvalent. The same applies to all substituents in this specification that may have different names based on their valency.

[0083] A "haloalkoxy" is an alkoxy group defined above in which one or more hydrogen atoms are replaced by halogens.

[0084] "Thioalkyl" refers to the group "alkyl-S-".

[0085] "Thiohaloalkyl" means alkyl-S- halogen.

[0086] "Thiocycloalkyl" means the group "C3-6 cycloalkyl-S-".

[0087] "Sulfonyl alkyl" refers to the group "C 1~6 It means "alkyl-S(O)2-".

[0088] "Sulfonyl haloalkyl" refers to halogenated carbon 1~6 It means alkyl-S(O)2.

[0089] "Sulfonylcycloalkyl" means the group "C3-6 cycloalkyl-S(O)2-".

[0090] "Amino" is the base-NR y R y This refers to, and here each R y These are independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, aryl, heterocyclyl, cycloalkyl, or heteroaryl, each of which is substituted as necessary, as defined herein.

[0091] "Aryl" refers to an aromatic carbocyclic group having a single ring (e.g., monocyclic) or multiple rings including a condensed system (e.g., bicyclic or tricyclic). As used herein, aryl refers to a ring carbon atom (i.e., C) with 6 to 20 carbon atoms. 6~20 aryl), 6 to 12 carbon ring atoms (i.e., C 6~12 aryl), or 6 to 10 carbon ring atoms (i.e., C 6~10 It contains an aryl group. Examples of aryl groups include phenyl, naphthyl, fluorenyl, and anthryl. However, aryl does not encompass or overlap with heteroaryls as defined below. If one or more aryl groups are fused with a heteroaryl, the resulting ring system is a heteroaryl. If one or more aryl groups are fused with a heterocyclyl, the resulting ring system is a heterocyclyl.

[0092] "Cyano" refers to the group -CN.

[0093] "Keto" or "oxo" refers to the base element = oxygen (O).

[0094] "Carbamoyl" is the base -OC(O)NR y R z The "O-carbamoyl" group and the group-NR y C(O)OR z This refers to both the "N-carbamoyl" group and the R group, where R y and R z These are independently selected from the group consisting of hydrogen, alkyl, aryl, haloalkyl, or heteroaryl, each of which may be substituted as needed.

[0095] "Carboxyl" refers to -C(O)OH.

[0096] "Ester" means both -OC(O)R and -C(O)OR, where R is a substituent, each of which may be substituted as necessary, as defined herein.

[0097] "Cycloalkyl" refers to a saturated or partially unsaturated cyclic alkyl group having a single ring or multiple rings, including fused ring systems, bridging ring systems, and spiro ring systems. In the case of a bicyclic ring containing only hydrocarbons or substituted hydrocarbons, it is also referred to herein as a "carbon bicyclic" ring system. The term "cycloalkyl" includes a cycloalkenyl group (i.e., a cyclic group having at least one double bond). As used herein, cycloalkyl is , 3 to 20 ring carbon atoms (i.e., C 3~20 Cycloalkyl), 3 to 12 ring carbon atoms (i.e., C 3~12 Cycloalkyl, or 3 to 6 ring carbon atoms (i.e., C 3~6 It has a cycloalkyl group. Examples of cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

[0098] Examples of bicyclic hydrocarbon ring systems (or carbon bicyclic ring systems) substituents include fused rings, bridged rings, and spiro rings, such as octahydro-1H-indenyl, naphthalenyl, bicyclo[1.1.1]pentanyl, bicyclo[2.2.2]octanyl, bicyclo[2.1.1]hexanyl, bicyclo[2.2.1]heptanyl; spiro[5.2]octanyl, spiro[4.3]octanyl, and spiro[5.4]decanyl, but are not limited to these.

[0099] A tricyclic group includes a ring system consisting of three condensed, bridged, or spiro rings, and includes, for example, adamantanyl (IUPAC name: tricyclo[3.3.1.13,7]decanyl), not limited to these.

[0100] Polycyclic hydrocarbon ring substituents include systems of three or more rings, and for example, cubanyl (IUPAC system name: pentacyclo[4.2.0.0 2,5 .0 3,8 .0 4,7 Contains octanil.

[0101] The expression -S(O)(NH)- is: [ka] It is represented by -S(O)(NR 8 )-The expression is: [ka] It is represented by, where R 8 This is defined herein.

[0102] -S(O) 0~2 The expression means that oxygen is either absent or present, and if present, it means that one or two oxygen atoms may be present. For example, S(O)OR 14 , SR 14 It is synonymous with [the above].

[0103] "Halogen" or "halo" includes fluoro, chloro, bromo, and iodine. "Haloalkyl" refers to an alkyl group, as defined above, in which one or more hydrogen atoms are replaced by halogens, whether unbranched or branched. For example, if a residue is substituted with more than one halogen, this may be referred to by using a prefix corresponding to the number of halogen moieties bonded. Dihaloalkyl and trihaloalkyl are alkyl groups substituted with two ("di") or three ("tri") halo groups, which may or may not be the same halogen. Examples of haloalkyls include difluoromethyl (-CHF2) and trifluoromethyl (-CF3).

[0104] A "heteroalkyl" is a group in which one or more carbon atoms (and any associated hydrogen atoms) are independently replaced by the same or different heteroatomic groups. The term "heteroalkyl" refers to an alkyl group. The term "heteroalkyl" includes unbranched or branched saturated chains having carbon and heteroatoms. For example, one, two, or three carbon atoms can be independently replaced by the same or different heteroatomic groups. Examples of heteroatomic groups include, but are not limited to, -NR-, -O-, -S-, -S(O)-, and -S(O)2-, where R is H, alkyl, aryl, cycloalkyl, heteroalkyl, heteroaryl, or heterocyclyl, each of which can be substituted as needed. Examples of heteroalkyl groups include -CH2OCH3, -CH2SCH3, -CH2S(O)CH3, and -CH2S(O)2CH3, where R is hydrogen, alkyl, aryl, arylalkyl, heteroalkyl, or heteroaryl, each of which can be substituted as needed. As used herein, a heteroalkyl group comprises one to ten carbon atoms, one to eight carbon atoms, or one to four carbon atoms, and one to three heteroatoms, one to two heteroatoms, or one heteroatom.

[0105] "Heteroaryl" means an aromatic group having a single ring, multiple rings, or multiple fused rings, each having one or more ring heteroatoms independently selected from nitrogen, oxygen, and sulfur. As used herein, heteroaryl refers to a ring group having 1 to 20 ring carbon atoms (i.e., C 1~20 Heteroaryl), 3 to 12 ring carbon atoms (i.e., C 3~12 Heteroaryl), or 3 to 8 carbon ring atoms (i.e., C 3~8 A heteroaryl group; and independently comprising 1 to 5 heteroatoms, 1 to 4 heteroatoms, 1 to 3 ring heteroatoms, 1 to 2 ring heteroatoms, or 1 ring heteroatom selected from nitrogen, oxygen, and sulfur. Examples of heteroaryl groups include pyrimidinyl, prinyl, pyridyl, pyridadinyl, benzothiazolyl, and pyrazolyl. Examples of condensed heteroaryl rings include, but are not limited to, benzo[d]thiazolyl, quinolinyl, isoquinolinyl, benzo[b]thiophenyl, indazolyl, benzo[d]imidazolyl, pyrazolo[1,5-a]pyridinyl, and imidazo[1,5-a]pyridinyl, where the heteroaryl may be bonded via any of the rings in this condensed system. Any aromatic ring having a single ring or multiple fused rings and containing at least one heteroatom is considered a heteroaryl, regardless of its bonding to the rest of the molecule (i.e., via any one of the fused rings). Heteroaryls do not encompass and do not overlap with the aryls as defined above.

[0106] A "heterocyclyl" is a saturated or unsaturated cyclic alkyl group having one or more cyclic heteroatoms independently selected from N, NO, O, S, S(O), S(O)(NH), S(O)(NR), and S(O)2. The term "heterocyclyl" encompasses heterocycloalkenyl groups (i.e., heterocyclyl groups having at least one double bond), bicyclic heterocyclyl groups, bridging heterocyclyl groups, condensed heterocyclyl groups, and spiroheterocyclyl groups. A heterocyclyl may consist of a single ring or multiple rings, which may be condensed, bridging, or spiro. Any non-aromatic ring containing at least one heteroatom is considered a heterocyclyl, regardless of its bonding (i.e., whether bonded via carbon atoms or heteroatoms). Furthermore, the term heterocyclyl is intended to encompass any non-aromatic ring containing at least one heteroatom, regardless of its bonding to the rest of the molecule, and this ring may be fused to an aryl or heteroaryl ring. Where used herein, heterocyclyl means,

[0107] Having 4 to 20 ring atoms (i.e., 4- to 20 membered heterocyclines), 4 to 12 ring atoms (i.e., 4- to 12 membered heterocyclines), 4 to 10 ring atoms (i.e., 4- to 10 membered heterocyclines), 4 to 8 ring atoms (i.e., 4- to 8 membered heterocyclines), or 4 to 6 ring carbon atoms (i.e., 4- to 6 membered heterocyclines); A heterocyclyl group having 1 to 5 ring heteroatoms, 1 to 4 ring heteroatoms, 1 to 3 ring heteroatoms, 1 to 2 ring heteroatoms, or 1 ring heteroatom, selected from nitrogen, sulfur, or oxygen, and the bonding sites to other substituents may be via carbon or, if appropriate, via heteroatoms. A heterocyclyl may contain one or more oxo and / or thioxo groups. Examples of heterocyclyl groups include pyrrolidinyl, piperidinyl, piperadinyl oxetanyl, dioxolanyl, azetidinyl, azetidinyl, morpholinyl, thiomorpholinyl, dioxothiomorpholinyl, 4- to 7-membered sultam, 4- to 7-membered cyclic carbamates, 4- to 7-membered cyclic carbonates, 4- to 7-membered cyclic sulfides, [ka] Examples include (where J is a substituent as needed), and morpholinyl. As used herein, the term “bridged heterocyclyl” means a 4- to 10-membered cyclic moiety in which two non-adjacent atoms of the heterocyclyl are bonded to one or more (e.g., one or two) 4- to 10-membered cyclic moieties having at least one heteroatom (where each heteroatom is independently selected from nitrogen, oxygen, and sulfur). As used herein, bridged heterocyclyls encompass bicyclic and tricyclic systems. Also as used herein, the term “spiroheterocyclyl” means a cyclic system in which a 3- to 10-membered heterocyclyl has one or more further rings, where one or more of these further rings are 3- to 10-membered cycloalkyls or 3- to 10-membered heterocyclyls, and one of the atoms of this one or more further rings is also an atom of the 3- to 10-membered heterocyclyl. Non-exclusive examples of spiroheterocyclyl rings include bicyclic and tricyclic ring systems such as 2-oxa-7-azaspiro[3.5]nonanyl, 2-oxa-6-azaspiro[3.4]octanyl, and 6-oxa-1-azaspiro[3.3]heptanyl. Examples of condensed heterocyclyl rings include, but are not limited to, 1,2,3,4-tetrahydroisoquinolinyl, 1-oxo-1,2,3,4-tetrahydroisoquinolinyl, 1-oxo-1,2-dihydroisoquinolinyl, 4,5,6,7-tetrahydrothieno[2,3-c]pyridinyl, indolinyl, and isoindolinyl, where the heterocyclyl may be linked via any of the rings in the condensation system. As used herein, a bicyclic heterocyclyl group is a heterocyclyl group bonded at two points to another cyclic group, where the other cyclic group may be a heterocyclic group or a carbocyclic group.

[0108] As used herein, the term “nitrogen- or sulfur-containing heterocyclil” means a heterocyclil moiety that contains at least one nitrogen atom, at least one sulfur atom, or both a nitrogen atom and a sulfur atom within its ring structure. It should be understood that other heteroatoms, including oxygen, may be present in addition to nitrogen, sulfur, or combinations thereof. Examples of nitrogen- or sulfur-containing heterocyclils include morpholinyl, thiomorpholinyl, thiazolyl, isothiazolyl, oxazolidinone, 1,2-dithiolyl, piperidinyl, and piperazinyl.

[0109] "Hydroxy" or "hydroxyl" refers to the group -OH. "Hydroxyalkyl" refers to an alkyl group, either unbranched or branched, as defined above, in which one or more hydrogen atoms are replaced by hydroxyl groups.

[0110] "Nitro" refers to the group -NO2.

[0111] "Sulfonyl" refers to the group -S(O)2R, where R is a substituent or a defined group.

[0112] "Alkylsulfonyl" refers to the group -S(O)2R, where R is an alkyl group.

[0113] "Sulfinyl" refers to the group -S(O)R, where R is a substituent or a defined group.

[0114] "Alkyl sulfinyl" refers to the group -S(O)R, where R is an alkyl group.

[0115] A "polycyclic" ring system refers to a ring system containing more than three rings.

[0116] "Thiocyanate" - SCN.

[0117] "Thiol" refers to the group -SH.

[0118] "Thioxo" or "thione" refers to the group (=S) or (S).

[0119] Certain commonly used alternative chemical names may be used. For example, divalent groups such as divalent "alkyl" groups and divalent "aryl" groups may also be referred to as "alkylene" or "alkylenyl" groups, or "arylene" or "aryrenyl" groups, respectively. Also, unless otherwise expressly indicated, when a combination of groups is referred to as a single part herein (e.g., arylalkyl), the last group listed contains the atom to which this part is bonded to the remainder of the molecule.

[0120] The terms “as needed” or “as required” mean that the event or situation described thereafter may or may not occur, and that this description includes both cases where such event or situation occurs and cases where it does not. The term “substituted as required” means that any one or more hydrogen atoms on the specified atom or group may or may not be replaced by a non-hydrogen portion. “Substituted as required” can range from zero to the maximum number of possible substitutions, and each instance is independent. Where the term “substituted” is used, the substitution must occur at the position of the substituteable hydrogen atoms of the substituent indicated. A substitution as required may be the same as or different from a substitution (required).

[0121] If a part is "substituted as needed," and this reference is made to any common term such as "alkyl," "alkenyl," "alkynyl," "haloalkyl," "cycloalkyl," "aryl," or "heteroaryl," then this common term is (C 1~3 (Alkyl), (C 4~6 Alkyl), -O(C 1~4 (Alkyl), (C 3~10 Cycloalkyl), and O-(C 3~10These can be any antecedents that specifically describe them, such as cycloalkyl. For example, "any aryl" includes both "aryl" and "-O(aryl)," as well as examples of aryls such as phenyl or naphthyl. Similarly, the term "any heterocyclyl" includes both the term "heterocyclyl" and "O-(heterocyclyl)," as well as examples of heterocyclyls such as oxetanyl, tetrahydropyranil, morpholino, and piperidinyl. In the same manner, the term "any heteroaryl" includes the terms "heteroaryl" and "O-(heteroaryl)," as well as specific heteroaryls such as pyridine.

[0122] Some compounds exist as tautomers. Tautomers exist in equilibrium with each other. For example, amide-containing compounds may exist in equilibrium with imido acid tautomers. Regardless of which tautomers are shown, and regardless of the nature of the equilibrium between the tautomers, it is understood by the stoichiographer that these compounds encompass both amide tautomers and imido acid tautomers. Therefore, amide-containing compounds are understood to encompass their imido acid tautomers. Similarly, imido acid-containing compounds are understood to encompass their amide tautomers.

[0123] Any formula or structure given herein is also intended to represent both the unlabeled and isotope-labeled forms of the compound. An isotope-labeled compound has the structure represented by the formula given herein, except that one or more atoms are replaced by atoms having a selected atomic mass or mass number. Examples of isotopes that can be incorporated into the compounds of this disclosure are, but are not limited to, 2 H (deuterium, D), 3 H (tritium), 11 C, 13 C, 14 C, 15 N, 18 F, 31 P, 32 P, 35 S, 36 Cl and 125Includes isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine, and chlorine, such as I. Various isotope-labeled compounds of this disclosure, for example, radioactive isotopes, for example, 3 H, 13 C and 14 Compounds incorporating 1C. Such isotope-labeled compounds may be useful in metabolic studies, reaction kinetic studies, detection or imaging techniques, such as positron emission tomography (PET) or single-photon emission computed tomography (SPECT), including drug or substrate tissue distribution assays, or in patient radiotherapy.

[0124] This disclosure also includes “deuterated analogues” of compounds of formula I, in which 1 to n hydrogens attached to a carbon atom are replaced by deuterium, where n is the number of hydrogens in the molecule. Such compounds exhibit increased resistance to metabolism and are therefore useful for increasing the half-life of any compound of formula I when administered to mammals, particularly humans. See, for example, Foster, “Deuterium Isotope Effects in Studies of Drug Metabolism,” Trends Pharmacol. Sci., Vol. 5(No. 12): pp. 524-527 (1984). Such compounds are synthesized by means well known in the art, for example, by utilizing starting materials in which one or more hydrogens are replaced by deuterium.

[0125] The deuterium-labeled or deuterium-substituted therapeutic compounds of this disclosure may have improved DMPK (drug metabolism and pharmacokinetic) properties with respect to distribution, metabolism, and excretion (ADME). Substitution with heavier isotopes, such as deuterium, may provide certain therapeutic benefits resulting from greater metabolic stability, e.g., increased in vivo half-life, reduced dose requirement, and / or improved therapeutic index. 18F-labeled compounds may be useful for PET or SPECT studies. The isotope-labeled compounds and their prodrugs of this disclosure can generally be prepared by substituting an unlabeled reagent with a readily available isotope-labeled reagent, or by performing the procedures disclosed in the scheme or in the examples and preparations below. In this context, deuterium is understood to be a substituent of the compound of formula I.

[0126] The concentrations of such heavier isotopes, particularly deuterium, can be defined by the isotopic enrichment factor. In the compounds of this disclosure, any atom not specifically designated as a particular isotope represents any stable isotope of that atom. Unless otherwise stated, when a position is specifically designated as "H" or "hydrogen," that position is understood to have hydrogen in its natural abundance isotopic composition. Therefore, in the compounds of this disclosure, any atom specifically designated as deuterium (D) represents deuterium.

[0127] In many cases, the compounds of this disclosure have an amino group and / or a carboxyl group or the same The presence of similar groups can form acid salts and / or base salts.

[0128] Pharmaceutically acceptable salts, hydrates, solvates, tautomers, polymorphs, and prodrugs of the compounds described herein are also provided. "Pharmacologically acceptable" or "physiologically acceptable" means compounds, salts, compositions, dosage forms and other materials that are useful for preparing pharmaceutical compositions suitable for veterinary or human pharmaceutical use.

[0129] The term “pharmaceutically acceptable salt” of a given compound means a salt that maintains the biological efficacy and properties of the given compound and is free from biological and other undesirable aspects. Examples of “pharmaceutically acceptable salts” or “physiologically acceptable salts” include salts with inorganic acids and salts with organic acids. Furthermore, if the compounds described herein are obtained as acid addition salts, their free base can be obtained by basicizing a solution of this acid salt. Conversely, if the product is a free base, the addition salt, in particular a pharmaceutically acceptable addition salt, can be produced by dissolving this free base in a suitable organic solvent and treating this solution with an acid, following conventional procedures for preparing acid addition salts from base compounds. Those skilled in the art will recognize the various synthetic methodologies that can be used to prepare non-toxic pharmaceutically acceptable addition salts. Pharmaceutically acceptable acid addition salts can be prepared from inorganic and organic acids. Examples of salts derived from inorganic acids include hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, and phosphoric acid. Examples of salts derived from organic acids include acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, malic acid, malonic acid, succinic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, and salicylic acid. Similarly, pharmaceutically acceptable base addition salts can be prepared from inorganic and organic bases. Examples of salts derived from inorganic bases include salts of sodium, potassium, lithium, ammonium, calcium, and magnesium.Examples of salts derived from organic bases include alkylamines (i.e., NH2(alkyl)), dialkylamines (i.e., HN(alkyl)2), trialkylamines (i.e., N(alkyl)3), substituted alkylamines (i.e., NH2(substituted alkyl)), di(substituted alkyl)amines (i.e., HN(substituted alkyl)2), tri(substituted alkyl)amines (i.e., N(substituted alkyl)3), alkenylamines (i.e., NH2(alkenyl)), dialkenylamines (i.e., HN(alkenyl)2), trialkenylamines (i.e., N(alkenyl)3), substituted alkenylamines (i.e., NH2(substituted alkenyl)), di(substituted alkenyl)amines (i.e., HN(substituted alkenyl)2), and tri(substituted alkenyl) Examples of suitable amines include, but are not limited to, salts of primary, secondary, and tertiary amines, such as amines (i.e., N(substituted alkenyl)3, mono-, di-, or tri-cycloalkylamines (i.e., NH2(cycloalkyl), HN(cycloalkyl)2, N(cycloalkyl)3), mono-, di-, or tri-arylamines (i.e., NH2(aryl), HN(aryl)2, N(aryl)3), or mixed amines. Specific examples of suitable amines include, for illustrative purposes only, isopropylamine, trimethylamine, diethylamine, tri(iso-propyl)amine, tri(n-propyl)amine, ethanolamine, 2-dimethylaminoethanol, piperazine, piperidine, morpholine, and N-ethylpiperidine.

[0130] The term "substituted" means that one or more hydrogen atoms of a specified atom or group are replaced by one or more substituents other than hydrogen, provided that the hydrogen atoms do not exceed the normal valence of the specified atom. Examples of one or more substituents include alkyl, alkenyl, alkynyl, alkoxy, acyl, amino, amide, amidino, aryl, azide, carbamoyl, carboxyl, carboxyl ester, cyano, guanidino, halo, haloalkyl, haloalkoxy, heteroalkyl, heteroaryl, heterocyclyl, hydroxy, hydrazino, imino, oxo, and nitrate substituents.Examples include, but are not limited to, alkylsulfinyls, sulfonic acids, alkylsulfonyls, thiocyanates, thiols, thiones, or combinations thereof. Polymers or similar infinite structures achieved by defining substituents having an unlimited number of additional substituents (e.g., substituted aryls having a substituted alkyl, where the substituted alkyl itself is substituted with a substituted aryl group, and this substituted aryl group is further substituted with a substituted heteroalkyl group, etc.) are not intended to be included herein. Unless otherwise stated, the maximum number of consecutive substitutions in compounds described herein is three. For example, consecutive substitutions of a substituted aryl group having two other substituted aryl groups are limited to ((substituted aryl)substituted aryl)substituted aryls. Similarly, the above definitions are not intended to include unacceptable substitution patterns (e.g., a methyl group substituted with five fluorine atoms or a heteroaryl group having two adjacent oxygen ring atoms). Such unacceptable substitution patterns are well known to those skilled in the art. When used to modify a chemical group, the term “substituted” may refer to other chemical groups as defined herein. Unless otherwise specified, when a group is described as being substituted as necessary, any substituent on that group itself is unsubstituted. For example, in some embodiments, the term “substituted alkyl” means an alkyl group having one or more substituents, including hydroxyl, halo, alkoxy, cycloalkyl, heterocyclyl, aryl, and heteroaryl substituents. In other embodiments, these one or more substituents may be further substituted with halo, alkyl, haloalkyl, hydroxyl, alkoxy, cycloalkyl, heterocyclyl, aryl, or heteroaryl substituents, each of which is substituted. In other embodiments, these substituents may be further substituted with halo, alkyl, haloalkyl, alkoxy, hydroxyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl substituents, each of which is unsubstituted.Those skilled in the art will recognize that the substituents and other parts of the compounds in the general formulas herein should be selected for the purpose of providing compounds that are sufficiently stable to provide pharmaceutically useful compounds that can be formulated into acceptable and stable pharmaceutical compositions. Compounds having such stability are intended to fall within the scope of the present invention. It should be understood by those skilled in the art that no combination of the definitions and substituents described above should result in unfeasible species or compounds.

[0131] As used herein, “pharmaceutically acceptable carrier” or “pharmaceutically acceptable excipient” includes all solvents, dispersions, coatings, antimicrobial and antifungal agents, isotonic agents and absorption retarders, etc. The use of such media and agents for pharmaceutically active substances is well known in the art. Their use in therapeutic compositions is envisioned unless any conventional media and agent is incompatible with the active ingredient. Additional active ingredients may also be incorporated into these compositions.

[0132] As used herein, “pharmaceutically acceptable carrier” or “pharmaceutically acceptable excipient” includes all solvents, dispersions, coatings, antimicrobial and antifungal agents, isotonic agents and absorption retarders, etc. The use of such media and agents for pharmaceutically active substances is well known in the art. Their use in therapeutic compositions is envisioned unless any conventional media and agent is incompatible with the active ingredient. Additional active ingredients may also be incorporated into these compositions.

[0133] A "solvate" is formed by the interaction of a solvent and a compound. Solvates of salts of the compounds described herein are also provided. Hydrates of the compounds described herein are also provided. Pharmaceutical composition

[0134] While the active ingredients can be administered individually, these active ingredients can be combined into a pharmaceutical formulation (a set of ingredients). It may be preferable to provide the formulation as a finished product. The formulation of the present invention contains, for both veterinary and human use, at least one active ingredient as defined above, together with one or more acceptable carriers therefor, and optionally other therapeutic ingredients. This carrier(s) must be “acceptable” in the sense that they are compatible with the other ingredients of the formulation and must be physiologically harmless to the recipient.

[0135] Examples of these formulations include those suitable for the above-mentioned routes of administration. For convenience, these formulations may be provided in unit dosage forms and may be prepared by any method well known in the field of pharmacy. The techniques and formulations are generally found in Remington's Pharmaceutical Sciences (Mack Publishing Co., Easton, PA). Such methods involve combining the active ingredient with one or more inactive components (e.g., carriers, pharmaceutical excipients) that constitute secondary components. Generally, these formulations are prepared by uniformly and closely combining a liquid carrier, a finely divided solid carrier, or both, and then, if necessary, shaping the product.

[0136] In certain embodiments, formulations suitable for oral administration are provided as discontinuous units such as capsules, cachets, or tablets, each containing a predetermined amount of the active ingredient.

[0137] In certain embodiments, these pharmaceutical formulations contain one or more compounds of the present invention together with one or more pharmaceutically acceptable carriers or excipients, and optionally other therapeutic agents. Pharmaceutical formulations containing the active ingredient may be in any form suitable for the intended method of administration. For example, when used for oral use, tablets, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules, syrups or elixirs may be prepared. Compositions intended for oral use may be prepared according to any method known in the art for the manufacture of pharmaceutical compositions, and such compositions may contain one or more agents, such as sweeteners, flavoring agents, colorants, and preservatives, for the purpose of providing a palatable preparation. Tablets containing the active ingredient as a mixture with non-toxic, pharmaceutically acceptable excipients suitable for the manufacture of tablets are acceptable. These excipients may include, for example, inert diluents such as calcium carbonate or sodium carbonate, lactose, lactose monohydrate, croscarmellose sodium, povidone, calcium phosphate or sodium phosphate; granulating and disintegrating agents such as corn starch or alginic acid; binders such as cellulose, microcrystalline cellulose, starch, gelatin or acacia gum; and lubricants such as magnesium stearate, stearic acid or talc. The tablets may be uncoated or coated by known techniques, including microencapsulation to provide a longer-lasting effect by delaying disintegration and adsorption in the gastrointestinal tract. For example, time-delaying materials such as glyceryl monostearate or glyceryl distearate may be used alone or with wax.

[0138] The amount of active ingredient combined with an inactive ingredient to manufacture a dosage form varies depending on the host being treated and the specific mode of administration. For example, in some embodiments, a dosage form for oral administration to humans contains approximately 1 to 1000 mg of active ingredient combined with a suitable and convenient amount of carrier material (e.g., an inactive ingredient or excipient material). In certain embodiments, this carrier material varies from about 5 to about 95% (by weight) of the total composition. In some embodiments, the pharmaceutical compositions described herein contain about 1 to 800 mg, 1 to 600 mg, 1 to 400 mg, 1 to 200 mg, 1 to 100 mg, or 1 to 50 mg of the compound of formula I, or a pharmaceutically acceptable salt thereof. In application, the pharmaceutical compositions described herein contain about 400 mg or less of the compound of formula I. In some embodiments, the pharmaceutical compositions described herein contain about 100 mg of the compound of formula I, or a pharmaceutically acceptable salt thereof.

[0139] In addition to the components specifically mentioned above, it should be understood that the formulations disclosed herein may contain other agents that are conventional in the art with respect to the type of formulation in question, such as flavoring and odor-masking agents, which may be suitable for oral administration.

[0140] A veterinary composition is further provided that contains at least one of the active ingredients defined above together with a veterinary carrier.

[0141] A veterinary carrier is a substance useful for administering a composition, and can be a solid, liquid, or gaseous substance that is otherwise inert or acceptable in the veterinary field and compatible with the active ingredient. These veterinary compositions can be administered orally, parenterally, or by any other desired route.

[0142] The effective dose of the active ingredient depends at least on the nature of the condition being treated, its toxicity, whether the compound is used prophylactically (at a lower dose), the method of delivery, and the pharmaceutical formulation, and is determined by the clinician using conventional dose-increase studies. Route of administration

[0143] One or more compounds of formula I (hereinafter referred to as the active ingredient), or pharmaceutically acceptable salts thereof, are administered by any route appropriate to the condition to be treated. Appropriate routes include oral, rectal, nasal, topical (including buccal and sublingual), vaginal, and parenteral (including subcutaneous, intramuscular, intravenous, intradermal, intrasacral, and epidural). It is understood that the preferred route may vary, for example, depending on the recipient's condition. One advantage of the compounds of the present invention is that these compounds are orally bioavailable and can be administered orally. Accordingly, in one embodiment, the pharmaceutical composition described herein is in oral dosage form. In certain embodiments, the pharmaceutical composition described herein is in oral solid dosage form. Ultimately, determining the appropriate dose and route of administration for a particular patient with a particular disease or disorder to be treated is within the discretion of a trained physician.

[0144] Formulation Example 1 Prepare hard gelatin capsules containing the following ingredients: amount Ingredients (mg / capsule) Active ingredients 30.0 Starch 305.0 Magnesium stearate 5.0 The above ingredients are mixed and then filled into hard gelatin capsules.

[0145] Formulation Example 2 The tablet formulation is prepared using the following ingredients: amount Ingredients (mg / tablet) Active ingredients 25.0 Cellulose, microcrystalline 200.0 Colloidal silicon dioxide 10.0 Stearic acid 5.0 These ingredients are blended and then compressed to form tablets.

[0146] Formulation Example 3 Prepare a dry powder inhalation preparation containing the following ingredients: Ingredients Weight% Active ingredients 5 Lactose 95 The active ingredient is mixed with lactose, and this mixture is added to a dry powder inhalation device.

[0147] Formulation Example 4 Prepare tablets, each containing 50 mg of the active ingredient, as follows: amount Ingredients (mg / tablet) Active ingredient 50.0 mg Starch 45.0mg Microcrystalline cellulose 35.0 mg Polyvinylpyrrolidone (As a 10% solution in sterile water) 4.0 mg Carboxymethyl starch sodium 4.5 mg Magnesium stearate 0.5 mg Talcum 1.0mg Total 140mg

[0148] The active ingredients, starch, and cellulose are passed through a No. 20 mesh US sieve and thoroughly mixed. A solution of polyvinylpyrrolidone is mixed with the resulting powder and then passed through a 16 mesh US sieve. The resulting granules are dried at 50°C to 60°C and then passed through a 16 mesh US sieve. Carboxymethyl sodium starch, magnesium stearate, and talc, which have been previously passed through a No. 30 mesh US sieve, are then added to these granules, mixed, and compressed in a tablet press to obtain tablets, each weighing 120 mg.

[0149] Formulation Example 5 Prepare suppositories, each containing 25 mg of the active ingredient, as follows: Ingredients Quantity Active ingredient 25mg Until saturated fatty acid glycerides reach 2,000 mg The active ingredient is passed through a No. 60 mesh US sieve and suspended in pre-melted saturated fatty acid glycerides using the minimum heat required. This mixture is then poured into suppository forms with a nominal capacity of 2.0 g and allowed to cool.

[0150] Formulation Example 6 Prepare suppositories containing 50 mg of the active ingredient per 5.0 mL dose as follows: Ingredients Quantity Active ingredient 50.0 mg Xanthan gum 4.0 mg Sodium carboxymethylcellulose (11%) Microcrystalline cellulose (89%) 50.0 mg Sucrose 1.75g Sodium benzoate 10.0 mg Flavoring and coloring qv Add purified water until it reaches 5.0 mL. The active ingredients, sucrose, and xanthan gum are blended and passed through a No. 10 mesh US sieve, then mixed with a pre-prepared aqueous solution of microcrystalline cellulose and sodium carboxymethylcellulose. Sodium benzoate, flavor, and coloring are diluted with some water and added while stirring. Then, enough water is added to produce the required volume.

[0151] Formulation Example 7 Subcutaneous formulations can be prepared as follows: Ingredients Quantity Active ingredient 5.0 mg Corn oil 1.0 mL

[0152] Formulation Example 8 Prepare an injectable formulation having the following composition: Ingredients Quantity Active ingredient 2.0mg / mL Mannitol, USP 50 mg / mL Gluconic acid, USP qs (pH 5~6) Water (distilled, sterile) up to 1.0 mL (qs) Nitrogen gas, NF qs

[0153] Formulation Example 9 Prepare a topical preparation having the following composition: Ingredients (grams) Active ingredient 0.2~10 Span 60 2.0 Tween 60 2.0 Mineral oil 5.0 Petrolatum 0.10 Methylparaben 0.15 Propylparaben 0.05 BHA (Butylated Hydroxyanisole) 0.01 Water up to 100 qs

[0154] Combine all of the above ingredients except water, and heat to 60°C while stirring. Then, add a sufficient amount of 60°C water while stirring vigorously to emulsify the ingredients, and then add a sufficient amount of water to make 100g.

[0155] Formulation Example 10 sustained release composition Range of ingredients by weight % Active ingredient 50~95 Microcrystalline cellulose (filler) 1-35 Methacrylic acid copolymer 1-35 Sodium hydroxide 0.1~1.0 Hydroxypropyl methylcellulose 0.5~5.0 Magnesium stearate 0.5~5.0

[0156] The sustained-release agent of this disclosure may be prepared as follows: the compound, a pH-dependent binder, and any excipients as needed are closely mixed (dry blended). The dry-blended mixture is then granulated in the presence of an aqueous solution of a strong base (sprayed onto the blended powder). The granules are dried, sieved, mixed with a lubricant as needed (e.g., talc or magnesium stearate), and compressed into tablets. A preferred aqueous solution of a strong base is a solution of an alkali metal hydroxide, such as sodium hydroxide or potassium hydroxide, preferably sodium hydroxide, in water (optionally containing up to 25% of a water-miscible solvent (e.g., a lower alcohol)).

[0157] The resulting tablets may be coated with a film-forming agent as needed to improve identification, taste masking, and ease of swallowing. This film-forming agent is typically present in an amount ranging from 2% to 4% of the tablet's weight. Suitable film-forming agents are well known in the art and include hydroxypropyl methylcellulose and cationic methacrylate copolymers (dimethylaminoethyl methacrylate / methyl-butyl methacrylate copolymer - Eudragit® E-Roehm.Pharma). These film-forming agents may contain colorants, plasticizers, and other auxiliary components as needed.

[0158] The compressed tablets preferably have sufficient hardness to withstand a compression of 8 kp. The size of the tablets depends primarily on the amount of compound in the tablet. These tablets contain 300 to 1100 mg of the compound free base. Preferably, these tablets contain amounts of the compound free acid in the range of 400 to 600 mg, 650 to 850 mg, and 900 to 1100 mg.

[0159] To influence the dissolution rate, the time for wet mixing of the compound-containing powder is controlled. Preferably, the total powder mixing time, i.e., the time the powder is exposed to the sodium hydroxide solution, is in the range of 1 to 10 minutes, preferably 2 to 5 minutes. After granulation, the particles are removed from the granulator and placed in a fluidized bed dryer at approximately 60°C for drying.

[0160] Formulation Example 11 The tablet formulation is prepared using the following ingredients: amount Ingredients (mg / tablet) Active ingredients 300.0 Cellulose, microcrystalline 100.0 Colloidal silicon dioxide 10.0 Stearic acid 5.0 These ingredients are blended and then compressed to form tablets.

[0161] method In this specification, a method for treating and / or preventing hyperlipidemia is provided in a subject requiring treatment and / or prevention of hyperlipidemia, the method comprising the step of administering to the subject a therapeutically effective amount of a compound of formula (I). For example, the compounds in this specification are for primary (hereditary) dyslipidemia (e.g., familial hypercholesterolemia, Wolmann disease, and cholesteryl ester storage disease), as well as secondary (acquired) dyslipidemia (e.g., diabetes mellitus, elevated cholesterol (especially elevated LDL cholesterol), combined hyperlipidemia / type IIb, elevated triglycerides, alcohol abuse, chronic kidney disease, hypothyroidism, and primary biliary cirrhosis. It can be used to treat hyperlipidemia associated with ry Cholangitis.

[0162] In this specification, a method is provided for treating and / or preventing metabolic disorders in a subject that requires treatment and / or prevention of such metabolic disorders, including but not limited to diabetes mellitus (including type 1 and type 2 diabetes mellitus), metabolic syndromes, dyslipidemia, obesity, insulin resistance, hypertension, elevated serum cholesterol, and hypertriglycerides, the method comprising the step of administering to the subject a therapeutically effective amount of a compound of formula (I).

[0163] In this specification, a method for treating and / or preventing liver disease in a patient requiring treatment and / or prevention of liver disease is also disclosed, the method comprising the step of administering to the patient a therapeutically effective amount of the compound of formula (I). The presence of active liver disease can be detected by the presence of elevated enzyme levels in the blood. Specifically, it is known that blood levels of alanine aminotransferase (ALT) and aspartate aminotransferase (AST) higher than the clinically acceptable normal range are indicators of ongoing liver damage. Daily monitoring of blood levels of ALT and AST in patients with liver disease is clinically used to measure the progression of liver disease during medical treatment. A decrease in elevated ALT and AST to the acceptable normal range has been adopted as clinical evidence reflecting a decrease in the severity of ongoing liver damage in the patient.

[0164] In certain embodiments, this liver disease is a chronic liver disease. Chronic liver disease involves the progressive destruction and regeneration of the liver parenchyma, resulting in fibrosis and cirrhosis. Generally, chronic liver disease can be caused by viruses (e.g., hepatitis B, hepatitis C, cytomegalovirus (CMV), or Epstein-Barr virus (EBV)), toxic drugs or medications (e.g., alcohol, methotrexate, or nitrofurantoin), metabolic diseases (e.g., non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), hemochromatosis, or Wilson's disease), autoimmune diseases (e.g., autoimmune chronic hepatitis, primary biliary cirrhosis (formerly known as primary biliary cirrhosis), or primary sclerosing cholangitis), or other causes (e.g., right heart failure).

[0165] In one embodiment, a method for reducing the level of cirrhosis is provided herein. In one embodiment, cirrhosis is pathologically characterized by loss of normal microscopic lobular architecture, accompanied by fibrosis and nodular regeneration. Methods for measuring the degree of cirrhosis are well known in the art. In one embodiment, the level of cirrhosis is reduced by about 5% to about 100%. In one embodiment, the level of cirrhosis is reduced in a subject by at least about 5%, at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, or about 100%.

[0166] In certain embodiments, this liver disease is a metabolic liver disease. In one embodiment, this liver disease is non-alcoholic fatty liver disease (NAFLD). NAFLD is associated with insulin resistance and metabolic syndromes (obesity, combined hyperlipidemia, diabetes mellitus (type II), and hypertension). NAFLD is thought to encompass a range of disease activity and begins as fatty accumulation in the liver (hepatic steatohepatopathy).

[0167] Both obesity and insulin resistance have been shown to play a significant role in the disease process of NAFLD. In addition to poor diet, there are several other known causes of NAFLD. For example, NAFLD can be caused by certain medications, such as amiodarone, antiviral drugs (e.g., nucleoside analogs), aspirin (rarely as part of Reye's syndrome in children), corticosteroids, methotrexate, tamoxifen, or tetracycline. NAFLD has also been linked to the consumption of soft drinks in the presence of high-fructose corn syrup, which can lead to increased accumulation of abdominal fat, although the consumption of sucrose shows a similar effect (presumably due to its breakdown into fructose). Genetic characteristics are also known to play a role, and two genetic variations for this susceptibility have been identified.

[0168] If left untreated, NAFLD can progress to non-alcoholic steatohepatitis (NASH), the most extreme form of NAFLD, a condition in which steatosis is accompanied by inflammation and fibrosis. NASH is considered a major cause of cirrhosis of the liver. Accordingly, in this specification, a method for treating and / or preventing non-alcoholic steatohepatitis (NASH) is provided in a patient who requires treatment and / or prevention of NASH, the method comprising the step of administering to the patient a therapeutically effective amount of a compound of formula (I).

[0169] In this specification, a method for treating and / or preventing hepatic fibrosis in a patient requiring treatment and / or prevention of hepatic fibrosis is also provided, the method comprising the step of administering to the patient a therapeutically effective amount of the compound of formula (I). Hepatic fibrosis is an excessive accumulation of extracellular matrix proteins, such as collagen, which occurs in most types of chronic liver disease. In certain embodiments, advanced hepatic fibrosis leads to cirrhosis and liver failure. Methods for measuring the histology of the liver, such as changes in the degree of fibrosis, lobular hepatitis, and periportal bridging necrosis, are well known in the art. In one embodiment, the treatment described herein may improve a patient's fibrosis from baseline, for example, from F4 to F3, from F3 to F2, or from F2 to F1. In one embodiment, the patient's fibrosis score improves by 1 or more after 24 weeks of daily treatment.

[0170] In one embodiment, the level of hepatic fibrosis (which is the formation of fibrous tissue, fibroids, or fibrous degeneration) is reduced by more than about 90%. In one embodiment, the level of hepatic fibrosis (which is the formation of fibrous tissue, fibroids, or fibrous degeneration) is reduced by at least about 90%, at least about 80%, at least about 70%, at least about 60%, at least about 50%, at least about 40%, at least about 30%, at least about 20%, at least about 10%, at least about 5%, or at least about 2%.

[0171] In one embodiment, the compounds provided herein reduce the level of fibrosis in the liver. Hepatic fibrosis is a process that results in the accumulation of excess extracellular matrix components in the liver, known as fibrosis. This is seen in, for example, chronic viral hepatitis B and C, alcoholic liver disease, drug-induced liver disease, hemochromatosis, autoimmune hepatitis, Wilson's disease, and primary biliary cirrhosis. It is observed in numerous conditions, including cholangitis (formerly known as primary biliary cirrhosis), sclerosing cholangitis, and hepatic schistosomiasis. In one embodiment, the level of fibrosis is reduced by more than about 90%. In one embodiment, the level of fibrosis is at least about 90%, at least about 80%, at least about 70%, at least about 60%, at least about 50%, at least about 40%, at least about 30%, at least about 20%, and at least It will decrease by about 10%, at least about 5%, or at least 2%.

[0172] In other embodiments, a method for treating and / or preventing primary sclerosing cholangitis (PSC) is provided herein for a patient who requires treatment and / or prevention of primary sclerosing cholangitis (PSC), the method comprising administering to the patient a therapeutically effective amount of the compound of formula (I).

[0173] In this specification, methods for treating or preventing cardiovascular disorders in patients requiring treatment or prevention of such disorders are also disclosed, the methods comprising the step of administering a therapeutically effective amount of a compound of formula (I). Cardiovascular disorders include, for example, one or more of the following: heart failure (including congestive heart failure, diastolic heart failure, systolic heart failure, and heart failure with preserved ejection fraction), acute heart failure, ischemia, recurrent ischemia, myocardial infarction, arrhythmia, angina pectoris (including exercise-induced angina, variant angina, stable angina, and unstable angina), acute coronary syndrome, diabetes mellitus, intermittent claudication, and idiopathic pulmonary fibrosis.

[0174] In this specification, a method for improving pathological outcomes or results related to oxidative stress in a patient who requires improvement of pathological outcomes or results related to oxidative stress is also provided, the method comprising the step of administering to the patient a therapeutically effective amount of a mitochondrial uncoupling compound.

[0175] Combination therapy The compounds of this disclosure are intended to be used in desired combination products. Such products may be in the form of a single compound, but it is sometimes preferable to co-formulate two or more compounds into a single dosage form.

[0176] Patients treated with the administration of the mitochondrial uncoupling compounds of this disclosure often exhibit diseases or conditions that may benefit from treatment with other therapeutic agents. These diseases or conditions may be of a neurodegenerative nature or may be associated with cancer, metabolic disorders, liver diseases, and gastrointestinal disorders, etc. Thus, one aspect of this disclosure is a method for treating metabolic diseases or conditions, or neurodegenerative disorders, liver diseases or conditions, or cancer, etc., the method comprising the step of administering the compound in combination with one or more compounds useful for treating such diseases to a subject in need, particularly a human subject.

[0177] In some embodiments, the compounds of the Disclosure are formulated together with one or more further active ingredients. In some embodiments, the other active ingredients are administered in a different dosage form approximately simultaneously. In some embodiments, the other active ingredients may be administered sequentially and at a different time than the compounds of the Disclosure.

[0178] Combinations for liver diseases and conditions In some embodiments, the therapeutic agent or combination of therapeutic agents includes ACE inhibitors, acetyl-CoA carboxylase inhibitors, adenosine A3 receptor agonists, adiponectin receptor agonists, AKT protein kinase inhibitors, AMP-activated protein kinase (AMPK), amyrin receptor agonists, angiotensin II AT-1 receptor antagonists, autotaxin inhibitors, bioactive lipids, calcitonin agonists, caspase inhibitors, caspase-3 stimulants, cathepsin inhibitors, caveolin 1 inhibitors, CCR2 chemokine antagonists, CCR3 chemokine antagonists, CCR5 chemokine antagonists, chloride channel stimulants, CNR1 inhibitors, cyclin D1 inhibitors, cytochrome P450 7A1 inhibitors, DGAT1 / 2 inhibitors, dipeptidyl peptidase IV inhibitors, endothelin modulators, eotaxin ligand inhibitors, and extracellular macules. Trix protein modulator, farnesoid X receptor agonist, fatty acid synthase inhibitor, FGF1 receptor agonist, fibroblast growth factor (FGF-15, FGF-19, FGF-21) ligand, galectin-3 inhibitor, glucagon receptor agonist, glucagon-like peptide 1 agonist, G protein-coupled bile acid receptor 1 agonist, Hedgehog (Hh) modulator, hepatitis C virus NS3 protease inhibitor, hepatocyte nuclear factor 4 alpha modulator (HNF4A), hepatocyte growth factor modulator, HMG CoA reductase inhibitors, IL-10 agonists, IL-17 antagonists, ileal sodium bile acid cotransporter inhibitors, insulin sensitizers, integrin modulators, interleukin-1 receptor-related kinase 4 (IRAK4) inhibitors, Jak2 tyrosine kinase inhibitors, Klotho beta stimulants, 5-lipoxygenase inhibitors, lipoprotein lipase inhibitors, liver X receptor, LPL gene stimulants, lysophosphatidic acid-1 receptor antagonists, lysyl oxidase homolog 2 inhibitors, matrix metalloproteinase (MMP) inhibitors, MEKK-5 protein kinase inhibitors, membrane copper amine oxidase (VAP-1) inhibitors, methionine aminopeptidase-2 inhibitors, methyl CpG-binding protein 2 modulators, microRNA-21 (miR-21) inhibitors, myelin basic protein stimulants, NACHT LRRPYD domain protein 3 (NLRP3) inhibitors, NAD-dependent deacetylase sirtuin stimulants, NADPH oxidase inhibitors (NOX), nicotinic acid receptor 1 agonists, P2Y13 purine receptor stimulants, PDE3 inhibitors, PDE4 inhibitors, PDE5 inhibitors, PDGF receptor beta modulators, phospholipase C inhibitors, PPAR alpha agonists, PPAR delta agonists, PPAR gamma agonists, PPAR gamma modulators, protease-activated receptor-2 antagonists, protein kinase modulators, Rho-related protein kinase inhibitors, sodium glucose transporter-2 These include inhibitors, SREBP transcription factor inhibitors, STAT-1 inhibitors, stearoyl-CoA desaturase-1 inhibitors, cytokine signaling-1 stimulant suppressors, cytokine signaling-3 stimulant suppressors, transforming growth factor β (TGF-β), transforming growth factor β-activated kinase 1 (TAK1), thyroid hormone receptor beta agonists, TLR-4 antagonists, transglutaminase inhibitors, tyrosine kinase receptor modulators, GPCR modulators, nuclear hormone receptor modulators, WNT modulators, or YAP / TAZ modulators.

[0179] Non-limiting examples of therapeutic agents and targets include the following: ACE inhibitors, for example, enalapril; Acetyl-CoA carboxylase (ACC) inhibitors, e.g., DRM-01, NDI-010976 (firsocostat), gemcabene, PF-05175157, QLT-091382, PF-05221304; Adenosine receptor agonists, e.g., CF-102 (namodenoson), CF-101, CF-502, CGS21680; Adiponectin receptor agonists, e.g., ADP-355; Amylin / calcitonin receptor agonists, e.g., KBP-042; AMP-activated protein kinase stimulants, e.g., O-304; Angiotensin II AT-1 receptor antagonists, e.g., irbesartan; Autotaxin inhibitors, e.g., PAT-505, PAT-048, GLPG-1690, X-165, PF-8380, AM-063; Bioactive lipids, e.g., DS-102; Cannabinoid receptor type 1 (CNR1) inhibitors, e.g., namacizumab, GWP-42004; Caspase inhibitors, such as emricasan; Pan cathepsin B inhibitors, e.g., VBY-376; Total cathepsin inhibitors, e.g., VBY-825; CCR2 / CCR5 chemokine antagonists, such as cenicriviroc; CCR2 chemokine antagonists, such as propagermanium; CCR3 chemokine antagonists, such as bertilimumab; Chloride channel stimulants, such as cobiprostone; Diglyceride acyltransferase 2 (DGAT2) inhibitors, e.g., IONIS-DGAT2Rx, PF-06865571; Diglyceride acyltransferase 1 (DGAT1) inhibitors, e.g., GSK-3008356; Dipeptidyl peptidase IV inhibitors, such as linagliptin and evogliptin; Eotaxin ligand inhibitors, e.g., vertilimumab; Extracellular matrix protein modulators, e.g., CNX-024; Farnesoid X receptor (FXR) agonists, e.g., AGN-242266, AKN-083, EDP-305, GNF-5120, GS-9674, LJN-452 (tropifexor), LMB-763, obeticholic acid, Px-102, Px-103, M790, M780, M450, M480, PX20606, EYP-001, INT-2228; Farnesoid X receptor (FXR) / G protein-coupled bile acid receptor 1 (TGR5) agonists, e.g., INT-767; Fatty acid synthase inhibitors, e.g., TVB-2640; Fibroblast growth factor 19 (rhFGF19) / cytochrome P450 (CYP) 7A1 inhibitors, e.g., NGM-282; Fibroblast growth factor 21 (FGF-21) ligands, e.g., BMS-986171, BMS-986036; Fibroblast growth factor 21 (FGF-21) / glucagon-like peptide 1 (GLP-1) agonists, e.g., YH-25723; Galectin-3 inhibitors, e.g., GR-MD-02; Glucagon-like peptide-1 (GLP1R) agonists, e.g., AC-3174, liraglutide, semaglutide; G protein-coupled bile acid receptor 1 (TGR5) agonists, e.g., RDX-009, INT-777; Heat shock protein 47 (HSP47) inhibitors, e.g., ND-L02-s0201; HMG CoA reductase inhibitors, such as atorvastatin, fluvastatin, pitavastatin, pravastatin, rosuvastatin, and simvastatin; IL-10 agonists, such as peg-ilodecakin; Ileal sodium bile acid cotransporter inhibitors, e.g., A-4250, volixibat potassium ethanolate hydrate (SHP-262), GSK2330672; Insulin sensitizers, e.g., KBP-042, MSDC-0602K, Px-102, RG-125 (AZD4076), VVP-100X; Beta-Klotho (KLB)-FGF1c agonist, e.g., NGM-313; 5-lipoxygenase inhibitors, e.g., tipelukast (MN-001); Lipoprotein lipase inhibitors, e.g., CAT-2003; LPL gene stimulating substances, such as alipogen tiparvovec; Liver X receptor (LXR) inhibitors, e.g., PX-L603, PX-L493, BMS-852927, T-0901317, GW-3965, SR-9238; Lysophosphatidic acid-1 receptor antagonists, e.g., BMT-053011, UD-009, AR-479, ITMN-10534, BMS-986020, KI-16198; Lysyl oxidase homolog 2 inhibitors, such as simtuzumab; MEKK-5 protein kinase (ASK-1) inhibitors, such as selonsertib; Semicarbazide-sensitive amine oxidase / vascular adhesion protein-1 (SSAO / VAP-1) inhibitors, e.g., PXS-4728A; Methionine aminopeptidase-2 inhibitors, e.g., ZGN-839; Methyl CpG-binding protein 2 modulators, e.g., mercaptamine; Mineralocorticoid receptor antagonists (MCRAs), e.g., MT-3995; Myelin basic protein stimulants, such as oresoxime; Myeloperoxidase inhibitors, e.g., PF-06667272; NADPH oxidase 1 / 4 inhibitors, e.g., GKT-831; Nicotinic acid receptor 1 agonists, e.g., ARI-3037MO; NACHT LRR PYD domain protein 3 (NLRP3) inhibitors, e.g., KDDF-201406-03, NBC-6; Nuclear receptor modulators, e.g., DUR-928; P2Y13 purine receptor stimulants, e.g., CER-209; PDE3 / 4 inhibitors, e.g., tipercast (MN-001); PDE5 inhibitors, e.g., sildenafil; PDGF receptor beta-modulators, e.g., BOT-191, BOT-509; PPAR agonists, e.g., elafibranor (GFT-505), MBX-8025, deuterated pioglitazone R-enantiomer, pioglitazone, DRX-065, saroglitazar, IVA-337; Protease-activated receptor-2 antagonists, e.g., PZ-235; Protein kinase modulators, e.g., CNX-014; Rho-related protein kinase (ROCK) inhibitors, e.g., KD-025; Sodium glucose transporter-2 (SGLT2) inhibitors, such as ipragliflozin, etavonate remogliflozin, ertugliflozin, dapagliflozin, and sotagliflozin; SREBP transcription factor inhibitors, e.g., CAT-2003, MDV-4463; Stearoyl-CoA desaturase-1 inhibitors, such as aramchol; Thyroid hormone receptor beta-agonists, e.g., MGL-3196, MGL-3745, VK-2809; TLR-4 antagonist, e.g., JKB-121; Tyrosine kinase receptor modulators, e.g., CNX-025; GPCR modulators, e.g., CNX-023; Nuclear hormone receptor modulators, e.g., Px-102; In some embodiments, the therapeutic agent, or combination of several therapeutic agents, is A-4250, AC-3174, acetylsalicylic acid, AK-20, alipogentiparvovec, alamcol, ARI-3037MO, ASP-8232, vertilimmab, anhydrous betaine, BI-1467335, BMS-986036, BMS-986171, BMT-053011, BOT-191, BTT-1023, CAT-2003, senicliviroc, CER-209, CF-102, CGS21680, CNX-014, CNX-023, CNX-024, CNX-025, Cobiprostone, Coleseveram, Dapagliflozin, Deuterated Pioglitazone R-enantiomer, 2,4-Dinitrophenol, DRX-065, DS-102, DUR-928, EDP-305, Elafibranol (GFT-505), Emricasan, Enalapril, Erzggliflozin, Evogliptin, F-351, GKT-831, GNF-5120, GRI-0621, GR-MD-02, Seroncertib, GS-9674, Hydrochlorothiazide, Icosapent ethyl ester, IMM-124-E, INT-767, IONIS-DGAT2Rx, Ipragliflozin, Irbesalta (Irbesarta), Propagermanium, IVA-337, JKB-121, KB-GE-001, KBP-042, KD-025, M790, M780, M450, Metformin, Sildenafil, LC-280126, Linagliptin, Liraglutide, LJN-452, LMB-763, MBX-8025, MDV-4463, Mercaptamine, MGL-3196, MGL-3745, MSDC-0602K, Namacizumab, NC-101, NDI-010976, ND-L02-s0201, NGM-282, N GM-313, NGM-386, NGM-395, norursodeoxycholic acid, O-304, obeticholic acid, 25HC3S, oresoxime, PAT-505, PAT-048, pegylodecaquin, pioglitazone, pirfenidone, PRI-724, PX20606, Px-102, PX-L603, PX-L493, PXS-4728A, PZ-235, RDX-009, remogliflozin ethavone, RG-125 (AZD4076), saroglitazal, semaglutide, simtuzumab, solithromycin, sotagliflozin These are din, statins (atorvastatin, fluvastatin, pitavastatin, pravastatin, rosuvastatin, simvastatin), TCM-606F, TEV-45478, tipercast (MN-001), TLY-012, TRX-318, TVB-2640, UD-009, ursodeoxycholic acid, VBY-376, VBY-825, VK-2809, bismodegib, porixibat potassium ethanolate hydrate (SHP-626), VVP-100X, WAV-301, WNT-974, or ZGN-839.

[0180] Combinations for metabolic disorders or conditions Examples of metabolic disorders include, but are not limited to, diabetes mellitus (including type 1 and type 2 diabetes mellitus), metabolic syndromes, dyslipidemia, obesity, insulin resistance, hypertension, high serum cholesterol, and high triglycerides.

[0181] Examples of therapeutic agents used to treat metabolic disorders include antihypertensive agents and lipid-lowering agents. Further therapeutic agents used to treat metabolic disorders include insulin, sulfonylurea, biguanides, α-glucosidase inhibitors, and incretin mimetic compounds. Thus, one aspect of the present disclosure is a method for treating metabolic diseases, the method comprising the step of administering the compounds of the present disclosure, in combination with one or more compounds useful for treating metabolic diseases, to a subject in need, in particular a human subject. [Examples]

[0182] The following embodiments are included to demonstrate specific embodiments of the Disclosure. Those skilled in the art should recognize that the techniques disclosed in the following embodiments represent techniques that function well in the implementation of the Disclosure and can therefore be considered to constitute a particular mode for its implementation. However, those skilled in the art should recognize that many modifications can be made in light of the Disclosure to the specific embodiments disclosed, and that similar or equivalent results can still be obtained without departing from the spirit and scope of the Disclosure. List of abbreviations and acronyms Abbreviations and their meanings ℃ (degrees C) Acetyl aq. Water-based br wide BSA (Bovine Serum Albumin) d double line DCM Dichloromethane dd double line double line ddd Double line double line double line DMA (dimethylacetamide) DMF Dimethylformamide DMSO (Dimethyl Sulfoxide) dt double line-triple line EC 50 Half of the maximum effective concentration EDCI 1-Ethyl-3-(3-dimethylaminopropyl)-3-ethylcarbodiimide EDTA (Ethylenediaminetetraacetic acid) Eq or equiv. Equivalent ESI Electrospray Interface Et ethyl HCl ethyl acetate EtOH Ethanol (ethyl alcohol) FBS Fetal Bovine Serum g grams HATU 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate HEPES 2-[4-(2-hydroxyethyl)piperazine-1-yl]ethanesulfonic acid HCl (hydrochloric acid) HOBT 1-hydroxybenzotriazole HPLC (High-Pressure Liquid Chromatography) Hrs time Hz (Hertz) i-pr isopropyl J coupling constant (MHz) LCMS Liquid Chromatography-Mass Spectrometry M molar concentration m multiplet M+ Mass Peak M+H mass peak + hydrogen MH mass peak - hydrogen Me methyl MeCN acetonitrile MeOH (Methanol / Methyl Alcohol) Mg milligrams MgSO4 Magnesium Sulfate MHz (megahertz) Minutes ml / mL (milliliters) mM millimolar concentration mmol millimol MS mass spectrometry μwave microwave n - Normal nBu / Bu n-butyl (n-butyl) nL nanoliter nm (nanometer) NMP 1-methylpyrrolidine-2-one NMR nuclear magnetic resonance NP-40 Nonylphenoxypolyethoxyethanol Ph Phenyl q quadruple line A sufficient amount to achieve the functions described in qs RP inverse phase Rt room temperature s Single line t triple line T3P 1-Propanephosphonic Acid Anhydride TBTU O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate THF (Tetrahydrofuran)

[0183] Sources of chemicals Some of the intermediates used herein are commercially available. Sources include: J&W Pharmalab,3930 Nebraska Ave.,Levittown,PA 19056 USA; TCI America,9211 North Harborgate Street,Portland,OR 97203,USA; SpiroChem AG,Rosental area,WRO-1047-3,Mattenstrasse 24,4058 Basel,Switzerland; Synnovator, Inc., 104 TW Alexander Dr, Durham, NC 27709; and Ark Pharma, Inc., 3860 N. Ventura Drive, Arlington Heights, IL 60004, USA. These are some examples.

[0184] General synthesis 1 [ka] Example 1: Preparation of 4-fluoro-2-(methylsulfonamide)-N-(3-(trifluoromethyl)bicyclo[1.1.1]pentan-1-yl)benzamide

[0185] Step 1: Pyridine (7.86 mL, 97.1 mmol) was added to a solution of methyl 2-amino-4-fluorobenzoate (1.64 g, 9.71 mmol) and methanesulfonyl chloride (5.28 mL, 115 mmol) in dichloromethane (100 mL). This solution was stirred at room temperature for 18 hours. The reaction was quenched with 1 N HCl and stirred for 5 minutes. The mixture was extracted with DCM (three times). The combined organic layer was washed with brine. The mixture was dried over anhydrous MgSO4, filtered, and concentrated. The crude product was purified by silica gel chromatography to obtain methyl 4-fluoro-2-(methylsulfonamide)benzoate.

[0186] Step 2: To a solution of methyl 4-fluoro-2-(methylsulfonamide)benzoate (1.65 g, 6.67 mmol) in THF / MeOH / water (1:1:1, 66.0 mL), lithium hydroxide monohydrate (1.40 g, 33.4 mmol) was added. This mixture was stirred at room temperature for 18 hours. The reaction was quenched with 1 N HCl and then concentrated. The crude product was diluted with water and extracted with SiO2 (three times). The combined organic layers were washed with brine, dried over MgSO4, filtered, and concentrated to obtain 4-fluoro-2-(methylsulfonamide)benzoic acid, which was used without further purification.

[0187] Step 3: A mixture of 4-fluoro-2-(methylsulfonamide)benzoic acid (650 mg, 2.79 mmol), 3-(trifluoromethyl)bicyclo[1.1.1]pentane-1-amine hydrochloride (706 mg, 3.76 mmol), EDCI (801 mg, 4.18 mmol), and HOBT (565 mg, 4.18 mmol) in DMF (30.0 mL) was stirred for 5 minutes. N,N-diisopropylethylamine (2.43 mL, 13.9 mmol) was added, and the solution was stirred at room temperature for 18 hours. This solution was concentrated, diluted with ethyl acetate, and its pH was adjusted to 3 by adding 1N HCl. The mixture was extracted with phenylethylamine (3 times), and the combined organic layer was washed with brine, dried over anhydrous MgSO4, filtered, and concentrated. This crude product was purified by silica gel chromatography and then crystallization to obtain 4-fluoro-2-(methylsulfonamide)-N-(3-(trifluoromethyl)bicyclo[1.1.1]pentan-1-yl)benzamide. 1 H NMR (400 MHz, DMSO-d6) δ 11.47 (s, 1H), 9.56 (s, 1H), 7.93 (dd, J = 9.0, 6.3 Hz, 1H), 7.31 (dd, J = 11.2, 2.6 Hz, 1H), 7.05 (td, J = 8.5, 2.6 Hz, 1H), 3.23 (s, 3H), 2.35 (s, 6H). LCMS-ESI + (m / z): [M+H] + calcd 367.07;found 367.01.

[0188] [ka] Example 2: Preparation of 2-(cyclopropanesulfonamide)-4-fluoro-N-(3-(trifluoromethyl)bicyclo[1.1.1]pentan-1-yl)benzamide Step 1: A mixture of 7-fluoro-2H-benzo[d][1,3]oxazine-2,4(1H)-dione (50.0 mg, 0.276 mmol), 3-(trifluoromethyl)bicyclo[1.1.1]pentan-1-amine hydrochloride (51.8 mg, 0.276 mmol), and sodium hydroxide (20.0 mg, 0.500 mmol) in 1,4-dioxane (3.0 mL) was heated at 105°C for 18 hours. The mixture was filtered, and the filtrate was concentrated. The crude product was purified by silica gel chromatography to obtain 2-amino-4-fluoro-N-(3-(trifluoromethyl)bicyclo[1.1.1]pentan-1-yl)benzamide. LCMS-ESI + (m / z): [M+H] + calcd 289.10;found 289.48.

[0189] Step 2: Stir the solution of 2-amino-4-fluoro-N-(3-(trifluoromethyl)bicyclo[1.1.1]pentan-1-yl)benzamide (32.0 mg, 0.111 mmol), methanesulfonyl chloride (0.113 mL, 1.11 mmol), and pyridine (0.135 mL, 1.67 mmol) in DCM (2.0 mL) at room temperature for 18 hours. The mixture was then concentrated, and the crude product was purified by reverse-phase chromatography to obtain 2-(cyclopropanesulfonamide)-4-fluoro-N-(3-(trifluoromethyl)bicyclo[1.1.1]pentan-1-yl)benzamide. 1 1H NMR (400 MHz, DMSO-d6) δ 11.42 (s, 1H), 9.59 (s, 1H), 7.92 (dd, J = 8.9, 6.3 Hz, 1H), 7.35 (dd, J = 11.1, 2.6 Hz, 1H), 7.08 (td, J = 8.5, 2.6 Hz, 1H), 2.89 (p, J = 6.4 Hz, 1H), 2.36 (s, 6H), 1.03 - 0.99 (m, 4H). LCMS-ESI + (m / z): [M+H] +calcd 393.09;found 393.75.

[0190] [ka] Example 3: Preparation of 2-((4-(tert-butyl)phenyl)sulfonamide)-4-fluoro-N-(3-(trifluoromethyl)bicyclo[1.1.1]pentan-1-yl)benzamide Following general synthesis 1, 1.5 equivalents of 4-tert-butylbenzenesulfonyl chloride were used in step 1, and the reaction mixture was stirred at room temperature for 48 hours. 3-(trifluoromethyl)bicyclo[1.1.1]pentan-1-amine hydrochloride was used in step 3 to obtain 2-((4-(tert-butyl)phenyl)sulfonamide)-4-fluoro-N-(3-(trifluoromethyl)bicyclo[1.1.1]pentan-1-yl)benzamide after purification by reverse-phase chromatography. 1 H NMR (400 MHz, DMSO-d6) δ 11.81 (s, 1H), 9.49 (s, 1H), 7.81 (dd, J = 8.9, 6.2 Hz, 1H), 7.76 - 7.66 (m, 2H), 7.63 - 7.57 (m, 2H), 7.25 (dd, J = 10.9, 2.6 Hz, 1H), 7.04 (td, J = 8.6, 2.6 Hz, 1H), 2.32 (s, 6H), 1.26 (s, 9H). LCMS-ESI + (m / z): [M+H] + calcd 485.15;found 485.09.

[0191] [ka] Example 4: Preparation of 2-((4-(tert-butyl)phenyl)sulfonamide)-4-(trifluoromethyl)-N-(3-(trifluoromethyl)bicyclo[1.1.1]pentan-1-yl)benzamide According to General Synthesis 1, 2-amino-4-(trifluoromethyl)methyl benzoate and 4-tert-butylbenzenesulfonyl chloride (1.2 equivalents) were used in step 1, and then 3-(trifluoromethyl)bicyclo[1.1.1]pentan-1-amine hydrochloride was used in step 3 to synthesize 2-((4-(tert-butyl)phenyl)sulfonamide)-4-(trifluoromethyl)-N-(3-(trifluoromethyl)bicyclo[1.1.1]pentan-1-yl)benzamide, which was then purified by reverse-phase chromatography. 1 H NMR (400 MHz, DMSO-d6) δ 11.28 (s, 1H), 9.62 (s, 1H), 7.88 (d, J = 8.3 Hz, 1H), 7.69 - 7.62 (m, 3H), 7.62 - 7.53 (m, 3H), 2.33 (s, 6H), 1.25 (s, 9H). LCMS-ESI + (m / z): [M+H] + calcd 535.15;found 535.08.

[0192] [ka] Example 5: Preparation of 4-fluoro-2-((4-(methylsulfonyl)phenyl)sulfonamide)-N-(3-(trifluoromethyl)bicyclo[1.1.1]pentan-1-yl)benzamide According to General Synthesis 1, 4-(methylsulfonyl)benzenesulfonyl chloride (1.2 equivalents) was used in step 1, and 3-(trifluoromethyl)bicyclo[1.1.1]pentan-1-amine hydrochloride was used in step 3 to synthesize 4-fluoro-2-((4-(methylsulfonyl)phenyl)sulfonamide)-N-(3-(trifluoromethyl)bicyclo[1.1.1]pentan-1-yl)benzamide, which was then purified by reverse-phase chromatography. 1 H NMR (400 MHz, DMSO-d6) δ 11.84 (s, 1H), 9.48 (s, 1H), 8.11 (d, J = 8.3 Hz, 2H), 8.02 (d, J = 8.5 Hz, 2H), 7.79 (dd, J = 8.9, 6.2 Hz, 1H), 7.27 (d, J = 10.5 Hz, 1H), 7.16 - 7.06 (m, 1H), 3.29 (s, 3H), 2.31 (s, 6H). LCMS-ESI + (m / z): [M+H] + calcd 507.07; found 507.04.

[0193] [ka] Example 6: Preparation of 2-((4-(trifluoromethoxy)phenyl)sulfonamide)-4-(trifluoromethyl)-N-(3-(trifluoromethyl)bicyclo[1.1.1]pentan-1-yl)benzamide According to General Synthesis 1, 2-amino-4-(trifluoromethyl)methyl benzoate and 4-(trifluoromethoxy)benzenesulfonyl chloride (2 × 1.5 equivalents) were used in step 1 at room temperature for 36 hours, and then 3-(trifluoromethyl)bicyclo[1.1.1]pentan-1-amine hydrochloride was used in step 3 to synthesize 2-((4-(trifluoromethoxy)phenyl)sulfonamide)-4-(trifluoromethyl)-N-(3-(trifluoromethyl)bicyclo[1.1.1]pentan-1-yl)benzamide, which was then purified by reverse-phase chromatography. 1 H NMR (400 MHz, DMSO-d6) δ 11.22 (s, 1H), 9.60 (s, 1H), 7.89 - 7.81 (m, 3H), 7.66 - 7.54 (m, 4H), 2.31 (s, 6H). LCMS-ESI + (m / z): [M+H] + calcd 563.07;found 563.05.

[0194] [ka] Example 7: 2-((4-(tert-butyl)phenyl)sulfonamide)-N-(3-cyanobicyclo[1.1.1]pentan-1-yl)-4-(trifluoromethyl) Preparation of benzamide According to General Synthesis 1, 2-amino-4-(trifluoromethyl)methyl benzoate and 4-tert-butylbenzenesulfonyl chloride (1.2 equivalents) were used in step 1, and then 3-aminobicyclo[1.1.1]pentan-1-carbonitrile was used in step 3 to synthesize 2-((4-(tert-butyl)phenyl)sulfonamide)-N-(3-cyanobicyclo[1.1.1]pentan-1-yl)-4-(trifluoromethyl)benzamide, which was then purified by reverse-phase chromatography. 1 H NMR (400 MHz, DMSO-d6) δ 11.23 (s, 1H), 9.60 (s, 1H), 7.84 (d, J = 8.2 Hz, 1H), 7.68 - 7.62 (m, 3H), 7.62 - 7.53 (m, 3H), 2.58 (s, 6H), 1.26 (s, 9H). LCMS-ESI + (m / z): [M+H] + calcd 492.16;found 492.10.

[0195] [ka] Example 8: Preparation of 2-((4-(methylsulfonyl)phenyl)sulfonamide)-4-(trifluoromethyl)-N-(3-(trifluoromethyl)bicyclo[1.1.1]pentan-1-yl)benzamide According to General Synthesis 1, 2-amino-4-(trifluoromethyl)methyl benzoate and 4-(methylsulfonyl)benzenesulfonyl chloride (2.5 equivalents) were used in step 1 at room temperature for 48 hours, and then 3-(trifluoromethyl)bicyclo[1.1.1]pentan-1-amine hydrochloride was used in step 3 to synthesize 2-((4-(methylsulfonyl)phenyl)sulfonamide)-4-(trifluoromethyl)-N-(3-(trifluoromethyl)bicyclo[1.1.1]pentan-1-yl)benzamide, which was then purified by reverse-phase chromatography. 1 H NMR (400 MHz, DMSO-d6) δ 11.28 (s, 1H), 9.60 (s, 1H), 8.11 (d, J = 8.5 Hz, 2H), 7.95 (d, J = 8.5 Hz, 2H), 7.86 (d, J = 8.2 Hz, 1H), 7.71 - 7.60 (m, 2H), 3.28 (s, 3H), 2.30 (s, 6H). LCMS-ESI + (m / z): [M+H] + calcd 577.06;found 577.06.

[0196] [ka] Example 9: Preparation of N-(4-fluorobicyclo[2.2.2]octan-1-yl)-2-((4-(methylsulfonyl)phenyl)sulfonamide)-4-(trifluoromethyl)benzamide According to General Synthesis 1, 2-amino-4-(trifluoromethyl)methyl benzoate and 4-(methylsulfonyl)benzenesulfonyl chloride (2.5 equivalents) were used in step 1 at room temperature for 48 hours, and then 4-fluorobicyclo[2.2.2]octane-1-amine hydrochloride was used in step 3 to synthesize N-(4-fluorobicyclo[2.2.2]octane-1-yl)-2-((4-(methylsulfonyl)phenyl)sulfonamide)-4-(trifluoromethyl)benzamide, which was then purified by reverse-phase chromatography. 1H NMR (400 MHz, DMSO-d6) δ 10.98 (s, 1H), 8.18 (s, 1H), 8.11 (d, J = 8.5 Hz, 2H), 7.93 (d, J = 8.5 Hz, 2H), 7.79 (d, J = 8.1 Hz, 1 H), 7.65 - 7.53 (m, 2H), 3.28 (s, 3H), 2.07 - 1.98 (m, 6H), 1.89 - 1.79 (m, 6H). LCMS-ESI + (m / z): [M+H] + calcd 549.11;found 549.12.

[0197] [ka] Example 10: Preparation of N-((3s,5s,7s)-adamantan-1-yl)-2-((4-(methylsulfonyl)phenyl)sulfonamide)-4-(trifluoromethyl)benzamide According to General Synthesis 1, 2-amino-4-(trifluoromethyl)methyl benzoate and 4-(methylsulfonyl)benzenesulfonyl chloride (2.5 equivalents) were used in step 1 at room temperature for 48 hours, and then 1-adamantylamine was used in step 3 to synthesize N-((3s,5s,7s)-adamantan-1-yl)-2-((4-(methylsulfonyl)phenyl)sulfonamide)-4-(trifluoromethyl)benzamide, which was then purified by crystallization. 1 H NMR (400 MHz, DMSO-d6) δ 11.11 (s, 1H), 8.19 - 8.05 (m, 3H), 7.94 (d, J = 8.5 Hz, 2H), 7.83 (d, J = 8.1 Hz, 1H), 7.65 - 7.53 (m, 2H), 3.27 (s, 3H), 2.04 (bs, 3H), 1.95 (d, J = 2.8 Hz, 6H), 1.64 (BS, 6H). LCMS-ESI + (m / z): [M+H] +calcd 557.14;found 557.11.

[0198] [ka] Example 11: Preparation of 2-((4-(methylsulfonyl)phenyl)sulfonamide)-N-(3-phenylbicyclo[1.1.1]pentan-1-yl)-4-(trifluoromethyl)benzamide According to General Synthesis 1, 2-amino-4-(trifluoromethyl)methyl benzoate and 4-(methylsulfonyl)benzenesulfonyl chloride (2.5 equivalents) were used in step 1 at room temperature for 48 hours, and then 3-phenylbicyclo[1.1.1]pentan-1-amine hydrochloride was used in step 3 to synthesize 2-((4-(methylsulfonyl)phenyl)sulfonamide)-N-(3-phenylbicyclo[1.1.1]pentan-1-yl)-4-(trifluoromethyl)benzamide, which was then purified by crystallization. 1 1H NMR (400 MHz, DMSO-d6) δ 11.58 (s, 1H), 9.52 (s, 1H), 8.12 (d, J = 8.5 Hz, 2H), 8.00 - 7.94 (m, 2H), 7.91 (d, J = 8.2 Hz, 1H), 7.72 (s, 1H), 7.68 - 7.59 (m, 1H), 7.37 - 7.30 (m, 2H), 7.30 - 7.21 (m, 3H), 3.28 (s, 3H), 2.32 (s, 6H). LCMS-ESI + (m / z): [M+H] + calcd 565.11;found 565.02.

[0199] [ka] Example 12: Preparation of 4-fluoro-2-((4-(methylsulfonyl)phenyl)sulfonamide)-N-(3-phenylbicyclo[1.1.1]pentan-1-yl)benzamide Following general synthesis method 1, 4-(methylsulfonyl)benzenesulfonyl chloride (1.2 equivalents) was used in step 1, and 3-phenylbicyclo[1.1.1]pentan-1-amine hydrochloride was used in step 3 to synthesize 4-fluoro-2-((4-(methylsulfonyl)phenyl)sulfonamide)-N-(3-phenylbicyclo[1.1.1]pentan-1-yl)benzamide, which was then purified by reverse-phase chromatography. 1 H NMR (400 MHz, DMSO-d6) δ 12.16 (s, 1H), 9.39 (s, 1H), 8.12 (d, J = 8.5 Hz, 2H), 8.04 (d, J = 8.6 Hz, 2H), 7.84 (dd, J = 8.9, 6.2 Hz, 1H), 7.37 - 7.18 (m, 6H), 7.15 - 7.04 (m, 1H), 3.29 (s, 3H), 2.33 (s, 6H). LCMS-ESI + (m / z): [M+H] + calcd 515.11;found 515.01.

[0200] [ka] Example 13: Preparation of 4-(tert-butyl)-2-((4-(methylsulfonyl)phenyl)sulfonamide)-N-(3-(trifluoromethyl)bicyclo[1.1.1]pentan-1-yl)benzamide According to General Synthesis 1, 2-amino-4-(tert-butyl)methyl benzoate and 4-(methylsulfonyl)benzenesulfonyl chloride (1.5 equivalents) were used in step 1, and then 3-(trifluoromethyl)bicyclo[1.1.1]pentan-1-amine hydrochloride was used in step 3 to synthesize 4-(tert-butyl)-2-((4-(methylsulfonyl)phenyl)sulfonamide)-N-(3-(trifluoromethyl)bicyclo[1.1.1]pentan-1-yl)benzamide, which was then purified by reverse-phase chromatography. 1H NMR (400 MHz, DMSO-d6) δ 11.54 (s, 1H), 9.37 (s, 1H), 8.09 (d, J = 8.5 Hz, 2H), 7.94 (d, J = 8.5 Hz, 2H), 7.61 (d, J = 8.4 Hz, 1H), 7.42 (d, J = 1.9 Hz, 1H), 7.22 (dd, J = 8.4, 1.9 Hz, 1H), 3.27 (s, 3H), 2.31 (s, 6H), 1.22 (s, 9H). LCMS-ESI + (m / z): [M+H] + calcd 545.14;found 545.00.

[0201] [ka] Example 14: 4-(tert-butyl)-N-(3-cyanobicyclo[1.1.1] Preparation of pentan-1-yl)-2-((4-(methylsulfonyl)phenyl)sulfonamide)benzamide According to General Synthesis 1, 2-amino-4-(tert-butyl)methyl benzoate and 4-(methylsulfonyl)benzenesulfonyl chloride (1.5 equivalents) were used in step 1, and then 3-aminobicyclo[1.1.1]pentan-1-carbonitrile was used in step 3 to synthesize 4-(tert-butyl)-N-(3-cyanobicyclo[1.1.1]pentan-1-yl)-2-((4-(methylsulfonyl)phenyl)sulfonamide)benzamide, which was then purified by reverse-phase chromatography. 1 H NMR (400 MHz, DMSO-d6) δ 11.48 (s, 1H), 9.35 (s, 1H), 8.10 (d, J = 8.5 Hz, 2H), 7.94 (d, J = 8.5 Hz, 2H), 7.58 (d, J = 8.4 Hz, 1H), 7.40 (d, J = 1.9 Hz, 1H), 7.21 (dd, J = 8.3, 1.9 Hz, 1H), 3.28 (s, 3H), 2.55 (s, 6H), 1.21 (s, 9H). LCMS-ESI + (m / z): [M+H] + calcd 502.15;found 501.99.

[0202] [ka] Example 15: Preparation of 4-(tert-butyl)-2-((4-(methylsulfonyl)phenyl)sulfonamide)-N-(3-phenylbicyclo[1.1.1]pentan-1-yl)benzamide According to General Synthesis 1, 2-amino-4-(tert-butyl)methyl benzoate and 4-(methylsulfonyl)benzenesulfonyl chloride (1.5 equivalents) were used in step 1, and then 3-phenylbicyclo[1.1.1]pentan-1-amine hydrochloride was used in step 3 to synthesize 4-(tert-butyl)-2-((4-(methylsulfonyl)phenyl)sulfonamide)-N-(3-phenylbicyclo[1.1.1]pentan-1-yl)benzamide, which was then purified by crystallization. 1 H NMR (400 MHz, DMSO-d6) δ 11.84 (s, 1H), 9.27 (s, 1H), 8.10 (d, J = 8.5 Hz, 2H), 7.96 (d, J = 8.5 Hz, 2H), 7.66 (d, J = 8.4 Hz, 1H), 7.45 (d, J = 1.9 Hz, 1H), 7.38 - 7.16 (m, 6H), 3.27 (s, 3H), 2.33 (s, 6H), 1.23 (s, 9H). LCMS-ESI + (m / z): [M+H] + calcd 553.18;found 553.11.

[0203] [ka] Example 16: Preparation of 2-((4-(tert-butyl)phenyl)sulfonamide)-4-(methylsulfonyl)-N-(3-(trifluoromethyl)bicyclo[1.1.1]pentan-1-yl)benzamide According to General Synthesis 1, 2-amino-4-(methylsulfonyl)methyl benzoate and 4-tert-butylbenzenesulfonyl chloride (1.5 equivalents) are used in step 1, and then 3-(trifluoromethyl)bicyclo[1.1.1]pentan-1-amine hydrochloride is used in step 3 to produce 2-((4-(tert-butyl)phenyl)sulfonamide)-4-(methylsulfonyl)-N-(3-(trifluoromethyl)bicyclo[1.1.1]pentan-1amine). Tan-1-yl)benzamide was synthesized and then purified by crystallization. 1 1H NMR (400 MHz, DMSO-d6) δ 11.25 (s, 1H), 9.63 (s, 1H), 7.95 (d, J = 1.7 Hz, 1H), 7.90 (d, J = 8.3 Hz, 1H), 7.73 (d, J = 8.1 Hz, 1H), 7.67 (d, J = 8.6 Hz, 2H), 7.59 (d, J = 8.6 Hz, 2H), 3.21 (s, 3H), 2.33 (s, 6H), 1.25 (s, 9H). LCMS-ESI + (m / z): [M+H] + calcd 545.14;found 545.08.

[0204] [ka] Example 17: Preparation of 2-((4-(1H-tetrazole-1-yl)phenyl)sulfonamide)-4-(trifluoromethyl)-N-(3-(trifluoromethyl)bicyclo[1.1.1]pentan-1-yl)benzamide According to General Synthesis 1, 2-amino-4-(trifluoromethyl)methyl benzoate and 4-(1H-tetrazole-1-yl)benzenesulfonyl chloride (1.5 equivalents) were used in step 1, and then 3-(trifluoromethyl)bicyclo[1.1.1]pentan-1-amine hydrochloride was used in step 3 to synthesize 2-((4-(1H-tetrazole-1-yl)phenyl)sulfonamide)-4-(trifluoromethyl)-N-(3-(trifluoromethyl)bicyclo[1.1.1]pentan-1-yl)benzamide, which was then purified by reverse-phase chromatography. 1 H NMR (400 MHz, DMSO-d6) δ 11.33 (s, 1H), 10.20 (s, 1H), 9.61 (s, 1H), 8.15 (d, J = 8.8 Hz, 2H), 7.99 (d, J = 8.8 Hz, 2H), 7.86 (d, J = 8.2 Hz, 1H), 7.73(s, 1H), 7.65 - 7.58 (m, 1H), 2.32 (s, 6H). LCMS-ESI + (m / z): [M+H] + calcd 547.10 ;found 547.05.

[0205] [ka] Example 18: Preparation of N-(3-cyanobicyclo[1.1.1]pentan-1-yl)-2-((4-(methylsulfonyl)phenyl)sulfonamide)-4-(trifluoromethyl)benzamide According to General Synthesis 1, 2-amino-4-(trifluoromethyl)methyl benzoate and 4-(methylsulfonyl)benzenesulfonyl chloride (1.95 equivalents) were used in step 1 at room temperature for 48 hours, and then 3-aminobicyclo[1.1.1]pentan-1-carbonitrile was used in step 3 to synthesize N-(3-cyanobicyclo[1.1.1]pentan-1-yl)-2-((4-(methylsulfonyl)phenyl)sulfonamide)-4-(trifluoromethyl)benzamide, which was then purified by reverse-phase chromatography. 1 H NMR (400 MHz, DMSO-d6) δ 11.23 (s, 1H), 9.57 (s, 1H), 8.11 (d, J = 8.5 Hz, 2H), 7.95 (d, J = 8.5 Hz, 2H), 7.82 (d, J = 8.1 Hz, 1H), 7.69 - 7.57 (m, 2H), 3.29 (s, 3H), 2.54 (s, 6H). LCMS-ESI + (m / z): [M+H] + calcd 514.07;found 514.09.

[0206] [ka] Example 19: Preparation of 2-((1-methyl-1H-pyrazole)-4-sulfonamide)-4-(trifluoromethyl)-N-(3-(trifluoromethyl)bicyclo[1.1.1]pentan-1-yl)benzamide According to General Synthesis 1, 2-amino-4-(trifluoromethyl)methyl benzoate and 1-methyl-1H-pyrazole-4-sulfonyl chloride (2.25 equivalents) were used in step 1 at room temperature for 72 hours, and then 3-(trifluoromethyl)bicyclo[1.1.1]pentan-1-amine hydrochloride was used in step 3 to synthesize 2-((1-methyl-1H-pyrazole)-4-sulfonamide)-4-(trifluoromethyl)-N-(3-(trifluoromethyl)bicyclo[1.1.1]pentan-1-yl)benzamide, which was then purified by crystallization. 1H NMR (400 MHz, DMSO-d6) δ 11.16 (s, 1H), 9.69 (s, 1H), 8.33 (s, 1H), 7.92 (d, J = 8.3 Hz, 1H), 7.72 (d, J = 8.1 Hz, 2H), 7.59 (d, J = 8.2 Hz, 1H), 3.82 (s, 3H), 2.35 (s, 6H). LCMS-ESI + (m / z): [M+H] + calcd 483.09;found 483.1.

[0207] [ka] Example 20: Preparation of N-(3-fluorobicyclo[1.1.1]pentan-1-yl)-2-((4-(methylsulfonyl)phenyl)sulfonamide)-4-(trifluoromethyl)benzamide According to General Synthesis 1, 2-amino-4-(trifluoromethyl)methyl benzoate and 4-(methylsulfonyl)benzenesulfonyl chloride (1.95 equivalents) were used in step 1 at room temperature for 48 hours, and then 3-fluorobicyclo[1.1.1]pentan-1-amine hydrochloride was used in step 3 to synthesize N-(3-fluorobicyclo[1.1.1]pentan-1-yl)-2-((4-(methylsulfonyl)phenyl)sulfonamide)-4-(trifluoromethyl)benzamide, which was then purified by crystallization. 1 H NMR (400 MHz, DMSO-d6) δ 11.27 (s, 1H), 9.54 (s, 1H), 8.10 (d, J = 8.5 Hz, 2H), 7.94 (d, J = 8.5 Hz, 2H), 7.86 (d, J = 8.2 Hz, 1H), 7.70 - 7.58 (m, 2H), 3.28 (s, 3H), 2.38 (d, J = 2.2 Hz, 6H). LCMS-ESI + (m / z): [M+H] + calcd 507.07;found 507.07.

[0208] [ka] Example 21: 4-Fluoro-N-(3-Fluorobicyclo[1.1.1]pentane- Preparation of 1-yl)-2-((4-(methylsulfonyl)phenyl)sulfonamide)benzamide Following general synthesis method 1, 4-(methylsulfonyl)benzenesulfonyl chloride (1.2 equivalents) was used in step 1, and 3-fluorobicyclo[1.1.1]pentan-1-amine hydrochloride was used in step 3 to synthesize 4-fluoro-N-(3-fluorobicyclo[1.1.1]pentan-1-yl)-2-((4-(methylsulfonyl)phenyl)sulfonamide)benzamide, which was then purified by reverse-phase chromatography. 1 H NMR (400 MHz, DMSO-d6) δ 11.84 (s, 1H), 9.42 (s, 1H), 8.10 (d, J = 8.5 Hz, 2H), 8.02 (d, J = 8.5 Hz, 2H), 7.80 (dd, J = 8.9, 6.2 Hz, 1H), 7.26 (d, J = 9.9 Hz, 1H), 7.15 - 7.05 (m, 1H), 3.29 (s, 3H), 2.39 (d, J = 2.2 Hz, 6H). LCMS-ESI + (m / z): [M+H] + calcd 457.07;found 457.00.

[0209] [ka] Example 22: Preparation of 4-fluoro-2-((3-(methylsulfonyl)phenyl)sulfonamide)-N-(3-(trifluoromethyl)bicyclo[1.1.1]pentan-1-yl)benzamide According to General Synthesis 1, 4-(methylsulfonyl)benzenesulfonyl chloride (1.2 equivalents) was used in step 1, and 3-(trifluoromethyl)bicyclo[1.1.1]pentan-1-amine hydrochloride was used in step 3 to synthesize 4-fluoro-2-((3-(methylsulfonyl)phenyl)sulfonamide)-N-(3-(trifluoromethyl)bicyclo[1.1.1]pentan-1-yl)benzamide, which was then purified by crystallization. 1 H NMR (400 MHz, DMSO-d6) δ 11.91 (s, 1H), 9.49 (s, 1H), 8.26 - 8.17 (m, 2H), 8.13 (d, J = 8.3 Hz, 1H), 7.87 (t, J = 7.9 Hz, 1H), 7.80 (dd, J = 8.9, 6.2 Hz, 1H), 7.32 - 7.20 (m, 1H), 7.16 - 7.02 (m, 1H), 3.27 (s, 3H), 2.31 (s, 6H). LCMS-ESI + (m / z): [M+H] + calcd 507.07;found 507.02.

[0210] [ka] Example 23: Preparation of N-(bicyclo[1.1.1]pentan-1-yl)-2-((4-(methylsulfonyl)phenyl)sulfonamide)-4-(trifluoromethyl)benzamide According to General Synthesis 1, 2-amino-4-(trifluoromethyl)methyl benzoate and 4-(methylsulfonyl)benzenesulfonyl chloride (1.95 equivalents) were used in step 1 at room temperature for 48 hours, and then bicyclo[1.1.1]pentan-1-amine hydrochloride was used in step 3 to synthesize N-(bicyclo[1.1.1]pentan-1-yl)-2-((4-(methylsulfonyl)phenyl)sulfonamide)-4-(trifluoromethyl)benzamide, which was then purified by crystallization. 1 1H NMR (400 MHz, methanol-d4) δ 8 .11 - 8.03 (m, 2H), 7.95 - 7.88 (m, 3H), 7.70 (d, J = 8.1 Hz, 1H), 7.47 (d, J = 8.2 Hz, 1H), 3.14 (s, 3H), 2.48 (s, 1H), 2.13 (s, 6H). LCMS-ESI + (m / z): [M+H] + calcd 489.08;found 489.06.

[0211] [ka] Example 24: Preparation of 2-((4-(ethylsulfonyl)phenyl)sulfonamide)-4-(trifluoromethyl)-N-(3-(trifluoromethyl)bicyclo[1.1.1]pentan-1-yl)benzamide According to General Synthesis 1, 2-amino-4-(trifluoromethyl)methyl benzoate and 4-(ethylsulfonyl)benzenesulfonyl chloride (1.3 equivalents) were used in step 1 at room temperature for 48 hours, and then 3-(trifluoromethyl)bicyclo[1.1.1]pentan-1-amine hydrochloride was used in step 3 to synthesize 2-((4-(ethylsulfonyl)phenyl)sulfonamide)-4-(trifluoromethyl)-N-(3-(trifluoromethyl)bicyclo[1.1.1]pentan-1-yl)benzamide, which was then purified by crystallization. 1 H NMR (400 MHz, DMSO-d6) δ 11.26 (s, 1H), 9.59 (s, 1H), 8.07 (d, J = 8.5 Hz, 2H), 7.95 (d, J = 8.5 Hz, 2H), 7.85 (d, J = 8.3 Hz, 1H), 7.68 - 7.59 (m, 2H), 3.36 (q, J = 7.3 Hz, 2H), 2.30 (s, 6H), 1.06 (t, J = 7.4 Hz, 3H). LCMS-ESI + (m / z): [M+H] + calcd 571.08;found 571.14.

[0212] [ka] Example 25: Preparation of N-(3-cyanobicyclo[1.1.1]pentan-1-yl)-2-((4-(ethylsulfonyl)phenyl)sulfonamide)-4-(trifluoromethyl)benzamide According to General Synthesis 1, 2-amino-4-(trifluoromethyl)methyl benzoate and 4-(ethylsulfonyl)benzenesulfonyl chloride (1.3 equivalents) were used in step 1 at room temperature for 48 hours, and then 3-aminobicyclo[1.1.1]pentan-1-carbonitrile was used in step 3 to synthesize N-(3-cyanobicyclo[1.1.1]pentan-1-yl)-2-((4-(ethylsulfonyl)phenyl)sulfonamide)-4-(trifluoromethyl)benzamide, which was then purified by reverse-phase chromatography. 1 H NMR (400 MHz, DMSO-d6) δ 11.21 (s, 1H), 9.57 (s, 1H), 8.07 (d, J = 8.6 Hz, 2H), 7.95 (d, J = 8.5 Hz, 2H), 7.81 (d, J = 8.1 Hz, 1H), 7.67 - 7.59 (m, 2H), 3.37 (q, J = 7.3 Hz, 2H), 2.54 (s, 6H), 1.06 (t, J = 7.4 Hz, 3H). LCMS-ESI + (m / z): [M+H] + calcd 528.09;found 528.13.

[0213] [ka] Example 26: Preparation of 2-((4-(ethylsulfonyl)phenyl)sulfonamide)-N-(3-fluorobicyclo[1.1.1]pentan-1-yl)-4-(trifluoromethyl)benzamide According to General Synthesis 1, 2-amino-4-(trifluoromethyl)methyl benzoate and 4-(ethylsulfonyl)benzenesulfonyl chloride (1.3 equivalents) were used in step 1 at room temperature for 48 hours, and then 3-fluorobicyclo[1.1.1]pentan-1-amine hydrochloride was used in step 3 to synthesize 2-((4-(ethylsulfonyl)phenyl)sulfonamide)-N-(3-fluorobicyclo[1.1.1]pentan-1-yl)-4-(trifluoromethyl)benzamide, which was then purified by reverse-phase chromatography. 1 H NMR (400 MHz, DMSO-d6) δ 11.25 (s, 1H), 9.53 (s, 1H), 8.06 (d, J = 8.3 Hz, 2H), 7.95 (d, J = 8.5 Hz, 2H), 7.86 (d, J = 8.2 Hz, 1H), 7.70 - 7.59 (m, 2H), 3.36 (q, J = 7.3 Hz, 2H), 2.38 (d, J = 2.2 Hz, 6H), 1.06 (t, J = 7.4 Hz, 3H). LCMS-ESI + (m / z): [M+H] + calcd 521.08;found 521.11.

[0214] [ka] Example 27: Preparation of N-(bicyclo[1.1.1]pentan-1-yl)-2-((4-(ethylsulfonyl)phenyl)sulfonamide)-4-(trifluoromethyl)benzamide According to General Synthesis 1, 2-amino-4-(trifluoromethyl)methyl benzoate and 4-(ethylsulfonyl)benzenesulfonyl chloride (1.3 equivalents) were used in step 1 at room temperature for 48 hours, and then bicyclo[1.1.1]pentan-1-amine hydrochloride was used in step 3 to synthesize N-(bicyclo[1.1.1]pentan-1-yl)-2-((4-(ethylsulfonyl)phenyl)sulfonamide)-4-(trifluoromethyl)benzamide, which was then purified by crystallization. 1H NMR (400 MHz, DMSO-d6) δ 11.58 (s, 1H), 9.40 (s, 1H), 8.06 (d, J = 8.5 Hz, 2H), 7.96 (d, J = 8.5 Hz, 2H), 7.87 (d, J = 8.2 Hz, 1H), 7.65 (s, 1H), 7.64 - 7.57 (m, 1H), 3.35 (q, J = 7.3 Hz, 2H), 2.06 (s, 6H), 1.06 (t, J = 7.3 Hz, 3H). LCMS-ESI + (m / z): [M+H] + calcd 503.09;found 503.06.

[0215] Example 28: Preparation of 2-((4-(cyclopropylsulfonyl)phenyl)sulfonamide)-4-fluoro-N-(3-(trifluoromethyl)bicyclo[1.1.1]pentan-1-yl)benzamide [ka] Step 1: Following Step 1 of General Synthesis 1, 4-iodobenzenesulfonyl chloride (1.3 equivalents) was used at room temperature for 48 hours to synthesize 4-fluoro-2-((4-iodophenyl)sulfonamide)methyl benzoate, which was then purified by silica gel chromatography (LCMS-ESI). + (m / z): [(M-CH3OH)+H] + calcd 403.93;found 404.04.

[0216] Step 2: In a 10 mL container, methyl 4-fluoro-2-((4-iodophenyl)sulfonamide)benzoate (100 mg, 0.230 mmol), sodium cyclopropanesulfinate (58.9 mg, 0.460 mmol), copper toluene trifluoromethanesulfonate complex (119 mg, 0.230 mmol), and DMSO (2.3 mL) were added. This mixture was degassed under nitrogen for 10 minutes. trans-1,2-diaminocyclohexane (55.2 μL, 0.460 mmol) was added, and this solution was heated at 120 °C for 10 hours, then stirred at room temperature for 48 hours. This mixture was diluted with water and extracted with ethyl acetate (three times). The combined organic layers were washed with brine, dried over MgSO4, filtered, and concentrated. This crude mixture was purified by silica gel chromatography to obtain methyl 2-((4-(cyclopropylsulfonyl)phenyl)sulfonamide)-4-fluorobenzoate. 1 ¹H NMR (400 MHz, chloroform-d) δ 11.04 (s, 1H), 8.09 - 8.02 (m, 2H), 8.02 - 7.94 (m, 3H), 7.47 (dd, J = 10.7, 2.5 Hz, 1H), 6.78 (ddd, J = 8.9, 7.5, 2.5 Hz, 1H), 3.89 (s, 3H), 2.49 - 2.40 (m, 1H), 1.40 - 1.33 (m, 2H), 1.12 - 1.05 (m, 2H).

[0217] Steps 3-4: Following general synthesis 1, 2-((4-(cyclopropylsulfonyl)phenyl)sulfonamide)-4-fluoro-N-(3-(trifluoromethyl)bicyclo[1.1.1]pentan-1-yl)benzamide was synthesized using 3-(trifluoromethyl)bicyclo[1.1.1]pentan-1-yl)benzamide in step 3 and purified by reverse-phase chromatography. 1H NMR (400 MHz, DMSO-d6) δ 11.84 (s, 1H), 9.49 (s, 1H), 8.08 (d, J = 8.5 Hz, 2H), 8.02 (d, J = 8.4 Hz, 2H), 7.79 (dd, J = 8.9, 6.2 Hz, 1H), 7.27 (dd, J = 10.5, 2.5 Hz, 1H), 7.16 - 7.07 (m, 1H), 3.00 - 2.88 (m, 1H), 2.30 (s, 6H), 1.18 - 1.02 (m, 4H). LCMS-ESI + (m / z): [M+H] + calcd 533.08;found 533.07.

[0218] [ka] Example 29: 2-((4-(1,1-dioxideisothiazolidined-2-yl)phenyl)sulfonamide)-4-(trifluoromethyl)-N-(3-(trifluoromethyl Preparation of bicyclo[1.1.1]pentan-1-yl)benzamide According to General Synthesis 1, 2-amino-4-(trifluoromethyl)methyl benzoate and 4-(1,1-dioxideisothiazolidine-2-yl)benzenesulfonyl chloride (1.3 equivalents) were used in step 1 at room temperature for 48 hours, and then 3-(trifluoromethyl)bicyclo[1.1.1]pentan-1-amine hydrochloride was used in step 3 to synthesize 2-((4-(1,1-dioxideisothiazolidine-2-yl)phenyl)sulfonamide)-4-(trifluoromethyl)-N-(3-(trifluoromethyl)bicyclo[1.1.1]pentan-1-yl)benzamide, which was then purified by crystallization. 1 H NMR (400 MHz, DMSO-d6) δ 11.25 (s, 1H), 9.66 (s, 1H), 7.87 (d, J = 8.3 Hz, 1H), 7.77 - 7.65 (m, 3H), 7.57 (d, J = 8.3 Hz, 1H), 7.31 - 7.18 (m, 2H), 3.77 (t, J = 6.5 Hz, 2H), 3.58 (t, J = 7.3 Hz, 2H), 2.45 - 2.37 (m, 2H), 2.34 (s, 6H). LCMS-ESI + (m / z): [M+H] + calcd 598.09;found 598.16.

[0219] [ka] Example 30: Preparation of 2-((4-(N,N-dimethylsulfamoyl)phenyl)sulfonamide)-N-(3-phenylbicyclo[1.1.1]pentan-1-yl)-4-(trifluoromethyl)benzamide According to General Synthesis 1, 2-amino-4-(trifluoromethyl)methyl benzoate and 4-(N,N-dimethylsulfamoyl)benzenesulfonyl chloride (1.3 equivalents) were used in Step 1 under reflux for 48 hours, and then 3-phenylbicyclo[1.1.1]pentan-1-amine hydrochloride was used in Step 3 to synthesize 2-((4-(N,N-dimethylsulfamoyl)phenyl)sulfonamide)-N-(3-phenylbicyclo[1.1.1]pentan-1-yl)-4-(trifluoromethyl)benzamide, which was then purified by crystallization. 1 H NMR (400 MHz, DMSO-d6) δ 11.53 (s, 1H), 9.51 (s, 1H), 7.99 - 7.85 (m, 5H), 7.70-7.57 (m, 2H), 7.38 - 7.30 (m, 2H), 7.30 - 7.18 (m, 3H), 2.60 (s, 6H), 2.32 (s, 6H). LCMS-ESI + (m / z): [M+H] + calcd 594.13;found 594.14.

[0220] [ka] Example 31: Preparation of N-(3-phenylbicyclo[1.1.1]pentan-1-yl)-2-((4-(trifluoromethoxy)phenyl)sulfonamide)-4-(trifluoromethyl)benzamide According to General Synthesis 1, 2-amino-4-(trifluoromethyl)methyl benzoate and 4-(trifluoromethoxy)benzenesulfonyl chloride (2.0 equivalents) were used in step 1 at room temperature for 7 days, and then 3-phenylbicyclo[1.1.1]pentan-1-amine hydrochloride was used in step 3 to produce N-(3-phenylbicyclo[1.1.1]pentan-1-yl)-2-((4-(trifluoromethoxy)phenyl)sulfonamide)-4-(tri Fluoromethylbenzamide was synthesized and then purified by silica gel chromatography. 1 H NMR (400 MHz, DMSO-d6) δ 11.51 (s, 1H), 9.52 (s, 1H), 7.93 (bs, 1H), 7.85 (d, J = 8.6 Hz, 2H), 7.71-7.43 (m, J = 34.0 Hz, 4H), 7.39 - 7.18 (m, 5H), 2.32 (s, 6H). LCMS-ESI + (m / z): [M+H] + calcd 571.11;found 571.19.

[0221] [ka] Example 32: Preparation of N-(3-cyanobicyclo[1.1.1]pentan-1-yl)-2-((4-(trifluoromethoxy)phenyl)sulfonamide)-4-(trifluoromethyl)benzamide According to General Synthesis 1, 2-amino-4-(trifluoromethyl)methyl benzoate and 4-(trifluoromethoxy)benzenesulfonyl chloride (2.0 equivalents) were used in step 1 at room temperature for 7 days, and then 3-aminobicyclo[1.1.1]pentan-1-carbonitrile was used in step 3 to synthesize N-(3-cyanobicyclo[1.1.1]pentan-1-yl)-2-((4-(trifluoromethoxy)phenyl)sulfonamide)-4-(trifluoromethyl)benzamide, which was then purified by reverse-phase chromatography. 1 H NMR (400 MHz, DMSO-d6) δ 11.18 (s, 1H), 9.57 (s, 1H), 7.88-7.78 (m, 3H), 7.65-7.53 (m, 4H), 2.56 (s, 6H). LCMS-ESI + (m / z): [M+H] + calcd 520.08;found 520.12.

[0222] [ka] Example 33: Preparation of 4-(trifluoromethyl)-N-(3-(trifluoromethyl)bicyclo[1.1.1]pentan-1-yl)-2-((4-((trifluoromethyl)sulfonyl)phenyl)sulfonamide)benzamide According to General Synthesis 1, 2-amino-4-(trifluoromethyl)methyl benzoate and 4-((trifluoromethyl)sulfonyl)benzenesulfonyl chloride (2.0 equivalents) were used in step 1 at room temperature for 36 hours, and then 3-(trifluoromethyl)bicyclo[1.1.1]pentan-1-amine hydrochloride was used in step 3 to synthesize 4-(trifluoromethyl)-N-(3-(trifluoromethyl)bicyclo[1.1.1]pentan-1-yl)-2-((4-((trifluoromethyl)sulfonyl)phenyl)sulfonamide)benzamide, which was then purified by reverse-phase chromatography. 1H NMR (400 MHz, DMSO-d6) δ 11.22 (s, 1H), 9.54 (s, 1H), 8.34 (d, J = 8.5 Hz, 2H), 8.15 - 8.02 (m, 2H), 7.83 (d, J = 8.2 Hz, 1H), 7.65 (bs, 1H), 7.56 (s, 1H), 2.27 (s, 6H). LCMS-ESI + (m / z): [M+H] + calcd 611.04;found 611.15.

[0223] [ka] Example 34: Preparation of 2-((4-((difluoromethyl)sulfonyl)phenyl)sulfonamide)-4-(trifluoromethyl)-N-(3-(trifluoromethyl)bicyclo[1.1.1]pentan-1-yl)benzamide According to General Synthesis 1, 2-amino-4-(trifluoromethyl)methyl benzoate and 4-((difluoromethyl)sulfonyl)benzenesulfonyl chloride (2.0 equivalents) were used in step 1 at room temperature for 36 hours, and then 3-(trifluoromethyl)bicyclo[1.1.1]pentan-1-amine hydrochloride was used in step 3 to synthesize 2-((4-((difluoromethyl)sulfonyl)phenyl)sulfonamide)-4-(trifluoromethyl)-N-(3-(trifluoromethyl)bicyclo[1.1.1]pentan-1-yl)benzamide, which was then purified by reverse-phase chromatography. 1 H NMR (400 MHz, DMSO-d6) δ 11.27 (s, 1H), 9.57 (s, 1H), 8.17 (d, J = 8.5 Hz, 2H), 8.05 (d, J = 8.5 Hz, 2H), 7.84 (d, J = 8.2 Hz, 1H), 7.70 - 7.62 (m, 1H), 7.61 (s, 1H), 7.39 (t, J = 51.8 Hz, 1H), 2.28 (s, 6H). LCMS-ESI +(m / z): [M+H] + calcd 593.05;found 593.16.

[0224] [ka] Example 35: Preparation of N-(3-cyanobicyclo[1.1.1]pentan-1-yl)-2-(naphthalene-2-sulfonamide)-4-(trifluoromethyl)benzamide According to General Synthesis 1, 2-amino-4-(trifluoromethyl)methyl benzoate and naphthalene-2-sulfonyl chloride (1.2 equivalents) were used in step 1 at room temperature for 36 hours, and then 3-aminobicyclo[1.1.1]pentane-1-carbonitrile was used in step 3 to synthesize N-(3-cyanobicyclo[1.1.1]pentan-1-yl)-2-(naphthalene-2-sulfonamide)-4-(trifluoromethyl)benzamide, which was then purified by reverse-phase chromatography. 1 H NMR (400 MHz, DMSO-d6) δ 11.31 (s, 1H), 9.56 (s, 1H), 8.47 (s, 1H), 8.13 (dd, J = 16.7, 8.3 Hz, 2H), 8.03 (d, J = 8.1 Hz, 1H), 7.82 - 7.62 (m, 5H), 7.53 (d, J = 8.2 Hz, 1H), 2.51 (s, 6H). LCMS-ESI + (m / z): [M+H] + calcd 486.11;found 486.17.

[0225] Example 36: Preparation of 2-((4-(1H-imidazole-1-yl)phenyl)sulfonamide)-N-(3-phenylbicyclo[1.1.1]pentan-1-yl)benzamide [ka] Steps 1-3: Following general synthesis 1, ethyl 2-aminobenzoate and 4-iodobenzenesulfonyl chloride (1.2 equivalents) were used in Step 1 at room temperature for 48 hours, and then 3-phenylbicyclo[1.1.1]pentan-1-amine hydrochloride was used in Step 3 to synthesize 2-((4-iodophenyl)sulfonamide)-N-(3-phenylbicyclo[1.1.1]pentan-1-yl)benzamide, which was then purified by silica gel chromatography. LCMS-ESI + (m / z): [M+H] + calcd 545.04;found 545.07.

[0226] Step 4: A 10 mL microwave vial contained 2-((4-iodophenyl)sulfonamide)-N-(3-phenylbicyclo[1.1.1]pentan-1-yl)benzamide (100 mg, 0.184 mmol), imidazole (16.3 mg, 0.239 mmol), cesium carbonate (150 mg, 0.459 mmol), copper(I) oxide (1.31 mg, 0.009 mmol), 8-hydroxyquinoline (5.33 mg, 0.037 mmol), PEG3350 (36.0 mg), and 2.0 mL of 15:1 DMA / water degassed under nitrogen. The mixture was then degassed under nitrogen for 10 minutes and subsequently heated at 110°C for 18 hours with stirring. The mixture was cooled to room temperature, filtered, and the solid was rinsed with ELISA. This solution was concentrated and then purified by reverse-phase chromatography to obtain 2-((4-(1H-imidazole-1-yl)phenyl)sulfonamide)-N-(3-phenylbicyclo[1.1.1]pentan-1-yl)benzamide. 1 H NMR (400 MHz, DMSO-d6) δ 11.74 (s, 1H), 9.34 (s, 1H), 9.13 (bs, 1H), 8.12 (s, 1H), 7.94 (s, 4H), 7.73 (d, J = 7.7 Hz, 1H), 7.61 - 7.46 (m, 3H), 7.36 - 7.21 (m, 5H), 7.21 - 7.13 (m, 1H), 2.34 (s, 6H). LCMS-ESI + (m / z): [M+H] + calcd 485.16;found 485.38.

[0227] [ka] Example 37: Preparation of N-(bicyclo[1.1.1]pentan-1-yl)-2-(phenylsulfonamide)-4-(trifluoromethyl)benzamide According to General Synthesis 1, 2-amino-4-(trifluoromethyl)methyl benzoate and benzenesulfonyl chloride (1.5 equivalents) were used in step 1 at room temperature for 7 days, and then bicyclo[1.1.1]pentan-1-amine hydrochloride was used in step 3 to synthesize N-(bicyclo[1.1.1]pentan-1-yl)-2-(phenylsulfonamide)-4-(trifluoromethyl)benzamide, which was then purified by reverse-phase chromatography. 1 H NMR (400 MHz, DMSO-d6) δ 11.55 (s, 1H), 9.44 (s, 1H), 7.86 (d, J = 8.3 Hz, 1H), 7.77 - 7.61 (m, 4H), 7.61 - 7.48 (m, 3H), 2.50 (s, 1H, invisible due to DMSO peak), 2.09 (s, 6H). LCMS-ESI + (m / z): [M+H] + calcd 411.10;found 411.17.

[0228] [ka] Example 38: Preparation of 2-(phenylsulfonamide)-4-(trifluoromethyl)-N-(3-(trifluoromethyl)bicyclo[1.1.1]pentan-1-yl)benzamide According to General Synthesis 1, 2-amino-4-(trifluoromethyl)methyl benzoate and benzenesulfonyl chloride (1.5 equivalents) were used in step 1 at room temperature for 7 days, and then 3-(trifluoromethyl)bicyclo[1.1.1]pentan-1-amine hydrochloride was used in step 3 to synthesize 2-(phenylsulfonamide)-4-(trifluoromethyl)-N-(3-(trifluoromethyl)bicyclo[1.1.1]pentan-1-yl)benzamide, which was then purified by crystallization. 1 H NMR (400 MHz, DMSO-d6) δ 11.29 (s, 1H), 9.64 (s, 1H), 7.86 (d, J = 8.2 Hz, 1H), 7.75 - 7.63 (m, 4H), 7.61 - 7.53 (m, 3H), 2.33 (s, 6H). LCMS-ESI + (m / z): [M+H] + calcd 479.09;found 479.12.

[0229] [ka] Example 39: Preparation of 2-((1-methyl-1H-pyrazole)-4-sulfonamide)-N-(3-phenylbicyclo[1.1.1]pentan-1-yl)-4-(trifluoromethyl)benzamide According to General Synthesis 1, 2-amino-4-(trifluoromethyl)methyl benzoate and 1-methyl-1H-pyrazole-4-sulfonyl chloride (2.25 equivalents) were used in step 1 at room temperature for 72 hours, and then 3-phenylbicyclo[1.1.1]pentan-1-amine hydrochloride was used in step 3 to synthesize 2-((1-methyl-1H-pyrazole)-4-sulfonamide)-N-(3-phenylbicyclo[1.1.1]pentan-1-yl)-4-(trifluoromethyl)benzamide, which was then purified by reverse-phase chromatography. 1H NMR (400 MHz, DMSO-d6) δ 11.44 (s, 1H), 9.61 (s, 1H), 8.35 (s, 1H), 7.98 (d, J = 8.2 Hz, 1H), 7.75 (s, 1H), 7.71 (s, 1H), 7.58 (d, J = 8.9 Hz, 1H), 7.37 - 7.20 (m, 5H), 3.83 (s, 3H), 2.37 (s, 6H). LCMS-ESI + (m / z): [M+H] + calcd 491.14;found 491.20.

[0230] [ka] Example 40: Preparation of N-(3-cyanobicyclo[1.1.1]pentan-1-yl)-2-((2,4,6-trichlorophenyl)sulfonamide)-4-(trifluoromethyl)benzamide According to General Synthesis 1, 2-amino-4-(trifluoromethyl)methyl benzoate and 2,4,6-trichlorobenzenesulfonyl chloride (2 equivalents) were used in step 1 at room temperature for 72 hours, and then 3-aminobicyclo[1.1.1]pentan-1-carbonitrile was used in step 3 to synthesize N-(3-cyanobicyclo[1.1.1]pentan-1-yl)-2-((2,4,6-trichlorophenyl)sulfonamide)-4-(trifluoromethyl)benzamide, which was then purified by reverse-phase chromatography. 1 1H NMR (400 MHz, DMSO-d6) δ 12.03 (s, 1H), 9.84 (s, 1H), 8.00-7.86 (m, 3H), 7.73 (s, 1H), 7.55 (s, 1H), 2.60 (s, 6H). LCMS-ESI + (m / z): [M+H] + calcd 537.98, found 538.02.

[0231] [ka] Example 41: Preparation of N-(3-cyanobicyclo[1.1.1]pentan-1-yl)-2-(phenylsulfonamide)-4-(trifluoromethyl)benzamide According to General Synthesis 1, 2-amino-4-(trifluoromethyl)methyl benzoate and benzenesulfonyl chloride (1.5 equivalents) were used in step 1 at room temperature for 7 days, and then 3-aminobicyclo[1.1.1]pentan-1-carbonitrile was used in step 3 to synthesize N-(3-cyanobicyclo[1.1.1]pentan-1-yl)-2-(phenylsulfonamide)-4-(trifluoromethyl)benzamide, which was then purified by reverse-phase chromatography. 1 H NMR (400 MHz, DMSO-d6) δ 11.22 (s, 1H), 9.61 (s, 1H), 7.82 (d, J = 8.2 Hz, 1H), 7.76 - 7.62 (m, 4H), 7.62 - 7.53 (m, 3H), 2.57 (s, 6H). LCMS-ESI + (m / z): [M+H] + calcd 436.09;found 436.13.

[0232] [ka] Example 42: Preparation of N-(3-cyanobicyclo[1.1.1]pentan-1-yl)-2-((4-(N,N-dimethylsulfamoyl)phenyl)sulfonamide)-4-(trifluoromethyl)benzamide According to General Synthesis 1, 2-amino-4-(trifluoromethyl)methyl benzoate and 4-(N,N-dimethylsulfamoyl)benzenesulfonyl chloride (1.3 equivalents) were used in Step 1 under reflux for 3 days, and then 3-aminobicyclo[1.1.1]pentan-1-carbonitrile was used in Step 3 to synthesize N-(3-cyanobicyclo[1.1.1]pentan-1-yl)-2-((4-(N,N-dimethylsulfamoyl)phenyl)sulfonamide)-4-(trifluoromethyl)benzamide, which was then purified by reverse-phase chromatography.1 H NMR (400 MHz, DMSO-d6) δ 11.18 (s, 1H), 9.56 (s, 1H), 7.92 (s, 4H), 7.81 (d, J = 8.2 Hz, 1H), 7.70 - 7.54 (m, 2H), 2.60 (s, 6H), 2.54 (s, 6H). LCMS-ESI + (m / z): [M+H] + calcd 543.10; found 543.17.

[0233] [ka] Example 43: Preparation of 2-((4-(1H-tetrazole-1-yl)phenyl)sulfonamide)-N-(3-phenylbicyclo[1.1.1]pentan-1-yl)-4-(trifluoromethyl)benzamide According to General Synthesis 1, 2-amino-4-(trifluoromethyl)methyl benzoate and 4-(1H-tetrazole-1-yl)benzenesulfonyl chloride (1.5 equivalents) were used in step 1, and then 3-phenylbicyclo[1.1.1]pentan-1-amine hydrochloride was used in step 3 to synthesize 2-((4-(1H-tetrazole-1-yl)phenyl)sulfonamide)-N-(3-phenylbicyclo[1.1.1]pentan-1-yl)-4-(trifluoromethyl)benzamide, which was then purified by crystallization. 1 H NMR (400 MHz, DMSO-d6) δ 11.58 (s, 1H), 10.21 (s, 1H), 9.52 (s, 1H), 8.16 (d, J = 8.4 Hz, 2H), 8.00 (d, J = 8.7 Hz, 2H), 7.91 (d, J = 8.3 Hz, 1H), 7.76 (s, 1H), 7.66-7.57 (m, 1H), 7.40 - 7.17 (m, 5H), 2.33 (s, 6H). LCMS-ESI + (m / z): [M+H] + calcd 555.14;found 555.08.

[0234] [ka] Example 44: Preparation of 2-((4-((difluoromethyl)sulfonyl)phenyl)sulfonamide)-N-(3-phenylbicyclo[1.1.1]pentan-1-yl)-4-(trifluoromethyl)benzamide According to General Synthesis 1, 2-amino-4-(trifluoromethyl)methyl benzoate and 4-((difluoromethyl)sulfonyl)benzenesulfonyl chloride (2.0 equivalents) were used in step 1 at room temperature for 36 hours, and then 3-phenylbicyclo[1.1.1]pentan-1-amine hydrochloride was used in step 3 to synthesize 2-((4-((difluoromethyl)sulfonyl)phenyl)sulfonamide)-N-(3-phenylbicyclo[1.1.1]pentan-1-yl)-4-(trifluoromethyl)benzamide, which was then purified by reverse-phase chromatography. 1 H NMR (400 MHz, DMSO-d6) δ 11.57 (s, 1H), 9.49 (s, 1H), 8.18 (d, J = 8.5 Hz, 2H), 8.07 (d, J = 8.5 Hz, 2H), 7.91 (d, J = 8.3 Hz, 1H), 7.65(s, 2H), 7.56 - 7.18 (m, 6H), 2.30 (s, 6H). LCMS-ESI + (m / z): [M+H] + calcd 601.09;found 601.18.

[0235] [ka] Example 45: Preparation of N-(bicyclo[2.2.1]heptan-1-yl)-2-((4-(methylsulfonyl)phenyl)sulfonamide)-4-(trifluoromethyl)benzamide According to General Synthesis 1, 2-amino-4-(trifluoromethyl)methyl benzoate and 4-(methylsulfonyl)benzenesulfonyl chloride (2.5 equivalents) were used in step 1 at room temperature for 48 hours, and then (1r,4r)-bicyclo[2.2.1]heptan-1-amine hydrochloride was used in step 3 to synthesize N-(bicyclo[2.2.1]heptan-1-yl)-2-((4-(methylsulfonyl)phenyl)sulfonamide)-4-(trifluoromethyl)benzamide, which was then purified by crystallization. 1 H NMR (400 MHz, DMSO-d6) δ 11.45 (s, 1H), 8.91 (s, 1H), 8.10 (d, J = 8.5 Hz, 2H), 8.00 - 7.85 (m, 3H), 7.69 (s, 1H), 7.61 (s, 1H), 3.26 (s, 3H), 2.13 (s, 1H), 1.76-1.57 (m, 8H), 1.41-1.29 (m, 2H). LCMS-ESI + (m / z): [M+H] + calcd 517.11;found 517.31.

[0236] [ka] Example 46: 4-bromo-2-((4-(methylsulfonyl)phenyl)sulfonamide)-N-(3-(trifluoromethyl)bicyclo[1.1.1]pentan-1-yl)benzamide According to General Synthesis 1, methyl 2-amino-4-bromobenzoate and 4-(methylsulfonyl)benzenesulfonyl chloride (2.0 equivalents) were used in step 1 at room temperature for 24 hours, and then 3-(trifluoromethyl)bicyclo[1.1.1]pentan-1-amine hydrochloride was used in step 3 to synthesize 4-bromo-2-((4-(methylsulfonyl)phenyl)sulfonamide)-N-(3-(trifluoromethyl)bicyclo[1.1.1]pentan-1-yl)benzamide, which was then purified by silica gel chromatography. 1 H NMR (400 MHz, DMSO-d6) δ 11.52 (s, 1H), 9.50 (s, 1H), 8.24-7.84 (m, 4H), 7.83-7.31 (m, 3H), 3.31 (s, 3H), 2.28 (s, 6H). LCMS-ESI + (m / z): [M+H] + calcd 566.99;found 566.99.

[0237] [ka] Example 47: Preparation of N-(bicyclo[1.1.1]pentan-1-yl)-4-bromo-2-(methylsulfonamide)benzamide According to General Synthesis 1, methyl 2-amino-4-bromobenzoate and methanesulfonyl chloride (7.0 equivalents) were used in step 1 at room temperature for 48 hours, and then bicyclo[1.1.1]pentan-1-amine hydrochloride was used in step 3 to synthesize N-(bicyclo[1.1.1]pentan-1-yl)-4-bromo-2-(methylsulfonamide)benzamide, which was then purified by reverse-phase chromatography. 1 H NMR (400 MHz, DMSO-d6) δ 11.47 (s, 1H), 9.40 (s, 1H), 7.78 (d, J = 8.5 Hz, 1H), 7.67 (d, J = 2.0 Hz, 1H), 7.38 (dd, J = 8.5, 2.0 Hz, 1H), 3.20 (s, 3H), 2.49 (s, 1H), 2.10 (s, 6H). LCMS-ESI + (m / z): [M+H] + calcd 359.01;found 359.01.

[0238] [ka] Example 48: Preparation of 4-bromo-2-(methylsulfonamide)-N-(3-(trifluoromethyl)bicyclo[1.1.1]pentan-1-yl)benzamide According to General Synthesis 1, methyl 2-amino-4-bromobenzoate and methanesulfonyl chloride (7.0 equivalents) were used in step 1 at room temperature for 48 hours, and then 3-(trifluoromethyl)bicyclo[1.1.1]pentan-1-amine hydrochloride was used in step 3 to synthesize 4-bromo-2-(methylsulfonamide)-N-(3-(trifluoromethyl)bicyclo[1.1.1]pentan-1-yl)benzamide, which was then purified by reverse-phase chromatography. 1 H NMR (400 MHz, DMSO-d6) δ 11.23 (s, 1H), 9.61 (s, 1H), 7.77 (d, J = 8.6 Hz, 1H), 7.68 (d, J = 2.0 Hz, 1H), 7.41 (dd, J = 8.5, 2.0 Hz, 1H), 3.21 (s, 3H), 2.35 (s, 6H). LCMS-ESI + (m / z): [M+H] + calcd 426.99;found 426.97.

[0239] [ka] Example 49: Preparation of 4-bromo-2-(methylsulfonamide)-N-(3-phenylbicyclo[1.1.1]pentan-1-yl)benzamide According to general synthesis 1, methyl 2-amino-4-bromobenzoate and methanesulfonyl chloride (7.0 equivalents) were used in step 1 at room temperature for 48 hours, and then 3-phenylbicyclo[1.1.1]pentane-1-amine hydrochloride was used in step 3 to produce 4-bromo-2-(methyl 2-bromobenzoate). (Tylsulfonamide)-N-(3-phenylbicyclo[1.1.1]pentan-1-yl)benzamide was synthesized and purified by crystallization. 1 H NMR (400 MHz, DMSO-d6) δ 11.49 (s, 1H), 9.51 (s, 1H), 7.83 (d, J = 8.6 Hz, 1H), 7.69 (d, J = 1.9 Hz, 1H), 7.40 (dd, J = 8.5, 2.0 Hz, 1H), 7.36 - 7.20 (m, 5H), 3.22 (s, 3H), 2.37 (s, 6H). LCMS-ESI + (m / z): [M+H] + calcd 435.04; found 435.08.

[0240] [ka] Example 50: Preparation of N-(bicyclo[1.1.1]pentan-1-yl)-2-(cyclopropanesulfonamide)-4-fluorobenzamide According to General Synthesis 1, cyclopropanesulfonyl chloride (6.0 equivalents) was used in step 1 at room temperature for 72 hours, and then bicyclo[1.1.1]pentan-1-amine hydrochloride was used in step 3 to synthesize N-(bicyclo[1.1.1]pentan-1-yl)-2-(cyclopropanesulfonamide)-4-fluorobenzamide, which was then purified by reverse-phase chromatography. 1 H NMR (400 MHz, DMSO-d6) δ 11.62 (s, 1H), 9.36 (s, 1H), 7.92 (dd, J = 8.9, 6.3 Hz, 1H), 7.34 (dd, J = 11.1, 2.6 Hz, 1H), 7.05 (ddd, J = 8.9, 8.1, 2.6 Hz, 1H), 2.90-2.81 (m, 1H), 2.49 (s, 1H), 2.11 (s, 6H), 1.04 - 0.96 (m, 4H). LCMS-ESI + (m / z): [M+H] + calcd 325.10;found 325.03.

[0241] [ka] Example 51: Preparation of 2-((4-carbamoylphenyl)sulfonamide)-N-(3-phenylbicyclo[1.1.1]pentan-1-yl)-4-(trifluoromethyl)benzamide According to General Synthesis 1, 4-carbamoylbenzenesulfonyl chloride (2.5 equivalents) was used in step 1 at 50°C for 72 hours, and then 3-phenylbicyclo[1.1.1]pentan-1-amine hydrochloride was used in step 3 to synthesize 2-((4-carbamoylphenyl)sulfonamide)-N-(3-phenylbicyclo[1.1.1]pentan-1-yl)-4-(trifluoromethyl)benzamide, which was then purified by crystallization. 1 H NMR (400 MHz, DMSO-d6) δ 11.52 (s, 1H), 9.53 (s, 1H), 8.15 (s, 1H), 8.01 (d, J = 8.5 Hz, 2H), 7.90 (d, J = 8.3 Hz, 1H), 7.79 (d, J = 8.5 Hz, 2H), 7.73 (s, 1H), 7.68 - 7.54 (m, 2H), 7.39 - 7.19 (m, 5H), 2.34 (s, 6H). LCMS-ESI + (m / z): [M+H] + calcd 530.14;found 529.95.

[0242] [ka] Example 52: Preparation of N-(bicyclo[1.1.1]pentan-1-yl)-2-((4-carbamoylphenyl)sulfonamide)-4-(trifluoromethyl)benzamide According to General Synthesis 1, 4-carbamoylbenzenesulfonyl chloride (2.5 equivalents) was used in step 1 at 50°C for 72 hours, and then bicyclo[1.1.1]pentan-1-amine hydrochloride was used in step 3 to synthesize 2-((4-carbamoylphenyl)sulfonamide)-N-(3-phenylbicyclo[1.1.1]pentan-1-yl)-4-(trifluoromethyl)benzamide, which was then purified by crystallization. 1H NMR (400 MHz, DMSO-d6) δ 11.53 (s, 1H), 9.41 (s, 1H), 8.14 (s, 1H), 7.99 (d, J = 8.5 Hz, 2H), 7.86 (d, J = 8.3 Hz, 1H), 7.77 (d, J = 8.5 Hz, 2H), 7.71 (d, J = 1.7 Hz, 1H), 7.66 - 7.51 (m, 2H), 2.49 (s, 1H, partially visible below the DMSO peak), 2.07 (s, 6H). LCMS-ESI + (m / z): [M+H] + calcd 454.10; found 454.04.

[0243] [ka] Example 53: Preparation of 2-((4-carbamoylphenyl)sulfonamide)-4-(trifluoromethyl)-N-(3-(trifluoromethyl)bicyclo[1.1.1]pentan-1-yl)benzamide According to General Synthesis 1, 4-carbamoylbenzenesulfonyl chloride (2.5 equivalents) was used in step 1 at 50°C for 72 hours, and then 3-(trifluoromethyl)bicyclo[1.1.1]pentan-1-amine hydrochloride was used in step 3 to synthesize 2-((4-carbamoylphenyl)sulfonamide)-N-(3-phenylbicyclo[1.1.1]pentan-1-yl)-4-(trifluoromethyl)benzamide, which was then purified by crystallization. 1 H NMR (400 MHz, DMSO-d6) δ 11.24 (s, 1H), 9.61 (s, 1H), 8.15 (s, 1H), 7.99 (d, J = 8.5 Hz, 2H), 7.85 (d, J = 8.3 Hz, 1H), 7.77 (d, J = 8.5 Hz, 2H), 7.70 (s, 1H), 7.66 - 7.56 (m, 2H), 2.31 (s, 6H). LCMS-ESI + (m / z): [M+H]+ calcd 522.09;found 521.95.

[0244] General synthesis 2 [ka] Example 54: Preparation of 2-((1-methylethyl)sulfonamide)-N-(3-phenylbicyclo[1.1.1]pentan-1-yl)-4-(trifluoromethyl)benzamide Step 1: A 20 mL microwave vial contained methyl 2-bromo-4-(trifluoromethyl)benzoate (306 mg, 1.08 mmol), propane-2-sulfonamide (266 mg, 2.16 mmol), tris(dibenzylideneacetone)dipalladium(0)-chloroform adduct (112 mg, 0.108 mmol), 4,5-bis(diphenylphosphin)-9,9-dimethylxanthene (188 mg, 0.324 mmol), tripotassium phosphate (1.15 g, 5.41 mmol), and toluene (10.0 mL). The vial was sealed, purged with nitrogen for 5 minutes, and then heated at 100°C for 18 hours. The reaction mixture was cooled to room temperature, concentrated, and diluted with water. The mixture was extracted with toluene (three times), washed with brine, dried over MgSO4, filtered, and concentrated. This crude product was purified by silica gel chromatography to obtain methyl 2-((1-methylethyl)sulfonamide)-4-(trifluoromethyl)benzoate. LCMS-ESI + (m / z): [M+H] + calcd 326.07;found 326.00.

[0245] Step 2: To a solution of methyl 2-((1-methylethyl)sulfonamide)-4-(trifluoromethyl)benzoate (304 mg, 0.935 mmol) in THF / MeOH / water (1:1:1, 30.0 mL), lithium hydroxide monohydrate (196 mg, 4.67 mmol) was added. The mixture was stirred at room temperature for 18 hours. The reaction was quenched with 1 N HCl and concentrated. The crude product was diluted with water and extracted with ELISA (three times). The combined organic layers were washed with brine, dried over MgSO4, filtered, and concentrated to obtain 2-((1-methylethyl)sulfonamide)-4-(trifluoromethyl)benzoic acid as a solid, which was used without further purification.

[0246] Step 3: A mixture of 2-((1-methylethyl)sulfonamide)-4-(trifluoromethyl)benzoic acid (45.0 mg, 0.145 mmol), 3-phenylbicyclo[1.1.1]pentan-1-amine hydrochloride (34.0 mg, 0.173 mmol), EDCI (33.7 mg, 0.217 mmol), and HOBT (29.3 mg, 0.217 mmol) in DMF (1.50 mL) was stirred for 5 minutes. N,N-diisopropylethylamine (126 μL, 0.723 mmol) was added, and the solution was stirred at room temperature for 1 hour. The solution was concentrated, and the crude product was purified by crystallization to obtain 2-((1-methylethyl)sulfonamide)-N-(3-phenylbicyclo[1.1.1]pentan-1-yl)-4-(trifluoromethyl)benzamide. 1 1H NMR (400 MHz, DMSO-d6) δ 11.21 (s, 1H), 9.72 (s, 1H), 8.05 (d, J = 8.2 Hz, 1H), 7.89 (s, 1H), 7.57 (d, J = 8.1 Hz, 1H), 7.38 - 7.19 (m, 5H), 3.51-3.38 (m, 1H), 2.39 (s, 6H), 1.26 (d, J = 6.8 Hz, 6H). LCMS-ESI + (m / z): [M+H] +calcd 453.15;found 453.00.

[0247] [ka] Example 55: Preparation of N-(bicyclo[1.1.1]pentan-1-yl)-2-((1-methylethyl)sulfonamide)-4-(trifluoromethyl)benzamide According to General Synthesis 2, N-(bicyclo[1.1.1]pentan-1-yl)-2-((1-methylethyl)sulfonamide)-4-(trifluoromethyl)benzamide was synthesized using bicyclo[1.1.1]pentan-1-amine hydrochloride in step 3, and then purified by reverse-phase chromatography. 1 H NMR (400 MHz, DMSO-d6) δ 11.18 (s, 1H), 9.60 (s, 1H), 7.99 (d, J = 8.3 Hz, 1H), 7.87 (s, 1H), 7.54 (dd, J = 8.0, 1.7 Hz, 1H), 3.48-3.36 (m, 1H), 2.12 (s, 6H), 2.50 (s, 1H, partially visible below the DMSO peak) 1.24 (d, J = 6.8 Hz, 6H). LCMS-ESI + (m / z): [M+H] + calcd 377.11;found 376.94.

[0248] [ka] Example 56: Preparation of 2-((1-methylethyl)sulfonamide)-4-(trifluoromethyl)-N-(3-(trifluoromethyl)bicyclo[1.1.1]pentan-1-yl)benzamide Following general synthesis method 2, 2-((1-methylethyl)sulfonamide)-4-(trifluoromethyl)-N-(3-(trifluoromethyl)bicyclo[1.1.1]pentan-1-yl)benzamide was synthesized using 3-(trifluoromethyl)bicyclo[1.1.1]pentan-1-yl)benzamide in step 3, and then purified by crystallization. 1 1H NMR (400 MHz, DMSO-d6) δ 11.00 (s, 1H), 9.81 (s, 1H), 8.00 (d, J = 8.3 Hz, 1H), 7.88 (s, 1H), 7.57 (d, J = 9.3 Hz, 1H), 3.45 (hept, J = 6.8 Hz, 1H), 2.37 (s, 6H), 1.25 (d, J = 6.8 Hz, 6H). LCMS-ESI + (m / z): [M+H] + calcd 445.10;found 444.90.

[0249] [ka] Example 57: N-(4-cyanobicyclo[2.2.2]octan-1-yl)-2-((1-methylethyl)sulfonamide)-4-(trifluoromethyl)benzamide preparation According to General Synthesis 2, N-(4-cyanobicyclo[2.2.2]octane-1-carbonitrile hydrochloride was used in step 3 to synthesize N-(4-cyanobicyclo[2.2.2]octane-1-yl)-2-((1-methylethyl)sulfonamide)-4-(trifluoromethyl)benzamide, which was then purified by crystallization. 1 1H NMR (400 MHz, DMSO-d6) δ 10.49 (s, 1H), 8.40 (s, 1H), 7.90 (d, J = 8.2 Hz, 1H), 7.84 (s, 1H), 7.55 (d, J = 8.2 Hz, 1H), 3.46 - 3.34 (m, 1H), 2.00 (s, 12H), 1.24 (d, J = 6.7 Hz, 6H). LCMS-ESI + (m / z): [M+H] + calcd 444.16;found 444.10.

[0250] [ka] Example 58: Preparation of 2-((4-sulfamoylphenyl)sulfonamide)-4-(trifluoromethyl)-N-(3-(trifluoromethyl)bicyclo[1.1.1]pentan-1-yl)benzamide According to General Synthesis 1, 4-sulfamoylbenzenesulfonyl chloride (1.5 equivalents) was used in step 1 at 50°C for 24 hours, and then 3-(trifluoromethyl)bicyclo[1.1.1]pentan-1-amine hydrochloride was used in step 3 to synthesize 2-((4-sulfamoylphenyl)sulfonamide)-4-(trifluoromethyl)-N-(3-(trifluoromethyl)bicyclo[1.1.1]pentan-1-yl)benzamide, which was then purified by reverse-phase chromatography. 1 H NMR (400 MHz, DMSO-d6) δ 11.37 (s, 1H), 9.64 (s, 1H), 8.02 - 7.83 (m, 5H), 7.69 (s, 1H), 7.66-7.57 (m, 3H), 2.32 (s, 6H). LCMS-ESI + (m / z): [M+H] + calcd 558.06;found 557.95.

[0251] [ka] Example 59: Preparation of 2-(pyridine-3-sulfonamide)-4-(trifluoromethyl)-N-(3-(trifluoromethyl)bicyclo[1.1.1]pentan-1-yl)benzamide According to General Synthesis 2, pyridine-3-sulfonamide was used in step 1, and then 3-(trifluoromethyl)bicyclo[1.1.1]pentan-1-amine hydrochloride was used in step 3 to synthesize 2-(pyridine-3-sulfonamide)-4-(trifluoromethyl)-N-(3-(trifluoromethyl)bicyclo[1.1.1]pentan-1-yl)benzamide, which was then purified by crystallization. 1 H NMR (400 MHz, DMSO-d6) δ 11.22 (s, 1H), 9.59 (s, 1H), 8.88 - 8.76 (m, 2H), 8.11 (ddd, J = 8.1, 2.5, 1.6 Hz, 1H), 7.85 (d, J = 8.2 Hz, 1H), 7.73 - 7.51 (m, 3H), 2.31 (s, 6H). LCMS-ESI + (m / z): [M+H] + calcd 480.08;found 480.09.

[0252] [ka] Example 60: Preparation of N-(3-cyanobicyclo[1.1.1]pentan-1-yl)-2-((1-methylethyl)sulfonamide)-4-(trifluoromethyl)benzamide According to General Synthesis 2, N-(3-cyanobicyclo[1.1.1]pentan-1-carbonitrile)-2-((1-methylethyl)sulfonamide)-4-(trifluoromethyl)benzamide was synthesized using 3-aminobicyclo[1.1.1]pentan-1-yl)-2-((1-methylethyl)sulfonamide)-4-(trifluoromethyl)benzamide, and then purified by reverse-phase chromatography. 1 H NMR (400 MHz, DMSO-d6) δ 10.95 (s, 1H), 9.78 (s, 1H), 7.96 (d, J = 8.3 Hz, 1H), 7.87 (s, 1H), 7.56 (d, J = 8.0 Hz, 1H), 3.46 (hept, J = 6.7 Hz, 1H), 2.61 (s, 6H), 1.24 (d, J = 6.8 Hz, 6H). LCMS-ESI + (m / z): [M+H] + calcd 402.11;found 402.01.

[0253] [ka] Example 61: Preparation of 4-methyl-2-((1-methylethyl)sulfonamide)-N-(3-(trifluoromethyl)bicyclo[1.1.1]pentan-1-yl)benzamide 4-methyl-2-((1-methylethyl)sulfonamide)-N-(3-(trifluoromethyl)bicyclo[1.1.1]pentan-1-yl)benzamide was synthesized using 2-bromo-4-methylbenzoic acid and 3-(trifluoromethyl)bicyclo[1.1.1]pentan-1-amine hydrochloride according to step 3 of general synthesis 1, and then propane-2-sulfonamide (1.5 equivalents) in general synthesis 8, and then purified by reverse-phase chromatography. 1 H NMR (400 MHz, DMSO-d6) δ 11.19 (s, 1H), 9.52 (s, 1H), 7.73 (d, J = 8.2 Hz, 1H), 7.42 (s, 1H), 6.99 (d, J = 8.2 Hz, 1H), 3.46 - 3.30 (m, 1H), 2.37-2.32 (m, J = 4.2 Hz, 9H), 1.23 (d, J = 6.8 Hz, 6H). LCMS-ESI + (m / z): [M+H] + calcd 391.13;found 391.06.

[0254] [ka] Example 62: 2-((2-methylthiazole)-5-sulfonamide)-4-(tri Preparation of fluoromethyl)-N-(3-(trifluoromethyl)bicyclo[1.1.1]pentan-1-yl)benzamide Following general synthesis method 2, 2-methylthiazole-5-sulfonamide was used in step 1, and then 3-(trifluoromethyl)bicyclo[1.1.1]pentan-1-amine hydrochloride was used in step 3 to synthesize 2-((2-methylthiazole)-5-sulfonamide)-4-(trifluoromethyl)-N-(3-(trifluoromethyl)bicyclo[1.1.1]pentan-1-yl)benzamide, which was then purified by reverse-phase chromatography. 1 H NMR (400 MHz, DMSO-d6) δ 11.38 (s, 1H), 9.70 (s, 1H), 8.08 (s, 1H), 7.92 (d, J = 8.2 Hz, 1H), 7.74 (s, 1H), 7.71-7.61 (m, 1H), 2.68 (s, 3H), 2.34 (s, 6H). LCMS-ESI + (m / z): [M+H] + calcd 500.05;found 500.07.

[0255] [ka] Example 63: Preparation of 2-((1-methylcyclopropane)-1-sulfonamide)-4-(trifluoromethyl)-N-(3-(trifluoromethyl)bicyclo[1.1.1]pentan-1-yl)benzamide Following general synthesis method 2, 1-methylcyclopropane-1-sulfonamide was used in step 1, and then 3-(trifluoromethyl)bicyclo[1.1.1]pentan-1-amine hydrochloride was used in step 3 to synthesize 2-((1-methylcyclopropane)-1-sulfonamide)-4-(trifluoromethyl)-N-(3-(trifluoromethyl)bicyclo[1.1.1]pentan-1-yl)benzamide, which was then purified by crystallization. 1H NMR (400 MHz, DMSO-d6) δ 10.97 (s, 1H), 9.85 (s, 1H), 8.00 (d, J = 8.3 Hz, 1H), 7.86 (s, 1H), 7.62 (d, J = 8.2 Hz, 1H), 2.38 (s, 6H), 1.35 (s, 3H), 1.17 - 1.08 (m, 2H), 0.87 (t, J = 3.2 Hz, 2H). LCMS-ESI + (m / z): [M+H] + calcd 457.10;found 457.07.

[0256] [ka] Example 64: Preparation of N-(3-cyanobicyclo[1.1.1]pentan-1-yl)-2-((1-methylcyclopropane)-1-sulfonamide)-4-(trifluoromethyl)benzamide According to General Synthesis 2, 1-methylcyclopropane-1-sulfonamide was used in step 1, and then 3-aminobicyclo[1.1.1]pentane-1-carbonitrile was used in step 3 to synthesize N-(3-cyanobicyclo[1.1.1]pentan-1-yl)-2-((1-methylcyclopropane)-1-sulfonamide)-4-(trifluoromethyl)benzamide, which was then purified by crystallization. 1 H NMR (400 MHz, DMSO-d6) δ 10.92 (s, 1H), 9.82 (s, 1H), 7.96 (d, J = 8.3 Hz, 1H), 7.84 (s, 1H ), 7.61 (d, J = 8.1 Hz, 1H), 2.61 (s, 6H), 1.34 (s, 3H), 1.18 - 1.08 (m, 2H), 0.92 - 0.81 (m, 2H). LCMS-ESI + (m / z): [M+H] + calcd 414.11;found 414.05.

[0257] [ka] Example 65: Preparation of 4-methyl-2-(pyridine-4-sulfonamide)-N-(3-(trifluoromethyl)bicyclo[1.1.1]pentan-1-yl)benzamide 4-methyl-2-(pyridine-4-sulfonamide)-N-(3-(trifluoromethyl)bicyclo[1.1.1]pentan-1-yl)benzamide was synthesized using 2-bromo-4-methylbenzoic acid and 3-(trifluoromethyl)bicyclo[1.1.1]pentan-1-amine hydrochloride according to step 3 of general synthesis 1, and then pyridine-4-sulfonamide (1.5 equivalents) was used in general synthesis 8, and the compound was purified by reverse-phase chromatography. 1 H NMR (400 MHz, DMSO-d6) δ 11.65 (s, 1H), 9.39 (s, 1H), 8.86 - 8.75 (m, 2H), 7.69 - 7.62 (m, 2H), 7.59 (d, J = 8.1 Hz, 1H), 7.30 (s, 1H), 7.05-7.00 (m, 1H), 2.34-2.29 (m, 9H). LCMS-ESI + (m / z): [M+H] + calcd 426.11;found 426.11.

[0258] [ka] Example 66: Preparation of N-(bicyclo[1.1.1]pentan-1-yl)-2-((1-methylcyclopropane)-1-sulfonamide)-4-(trifluoromethyl)benzamide According to General Synthesis 2, 1-methylcyclopropane-1-sulfonamide was used in step 1, and then bicyclo[1.1.1]pentan-1-amine hydrochloride was used in step 3 to synthesize N-(bicyclo[1.1.1]pentan-1-yl)-2-((1-methylcyclopropane)-1-sulfonamide)-4-(trifluoromethyl)benzamide, which was then purified by crystallization. 1H NMR (400 MHz, DMSO-d6) δ 11.13 (s, 1H), 9.64 (s, 1H), 7.99 (d, J = 8.3 Hz, 1H), 7.85 (s, 1H), 7.59 (d, J = 8.3 Hz, 1H), 2.13 (s, 6H), 1.34 (s, 3H), 1.19 - 1.04 (m, 2H), 0.92 - 0.77 (m, 2H). LCMS-ESI + (m / z): [M+H] + calcd 389.11;found 389.07.

[0259] [ka] Example 67: Preparation of N-(4-cyanobicyclo[2.2.2]octan-1-yl)-2-((1-methylcyclopropane)-1-sulfonamide)-4-(trifluoromethyl)benzamide According to General Synthesis 2, 1-methylcyclopropane-1-sulfonamide was used in step 1, and then 4-aminobicyclo[2.2.2]octane-1-carbonitrile hydrochloride was used in step 3 to synthesize N-(4-cyanobicyclo[2.2.2]octane-1-yl)-2-((1-methylcyclopropane)-1-sulfonamide)-4-(trifluoromethyl)benzamide, which was then purified by reverse-phase chromatography. 1 1H NMR (400 MHz, DMSO-d6) δ 10.54 (s, 1H), 8.45 (s, 1H), 7.91 (d, J = 8.2 Hz, 1H), 7.82 (d, J = 1.7 Hz, 1H), 7.64 - 7.53 (m, 1H), 2.01 (s, 12H), 1.34 (s, 3H), 1.16 - 1.06 (m, 2H), 0.90 - 0.76 (m, 2H). LCMS-ESI + (m / z): [M+H] + calcd 456.16;found 456.18.

[0260] [ka] Example 68: Preparation of N-(3-cyanobicyclo[1.1.1]pentan-1-yl)-2-((1-methylethyl)sulfonamide)-5-(trifluoromethyl)benzamide According to General Synthesis 2, methyl 2-bromo-5-(trifluoromethyl)benzoate was used in step 1, followed by 3-aminobicyclo[1.1.1]pentan-1-carbonitrile in step 3 to synthesize N-(3-cyanobicyclo[1.1.1]pentan-1-yl)-2-((1-methylethyl)sulfonamide)-5-(trifluoromethyl)benzamide, which was then purified by reverse-phase chromatography. 1 H NMR (400 MHz, DMSO-d6) δ 11.39 (s, 1H), 9.83 (s, 1H), 8.18 (s, 1H), 7.89 (dd, J = 8.8, 1.9 Hz, 1H), 7.79 (d, J = 8.8 Hz, 1H), 3.50 (hept, J = 7.0 Hz, 1H), 2.62 (s, 6H), 1.26 (d, J = 6.8 Hz, 6H). LCMS-ESI + (m / z): [M+H] + calcd 402.11;found 401.99.

[0261] [ka] Example 69: Preparation of 2-((1-methylethyl)sulfonamide)-5-(trifluoromethyl)-N-(3-(trifluoromethyl)bicyclo[1.1.1]pentan-1-yl)benzamide According to General Synthesis 2, 2-bromo-5-(trifluoromethyl)methyl benzoate was used in step 1, and then 3-(trifluoromethyl)bicyclo[1.1.1]pentan-1-amine hydrochloride was used in step 3 to synthesize 2-((1-methylethyl)sulfonamide)-5-(trifluoromethyl)-N-(3-(trifluoromethyl)bicyclo[1.1.1]pentan-1-yl)benzamide, which was then purified by crystallization. 1 1H NMR (40 0 MHz, DMSO-d6) δ 11.45 (s, 1H), 9.85 (s, 1H), 8.22 (s, 1H), 7.90 (dd, J = 8.9, 2.0 Hz, 1H), 7.80 (d, J = 8.8 Hz, 1H), 3.50 (hept, J = 6.6 Hz, 1H), 2.38 (s, 6H), 1.26 (d, J = 6.8 Hz, 6H). LCMS-ESI + (m / z): [M+H] + calcd 445.10;found 445.00.

[0262] [ka] Example 70: Preparation of N-(3-chlorobicyclo[1.1.1]pentan-1-yl)-2-((1-methylethyl)sulfonamide)-5-(trifluoromethyl)benzamide According to General Synthesis 2, methyl 2-bromo-5-(trifluoromethyl)benzoate was used in step 1, followed by 3-chlorobicyclo[1.1.1]pentan-1-amine hydrochloride in step 3 to synthesize N-(3-chlorobicyclo[1.1.1]pentan-1-yl)-2-((1-methylethyl)sulfonamide)-5-(trifluoromethyl)benzamide, which was then purified by reverse-phase chromatography. 1 H NMR (400 MHz, DMSO-d6) δ 11.42 (s, 1H), 9.81 (s, 1H), 8.20 (d, J = 1.0 Hz, 1H), 7.89 (dd, J = 8.8, 1.4 Hz, 1H), 7.79 (d, J = 8.8 Hz, 1H), 3.50 (hept, J = 6.7 Hz, 1H), 2.52 (s, 6H), 1.26 (d, J = 6.8 Hz, 6H). LCMS-ESI + (m / z): [M+H] + calcd 411.08;found 411.05.

[0263] [ka] Example 71: Preparation of N-(bicyclo[1.1.1]pentan-1-yl)-2-((1-methylethyl)sulfonamide)-5-(trifluoromethyl)benzamide According to General Synthesis 2, methyl 2-bromo-5-(trifluoromethyl)benzoate was used in step 1, and then bicyclo[1.1.1]pentan-1-amine hydrochloride was used in step 3 to synthesize N-(bicyclo[1.1.1]pentan-1-yl)-2-((1-methylethyl)sulfonamide)-5-(trifluoromethyl)benzamide, which was then purified by reverse-phase chromatography. 1 H NMR (400 MHz, DMSO-d6) δ 11.65 (s, 1H), 9.65 (s, 1H), 8.21 (s, 1H), 7.87 (dd, J = 8.9, 2.0 Hz, 1H), 7.79 (d, J = 8.8 Hz, 1H), 3.48 (hept, J = 7.0 Hz, 1H), 2.51 (DMSO Below the peak, 1H), 2.13 (s, 6H), 1.25 (d, J = 6.8 Hz, 6H). LCMS-ESI + (m / z): [M+H] + calcd 377.11;found 377.04.

[0264] [ka] Example 72: Preparation of N-(4-cyanobicyclo[2.2.2]octan-1-yl)-2-((1-methylethyl)sulfonamide)-5-(trifluoromethyl)benzamide According to General Synthesis 2, methyl 2-bromo-5-(trifluoromethyl)benzoate was used in step 1, followed by 4-aminobicyclo[2.2.2]octane-1-carbonitrile hydrochloride in step 3 to synthesize N-(4-cyanobicyclo[2.2.2]octane-1-yl)-2-((1-methylethyl)sulfonamide)-5-(trifluoromethyl)benzamide, which was then purified by reverse-phase chromatography. 1 1H NMR (400 MHz, DMSO-d6) δ 10.92 (s, 1H), 8.47 (s, 1H), 8.07 (s, 1H), 7.85 (d, J = 8.9 Hz, 1H), 7.77 (d, J = 8.7 Hz,1H), 3.50-3.39 (m, 1H), 2.01 (s, 12H), 1.24 (d, J = 6.8 Hz, 6H). LCMS-ESI + (m / z): [M+H] + calcd 444.16;found 444.09.

[0265] [ka] Example 73: Preparation of 2-(oxetane-3-sulfonamide)-5-(trifluoromethyl)-N-(3-(trifluoromethyl)bicyclo[1.1.1]pentan-1-yl)benzamide According to General Synthesis 2, 2-bromo-5-(trifluoromethyl)methyl benzoate and oxetane-3-sulfonamide were used in step 1, and then 3-(trifluoromethyl)bicyclo[1.1.1]pentan-1-amine hydrochloride was used in step 3 to synthesize 2-(oxetane-3-sulfonamide)-5-(trifluoromethyl)-N-(3-(trifluoromethyl)bicyclo[1.1.1]pentan-1-yl)benzamide, which was then purified by crystallization. 1H NMR (400 MHz, DMSO-d6) δ 11.53 (s, 1H), 9.79 (s, 1H), 8.17 (d, J = 0.9 Hz, 1H), 7.90 (d, J = 8.5 Hz, 1H), 7.73 (d, J = 8.7 Hz, 1H), 4.99 - 4.85 (m, 1H), 4.80 (t, J = 7.5 Hz, 2H), 4.66 (dd, J = 7.3, 5.8 Hz, 2H), 2.37 (s, 6H). LCMS-ESI + (m / z): [M+H] + calcd 459.08;found 459.19.

[0266] [ka] Example 74: Preparation of N-(3-chlorobicyclo[1.1.1]pentan-1-yl)-2-(oxetane-3-sulfonamide)-5-(trifluoromethyl)benzamide According to General Synthesis 2, 2-bromo-5-(trifluoromethyl)methyl benzoate and oxetane-3-sulfonamide were used in step 1, and then 3-chlorobicyclo[1.1.1]pentan-1-amine hydrochloride was used in step 3 to synthesize N-(3-chlorobicyclo[1.1.1]pentan-1-yl)-2-(oxetane-3-sulfonamide)-5-(trifluoromethyl)benzamide, which was then purified by crystallization. 1 H NMR (400 MHz, DMSO-d6) δ 11.51 (s, 1H), 9.75 (s, 1H), 8.16 (d, J = 1Hz, 1H), 7.89 (d, J = 8.4 Hz, 1H), 7.72 (d, J = 8.7 Hz, 1H), 4.95-4.85 (m, 1H), 4.80 (t, J = 7.5 Hz, 2H), 4.65 (t, J = 6.5 Hz, 2H), 2.51 (s, 6H). LCMS-ESI + (m / z): [M+H] +calcd 425.05;found 425.18.

[0267] [ka] Example 75: Preparation of N-(4-cyanobicyclo[2.2.2]octan-1-yl)-2-(oxetane-3-sulfonamide)-5-(trifluoromethyl)benzamide According to General Synthesis 2, 2-bromo-5-(trifluoromethyl)methyl benzoate and oxetane-3-sulfonamide were used in step 1, and then 4-aminobicyclo[2.2.2]octane-1-carbonitrile hydrochloride was used in step 3 to synthesize N-(4-cyanobicyclo[2.2.2]octane-1-yl)-2-(oxetane-3-sulfonamide)-5-(trifluoromethyl)benzamide, which was then purified by crystallization. 1 H NMR (400 MHz, DMSO-d6) δ 11.03 (s, 1H), 8.39 (s, 1H), 8.02 (d, J = 1.1 Hz, 1H), 7.85 (d, J = 8.4 Hz, 1H), 7.68 (d, J = 8.7 Hz, 1H), 4.89 - 4.72 (m, 3H), 4.68-4.57 (m, 2H), 2.00 (s, 12H). LCMS-ESI + (m / z): [M+H] + calcd 458.24;found 458.14.

[0268] [ka] Example 76: N-(4-cyanobicyclo[2.2.2]octan-1-yl)-2-((2-methylthiazole)-5-sulfonamide)-4-(trifluoromethyl)ben Preparation of Zuamide According to General Synthesis 2, 2-methylthiazole-5-sulfonamide was used in step 1, and then 4-aminobicyclo[2.2.2]octane-1-carbonitrile hydrochloride was used in step 3 to synthesize N-(4-cyanobicyclo[2.2.2]octane-1-yl)-2-((2-methylthiazole)-5-sulfonamide)-4-(trifluoromethyl)benzamide, which was then purified by reverse-phase chromatography. 1 H NMR (400 MHz, DMSO-d6) δ 11.06 (s, 1H), 8.27 (s, 1H), 8.02 (s, 1H), 7.86 (d, J = 8.1 Hz, 1H), 7.71 - 7.51 (m, 2H), 2.68 (s, 3H), 2.06-1.86 (m, 12H). LCMS-ESI + (m / z): [M+H] + calcd 499.11;found 499.09.

[0269] [ka] Example 77: Preparation of 4-cyano-N-(4-cyanobicyclo[2.2.2]octan-1-yl)-2-((1,1-dimethylethyl)sulfonamide)benzamide 4-cyano-N-(4-cyanobicyclo[2.2.2]octane-1-carbonitride hydrochloride) was synthesized using 2-bromo-4-cyanobenzoic acid and 4-aminobicyclo[2.2.2]octane-1-carbonitride hydrochloride, and then 2-methylpropane-2-sulfonamide (2.0 equivalents) was used in General Synthesis 8 to synthesize 4-cyano-N-(4-cyanobicyclo[2.2.2]octane-1-yl)-2-((1,1-dimethylethyl)sulfonamide)benzamide, which was then purified by reverse-phase chromatography. 1H NMR (400 MHz, DMSO-d6) δ 10.35 (s, 1H), 8.48 (s, 1H), 7.96 (d, J = 1.5 Hz, 1H), 7.83 (d, J = 8.1 Hz, 1H), 7.65 (d, J = 8.2 Hz, 1H), 1.99 (s, 12H), 1.28 (s, 9H). LCMS-ESI + (m / z): [M+H] + calcd 415.18;found 414.93.

[0270] [ka] Example 78: Preparation of 4-cyano-N-(4-cyanobicyclo[2.2.2]octan-1-yl)-2-((1-methylethyl)sulfonamide)benzamide 4-cyano-N-(4-cyanobicyclo[2.2.2]octane-1-carbonitride hydrochloride, followed by propane-2-sulfonamide (2.0 equivalents) in step 3 of general synthesis 1, was used to synthesize 4-cyano-N-(4-cyanobicyclo[2.2.2]octane-1-yl)-2-((1-methylethyl)sulfonamide)benzamide, which was then purified by reverse-phase chromatography. 1 1H NMR (400 MHz, DMSO-d6) δ 10.45 (s, 1H), 8.40 (s, 1H), 7.90 - 7.81 (m, 2H), 7.66 (dd, J = 8.1, 1.6 Hz, 1H), 3.51 (m, 1H), 1.99 (s, 12H), 1.24 (d, J = 6.8 Hz, 6H). LCMS-ESI + (m / z): [M+H] + calcd 401.16;found 401.09.

[0271] [ka] Example 79: Preparation of N-(3-chlorobicyclo[1.1.1]pentan-1-yl)-4-fluoro-2-(methylsulfonamide)benzamide Following general synthesis method 1, N-(3-chlorobicyclo[1.1.1]pentan-1-amine hydrochloride was used in step 3 to synthesize N-(3-chlorobicyclo[1.1.1]pentan-1-yl)-4-fluoro-2-(methylsulfonamide)benzamide, which was then purified by crystallization. 1 H NMR (400 MHz, DMSO-d6) δ 11.45 (s, 1H), 9.51 (s, 1H), 7.91 (dd, J = 9.0, 6.3 Hz, 1H), 7.31 (dd, J = 11.2, 2.6 Hz, 1H), 7.04 (td, J = 8.5, 2.6 Hz, 1H), 3.23 (s, 3H), 2.49 (s, 6H). LCMS-ESI + (m / z): [M+H] + calcd 333.05;found 332.91.

[0272] [ka] Example 80: Preparation of N-(3-chlorobicyclo[1.1.1]pentan-1-yl)-2-(methylsulfonamide)-5-(trifluoromethyl)benzamide According to General Synthesis 2, 2-bromo-5-(trifluoromethyl)methyl benzoate (1.0 equivalent) and methanesulfonamide (2.0 equivalents) were used in step 1, and then 3-chlorobicyclo[1.1.1]pentan-1-amine hydrochloride was used in step 3 to synthesize N-(3-chlorobicyclo[1.1.1]pentan-1-yl)-2-(methylsulfonamide)-5-(trifluoromethyl)benzamide, which was then purified by reverse-phase chromatography. 1 H NMR (400 MHz, DMSO-d6) δ 11.48 (s, 1H), 9.76 (s, 1H), 8.21 (s, 1H), 7.90 (dd, J = 8.8, 2.1 Hz, 1H), 7.73 (d, J = 8.8 Hz, 1H), 3.26 (s, 3H), 2.52 (s, 6H). LCMS-ESI + (m / z): [M+H] + calcd 383.04;found 383.06.

[0273] [ka] Example 81: Preparation of N-(4-(difluoromethyl)bicyclo[2.2.2]octan-1-yl)-2-(methylsulfonamide)-5-(trifluoromethyl)benzamide According to General Synthesis 2, methyl 2-bromo-5-(trifluoromethyl)benzoate (1. N-(4-(difluoromethyl)bicyclo[2.2.2]octan-1-yl)-2-(methylsulfonamide)-5-(trifluoromethyl)benzamide was synthesized using 0 equivalents of methanesulfonamide (2.0 equivalents) and 4-(difluoromethyl)bicyclo[2.2.2]octan-1-yl)-2-(methylsulfonamide)-5-(trifluoromethyl)benzamide, which was then purified by crystallization. 1 H NMR (400 MHz, DMSO-d6) δ 10.99 (s, 1H), 8.39 (s, 1H), 8.08 (d, J = 2.1 Hz, 1H), 7.86 (d, J = 8.7 Hz, 1H), 7.68 (d, J = 8.7 Hz, 1H), 5.72 (t, J = 56.8 Hz, 1H), 3.22 (s, 3H), 2.06 - 1.93 (m, 6H), 1.67 - 1.53 (m, 6H). LCMS-ESI + (m / z): [M+H] + calcd 441.13;found 441.13.

[0274] [ka] Example 82: Preparation of N-(4-fluorobicyclo[2.2.2]octan-1-yl)-2-(methylsulfonamide)-5-(trifluoromethyl)benzamide According to General Synthesis 2, 2-bromo-5-(trifluoromethyl)methyl benzoate (1.0 equivalent) and methanesulfonamide (2.0 equivalents) were used in step 1, and then 4-fluorobicyclo[2.2.2]octan-1-amine hydrochloride was used in step 3 to synthesize N-(4-fluorobicyclo[2.2.2]octan-1-yl)-2-(methylsulfonamide)-5-(trifluoromethyl)benzamide, which was then purified by crystallization. 1 H NMR (400 MHz, DMSO-d6) δ 10.94 (s, 1H), 8.38 (s, 1H), 8.07 (s, 1H), 7.86 (d, J = 8.8 Hz, 1H), 7.67 (d, J = 8.6 Hz, 1H), 3.22 (s, 3H), 2.23-2.09 (m, 6H), 1.94-1.81 (m, 6H). LCMS-ESI + (m / z): [M+H] + calcd 409.12;found 409.09.

[0275] General synthesis 3 [ka] Example 83: Preparation of 5-chloro-2-((1,1-dimethylethyl)sulfonamide)-N-(3-phenylbicyclo[1.1.1]pentan-1-yl)benzamide Step 1: 5-Chloro-2-iodobenzonitrile (0.989g, 3.75mmol), 2-methylpropane-2-sulfinamide (0.546g, 4.51mmol), (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphan) (0.130g, 0.225mmol), cesium carbonate (2.446g, 7.508m) To a mixture of (mol) and palladium(II) acetate (0.025 g, 0.11 mmol), 12 mL of 1,4-dioxane was added. The reaction mixture was stirred at 100°C for 18 hours and then quenched with water. The aqueous phase was extracted three times with ethyl acetate. The combined organic layers were washed with saturated sodium chloride aqueous solution and concentrated to obtain the residue. The crude product was purified by silica flash chromatography to obtain N-(4-chloro-2-cyanophenyl)-2-methylpropane-2-sulfinamide as a solid. LCMS-ESI + (m / z): [M+H] + calcd 257.05;found 256.78.

[0276] Step 2: N-(4-chloro-2-cyanophenyl)-2-methylpropane-2-sulfonamide (0.609 g, 2.37 mmol) was treated with a solution of 32% by weight peracetic acid in acetic acid (20.6 g, 271 mmol). The reaction mixture was stirred at room temperature for 3 hours and then quenched with saturated sodium bicarbonate aqueous solution. The mixture was then extracted three times with ethyl acetate. The organic phases were combined, washed with saturated sodium chloride aqueous solution, dried over anhydrous magnesium sulfate, filtered, and concentrated to obtain the residue, which yielded N-(4-chloro-2-cyanophenyl)-2-methylpropane-2-sulfonamide as a solid. LCMS-ESI - (m / z): [MH] - calcd 271.03;found 271.09.

[0277] Step 3: N-(4-chloro-2-cyanophenyl)-2-methylpropane-2-sulfonamide (0.575 g, 2.11 mmol) was dissolved in 18 mL of ethanol. 2 mL of water and sodium hydroxide pellet (1.257 g, 31.43 mmol) were added to this solution and stirred at 100°C for 18 hours. The reaction mixture was then acidified with 1 M aqueous hydrochloric acid. The aqueous phase was extracted three times with ethyl acetate. The organic phases were combined, washed with saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, filtered, and concentrated to obtain the residue, from which 5-chloro-2-((1,1-dimethylethyl)sulfonamide)benzoic acid was obtained as a solid. LCMS-ESI - (m / z): [MH] - calcd 290.03;found 290.06.

[0278] Step 4: A solution of 5-chloro-2-((1,1-dimethylethyl)sulfonamide)benzoic acid (0.041 g, 0.14 mmol), 3-phenylbicyclo[1.1.1]pentane-1-amine hydrochloride (0.069 g, 0.35 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.054 g, 0.35 mmol), and 1-hydroxybenzotriazole hydrate (0.054 g, 0.35 mmol) in 0.5 mL of dimethylformamide was treated with diisopropylethylamine (0.129 g, 0.998 mmol). The mixture was stirred at 60°C for 18 hours. This crude product was purified by reverse-phase HPLC to obtain 5-chloro-2-((1,1-dimethylethyl)sulfonamide)-N-(3-phenylbicyclo[1.1.1]pentan-1-yl)benzamide as a solid. 1 ¹H NMR (400 MHz, chloroform-d) δ 10.37 (s, 1H), 7.89 (d, J = 9.0 Hz, 1H), 7.43 - 7.22 (m, 7H), 6.60 (s, 1H), 2.46 (s, 6H), 1.41 (s, 9H). LCMS-ESI - (m / z): [MH] - calcd 431.12;found 431.36.

[0279] [ka] Example 84: Preparation of 5-chloro-2-((1,1-dimethylethyl)sulfonamide)-N-(3-(trifluoromethyl)bicyclo[1.1.1]pentan-1-yl)benzamide Following general synthesis method 3, 5-chloro-2-((1,1-dimethylethyl)sulfonamide)-N-(3-(trifluoromethyl)bicyclo[1.1.1]pentan-1-yl)benzamide was synthesized using 2.5 equivalents of 3-(trifluoromethyl)bicyclo[1.1.1]pentan-1-yl)benzamide in step 4. 1 ¹H NMR (400 MHz, chlorophosphamide) Lum-d) δ 10.27 (s, 1H), 7.89 (d, J = 9.5 Hz, 1H), 7.40-7.37 (m, 2H), 6.56 (s, 1H), 2.41 (s, 6H), 1.41 (s, 9H). LCMS-ESI - (m / z): [MH] - calcd 423.08;found 423.24.

[0280] [ka] Example 85: Preparation of 5-chloro-N-(3-cyanobicyclo[1.1.1]pentan-1-yl)-2-((1,1-dimethylethyl)sulfonamide)benzamide Following general synthesis method 3, 5-chloro-N-(3-cyanobicyclo[1.1.1]pentan-1-carbonitrile (2.5 equivalents) was used in step 4 to synthesize 5-chloro-N-(3-cyanobicyclo[1.1.1]pentan-1-yl)-2-((1,1-dimethylethyl)sulfonamide)benzamide. 1 ¹H NMR (400 MHz, chloroform-d) δ 10.23 (s, 1H), 7.88 (d, J = 9.0 Hz, 1H), 7.44 - 7.33 (m, 2H), 6.59 (s, 1H), 2.66 (s, 6H), 1.41 (s, 9H). LCMS-ESI - (m / z): [MH] - calcd 380.08;found 380.23.

[0281] General synthesis 4 [ka] Example 86: Preparation of 2-((4-(methylsulfonyl)phenyl)sulfonamide)-5-(trifluoromethyl)-N-(3-(trifluoromethyl)bicyclo[1.1.1]pentan-1-yl)benzamide Step 1: To a solution of 2-amino-5-(trifluoromethyl)methyl benzoate (0.261 g, 1.19 mmol) and 4-(methylsulfonyl)benzenesulfonyl chloride (0.300 g, 1.18 mmol) in 5 mL of acetonitrile, powdered metallic indium (0.027 g, 0.24 mmol) was added. This mixture was stirred at 110°C for 18 hours. The reaction product was then concentrated to obtain the residue. The crude product was purified by silica flash chromatography to obtain 2-((4-(methylsulfonyl)phenyl)sulfonamide)-5-(trifluoromethyl)benzoate as a solid. LCMS-ESI - (m / z): [MH] - calcd 436.01;found 436.18.

[0282] Step 2: Methyl 2-((4-(methylsulfonyl)phenyl)sulfonamide)-5-(trifluoromethyl)benzoate (0.083 mg, 0.19 mmol) in 3 mL of ethanol was treated with sodium hydroxide pellet (0.120 g, 3.0 mmol) and 0.3 mL of water. This mixture was stirred at 65°C for 18 hours. Water was then added, and the solution was acidified with 1 M aqueous hydrochloric acid. The aqueous phase was extracted three times with ethyl acetate. The organic phases were combined, washed with saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, filtered, and concentrated to obtain the residue, from which 2-((4-(methylsulfonyl)phenyl)sulfonamide)-5-(trifluoromethyl)benzoic acid was obtained as a solid. LCMS-ESI - (m / z): [MH] - calcd 422.00;found 422.08.

[0283] Step 3: A solution of 2-((4-(methylsulfonyl)phenyl)sulfonamide)-5-(trifluoromethyl)benzoic acid (0.040 g, 0.095 mmol), 3-(trifluoromethyl)bicyclo[1.1.1]pentane-1-amine hydrochloride (0.035 g, 0.19 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.036 g, 0.24 mmol), and 1-hydroxybenzotriazole hydrate (0.036 g, 0.24 mmol) in 0.5 mL of dimethylformamide was treated with diisopropylethylamine (0.085 g, 0.66 mmol). The mixture was stirred at 60°C for 18 hours. This crude product is purified by reverse-phase HPLC to obtain 2-((4-(methylsulfonyl)phenyl)sulfonamide)-5-(trifluoromethyl)-N-(3-(trifluoromethyl)bicyclo[1.1.1]pentan-1-yl)benz The amide was obtained as a solid. 1 H NMR (400 MHz, DMSO-d6) δ 11.94 (s, 1H), 9.75 (s, 1H), 8.10 (m, 5H), 7.87 (s, 1H), 7.65 (d, J = 8.6 Hz, 1H), 3.29 (s, 3H), 2.35 (s, 6H). LCMS-ESI + (m / z): [M+H] + calcd 557.06;found 556.83.

[0284] [ka] Example 87: Preparation of 2-((4-(methylsulfonyl)phenyl)sulfonamide)-N-(3-phenylbicyclo[1.1.1]pentan-1-yl)-5-(trifluoromethyl)benzamide) Following general synthesis method 4, 2-((4-(methylsulfonyl)phenyl)sulfonamide)-N-(3-phenylbicyclo[1.1.1]pentan-1-yl)-5-(trifluoromethyl)benzamide was synthesized using 3-phenylbicyclo[1.1.1]pentan-1-yl)-5-(trifluoromethyl)benzamide in step 3. 1 1H NMR (400 MHz, DMSO-d6) δ 12.26 (s, 1H), 9.68 (s, 1H), 8.20 - 8.07 (m, 5H), 7.88 (d, J = 8.4 Hz, 1H), 7.67 (d, J = 8.8 Hz, 1H), 7.39 - 7.21 (m, 5H), 3.29 (s, 3H), 2.37 (s, 6H). LCMS-ESI - (m / z): [MH] - calcd 563.09;found 563.32.

[0285] [ka] Example 88: Preparation of 4-Methoxy-2-((4-(methylsulfonyl)phenyl)sulfonamide)-N-(3-(trifluoromethyl)bicyclo[1.1.1]pentan-1-yl)benzamide According to General Synthesis 4, 4-methoxy-2-((4-(methylsulfonyl)phenyl)sulfonamide)-N-(3-(trifluoromethyl)bicyclo[1.1.1]pentan-1-yl)benzamide was synthesized using methyl 2-amino-4-methoxybenzoate (1.0 equivalent) in step 1. 1 H NMR (400 MHz, DMSO-d6) δ 12.09 (s, 1H), 9.32 (s, 1H), 8.10 (d, J = 8.6 Hz, 2H), 8.00 (d, J = 8.7 Hz, 2H), 7.70 (d, J = 8.9 Hz, 1H), 6.98 (d, J = 2.5 Hz, 1H), 6.76 (dd, J = 9.0, 2.5 Hz, 1H), 3.79 (s, 3H), 3.28 (s, 3H), 2.31 (s, 6H). LCMS-ESI - (m / z): [MH] - calcd 517.07;found 517.23.

[0286] [ka] Example 89: Preparation of 4-Methoxy-2-((4-(methylsulfonyl)phenyl)sulfonamide)-N-(3-phenylbicyclo[1.1.1]pentan-1-yl)benzamide 4-methoxy-2-((4-(methylsulfonyl)phenyl)sulfonamide)-N-(3-phenylbicyclo[1.1.1]pentan-1-yl)benzamide was synthesized according to General Synthesis 4, using methyl 2-amino-4-methoxybenzoate (1.0 equivalent) in step 1 and 3-phenylbicyclo[1.1.1]pentan-1-amine hydrochloride (2.0 equivalents) in step 3. 1H NMR (400 MHz, DMSO-d6) δ 12.40 (s, 1H), 9.22 (s, 1H), 8.11 (d, J = 8.6 Hz, 2H), 8.02 (d, J = 8.6 Hz, 2H), 7.75 (d, J = 9.0 Hz, 1H), 7.37 - 7.19 (m, 5H), 6.99 (d, J = 2.5 Hz, 1H), 6.75 (dd, J = 8.9, 2.5 Hz, 1H), 3.80 (s, 3H), 3.28 (s, 3H), 2.33 (s, 6H). LCMS-ESI - (m / z): [MH] - calcd 525.12;found 525.31.

[0287] [ka] Example 90: Preparation of 5-chloro-2-((4-(methylsulfonyl)phenyl)sulfonamide)-N-(3-(trifluoromethyl)bicyclo[1.1.1]pentan-1-yl)benzamide Following general synthesis method 4, 5-chloro-2-((4-(methylsulfonyl)phenyl)sulfonamide)-N-(3-(trifluoromethyl)bicyclo[1.1.1]pentan-1-yl)benzamide was synthesized using methyl 2-amino-5-chlorobenzoate (1.0 equivalent) in step 1. 1 ¹H NMR (400 MHz, chloroform-d) δ 10.72 (s, 1H), 8.02 - 7.92 (m, 4H), 7.67 (d, J = 8.8 Hz, 1H), 7.43 (dd, J = 8.9, 2.3 Hz, 1H), 7.31 (d, J = 2.3 Hz, 1H), 6.47 (s, 1H), 3.08 (s, 3H), 2.36 (s, 6H). LCMS-ESI - (m / z): [MH] - calcd 521.02;found 521.28 .

[0288] [ka] Example 91: Preparation of 5-chloro-2-((4-(methylsulfonyl)phenyl)sulfonamide)-N-(3-phenylbicyclo[1.1.1]pentan-1-yl)benzamide 5-chloro-2-((4-(methylsulfonyl)phenyl)sulfonamide)-N-(3-phenylbicyclo[1.1.1]pentan-1-yl)benzamide was synthesized according to General Synthesis 4, using methyl 2-amino-5-chlorobenzoate (1.0 equivalent) in step 1 and 3-phenylbicyclo[1.1.1]pentan-1-amine hydrochloride (2.0 equivalents) in step 3. 1 H NMR (400 MHz, chloroform-d) δ 10.88 (s, 1H), 7.98 (dd, J = 8.4, 6.1 Hz, 4H), 7.69 (d, J = 8.7 Hz, 1H), 7.42 (dd, J = 8.8, 2.3 Hz, 1H), 7.36 - 7.23 (m, 6H), 6.42 (s, 1H), 3.07 (s, 3H), 2.41 (s, 6H). LCMS-ESI - (m / z): [MH] - calcd 529.07;found 529.33.

[0289] [ka] Example 92: Preparation of 4,5-dichloro-2-((4-(methylsulfonyl)phenyl)sulfonamide)-N-(3-(trifluoromethyl)bicyclo[1.1.1]pentan-1-yl)benzamide Following general synthesis method 4, 4,5-dichloro-2-((4-(methylsulfonyl)phenyl)sulfonamide)-N-(3-(trifluoromethyl)bicyclo[1.1.1]pentan-1-yl)benzamide was synthesized using methyl 2-amino-4,5-dichlorobenzoate (1.0 equivalent) in step 1. 1H NMR (400 MHz, DMSO-d6) δ 11.34 (s, 1H), 9.56 (s, 1H), 8.14 - 8.08 (m, 2H), 8.01 - 7.93 (m, 3H), 7.64 (s, 1H), 3.29 (s, 3H), 2.28 (s, 6H). LCMS-ESI - (m / z): [MH] - calcd 554.98; found 555.28.

[0290] [ka] Example 93: Preparation of 4,5-dichloro-2-((4-(methylsulfonyl)phenyl)sulfonamide)-N-(3-phenylbicyclo[1.1.1]pentan-1-yl)benzamide 4,5-dichloro-2-((4-(methylsulfonyl)phenyl)sulfonamide)-N-(3-phenylbicyclo[1.1.1]pentan-1-yl)benzamide was synthesized according to General Synthesis 4, using methyl 2-amino-4,5-dichlorobenzoate (1.0 equivalent) in step 1 and 3-phenylbicyclo[1.1.1]pentan-1-amine hydrochloride (2.0 equivalents) in step 3. 1 H NMR (400 MHz, DMSO-d6) δ 11.68 (s, 1H), 9.49 (s, 1H), 8.20 - 7.95 (m, 5H), 7.66 (s, 1H), 7.29 (m, 5H), 3.29 (s, 3H), 2.30 (s, 6H). LCMS-ESI - (m / z): [MH] - calcd 563.03;found 563.36.

[0291] [ka] Example 94: Preparation of 5-bromo-2-((1,1-dimethylethyl)sulfonamide)-N-(3-phenylbicyclo[1.1.1]pentan-1-yl)benzamide Following general synthesis method 3, 5-bromo-2-((1,1-dimethylethyl)sulfonamide)-N-(3-phenylbicyclo[1.1.1]pentan-1-yl)benzamide was synthesized using 5-bromo-2-iodobenzonitrile in step 1. 1 H NMR (400 MHz, DMSO-d6) δ 11.04 (s, 1H), 9.64 (s, 1H), 8.02 (s, 1H), 7.68 (s, 2H), 7.34 - 7.20 (m, 5H), 2.37 (s, 6H), 1.28 (s, 9H). LCMS-ESI - (m / z): [MH] - calcd 475.07;found 475.46.

[0292] [ka] Example 95: Preparation of 5-bromo-2-((1,1-dimethylethyl)sulfonamide)-N-(3-(trifluoromethyl)bicyclo[1.1.1]pentan-1-yl)benzamide According to general synthesis method 3, 5-bromo-2-iodobenzonitrile is used in step 1, and 3-(trifluoromethyl)bicyclo[1.1.1]pentan-1-amine hydrochloride (2.0 equivalents) was used in step 4 to synthesize 5-bromo-2-((1,1-dimethylethyl)sulfonamide)-N-(3-(trifluoromethyl)bicyclo[1.1.1]pentan-1-yl)benzamide. 1 H NMR (400 MHz, DMSO-d6) δ 10.86 (s, 1H), 9.73 (s, 1H), 7.98 (d, J = 1.6 Hz, 1H), 7.72 - 7.66 (m, 2H), 2.35 (s, 6H), 1.27 (s, 9H). LCMS-ESI - (m / z): [MH] -calcd 467.03;found 467.38.

[0293] [ka] Example 96: Preparation of 5-cyano-2-((1,1-dimethylethyl)sulfonamide)-N-(3-phenylbicyclo[1.1.1]pentan-1-yl)benzamide 5-Bromo-2-((1,1-dimethylethyl)sulfonamide)benzoic acid was synthesized according to steps 1-3 of general synthesis 3, using 5-bromo-2-iodobenzonitrile in step 1. A solution of 5-bromo-2-((1,1-dimethylethyl)sulfonamide)benzoic acid (0.120 g, 0.357 mmol) in DMF was treated with copper(I) cyanide (0.064 g, 0.714 mmol). The mixture was stirred at 150°C for 18 hours. The reaction product was then acidified with 1 M aqueous hydrochloric acid. The aqueous phase was extracted three times with ethyl acetate. The organic phases were combined and concentrated to obtain the residue. The crude product was purified by silica flash chromatography to obtain 5-cyano-2-((1,1-dimethylethyl)sulfonamide)benzoic acid, which was then reacted according to step 4 of general synthesis 3 to obtain 5-cyano-2-((1,1-dimethylethyl)sulfonamide)-N-(3-phenylbicyclo[1.1.1]pentan-1-yl)benzamide as a solid. 1 H NMR (400 MHz, DMSO-d6) δ 11.69 (s, 1H), 9.70 (s, 1H), 8.34 (s, 1H), 7.99 - 7.83 (m, 2H), 7.39 - 7.20 (m, 5H), 2.38 (s, 6H), 1.32 (s, 9H). LCMS-ESI - (m / z): [MH] - calcd 422.15;found 422.29.

[0294] [ka] Example 97: Preparation of 5-cyano-2-((1,1-dimethylethyl)sulfonamide)-N-(3-(trifluoromethyl)bicyclo[1.1.1]pentan-1-yl)benzamide 5-Bromo-2-((1,1-dimethylethyl)sulfonamide)benzoic acid was synthesized according to steps 1 to 3 of general synthesis 3, using 5-bromo-2-iodobenzonitrile in step 1. A solution of 5-bromo-2-((1,1-dimethylethyl)sulfonamide)benzoic acid (0.120 g, 0.357 mmol) in DMF was treated with copper(I) cyanide (0.064 g, 0.714 mmol). This mixture was stirred at 150°C for 18 hours. The reaction product was then acidified with 1 M aqueous hydrochloric acid. The aqueous phase was extracted three times with ethyl acetate. The organic phases were combined and concentrated to obtain the residue. The crude product was purified by silica flash chromatography to obtain 5-cyano-2-((1,1-dimethylethyl)sulfonamide)benzoic acid, which was reacted with 3-(trifluoromethyl)bicyclo[1.1.1]pentan-1-amine hydrochloride (2.0 equivalents) according to step 4 of general synthesis 3 to obtain 5-cyano-2-((1,1-dimethylethyl)sulfonamide)-N-(3-(trifluoromethyl)bicyclo[1.1.1]pentan-1-yl)benzamide. 1 H NMR (400 MHz, DMSO-d6) δ 11.48 (s, 1H), 9.79 (s, 1H), 8.30 (s, 1H), 8.00 - 7.80 (m, 2H), 2.37 (s, 6H), 1.32 (s, 9H). LCMS-ESI - (m / z): [MH] - calcd 414.11;found 414.21.

[0295] [ka] Example 98: Preparation of 4-cyano-2-((1,1-dimethylethyl)sulfonamide)-N-(3-phenylbicyclo[1.1.1]pentan-1-yl)benzamide 4-bromobenzonitrile (1.068 g, 5.867 mmol), N-iodosuccinimide (1.452 g, 6.464 mmol), palladium(II) acetate (0.066 g, 0.29 mmol), and p-toluenesulfonic acid monohydrate (0.558 g, 2.94 mmol) were treated with 23 mL of 1,2-dichloroethane. The mixture was stirred at 70°C for 72 hours. The reaction product was then concentrated to obtain a residue, which was purified by silica flash chromatography to obtain 4-bromo-2-iodobenzonitrile. This compound was reacted according to steps 1 to 3 of General Synthesis 3 to obtain 4-bromo-2-((1,1-dimethylethyl)sulfonamide)benzoic acid. A solution of 4-bromo-2-((1,1-dimethylethyl)sulfonamide)benzoic acid (0.123 g, 0.366 mmol) in DMF was treated with copper(I) cyanide (0.098 g, 1.1 mmol). The mixture was stirred at 150°C for 18 hours. The reaction product was then acidified with 1 M aqueous hydrochloric acid. The aqueous phase was extracted three times with ethyl acetate. The organic phases were combined and concentrated to obtain the residue. The crude product was purified by silica flash chromatography to obtain 4-cyano-2-((1,1-dimethylethyl)sulfonamide)benzoic acid, which was reacted according to step 4 of General Synthesis 3 to obtain 4-cyano-2-((1,1-dimethylethyl)sulfonamide)-N-(3-phenylbicyclo[1.1.1]pentan-1-yl)benzamide as a solid. 1 H NMR (400 MHz, DMSO-d6) δ 11.01 (s, 1H), 9.77 (s, 1H), 8.00 (s, 1H), 7.96 (d, J = 8.2 Hz, 1H), 7.67 (d, J = 8.0 Hz, 1H), 7.36 - 7.19 (m, 5H), 2.38 (s, 6H), 1.30 (s, 9H). LCMS-ESI - (m / z): [MH] - calcd 422.15;found 422.29.

[0296] [ka] Example 99: Preparation of 4-cyano-2-((1,1-dimethylethyl)sulfonamide)-N-(3-(trifluoromethyl)bicyclo[1.1.1]pentan-1-yl)benzamide 4-bromobenzonitrile (1.068 g, 5.867 mmol), N-iodosuccinimide (1.452 g, 6.464 mmol), palladium(II) acetate (0.066 g, 0.29 mmol), and p-toluenesulfonic acid monohydrate (0.558 g, 2.94 mmol) were treated with 23 mL of 1,2-dichloroethane. The mixture was stirred at 70°C for 72 hours. The reaction product was then concentrated to obtain a residue, which was purified by silica flash chromatography to obtain 4-bromo-2-iodobenzonitrile. This compound was reacted according to steps 1 to 3 of General Synthesis 3 to obtain 4-bromo-2-((1,1-dimethylethyl)sulfonamide)benzoic acid. A solution of 4-bromo-2-((1,1-dimethylethyl)sulfonamide)benzoic acid (0.123 g, 0.366 mmol) in DMF was treated with copper(I) cyanide (0.098 g, 1.1 mmol). The mixture was stirred at 150°C for 18 hours. The reaction product was then acidified with 1 M aqueous hydrochloric acid. The aqueous phase was extracted three times with ethyl acetate. The organic phases were combined and concentrated to obtain the residue. The crude product was purified by silica flash chromatography to obtain 4-cyano-2-((1,1-dimethylethyl)sulfonamide)benzoic acid, which was then reacted with 3-(trifluoromethyl)bicyclo[1.1.1]pentan-1-amine hydrochloride (2.0 equivalents) according to step 4 of general synthesis 3 to obtain 4-cyano-2-((1,1-dimethylethyl)sulfonamide)-N-(3-(trifluoromethyl)bicyclo[1.1.1]pentan-1-yl)benzamide as a solid. 1 H NMR (400 MHz, DMSO-d6) δ 10.84 (s, 1H), 9.86 (s, 1H), 8.00 (s, 1H), 7.91 (d, J = 8.1 Hz, 1H), 7.68 (d, J = 8.2 Hz, 1H), 2.36 (s, 6H), 1.29 (s, 9H). LCMS-ESI -(m / z): [MH] - calcd 414.11;found 414.21.

[0297] [ka] Example 100: Preparation of 2-((1,1-dimethylethyl)sulfonamide)-5-(pyrimidine-2-yl)-N-(3-(trifluoromethyl)bicyclo[1.1.1]pentan-1-yl)benzamide 5-Bromo-2-((1,1-dimethylethyl)sulfonamide)-N-(3-(trifluoromethyl)bicyclo[1.1.1]pentan-1-yl)benzamide was synthesized according to Example 95. To a solution of 5-bromo-2-((1,1-dimethylethyl)sulfonamide)-N-(3-(trifluoromethyl)bicyclo[1.1.1]pentan-1-yl)benzamide (0.030 g, 0.064 mmol) in 0.5 mL of 1,4-dioxane, bis(triphenylphosphine)palladium(II) dichloride (0.007 g, 0.009 mmol) and 2-tributylstannylpyrimidine (0.035 g, 0.096 mmol) were added. The mixture was stirred at 120°C for 3 hours. The reaction product was then diluted with ethyl acetate and quenched by washing with 2 M aqueous potassium fluoride. The organic phase was concentrated to obtain a residue, which was purified by reverse-phase HPLC to obtain 2-((1,1-dimethylethyl)sulfonamide)-5-(pyrimidine-2-yl)-N-(3-(trifluoromethyl)bicyclo[1.1.1]pentan-1-yl)benzamide as a solid. 1 H NMR (400 MHz, DMSO-d6) δ 11.06 (s, 1H), 9.96 (s, 1H), 8.93 (d, J = 4.9 Hz, 2H), 8.78 (d, J = 1.8 Hz, 1H), 8.49 (dd, J = 8.9, 2.0 Hz, 1H), 7.90 (d, J = 8.9 Hz, 1H), 7.47 (t, J = 4.9 Hz, 1H), 2.39 (s, 6H), 1.31 (s, 9H). LCMS-ESI -(m / z): [M -H] - calcd 467.14;found 467.29.

[0298] [ka] Example 101: Preparation of 2-((4-(pyrimidine-2-yl)phenyl)sulfonamide)-4-(trifluoromethyl)-N-(3-(trifluoromethyl)bicyclo[1.1.1]pentan-1-yl)benzamide 2-((4-iodophenyl)sulfonamide)-4-(trifluoromethyl)-N-(3-(trifluoromethyl)bicyclo[1.1.1]pentan-1-yl)benzamide was synthesized according to general synthesis 4, using 4-iodobenzenesulfonyl chloride (1 equivalent) in step 1. To a solution of 2-((4-iodophenyl)sulfonamide)-4-(trifluoromethyl)-N-(3-(trifluoromethyl)bicyclo[1.1.1]pentan-1-yl)benzamide (0.050 g, 0.083 mmol) in 0.5 mL of 1,4-dioxane, bis(triphenylphosphine)palladium(II) dichloride (0.009 g, 0.01 mmol) and 2-tributylstannylpyrimidine (0.092 g, 0.25 mmol) were added. The mixture was stirred at 100°C for 18 hours. Next, the reaction product was diluted with ethyl acetate and quenched by washing with 2M aqueous potassium fluoride. The organic phase was concentrated to obtain a residue, which was purified by reverse-phase HPLC to obtain 2-((4-(pyrimidine-2-yl)phenyl)sulfonamide)-4-(trifluoromethyl)-N-(3-(trifluoromethyl)bicyclo[1.1.1]pentan-1-yl)benzamide as a solid. 1 H NMR (400 MHz, DMSO-d6) δ 11.20 (s, 1H), 9.58 (s, 1H), 8.96 (d, J = 4.9 Hz, 2H), 8.52 (d, J = 8.5 Hz, 2H), 7.88 - 7.81 (m, 3H), 7.73 (s, 1H), 7.61 (d, J = 8.1 Hz, 1H), 7.54 (t, J = 4.9 Hz, 1H), 2.27 (s, 6H). LCMS-ESI - (m / z): [MH] - calcd 555.09;found 555.29.

[0299] [ka] Example 102: Preparation of 2-((4-(dimethylamino)phenyl)sulfonamide)-4-(trifluoromethyl)-N-(3-(trifluoromethyl)bicyclo[1.1.1]pentan-1-yl)benzamide 2-((4-iodophenyl)sulfonamide)-4-(trifluoromethyl)-N-(3-(trifluoromethyl)bicyclo[1.1.1]pentan-1-yl)benzamide was synthesized according to general synthesis 4, using 4-iodobenzenesulfonyl chloride (1 equivalent) in step 1. 2-((4-iodophenyl)sulfonamide)-4-(trifluoromethyl)-N-(3-(trifluoromethyl)bicyclo[1.1.1]pentan-1-yl)benzamide (0.062 g, 0.10 mmol), copper(I) iodide (0.00 A solution of 4 g, 0.02 mmol) of 6,7-dihydroquinoline-8(5H)-oneoxime (0.004 g, 0.03 mmol) and potassium hydroxide (0.029 g, 0.51 mmol) in 0.2 mL of deionized water was purged with nitrogen gas. Then, 0.2 mL of 2 M dimethylamine in tetrahydrofuran (0.023 g, 0.51 mmol) was added. The mixture was stirred at 50°C for 7 days. The reaction product was then concentrated to obtain the residue. The crude product was purified by reverse-phase HPLC to obtain 2-((4-(dimethylamino)phenyl)sulfonamide)-4-(trifluoromethyl)-N-(3-(trifluoromethyl)bicyclo[1.1.1]pentan-1-yl)benzamide as a solid. 1 H NMR (400 MHz, DMSO-d6) δ 11.10 (s, 1H), 9.65 (s, 1H), 7.87 (d, J = 8.3 Hz, 1H), 7.73 (s, 1H), 7.51 (d, J = 7.9 Hz, 1H), 7.47 (d, J = 9.1 Hz, 2H), 6.71 (d, J = 9.1 Hz, 2H), 2.96 (s, 6H), 2.34 (s, 6H). LCMS-ESI - (m / z): [MH] - calcd 520.11;found 520.28.

[0300] [ka] Example 103: Preparation of 4-(N-(5-(trifluoromethyl)-2-((3-(trifluoromethyl)bicyclo[1.1.1]pentan-1-yl)carbamoyl)phenyl)sulfamoyl)phenylmethanesulfonate 2-((4-hydroxyphenyl)sulfonamide)-4-(trifluoromethyl)-N-(3-(trifluoromethyl)bicyclo[1.1.1]pentan-1-yl)benzamide was synthesized according to Example 102. A solution of 2-((4-hydroxyphenyl)sulfonamide)-4-(trifluoromethyl)-N-(3-(trifluoromethyl)bicyclo[1.1.1]pentan-1-yl)benzamide (0.017 g, 0.034 mmol) and triethylamine (0.010 g, 0.10 mmol) in 0.15 mL of dichloromethane was cooled to 0°C. Methanesulfonyl chloride (0.005 g, 0.04 mmol) was added. The mixture was stirred at 0°C for 1 hour, and then heated to room temperature for 18 hours. This crude reaction mixture was purified by reverse-phase HPLC to obtain 4-(N-(5-(trifluoromethyl)-2-((3-(trifluoromethyl)bicyclo[1.1.1]pentan-1-yl)carbamoyl)phenyl)sulfamoyl)phenylmethanesulfonate as a solid. 1 H NMR (400 MHz, DMSO-d6) δ 11.27 (s, 1H), 9.62 (s, 1H), 7.93 - 7.77 (m, 3H), 7.72 - 7.48 (m, 4H), 3.45 (s, 3H), 2.33 (s, 6H). LCMS-ESI - (m / z): [MH] - calcd 571.04;found 571.15 .

[0301] General synthesis 5 [ka] Example 104: 5-Cyano-N-(4-Cyanobicyclo[2.2.2]octane-1 Preparation of -yl)-2-(propylsulfonamide)benzamide Step 1: A mixture of 2-bromo-5-cyanobenzoic acid (1.2 g, 5.4 mmol), 4-aminobicyclo[2.2.2]octane-1-carbonitrile hydrochloride (1.1 g, 5.7 mmol), and O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate (TBTU, 1.9 g, 5.9 mmol) in magnetically stirred dichloromethane was treated with N,N-diisopropylethylamine (2.8 mL, 16 mmol). After stirring overnight at room temperature, the mixture was partitioned between ethyl acetate and saturated sodium chloride aqueous solution. The aqueous phase was extracted three times with ethyl acetate. The combined organic phases were sequentially washed with 10% aqueous hydrochloric acid, water, and saturated sodium bicarbonate aqueous solution, then dried over anhydrous magnesium sulfate, filtered, and concentrated to obtain the residue of 2-bromo-5-cyano-N-(4-cyanobicyclo[2.2.2]octan-1-yl)benzamide. LCMS-ESI + (m / z): [M+H] + calcd 358.06; found 358.15. This step can also be achieved using the coupling reagent 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide instead of TBTU; see step 4 of general synthesis 3.

[0302] Step 2: A solution of 2-bromo-5-cyano-N-(4-cyanobicyclo[2.2.2]octan-1-yl)benzamide (50 mg, 0.14 mmol) and propane-1-sulfonamide (26 mg, 0.21 mmol) in 1 mL of toluene was treated with tris(dibenzylideneacetone)dipalladium(0) (13 mg, 0.014 mmol), 9,9-dimethyl-4,5-bis(diphenylphosphin)xanthene (16 mg, 0.028 mmol), and tricalcium phosphate (59 mg, 0.28 mmol). This solution was heated to 110°C and stirred for 4 hours. The volatile substances were then removed from the mixture under reduced pressure, dissolved in ethyl acetate, and washed with water. The aqueous phase was extracted with ethyl acetate, and the organic phase was combined, washed with brine, dried over anhydrous magnesium sulfate, filtered, and concentrated to obtain the residue. The residue was purified by silica flash chromatography to obtain 5-cyano-N-(4-cyanobicyclo[2.2.2]octan-1-yl)-2-(propylsulfonamide)benzamide. 1 H NMR (400 MHz, DMSO-d6) δ 11.12 (s, 1H), 8.33 (s, 1H), 8.27 (d, J = 1.9 Hz, 1H), 7.95 (dd, J = 8.7, 1.8 Hz, 1H), 7.65 (d, J = 8.7 Hz, 1H), 3.35 - 3.29 (m, 2H), 2.00 (s, 12H), 1.65 (h, J = 7.4 Hz, 2H), 0.93 (t, J = 7.4 Hz, 3H). LCMS-ESI - (m / z): [MH] - calcd 399.15;found 399.24.

[0303] [ka] Example 105: Preparation of N-(4-cyanobicyclo[2.2.2]octan-1-yl)-2-(methylsulfonamide)-5-(trifluoromethyl)benzamide Step 1: Preparation of methyl 2-(methylsulfonamide)-5-(trifluoromethyl)benzoate A solution of methyl 2-amino-5-(trifluoromethyl)benzoate (1.5 g, 6.9 mmol) in dichloromethane (20 mL) was sequentially treated with pyridine (5.6 mL, 69 mmol) and methanesulfonyl chloride (5.4 mL, 69 mmol). Alternatively, this mixture was magnetically stirred and allowed to stand at room temperature for 4 weeks. The reaction mixture was treated with 10% hydrochloric acid (approximately 30 mL), stirred for 15 minutes, and then diluted with ethyl acetate. The entire mixture was filtered through a Celite diatomaceous earth frit pad. The aqueous phase was then extracted twice with ethyl acetate. The combined organic phases were washed once with a saturated sodium chloride solution (mixed with some 10% hydrochloric acid), dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure to obtain a mixture of the desired intermediate and the bis-sulfonylation product (2-(N-(methylsulfonyl)methylsulfonamide)-5-(trifluoromethyl)methyl benzoate), which was then subjected to hydrolysis without further purification. Step 2: Preparation of 2-(methylsulfonamide)-5-(trifluoromethyl)benzoic acid

[0304] A mixture containing both 2-(N-(methylsulfonyl)methylsulfonamide)-5-(trifluoromethyl)methyl benzoate and 2-(methylsulfonamide)-5-(trifluoromethyl)methyl benzoate (unknown ratio, estimated 6.9 mmol total) was placed in tetrahydrofuran (30 mL) as a suspension and treated with water and methanol (10 mL each), then sodium hydroxide (1.7 g, 42 mmol) was added. The mixture was left to stand overnight at room temperature, and then heated at 65°C with stirring the following day. After this hydrolysis was complete, the mixture was acidified with 10% hydrochloric acid and extracted three times with ethyl acetate (3 × 30 mL). The combined organic layer was washed once with saturated sodium chloride aqueous solution, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The desired substance was crystallized from methanol / water and dried under reduced pressure to obtain the desired intermediate. LCMS-ESI - (m / z): [MH]- calcd 282.01;found 282.02. Step 3: Preparation of (4-carbamoylbicyclo[2.2.2]octan-1-yl)carbamate tert-butyl

[0305] To a mixture of 4-((tert-butoxycarbonyl)amino)bicyclo[2.2.2]octane-1-carboxylic acid (6.7 g, 25 mmol) in 2-methyltetrahydrofuran (200 mL), which was being cooled in an ice bath, 1-hydroxybenzotriazole hydrate (HOBT, 5.4 g, 35 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDC, 5.4 g, 35 mmol), and N,N-diisopropylethylamine (12 mL, 70 mmol) were added in sequence. The suspension was stirred in an ice bath for 30 minutes, then at room temperature for 3 hours. The mixture was sonicated for about 2 minutes, then vigorously stirred, during which time the mixture was cooled again in an ice bath. A solution of ammonium hydroxide (28.0-30.0% NH3-based, 17 mL, 125 mmol) was added, the cooling bath was removed, and the mixture was stirred at room temperature overnight. Volatile substances were removed under reduced pressure, and the residue was partitioned between water (approximately 30 mL) and ethyl acetate (approximately 200 mL). The aqueous phase was extracted twice with ethyl acetate. The combined organic matter was washed sequentially with 10% aqueous hydrochloric acid, water, and saturated sodium bicarbonate aqueous solution, then dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure to obtain the desired intermediate. LCMS-ESI + (m / z): [M+H] + calcd 269.18;found 269.06. Step 4: Preparation of tert-butyl (4-cyanobicyclo[2.2.2]octan-1-yl)carbamate

[0306] Add phosphorus oxychloride (9.0 mL, 96 mmol) to a solution of (4-carbamoylbicyclo[2.2.2]octan-1-yl)carbamate tert-butyl (5.2 g, 19 mmol) in pyridine (80 mL) while magnetically stirring with a syringe (in a cooled ice bath). The mixture was slowly added via a pipette. This mixture was stirred in an ice bath for 30 minutes, then removed from the bath and stirred for another 30 minutes. The mixture was then added to ice water (approximately 400 mL) via a pipette. The solid was collected by filtration, washed with water, and dried under reduced pressure to obtain the desired intermediate. LCMS-ESI + (m / z): [M+H] + calcd 251.17;found 251.01. Step 5: Preparation of 4-aminobicyclo[2.2.2]octane-1-carbonitrile hydrochloride

[0307] (4-Cyanobicyclo[2.2.2]octan-1-yl)carbamate tert-butyl (0.60 g, 2.4 mmol) was placed in water as a suspension in a sealed container, heated at 160°C for 22 hours, and then allowed to cool. This mixture was treated with concentrated hydrochloric acid (0.5 mL) and then concentrated to obtain the desired intermediate (LCMS-ESI + (m / z): [M+H] + calcd 151.12;found 150.95) and 4-aminobicyclo[2.2.2]octane-1-carboxamide hydrochloride (LCMS-ESI + (m / z): [M+H] + A mixture was obtained with calcd 169.13;found 169.01), which was carried over to the next stage without further separation. Step 6 (General Synthesis 6): Preparation of N-(4-cyanobicyclo[2.2.2]octan-1-yl)-2-(methylsulfonamide)-5-(trifluoromethyl)benzamide

[0308] A mixture of 2-(methylsulfonamide)-5-(trifluoromethyl)benzoic acid (0.12 g, 0.42 mmol) and 4-aminobicyclo[2.2.2]octane-1-carbonitrile hydrochloride (contaminated with 4-aminobicyclo[2.2.2]octane-1-carboxamide hydrochloride, 87 mg, approximately 0.47 mmol) in N,N-dimethylformamide (DMF, 1 mL) was treated with N,N-diisopropylethylamine (0.37 mL, 2.1 mmol) and then sonicated for approximately 1 minute. Next, a solution of 1-propanephosphonic acid anhydride (T3P, 50% by weight in DMF, 0.74 mL, 1.27 mmol) was added, and the mixture was stirred overnight at 85°C. The reaction mixture was poured into ice water (approximately 30 mL), and the resulting aqueous mixture was extracted three times with ethyl acetate. The combined extracts were washed once with saturated sodium chloride aqueous solution, dried over anhydrous magnesium sulfate, filtered, and concentrated to dryness under reduced pressure. The residue was purified first by flash chromatography (silica gel) and then by reverse-phase HPLC (acetonitrile / water / 0.1% trifluoroacetic acid) to obtain the desired product. 1 H NMR (400 MHz, DMSO-d6) δ 10.90 (s, 1H), 8.39 (s, 1H), 8.06 (d, J = 2.2 Hz, 1H), 7.86 (d, J = 8.7 Hz, 1H), 7.67 (d, J = 8.7 Hz, 1H), 3.21 (s, 3H), 2.01 (s, 12H). LCMS-ESI + (m / z): [M+H] + calcd 416.12;found 416.06.

[0309] [ka] Example 106: Synthesis of 2-((4-(1,1-dioxidethiomorpholino)phenyl)sulfonamide)-4-(trifluoromethyl)-N-(3-(trifluoromethyl)bicyclo[1.1.1]pentan-1-yl)benzamide 2-((4-iodophenyl)sulfonamide)-4-(trifluoromethyl)-N- (3-(trifluoromethyl)bicyclo[1.1.1]pentan-1-yl)benzamide was synthesized according to general synthesis 4, using 4-iodobenzenesulfonyl chloride (1 equivalent) in step 1. 2-((4-iodophenyl)sulfonamide)-4-(trifluoromethyl)-N-(3-(trifluoromethyl)bicyclo[1.1.1]pentan-1-yl)benzamide (39 mg, 0.065 mmol), tricalcium phosphate monohydrate (82 mg, 0.39 mmol), rac-2,2'-bis(diphenylphosphino)-1,1'-binaphthylene (6.0 mg, 0.0097 mmol), thiomorpholine-1,1-dioxide (26 mg, 0.19 mmol), and tris(dibenzylideneacetone)dipalladium(0) (5.2 mg, 0.0065 mmol) were dissolved in 1,4-dioxane. This mixture was purged under nitrogen and heated overnight with stirring at 100°C, then cooled, water was added, and it was extracted three times with ethyl acetate. The combined organic layers were washed with brine, dried over magnesium sulfate, filtered, and concentrated. The crude product was purified using RP-HPLC to obtain 2-((4-(1,1-dioxide thiomorpholino)phenyl)sulfonamide)-4-(trifluoromethyl)-N-(3-(trifluoromethyl)bicyclo[1.1.1]pentan-1-yl)benzamide. 1 H NMR (400 MHz, DMSO-d6) δ 11.19 (s, 1H), 9.67 (s, 1H), 7.88 (d, J = 8.2 Hz, 1H), 7.72 (s, 1H), 7.53 (d, J = 9.1 Hz, 3H), 7.10 (d, J = 9.1 Hz, 2H), 3.93 - 3.84 (m, 4H), 3.14 - 3.04 (m, 4H), 2.35 (s, 6H). LCMS-ESI - (m / z): [MH] - calcd 610.09;found 610.30.

[0310] [ka] Example 107: Synthesis of 2-((4-(methylsulfonamide)phenyl)sulfonamide)-4-(trifluoromethyl)-N-(3-(trifluoromethyl)bicyclo[1.1.1]pentan-1-yl)benzamide 2-((4-iodophenyl)sulfonamide)-4-(trifluoromethyl)-N-(3-(trifluoromethyl)bicyclo[1.1.1]pentan-1-yl)benzamide was synthesized according to general synthesis 4, using 4-iodobenzenesulfonyl chloride (1 equivalent) in step 1. 2-((4-iodophenyl)sulfonamide)-4-(trifluoromethyl)-N-(3-(trifluoromethyl)bicyclo[1.1.1]pentan-1-yl)benzamide (31 mg, 0.051 mmol), methanesulfonamide (24 mg, 0.26 mmol), copper(I) oxide (2.5 mg, 0.017 mmol), and cesium carbonate (50 mg, 0.15 mmol) were placed in water and reacted at 150°C for 5 hours with stirring. This mixture was acidified with acetic acid and then purified by RP-HPLC to obtain 2-((4-(methylsulfonamide)phenyl)sulfonamide)-4-(trifluoromethyl)-N-(3-(trifluoromethyl)bicyclo[1.1.1]pentan-1-yl)benzamide. 1 H NMR (400 MHz, DMSO-d6) δ 11.12 (s, 1H), 10.47 (s, 1H), 9.63 (s, 1H), 7.85 (d, J = 7.8 Hz, 1H), 7.69 (s, 1H), 7.65 (d, J = 8.8 Hz, 2H), 7.59 (d, J = 7.6 Hz, 1H), 7.27 (d, J = 9.0 Hz, 2H), 3.10 (s, 3H), 2.33 (s, 6H). LCMS-ESI - (m / z): [MH] - calcd 570.06;found 570.13.

[0311] General Synthesis 7 and 8 [ka] Example 108: Preparation of 2-((1-cyanocyclopropane)-1-sulfonamide)-5-(trifluoromethyl)-N-(3-(trifluoromethyl)bicyclo[1.1.1]pentan-1-yl)benzamide Step 1 (General Synthesis 7): Preparation of 2-iodo-5-(trifluoromethyl)-N-(3-(trifluoromethyl)bicyclo[1.1.1]pentan-1-yl)benzamide A mixture of 2-iodo-5-(trifluoromethyl)benzoic acid (0.79 g, 2.5 mmol), 3-(trifluoromethyl)bicyclo[1.1.1]pentan-1-amine hydrochloride (0.52 g, 2.8 mmol), and O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate (TBTU, 0.88 g, 2.75 mmol) in dichloromethane (15 mL) was treated with N,N-diisopropylethylamine (1.3 mL, 7.5 mmol). This mixture was stirred overnight at room temperature. The mixture was then partitioned between ethyl acetate and saturated sodium bicarbonate aqueous solution. The latter was extracted three times with ethyl acetate. The combined organic extracts were sequentially washed with 10% aqueous hydrochloric acid and saturated sodium chloride aqueous solution, dried over anhydrous magnesium sulfate, filtered, and concentrated to dryness under reduced pressure to obtain the desired intermediate. LCMS-ESI - (m / z): [MH] - calcd 447.97;found 448.03.

[0312] Step 2: Preparation of 1-cyanocyclopropane-1-sulfonamide A solution of tert-butyl ((1-cyanocyclopropyl)sulfonyl)carbamate (enamine, 0.30 g, 1.2 mmol) was cooled in an ice bath, during which trifluoroacetic acid (0.93 mL, 12 mmol) was added dropwise. The mixture was gradually heated to room temperature while the bath was being depleted. Once LC / MS analysis indicated the conversion was complete, the mixture was concentrated under reduced pressure. The residue was evaporated once with diethyl ether and then carried over to the next stage without further purification. LC / MS-ESI - (m / z): [MH] - calcd 145.01;found 144.92.

[0313] Step 3 (General Synthesis 8): Preparation of 2-((1-cyanocyclopropane)-1-sulfonamide)-5-(trifluoromethyl)-N-(3-(trifluoromethyl)bicyclo[1.1.1]pentan-1-yl)benzamide A mixture of 1-cyanocyclopropane-1-sulfonamide (0.18 g, 1.2 mmol), 2-iodo-5-(trifluoromethyl)-N-(3-(trifluoromethyl)bicyclo[1.1.1]pentan-1-yl)benzamide (0.19 g, 0.41 mmol), copper(I) iodide (16 mg, 0.08 mmol), sarcosine (9 mg, 0.1 mmol), and potassium carbonate (approximately 325 mesh, 170 mg, 1.2 mmol) or preferably tricalcium phosphate (0.25 g, 1.2 mmol) in N,N-dimethylformamide (3 mL) was heated in a 100°C block for approximately 3 days. After cooling, the mixture was partitioned between ethyl acetate and 10% hydrochloric acid. The aqueous phase was divided three times with ethyl acetate. Extraction was performed. The combined extracts were washed once each with water and saturated sodium chloride aqueous solution, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by reverse-phase high-performance liquid chromatography (RP-HPLC, acetonitrile / water / 0.1% trifluoroacetic acid) to obtain the desired product. 1H NMR (400 MHz, DMSO-d6) δ 12.12 (bs, 1H), 10.01 (bs, 1H), 8.23 ​​(d, J = 2.1 Hz, 1H), 8.04 - 7.84 (m, 1H), 7.78 (d, J = 8.7 Hz, 1H), 2.38 (s, 6H), 1.88 (m, 2H), 1.67 (m, 2H). LCMS-ESI - (m / z): [MH] - calcd 466.07;found 466.22.

[0314] [ka] Example 109: Synthesis of 2-((4-(methylsulfonamide)phenyl)sulfonamide)-4-(trifluoromethyl)-N-(3-(trifluoromethyl)bicyclo[1.1.1]pentan-1-yl)benzamide 2-bromo-4-(trifluoromethyl)-N-(3-(trifluoromethyl)bicyclo[1.1.1]pentan-1-yl)benzamide was synthesized by subjecting 2-bromo-4-(trifluoromethyl)benzonitrile to steps 3 and 4 of general synthesis 3, and using 3-(trifluoromethyl)bicyclo[1.1.1]pentan-1-amine hydrochloride (1.5 equivalents) in step 4. 2-((4-(methylsulfonamide)phenyl)sulfonamide)-4-(trifluoromethyl)-N-(3-(trifluoromethyl)bicyclo[1.1.1]pentan-1-yl)benzamide was prepared using general synthesis 8, with 2-bromo-4-(trifluoromethyl)-N-(3-(trifluoromethyl)bicyclo[1.1.1]pentan-1-yl)benzamide (1 equivalent) and 4-fluorobenzenesulfonamide (3 equivalents). 1H NMR (400 MHz, DMSO-d6) δ 11.19 (s, 1H), 9.62 (s, 1H), 7.86 (d, J = 8.0 Hz, 1H), 7.77 (dd, J = 8.8, 5.0 Hz, 2H), 7.67 (s, 1H), 7.60 (d, J = 6.8 Hz, 1H), 7.42 (t, J = 8.7 Hz, 2H), 2.33 (s, 6H). LCMS-ESI - (m / z): [MH] - calcd 495.06;found 495.19.

[0315] [ka] Example 110: Synthesis of 2-((1,1-dimethylethyl)sulfonamide)-4-(trifluoromethyl)-N-(3-(trifluoromethyl)bicyclo[1.1.1]pentan-1-yl)benzamide 2-bromo-4-(trifluoromethyl)-N-(3-(trifluoromethyl)bicyclo[1.1.1]pentan-1-yl)benzamide was synthesized by subjecting 2-bromo-4-(trifluoromethyl)benzonitrile to steps 3 and 4 of general synthesis 3, and using 3-(trifluoromethyl)bicyclo[1.1.1]pentan-1-amine hydrochloride (1.5 equivalents) in step 4. 2-((1,1-dimethylethyl)sulfonamide)- 4-(trifluoromethyl)-N-(3-(trifluoromethyl)bicyclo[1.1.1]pentan-1-yl)benzamide was prepared using general synthesis method 8, with 2-bromo-4-(trifluoromethyl)-N-(3-(trifluoromethyl)bicyclo[1.1.1]pentan-1-yl)benzamide (1 equivalent) and 2-methylpropane-2-sulfonamide (3 equivalents). 1 H NMR (400 MHz, DMSO-d6) δ 10.94 (s, 1H), 9.86 (s, 1H), 8.02 (s, 1H), 7.97 (d, J = 8.2 Hz, 1H), 7.56 (d, J = 8.2 Hz, 1H), 2.37 (s, 6H), 1.29 (s, 9H). LCMS-ESI - (m / z): [MH] - calcd 457.10;found 457.24.

[0316] [ka] Example 111: Synthesis of 2-((4-methoxyphenyl)sulfonamide)-4-(trifluoromethyl)-N-(3-(trifluoromethyl)bicyclo[1.1.1]pentan-1-yl)benzamide 2-bromo-4-(trifluoromethyl)-N-(3-(trifluoromethyl)bicyclo[1.1.1]pentan-1-yl)benzamide was synthesized by subjecting 2-bromo-4-(trifluoromethyl)benzonitrile to steps 3 and 4 of general synthesis 3, and using 3-(trifluoromethyl)bicyclo[1.1.1]pentan-1-amine hydrochloride (1.5 equivalents) in step 4. 2-((4-methoxyphenyl)sulfonamide)-4-(trifluoromethyl)-N-(3-(trifluoromethyl)bicyclo[1.1.1]pentan-1-yl)benzamide was prepared using general synthesis 8, with 2-bromo-4-(trifluoromethyl)-N-(3-(trifluoromethyl)bicyclo[1.1.1]pentan-1-yl)benzamide (1 equivalent) and 4-methoxybenzenesulfonamide (3 equivalents). 1 H NMR (400 MHz, DMSO-d6) δ 11.17 (s, 1H), 9.64 (s, 1H), 7.86 (d, J = 8.1 Hz, 1H), 7.70 (s, 1H), 7.65 (d, J = 8.9 Hz, 2H), 7.56 (d, J = 8.5 Hz, 1H), 7.07 (d, J = 9.0 Hz, 2H), 3.80 (s, 3H), 2.34 (s, 6H). LCMS-ESI- (m / z): [MH] - calcd 507.08;found 507.24.

[0317] [ka] Example 112: Synthesis of 2-((4-(2-methoxyethoxy)phenyl)sulfonamide)-4-(trifluoromethyl)-N-(3-(trifluoromethyl)bicyclo[1.1.1]pentan-1-yl)benzamide 2-Bromo-4-(trifluoromethyl)-N-(3-(trifluoromethyl)bicyclo[1.1.1]pentan-1-yl)benzamide and 2-bromo-4-(trifluoromethyl)benzonitrile are subjected to steps 3 and 4 of the general synthesis 3, and 3-(trifluoromethyl)bicyclo[1.1.1]pentan-1-amine hydrochloride (1.5 equivalents) is added in step 4. It was synthesized using the following method. 4-(2-methoxyethoxy)benzenesulfonamide was prepared by treating 4-fluorobenzenesulfonamide (100 mg, 0.57 mmol) with sodium hydroxide (110 mg, 2.9 mmol) in 0.33 mL of 2-methoxyethanol (7.4 mmol), heating the mixture overnight with stirring at 110°C, and purifying the product by silica flash chromatography. 2-((4-(2-methoxyethoxy)phenyl)sulfonamide)-4-(trifluoromethyl)-N-(3-(trifluoromethyl)bicyclo[1.1.1]pentan-1-yl)benzamide was prepared using general synthesis method 8, with 2-bromo-4-(trifluoromethyl)-N-(3-(trifluoromethyl)bicyclo[1.1.1]pentan-1-yl)benzamide (1 equivalent) and 4-(2-methoxyethoxy)benzenesulfonamide (3 equivalents). 1 H NMR (400 MHz, DMSO-d6) δ 11.13 (s, 1H), 9.64 (s, 1H), 7.86 (d, J = 8.2 Hz, 1H), 7.70 (s, 1H), 7.62 (d, J = 9.0 Hz, 2H), 7.57 (d, J = 8.3 Hz, 1H), 7.08 (d, J = 9.0 Hz, 2H), 4.20 - 4.05 (m, 2H), 3.70 - 3.58 (m, 2H), 3.28 (s, 3H), 2.34 (s, 6H). LCMS-ESI - (m / z): [MH] - calcd 551.11;found 551.23.

[0318] [ka] Example 113: Synthesis of 2-((4-(2-(methylthio)ethoxy)phenyl)sulfonamide)-4-(trifluoromethyl)-N-(3-(trifluoromethyl)bicyclo[1.1.1]pentan-1-yl)benzamide 2-Bromo-4-(trifluoromethyl)-N-(3-(trifluoromethyl)bicyclo[1.1.1]pentan-1-yl)benzamide was synthesized by subjecting 2-bromo-4-(trifluoromethyl)benzonitrile to steps 3 and 4 of general synthesis 3, and using 3-(trifluoromethyl)bicyclo[1.1.1]pentan-1-amine hydrochloride (1.5 equivalents) in step 4. 4-(2-(methylthio)ethoxy)benzenesulfonamide was prepared by treating 4-fluorobenzenesulfonamide (100 mg, 0.57 mmol) with sodium hydroxide (110 mg, 2.9 mmol) in 0.5 mL of 2-(methylthio)ethanol (6.0 mmol), heating the mixture overnight with stirring at 110°C, and purifying the product by silica flash chromatography. 2-((4-(2-(methylthio)ethoxy)phenyl)sulfonamide)-4-(trifluoromethyl)-N-(3-(trifluoromethyl)bicyclo[1.1.1]pentan-1-yl)benzamide was prepared using general synthesis method 8, with 2-bromo-4-(trifluoromethyl)-N-(3-(trifluoromethyl)bicyclo[1.1.1]pentan-1-yl)benzamide (1 equivalent) and 4-(2-(methylthio)ethoxy)benzenesulfonamide (3 equivalents).1 1H NMR (400 MHz, DMSO-d6) δ 11.16 (s, 1H), 9.66 (s, 1H), 7.86 (d, J = 8.1 Hz, 1H), 7.70 (s, 1H), 7.63 (d, J = 8.9 Hz, 2H), 7.58 (d, J = 7.8 Hz, 1H), 7.09 (d, J = 9.0 Hz, 2H), 4.19 (t, J = 6.5 Hz, 2H), 2.83 (t, J = 6.5 Hz, 2H), 2.33 (s, 6H), 2.12 (s, 3H). LCMS-ESI + (m / z): [M+H] + calcd 569.10;found 568.87.

[0319] [ka] Example 114: Synthesis of N-(4-cyanobicyclo[2.2.2]octan-1-yl)-2-((1,1-dimethylethyl)sulfonamide)-4-(trifluoromethyl)benzamide N-(4-cyanobicyclo[2.2.2]octane-1-yl)-2-((1,1-dimethylethyl)sulfonamide)-4-(trifluoromethyl)benzamide was synthesized according to General Synthesis 3, using 2-bromo-4-(trifluoromethyl)benzonitrile (1 equivalent) in step 1 and 4-aminobicyclo[2.2.2]octane-1-carbonitride hydrochloride (1.8 equivalents) in step 4. 1 H NMR (400 MHz, DMSO-d6) δ 10.42 (s, 1H), 8.49 (s, 1H), 7.96 (s, 1H), 7.87 (d, J = 8.1 Hz, 1H), 7.53 (d, J = 8.2 Hz, 1H), 2.00 (s, 12H), 1.27 (s, 9H). LCMS-ESI - (m / z): [MH] - calcd 456.16;found 456.32.

[0320] [ka] Example 115: Synthesis of 2-((4-(2-(methylsulfonyl)ethoxy)phenyl)sulfonamide)-4-(trifluoromethyl)-N-(3-(trifluoromethyl)bicyclo[1.1.1]pentan-1-yl)benzamide 2-((4-(2-(methylthio)ethoxy)phenyl)sulfonamide)-4-(trifluoromethyl)-N-(3-(trifluoromethyl)bicyclo[1.1.1]pentan-1-yl)benzamide, prepared according to the procedure described in Example 113, was treated with a solution of 32% by weight peracetic acid in acetic acid. After stirring at room temperature for 5 hours, the reaction product was diluted with water. The aqueous phase was extracted three times with ethyl acetate and then concentrated to obtain the residue. The crude product was purified by RP-HPLC to obtain 2-((4-(2-(methylsulfonyl)ethoxy)phenyl)sulfonamide)-4-(trifluoromethyl)-N-(3-(trifluoromethyl)bicyclo[1.1.1]pentan-1-yl)benzamide. 1 1H NMR (400 MHz, DMSO-d6) δ 11.20 (s, 1H), 9.67 (s, 1H), 7.87 (d, J = 8.2 Hz, 1H), 7.71 (s, 1H), 7.66 (d, J = 8.9 Hz, 2H), 7.57 (d, J = 8.0 Hz, 1H), 7.14 (d, J = 8.9 Hz, 2H), 4.39 (t, J = 5.6 Hz, 2H), 3.64 (t, J = 5.5 Hz, 2H), 3.05 (s, 3H), 2.34 (s, 6H). LCMS-ESI - (m / z): [MH] - calcd 599.07;found 599.29.

[0321] [ka] Example 116: Synthesis of 2-(ethylsulfonamide)-4-(trifluoromethyl)-N-(3-(trifluoromethyl)bicyclo[1.1.1]pentan-1-yl)benzamide 2-bromo-4-(trifluoromethyl)-N-(3-(trifluoromethyl)bicyclo[1.1.1]pentan-1-yl)benzamide was synthesized by subjecting 2-bromo-4-(trifluoromethyl)benzonitrile to steps 3 and 4 of general synthesis 3, and using 3-(trifluoromethyl)bicyclo[1.1.1]pentan-1-amine hydrochloride (1.5 equivalents) in step 4. 2-(ethylsulfonamide)-4-(trifluoromethyl)-N-(3-(trifluoromethyl)bicyclo[1.1.1]pentan-1-yl)benzamide was prepared using general synthesis procedure 8, with 2-bromo-4-(trifluoromethyl)-N-(3-(trifluoromethyl)bicyclo[1.1.1]pentan-1-yl)benzamide (1 equivalent) and ethanesulfonamide (3 equivalents). 1 H NMR (400 MHz, DMSO-d6) δ 11.03 (s, 1H), 9.80 (s, 1H), 8.00 (d, J = 8.2 Hz, 1H), 7.82 (s, 1H), 7.59 (d, J = 8.3 Hz, 1H), 3.30 (q, J = 7.3 Hz, 2H), 2.37 (s, 6H), 1.19 (t, J = 7.3 Hz, 3H). LCMS-ESI - (m / z): [MH] - calcd 429.07;found 429.15.

[0322] General synthesis 9 [ka] Step 1 (General Synthesis 9): Preparation of 2-((1,1-dimethylethyl)sulfonamide)-5-(trifluoromethyl)benzoic acid A mixture of 2-bromo-5-(trifluoromethyl)benzoic acid (6.5 g, 24 mmol), 2-methylpropane-2-sulfonamide (4.6 g, 34 mmol), copper(I) iodide (0.92 g, 4.8 mmol), and potassium carbonate (8.4 g, 61 mmol) in N,N-dimethylformamide (DMF, 60 mL) was heated overnight at 100°C. After cooling, the mixture was diluted with water and acidified with hydrochloric acid. This mixture was extracted three times with ethyl acetate. The combined extract was washed with saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography (silica gel) to obtain the desired intermediate. LCMS-ESI - (m / z): [MH] - calcd 324.06;found 324.05.

[0323] Step 2: Preparation of 2-((1,1-dimethylethyl)sulfonamide)-N-(8-(methylsulfonyl)-8-azabicyclo[3.2.1]octan-3-yl)-5-(trifluoromethyl)benzamide The title compound is used as a mixture of diastereomers, specifically 2-((1,1-dimethylethyl) It was prepared from sulfonamide)-5-(trifluoromethyl)benzoic acid (115 mg, 0.35 mmol) and 8-(methylsulfonyl)-8-azabicyclo[3.2.1]octane-3-amine (79 mg, 0.39 mmol) according to general synthesis 10. 1 1H NMR (400 MHz, DMSO-d6) δ 11.56 (s, 1H, diastereomer 1), 11.02 (s, 1H, diastereomer 2), 9.01 (d, J = 7.9 Hz, 1H, diastereomer 1), 8.75 (m, 1H, diastereomer 2), 8.18 (d, J = 2.0 Hz, 1H, diastereomer 1), 7.96 (d, J = 2.0 Hz, 1H, diastereomer 2), 7.93 (d, J = 3.0 Hz, 1H, diastereomer 1), 7.91 (d, J = 3.0 Hz, 1H, diastereomer -2), 7.86 (m, 2H, diastereomers 1 and 2), 4.34 (tt, J = 11.6, 6.0 Hz, 1H, diastereomer 1), 4.20 (m, 2H, diastereomer 1), 4.15 (s, 2H, diastereomer 2), 4.09 - 3.98 (m, 1H, diastereomer 2), 2.96 (s, 3H, diastereomer 1), 2.96 (s, 3H, diastereomer 2), 2.13 (m, 2H), 2.09 - 1.95 (m, 8H), 1.92 (dd, J = 5.9, 3.0 Hz, 1H, diastereomer 1), 1.89 (dd, J = 6.2, 2.8 Hz, 1H, diastereomer 2), 1.84 - 1.71 (m, 4H), 1.31 (s, 18H, diastereomers 1 and 2). LCMS-ESI - (m / z): [MH] - calcd 510.14;found 510.31.

[0324] General synthesis 10 [ka] Example 117: N-(4-cyanobicyclo[2.2.2]octan-1-yl)-2-(methylsulfonamide)-4-(pentafluoro-λ) 6 Preparation of sulfanyl benzamide 2-(methylsulfonamide)-4-(pentafluoro-λ) in dichloromethane being magnetically stirred. 6A mixture of -sulfanyl)benzoic acid (0.15 g, 0.44 mmol, as described in Example 146), 4-aminobicyclo[2.2.2]octane-1-carbonitrile hydrochloride (86 mg, 0.46 mmol), and O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate (TBTU, 0.15 g, 0.48 mmol) was treated with N,N-diisopropylethylamine (0.23 mL, 1.3 mmol). After stirring overnight at room temperature, the mixture was purified by RP-HPLC (acetonitrile / water / 0.1% trifluoroacetic acid) to obtain the desired product. 1 H NMR (400 MHz, DMSO-d6) δ 10.22 (s, 1H), 8.29 (s, 1H), 7.85 (d, J = 2.2 Hz, 1H), 7.83 (d, J = 8.7 Hz, 1H), 7.77 (dd, J = 8.7, 2.2 Hz, 1H), 3.12 (s, 3H), 1.99 (s, 12H). LCMS-ESI - (m / z): [MH] - calcd 472.09;found 472.22.

[0325] [ka] Example 118: Synthesis of N-(4-cyanobicyclo[2.2.2]octan-1-yl)-2-((4-(methylsulfonyl)phenyl)sulfonamide)-5-(trifluoromethyl)benzamide 4-(methylsulfonyl)benzenesulfonamide was prepared by treating 4-(methylsulfonyl)benzenesulfonyl chloride (500 mg, 2.0 mmol) with a 28 wt% aqueous solution of ammonium hydroxide in methanol (0.55 mL, 4.0 mmol) at 0°C. After warming to room temperature for 3 hours with stirring, the solid 4-(methylsulfonyl)benzenesulfonamide was collected by filtration, washed with water, and dried under a reduced pressure atmosphere. 2-((4-(methylsulfonyl)phenyl)sulfonamide)-5-(trifluoromethyl)benzoic acid was prepared using 4-(methylsulfonyl)benzenesulfonamide (1.2 equivalents) according to General Synthesis 9. 2-((4-(methylsulfonyl)phenyl)sulfonamide)-5-(trifluoromethyl)benzoic acid was subjected to general synthesis 10 to obtain N-(4-cyanobicyclo[2.2.2]octan-1-yl)-2-((4-(methylsulfonyl)phenyl)sulfonamide)-5-(trifluoromethyl)benzamide. 1 H NMR (400 MHz, DMSO-d6) δ 11.51 (s, 1H), 8.38 (s, 1H), 8.12 (d, J = 8.6 Hz, 2H), 8.04 (d, J = 8.6 Hz, 2H), 7.97 (s, 1H), 7.83 (d, J = 8.7 Hz, 1H), 7.61 (d, J = 8.6 Hz, 1H), 3.30 (s, 3H), 2.02 - 1.89 (m, 12H). LCMS-ESI - (m / z): [MH] - calcd 554.10;found 554.34.

[0326] [ka] Example 119: Synthesis of N-(4-cyanobicyclo[2.2.2]octan-1-yl)-2-((4-fluorophenyl)sulfonamide)-5-(trifluoromethyl)benzamide 2-((4-fluorophenyl)sulfonamide)-5-(trifluoromethyl)benzoic acid was prepared using general synthesis method 9 with 4-fluorobenzenesulfonamide (1.2 equivalents). 2-((4-fluorophenyl)sulfonamide)-5-(trifluoromethyl)benzoic acid was subjected to general synthesis method 10 to obtain N-(4-cyanobicyclo[2.2.2]octan-1-yl)-2-((4-fluorophenyl)sulfonamide)-5-(trifluoromethyl)benzamide. 1 H NMR (400 MHz, DMSO-d6) δ 11.39 (s, 1H), 8.38 (s, 1H), 7.96 (s, 1H), 7.89 - 7.83 (m, 2H), 7.82 (d, J = 8.2 Hz, 1H), 7.61 (d, J = 8.6 Hz, 1H), 7.43 (t, J = 8.8 Hz, 2H), 1.99 (s, 12H). LCMS-ESI - (m / z): [MH] - calcd 494.12;found 494.33.

[0327] [ka] Example 120: Synthesis of N-(4-cyanobicyclo[2.2.2]octan-1-yl)-2-(ethylsulfonamide)-5-(trifluoromethyl)benzamide 2-(ethylsulfonamide)-5-(trifluoromethyl)benzoic acid was prepared using general synthesis method 9 with ethanesulfonamide (1.5 equivalents). 2-(ethylsulfonamide)-5-(trifluoromethyl)benzoic acid was subjected to general synthesis method 10 to obtain N-(4-cyanobicyclo[2.2.2]octan-1-yl)-2-(ethylsulfonamide)-5-(trifluoromethyl)benzamide. 1 1H NMR (400 MHz, DMSO-d6) δ 10.94 (s, 1H), 8.46 (s, 1H), 8.07 (s, 1H), 7.86 (d, J = 8.7 Hz, 1H), 7.71 (d, J = 8.7 Hz, 1H), 3.32 - 3.26 (m, 2H), 2.00 (s, 12H), 1.17 (t, J = 7.3 Hz, 3H). LCMS-ESI - (m / z): [MH] - calcd 428.13;found 428.29.

[0328] [ka] Example 121: Synthesis of N-(4-cyanobicyclo[2.2.2]octan-1-yl)-2-((4-methoxyphenyl)sulfonamide)-5-(trifluoromethyl)benzamide 2-((4-methoxyphenyl)sulfonamide)-5-(trifluoromethyl)benzoic acid was prepared using general synthesis method 9 with 4-methoxybenzenesulfonamide (1.3 equivalents). 2-((4-methoxyphenyl)sulfonamide)-5-(trifluoromethyl)benzoic acid was subjected to general synthesis method 10 to obtain N-(4-cyanobicyclo[2.2.2]octan-1-yl)-2-((4-methoxyphenyl)sulfonamide)-5-(trifluoromethyl)benzamide. 1 H NMR (400 MHz, DMSO-d6) δ 11.30 (s, 1H), 8.37 (s, 1H), 7.95 (s, 1H), 7.80 (d, J = 8.7 Hz, 1H), 7.76 - 7.67 (m, 2H), 7.63 (d, J = 8.6 Hz, 1H), 7.20 - 6.94 (m, 2H), 3.80 (s, 3H), 1.99 (s, 12H). LCMS-ESI - (m / z): [MH] - calcd 506.14;found 506.31.

[0329] [ka] Example 122: Synthesis of N-(4-cyanobicyclo[2.2.2]octan-1-yl)-2-(phenylsulfonamide)-5-(trifluoromethyl)benzamide 2-(phenylsulfonamide)-5-(trifluoromethyl)benzoic acid was prepared using general synthesis method 9 with benzenesulfonamide (1.3 equivalents). 2-(phenylsulfonamide)-5-(trifluoromethyl)benzoic acid was subjected to general synthesis method 10 to obtain N-(4-cyanobicyclo[2.2.2]octan-1-yl)-2-(phenylsulfonamide)-5-(trifluoromethyl)benzamide. 1 H NMR (400 MHz, DMSO-d6) δ 11.42 (s, 1H), 8.36 (s, 1H), 7.96 (s, 1H), 7.85 - 7.75 (m, 3H), 7.65 (m, 2H), 7.58 (m, 2H), 1.99 (s, 12H). LCMS-ESI - (m / z): [MH] - calcd 476.13;found 476.34.

[0330] [ka] Example 123: Synthesis of 5-cyano-N-(4-cyanobicyclo[2.2.2]octan-1-yl)-2-((1,1-dimethylethyl)sulfonamide)benzamide 5-Cyano-2-((1,1-dimethylethyl)sulfonamide)benzoic acid was prepared using General Synthesis 9 with 2-methylpropane-2-sulfonamide (1.3 equivalents) and 2-bromo-5-cyanobenzoic acid (1.0 equivalent). 5-Cyano-2-((1,1-dimethylethyl)sulfonamide)benzoic acid was subjected to General Synthesis 10 to obtain 5-Cyano-N-(4-cyanobicyclo[2.2.2]octan-1-yl)-2-((1,1-dimethylethyl)sulfonamide)benzamide. 1 1H NMR (400 MHz, DMSO-d6) δ 11.04 (s, 1H), 8.41 (s, 1H), 8.24 (d, J = 1.8 Hz, 1H), 7.92 (dd, J = 8.8, 1.5 Hz, 1H), 7.83 (d, J = 8.8 Hz, 1H), 2.00 (s, 12H), 1.29 (s, 9H). LCMS-ESI + (m / z): [M+H] + calcd 415.18;found 414.81.

[0331] [ka] Example 124: Synthesis of 5-cyano-N-(4-cyanobicyclo[2.2.2]octan-1-yl)-2-(cyclopropanesulfonamide)benzamide 5-Cyano-N-(4-Cyanobicyclo[2.2.2]octan-1-yl)-2-(cyclopropanesulfonamide)benzamide was prepared by following general synthesis method 5, using cyclopropane-1-sulfonamide (1.5 equivalents) in step 2. 1 1H NMR (400 MHz, DMSO-d6) δ 11.15 (s, 1H), 8.33 (s, 1H), 8.31 - 8.22 (m, 1H), 7.95 (d, J = 8.6 Hz, 1H), 7.69 (d, J = 8.7 Hz, 1H), 2.94 - 2.84 (m, 1H), 2.00 (s, 12H), 1.03 (d, J = 6.3 Hz, 4H). LCMS-ESI - (m / z): [MH] - calcd 397.13;found 397.29.

[0332] [ka] Example 125: Synthesis of N-(4-cyanobicyclo[2.2.2]octan-1-yl)-2-(cyclopropanesulfonamide)-5-(trifluoromethyl)benzamide N-(4-cyanobicyclo[2.2.2]octan-1-yl)-2-(cyclopropanesulfonamide)-5-(trifluoromethyl)benzamide was prepared according to General Synthesis 5, using 2-bromo-5-(trifluoromethyl)benzoic acid (1.0 equivalent) in step 1 and cyclopropane-1-sulfonamide (1.5 equivalents) in step 2. 1 H NMR (400 MHz, DMSO-d6) δ 10.92 (s, 1H), 8.44 (s, 1H), 8.07 (s, 1H), 7.87 (d, J = 8.8 Hz, 1H), 7.75 (d, J = 8.7 Hz, 1H), 2.82 (p, J = 6.4 Hz, 1H), 2.01 (s, 12H), 1.00 (d, J = 5.7 Hz, 4H). LCMS-ESI - (m / z): [MH] - calcd 440.13;found 440.30.

[0333] [ka] Example 126: Synthesis of N-(4-cyanobicyclo[2.2.2]octan-1-yl)-2-(propylsulfonamide)-5-(trifluoromethyl)benzamide N-(4-cyanobicyclo[2.2.2]octan-1-yl)-2-(propylsulfonamide)-5-(trifluoromethyl)benzamide was prepared according to General Synthesis 5, using 2-bromo-5-(trifluoromethyl)benzoic acid (1.0 equivalent) in step 1 and propane-1-sulfonamide (1.7 equivalents) in step 2. 1 H NMR (400 MHz, DMSO-d6) δ 10.93 (s, 1H), 8.46 (s, 1H), 8.06 (s, 1H), 7.86 (d, J = 8.7 Hz, 1H), 7.71 (d, J = 8.7 Hz, 1H), 3.35 - 3.21 (m, 2H), 2.01 (s, 12H), 1.65 (h, J = 7.4 Hz, 2H), 0.93 (t, J = 7.4 Hz, 3H). LCMS-ESI - (m / z): [MH] - calcd 442.14;found 442.27.

[0334] [ka] Example 127: Synthesis of 2-(butylsulfonamide)-N-(4-cyanobicyclo[2.2.2]octan-1-yl)-5-(trifluoromethyl)benzamide 2-(butylsulfonamide)-N-(4-cyanobicyclo[2.2.2]octan-1-yl)-5-(trifluoromethyl)benzamide was prepared according to General Synthesis 5, using 2-bromo-5-(trifluoromethyl)benzoic acid (1.0 equivalent) in step 1 and butane-1-sulfonamide (1.7 equivalents) in step 2. 1 H NMR (400 MHz, DMSO-d6) δ 10.96 (s, 1H), 8.46 (s, 1H), 8.07 (s, 1H), 7.87 (d, J = 8.7 Hz, 1H), 7.71 (d, J = 8.7 Hz, 1H), 3.32 - 3.27 (m, 2H), 2.01 (s, 12H), 1.60 (p, J = 7.5 Hz, 2H), 1.33 (h, J = 7.4 Hz, 2H), 0.82 (t, J = 7.3 Hz, 3H). LCMS-ESI + (m / z): [M+H] + calcd 458.17;found 458.00.

[0335] [ka] Example 128: Synthesis of N-(4-cyanobicyclo[2.2.2]octan-1-yl)-2-((2-methoxyethyl)sulfonamide)-5-(trifluoromethyl)benzamide N-(4-cyanobicyclo[2.2.2]octan-1-yl)-2-((2-methoxyethyl)sulfonamide)-5-(trifluoromethyl)benzamide was prepared according to General Synthesis 5, using 2-bromo-5-(trifluoromethyl)benzoic acid (1.0 equivalent) in step 1 and 2-methoxyethane-1-sulfonamide (1.5 equivalents) in step 2. 1 H NMR (400 MHz, DMSO-d6) δ 11.09 (s, 1H), 8.41 (s, 1H), 8.07 (s, 1H), 7.85 (d, J = 8.7 Hz, 1H), 7.72 (d, J = 8.7 Hz, 1H), 3.64 (t, J = 5.1 Hz, 2H), 3.60 - 3.56 (m, 2H), 3.10 (s, 3H), 2.01 (s, 12H). LCMS-ESI + (m / z): [M+H] + calcd 460.15;found 460.00.

[0336] [ka] Example 129: 2-(butylsulfonamide)-5-cyano-N-(4-cyanobic acid Synthesis of chloro[2.2.2]octan-1-yl)benzamide 2-(butylsulfonamide)-5-cyano-N-(4-cyanobicyclo[2.2.2]octan-1-yl)benzamide was prepared by following general synthesis 5, using butane-1-sulfonamide (1.5 equivalents) in step 2. 1H NMR (400 MHz, DMSO-d6) δ 11.14 (s, 1H), 8.34 (s, 1H), 8.27 (d, J = 1.9 Hz, 1H), 7.95 (dd, J = 8.7, 1.9 Hz, 1H), 7.66 (d, J = 8.7 Hz, 1H), 3.39 - 3.29 (m, 2H), 2.00 (s, 12H), 1.60 (p, J = 7.5 Hz, 2H), 1.33 (h, J = 7.4 Hz, 2H), 0.82 (t, J = 7.3 Hz, 3H). LCMS-ESI - (m / z): [MH] - calcd 413.16;found 413.26.

[0337] [ka] Example 130: Synthesis of N-(4-cyanobicyclo[2.2.2]octan-1-yl)-2-(pyrrolidine-1-sulfonamide)-5-(trifluoromethyl)benzamide N-(4-cyanobicyclo[2.2.2]octan-1-yl)-2-(pyrrolidine-1-sulfonamide)-5-(trifluoromethyl)benzamide was prepared according to General Synthesis 5, using 2-bromo-5-(trifluoromethyl)benzoic acid (1.0 equivalent) in step 1 and pyrrolidine-1-sulfonamide (1.5 equivalents) in step 2. 1 H NMR (400 MHz, DMSO-d6) δ 10.92 (s, 1H), 8.47 (s, 1H), 8.04 (s, 1H), 7.86 (d, J = 8.7 Hz, 1H), 7.70 (d, J = 8.7 Hz, 1H), 3.18 (t, J = 6.7 Hz, 4H), 2.01 (s, 12H), 1.79 - 1.71 (m, 4H). LCMS-ESI - (m / z): [MH] - calcd 469.15;found 469.32.

[0338] [ka] Example 131: Synthesis of 5-cyano-N-(4-cyanobicyclo[2.2.2]octan-1-yl)-2-(pyrrolidine-1-sulfonamide)benzamide 5-Cyano-N-(4-Cyanobicyclo[2.2.2]octan-1-yl)-2-(pyrrolidine-1-sulfonamide)benzamide was prepared by following the general synthesis 5, using pyrrolidine-1-sulfonamide (1.5 equivalents) in step 2. 1 H NMR (400 MHz, DMSO-d6) δ 11.12 (s, 1H), 8.35 (s, 1H), 8.25 (s, 1H), 7.94 (d, J = 8.7 Hz, 1H), 7.63 (d, J = 8.7 Hz, 1H), 3.19 (t, J = 6.6 Hz, 4H), 2.00 (s, 12H), 1.79 - 1.72 (m, 4H). LCMS-ESI - (m / z): [MH] - calcd 426.16;found 426.30.

[0339] [ka] Example 132: Synthesis of 2-(azetidine-1-sulfonamide)-5-cyano-N-(4-cyanobicyclo[2.2.2]octan-1-yl)benzamide 2-(azetidine-1-sulfonamide)-5-cyano-N-(4-cyanobicyclo[2.2.2]octan-1-yl)benzamide was prepared by following general synthesis 5, using azetidine-1-sulfonamide (1.5 equivalents) in step 2. 1H NMR (400 MHz, DMSO-d6) δ 11.25 (s, 1H), 8.35 (s, 1H), 8.28 (s, 1H), 7.96 (d, J = 8.1 Hz, 1H), 7.64 (d, J = 8.6 Hz, 1H), 3.82 (t, J = 7.6 Hz, 4H), 2.14 (p, J = 7.4 Hz, 2H), 2.00 (s, 12H). LCMS-ESI - (m / z): [MH] - calcd 412.14;found 412.30.

[0340] [ka] Example 133: Synthesis of N-(4-cyanobicyclo[2.2.2]octan-1-yl)-2-(ethylsulfonamide)-4-(trifluoromethyl)benzamide 2-Bromo-N-(4-cyanobicyclo[2.2.2]octane-1-yl)-4-(trifluoromethyl)benzamide was prepared by following step 4 of general synthesis 3 using 2-bromo-4-(trifluoromethyl)benzoic acid (1.0 equivalent) and 4-aminobicyclo[2.2.2]octane-1-carbonitride hydrochloride (1.2 equivalents). N-(4-cyanobicyclo[2.2.2]octane-1-yl)-2-(ethylsulfonamide)-4-(trifluoromethyl)benzamide was prepared by following general synthesis 8 using 2-bromo-N-(4-cyanobicyclo[2.2.2]octane-1-yl)-4-(trifluoromethyl)benzamide (1.0 equivalent) and ethanesulfonamide (3.0 equivalents). 1 H NMR (400 MHz, DMSO-d6) δ 10.47 (s, 1H), 8.37 (s, 1H), 7.89 (d, J = 8.1 Hz, 1H), 7.77 (s, 1H), 7.56 (d, J = 7.9 Hz, 1H), 3.24 (q, J = 7.3 Hz, 2H), 2.00 (s, 12H), 1.18 (t, J = 7.3 Hz, 3H). LCMS-ESI- (m / z): [MH] - calcd 428.13;found 428.24.

[0341] [ka] Example 134: N-(4-cyanobicyclo[2.2.2]octan-1-yl)-4 Synthesis of -fluoro-2-((3,3,3-trifluoropropyl)sulfonamide)benzamide 4-Fluoro-2-((3,3,3-trifluoropropyl)sulfonamide)benzoic acid was prepared using 2-bromo-4-fluorobenzoic acid (1.0 equivalent) and 3,3,3-trifluoropropane-1-sulfonamide (1.2 equivalents) according to General Synthesis 9. 4-Fluoro-2-((3,3,3-trifluoropropyl)sulfonamide)benzoic acid was subjected to General Synthesis 10 to obtain N-(4-cyanobicyclo[2.2.2]octan-1-yl)-4-fluoro-2-((3,3,3-trifluoropropyl)sulfonamide)benzamide. 1 H NMR (400 MHz, DMSO-d6) δ 11.18 (s, 1H), 8.18 (s, 1H), 7.83 (dd, J = 8.8, 6.4 Hz, 1H), 7.31 (dd, J = 10.9, 2.5 Hz, 1H), 7.07 (td, J = 8.5, 2.3 Hz, 1H), 3.63 - 3.53 (m, 2H), 2.81 - 2.62 (m, 2H), 1.98 (s, 12H). LCMS-ESI - (m / z): [MH] - calcd 446.12;found 446.22.

[0342] [ka] Example 135: Synthesis of 4-chloro-N-(4-cyanobicyclo[2.2.2]octan-1-yl)-2-((3,3,3-trifluoropropyl)sulfonamide)benzamide 4-Chloro-2-((3,3,3-trifluoropropyl)sulfonamide)benzoic acid was prepared using 2-bromo-4-chlorobenzoic acid (1.0 equivalent) and 3,3,3-trifluoropropane-1-sulfonamide (1.2 equivalents) according to General Synthesis 9. 4-Chloro-2-((3,3,3-trifluoropropyl)sulfonamide)benzoic acid was subjected to General Synthesis 10 to obtain 4-Chloro-N-(4-cyanobicyclo[2.2.2]octan-1-yl)-2-((3,3,3-trifluoropropyl)sulfonamide)benzamide. 1 H NMR (400 MHz, DMSO-d6) δ 10.92 (s, 1H), 8.22 (s, 1H), 7.74 (d, J = 8.5 Hz, 1H), 7.52 (d, J = 2.0 Hz, 1H), 7.30 (dd, J = 8.4, 1.8 Hz, 1H), 3.62 - 3.51 (m, 2H), 2.80 - 2.64 (m, 2H), 1.98 (s, 12H). LCMS-ESI - (m / z): [MH] - calcd 462.09;found 462.27.

[0343] [ka] Example 136: Preparation of 3-fluoro-2-(methylsulfonamide)-N-(3-(trifluoromethyl)bicyclo[1.1.1]pentan-1-yl)benzamide Step 1: Preparation of 3-fluoro-2-(methylsulfonamide)benzoic acid The title intermediate was prepared from 2-amino-3-fluorobenzoic acid by a method similar to that used to obtain 2-(methylsulfonamide)-5-(trifluoromethyl)benzoic acid from 2-amino-5-(trifluoromethyl)benzoic acid. 1H NMR (400 MHz, DMSO-d6) δ 13.67 (bs, 1H), 9.60 (bs, 1H), 7.70 (dt, J = 7.8, 1.2 Hz, 1H), 7.55 (ddd, J = 10.8, 8.3, 1.5 Hz, 1H), 7.35 (td, J = 8.1, 5.1 Hz, 1H), 3.15 (s, 3H).

[0344] Step 2: Preparation of 3-fluoro-2-(methylsulfonamide)-N-(3-(trifluoromethyl)bicyclo[1.1.1]pentan-1-yl)benzamide The title compound was prepared according to step 3 of general synthesis 4 by coupling 3-fluoro-2-(methylsulfonamide)benzoic acid (0.13 g, 0.54 mmol) with 3-(trifluoromethyl)bicyclo[1.1.1]pentane-1-amine hydrochloride (0.11 g, 0.57 mmol). 1 H NMR (400 MHz, DMSO-d6) δ 9.57 (s, 1H), 9.29 (s, 1H), 7.45 (ddd, J = 10.1, 7.2, 2.6 Hz, 1H), 7.38 (m, 2H), 3.09 (s, 3H), 2.32 (s, 6H). LCMS-ESI + (m / z): [M+H] + calcd 367.1;found 367.0).

[0345] [ka] Example 137: Preparation of N-(bicyclo[1.1.1]pentan-1-yl)-4-fluoro-2-(methylsulfonamide)benzamide A mixture of 4-fluoro-2-(methylsulfonamide)benzoic acid (0.12 g, 0.52 mmol) and 1-bicyclo[1.1.1]pentane-1-amine hydrochloride (65 mg, 0.54 mmol, 1.05 equivalents) in N,N-dimethylformamide (DMF, 2.5 mL) was treated with N,N-diisopropylethylamine (DIEA, 0.27 mL, 1.5 mmol). After brief sonication, the mixture was treated with 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate (hereafter referred to as "HATU", 0.24 g, 0.64 mmol). After the coupling reaction was considered complete, the mixture was concentrated under reduced pressure and purified by reverse-phase HPLC (acetonitrile / water / 0.1% trifluoroacetic acid) to obtain the desired product. 1 H NMR (400 MHz, DMSO-d6) δ 11.70 (s, 1H), 9.34 (s, 1H), 7.93 (dd, J = 8.9, 6.3 Hz, 1H), 7.30 (dd, J = 11.2, 2.6 Hz, 1H), 7.01 (ddd, J = 8.9, 8.1, 2.6 Hz, 1H), 3.22 (s, 3H), 2.49 (s, 1H), 2.10 (s, 6H). LCMS-ESI + (m / z): [M+H] + calcd 299.1;found 299.0.

[0346] [ka] Example 138: Preparation of 2-(methylsulfonamide)-N-(3-(trifluoromethyl)bicyclo[1.1.1]pentan-1-yl)benzamide A mixture of 2-(methylsulfonamide)benzoic acid (76 mg, 0.35 mmol) in N,N-dimethylformamide / pyridine (5:1, 3 mL) and THF (0.50 mL) was sonicated and then treated with 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate (HATU, 0.17 g, 0.44 mmol). After 90 minutes, this mixture was treated with N,N-diisopropylethylamine (DIEA, 75 μL, 0.42 mmol) and 3-(trifluoromethyl)bicyclo[1.1.1]pentane-1-amine hydrochloride (73 μL). The mixture was sequentially treated with (g, 0.39 mmol). The reaction mixture was sonicated for 1 minute, then concentrated after 20 minutes, and purified by reverse-phase high-performance liquid chromatography (acetonitrile / water / 0.1% trifluoroacetic acid) to obtain the title product. 1 1H NMR (400 MHz, DMSO-d6) δ 11.08 (s, 1H), 9.55 (s, 1H), 7.83 (dd, J = 7.8, 1.3 Hz, 1H), 7.64 - 7.48 (m, 2H), 7.18 (ddd, J = 8.3, 6.3, 2.2 Hz, 1H), 3.15 (s, 3H), 2.35 (s, 6H). LCMS-ESI + (m / z): [M+H] + calcd 349.08;found 349.01.

[0347] [ka] Example 139: Preparation of N-(cuban-1-yl)-4-fluoro-2-(methylsulfonamide)benzamide Similar to step 3 of general synthesis 4, 4-fluoro-2-(methylsulfonamide)benzoic acid (80 mg, 0.34 mmol) was coupled with cubane-1-amine hydrochloride (PharmaBlock, 1.05 equivalents) to obtain the desired product. 1 1H NMR (400 MHz, DMSO-d6) δ 11.76 (s, 1H), 9.51 (s, 1H), 8.02 (dd, J = 9.0, 6.3 Hz, 1H), 7.31 (dd, J = 11.2, 2.6 Hz, 1H), 7.05 (ddd, J = 8.9, 8.1, 2.6 Hz, 1H), 4.20 (m, 3H), 3.94 (m, 4H), 3.22 (s, 3H). LCMS-ESI + (m / z): [M+H] + calcd 335.1;found: 335.0.

[0348] [ka] Example 140: Preparation of 5-fluoro-2-(methylsulfonamide)-N-(3-(trifluoromethyl)bicyclo[1.1.1]pentan-1-yl)benzamide Similar to step 3 of general synthesis 4, 5-fluoro-2-(methylsulfonamide)benzoic acid (enamine, 0.10 g, 0.43 mmol) was coupled with 3-(trifluoromethyl)bicyclo[1.1.1]pentane-1-amine hydrochloride (1.1 equivalents) to obtain the desired product. 1 H NMR (400 MHz, DMSO-d6) δ 10.68 (s, 1H), 9.55 (s, 1H), 7.68 (dd, J = 9.7, 3.0 Hz, 1H), 7.55 (dd, J = 9.1, 5.0 Hz, 1H), 7.44 (ddd, J = 9.1, 8.0, 2.9 Hz, 1H), 3.10 (s, 3H), 2.35 (s, 6H). LCMS-ESI + (m / z): [M+H] + calcd 367.1;found 367.0.

[0349] [ka] Example 141: Preparation of 2-((2,4-dichlorophenyl)sulfonamide)-N-(3-(trifluoromethyl)bicyclo[1.1.1]pentan-1-yl)benzamide Made Step 1: Preparation of 2-((2,4-dichlorophenyl)sulfonamide)benzoic acid A mixture of anthranilic acid (1.4 g, 10 mmol) in water (100 mL) was treated with sodium hydroxide (0.57 g, 14 mmol). This mixture was sonicated for 2 minutes, after which 2,4-dichlorobenzenesulfonyl chloride (2.5 g, 10 mmol) was added all at once. This mixture was sonicated for approximately 20 minutes, followed by magnetic stirring overnight. The next day, the mixture was heated at 75°C for 1 hour. After cooling, the mixture was treated with dichloromethane, and the resulting two-phase mixture was made monobasic with hydrochloric acid to approximately pH 1. The aqueous phase was extracted three times with dichloromethane. The combined organic extracts were dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by reverse-phase HPLC (acetonitrile / water / 0.1% trifluoroacetic acid) to obtain the desired intermediate. 1 H NMR (400 MHz, DMSO-d6) δ 11.77 (s, 1H), 8.19 (d, J = 8.6 Hz, 1H), 7.95 (dd, J = 8.0, 1.6 Hz, 1H), 7.88 (d, J = 2.1 Hz, 1H), 7.68 (dd, J = 8.6, 2.1 Hz, 1H), 7.50 (ddd, J = 8.4, 7.3, 1.7 Hz, 1H), 7.38 (dd, J = 8.5, 1.1 Hz, 1H), 7.16 - 7.07 (m, 1H).

[0350] Step 2: Preparation of 2-((2,4-dichlorophenyl)sulfonamide)-N-(3-(trifluoromethyl)bicyclo[1.1.1]pentan-1-yl)benzamide Similar to step 3 of general synthesis 4, 2-((2,4-dichlorophenyl)sulfonamide)benzoic acid (0.13 g, 0.36 mmol) was coupled with 3-(trifluoromethyl)bicyclo[1.1.1]pentane-1-amine hydrochloride (1.05 equivalents) to obtain the desired product. 1 H NMR (400 MHz, DMSO-d6) δ 11.86 (s, 1H), 9.57 (s, 1H), 8.09 (d, J = 8.6 Hz, 1H), 7.89 (d, J = 2.1 Hz, 1H), 7.72 (dd, J = 8.0, 1.4 Hz, 1H), 7.64 (dd, J = 8.6, 2.1 Hz, 1H), 7.42 (m, 2H), 7.13 (td, J = 7.5, 1.5 Hz, 1H), 2.36 (s, 6H). LCMS-ESI + (m / z): [M+H] + calcd 479.0;found 478.9.

[0351] [ka] Example 142: Preparation of 2-fluoro-6-(methylsulfonamide)-N-(3-(trifluoromethyl)bicyclo[1.1.1]pentan-1-yl)benzamide Step 1: Preparation of 2-fluoro-6-(methylsulfonamide)benzoic acid A mixture of 2-amino-6-fluorobenzoic acid (2.1 g, 14 mmol) and saturated sodium bicarbonate aqueous solution (21 mL) was sonicated, and then methanesulfonyl chloride (1.3 mL, 16 mmol) was added to this magnetically stirred mixture. 1,4-dioxane (12 mL) was added, and stirring was continued. The mixture was acidified with hydrochloric acid to approximately pH 1. No gas generation was observed. The mixture was partitioned with dichloromethane. The aqueous phase was extracted three times with dichloromethane. The combined organic extract was dried over anhydrous magnesium sulfate, filtered, and concentrated. The residue was purified by reverse-phase HPLC (acetonitrile / water / 0.1% trifluoroacetic acid) to obtain the desired intermediate. 1 H NMR (400 MHz, DMSO-d6) δ 10.58 (s, 1H), 10.50 (s, 1H), 7.97 (dd, J = 8.8, 6.3 Hz, 1H), 7.80 - 7.68 (m, 2H), 7.50 - 7.40 (m, 2H), 7.35 (dd, J = 11.1, 2.6 Hz, 1H), 7.14 (td, J = 8.5, 2.5 Hz, 1H), 3.21 (s, 3H).

[0352] Step 2: 2-Fluoro-6-(methylsulfonamide)-N-(3-(trifluoro Preparation of methyl)bicyclo[1.1.1]pentan-1-yl)benzamide Similar to step 3 of general synthesis 4, 2-fluoro-6-(methylsulfonamide)benzoic acid (88 mg, 0.38 mmol) was coupled with 3-(trifluoromethyl)bicyclo[1.1.1]pentane-1-amine hydrochloride (1.05 equivalents) to obtain the desired product. 1 H NMR (400 MHz, DMSO-d6) δ 9.51 (s, 1H), 9.33 (s, 1H), 7.48 (td, J = 8.3, 6.4 Hz, 1H), 7.33 - 7.23 (m, 1H), 7.13 (ddd, J = 9.5, 8.4, 1.0 Hz, 1H), 3.08 (s, 3H), 2.33 (s, 6H). LCMS-ESI +(m / z): [M+H] + calcd 367.1;found 367.0.

[0353] [ka] Example 143: Preparation of 2-((2,2,2-trifluoroethyl)sulfonamide)-N-(3-(trifluoromethyl)bicyclo[1.1.1]pentan-1-yl)benzamide Step 1: Preparation of 2-((2,2,2-trifluoroethyl)sulfonamide)benzoic acid A mixture of 2-aminobenzoic acid (0.75 g, 5.5 mmol) and pyridine (0.67 mL, 8.2 mmol) in dichloromethane (15 mL) was cooled in an ice / acetone bath and treated dropwise with a solution of 2,2,2-trifluoroethylsulfonyl chloride (1.0 g, 5.5 mmol) in dichloromethane (2 mL). The stirred mixture was gradually heated to room temperature while the bath was being depleted. Aqueous hydrochloric acid (10%, approximately 20 mL) was added. The resulting two-phase suspension was stirred for 3 days. The solid was collected by filtration, washed with dichloromethane, and dried to obtain the desired intermediate. 1 H NMR (400 MHz, DMSO-d6) δ 11.26 (s, 1H), 8.02 (ddd, J = 7.9, 1.5, 0.6 Hz, 1H), 7.70 - 7.60 (m, 2H), 7.24 (ddd, J = 7.9, 6.7, 1.8 Hz, 1H), 4.83 (q, J = 9.8 Hz, 2H).

[0354] Step 2: 2-((2,2,2-trifluoroethyl)sulfonamide)-N-(3-(trifluoromethyl)bicyclo[1.1.1]pentan-1-yl)benzamide Similar to step 3 of general synthesis 4, 2-((2,2,2-trifluoroethyl)sulfonamide)benzoic acid (0.10 g, 0.35 mmol) was coupled with 3-(trifluoromethyl)bicyclo[1.1.1]pentane-1-amine hydrochloride (1.05 equivalents) to obtain the desired product. 1 H NMR (400 MHz, DMSO-d6) δ 11.62 (s, 1H), 9.59 (s, 1H), 7.86 - 7.78 (m, 1H), 7.60 - 7.54 (m, 2H), 7.23 (ddd, J = 8.3, 5.1, 3.4 Hz, 1H), 4.77 (q, J = 9.8 Hz, 2H), 2.35 (s, 6H). LCMS-ESI + (m / z): [M+H] + calcd 417.1;found 417.0.

[0355] [ka] Example 144: Preparation of N-(3-(trifluoromethyl)bicyclo[1.1.1]pentan-1-yl)-2-((trifluoromethyl)sulfonamide)benzamide 2-((trifluoromethyl)sulfonamide)benzoic acid (0.10g, 0.37mm) A sealed mixture of ol) and thionyl chloride (0.46 mL, 6.3 mmol) was heated at 85 °C overnight. The mixture was concentrated under reduced pressure and co-evaporated once from toluene. The putative acid chloride was taken up in dichloromethane (1 mL) and added dropwise to a suspension of 3-(trifluoromethyl)bicyclo[1.1.1]pentane-1-amine hydrochloride (70 mg, 0.37 mmol) and sodium hydrogen carbonate (0.16 g, 1.9 mmol) in dichloromethane (3 mL). The mixture was stirred at room temperature for approximately 10 days. The mixture was then partitioned between ethyl acetate and 1% aqueous hydrochloric acid. The aqueous phase was extracted twice with ethyl acetate. The combined organic extracts were washed once with saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, filtered, and concentrated to dryness under reduced pressure. The residue was purified by reverse-phase HPLC (acetonitrile / water / 0.1% trifluoroacetic acid) to afford the desired product. 1 H NMR (400 MHz, DMSO-d6) δ 9.93 (s, 1H), 7.75 (dd, J = 7.8, 1.6 Hz, 1H), 7.48 (td, J = 7.7, 7.2, 1.6 Hz, 1H), 7.41 (dd, J = 8.2, 1.2 Hz, 1H), 7.26 (t, J = 7.6 Hz, 1H), 2.32 (s, 6H). LCMS-ESI + (m / z): [M+H] + calcd 403.1;found 403.1。

[0356]

Chemical Structure

[0357] [ka] Example 146: 2-(methylsulfonamide)-4-(pentafluoro-λ) 6 Preparation of -sulfanyl)-N-(3-(trifluoromethyl)bicyclo[1.1.1]pentan-1-yl)benzamide Step 1: 2-nitro-4-(pentafluoro-λ) 6 Preparation of sulfanyl)benzoic acid Inside the pressure vessel, 4-(pentafluoro-λ 6 (-Sulfanyl)benzoic acid (10 g, 41 mmol) was placed as a suspension in nitric acid (fuming, 98%, 80 mL) and sonicated to obtain a homogeneous suspension. Sulfuric acid (fuming, 5 ml) was added. The container was sealed and the suspension was stirred at 100°C for 2 days. After cooling to room temperature, the suspension was poured onto ice (approximately 800 g) and stirred vigorously. The solid was collected by filtration to obtain the desired substance. Further substances were obtained by post-treatment by extraction of the filtrate. LCMS-ESI - (m / z): [MH] - calcd 291.98;found 291.77.

[0358] Step 2: 2-amino-4-(pentafluoro-λ) 6 Preparation of sulfanyl)benzoic acid A slurry of Raney nickel (approximately 2 mL) is mixed with 2-nitro-4-(pentafluoro-λ) 6 The solution of sulfanyl)benzoic acid (2.9, 9.8 mmol) in methanol (100 mL) was added. The resulting suspension was stirred under a hydrogen atmosphere for 3 hours and then filtered through a Celite diatomaceous earth pad. The filtrate was concentrated under reduced pressure to obtain the desired substance. LCMS-ESI + (m / z): [M+H] + calcd 264.00;found 263.96.

[0359] Step 3: 2-amino-4-(pentafluoro-λ) 6 Preparation of methyl sulfanylbenzoate 2-amino-4-(pentafluoro-λ) 6 To a cold (ice bath) mixture of -sulfanyl)benzoic acid (2.45 mmol) in 2-methyltetrahydrofuran (50 mL) and methanol (10 mL), a solution of 2.0 M trimethylsilyldiazomethane (1.8 mL, 3.7 mmol) in hexane was added via syringe over 5 minutes. After stirring overnight at room temperature, the mixture was cooled in an ice bath and quenched by adding acetic acid (3 mL). The mixture was concentrated under reduced pressure, and the resulting residue was purified by flash chromatography (silica gel) to obtain the desired substance. LCMS-ESI + (m / z): [M+H] + calcd 278.02;found 277.94.

[0360] Step 4: 2-(methylsulfonamide)-4-(pentafluoro-λ) 6 Preparation of sulfanyl)benzoic acid The title intermediate is 2-amino-4-(pentafluoro-λ 64-fluoro-2-(methylsulfonamide)benzoic acid was prepared from methyl-sulfanyl)benzoate by a method similar to that used to obtain methyl 2-amino-4-fluorobenzoate (general synthesis 1, steps 1 and 2). LCMS-ESI + (m / z): [M+H] + calcd 339.98;found 340.16.

[0361] Step 5: 2-(methylsulfonamide)-4-(pentafluoro-λ) 6 Preparation of -sulfanyl)-N-(3-(trifluoromethyl)bicyclo[1.1.1]pentan-1-yl)benzamide Similar to step 3 of general synthesis 4, 2-(methylsulfonamide)-4-(pentafluoro-λ 6 The desired product was obtained by coupling sulfanyl)benzoic acid (98 mg, 0.29 mmol) with 3-(trifluoromethyl)bicyclo[1.1.1]pentane-1-amine hydrochloride (1.2 equivalents). 1 H NMR (400 MHz, DMSO-d6) δ 10.88 (s, 1H), 9.72 (s, 1H), 7.97 (d, J = 8.8 Hz, 1H), 7.94 (d, J = 2.3 Hz, 1H), 7.78 (dd, J = 8.8, 2.3 Hz, 1H), 3.18 (s, 3H), 2.37 (s, 6H) LCMS-ESI - (m / z): [MH] - calcd 473.0;found 473.3.

[0362] [ka] Example 147: Preparation of 2-(methylsulfonamide)-4-(trifluoromethyl)-N-(3-(trifluoromethyl)bicyclo[1.1.1]pentan-1-yl)benzamide Similar to step 3 of general synthesis 4, 2-(methylsulfonamide)-4-(trifluoromethyl)benzoic acid (0.13 g, 0.45 mmol) is converted to 3-(trifluoromethyl)bisic acid. The desired product was obtained by coupling with [1.1.1]pentan-1-amine hydrochloride (1.05 equivalents). 1 H NMR (400 MHz, DMSO-d6) δ 11.01 (s, 1H), 9.73 (s, 1H), 8.00 (d, J = 8.2 Hz, 1H), 7.79 (d, J = 1.7 Hz, 1H), 7.58 (dd, J = 8.4, 1.8 Hz, 1H), 3.21 (s, 3H), 2.37 (s, 6H). LCMS-ESI - (m / z): [MH] - calcd 415.1;found 415.4.

[0363] [ka] Example 148: Preparation of 4-cyano-2-(methylsulfonamide)-N-(3-(trifluoromethyl)bicyclo[1.1.1]pentan-1-yl)benzamide Step 1: Preparation of 4-iodo-2-(methylsulfonamide)benzoic acid The title intermediate was prepared by a method similar to that used to obtain 2-(methylsulfonamide)-5-(trifluoromethyl)benzoic acid from methyl 2-amino-4-iodobenzoate. LCMS-ESI - (m / z): [MH] - calcd 339.92;found 340.04.

[0364] Step 2: Preparation of 4-cyano-2-(methylsulfonamide)benzoic acid A mixture of 4-iodo-2-(methylsulfonamide)benzoic acid (0.95 g, 2.8 mmol) and cuprous cyanide (0.32 g, 3.6 mmol) in N,N-dimethylformamide (DMF, 5 mL) was stirred overnight at 140°C. This mixture was filtered through a Celite diatomaceous earth pad, and the filtrate was concentrated under reduced pressure. The residue was placed in water (approximately 25 mL), treated with N,N-ethylenediamine (approximately 5 mL), and then acidified with 10% aqueous hydrochloric acid. The aqueous mixture was extracted three times with ethyl acetate. The combined extracts were washed once each with water, 10% aqueous hydrochloric acid, and saturated sodium chloride aqueous solution. The combined organic layers were dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure to obtain the desired intermediate. LCMS-ESI - (m / z): [MH] - calcd 239.02;found 239.03.

[0365] Step 3: Preparation of 4-cyano-2-(methylsulfonamide)-N-(3-(trifluoromethyl)bicyclo[1.1.1]pentan-1-yl)benzamide Similar to step 3 of general synthesis 4, 4-cyano-2-(methylsulfonamide)benzoic acid (0.12 g, 0.50 mmol) was coupled with 3-(trifluoromethyl)bicyclo[1.1.1]pentane-1-amine hydrochloride (1.05 equivalents) to obtain the desired product. 1 H NMR (400 MHz, DMSO-d6) δ 10.95 (s, 1H), 9.73 (s, 1H), 7.93 (d, J = 8.2 Hz, 1H), 7.86 (d, J = 1.5 Hz, 1H), 7.67 (dd, J = 8.2, 1.6 Hz, 1H), 3.28 (s, 3H), 2.36 (s, 6H). LCMS-ESI - (m / z): [MH] - calcd 372.1;found 372.3.

[0366] [ka] Example 149: 4-Fluoro-2-(pyrimidine-2-sulfonamide)-N-(3 Preparation of (trifluoromethyl)bicyclo[1.1.1]pentan-1-yl)benzamide Step 1: Preparation of 4-fluoro-2-(N-(pyrimidine-2-ylsulfonyl)pyrimidine-2-sulfonamide)methyl benzoate The suspension of 2-mercaptopyrimidine (1.1 g, 10 mmol, 1.0 equivalent) in a mixture of dichloromethane (50 mL) and 1 M hydrochloric acid solution (containing 25 wt% calcium chloride) (50 mL) was sonicated until homogeneous, and then cooled to an internal temperature of -30 to -25°C. Calcium chloride hexahydrate (38 g) was dissolved in sodium hypochlorite (8.25% solution, 1 M, 33 mL, 33 mmol, 3.3 equivalents), and the resulting clear solution was added dropwise to the stirred 2-mercaptopyrimidine solution while maintaining its internal temperature at -30 to -25°C. The resulting slurry was stirred at -30 to -25°C (internal temperature) for 15 minutes, then diluted with ice / water (50 mL), and poured into a separatory funnel (pre-cooled with ice water). The organic phase was quickly separated and collected in a flask cooled in a dry ice-acetone bath. Methyl 2-amino-4-fluorobenzoate (3.4 g, 20 mmol, 2.0 equivalents) was added with stirring. The flask was placed in an ice bath, and the mixture was stirred at 0°C for 60 minutes. Anhydrous magnesium sulfate was added to the resulting suspension. The slurry was filtered and concentrated under reduced pressure. The residue was taken into warm toluene to obtain a suspension, which was filtered, and the unreacted methyl 2-amino-4-fluorobenzoate was recovered. The concentrated filtrate was purified by flash chromatography (silica gel) to obtain the desired intermediate. 1H NMR (400 MHz, DMSO-d6) δ 10.96 (s, 1H), 9.03 (d, J = 4.9 Hz, 2H), 8.71 (d, J = 4.8 Hz, 2H), 7.99 (dd, J = 8.9, 6.5 Hz, 1H), 7.81 (t, J = 4.9 Hz, 1H), 7.47 - 7.31 (m, 2H), 7.08 (td, J = 8.5, 2.5 Hz, 1H), 3.85 (s, 3H).

[0367] Step 2: Preparation of 4-fluoro-2-(pyrimidine-2-sulfonamide)benzoic acid A solution of 4-fluoro-2-(N-(pyrimidine-2-ylsulfonyl)pyrimidine-2-sulfonamide)methyl benzoate (0.92 g, 2.0 mmol) in tetrahydrofuran (15 mL) was treated with a solution of aqueous sodium hydroxide (4 M, 2.0 mL, 8.1 mmol). Water was added to the resulting suspension to obtain a homogeneous mixture, which was stirred at room temperature for 4 hours and then refrigerated overnight. An additional volume of sodium hydroxide solution (0.5 mL) was added. Once this reaction was complete, the mixture was acidified to approximately pH 1 by adding 10% aqueous hydrochloric acid. The aqueous phase was extracted three times with ethyl acetate. The combined extracts were washed once with saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, filtered, and concentrated to dryness under reduced pressure. The residue was ground with hot isopropanol. After cooling, the solid was collected by filtration, washed with cold isopropanol, and dried to obtain the desired intermediate. LCMS-ESI - (m / z): [MH] - calcd 296.02;found 296.17.

[0368] Step 3: Preparation of 4-fluoro-2-(pyrimidine-2-sulfonamide)-N-(3-(trifluoromethyl)bicyclo[1.1.1]pentan-1-yl)benzamide According to general synthesis method 4, 4-fluoro-2-(pyrimidine-2-sulfonamide)benzoic acid (86 mg, 0.29 mmol) was coupled with 3-(trifluoromethyl)bicyclo[1.1.1]pentane-1-amine hydrochloride (0.32 mmol, 1.1 equivalents) in step 3 to obtain the desired product. 1 H NMR (400 MHz, DMSO-d6) δ 12.14 (s, 1H), 9.62 (s, 1H), 9.02 (d, J = 4.9 Hz, 2H), 7.87 (dd, J = 8.9, 6.2 Hz, 1H), 7.81 (t, J = 4.9 Hz, 1H), 7.33 (dd, J = 11.0, 2.6 Hz, 1H), 7.15 - 6.94 (m, 1H), 2.36 (s, 6H). LCMS-ESI + (m / z): [M+H] + calcd 431.07;found 431.06.

[0369] [ka] Example 150: 5-(methylsulfonyl)-2-((4-(pentafluoro-λ 6 Preparation of -sulfanyl)phenyl)sulfonamide)-N-(3-(trifluoromethyl)bicyclo[1.1.1]pentan-1-yl)benzamide 5-(methylsulfonyl)-2-((4-(pentafluoro-λ 6 Preparation of -sulfanyl)phenyl)sulfonamide)-N-(3-(trifluoromethyl)bicyclo[1.1.1]pentan-1-yl)benzamide The desired product was synthesized according to General Synthesis 4, using 2-amino-5-(methylsulfonyl)methyl benzoate (as otherwise specified...

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[Claim 1] The need to provide an uncoupling compound for treating a disease or condition mediated by mitochondria.

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